Hein J. Verberne

1. Treadmill exercise is the most widely used stress modality. Several treadmill exercise protocols are described which differ in the speed and grade of treadmill inclination and may be more appropriate for specific patient populations. The Bruce and modified Bruce protocosls are the most widely used exercise protocols. 2. Upright bicycle exercise is commonly used in Europe. This is preferable if dynamic first-pass imaging is planned during exercise. Supine or semisupine exercise is relatively suboptimal and should only be used while performing exercise radionuclide angiocardiography.

Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study).

Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability.Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p < 0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037).

Since the publication of the European Association of Nuclear Medicine (EANM) procedural guidelines for radionuclide myocardial perfusion imaging (MPI) in 2005, many small and some larger steps of progress have been made, improving MPI procedures. In this paper, the major changes from the updated 2015 procedural guidelines are highlighted, focusing on the important changes related to new instrumentation with improved image information and the possibility to reduce radiation exposure, which is further discussed in relation to the recent developments of new International Commission on Radiological Protection (ICRP) models. Introduction of the selective coronary vasodilator regadenoson and the use of coronary CT-contrast agents for hybrid imaging with SPECT/CT angiography are other important areas for nuclear cardiology that were not included in the previous guidelines. A large number of minor changes have been described in more detail in the fully revised version available at the EANM home page: http://eanm.org/publications/guidelines/2015_07_EANM_FINAL_myocardial_perfusion_guideline.pdf .

AimsTo derive a more precise estimate of the prognostic significance of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters [early heart mediastinal ratio (H/M), late H/M, and myocardial washout] in heart failure (HF).

Cardiovascular diseases are the leading cause of death not only in Europe but also in the rest of the World. Preventive measures, however, often fail and cardiovascular disease may manifest as an acute coronary syndrome, stroke or even sudden death after years of silent progression. Thus, there is a considerable need for innovative diagnostic and therapeutic approaches to improve the quality of care and limit the burden of cardiovascular diseases. During the past 10 years, several retrospective and prospective clinical studies have been published using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to quantify inflammation in atherosclerotic plaques. However, the current variety of imaging protocols used for vascular (arterial) imaging with FDG PET considerably limits the ability to compare results between studies and to build large multicentre imaging registries. Based on the existing literature and the experience of the Members of the European Association of Nuclear Medicine (EANM) Cardiovascular Committee, the objective of this position paper was to propose optimized and standardized protocols for imaging and interpretation of PET scans in atherosclerosis. These recommendations do not, however, replace the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual study protocols used and the individual patient, in consultation with the patient and, where appropriate and necessary, the patient's guardian or carer. These recommendations suffer from the absence of conclusive evidence on many of the recommendations. Therefore, they are not intended and should not be used as "strict guidelines" but should, as already mentioned, provide a basis for standardized clinical atherosclerosis PET imaging protocols, which are subject to further and continuing evaluation and improvement. However, this EANM position paper might indeed be a first step towards "official" guidelines on atherosclerosis imaging with PET.

These guidelines update the previous EANM 2009 guidelines on the diagnosis of pulmonary embolism (PE). Relevant new aspects are related to (a) quantification of PE and other ventilation/perfusion defects; (b) follow-up of patients with PE; (c) chronic PE; and (d) description of additional pulmonary physiological changes leading to diagnoses of left ventricular heart failure (HF), chronic obstructive pulmonary disease (COPD) and pneumonia. The diagnosis of PE should be reported when a mismatch of one segment or two subsegments is found. For ventilation, Technegas or krypton gas is preferred over diethylene triamine pentaacetic acid (DTPA) in patients with COPD. Tomographic imaging with V/PSPECT has higher sensitivity and specificity for PE compared with planar imaging. Absence of contraindications makes V/PSPECT an essential method for the diagnosis of PE. When V/PSPECT is combined with a low-dose CT, the specificity of the test can be further improved, especially in patients with other lung diseases. Pitfalls in V/PSPECT interpretation are discussed. In conclusion, V/PSPECT is strongly recommended as it accurately establishes the diagnosis of PE even in the presence of diseases like COPD, HF and pneumonia and has no contraindications.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

HomeCirculation: Cardiovascular ImagingVol. 14, No. 7ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2—Evidence Base and Standardized Methods of Imaging Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2—Evidence Base and Standardized Methods of Imaging Sharmila Dorbala, MD, MPH, FASNC, Chair, Yukio Ando, MD, PhD, Sabahat Bokhari, MD, Angela Dispenzieri, MD, Rodney H. Falk, MD, Victor A. Ferrari, MD, Marianna Fontana, PhD, Olivier Gheysens, MD, PhD, Julian D. Gillmore, MD, PhD, Andor W. J. M. Glaudemans, MD, PhD, Mazen A. Hanna, MD, Bouke P. C. Hazenberg, MD, PhD, Arnt V. Kristen, MD, Raymond Y. Kwong, MD, MPH, Mathew S. Maurer, MD, Giampaolo Merlini, MD, Edward J. Miller, MD, PhD, James C. Moon, MD, Venkatesh L. Murthy, MD, PhD, C. Cristina Quarta, MD, PhD, Claudio Rapezzi, MD, Frederick L. Ruberg, MD, Sanjiv J. Shah, MD, Riemer H. J. A. Slart, MD, Hein J. Verberne, MD, PhD and Jamieson M. Bourque, MD, MHS, FASNC, Co-Chair Sharmila DorbalaSharmila Dorbala Search for more papers by this author , Yukio AndoYukio Ando Search for more papers by this author , Sabahat BokhariSabahat Bokhari Search for more papers by this author , Angela DispenzieriAngela Dispenzieri Search for more papers by this author , Rodney H. FalkRodney H. Falk Search for more papers by this author , Victor A. FerrariVictor A. Ferrari Search for more papers by this author , Marianna FontanaMarianna Fontana Search for more papers by this author , Olivier GheysensOlivier Gheysens Search for more papers by this author , Julian D. GillmoreJulian D. Gillmore Search for more papers by this author , Andor W. J. M. GlaudemansAndor W. J. M. Glaudemans Search for more papers by this author , Mazen A. HannaMazen A. Hanna Search for more papers by this author , Bouke P. C. HazenbergBouke P. C. Hazenberg Search for more papers by this author , Arnt V. KristenArnt V. Kristen Search for more papers by this author , Raymond Y. KwongRaymond Y. Kwong Search for more papers by this author , Mathew S. MaurerMathew S. Maurer Search for more papers by this author , Giampaolo MerliniGiampaolo Merlini Search for more papers by this author , Edward J. MillerEdward J. Miller Search for more papers by this author , James C. MoonJames C. Moon Search for more papers by this author , Venkatesh L. MurthyVenkatesh L. Murthy Search for more papers by this author , C. Cristina QuartaC. Cristina Quarta Search for more papers by this author , Claudio RapezziClaudio Rapezzi Search for more papers by this author , Frederick L. RubergFrederick L. Ruberg Search for more papers by this author , Sanjiv J. ShahSanjiv J. Shah Search for more papers by this author , Riemer H. J. A. SlartRiemer H. J. A. Slart Search for more papers by this author , Hein J. VerberneHein J. Verberne Search for more papers by this author and Jamieson M. BourqueJamieson M. Bourque Search for more papers by this author Originally published1 Jul 2021https://doi.org/10.1161/HCI.0000000000000029Circulation: Cardiovascular Imaging. 2021;14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 1, 2021: Ahead of Print PreambleCardiac amyloidosis is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. Due to the relative rarity of cardiac amyloidosis, clinical and diagnostic expertise in the recognition and evaluation of individuals with suspected amyloidosis is mostly limited to a few expert centers. Electrocardiography, echocardiography, and radionuclide imaging have been used for the evaluation of cardiac amyloidosis for over 40 years.1-3 Although cardiovascular magnetic resonance (CMR) has also been in clinical practice for several decades, it was not applied to cardiac amyloidosis until the late 1990s. Despite an abundance of diagnostic imaging options, cardiac amyloidosis remains largely underrecognized or delayed in diagnosis.4 While advanced imaging options for noninvasive evaluation have substantially expanded, the evidence is predominately confined to single-center small studies or limited multicenter larger experiences, and there continues to be no clear consensus on standardized imaging pathways in cardiac amyloidosis. This lack of guidance is particularly problematic given that there are numerous emerging therapeutic options for this morbid disease, increasing the importance of accurate recognition at earlier stages. Imaging provides non-invasive tools for follow-up of disease remission/progression complementing clinical evaluation. Additional areas not defined include appropriate clinical indications for imaging, optimal imaging utilization by clinical presentation, accepted imaging methods, accurate image interpretation, and comprehensive and clear reporting. Prospective randomized clinical trial data for the diagnosis of amyloidosis and for imaging-based strategies for treatment are not available. A consensus of expert opinion is greatly needed to guide the appropriate clinical utilization of imaging in cardiac amyloidosis.IntroductionThe American Society of Nuclear Cardiology (ASNC) has assembled a writing group with expertise in cardiovascular imaging and amyloidosis, with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), the American Society of Echocardiography (ASE), the European Association of Nuclear Medicine (EANM), the Heart Failure Society of America (HFSA), the International Society of Amyloidosis (ISA), the Society for Cardiovascular Magnetic Resonance (SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This writing group has developed a joint expert consensus document on imaging cardiac amyloidosis, divided into two parts. Part 1 has the following aims:Perform and document a comprehensive review of existing evidence on the utility of echocardiography, CMR, and radionuclide imaging in screening, diagnosis, and management of cardiac amyloidosis.Define standardized technical protocols for the acquisition, interpretation, and reporting of these noninvasive imaging techniques in the evaluation of cardiac amyloidosis.Part 2 of this expert consensus statement addresses the development of consensus diagnostic criteria for cardiac amyloidosis, identifies consensus clinical indications, and provides ratings on appropriate utilization in these clinical scenarios.Purpose of the Expert Consensus DocumentThe overall goal of this multi-societal expert consensus document on noninvasive cardiovascular imaging in cardiac amyloidosis is to standardize the selection and performance of echocardiography, CMR, and radionuclide imaging in the evaluation of this highly morbid condition, and thereby improve healthcare quality and outcomes of individuals with known or suspected cardiac amyloidosis. We hope that research generated to validate the recommendations of this consensus document will form the basis for evidence-based guidelines on cardiac amyloidosis imaging within the next few years.Overview of Cardiac AmyloidosisCardiac amyloidosis is a cardiomyopathy that results in restrictive physiology from the myocardial accumulation of misfolded protein deposits, termed amyloid fibrils, causing a clinically diverse spectrum of systemic diseases. Most cases of cardiac amyloidosis result from two protein precursors: amyloid immunoglobulin light chain (AL), in which the misfolded protein is a monoclonal immunoglobulin light chain typically produced by bone marrow plasma cells, and amyloid transthyretin (ATTR) amyloidosis, in which the misfolded protein is transthyretin (TTR), a serum transport protein for thyroid hormone and retinol that is synthesized primarily by the liver.3 ATTR amyloidosis is further subtyped by the sequence of the TTR protein into wild-type (ATTRwt) or hereditary (ATTRv), the latter resulting from genetic variants in the TTR gene.5,6 Cardiac involvement in systemic AL amyloidosis is common (up to 75%, depending on diagnostic criteria),7 and in the case of ATTRwt amyloidosis, is the dominant clinical feature seen in all cases.The different types of cardiac amyloidosis display significant heterogeneity in clinical course, prognosis, and treatment approach.8 AL amyloidosis is characterized by a rapidly progressive clinical course, and if untreated, the median survival is less than 6 months. ATTRv amyloidosis follows a varied clinical course depending upon the specific mutation inherited with either cardiomyopathy and/or sensory/autonomic polyneuropathy.9 Furthermore, ATTR amyloidosis (both wild-type and hereditary) is characterized by an age-dependent penetrance, with the clinical phenotype developing as age advances.The diagnosis of cardiac amyloidosis remains challenging owing to a number of factors, which include the relative rarity of the disease, clinical overlap with more common diseases that result in thickening of the myocardium (ie, hypertension, chronic renal failure, hypertrophic cardiomyopathy, aortic stenosis), unfamiliarity with the proper diagnostic algorithm, and a perceived lack of definitive treatment. While systemic AL amyloidosis is indeed a rare disease affecting approximately 8 to 1210,11 per million person years, and as high as 40.5 per million person years in 2015,12 ATTRwt cardiac amyloidosis appears quite common, with recent reports using contemporary diagnostic strategies that place the prevalence in as many as 10% to 16% of older patients with heart failure or with aortic stenosis.13-15 In addition, the most common mutation associated with ATTRv amyloidosis has been reproducibly demonstrated in 3.4% of African Americans.16 While the penetrance remains disputed, this suggests there are approximately 2 million people in the United States who are carriers of an amyloidogenic mutation and are at risk for cardiac amyloidosis. It is clear both ATTRv and ATTRwt cardiac amyloidosis are underrecognized, yet important causes of diastolic heart failure.17Treatment options are rapidly expanding. Anti-plasma cell therapeutics have extended median survival in AL amyloidosis beyond 5 years, 7 with increasing survival beyond 10 years. We are potentially nearing a similar sea change in the management of ATTR amyloidosis. ATTR amyloidosis was previously only treated by solid-organ transplantation, as conventional highly effective heart-failure therapy is poorly tolerated and contraindicated in advanced cardiac amyloidosis. Although early clinical trials of amyloid specific antibodies have been unsuccessful to date,18-20 one remains under study in a Phase I clinical trial.21 Novel therapeutics that suppress TTR expression have been studied in Phase 3 clinical trials and received FDA approval18,19 for ATTRv with polyneuropathy. Additionally, a randomized clinical trial of TTR stabilizer therapy demonstrated a reduction in all-cause mortality in ATTR cardiomyopathy22; this agent has recently received FDA approval for ATTR cardiomyopathy. As these exciting prospects move into the clinical realm, it is evident early diagnosis will be essential to afford the most effective treatment options for both AL and ATTR cardiac amyloidosis.Biomarkers and Biopsy in Cardiac AmyloidosisDespite these advances in treatment, the challenge persists to increase recognition and achieve effective, timely diagnosis. In the past, a diagnosis of cardiac amyloidosis required an endomyocardial biopsy, which remains the gold standard, as it is virtually 100% accurate, assuming appropriate sampling, for the detection of amyloid deposits.23 Specific identification of the precursor protein can be accomplished from the tissue specimen through immunohistochemistry, albeit with limitations,24 or laser-capture tandem mass spectrometry (LC/MS/MS). This latter technique is considered the definitive test for precursor protein identification.25 While ATTR cardiac amyloidosis can now be diagnosed accurately without the need of cardiac biopsy,3 AL amyloidosis requires demonstration of light-chain amyloid fibrils in tissue (although not necessarily the heart) prior to administration of chemotherapy. Even for ATTR cardiac amyloidosis, a cardiac biopsy remains necessary in the context of equivocal imaging or the co-existence of a monoclonal gammopathy.Clinical suspicion of cardiac amyloidosis can be raised by the constellation of clinical signs and symptoms, specific demographics (ie, age, race, country of family origin), electrocardiography, and suggestive non-invasive imaging findings. Endomyocardial biopsy, although highly sensitive (100%),23 is impractical as a screening test for cardiac amyloidosis, given its inherent risk and requirement of pathologic expertise, which is limited to a few academic centers. Other limitations of endomyocardial biopsy include: inability to quantify whole-heart amyloid burden, inability to evaluate systemic disease burden, and, for these same reasons, limited assessment of response to therapy. Thus, contemporary imaging techniques, including CMR, radionuclide imaging with bone-avid radiotracers, and echocardiography with longitudinal strain quantification, have evolved as the principal means for diagnosis and management of cardiac amyloidosis.The current diagnostic approach for cardiac amyloidosis involves the use of one or more of these imaging modalities in conjunction with assessment of a plasma-cell disorder (Figure 1).3 Serum plasma electrophoresis is an insensitive test for AL amyloidosis and thus is unreliable for diagnosing AL amyloidosis. Serum and urine immunofixation and the measurement of serum free light chains (FLC) are necessary for the diagnosis of AL amyloidosis. In cases of confirmed ATTR amyloidosis, TTR gene sequencing is performed to establish ATTRwt vs ATTRv. In AL amyloidosis, the concentration of the affected FLC, in conjunction with serum N-terminal-pro brain natriuretic peptide (NT-proBNP) and cardiac troponin T or I, can be utilized to assign a disease stage that confers highly reproducible prognostic information.26 Furthermore, a cardiac staging system based on NT-proBNP and cardiac troponins (along with differential FLC levels) allows the stratification of patients into stages widely used in clinical practice for modulating the therapy intensity in AL amyloidosis.26 A European study identified a stage 3b subgroup with very advanced cardiac involvement; these patients had high concentrations of NT-proBNP (>8500 ng/L) and a very poor prognosis, which warrants further study.27 Furthermore, a reduction in FLC following anti-plasma cell treatment, termed a hematologic response, is typically followed within 6 to 12 months by a reduction in NT-pro-BNP and troponin, termed an organ-specific response, which is associated with improved symptoms of heart failure and extended survival.28 The FLC-based and NT-proBNP-based hematology and cardiac responses have been extensively validated in AL amyloidosis.29 In ATTR cardiac amyloidosis, NT-pro-BNP, cardiac troponin, and estimated glomerular filtration rate have also been validated as diagnostic markers in different risk-prediction models,30-32 with changes in NT pro-BNP useful to follow disease progression.18,22 Biomarker evaluation is an integral part of the management of patients with AL and ATTR cardiac amyloidosis.Download figureDownload PowerPointFigure 1. Systematic evaluation of cardiac amyloidosis. A comprehensive evaluation of cardiac amyloidosis includes consideration of clinical symptoms, evaluation of cardiac involvement (biomarkers and cardiac imaging), evaluation of systemic amyloidosis (serum, urine testing, and biopsy), followed by typing of amyloid deposits into AL or ATTR, and documentation of mutations in patients with ATTR amyloidosis. *Clinical symptoms: heart failure, peripheral/autonomic neuropathy, macroglossia, carpal tunnel syndrome, periorbital bruising, stroke, atrial fibrillation, postural hypotension, fatigue, weight loss, pedal edema, renal dysfunction, diarrhea, constipation. †Evaluation for cardiac amyloidosis: ECG, ECHO, CMR, EMB, 99mTc-PYP/DPD/HMDP/123I-mIBG/PET, NT-proBNP, troponin T. ‡Evaluation for systemic amyloidosis: AL: detect plasma cell clone: serum and urine immunofixation, serum FLC assay and immunoglobulin analysis; AL: detect systemic organ involvement: 24-hour urine protein, Alkaline phosphatase, eGFR, cardiac biomarkers (NT-proBNP, troponins); Tissue biopsy: EMB/Fatpad/ Bone marrow/Other with Congo red staining. §Confirm Amyloidosis Type: ATTR: IHC and MS of Biopsy or 99mTc- PYP/DPD/HMDP Grade 2 or 3 if a clonal process is excluded; AL: MS or IHC of Biopsy. ¥Confirm TTR Mutation in Patients with ATTR amyloidosis: genetic testing for TTR mutations. AL, amyloid light chain; ATTR, amyloid transthyretin; CMR, cardiac magnetic resonance imaging; DPD, -3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram; EMB, endomyocardial biopsy; ECHO, echocardiogram; eGFR, estimated glomerular filtration rate; HMDP, hydroxymethylenediphosphonate; IHC, immunohistochemistry; mIBG, meta-iodobenzylguanidine; MS, mass spectroscopy; v, hereditary; PYP, pyrophosphate; Tc, technetium; wt, wild-type.Evolution of Imaging in Cardiac AmyloidosisDespite the widespread utilization of serum biomarkers for risk assessment of cardiac amyloidosis, biomarkers themselves are non-specific for the diagnosis of amyloidosis. This lack of specificity is primarily due to confounding by renal function and overlap with other cardiomyopathies that also result in abnormalities of NT-pro BNP and troponin. For this reason, imaging remains a requisite component of the diagnostic algorithm for cardiac amyloidosis. In addition, imaging alone captures the cardiac functional impairment caused by amyloid infiltration and affords insight into hemodynamics. Finally, imaging has the potential to directly visualize cardiac remodeling that may result from both FLC reduction, TTR stabilization/suppression, and/or the anti-amyloid specific therapies in development. This consensus document serves as means to summarize the interpretation and application of multimodal imaging in cardiac amyloidosis.The first descriptions of echocardiographic findings in cardiac amyloidosis were reported more than 40 years ago.1,33 Since that time, echocardiography has become a standard part of the diagnostic assessment in patients with suspected or confirmed cardiac amyloidosis.34-37 The initial studies of echocardiography in cardiac amyloidosis occurred when only M-mode echocardiography was routinely available and predated the advent of clinical 2D and Doppler echocardiography. Nevertheless, these early studies recognized many of the findings of cardiac amyloidosis still used today in clinical practice,34-41 along with more recent advances as discussed in subsequent sections.1,33 Echocardiography has the advantage of portability, bedside availability, conspicuous presence, and superior diastolic function assessment. Thus, while echocardiography is not sufficient by itself, to make the diagnosis of cardiac amyloidosis, it is an essential part of the diagnostic evaluation and ongoing management of patients with this disorder.Cardiovascular magnetic resonance in cardiac amyloidosis provides structural and functional information that complements echocardiography.42 Cardiovascular magnetic resonance may have advantages when acoustic windows are poor, for characterization of the right ventricle, tissue characterization based on the contrast-enhanced patterns of myocardial infiltration, and precise quantification of cardiac chamber volumes and ventricular mass. However, CMR with late gadolinium enhancement (LGE) may be relatively contraindicated in patients with suspected cardiac amyloidosis and concomitant renal failure—a frequent occurrence. Moreover, in centers where CMR scanning in patients with pacemakers is not yet routine, echocardiography may be the only option for imaging cardiac structure and function. Although both the echocardiographic and CMR assessment of structure and function alone may be non-specific, some features provide more specificity, including biventricular long axis function impairment, apical sparing, reduced stroke volume index, pericardial effusion, marked biatrial enlargement, atrial appendage thrombus in sinus rhythm, sparkling texture of the myocardium, and/or disproportionate increase in left ventricular (LV) mass for electrocardiogram (ECG) voltages. Given the limitations of assessment of structure and function alone (by echo or CMR), tissue characterization by CMR adds high value, as discussed in subsequent sections.Radionuclide imaging provides critical information on amyloid type that complements cardiac structural and functional characterization by echocardiography and CMR. It has long been appreciated that there is a unique myocardial uptake pattern in amyloid by scintigraphy with 99mTechnetium (Tc)-bisphosphonate derivatives (99mTc-pyrophosphate [PYP], 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), 99mTc hydroxymethylene- diphosphonate [99mTc-HMDP]). Many studies dating from the 1970s and 80s suggested 99mTc-PYP could assist in diagnosing amyloidosis.2,43-48 However, there was variable diagnostic accuracy, which limited early use of the technique, owing to the study of mixed patients populations with undifferentiated ATTR and AL subtypes. Subsequent studies comparing 99mTc-bisphosphonate scintigraphy to gold standard endomyocardial biopsy discovered that ATTR cardiac amyloidosis has avidity for bone radiotracers, whereas AL cardiac amyloidosis has minimal or no avidity for these tracers. Therefore, bone-avid radiotracers can definitively diagnose amyloid type when a plasma cell dyscrasia is excluded. Recognition of preferential ATTR binding to bone-avid 99mTc-bisphosphonate-based radiotracers resulted in renewed interest and greater clinical application of cardiac scintigraphy with 99mTc-PYP, 99mTc-DPD, and 99mTc-HMDP. Although there is no direct comparison between these tracers, the information available suggests they can be used interchangeably. This is fortunate, given that there is limited access to 99mTc-DPD and 99mTc-HDMP in the United States and 99mTc-PYP in Europe.Evidence Base for Cardiac Amyloidosis ImagingDiagnosisCardiac amyloidosis is substantially underdiagnosed due to varied clinical manifestations, especially in the early stages of disease. An ideal non-invasive diagnostic method would identify cardiac involvement in amyloidosis and would also confirm the etiologic subtype. No existing diagnostic tools can provide this information individually, necessitating a multimodality cardiac imaging approach.EchocardiographyEchocardiography plays a major role in the non-invasive diagnosis of cardiac amyloidosis due to its assessment of structure and function and its pervasive use in patients with concerning cardiac symptoms. The evaluation of cardiac amyloidosis using echocardiography focuses on morphological findings related to amyloid infiltration, in particular, thickened LV walls >1.2 cm in the absence of any other plausible causes of LV hypertrophy (Figure 2).28 Although increased LV mass in the setting of low voltage ECG is suggestive of cardiac amyloidosis, a definitive distinction by echocardiography of amyloidosis from hypertrophic cardiomyopathy or other causes of LV hypertrophy is challenging.49 Other echocardiographic findings that suggest infiltrative disease include normal to small LV cavity size; biatrial enlargement and dysfunction41; left atrial and left atrial appendage stasis and thrombi; thickened valves; right ventricular and interatrial septal thickening; pericardial effusion; and a restrictive transmitral Doppler filling pattern.50-54 Several of these features, including an overt restrictive mitral inflow pattern are uncommon until late in the disease process.34,51 However, reduced LV systolic thickening, filling pressures, cardiac output,38 early diastolic dysfunction,39,40 and signs of raised filling pressures are commonly seen.34,52 A granular sparkling appearance of the myocardial walls may be appreciated, but it is not considered a highly specific finding and can be seen in other conditions, such as end-stage renal disease. The echocardiographic shift from fundamental to harmonic imaging has confounded this phenotype.Download figureDownload PowerPointFigure 2. Characteristic appearance of cardiac amyloidosis on echocardiography. (A)-(D) 2D echocardiography. (A) (parasternal long axis) and (B) (parasternal short axis) demonstrate increased LV wall thickness with a sparkling texture of the myocardium (yellow arrows) in a patient with primary (AL) cardiac amyloidosis. Also, note the small pericardial effusion (white arrows), which is often seen in patients with cardiac amyloidosis. (C) (apical 4-chamber view) demonstrates increased biventricular wall thickness, biatrial enlargement, and increased thickening of the interatrial septum (yellow arrow) and mitral valve leaflets (white arrow) in a patient with wild-type transthyretin cardiac amyloidosis. (D) Tissue Doppler imaging (TDI) tracing taken at the septal mitral annulus in a patient with ATTR cardiac amyloidosis. The TDI tracings shows the ‘‘5-5-5’’ sign (s’ [systolic], e’ [early diastolic], and a’ [late (atrial) diastolic] tissue velocities are all <5 cm/s), which is seen in patients with more advanced cardiac amyloidosis. The dotted lines denote the 5 cm/s cut-off for systolic and diastolic tissue velocities. In addition to the decreased tissue velocities, isovolumic contraction and relaxation times (IVCT and IVRT, respectively) are increased and ejection time (ET) is decreased, findings also seen in patients with cardiac amyloidosis especially as the disease becomes more advanced.Tissue Doppler imaging (TDI) and speckle-tracking echocardiography (STE) refine the non-invasive recognition of cardiac amyloidosis by quantitating longitudinal systolic function.51,55,56 A pattern of reduced longitudinal shortening with preserved LV ejection fraction and radial shortening is characteristic of cardiac amyloidosis and can differentiate it from other causes of increased LV wall thickness. Longitudinal systolic function is commonly impaired, even in the earlier phases of the disease, when radial thickening and circumferential shortening are still preserved.34,51,57-62 Both AL and ATTR cardiac amyloidosis patients demonstrate a typical pattern of distribution of STE-derived longitudinal strain in which basal LV segments are severely impaired while apical segments are relatively spared (Figure 3).51,63 Conversely, patients with other causes of LV hypertrophy (ie, aortic stenosis, hypertrophic cardiomyopathy) typically show reduced LV longitudinal strain in the regions of maximal hypertrophy.63,64Download figureDownload PowerPointFigure 3. Left ventricular longitudinal strain abnormalities. (A) (apical 4-chamber view), (B) (apical 2-chamber view), (C) (apical 3-chamber view) all show abnormal longitudinal strain in the basal and mid segments with relative preservation in the apical segments (purple and green curves, white arrows) in a patient with ATTRv cardiac amyloidosis. (D) shows the corresponding bullseye map of the longitudinal strain pattern throughout the left ventricle with the ‘‘cherry-on-the-top’’ sign (red denotes normal longitudinal strain at the apex and pink/blue denotes abnormal longitudinal strain at the mid/basal left ventricle).Another abnormal quantitative measure of LV contractility in cardiac amyloidosis is the myocardial contraction fraction (MCF), the ratio of stroke volume to myocardial volume. The MCF is an index of the volumetric shortening of the myocardium that is independent of chamber size and geometry and highly correlated with LV longitudinal strain.65-67 Abnormalities beyond the left ventricle can also suggest cardiac amyloidosis. Recently, it has been reported that the stroke volume index has a prognostic performance similar to LV strain in predicting survival in AL cardiac amyloidosis, independently of biomarker staging. Because the stroke volume index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL cardiac amyloidosis patients. Left atrial reservoir and pump functions measured by strain are frequently impaired, irrespective of left atrial size, suggesting that both raised LV filling pressures and direct atrial amyloid infiltration (as documented by CMR studies) contribute to left atrial dysfunction.41,68 This dysfunction may result in the formation of atrial and atrial appendage thrombi, even in the setting of normal sinus rhythm, exposing patients to higher relative risk for embolic strokes. Although data are not available, clinical experience from major amyloidosis centers suggest the highly thrombogenic milieu of the left atrium increases cardioembolic risk in these patients.69 The right ventricle is often affected due to a combination of increased afterload from pulmonary hypertension and intrinsic right ventricular amyloid infiltration, resulting in reduced tricuspid annular plane systolic excursion, tissue Doppler systolic velocity, and longitudinal strain.70As echocardiographic findings lack the tissue characterization provided by CMR, echocardiographic diagnosis of cardiac amyloidosis relies on the presence of highly suggestive findings that can confirm diagnostic suspicion.34,71Ta

In 18 dogs on total cardiopulmonary bypass, the average interval between local activations during artificially induced ventricular fibrillation (VF interval) was measured from extracellular electrograms, simultaneously recorded from up to 32 ventricular sites. VF intervals were used as an index of local refractoriness, based on the assumption that during ventricular fibrillation, cells are reexcited as soon as they have recovered their excitability. In support of this, microelectrode recordings in two hearts during ventricular fibrillation did not show a diastolic interval between successive action potentials. Refractory periods determined at a basic cycle length of 300 msec with the extrastimulus method correlated well with VF intervals measured at the same sites. Thus, this technique allows assessment of spatial dispersion of refractoriness during brief interventions such as sympathetic stimulation. The responses to left, right, and combined stellate ganglion stimulation varied substantially among individual hearts. This was observed both in dogs with an intact (n = 12) and decentralized (n = 6) autonomic nervous system. Individual ventricular sites could show effects of both left and right stellate ganglion stimulation (42% of tested sites) or show effects of left-sided stimulation only (31%) or right-sided stimulation only (14%). In 13% of sites, no effects of stellate stimulation were observed. Apart from these regional effects, the responses could be qualitatively different; that is, within the same heart, the VF interval prolonged at one site but shortened at another in response to the same intervention, although shortening was the general effect and prolongation the exception. Whenever sites responded to stellate ganglion stimulation with a shortening of VF interval, this shortening was approximately 10% for left, right, or combined stimulation, whether the autonomic nervous system was intact or decentralized. In six of 12 hearts in the intact group, there was a distinct regional effect of left stellate ganglion stimulation; in the other six hearts, the effects were distributed homogeneously over the ventricles. In three hearts, the effect of left stellate ganglion stimulation was strongest in the posterior wall, and in the other three hearts, in the anterior wall. The effects of right stellate ganglion stimulation were restricted to the anterior or lateral part of the left ventricle. Dispersion of VF intervals increased after left and combined stellate ganglion stimulation in the intact group and after right stellate ganglion stimulation in the decentralized group, but not significantly in every heart. This points to a marked individual variation with regard to the effects of sympathetic stimulation on electrophysiological properties of the heart.

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis.In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.

Individuals of south Asian origin have a very high risk of developing type 2 diabetes compared with white Caucasians. We aimed to assess volume and activity of brown adipose tissue (BAT), which is thought to have a role in energy metabolism by combusting fatty acids and glucose to produce heat and might contribute to the difference in incidence of type 2 diabetes between ethnic groups.We enrolled Dutch nationals with south Asian ancestry and matched Caucasian participants at The Rijnland Hospital (Leiderdorp, Netherlands). Eligible participants were healthy lean men aged 18-28 years, and we matched groups for BMI. We measured BAT volume and activity with cold-induced (18)F-fluorodeoxyglucose ((18)F-FDG) PET CT scans, and assessed resting energy expenditure, non-shivering thermogenesis, and serum parameters. This study is registered with the Netherlands Trial Register, number 2473.Between March 1, 2013, and June 1, 2013, we enrolled 12 participants in each group; one Caucasian participant developed hyperventilation after (18)F-FDG administration, and was excluded from all cold-induced and BAT measurements. Compared with Caucasian participants, south Asian participants did not differ in age (mean 23.6 years [SD 2.8] for south Asians vs 24.6 years [2.8] for Caucasians) or BMI (21.5 kg/m(2) [2.0] vs 22.0 kg/m(2) [1.6]), but were shorter (1.74 m [0.06] vs 1.85 m [0.04]) and lighter (65.0 kg [8.5] vs 75.1 kg [7.2]). Thermoneutral resting energy expenditure was 1297 kcal per day (SD 123) in south Asian participants compared with 1689 kcal per day (193) in white Caucasian participants (difference -32%, p=0.0008). On cold exposure, shiver temperature of south Asians was 2.0°C higher than Caucasians (p=0.0067) and non-shivering thermogenesis was increased by 20% in white Caucasians (p<0.0001) but was not increased in south Asians. Although the maximum and mean standardised uptake values of (18)F-FDG in BAT did not differ between groups, total BAT volume was lower in south Asians (188 mL [SD 81]) than it was in Caucasians (287 mL [169]; difference -34%, p=0.04). Overall, BAT volume correlated positively with basal resting energy expenditure in all assessable individuals (β=0.44, p=0.04).Lower resting energy expenditure, non-shivering thermogenesis, and BAT volumes in south Asian populations might underlie their high susceptibility to metabolic disturbances, such as obesity and type 2 diabetes. Development of strategies to increase BAT volume and activity might help prevent and treat such disorders, particularly in south Asian individuals.Dutch Heart Foundation (2009T038) and Dutch Diabetes Research Foundation (2012.11.1500).

Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.

Adequate suppression of cardiac glucose metabolism increases the interpretability and diagnostic reliability of (18)F-FDG PET studies performed to detect cardiac inflammation and infection. There are no standardized guidelines, though prolonged fasting (>6 h), carbohydrate-restricted diets, fatty meals, and heparin loading all have been proposed. The aim of this study was to compare the 3 preparatory protocols used in our institution.(18)F-FDG PET scans were selected and grouped according to 3 preparatory protocols (50 consecutive scans per group): 6-h fast (group 1), low-carbohydrate diet plus 12-h fast (group 2), and low-carbohydrate diet plus 12-h fast plus intravenous heparin preadministration (50 IU/kg) (group 3). Consecutive scans were retrospectively included from time frames during which the particular protocol was used. Group 1 included oncologic indications, and groups 2 and 3 infection or inflammation detection. Cardiac segments for which inflammation or infection foci had been confirmed on other imaging modalities were excluded from the analysis. (18)F-FDG uptake in normal myocardium was scored according to a scale ranging from 0 (uptake less than that in left ventricle blood pool) to 4 (diffuse uptake greater than that in liver). Adequate suppression was defined as uptake less than that in liver and without any focus (scores 0-2).Adequate suppression differed significantly between groups: 28% in group 1, 54% in group 2, and 88% in group 3 (P< 0.0001 for all comparisons).Single-dose heparin administration before (18)F-FDG PET in addition to a low-carbohydrate diet significantly outperforms a low-carbohydrate diet alone in adequately suppressing cardiac glucose metabolism.

Cardiac amyloidosis is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. Because of the relative rarity of cardiac amyloidosis, clinical and diagnostic expertise in the recognition and evaluation of individuals with suspected amyloidosis is mostly limited to a few expert centers. Electrocardiography, echocardiography, and radionuclide imaging have been used for the evaluation of cardiac amyloidosis for over 40 years. 1 Child J.S. Levisman J.A. Abbasi A.S. MacAlpin R.N. Echocardiographic manifestations of infiltrative cardiomyopathy: a report of seven cases due to amyloid. Chest. 1976; 70: 726-731 Abstract Full Text Full Text PDF PubMed Google Scholar , 2 Braun S.D. Lisbona R. Novales-Diaz J.A. Sniderman A. Myocardial uptake of 99mTc-phosphate tracer in amyloidosis. Clin Nucl Med. 1979; 4: 244-245 Crossref PubMed Google Scholar , 3 Gillmore J.D. Maurer M.S. Falk R.H. Merlini G. Damy T. Dispenzieri A. et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016; 133: 2404-2412 Crossref PubMed Google Scholar Although cardiovascular magnetic resonance (CMR) has also been in clinical practice for several decades, it was not applied to cardiac amyloidosis until the late 1990s. Despite an abundance of diagnostic imaging options, cardiac amyloidosis remains largely underrecognized or delayed in diagnosis. 4 Alexander K.M. Orav J. Singh A. Jacob S.A. Menon A. Padera R.F. et al. Geographic disparities in reported US amyloidosis mortality from 1979 to 2015: potential underdetection of cardiac amyloidosis. JAMA Cardiol. 2018; 3: 865-870 Crossref PubMed Scopus (7) Google Scholar Although advanced imaging options for noninvasive evaluation have substantially expanded, the evidence is predominately confined to single-center small studies or limited multicenter larger experiences, and there continues to be no clear consensus on standardized imaging pathways in cardiac amyloidosis. This lack of guidance is particularly problematic given that there are numerous emerging therapeutic options for this morbid disease, increasing the importance of accurate recognition at earlier stages. Imaging provides noninvasive tools for follow-up of disease remission/progression complementing clinical evaluation. Additional areas not defined include appropriate clinical indications for imaging, optimal imaging utilization by clinical presentation, accepted imaging methods, accurate image interpretation, and comprehensive and clear reporting. Prospective randomized clinical trial data for the diagnosis of amyloidosis and for imaging-based strategies for treatment are not available. A consensus of expert opinion is greatly needed to guide the appropriate clinical utilization of imaging in cardiac amyloidosis.

<h3>Background</h3> Fractional flow reserve (FFR) aims to identify the extent of epicardial disease, but may be obscured by involvement of the coronary microvasculature. We documented the impact of hyperaemic stenosis resistance (HSR) and hyperaemic microvascular resistance (HMR) on FFR, and its relationship with myocardial ischaemia in patients with stable coronary artery disease. <h3>Methods and results</h3> We evaluated 255 coronary arteries with stenoses of intermediate severity by means of intracoronary pressure and flow measurements to determine FFR, HSR and HMR. Myocardial perfusion scintigraphy (MPS) was performed to identify inducible myocardial ischaemia. In 178 patients, HMR was additionally determined in a reference coronary artery. Target vessel HMR was stratified according to reference vessel HMR tertiles. The diagnostic OR for inducible ischaemia on MPS of a positive compared with a negative FFR was significantly higher only in the presence of a high HMR (at the 0.75 and 0.80 FFR cut-off). Among stenoses with a positive FFR, the prevalence of ischaemia was significantly higher when HMR was high despite equivalent FFR across the HMR groups. This was paralleled by a concomitant significant increase in HSR with increasing HMR across groups. The relation between FFR and HSR (r²=0.54, p&lt;0.001) was modulated by the magnitude of HMR, and improved substantially after adjustment for HMR (adjusted-r²=0.73, p&lt;0.001), where, for epicardial disease of equivalent severity, FFR increased with increasing HMR. <h3>Conclusions</h3> Identification of epicardial disease severity by FFR is partly obscured by the microvascular resistance, which illustrates the necessity of combined pressure and flow measurements in daily practice.

Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. This study used 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B–containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD).Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing.Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.

This study assessed 5 frequently applied arterial 18fluorodeoxyglucose (18F-FDG) uptake metrics in healthy control subjects, those with risk factors and patients with cardiovascular disease (CVD), to derive uptake thresholds in each subject group. Additionally, we tested the reproducibility of these measures and produced recommended sample sizes for interventional drug studies.18F-FDG positron emission tomography (PET) can identify plaque inflammation as a surrogate endpoint for vascular interventional drug trials. However, an overview of 18F-FDG uptake metrics, threshold values, and reproducibility in healthy compared with diseased subjects is not available.18F-FDG PET/CT of the carotid arteries and ascending aorta was performed in 83 subjects (61 ± 8 years) comprising 3 groups: 25 healthy controls, 23 patients at increased CVD risk, and 35 patients with known CVD. We quantified 18F-FDG uptake across the whole artery, the most-diseased segment, and within all active segments over several pre-defined cutoffs. We report these data with and without background corrections. Finally, we determined measurement reproducibility and recommended sample sizes for future drug studies based on these results.All 18F-FDG uptake metrics were significantly different between healthy and diseased subjects for both the carotids and aorta. Thresholds of physiological 18F-FDG uptake were derived from healthy controls using the 90th percentile of their target to background ratio (TBR) value (TBRmax); whole artery TBRmax is 1.84 for the carotids and 2.68 in the aorta. These were exceeded by >52% of risk factor patients and >67% of CVD patients. Reproducibility was excellent in all study groups (intraclass correlation coefficient >0.95). Using carotid TBRmax as a primary endpoint resulted in sample size estimates approximately 20% lower than aorta.We report thresholds for physiological 18F-FDG uptake in the arterial wall in healthy subjects, which are exceeded by the majority of CVD patients. This remains true, independent of readout vessel, signal quantification method, or the use of background correction. We also confirm the high reproducibility of 18F-FDG PET measures of inflammation. Nevertheless, because of overlap between subject categories and the relatively small population studied, these data have limited generalizability until substantiated in larger, prospective event-driven studies. (Vascular Inflammation in Patients at Risk for Atherosclerotic Disease; NTR5006).

Abstract The use of cardiac PET, and in particular of quantitative myocardial perfusion PET, has been growing during the last years, because scanners are becoming widely available and because several studies have convincingly demonstrated the advantages of this imaging approach. Therefore, there is a need of determining the procedural modalities for performing high-quality studies and obtaining from this demanding technique the most in terms of both measurement reliability and clinical data. Although the field is rapidly evolving, with progresses in hardware and software, and the near perspective of new tracers, the EANM Cardiovascular Committee found it reasonable and useful to expose in an updated text the state of the art of quantitative myocardial perfusion PET, in order to establish an effective use of this modality and to help implementing it on a wider basis. Together with the many steps necessary for the correct execution of quantitative measurements, the importance of a multiparametric approach and of a comprehensive and clinically useful report have been stressed.

<h2>Abstract</h2> Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

Abstract With this document, we provide a standard for PET/(diagnostic) CT imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is). This standard should be applied in clinical practice and integrated in clinical (multicenter) trials for optimal procedural standardization. A major focus is put on procedures using [ 18 F]FDG, but 4Is PET radiopharmaceuticals beyond [ 18 F]FDG are also described in this document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicenter trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Finally, PET/MR applications in 4Is cardiovascular diseases are also briefly described. Diagnosis and management of 4Is-related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/MR, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.

In daily clinical practice, clinicians integrate available data to ascertain the diagnostic and prognostic probability of a disease or clinical outcome for their patients. For patients with suspected or known cardiovascular disease, several anatomical and functional imaging techniques are commonly performed to aid this endeavor, including coronary computed tomography angiography (CCTA) and nuclear cardiology imaging. Continuous improvement in positron emission tomography (PET), single-photon emission computed tomography (SPECT), and CT hardware and software has resulted in improved diagnostic performance and wide implementation of these imaging techniques in daily clinical practice. However, the human ability to interpret, quantify, and integrate these data sets is limited. The identification of novel markers and application of machine learning (ML) algorithms, including deep learning (DL) to cardiovascular imaging techniques will further improve diagnosis and prognostication for patients with cardiovascular diseases. The goal of this position paper of the European Association of Nuclear Medicine (EANM) and the European Association of Cardiovascular Imaging (EACVI) is to provide an overview of the general concepts behind modern machine learning-based artificial intelligence, highlights currently prefered methods, practices, and computational models, and proposes new strategies to support the clinical application of ML in the field of cardiovascular imaging using nuclear cardiology (hybrid) and CT techniques.

The aim was to examine whether ischaemic preconditioning delays the onset of cellular electrical uncoupling during ischaemia, and whether the effect of preconditioning is mediated by the activation of ATP sensitive K+ channels (IK-ATP).Onset of uncoupling, action potential duration (APD80), and conduction velocity were measured in an isolated perfused rabbit papillary muscle. Preconditioning consisted of 10 min occlusion and 10 min reperfusion prior to 40 min sustained ischaemia. Five groups were studied: (1) control (sustained ischaemia only); (2) preconditioning; (3) preconditioning with 20 microM glibenclamide, a blocker of IK-ATP, added for 10 min during the reperfusion period; (4) sustained ischaemia after 15 min perfusion with 20 microM cromakalim (BRL 34915), an opener of IK-ATP; (5) sustained ischaemia after 10 min perfusion with 20 microM glibenclamide without preconditioning.Uncoupling started at 15.0(SEM 0.7) min of ischaemia in the control group and at 22.8(1.5) min after preconditioning (p < 0.001 v control group). Blocking IK-ATP during the preconditioning protocol with glibenclamide abolished the delay of uncoupling: onset was at 14.7(1.2) min. Activation of IK-ATP with cromakalim resulted in uncoupling at 23.3(1.9) min (p < 0.002 v control). Glibenclamide without preconditioning had no effect on uncoupling: onset was at 15.6(1.0) min. APD80 during ischaemia was significantly shorter in the preconditioning and cromakalim groups than in the control group from 5 min of ischaemia onward. In the preconditioning+glibenclamide group and the glibenclamide group APD80 was at no point significantly different from the control group. Conduction velocity during ischaemia decreased to about 70% of baseline after 10 min and was not different between the five groups.(1) Preconditioning delays the onset of electrical uncoupling; (2) the protective effect of preconditioning may be caused by activation of the IK-ATP channel; (3) the protective effect is associated with reduction of action potential duration, but not with changes of conduction velocity.

Cardiac sympathetic neuronal function and activity can be assessed noninvasively by the use of I-metaiodobenzylguanidine (I-MIBG), an analogue of norepinephrine [1]. In the past two decades, a large number of investigators have demonstrated decreased myocardial I-MIBG uptake in patients with chronic heart failure (CHF) and have shown that those with the lowest uptake tend to have the poorest prognosis [2–12]. There have also been findings suggesting that abnormalities of myocardial I-MIBG uptake may be predictive of increased risk of ventricular arrhythmia and sudden cardiac death [13, 14]. One factor that has constrained acceptance of cardiac I-MIBG imaging as a clinical management tool in heart failure has been the variability of the technical aspects of the procedure. Although most reports include the heart-to-mediastinum (H/M) ratio as the measure of myocardial uptake, the methods used to obtain this parameter have shown considerable variation. However, the influence of procedural and acquisition parameters on the reproducibility of this measurement technique have only occasionally been considered.

Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current 'gold standard' for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans.BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations.Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not.Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects.NTR 2473.

The purpose of this study was to determine the most appropriate prognostic endpoint for myocardial (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with chronic heart failure (CHF) based on aggregate results from multiple studies published in the past decade.Original individual late (3-5 h) heart/mediastinum (H/M) ratio data of 636 CHF patients were retrieved from six studies from Europe and the USA. All-cause mortality, cardiac mortality, arrhythmic events, and heart transplantation were investigated to determine which provided the strongest prognostic significance for the MIBG imaging data. The majority of patients was male (78%), had a decreased left ventricular ejection fraction (31.1 ± 12.5%), and a mean late H/M of 1.67 ± 0.47. During follow-up (mean 36.9 ± 20.1 months), there were 83 deaths, 67 cardiac deaths, 33 arrhythmic events, and 56 heart transplants. In univariate regression analysis, late H/M was a significant predictor of all event categories, but lowest hazard ratios (HRs) were for the composite endpoint of any event (HR = 0.30, 95% CI 0.19-0.46), all-cause (HR = 0.29, 95% CI 0.16-0.53), and cardiac mortality (HR = 0.28, 95% CI 0.14-0.55). In multivariate analysis, late H/M was an independent predictor for all event categories, except for arrhythmias.This pooled individual patient data meta-analysis showed that, in CHF patients, the late H/M ratio is not only useful as a dichotomous predictor of events (high vs. low risk), but also has prognostic implication over the full range of the outcome value for all event categories except arrhythmias.

Background— Abnormalities in the coronary microcirculation are increasingly recognized as an elementary component of ischemic heart disease, which can be accurately assessed by coronary flow velocity reserve in reference vessels (refCFVR). We studied the prognostic value of refCFVR for long-term mortality in patients with stable coronary artery disease. Methods and Results— We included patients with stable coronary artery disease who underwent intracoronary physiological evaluation of ≥1 coronary lesion of intermediate severity between April 1997 and September 2006. RefCFVR was assessed if a coronary artery with &lt;30% irregularities was present. RefCFVR &gt;2.7 was considered normal. Patients underwent revascularization of all ischemia-causing lesions. Long-term follow-up was performed to document the occurrence of (cardiac) mortality. RefCFVR was determined in 178 patients. Kaplan–Meier estimates of 12-year all-cause mortality were 16.7% when refCFVR &gt;2.7 and 39.6% when refCFVR ≤2.7 ( P &lt;0.001), whereas Kaplan–Meier estimates for cardiac mortality were 7.7% when refCFVR &gt;2.7 and 31.6% when refCFVR ≤2.7 ( P &lt;0.001). After multivariable adjustment, refCFVR ≤2.7 was associated with a 2.24-fold increase in all-cause mortality hazard (hazard ratio, 2.24; 95% confidence interval, 1.13–4.44; P =0.020) and a 3.32-fold increase in cardiac mortality hazard (hazard ratio, 3.32; 95% confidence interval, 1.27–8.67; P =0.014). Impairment of refCFVR originated from significantly higher baseline flow velocity in the presence of significantly lower reference vessel baseline microvascular resistance ( P &lt;0.001), indicating impaired coronary autoregulation as its cause. Conclusions— In patients with stable coronary artery disease, impaired refCFVR, resulting from increased baseline flow velocity indicating impaired coronary autoregulation, is associated with a significant increase in fatal events at long-term follow-up.

We sought to compare the diagnostic accuracy of basal stenosis resistance index (BSR), instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) for stenosis-specific myocardial ischaemia identified by means of a combined reference standard of myocardial perfusion scintigraphy and the hyperaemic stenosis resistance index.BSR and FFR were determined for 299 coronary stenoses, iFR was determined for 85 coronary stenoses (iFR cohort). The discriminative value for stenosis-specific myocardial ischaemia was compared by means of the area under the receiver operating characteristic (ROC) curves (AUC). Classification agreement with the reference standard was determined according to ROC curve-derived ischaemic cut-off values, as well as according to clinical cut-off values, equivalent to the 0.80 FFR cut-off. Across all stenoses, the discriminative value of BSR and FFR was equivalent (AUC: 0.90 and 0.91, respectively, p=0.46). In the iFR cohort, the discriminative value was equivalent for BSR, iFR, and FFR (AUC: 0.88, 0.84, and 0.88, respectively; p≥0.20 for all). At both ischaemic as well as clinical cut-off values, classification agreement with the reference standard was equivalent for BSR and FFR across all stenoses, as well as for BSR, iFR, and FFR in the iFR cohort.BSR, iFR, and FFR have equivalent diagnostic accuracy for the detection of ischaemia-generating coronary stenoses.

Recently, 18F-fluorodeoxyglucose positron emission tomography with low-dose computed tomography for attenuation correction and anatomical correlation (18F-FDG-PET/CT) has seen increasing use to help diagnose prosthetic heart valve (PHV) endocarditis. Based on the available evidence, 18F-FDG-PET/CT

Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients.CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001.One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI.Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis.Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.

An increasing number of Nuclear Medicine sites in Europe are using cardiac-centered gamma cameras for myocardial perfusion scintigraphy (MPS). Three cardiac-centered gamma cameras are currently the most frequently used in Europe: the D-SPECT (Spectrum Dynamics), the Alcyone (Discovery NM 530c and Discovery NM/CT 570c; General Electric Medical Systems), and the IQ-SPECT (Siemens Healthcare). The increased myocardial count sensitivity of these three cardiac-centered systems has allowed for a decrease in the activities of radiopharmaceuticals injected to patients for myocardial perfusion imaging and, consequently, radiation exposure of patients. When setting up protocols for MPS, the overall objective should be to maintain high diagnostic accuracy of MPS, while injecting the lowest activities reasonably achievable to reduce the level of radiation exposure of patient and staff. These guidelines aim at providing recommendations for acquisition protocols and image interpretation using cardiac-centered cameras. As each imaging system has specific design and features for image acquisition and analysis, these guidelines have been separated into three sections for each gamma camera system. These recommendations have been written by the members of the Cardiovascular Committee of EANM and were based on their own experience with each of these systems and on the existing literature.

To the Editor: Proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) therapy reduces cardiovascular (CV) risk by lowering low-density lipoprotein cholesterol (LDL-C) levels, with a neutral effect on C-reactive protein (CRP) ([1][1]). In view of the use of CRP as an inflammatory biomarker

We sought to perform a direct comparison between perfusion scintigraphic results and intracoronary-derived hemodynamic variables (fractional flow reserve [FFR]; absolute and relative coronary flow velocity reserve [CFVR and rCFVR, respectively]) in patients with two-vessel disease.There is limited information on the diagnostic accuracy of intracoronary-derived variables (CFVR, FFR and rCFVR) in patients with multivessel disease.Dipyridamole technetium-99m sestamibi (MIBI) single-photon emission computed tomography (SPECT) was performed in 127 patients. The presence of reversible perfusion defects in the region of interest was determined. Within one week, angiography was performed; CFVR, rCFVR and FFR were determined in 161 coronary lesions after intracoronary administration of adenosine. The predictive value for the presence of reversible perfusion defects on MIBI SPECT of CFVR, rCFVR and FFR was evaluated by the area under the curve (AUC) of the receiver operating characteristics curves.The mean percentage diameter stenosis was 57% (range 35% to 85%), as measured by quantitative coronary angiography. Using per-patient analysis, the AUCs for CFVR (0.70 +/- 0.052), rCFVR (0.72 +/- 0.051) and FFR (0.76 +/- 0.050) were not significantly different (p = NS). The percentages of agreement with the results of MIBI SPECT were 76%, 78% and 77% for CFVR, rCFVR and FFR, respectively. Per-lesion analysis, using all 161 measured lesions, yielded similar results.The diagnostic accuracy of three intracoronary-derived hemodynamic variables, as compared with the results of perfusion scintigraphy, is similar in patients with two-vessel coronary artery disease. Cut-offvalues of 2.0 for CFVR, 0.65 for rCFVR and 0.75 for FFR can be used for clinical decision-making in this patient cohort. Discordant results were obtained in 23% of the cases that require prospective evaluation for appropriate patient management.

Although several myocardial iodine 123 metaiodobenzylguanidine (MIBG) indices are increasingly used to detect alterations in myocardial sympathetic activity in various forms of cardiac pathology, published measurements of normal values and within-subject variability are lacking. Twenty-five healthy volunteers underwent planar and single photon emission computed tomography (SPECT) imaging. Heart-mediastinum ratio (H/M) and myocardial washout were calculated from planar images comparing three different methods for the assessment of myocardial activity: (1) global region over the myocardium (cavity included), (2) global region over the myocardium (cavity excluded), and (3) fixed small myocardial region. Segmental (relative) uptake and washout were assessed by SPECT. For all MIBG indices, the interindividual variation was the lowest for methods 1 and 2. In SPECT this variation was low for relative segmental uptake compared with washout. In 9 subjects a second MIBG scintigraphy was performed after 3 months. The within-subject variability of H/M and washout assessed by planar methods 1 and 2 was 5%, whereas it was approximately 9% for planar method 3. For relative segmental uptake from SPECT, this variability was 5%. MIBG H/M (planar) and relative segmental uptake (SPECT) show a low interindividual and within-subject variability. This enables the detection of small (regional) variations in myocardial sympathetic nervous function, especially to monitor the effect of therapeutic interventions in patients with various cardiac diseases. (J Nucl Cardiol 2004;11: 126-33.)

This study aimed to investigate the roles of intracoronary derived coronary flow velocity reserve (CFVR) and myocardial perfusion scintigraphy (single photon emission computed tomography, or SPECT) for management of an intermediate lesion in patients with multivessel coronary artery disease.Evaluation of the functional significance of intermediate coronary narrowings (40% to 70% diameter stenosis) is important for clinical decision making and risk stratification.In a prospective, multicenter study, SPECT was performed in 191 patients with stable angina and multivessel disease and scheduled for angioplasty (percutaneous transluminal coronary angioplasty, or PTCA) of a severe coronary narrowing. Coronary flow velocity reserve was determined selectively distal to an intermediate lesion in another artery using a Doppler guidewire. Percutaneous transluminal coronary angioplasty of the intermediate lesion was deferred when SPECT was negative or CFVR greater-than-or-equal 2.0. Patients were followed for one year to document major cardiac events (death, infarction, revascularization), related to the intermediate lesion.Reversible perfusion defects were documented in the area of the intermediate lesion in 30 (16%) patients; CFVR was positive in 46 (24%) patients. Percutaneous transluminal coronary angioplasty of the intermediate lesion was deferred in 182 patients. During follow-up, 19 events occurred (3 myocardial infarctions, 16 revascularizations). Coronary flow velocity reserve was a more accurate predictor of cardiac events than was SPECT; relative risk: CFVR 3.9 (1.7 to 9.1), p < 0.05; SPECT 0.5 (0.1 to 3.2), p = NS. Multivariate analysis revealed CFVR as the only significant predictor for cardiac events.Deferral of PTCA of intermediate lesions in multivessel disease is safe when CFVR greater-than-or-equal 2.0 (event rate 6%). This selective evaluation of coronary lesion severity during cardiac catheterization allows a more accurate risk stratification than does SPECT, which is important for clinical decision making in this patient cohort.

Dispersion in refractoriness is considered a major factor in induction and persistence of cardiac arrhythmias. The sympathetic nervous system is known to modulate refractoriness. An index of refractoriness has therefore been assessed in normal and ischaemic myocardium simultaneously at multiple sites, with and without sympathetic stimulation.In six dogs on total cardiopulmonary bypass the average interval between local activations was measured during artificially induced ventricular fibrillation from extracellular electrograms simultaneously recorded from 32 ventricular sites. These local ventricular fibrillation intervals may be used as an index of local refractoriness.During regional ischaemia, ventricular fibrillation intervals of ischaemic sites could prolong by up to 60% after 3 min following coronary occlusion. Left stellate ganglion stimulation during ischaemia produced either no response or prolonged the ventricular fibrillation intervals even further at ischaemic sites, whereas ventricular fibrillation intervals at non-ischaemic sites shortened. Dispersion in refractoriness across the ischaemic border increased by 14-59% in individual hearts following sympathetic stimulation during acute, regional ischaemia.Due to opposite effects on normal and ischaemic myocardium, sympathetic stimulation increases the difference in refractoriness over the ischaemic border. This may enhance the chance for regional conduction block and the propensity to re-entrant arrhythmias.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibro-fatty replacement of RV myocardium. However, patchy inflammatory infiltrates in the RV are also consistently reported using autopsy and myocardial biopsy. Although the role of inflammation in ARVC/D is unresolved, the ability to assess inflammation non-invasively may aid in the diagnostic process. We aimed to establish whether cardiac inflammation can be assessed non-invasively in ARVC/D patients.In eight ARVC/D patients and nine controls (haematology/oncology patients), the level of inflammatory activation was assessed by measuring plasma levels of inflammatory cytokines. Regional myocardial inflammation was assessed with (67)Ga scintigraphy.ARVC/D patients had higher plasma levels than controls of the pro-inflammatory cytokines interleukin (IL)-1β (1.22 ± 0.07 vs 0.08 ± 0.01 pg/ml, p < 0.0001), IL-6 (3.16 ± 0.44 vs 0.38 ± 0.04 pg/ml, p < 0.0001) and tumour necrosis factor (TNF)-α (9.16 ± 0.90 vs 0.40 ± 0.06 pg/ml, p < 0.0001), while levels of the anti-inflammatory cytokine IL-10 were not significantly different (1.36 ± 0.15 vs 1.20 ± 0.30 pg/ml, p = 0.74). (67)Ga uptake in the RV was higher in ARVC/D patients than in controls. In ARVC/D patients, (67)Ga uptake in the RV wall was higher than in the interventricular septum or left ventricular wall.Inflammation in the RV wall of ARVC/D patients can be detected non-invasively with the combined analysis of plasma levels of inflammatory cytokines and cardiac (67)Ga scintigraphy.

The objective of this study was to describe postoperative undernutrition in terms of postoperative losses of appendicular skeletal muscle mass (ASMM) with respect to complications, quality of life, readmission, and 1-y mortality after cardiac surgery.Patients undergoing cardiac surgery were prospectively followed. ASMM was measured 2 wk before and 2 mo after surgery using dual-energy X-ray absorptiometry. ASMM consists of arm skeletal muscle mass (SMM) and leg SMM. The association between ≥5% of ASMM decrease and postoperative outcome was analyzed using the chi-square test. A similar approach was used to analyze arm SMM and leg SMM decreases separately.Twenty-nine patients were included (23 male, 34.5% ≥65 y old). Postoperatively, seven patients (24.1%) lost ≥5% ASMM. When analyzed separately, a ≥5% decrease in leg SMM was associated with a decrease in experienced vitality (odds ratio 13.0, 95% confidence interval 1.32-128.11, P = 0.03). In contrast, a ≥5% loss of arm SMM was associated with fewer in-hospital complications (odds ratio 0.20, 95% confidence interval 0.04-0.98, P = 0.04). These patients were characterized by a higher preoperative fat-free mass index (kilograms per meter squared; P = 0.01).The results suggest that a preoperatively higher fat-free mass index indicates better ability to cope with operative stress, resulting in fewer complications. In addition, postoperative loss of muscle mass was associated with decreased vitality. We advocate further research investigating the effect of preoperative and postoperative nutritional intervention combined with physical exercise programs to increase lean body mass and thereby improve postoperative recovery after cardiac surgery.

The role of brown adipose tissue (BAT) in adult metabolism is poorly understood. This study aimed to examine the differential effects of an overnight fast and the postprandial state on BAT activity.We included 10 healthy, lean male volunteers. BAT uptake of glucose was visualized using (18)F-FDG PET/CT during mild cold exposure. Each subject underwent PET/CT twice. The first scan was obtained after an overnight fast; the second after a standardized meal.(18)F-FDG uptake in BAT was observed in 6 of 10 volunteers. These subjects were found to have a higher maximal standardized uptake value when fasting (median, 13.1 g/mL; range, 6.1-27.6 g/mL) than when in the postprandial state (median, 6.8 g/mL; range, 2.1-13.4 g/mL) (P = 0.03).Cold-stimulated (18)F-FDG uptake by BAT in humans is more pronounced during fasting. The lower maximal standardized uptake value in the postprandial state may be explained by increased insulin-stimulated glucose uptake in muscle.

Patients with clinical suspicion of large-vessel vasculitis (LVV) may present with nonspecific signs and symptoms and increased inflammatory parameters and may remain without diagnosis after routine diagnostic procedures. Both the nonspecificity of the radiopharmaceutical 18 F-FDG and the synergy of integrating functional and anatomical images with PET/CT offer substantial benefit in the diagnostic work-up of patients with clinical suspicion for LVV. A negative temporal artery biopsy, an ultrasonography without an arterial halo, or a MRI without aortic wall thickening or oedema do not exclude the presence of LVV and should therefore not exclude the use of 18 F-FDG PET/CT when LVV is clinically suspected. This overview further discusses the notion that there is substantial underdiagnosis of LVV. Late diagnosis of LVV may lead to surgery or angioplasty in occlusive forms and is often accompanied by serious aortic complications and a fatal outcome. In contrast to the American College of Rheumatology 1990 criteria for vasculitis, based on late LVV effects like arterial stenosis and/or occlusion, 18 F-FDG PET/CT sheds new light on the classification of giant cell arteritis (GCA) and Takayasu arteritis (TA). The combination of these observations makes the role of 18 F-FDG PET/CT in the assessment of patients suspected for having LVV promising.

Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold. <b>Methods:</b> This was a prospective observational study. We included 10 young obese, 11 old lean, and 14 young lean healthy men. All subjects underwent ¹⁸F-FDG PET/CT and ¹²³I-<i>meta</i>-iodobenzylguanidine (¹²³I-<i>m</i>IBG) SPECT/CT after an overnight fast and 2 h of cold exposure. Metabolic BAT activity was expressed as volume and as SUV_max of ¹⁸F-FDG. BAT SNS activity was expressed as volume and as the ratio between ¹²³I-<i>m</i>IBG uptake in BAT and a reference region (SQUV_max of ¹²³I-<i>m</i>IBG). <b>Results:</b> SUV_max, BAT volume, and SQUV_max were significantly different between young and old (SUV_max, 7.9 [range, 4.2–17.3] vs. 2.9 [range, 0.0–4.0]; volume, 124.8 [range, 10.9–338.8] vs. 3.4 [range, 0.0–10.9]; and SQUV_max, 2.7 [range, 1.9–4.7] vs. 0.0 [range, 0.0–2.2], respectively) (all <i>P</i> &lt; 0.01) but not between lean and obese (SUV_max, 7.9 [range, 4.2–17.3] vs. 4.0 [range, 0.0–13.5] [<i>P</i> = 0.69]; volume, 124.8 [range, 10.9–338.8] vs. 11.8 [range, 0.0–190.2] [<i>P</i> = 0.64]; and SQUV_max, 2.7 [range, 1.9–4.7] vs. 1.7 [range, 0–3.5] [<i>P</i> = 0.69], respectively). We found a strong positive correlation between BAT activity measured with ¹⁸F-FDG and ¹²³I<i>-m</i>IBG in the whole group of BAT-positive subjects (ρ = 0.82, <i>P</i> &lt; 0.01). <b>Conclusion:</b> Both sympathetic drive and BAT activity are lower in older but not in obese men.

CKD associates with a 1.5- to 3.5-fold increased risk for cardiovascular disease. Both diseases are characterized by increased inflammation, and in patients with CKD, elevated C-reactive protein level predicts cardiovascular risk. In addition to systemic inflammation, local arterial inflammation, driven by monocyte-derived macrophages, predicts future cardiovascular events in the general population. We hypothesized that subjects with CKD have increased arterial and cellular inflammation, reflected by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography computed tomography (PET/CT) of the arterial wall and a migratory phenotype of monocytes. We assessed 18F-FDG uptake in the arterial wall in 14 patients with CKD (mean±SD age: 59±5 years, mean±SD eGFR: 37±12 ml/min per 1.73 m2) but without cardiovascular diseases, diabetes, or inflammatory conditions and in 14 control subjects (mean age: 60±11 years, mean eGFR: 86±16 ml/min per 1.73 m2). Compared with controls, patients with CKD showed increased arterial inflammation, quantified as target-to-background ratio (TBR) in the aorta (TBRmax: CKD, 3.14±0.70 versus control, 2.12±0.27; P=0.001) and the carotid arteries (TBRmax: CKD, 2.45±0.65 versus control, 1.66±0.27; P<0.001). Characterization of circulating monocytes using flow cytometry revealed increased chemokine receptor expression and enhanced transendothelial migration capacity in patients with CKD compared with controls. In conclusion, this increased arterial wall inflammation, observed in patients with CKD but without overt atherosclerotic disease and with few traditional risk factors, may contribute to the increased cardiovascular risk associated with CKD. The concomitant elevation of monocyte activity may provide novel therapeutic targets for attenuating this inflammation and thereby preventing CKD-associated cardiovascular disease.

Circulating monocytes infiltrate the plaque and differentiate into macrophages, contributing to an inflammatory environment which is associated with higher risk of cardiovascular events. Although the pivotal role of circulating monocytes in plaque inflammation has been firmly established, the search continues to identify specific monocyte subsets that may be especially atherogenic. Therefore, we evaluated the relation between monocyte phenotype, particularly surface receptor expression, and arterial wall inflammation in patients at increased cardiovascular risk.We performed a multivariate linear regression analysis in 79 patients at increased cardiovascular risk who had both an 18F-fluorodeoxyglucose positron emission tomography/computed tomography to assess arterial wall inflammation and extensive monocyte characterization (using flow cytometry). We found that CCR2, a monocyte chemokine receptor essential for transmigration, significantly correlates with arterial wall inflammation. This relationship was independent of traditional cardiovascular risk factors and statin use (β = 0.429, P = 0.015). We found no relation between arterial wall inflammation and monocyte count or monocyte subsets, namely CD14+CD16-, CD14+CD16+, CD14+CD16 ++, CCR5+, CD18+, CD11b+, or CD11c+ monocytes.Monocyte CCR2 expression is associated with arterial wall inflammation in patients at increased cardiovascular risk. Our data warrant further studies to assess if inhibition of CCR2 may attenuate atherosclerotic plaque inflammation.

Planar myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy is a highly reproducible technique. However, differences in collimator use are one of the most important factors that cause variation among institutions and studies in heart-to-mediastinum (H/M) ratio. Therefore, standardization among various gamma camera-collimator combinations is needed. Previously, a phantom has been developed to cross-calibrate different acquisition conditions in Japan. For further cross-calibration of European myocardial 123I-mIBG imaging, the aim of this study was to collect 123I-mIBG data for H/M ratios from common European gamma camera vendors. 210 experiments were performed in 27 European institutions. Based on these experiments, conversion coefficients for each gamma camera-collimator combination were calculated. An averaged conversion coefficient of 0.88 was used to calculate a standardized H/M ratio. On average, LE-collimator-derived H/M ratios were significantly lower compared to ME-collimator-derived H/M ratios. The mean conversion coefficients ranged from 0.553 to 0.605 for the LE-collimator group and from 0.824 to 0.895 for the ME-collimator group. Clinically established H/M ratios can be converted into standardized H/M ratios using cross-calibrated conversion coefficients. This standardization is important for identifying appropriate thresholds for adequate risk stratification. In addition, this cross-calibration enables comparison between different national and international data.

In the last decade, myocardial perfusion imaging (MPI) with PET has emerged to play a pivotal role in the clinical routine process for the detection of hemodynamically significant obstructive coronary artery disease (CAD) and cardiovascular risk stratification ([1][1]–[5][2]). The high spatial and

Abstract With this summarized document we share the standard for positron emission tomography (PET)/(diagnostic)computed tomography (CT) imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is) as recently published in the European Journal of Nuclear Medicine and Molecular Imaging. This standard should be applied in clinical practice and integrated in clinical (multicentre) trials for optimal standardization of the procedurals and interpretations. A major focus is put on procedures using [18F]-2-fluoro-2-deoxyglucose ([18F]FDG), but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this summarized document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicentre trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Diagnosis and management of 4Is related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/magnetic resonance, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.

HomeCirculation: Cardiovascular ImagingVol. 14, No. 7ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2—Diagnostic Criteria and Appropriate Utilization Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2—Diagnostic Criteria and Appropriate Utilization Sharmila Dorbala, MD, MPH, FASNC, Chair, Yukio Ando, MD, PhD, Sabahat Bokhari, MD, Angela Dispenzieri, MD, Rodney H. Falk, MD, Victor A. Ferrari, MD, Marianna Fontana, PhD, Olivier Gheysens, MD, PhD, Julian D. Gillmore, MD, PhD, Andor W. J. M. Glaudemans, MD, PhD, Mazen A. Hanna, MD, Bouke P. C. Hazenberg, MD, PhD, Arnt V. Kristen, MD, Raymond Y. Kwong, MD, MPH, Mathew S. Maurer, MD, Giampaolo Merlini, MD, Edward J. Miller, MD, PhD, James C. Moon, MD, Venkatesh L. Murthy, MD, PhD, C. Cristina Quarta, MD, PhD, Claudio Rapezzi, MD, Frederick L. Ruberg, MD, Sanjiv J. Shah, MD, Riemer H. J. A. Slart, MD, Hein J. Verberne, MD, PhD and Jamieson M. Bourque, MD, MHS, FASNC, Co-Chair Sharmila DorbalaSharmila Dorbala , Yukio AndoYukio Ando , Sabahat BokhariSabahat Bokhari , Angela DispenzieriAngela Dispenzieri , Rodney H. FalkRodney H. Falk , Victor A. FerrariVictor A. Ferrari , Marianna FontanaMarianna Fontana , Olivier GheysensOlivier Gheysens , Julian D. GillmoreJulian D. Gillmore , Andor W. J. M. GlaudemansAndor W. J. M. Glaudemans , Mazen A. HannaMazen A. Hanna , Bouke P. C. HazenbergBouke P. C. Hazenberg , Arnt V. KristenArnt V. Kristen , Raymond Y. KwongRaymond Y. Kwong , Mathew S. MaurerMathew S. Maurer , Giampaolo MerliniGiampaolo Merlini , Edward J. MillerEdward J. Miller , James C. MoonJames C. Moon , Venkatesh L. MurthyVenkatesh L. Murthy , C. Cristina QuartaC. Cristina Quarta , Claudio RapezziClaudio Rapezzi , Frederick L. RubergFrederick L. Ruberg , Sanjiv J. ShahSanjiv J. Shah , Riemer H. J. A. SlartRiemer H. J. A. Slart , Hein J. VerberneHein J. Verberne and Jamieson M. BourqueJamieson M. Bourque Originally published1 Jul 2021https://doi.org/10.1161/HCI.0000000000000030Circulation: Cardiovascular Imaging. 2021;14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 1, 2021: Ahead of Print Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.IntroductionCardiac amyloidosis is increasingly recognized as an important cause of heart failure with preserved ejection fraction (EF)1 and carries a high morbidity and mortality.2,3 Emerging imaging methods have facilitated earlier diagnosis4–6 and improved prognostication7,8 and management. The diagnostic criteria for cardiac amyloidosis, however, need to be updated to include these novel imaging tools.A multi-societal writing group with expertise in cardiovascular imaging and cardiac amyloidosis has been assembled by the American Society of Nuclear Cardiology (ASNC) with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), the American Society of Echocardiography (ASE), the European Association of Nuclear Medicine (EANM), the Heart Failure Society of America (HFSA), the International Society of Amyloidosis (ISA), the Society for Cardiovascular Magnetic Resonance (SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This writing group has established consensus recommendations on imaging cardiac amyloidosis from this panel of multidisciplinary experts. Part 1 documents the evidence base for multimodality imaging in cardiac amyloidosis and defines standardized imaging protocols. Part 2 has the following aims:Develop consensus diagnostic criteria for cardiac amyloidosis incorporating advanced echocardiography, cardiovascular magnetic resonance (CMR), and radionuclide imaging.Identify consensus clinical indications for noninvasive imaging in cardiac amyloidosis to guide patient management through a rigorous application of the modified Delphi method.Address the appropriate utilization of echocardiography, CMR, and radionuclide imaging in these clinical scenarios.Diagnostic Criteria, Clinical Indications, and Appropriate UtilizationExpert consensus criteria were developed based on histologic, clinical, and imaging features with accompanying certainty of recommendation. The appropriate utilization of multiple imaging modalities was assessed using clinical scenarios that represent diverse patient presentations and address the diagnostic and prognostic capabilities of noninvasive imaging. The goal of this document is to determine which modalities may be reasonable for a specific indication rather than to identify one test that is best.MethodsIn order to accomplish this goal, a rating panel of clinical experts in cardiac amyloidosis was assembled. As recommended by the RAND-UCLA Appropriateness Manual, this group included representatives from relevant clinical societies, all of whom have extensive expertise in the management of cardiac amyloidosis.9 The group was recruited internationally from diverse geographical locations. All group representatives practice in academic settings, which is typical given the clinical complexity of this disorder. Experts with extensive imaging expertise were expressly excluded from this panel to prevent bias in the scoring process, as experts with expertise in a single imaging modality might tend to rate their favored imaging modality as more appropriate than the remainder. The final ratings panel included seven clinical experts.9 This group developed expert consensus recommendations on criteria for the diagnosis of cardiac amyloidosis via histologic, imaging, and cardiac biomarkers. The rating panel then engaged in an exercise using the modified Delphi technique for a robust evaluation of appropriateness.10Indication DevelopmentA standardized approach was used to ensure inclusion of the majority of clinical scenarios encountered in the evaluation and management of cardiac amyloidosis. Despite best efforts, however, the writing group acknowledges that clinical presentations vary, and not every relevant clinical scenario is represented. These scenarios were organized into several broad categories representing key areas of cardiac amyloidosis clinical care:Assessment for cardiac involvement in asymptomatic individuals;Screening for cardiac amyloidosis in patients with symptomatic heart failure;Evaluation of biopsy-proven light chain (AL) and amyloidogenic transthyretin (ATTR) cardiac amyloidosis;Follow-up testing for new or worsening cardiac symptoms;Other diverse clinical scenarios/conditions; andPrior testing suggestive of cardiac amyloidosis.Once a final list was developed, the larger writing group, comprised of imaging experts in the various disciplines, provided feedback prior to the final indication determination.Rating ProcessOnce the indications were finalized, the rating panel scored them independently. For each indication, the rating panel was asked to rate its appropriateness in the evaluation and management of cardiac amyloidosis. The following definition of appropriate use was adapted from prior appropriate use documents11–13:An appropriate imaging study is one in which the expected incremental information, combined with clinical judgement, exceeds the expected negative consequences by a sufficiently wide margin for a specific indication that the procedure is generally considered acceptable care and a reasonable approach for the indication.14The rating group used a scale from 1 to 9. These scores were divided into three general categories: Appropriate (A), May Be Appropriate (M), or Rarely Appropriate (R) in accordance with published appropriate use criteria methodology and prior appropriate use documents.12,15–17Appropriate (Score 7–9)An indication scored from 7 to 9 represents an appropriate option for management of patients in this population due to benefits generally outweighing risks; it should be viewed as an effective option for individual care plans, although the imaging procedure may not always be necessary depending on physician judgement and patient-specific preferences (ie, the procedure is generally acceptable and is generally reasonable for the indication).May Be Appropriate (Score 4–6)An indication scored from 4 to 6 is considered at times an appropriate option for management of patients in this population due to variable evidence or agreement regarding the risk-benefit ratio, potential benefit based on practice experience in the absence of evidence, and/or variability in the population; the effectiveness of this indication for individual care must be determined by a patient's physician in consultation with the patient based on additional clinical variables and judgement along with patient preferences (ie, the procedure may be acceptable and may be reasonable for the indication). A categorization of May Be Appropriate may also imply that further research and/or patient information is needed to classify the indication definitively.Rarely Appropriate (Score 1–3)An indication scored from 1 to 3 is rarely an appropriate option for management of patients in this population for this clinical indication due to a lack of a clear benefit/risk advantage; it is rarely an effective option for individual care plans; exceptions should have documentation of the clinical reasons for proceeding with this care option (ie, procedure is not generally acceptable and is not generally reasonable for the indication).The division of the scores into these three broad categories is somewhat arbitrary, and the raters were instructed to consider the numeric range as a continuum. Recognizing that there is variability in many patient factors, local practice patterns, and a lack of data on use of imaging across clinical scenarios and indications, the rating panel members were asked to independently rate the appropriateness of using each imaging modality for the general category and the specific clinical indication based on the best available evidence, including guidelines and key references wherever possible.10After rating the indications independently, the total results were tabulated, and each rater was provided with their individual scores and de-identified scores from all other panel members. The panel was convened for conference calls for discussion of each indication. The clinical indications were modified if needed based on the discussion. This meeting was facilitated by non-rating representatives of the writing panel who served as unbiased moderators and facilitated group dynamics to optimize the process. The moderators were free of significant relationships with industry and were unbiased relative to the topics under consideration. Following the meeting, panel members were asked to independently provide their scores for each clinical indication in a second round of ratings, taking into consideration the discussion from the call. For indications with continued significant dispersion of scores, a second conference call and third round of ratings occurred.Median scores were calculated. A median panel score of 7 to 9 without disagreement was considered "Appropriate." A median panel score of 1 to 3 without disagreement was considered "Rarely Appropriate." A median panel score of 4 to 6 or any median with disagreement was classified as "May Be Appropriate." Agreement was classified as having no more than two panelists provide ratings in an alternate category (this corresponded to >70% consensus).9,16AssumptionsThe following list of assumptions to be followed was adapted from methodology recommendations and prior appropriate use documents and was communicated to the expert rating panel members prior to their rating of the indications.12,15,17,18All imaging studies are assumed to be locally available and to be performed in accredited imaging laboratories in accordance with published criteria for quality cardiac diagnostic testing using state-of-the-art, certified imaging equipment.All imaging is assumed to be performed according to the standard of care as defined by the peer-reviewed medical literature.All interpreting physicians are qualified and certified to supervise the imaging procedure and appropriately report the findings.In clinical scenarios, the clinical status listed is assumed to be valid as stated (asymptomatic patients are truly asymptomatic) and no extenuating circumstances are to be taken into consideration (patient willingness to receive treatment, clinical stability) unless specifically noted.Appropriateness should be rated independently of the appropriateness of any prior diagnostic imaging that may have been performed.All patients are assumed to be receiving optimal therapy conforming to current standards of care, including contemporary heart failure therapy and cardiovascular risk-factor modification, unless specifically noted.Imaging indicated for surveillance to assess disease progression or response to therapy is assumed to be performed solely because the indicated time period elapsed rather than due to any change in clinical circumstances.Radiation risk was not considered. Although theoretical concerns have been raised that diagnostic imaging-related ionizing radiation may result eventually in an increased risk of cancer in the exposed population, this has not been proven. Moreover, in this population with high risk for heart failure and neuropathy, the benefit of a small dose of radiation was felt to outweigh the risk, especially when compared to a strategy with invasive endomyocardial biopsy. This risk can be minimized by preventing inappropriate use and by optimizing studies with the lowest radiation dose possible.19Cost of the imaging procedures is not to be considered in accordance with recommended appropriateness scoring methods.9 Cost is recognized to be an important issue from a policy perspective, but expert physician appropriateness rating has been shown to agree with cost-effectiveness models.20,21DefinitionsNo cardiac symptomsThe absence of the following symptoms was used to indicate that no cardiac symptoms are present. These include chest pain, fatigue, effort intolerance, shortness of breath, palpitations, dizziness/lightheadedness, syncope, orthopnea, paroxysmal nocturnal dyspnea, bloating, leg swelling, leg or jaw claudication.TTR gene carrierA TTR gene carrier refers to individuals who harbor one of the more than 120 mutations in the transthyretin gene that have been associated with the development of transthyretin amyloidosis.22Recurrent testingRecurrent testing refers to performance of the same imaging modality more than once, excluding non-diagnostic studies, to identify cardiac involvement in the setting of prior negative testing; the interval between studies is not addressed.Biopsy-proven AL cardiac amyloidosisThe diagnosis of AL amyloidosis requires a positive tissue biopsy showing amyloid deposits in the presence of clinical, imaging, or laboratory signs of organ involvement. The amyloid deposits should exhibit a characteristic affinity for Congo red staining with birefringence under polarized light. Typing of AL amyloidosis is confirmed on immunohistochemistry and/or mass spectroscopy. Electron microscopy of amyloid deposits is rarely performed but reveals prototypic rigid, nonbranching 10- to 12-nm width fibrils. Amyloid deposits can be detected at accessible sites, such as abdominal fat, bone marrow, or minor salivary glands, and the biopsy of the involved organ is not always necessary.23Abnormal NT-proBNP and Troponin TCardiac biomarkers (N terminal—pro brain natriuretic peptide, NT-proBNP and troponins) are used for staging with different cutoffs.24–26 In AL amyloidosis, NT-proBNP has >99% diagnostic sensitivity, with all patients with heart involvement having an elevated (≥332 ng/L) NT-proBNP.27Monoclonal gammopathy of uncertain significance (MGUS)A premalignant, clonal plasma cell disorder characterized by the presence of a usually small monoclonal (M) protein and <10% clonal plasma cell clones in the bone marrow in the absence of multiple myeloma or related lymphoplasmacytic malignancies.28,29Abnormal free light chains (FLCs)Abnormal FLCs are defined by an abnormal serum Kappa and Lambda immunoglobulin FLC ratio. The reference interval of FLC ratio may vary by the assay method used or in the setting of renal failure. The reference range of the FLC ratio as measured by Binding Site is between 0.26 and 1.65 in patients with normal renal function or between 0.31 and 3.7 in patients with renal failure. The reference range of the FLC ratio as measured by Siemens is between 0.31 and 1.56.Symptomatic heart failureSymptomatic heart failure refers to patients who have New York Heart Association (NYHA) Class II or greater symptoms adapted from Dolghin et al 30 from original source.31Unexplained heart failureUnexplained heart failure refers to heart failure without a known etiology, in particular, ischemic heart disease or valvular heart disease.Increased wall thicknessEcho mean left ventricular (LV) wall thickness of >12 mm with no other known cardiac cause.23Preserved LV ejection fractionHeart failure with preserved ejection fraction is defined per ACC/AHA heart failure guidelines as an LV ejection fraction of ≥40%.32Low-flow aortic stenosisA low-flow aortic stenosis was defined as low transvalvular mean aortic gradient (≤40 mmHg) or stroke volume index of <35 mL/m in the context of reduced LV ejection fraction (classical low flow) or preserved LV ejection fraction (paradoxical low flow).33Unexplained peripheral sensorimotor neuropathyPatient-reported paresthesias typical for this type of neuropathy in which no known cause has been identified (eg, diabetes, alcohol abuse, or toxicity).Known or suspected familial amyloidosisDocumented amyloidosis in one or more closely related family members, such as a parent, brother or sister, uncle or aunt, and particularly so if a mutation of an amyloidogenic protein has been identified. In addition, an unexplained clinical picture of peripheral polyneuropathy and/or cardiomyopathy in several family members in a number of generations.Biopsy-proven ATTR cardiac amyloidosisEndomyocardial biopsy showing amyloid deposits, which are confirmed on immunohistochemistry and/or mass spectroscopy to be transthyretin.Contraindication to Cardiac Magnetic Resonance (CMR)As the CMR scanner generates a very powerful static magnetic field, certain implanted cardiac devices and ferromagnetic prostheses may pose a safety concern from movement, arrhythmia induction, or tissue heating from the magnetic fields. Each device must be evaluated on an individual basis for safety before proceeding with CMR. Due to a potential risk of nephrogenic systemic fibrosis, gadolinium use is contraindicated in individuals with estimated glomerular filtration rate (GFR) <30 ml/min/1.73 m−2.34Unexplained bilateral carpal tunnel syndromeCarpal tunnel syndrome is defined as a symptomatic compression neuropathy of the median nerve at the level of the wrist, characterized physiologically by evidence of increased pressure within the carpal tunnel and decreased function of the nerve at that level.35 Bilateral carpal tunnel syndrome in the absence of rheumatoid arthritis or known trauma is defined as unexplained.Unexplained biceps tendon ruptureBiceps tendon rupture in the absence of trauma, such as severe heavy lifting.Echo, CMR, or 99mTc-PYP/DPD/HMDP imaging study suggestive of cardiac amyloidosisAn echocardiogram, CMR, or 99mTc-pyrophosphate(99mTc-PYP)/99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD)/99mTc-hydroxy methylenediphosphonate (99mTc-HMDP) radionuclide imaging study with findings of cardiac amyloidosis as specified in Table 1, Expert Consensus Recommendations for Diagnosis of Cardiac Amyloidosis.Table 1. Expert Consensus Recommendations for Diagnosis of Cardiac AmyloidosisTable 1. Expert Consensus Recommendations for Diagnosis of Cardiac AmyloidosisDiagnostic Criteria for Cardiac AmyloidosisThe current diagnosis of cardiac amyloidosis is not standardized. A multicenter consensus paper has proposed a diagnostic algorithm for the evaluation of ATTR cardiac amyloidosis incorporating echocardiography, CMR, and bone-avid radiotracers36; however, no formal diagnostic criteria have been reported. An international consensus document on AL amyloidosis defines cardiac involvement by either endomyocardial biopsy or by systemic biopsy demonstrating AL amyloid and elevated LV wall thickness on echocardiography without alternative cardiac cause.23 However, advances in noninvasive imaging and cardiac biomarkers in cardiac amyloidosis during the past two decades have led to improved methods of assessment beyond echocardiographic wall thickness. These tools have extensive validation in the literature, as described above, but were not included in the consensus document. They allow for more sensitive and earlier detection of disease. Therefore, there is a need for updated diagnostic criteria that incorporate these novel methods. Expert consensus recommendations for criteria for diagnosis of cardiac amyloidosis are provided in Table 1 with accompanying certainty of recommendation. Cardiac amyloidosis is confirmed with a positive endomyocardial biopsy for amyloid fibrils. In the absence of endomyocardial biopsy-proven disease, cardiac amyloidosis can be diagnosed using a combination of extracardiac biopsy, 99mTc-PYP/DPD/HMDP scintigraphy, myocardial uptake of targeted positron emission tomography (PET) amyloid tracers, and echocardiographic and CMR findings as shown in Table 1. In the absence of a clonal plasma cell process, 99mTc-PYP/DPD/HMDP scintigraphy consistent with ATTR cardiac amyloidosis combined with consistent echo or CMR findings obviates the need for invasive endomyocardial or extracardiac biopsy.Appropriate Utilization of Multimodality Imaging in Cardiac AmyloidosisThe appropriate utilization ratings for echocardiography, CMR, and radionuclide scintigraphy (99mTc-PYP/DPD/HMDP) for the 32 clinical indications are provided in Table 2. There were 30 evaluable indications for echocardiography, of which 27 were rated as "Appropriate" and 3 "May Be Appropriate." Cardiac magnetic resonance likewise had 30 evaluable indications, of which 19 were rated as "Appropriate," 9 as "May Be Appropriate," and 2 as "Rarely Appropriate." 99mTc-PYP/DPD/HMDP scintigraphy had 31 evaluable indications, of which 10 were "Appropriate," 6 were "May Be Appropriate," and 15 "Rarely Appropriate." Echocardiography was rated as "Appropriate" for all assessed clinical indications except for some more frequent intervals of assessment of cardiac response to therapy or disease progression, which were rated as "May Be Appropriate." Except for new onset symptomatic heart failure, CMR had more mixed ratings. 99mTc-PYP/DPD/HMDP scintigraphy was rated as "Appropriate" or "May Be Appropriate" for all indications other than those involving suspected light-chain amyloidosis or biopsy-proven AL or ATTR cardiac amyloidosis, which were classified as "Rarely Appropriate."Table 2. Appropriate Utilization Rating of Multimodality Imaging for the Assessment of Cardiac AmyloidosisTable 2. Appropriate Utilization Rating of Multimodality Imaging for the Assessment of Cardiac AmyloidosisAlthough cost considerations, radiation risk, and availability of technology were not considered during the rating process, the rating panel did want to emphasize that these issues may influence the choice of imaging modality, particularly with regard to the frequency of repeat testing. The panel also wanted to stress the importance of consideration of referral to specialized amyloidosis centers, particularly in familial amyloidosis, AL cardiac amyloidosis, or for consideration of novel therapies.Clinical Scenario #1: Identifying Cardiac Involvement: No Cardiac SymptomsFor asymptomatic gene carriers, echocardiography and radionuclide scintigraphy (99mTc-PYP/DPD/HMDP) were rated as "Appropriate," while CMR was rated "May Be Appropriate." Because the age of onset and phenotypic manifestation of disease vary by the type of mutation, imaging was determined by the panel to be appropriate in some situations but not for others, resulting in a rating of "May Be Appropriate." In particular, the panel discussed that extracellular volume (ECV) assessment by CMR has the potential to identify disease earlier in asymptomatic gene carriers compared with echocardiography. For asymptomatic patients with elevated cardiac biomarkers and either biopsy-proven systemic AL amyloidosis or MGUS with abnormal FLC levels, echocardiography and CMR were rated as "Appropriate," but 99mTc-PYP/DPD/HMDP scintigraphy was "Rarely Appropriate." The panel discussed that the magnitude of biomarker abnormality should play a role in determining the use of imaging. In particular, due to the high prevalence of MGUS, as well as ATTR wild-type (ATTRwt) in older individuals, use of imaging may be guided by serum biomarker levels, particularly in AL amyloidosis patients, in whom NT-proBNP is a sensitive marker of cardiac involvement.Clinical Scenario #2: Screening for Cardiac Amyloidosis: New Symptomatic Heart FailureIn the nine clinical indications encompassing patients with new symptomatic heart failure considered in this document, echocardiography and CMR were rated as uniformly "Appropriate" for screening for cardiac amyloidosis. This is consistent with the appropriate rating given to CMR and echocardiography for evaluation of newly suspected heart failure in the most recent appropriate utilization report addressing heart failure.1899mTc-PYP/DPD/HMDP scintigraphy was also "Appropriate" for all of these indications except the two addressing patients in whom AL cardiac amyloidosis is suspected due to elevated FLC levels or monoclonal gammopathy, in whom bone scintigraphy alone is insufficient to establish the type of cardiac amyloidosis and for whom a biopsy is required. 99mTc-PYP/DPD/HMDP scintigraphy may occasionally be considered prior to endomyocardial biopsy in instances where ATTR cardiac amyloidosis is in the differential diagnosis. The panel discussed that individuals with unexplained peripheral sensorimotor neuropathy should have diabetes mellitus and other causes of neuropathy excluded as a cause and may benefit from FLC level testing or genetic sequencing of amyloidogenic proteins to guide need for imaging.Clinical Scenarios #3 and #4: Evaluation of Biopsy-Proven AL and ATTR Cardiac AmyloidosisAlthough biopsy-proven AL and ATTR cardiac amyloidosis qualifies as a definitive diagnosis, imaging was still considered to assess amyloid burden, response to therapy, or eligibility for stem cell transplant. For these indications, 99mTc-PYP/DPD/HMDP scintigraphy is not performed clinically and was rated as "Rarely Appropriate." For quantifying cardiac amyloid burden, echocardiography and CMR were rated as "Appropriate." With regard to assessing cardiac response to therapy and disease progression in AL and ATTR cardiac amyloidosis, the raters agreed that assessment every 24 months was "Appropriate." More frequent evaluation varied across expert amyloidosis centers.Clinical Scenario #5: Follow-Up Testing: New or Worsening Cardiac SymptomsIn TTR gene carriers or patients with AL or ATTR amyloidosis who have new or worsening cardiac symptoms, the panel rated echocardiography, CMR, and 99mTc-PYP/DPD/HMDP scintigraphy as "Appropriate." 99mTc-PYP/DPD/HMDP scintigraphy was rated as "Rarely Appropriate" for patients with AL amyloidosis. Notably, ATTR cardiac amyloidosis has been reported in long-term survivors of AL amyloidosis, and 99mTc-PYP/DPD/HMDP scintigraphy may have a potential role in those rare instances.37Clinical Scenario #6: Other Indications and Prior TestingThe rating panel evaluated several clinical indications emerging as high risk for potential cardiac amyloidosis and rated echocardiography as "Appropriate" and CMR and 99mTc-PYP/DPD/HMDP scintigraphy as "May Be Appropriate." The evolving literature suggesting possible ATTR cardiac amyloidosis in patients with bilateral carpal tunnel syndrome, biceps tendon rupture, and unexplained neuropathy suggest that CMR and 99mTc-PYP/DPD/HMDP scintigraphy likely have a clinical role. However, the panel chose a rating of "May Be Appropriate" due to the lack of definitive evidence and the need for more research to clarify the prevalence of cardiac amyloidosis and the role of imaging in these subgroups and other emerging high-risk cohorts (eg, transcutaneous aortic valve replacement [TAVR], 5 hip and knee arthroplasty38).Clinical Scenario #7: Prior Testing Suggestive of Cardiac AmyloidosisIn patients with an echocardiogram suggestive of cardiac amyloidosis, CMR was rated as "Appropriate" and likewise echocardiography was "Appropriate" with a suggestive CMR. 99mTc-PYP/DPD/HMDP scintigraphy was rated as "May Be Appropriate," as its use should be limited to suspected cases of ATTR cardiac amyloidosis. It should be noted that the most common

There are 2 primary reasons for an addendum. The first is that the document reviewer list is being updated to include Dr Richard Cheng and Dr Roy John, who have critically reviewed the document, but were inadvertently not listed as reviewers. In addition, since the publication of this document and the introduction of approved therapies for transthyretin cardiac amyloidosis, the clinical use of bone tracer cardiac scintigraphy has been extended to populations with a lower prevalence of transthyretin cardiac amyloidosis.

This information statement from the Society of Nuclear Medicine and Molecular Imaging, American Society of Nuclear Cardiology, and European Association of Nuclear Medicine describes the performance, interpretation, and reporting of hot spot imaging in nuclear cardiology. The field of nuclear cardiology has historically focused on cold spot imaging for the interpretation of myocardial ischemia and infarction. Hot spot imaging has been an important part of nuclear medicine, particularly for oncology or infection indications, and the use of hot spot imaging in nuclear cardiology continues to expand. This document focuses on image acquisition and processing, methods of quantification, indications, protocols, and reporting of hot spot imaging. Indications discussed include myocardial viability, myocardial inflammation, device or valve infection, large vessel vasculitis, valve calcification and vulnerable plaques, and cardiac amyloidosis. This document contextualizes the foundations of image quantification and highlights reporting in each indication for the cardiac nuclear imager.

The aim of this article is to examine whether cardiac resynchronization therapy (CRT) induces improvements in the neurohumoral system.Thirteen patients with HF (left ventricular (LV) ejection fraction <35%) were included. Before and after 6 months of CRT, myocardial (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptake indices, used as an index of neural norepinephrine reuptake and retention, and brain natriuretic peptide (BNP) levels, used as an index of LV end-diastolic pressure, NYHA classification and echocardiographic indices were assessed. Six months of CRT resulted in significant improvement in (1) NYHA classification and reduction in QRS width (P < 0.001), (2) decrease of LV end-diastolic diameter (P = 0.005), LV end-systolic diameter (P = 0.005), septal to lateral delay (P = 0.01) and mitral regurgitation (MR, P = 0.04), (3) delayed (123)I-MIBG heart/mediastinum ratios improved (P = 0.03) and (123)I-MIBG washout decreased (P = 0.001), and (4) BNP levels decreased (P = 0.001).Parallel to significant functional improvement and echocardiographic reverse remodeling and resynchronization, our data indicate that CRT induces favorable changes in the neurohumoral system.

There is lack of validation and standardisation of acquisition parameters for myocardial (123)I-metaiodobenzylguanidine (MIBG). This lack of standardisation hampers large scale implementation of (123)I-MIBG parameters in the evaluation of patients with chronic heart failure (CHF).In a retrospective multi-centre study (123)I-MIBG planar scintigrams obtained on 290 CHF patients (82% male; 58% dilated cardiomyopathy; New York Heart Association [NYHA classification] > I) were reanalysed to determine the late heart-to-mediastinum ratio (H/M).There was a large variation in acquisition parameters. Multivariate forward stepwise regression showed that a significant proportion (31%, p < 0.001) of the variation in late H/M could be explained by a model containing patient-related variables and acquisition parameters. Left ventricular ejection fraction (p < 0.001), type of collimation (p < 0.001), acquisition duration (p = 0.001), NYHA class (p = 0.028) and age (p = 0.034) were independent predictors of late H/M.Acquisitions parameters are independent contributors to the variation of semi-quantitative measurements of cardiac (123)I-MIBG uptake. Improved standardisation of cardiac (123)I-MIBG imaging parameters would contribute to increased clinical applicability for this procedure.

Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression.Right ventricular heart failure was induced in male Wistar rats by intraperitoneal injection of monocrotaline (MCT). Two groups were studied: MCT-treated rats (MCT-rats), and age-matched controls (CON-rats). Serial echocardiography and in vivo 67-Gallium ((67)Ga) scintigraphy were performed. Local inflammation in the RV was assessed by (i) ex vivo semi-quantitative (67)Ga autoradiography, (ii) immunohistochemistry of myeloperoxidase (MPO), a marker of neutrophil activity, and (iii) mRNA assays of tumour necrosis factor-alpha (TNF-alpha). In MCT-rats, (67)Ga scintigraphy showed increased myocardial uptake which started during the early stages of RV disease. (67)Ga autoradiography revealed that this increased (67)Ga uptake occurred in the RV and inter-ventricular septum, but not in the LV. The stage-dependent increases of in vivo (67)Ga RV myocardial uptake were paralleled by increases in mRNA gene expression for TNF-alpha in RV, and increased MPO staining in RV.Development and progression of RV heart failure is associated with an early increase in RV inflammation. (67)Ga scintigraphy may be used for the serial assessment of inflammation and monitoring of disease progression in RV heart failure.

South Asians have a disproportionately high risk of developing abdominal obesity, insulin resistance and type 2 diabetes. Brown adipose tissue (BAT) has been identified as a possible target to fight obesity and protect against metabolic disturbance. We explored whether lower BAT activity in South Asians compared with Europids may contribute to the high risk of metabolic disturbance.We studied 20 healthy men (ten Europids/ten South Asians, BMI 19-25 kg/m(2), age 18-32 years). Following 2 h of cold exposure (16-18°C) after an overnight fast, (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomography-computed tomography (CT) and (123)I-metaiodobenzylguanidine ((123)I-MIBG) single-photon emission computed tomography-CT were performed to visualise metabolic BAT activity and sympathetic stimulation of BAT. Metabolic BAT activity was defined as maximal standardised uptake value (SUV(max)) of (18)F-FDG, and sympathetic stimulation of BAT as semiquantitative uptake value (SQUV) of (123)I-MIBG. We performed hyperinsulinaemic-euglycaemic clamps to assess insulin sensitivity. Spearman's correlations for SUV(max) of (18)F-FDG and both SQUV of (123)I-MIBG and insulin sensitivity were determined.The median (interquartile range) SUV(max) of (18)F-FDG in South Asians (7.5 [2.2-10.6] g/ml) was not different from the median SUV(max) obtained in Europids (4.5 [2.2-8.4] g/ml; p = 0.59). There was no correlation between BAT activity and insulin sensitivity. Correlations between SQUV of (123)I-MIBG and SUV(max) of (18)F-FDG were positive, both in the total population (ρ = 0.80, p < 0.001) and after stratification by ethnicity (Europids, ρ = 0.65, p = 0.04; South Asians, ρ = 0.83, p = 0.01).This is the first study to prospectively investigate ethnic differences in metabolic BAT activity during cold exposure. We did not find differences in BAT activity between South Asians and Europids. Therefore, it seems unlikely that BAT plays an important role in the development of unfavourable metabolic profiles in South Asians.

Brown adipose tissue (BAT) has become a focus of research in the hope of finding a new target to fight obesity. Metabolic BAT activity can be visualized with (18)F-FDG PET/CT. Furthermore, the sympathetic innervation of BAT can be visualized with the radiolabeled norepinephrine analog (123)I-metaiodobenzylguanidine ((123)I-MIBG). We aimed to determine whether (123)I-MIBG SPECT/CT and (18)F-FDG PET/CT identify the same anatomic regions as active BAT in adult humans. Furthermore, we investigated whether the magnitude of BAT activity measured by these techniques correlated. Finally, we tried to establish the optimal time interval between (123)I-MIBG administration and subsequent SPECT/CT acquisition to visualize sympathetic stimulation of BAT.Ten lean (body mass index, 19-25 kg/m(2)), healthy Caucasian men (age, 18-32 y) underwent one (18)F-FDG PET/CT and two (123)I-MIBG-SPECT/CT scans within a 2-wk interval. On 2 separate occasions, the subjects were exposed to mild cold (17°C) for 2 h after an overnight fast. After 1 h of cold exposure, (18)F-FDG (one occasion) or (123)I-MIBG (other occasion) was administered. (18)F-FDG PET/CT was performed at 1 h after (18)F-FDG administration, and (123)I-MIBG-SPECT/CT was performed at 4 and 24 h after (123)I-MIBG injection.(18)F-FDG uptake in BAT was observed in 8 of 10 subjects, whereas (123)I-MIBG uptake was observed in 7 of 10 subjects in both the SPECT/CT scans acquired at 4 h after (123)I-MIBG administration and the SPECT/CT scans acquired at 24 h after (123)I-MIBG administration. All subjects who showed (123)I-MIBG uptake in BAT also showed (18)F-FDG uptake in BAT. There was no statistically significant correlation between maximal standardized uptake value of (18)F-FDG and semiquantitative uptake of (123)I-MIBG at 4 h after administration. However, a positive correlation was found between the maximal standardized uptake value of (18)F-FDG and semiquantitative uptake of (123)I-MIBG at 24 h after administration (r = 0.64, P = 0.04).(123)I-MIBG SPECT/CT, as a marker of sympathetic activity, and (18)F-FDG PET/CT, as a marker of metabolic activity, identified the same anatomic regions as active BAT. Moreover, when (123)I-MIBG SPECT/CT was performed at 24 h after (123)I-MIBG administration, the magnitude of BAT activity measured with these techniques correlated strongly. This finding not only supports that BAT activity in humans is sympathetically influenced but also identifies (123)I-MIBG SPECT/CT, when performed 24 h after (123)I-MIBG injection, as a method to visualize and quantify sympathetic stimulation of BAT.

Understanding how leukocytes impact atherogenesis contributes critically to our concept of atherosclerosis development and the identification of potential therapeutic targets. The study evaluates an in vivo imaging approach to visualize peripheral blood mononuclear cell (PBMC) accumulation in atherosclerotic lesions of cardiovascular (CV) patients using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT). At baseline, CV patients and healthy controls underwent 18fluorodeoxyglucose positron emission tomography-computed tomography and magnetic resonance imaging to assess arterial wall inflammation and dimensions, respectively. For in vivo trafficking, autologous PBMCs were isolated, labeled with technetium-99m, and visualized 3, 4.5, and 6 h post-infusion with SPECT/CT. Ten CV patients and 5 healthy controls were included. Patients had an increased arterial wall inflammation (target-to-background ratio [TBR] right carotid 2.00 ± 0.26 in patients vs. 1.51 ± 0.12 in controls; p = 0.022) and atherosclerotic burden (normalized wall index 0.52 ± 0.09 in patients vs. 0.33 ± 0.02 in controls; p = 0.026). Elevated PBMC accumulation in the arterial wall was observed in patients; for the right carotid, the arterial-wall-to-blood ratio (ABR) 4.5 h post-infusion was 2.13 ± 0.35 in patients versus 1.49 ± 0.40 in controls (p = 0.038). In patients, the ABR correlated with the TBR of the corresponding vessel (for the right carotid: r = 0.88; p < 0.001). PBMC accumulation is markedly enhanced in patients with advanced atherosclerotic lesions and correlates with disease severity. This study provides a noninvasive imaging tool to validate the development and implementation of interventions targeting leukocytes in atherosclerosis.

This review focuses on the diagnostic value of hybrid F18-FDG Positron Emission Tomography/Computerized tomography (PET/CT) in fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Due to the wide range of possible causes both FUO and IUO remain a clinical challenge for both patients and physicians. In addition, the aetiology of IUO shows the same variation in diseases as the FUO spectrum and probably requires the same diagnostic approach as FUO. There are numerous historically used diagnostic approaches incorporating invasive and non-invasive, and imaging techniques, all with relative high specificity but limited sensitivity. This hampers the generalization of these diagnostic approaches. However, recently published reports show that F18-FDG PET/CT in FUO and IUO has a high sensitivity and a relative non-specificity for malignancy, infection and inflammation. This makes F18-FDG PET/CT an ideal diagnostic tool to start the diagnostic process and to guide subsequent focused diagnostic approaches with higher specificity. In addition, F18-FDG PET/CT has a relative high negative predictive value. Therefore F18 FDG PET/CT should be incorporated in the routine diagnostic work-up of patients with FUO and IUO, preferably at an early stage in the diagnostic process.

Introduction For patients with oligometastatic recurrence of prostate cancer (PC), stereotactic body radiation therapy (SBRT) represents an attractive treatment option, as it is safe without major side effects. The aim of this study was to investigate the impact of SBRT in delaying the start of androgen deprivation therapy (ADT). Patients and Methods Forty-three patients treated with SBRT for oligometastatic recurrence (< 5 metastases) of hormone-sensitive PC, defined with [18F]fluoromethylcholine positron emission tomography/computed tomography were included. As a control group, 20 patients with oligometastatic disease not treated with SBRT were identified from another hospital. Data were collected retrospectively. Results A post-SBRT prostate-specific antigen (PSA) response was seen in 29 (67.4%) of 43 patients. Median ADT–free survival (ADT-FS) was 15.6 months (95% confidence interval [CI], 11.7-19.5) for the whole group, and 25.7 months (95% CI, 9.0-42.4) for patients with a PSA response. Seven patients were treated with a second course of SBRT because of oligometastatic disease recurrence; the ADT-FS in this group was 32.1 months (95% CI, 7.8-56.5). Compared with the control group, the ADT-FS from first diagnosis of metastasis was significantly longer, with 17.3 (95% CI, 13.7-20.9) months versus 4.19 months (95% CI, 0.0-9.0), P < .001. Also, time between diagnosis of the metastasis until progression of disease during ADT use (castration resistance) was longer for the SBRT-treated patients (mean 66.6, 95% CI, 53.5-79.8, vs. 36.41, 95% CI, 26.0-46.8 months, P = .020). There were no grade III or IV adverse events reported. Conclusion SBRT can safely and effectively be used to postpone ADT in appropriately selected patients with oligometastatic recurrence of PC.

Chronic heart failure (CHF) is a life-threatening clinical syndrome, partly due to sudden cardiac death (SCD). Implantable cardioverter defibrillators (ICD) for primary prevention of SCD have improved overall survival of CHF patients. However, a high percentage of patients never receives appropriate ICD therapy. This prospective multicentre study evaluated whether cardiac sympathetic activity assessed by 123I-mIBG scintigraphy could be helpful in selecting patients for ICD implantation.135 stable CHF subjects (age 64.5±9.3years, 79% male, LVEF 25±6%) referred for prophylactic ICD implantation were enrolled in 13 institutions. All subjects underwent planar and SPECT 123I-mIBG scintigraphy. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO) and late summed scores were calculated. The primary endpoint was appropriate ICD therapy. The secondary endpoint was defined as the combined endpoint of all first cardiac events: appropriate ICD therapy, progression of heart failure (HF) and cardiac death.During a median follow-up of 30months (6-68months), 24 subjects (17.8%) experienced a first cardiac event (appropriate ICD therapy [12], HF progression [6], cardiac death [6]). Late H/M ratio and defect size of 123I-mIBG SPECT were not associated with appropriate ICD therapy. However, late H/M ratio was independently associated with the combined endpoint (HR 0.135 [0.035-0.517], p=0.001). Post-hoc analysis showed that the combination of late H/M ratio (HR 0.461 [0.281-0.757]) and LVEF (HR 1.052 [1.021-1.084]) was significantly associated with freedom of appropriate ICD therapy (p<0.001).123I-mIBG scintigraphy seems to be helpful in selecting CHF subjects who might not benefit from ICD implantation.

Despite therapeutic improvement, the prognosis of chronic heart failure (CHF) remains unfavorable partly due to arrhythmia and sudden cardiac death (SCD). This prospective study evaluated myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy as a predictor of arrhythmic events (AE) in CHF patients.170 CHF patients referred for implantable cardioverter-defibrillator (ICD) implantation for both primary and secondary prevention were enrolled. All patients underwent planar and SPECT imaging. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO), early and late summed SPECT scores were calculated The primary endpoint was an AE: sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD therapy or SCD. The secondary endpoint was appropriate ICD therapy.During a median follow-up of 23.3 months, 69 patients experienced an AE. Early summed score (ESS) was the only independent predictor of AE [HR 1.023 (1.003-1.043)]. Focussing on only patients with an ICD for primary prevention, ESS was the only independent predictor of AE [HR 1.028 (1.007-1.050)]. 123I-mIBG-derived parameters failed to be independent predictors of appropriate ICD therapy. However there was a "bell-shaped" relation between 123I-mIBG scintigraphy-derived parameters and AE and appropriate ICD therapy, i.e., those with intermediate 123I-mIBG abnormalities tended to be at higher risk of events.Although SPECT 123I-mIBG scintigraphy was associated with AE in CHF patients with ICD implantation for primary and secondary prevention, no association was found between 123I-mIBG scintigraphy-derived parameters and appropriate ICD therapy.

Abstract Cardiac sympathetic activity plays a key role in supporting cardiac function in both health and disease conditions, and nuclear cardiac imaging has always represented the only way for the non-invasive evaluation of the functional integrity of cardiac sympathetic terminals, mainly through the use of radiopharmaceuticals that are analogues of norepinephrine and, in particular, with the use of 123I-mIBG imaging. This technique demonstrates the presence of cardiac sympathetic dysfunction in different cardiac pathologies, linking the severity of sympathetic nervous system impairment to adverse patient’s prognosis. This article will outline the state-of-the-art of cardiac 123I-mIBG imaging and define the value and clinical applications in the different fields of cardiovascular diseases.

To assess whether patients with aortic valve stenosis (AS) with elevated lipoprotein(a) (Lp(a)) are characterised by increased valvular calcification activity compared with those with low Lp(a).We performed 18F-sodium fluoride (18F-NaF) positron emission tomography/CT in patients with mild to moderate AS (peak aortic jet velocity between 2 and 4 m/s) and high versus low Lp(a) (>50 mg/dL vs <50 mg/dL, respectively). Subjects were matched according to age, gender, peak aortic jet velocity and valve morphology. We used a target to background ratio with the most diseased segment approach to compare 18F-NaF uptake.52 individuals (26 matched pairs) were included in the analysis. The mean age was 66.4±5.5 years, 44 (84.6%) were men, and the mean aortic valve velocity was 2.80±0.49 m/s. The median Lp(a) was 79 (64-117) mg/dL and 7 (5-11) mg/dL in the high and low Lp(a) groups, respectively. Systolic blood pressure and low-density-lipoprotein cholesterol (corrected for Lp(a)) were significantly higher in the low Lp(a) group (141±12 mm Hg vs 128±12 mm Hg, 2.5±1.1 mmol/L vs 1.9±0.8 mmol/L). We found no difference in valvular 18F-NaF uptake between the high and low Lp(a) groups (3.02±1.26 vs 3.05±0.96, p=0.902). Linear regression analysis showed valvular calcium score to be the only significant determinant of valvular 18F-NaF uptake (β=0.63; 95% CI 0.38 to 0.88 per 1000 Agatston unit increase, p<0.001). Lp(a) was not associated with 18F-NaF uptake (β=0.17; 95% CI -0.44 to 0.88, p=0.305 for the high Lp(a) group).Among patients with mild to moderate AS, calcification activity is predominantly determined by established calcium burden. The results do not support our hypothesis that Lp(a) is associated with valvular 18F-NaF uptake.

In recognition of hypoxia’s involvement in atherogenesis, it has been suggested that plaque hypoxia be used as a target for molecular imaging to identify high-risk patients, anticipate acute cardiovascular events, and monitor atheroma therapies [(1)][1]. We demonstrate the potential of hypoxia

Risk stratification has become increasingly important in the management of patients with suspected or known ischaemic heart disease (IHD). Recent guidelines recommend that these patients have their care driven by risk assessment. The purpose of this position statement is to summarize current evidence on the value of cardiac single-photon emission computed tomography, positron emission tomography, and hybrid imaging in risk stratifying asymptomatic or symptomatic patients with suspected IHD, patients with stable disease, patients after coronary revascularization, heart failure patients, and specific patient population. In addition, this position statement evaluates the impact of imaging results on clinical decision-making and thereby its role in patient management. The document represents the opinion of the European Association of Nuclear Medicine (EANM) Cardiovascular Committee and of the European Association of Cardiovascular Imaging (EACVI) and intends to stimulate future research in this field.

Objectives The goal of this multicenter retrospective study was to evaluate the contribution of 18F-FDG PET/CT in the diagnosis of patients with inflammation of unknown origin (IUO). In addition, C-reactive protein (CRP) level and erythrocyte sedimentation rate were assessed as possible predictors for the outcome of 18F-FDG PET/CT. Methods Inflammation of unknown origin was defined as prolonged and perplexing inflammation, with repeated CRP levels more than 20 mg/L or erythrocyte sedimentation rate more than 20 mm/h, body temperature of less than 38.3°C, and without a diagnosis after a variety of conventional diagnostic procedures. A total of 140 patients with IUO (67 men, 73 women; mean age, 64.2 years; age range, 18–87 years) underwent 18F-FDG PET/CT. 18F-FDG PET/CT was considered helpful when the imaging findings led to a diagnosis, either confirmed by histopathology, microbiological assays, clinical and imaging follow-up, or response to treatment. Results In 104 patients (73%), a final diagnosis could be established as follows: infection in 35 patients, malignancy in 18 patients, noninfectious inflammatory disease in 44 patients, and a variety of uncommon conditions in 7 patients. 18F-FDG PET/CT was true positive in 95 patients, true negative in 30 patients (ie, self-limiting conditions), false positive in 6 patients, and false negative in 9 patients (predominantly systemic diseases). In this population, the positive predictive value, negative predictive value, and diagnostic accuracy of 18F-FDG PET/CT were 94%, 77%, and 89%, respectively. In a multivariate analysis, CRP was the only independent predictor for the outcome of 18F-FDG PET/CT. Conclusions 18F-FDG PET/CT correctly identified or excluded a causal explanation in approximately 90% of patients with IUO. However, a negative 18F-FDG PET/CT is indicative for a self-limiting condition only after systemic diseases are excluded by other diagnostic tests.

Increasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)).Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) <2.6 for >6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay.Overall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8-2.2]) have an almost 1.2-fold higher (18)F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3-2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls.A subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk management.

Myocardial sympathetic imaging with 123I-meta-iodobenzylguanidine (123I-mIBG) has gained clinical momentum. Although the need for standardization of 123I-mIBG myocardial uptake has been recognized, the availability of practical clinical standardization approaches is limited. The need for standardization includes the heart-to-mediastinum ratio (HMR) and washout rate with planar imaging, and myocardial defect scoring with single-photon emission computed tomography (SPECT). The planar HMR shows considerable variation due to differences in collimator design. These camera–collimator differences can be overcome by cross-calibration phantom experiments. The principles of these cross-calibration phantom experiments are summarized in this article. 123I-mIBG SPECT databases were compiled by Japanese Society of Nuclear Medicine working group. Literature was searched based on the words "123I-mIBG quantification method", "standardization", "heart-to-mediastinum ratio", and its application to "risk model". Calibration phantom experiments have been successfully performed in Japan and Europe. The benefit of these cross-calibration phantom experiments is that variation in the HMR between institutions is minimized including low-energy, low–medium-energy and medium-energy collimators. The use of myocardial 123I-mIBG SPECT can be standardized using 123I-mIBG normal databases as a basis for quantitative evaluation. This standardization method can be applied in cardiac event prediction models. Standardization of myocardial 123I-mIBG outcome parameters may facilitate a universal implementation of myocardial 123I-mIBG scintigraphy.

<h2>Abstract</h2><h3>Background and aims</h3> Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol. <h3>Methods</h3> In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to <i>ABCA1</i> and/or <i>APOA1</i> loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and ¹⁸F-FDG PET/CT to quantify arterial wall inflammation. <h3>Results</h3> A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm², <i>p</i> = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, <i>p</i> = 0.33) after 24 weeks. <h3>Conclusion</h3> In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.

The albumin cobalt-binding test (Ischemia Technologies), which measures the concentration of ischemia-modified albumin (IMA), has been cleared by the US Food and Drug Administration for use as a rule-out marker for acute myocardial ischemia (1). The test is based on the reduced capacity of human albumin to bind cobalt as a result of structural changes in the NH2 terminus of the albumin molecule in conditions of myocardial ischemia (2)(3). Moreover, IMA concentrations correlated with disease severity in systemic sclerosis (4), and an exercise-induced decrease in IMA concentrations correlated with the ankle-brachial index in patients with peripheral artery sclerosis (5). Little is known, however, about the relationship between exercise-induced myocardial ischemia, albumin kinetics, and IMA kinetics. We therefore investigated this relationship in 38 patients with chest complaints and suspected coronary artery disease who were undergoing symptom-limited exercise myocardial perfusion scintigraphy. Myocardial perfusion scintigraphy was performed according to the guidelines of the American Society of Nuclear Cardiology (6), with a 2-day stress/rest protocol. A dose of 500 MBq of [99mTc]-Tetrofosmin was administered at rest and at peak exercise. Electrocardiogram-gated single photon emission tomography imaging was started 45 min to 1 h after the administration of radioactive-labeled tracer. All patients exercised on a bicycle ergometer with a starting workload of 50 W, increasing every 2 min by 25 W. Endpoints for exercise included achievement of at least 85% of the age-predicted heart …

Objectives The objective of this study was to determine the predictive value of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to a positive fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) result in patients with inflammation of unknown origin and fever of unknown origin. Patients and methods Individual data of 498 patients were retrieved from three retrospective studies. Receiver operating characteristic derived areas under the curve were used to assess 18F-FDG PET/CT versus age, CRP, and ESR. The discriminative value of age, CRP, and ESR related to 18F-FDG PET/CT was examined using the net reclassification improvement (NRI). Results A diagnosis was established in 331 patients; 18F-FDG PET/CT had a diagnostic accuracy of 89%. 18F-FDG PET/CT had the highest area under the curve (0.89, P<0.001). The addition of 18F-FDG PET/CT to a diagnosis prediction model including age, CRP, and ESR resulted in an NRI of 42% (P<0.001). In the same model with CRP values below 20 mg/l or ESR values below 20 mm/h, the NRI was 64% (P<0.001) and 29% (P=0.059), respectively. In 30 of 91 patients with CRP less than 10 mg/l, a diagnosis could be established; 18F-FDG PET/CT was 100% true negative only in patients with CRP levels less than 5 mg/l. Conclusion In patients with fever of unknown origin or inflammation of unknown origin, compared with elevated ESR levels, elevated CRP levels more often indicate a true positive 18F-FDG PET/CT outcome. In addition, 18F-FDG PET/CT, compared with CRP and ESR, shows the highest discrimination of patients with possible disabling disease.

It remains challenging to identify patients at risk of anthracycline-induced cardiotoxicity. To better understand the different risk-stratifying approaches, we evaluated 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and its interrelationship with conventional echocardiography, 2D strain imaging and several biomarkers. We performed 123I-mIBG scintigraphy, conventional and strain echocardiography and biomarker (NT-proBNP, TNF-α, galectin-3, IL-6, troponin I, ST-2 and sFlt-1) assessment in 59 breast cancer survivors 1 year after anthracycline treatment. Interobserver and intermethod variability was calculated on planar and SPECT 123I-mIBG scintigraphy, using the heart/mediastinum (H/M) ratio and washout (WO). Pearson's r and multivariate analyses were performed to identify correlations and independent predictors of 123I-mIBG scintigraphy results. Delayed planar anterior whole-heart ROI (WH) H/M ratios and WO were the most robust 123I-mIBG parameters. Significant correlations were observed between 123I-mIBG parameters and several conventional echo parameters, global longitudinal and radial strain (GLS and GRS) and galectin-3. The highest Pearson's r was observed between delayed H/M ratio and GRS (Pearson's r 0.36, p = 0.01). Multivariate analysis showed that GRS was the only independent predictor of the delayed WH H/M ratio (p = 0.023). The delayed planar H/M ratio is the most robust 123I-mIBG parameter. It correlates with several conventional echocardiographic parameters, GLS, GRS and galectin-3. Of these, only GRS predicts the H/M ratio.

The report of an imaging procedure is a critical component of an examination, being the final and often the only communication from the interpreting physician to the referring or treating physician. Very limited evidence and few recommendations or guidelines on reporting imaging studies are available; therefore, an European position statement on how to report nuclear cardiology might be useful. The current paper combines the limited existing evidence with expert consensus, previously published recommendations as well as current clinical practices. For all the applications discussed in this paper (myocardial perfusion, viability, innervation, and function as acquired by single photon emission computed tomography and positron emission tomography or hybrid imaging), headings cover laboratory and patient demographics, clinical indication, tracer administration and image acquisition, findings, and conclusion of the report. The statement also discusses recommended terminology in nuclear cardiology, image display, and preliminary reports. It is hoped that this statement may lead to more attention to create well-written and standardized nuclear cardiology reports and eventually lead to improved clinical outcome.

Retrospective studies have shown that outdoor temperature influences the prevalence of detectable brown adipose tissue (BAT). Prospective studies use acute cold exposure to activate BAT. In prospective studies, BAT might be preconditioned in winter months leading to an increased BAT response to various stimuli. Therefore the aim of this study was to assess whether outdoor temperatures and other weather characteristics modulate the response of BAT to acute cold. To assess metabolic BAT activity and sympathetic outflow to BAT, 64 (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) and 56 additional (123)I-meta-iodobenzylguanidine ((123)I-mIBG) single-photon emission computed tomography-CT (SPECT-CT) scans, respectively, of subjects participating in previously executed trials were retrospectively included. BAT activity was measured in subjects after an overnight fast, following 2 h of cold exposure (∼17°C). The average daytime outdoor temperatures and other weather characteristics were obtained from the Dutch Royal Weather Institute. Forty-nine subjects were BAT positive. One week prior to the scan, outdoor temperature was significantly lower in the BAT-positive group compared with the BAT-negative group. Higher outdoor temperatures on preceding days resulted in lower stimulated metabolic BAT activity and volume (all P < 0.01). Outdoor temperatures did not correlate with sympathetic outflow to BAT. In conclusion, outdoor temperatures influence metabolic BAT activity and volume, but not sympathetic outflow to BAT, in subjects exposed to acute cold. To improve the consistency of the findings of future BAT studies in humans and to exclude bias introduced by outdoor temperatures, these studies should be planned in periods of similar outdoor temperatures.

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic inflammatory disease with involvement of axial and sacroiliac joints. In addition, patients with AS have increased risk of cardiovascular disease (CVD), which might be attributed to enhanced inflammatory activity of the arterial wall. In the present study, we compared the level of carotid arterial wall inflammation in patients with AS with healthy controls using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography with CT. As arterial wall inflammation is reduced by statin therapy, we subsequently assessed the effect of 3-month statin therapy on arterial wall inflammation in AS. <h3>Methods and results</h3> We included 24 patients with AS (age 44±10, 72% males) without a history of CVD and 20 controls matched for age and gender. Patients with AS had lower high-density lipoprotein cholesterol and increased C reactive protein (CRP) compared with controls. The 10-year CVD risk was 2% in both groups. Notwithstanding, patients with AS had a 20% increase in arterial wall ¹⁸F-FDG uptake compared with controls. Three–month atorvastatin 40 mg daily significantly lowered low-density lipoprotein cholesterol (baseline 3.55±1.15 mmol/L, −53%) and CRP (baseline 5.0 (1.5–9.3) mg/L, −58%) with a concomitant decrease of carotid arterial wall inflammation (maximum target-to-background ratio from 1.90±0.30 to 1.67±0.27; p=0.009). <h3>Conclusions</h3> Patients with AS and without other CVD risk factors have increased arterial wall inflammation, which decreases upon statin therapy. These subjects are not identified as being at risk in current cardiovascular prevention guidelines. Our data support the need to revise CV disease management in AS, with perhaps a role for early statin therapy.

Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects.Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min.Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading.Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.

Background The role of kidney hypoxia is considered pivotal in the progression of chronic kidney disease. A widely used method to assess kidney oxygenation is blood oxygen level dependent ( BOLD )–magnetic resonance imaging ( MRI ), but its interpretation remains problematic. The BOLD ‐ MRI signal is the result of kidney oxygen consumption (a proxy of glomerular filtration) and supply (ie, glomerular perfusion). Therefore, we hypothesized that with pharmacological modulation of kidney blood flow, renal oxygenation, as assessed by BOLD ‐ MRI , correlates to filtration fraction (ie, glomerular filtration rate/effective renal plasma flow) in healthy humans. Methods and Results Eight healthy volunteers were subjected to continuous angiotensin‐ II infusion at 0.3, 0.9, and 3.0 ng/kg per minute. At each dose, renal oxygenation and blood flow were assessed using BOLD and phase‐contrast MRI . Subsequently, “gold standard” glomerular filtration rate/effective renal plasma flow measurements were performed under the same conditions. Renal plasma flow decreased dose dependently from 660±146 to 467±103 mL/min per 1.73 m 2 (F[3, 21]=33.3, P &lt;0.001). Glomerular filtration rate decreased from 121±23 to 110±18 mL/min per 1.73 m 2 (F[1.8, 2.4]=6.4, P =0.013). Cortical transverse relaxation rate (R2*; increases in R2* represent decreases in oxygenation) increased by 7.2±3.8% (F[3, 21]=7.37, P =0.001); medullar R2* did not change. Cortical R2* related to filtration fraction ( R 2 0.46, P &lt;0.001). Conclusions By direct comparison between “gold standard” kidney function measurements and BOLD MRI , we showed that cortical oxygenation measured by BOLD MRI relates poorly to glomerular filtration rate but is associated with filtration fraction. For future studies, there may be a need to include renal plasma flow measurements when employing renal BOLD ‐ MRI .

The significance of and threshold values for the standardized uptake value (SUV) in FDG PET/CT to diagnose prosthetic heart valve (PHV) endocarditis (PVE) are unclear at present. A literature search was performed in the PubMed and EMBASE medical databases, comprising the following terms: (FDG OR *fluorode* OR *fluoro-de*) AND (endocarditis OR prosthetic heart valve OR valve replacement). Studies reporting SUVs correlated to the diagnosis of PVE were selected for analysis. 8 studies were included, with a total of 330 PHVs assessed. SUVs for PVE varied substantially across studies due to differences in acquisition, reconstruction, and measurement protocols, with median SUVmax values for rejected PVE ranging from 0.5 to 4.9 and for definite PVE ranging from 4.2 to 7.4. Reported SUV values for PVE are not interchangeable between sites, and further standardization of quantification is desirable. To this end, optimal protocols for patient preparation, image acquisition, and reconstruction and measurement methods need to be standardized across centers.

Abstract Aims Impaired myocardial perfusion reserve (MPR) may occur earlier than coronary atherosclerosis and it may be an early manifestation of developing coronary artery disease (CAD) in patients with resistant hypertension (RH). We evaluated the relationship between RH and MPR in patients with systemic arterial hypertension after balancing for coronary risk factors. Methods and results We studied 360 subjects without overt CAD and normal myocardial perfusion at stress-rest 82Rb positron emission tomography/computed tomography. To account for differences in baseline characteristics between patients with resistant and controlled hypertension, we created a propensity score-matched cohort considering clinical variables and coronary risk factors. Before matching, patients with RH were significantly older, had higher prevalence of male gender and hypercholesterolaemia, and showed significantly lower global hyperaemic myocardial blood flow (MBF) and MPR compared with those with controlled hypertension, while baseline MBF and coronary artery calcium (CAC) content were similar in both groups. After matching, there were no significant differences in clinical variables and coronary risk factors between patients with resistant and controlled hypertension, but patients with RH still had lower hyperaemic MBF and MPR (both P &lt; 0.001). At univariable and multivariable linear regression analyses, age, RH, and CAC resulted significant predictors of lower MPR values (all P &lt; 0.05). Conclusion After balancing clinical characteristic by propensity score analysis, patients with RH had a blunted hyperaemic MBF and MPR compared with patients with controlled hypertension. The identification of impaired MPR could help to identify early structural alterations of the arterial walls in patients with RH.

Graves's disease (GD) is the most common cause of hyperthyroidism. Maximal 30% of pediatric GD patients achieve remission with antithyroid drugs. The majority of patients therefore require definitive treatment. Both thyroidectomy and radioactive iodine (RAI) are often used as definitive treatment for GD. However, data on efficacy and short- and long-term side effects of RAI treatment for pediatric GD are relatively scarce.A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting the efficacy or short- and long-term side effects of RAI treatment in pediatric GD.Twenty-three studies evaluating 1,283 children and adolescents treated with RAI for GD were included. The treatment goal of RAI treatment changed over time, from trying to achieve euthyroidism in the past to aiming at complete thyroid destruction and subsequent hypothyroidism in the last 3 decades. The reported efficacy of a first RAI treatment when aiming at hypothyroidism ranged from 42.8 to 97.5%, depending on the activity administered. The efficacy seems to increase with higher RAI activities. When aiming at hypothyroidism, both short- and long-term side effects of treatment are very rare. Long-term side effects were mainly seen in patients in whom treatment aimed at achieving euthyroidism.RAI is a safe definitive treatment option for pediatric GD when aiming at complete thyroid destruction. When aiming at hypothyroidism, the efficacy of treatment seems to increase with a higher RAI activity. Prospective studies are needed to determine the optimal RAI dosing regimen in pediatric GD.

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.

Inflammation is a core component of residual cardiovascular risk in type 2 diabetes. With new anti-inflammatory therapeutics entering the field, accurate markers to evaluate their effectiveness in reducing cardiovascular disease are paramount. Gallium-68-labelled DOTATATE (68Ga-DOTATATE) has recently been proposed as a more specific marker of arterial wall inflammation than 18F-fluorodeoxyglucose (18F-FDG). This study set out to investigate whether 68Ga-DOTATATE uptake is amenable to therapeutic intervention in individuals with type 2 diabetes.Individuals aged >50 years with type 2 diabetes underwent 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) at baseline and after 3 months treatment with atorvastatin 40 mg once daily. Primary outcome was the difference in coronary 68Ga-DOTATATE uptake, expressed as target-to-background ratio (TBR). The secondary outcome was difference in bone marrow and splenic uptake, expressed as the standardised uptake value (SUV).Twenty-two individuals with type 2 diabetes (mean age 63.2±6.4 years, 82% male, LDL-cholesterol 3.42±0.81 mmol/l, HbA1c 55±12 mmol/mol [7.2%±3.2%]) completed both 68Ga-DOTATATE PET/CT scans. The maximum TBR was -31% (95% CI -50, -12) lower in the coronary arteries, and bone marrow and splenic 68Ga-DOTATATE uptake was also significantly lower post statin treatment, with a mean percentage reduction of -15% (95% CI -27, -4) and -17% (95% CI -32, -2), respectively.68Ga-DOTATATE uptake across the cardio-haematopoietic axis was lower after statin therapy in individuals with type 2 diabetes. Therefore, 68Ga-DOTATATE is promising as a metric for vascular and haematopoietic inflammation in intervention studies using anti-inflammatory therapeutics in individuals with type 2 diabetes.ClinicalTrials.gov NCT05730634.

Thyroid storm is a rare and life-threatening complication of untreated thyrotoxicosis. A number of neurological complications have been described in association with thyrotoxicosis. We report the case of a 28-year-old woman with a thyroid storm on the basis of Graves' disease and probably triggered by a surgical procedure. She developed cerebral venous thrombosis (CVT) of the left transverse and rectus sinus with a venous infarction of the left thalamus. Except for an increased factor VIII clotting activity there were no thrombophilic abnormalities. Similar cases have been described in the literature and the reported incidence of the combination of CVT and thyrotoxicosis is significantly higher than expected by chance alone (0.1 x 10(-6) per year vs. 0.0032 x 10(-6)/year). This case is consistent with the assumption that thyrotoxicosis, probably through a factor VIII-mediated hypercoagulability, may be a predisposing factor for the development of CVT.

In patients with decreased left ventricular ejection fraction and conduction disease, ventricular mechanical dyssynchrony has been demonstrated. To date, resynchronization by biventricular pacing is increasingly used since it improves ventricular function and exercise capacity in patients with heart failure. To optimize and evaluate the effect of resynchronization therapy and to identify patients who may benefit from biventricular pacing the assessment of left ventricular synchronicity is essential. Therefore, a non-invasive and reproducible technique to obtain information on ventricular synchrony is clinically valuable. In this review, the technical background and the role of phase analysis of gated blood-pool nuclear ventriculography in the assessment of ventricular mechanical synchrony, especially in heart failure patients subjected to biventricular pacing, will be discussed.

Right ventricular (RV) function is the major determinant of survival in patients with pulmonary hypertension. Yet, the pathophysiologic basis of RV disease is unresolved. We aimed to study the role of apoptosis in RV disease by monitoring it serially during disease progression using in vivo (99m)Tc-annexin-V ((99m)Tc-annexin) scintigraphy and study whether the reduction in apoptosis resulting from chronic treatment with valsartan can be detected by (99m)Tc-annexin scintigraphy.RV disease after pulmonary hypertension was induced by monocrotaline injection in rats. The following 3 groups were studied: rats treated with monocrotaline (monocrotaline rats), rats treated with monocrotaline plus valsartan (valsartan rats), and age-matched controls (control rats). Serial echocardiography and in vivo (99m)Tc-annexin scintigraphy were performed. Apoptosis was confirmed by (99m)Tc-annexin autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Fibrosis was assessed by picrosirius red staining.In monocrotaline rats, in vivo (99m)Tc-annexin uptake peaked early and declined thereafter but remained elevated, compared with baseline. These stage-dependent changes of in vivo (99m)Tc-annexin uptake were paralleled by changes in autoradiography and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling. Valsartan rats had longer RV failure-free survival than did monocrotaline rats and had reduced apoptosis. These changes were accompanied by commensurate delays in RV hypertrophy and RV dilation. Valsartan rats also had less fibrosis than monocrotaline rats at all disease stages.RV disease progression is associated with an early increase in RV apoptosis, as monitored using serial in vivo (99m)Tc-annexin scintigraphy. Delay in RV disease progression by valsartan is accompanied by reduction in RV apoptosis. Apoptosis plays a role in RV disease progression and may be assessed by serial in vivo (99m)Tc-annexin scintigraphy.

It has been argued that hyperaemic microvascular resistance (HMR), defined as the ratio of mean distal coronary pressure to flow velocity, is overestimated in the presence of a coronary stenosis compared to actual microvascular resistance (MR), due to neglecting collateral flow. We aimed to test the hypothesis that HMR allows accurate identification of microvascular functional abnormalities by evaluating the association between high or low HMR and the presence of myocardial ischaemia on non-invasive stress testing.Myocardial perfusion scintigraphy was performed in 228 patients, with 299 lesions to identify reversible myocardial ischaemia. Intracoronary distal pressure and flow velocity were assessed during adenosine-induced hyperaemia (20-40 µg, intracoronary) to determine hyperaemic stenosis resistance (HSR) and HMR. HMR >1.9 mmHg/cm/s was defined as high. The diagnostic odds ratio (OR) for myocardial ischaemia for lesions associated with high compared to low HMR was 2.6 (95% confidence interval [CI]: 1.5-4.4; p<0.001) overall, 3.3 (95% CI: 1.2-9.0; p=0.02) for lesions with HSR >0.8 mmHg/cm/s, and 1.3 (95% CI: 0.6-2.9; p=0.52) for lesions with HSR ≤0.8 mmHg/cm/s.The increased risk of myocardial ischaemia in the presence of high HMR, uncorrected for collateral flow, demonstrates that HMR is reflective of an increase in actual MR, identifying pertinent pathophysiological alterations in the microvasculature.

Abstract Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma.

In the event of obstructive coronary artery disease, collateral arteries have been deemed an alternative blood source to preserve myocardial tissue perfusion and function. Monocytes play an important role in modulating this process, by local secretion of growth factors and extracellular matrix degrading enzymes. Extensive efforts have focused on developing compounds for augmenting the growth of collateral vessels (arteriogenesis). Nonetheless, clinical trials investigating the therapeutic potential of these compounds resulted in disappointing outcomes. Previous studies focused on developing compounds that stimulated collateral vessel growth by enhancing monocyte survival and activity. The limited success of these compounds in clinical studies, led to a paradigm shift in arteriogenesis research. Recent studies have shown genetic heterogeneity between CAD patients with sufficient and insufficient collateral vessels. The genetic predispositions in patients with poorly developed collateral vessels include overexpression of arteriogenesis inhibiting signaling pathways. New directions of arteriogenesis research focus on attempting to block such inhibitory pathways to ultimately promote arteriogenesis. Methods to detect collateral vessel growth are also critical in realizing the therapeutic potential of newly developed compounds. Traditional invasive measurements of intracoronary derived collateral flow index remain the gold standard in quantifying functional capacity of collateral vessels. However, advancements made in hybrid diagnostic imaging modalities will also prove to be advantageous in detecting the effects of pro-arteriogenic compounds.