Juhani Knuuti

2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation The Task Force for the management of acute myocardial infarction in patients presenting with 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

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 …

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.

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.

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.

### 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 …

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

An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

Non-thrombotic PE does not represent a distinct clinical syndrome. It may be due to a variety of embolic materials and result in a wide spectrum of clinical presentations, making the diagnosis difficult. With the exception of severe air and fat embolism, the haemodynamic consequences of non-thrombotic emboli are usually mild. Treatment is mostly supportive but may differ according to the type of embolic material and clinical severity.

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 . …

AAA : abdominal aortic aneurysm ACEI : angiotensin converting enzyme inhibitor ACS : acute coronary syndromes AF : atrial fibrillation AKI : acute kidney injury AKIN : Acute Kidney Injury Network ARB : angiotensin receptor blocker ASA : American Society of Anesthesiologists b.i.d. : bis in diem (twice daily) BBSA : Beta-Blocker in Spinal Anesthesia BMS : bare-metal stent BNP : B-type natriuretic peptide bpm : beats per minute CABG : coronary artery bypass graft CAD : coronary artery disease CARP : Coronary Artery Revascularization Prophylaxis CAS : carotid artery stenting CASS : Coronary Artery Surgery Study CEA : carotid endarterectomy CHA2DS2-VASc : cardiac failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–74 and sex category (female) CI : confidence interval CI-AKI : contrast-induced acute kidney injury CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease Epidemiology Collaboration Cmax : maximum concentration CMR : cardiovascular magnetic resonance COPD : chronic obstructive pulmonary disease CPG : Committee for Practice Guidelines CPX/CPET : cardiopulmonary exercise test CRP : C-reactive protein CRT : cardiac resynchronization therapy CRT-D : cardiac resynchronization therapy defibrillator CT : computed tomography cTnI : cardiac troponin I cTnT : cardiac troponin T CVD : cardiovascular disease CYP3a4 : cytochrome P3a4 enzyme DAPT : dual anti-platelet therapy DECREASE : Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography DES : drug-eluting stent DIPOM : DIabetic Post-Operative Mortality and Morbidity DSE : dobutamine stress echocardiography ECG : electrocardiography/electrocardiographically/electrocardiogram eGFR : estimated glomerular filtration rate ESA : European Society of Anaesthesiology ESC : European Society of Cardiology EVAR : endovascular abdominal aortic aneurysm repair FEV1 : Forced expiratory volume in 1 second HbA1c : glycosylated haemoglobin HF-PEF : heart failure with preserved left ventricular ejection fraction HF-REF : heart failure with reduced left ventricular ejection fraction ICD : implantable cardioverter defibrillator ICU : intensive care unit IHD : ischaemic heart disease INR : international normalized ratio IOCM : iso-osmolar contrast medium KDIGO : Kidney Disease: Improving Global Outcomes LMWH : low molecular weight heparin LOCM : low-osmolar contrast medium LV : left ventricular LVEF : left ventricular ejection fraction MaVS : Metoprolol after Vascular Surgery MDRD : Modification of Diet in Renal Disease MET : metabolic equivalent MRI : magnetic resonance imaging NHS : National Health Service NOAC : non-vitamin K oral anticoagulant NSQIP : National Surgical Quality Improvement Program NSTE-ACS : non-ST-elevation acute coronary syndromes NT-proBNP : N-terminal pro-BNP O2 : oxygen OHS : obesity hypoventilation syndrome OR : odds ratio P gp : platelet glycoprotein PAC : pulmonary artery catheter PAD : peripheral artery disease PAH : pulmonary artery hypertension PCC : prothrombin complex concentrate PCI : percutaneous coronary intervention POBBLE : Peri-Operative Beta-BLockadE POISE : Peri-Operative ISchemic Evaluation POISE-2 : Peri-Operative ISchemic Evaluation 2 q.d. : quaque die (once daily) RIFLE : Risk, Injury, Failure, Loss, End-stage renal disease SPECT : single photon emission computed tomography SVT : supraventricular tachycardia SYNTAX : Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery TAVI : transcatheter aortic valve implantation TdP : torsades de pointes TIA : transient ischaemic attack TOE : transoesophageal echocardiography TOD : transoesophageal doppler TTE : transthoracic echocardiography UFH : unfractionated heparin VATS : video-assisted thoracic surgery VHD : valvular heart disease VISION : Vascular Events In Noncardiac Surgery Patients Cohort Evaluation VKA : vitamin K antagonist VPB : ventricular premature beat VT : ventricular tachycardia Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting health professionals 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 …

abdominal aorta aneurysm ankle-brachial index Asymptomatic Carotid Atherosclerosis Study angiotensin-converting enzyme inhibitors acute coronary syndrome asymptomatic carotid atherosclerosis risk of stroke Asymptomatic Carotid Surgery Trial Asymptomatic Carotid Trial atrial fibrillation Aggressive detection and Management of the Extension of atherothrombosis in high Risk coronary patients In comparison with standard of Care for coronary Atherosclerosis angiotensin-receptor blockers absolute risk reduction angioplasty and stenting for renal artery lesions bypass versus angioplasty in severe ischaemia of the leg Best Endovascular vs. Best Surgical Therapy in Patients with Critical Limb Ischaemia best medical therapy blood pressure coronary artery bypass grafting coronary artery disease Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events Carotid ACCULINK/ACCUNET Post-Approval Trial to Uncover Rare Events Clopidogrel and Aspirin for the Reduction of Emboli in Symptomatic carotid Stenosis Clopidogrel and Acetylsalicylic Acid in Bypass Surgery for Peripheral Arterial disease carotid artery stenting common carotid artery carotid endarterectomy common femoral artery Congestive heart failure, Hypertension, Age ≥75 (2 points), Diabetes mellitus, Stroke or TIA (2 points), Vascular disease, Age 65–74 years, Sex category Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance confidence interval chronic kidney disease Claudication: exercise versus endoluminal revascularization Chronic limb-threatening ischaemia chronic mesenteric ischaemia Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Cardiovascular Outcomes in Renal Atherosclerotic Lesions cardiopulmonary bypass Committee for Practice Guidelines Carotid Revascularization Endarterectomy versus Stenting Trial computed tomography angiography cardiovascular dual antiplatelet therapy drug eluting stent digital subtraction angiography duplex ultrasound electrocardiogram European Carotid Surgery Trial embolus protection device European Society of Cardiology European Stroke Organisation European Society of Vascular Surgery Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease Endarterectomy vs Stenting in Patients with Symptomatic Severe Carotid Stenosis endovascular therapy exercise therapy fibromuscular dysplasia great saphenous vein high-density lipoprotein cholesterol Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training high-intensity transient signal Heart Outcomes Prevention Trial hazard ratio intermittent claudication internal carotid artery implantable cardioverter defibrillator International Carotid Stenting Study international normalized ratio INternational VErapamil-SR/Trandolapril Study low-density lipoprotein cholesterol lower extremity artery disease left ventricular major adverse cardiovascular event myocardial infarction magnetic resonance angiography MultiCenter Randomized Clinical Trial of Ischemic Stroke in the Netherlands magnetic resonance imaging multisite artery disease maximal walking distance North American Symptomatic Carotid Endarterectomy Trial number needed to harm number needed to treat non-vitamin K oral anticoagulant oral anticoagulation Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial odds ratio peripheral arterial diseases percutaneous coronary intervention Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 PROlonging Dual antiplatelet treatment after Grading stent-induced intimal hYperplasia study percutaneous transluminal angioplasty quality of life renin–angiotensin–aldosterone system renal artery disease renal artery stenosis randomized clinical trial Reduction of Atherothrombosis for Continued Health Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation relative risk renal resistive index Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy single antiplatelet therapy systolic blood pressure superficial femoral artery Stent Protected Angioplasty versus Carotid Endarterectomy Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function Efficacy and Safety of XRP0038/NV1FGF in Critical Limb Ischaemia Patients With Skin Lesions transcatheter aortic valve implantation toe-brachial index transcutaneous oxygen pressure transient ischaemic attack transthoracic echocardiography upper extremity artery disease vertebral artery Vertebral Artery Stenting Trial valvular heart disease vitamin K antagonist walking distance wound, ischaemia and foot infection Guidelines summarize and evaluate available evidence with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision making of health professionals in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of guidelines have been issued in recent years by the European Society of Cardiology (ESC), by the European Society of Vascular Surgery (ESVS) and by the European Stroke Organization (ESO), as well as by other societies and organisations. 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 (https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). 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, including representation from the ESVS and ESO 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 management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy and approved by the ESVS and ESO. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Table 1, Table 2.Table 1Classes of recommendations.Table 2Levels of evidence.Level of evidence AData derived from multiple randomized clinical trials or meta-analyses.Level of evidence BData derived from a single randomized clinical trial or large non-randomized studies.Level of evidence CConsensus of opinion of the experts and/or small studies, retrospective studies, registries. Open table in a new tab The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that 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 were notified to the ESC and updated. The Task Force received its entire financial support from the ESC and ESVS without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts, and in this case by ESVS- and ESO-appointed experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG and ESVS for publication in the European Heart Journal and in the European Journal of Vascular and Endovascular Surgery. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC Guidelines in collaboration with ESVS also includes the creation of educational tools and implementation programmes for the recommendations including condensed pocket guideline versions, summary slides, booklets with essential messages, summary cards for non-specialists and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available via the ESC Website and hosted on the EHJ Website. The National Societies of the ESC are encouraged to endorse, translate and implement all 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, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC Guidelines developed in collaboration with ESVS 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 or the patient's caregiver where appropriate and/or necessary. 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 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.

As a consequence of improved technology, there is growing clinical interest in the use of multi-detector row computed tomography (MDCT) for non-invasive coronary angiography. Indeed, the accuracy of MDCT to detect or exclude coronary artery stenoses has been high in many published studies. This report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT (WG 5) of the European Society of Cardiology and the European Council of Nuclear Cardiology summarizes the present state of cardiac CT technology, as well as the currently available data concerning its accuracy and applicability in certain clinical situations. Besides coronary CT angiography, the use of CT for the assessment of cardiac morphology and function, evaluation of perfusion and viability, and analysis of heart valves is discussed. In addition, recommendations for clinical applications of cardiac CT imaging are given and limitations of the technique are described.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

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 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.

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

This article is accompanied by the following Invited Commentary: Longrois D, Hoeft A, De Hert S. 2014 European Society of Cardiology/European Society of Anaesthesiology guidelines on non-cardiac surgery: cardiovascular assessment and management. A short explanatory statement from the European Society of Anaesthesiology members who participated in the European Task Force. Eur J Anaesthesiol 2014; 31:513–516. ESC Committee for Practice Guidelines: Jose Luis Zamorano (Chairperson) (Spain), Stephan Achenbach (Germany), Helmut Baumgartner (Germany), Jeroen J. Bax (Netherlands), Héctor Bueno (Spain), Veronica Dean (France), Christi Deaton (UK), Cetin Erol (Turkey), Robert Fagard (Belgium), Roberto Ferrari (Italy), David Hasdai (Israel), Arno W. Hoes (Netherlands), Paulus Kirchhof (Germany/UK), Juhani Knuuti (Finland), Philippe Kolh (Belgium), Patrizio Lancellotti (Belgium), Ales Linhart (Czech Republic), Petros Nihoyannopoulos (UK), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Per Anton Sirnes (Norway), Juan Luis Tamargo (Spain), Michal Tendera (Poland), Adam Torbicki (Poland), William Wijns (Belgium), Stephan Windecker (Switzerland). ESA Clinical Guidelines Committee: Maurizio Solca (Chairperson) (Italy), Jean-François Brichant (Belgium), Stefan De Herta (Belgium), Edoardo de Robertisb (Italy), Dan Longroisc (France), Sibylle Kozek Langenecker (Austria), Josef Wichelewski (Israel). a Scientific Committee Chairperson & ESA Board Representative, πbNASC Chairperson,cEBA/UEMS representative Document Reviewers: Massimo Piepoli (Review coordinator) (Italy), William Wijns (Review coordinator) (Belgium), Stefan Agewall (Denmark), Claudio Ceconi (Italy), Antonio Coca (Spain), Ugo Corrà (Italy), Raffaele De Caterina (Italy), Carlo Di Mario (UK), Thor Edvardsen (Norway), Robert Fagard (Belgium), Giuseppe Germano (Italy), Fabio Guarracino (Italy), Arno Hoes (Netherlands), Torben Joergensen (Denmark), Peter Jüni (Switzerland), Pedro Marques-Vidal (Switzerland), Christian Mueller (Switzerland), Öztekin Oto (Turkey), Philippe Pibarot (Canada), Piotr Ponikowski (Poland), Olav FM Sellevold (Norway), Filippos Triposkiadis (Greece), Stephan Windecker (Switzerland), Patrick Wouters (Belgium). ESC National Cardiac Societies document reviewers listed in appendix The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines Keywords: Guidelines, Non-cardiac surgery, Preoperative cardiac risk assessment, Preoperative cardiac testing, Preoperative coronary artery revascularization, Perioperative cardiac management, Anti-thrombotic therapy, Beta-blockers, Valvular disease, Arrhythmias, Heart failure, Renal disease, Pulmonary disease, Cerebrovascular disease, Anaesthesiology, Postoperative cardiac surveillance Table of Contents Abbreviations and acronyms 520 Preamble 522 Introduction 523 2.1. Magnitude of the problem 523 2.2. Change in population demographics 524 2.3. Purpose and organization 524 Preoperative evaluation 525 3.1. Surgical risk for cardiac events 525 3.2. Type of surgery 526 3.2.1. Endovascular versus open vascular procedures 526 3.2.2. Open versus laparoscopic or thoracoscopic procedures 526 3.3. Functional capacity 527 3.4. Risk indices 528 3.5. Biomarkers 529 3.6. Non-invasive testing 529 3.6.1. Non-invasive testing of cardiac disease 530 3.6.2. Non-invasive testing of ischaemic heart disease 530 3.7. Invasive coronary angiography 532 Risk-reduction strategies 532 4.1. Pharmacological 532 4.1.1. Beta-blockers 532 4.1.2. Statins 535 4.1.3. Nitrates 536 4.1.4. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers 536 4.1.5. Calcium channel blockers 537 4.1.6. Alpha2 receptor agonists 537 4.1.7. Diuretics 537 4.2. Perioperative management in patients on antiplatelet agents 538 4.2.1. Aspirin 538 4.2.2. Dual antiplatelet therapy 538 4.2.3. Reversal of antiplatelet therapy 539 4.3. Perioperative management in patients on anticoagulants 539 4.3.1. Vitamin K antagonists 539 4.3.2. Non-vitamin K antagonist oral anticoagulants 540 4.3.3. Reversal of anticoagulant therapy 541 4.4. Revascularization 542 4.4.1. Prophylactic revascularization in patients with asymptomatic or stable ischaemic heart disease 543 4.4.2. Type of prophylactic revascularization in patients with stable ischaemic heart disease 544 4.4.3. Revascularization in patients with NSTE-ACS 544 Specific diseases 545 5.1. Chronic heart failure 545 5.2. Arterial hypertension 547 5.3. Valvular heart disease 548 5.3.1. Patient evaluation 548 5.3.2. Aortic stenosis 548 5.3.3. Mitral stenosis 548 5.3.4. Primary aortic regurgitation and mitral regurgitation 548 5.3.5. Secondary mitral regurgitation 549 5.3.6. Patients with prosthetic valve(s) 549 5.3.7. Prophylaxis of infective endocarditis 549 5.4. Arrhythmias 550 5.4.1. New onset ventricular arrhythmias in the preoperative period 550 5.4.2. Management of supraventricular arrhythmias and atrial fibrillation in the preoperative period 550 5.4.3. Perioperative bradyarrhythmias 550 5.4.4. Perioperative management of patients with pacemaker/implantable cardioverter defibrillator 551 5.5. Renal disease 551 5.6. Cerebrovascular disease 553 5.7. Peripheral artery disease 554 5.8. Pulmonary disease 555 5.9. Congenital heart disease 557 Perioperative monitoring 557 6.1. Electrocardiography 557 6.2. Transoesophageal echocardiography 558 6.3. Right heart catheterization 559 6.4. Disturbed glucose metabolism 559 6.5. Anaemia 560 Anaesthesia 560 7.1. Intraoperative anaesthetic management 560 7.2. Neuraxial techniques 561 7.3. Perioperative goal-directed therapy 561 7.4. Risk stratification after surgery 562 7.5. Early diagnosis of postoperative complications 562 7.6. Postoperative pain management 562 Gaps in evidence 563 Summary 563 Appendix 566 References 566 Abbreviations and acronyms AAA abdominal aortic aneurysm ACEI angiotensin converting enzyme inhibitor ACS acute coronary syndromes AF atrial fibrillation AKI acute kidney injury AKIN Acute Kidney Injury Network ARB angiotensin receptor blocker ASA American Society of Anesthesiologists b.i.d. bis in die (twice daily) BBSA beta-blocker in spinal anaesthesia BMS bare-metal stent BNP B-type natriuretic peptide CABG coronary artery bypass graft CAD coronary artery disease CARP Coronary Artery Revascularization Prophylaxis CAS carotid artery stenting CASS Coronary Artery Surgery Study CEA carotid endarterectomy CHA2DS2-VASc cardiac failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–74 and sex category (female) CI confidence interval CI-AKI contrast-induced acute kidney injury CKD chronic kidney disease CKD-EPI Chronic Kidney Disease Epidemiology Collaboration Cmax maximum concentration CMR cardiovascular magnetic resonance COPD chronic obstructive pulmonary disease CPG Committee for Practice Guidelines CPX/CPET cardiopulmonary exercise test CRP C-reactive protein CRT cardiac resynchronisation therapy CRT-D cardiac resynchronization therapy defibrillator CT computed tomography cTnI cardiac troponin I cTnT cardiac troponin T CVD cardiovascular disease CYP3a4 cytochrome P3a4 enzyme DECREASE Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography DES drug-eluting stent DIPOM Diabetic Postoperative Mortality and Morbidity DSE dobutamine stress echocardiography ECG electrocardiography/electrocardiographically/electrocardiogram eGFR estimated glomerular filtration rate ESA European Society of Anaesthesiology ESC European Society of Cardiology EVAR endovascular abdominal aortic aneurysm repair FEV1 Forced expiratory volume in 1 second HbA1c glycosylated haemoglobin HF-PEF heart failure with preserved left ventricular ejection fraction HF-REF heart failure with reduced left ventricular ejection fraction ICD implantable cardioverter defibrillator IHD ischaemic heart disease INR international normalized ratio IOMC iso-osmolar contrast medium KDIGO Kidney Disease: Improving Global Outcomes LMWH low-molecular weight heparin LOCM low-osmolar contrast medium LV left ventricular LVEF left ventricular ejection fraction MaVS Metoprolol after Vascular Surgery MDRD Modification of Diet in Renal Disease MET metabolic equivalent MRI magnetic resonance imaging NHS National Health Service NOAC non-vitamin K oral anticoagulant NSQIP National Surgical Quality Improvement Program NSTE-ACS non–ST-elevation acute coronary syndromes NT-proBNP N-terminal pro-brain natriuretic peptide O2 oxygen OHS obesity hypoventilation syndrome OR odds ratio P gp platelet glycoprotein PAC pulmonary artery catheter PAD peripheral artery disease PAH pulmonary artery hypertension PCC prothrombin complex concentrate PCI percutaneous coronary intervention POBBLE PeriOperative Beta-BLockadE POISE PeriOperative ISchemic Evaluation POISE-2 Perioperative ischemic evaluation 2 q.d. quaque die (once daily) RIFLE Risk, Injury, Failure, Loss, End-stage renal disease SPECT single photon emission computed tomography SVT supraventricular tachycardia SYNTAX Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery TAVI transcatheter aortic valve implantation TIA transient ischaemic attack TOE transoesophageal echocardiography TTE transthoracic echocardiography UFH unfractionated heparin VATS video-assisted thoracic surgery VHD valvular heart disease VISION Vascular Events In Noncardiac Surgery Patients Cohort Evaluation VKA vitamin K antagonist VPB ventricular premature beat VT ventricular tachycardia 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 health professionals 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 and recommendations should help the health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA) as well as by other societies and organisations. 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/ESA Guidelines can be found on the ESC Web Site (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). These ESC/ESA Guidelines represent the official position of these two societies on this given topic and are regularly updated. Members of this Task Force were selected by the ESC and ESA 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 management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to the ESC Committee for Practice Guidelines (CPG) and ESA Guidelines Committee 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 management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2.Table 1: Classes of recommendationsTable 2: Levels of evidenceThe experts of the writing and reviewing panels filled in declarations of interest forms 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 Web Site (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC/ESA and updated. The Task Force received its entire financial support from the ESC and ESA 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 and Joint Guidelines undergo extensive review by the CPG and partner Guidelines Committee 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/ESA for simultaneous publication in the European Heart Journal and joint partner journal, in this instance the European Journal of Anaesthesiology. It was developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC/ESA 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, summary cards for non-specialists, 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 and ESA Websites. The National Societies of the ESC and of the ESA 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, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC/ESA 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/ESA 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 the patient's caregiver where appropriate and/or necessary. 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 2.1. Magnitude of the problem The present guidelines focus on the cardiovascular management of patients in whom heart disease is a potential source of complications during non-cardiac surgery. The risk of perioperative complications depends on the condition of the patient before surgery, the prevalence of comorbidities, and the urgency, magnitude, type and duration of the surgical procedure. More specifically, cardiac complications can arise in patients with documented or asymptomatic ischaemic heart disease (IHD), left ventricular (LV) dysfunction, valvular heart disease (VHD), and arrhythmias, who undergo surgical procedures that are associated with prolonged haemodynamic and cardiac stress. In the case of perioperative myocardial ischaemia, two mechanisms are important: (i) a mismatch in the supply–demand ratio of blood flow in response to metabolic demand due to a coronary artery stenosis that may become flow-limiting by perioperative haemodynamic fluctuations; and (ii) acute coronary syndromes (ACS) due to stress-induced rupture of a vulnerable atherosclerotic plaque in combination with vascular inflammation and altered vasomotion as well as haemostasis. LV dysfunction and arrhythmias may occur for various reasons at all ages. Because the prevalence of not only IHD but also VHD and arrhythmias increases with age, 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 group; and (ii) the average risk of cardiac complications in this cohort. Unfortunately, systematic data on the annual number and type of operations, and on patient outcomes, are only available at a national level in 23 (41%) European countries.1 Moreover, data definitions, as well as data quantity and quality, vary. A recent modelling strategy based on available worldwide data in 2004 estimated the number of major operations to be at an annual rate of 4%.1 When applied to Europe, with an overall population of over 500 million, this figure translates into a crude estimate of 19 million major procedures annually. While the majority of the procedures are performed in patients with minimal cardiovascular risk, 30% of the patients undergo extensive surgical procedures in the presence of cardiovascular comorbidity. Hence, 5.7 million procedures annually are performed in European patients who present with increased risk of cardiovascular complications. Worldwide, non-cardiac surgery is associated with an average overall complication rate of between 7% and 11% and a mortality rate between 0.8% and 1.5% depending on safety precautions.2 Up to 42% of these are caused by cardiac complications.3 When applied to the population in the European Union member states, these figures translate into at least 167 000 cardiac complications, of which 19 000 are life-threatening, due to non-cardiac surgical procedures annually. 2.2. Change in population demographics 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.4 In Europe, it is estimated that the number of patients undergoing surgery will increase by 25% by 2020. For the same time period, the elderly population will increase by 50%. The total number of surgical procedures may increase even faster because of the rising frequency of interventions with age.5 The results of the United States National Hospital Discharge Survey show that the number of surgical procedures will increase in almost all age groups, and that the largest increase will occur in the middle-aged and elderly. Demographics of patients undergoing surgery show a trend towards an increasing number of elderly patients and comorbidities.6 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 comorbidities in elderly patients presenting for general surgery, cardiovascular disease (CVD) is the most prevalent.7 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. Thus, these conditions should have greater impact on the evaluation of patient risk than age alone. 2.3. Purpose and organization These guidelines are intended for physicians and collaborators involved in the preoperative, operative and postoperative care of patients undergoing non-cardiac surgery. 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 that 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 provide the ideal evidence-base for the guidelines, are sparse. Consequently, when no trials are available on a specific cardiac-management regimen in the surgical setting, data from the non-surgical setting are extrapolated, and similar recommendations made, but with different levels of evidence. Anaesthesiologists, who are experts on the specific demands of the proposed surgical procedure, will usually coordinate the preoperative evaluation. The majority of patients with stable heart disease can undergo low and intermediate risk surgery (Table 3) without additional evaluation. Selected patients require evaluation by a team of integrated multidisciplinary specialists including anaesthesiologists, cardiologists and surgeons, and when appropriate an extended team (e.g. internists, intensivists, pulmonologists or geriatricians).8 Selected patients include those identified by the anaesthesiologist due to suspected or known cardiac disease with sufficient complexity to carry a potential perioperative risk (e.g. congenital heart disease, unstable symptoms or low functional capacity), patients in whom preoperative medical optimization is expected to reduce perioperative risk before low- and intermediate-risk surgery, and patients with known or high risk of cardiac disease undergoing high-risk surgery. Guidelines have the potential to improve postoperative outcomes and 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.Table 3: Surgical risk estimate according to type of surgery or interventiona,bBecause of the availability of new evidence and the international impact of the controversy regarding the DECREASE trials, the ESC/ESA and American College of Cardiology/American Heart Association both began the process of revising their respective guidelines concurrently. The respective writing committees independently performed their literature review and analysis, and then developed their recommendations. Once peer review of both guidelines was completed, the writing committees chose to discuss their respective recommendations regarding beta-blocker therapy and other relevant issues. Any differences in recommendations were discussed and clearly articulated in the text. However, the writing committees aligned a few recommendations to avoid confusion within the clinical community except where international practice variation was prevalent. Following the development and introduction of perioperative cardiac guidelines, their effect on outcome should be monitored. The objective evaluation of changes in outcome will form an essential part of future perioperative guideline development.Table: No title available.3. PREOPERATIVE EVALUATION 3.1. Surgical risk for cardiac events Cardiac complications after non-cardiac surgery depend on patient-related risk factors, on the type of surgery and on the circumstances under which it takes place.9 Surgical factors that influence cardiac risk are related to the urgency, invasiveness, type and duration of the procedure, as well as the change in body core temperature, blood loss, and fluid shifts.5 Every operation elicits a stress response. This response is initiated by tissue injury and mediated by neuroendocrine factors, and may induce sympatho-vagal imbalance. 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, potentially resulting in increased coronary thrombogenicity. The extent of such changes is proportionate to the extent and duration of the intervention. These factors, together with patient position, temperature management, bleeding, and type of anaesthesia may contribute to haemodynamic derangements leading to myocardial ischaemia and heart failure. General, locoregional and neuraxial anaesthesia differ regarding the stress response evoked by surgery. Less invasive anaesthetic techniques may reduce early mortality in patients at intermediate- to high-cardiac risk and limit postoperative complications.10 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.9 With regard to cardiac risk, surgical interventions, which include open or endovascular procedures, can be broadly divided into low-risk, intermediate-risk and high-risk groups, with estimated 30-day cardiac event rates (cardiac death and myocardial infarction) of <1%, 1–5%, and >5%, respectively (Table 3). The need for, and value of, preoperative 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 a perforated viscus, cardiac evaluation will not change the course and result of the intervention but may influence the management in the immediate perioperative period. In non-emergency but urgent surgical conditions such as bypass for acute limb ischaemia or treatment of bowel obstruction, the morbidity and mortality of the untreated underlying condition may 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 infrainguinal bypass, or extra-anatomical reconstruction instead of an aortic procedure, even when these may yield less favourable results in the long term. Finally, in some situations, the cardiac evaluation (in as far as it can reliably predict perioperative cardiac complications and late survival) should be taken into consideration when deciding whether to perform an intervention or manage conservatively. 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. 3.2. Type of surgery In general, endoscopic and endovascular techniques speed recovery, decrease hospital stay, and reduce the rate of complications.12 However, randomized clinical trials comparing laparoscopic with open techniques exclude older, sicker and urgent patients, and results from an expert-based randomized trial (laparoscopic versus open cholecystectomy) have shown no significant differences in conversion rate, pain, complications, length of hospital stay or readmissions.13 The wide variety of surgical procedures in a myriad of different contexts makes assigning a specific risk of a major adverse cardiac event to each procedure difficult. When alternative methods to the classical open surgery are considered, either through endovascular or less-invasive endoscopic procedures, the potential trade-offs between early benefits due to reduced morbidity and mid- to long-term efficacy need to be taken into account. 3.2.1. Endovascular versus open vascular procedures Vascular interventions are of specific interest, not only because they carry the highest risk of cardiac complications, but also because of the many studies that have shown that this risk can be influenced by adequate perioperative measures in these patients.14 Open aortic and infrainguinal procedures have both to be considered as high-risk procedures. Although it is a less-extensive intervention, infrainguinal revascularization entails a cardiac risk similar to or even higher than that of 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. Endovascular AAA repair (EV

Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols.We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with (15)O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT.Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy.To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve.A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin-labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results.Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD.Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve ≤0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88%-98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of specificity (P < .001) but not in terms of sensitivity (P > .99) using the predefined absolute margin of 10%. Diagnostic accuracy was highest for PET (85%; 95% CI, 80%-90%) compared with that of CCTA (74%; 95% CI, 67%-79%; P = .003) and SPECT (77%; 95% CI, 71%-83%; P = .02). Diagnostic accuracy was not enhanced by either hybrid SPECT and CCTA (76%; 95% CI, 70%-82%; P = .75) or by PET and CCTA (84%; 95% CI, 79%-89%; P = .82), but resulted in an increase in specificity (P = .004) at the cost of a decrease in sensitivity (P = .001).This controlled clinical head-to-head comparative study revealed PET to exhibit the highest accuracy for diagnosis of myocardial ischemia. Furthermore, a combined anatomical and functional assessment does not add incremental diagnostic value but guides clinical decision-making in an unsalutary fashion.

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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.

During the last 16 months, a Task Force established by the Guideline Committees of the European Society of Cardiology (ESC) and European Society of Anaesthesiology (ESA) has been working on a new Guideline document on cardiovascular assessment and management of patients undergoing non-cardiac surgery. The clinical scenario is common and the optimal management strategy for these patients is discussed by cardiologists, anaesthesiologists, surgeons, and other doctors and health personnel in our daily practice. The field is wide and complex, and is evolving with many new developments. The ESC decided in December 2012 to write a new Guideline on perioperative care, and established, together with the ESA, a new task force of experts co-chaired by Professor Steen D. Kristensen, Aarhus, Denmark ( Figure 1 ) and Professor Juhani Knuuti, Turku, Finland ( Figure 2 ). Figure 1 Professor Steen D. Kristensen. Figure 2 Professor Juhani Knuuti. The Guideline will cover the entire field including surgical risk assessment, pre-operative evaluation, and optimal perioperative management, and will also address relevant cardiological and anaesthesiological issues in patients with specific cardiac diseases and common co-morbidities scheduled to undergo non-cardiac surgery. The goal is to provide optimal guidance in the clinical decision-making process for patients undergoing non-cardiac surgery. Key areas with …

To investigate whether revascularisation improves prognosis compared with medical treatment among patients with stable coronary artery disease.Bayesian network meta-analyses to combine direct within trial comparisons between treatments with indirect evidence from other trials while maintaining randomisation.A strategy of initial medical treatment compared with revascularisation by coronary artery bypass grafting or Food and Drug Administration approved techniques for percutaneous revascularization: balloon angioplasty, bare metal stent, early generation paclitaxel eluting stent, sirolimus eluting stent, and zotarolimus eluting (Endeavor) stent, and new generation everolimus eluting stent, and zotarolimus eluting (Resolute) stent among patients with stable coronary artery disease.Medline and Embase from 1980 to 2013 for randomised trials comparing medical treatment with revascularisation.All cause mortality.100 trials in 93,553 patients with 262,090 patient years of follow-up were included. Coronary artery bypass grafting was associated with a survival benefit (rate ratio 0.80, 95% credibility interval 0.70 to 0.91) compared with medical treatment. New generation drug eluting stents (everolimus: 0.75, 0.59 to 0.96; zotarolimus (Resolute): 0.65, 0.42 to 1.00) but not balloon angioplasty (0.85, 0.68 to 1.04), bare metal stents (0.92, 0.79 to 1.05), or early generation drug eluting stents (paclitaxel: 0.92, 0.75 to 1.12; sirolimus: 0.91, 0.75 to 1.10; zotarolimus (Endeavor): 0.88, 0.69 to 1.10) were associated with improved survival compared with medical treatment. Coronary artery bypass grafting reduced the risk of myocardial infarction compared with medical treatment (0.79, 0.63 to 0.99), and everolimus eluting stents showed a trend towards a reduced risk of myocardial infarction (0.75, 0.55 to 1.01). The risk of subsequent revascularisation was noticeably reduced by coronary artery bypass grafting (0.16, 0.13 to 0.20) followed by new generation drug eluting stents (zotarolimus (Resolute): 0.26, 0.17 to 0.40; everolimus: 0.27, 0.21 to 0.35), early generation drug eluting stents (zotarolimus (Endeavor): 0.37, 0.28 to 0.50; sirolimus: 0.29, 0.24 to 0.36; paclitaxel: 0.44, 0.35 to 0.54), and bare metal stents (0.69, 0.59 to 0.81) compared with medical treatment.Among patients with stable coronary artery disease, coronary artery bypass grafting reduces the risk of death, myocardial infarction, and subsequent revascularisation compared with medical treatment. All stent based coronary revascularisation technologies reduce the need for revascularisation to a variable degree. Our results provide evidence for improved survival with new generation drug eluting stents but no other percutaneous revascularisation technology compared with medical treatment.

Ectopic fat accumulation within and around the myocardial wall has been implicated in the pathogenesis of heart disease in obesity. We evaluated myocardial and epicardial fat, left ventricular (LV) function, and metabolic risk factors in nine (five lean, four moderately obese) men.Myocardial fat percent was quantified in the septum by proton magnetic resonance spectroscopy. Reproducibility was assessed by triplicate systolic and diastolic measurements. LV parameters and epicardial fat were determined by magnetic resonance imaging. Waist-to-hip ratio and liver enzymes (alanine transaminase) were used as surrogate markers of visceral and liver fat contents.Myocardial fat (2.1 +/- 0.5 vs. 0.8 +/- 0.1, P = 0.03) and epicardial fat (120 +/- 33 vs. 55 +/- 12 g, P = 0.08) were higher in obese than lean subjects. Individuals with above-median alanine transaminase values had a 4-fold elevation in myocardial fat. The coefficient of variation of repeated myocardial fat percent determinations was 17 +/- 3 and 23 +/- 3% in systole and diastole, respectively. Myocardial fat was correlated with free fatty acid (FFA) levels (r = 0.76; P = 0.017), epicardial fat (r = 0.69; P = 0.042), and waist-to-hip ratio (r = 0.70; P = 0.035), and it showed a tendency to associate positively with LV work. Epicardial fat was associated with peripheral vascular resistance (positively) and the cardiac index (negatively). FFA levels were significantly correlated with LV mass (r = 0.72; P = 0.030) and forward work (r = 0.74; P = 0.023).The accumulation of triglyceride in and around the myocardium of moderately obese individuals is significant, and it is related to FFA exposure, generalized ectopic fat excess, and peripheral vascular resistance. These changes precede LV overload and hypertrophy.

The benefits of cardiac imaging are immense, and modern medicine requires the extensive and versatile use of a variety of cardiac imaging techniques. Cardiologists are responsible for a large part of the radiation exposures every person gets per year from all medical sources. Therefore, they have a particular responsibility to avoid unjustified and non-optimized use of radiation, but sometimes are imperfectly aware of the radiological dose of the examination they prescribe or practice. This position paper aims to summarize the current knowledge on radiation effective doses (and risks) related to cardiac imaging procedures. We have reviewed the literature on radiation doses, which can range from the equivalent of 1-60 milliSievert (mSv) around a reference dose average of 15 mSv (corresponding to 750 chest X-rays) for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multidetector coronary angiography, or a myocardial perfusion imaging scintigraphy. We provide a European perspective on the best way to play an active role in implementing into clinical practice the key principle of radiation protection that: 'each patient should get the right imaging exam, at the right time, with the right radiation dose'.

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.

The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD.A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001).In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively.http://www.clinicaltrials.gov. Unique identifier: NCT00979199.

Fractional flow reserve (FFR) computation from coronary computed tomography angiography (CTA) datasets (FFRCT) has emerged as a promising noninvasive test to assess hemodynamic severity of coronary artery disease (CAD), but has not yet been compared with traditional functional imaging.The purpose of this study was to evaluate the diagnostic performance of FFRCT and compare it with coronary CTA, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) for ischemia diagnosis.This subanalysis involved 208 prospectively included patients with suspected stable CAD, who underwent 256-slice coronary CTA, 99mTc-tetrofosmin SPECT, [15O]H2O PET, and routine 3-vessel invasive FFR measurements. FFRCT values were retrospectively derived from the coronary CTA images. Images from each modality were interpreted by core laboratories, and their diagnostic performances were compared using invasively measured FFR ≤0.80 as the reference standard.In total, 505 of 612 (83%) vessels could be evaluated with FFRCT. FFRCT showed a diagnostic accuracy, sensitivity, and specificity of 87%, 90%, and 86% on a per-vessel basis and 78%, 96%, and 63% on a per-patient basis, respectively. Area under the receiver-operating characteristic curve (AUC) for identification of ischemia-causing lesions was significantly greater for FFRCT (0.94 and 0.92) in comparison with coronary CTA (0.83 and 0.81; p < 0.01 for both) and SPECT (0.70 and 0.75; p < 0.01 for both), on a per-vessel and -patient level, respectively. FFRCT also outperformed PET on a per-vessel basis (AUC 0.87; p < 0.01), but not on a per-patient basis (AUC 0.91; p = 0.56). In the intention-to-diagnose analysis, PET showed the highest per-patient and -vessel AUC followed by FFRCT (0.86 vs. 0.83; p = 0.157; and 0.90 vs. 0.79; p = 0.005, respectively).In this study, FFRCT showed higher diagnostic performance than standard coronary CTA, SPECT, and PET for vessel-specific ischemia, provided coronary CTA images were evaluable by FFRCT, whereas PET had a favorable performance in per-patient and intention-to-diagnose analysis. Still, in patients in whom 3-vessel FFRCT could be analyzed, FFRCT holds clinical potential to provide anatomic and hemodynamic significance of coronary lesions.

Acute coronary syndromes Bare-metal stents Coronary artery bypass grafting Coronary artery disease Drug-eluting stents EuroSCORE Guidelines Heart Team Myocardial infarction Myocardial ischaemia Myocardial revascularization Medical therapy Percutaneous coronary intervention Recommendation Revascularisation Risk stratification Stents Stable angina Stable coronary artery disease ST-segment elevation myocardial infarction SYNTAX score

Recent studies have demonstrated improved diagnostic accuracy for detecting coronary artery disease (CAD) when myocardial blood flow (MBF) is quantified in absolute terms, but there are no uniformly accepted cutoff values for hemodynamically significant CAD. The goal of this study was to determine cutoff values for absolute MBF and to evaluate the diagnostic accuracy of quantitative [15O]H2O positron emission tomography (PET). A total of 330 patients underwent both quantitative [15O]H2O PET imaging and invasive coronary angiography in conjunction with fractional flow reserve measurements. A stenosis >90% and/or fractional flow reserve ≤0.80 was considered obstructive; a stenosis <30% and/or fractional flow reserve >0.80 was nonobstructive. Hemodynamically significant CAD was diagnosed in 116 (41%) of 281 patients who fulfilled study criteria for CAD. Resting perfusion was 1.00 ± 0.25 and 0.92 ± 0.23 ml/min/g in regions supplied by nonstenotic and significantly stenosed vessels, respectively (p < 0.001). During stress, perfusion increased to 3.26 ± 1.04 ml/min/g and 1.73 ± 0.67 ml/min/g, respectively (p < 0.001). The optimal cutoff values were 2.3 and 2.5 for hyperemic MBF and myocardial flow reserve, respectively. For MBF, these cutoff values showed a sensitivity, specificity, and accuracy for detecting significant CAD of 89%, 84%, and 86%, respectively, at a per-patient level and 87%, 85%, and 85% at a per-vessel level. The corresponding myocardial flow reserve values were 86%, 72%, and 78% (per patient) and 80%, 82%, and 81% (per vessel). Age and sex significantly affected diagnostic accuracy of quantitative PET. Quantitative MBF measurements with the use of [15O]H2O PET provided high diagnostic performance, but both sex and age should be taken into account.

To develop prediction models that better estimate the pretest probability of coronary artery disease in low prevalence populations.Retrospective pooled analysis of individual patient data.18 hospitals in Europe and the United States.Patients with stable chest pain without evidence for previous coronary artery disease, if they were referred for computed tomography (CT) based coronary angiography or catheter based coronary angiography (indicated as low and high prevalence settings, respectively).Obstructive coronary artery disease (≥ 50% diameter stenosis in at least one vessel found on catheter based coronary angiography). Multiple imputation accounted for missing predictors and outcomes, exploiting strong correlation between the two angiography procedures. Predictive models included a basic model (age, sex, symptoms, and setting), clinical model (basic model factors and diabetes, hypertension, dyslipidaemia, and smoking), and extended model (clinical model factors and use of the CT based coronary calcium score). We assessed discrimination (c statistic), calibration, and continuous net reclassification improvement by cross validation for the four largest low prevalence datasets separately and the smaller remaining low prevalence datasets combined.We included 5677 patients (3283 men, 2394 women), of whom 1634 had obstructive coronary artery disease found on catheter based coronary angiography. All potential predictors were significantly associated with the presence of disease in univariable and multivariable analyses. The clinical model improved the prediction, compared with the basic model (cross validated c statistic improvement from 0.77 to 0.79, net reclassification improvement 35%); the coronary calcium score in the extended model was a major predictor (0.79 to 0.88, 102%). Calibration for low prevalence datasets was satisfactory.Updated prediction models including age, sex, symptoms, and cardiovascular risk factors allow for accurate estimation of the pretest probability of coronary artery disease in low prevalence populations. Addition of coronary calcium scores to the prediction models improves the estimates.

The aim of this study was to compare fully quantitative cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) myocardial perfusion and myocardial perfusion reserve (MPR) measurements in patients with coronary artery disease (CAD). Absolute quantification of myocardial perfusion and MPR with PET have proven diagnostic and prognostic roles in patients with CAD. Quantitative CMR perfusion imaging has been established more recently and has been validated against PET in normal hearts. However, there are no studies comparing fully quantitative CMR against PET perfusion imaging in patients with CAD. Forty-one patients with known or suspected CAD prospectively underwent quantitative 13N-ammonia PET and CMR perfusion imaging before coronary angiography. The CMR-derived MPR (MPRCMR) correlated well with PET-derived measurements (MPRPET) (r = 0.75, p < 0.0001). MPRCMR and MPRPET for the 2 lowest scoring segments in each coronary territory also correlated strongly (r = 0.79, p < 0.0001). Absolute CMR perfusion values correlated significantly, but weakly, with PET values both at rest (r = 0.32; p = 0.002) and during stress (r = 0.37; p < 0.0001). Area under the receiver-operating characteristic curve for MPRPET to detect significant CAD was 0.83 (95% confidence interval: 0.73 to 0.94) and for MPRCMR was 0.83 (95% confidence interval: 0.74 to 0.92). An MPRPET ≤1.44 predicted significant CAD with 82% sensitivity and 87% specificity, and MPRCMR ≤1.45 predicted significant CAD with 82% sensitivity and 81% specificity. There is good correlation between MPRCMR and MPRPET. For the detection of significant CAD, MPRPET and MPRCMR seem comparable and very accurate. However, absolute perfusion values from PET and CMR are only weakly correlated; therefore, although quantitative CMR is clinically useful, further refinements are still required.

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In the diagnosis of obstructive coronary artery disease (CAD), computed tomography (CT) is an accurate, noninvasive alternative to invasive coronary angiography (ICA). However, the comparative effectiveness of CT and ICA in the management of CAD to reduce the frequency of major adverse cardiovascular events is uncertain.We conducted a pragmatic, randomized trial comparing CT with ICA as initial diagnostic imaging strategies for guiding the treatment of patients with stable chest pain who had an intermediate pretest probability of obstructive CAD and were referred for ICA at one of 26 European centers. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. Key secondary outcomes were procedure-related complications and angina pectoris.Among 3561 patients (56.2% of whom were women), follow-up was complete for 3523 (98.9%). Major adverse cardiovascular events occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 (3.0%) in the ICA group (hazard ratio, 0.70; 95% confidence interval [CI], 0.46 to 1.07; P = 0.10). Major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13 to 0.55). Angina during the final 4 weeks of follow-up was reported in 8.8% of the patients in the CT group and in 7.5% of those in the ICA group (odds ratio, 1.17; 95% CI, 0.92 to 1.48).Among patients referred for ICA because of stable chest pain and intermediate pretest probability of CAD, the risk of major adverse cardiovascular events was similar in the CT group and the ICA group. The frequency of major procedure-related complications was lower with an initial CT strategy. (Funded by the European Union Seventh Framework Program and others; DISCHARGE ClinicalTrials.gov number, NCT02400229.).

Advances of cardiac computed tomography angiography (CTA) have been developed for dose reduction, but their efficacy in clinical practice is largely unknown. This study was designed to evaluate radiation dose exposure and utilization of dose-saving strategies for contrast-enhanced cardiac CTA in daily practice. Sixty one hospitals from 32 countries prospectively enrolled 4502 patients undergoing cardiac CTA during one calendar month in 2017. Computed tomography angiography scan data and images were analysed in a central core lab and compared with a similar dose survey performed in 2007. Linear regression analysis was performed to identify independent predictors associated with dose. The most frequent indication for cardiac CTA was the evaluation of coronary artery disease in 89% of patients. The median dose-length product (DLP) of coronary CTA was 195 mGy*cm (interquartile range 110–338 mGy*cm). When compared with 2007, the DLP was reduced by 78% (P < 0.001) without an increase in non-diagnostic coronary CTAs (1.7% in 2007 vs. 1.9% in 2017 surveys, P = 0.55). A 37-fold variability in median DLP was observed between the hospitals with lowest and highest DLP (range of median DLP 57–2090 mGy*cm). Independent predictors for radiation dose of coronary CTA were: body weight, heart rate, sinus rhythm, tube voltage, iterative image reconstruction, and the selection of scan protocols. This large international radiation dose survey demonstrates considerable reduction of radiation exposure in coronary CTA during the last decade. However, the large inter-site variability in radiation exposure underlines the need for further site-specific training and adaptation of contemporary cardiac scan protocols.

Abstract Nearly half of all patients with heart failure (HF) have a normal left ventricular (LV) ejection fraction (EF) and the condition is termed heart failure with preserved ejection fraction (HFpEF). It is assumed that in these patients HF is due primarily to LV diastolic dysfunction. The prognosis in HFpEF is almost as severe as in HF with reduced EF (HFrEF). In contrast to HFrEF where drugs and devices are proven to reduce mortality, in HFpEF there has been limited therapy available with documented effects on prognosis. This may reflect that HFpEF encompasses a wide range of different pathological processes, which multimodality imaging is well placed to differentiate. Progress in developing therapies for HFpEF has been hampered by a lack of uniform diagnostic criteria. The present expert consensus document from the European Association of Cardiovascular Imaging (EACVI) provides recommendations regarding how to determine elevated LV filling pressure in the setting of suspected HFpEF and how to use multimodality imaging to determine specific aetiologies in patients with HFpEF.

Abstract Aims To provide a pooled estimation of contemporary pre-test probabilities (PTPs) of significant coronary artery disease (CAD) across clinical patient categories, re-evaluate the utility of the application of diagnostic techniques according to such estimates, and propose a comprehensive diagnostic technique selection tool for suspected CAD. Methods and results Estimates of significant CAD prevalence across sex, age, and type of chest pain categories from three large-scale studies were pooled (n = 15 815). The updated PTPs and diagnostic performance profiles of exercise electrocardiogram, invasive coronary angiography, coronary computed tomography angiography (CCTA), positron emission tomography (PET), stress cardiac magnetic resonance (CMR), and SPECT were integrated to define the PTP ranges in which ruling-out CAD is possible with a post-test probability of &amp;lt;10% and &amp;lt;5%. These ranges were then integrated in a new colour-coded tabular diagnostic technique selection tool. The Bayesian relationship between PTP and the rate of diagnostic false positives was explored to complement the characterization of their utility. Pooled CAD prevalence was 14.9% (range = 1–52), clearly lower than that used in current clinical guidelines. Ruling-out capabilities of non-invasive imaging were good overall. The greatest ruling-out capacity (i.e. post-test probability &amp;lt;5%) was documented by CCTA, PET, and stress CMR. With decreasing PTP, the fraction of false positive findings rapidly increased, although a lower CAD prevalence partially cancels out such effect. Conclusion The contemporary PTP of significant CAD across symptomatic patient categories is substantially lower than currently assumed. With a low prevalence of the disease, non-invasive testing can rarely rule-in the disease and focus should shift to ruling-out obstructive CAD. The large proportion of false positive findings must be taken into account when patients with low PTP are investigated.

Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials.

Positron emission tomography permits noninvasive measure- ment of regional glucose uptake in vivo in humans.We em- ployed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles.Six normal men were studied twice under euglycemic hyperinsulinemic (serum insu- lin -500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0±0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1±0.01mmol/liter).Regional glucose uptake rates were measured using positron emission tomography-derived 'F- fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L.,

To elucidate the role of adipose tissue glucose uptake in whole-body metabolism, sc and visceral adipose tissue glucose uptake and perfusion were measured in 10 nonobese and 10 age-matched obese men with positron emission tomography using [(18)F]-2-fluoro-2-deoxy-D-glucose, and [(15)O]-labeled water during normoglycemic hyperinsulinemia. Whole-body and skeletal muscle glucose uptake rates per kilogram were lower in obese than in nonobese subjects (P < 0.01). Compared with nonobese, the obese subjects had 67% lower abdominal sc and 58% lower visceral adipose tissue glucose uptake per kilogram of fat. In both groups, insulin stimulated glucose uptake per kilogram fat was significantly higher in visceral fat depots than in sc regions (P < 0.01). Both sc and visceral adipose tissue blood flow expressed per kilogram and minute was impaired in the obese subjects, compared with the nonobese (P < 0.05). Fat masses measured with magnetic resonance images were higher in obese than in nonobese individuals. If regional glucose uptake rates were expressed as per total fat mass, total glucose uptake rates per depot were similar in obese and nonobese subjects and represented 4.1% of whole-body glucose uptake in obese and 2.6% in nonobese subjects (P < 0.02 between the groups). In conclusion, insulin-stimulated glucose uptake per kilogram fat is higher in visceral than in sc adipose tissue. Glucose uptake and blood flow in adipose tissue exhibit insulin resistance in obesity, but because of the larger fat mass, adipose tissue does not seem to contribute substantially to the reduced insulin stimulated whole-body glucose uptake in obesity.

Background— The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy. Methods and Results— Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [ 15 O]H 2 O, [ 11 C]acetate, and [ 11 C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9±8.5% to 34.8±12% ( P =0.027 versus placebo). Myocardial FFA uptake was unchanged, and β-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9±0.7 versus 5.5±0.6 mmol/L, P =0.047; insulin: 10±6.9 versus 7.6±3.6 mU/L, P =0.031; homeostasis model assessment index: 2.75±2.28 versus 1.89±1.06, P =0.027). The degree of β-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% ( P &lt;0.001). Conclusions— In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater β1-adrenoceptor occupancy, suggesting a synergistic mechanism.

To assess the efficacy and safety of bone marrow cell (BMC) therapy after thrombolytic therapy of an acute ST-elevation myocardial infarction (STEMI).Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI) 2-6 days after STEMI were randomly assigned to receive intracoronary BMCs (n = 40) or placebo medium (n = 40), collected and prepared 3-6 h prior PCI and injected into the infarct artery immediately after stenting. Efficacy was assessed by the measurement of global left ventricular ejection fraction (LVEF) by left ventricular angiography and 2-D echocardiography, and safety by measuring arrhythmia risk variables and restenosis of the stented vessel by intravascular ultrasound. At 6 months, BMC group had a greater absolute increase of global LVEF than placebo group, measured either by angiography (mean +/- SD increase 7.1 +/- 12.3 vs. 1.2 +/- 11.5%, P = 0.05) or by 2-D echocardiography (mean +/- SD increase 4.0 +/- 11.2 vs. -1.4 +/- 10.2%, P = 0.03). No differences were observed between the groups in the adverse clinical events, arrhythmia risk variables, or the minimal lumen diameter of the stented coronary lesion.Intracoronary BMC therapy is associated with an improvement of global LVEF and neutral effects on arrhythmia risk profile and restenosis of the stented coronary lesions in patients after thrombolytic therapy of STEMI.

Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM).Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8+/-8.0 years, ejection fraction 33+/-8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate-pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071+/-0.019 to 0.055+/-0.016 min(-1), P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4+/-12.6 to 31.6+/-13.3 mm Hg x L x g(-1), P<0.05).Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.

Disturbances of coronary circulation have been reported in diabetic patients with microvascular complications but without obstructive coronary atherosclerosis. The aim of the present study was to investigate coronary flow reserve in young adult patients with IDDM but without microalbuminuria and diabetic autonomic neuropathy. Coronary flow reserve was determined in 12 nonsmoking male patients with IDDM (age 30.0 +/- 6.6 years) and 12 healthy matched volunteers. Groups were similar with respect to blood pressure and serum lipid concentrations, and no subject had a positive family history of coronary heart disease. The patients with IDDM had normal exercise echocardiography and autonomic nervous function tests. Five patients had minimal background retinopathy, and none had microalbuminuria. Positron emission tomography and [15O]H2O were used to measure myocardial blood flow at rest and after dipyridamole administration. The studies were performed during euglycemic hyperinsulinemia (serum insulin approximately 70 mU/l). The baseline myocardial blood flow was similar in patients with IDDM and in control subjects (0.84 +/- 0.18 vs. 0.88 +/- 0.25 ml x g(-1) x min(-1), NS). The myocardial blood flow during hyperemia was 29% lower in patients with IDDM (3.17 +/- 1.57) compared with the control subjects (4.45 +/- 1.37 ml x g(-1) x min(-1), P < 0.05). Consequently, coronary flow reserve (the ratio of flow during hyperemia and at rest) was lower in diabetic patients than in control subjects (3.76 +/- 1.69 vs. 5.31 +/- 1.86, P < 0.05) and the total coronary resistance during hyperemia was higher in diabetic patients (53.7 +/- 31.5) compared with the control subjects (31.4 +/- 11.6 mmHg x min x g x ml(-1), P < 0.05). The coronary flow reserve was similar in diabetic patients with and without mild background retinopathy. No association was found between the coronary flow reserve and serum lipid or HbA1c values in either group. Coronary flow reserve is impaired in young adult males with IDDM and no or minimal microvascular complications and without any evidence of coronary heart disease. This abnormality cannot be explained by standard coronary heart disease risk factors. The results imply early impairment of coronary vascular reactivity in IDDM patients, which may represent an early precursor of future coronary heart disease or may contribute to the pathogenesis of diabetic cardiomyopathy.

The purpose of this study was to investigate whether functional abnormalities in coronary vasomotion are present in young healthy asymptomatic men fulfilling the World Health Organization (WHO) criteria for borderline hypertension.Previous studies have reported reduced coronary flow reserve in middle-aged subjects with sustained hypertension and hypertension-induced microvascular heart disease or left ventricular hypertrophy.Myocardial blood flow was measured at baseline and during dipyridamole-induced hyperemia by means of positron emission tomography and oxygen-15-labeled water in asymptomatic young men with borderline hypertension (group 1: n = 16, mean +/- SD age 37 +/- 4 years, 24-h ambulatory blood pressure 135 +/- 10/81 +/- 9 mm Hg) and matched healthy control subjects (group 2: n = 19, age 35 +/- 3 years, 24-h ambulatory blood pressure 119 +/- 8/69 +/- 8 mm Hg, p < 0.001). Left ventricular (LV) mass, dimensions and function were measured by echocardiography.LV mass, dimensions and diastolic function were similar in the study groups. Baseline myocardial blood flow was similar (0.83 +/- 0.21 vs. 0.80 +/- 0.22 ml/g per min, group 1 vs. group 2, respectively, p = NS), and a significant increase in flow was detected after dipyridamole infusion (0.56 mg/kg body weight in 4 min intravenously) in both groups. However, the flow response to dipyridamole was significantly lower in group 1, leading to lower hyperemic flow in group 1 than in group 2 (2.85 +/- 1.20 vs. 3.80 +/- 1.44 ml/g per min, respectively). Consequently, the coronary flow response was lower in hypertensive than in normotensive men (3.46 +/- 1.23 vs. 4.99 +/- 2.5 ml/g per min, group 1 vs. group 2, respectively, p < 0.05).These results demonstrate reduced coronary reactivity present in young asymptomatic men with borderline hypertension and no signs of hypertension-induced angina or left ventricular hypertrophy. Because baseline basal myocardial blood flow was unchanged, the reduction in coronary flow reserve depends on an impaired maximal vasodilator capacity.

Encouraged by the clinical success of cardiac resynchronization therapy (CRT), the implantation rate has increased exponentially, although several limitations and unresolved issues of CRT have been identified. This review concerns issues that are encountered during implantation of CRT devices, including the role of electroanatomical mapping, whether CRT implantation should be accompanied by simultaneous atrioventricular nodal ablation in patients with atrial fibrillation, procedural complications, and when to consider surgical left ventricular lead positioning. Furthermore, (echocardiographic) CRT optimization and assessment of CRT benefits after implantation are highlighted. Also, controversial issues such as the potential value of CRT in patients with mild heart failure or narrow QRS complex are addressed. Finally, open questions concerning when to combine CRT with implantable cardioverter-defibrillator therapy and the cost-effectiveness of CRT are discussed.

Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 +/- 2 years, body mass index [BMI] 22 +/- 1 kg/m2, VO2max 39 +/- 4 ml.kg-1.min-1) and men matched for age (31 +/- 2 years), BMI (23 +/- 1 kg/m2), and VO2max (44 +/- 3 ml.kg-1.min-1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU.kg-1.min-1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 +/- 6 mumol.kg body wt-1.min-1) than in men (37 +/- 3 mumol.kg body wt-1.min-1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 +/- 10 vs. 77 +/- 7 mumol.kg muscle-1.min-1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 +/- 58) and men (749 +/- 62 mumol.kg muscle-1.min-1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

Detection of early vascular changes indicated by lowered coronary flow reserve (CFR) would allow early treatment and prevention of atherosclerosis. The purpose of this study was to test whether it is possible to reproducibly measure CFR with transthoracic Doppler echocardiography (TTE) in healthy volunteers. We measured CFR using dipyridamole infusion in ten healthy male volunteers with two methods: TTE and positron emission tomography (PET) with oxygen-15-labelled water (group A). However, CFR was assessed twice with TTE in eight healthy male volunteers (group B) to study the reproducibility of this method. We compared CFRs obtained using TTE flow measurements in the left anterior descending coronary artery (LAD) and PET flow measurements in the corresponding myocardial area. Coronary flow in LAD could be measured in all subjects using TTE. By TTE, an average CFR based on peak diastolic flow velocity (PDV) was 2.72 +/- 1.16, mean diastolic flow velocity (MDV) 2.56 +/- 1.06 and velocity time integral (VTI) 1.87 +/- 0.49. The results were reproducible in two repeated TTE studies (coefficient of variation in MDV 6.1 +/- 4.3%, n=8). By PET, CFR was 2.52 +/- 0.84. CFR assessed by TTE correlated closely with that measured by PET (MDV r=0.942, P<0.001; PDV r=0.912, P<0.002 and VTI r=0.888, P<0.006) and intraclass correlation was 0.929 (MDV) and tolerance limits for differences of CFRs was -0.78 to 0.72. We show that CFR measured by TTE has an excellent correlation with CFR measured by PET. We also found that TTE measurements of CFR were highly reproducible.

We sought to investigate whether functional abnormalities in coronary vasomotion exist in young adults by studying 15 men (age 31 ± 8 years [mean ± SD]) with familial hypercholesterolemia (FH) and a matched group of 20 healthy control subjects. Precursors of morphologic coronary artery disease are known to be present in adolescents and young adults with a high risk factor profile. Myocardial blood flow was measured at the basal state and during dipyridamole-induced hyperemia using positron emission tomography and oxygen-15 llabeled water. Serum total and low density lipoprotein cholesterol concentrations were higher in the patients than in the control subjects (mean ± SD): 7.7 ± 1.9 versus 5.3 ± 1.5 mmol/liter (298 ± 73 vs. 205 ± 58 mg/dl) and 6.1 ± 1.8 versus 3.5 ± 1.4 mmol/liter (236 ± 70 vs. 135 ± 54 mg/dl), respectively (both p < 0.001). The baseline myocardial blood flow was similar in the patients and control subjects: 0.92 ± 0.24 versus 0.83 ± 0.13 ml/g per min, respectively (p = 0.21). A significant increase in flow was observed in both groups after dipyridamole infusion, but the flow at maximal vasodilation was 29% lower in the patients: 3.19 ± 1.59 versus 4.49 ± 1.27 ml/g per min (p = 0.011). Consequently, coronary flow reserve (the ratio of hyperemia flow to basal flow) was 35% lower in the patients than in the control subjects: 3.5 ± 1.6 versus 5.4 ± 1.5 (p = 0.0008). Total coronary resistance during hyperemia was higher in the patients than in the control subjects: 36 ± 25 versus 21 ± 10 mm Hg/min per g per ml (p = 0.045). Coronary flow reserve was inversely associated with serum total cholesterol concentration: r =−0.43 (p = 0.009). Coronary flow reserve is reduced in young men with FH, and, consequently, coronary resistance during hyperemia is increased. The results demonstrate very early impairment of coronary vasomotion in hypercholesterolemic patients.

heart is an aerobic organ that relies almost exclusively on the aerobic oxidation of substrates for generation of energy.Consequently, there is close coupling between myocardial oxygen consumption (MV ˙O2 ) and the main determinants of systolic function: heart rate, contractile state, and wall stress. 1 As in any mechanical pump, only part of the energy invested is converted to external power.In the case of the heart, the ratio of useful energy produced (ie, stroke work [SW]) to oxygen consumed is defined as mechanical efficiency, as originally proposed by Bing et al. 2 Under normal conditions this ratio is Ϸ25%, and the residual energy mainly dissipates as heat. 3In pathophysiological disease states, such as heart failure, mechanical efficiency is reduced, and it has been hypothesized that the increased energy expenditure relative to work contributes to progression of the disease. 4,5Moreover, therapeutic interventions that enhance mechanical efficiency have proven to be beneficial with respect to outcome. 6It is therefore desirable to quantify efficiency of the heart to study disease processes and monitor interventions.Both cardiac oxidative metabolism and mechanical work, and thus efficiency, can be quantified through invasive measurements.Although these measurements are accurate and currently considered the gold standard, in clinical practice they are limited because of the need for dual-sided heart catheterization and selective catheterization of the coronary sinus.Recent advances in imaging techniques, however, offer the possibility to noninvasively estimate MV ˙O2 and mechanical work by positron emission tomography and echocardiography or by magnetic resonance imaging, respectively.This review discusses the principles of mechanical efficiency, together with its invasive and noninvasive assessment, as well as their strengths and pitfalls.Finally, results from clinical pathophysiological studies are discussed.

Background— Disturbances of autonomic function after infarction are associated with both total mortality and sudden death. Although many imaging techniques for assessing the cardiac autonomic nervous system have been studied, the clinical usefulness of these techniques remains uncertain. This exploratory pilot study examined the relationship between abnormalities of ventricular sympathetic innervation delineated by scintigraphic imaging with 123 I- m IBG and inducible ventricular tachyarrhythmias in patients with left ventricular dysfunction and previous myocardial infarction. Methods and Results— Fifty patients underwent electrophysiological (EP) testing and 15-minute and 4-hour planar and single photon emission computed tomography (SPECT) imaging with 123 I- m IBG and SPECT imaging with 99m Tc-tetrofosmin. The primary efficacy variables were the 4-hour heart:mediastinum ratio (H/M) and the 123 I- m IBG/ 99m Tc-tetrofosmin SPECT mismatch score. EP studies were categorized as positive (EP + ) or negative (EP − ) for inducibility of sustained (&gt;30 seconds) ventricular tachyarrhythmias. Thirty patients were EP + , and 20 were EP − . There were no significant differences in the 4-hour H/M ratios or 123 I- m IBG/ 99m Tc-tetrofosmin SPECT mismatch scores between the two groups. In a multivariable analysis using all 123 I- m IBG and 99m Tc-tetrofosmin SPECT measurements, the only variable that showed a significant difference between EP + and EP − patients was the 4-hour 123 I- m IBG SPECT defect score. A 4-hour 123 I- m IBG SPECT defect score of ≥37 yielded a sensitivity of 77% and specificity of 75% for predicting EP results. Conclusions— The standard indices of 123 I- m IBG imaging (H/M and innervation-perfusion mismatch score) are not predictive of EP test results. The association of 123 I- m IBG SPECT defect severity with EP test inducibility in this exploratory study will require confirmation in a larger cohort of patients.

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6+/-4.6 versus 26.1+/-5.0 micromol (100 g)-1 min-1, P<0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P<0.05 between 30% and 75% of VO2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Background— The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow and compared that with relative uptake. Methods and Results— One hundred four patients with moderate (30%–70%) pretest likelihood of coronary artery disease (CAD) underwent PET imaging during adenosine stress using 15 O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis. Conclusions— The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation of myocardial perfusion. As expected, multivessel disease is more accurately detected. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00627172.

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [ 15 O]H 2 O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[ 18 F]fluoro-d-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 ± 2.0%) and high (17.4 ± 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level ( P = 0.012) and muscle ( P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake ( P = 0.040) and glucose extraction rate ( P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 ( P &lt; 0.05) and lower coronary flow reserve ( P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.

<h3>Background & Aims</h3> Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined ¹¹C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings. <h3>Methods</h3> Anesthetized pigs underwent ¹¹C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma ¹¹C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis. <h3>Results</h3> In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean ± standard error of the mean, 0.16 ± 0.01 vs 0.08 ± 0.01 μmol/min/mL; <i>P</i> = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, <i>P</i> = .016), adipose tissue (r = 0.58, <i>P</i> = .024), and systemic insulin resistance (r = 0.62, <i>P</i> = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, <i>P</i> = .003). <h3>Conclusions</h3> PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

The purpose of this study was to compare myocardial blood flow (MBF) and myocardial flow reserve (MFR) estimates from rubidium-82 positron emission tomography (82Rb PET) data using 10 software packages (SPs) based on 8 tracer kinetic models. It is unknown how MBF and MFR values from existing SPs agree for 82Rb PET. Rest and stress 82Rb PET scans of 48 patients with suspected or known coronary artery disease were analyzed in 10 centers. Each center used 1 of 10 SPs to analyze global and regional MBF using the different kinetic models implemented. Values were considered to agree if they simultaneously had an intraclass correlation coefficient >0.75 and a difference <20% of the median across all programs. The most common model evaluated was the Ottawa Heart Institute 1-tissue compartment model (OHI-1-TCM). MBF values from 7 of 8 SPs implementing this model agreed best. Values from 2 other models (alternative 1-TCM and Axially distributed) also agreed well, with occasional differences. The MBF results from other models (e.g., 2-TCM and retention) were less in agreement with values from OHI-1-TCM. SPs using the most common kinetic model—OHI-1-TCM—provided consistent results in measuring global and regional MBF values, suggesting that they may be used interchangeably to process data acquired with a common imaging protocol.

Background— 18 F-Galacto-RGD is a positron emission tomography (PET) tracer binding to α v β 3 integrin that is expressed by macrophages and endothelial cells in atherosclerotic lesions. Therefore, we evaluated 18 F-galacto-RGD for imaging vascular inflammation by studying its uptake into atherosclerotic lesions of hypercholesterolemic mice in comparison to deoxyglucose. Methods and results— Hypercholesterolemic LDLR −/− ApoB 100/100 mice on a Western diet and normally fed adult C57BL/6 control mice were injected with 18 F-galacto-RGD and 3 H-deoxyglucose followed by imaging with a small animal PET/CT scanner. The aorta was dissected 2 hours after tracer injection for biodistribution studies, autoradiography, and histology. Biodistribution of 18 F-galacto-RGD was higher in the atherosclerotic than in the normal aorta. Autoradiography demonstrated focal 18 F-galacto-RGD uptake in the atherosclerotic plaques when compared with the adjacent normal vessel wall or adventitia. Plaque-to-normal vessel wall ratios were comparable to those of deoxyglucose. Although angiogenesis was not detected, 18 F-galacto-RGD uptake was associated with macrophage density and deoxyglucose accumulation in the plaques. Binding to atherosclerotic lesions was efficiently blocked in competition experiments. In vivo imaging visualized 18 F-galacto-RGD uptake colocalizing with calcified lesions of the aortic arch as seen in CT angiography. Conclusions— 18 F-Galacto-RGD demonstrates specific uptake in atherosclerotic lesions of mouse aorta. In this model, its uptake was associated with macrophage density. 18 F-Galacto-RGD is a potential tracer for noninvasive imaging of inflammation in atherosclerotic lesions.

The hypothesis proposed is that heart failure (HF) is associated with a reactive hyperadrenergic state that increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. We propose that increased FFA-induced mitochondrial uncoupling and substantial oxygen wastage is closely associated with the generation of reactive oxygen species, inflammatory markers, and the development of insulin resistance. The therapeutic aims of metabolic therapy are as follows: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are achieved, respectively, by the following: 1) the use of beta-adrenergic blockade and all measures that relieve the mechanical load on the heart; 2) the use of drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline), although without clinical evidence that the heart is their major site of action in HF; and 3) increase of the transport of glucose into the cells by exercise and metformin. Of these measures, only data concerning the reduction of mortality as the result of exercise are available. Of all the other measures, there are substantial positive data on the use of trimetazidine that demonstrate metabolic and clinical benefit with almost no side effects, but data from a large outcome trial are lacking. Our data suggest a major extracardiac site of trimetazidine action. Ranolazine, which inhibits the late sodium inward current, requires testing in human HF. Insulin to reduce hyperglycemia and FFAs is untested in HF, with incretins such as glucagon-like peptide-1 on the horizon. Other future therapies may include malonyl-coenzyme A regulators to inhibit fatty acid oxidation, fish oil omega-3, and activators of protein kinase C-epsilon.

For decades it was believed that direct and indirect heating (the latter of which elevates blood and core temperatures without directly heating the area being evaluated) increases skin but not skeletal muscle blood flow. Recent results, however, suggest that passive heating of the leg may increase muscle blood flow. Using the technique of positron-emission tomography, the present study tested the hypothesis that both direct and indirect heating increases muscle blood flow. Calf muscle and skin blood flows were evaluated from eight subjects during normothermic baseline, during local heating of the right calf [only the right calf was exposed to the heating source (water-perfused suit)], and during indirect whole body heat stress in which the left calf was not exposed to the heating source. Local heating increased intramuscular temperature of the right calf from 33.4 ± 1.0°C to 37.4 ± 0.8°C, without changing intestinal temperature. This stimulus increased muscle blood flow from 1.4 ± 0.5 to 2.3 ± 1.2 ml·100 g⁻¹·min⁻¹ (P < 0.05), whereas skin blood flow under the heating source increased from 0.7 ± 0.3 to 5.5 ± 1.5 ml·100 g⁻¹·min⁻¹ (P < 0.01). While whole body heat stress increased intestinal temperature by ∼1°C, muscle blood flow in the calf that was not directly exposed to the water-perfused suit (i.e., indirect heating) did not increase during the whole body heat stress (normothermia: 1.6 ± 0.5 ml·100 g⁻¹·min⁻¹; heat stress: 1.7 ± 0.3 ml·100 g⁻¹·min⁻¹; P = 0.87). Whole body heating, however, reflexively increased calf skin blood flow (to 4.0 ± 1.5 ml·100 g⁻¹·min⁻¹) in the area not exposed to the water-perfused suit. These data show that local, but not indirect, heating increases calf skeletal muscle blood flow in humans. These results have important implications toward the reconsideration of previously accepted blood flow distribution during whole body heat stress.

Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood.Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B(167) isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment.VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B-induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B-induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.

The purpose of this study was to examine the roles of adolescence risk factors in predicting coronary artery calcium (CAC). Elevated coronary heart disease risk factor levels in adolescence may predict subsequent CAC independently of change in risk factor levels from adolescence to adulthood. CAC was assessed in 589 subjects 40 to 46 years of age from the Cardiovascular Risk in Young Finns Study. Risk factor levels were measured in 1980 (12 to 18 years) and in 2007. The prevalence of any CAC was 19.2% (27.9% in men and 12.2% in women). Age, levels of systolic blood pressure (BP), total cholesterol, and low-density lipoprotein cholesterol (LDL-C) in adolescence, as well as systolic BP, total cholesterol, diastolic BP, and pack-years of smoking in adulthood were higher among subjects with CAC than those without CAC. Adolescence LDL-C and systolic BP levels predicted CAC in adulthood independently of 27-year changes in these risk factors. The multivariable odds ratios were 1.34 (95% confidence interval: 1.05 to 1.70; p = 0.02) and 1.38 (95% confidence interval: 1.08 to 1.77; p = 0.01), for 1-SD increase in adolescence LDL-C and systolic BP, respectively. Exposure to both of these risk factors in adolescence (defined as values at or above the age- and sex-specific 75th percentile) substantially increased the risk of CAC (multivariable odds ratio: 3.5 [95% confidence interval: 1.7 to 7.2; p = 0.007]) between groups with no versus both risk factors. Elevated adolescence LDL-C and systolic BP levels are independent predictors of adulthood CAC, indicating that adolescence risk factor levels play an important role in the pathogenesis of coronary heart disease.

Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.

Arrhythmogenic cardiomyopathy (AC) is a progressive disease with high risk of life-threatening ventricular arrhythmias. A genetic mutation is found in up to 50–60% of probands, mostly affecting desmosomal genes. Diagnosis of AC is made by a combination of data from different modalities including imaging, electrocardiogram, Holter monitoring, family history, genetic testing, and tissue properties. Being a progressive cardiomyopathy, repeated cardiac imaging is needed in AC patients. Repeated imaging is important also for risk assessment of ventricular arrhythmias. This expert consensus document gives clinical recommendations for how to use multi-modality imaging in the different aspects of AC disease, including diagnosis, family screening, follow-up, risk assessment, and differential diagnosis.

Cardiovascular events remain one of the most frequent causes of mortality and morbidity worldwide. The majority of cardiac events occur in individuals without known coronary artery disease (CAD) and in low- to intermediate-risk subjects. Thus, the development of improved preventive strategies may substantially benefit from the identification, among apparently intermediate-risk subjects, of those who have a high probability for developing future cardiac events. Cardiac computed tomography and myocardial perfusion scintigraphy (MPS) by single photon emission computed tomography may play a role in this setting. In fact, absence of coronary calcium in cardiac computed tomography and inducible ischaemia in MPS are associated with a very low rate of major cardiac events in the next 3-5 years. Based on current evidence, the evaluation of coronary calcium in primary prevention subjects should be considered in patients classified as intermediate-risk based on traditional risk factors, since high calcium scores identify subjects at high-risk who may benefit from aggressive secondary prevention strategies. In addition, calcium scoring should be considered for asymptomatic type 2 diabetic patients without known CAD to select those in whom further functional testing by MPS or other stress imaging techniques may be considered to identify patients with significant inducible ischaemia. From available data, the use of MPS as first line testing modality for risk stratification is not recommended in any category of primary prevention subjects with the possible exception of first-degree relatives of patients with premature CAD in whom MPS may be considered. However, the Working Group recognizes that neither the use of computed tomography for calcium imaging nor of MPS have been proven to significantly improve clinical outcomes of primary prevention subjects in prospective controlled studies. This information would be crucial to adequately define the role of imaging approaches in cardiovascular preventive strategies.

We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DΔNΔC gene therapy in patients with refractory angina.Thirty patients were randomized to AdVEGF-DΔNΔC (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00 ± 0.36) at 3 months (1.31 ± 0.46, P = 0.045) and 12 months (1.44 ± 0.48, P = 0.009) whereas MPR in the reference area tended to decrease (2.05 ± 0.69, 1.76 ± 0.62, and 1.87 ± 0.69; baseline, 3 and 12 months, respectively, P = 0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months (1.26 ± 0.37, 1.57 ± 0.55, and 1.48 ± 0.48; respectively, P = 0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94 ± 0.32 and 1.76 ± 0.41 baseline and 12 months, respectively, P = 0.023).AdVEGF-DΔNΔC gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.

To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients.Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies.Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators.Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups.Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)).In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients.PROSPERO CRD42012002780.

Ginsenoside Rd is an active ingredient in Panax ginseng CA Mey and can be absorbed into the adipose tissue. Adipokines play an important role in the treatment of cardiovascular diseases. However, the potential benefit of Rd on heart failure (HF) and the underlying mechanism associated with the crosstalk between adipocytes and cardiomyocytes remains to be illustrated. Here, the results identified that Rd improved cardiac function and inhibited cardiac pathological changes in transverse aortic constriction (TAC), coronary ligation (CAL) and isoproterenol (ISO)-induced HF mice. And Rd promoted the release of omentin from the adipose tissue and up-regulated omentin expression in lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes. Further, Rd could increase TBK1 and AMPK phosphorylation in adipocytes. And also, the TBK1-AMPK signaling pathway regulated the expression of omentin in LPS-induced adipocytes. Moreover, the omentin mRNA expression was significantly decreased by TBK1 knockdown in LPS-induced 3T3-L1 adipocytes. Additionally, molecular docking and SPR analysis confirmed that Rd had a certain binding ability with TBK1, and co-treatment with TBK1 inhibitors or TBK1 knockdown partially abolished the effect of Rd on increasing the omentin expression and the ratio of p-AMPK to AMPK in adipocytes. Moreover, we found that circulating omentin level diminished in the HF patients compared with healthy subjects. Meanwhile, the adipose tissue-specific overexpression of omentin improved cardiac function, reduced myocardial infarct size and ameliorated cardiac pathological features in CAL-induced HF mice. Consistently, exogenous omentin reduced mtROS levels and restored ΔψM to improve oxygen and glucose deprivation (OGD)-induced cardiomyocytes injury. Further, omentin inhibited the WNT5A/Ca2+ signaling pathway and promoted mitochondrial biogenesis function to ameliorate myocardial ischemia injury. However, WNT5A knockdown inhibited the impairment of mitochondrial biogenesis and partially counteracted the cardioprotective effect of omentin in vitro. Therefore, this study indicated that Rd promoted omentin secretion from adipocytes through the TBK1-AMPK pathway to improve mitochondrial biogenesis function via WNT5A/Ca2+ signaling pathway to ameliorate myocardial ischemia injury, which provided a new therapeutic mechanism and potential drugs for the treatment of HF.

AimsHybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor setting.

Sudden cardiac death in young athletes is rare but tragic. The cardiology community is faced with the challenge of providing a sensible strategy for the prevention of SCD while simultaneously reaffirming that the benefits of regular exercise far outweigh potential risks. At present, there is a broad range of screening recommendations dependent upon country, sporting discipline, and competition level. While much recent debate has focused on the efficacy of screening with electrocardiography, a number of sporting bodies also mandate the inclusion of exercise testing and echocardiography in screening protocols. Cardiac magnetic resonance imaging, coronary calcium scoring and computed tomography coronary angiography have also been promoted as potentially valuable screening tools for competitive athletes. This review will examine the controversial topic of utilizing cardiac imaging for athlete pre-participation screening. Specifically, the limitations of screening for relatively rare disorders using imaging tools with uncertain or imperfect accuracy will be addressed. Current evidence suggests that the accuracy of all cardiac imaging modalities is insufficient to justify their use as primary screening modalities in athletes. Atypical findings such as marked cardiac dilation, reduced deformation, or small patches of delayed gadolinium enhancement may be commonly encountered in well-trained athletes, but, at present, the prognostic significance of such findings is unknown. Resulting uncertainty for the clinician and athlete has the potential for psychological stress, further testing, and unnecessary exclusions from competition. However, these concerns must not be confused with the extremely useful applications of cardiac imaging for the assessment of athletes with symptoms, an abnormal electrocardiogram or a positive family history. As modern imaging further enhances our understanding of the spectrum of athlete's heart, its role may expand from the assessment of athletes with suspected disease to being part of comprehensive pre-participation screening in apparently healthy athletes.

The prevalence of obstructive coronary artery disease (CAD) in symptomatic patients referred for diagnostic testing has declined, warranting optimization of individualized diagnostic strategies. This study sought to present a simple, clinically applicable tool enabling estimation of the likelihood of obstructive CAD by combining a pre-test probability (PTP) model (Diamond-Forrester approach using sex, age, and symptoms) with clinical risk factors and coronary artery calcium score (CACS). The new tool was developed in a cohort of symptomatic patients (n = 41,177) referred for diagnostic testing. The risk factor–weighted clinical likelihood (RF-CL) was calculated through PTP and risk factors, while the CACS–weighted clinical likelihood (CACS-CL) added CACS. The 2 calculation models were validated in European and North American cohorts (n = 15,411) and compared with a recently updated PTP table. The RF-CL and CACS-CL models predicted the prevalence of obstructive CAD more accurately in the validation cohorts than the PTP model, and markedly increased the area under the receiver-operating characteristic curves of obstructive CAD: for the PTP model, 72 (95% confidence intervals [CI]: 71 to 74); for the RF-CL model, 75 (95% CI: 74 to 76); and for the CACS-CL model, 85 (95% CI: 84 to 86). In total, 38% of the patients in the RF-CL group and 54% in the CACS-CL group were categorized as having a low clinical likelihood of CAD, as compared with 11% with the PTP model. A simple risk factor and CACS-CL tool enables improved prediction and discrimination of patients with suspected obstructive CAD. The tool empowers reclassification of patients to low likelihood of CAD, who need no further testing.

Virtually all tissues in the human body rely on aerobic metabolism for energy production and are therefore critically dependent on continuous supply of oxygen. Oxygen is provided by blood flow, and, in essence, changes in organ perfusion are also closely associated with alterations in tissue metabolism. In response to acute exercise, blood flow is markedly increased in contracting skeletal muscles and myocardium, but perfusion in other organs (brain and bone) is only slightly enhanced or is even reduced (visceral organs). Despite largely unchanged metabolism and perfusion, repeated exposures to altered hemodynamics and hormonal milieu produced by acute exercise, long-term exercise training appears to be capable of inducing effects also in tissues other than muscles that may yield health benefits. However, the physiological adaptations and driving-force mechanisms in organs such as brain, liver, pancreas, gut, bone, and adipose tissue, remain largely obscure in humans. Along these lines, this review integrates current information on physiological responses to acute exercise and to long-term physical training in major metabolically active human organs. Knowledge is mostly provided based on the state-of-the-art, noninvasive human imaging studies, and directions for future novel research are proposed throughout the review.

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%–50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887). Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%–50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887). Ischemic cardiovascular diseases remain the leading cause of morbidity and mortality worldwide,1Moran A.E. Forouzanfar M.H. Roth G.A. Mensah G.A. Ezzati M. Flaxman A. Murray C.J. Naghavi M. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study.Circulation. 2014; 129: 1493-1501Crossref PubMed Scopus (402) Google Scholar despite the success of revascularization therapy and medical treatments (e.g., statins and anti-hypertensive and anti-platelet drugs). Patients with myocardial infarction may suffer from impaired cardiac function owing to the loss of billions of cardiomyocytes, which normally do not regenerate following ischemic injury.2Foglia M.J. Poss K.D. Building and re-building the heart by cardiomyocyte proliferation.Development. 2016; 143: 729-740Crossref PubMed Scopus (138) Google Scholar Myocardial regions surrounding the core of a myocardial infarction are poorly perfused at rest or during stress. Although this myocardial tissue has reduced contractility, it remains viable and may be recoverable with revascularization therapy.3Ryan M.J. Perera D. Identifying and managing hibernating myocardium: what’s new and what remains unknown?.Curr. Heart Fail. Rep. 2018; 15: 214-223Crossref PubMed Scopus (12) Google Scholar Combining therapeutic angiogenesis with revascularization could improve outcomes in patients with myocardial infarction by promoting the growth of new blood vessels and regeneration of injured myocardium.4Hughes G.C. Annex B.H. Angiogenic therapy for coronary artery and peripheral arterial disease.Expert Rev. Cardiovasc. Ther. 2005; 3: 521-535Crossref PubMed Scopus (33) Google Scholar Modalities for targeted delivery of angiogenic factors include transplantation of ex vivo expanded cells, gene therapy with naked DNA plasmids or viral vectors, and administration of recombinant proteins.5Johnson T. Zhao L. Manuel G. Taylor H. Liu D. Approaches to therapeutic angiogenesis for ischemic heart disease.J. Mol. Med. 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Gorbatov R. et al.Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.Nat. Biotechnol. 2013; 31: 898-907Crossref PubMed Scopus (388) Google Scholar AZD8601 is a clinical-grade VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for efficient VEGF-A protein production with minimal induction of innate immune responses.28Sun N. Ning B. Hansson K.M. Bruce A.C. Seaman S.A. Zhang C. Rikard M. DeRosa C.A. Fraser C.L. Wågberg M. et al.Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing.Sci. Rep. 2018; 8: 17509Crossref PubMed Scopus (35) Google Scholar, 29Carlsson L. Clarke J.C. Yen C. Gregoire F. Albery T. Billger M. et al.Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine.Mol. Ther. Methods Clin. 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Billger M. et al.Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine.Mol. Ther. Methods Clin. Dev. 2018; 9: 330-346Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 30Pehrsson S. Hölttä M. Linhardt G. Danielson R.F. Carlsson L. Rapid production of human VEGF-A following intradermal injection of modified VEGF-A mRNA demonstrated by cutaneous microdialysis in the rabbit and pig in vivo.BioMed Res. Int. 2019; 2019: 3915851Crossref PubMed Scopus (8) Google Scholar with no apparent acute toxicity or inflammation in rats and cynomolgus monkeys.29Carlsson L. Clarke J.C. Yen C. Gregoire F. Albery T. Billger M. et al.Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine.Mol. Ther. Methods Clin. Dev. 2018; 9: 330-346Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Injection of AZD8601 also enhanced blood flow and increased blood vessel density in the skin and heart in animal models.28Sun N. Ning B. Hansson K.M. Bruce A.C. Seaman S.A. Zhang C. Rikard M. DeRosa C.A. Fraser C.L. Wågberg M. et al.Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing.Sci. Rep. 2018; 8: 17509Crossref PubMed Scopus (35) Google Scholar,29Carlsson L. Clarke J.C. Yen C. Gregoire F. Albery T. Billger M. et al.Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine.Mol. Ther. Methods Clin. Dev. 2018; 9: 330-346Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Furthermore, epicardial injection of AZD8601 improved cardiac function in pigs following experimental myocardial infarction.29Carlsson L. Clarke J.C. Yen C. Gregoire F. Albery T. Billger M. et al.Biocompatible, purified VEGF-A mRNA improves cardiac function after intracardiac injection 1 week post-myocardial Infarction in swine.Mol. Ther. Methods Clin. Dev. 2018; 9: 330-346Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar AZD8601 was injected intradermally in men with type 2 diabetes in a randomized, double-blind, placebo-controlled, first-in-human phase 1 study.31Gan L.M. Lagerström-Fermér M. Carlsson L.G. Arfvidsson C. Egnell A.C. Rudvik A. Kjaer M. Collén A. Thompson J.D. Joyal J. et al.Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.Nat. Commun. 2019; 10: 871Crossref PubMed Scopus (56) Google Scholar Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression 4−24 h after administration as well as transient local enhancement of basal skin blood flow at 4 h and 7 days after administration.31Gan L.M. Lagerström-Fermér M. Carlsson L.G. Arfvidsson C. Egnell A.C. Rudvik A. Kjaer M. Collén A. Thompson J.D. Joyal J. et al.Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes.Nat. Commun. 2019; 10: 871Crossref PubMed Scopus (56) Google Scholar Here, we describe the design of EPICCURE, an ongoing safety study of epicardial injections of AZD8601 in patients with moderately impaired systolic function who are undergoing elective coronary artery bypass grafting. Before surgery, quantitative 15O-water PET is used to identify and map each patient’s areas of ischemic but viable myocardium for targeted epicardial injections of AZD8601. During follow-up, quantitative 15O-water PET is used to measure potential improvements in myocardial perfusion. EPICCURE is a randomized, placebo-controlled, double-blind, multicenter, 6-month, phase 2a clinical trial of the safety, tolerability, and exploratory efficacy of epicardial injections of AZD8601 in patients with stable coronary artery disease and moderately decreased left ventricular ejection fraction who are undergoing coronary artery bypass grafting surgery. The study started in February 2018 and is recruiting patients at two sites in Finland. In addition, one site in Germany, two sites in the Netherlands, and one other site in Finland (pending) have ethical and regulatory approval. EPICCURE is registered as ClinicalTrials.gov: NCT03370887 and conforms to the principles of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice, the AstraZeneca policy on Bioethics and Human Biological Samples, and all applicable regulatory requirements. Local ethics committees reviewed and approved the study protocol, and participants gave their written informed consent before study enrollment. A 10-min extension of cardioplegia was considered ethically acceptable to allow epicardial injections after completion of the peripheral anastomoses. The primary objective of EPICCURE is to assess the safety and tolerability of AZD8601. Exploratory objectives include assessing efficacy based on 15O-water PET quantification of myocardial blood flow as well as echocardiography, clinical symptoms, biomarkers, and functional tests (Box 1). Primary•Safety and tolerability of AZD8601 Exploratory•Effect of AZD8601 on○regional and global stress myocardial blood flow measured with 15O-water PET○regional and global myocardial blood flow reserve measured with 15O-water PET○left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular ejection fraction measured by echocardiography○regional myocardial wall motion measured by echocardiography and strain analysis○cardiac function under adenosine stress measured by echocardiography, including CFVR in the left anterior descending artery○clinical symptoms: NYHA functional class, SAQ, and KCCQ•Change in troponin T and NT-proBNP levels from baseline•VEGF-A protein concentration in plasma•Sample collection for○biomarkers○AZD8601 plasma concentrations○anti-drug immunogenicity•Optional digital 6MWT and MCWS in some centers 6MWT, 6-minute walk test; CFVR, coronary flow velocity reserve; KCCQ, Kansas City Cardiomyopathy Questionnaire; MCWS, maximum continuously walked steps; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PET, positron emission tomography; SAQ, Seattle Angina Questionnaire; VEGF-A, vascular endothelial growth factor A. Eligible patients are men and women aged 18 years or older who are scheduled for elective coronary artery bypass grafting surgery within 15–90 days and whose left ventricular ejection fraction is between 30% and 50%. Patients taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, or beta-blockers must be on a stable dose for at least 2 weeks before screening. Men must be surgically sterile or using barrier contraception to prevent pregnancy in partners, and women must be unable to have children (post-menopausal or surgically sterile). Key exclusion criteria are listed in Box 2. •BMI > 35 kg/m2 or poor image window for echocardiography•Indication for emergency coronary artery bypass grafting•Severe comorbidities or history of disease or disorder that would put the patient at risk, affect participation, or influence study results•eGFR ≤ 30 mL/min•History of ventricular arrhythmia (Lown grade ≥ 3) without implantable cardiac defibrillator•Contraindication for CFVR or sMBF measurement procedure•Concomitant use of medications associated with Torsades de Pointes•History of QT prolongation associated with medication that required discontinuation of that medication•Congenital long QT syndrome•Symptomatic arrythmia or arrythmia that requires treatment•Atrial fibrillation (including paroxysmal atrial fibrillation)•Hepatitis B or C virus or HIV seropositivity•History of drug or alcohol abuse BMI, body mass index; CFVR, coronary flow velocity reserve; eGFR, estimated glomerular filtration rate; HIV, human immunodeficiency virus; QT, electrocardiographic interval from the onset of the QRS complex to the end of the T wave; sMBF, stress myocardial blood flow. Enrolled participants (N = 24) are randomized at least 14 days before coronary artery bypass grafting to receive AZD8601 3 mg, AZD8601 30 mg, or placebo in a ratio of 1:1:1 (n = 8 per group) (Figure 1). Participants are divided into two sequential ascending-dose cohorts (n = 12 per cohort) and randomized 2:1 to AZD8601 (n = 8) or placebo (n = 4), with AZD8601 doses of 3 mg in the first cohort and 30 mg in the second cohort (Figure 2). Within each cohort, two sentinel participants are randomized 1:1 to AZD8601 or placebo, followed by another two sentinel participants randomized 1:1 to AZD8601 or placebo, followed by the remaining eight participants randomized to 3:1 to AZD8601 or placebo. Safety data from up to 1 month after administration are reviewed by the safety review committee before the treatment of participants in the next sentinel sub-group within each cohort and before the treatment of participants in the high-dose cohort (Figure 2). aScreening and randomization visits can be combined provided that 15O-water PET and CFVR assessments are carried out on separate days. bThe 14-day time-window before surgery on day 0 can be reduced if the pre-operative conference, randomization, and delivery of AZD8601/placebo can be accommodated within a shorter period. cIncludes CFVR in the left anterior descending artery (for sites able to assess CFVR). dKansas City Cardiomyopathy Questionnaire, Seattle Angina Questionnaire, and NYHA classification. eIncludes high-sensitivity troponin T and NT-proBNP. fOptional digital assessments via mobile phone app. X, assessment times; XXXXX, daily assessments during stay in hospital; 6MWT, 6-min walking test; CFVR, coronary flow velocity reserve; CT, computed tomography; MCWS, maximum continuously walked steps; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PET, positron emission tomography; TC, teleconference; VEGF-A, vascular endothelial growth factor. Sequential low-dose and high-dose cohorts each include 12 participants, with 8 randomized to AZD8601 and 4 randomized to placebo. Each dose cohort includes 3 sequential sentinel sub-cohorts: the first and second sub-cohort each include 2 participants, randomized to AZD8601 (n = 1) or placebo (n = 1), and the third sentinel cohort includes 8 participants, randomized to AZD8601 (n = 6) or placebo (n = 2). Safety data at 1 month is reviewed before initiation of the next cohort or sub-cohort. Participants and the study team will remain blinded to treatment assignments throughout the study. Investigators will remain blinded unless they need to know a patient’s assigned treatment in a medical emergency. The safety review committee is unblinded. The placebo solution for injection matches the appearance of AZD8601, so the identity of the treatment cannot be discerned. Randomization is carried out by the contract research organization (Parexel) using an algorithm provided by the sponsor (AstraZeneca). At baseline, participants have a 15O-water PET scan to quantify pre-operative myocardial blood flow at rest and during adenosine stress. This is paired with the baseline contrast-enhanced coronary computed tomography (CT) angiogram to generate a perfusion map that combines coronary anatomy and myocardial blood flow. The perfusion map is used to design an individualized injection map that guides placement of each patient’s injections during surgery (Figure 3). Ischemic regions are identified as those with stress myocardial blood flow below 2.3 mL/g/min (±0.3 mL/g/min) or below 80% (±10%) of the segment with highest stress myocardial blood flow on 15O-water PET.32Kajander S.A. Joutsiniemi E. Saraste M. Pietilä M. Ukkonen H. Saraste A. Sipilä H.T. Teräs M. Mäki M. Airaksinen J. et al.Clinical value of absolute quantification of myocardial perfusion with (15)O-water in coronary artery disease.Circ. Cardiovasc. Imaging. 2011; 4: 678-684Crossref PubMed Scopus (135) Google Scholar,33Danad I. Uusitalo V. Kero T. Saraste A. Raijmakers P.G. Lammertsma A.A. Heymans M.W. Kajander S.A. Pietilä M. James S. et al.Quantitative assessment of myocardial perfusion in the detection of significant coronary artery disease: cutoff values and diagnostic accuracy of quantitative [(15)O]H2O PET imaging.J. Am. Coll. Cardiol. 2014; 64: 1464-1475Crossref PubMed Scopus (168) Google Scholar Target regions of ischemic but viable myocardium are identified as ischemic regions with resting myocardial blood flow above 0.6 mL/g/min on 15O-water PET. On the individualized injection map, 30 epicardial injection sites with approximately 1 cm spacing are identified within the target regions. The individualized injection map is designed in a pre-operative conference involving the responsible surgeon, PET physician and cardiologist from the study site, the responsible person from the PET core laboratory, and at least one other cardiothoracic surgeon from another hospital. The individualized injection map is based on a hybrid image showing 3D-rendered coronary anatomy (coronary CT angiography) and left ventricular myocardial blood flow during adenosine stress (15O-water PET). Green or blue shading indicates stress myocardial blood flow < 2.3 mL/g/min. The red overlay on the left panel indicates the target region of the left coronary artery territory for epicardial injections of AZD8601 (stress myocardial blood flow < 2.3 mL/g/min and resting myocardial blood flow > 0.6 mL/g/min). Treatment is focused on the largest ischemic area, with any remaining injections used for partial treatment of the second-largest area. White arrows, left anterior descending coronary artery; yellow arrows, left circumflex coronary artery branches; red arrows, right coronary artery. During surgery, participants receive 30 epicardial injections of 200 μL volume each, guided by their individualized injection map to target ischemic but viable myocardial regions. Injections are given under cardioplegia immediately after bypass grafting and before reperfusion. Participants receive their randomly assigned treatment of AZD8601 3 mg (0.1 mg per injection site; 0.5 mg/mL solution), AZD8601 30 mg (1 mg per injection site; 5 mg/mL solution), or matching placebo. The injection procedure is documented by filming or photography, and the surgeon records the actual injection sites on the individualized injection map (Figure 3). Injections are performed using a 30G (approximately 0.3 mm diameter) × 13 mm hypodermic needle coupled to a 1 mL syringe. Comments are recorded on the

Fluorine-18 flurpiridaz is a novel positron emission tomography (PET) myocardial perfusion imaging tracer. This study sought to assess the diagnostic efficacy of flurpiridaz PET versus technetium-99m–labeled single photon emission computed tomography SPECT for the detection and evaluation of coronary artery disease (CAD), defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). Flurpiridaz safety was also evaluated. In this phase III prospective multicenter clinical study, 795 patients with known or suspected CAD from 72 clinical sites in the United States, Canada, and Finland were enrolled. A total of 755 patients were evaluable, and the mean age was 62.3 ± 9.5 years, 31% were women, 55% had body mass index ≥30 kg/m2, and 71% had pharmacological stress. Patients underwent 1-day rest-stress (pharmacological or exercise) flurpiridaz PET and 1- or 2-day rest-stress Tc-99m–labeled SPECT and ICA. Images were read by 3 experts blinded to clinical and ICA data. Sensitivity of flurpiridaz PET (for detection of ≥50% stenosis by ICA) was 71.9% (95% confidence interval [CI]: 67.0% to 76.3%), significantly (p < 0.001) higher than SPECT (53.7% [95% CI: 48.5% to 58.8%]), while specificity did not meet the prespecified noninferiority criterion (76.2% [95% CI: 71.8% to 80.1%] vs. 86.6% [95% CI: 83.2% to 89.8%]; p = NS). Receiver-operating characteristic curve analysis demonstrated superior discrimination of CAD by flurpiridaz PET versus SPECT in the overall population, in women, obese patients, and patients undergoing pharmacological stress testing (p < 0.001 for all). Flurpiridaz PET was superior to SPECT for defect size (p < 0.001), image quality (p < 0.001), diagnostic certainty (p < 0.001), and radiation exposure (6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv; p < 0.001). Flurpiridaz PET was safe and well tolerated. Flurpiridaz PET myocardial perfusion imaging shows promise as a new tracer for CAD detection and assessment of women, obese patients, and patients undergoing pharmacological stress testing. A second phase III Food and Drug Administration trial is ongoing. (A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD; NCT01347710)