Jeroen J. Bax

Supplementary Table 9, column 'Edoxaban', row 'eGFR category', '95 mL/min' (page 15). The cell should be coloured green instead of yellow. It should also read mginstead of mg (use with caution in 'supranormal' renal function).In the above-indicated cell, a footnote has also been added to state: Edoxaban should be used in patients with high creatinine clearance only after a careful evaluation of the individual thromboembolic and bleeding risk.Supplementary Table 9, column 'Edoxaban', row 'Dose reduction in selected patients' (page 16). The cell should read Edoxaban 60 mg reduced to 30 mg once daily if any of the following: creatinine clearance 15-50 mL/min, body weight <60 kg, concomitant use of dronedarone, erythromycin, ciclosporine or ketokonazoleinstead of Edoxaban 60 mg reduced to 30 mg once daily, and edoxaban 30 mg reduced to 15mg once daily, if any of the following: creatinine clearance of 30-50 mL/min, body weight <60 kg, concomitant us of verapamil or quinidine or dronedarone.

ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation : The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).

ABCD : Appropriate Blood pressure Control in Diabetes ABI : ankle–brachial index ABPM : ambulatory blood pressure monitoring ACCESS : Acute Candesartan Cilexetil Therapy in Stroke Survival ACCOMPLISH : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension ACCORD : Action to Control Cardiovascular Risk in Diabetes ACE : angiotensin-converting enzyme ACTIVE I : Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ADVANCE : Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation AHEAD : Action for HEAlth in Diabetes ALLHAT : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack ALTITUDE : ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints ANTIPAF : ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation APOLLO : A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People ARB : angiotensin receptor blocker ARIC : Atherosclerosis Risk In Communities ARR : aldosterone renin ratio ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASCOT-LLA : Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm ASTRAL : Angioplasty and STenting for Renal Artery Lesions A-V : atrioventricular BB : beta-blocker BMI : body mass index BP : blood pressure BSA : body surface area CA : calcium antagonist CABG : coronary artery bypass graft CAPPP : CAPtopril Prevention Project CAPRAF : CAndesartan in the Prevention of Relapsing Atrial Fibrillation CHD : coronary heart disease CHHIPS : Controlling Hypertension and Hypertension Immediately Post-Stroke CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease—EPIdemiology collaboration CONVINCE : Controlled ONset Verapamil INvestigation of CV Endpoints CT : computed tomography CV : cardiovascular CVD : cardiovascular disease D : diuretic DASH : Dietary Approaches to Stop Hypertension DBP : diastolic blood pressure DCCT : Diabetes Control and Complications Study DIRECT : DIabetic REtinopathy Candesartan Trials DM : diabetes mellitus DPP-4 : dipeptidyl peptidase 4 EAS : European Atherosclerosis Society EASD : European Association for the Study of Diabetes ECG : electrocardiogram EF : ejection fraction eGFR : estimated glomerular filtration rate ELSA : European Lacidipine Study on Atherosclerosis ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EXPLOR : Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination FDA : U.S. Food and Drug Administration FEVER : Felodipine EVent Reduction study GISSI-AF : Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation HbA1c : glycated haemoglobin HBPM : home blood pressure monitoring HOPE : Heart Outcomes Prevention Evaluation HOT : Hypertension Optimal Treatment HRT : hormone replacement therapy HT : hypertension HYVET : HYpertension in the Very Elderly Trial IMT : intima-media thickness I-PRESERVE : Irbesartan in Heart Failure with Preserved Systolic Function INTERHEART : Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries INVEST : INternational VErapamil SR/T Trandolapril ISH : Isolated systolic hypertension JNC : Joint National Committee JUPITER : Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin LAVi : left atrial volume index LIFE : Losartan Intervention For Endpoint Reduction in Hypertensives LV : left ventricle/left ventricular LVH : left ventricular hypertrophy LVM : left ventricular mass MDRD : Modification of Diet in Renal Disease MRFIT : Multiple Risk Factor Intervention Trial MRI : magnetic resonance imaging NORDIL : The Nordic Diltiazem Intervention study OC : oral contraceptive OD : organ damage ONTARGET : ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial PAD : peripheral artery disease PATHS : Prevention And Treatment of Hypertension Study PCI : percutaneous coronary intervention PPAR : peroxisome proliferator-activated receptor PREVEND : Prevention of REnal and Vascular ENdstage Disease PROFESS : Prevention Regimen for Effectively Avoiding Secondary Strokes PROGRESS : Perindopril Protection Against Recurrent Stroke Study PWV : pulse wave velocity QALY : Quality adjusted life years RAA : renin-angiotensin-aldosterone RAS : renin-angiotensin system RCT : randomized controlled trials RF : risk factor ROADMAP : Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention SBP : systolic blood pressure SCAST : Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke SCOPE : Study on COgnition and Prognosis in the Elderly SCORE : Systematic COronary Risk Evaluation SHEP : Systolic Hypertension in the Elderly Program STOP : Swedish Trials in Old Patients with Hypertension STOP-2 : The second Swedish Trial in Old Patients with Hypertension SYSTCHINA : SYSTolic Hypertension in the Elderly: Chinese trial SYSTEUR : SYSTolic Hypertension in Europe TIA : transient ischaemic attack TOHP : Trials Of Hypertension Prevention TRANSCEND : Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease UKPDS : United Kingdom Prospective Diabetes Study VADT : Veterans' Affairs Diabetes Trial VALUE : Valsartan Antihypertensive Long-term Use Evaluation WHO : World Health Organization ### 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 : The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer.It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. This process can be modified by lifestyle adjustments, pharmacological therapies, and invasive interventions designed to achieve disease stabilization or regression. The disease can have long, stable periods but can also become unstable at any time, typically due to an acute atherothrombotic event caused by plaque rupture or erosion. However, the disease is chronic, most often progressive, and hence serious, even in clinically apparently silent periods. The dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either acute coronary syndromes (ACS) or chronic coronary syndromes (CCS). The Guidelines presented here refer to the management of patients with CCS. The natural history of CCS is illustrated in Figure 1.

99mTc : technetium-99m 201TI : thallium 201 ABCB1 : ATP-binding cassette sub-family B member 1 ABI : ankle-brachial index ACC : American College of Cardiology ACCF : American College of Cardiology Foundation ACCOMPLISH : Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension ACE : angiotensin converting enzyme ACIP : Asymptomatic Cardiac Ischaemia Pilot ACS : acute coronary syndrome ADA : American Diabetes Association ADP : adenosine diphosphate AHA : American Heart Association ARB : angiotensin II receptor antagonist ART : Arterial Revascularization Trial ASCOT : Anglo-Scandinavian Cardiac Outcomes Trial ASSERT : Asymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial AV : atrioventricular BARI 2D : Bypass Angioplasty Revascularization Investigation 2 Diabetes BEAUTIFUL : Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction BIMA : bilateral internal mammary artery BMI : body mass index BMS : bare metal stent BNP : B-type natriuretic peptide BP : blood pressure b.p.m. : beats per minute CABG : coronary artery bypass graft CAD : coronary artery disease CAPRIE : Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events CASS : Coronary Artery Surgery Study CCB : calcium channel blocker CCS : Canadian Cardiovascular Society CFR : coronary flow reserve CHARISMA : Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance CI : confidence interval CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease Epidemiology Collaboration CMR : cardiac magnetic resonance CORONARY : The CABG Off or On Pump Revascularization Study COURAGE : Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation COX-1 : cyclooxygenase-1 COX-2 : cyclooxygenase-2 CPG : Committee for Practice Guidelines CT : computed tomography CTA : computed tomography angiography CV : cardiovascular CVD : cardiovascular disease CXR : chest X-ray CYP2C19*2 : cytochrome P450 2C19 CYP3A : cytochrome P3A CYP3A4 : cytochrome P450 3A4 CYP450 : cytochrome P450 DANAMI : Danish trial in Acute Myocardial Infarction DAPT : dual antiplatelet therapy DBP : diastolic blood pressure DECOPI : Desobstruction Coronaire en Post-Infarctus DES : drug-eluting stents DHP : dihydropyridine DSE : dobutamine stress echocardiography EACTS : European Association for Cardiothoracic Surgery EECP : enhanced external counterpulsation EMA : European Medicines Agency EASD : European Association for the Study of Diabetes ECG : electrocardiogram Echo : echocardiogram ED : erectile dysfunction EF : ejection fraction ESC : European Society of Cardiology EXCEL : Evaluation of XIENCE PRIME or XIENCE V vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization FAME : Fractional Flow Reserve vs. Angiography for Multivessel Evaluation FDA : Food & Drug Administration (USA) FFR : fractional flow reserve FREEDOM : Design of the Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease GFR : glomerular filtration rate HbA1c : glycated haemoglobin HDL : high density lipoprotein HDL-C : high density lipoprotein cholesterol HR : hazard ratio HRT : hormone replacement therapy hs-CRP : high-sensitivity C-reactive protein HU : Hounsfield units ICA : invasive coronary angiography IMA : internal mammary artery IONA : Impact Of Nicorandil in Angina ISCHEMIA : International Study of Comparative Health Effectiveness with Medical and Invasive Approaches IVUS : intravascular ultrasound JSAP : Japanese Stable Angina Pectoris KATP : ATP-sensitive potassium channels LAD : left anterior descending LBBB : left bundle branch block LIMA : Left internal mammary artery LDL : low density lipoprotein LDL-C : low density lipoprotein cholesterol LM : left main LMS : left main stem LV : left ventricular LVEF : left ventricular ejection fraction LVH : left ventricular hypertrophy MACE : major adverse cardiac events MASS : Medical, Angioplasty, or Surgery Study MDRD : Modification of Diet in Renal Disease MERLIN : Metabolic Efficiency with Ranolazine for Less Ischaemia in Non-ST-Elevation Acute Coronary Syndromes MERLIN-TIMI 36 : Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes: Thrombolysis In Myocardial Infarction MET : metabolic equivalents MI : myocardial infarction MICRO-HOPE : Microalbuminuria, cardiovascular and renal sub-study of the Heart Outcomes Prevention Evaluation study MPI : myocardial perfusion imaging MRI : magnetic resonance imaging NO : nitric oxide NSAIDs : non-steroidal anti-inflammatory drugs NSTE-ACS : non-ST-elevation acute coronary syndrome NYHA : New York Heart Association OAT : Occluded Artery Trial OCT : optical coherence tomography OMT : optimal medical therapy PAR-1 : protease activated receptor type 1 PCI : percutaneous coronary intervention PDE5 : phosphodiesterase type 5 PES : paclitaxel-eluting stents PET : positron emission tomography PRECOMBAT : Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease PTP : pre-test probability PUFA : polyunsaturated fatty acid PVD : peripheral vascular disease QoL : quality of life RBBB : right bundle branch block REACH : Reduction of Atherothrombosis for Continued Health RITA-2 : Second Randomized Intervention Treatment of Angina ROOBY : Veterans Affairs Randomized On/Off Bypass SAPT : single antiplatelet therapy SBP : systolic blood pressure SCAD : stable coronary artery disease SCORE : Systematic Coronary Risk Evaluation SCS : spinal cord stimulation SES : sirolimus-eluting stents SIMA : single internal mammary artery SPECT : single photon emission computed tomography STICH : Surgical Treatment for Ischaemic Heart Failure SWISSI II : Swiss Interventional Study on Silent Ischaemia Type II SYNTAX : SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery TC : total cholesterol TENS : transcutaneous electrical neural stimulation TERISA : Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina TIME : Trial of Invasive vs. Medical therapy TIMI : Thrombolysis In Myocardial Infarction TMR : transmyocardial laser revascularization TOAT : The Open Artery Trial WOEST : What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing Guidelines summarize and evaluate all evidence available, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well …

Kristian Thygesen∗ (Denmark) Joseph S. Alpert∗ (USA) Allan S. Jaffe (USA) Bernard R. Chaitman (USA) Jeroen J. Bax (The Netherlands) David A. Morrow (USA) Harvey D. White∗ (New Zealand) Hans Mickley (Denmark) Filippo Crea (Italy) Frans Van de Werf (Belgium) Chiara Bucciarelli-Ducci (

The ESC/EACTS Guidelines represent the views of the ESC and the EACTS and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient and, where appropriate and necessary, the patient's guardian or carer.It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

ESC Guidelines for the

ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American–Australian–African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association ANDROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d. for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid (ASA) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospective, randomized, double-blind, Active-controlled, superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die (twice daily) b.p.m. : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex category (female) CHADS2 : Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke (doubled) CI : confidence interval CRAFT : Controlled Randomized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : Randomized Double blind trIal to evaluate efficacy and safety of drOnedarone (400 mg b.i.d.) vs . amiodaroNe (600 mg q.d. for 28 daYS, then 200 mg qd thereafter) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v. : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d. : omni die (every day) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy PCI : percutaneous coronary intervention PREVAIL : Prospective Randomized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ROCKET-AF : Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d. : ter in die (three times daily) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on …

Guidelines and Expert Consensus Documents summarize and evaluate all available evidence with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome and the risk–benefit ratio of diagnostic or therapeutic means. Guidelines are no substitutes for textbooks and their legal implications have been discussed previously. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by his/her responsible physician(s). The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). Members of this Task Force were selected by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) to represent all physicians involved with the medical and surgical care of patients with coronary artery disease (CAD). A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for society are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The members of the Task Force have provided disclosure statements of all relationships that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at European Heart House, headquarters of the ESC. Any changes in conflict of interest that arose during the writing period were notified to the ESC. The Task Force report received its entire financial support from the ESC and EACTS, without any involvement of the pharmaceutical, device, or surgical industry. ESC …

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians and other healthcare providers in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC Web Site in the guidelines section (www.escardio.org). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise …

Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks, and their legal implications have been discussed previously. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by his/her responsible physician(s). A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/guidelines/rules). Members of this Task Force were selected by the ESC to represent all physicians involved with the medical care of patients in this pathology. In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger populations are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing and reviewing panels have provided disclosure statements of all relationships they may have which …

### Abbreviations 1st AV : First-degree atrioventricular block AF : atrial fibrillation AT : atrial tachyarrhythmia ATP : Anti-tachycardia pacing AV : atrioventricular BBB : bundle branch block CHF : congestive heart failure CI : confidence interval CPG : Committee for Practice Guidelines CRT : cardiac resynchronization therapy CRT-D : cardiac resynchronization therapy and defibrillator CRT-P : cardiac resynchronization therapy and pacemaker ECG : electrocardiogram EDMD : Emery-Dreifuss muscular dystrophy EF : ejection fraction EPS : electrophysiological study ESC : European Society of Cardiology HCM : hypertrophic cardiomyopathy HF : heart failure HR : hazard ratio HV : His-ventricular ICD : implantable cardioverter defibrillator ILR : implantable loop recorder IVCD : intraventricular conduction delay LBBB : left bundle branch block LQTS : long QT syndrome LV : left ventricular LVEF : left ventricular ejection fraction LVSD : left ventricular systolic dysfunction MR : mitral regurgitation MRI : magnetic resonance imaging NYHA : New York Heart Association PM : pacemaker OR : odds ratio QALY : quality-adjusted life year RBBB : right bundle branch block RCT : randomized controlled trial RV : right ventricular SB : sinus bradycardia SNRT : sinus node recovery time SR : sinus rhythm SSS : sick sinus syndrome TAVI : transcatheter aortic valve implantation VF : ventricular fibrillation VT : ventricular tachycardia VV : interventricular (delay) ### Acronyms of the trials referenced in the recommendations or reported in the tables ADEPT : ADvanced Elements of Pacing Randomized Controlled Trial ADOPT : Atrial Dynamic Overdrive Pacing Trial AOPS : Atrial Overdrive Pacing Study APAF : Ablate and Pace in Atrial Fibrillation ASSERT : ASymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial ATTEST : ATrial Therapy Efficacy and Safety Trial AVAIL CLS/CRT : AV Node Ablation with CLS and CRT Pacing Therapies for Treatment of AF trial B4 : Bradycardia detection in Bundle Branch Block BELIEVE : Bi vs. Left Ventricular Pacing: an International Pilot Evaluation on Heart Failure Patients with Ventricular Arrhythmias BIOPACE : Biventricular pacing for atrioventricular block to prevent cardiac desynchronization BLOCK-HF : Biventricular versus right ventricular pacing in patients with AV block B-LEFT : Biventricular versus LEFT Univentricular Pacing with ICD Back-up in Heart Failure Patients CARE-HF : CArdiac REsynchronization in Heart Failure CLEAR : CLinical Evaluation on Advanced Resynchronization COMBAT : COnventional vs. Biventricular Pacing in Heart Failure and Bradyarrhythmia COMPANION : COmparison of Medical Therapy, Pacing and Defibrillation in Heart Failure DANPACE : DANish Multicenter Randomized Trial on Single Lead Atrial PACing vs. Dual Chamber Pacing in Sick Sinus Syndrome DECREASE-HF : The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure FREEDOM : Optimization Study Using the QuickOpt Method GREATER-EARTH : Evaluation of Resynchronization Therapy for Heart Failure in Patients with a QRS Duration GREATER Than 120 ms LESSER-EARTH : Evaluation of Resynchronization Therapy for Heart Failure in Patients with a QRS Duration Lower Than 120 ms HOBIPACE : HOmburg BIventricular PACing Evaluation IN-CHF : Italian Network on Congestive Heart Failure ISSUE : International Study on Syncope of Unexplained Etiology MADIT : Multicenter Automatic Defibrillator Trial MIRACLE : Multicenter InSync RAndomized CLinical Evaluation MOST : MOde Selection Trial in Sinus-Node Dysfunction MUSTIC : MUltisite STimulation In Cardiomyopathies OPSITE : Optimal Pacing SITE PACE : Pacing to Avoid Cardiac Enlargement PAVE : Left Ventricular-Based Cardiac Stimulation Post AV Nodal Ablation Evaluation PATH-CHF : PAcing THerapies in Congestive Heart Failure II Study Group PIPAF : Pacing In Prevention of Atrial Fibrillation Study PIRAT : Prevention of Immediate Reinitiation of Atrial Tachyarrhythmias POT : Prevention Or Termination Study PREVENT-HF : PREventing VENTricular Dysfunction in Pacemaker Patients Without Advanced Heart Failure PROSPECT : PRedictors Of Response to Cardiac Resynchronization Therapy RAFT : Resynchronization–Defibrillation for Ambulatory Heart Failure Trial RethinQ : Cardiac REsynchronization THerapy IN Patients with Heart Failure and Narrow QRS REVERSE : REsynchronization reVErses Remodelling in Systolic left vEntricular dysfunction SAFARI : Study of Atrial Fibrillation Reduction SCD HeFT : Sudden Cardiac Death in Heart Failure Trial SMART-AV : The SMARTDelay Determined AV Optimization: a Comparison with Other AV Delay Methods Used in Cardiac Resynchronization Therapy SYDIT : The SYncope DIagnosis and Treatment SYNPACE : Vasovagal SYNcope and PACing TARGET : TARgeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy THEOPACE : Effects of Oral THEOphylline and of Permanent PACEmaker on the Symptoms and Complications of Sick Sinus Syndrome VASIS-PM : VAsovagal Syncope International Study on PaceMaker therapy V-HeFT : Vasodilator in HEart Failure Trial VPSII : Second Vasovagal Pacemaker Study (VPS II) Additional references are mentioned with ‘w’ in the main text and can be found on the online addenda along with 5 figures (1, 6, 7, 9, 11, 12) and 10 tables (3, 4, 5, 9, 11, 12, 19, 21, 22, 23). They are available on the ESC website only at http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/cardiac-pacing-and-cardiac-resynchronisation-therapy.aspx Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a …

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk/benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. Unpublished clinical trial results have not been taken into account. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 . The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period …

HomeCirculationVol. 138, No. 20Fourth Universal Definition of Myocardial Infarction (2018) Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBFourth Universal Definition of Myocardial Infarction (2018) Kristian Thygesen, Joseph S. Alpert, Allan S. Jaffe, Bernard R. Chaitman, Jeroen J. Bax, David A. Morrow, Harvey D. White and The Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction Kristian ThygesenKristian Thygesen *Corresponding authors. Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, DK-8200 Aarhus N, Denmark. Tel: +45 78452262, Fax: +45 78452260, Email: E-mail Address: [email protected]; E-mail Address: [email protected]. Search for more papers by this author , Joseph S. AlpertJoseph S. Alpert Joseph S. Alpert, Department of Medicine, University of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245037, Tucson AZ 85724-5037, USA. Tel: +1 5206262763, Email: E-mail Address: [email protected]. Search for more papers by this author , Allan S. JaffeAllan S. Jaffe Search for more papers by this author , Bernard R. ChaitmanBernard R. Chaitman Search for more papers by this author , Jeroen J. BaxJeroen J. Bax Search for more papers by this author , David A. MorrowDavid A. Morrow Search for more papers by this author , Harvey D. WhiteHarvey D. White Harvey D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel: +64 96309992, Fax: 00 64 9 6309915, Email: E-mail Address: [email protected]. Search for more papers by this author and The Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction Search for more papers by this author Originally published24 Aug 2018https://doi.org/10.1161/CIR.0000000000000617Circulation. 2018;138:e618–e651is corrected byCorrection to: Fourth Universal Definition of Myocardial Infarction (2018)Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 25, 2018: Ahead of Print Abbreviations and AcronymsACCAmerican College of CardiologyACSAcute coronary syndromeAHAAmerican Heart AssociationARC-2Academic Research Consortium-2AUCArea under the curveCADCoronary artery diseaseCABGCoronary artery bypass graftingCKDChronic kidney diseaseCK-MBCreatine kinase MB isoformCMRCardiac magnetic resonanceCTCAComputed tomographic coronary angiographycTnCardiac troponincTnICardiac troponin IcTnTCardiac troponin TCTComputed tomographyCVCoefficient of variationEFEjection fractionECGElectrocardiogram or electrocardiographicHFHeart failurehs-cTnHigh-sensitivity cardiac troponinIFCCInternational Federation of Clinical Chemistry and Laboratory MedicineISFCInternational Society and Federation of CardiologyLADLeft anterior descending arteryLBBBLeft bundle branch blockLoDLimit of detectionLGELate gadolinium enhancementLGE-CMRLate gadolinium enhancement cardiac magnetic resonanceLVLeft ventricularLVHLeft ventricular hypertrophyMIMyocardial infarctionMINOCAMyocardial infarction with nonobstructive coronary arteriesMONICAMONItoring of trends and determinants in CArdiovascular diseaseMPSMyocardial perfusion scintigraphyNHLBINational Heart, Lung, and Blood InstituteNSTEMINon–ST-elevation myocardial infarctionPETPositron emission tomographyPCIPercutaneous coronary interventionPOCPoint of careRBBBRight bundle branch blockSPECTSingle photon emission computed tomographySTEMIST-elevation myocardial infarctionST-TST-segment–T waveTIMIThrombolysis in Myocardial InfarctionTTSTakotsubo syndromeUDMIUniversal Definition of Myocardial InfarctionURLUpper reference limitWHFWorld Heart FederationWHOWorld Health OrganizationTable of contentsAbbreviations and Acronyms e6191. What Is New in the Universal Definition of Myocardial Infarction? e6202. Universal Definitions of Myocardial Injury and Myocardial Infarction: Summary e6213. Introduction e6214. Pathological Characteristics of Myocardial Ischemia and Infarction e6225. Biomarker Detection of Myocardial Injury and Infarction e6236. Clinical Presentations of Myocardial Infarction e6237. Clinical Classification of Myocardial Infarction e6247.1. Myocardial Infarction Type 1 e6247.2. Myocardial Infarction Type 2 e6257.3. Myocardial Infarction Type 2 and Myocardial Injury e6267.4. Myocardial Infarction Type 3 e6268. Coronary Procedure–Related Myocardial Injury e6289. Myocardial Infarction Associated With Percutaneous Coronary Intervention (Type 4a Myocardial Infarction) e62910. Stent/Scaffold Thrombosis Associated With Percutaneous Coronary Intervention (Type 4b Myocardial Infarction) e62911. Restenosis Associated With Percutaneous Coronary Intervention (Type 4c Myocardial Infarction) e63012. Myocardial Infarction Associated With Coronary Artery Bypass Grafting (Type 5 Myocardial Infarction) e63013. Other Definitions of Myocardial Infarction Related to Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting e63114. Recurrent Myocardial Infarction e63115. Reinfarction e63116. Myocardial Injury and Infarction Associated With Cardiac Procedures Other Than Revascularization e63117. Myocardial Injury and Infarction Associated With Noncardiac Procedures e63118. Myocardial Injury or Infarction Associated With Heart Failure e63219. Takotsubo Syndrome e63220. Myocardial Infarction With Nonobstructive Coronary Arteries e63321. Myocardial Injury and/or Infarction Associated With Kidney Disease e63322. Myocardial Injury and/or Infarction in Critically Ill Patients e63423. Biochemical Approach for Diagnosing Myocardial Injury and Infarction e63424. Analytical Issues of Cardiac Troponins e63525. The 99th Percentile Upper Reference Limit e63626. Operationalizing Criteria for Myocardial Injury and Infarction e63627. Electrocardiographic Detection of Myocardial Infarction e63728. Application of Supplemental Electrocardiogram Leads e63829. Electrocardiographic Detection of Myocardial Injury e63930. Prior or Silent/Unrecognized Myocardial Infarction e63931. Conditions That Confound the Electrocardiographic Diagnosis of Myocardial Infarction e63932. Conduction Disturbances and Pacemakers e64033. Atrial Fibrillation e64034. Imaging Techniques e64034.1. Echocardiography e64034.2. Radionuclide Imaging e64134.3. Cardiac Magnetic Resonance Imaging e64134.4. Computed Tomographic Coronary Angiography e64135. Applying Imaging in Acute Myocardial Infarction e64136. Applying Imaging in Late Presentation of Myocardial Infarction e64237. Regulatory Perspective on Myocardial Infarction in Clinical Trials e64338. Silent/Unrecognized Myocardial Infarction in Epidemiological Studies and Quality Programs e64339. Individual and Public Implications of the Myocardial Infarction Definition e64340. Global Perspectives of the Definition of Myocardial Infarction e64441. Using the Universal Definition of Myocardial Infarction in the Healthcare System e644Appendix e645Acknowledgment e645References e6451. What is new in the Universal Definition of Myocardial Infarction?2. Universal Definitions of Myocardial Injury and Myocardial Infarction: Summary3. IntroductionIn the late 19th century, postmortem examinations demonstrated a possible relationship between thrombotic occlusion of a coronary artery and myocardial infarction (MI).1 However, it was not until the beginning of the 20th century that the first clinical descriptions appeared describing a connection between the formation of a thrombus in a coronary artery and its associated clinical features.2,3 Despite these landmark observations, considerable time elapsed before general clinical acceptance of this entity was achieved, in part due to 1 autopsy study that showed no thrombi in the coronary arteries of 31% of deceased patients with an MI.4 The clinical entity was referred to as coronary thrombosis, although use of the term “MI” ultimately prevailed. Over the years, several different definitions of MI have been used, leading to controversy and confusion. Hence, a general and worldwide definition for MI was needed. This occurred for the first time in the 1950–1970s, when working groups from the World Health Organization (WHO) established a primarily electrocardiographic (ECG)–based definition of MI intended for epidemiological use.5 The original description, with minor modifications, is still used in epidemiological surveys (Figure 1).6–8Download figureDownload PowerPointFigure 1. History of documents on the definition of myocardial infarction. ACC indicates American College of Cardiology; AHA, American Heart Association; ESC, European Society of Cardiology; ISFC, International Society and Federation of Cardiology; MONICA, MONItoring of trends and determinants in CArdiovascular disease; NHLBI, National Heart, Lung, and Blood Institute; UDMI, Universal Definition of Myocardial Infarction; WHF, World Heart Federation; WHO, World Health Organization.With the introduction of more sensitive cardiac biomarkers, the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) collaborated to redefine MI using a biochemical and clinical approach, and reported that myocardial injury detected by abnormal biomarkers in the setting of acute myocardial ischemia should be labeled as MI.9 The principle was further refined by the Global MI Task Force, leading to the Universal Definition of Myocardial Infarction Consensus Document in 2007, introducing a novel MI classification system with 5 subcategories.10 This document, endorsed by the ESC, the ACC, the American Heart Association (AHA), and the World Heart Federation (WHF), was adopted by the WHO.11 The development of even more sensitive assays for markers of myocardial injury made further revision of the document necessary, particularly for patients who undergo coronary procedures or cardiac surgery. As a result, the Joint ESC/ACC/AHA/WHF Task Force produced the Third Universal Definition of Myocardial Infarction Consensus Document in 2012.12Studies have shown that myocardial injury, defined by an elevated cardiac troponin (cTn) value, is frequently encountered clinically and is associated with an adverse prognosis.13,14 Although myocardial injury is a prerequisite for the diagnosis of MI, it is also an entity in itself. To establish a diagnosis of MI, criteria in addition to abnormal biomarkers are required. Nonischemic myocardial injury may arise secondary to many cardiac conditions such as myocarditis, or may be associated with noncardiac conditions such as renal failure.15 Therefore, for patients with increased cTn values, clinicians must distinguish whether patients have suffered a nonischemic myocardial injury or one of the MI subtypes. If there is no evidence to support the presence of myocardial ischemia, a diagnosis of myocardial injury should be made. This diagnosis can be changed if subsequent evaluation indicates criteria for MI. The current Fourth Universal Definition of Myocardial Infarction Consensus Document reflects these considerations through adhering to the clinical approach of the definition of MI.Clinical Criteria for MIThe clinical definition of MI denotes the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia.4. Pathological characteristics of myocardial ISCHEMIA and infarctionMI is defined pathologically as myocardial cell death due to prolonged ischemia. Diminished cellular glycogen, and relaxed myofibrils and sarcolemmal disruption, are the first ultrastructural changes and are seen as early as 10–15 minutes after the onset of ischemia.16 Mitochondrial abnormalities are observed as early as 10 minutes after coronary occlusion by electron microscopy and are progressive.17 It can take hours before myocyte necrosis can be identified by postmortem examination in humans; this is in contrast to animal models, in which biochemical evidence of myocardial cell death due to apoptosis can be detected within 10 minutes of induced myocardial ischemia in association with myocyte death.15 Experimentally, necrosis progresses from the subendocardium to the subepicardium over several hours. The time course may be prolonged by increased collateral flow, reduced determinants of myocardial oxygen consumption, and intermittent occlusion/reperfusion, which can precondition the heart.18 Timely implementation of reperfusion therapy, when appropriate, reduces ischemic injury of the myocardium.19,205. Biomarker detection of myocardial injury and infarctionCardiac troponin I (cTnI) and T (cTnT) are components of the contractile apparatus of myocardial cells and are expressed almost exclusively in the heart.21,22 Increases in cTnI values have not been reported to occur following injury to noncardiac tissues. The situation is more complex for cTnT. Biochemical data indicate that injured skeletal muscle expresses proteins that are detected by the cTnT assay, leading to some situations where elevations of cTnT could emanate from skeletal muscle.23–27 Recent data suggest that the frequency of such elevations in the absence of ischemic heart disease may be higher than originally thought.28,29 cTnI and cTnT are the preferred biomarkers for the evaluation of myocardial injury,12,21,22,30 and high-sensitivity (hs)–cTn assays are recommended for routine clinical use.22 Other biomarkers, for example, wwm (CK-MB), are less sensitive and less specific.31 Myocardial injury is defined as being present when blood levels of cTn are increased above the 99th percentile upper reference limit (URL).12,21,22,30 The injury may be acute, as evidenced by a newly detected dynamic rising and/or falling pattern of cTn values above the 99th percentile URL, or chronic, in the setting of persistently elevated cTn levels.Criteria for Myocardial InjuryDetection of an elevated cTn value above the 99th percentile URL is defined as myocardial injury. The injury is considered acute if there is a rise and/or fall of cTn values.Although elevated cTn values reflect injury to myocardial cells, they do not indicate the underlying pathophysiological mechanisms, and can arise following preload-induced mechanical stretch or physiological stresses in otherwise normal hearts.32–34 Various causes have been suggested for the release of structural proteins from the myocardium, including normal turnover of myocardial cells, apoptosis, cellular release of cTn degradation products, increased cellular wall permeability, the formation and release of membranous blebs, and myocyte necrosis.27,35 Yet, it is not clinically possible to distinguish which increases of cTn levels are due to which mechanisms.36 However, regardless of the mechanism, acute myocardial injury, when associated with a rising and/or falling pattern of cTn values with at least 1 value above the 99th percentile URL and caused by myocardial ischemia, is designated as an acute MI.12,21,22,30 Histological evidence of myocardial injury with myocyte death can be detected in clinical conditions associated with nonischemic mechanisms of myocardial injury as well37,38 (Figure 2).Myocardial ischemic or nonischemic conditions associated with increased cTn values are presented in Table 1. The complexity of clinical circumstances may sometimes make it difficult to discriminate specific individual mechanism(s) of myocardial injury. In this situation, the multifactorial contributions resulting in myocardial injury should be described in the patient record.Download figureDownload PowerPointFigure 2. Spectrum of myocardial injury, ranging from no injury to myocardial infarction. Various clinical entities may involve these myocardial categories (eg, ventricular tachyarrhythmia, heart failure, kidney disease, hypotension/shock, hypoxemia and anemia). cTn indicates cardiac troponin; and URL upper reference limit.*No myocardial injury, cTn values ≤99th percentile URL or not detectable.†Myocardial injury, cTn values >99th percentile URL.‡Myocardial infarction, clinical evidence of myocardial ischemia and a rise and/or fall of cTn values >99th percentile URL.Table 1. Reasons for the Elevation of Cardiac Troponin Values Because of Myocardial InjuryMyocardial injury related to acute myocardial ischemia Atherosclerotic plaque disruption with thrombosisMyocardial injury related to acute myocardial ischemia because of oxygen supply/demand imbalance Reduced myocardial perfusion, eg, • Coronary artery spasm, microvascular dysfunction • Coronary embolism • Coronary artery dissection • Sustained bradyarrhythmia • Hypotension or shock • Respiratory failure • Severe anemia Increased myocardial oxygen demand, eg, • Sustained tachyarrhythmia • Severe hypertension with or without left ventricular hypertrophyOther causes of myocardial injury Cardiac conditions, eg, • Heart failure • Myocarditis • Cardiomyopathy (any type) • Takotsubo syndrome • Coronary revascularization procedure • Cardiac procedure other than revascularization • Catheter ablation • Defibrillator shocks • Cardiac contusion Systemic conditions, eg, • Sepsis, infectious disease • Chronic kidney disease • Stroke, subarachnoid hemorrhage • Pulmonary embolism, pulmonary hypertension • Infiltrative diseases, eg, amyloidosis, sarcoidosis • Chemotherapeutic agents • Critically ill patients • Strenuous exerciseFor a more comprehensive listing, see references 39-41.6. Clinical presentations of myocardial infarctionOnset of myocardial ischemia is the initial step in the development of MI and results from an imbalance between oxygen supply and demand. Myocardial ischemia in a clinical setting can most often be identified from the patient’s history and from the ECG. Possible ischemic symptoms include various combinations of chest, upper extremity, mandibular, or epigastric discomfort during exertion or at rest, or an ischemic equivalent such as dyspnea or fatigue. Often, the discomfort is diffuse; not localized, nor positional, nor affected by movement of the region. However, these symptoms are not specific for myocardial ischemia and can be observed in other conditions such as gastrointestinal, neurological, pulmonary, or musculoskeletal complaints. MI may occur with atypical symptoms such as palpitations or cardiac arrest, or even without symptoms.12 Very brief episodes of ischemia too short to cause necrosis can also cause cTn release and elevations. The involved myocytes can subsequently die due to apoptosis.42If myocardial ischemia is present clinically or detected by ECG changes together with myocardial injury, manifested by a rising and/or falling pattern of cTn values, a diagnosis of acute MI is appropriate. If myocardial ischemia is not present clinically, then elevated cTn levels may be indicative of acute myocardial injury if the pattern of values is rising and/or falling, or related to more chronic ongoing injury if the pattern is unchanging.14 Similar considerations are relevant when evaluating events that are potentially related to procedures that may cause myocardial injury and/or MI. Additional evaluations may lead to a need for the initial diagnosis to be revised.Patients with suspected acute coronary syndrome (ACS) that are ruled out for MI with normal cardiac biomarker values (≤99th percentile URL) may have unstable angina or an alternative diagnosis. These patients should be evaluated and treated accordingly.11,437. Clinical classification of myocardial infarctionFor the sake of immediate treatment strategies such as reperfusion therapy, it is usual practice to designate MI in patients with chest discomfort or other ischemic symptoms, who develop new ST-segment elevations in 2 contiguous leads or new bundle branch blocks with ischemic repolarization patterns as an ST-elevation MI (STEMI) (see section 27). In contrast, patients without ST-segment elevation at presentation are usually designated non–ST-elevation MI (NSTEMI). The categories of patients with STEMI, NSTEMI, or unstable angina are customarily included in the concept of ACS. In addition to these categories, MI may be classified into various types based on pathological, clinical, and prognostic differences, along with different treatment strategies.7.1. Myocardial Infarction Type 1MI caused by atherothrombotic coronary artery disease (CAD) and usually precipitated by atherosclerotic plaque disruption (rupture or erosion) is designated as a type 1 MI. The relative burden of atherosclerosis and thrombosis in the culprit lesion varies greatly, and the dynamic thrombotic component may lead to distal coronary embolization resulting in myocyte necrosis.44,45 Plaque rupture may not only be complicated by intraluminal thrombosis but also by hemorrhage into the plaque through the disrupted surface (Figure 3).44,45Download figureDownload PowerPointFigure 3. Myocardial infarction type 1.Criteria for Type 1 MIDetection of a rise and/or fall of cTn values with at least 1 value above the 99th percentile URL and with at least 1 of the following:Symptoms of acute myocardial ischemia;New ischemic ECG changes;Development of pathological Q waves;Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology;Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy.*cTn indicates cardiac troponin; ECG, electrocardiogram; URL, upper reference limit.*Postmortem demonstration of an atherothrombus in the artery supplying the infarcted myocardium, or a macroscopically large circumscribed area of necrosis with or without intramyocardial hemorrhage, meets the type 1 MI criteria regardless of cTn values.It is essential to integrate the ECG findings with the aim of classifying type 1 MI into STEMI or NSTEMI in order to establish the appropriate treatment according to current Guidelines.46,477.2. Myocardial Infarction Type 2The pathophysiological mechanism leading to ischemic myocardial injury in the context of a mismatch between oxygen supply and demand has been classified as type 2 MI.10,12 By definition, acute atherothrombotic plaque disruption is not a feature of type 2 MI. In patients with stable known or presumed CAD, an acute stressor such as an acute gastrointestinal bleed with a precipitous drop in hemoglobin or a sustained tachyarrhythmia with clinical manifestations of myocardial ischemia, may result in myocardial injury and a type 2 MI. These effects are due to insufficient blood flow to the ischemic myocardium to meet the increased myocardial oxygen demand of the stressor. Ischemic thresholds may vary substantially in individual patients depending on the magnitude of the stressor, the presence of noncardiac comorbidities, and the extent of underlying CAD and cardiac structural abnormalities.Studies have shown variable occurrences of type 2 MI depending on criteria used for diagnosis. Some reports rely on specific predetermined oxygen mismatch criteria,48,49 whereas others apply more liberal criteria. Most studies show a higher frequency of type 2 MI in women. The short- and long-term mortality rates for patients with type 2 MI are generally higher than for type 1 MI patients in most but not all studies due to an increased prevalence of comorbid conditions.49–57 Coronary atherosclerosis is a common finding in type 2 MI patients selected for coronary angiography. In general, these patients have a worse prognosis than those without CAD.54–57 Prospective evaluations of the importance of CAD with type 2 MI using consistent definitions and approaches are needed.It has been shown that the frequency of ST-segment elevation in type 2 MI varies from 3% to 24%.53 In some cases, coronary embolism caused by thrombi, calcium or vegetation from the atria or ventricles, or acute aortic dissection may result in a type 2 MI. Spontaneous coronary artery dissection with or without intramural hematoma is another non-atherosclerotic condition that may occur, especially in young women. It is defined as spontaneous dissection of the coronary artery wall with accumulation of blood within the false lumen, which can compress the true lumen to varying degrees (Figure 4).58Download figureDownload PowerPointFigure 4. Myocardial infarction type 2.All of the clinical information available should be considered in distinguishing type 1 MI from type 2 MI. The context and mechanisms of type 2 MI should be considered when establishing this diagnosis (Figure 5). The myocardial oxygen supply/demand imbalance attributable to acute myocardial ischemia may be multifactorial, related either to: reduced myocardial perfusion due to fixed coronary atherosclerosis without plaque rupture, coronary artery spasm, coronary microvascular dysfunction (which includes endothelial dysfunction, smooth muscle cell dysfunction, and the dysregulation of sympathetic innervation), coronary embolism, coronary artery dissection with or without intramural hematoma or other mechanisms that reduce oxygen supply such as severe bradyarrhythmia, respiratory failure with severe hypoxemia severe anemia, and hypotension/shock; or to increased myocardial oxygen demand due to sustained tachyarrhythmia or severe hypertension with or without left ventricular hypertrophy. In patients who undergo timely coronary angiography, description of a ruptured plaque with thrombus in the infarct-related artery may be helpful in making the distinction between type 2 MI vs. type 1 MI, but angiography is not always definitive, clinically indicated, or required to establish the diagnosis of type 2 MI.Criteria for Type 2 MIDetection of a rise and/or fall of cTn values with at least 1 value above the 99th percentile URL, and evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute coronary atherothrombosis, requiring at least 1 of the following:Symptoms of acute myocardial ischemia;New ischemic ECG changes;Development of pathological Q waves;Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiologyDownload figureDownload PowerPointFigure 5. Framework for type 2 myocardial infarction considering the clinical context and pathophysiological mechanisms attributable to acute myocardial ischemia. The illustration above is modified from Januzzi and Sandoval.59It appears advisable in the acute setting to treat the underlying ischemic imbalance of oxygen supply and demand. This treatment may include volume adjustment, blood pressure management, administration of blood products, heart-rate control, and respiratory support.47,48 Depending on the clinical situation, coronary evaluations may be indicated to assess the likelihood of CAD. If it is present, the MI Guidelines may be applied in accordance with the ECG findings of STEMI or NSTEMI.46,47 However, if CAD is absent, the benefits of cardiovascular risk reduction strategies with type 2 MI remain uncertain.7.3. Myocardial Infarction Type 2 and Myocardial InjuryType 2 MI and myocardial injury are frequently encountered in clinical practice and both are related to a poor outcome.13,14,49,51,56 A conceptual model to facilitate the clinical distinction between acute ischemic myocardial injury with or without an acute atherothrombotic event (type 1 or type 2 MI) vs. conditions without acute ischemic myocardial injury is displayed in Figure 6. Acute MI requires a rising and/or falling pattern of cTn values. Acute myocardial injury may also manifest such a pattern but if the injury is related to structural heart disease, the cTn values may be stable and unchanging. Type 2 MI and nonischemic myocardial injury may coexist. It should be recognized that some disease entities may be on both sides of the diagram (eg, acute heart failure that may occur in the context of acute myocardial ischemia). Nevertheless, abnormal cTn values in the setting of acute and/or chronic heart failure are often better categorized as a myocardial injury condition. Few studies have compared the incidence and clinical features of type 2 MI versus myocardial injury without acute myocardial ischemia.Download figureDownload PowerPointFigure 6. A model for interpreting myocardial injury. Ischemic thresholds vary substantially in relation to the magnitude of the stressor and the extent of underlying cardiac disease. MI indicates myocardial infarction; URL, upper reference limit.*Stable denotes ≤20% variation of troponin values in the appropriate clinical context.†Ischemia denotes signs and/or symptoms of clinical myocardial ischemia.7.4. Myocardial Infarction Type 3The detection of cardiac biomarkers in the blood is fundamental for establishing the diagnosis of MI.10,12 However, patients can manifest a typical presentation of myocardial ischemia/infarction, including presumed new ischemic ECG changes or ventricular fibrillation, and die before it is possible to obtain blood for cardiac biomarker determination; or the patient may succumb soon after the onset of symptoms before an elevation of biomarker values has occurred. Such patients are designated as having a type 3 MI, when suspicion for an acute myocardial ischemic event is high, even when cardiac biomarker evidence of MI is lacking.10,12 This category allows the separation of fatal MI events from the much larger group of sudden death episodes that may be cardiac (nonischemic) or noncardiac in origin. When a type 3 MI is diagnosed and a subsequent autopsy reveal

Background— Data from single-center studies suggest that echocardiographic parameters of mechanical dyssynchrony may improve patient selection for cardiac resynchronization therapy (CRT). In a prospective, multicenter setting, the Predictors of Response to CRT (PROSPECT) study tested the performance of these parameters to predict CRT response. Methods and Results— Fifty-three centers in Europe, Hong Kong, and the United States enrolled 498 patients with standard CRT indications (New York Heart Association class III or IV heart failure, left ventricular ejection fraction ≤35%, QRS ≥130 ms, stable medical regimen). Twelve echocardiographic parameters of dyssynchrony, based on both conventional and tissue Doppler–based methods, were evaluated after site training in acquisition methods and blinded core laboratory analysis. Indicators of positive CRT response were improved clinical composite score and ≥15% reduction in left ventricular end-systolic volume at 6 months. Clinical composite score was improved in 69% of 426 patients, whereas left ventricular end-systolic volume decreased ≥15% in 56% of 286 patients with paired data. The ability of the 12 echocardiographic parameters to predict clinical composite score response varied widely, with sensitivity ranging from 6% to 74% and specificity ranging from 35% to 91%; for predicting left ventricular end-systolic volume response, sensitivity ranged from 9% to 77% and specificity from 31% to 93%. For all the parameters, the area under the receiver-operating characteristics curve for positive clinical or volume response to CRT was ≤0.62. There was large variability in the analysis of the dyssynchrony parameters. Conclusion— Given the modest sensitivity and specificity in this multicenter setting despite training and central analysis, no single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines. Efforts aimed at reducing variability arising from technical and interpretative factors may improve the predictive power of these echocardiographic parameters in a broad clinical setting.

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians and other healthcare providers in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC Web Site in the guidelines section (www.escardio.org). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2. The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report was entirely supported financially by the ESC and was developed without any involvement of the industry. The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines and Expert Consensus Documents or statements. Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. The document is revised, and finally approved by the CPG and subsequently published. After publication, dissemination of the message is of paramount importance. Pocket-sized versions and personal digital assistant (PDA)-downloadable versions are useful at the point of care. Some surveys have shown that the intended end-users are sometimes not aware of the existence of guidelines, or simply do not translate them into practice, so this is why implementation programmes for new guidelines form an important component of the dissemination of knowledge. Meetings are organized by the ESC, and directed towards its member National Societies and key opinion leaders in Europe. Implementation meetings can also be undertaken at national levels, once the guidelines have been endorsed by the ESC member societies, and translated into the national language. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Thus, the task of writing Guidelines or Expert Consensus documents covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. The loop between clinical research, writing of guidelines, and implementing them into clinical practice can then only be completed if surveys and registries are performed to verify that real-life daily practice is in keeping with what is recommended in the guidelines. Such surveys and registries also make it possible to evaluate the impact of implementation of the guidelines on patient outcomes. Guidelines and recommendations should help physicians and other healthcare providers to make decisions in their daily practice. However, the ultimate judgement regarding the care of an individual patient must be made by the physician in charge of his/her care. The aim of this document is to provide practical guidelines for the diagnosis, assessment, and treatment of acute and chronic heart failure (HF). These guidelines are a development and revision of guidelines published in 1995,1 1997,2 2001,3 and 2005.4,5 Much new information relating to the treatment of HF has emerged. This has necessitated a revision of some previous recommendations. The recommendations are relevant to clinical practice, epidemiological surveys, observational studies, and clinical trials. Particular attention in this revision has been given to the simplification and clarity of recommendations, and to the problems associated with implementation. The intention has been to merge and modify previous documents relating to HF. The guidelines are intended as a support for practising physicians and other healthcare professionals providing advice on how to manage these patients, including recommendations for referral. Documented and published evidence on diagnosis, efficacy, and safety of therapeutic interventions is the main basis for these guidelines. Where evidence is lacking or does not resolve a clinical issue, a consensus opinion is presented. ESC Guidelines are relevant to 51 member states with diverse economies and, therefore, recommendations based on cost-effectiveness have, in general, been avoided. National health policy as well as clinical judgement may dictate the order of priorities in implementation. The recommendations in these guidelines should always be considered in the light of national policies and local regulatory guidance on the use of any diagnostic procedure, medicine, or device. This report was drafted by a Writing Group of the Task Force (see title page) appointed by the CPG of the ESC. Within this Task Force, statements of conflicts of interests were collected, which are available at the ESC Office. The draft was sent to the CPG and the document reviewers (see title page). After consideration of their input, the document was updated, reviewed, and then approved for publication by the entire Task Force. An evidence-based approach has been used to generate the grade of any recommendation in the guidelines, with an additional assessment of the quality of the evidence. For the diagnosis of HF, evidence is incomplete. Where that is so, recommendations and statements are based on a consensus of expert opinions. Many definitions of HF have been put forward over the last 50 years.6 These highlight one or several features of this complex syndrome such as haemodynamics, oxygen consumption, or exercise capacity. In recent years, most definitions have emphasized the need for both the presence of symptoms of HF and physical signs of fluid retention.5,7–9 HF is a syndrome in which the patients should have the following features: symptoms of HF, typically shortness of breath at rest or during exertion, and/or fatigue; signs of fluid retention such as pulmonary congestion or ankle swelling; and objective evidence of an abnormality of the structure or function of the heart at rest (Table 3). A clinical response to treatment directed at HF alone is not sufficient for the diagnosis, but is helpful when the diagnosis remains unclear after appropriate diagnostic investigations. Patients with HF would usually be expected to show some improvement in symptoms and signs in response to those treatments from which a relatively fast symptomatic improvement could be anticipated (e.g. diuretic or vasodilator administration). The major and common clinical manifestations of HF are shown in Table 4. Asymptomatic structural or functional abnormalities of the heart are considered as precursors of symptomatic HF and are associated with a high mortality.10,11 Treatment is available for these conditions, when diagnosed, and for that reason these conditions are included in these guidelines. An advantage of the definition of HF used here is that it is practical and allows a more precise approach both in clinical practice and when undertaking observational surveys, epidemiological studies, or clinical trials. HF should never be a sole diagnosis. The cause should always be sought. Many additional words or phrases are used to characterize patients with HF. These terms can overlap, and physicians do sometimes use words with a slightly different meaning. The word ‘acute’ in the context of acute HF has become confusing because some clinicians use the word to indicate severity (the medical emergency of life-threatening pulmonary oedema) and others use the word to indicate decompensated, recent-onset, or even new-onset HF.4 The word is then an indicator of time rather than severity. The words acute, advanced, and decompensated should not be used interchangeably when applied to HF. A useful classification of HF based on the nature of the clinical presentation is shown in Table 5. A distinction is made between new-onset HF, transient HF, and chronic HF. New-onset HF is self-explanatory and refers to the first presentation. Transient HF refers to symptomatic HF over a limited time period, although long-term treatment may be indicated. Examples would be patients with mild myocarditis from which recovery is near complete, patients with a myocardial infarction (MI) who need diuretics in the coronary care unit but in whom long-term treatment is not necessary, or transient HF caused by ischaemia and resolved by revascularization. Worsening HF on a background of chronic HF (decompensation) is by far the most common form of HF leading to hospital admission, accounting for 80% of cases. Treatment should be based on the clinical presentation for which specific therapy is indicated (e.g. pulmonary oedema, hypertension emergency, acute MI). A distinction is frequently made between systolic and diastolic HF.12,13 The distinction is somewhat arbitrary.14–16 Patients with diastolic HF have symptoms and/or signs of HF and a preserved left ventricular ejection fraction (LVEF) >40–50%.17 There is no consensus concerning the cut-off for preserved EF. The EF is the stroke volume divided by the end-diastolic volume for the relevant ventricular chamber of the heart and is therefore largely determined by the end-diastolic volume of the ventricular chamber (i.e. a dilated heart). An EF below or above 40%, distinguishes between large or normal left end-diastolic ventricular volumes. The distinction has arisen largely because in the past most patients admitted to hospitals for investigation or entered into clinical trials have had dilated hearts with a reduced EF <35 or 40%. Most patients with HF have evidence of both systolic and diastolic dysfunction at rest or on exercise. Diastolic and systolic HFs should not be considered as separate entities.18 Other phrases have been used to describe diastolic HF, such as HF with preserved ejection fraction (HFPEF), HF with normal ejection fraction (HFNEF), or HF with preserved systolic function (HFPSF). We have elected to use the abbreviation HFPEF in this document. Many other phrases have been used in describing patients with HF that do not have aetiological significance. Forward and backward HF are old terms used to express the concept that perfusion of tissue and an increase in the left atrial pressure can under some circumstance such as acute HF and cardiogenic shock contribute to the pathophysiology.19,20 Preload and afterload are terms linked to the left and/or right atrial pressures (often reflecting volume overload) and the work of the myocardium (often reflecting pressure overload or high impedance). However, measures of these parameters are often imprecise. Right and left HF refer to syndromes presenting predominantly with congestion of the systemic or pulmonary veins, leading to signs of fluid retention with ankle swelling or pulmonary oedema, respectively. The most common cause of right ventricular failure is a raised pulmonary artery pressure due to failure of the LV leading to poor perfusion of the kidney, retention of salt and water, and accumulation of fluid in the systemic circulation. High and low output HF refer to the observation that a number of specific medical conditions lead to a clinical picture which mimics the signs and symptoms of HF. Common causes of high output states mimicking HF are anaemia, thyrotoxicosis, septicaemia, liver failure, arteriovenous shunts, Paget's disease, and beri-beri. In these conditions, the primary abnormality is not disease of the heart and the conditions are reversible with treatment. The conditions are better labelled as HF secondary to circulatory high output conditions and are important because they are treatable and should be excluded when diagnosing HF. Mild, moderate, or severe HF is used as a clinical symptomatic description, where mild is used for patients who can move around with no important limitations of dyspnoea or fatigue, severe for patients who are markedly symptomatic and need frequent medical attention, and moderate for the remaining patient cohort. Two classifications (Table 6) of the severity of HF are commonly employed. One is based on symptoms and exercise capacity [the New York Heart Association (NYHA) functional classification21,22]. The NYHA functional classification has proved to be clinically useful and it is employed routinely in most randomized clinical trials. The other describes HF in stages based on structural changes and symptoms. All patients with overt HF are in stages C and D.7 Much is now known about the epidemiology of HF.23–27 The ESC represents countries with a population of >900 million, and there are at least 15 million patients with HF in those 51 countries. The prevalence of asymptomatic ventricular dysfunction is similar, so that HF or asymptomatic ventricular dysfunction is evident in ~4% of the population. The prevalence of HF is between 2 and 3% and rises sharply at ~75 years of age, so the prevalence in 70- to 80-year-old people is between 10 and 20%. In younger age groups HF is more common in men because the most common cause, coronary heart disease, occurs in earlier decades. In the elderly, the prevalence is equal between the sexes. The overall prevalence of HF is increasing because of the ageing of the population, the success in prolonging survival in patients suffering coronary events, and the success in postponing coronary events by effective prevention in those at high risk or those who have already survived a first event (secondary prevention).28,29 In some countries the age-adjusted mortality from HF is falling at least in part due to modern treatment.28,30–32 The mean age of patients with HF in the community in developed countries is 75 years. HFPEF is more common in the elderly, women, and those with hypertension or diabetes. HF is the cause of 5% of acute hospital admissions, is present in 10% of patients in hospital beds, and accounts for ~2% of national expenditure on health, mostly due to the cost of hospital admissions.33 Substantial under-reporting is probably due to clinicians' preference for aetiological diagnoses (e.g. aortic stenosis) or the diagnosis of a major co-morbidity (e.g. diabetes). The outlook is, in general, gloomy, although some patients can live for many years.23,29,34,35 Overall 50% of patients are dead at 4 years. Forty per cent of patients admitted to hospital with HF are dead or readmitted within 1 year. Studies show that the accuracy of diagnosis of HF by clinical means alone is often inadequate, particularly in women, the elderly, and the obese.36,37 HFPEF (EF >45–50%) is present in half the patients with HF. The prognosis in more recent studies has been shown to be essentially similar to that of systolic HF.38,39 There are only a limited number of ways in which the function of the heart can be affected. The most common causes of functional deterioration of the heart are damage or loss of heart muscle, acute or chronic ischaemia, increased vascular resistance with hypertension, or the development of a tachyarrhythmia such as atrial fibrillation (AF). Coronary heart disease is by far the most common cause of myocardial disease, being the initiating cause in ~70% of patients with HF.28,40 Valve disease accounts for 10% and cardiomyopathies for another 10% (Table 7). A cardiomyopathy is a myocardial disorder in which the heart muscle is structurally and functionally abnormal [in the absence of coronary artery disease (CAD), hypertension, valvular disease, or congenital heart disease] sufficient to cause the observed myocardial abnormality.41 A classification of the cardiomyopathies has been published recently by the Working Group on Myocardial and Pericardial Diseases of the ESC.41 The American Heart Association has issued a scientific statement.42 Both take into account the great advances made recently in understanding the genetic origins and the biology of the cardiomyopathies. The European proposal was guided by the relevance of the new classification to everyday clinical practice and maintains the previously defined morpho-functional phenotypes which are further subdivided into familial/genetic and non-familial/non-genetic forms. The European classification abandoned the older distinction between ‘primary’ and ‘secondary’ cardiomyopathies, and does not include ion channelopathies among cardiomyopathies. In 1933 Sir Thomas Lewis wrote in his textbook on heart disease that ‘The very essence of cardiovascular medicine is the recognition of early heart failure’.43 The symptoms and signs of HF are the key to early detection because that is what causes patients to seek medical attention. Taking a good history and careful physical examination are skills, which are essential to master (Table 8). Breathlessness, tiredness, and fatigue are the characteristic symptoms, but eliciting and assessing these symptoms particularly in the elderly requires experience and skill.44–46 The clinical signs of HF (Table 9) should be assessed in a careful clinical examination, including observation, palpation, and auscultation.47–51 Like symptoms, the signs of early HF can be difficult to interpret, not only in elderly patients, but also in the obese. The clinical suspicion of HF must then be confirmed by more objective tests particularly targeting assessment of cardiac function. The origins of the symptoms of HF are not fully understood.52–55 Increased pulmonary capillary pressure is undoubtedly responsible for pulmonary oedema and shortness of breath in the context of acute HF with evidence of fluid overload. In contrast, studies conducted during exercise in patients with chronic HF demonstrate only a weak relationship between capillary pressure and exercise performance. HF is a condition which eventually results in pathology in almost all body organs. Tiredness and fatigue are frequently reported symptoms, but are non-specific with multiple causes. Loss of skeletal muscle mass and strength is a late manifestation.55,56 Signals from skeletal muscle are often interpreted by the brain as breathlessness or as fatigue. This may explain why the response to treatment may be slow in patients with HF because the quality of skeletal muscle must be restored. Variation in the degree of mitral regurgitation or transitory dysrhythmia, common in HF, will also exacerbate breathlessness. There is a poor relationship between symptoms and the severity of cardiac dysfunction. Symptoms do relate more closely to prognosis if persistent after therapy and can then be used to classify the severity of HF and to monitor the effects of therapy. However, symptoms alone should not guide the optimal titration of neurohormonal inhibitors such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, or aldosterone antagonists, because these drugs impact on mortality in a manner that is not closely related to symptoms. Patients should be titrated to the optimal, tolerated dose. The severity of heart failure is most often classified using the NYHA functional classification. A more recent classification is based on both the structure of the heart and symptoms. In the context of MI, two other classifications of the severity of HF, the Killip57 and Forrester58 classifications, are used (Table 10). An algorithm for the diagnosis of HF or LV dysfunction is shown in Figure 1. The diagnosis of HF is not sufficient alone. Appropriate investigations are required to establish the cause of the HF, because although the general treatment of HF is common to most patients, some causes require specific treatments and may be correctable. Several diagnostic tests are employed routinely to confirm or rule out the diagnosis of HF (Table 11). Diagnostic tests are usually most sensitive for the detection of patients with HF and reduced EF. Diagnostic findings are often less pronounced in patients with HFPEF. Echocardiography is the most useful method for evaluating systolic and diastolic dysfunction. The following investigations are considered appropriate in patients with HF. However, the recommendations largely represent expert consensus opinion without adequate documented evidence. Level of evidence C applies unless otherwise stated. An electrocardiogram (ECG) should be performed in every patient with suspected heart failure. Electrocardiographic changes are common in patients suspected of having HF (Table 12). An abnormal ECG has little predictive value for the presence of HF. If the ECG is completely normal, HF, especially with systolic dysfunction, is unlikely (<10%). Chest X-ray is an essential component of the diagnostic work-up in heart failure. It permits assessment of pulmonary congestion and may demonstrate important pulmonary or thoracic causes of dyspnoea. The chest X-ray (in two planes) is useful to detect cardiomegaly, pulmonary congestion, and pleural fluid accumulation, and can demonstrate the presence of pulmonary disease or infection causing or contributing to dyspnoea (Table 13). Apart from congestion, findings are predictive of HF only in the context of typical signs and symptoms. Cardiomegaly can be absent not only in acute but also in chronic HF. A routine diagnostic evaluation of patients with suspected HF includes a complete blood count (haemoglobin, leukocytes, and platelets), serum electrolytes, serum creatinine, estimated glomerular filtration rate (GFR), glucose, liver function tests, and urinalysis. Additional tests should be considered according to the clinical picture (Table 14). Marked haematological or electrolyte abnormalities are uncommon in untreated mild to moderate HF, although mild anaemia, hyponatraemia, hyperkalaemia, and reduced renal function are common, especially in patients treated with diuretics and ACEI/ARB/aldosterone antagonist therapy. Appropriate laboratory monitoring is essential during the initiation, titration, and follow-up phases in patients receiving drug therapy for HF. Plasma concentrations of natriuretic peptides are useful biomarkers in the diagnosis of HF and in the management of patients with established chronic HF. Evidence exists supporting their use for diagnosing, staging, making hospitalization/discharge decisions, and identifying patients at risk for clinical events. The evidence for their use in monitoring and adjusting drug therapy is less clearly established. A normal concentration in an untreated patient has a high negative predictive value and makes HF an unlikely cause of symptoms. This may play an important role especially in primary care. High levels of natriuretic peptides despite optimal treatment indicate a poor prognosis. B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) measurements were introduced as tools for diagnosis59 and management60 of HF (Figure 1). They rise in response to an increase in myocardial wall stress. Usually, lower levels are observed in patients with preserved LV systolic function. There is no definitive cut-off value recognized for either of the two natriuretic peptides commonly assessed for the diagnosis of HF in the emergency department. Due to the relatively long half-lives of natriuretic peptides, abrupt changes in LV filling pressures may not be reflected by rapid changes in peptides. Conditions other than HF associated with elevated natriuretic peptide levels include: LV hypertrophy, tachycardia, right ventricular overload, myocardial ischaemia, hypoxaemia, renal dysfunction, advanced age, liver cirrhosis, sepsis, and infection. Obesity and treatment may decrease natriuretic peptide levels. Natriuretic peptides may also be useful in assessing prognosis prior to hospital discharge and in monitoring the effectiveness of HF therapy.61,62 Troponin I or T should be sampled in suspected HF when the clinical picture suggests an acute coronary syndrome (ACS). An increase in cardiac troponins indicates myocyte necrosis and, if indicated, the potential for revascularization should be considered and an appropriate diagnostic work-up performed. An increase in troponin also occurs in acute myocarditis. Mild increases in cardiac troponins are frequently seen in severe HF or during episodes of HF decompensation in patients without evidence of myocardial ischaemia due to ACS and in situations such as sepsis. An elevated troponin is a strong prognostic marker in HF, especially in the presence of elevated natriuretic peptides.63 HF is accompanied by an increase in various other neurohormonal markers (norepinephrine, renin, aldosterone, endothelin, arginine vasopressin). Although useful in research, evaluation of neuroendocrine activation is not required for diagnostic or prognostic purposes in individual patients. The term echocardiography is used to refer to all cardiac ultrasound imaging techniques, including pulsed and continuous wave Doppler, colour Doppler and tissue Doppler imaging (TDI). Confirmation by echocardiography of the diagnosis of heart failure and/or cardiac dysfunction is mandatory and should be performed shortly following suspicion of the diagnosis of HF. Echocardiography is widely available, rapid, non-invasive, and safe, and provides extensive information on cardiac anatomy (volumes, geometry, mass), wall motion, and valvular function. The study provides essential information on the aetiology of HF. In general a diagnosis of heart failure should include an echocardiogram. The most practical measurement of ventricular function for distinguishing between patients with systolic dysfunction and patients with preserved systolic function is the LVEF (normal >45–50%). This cut-off is somewhat arbitrary. LVEF is not synonymous with indices of contractility as it is strongly dependent on volumes, preload, afterload, heart rate, and valvular function. Stroke volume may be maintained by cardiac dilatation and increased volumes. Tables 15 and 16 present the most common echocardiographic and Doppler abnormalities in HF. Assessment of diastolic function using evaluation of the ventricular filling pattern is important for detecting abnormalities of diastolic function or filling in patients with HF. This can be the predominant functional abnormality of the heart, thus fulfilling the third component necessary for the diagnosis of heart failure. This is especially true in symptomatic patients with preserved LVEF. A recent consensus paper from the Heart Failure Association has focused on the assessment of diastolic dysfunction in HFPEF.64 There are three types of abnormal filling patterns recognized conventionally in patients in sinus rhythm. Doppler echocardiography allows estimation of the systolic pulmonary artery pressure. This is derived from calculation of the right ventricular systolic pressure estimated from the peak velocity of the tricuspid regurgitant jet velocity present in most subjects. It also permits an assessment of stroke volume and cardiac output by measurement of the velocity time integral (VTI) of the aortic flow. Echocardiography plays a major role in confirming the diagnosis of HFPEF. The diagnosis of HFPEF requires three conditions to be satisfied: Transoesophageal echocardiography (TOE) is recommended in patients who have an inadequate transthoracic echo window (obesity, ventilated patients), in complicated valvular patients (especially aortic, mitral, and mechanical valves), in suspected endocarditis, in congenital heart disease, or to exclude a thrombus in the left atrial appendage in patients with AF. Stress echocardiography (dobutamine or exercise echo) is used to detect ventricular dysfunction caused by ischaemia and to assess myocardial viability in the presence of marked hypokinesis or akinesis. It may also be useful in identifying myocardial stunning, hibernation, and in relating HF symptoms to valvular abnormalities. In patients with HF, stress echo may have a lower sensitivity and specificity due to LV dilatation or the presence of bundle branch block. In patients in whom echocardiography at rest has not provided adequate information and in patients with suspected CAD, further non-invasive imaging may include cardiac magnetic resonance imaging (CMR), cardiac CT, or radionuclide imaging. CMR is a versatile, highly accurate, reproducible, non-invasive imaging technique for the assessment of left and right ventricular volumes, global function, regional wall motion, myocardial thickness, thickening, myocardial mass and tumours, cardiac valves, congenital defects, and pericardial disease.65,66 It has become the gold standard of accurac

European Journal of Heart FailureVolume 14, Issue 8 p. 803-869 ESC GuidelineFree Access ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC Authors/Task Force Members, Authors/Task Force MembersSearch for more papers by this authorJohn J.V. McMurray, Corresponding Author John J.V. McMurray Chairperson UKCorresponding author. Chairperson: Professor John J.V. McMurray, University of Glasgow G12 8QQ, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email: [email protected]Search for more papers by this authorStamatis Adamopoulos, Stamatis Adamopoulos GreeceSearch for more papers by this authorStefan D. Anker, Stefan D. Anker GermanySearch for more papers by this authorAngelo Auricchio, Angelo Auricchio SwitzerlandSearch for more papers by this authorMichael Böhm, Michael Böhm GermanySearch for more papers by this authorKenneth Dickstein, Kenneth Dickstein NorwaySearch for more papers by this authorVolkmar Falk, Volkmar Falk SwitzerlandSearch for more papers by this authorGerasimos Filippatos, Gerasimos Filippatos GreeceSearch for more papers by this authorCândida Fonseca, Cândida Fonseca PortugalSearch for more papers by this authorMiguel Angel Gomez-Sanchez, Miguel Angel Gomez-Sanchez SpainSearch for more papers by this authorTiny Jaarsma, Tiny Jaarsma SwedenSearch for more papers by this authorLars Køber, Lars Køber DenmarkSearch for more papers by this authorGregory Y.H. Lip, Gregory Y.H. Lip UKSearch for more papers by this authorAldo Pietro Maggioni, Aldo Pietro Maggioni ItalySearch for more papers by this authorAlexander Parkhomenko, Alexander Parkhomenko UkraineSearch for more papers by this authorBurkert M. Pieske, Burkert M. Pieske AustriaSearch for more papers by this authorBogdan A. Popescu, Bogdan A. Popescu RomaniaSearch for more papers by this authorPer K. Rønnevik, Per K. Rønnevik NorwaySearch for more papers by this authorFrans H. Rutten, Frans H. Rutten The NetherlandsSearch for more papers by this authorJuerg Schwitter, Juerg Schwitter SwitzerlandSearch for more papers by this authorPetar Seferovic, Petar Seferovic SerbiaSearch for more papers by this authorJanina Stepinska, Janina Stepinska PolandSearch for more papers by this authorPedro T. Trindade, Pedro T. Trindade SwitzerlandSearch for more papers by this authorAdriaan A. Voors, Adriaan A. Voors The NetherlandsSearch for more papers by this authorFaiez Zannad, Faiez Zannad FranceSearch for more papers by this authorAndreas Zeiher, Andreas Zeiher GermanySearch for more papers by this authorESC Committee for Practice Guidelines (CPG), ESC Committee for Practice Guidelines (CPG)Search for more papers by this authorJeroen J. Bax, Jeroen J. Bax CPG Chairperson The NetherlandsSearch for more papers by this authorHelmut Baumgartner, Helmut Baumgartner GermanySearch for more papers by this authorClaudio Ceconi, Claudio Ceconi ItalySearch for more papers by this authorVeronica Dean, Veronica Dean FranceSearch for more papers by this authorChristi Deaton, Christi Deaton UKSearch for more papers by this authorRobert Fagard, Robert Fagard BelgiumSearch for more papers by this authorChristian Funck-Brentano, Christian Funck-Brentano FranceSearch for more papers by this authorDavid Hasdai, David Hasdai IsraelSearch for more papers by this authorArno Hoes, Arno Hoes The NetherlandsSearch for more papers by this authorPaulus Kirchhof, Paulus Kirchhof Germany UKSearch for more papers by this authorJuhani Knuuti, Juhani Knuuti FinlandSearch for more papers by this authorPhilippe Kolh, Philippe Kolh BelgiumSearch for more papers by this authorTheresa McDonagh, Theresa McDonagh UKSearch for more papers by this authorCyril Moulin, Cyril Moulin FranceSearch for more papers by this authorBogdan A. Popescu, Bogdan A. Popescu RomaniaSearch for more papers by this authorŽeljko Reiner, Željko Reiner CroatiaSearch for more papers by this authorUdo Sechtem, Udo Sechtem GermanySearch for more papers by this authorPer Anton Sirnes, Per Anton Sirnes NorwaySearch for more papers by this authorMichal Tendera, Michal Tendera PolandSearch for more papers by this authorAdam Torbicki, Adam Torbicki PolandSearch for more papers by this authorAlec Vahanian, Alec Vahanian FranceSearch for more papers by this authorStephan Windecker, Stephan Windecker SwitzerlandSearch for more papers by this authorDocument Reviewers, Document ReviewersSearch for more papers by this authorTheresa McDonagh, Theresa McDonagh CPG Co-Review Coordinator UKSearch for more papers by this authorUdo Sechtem, Udo Sechtem CPG Co-Review Coordinator GermanySearch for more papers by this authorLuis Almenar Bonet, Luis Almenar Bonet SpainSearch for more papers by this authorPanayiotis Avraamides, Panayiotis Avraamides CyprusSearch for more papers by this authorHisham A. Ben Lamin, Hisham A. Ben Lamin LibyaSearch for more papers by this authorMichele Brignole, Michele Brignole ItalySearch for more papers by this authorAntonio Coca, Antonio Coca SpainSearch for more papers by this authorPeter Cowburn, Peter Cowburn UKSearch for more papers by this authorHenry Dargie, Henry Dargie UKSearch for more papers by this authorPerry Elliott, Perry Elliott UKSearch for more papers by this authorFrank Arnold Flachskampf, Frank Arnold Flachskampf SwedenSearch for more papers by this authorGuido Francesco Guida, Guido Francesco Guida ItalySearch for more papers by this authorSuzanna Hardman, Suzanna Hardman UKSearch for more papers by this authorBernard Iung, Bernard Iung FranceSearch for more papers by this authorBela Merkely, Bela Merkely HungarySearch for more papers by this authorChristian Mueller, Christian Mueller SwitzerlandSearch for more papers by this authorJohn N. Nanas, John N. Nanas GreeceSearch for more papers by this authorOlav Wendelboe Nielsen, Olav Wendelboe Nielsen DenmarkSearch for more papers by this authorStein Ørn, Stein Ørn NorwaySearch for more papers by this authorJohn T. Parissis, John T. Parissis GreeceSearch for more papers by this authorPiotr Ponikowski, Piotr Ponikowski PolandSearch for more papers by this author Authors/Task Force Members, Authors/Task Force MembersSearch for more papers by this authorJohn J.V. McMurray, Corresponding Author John J.V. McMurray Chairperson UKCorresponding author. Chairperson: Professor John J.V. McMurray, University of Glasgow G12 8QQ, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email: [email protected]Search for more papers by this authorStamatis Adamopoulos, Stamatis Adamopoulos GreeceSearch for more papers by this authorStefan D. Anker, Stefan D. Anker GermanySearch for more papers by this authorAngelo Auricchio, Angelo Auricchio SwitzerlandSearch for more papers by this authorMichael Böhm, Michael Böhm GermanySearch for more papers by this authorKenneth Dickstein, Kenneth Dickstein NorwaySearch for more papers by this authorVolkmar Falk, Volkmar Falk SwitzerlandSearch for more papers by this authorGerasimos Filippatos, Gerasimos Filippatos GreeceSearch for more papers by this authorCândida Fonseca, Cândida Fonseca PortugalSearch for more papers by this authorMiguel Angel Gomez-Sanchez, Miguel Angel Gomez-Sanchez SpainSearch for more papers by this authorTiny Jaarsma, Tiny Jaarsma SwedenSearch for more papers by this authorLars Køber, Lars Køber DenmarkSearch for more papers by this authorGregory Y.H. Lip, Gregory Y.H. Lip UKSearch for more papers by this authorAldo Pietro Maggioni, Aldo Pietro Maggioni ItalySearch for more papers by this authorAlexander Parkhomenko, Alexander Parkhomenko UkraineSearch for more papers by this authorBurkert M. Pieske, Burkert M. Pieske AustriaSearch for more papers by this authorBogdan A. Popescu, Bogdan A. Popescu RomaniaSearch for more papers by this authorPer K. Rønnevik, Per K. Rønnevik NorwaySearch for more papers by this authorFrans H. Rutten, Frans H. Rutten The NetherlandsSearch for more papers by this authorJuerg Schwitter, Juerg Schwitter SwitzerlandSearch for more papers by this authorPetar Seferovic, Petar Seferovic SerbiaSearch for more papers by this authorJanina Stepinska, Janina Stepinska PolandSearch for more papers by this authorPedro T. Trindade, Pedro T. Trindade SwitzerlandSearch for more papers by this authorAdriaan A. Voors, Adriaan A. Voors The NetherlandsSearch for more papers by this authorFaiez Zannad, Faiez Zannad FranceSearch for more papers by this authorAndreas Zeiher, Andreas Zeiher GermanySearch for more papers by this authorESC Committee for Practice Guidelines (CPG), ESC Committee for Practice Guidelines (CPG)Search for more papers by this authorJeroen J. Bax, Jeroen J. Bax CPG Chairperson The NetherlandsSearch for more papers by this authorHelmut Baumgartner, Helmut Baumgartner GermanySearch for more papers by this authorClaudio Ceconi, Claudio Ceconi ItalySearch for more papers by this authorVeronica Dean, Veronica Dean FranceSearch for more papers by this authorChristi Deaton, Christi Deaton UKSearch for more papers by this authorRobert Fagard, Robert Fagard BelgiumSearch for more papers by this authorChristian Funck-Brentano, Christian Funck-Brentano FranceSearch for more papers by this authorDavid Hasdai, David Hasdai IsraelSearch for more papers by this authorArno Hoes, Arno Hoes The NetherlandsSearch for more papers by this authorPaulus Kirchhof, Paulus Kirchhof Germany UKSearch for more papers by this authorJuhani Knuuti, Juhani Knuuti FinlandSearch for more papers by this authorPhilippe Kolh, Philippe Kolh BelgiumSearch for more papers by this authorTheresa McDonagh, Theresa McDonagh UKSearch for more papers by this authorCyril Moulin, Cyril Moulin FranceSearch for more papers by this authorBogdan A. Popescu, Bogdan A. Popescu RomaniaSearch for more papers by this authorŽeljko Reiner, Željko Reiner CroatiaSearch for more papers by this authorUdo Sechtem, Udo Sechtem GermanySearch for more papers by this authorPer Anton Sirnes, Per Anton Sirnes NorwaySearch for more papers by this authorMichal Tendera, Michal Tendera PolandSearch for more papers by this authorAdam Torbicki, Adam Torbicki PolandSearch for more papers by this authorAlec Vahanian, Alec Vahanian FranceSearch for more papers by this authorStephan Windecker, Stephan Windecker SwitzerlandSearch for more papers by this authorDocument Reviewers, Document ReviewersSearch for more papers by this authorTheresa McDonagh, Theresa McDonagh CPG Co-Review Coordinator UKSearch for more papers by this authorUdo Sechtem, Udo Sechtem CPG Co-Review Coordinator GermanySearch for more papers by this authorLuis Almenar Bonet, Luis Almenar Bonet SpainSearch for more papers by this authorPanayiotis Avraamides, Panayiotis Avraamides CyprusSearch for more papers by this authorHisham A. Ben Lamin, Hisham A. Ben Lamin LibyaSearch for more papers by this authorMichele Brignole, Michele Brignole ItalySearch for more papers by this authorAntonio Coca, Antonio Coca SpainSearch for more papers by this authorPeter Cowburn, Peter Cowburn UKSearch for more papers by this authorHenry Dargie, Henry Dargie UKSearch for more papers by this authorPerry Elliott, Perry Elliott UKSearch for more papers by this authorFrank Arnold Flachskampf, Frank Arnold Flachskampf SwedenSearch for more papers by this authorGuido Francesco Guida, Guido Francesco Guida ItalySearch for more papers by this authorSuzanna Hardman, Suzanna Hardman UKSearch for more papers by this authorBernard Iung, Bernard Iung FranceSearch for more papers by this authorBela Merkely, Bela Merkely HungarySearch for more papers by this authorChristian Mueller, Christian Mueller SwitzerlandSearch for more papers by this authorJohn N. Nanas, John N. Nanas GreeceSearch for more papers by this authorOlav Wendelboe Nielsen, Olav Wendelboe Nielsen DenmarkSearch for more papers by this authorStein Ørn, Stein Ørn NorwaySearch for more papers by this authorJohn T. Parissis, John T. Parissis GreeceSearch for more papers by this authorPiotr Ponikowski, Piotr Ponikowski PolandSearch for more papers by this author First published: 18 February 2014 https://doi.org/10.1093/eurjhf/hfs105Citations: 1,653 Other ESC entities having participated in the development of this document: Associations: European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Echocardiography (EAE), European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) Working Groups: Acute Cardiac Care, Cardiovascular Pharmacology and Drug Therapy, Cardiovascular Surgery, Grown-up Congenital Heart Disease, Hypertension and the Heart, Myocardial and Pericardial Diseases, Pulmonary Circulation and Right Ventricular Function, Thrombosis, Valvular Heart Disease Councils: Cardiovascular Imaging, Cardiovascular Nursing and Allied Professions, Cardiology Practice, Cardiovascular Primary Care The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC. Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abbreviations and acronyms ACE angiotensin-converting enzyme ACHD adult congenital heart disease AF atrial fibrillation AF-CHF Atrial Fibrillation and Congestive Heart Failure AHF acute heart failure AIRE Acute Infarction Ramipril Efficacy ARB angiotensin receptor blocker ARR absolute risk reduction ATLAS Assessment of Treatment with Lisinopril And Survival AV atrioventricular AVP arginine vasopressin BEAUTIFUL MorBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction BEST Beta-Blocker Evaluation of Survival Trial BiVAD bi-ventricular assist device BNP B-type natriuretic peptide b.p.m. beats per minute BTC bridge to candidacy BTD bridge to decision BTR bridge to recovery BTT bridge to transplantation CABG coronary artery bypass graft CAD coronary artery disease CARE-HF Cardiac Resynchronization in Heart Failure Study CCB calcium-channel blocker CHA2DS2-VASc Cardiac failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled)-Vascular disease, Age 65–74 and Sex category (Female) CHARM Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity CIBIS II Cardiac Insufficiency Bisoprolol Study II CMR cardiac magnetic resonance COMET Carvedilol or Metoprolol European Trial COMPANION Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure CONSENSUS Cooperative North Scandinavian Enalapril Survival Study COPD chronic obstructive pulmonary disease COPERNICUS Carvedilol Prospective Randomized Cumulative Survival CORONA Controlled Rosuvastatin Multinational Trial in Heart Failure CPAP continuous positive airway pressure CRT cardiac resynchronization therapy CRT-D cardiac resynchronization therapy-defibrillator CRT-P cardiac resynchronization therapy-pacemaker CT computed tomography DEFINITE Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation DIG Digitalis Investigation Group DT destination therapy ECG electrocardiogram ECMO extracorporeal membrane oxygenation EF ejection fraction eGFR estimated glomerular filtration rate ELITE II Second Evaluation of Losartan in the Elderly Trial EMPHASIS-HF Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure GFR glomerular filtration rate GISSI-HF Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-heart failure H-ISDN hydralazine and isosorbide dinitrate HAS-BLED Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly (1 point each) HEAAL Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan HF heart failure HF-ACTION Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training HF-PEF heart failure with 'preserved' ejection fraction HF-REF heart failure with reduced ejection fraction I-PRESERVE Irbesartan in heart failure with preserved systolic function i.v. intravenous IABP intra-aortic balloon pump ICD implantable cardioverter-defibrillator LA left atrial LBBB left bundle branch block LV left ventricular LVAD left ventricular assist device LVEF left ventricular ejection fraction MADIT-II Multicenter Automatic Defibrillator Implantation Trial II MCS mechanical circulatory support MDCT multi-detector computed tomography MERIT-HF Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure MRA mineralocorticoid receptor antagonist MR-proANP mid-regional atrial (or A-type) natriuretic peptide MUSTIC Multisite Stimulation in Cardiomyopathies NIPPV non-invasive positive pressure ventilation NNT number needed to treat NSAID non-steroidal anti-inflammatory drug NYHA New York Heart Association OPTIMAAL Optimal Therapy in Myocardial infarction with the Angiotensin II Antagonist Losartan PEP-CHF Perindopril for Elderly People with Chronic Heart failure PET positron emission tomography PUFA polyunsaturated fatty acid RAFT Resynchronization/Defibrillation for Ambulatory Heart Failure Trial RALES Randomised Aldactone Evaluation Study RCT randomized controlled trial RRR relative risk reduction SAVE Survival and Ventricular Enlargement SCD-HeFT Sudden Cardiac Death in Heart Failure Trial SENIORS Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure SHIFT Systolic Heart failure treatment with the If inhibitor ivabradine Trial SOLVD Studies of Left Ventricular Dysfunction SPECT single-photon emission computed tomography STICH Surgical Treatment for Ischemic Heart Failure TAPSE tricuspid annular plane systolic excursion TDI tissue Doppler imaging TOE transoesophageal echocardiography TRACE TRAndolapril Cardiac Evaluation Val-HeFT Valsartan Heart Failure Trial VALIANT Valsartan In Acute myocardial infarction VO2 maximal oxygen consumption 1. Preamble Guidelines summarize and evaluate all available evidence at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes, but are complements, for textbooks and cover the European Society of Cardiology (ESC) Core Curriculum topics. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible physician(s). A large number of Guidelines have been issued in recent years by the ESC as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for diagnosis, management, and/or prevention of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular treatment options were weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2. Table 1. Classes of recommendations Table 2. Levels of evidence The experts of the writing and reviewing panels filled in declarations of interest forms of all relationships which might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines produced by Task Forces, expert groups, or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions, it is approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The task of developing ESC Guidelines covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement the guidelines, condensed pocket guidelines versions, summary slides, booklets with essential messages, and an electronic version for digital applications (smartphones, etc.) are produced. These versions are abridged and, thus, if needed, one should always refer to the full text version which is freely available on the ESC website. The National Societies of the ESC are encouraged to endorse, translate, and implement the ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, and implementing them into clinical practice. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and, where appropriate and necessary, the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. 2. Introduction The aim of this document is to provide practical, evidence-based guidelines for the diagnosis and treatment of heart failure (HF). The principal changes from the 2008 guidelines1 relate to: an expansion of the indication for mineralocorticoid (aldosterone) receptor antagonists (MRAs); a new indication for the sinus node inhibitor ivabradine; an expanded indication for cardiac resynchronization therapy (CRT); new information on the role of coronary revascularization in HF; recognition of the growing use of ventricular assist devices; and the emergence of transcatheter valve interventions. There are also changes to the structure and format of the guidelines. Therapeutic recommendations now state the treatment effect supported by the class and level of recommendation in tabular format; in the case of chronic heart failure due to left ventricular (LV) systolic dysfunction, the recommendations focus on mortality and morbidity outcomes. Detailed summaries of the key evidence supporting generally recommended treatments have been provided. Practical guidance is provided for the use of the more important disease-modifying drugs and diuretics. When possible, other relevant guidelines, consensus statements, and position papers have been cited to avoid unduly lengthy text. All tables should be read in conjunction with their accompanying text and not read in isolation. 3. Definition and diagnosis Definition of heart failure Heart failure can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures).1 For the purposes of these guidelines, HF is defined, clinically, as a syndrome in which patients have typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles, and displaced apex beat) resulting from an abnormality of cardiac structure or function. The diagnosis of HF can be difficult (see Section 3.6). Many of the symptoms of HF are non-discriminating and, therefore, of limited diagnostic value.2–6 Many of the signs of HF result from sodium and water retention and resolve quickly with diuretic therapy, i.e. may be absent in patients receiving such treatment. Demonstration of an underlying cardiac cause is therefore central to the diagnosis of HF (see Section 3.6). This is usually myocardial disease causing systolic ventricular dysfunction. However, abnormalities of ventricular diastolic function or of the valves, pericardium, endocardium, heart rhythm, and conduction can also cause HF (and more than one abnormality can be present) (see Section 3.5). Identification of the underlying cardiac problem is also crucial for therapeutic reasons, as the precise pathology determines the specific treatment used (e.g. valve surgery for valvular disease, specific pharmacological therapy for LV systolic dysfunction, etc.). Terminology related to left ventricular ejection fraction The main terminology used to describe HF is historical and is based on measurement of LV ejection fraction (EF). Mathematically, EF is the stroke volume (which is the end-diastolic volume minus the end-systolic volume) divided by the end-diastolic volume. In patients with reduced contraction and emptying of the left ventricle (i.e. systolic dysfunction), stroke volume is maintained by an increase in end-diastolic volume (because the left ventricle dilates), i.e. the heart ejects a smaller fraction of a larger volume. The more severe the systolic dysfunction, the more the EF is reduced from normal and, generally, the greater the end-diastolic and end-systolic volumes. The EF is considered important in HF, not only because of its prognostic importance (the lower the EF the poorer the survival) but also because most clinical trials selected patients based upon EF (usually measured using a radionuclide technique or echocardiography). The major trials in patients with HF and a reduced EF (HF-REF), or 'systolic HF', mainly enrolled patients with an EF ≤35%, and it is only in these patients that effective therapies have been demonstrated to date. Other, more recent, trials enrolled patients with HF and an EF >40–45% and no other causal cardiac abnormality (such as valvular or pericardial disease). Some of these patients did not have an entirely normal EF (generally considered to be >50%) but also did not have a major reduction in systolic function either. Because of this, the term HF with 'preserved' EF (HF-PEF) was created to describe these patients. Patients with an EF in the range 35–50% therefore represent a 'grey area' and most probably have primarily mild systolic dysfunction. The diagnosis of HF-PEF is more difficult than the diagnosis of HF-REF because it is largely one of exclusion, i.e. potential non-cardiac causes of the patient's symptoms (such as anaemia or chronic lung disease) must first be discounted (Table 3).7,8 Usually these patien

The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood.The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome.Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer.It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

![Graphic][1] Myocardial infarction is a major cause of death and disability worldwide. Coronary atherosclerosis is a chronic disease with stable and unstable periods. During unstable periods with activated inflammation in the vascular wall, patients may develop a myocardial infarction. Myocardial infarction may be a minor event in a lifelong chronic disease, it may even go undetected, but it may also be a major catastrophic event leading to sudden death or severe haemodynamic deterioration. A myocardial infarction may be the first manifestation of coronary artery disease, or it may occur, repeatedly, in patients with established disease. Information on myocardial infarction attack rates can provide useful data regarding the burden of coronary artery disease within and across populations, especially if standardized data are collected in a manner that demonstrates the distinction between incident and recurrent events. From the epidemiological point of view, the incidence of myocardial infarction in a population can be used as a proxy for the prevalence of coronary artery disease in that population. Furthermore, the term myocardial infarction has major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world, and it is an outcome measure in clinical trials and observational studies. With these perspectives, myocardial infarction may be defined from a number of different clinical, electrocardiographic, biochemical, imaging, and pathological characteristics. In the past, a general consensus existed for the clinical syndrome designated as myocardial infarction. In studies of disease prevalence, the World Health Organization (WHO) defined myocardial infarction from symptoms, ECG abnormalities, and enzymes. However, the development of more sensitive and specific serological biomarkers and precise imaging techniques allows detection of ever smaller amounts of myocardial necrosis. Accordingly, current clinical practice, health care delivery systems, as well as epidemiology and clinical trials all require a … [1]: /embed/inline-graphic-1.gif

The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer.It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

Table 1. Classes of recommendation Table 2. Levels of evidence Table 3. Estimated fetal and maternal effective doses for various diagnostic and interventional radiology procedures Table 4. Predictors of maternal cardiovascular events and risk score from the CARPREG study Table 5. Predictors of maternal cardiovascular events identified in congential heart diseases in the ZAHARA and Khairy study Table 6. Modified WHO classification of maternal cardiovascular risk: principles Table 7. Modified WHO classification of maternal cardiovascular risk: application Table 8. Maternal predictors of neonatal events in women with heart disease Table 9. General recommendations Table 10. Recommendations for the management of congenital heart disease Table 11. Recommendations for the management of aortic disease Table 12. Recommendations for the management of valvular heart disease Table 13. Recommendations for the management of coronary artery disease Table 14. Recommendations for the management of cardiomyopathies and heart failure Table 15. Recommendations for the management of arrhythmias Table 16. Recommendations for the management of hypertension Table 17. Check list for risk factors for venous thrombo-embolism Table 18. Prevalence of congenital thrombophilia and the associated risk of venous thrombo-embolism during pregnancy Table 19. Risk groups according to risk factors: definition and preventive measures Table 20. Recommendations for the prevention and management of venous thrombo-embolism in pregnancy and puerperium Table 21. Recommendations for drug use ABPM : ambulatory blood pressure monitoring ACC : American College of Cardiology ACE : angiotensin-converting enzyme ACS : acute coronary syndrome AF : atrial fibrillation AHA : American Heart Association aPTT : activated partial thromboplastin time ARB : angiotensin receptor blocker AS : aortic stenosis ASD : atrial septal defect AV : atrioventricular AVSD : atrioventricular septal defect BMI : body mass index BNP : B-type natriuretic peptide BP : blood pressure CDC : Centers for Disease Control CHADS : congestive heart failure, hypertension, age (>75 years), diabetes, stroke CI : confidence interval CO : cardiac output CoA : coarction of the aorta CT : computed tomography CVD : cardiovascular disease DBP : diastolic blood pressure DCM : dilated cardiomyopathy DVT : deep venous thrombosis ECG : electrocardiogram EF : ejection fraction ESC : European Society of Cardiology ESH : European Society of Hypertension ESICM : European Society of Intensive Care Medicine FDA : Food and Drug Administration HCM : hypertrophic cardiomyopathy ICD : implantable cardioverter-defibrillator INR : international normalized ratio i.v. : intravenous LMWH : low molecular weight heparin LV : left ventricular LVEF : left ventricular ejection fraction LVOTO : left ventricular outflow tract obstruction MRI : magnetic resonance imaging MS : mitral stenosis NT-proBNP : N-terminal pro B-type natriuretic peptide NYHA : New York Heart Association OAC : oral anticoagulant PAH : pulmonary arterial hypertension PAP : pulmonary artery pressure PCI : percutaneous coronary intervention PPCM : peripartum cardiomyopathy PS : pulmonary valve stenosis RV : right ventricular SBP : systolic blood pressure SVT : supraventricular tachycardia TGA : complete transposition of the great arteries TR : tricuspid regurgitation UFH : unfractionated heparin VSD : ventricular septal defect VT : ventricular tachycardia VTE : venous thrombo-embolism WHO : World Health Organization Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes but are complements for textbooks and cover the European Society of Cardiology (ESC) Core Curriculum topics. Guidelines and recommendations should help the …

2D : two-dimensional 3D : three-dimensional ABI : ankle–brachial index ACAS : Asymptomatic Carotid Atherosclerosis Study ACCF : American College of Cardiology Foundation ACE : angiotensin-converting enzyme ACS : acute coronary syndrome ACST : Asymptomatic Carotid Surgery Trial ALI : acute limb ischaemia ASTRAL : Angioplasty and Stenting for Renal Artery Lesions trial BASIL : Bypass versus Angioplasty in Severe Ischaemia of the Leg BOA : Dutch Bypass Oral Anticoagulants or Aspirin CABG : coronary artery bypass grafting CAD : coronary artery disease CAPRIE : Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events CAPTURE : Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events CARP : Coronary Artery Revascularization Prophylaxis CAS : carotid artery stenting CASPAR : Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial Disease CASS : Coronary Artery Surgery Study CAVATAS : CArotid and Vertebral Artery Transluminal Angioplasty Study CEA : carotid endarterectomy CHARISMA : Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance CI : confidence interval CLEVER : Claudication: Exercise Versus Endoluminal Revascularization CLI : critical limb ischaemia CORAL : Cardiovascular Outcomes in Renal Atherosclerotic Lesions COURAGE : Clinical Outcomes Utilization Revascularization and Aggressive Drug Evaluation CPG : Committee for Practice Guidelines CREST : Carotid Revascularization Endarterectomy vs. Stenting Trial CT : computed tomography CTA : computed tomography angiography CVD : cardiovascular disease DECREASE-V : Dutch Echocardiographic Cardiac Risk Evaluation DRASTIC : Dutch Renal Artery Stenosis Intervention Cooperative Study DSA : digital subtraction angiography DUS : duplex ultrasound/duplex ultrasonography EACTS : European Association for Cardio-Thoracic Surgery EAS : European Atherosclerosis Society ECST : European Carotid Surgery Trial EPD : embolic protection device ESC : European Society of Cardiology ESH : European Society of Hypertension ESRD : end-stage renal disease EUROSCORE : European System for Cardiac Operative Risk Evaluation EVA-3S : Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis EXACT : Emboshield and Xact Post Approval Carotid Stent Trial GALA : General Anaesthesia versus Local Anaesthesia for Carotid Surgery GFR : glomerular filtration rate GRACE : Global Registry of Acute Coronary Events HbA1c : glycated haemoglobin HDL : high-density lipoprotein HOPE : Heart Outcomes Prevention Evaluation HR : hazard ratio IC : intermittent claudication ICSS : International Carotid Stenting Study IMT : intima–media thickness ITT : intention to treat LDL : low-density lipoprotein LEAD : lower extremity artery disease MACCEs : major adverse cardiac and cerebrovascular events MDCT : multidetector computed tomography MONICA : Monitoring of Trends and Determinants in Cardiovascular Disease MRA : magnetic resonance angiography MRI : magnetic resonance imaging NASCET : North American Symptomatic Carotid Endarterectomy Trial ONTARGET : Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial OR : odds ratio PAD : peripheral artery diseases PARTNERS : Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival PCI : percutaneous coronary intervention PET : positron emission tomography PRO-CAS : Predictors of Death and Stroke in CAS PTA : percutaneous transluminal angioplasty RAAS : renin–angiotensin–aldosterone system RADAR : Randomized, Multicentre, Prospective Study Comparing Best Medical Treatment Versus Best Medical Treatment Plus Renal Artery Stenting in Patients With Haemodynamically Relevant Atherosclerotic Renal Artery Stenosis RAS : renal artery stenosis RCT : randomized controlled trial REACH : Reduction of Atherothrombosis for Continued Health RR : risk ratio SAPPHIRE : Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy SCAI : Society for Cardiovascular Angiography and Interventions SIR : Society of Interventional Radiology SPACE : Stent-Protected Angioplasty versus Carotid Endarterectomy SPARCL : Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study STAR : Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function SSYLVIA : Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries SVMB : Society for Vascular Medicine and Biology TASC : TransAtlantic Inter-Society Consensus TIA : transient ischaemic attack UEAD : upper extremity artery disease VA : vertebral artery Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes but are complements for textbooks and cover the ESC Core Curriculum topics. Guidelines and recommendations should help the physicians to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible physician(s). A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for diagnosis, management, and/or prevention of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular treatment options were weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 . …

Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report received its entire financial support from …

Guidelines and Expert Consensus Documents aim to present management recommendations based on all of the relevant evidence on a particular subject in order to help physicians select the best possible management strategies for the individual patient suffering from a specific condition, taking into account the impact on outcome and also the risk–benefit ratio of a particular diagnostic or therapeutic procedure. Numerous studies have demonstrated that patient outcomes improve when guideline recommendations, based on the rigorous assessment of evidence-based research, are applied in clinical practice. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and also by other organizations or related societies. The profusion of documents can put at stake the authority and credibility of guidelines, particularly if discrepancies appear between different documents on the same issue, as this can lead to confusion in the minds of physicians. In order to avoid these pitfalls, the ESC and other organizations have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents. The ESC recommendations for guidelines production can be found on the ESC website.1 It is beyond the scope of this preamble to recall all but the basic rules. In brief, the ESC appoints experts in the field to carry out a comprehensive review of the literature, with a view to making a critical evaluation of the use of diagnostic and therapeutic procedures and assessing the risk–benefit ratio of the therapies recommended for management and/or prevention of a given condition. Estimates of expected health outcomes are included, where data exist. The strength of evidence for or against particular procedures or treatments is weighed according to predefined scales for grading recommendations and levels of evidence, as outlined in what follows. The Task Force members of the writing panels, …

This study sought to determine the diagnostic accuracy of 64-slice computed tomographic coronary angiography (CTCA) to detect or rule out significant coronary artery disease (CAD).CTCA is emerging as a noninvasive technique to detect coronary atherosclerosis.We conducted a prospective, multicenter, multivendor study involving 360 symptomatic patients with acute and stable anginal syndromes who were between 50 and 70 years of age and were referred for diagnostic conventional coronary angiography (CCA) from September 2004 through June 2006. All patients underwent a nonenhanced calcium scan and a CTCA, which was compared with CCA. No patients or segments were excluded because of impaired image quality attributable to either coronary motion or calcifications. Patient-, vessel-, and segment-based sensitivities and specificities were calculated to detect or rule out significant CAD, defined as >or=50% lumen diameter reduction.The prevalence among patients of having at least 1 significant stenosis was 68%. In a patient-based analysis, the sensitivity for detecting patients with significant CAD was 99% (95% confidence interval [CI]: 98% to 100%), specificity was 64% (95% CI: 55% to 73%), positive predictive value was 86% (95% CI: 82% to 90%), and negative predictive value was 97% (95% CI: 94% to 100%). In a segment-based analysis, the sensitivity was 88% (95% CI: 85% to 91%), specificity was 90% (95% CI: 89% to 92%), positive predictive value was 47% (95% CI: 44% to 51%), and negative predictive value was 99% (95% CI: 98% to 99%).Among patients in whom a decision had already been made to obtain CCA, 64-slice CTCA was reliable for ruling out significant CAD in patients with stable and unstable anginal syndromes. A positive 64-slice CTCA scan often overestimates the severity of atherosclerotic obstructions and requires further testing to guide patient management.

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

This study was designed to predict the response and prognosis after cardiac resynchronization therapy (CRT) in patients with end-stage heart failure (HF). Cardiac resynchronization therapy improves HF symptoms, exercise capacity, and left ventricular (LV) function. Because not all patients respond, preimplantation identification of responders is needed. In the present study, response to CRT was predicted by the presence of LV dyssynchrony assessed by tissue Doppler imaging. Moreover, the prognostic value of LV dyssynchrony in patients undergoing CRT was assessed. Eighty-five patients with end-stage HF, QRS duration &gt;120 ms, and left bundle-branch block were evaluated by tissue Doppler imaging before CRT. At baseline and six months follow-up, New York Heart Association functional class, quality of life and 6-min walking distance, LV volumes, and LV ejection fraction were determined. Events (death, hospitalization for decompensated HF) were obtained during one-year follow-up. Responders (74%) and nonresponders (26%) had comparable baseline characteristics, except for a larger dyssynchrony in responders (87 ± 49 ms vs. 35 ± 20 ms, p &lt; 0.01). Receiver-operator characteristic curve analysis demonstrated that an optimal cutoff value of 65 ms for LV dyssynchrony yielded a sensitivity and specificity of 80% to predict clinical improvement and of 92% to predict LV reverse remodeling. Patients with dyssynchrony ≥65 ms had an excellent prognosis (6% event rate) after CRT as compared with a 50% event rate in patients with dyssynchrony &lt;65 ms (p &lt; 0.001). Patients with LV dyssynchrony ≥65 ms respond to CRT and have an excellent prognosis after CRT.

Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

Abstract Aims The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. Methods and results In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5–23.1%] vs. 15.7% (IQR 14.5–21.1%)}, diabetes [7.7% (IQR 7.1–10.1%) vs. 5.6% (IQR 4.8–7.0%)], and among males smoking [43.8% (IQR 37.4–48.0%) vs. 26.0% (IQR 20.9–31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0–10.8) vs. 16.7% (IQR 13.9–19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655–8115)] compared with high-income [2235 (IQR 1896–3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. Conclusion A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.

Currently, one third of patients treated with cardiac resynchronization therapy (CRT) do not respond. Nonresponse to CRT may be explained by the presence of scar tissue in the posterolateral left ventricular (LV) segments, which may result in ineffective LV pacing and inadequate LV resynchronization. In the present study, the relationship between transmural posterolateral scar tissue and response to CRT was evaluated.Forty consecutive patients with end-stage heart failure (NYHA class III/IV), LV ejection fraction < or =35%, QRS duration >120 ms, left bundle-branch block, and chronic coronary artery disease were included. The localization and transmurality of scar tissue were evaluated with contrast-enhanced MRI. Next, LV dyssynchrony was assessed at baseline and immediately after implantation with tissue Doppler imaging. Clinical parameters, LV volumes, and LV ejection fraction were assessed at baseline and at a 6-month follow-up. Fourteen patients (35%) had a transmural (>50% of LV wall thickness) posterolateral scar. In contrast to patients without posterolateral scar tissue, these patients showed a low response rate (14% versus 81%; P<0.05) and did not show improvement in clinical or echocardiographic parameters. In addition, LV dyssynchrony remained unchanged after CRT implantation (84+/-46 versus 78+/-41 ms; P=NS). Patients without posterolateral scar tissue and severe baseline dyssynchrony (> or =65 ms) showed an excellent response rate of 95% compared with patients with a posterolateral scar and/or absent LV dyssynchrony (11%).CRT does not reduce LV dyssynchrony in patients with transmural scar tissue in the posterolateral LV segments, resulting in clinical and echocardiographic nonresponse to CRT.

Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients.

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence available at the time of their publication.The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic, or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery.

The European Society of Cardiology (ESC) Atlas has been compiled by the European Heart Agency to document cardiovascular disease (CVD) statistics of the 56 ESC member countries. A major aim of this 2017 data presentation has been to compare high-income and middle-income ESC member countries to identify inequalities in disease burden, outcomes, and service provision. The Atlas utilizes a variety of data sources, including the World Health Organization, the Institute for Health Metrics and Evaluation, and the World Bank to document risk factors, prevalence, and mortality of cardiovascular disease and national economic indicators. It also includes novel ESC-sponsored survey data of health infrastructure and cardiovascular service provision provided by the national societies of the ESC member countries. Data presentation is descriptive with no attempt to attach statistical significance to differences observed in stratified analyses. Important differences were identified between the high-income and middle-income member countries of the ESC with regard to CVD risk factors, disease incidence, and mortality. For both women and men, the age-standardized prevalence of hypertension was lower in high-income countries (18% and 27%) compared with middle-income countries (24% and 30%). Smoking prevalence in men (not women) was also lower (26% vs. 41%) and together these inequalities are likely to have contributed to the higher CVD mortality in middle-income countries. Declines in CVD mortality have seen cancer becoming a more common cause of death in a number of high-income member countries, but in middle-income countries declines in CVD mortality have been less consistent where CVD remains the leading cause of death. Inequalities in CVD mortality are emphasized by the smaller contribution they make to potential years of life lost in high-income countries compared with middle-income countries both for women (13% vs. 23%) and men (20% vs. 27%). The downward mortality trends for CVD may, however, be threatened by the emerging obesity epidemic that is seeing rates of diabetes increasing across all the ESC member countries. Survey data from the National Cardiac Societies showed that rates of cardiac catheterization and coronary artery bypass surgery, as well as the number of specialist centres required to deliver them, were greatest in the high-income member countries of the ESC. The Atlas confirmed that these ESC member countries, where the facilities for the contemporary treatment of coronary disease were best developed, were often those in which declines in coronary mortality have been most pronounced. Economic resources were not the only driver for delivery of equitable cardiovascular health care, as some middle-income ESC member countries reported rates for interventional procedures and device implantations that matched or exceeded the rates in wealthier member countries. In documenting national CVD statistics, the Atlas provides valuable insights into the inequalities in risk factors, health care delivery, and outcomes of CVD across the ESC member countries. The availability of these data will underpin the ESC’s ambitious mission ‘to reduce the burden of cardiovascular disease’ not only in its member countries but also in nation states around the world.

The ESC/EACTS Guidelines represent the views of the ESC and the EACTS and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC and the EACTS are not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC/EACTS Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC/EACTS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC/EACTS Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC/EACTS Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

In patients with severe heart failure and dilated cardiomyopathy, cardiac resynchronization therapy (CRT) improves left ventricular (LV) systolic function associated with LV reverse remodeling and favorable 1-year survival. However, it is unknown whether LV reverse remodeling translates into a better long-term prognosis and what extent of reverse remodeling is clinically relevant, which were investigated in this study.Patients (n=141) with advanced heart failure (mean+/-SD age, 64+/-11 years; 73% men) who received CRT were followed up for a mean (+/-SD) of 695+/-491 days. The extent of reduction in LV end-systolic volume (LVESV) at 3 to 6 months relative to baseline was examined for its predictive value on long-term clinical outcome. The cutoff value for LV reverse remodeling in predicting mortality was derived from the receiver operating characteristic curve. Then the relation between potential predictors of mortality and heart failure hospitalizations were compared by Kaplan-Meier survival analysis, followed by Cox regression analysis. There were 22 (15.6%) deaths, mostly due to heart failure or sudden cardiac death. The receiver operating characteristic curve found that a reduction in LVESV of > or =9.5% had a sensitivity of 70% and specificity of 70% in predicting all-cause mortality and of 87% and 69%, respectively, for cardiovascular mortality. With this cutoff value, there were 87 (61.7%) responders to reverse remodeling. In Kaplan-Meier survival analysis, responders had significantly lower all-cause morality (6.9% versus 30.6%, log-rank chi2=13.26, P=0.0003), cardiovascular mortality (2.3% versus 24.1%, log-rank chi2=17.1, P<0.0001), and heart failure events (11.5% versus 33.3%, log-rank chi2=8.71, P=0.0032) than nonresponders. In the Cox regression analysis model, the change in LVESV was the single most important predictor of all-cause (beta=1.048, 95% confidence interval=1.019 to 1.078, P=0.001) and cardiovascular (beta=1.072, 95% confidence interval=1.033 to 1.112, P<0.001) mortality. Clinical parameters were unable to predict any outcome event.A reduction in LVESV of 10% signifies clinically relevant reverse remodeling, which is a strong predictor of lower long-term mortality and heart failure events. This study suggests that assessing volumetric changes after an intervention in patients with heart failure provides information predictive of natural history outcomes.

This study evaluated the relative merits of the most frequently used techniques for predicting improvement in regional contractile function after coronary revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease.Several techniques have been proposed for predicting improvement in regional contractile function after revascularization, including thallium-201 (Tl-201) stress-redistribution-reinjection, Tl-201 rest-redistribution, fluorine-18 fluorodeoxyglucose with positron emission tomography, technetium-99m sestamibi imaging and low dose dobutamine echocardiography (LDDE).A systematic review of all reports on prediction of functional recovery after revascularization in patients with chronic coronary artery disease (published between 1980 and March 1997) revealed 37 with sufficient details for calculating the sensitivity and specificity of each imaging modality. From the pooled data, 95% and 99% confidence intervals were also calculated.Sensitivity for predicting regional functional recovery after revascularization was high for all techniques. The specificity of both Tl-201 protocols was significantly lower (p < 0.05) and LDDE significantly higher (p < 0.01) than that of the other techniques.Pooled analysis of 37 studies showed that although all techniques accurately identify segments with improved contractile function after revascularization, the Tl-201 protocols may overestimate functional recovery. The evidence available thus far indicates that LDDE appears to have the highest predictive accuracy.

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

ContextPatients who undergo major vascular surgery are at increased risk of perioperative cardiac complications. High-risk patients can be identified by clinical factors and noninvasive cardiac testing, such as dobutamine stress echocardiography (DSE); however, such noninvasive imaging techniques carry significant disadvantages. A recent study found that perioperative β-blocker therapy reduces complication rates in high-risk individuals.ObjectiveTo examine the relationship of clinical characteristics, DSE results, β-blocker therapy, and cardiac events in patients undergoing major vascular surgery.Design and SettingCohort study conducted in 1996-1999 in the following 8 centers: Erasmus Medical Centre and Sint Clara Ziekenhuis, Rotterdam, Twee Steden Ziekenhuis, Tilburg, Academisch Ziekenhuis Utrecht, Utrecht, and Medisch Centrum Alkmaar, Alkmaar, the Netherlands; Ziekenhuis Middelheim, Antwerp, Belgium; and San Gerardo Hospital, Monza, Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, Italy.PatientsA total of 1351 consecutive patients scheduled for major vascular surgery; DSE was performed in 1097 patients (81%), and 360 (27%) received β-blocker therapy.Main Outcome MeasureCardiac death or nonfatal myocardial infarction within 30 days after surgery, compared by clinical characteristics, DSE results, and β-blocker use.ResultsForty-five patients (3.3%) had perioperative cardiac death or nonfatal myocardial infarction. In multivariable analysis, important clinical determinants of adverse outcome were age 70 years or older; current or prior angina pectoris; and prior myocardial infarction, heart failure, or cerebrovascular accident. Eighty-three percent of patients had less than 3 clinical risk factors. Among this subgroup, patients receiving β-blockers had a lower risk of cardiac complications (0.8% [2/263]) than those not receiving β-blockers (2.3% [20/855]), and DSE had minimal additional prognostic value. In patients with 3 or more risk factors (17%), DSE provided additional prognostic information, for patients without stress-induced ischemia had much lower risk of events than those with stress-induced ischemia (among those receiving β-blockers, 2.0% [1/50] vs 10.6% [5/47]). Moreover, patients with limited stress-induced ischemia (1-4 segments) experienced fewer cardiac events (2.8% [1/36]) than those with more extensive ischemia (≥5 segments, 36% [4/11]).ConclusionThe additional predictive value of DSE is limited in clinically low-risk patients receiving β-blockers. In clinical practice, DSE may be avoided in a large number of patients who can proceed safely for surgery without delay. In clinically intermediate- and high-risk patients receiving β-blockers, DSE may help identify those in whom surgery can still be performed and those in whom cardiac revascularization should be considered.

Echocardiography plays an evolving and important role in the care of heart failure patients treated with biventricular pacing, or cardiac resynchronization therapy (CRT). Numerous recent published reports have utilized echocardiographic techniques to potentially aide in patient selection for CRT prior to implantation and to optimized device settings afterwards. However, no ideal approach has yet been found. This consensus report evaluates the contemporary applications of echocardiography for CRT including relative strengths and technical limitations of several techniques and proposes guidelines regarding current and possible future clinical applications. Principal methods advised to qualify abnormalities in regional ventricular activation, known as dyssynchrony, include longitudinal velocities by color-coded tissue Doppler and the difference in left ventricular to right ventricular ejection using routine pulsed Doppler, or interventricular mechanical delay. Supplemental measures of radial dynamics which may be of additive value include septal-to-posterior wall delay using M-mode in patients with non-ischemic disease with technically high quality data, or using speckle tracking radial strain. A simplified post-CRT screening for atrioventricular optimization using Doppler mitral inflow velocities is also proposed. Since this is rapidly changing field with new information being added frequently, future modification and refinements in approach are anticipated to continue.

The purpose of this study was to compare myocardial triglyceride content and function between patients with uncomplicated type 2 diabetes mellitus (T2DM) and healthy subjects within the same range of age and body mass index (BMI), and to study the associations between myocardial triglyceride content and function.T2DM is a major risk factor for cardiovascular disease. Increasing evidence is emerging that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, by causing lipotoxic injury and myocardial steatosis.Myocardial triglyceride content and myocardial function were measured in 38 T2DM patients and 28 healthy volunteers in the same range of age and BMI by proton magnetic resonance (MR) spectroscopy and MR imaging, respectively. Myocardial triglyceride content was calculated as a percentage relative to the signal of myocardial water.Myocardial triglyceride content was significantly higher in T2DM patients compared with healthy volunteers (0.96 +/- 0.07% vs. 0.65 +/- 0.05%, p < 0.05). Systolic function did not significantly differ between both groups. Indexes of diastolic function, including the ratio of maximal left ventricular early peak filling rate and the maximal left ventricular atrial peak filling rate (E/A) and E peak deceleration, were significantly impaired in T2DM compared with those in healthy subjects (1.08 +/- 0.04 ml/s(2) x 10(-3) vs. 1.24 +/- 0.06 ml/s(2) x 10(-3) and 3.6 +/- 0.2 ml/s(2) x 10(-3) vs. 4.4 +/- 0.3 ml/s(2) x 10(-3), respectively, p < 0.05). Multivariable analysis indicated that myocardial triglyceride content was associated with E/A and E peak deceleration, independently of diabetic state, age, BMI, heart rate, visceral fat, and diastolic blood pressure.Myocardial triglyceride content is increased in uncomplicated T2DM and is associated with impaired left ventricular diastolic function, independently of age, BMI, heart rate, visceral fat, and diastolic blood pressure.

In the present study, the anatomy of the aortic root was assessed noninvasively with multislice computed tomography (MSCT).Transcatheter aortic valve replacement has been proposed as an alternative to surgery in high-risk patients with severe aortic stenosis. For this procedure, detailed knowledge of aortic annulus diameters and the relation between the annulus and the coronary arteries is needed.In 169 patients (111 men, age 54 +/- 11 years), a 64-slice MSCT scan was performed for evaluation of coronary artery disease. Of these, 150 patients had no or mild aortic stenosis, and 19 patients had moderate to severe aortic stenosis. Reconstructed coronal and sagittal views were used for assessment of the aortic annulus diameter in 2 directions. In addition, the distance between the annulus and the ostium of the right and left coronary arteries and the length of the coronary leaflets were assessed. The LV outflow tract and interventricular septum were analyzed on the single oblique sagittal view at end-diastole.The diameter of the aortic annulus was 26.3 +/- 2.8 mm on the coronal view, and 23.5 +/- 2.7 mm on the sagittal view. Mean difference between the 2 diameters was 2.9 +/- 1.8 mm, indicating an oval shape of the aortic annulus. Mean distance between the aortic annulus and the ostium of the right coronary artery was 17.2 +/- 3.3 mm, and mean distance between the annulus and the ostium of the left coronary artery was 14.4 +/- 2.9 mm. In 82 patients (49%), the length of the left coronary leaflet exceeded the distance between the annulus and the ostium of the left coronary artery. There were no significant differences in the diameter of annulus, diameter of sinus of Valsalva, or the distance between the annulus, left coronary leaflet, and the ostium of the left coronary artery, between the patient with and without severe aortic stenosis.The MSCT can provide detailed information on the shape of the aortic annulus and the relation between the annulus and the ostia of the coronary arteries. Thereby, MSCT may be helpful for avoiding paravalvular leakage and coronary occlusion and may facilitate the selection of candidates for transcatheter aortic valve replacement.

This study sought to determine the prognostic value of multislice computed tomography (MSCT) coronary angiography in patients with known or suspected coronary artery disease (CAD).It is expected that MSCT will be used increasingly as an alternative imaging modality in the diagnosis of patients with suspected CAD. Data on the prognostic value of MSCT, however, are currently not available.A total of 100 patients (73 men, age 59 +/- 12 years) who were referred for further cardiac evaluation due to suspicion of significant CAD underwent additional MSCT coronary angiography to evaluate the presence and severity of CAD. Patients were followed up for the occurrence of: 1) cardiac death, 2) nonfatal myocardial infarction, 3) unstable angina requiring hospitalization, and 4) revascularization.Coronary plaques were detected in 80 (80%) patients. During a mean follow-up of 16 months, 33 events occurred in 26 patients. In patients with normal coronary arteries on MSCT, the first-year event rate was 0% versus 30% in patients with any evidence of CAD on MSCT. The observed event rate was highest in the presence of obstructive lesions (63%) and when obstructive lesions were located in the left main (LM)/left anterior descending (LAD) coronary arteries (77%). Nonetheless, an elevated event rate was also observed in patients with nonobstructive CAD (8%). In multivariate analysis, significant predictors of events were the presence of CAD, obstructive CAD, obstructive CAD in LM/LAD, number of segments with plaques, number of segments with obstructive plaques, and number of segments with mixed plaques.Multislice computed tomography coronary angiography provides independent prognostic information over baseline clinical risk factors in patients with known and suspected CAD. An excellent prognosis was noted in patients with a normal MSCT.

Patients undergoing major vascular surgery are at increased risk of perioperative mortality due to underlying coronary artery disease. Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (statins) may reduce perioperative mortality through the improvement of lipid profile, but also through the stabilization of coronary plaques on the vascular wall.To evaluate the association between statin use and perioperative mortality, we performed a case-controlled study among the 2816 patients who underwent major vascular surgery from 1991 to 2000 at the Erasmus Medical Center. Case subjects were all 160 (5.8%) patients who died during the hospital stay after surgery. From the remaining patients, 2 controls were selected for each case and were stratified according to calendar year and type of surgery. For cases and controls, information was obtained regarding statin use before surgery, the presence of cardiac risk factors, and the use of other cardiovascular medication. A vascular complication during the perioperative phase was the primary cause of death in 104 (65%) case subjects. Statin therapy was significantly less common in cases than in controls (8% versus 25%; P<0.001). The adjusted odds ratio for perioperative mortality among statin users as compared with nonusers was 0.22 (95% confidence interval 0.10 to 0.47). Similar results were obtained in subgroups of patients according to the use of cardiovascular therapy and the presence of cardiac risk factors.This case-controlled study provides evidence that statin use reduces perioperative mortality in patients undergoing major vascular surgery.

Cardiac resynchronization therapy (CRT) has been used extensively over the last years in the therapeutic management of patients with end-stage heart failure. Data from 4,017 patients have been published in eight large, randomized trials on CRT. Improvement in clinical end points (symptoms, exercise capacity, quality of life) and echocardiographic end points (systolic function, left ventricular size, mitral regurgitation) have been reported after CRT, with a reduction in hospitalizations for decompensated heart failure and an improvement in survival. However, individual results vary, and 20% to 30% of patients do not respond to CRT. At present, the selection criteria include severe heart failure (New York Heart Association functional class III or IV), left ventricular ejection fraction <35%, and wide QRS complex (>120 ms). Assessment of inter- and particularly intraventricular dyssynchrony as provided by echocardiography (predominantly tissue Doppler imaging techniques) may allow improved identification of potential responders to CRT. In this review a summary of the clinical and echocardiographic results of the large, randomized trials is provided, followed by an extensive overview on the currently available echocardiographic techniques for assessment of LV dyssynchrony. In addition, the value of LV scar tissue and venous anatomy for the selection of potential candidates for CRT are discussed.

The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

The aim of this study was to perform a head-to-head comparison between multi-slice computed tomography (MSCT) and myocardial perfusion imaging (MPI) in patients with an intermediate likelihood of coronary artery disease (CAD) and to compare non-invasive findings to invasive coronary angiography.Multi-slice computed tomography detects atherosclerosis, whereas MPI detects ischemia; how these 2 techniques compare in patients with an intermediate likelihood of CAD is unknown.A total of 114 patients, mainly with intermediate likelihood of CAD, underwent both MSCT and MPI. The MSCT studies were classified as having no CAD, nonobstructive (<50% luminal narrowing) CAD, or obstructive CAD. Myocardial perfusion imaging examinations were classified as showing normal or abnormal (reversible and/or fixed defects). In a subset of 58 patients, invasive coronary angiography was performed.On the basis of the MSCT data, 41 patients (36%) were classified as having no CAD, of whom 90% had normal MPI. A total of 33 patients (29%) showed non-obstructive CAD, whereas at least 1 significant (> or =50% luminal narrowing) lesion was observed in the remaining 40 patients (35%). Only 45% of patients with an abnormal MSCT had abnormal MPI; even in patients with obstructive CAD on MSCT, 50% still had a normal MPI. In the subset of patients undergoing invasive angiography, the agreement with MSCT was excellent (90%).Myocardial perfusion imaging and MSCT provide different and complementary information on CAD, namely, detection of atherosclerosis versus detection of ischemia. As compared to invasive angiography, MSCT has a high accuracy for detecting CAD in patients with an intermediate likelihood of CAD.

The aim was to validate, update, and extend the Diamond-Forrester model for estimating the probability of obstructive coronary artery disease (CAD) in a contemporary cohort.Prospectively collected data from 14 hospitals on patients with chest pain without a history of CAD and referred for conventional coronary angiography (CCA) were used. Primary outcome was obstructive CAD, defined as ≥ 50% stenosis in one or more vessels on CCA. The validity of the Diamond-Forrester model was assessed using calibration plots, calibration-in-the-large, and recalibration in logistic regression. The model was subsequently updated and extended by revising the predictive value of age, sex, and type of chest pain. Diagnostic performance was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) and reclassification was determined. We included 2260 patients, of whom 1319 had obstructive CAD on CCA. Validation demonstrated an overestimation of the CAD probability, especially in women. The updated and extended models demonstrated a c-statistic of 0.79 (95% CI 0.77-0.81) and 0.82 (95% CI 0.80-0.84), respectively. Sixteen per cent of men and 64% of women were correctly reclassified. The predicted probability of obstructive CAD ranged from 10% for 50-year-old females with non-specific chest pain to 91% for 80-year-old males with typical chest pain. Predictions varied across hospitals due to differences in disease prevalence.Our results suggest that the Diamond-Forrester model overestimates the probability of CAD especially in women. We updated the predictive effects of age, sex, type of chest pain, and hospital setting which improved model performance and we extended it to include patients of 70 years and older.

Background— The relation between infarct tissue heterogeneity on contrast-enhanced MRI and the occurrence of spontaneous ventricular arrhythmia (or sudden cardiac death) is unknown. Therefore, the study purpose was to evaluate the predictive value of infarct tissue heterogeneity assessed with contrast-enhanced MRI on the occurrence of spontaneous ventricular arrhythmia with subsequent implantable cardioverter-defibrillator (ICD) therapy (as surrogate of sudden cardiac death) in patients with previous myocardial infarction. Methods and Results— Ninety-one patients (age, 65�11 years) with previous myocardial infarction scheduled for ICD implantation underwent cine MRI to evaluate left ventricular function and volumes and contrast-enhanced MRI for characterization of scar tissue (infarct gray zone as measure of infarct tissue heterogeneity, infarct core, and total infarct size). Appropriate ICD therapy was documented in 18 patients (20%) during a median follow-up of 8.5 months (interquartile range, 2.1 to 20.3). Multivariable Cox proportional hazards analysis revealed that infarct gray zone was the strongest predictor of the occurrence of spontaneous ventricular arrhythmia with subsequent ICD therapy (hazard ratio, 1.49/10 g; CI, 1.01 to 2.20; χ 2 =4.0; P =0.04). Conclusions— Infarct tissue heterogeneity on contrast-enhanced MRI is the strongest predictor of spontaneous ventricular arrhythmia with subsequent ICD therapy (as surrogate of sudden cardiac death) among other clinical and MRI variables, that is, total infarct size and left ventricular function and volumes, in patients with previous myocardial infarction.

We evaluated patients with end-stage heart failure who have a high likelihood of response to cardiac resynchronization therapy (biventricular pacing). It appears that 20% of patients do not respond to this expensive therapy despite the use of selection criteria (dilated cardiomyopathy, heart failure, New York Heart Association class II or IV, left ventricular ejection fraction <35%, left bundle branch block, and QRS >120 ms). The presence of left ventricular dyssynchrony is needed to result in improvement after cardiac resynchronization therapy.

The purpose of this study was to assess the incidence, predictors, and outcome of inappropriate shocks in implantable cardioverter-defibrillator (ICD) patients.Despite the benefits of ICD therapy, inappropriate defibrillator shocks continue to be a significant drawback. The prognostic importance of inappropriate shocks outside the setting of a clinical trial remains unclear.From 1996 to 2006, all recipients of defibrillator devices equipped with intracardiac electrogram storage were included in the current analysis and clinically assessed at implantation. During follow-up, the occurrence of inappropriate ICD shocks and all-cause mortality was noted.A total of 1,544 ICD patients (79% male, age 61 ± 13 years) were included in the analysis. During the follow-up period of 41 ± 18 months, 13% experienced ≥1 inappropriate shocks. The cumulative incidence steadily increased to 18% at 5-year follow-up. Independent predictors of the occurrence of inappropriate shocks included a history of atrial fibrillation (hazard ratio [HR]: 2.0, p < 0.01) and age younger than 70 years (HR: 1.8, p = 0.01). Experiencing a single inappropriate shock resulted in an increased risk of all-cause mortality (HR: 1.6, p = 0.01). Mortality risk increased with every subsequent shock, up to an HR of 3.7 after 5 inappropriate shocks.In a large cohort of ICD patients, inappropriate shocks were common. The most important finding is the association between inappropriate shocks and mortality, independent of interim appropriate shocks.

Patients with end-stage heart failure and a wide QRS complex are considered candidates for cardiac resynchronization therapy (CRT). However, 20% to 30% of patients do not respond to CRT. Lack of left ventricular dyssynchrony may explain the nonresponse. Accordingly, we evaluated the presence of left ventricular dyssynchrony using tissue Doppler imaging (TDI) in 90 consecutive patients with heart failure.Ninety patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association class III-IV) were prospectively evaluated. Based on QRS duration, 30 consecutive patients with a narrow QRS complex were included (QRS duration <or=120 ms), 30 patients with an intermediate QRS duration (120-150 ms), and 30 patients with a wide QRS complex (>150 ms). All patients underwent TDI to assess left ventricular dyssynchrony. Extensive left ventricular dyssynchrony was defined as an electromechanical delay on TDI between the septum and lateral wall, the so-called septal-to-lateral delay, of >60 ms. Severe dyssynchrony was observed in 27% of patients with narrow QRS complex, 60% with intermediate QRS duration, and 70% with wide QRS complex. No relation existed between QRS duration and septal-to-lateral delay.From 30% to 40% of heart failure patients with QRS duration >120 ms do not exhibit left ventricular dyssynchrony, which may explain the nonresponse to CRT. Alternatively, 27% of patients with heart failure and a narrow QRS complex show significant left ventricular dyssynchrony and may be candidates for CRT.

The purpose of this research was to perform a feasibility study of prophylactic coronary revascularization in patients with preoperative extensive stress-induced ischemia.Prophylactic coronary revascularization in vascular surgery patients with coronary artery disease does not improve postoperative outcome. If a beneficial effect is to be expected, then at least those with extensive coronary artery disease should benefit from this strategy.One thousand eight hundred eighty patients were screened, and those with > or =3 risk factors underwent cardiac testing using dobutamine echocardiography (17-segment model) or stress nuclear imaging (6-wall model). Those with extensive stress-induced ischemia (> or =5 segments or > or =3 walls) were randomly assigned for additional revascularization. All received beta-blockers aiming at a heart rate of 60 to 65 beats/min, and antiplatelet therapy was continued during surgery. The end points were the composite of all-cause death or myocardial infarction at 30 days and during 1-year follow-up.Of 430 high-risk patients, 101 (23%) showed extensive ischemia and were randomly assigned to revascularization (n = 49) or no revascularization. Coronary angiography showed 2-vessel disease in 12 (24%), 3-vessel disease in 33 (67%), and left main in 4 (8%). Two patients died after revascularization, but before operation, because of a ruptured aneurysm. Revascularization did not improve 30-day outcome; the incidence of the composite end point was 43% versus 33% (odds ratio 1.4, 95% confidence interval 0.7 to 2.8; p = 0.30). Also, no benefit during 1-year follow-up was observed after coronary revascularization (49% vs. 44%, odds ratio 1.2, 95% confidence interval 0.7 to 2.3; p = 0.48).In this randomized pilot study, designed to obtain efficacy and safety estimates, preoperative coronary revascularization in high-risk patients was not associated with an improved outcome.

Cardiac resynchronization therapy (CRT) has been proposed as an alternative treatment in patients with severe, drug-refractory heart failure. The clinical results are promising, and improvement in symptoms, exercise capacity, and systolic left ventricular (LV) function have been demonstrated after CRT, accompanied by a reduction in hospitalization and a superior survival as compared with optimized medical therapy alone. However, 20% to 30% of patients do not respond to CRT. Currently, patients are selected mainly on electrocardiogram criteria (wide QRS complex, left bundle branch block configuration). In view of the 20% to 30% of nonresponders, additional selection criteria are needed. Echocardiography (and, in particular, tissue Doppler imaging) may allow further identification of potential responders to CRT, based on assessment of inter- and intraventricular dyssynchrony. In addition, echocardiography may allow optimal LV lead positioning and follow-up after CRT. In the current review, the different echocardiographic approaches to predict response to CRT are discussed. In addition, the use of echocardiography to guide LV lead positioning and follow-up after CRT are addressed.

The aim of the current study was to evaluate the relation between the extent of left ventricular (LV) reverse remodeling and clinical/echocardiographic improvement after 6 months of cardiac resynchronization therapy (CRT) as well as long-term outcome. Despite the current selection criteria, individual response to CRT varies significantly. Furthermore, it has been suggested that reduction in left ventricular end-systolic volume (LVESV) after CRT is related to outcome. A total of 302 CRT candidates were included. Clinical status and echocardiographic evaluation were performed before implantation and after 6 months of CRT. Long-term follow-up included all-cause mortality and hospitalizations for heart failure. Based on different extents of LV reverse remodeling, 22% of patients were classified as super-responders (decrease in LVESV ≥30%), 35% as responders (decrease in LVESV 15% to 29%), 21% as nonresponders (decrease in LVESV 0% to 14%), and 22% negative responders (increase in LVESV). More extensive LV reverse remodeling resulted in more clinical improvement, with a larger increase in LV function and more reduction in mitral regurgitation. In addition, more LV reverse remodeling resulted in less heart failure hospitalizations and lower mortality during long-term follow-up (22 ± 11 months); 1- and 2-year hospitalization-free survival rates were 90% and 70% in the negative responder group compared with 98% and 96% in the super-responder group (log-rank p value <0.001). The extent of LV reverse remodeling at midterm follow-up is predictive for long-term outcome in CRT patients.

The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

The objective of this study was to assess the usefulness of each type of strain for left ventricular (LV) dyssynchrony assessment and its predictive value for a positive response after cardiac resynchronization therapy (CRT). Furthermore, changes in extent of LV dyssynchrony for each type of strain were evaluated during follow-up. Different echocardiographic techniques have been proposed for assessment of LV dyssynchrony. The novel 2-dimensional (2D) speckle tracking strain analysis technique can provide information on radial strain (RS), circumferential strain (CS), and longitudinal strain (LS). In 161 patients, 2D echocardiography was performed at baseline and after 6 months of CRT. Extent of LV dyssynchrony was calculated for each type of strain. Response to CRT was defined as a decrease in LV end-systolic volume ≥15% at follow-up. At follow-up, 88 patients (55%) were classified as responders. Differences in baseline LV dyssynchrony between responders and nonresponders were noted only for RS (251 ± 138 ms vs. 94 ± 65 ms; p < 0.001), whereas no differences were noted for CS and LS. A cut-off value of radial dyssynchrony ≥130 ms was able to predict response to CRT with a sensitivity of 83% and a specificity of 80%. In addition, a significant decrease in extent of LV dyssynchrony measured with RS (from 251 ± 138 ms to 98 ± 92 ms; p < 0.001) was demonstrated only in responders. Speckle tracking radial strain analysis constitutes the best method to identify potential responders to CRT. Reduction in LV dyssynchrony after CRT was only noted in responders.

The aim of the current study was to evaluate echocardiographic parameters after 6 months of cardiac resynchronization therapy (CRT) as well as long-term outcome in patients with the left ventricular (LV) lead positioned at the site of latest activation (concordant LV lead position) as compared with that seen in patients with a discordant LV lead position.A nonoptimal LV pacing lead position may be a potential cause for nonresponse to CRT.The site of latest mechanical activation was determined by speckle tracking radial strain analysis and related to the LV lead position on chest X-ray in 244 CRT candidates. Echocardiographic evaluation was performed after 6 months. Long-term follow-up included all-cause mortality and hospitalizations for heart failure.Significant LV reverse remodeling (reduction in LV end-systolic volume from 189 +/- 83 ml to 134 +/- 71 ml, p < 0.001) was noted in the group of patients with a concordant LV lead position (n = 153, 63%), whereas patients with a discordant lead position showed no significant improvements. In addition, during long-term follow-up (32 +/- 16 months), less events (combined for heart failure hospitalizations and death) were reported in patients with a concordant LV lead position. Moreover, a concordant LV lead position appeared to be an independent predictor of hospitalization-free survival after long-term CRT (hazard ratio: 0.22, p = 0.004).Pacing at the site of latest mechanical activation, as determined by speckle tracking radial strain analysis, resulted in superior echocardiographic response after 6 months of CRT and better prognosis during long-term follow-up.

This study evaluated myocardial function in relation to high-energy phosphate (HEP) metabolism in asymptomatic patients with uncomplicated type 2 diabetes mellitus using magnetic resonance (MR) techniques. Myocardial dysfunction may occur in patients with type 2 diabetes mellitus in the absence of coronary artery disease or left ventricular (LV) hypertrophy. The mechanisms underlying this diabetic cardiomyopathy are largely unknown, but may involve altered myocardial energy metabolism. We assessed myocardial systolic and diastolic function and HEP metabolism in 12 asymptomatic normotensive male patients with recently diagnosed, well-controlled type 2 diabetes and 12 controls, using MR imaging and phosphorus-31-nuclear MR spectroscopy (31P-MRS) on a 1.5 T clinical scanner; 31P-MR spectra were quantified, and myocardial HEP metabolism was expressed as phosphocreatine to adenosine-triphosphate (PCr/ATP) ratio. No differences were found in LV mass and systolic function between patients and controls. However, early (E) acceleration peak, deceleration peak, peak filling rate, and transmitral early-to-late diastolic peak flow (E/A) ratio, all indexes of diastolic function, were significantly decreased in patients compared with controls (p < 0.02). In addition, myocardial PCr/ATP in patients was significantly lower than in controls (1.47 vs. 1.88, p < 0.01). Inverse associations were found between myocardial PCr/ATP and E acceleration peak, E deceleration peak, and E peak filling rate (all, p < 0.05). These results indicate that altered myocardial energy metabolism may contribute to LV diastolic functional changes in patients with recently diagnosed, well-controlled and uncomplicated type 2 diabetes.

3D transesophageal echocardiography (TEE) may provide more accurate aortic annular and left ventricular outflow tract (LVOT) dimensions and geometries compared with 2D TEE. We assessed agreements between 2D and 3D TEE measurements with multislice computed tomography (MSCT) and changes in annular/LVOT areas and geometries after transcatheter aortic valve implantations (TAVI).Two-dimensional circular (pixr(2)), 3D circular, and 3D planimetered annular and LVOT areas by TEE were compared with "gold standard" MSCT planimetered areas before TAVI. Mean MSCT planimetered annular area was 4.65+/-0.82 cm(2) before TAVI. Annular areas were underestimated by 2D TEE circular (3.89+/-0.74 cm(2), P<0.001), 3D TEE circular (4.06+/-0.79 cm(2), P<0.001), and 3D TEE planimetered annular areas (4.22+/-0.77 cm(2), P<0.001). Mean MSCT planimetered LVOT area was 4.61+/-1.20 cm(2) before TAVI. LVOT areas were underestimated by 2D TEE circular (3.41+/-0.89 cm(2), P<0.001), 3D TEE circular (3.89+/-0.94 cm(2), P<0.001), and 3D TEE planimetered LVOT areas (4.31+/-1.15 cm(2), P<0.001). Three-dimensional TEE planimetered annular and LVOT areas had the best agreement with respective MSCT planimetered areas. After TAVI, MSCT planimetered (4.65+/-0.82 versus 4.20+/-0.46 cm(2), P<0.001) and 3D TEE planimetered (4.22+/-0.77 versus 3.62+/-0.43 cm(2), P<0.001) annular areas decreased, whereas MSCT planimetered (4.61+/-1.20 versus 4.84+/-1.17 cm(2), P=0.002) and 3D TEE planimetered (4.31+/-1.15 versus 4.55+/-1.21 cm(2), P<0.001) LVOT areas increased. Aortic annulus and LVOT became less elliptical after TAVI.Before TAVI, 2D and 3D TEE aortic annular/LVOT circular geometric assumption underestimated the respective MSCT planimetered areas. After TAVI, 3D TEE and MSCT planimetered annular areas decreased as it assumes the internal dimensions of the prosthetic valve. However, planimetered LVOT areas increased due to a more circular geometry.

Transcatheter aortic valve replacement (TAVR) is being increasingly performed in patients with bicuspid aortic valve stenosis (AS). This study sought to compare the procedural and clinical outcomes in patients with bicuspid versus tricuspid AS from the Bicuspid AS TAVR multicenter registry. Outcomes of 561 patients with bicuspid AS and 4,546 patients with tricuspid AS were compared after propensity score matching, assembling 546 pairs of patients with similar baseline characteristics. Procedural and clinical outcomes were recorded according to Valve Academic Research Consortium-2 criteria. Compared with patients with tricuspid AS, patients with bicuspid AS had more frequent conversion to surgery (2.0% vs. 0.2%; p = 0.006) and a significantly lower device success rate (85.3% vs. 91.4%; p = 0.002). Early-generation devices were implanted in 320 patients with bicuspid and 321 patients with tricuspid AS, whereas new-generation devices were implanted in 226 and 225 patients with bicuspid and tricuspid AS, respectively. Within the group receiving early-generation devices, bicuspid AS had more frequent aortic root injury (4.5% vs. 0.0%; p = 0.015) when receiving the balloon-expanding device, and moderate-to-severe paravalvular leak (19.4% vs. 10.5%; p = 0.02) when receiving the self-expanding device. Among patients with new-generation devices, however, procedural results were comparable across different prostheses. The cumulative all-cause mortality rates at 2 years were comparable between bicuspid and tricuspid AS (17.2% vs. 19.4%; p = 0.28). Compared with tricuspid AS, TAVR in bicuspid AS was associated with a similar prognosis, but lower device success rate. Procedural differences were observed in patients treated with the early-generation devices, whereas no differences were observed with the new-generation devices.

Atrial fibrillation (AF), the most common atrial arrhythmia, has a complex aetiology and causes relevant morbidity and mortality due to different mechanisms, including but not limited to stroke, heart failure, and tachy- or bradyarrhythmia. Current therapeutic options (rate control, rhythm control, antithrombotic therapy, ‘upstream therapy’) only prevent a part of this burden of disease. Several new treatment modalities are therefore under evaluation in controlled trials. Given the multifold clinical consequences of AF, trials in AF patients should assess the effect of therapy in each of the main outcome domains. This paper describes an expert consensus of required outcome parameters in seven relevant outcome domains, namely death, stroke, symptoms and quality of life, rhythm, left ventricular function, cost, and emerging outcome parameters. In addition to these ‘requirements’ for outcome assessment in AF trials, further, more detailed outcome parameters are described. In addition to a careful selection of a relevant primary outcome parameter, coverage of outcomes in all major domains of AF-related morbidity and mortality is desirable for any clinical trial in AF.

OBJECTIVES This study was designed to address, in patients with severe ischemic left ventricular dysfunction, whether dobutamine stress echocardiography (DSE) can predict improvement of left ventricular ejection fraction (LVEF), functional status and long-term prognosis after revascularization. BACKGROUND Dobutamine stress echocardiography can predict improvement of wall motion after revascularization. The relation between viability, improvement of function, improvement of heart failure symptoms and long-term prognosis has not been studied. METHODS We studied 68 patients with DSE before revascularization; 62 patients underwent resting echocardiography/radionuclide ventriculography before and three months after revascularization. Long-term follow-up data (New York Heart Association [NYHA] functional class, Canadian Cardiovascular Society [CCS] classification and events) were acquired up to two years. RESULTS Patients with ≥4 viable segments on DSE (group A, n = 22) improved in LVEF at three months (from 27 ± 6% to 33 ± 7%, p < 0.01), in NYHA functional class (from 3.2 ± 0.7 to 1.6 ± 0.5, p < 0.01) and in CCS classification (from 2.9 ± 0.3 to 1.2 ± 0.4, p < 0.01); in patients with <4 viable segments (group B, n = 40) LVEF and NYHA functional class did not improve, whereas CCS classification improved significantly (from 3.0 ± 0.8 to 1.3 ± 0.5, p < 0.01). A higher event rate was observed at long-term follow-up in group B versus group A (47% vs. 17%, p < 0.05). CONCLUSIONS Patients with substantial viability on DSE demonstrated improvement in LVEF and NYHA functional class after revascularization; viability was also associated with a favorable prognosis after revascularization.

Approximately 50% of the patients with chronic obstructive coronary artery disease resulting in chronic contractile dysfunction have hibernating myocardium and may benefit from revascularization. This pooled analysis describes the relative merits of dobutamine echocardiography, thallium-201 and technetium-99m scintigraphy, positron emission tomography, and magnetic resonance imaging, for the diagnosis of hibernating myocardium and prediction of patient outcomes.

Adverse cardiac events are common after vascular surgery. We hypothesized that perioperative statin therapy would improve postoperative outcomes.In this double-blind, placebo-controlled trial, we randomly assigned patients who had not previously been treated with a statin to receive, in addition to a beta-blocker, either 80 mg of extended-release fluvastatin or placebo once daily before undergoing vascular surgery. Lipid, interleukin-6, and C-reactive protein levels were measured at the time of randomization and before surgery. The primary end point was the occurrence of myocardial ischemia, defined as transient electrocardiographic abnormalities, release of troponin T, or both, within 30 days after surgery. The secondary end point was the composite of death from cardiovascular causes and myocardial infarction.A total of 250 patients were assigned to fluvastatin, and 247 to placebo, a median of 37 days before vascular surgery. Levels of total cholesterol, low-density lipoprotein cholesterol, interleukin-6, and C-reactive protein were significantly decreased in the fluvastatin group but were unchanged in the placebo group. Postoperative myocardial ischemia occurred in 27 patients (10.8%) in the fluvastatin group and in 47 (19.0%) in the placebo group (hazard ratio, 0.55; 95% confidence interval [CI], 0.34 to 0.88; P=0.01). Death from cardiovascular causes or myocardial infarction occurred in 12 patients (4.8%) in the fluvastatin group and 25 patients (10.1%) in the placebo group (hazard ratio, 0.47; 95% CI, 0.24 to 0.94; P=0.03). Fluvastatin therapy was not associated with a significant increase in the rate of adverse events.In patients undergoing vascular surgery, perioperative fluvastatin therapy was associated with an improvement in postoperative cardiac outcome. (Current Controlled Trials number, ISRCTN83738615.)

This study sought to describe the impact of statins on individual coronary atherosclerotic plaques.Although statins reduce the risk of major adverse cardiovascular events, their long-term effects on coronary atherosclerosis remain unclear.We performed a prospective, multinational study consisting of a registry of consecutive patients without history of coronary artery disease who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. Atherosclerotic plaques were quantitatively analyzed for percent diameter stenosis (%DS), percent atheroma volume (PAV), plaque composition, and presence of high-risk plaque (HRP), defined by the presence of ≥2 features of low-attenuation plaque, positive arterial remodeling, or spotty calcifications.Among 1,255 patients (60 ± 9 years of age; 57% men), 1,079 coronary artery lesions were evaluated in statin-naive patients (n = 474), and 2,496 coronary artery lesions were evaluated in statin-taking patients (n = 781). Compared with lesions in statin-naive patients, those in statin-taking patients displayed a slower rate of overall PAV progression (1.76 ± 2.40% per year vs. 2.04 ± 2.37% per year, respectively; p = 0.002) but more rapid progression of calcified PAV (1.27 ± 1.54% per year vs. 0.98 ± 1.27% per year, respectively; p < 0.001). Progression of noncalcified PAV and annual incidence of new HRP features were lower in lesions in statin-taking patients (0.49 ± 2.39% per year vs. 1.06 ± 2.42% per year and 0.9% per year vs. 1.6% per year, respectively; all p < 0.001). The rates of progression to >50% DS were not different (1.0% vs. 1.4%, respectively; p > 0.05). Statins were associated with a 21% reduction in annualized total PAV progression above the median and 35% reduction in HRP development.Statins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features. Statins did not affect the progression of percentage of stenosis severity of coronary artery lesions but induced phenotypic plaque transformation. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411).

The Lee risk index was developed to predict major cardiac complications in noncardiac surgery. We retrospectively evaluated its ability to predict cardiovascular death in the large cohort of patients who recently underwent noncardiac surgery in our institution.The administrative database of the Erasmus MC, Rotterdam, The Netherlands, contains information on 108 593 noncardiac surgical procedures performed from 1991 to 2000. The Lee index assigns 1 point to each of the following characteristics: high-risk surgery, ischemic heart disease, heart failure, cerebrovascular disease, renal insufficiency, and diabetes mellitus. We retrospectively used available information in our database to adapt the Lee index calculated the adapted index for each procedure, and analyzed its relation to cardiovascular death.A total of 1877 patients (1.7%) died perioperatively, including 543 (0.5%) classified as cardiovascular death. The cardiovascular death rates were 0.3% (255/75 352) for Lee Class 1, 0.7% (196/28 892) for Class 2, 1.7% (57/3380) for Class 3, and 3.6% (35/969) for Class 4. The corresponding odds ratios were 1 (reference), 2.0, 5.1, and 11.0, with no overlap for the 95% confidence interval of each class. The C statistic for the prediction of cardiovascular mortality using the Lee index was 0.63. If age and more detailed information regarding the type of surgery was retrospectively added, the C statistic in this exploratory analysis improved to 0.85.The adapted Lee index was predictive of cardiovascular mortality in our administrative database, but its simple classification of surgical procedures as high-risk versus not high-risk seems suboptimal. Nevertheless, if the goal is to compare outcomes across hospitals or regions using administrative data, the use of the adapted Lee index, as augmented by age and more detailed classification of type of surgery, is a promising option worthy of prospective testing.

Cardiac pacing is the only effective treatment for patients with sick sinus syndrome and atrioventricular conduction disorders. In cardiac pacing, the endocardial pacing lead is typically positioned at the right ventricular (RV) apex. At the same time, there is increasing indirect evidence, derived from large pacing mode selection trials and observational studies, that conventional RV apical pacing may have detrimental effects on cardiac structure and left ventricular function, which are associated with the development of heart failure. These detrimental effects may be related to the abnormal electrical and mechanical activation pattern of the ventricles (or ventricular dyssynchrony) caused by RV apical pacing. Still, it remains uncertain if the deterioration of left ventricular function as noted in a proportion of patients receiving RV apical pacing is directly related to acutely induced left ventricular dyssynchrony. The upgrade from RV pacing to cardiac resynchronization therapy may partially reverse the deleterious effects of RV pacing. It has even been suggested that selected patients with a conventional pacemaker indication should receive cardiac resynchronization therapy to avoid the deleterious effects. This review will provide a contemporary overview of the available evidence on the detrimental effects of RV apical pacing. Furthermore, the available alternatives for patients with a standard pacemaker indication will be discussed. In particular, the role of cardiac resynchronization therapy and alternative RV pacing sites in these patients will be reviewed.

Abstract Artificial intelligence (AI) has transformed key aspects of human life. Machine learning (ML), which is a subset of AI wherein machines autonomously acquire information by extracting patterns from large databases, has been increasingly used within the medical community, and specifically within the domain of cardiovascular diseases. In this review, we present a brief overview of ML methodologies that are used for the construction of inferential and predictive data-driven models. We highlight several domains of ML application such as echocardiography, electrocardiography, and recently developed non-invasive imaging modalities such as coronary artery calcium scoring and coronary computed tomography angiography. We conclude by reviewing the limitations associated with contemporary application of ML algorithms within the cardiovascular disease field.

The purpose of this study was to evaluate whether 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging predicts ventricular arrhythmias causing appropriate implantable cardioverter-defibrillator (ICD) therapy (primary end point) and the composite of appropriate ICD therapy or cardiac death (secondary end point).Although cardiac sympathetic denervation is associated with ventricular arrhythmias, limited data are available on the predictive value of sympathetic nerve imaging with 123-I MIBG on the occurrence of arrhythmias.Before ICD implantation, patients underwent 123-I MIBG and myocardial perfusion imaging. Early and late 123-I MIBG (planar and single-photon emission computed tomography [SPECT]) imaging was performed to assess cardiac innervation (heart-to-mediastinum ratio, cardiac washout rate, and 123-I MIBG SPECT defect score). Stress-rest myocardial perfusion imaging was performed to assess myocardial infarction and perfusion abnormalities (perfusion defect scores). During follow-up, appropriate ICD therapy and cardiac death were documented.One-hundred sixteen heart failure patients referred for ICD therapy were enrolled. During a mean follow-up of 23 +/- 15 months, appropriate ICD therapy (primary end point) was documented in 24 (21%) patients and appropriate ICD therapy or cardiac death (secondary end point) in 32 (28%) patients. Late 123-I MIBG SPECT defect score was an independent predictor for both end points. Patients with a large late 123-I MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52% vs. 5%, p < 0.01) and appropriate ICD therapy or cardiac death (57% vs. 10%, p < 0.01) than patients with a small defect (summed score </=26) at 3-year follow-up.Cardiac sympathetic denervation predicts ventricular arrhythmias causing appropriate ICD therapy as well as the composite of appropriate ICD therapy or cardiac death.

The association of atherosclerotic features with first acute coronary syndromes (ACS) has not accounted for plaque burden. The purpose of this study was to identify atherosclerotic features associated with precursors of ACS. We performed a nested case-control study within a cohort of 25,251 patients undergoing coronary computed tomographic angiography (CTA) with follow-up over 3.4 ± 2.1 years. Patients with ACS and nonevent patients with no prior coronary artery disease (CAD) were propensity matched 1:1 for risk factors and coronary CTA–evaluated obstructive (≥50%) CAD. Separate core laboratories performed blinded adjudication of ACS and culprit lesions and quantification of baseline coronary CTA for percent diameter stenosis (%DS), percent cross-sectional plaque burden (PB), plaque volumes (PVs) by composition (calcified, fibrous, fibrofatty, and necrotic core), and presence of high-risk plaques (HRPs). We identified 234 ACS and control pairs (age 62 years, 63% male). More than 65% of patients with ACS had nonobstructive CAD at baseline, and 52% had HRP. The %DS, cross-sectional PB, fibrofatty and necrotic core volume, and HRP increased the adjusted hazard ratio (HR) of ACS (1.010 per %DS, 95% confidence interval [CI]: 1.005 to 1.015; 1.008 per percent cross-sectional PB, 95% CI: 1.003 to 1.013; 1.002 per mm3 fibrofatty plaque, 95% CI: 1.000 to 1.003; 1.593 per mm3 necrotic core, 95% CI: 1.219 to 2.082; all p < 0.05). Of the 129 culprit lesion precursors identified by coronary CTA, three-fourths exhibited <50% stenosis and 31.0% exhibited HRP. Although ACS increases with %DS, most precursors of ACS cases and culprit lesions are nonobstructive. Plaque evaluation, including HRP, PB, and plaque composition, identifies high-risk patients above and beyond stenosis severity and aggregate plaque burden.

Eur Heart J 2021;42:373–498; doi:10.1093/eurheartj/ehaa612 Amendments have been made to the originally published supplementary data of this manuscript. Specifically: These have been corrected online.

To determine the ranges of pre-test probability (PTP) of coronary artery disease (CAD) in which stress electrocardiogram (ECG), stress echocardiography, coronary computed tomography angiography (CCTA), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance (CMR) can reclassify patients into a post-test probability that defines (>85%) or excludes (<15%) anatomically (defined by visual evaluation of invasive coronary angiography [ICA]) and functionally (defined by a fractional flow reserve [FFR] ≤0.8) significant CAD.A broad search in electronic databases until August 2017 was performed. Studies on the aforementioned techniques in >100 patients with stable CAD that utilized either ICA or ICA with FFR measurement as reference, were included. Study-level data was pooled using a hierarchical bivariate random-effects model and likelihood ratios were obtained for each technique. The PTP ranges for each technique to rule-in or rule-out significant CAD were defined. A total of 28 664 patients from 132 studies that used ICA as reference and 4131 from 23 studies using FFR, were analysed. Stress ECG can rule-in and rule-out anatomically significant CAD only when PTP is ≥80% (76-83) and ≤19% (15-25), respectively. Coronary computed tomography angiography is able to rule-in anatomic CAD at a PTP ≥58% (45-70) and rule-out at a PTP ≤80% (65-94). The corresponding PTP values for functionally significant CAD were ≥75% (67-83) and ≤57% (40-72) for CCTA, and ≥71% (59-81) and ≤27 (24-31) for ICA, demonstrating poorer performance of anatomic imaging against FFR. In contrast, functional imaging techniques (PET, stress CMR, and SPECT) are able to rule-in functionally significant CAD when PTP is ≥46-59% and rule-out when PTP is ≤34-57%.The various diagnostic modalities have different optimal performance ranges for the detection of anatomically and functionally significant CAD. Stress ECG appears to have very limited diagnostic power. The selection of a diagnostic technique for any given patient to rule-in or rule-out CAD should be based on the optimal PTP range for each test and on the assumed reference standard.

This study was designed to determine whether multislice computed tomography (MSCT) coronary angiography has incremental prognostic value over single-photon emission computed tomography myocardial perfusion imaging (MPI) in patients with suspected coronary artery disease (CAD).Although MSCT is used for the detection of CAD in addition to MPI, its incremental prognostic value is unclear.In 541 patients (59% male, age 59 +/- 11 years) referred for further cardiac evaluation, both MSCT and MPI were performed. The following events were recorded: all-cause death, nonfatal infarction, and unstable angina requiring revascularization.In the 517 (96%) patients with an interpretable MSCT, significant CAD (MSCT > or =50% stenosis) was detected in 158 (31%) patients, and abnormal perfusion (summed stress score [SSS]: > or =4) was observed in 168 (33%) patients. During follow-up (median 672 days; 25th, 75th percentile: 420, 896), an event occurred in 23 (5.2%) patients. After correction for baseline characteristics in a multivariate model, MSCT emerged as an independent predictor of events with an incremental prognostic value to MPI. The annualized hard event rate (all-cause mortality and nonfatal infarction) in patients with none or mild CAD (MSCT <50% stenosis) was 1.8% versus 4.8% in patients with significant CAD (MSCT > or =50% stenosis). A normal MPI (SSS <4) and abnormal MPI (SSS > or =4) were associated with an annualized hard event rate of 1.1% and 3.8%, respectively. Both MSCT and MPI were synergistic, and combined use resulted in significantly improved prediction (log-rank test p value <0.005).MSCT is an independent predictor of events and provides incremental prognostic value to MPI. Combined anatomical and functional assessment may allow improved risk stratification.

Tricuspid regurgitation is associated with increased rates of heart failure (HF) and mortality. Transcatheter tricuspid valve interventions (TTVI) are promising, but the clinical benefit is unknown. The purpose of this study was to investigate the potential benefit of TTVI over medical therapy in a propensity score matched population. The TriValve (Transcatheter Tricuspid Valve Therapies) registry collected 472 patients from 22 European and North American centers who underwent TTVI from 2016 to 2018. A control cohort formed by 2 large retrospective registries enrolling medically managed patients with ≥ moderate tricuspid regurgitation in Europe and North America (n = 1,179) were propensity score 1:1 matched (distance ± 0.2 SD) using age, EuroSCORE II, and systolic pulmonary artery pressure. Survival was tested with Cox regression analysis. Primary endpoint was 1-year mortality or HF rehospitalization or the composite. After matching, 268 adequately matched pairs of patients were identified. Compared with control subjects, TTVI patients had lower 1-year mortality (23 ± 3% vs. 36 ± 3%; p = 0.001), rehospitalization (26 ± 3% vs. 47 ± 3%; p < 0.0001), and composite endpoint (32 ± 4% vs. 49 ± 3%; p = 0.0003). TTVI was associated with greater survival and freedom from HF rehospitalization (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.46 to 0.79; p = 0.003 unadjusted), which remained significant after adjusting for sex, New York Heart Association functional class, right ventricular dysfunction, and atrial fibrillation (HR: 0.39; 95% CI: 0.26 to 0.59; p < 0.0001) and after further adjustment for mitral regurgitation and pacemaker/defibrillator (HR: 0.35; 95% CI: 0.23 to 0.54; p < 0.0001). In this propensity-matched case-control study, TTVI is associated with greater survival and reduced HF rehospitalization compared with medical therapy alone. Randomized trials should be performed to confirm these results.

IGF-I is a key factor in intrauterine development and postnatal growth and metabolism. The secretion of IGF-I in utero is not dependent on GH, whereas in childhood and adult life, IGF-I secretion seems to be mainly controlled by GH, as revealed from studies on patients with GHRH receptor and GH receptor mutations.

Valvular heart disease (VHD) is an important cause of mortality and morbidity and has been subject to important changes in management. The VHD II survey was designed by the EURObservational Research Programme of the European Society of Cardiology to analyze actual management of VHD and to compare practice with guidelines.Patients with severe native VHD or previous valvular intervention were enrolled prospectively across 28 countries over a 3-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients, corresponding to Class I recommendations specified in the 2012 European Society of Cardiology and in the 2014 American Heart Association/American College of Cardiology VHD guidelines.A total of 7247 patients (4483 hospitalized, 2764 outpatients) were included in 222 centers. Median age was 71 years (interquartile range, 62-80 years); 1917 patients (26.5%) were ≥80 years; and 3416 were female (47.1%). Severe native VHD was present in 5219 patients (72.0%): aortic stenosis in 2152 (41.2% of native VHD), aortic regurgitation in 279 (5.3%), mitral stenosis in 234 (4.5%), mitral regurgitation in 1114 (21.3%; primary in 746 and secondary in 368), multiple left-sided VHD in 1297 (24.9%), and right-sided VHD in 143 (2.7%). Two thousand twenty-eight patients (28.0%) had undergone previous valvular intervention. Intervention was performed in 37.0% and scheduled in 26.8% of patients with native VHD. The decision for intervention was concordant with Class I recommendations in symptomatic patients with severe single left-sided native VHD in 79.4% (95% CI, 77.1-81.6) for aortic stenosis, 77.6% (95% CI, 69.9-84.0) for aortic regurgitation, 68.5% (95% CI, 60.8-75.4) for mitral stenosis, and 71.0% (95% CI, 66.4-75.3) for primary mitral regurgitation. Valvular interventions were performed in 2150 patients during the survey; of them, 47.8% of patients with single left-sided native VHD were in New York Heart Association class III or IV. Transcatheter procedures were performed in 38.7% of patients with aortic stenosis and 16.7% of those with mitral regurgitation.Despite good concordance between Class I recommendations and practice in patients with aortic VHD, the suboptimal number in mitral VHD and late referral for valvular interventions suggest the need to improve further guideline implementation.

Restrictive mitral annuloplasty with revascularization is considered the best approach to ischemic mitral regurgitation with heart failure, but late results are controversial. We report late outcome in relation to preoperative left ventricular end-diastolic diameter (LVEDD) cutoff values, previously identified to predict intermediate-term left ventricular reverse remodeling.One hundred consecutive ischemic mitral regurgitation patients underwent restrictive mitral annuloplasty (stringent downsizing by two ring sizes; median size, 26) and coronary revascularization. Survivors were clinically and echocardiographically assessed at intermediate (18 months) and late (mean, 46 months) follow-up.Early mortality was 8%, and late mortality was 18%. Actuarial 1-, 3-, and 5-year survival rates were 87% +/- 3.4%, 80% +/- 4.1%, and 71% +/- 5.1%. Mortality predictors (Cox regression) were preoperative inotropic support (hazard ratio, 6.2; 95% confidence interval, 2.3 to 16.9) and preoperative LVEDD greater than 65 mm (hazard ratio, 4.5; 95% confidence interval, 1.9 to 10.9). Five-year survival rate for patients with LVEDD of 65 mm or less was 80% +/- 5.2%, versus 49% +/- 11% for LVEDD greater than 65 mm (p = 0.002). At 4.3 years' follow-up, New York Heart Association functional class had improved from 2.9 +/- 0.8 to 1.6 +/- 0.6 (p < 0.01). Mitral regurgitation grade was 0.8 +/- 0.7, and was less than grade 2+ in 85% of patients. Left ventricular reverse remodeling was sustained with time for the LVEDD of 65 mm or less group. Late deaths did not show intermediate-term systolic left ventricular reverse remodeling, indicating a more extensive intrinsic left ventricular abnormality.At 4.3 years' follow-up, intermediate-term cutoff values for left ventricular reverse remodeling proved to be predictors for late mortality. For patients with preoperative LVEDD of 65 mm or less, restrictive mitral annuloplasty with revascularization provides a cure for ischemic mitral regurgitation and heart failure; however, when LVEDD exceeds 65 mm, outcome is poor and a ventricular approach should be considered.

ESC Committee for Practice Guidelines (CPG): Alec Vahanian (Chairperson) (France), Angelo Auricchio (Switzerland), Jeroen J. Bax (The Netherlands), Claudio Ceconi (Italy), Veronica Dean (France), Gerasimos Filippatos (Greece), Christian Funck-Brentano (France), Richard Hobbs (UK), Peter Kearney (Ireland), Theresa McDonagh (UK), Keith McGregor (France), Bogdan A. Popescu (Romania), Zeljko Reiner (Croatia), Udo Sechtem (Germany), Per Anton Sirnes (Norway), Michal Tendera (Poland), Panos Vardas (Greece), Petr Widimsky (Czech Republic) Document Reviewers: Raffaele De Caterina (CPG Review Coordinator) (Italy), Stefan Agewall (Norway), Nawwar Al Attar (France), Felicita Andreotti (Italy), Stefan D. Anker (Germany), Gonzalo Baron-Esquivias (Spain), Guy Berkenboom (Belgium), Laurent Chapoutot (France), Renata Cifkova (Czech Republic), Pompilio Faggiano (Italy), Simon Gibbs (UK), Henrik Steen Hansen (Denmark), Laurence Iserin (France), Carsten W. Israel (Germany), Ran Kornowski (Israel), Nekane Murga Eizagaechevarria (Spain), Mauro Pepi (Italy), Massimo Piepoli (Italy), Hans Joachim Priebe (Germany), Martin Scherer (Germany), Janina Stepinska (Poland), David Taggart (UK), Marco Tubaro (Italy)Table 1Table 2Preamble Guidelines and Expert Consensus Documents aim to present management and recommendations based on the relevant evidence on a particular subject in order to help physicians to select the best possible management strategies for the individual patient with a specific condition, taking into account not only the impact on outcome but also the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.1 A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and also by other organizations or related societies. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC guidelines and Expert Consensus Documents can be found on the ESC website in the guidelines section (www.escardio.org). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighted and graded according to predefined scales, as outlined in Tables 1 and 2.Table 1: Classes of recommendationsTable 2: Level of evidenceThe experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report is entirely supported financially by the ESC without any involvement of industry. The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines and Expert Consensus Documents or statements. Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. The document is revised, and finally approved by the CPG and subsequently published. After publication, dissemination of the message is of paramount importance. Pocketsize versions and personal digital assistant (PDA)-downloadable versions are useful at the point of care. Some surveys have shown that the intended end-users are sometimes not aware of the existence of guidelines, or simply do not translate them into practice, so this is why implementation programmes for new guidelines form an important component of the dissemination of knowledge. Meetings are organized by the ESC, and are directed towards its member National Societies and key opinion leaders in Europe. Implementation meetings can also be undertaken at national levels, once the guidelines have been endorsed by the ESC member societies, and translated into the national language. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.2 Thus, the task of writing Guidelines or Expert Consensus Documents covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. The development of clinical guidelines and implementation into clinical practice can then only be completed if surveys and registries are performed to verify its use in real-life daily practices. Such surveys and registries also make it possible to evaluate the impact of implementation of the guidelines on patient outcomes. Guidelines and recommendations should help physicians and other healthcare providers to make decisions in their daily practice. However, the physician in charge of his/her care must make the ultimate judgement regarding the care of an individual patient. Introduction Magnitude of the problem The present guidelines focus on the cardiological management of patients undergoing non-cardiac surgery, i.e. patients in whom heart disease is a potential source of complications during surgery. The risk of perioperative complications depends on the condition of the patient prior to surgery, the prevalence of co-morbidities, and the magnitude and duration of the surgical procedure.3 More specifically, cardiac complications can arise in patients with documented or asymptomatic ischaemic heart disease (IHD), left ventricular (LV) dysfunction, and valvular heart disease (VHD) who undergo procedures that are associated with prolonged haemodynamic and cardiac stress. In the case of perioperative myocardial ischaemia, two mechanisms are important: (i) chronic mismatch in the supply-to-demand ratio of blood flow response to metabolic demand, which clinically resembles stable IHD due to a flow limiting stenosis in coronary conduit arteries; and (ii) coronary plaque rupture due to vascular inflammatory processes presenting as acute coronary syndromes (ACSs). Hence, although LV dysfunction may occur for various reasons in younger age groups, perioperative cardiac mortality and morbidity are predominantly an issue in the adult population undergoing major non-cardiac surgery. The magnitude of the problem in Europe can best be understood in terms of (i) the size of the adult non-cardiac surgical cohort; and (ii) the average risk of cardiac complications within this cohort. Unfortunately, at a European level, no systematic data are available on the annual number and type of operations, nor on patient outcome. Information is collected at the national level in several countries, but data definitions, amount of data, and data quality vary greatly. In The Netherlands, with a population of 16 million, throughout 1991–2005, 250 000 major surgical procedures were conducted on average annually in patients above the age of 20 years, implying an annual rate of 1.5%.4 When applied to Europe, with an overall population of 490 million, this figure translates into a crude estimate of 7 million major procedures annually in patients who present with cardiac risk. Data on cardiac outcome can be derived from the few large-scale clinical trials and registries that have been undertaken in patients undergoing non-cardiac surgery. Lee et al.5 studied 4315 patients undergoing elective major non-cardiac procedures in a tertiary care teaching hospital throughout 1989–1994. They observed that 92 (2.1%) patients suffered major cardiac complications, including cardiac death and myocardial infarction (MI). In a cohort of 108 593 consecutive patients who underwent surgery throughout 1991–2000 in a university hospital in The Netherlands, perioperative mortality occurred in 1877 (1.7%) patients, with a cardiovascular cause being identified in 543 cases (0.5%).6 The Dutch Echocardiographic Cardiac Risk Evaluating Applying Stress Echo (DECREASE) -I, -II and -IV trials enrolled 3893 surgical patients throughout 1996–2008, and these comprised intermediate-risk and high-risk patients of whom 136 (3.5%) suffered perioperative cardiac death or MI.7–9 A final piece of evidence with respect to patient outcome is derived from the Perioperative Ischaemic Evaluation (POISE) trial, which was conducted throughout 2002–2007, and enrolled 8351 patients undergoing non-cardiac surgery.10 Perioperative mortality occurred in 226 patients (2.7%), of whom 133 (1.6%) suffered cardiovascular death, whereas non-fatal MI was observed in another 367 (4.4%) subjects. Differences in incidences between the studies are mainly explained by patient selection and endpoint MI definitions—major non-cardiac surgery is associated with an incidence of cardiac death of between 0.5 and 1.5%, and of major cardiac complications of between 2.0 and 3.5%. When applied to the population in the European Union member states these figures translate into 150 000–250 000 life-threatening cardiac complications due to non-cardiac surgical procedures annually. Impact of the ageing population Within the next 20 years, the acceleration in ageing of the population will have a major impact on perioperative patient management. It is estimated that elderly people require surgery four times more often than the rest of the population.11 Although exact data regarding the number of patients undergoing surgery in Europe are lacking, it is estimated that this number will increase by 25% by 2020, and for the same time period the elderly population will increase by >50%. The total number of surgical procedures will increase even faster because of the rising frequency of interventions with age.12 Results of the US National Hospital Discharge Survey show that, in general, the number of surgical procedures will increase in almost all age groups, but that the largest increase will occur in the middle aged and elderly (Table 3).Table 3: Change in numbers of discharges for surgical procedures by age for the time periods 1994/95 and 2004/05 as reported from the 2005 US National Hospital Discharge Survey (non-federal short-stay hospitals)15Demographics of patients undergoing surgery show a trend towards an increasing number of elderly patients and co-morbidities.13 Although mortality from cardiac disease is decreasing in the general population, the prevalence of IHD, heart failure, and cardiovascular risk factors, especially diabetes, is increasing. Among the significant co-morbidities in elderly patients presenting for general surgery, cardiovascular disease (CVD) is the most prevalent. It is estimated from primary care data that in the 75–84 year age group 19% of men and 12% of women have some degree of CVD.14 Age per se, however, seems to be responsible for only a small increase in the risk of complications; greater risks are associated with urgency and significant cardiac, pulmonary, and renal disease. The number of affected individuals is likely to be higher in countries with high CVD mortality, particularly in Central and Eastern Europe. These conditions should, therefore, have a greater impact on the evaluation of patient risk than age alone. Purpose Currently there are no official ESC guidelines on pre-operative risk assessment and perioperative cardiac management. The objective is to endorse a standardized and evidence-based approach to perioperative cardiac management. The guidelines recommend a practical, stepwise evaluation of the patient, which integrates clinical risk factors and test results with the estimated stress of the planned surgical procedure. This results in an individualized cardiac risk assessment, with the opportunity to initiate medical therapy, coronary interventions, and specific surgical and anaesthetic techniques in order to optimize the patient's perioperative condition. Compared with the non-surgical setting, data from randomized clinical trials, which are the ideal evidence base for the guidelines, are sparse. Therefore, when no trials are available on a specific cardiac management regimen in the surgical setting, data from the non-surgical setting are used, and similar recommendations made, but with different levels of evidence. Emphasis is placed on the restricted use of prophylactic coronary revascularization, as this is rarely indicated simply to ensure the patient survives surgery. Pre-operative evaluation requires an integrated multidisciplinary approach from anaesthesiologists, cardiologists, internists, pulmonologists, geriatricians, and surgeons. Anaesthesiologists, who are experts on the specific demands of the proposed surgical procedure, usually coordinate the process. Guidelines have the potential to improve post-operative outcome. However, as shown in an observational study of 711 vascular surgery patients from The Netherlands, adherence to guidelines is poor.16–18 Although 185 of a total of 711 patients (26%) fulfilled the American College of Cardiology (ACC)/American Heart Association (AHA) guideline criteria for pre-operative non-invasive cardiac testing, clinicians had performed testing in only 38 of those cases (21%).16 The guideline-recommended medical therapy for the perioperative period, namely the combination of aspirin and statins in all patients and β-blockers in patients with ischaemic heart disease, was followed in only 41% of cases.18 Significantly, the use of evidence-based medication during the perioperative period was associated with a reduction in 3-year mortality after adjustment for clinical characteristics [hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45–0.94]. These data highlight the existence of a clear opportunity for improving the quality of care in this high-risk group of patients. In addition to promoting an improvement in immediate perioperative care, guidelines should provide long-term advice, as patients should live long enough to enjoy the benefits of surgery. Following the development and introduction of perioperative cardiac guidelines, their effect on outcome should be monitored. The objective evaluation of changes in outcome will be an essential part of future perioperative guideline developments. Pre-operative evaluation Surgical risk for cardiac events Cardiac complications after non-cardiac surgery depend not only on specific risk factors but also on the type of surgery and the circumstances under which it takes place.19 Surgical factors that influence cardiac risk are related to the urgency, magnitude, type, and duration of the procedure, as well as the change in body core temperature, blood loss, and fluid shifts.12 Every operation elicits a stress response. This response is initiated by tissue injury and mediated by neuroendocrine factors, and may induce tachycardia and hypertension. Fluid shifts in the perioperative period add to the surgical stress. This stress increases myocardial oxygen demand. Surgery also causes alterations in the balance between prothrombotic and fibrinolytic factors, resulting in hypercoagulability and possible coronary thrombosis (elevation of fibrinogen and other coagulation factors, increased platelet activation and aggregation, and reduced fibrinolysis). The extent of such changes is proportionate to the extent and duration of the intervention. All these factors may cause myocardial ischaemia and heart failure. Certainly in patients at elevated risk, attention to these factors should be given and lead, if indicated, to adaptations in the surgical plan. Although patient-specific factors are more important than surgery-specific factors in predicting the cardiac risk for non-cardiac surgical procedures, the type of surgery cannot be ignored when evaluating a particular patient undergoing an intervention.6,20 With regard to cardiac risk, surgical interventions can be divided into low-risk, intermediate-risk, and high-risk groups with estimated 30-day cardiac event rates (cardiac death and MI) of <1, 1–5, and >5%, respectively (Table 4). Although only a rough estimation, this risk stratification provides a good indication of the need for cardiac evaluation, drug treatment, and assessment of risk for cardiac events.Table 4: Surgical riska estimate (modified from Boersma et al. 6)The high-risk group consists of major vascular interventions. In the intermediate-risk category the risk also depends on the magnitude, duration, location, blood loss, and fluid shifts related to the specific procedure. In the low-risk category the cardiac risk is negligible unless strong patient-specific risk factors are present. The need for, and value of, pre-operative cardiac evaluation will also depend on the urgency of surgery. In the case of emergency surgical procedures, such as those for ruptured abdominal aortic aneurysm (AAA), major trauma, or for perforated viscus, cardiac evaluation will not change the course and result of the intervention but may influence the management in the immediate postoperative period. In non-emergent but urgent untreated surgical conditions such as bypass for acute limb ischaemia or treatment of bowel obstruction, the morbidity and mortality of the untreated underlying condition will outweigh the potential cardiac risk related to the intervention. In these cases, cardiological evaluation may influence the perioperative measures taken to reduce the cardiac risk, but will not influence the decision to perform the intervention. In some cases, the cardiac risk can also influence the type of operation and guide the choice to less invasive interventions, such as peripheral arterial angioplasty instead of infra-inguinal bypass, or extra-anatomic reconstruction instead of an aortic procedure, even when these may yield less favourable results in the long term. Lastly, in some situations, the cardiac evaluation, in as far as it can reliably predict perioperative cardiac complications and estimate late survival, should be taken into consideration even when deciding whether to perform an intervention or not. This is the case in certain prophylactic interventions such as the treatment of small AAAs or asymptomatic carotid stenosis where the life expectancy of the patient and the risk of the operation are important factors in evaluating the potential benefit of the surgical intervention. Vascular interventions are of specific interest, not only because they carry the highest risk of cardiac complications, explained by the high probability that the atherosclerotic process also affects the coronary arteries, but also because of the many studies that have shown that this risk can be influenced by adequate perioperative measures in these patients. Open aortic and infra-inguinal procedures have both to be considered as high-risk procedures.6 Although a less extensive intervention, infra-inguinal revascularization entails a cardiac risk similar to or even higher than aortic procedures. This can be explained by the higher incidence of diabetes, renal dysfunction, IHD, and advanced age in this patient group. This also explains why the risk related to peripheral artery angioplasties, which are minimally invasive procedures, is not negligible. Several randomized trials, as well as community-based studies, have shown that the cardiac risk is substantially lower after endovascular aortic aneurysm repair than after open repair.21 This can be related to the lesser tissue damage and the avoidance of aortic cross-clamping and post-operative ileus. However, long-term survival does not seem to be influenced by the surgical technique that is used, but is determined by the underlying cardiac disease.22 Carotid endarterectomy is considered to be an intermediate-risk procedure. Nevertheless, elevated cardiac risk and late survival should be taken into account in the decision-making process and can influence the choice between endarterectomy or stenting. Laparoscopic procedures have the advantage of causing less tissue trauma and intestinal paralysis than open procedures, resulting in less incisional pain and diminished post-operative fluid shifts related to bowel paralysis.23 On the other hand, the pneumoperitoneum used in these procedures results in elevated intra-abdominal pressure and a reduction in venous return. It will result in a decrease in cardiac output and an increase in systemic vascular resistance. Therefore, cardiac risk in patients with heart failure is not diminished in patients undergoing laparoscopy compared with open surgery, and both should be evaluated in the same way. This is especially true in patients undergoing interventions for morbid obesity.24,25Table 3Functional capacity Determination of functional capacity is considered to be a pivotal step in pre-operative cardiac risk assessment. Functional capacity is measured in metabolic equivalents (METs). One MET equals the basal metabolic rate. Exercise testing provides an objective assessment of functional capacity. Without testing, functional capacity can be estimated by the ability to perform the activities of daily living. Given that 1 MET represents metabolic demand at rest, climbing two flights of stairs demands 4 METs, and strenuous sports such as swimming >10 METS (Fig. 1).Fig. 1The inability to climb two flights of stairs or run a short distance (<4 METs) indicates poor functional capacity and is associated with an increased incidence of post-operative cardiac events. After thoracic surgery, a poor functional capacity has been associated with an increased mortality (relative risk 18.7, 95% CI 5.9–59). However, in comparison with thoracic surgery, a poor functional status was not associated with an increased mortality after other non-cardiac surgery (relative risk 0.47, 95% CI 0.09–2.5).28 This may reflect the importance of pulmonary function, strongly related to functional capacity, as a major predictor of survival after thoracic surgery. These findings were confirmed in a study of 5939 patients scheduled for non-cardiac surgery in which the prognostic importance of pre-operative functional capacity was measured in METs.29 Using receiver operating characteristic (ROC) curve analysis, the association of functional capacity with post-operative cardiac events or death showed an area under the ROC curve of just 0.664, compared with 0.814 for age. Considering the relatively weak association between functional capacity and post-operative cardiac outcome, what importance should we attach to functional capacity assessment in the pre-operative evaluation of the risk of non-cardiac surgery? When functional capacity is high, the prognosis is excellent, even in the presence of stable IHD or risk factors.30 In this case, perioperative management will rarely be changed as a result of further cardiac testing and the planned surgical procedure can proceed. Using functional capacity evaluation prior to surgery, the ability to climb two flights of stairs or run for a short distance indicated a good functional capacity. On the other hand, when functional capacity is poor or unknown, the presence and number of risk factors in relation to the risk of surgery will determine pre-operative risk stratification and perioperative management. Risk indices Effective strategies aimed at reducing the risk of perioperative cardiac complications should involve cardiac evaluation using medical history prior to the surgical procedure, for two main reasons. First, patients with an anticipated low cardiac risk—after thorough evaluation—can be operated on safely without further delay. It is unlikely that risk reduction strategies can reduce the perioperative risk further. Secondly, risk reduction by pharmacological treatment is most cost-effective in patients with a suspected increased cardiac risk. Additional non-invasive cardiac imaging techniques are tools to identify patients at higher risk. However, imaging techniques should be reserved for those patients in whom test results would influence and change management. Obviously, the intensity of the pre-operative cardiac evaluation must be tailored to the patient's clinical condition and the urgency of the circumstances requiring surgery. When emergency surgery is needed, the evaluation must necessarily be limited. However, most clinical circumstances allow the application of a more extensive, systematic approach, with cardiac risk evaluation that is initially based on clinical characteristics and type of surgery, and then extended—if indicated—to resting electrocardiography (ECG), laboratory measurements, and non-invasive (stress) testing. During the last 30 years, several risk indices have been developed, based on multivariable analyses of observational data, which represent the relationship between clinical characteristics and perioperative cardiac mortality and morbidity. The indices that were developed by Goldman (1977), Detsky (1986), and Lee (1999) became well known.5,31,32 The Lee index, which is in fact a modification of the original Goldman index, is considered by many clinicians and researchers to be the best currently available cardiac risk prediction index in non-cardiac surgery. It was developed using prospectively collected data on 2893 unselected patients (and validated in another 1422 patients) who underwent a wide spectrum of procedures. They were followed systematically throughout the post-operative phase for a range of clinically relevant cardiac outcomes. The Lee index contains five independent clinical determinants of major perioperative cardiac events: a history of IHD, a history of cerebrovascular disease, heart failure, insulin-dependent diabetes mellitus, and impaired renal function. High-risk type of surgery is the sixth factor that is included in the index. All factors contribute equally to the index (with 1 point each), and the incidence of major cardiac complications is estimated at 0.4, 0.9, 7, and 11% in patients with an index of 0, 1, 2, and ≥3 points, respectively. The area under the ROC curve in the validation data set was 0.81, indicating that the index has a high capability for discriminating between patients with and without a major cardiac event. However, the patients studied by Lee et al. cannot be considered to be an average, unselected non-cardiac surgical cohort. Patients undergoing thoracic (12%), vascular (21%), and orthopaedic surgery (35%) were over-represented. Furthermore, despite its respectable size, the study was too underpowered to reveal a broad range of cardiac outcome determinants, as only 56 cardiac events were observed in the derivation cohort. Several external validation studies have suggested that the Lee index is probably suboptimal for identifying patients with multiple risk factors.6 In fact, the type of surgery was only classified as two subtypes: first, high-risk, including intraperitoneal, intrathoracic, and suprainguinal vascular procedures; and, second, all remaining non-laparoscopic procedures, mainly including orthopaedic, abdominal, and other vascular procedures. Evidence exists that a more subtle classification, such as the Erasmus model, results in better risk discrimination.6 In this model, an extensive description of the type of surgery and age increased the prognostic value of the model for perioperative cardiac events (area under the ROC curve for the prediction of cardiovascular mortality increased from 0.63 to 0.85) (Table 5).Table 5: Lee index and Erasmus model: clinical risk factors used for pre-operative cardiac risk stratification5,6Table 4Biomarkers A biological marker—biomarker—is a characteristic that can be objectively measured and evaluated and which is an indicator of abnormal biological and pathogenic processes or responses to therapeutic interventions. In the perioperative setting, biomarkers can be divided into markers focusing on myocardial ischaemia and damage, inflammation, and LV function. Cardiac troponins T and I (cTnT and cTnI) are the preferred markers for the diagnosis of MI because they demonstrate sensitivity and tissue specificity superior to other available biomarkers.33,34 The prognostic information is independent of, and complementary to, other important cardiac indicators of risk such as ST deviation and LV function. The prognostic significance of even small elevations in troponins has been independently confirmed in community-based studies and in clinical trials (TACTICS-TIMI 18, FRISC II, OPUS-TIMI),35,36 not only in high-risk, but also in intermediate-risk groups. cTnI and CTnT seem to be of similar value for risk assessment in acute coronary syndrome (ACS) in the presence and absence of renal failure.33 The prognosis for all-cause death in patients with end-stage renal disease and with even minor elevations in cTnT is 2–5 times worse than for those with undetectable values. Existing evidence suggests that even small increases in cTnT in the perioperative period reflect clinically relevant myocardial injury with worsened cardiac prognosis and outcome.37 The development of new biomarkers, including high-sensitivity troponins, will further enhance the assessment of myocardial damage. It should be noted that troponin elevation may be observed in many other conditions. The diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) should never be made solely on the basis of biomarkers. Inflammatory mar

Previous studies have suggested that bone marrow cell injection may improve myocardial perfusion and left ventricular (LV) function in patients with chronic myocardial ischemia.To investigate the effect of intramyocardial bone marrow cell injection on myocardial perfusion and LV function in patients with chronic myocardial ischemia.Randomized, double-blind, placebo-controlled trial at a Netherlands university hospital, May 1, 2005-March 3, 2008 (6-month follow-up ended September 2008) of 50 patients with chronic myocardial ischemia (mean age [SD], 64 [8] years; 43 men).severe angina pectoris despite optimal medical therapy and myocardial ischemia. All patients were ineligible for conventional revascularization.Intramyocardial injection of 100 x 10(6) autologous bone marrow-derived mononuclear cells or placebo solution.Primarily, the summed stress score, a 17-segment score for stress myocardial perfusion assessed by Tc-99m tetrofosmin single-photon emission computed tomography (SPECT). Secondary included LV ejection fraction (LVEF), Canadian Cardiovascular Society (CCS) class, and Seattle Angina Questionnaire quality-of-life score (mean difference >5% considered clinically significant).After 3-month follow-up, the summed stress score (mean [SD]) improved from 23.5 (4.7) to 20.1 (4.6) (P < .001) in the bone marrow cell group, compared with a decrease from 24.8 (5.5) to 23.7 (5.4) (P = .004) in the placebo group. In the bone marrow cell-treated patients who underwent magnetic resonance imaging (MRI), a 3% absolute increase in LVEF was observed at 3 months (95% CI, 0.5% to 4.7%; n = 18), but the placebo group showed no improvement. CCS angina score improved significantly in the bone marrow cell group (6-month absolute difference, -0.79; 95% CI, -1.10 to -0.48; P < .001) compared with no significant improvement in the placebo group. Quality-of-life score increased from 56% (9%) to 64% (12%) at 3 months and 69% (12%) at 6 months in bone marrow cell-treated patients, compared with a smaller increase in the placebo group from 57% (11%) to 61% (14%) to 64% (17%). The improvements in CCS class and quality of life score were significantly greater in bone marrow cell-treated patients than in placebo-treated patients (P = .03 and P = .04, respectively).In this short-term study of patients with chronic myocardial ischemia refractory to medical treatment, intramyocardial bone marrow cell injection resulted in a statistically significant but modest improvement in myocardial perfusion compared with placebo. Further studies are required to assess long-term results and efficacy for mortality and morbidity.trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927.

In Brief Objective: This study evaluated the effectiveness and safety of beta-blockers and statins for the prevention of perioperative cardiovascular events in intermediate-risk patients undergoing noncardiovascular surgery. Summary Background Data: Beta-blockers and statins reduce perioperative cardiac events in high-risk patients undergoing vascular surgery by restoring the myocardial oxygen supply/demand balance and/or stabilizing coronary plaques. However, their effects in intermediate-risk patients remained ill-defined. Methods: In this randomized open-label 2 × 2 factorial design trial 1066 intermediate cardiac risk patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median: 34 days). Intermediate risk was defined by an estimated risk of perioperative cardiac death and myocardial infarction (MI) of 1% to 6%, using clinical data and type of surgery. Starting dose of bisoprolol was 2.5 mg daily, titrated to a perioperative heart rate of 50 to 70 beats per minute. Fluvastatin was prescribed in a fixed dose of 80 mg. The primary end point was the composite of 30-day cardiac death and MI. This study is registered in the ISRCTN registry and has the ID number ISRCTN47637497. Results: Patients randomized to bisoprolol (N = 533) had a lower incidence of perioperative cardiac death and nonfatal MI than those randomized to bisoprolol-control (2.1% vs. 6.0% events; hazard ratios: 0.34; 95% confidence intervals: 0.17–0.67; P = 0.002). Patients randomized to fluvastatin experienced a lower incidence of the end point than those randomized to fluvastatin-control therapy (3.2% vs. 4.9% events; hazard ratios: 0.65; 95% confidence intervals: 0.35–1.10), but statistical significance was not reached (P = 0.17). Conclusion: Bisoprolol was associated with a significant reduction of 30-day cardiac death and nonfatal MI, while fluvastatin showed a trend for improved outcome. In this randomized trial including 1066 patients beta-blocker therapy was associated with a significant reduction (hazard ratios: 0.34, 95% confidence intervals: 0.17–0.67) in perioperative cardiovascular events in intermediate-risk patients undergoing noncardiovascular surgery. However, statin therapy was not associated with a significant reduction in perioperative cardiovascular events (hazard ratios: 0.65; 95% confidence intervals: 0.35–1.10).

The Collaboration of the European Society for Vascular Surgery (ESVS) and the European Society of Cardiology (ESC) in new Guidelines for Peripheral Arterial Diseases (PAD) is new and very welcome.1Aboyans V. Ricco J.B. Bartelink M.E.L. Björck M. Brodmann M. Cohnert T. et al.2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS).Eur J Vasc Endovasc Surg. 2018; 55: 305-368Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar The ESVS Carotid and Vertebral Guidelines have just been published2Naylor A.R. Ricco J.B. de Borst G.J. Debus S. de Haro J. Halliday A. et al.Management of atherosclerotic carotid and Vertebral artery disease: 2017 Clinical practice Guidelines of the European Society for Vascular Surgery (ESVS).Eur J Vasc Endovasc Surg. 2018; 55: 3-81Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar and, in this issue, the ESC & ESVS PAD Guidelines will highlight the evidence and views of this multidisciplinary collaboration of specialists in vascular disease in Europe today. As we stress here, these Guidelines emphasise the importance of the multidisciplinary “Vascular Team” in holistic management of these patients, including comprehensive cardiovascular preventive measures and integrated cardiac risk management of PAD patients. Recommendations are provided in both Guideline documents and graded according to the ESC system. These include level of evidence (A, B, C) and the class of recommendation (I, II, III). Class I indicates general agreement on what is formally indicated, in Class IIa there is conflicting evidence or divergence of opinion, whereas, for Class IIb, usefulness is less well established and in Class III there is general agreement that a given treatment is not useful or may even be harmful. This system is now almost identical to the American Heart Association (AHA) grading system, facilitating future comparisons of Guideline recommendations between the USA and Europe.3Gerhard-Herman M.D. Gornik H.L. Barrett C. Barshes N.R. Corriere M.A. Drachman D.E. et al.2016 AHA/ACC Guideline on the management of patients with lower extremity peripheral artery disease: a report of the american College of Cardiology/american heart association task force on clinical practice guidelines.J Am Coll Cardiol. 2017; 69: e71-e126Crossref PubMed Scopus (361) Google Scholar The ESVS Carotid and Vertebral Guidelines cover 64 pages and 475 references, with an in-depth focus on all issues regarding management of cerebrovascular disease, while the new ESC & ESVS PAD Guideline had the challenge to produce a single document of 50 pages (and 420 references) covering a much wider range of topics, including some of particular interest to cardiologists, but of definite importance to surgeons, such as the cardiac conditions other than coronary artery disease in patients with PAD (i.e. heart failure, atrial fibrillation, valvular heart disease and vascular access). Both Guidelines emphasise the importance of investigating multisite artery disease. Importantly, in the new ESC & ESVS document, PAD encompasses all the peripheral territories, covering carotid and vertebral, mesenteric artery disease, renal artery disease, as well as upper and lower extremity artery diseases. The ESC & ESVS Guidelines address gaps in evidence as well as giving ‘To do and not to do’ messages, which may be of particular interest to non-vascular specialists or general practitioners. Where ESC covers antithrombotic drugs for a wide range of PAD, ESVS covers drug treatments for carotid and vertebral disease. Both Guidelines address the evidence for management of concurrent coronary and carotid disease, for carotid disease with major non-cardiac surgery and for occlusive disease of proximal common carotid and innominate arteries. The ESVS document takes more space to tackle newer issues which have become topical, such as the relationship (or not) of carotid disease to dementia, opportunities for future trials and, of course, the timing of carotid surgery, surgical techniques and complications that may occur. This document replaces the ESC 2011 Guidelines on PAD, with some significant differences. There is downgrading of the previous indications for revascularization of asymptomatic carotid stenosis and inclusion of data indicating that revascularisation of carotid stenosis for CABG is mostly unnecessary; other differences include the ‘how to do it and in whom’ boxes, such as for PAD detection, the useful figures on antiplatelet therapy for carotid disease and PAD, a helpful section on when oral anticoagulation is indicated, a reminder that using treadmill walking tests for PAD is valuable, the ‘WIFI’ classification for assessing amputation risk and an update of the co-incidence of other vascular diseases for each disease territory, an example being ‘39%–61% of patients with more than 70% carotid stenosis have CAD’. The cardiologist and vascular physician are well catered for in these new ESC & ESVS PAD Guidelines. The Surgeon will find it refreshing to see the evidence from their point of view, and can appreciate that, when cardiac disease is prevalent, close multidisciplinary collaboration is required to improve patient outcome. The neurologist and stroke interventionalist just might read both, since the European Stroke Organisation (ESO) endorses these new ESC/ESVS Guidelines. However, some interventionalists may be uncertain about their place in this new world – for example, should more cardiologists and surgeons provide acute endovascular interventions in PAD, or will they be constrained by local training requirements? Finally, this is a unique document summarizing the evidence and the optimal management for all peripheral territories and from this standpoint, it should definitely interest any training physician or surgeon who wants to have all the information in one place, written by experts from both societies. As a general rule for any ESC Guidelines document, this PAD Guidelines document has been reviewed (at least for Class I and III recommendations) by every National Cardiology Society prior to approval, but practice in every European Country is different – this has not been addressed, as Guidelines will not assess problems of European National Healthcare provision, which may be centrally- or Insurance-funded, driven by general practice budgets or by hospital profit. The ability of all European countries to provide the services described in these new Guidelines is uncertain. This should be our next aim in a new ESC & ESVS Collaboration – to provide standards for the care of patients with vascular disease in Europe, taking into account the regional differences in different countries. The ESVS and the ESC will join their efforts for a new joint endeavour – one aiming to improve delivery of the care recommended in these excellent Guidelines.

We sought to evaluate the outcomes of transcatheter mitral valve replacement (TMVR) for patients with degenerated bioprostheses [valve-in-valve (ViV)], failed annuloplasty rings [valve-in-ring (ViR)], and severe mitral annular calcification [valve-in-mitral annular calcification (ViMAC)].From the TMVR multicentre registry, procedural and clinical outcomes of ViV, ViR, and ViMAC were compared according to Mitral Valve Academic Research Consortium (MVARC) criteria. A total of 521 patients with mean Society of Thoracic Surgeons score of 9.0 ± 7.0% underwent TMVR (322 patients with ViV, 141 with ViR, and 58 with ViMAC). Trans-septal access and the Sapien valves were used in 39.5% and 90.0%, respectively. Overall technical success was excellent at 87.1%. However, left ventricular outflow tract obstruction occurred more frequently after ViMAC compared with ViR and ViV (39.7% vs. 5.0% vs. 2.2%; P < 0.001), whereas second valve implantation was more frequent in ViR compared with ViMAC and ViV (12.1% vs. 5.2% vs. 2.5%; P < 0.001). Accordingly, technical success rate was higher after ViV compared with ViR and ViMAC (94.4% vs. 80.9% vs. 62.1%; P < 0.001). Compared with ViMAC and ViV groups, ViR group had more frequent post-procedural mitral regurgitation ≥moderate (18.4% vs. 13.8% vs. 5.6%; P < 0.001) and subsequent paravalvular leak closure (7.8% vs. 0.0% vs. 2.2%; P = 0.006). All-cause mortality was higher after ViMAC compared with ViR and ViV at 30 days (34.5% vs. 9.9% vs. 6.2%; log-rank P < 0.001) and 1 year (62.8% vs. 30.6% vs. 14.0%; log-rank P < 0.001). On multivariable analysis, patients with failed annuloplasty rings and severe MAC were at increased risk of mortality after TMVR [ViR vs. ViV, hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.27-3.12; P = 0.003; ViMAC vs. ViV, HR 5.29, 95% CI 3.29-8.51; P < 0.001].The TMVR provided excellent outcomes for patients with degenerated bioprostheses despite high surgical risk. However, ViR and ViMAC were associated with higher rates of adverse events and mid-term mortality compared with ViV.

AF : atrial fibrillation AV : atrio-ventricular CPG : Committee for Practice Guidelines CRT : cardiac resynchronization therapy CRT-P : CRT with pacemaker function CRT-D : CRT with defibrillator function CTX : cardiac transplantation CV : cardiovascular EHRA : European Heart Rhythm Association ESC : European Society of Cardiology HF : heart failure HFA : Heart Failure Association Hosp : hospitalization ICD : implantable cardioverter defibrillator LBBB : left bundle branch block LV : left ventricular LVAD : left ventricular assist device LVEDD : left ventricular end-diastolic diameter LVEF : left ventricular ejection fraction LVESi : left ventricular stroke volume index LVESV : left ventricular end-systolic volume 6MWT : 6 min walk test NA : not applicable NIH : National Institutes of Health NS : not significant NYHA : New York Heart Association OMT : optimal medical therapy pVO2 : peak oxygen consumption QoL : quality of life RBBB : right bundle branch block RCT : randomized clinical trial SR : sinus rhythm VE/CO2 : ventilation/carbon dioxide ratio The Committee for Practice Guidelines (CPG) of the European Society of Cardiology recognizes that new evidence from clinical research trials may impact on current recommendations. The current heart failure (HF) guidelines1 were published in 2008 and the cardiac pacing guidelines in 2007.2 In order to keep these guidelines up to date, it would be appropriate to modify the recommendations and levels of evidence according to the most recent clinical trial evidence. This Focused Update on the use of devices in heart failure 2010 is the first publication of its kind from the CPG. Practice Guideline recommendations should represent evidence-based medicine. Traditionally, these recommendations are based on the outcomes in the cohort of patients described by the inclusion criteria in the protocols of randomized clinical trials (RCTs). More recently, based on the fact that the characteristics of the patients actually included in a trial may differ substantially from the eligibility criteria, Guideline Task Force members frequently favour restricting the applicability of these recommendations to the clinical profile and outcomes of the enrolled cohort, representing a more accurate interpretation of the evidence provided by a trial's result. In contrast to previous guidelines, this focused update considers the characteristics of the patients included in the trials and contains several examples. In MADIT-CRT, although the protocol permitted inclusion of patients in both New York Heart Association (NYHA) I and II function class, only 15% of the patients included in this trial were classified as NYHA I, many of whom had been previously symptomatic. Similarly, although the inclusion criteria permitted randomization of patients with a QRS width of ≥130 m, the favourable effect on the primary endpoint was limited to patients with a QRS width of ≥150 ms, a prospective, pre-specified cut-off. The text accompanying these recommendations explains and justifies the decisions to …

The incidence of cardiovascular disease (CVD) among women is lower before the menopause, which may be due to the atheroprotective effects of female sex hormones, including estrogens. This study explored whether women experienced acute coronary syndrome (ACS) more often during menstruation, when the levels of female sex hormones are low.All premenopausal women referred to the local cardiac rehabilitation program after ACS between August 2010 and September 2018 were contacted by telephone to gather information about their menstrual cycle, contraceptive use and whether ACS occurred during menstruation. Information on cardiovascular risk factors was collected using the clinical electronic health record.Of the 22 women fulfilling the inclusion criteria and having a regular menstrual cycle, 22.7% reported that they were diagnosed with ACS at the time of menstruation.The percentage of women who were menstruating whilst having their cardiovascular event is higher than the percentage expected if the event was unrelated to the menstrual cycle. To gain more insight into the effect of female sex hormones on ACS, it is suggested that information on the menstrual cycle is routinely collected from women admitted to hospital with the condition.