Imaging Features of Arrhythmogenic Cardiomyopathies.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by replacement of ventricular myocardium with fibrofatty tissue, predisposing the patient to ventricular arrhythmias and/or sudden cardiac death. Most cases of ACM are associated with pathogenic variants in genes that encode desmosomal proteins, an important cell-to-cell adhesion complex present in both the heart and skin tissue. Although ACM was first described as a disease predominantly of the right ventricle, it is now acknowledged that it can also primarily involve the left ventricle or both ventricles. The original right-dominant phenotype is traditionally diagnosed using the 2010 task force criteria, a multifactorial algorithm divided into major and minor criteria consisting of structural criteria based on two-dimensional echocardiographic, cardiac MRI, or right ventricular angiographic findings; tissue characterization based on endomyocardial biopsy results; repolarization and depolarization abnormalities based on electrocardiographic findings; arrhythmic features; and family history. Shortfalls in the task force criteria due to the modern understanding of the disease have led to development of the Padua criteria, which include updated criteria for diagnosis of the right-dominant phenotype and new criteria for diagnosis of the left-predominant and biventricular phenotypes. In addition to incorporating cardiac MRI findings of ventricular dilatation, systolic dysfunction, and regional wall motion abnormalities, the new Padua criteria emphasize late gadolinium enhancement at cardiac MRI as a key feature in diagnosis and imaging-based tissue characterization. Conditions to consider in the differential diagnosis of the right-dominant phenotype include various other causes of right ventricular dilatation such as left-to-right shunts and variants of normal right ventricular anatomy that can be misinterpreted as abnormalities. The left-dominant phenotype can mimic myocarditis at imaging and clinical examination. Additional considerations for the differential diagnosis of ACM, particularly for the left-dominant phenotype, include sarcoidosis and dilated cardiomyopathy. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Longitudinal Change and Predictors of Myocardial Flow Reserve by Positron Emission Tomography for the Evaluation of Cardiac Allograft Vasculopathy Following Heart Transplantation.

BACKGROUND: Positron emission tomography (PET) myocardial flow reserve (MFR) is a noninvasive method of detecting cardiac allograft vasculopathy in recipients of heart transplants (HTs). There are limited data on longitudinal change and predictors of MFR following HT. METHODS: We conducted a retrospective analysis of HT recipients undergoing PET myocardial perfusion imaging at an academic center. Multivariable linear and Cox regression models were constructed to identify longitudinal trends, predictors and the prognostic value of MFR after HT. RESULTS: Of HT recipients, 183 underwent 658 PET studies. The average MFR was 2.34 ± 0.70. MFR initially increased during the first 3 years following HT (+ 0.12 per year; P = 0.01) before beginning to decline at an annual rate of -0.06 per year (P < 0.001). MFR declines preceding acute rejection and improves after treatment. Treatment with mammalian target of rapamycin (mTOR) inhibitors (37.2%) slowed the rate of annual MFR decline (P = 0.03). Higher-intensity statin therapy was associated with improved MFR. Longer time post-transplant (P < 0.001), hypertension (P < 0.001), chronic kidney disease (P < 0.001), diabetes mellitus (P = 0.038), antibody-mediated rejection (P = 0.040), and cytomegalovirus infection (P = 0.034) were associated with reduced MFR. Reduced MFR (HR: 7.6, 95% CI: 4.4-13.4; P < 0.001) and PET-defined ischemia (HR: 2.3, 95% CI: 1.4-3.9; P < 0.001) were associated with a higher risk of the composite outcome of mortality, retransplantation, heart failure hospitalization, acute coronary syndrome, or revascularization. CONCLUSION: MFR declines after the third post-transplant year and is prognostic for cardiovascular events. Cardiometabolic risk-factor modification and treatment with higher-intensity statin therapy and mechanistic target of rapamycin inhibitors are associated with a higher MFR.

Mitral Annular Substrate and Ventricular Arrhythmias in Arrhythmogenic Mitral Valve Prolapse With Mitral Annular Disjunction.

BACKGROUND: In patients with bileaflet mitral valve prolapse (MVP), mitral annular disjunction (MAD) is associated with increased risk of sudden cardiac death via incompletely understood mechanisms. OBJECTIVES: This study assessed the substrate for ventricular arrhythmias in patients with bileaflet MVP and MAD as well as outcomes of catheter ablation with an emphasis on sustained, monomorphic ventricular tachycardia (VT). METHODS: A total of 18 consecutive patients (11 women, mean age 54 ± 15 years) with bileaflet MVP and MAD underwent catheter ablation for VT, and/or premature ventricular complexes (PVCs). Eight patients had a prior cardiac arrest. RESULTS: PVCs were targeted for ablation in all 18 patients (symptomatic PVCs n = 15, PVC-induced ventricular fibrillation n = 3). Sustained monomorphic VT was targeted in 7 of 18 patients. Electroanatomic mapping showed low voltage in the area of the mitral annulus corresponding to VT target sites in 6 of 7 patients with sustained VT. Four of 7 patients had low voltage in the areas of MAD. Six of 7 patients with VT were rendered noninducible post-ablation. The PVC burden was reduced from 11.0% ± 10.4% to 4.0% ± 5.5% (P = 0.004). Over a mean follow-up of 33.9 ± 43.4 months, no VTs recurred. There were no major complications. No repeat ablations for VT occurred. Five of 18 patients required repeat ablation for PVCs. CONCLUSIONS: In patients with bileaflet MVP and MAD undergoing catheter ablation, the mitral valve annulus often contains low-voltage areas harboring the substrate for monomorphic VT and PVCs. Ablation in these patients was safe and improved arrhythmia control.

Effects of Mitral Valve Prolapse on Quantification of Mitral Regurgitation and Ejection Fraction Using Cardiac MRI.

Purpose: To determine the impact of prolapsed volume on regurgitant volume (RegV), regurgitant fraction (RF), and left ventricular ejection fraction (LVEF) in patients with mitral valve prolapse (MVP) using cardiac MRI. Materials and Methods: Patients with MVP and mitral regurgitation who underwent cardiac MRI from 2005 to 2020 were identified retrospectively from the electronic record. RegV is the difference between left ventricular stroke volume (LVSV) and aortic flow. Left ventricular end-systolic volume (LVESV) and LVSV were obtained from volumetric cine images, with prolapsed volume inclusion (LVESVp, LVSVp) and exclusion (LVESVa, LVSVa) providing two estimates of RegV (RegVp, RegVa), RF (RFp, RFa), and LVEF (LVEFa, LVEFp). Interobserver agreement for LVESVp was assessed using intraclass correlation coefficient (ICC). RegV was also calculated independently using measurements from mitral inflow and aortic net flow phase-contrast imaging as the reference standard (RegVg). Results: The study included 19 patients (mean age, 28 years ± 16 [SD]; 10 male patients). Interobserver agreement for LVESVp was high (ICC, 0.98; 95% CI: 0.96, 0.99). Prolapsed volume inclusion resulted in higher LVESV (LVESVp: 95.4 mL ± 34.7 vs LVESVa: 82.4 mL ± 33.8; P < .001), lower LVSV (LVSVp: 100.5 mL ± 33.8 vs LVSVa: 113.5 mL ± 35.9; P < .001), and lower LVEF (LVEFp: 51.7% ± 5.7 vs LVEFa: 58.6% ± 6.3; P < .001). RegV was larger in magnitude when prolapsed volume was excluded (RegVa: 39.4 mL ± 21.0 vs RegVg: 25.8 mL ± 22.8; P = .02), with no evidence of a difference when including prolapsed volume (RegVp: 26.4 mL ± 16.4 vs RegVg: 25.8 mL ± 22.8; P > .99). Conclusion: Measurements that included prolapsed volume most closely reflected mitral regurgitation severity, but inclusion of this volume resulted in a lower LVEF.Keywords: Cardiac, MRI© RSNA, 2023See also commentary by Lee and Markl in this issue.

Utility of serum ketone levels for assessment of myocardial glucose suppression for 18F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis.

BACKGROUND: 18F-FDG PET/CT is used to diagnose cardiac sarcoidosis and endocarditis. It requires myocardial glucose utilization (MGU) suppression to avoid false positives, which occur in up to 20% of patients. Serum beta-hydroxybutyrate (BHB) levels may help identify incomplete suppression of MGU. We determined the optimal timing and diagnostic thresholds to identify incomplete suppression of MGU. METHODS AND RESULTS: We retrospectively identified 114 patients referred for 18F-FDG PET/CT for endocarditis, wherein myocardial uptake outside of paravalvular regions is not related to pathology and can be confidently ascribed as being due to inadequate suppression of MGU. Patients followed a high-fat, low-carbohydrate diet and received heparin. Serum BHB, insulin, glucose and hemoglobin A1c were measured. Maximum standardized uptake value (SUVmax) of left ventricle (LV) and mean SUV (SUVmean) in LV blood pool (LVBP) was measured. Logistic regression and area under the receiver-operating characteristic analyses were used to quantify the relationship between biomarkers and MGU suppression. A threshold of BHB ≥ 0.35 mmol·L-1 to detect suppression resulted in sensitivity of 88% and specificity of 61%. A threshold of BHB ≥ 0.95 mmol·L-1 resulted in sensitivity of 45% and specificity of 100%. AUC was 0.87. BHB measured ~ 4 hours prior to 18F-FDG injection performed similarly to or better than later timepoints. CONCLUSIONS: Serum BHB levels are useful for assessing suppression of MGU and could simplify interpretation of 18F-FDG PET/CT inflammation studies.

Society for Cardiovascular Magnetic Resonance 2021 cases of SCMR and COVID-19 case collection series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). "Cases of SCMR" is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. The COVID-19 Case Collection highlights the impact of coronavirus disease 2019 (COVID-19) on the heart as demonstrated on CMR. Each case in series consists of the clinical presentation and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2021 Cases of SCMR and the 2020 and 2021 COVID-19 Case Collection series of nine cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar literature search engine.

Entropy as a Measure of Myocardial Tissue Heterogeneity in Patients With Ventricular Arrhythmias.

OBJECTIVES: The authors investigated the incremental prognostic value of entropy, a novel measure of myocardial tissue heterogeneity by cardiac magnetic resonance (CMR) imaging in patients presenting with ventricular arrhythmias (VAs). BACKGROUND: CMR can characterize myocardial areas serving as arrhythmogenic substrate. METHODS: Consecutive patients undergoing CMR imaging for VAs were followed for major adverse cardiac events (MACEs) defined by all-cause death, incident VAs requiring therapy, or heart failure hospitalization. Entropy was derived from the probability distribution of pixel signal intensities of the left ventricular (LV) myocardium. RESULTS: A total of 583 patients (age 54 ± 15 years, female 39%, left ventricular ejection fraction [LVEF] 54 ± 13%) were followed for a median of 4.4 years and experienced 141 MACEs. Entropy showed strong unadjusted association with MACE (HR: 1.88; 95% CI: 1.63-2.17; P < 0.001). In a multivariable model including LVEF, QRS duration, late gadolinium enhancement, and presenting arrhythmia, entropy maintained independent association with MACE (HR: 1.61; 95% CI: 1.32-1.96; P < 0.001). Entropy was further significantly associated with MACE in patients without myocardial scar (HR: 2.43; 95% CI: 1.55-3.82; P < 0.001) and in those presenting with nonsustained VAs (HR: 2.16; 95% CI: 1.43-3.25; P < 0.001). Addition of LV entropy to the baseline multivariable model significantly improved model performance (C-statistic improvement: 0.725 to 0.754; P = 0.003) and risk reclassification. CONCLUSIONS: In patients with VAs, CMR-assessed LV entropy was independently associated with MACE and provided incremental prognostic value, on top of LVEF and late gadolinium enhancement. LV entropy assessment may help risk stratification in patients with absence of myocardial scar or with nonsustained VAs.

Imaging Coronary Allograft Vasculopathy with Cardiac PET and Cardiac MRI.

PURPOSE OF REVIEW: Coronary allograft vasculopathy (CAV) is a leading cause of morbidity and mortality in heart transplant patients. It presents a diagnostic challenge as early CAV is often clinically silent, and it affects both epicardial coronary arteries and microvasculature. This review outlines the role of cardiac positron emission tomography (PET) and cardiac magnetic resonance imaging (CMR) in the diagnosis and prognosis of CAV. RECENT FINDINGS: Relative myocardial perfusion imaging (MPI) and quantitative myocardial blood flow using cardiac PET are useful in the diagnosis and prognosis of CAV. Late gadolinium enhancement (LGE) and quantitative measures including myocardial perfusion reserve and mean diastolic rate using CMR are useful in the diagnosis and prognosis of CAV. Cardiac PET is now established as a non-invasive imaging modality for screening and monitoring for CAV, and CMR has demonstrated promise in this application. Further investigation of these modalities is needed with larger, multicenter studies that follow patients serially to demonstrate the clinical implications of using these modalities to detect early CAV and alter therapies to improve patient outcomes.

Resting Pd/Pa correlates with fractional flow reserve but not angiographic severity in calcified coronary arteries.

OBJECTIVE: Study the effect of coronary artery calcium (CAC) on resting coronary physiological indices. BACKGROUND: Prior studies found no correlation between angiographic stenosis and fractional flow reserve (FFR) in heavily calcified arteries. METHODS: Two hundred consecutive patients undergoing whole-cycle resting Pd/Pa and FFR evaluation of a single lesion of intermediate severity (40-80%) had CAC quantified based upon radiopacities at the site of the stenosis, where 0 = none or mild calcium, 1 = moderate calcium, and 2 = severe calcium. RESULTS: Mean age was 61 ± 11 years and 34% were female. The mean degree of stenosis, FFR, and resting Pd/Pa were 60 ± 12%, 0.83 ± 0.08, and 0.93 ± 0.05, respectively. Resting Pd/Pa correlated with degree of angiographic diameter stenosis (DS) as determined by quantitative coronary angiography (QCA) or visual estimation in arteries with calcium score of 0 or 1, but there was no correlation in severely calcified arteries. The diagnostic accuracy of DS ≥70% by QCA to predict hemodynamic significance was 68% with calcium scores of 0/1, but only 43% with calcium score = 2. Resting Pd/Pa was highly correlated with FFR irrespective of the degree of CAC (R2 = 0.68, p < .001) and the sensitivity of resting Pd/Pa ≤0.91 for predicting an FFR ≤0.80 was 0.67 in arteries with calcium scores of 0 or 1 and 0.69 in arteries with a calcium score of 2. CONCLUSIONS: There was no correlation between angiographic stenosis and either resting Pd/Pa or FFR in heavily calcified coronary artery lesions.

Angiographic severity does not correlate with fractional flow reserve in heavily calcified coronary arteries.

OBJECTIVES: To determine the relationship between severity of stenosis and hemodynamic significance in calcified coronary arteries. BACKGROUND: Severity of stenosis is widely used to determine the need for revascularization but the effect of lesion calcification on hemodynamic significance is not well understood. METHODS: Two hundred consecutive patients undergoing fractional flow reserve (FFR) testing of an intermediate coronary lesion with a pressure wire and intravenous infusion of adenosine were studied. Coronary calcium was quantified based upon radiopacities at the site of the stenosis on cineangiography using the method of Mintz et al. (0 = none or mild calcium, 1 = moderate calcium, 2 = severe calcium). RESULTS: Mean age was 61 ± 11 years, 66% were males, 87.5% had hypertension, 44.5% had diabetes, and 20.5% were current smokers. The mean coronary stenosis by quantitative coronary angiography was 60 ± 12% and the mean FFR was 0.83 ± 0.08. There were 109, 45, and 46 patients classified as Calcium Score of 0, 1, or 2, respectively. Compared to those with no/mild or moderate calcification, patients with severe coronary calcium were older and more likely to have chronic kidney disease and pulmonary disease. The correlation between angiographic severity and FFR decreased as lesion calcification increased [calcium score = 0 (R2 = 0.25, P < 0.005); calcium score = 1 (R2 = 0.11, P < 0.005); calcium score = 2 (R2 = 0.02, P = 0.35)]. CONCLUSIONS: In patients with heavily calcified coronary lesions, there was no association between angiographic stenosis and hemodynamic significance and FFR is needed to determine hemodynamic significance of intermediate lesions. © 2016 Wiley Periodicals, Inc.

Left Ventricular Dysfunction After Treatment With Ipilimumab for Metastatic Melanoma.

Ipilimumab is a monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) that is approved by the US Food and Drug Administration for the treatment of unresectable or metastatic melanoma. Ipilimumab is known to cause immune-mediated adverse reactions because of the resultant increase in T-cell activity. To date, there are no published reports of ipilimumab-related heart failure, although a recently published report describes a case of transient cardiomyopathy associated with its use. We report the case of a 60-year-old man who developed left ventricular dysfunction with an asymptomatic reduction in ejection fraction from 55%-60% at baseline to 40%-45% 4 months after completing a second course of treatment with ipilimumab for metastatic melanoma. Ipilimumab was not restarted, and the patient was initiated on lisinopril and carvedilol. Repeat echocardiograms 3 and 5 months later revealed ejection fractions of 40%-45% and 55%-60%, respectively.

Obesity and natriuretic peptides, BNP and NT-proBNP: mechanisms and diagnostic implications for heart failure.

Many advances have been made in the diagnosis and management of heart failure (HF) in recent years. Cardiac biomarkers are an essential tool for clinicians: point of care B-type natriuretic peptide (BNP) and its N-terminal counterpart (NT-proBNP) levels help distinguish cardiac from non-cardiac causes of dyspnea and are also useful in the prognosis and monitoring of the efficacy of therapy. One of the major limitations of HF biomarkers is in obese patients where the relationship between BNP and NT-proBNP levels and myocardial stiffness is complex. Recent data suggest an inverse relationship between BNP and NT-proBNP levels and body mass index. Given the ever-increasing prevalence of obesity world-wide, it is important to understand the benefits and limitations of HF biomarkers in this population. This review will explore the biology, physiology, and pathophysiology of these peptides and the cardiac endocrine paradox in HF. We also examine the clinical evidence, mechanisms, and plausible biological explanations for the discord between BNP levels and HF in obese patients.

Control of vascular smooth muscle cell growth by connexin 43.

Connexin 43 (Cx43), the principal gap junction protein in vascular smooth muscle cells (VSMCs), regulates movement of ions and other signaling molecules through gap junction intercellular communication (GJIC) and plays important roles in maintaining normal vessel function; however, many of the signaling mechanisms controlling Cx43 in VSMCs are not clearly described. The goal of this study was to investigate mechanisms of Cx43 regulation with respect to VSMC proliferation. Treatment of rat primary VSMCs with the cAMP analog 8Br-cAMP, the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 (BAY), or the Cx inducer diallyl disulfide (DADS) significantly reduced proliferation after 72 h compared with vehicle controls. Bromodeoxyuridine uptake revealed reduction (p < 0.05) in DNA synthesis after 6 h and flow cytometry showed reduced (40%) S-phase cell numbers after 16 h in DADS-treated cells compared with vehicle controls. Cx43 expression significantly increased after 270 min treatment with 8Br-cAMP, 8Br-cGMP, BAY or DADS. Inhibition of PKA, PKG or PKC reversed 8Br-cAMP-stimulated increases in Cx43 expression, whereas only PKG or PKC inhibition reversed 8Br-cGMP- and BAY-stimulated increases in total Cx43. Interestingly, stimulation of Cx43 expression by DADS was not dependent on PKA, PKG or PKC. Using fluorescence recovery after photobleaching, only 8Br-cAMP or DADS increased GJIC with 8Br-cAMP mediated by PKC and DADS mediated by PKG. Further, DADS significantly increased phosphorylation at MAPK-sensitive Serine (Ser)255 and Ser279, the cell cycle regulatory kinase-sensitive Ser262 and PKC-sensitive Ser368 after 30 min while 8Br-cAMP significantly increased phosphorylation only at Ser279 compared with controls. This study demonstrates that 8Br-cAMP- and DADS-enhanced GJIC rather than Cx43 expression and/or phosphorylation plays important roles in the regulation of VSMC proliferation and provides new insights into the growth-regulatory capacities of Cx43 in VSM.

Nox activator 1: a potential target for modulation of vascular reactive oxygen species in atherosclerotic arteries.

BACKGROUND: Despite a concerted effort by many laboratories, the critical subunits that participate in vascular smooth muscle cell (VSMC) NADPH oxidase function have yet to be elucidated. Given the potential therapeutic importance of cell-specific inhibition of NADPH oxidase, we investigated the role of Nox activator 1 (NoxA1), a homolog of p67phox, in VSMC NADPH oxidase function and atherosclerosis. METHODS AND RESULTS: The presence of NoxA1 in mouse aortic VSMCs was confirmed by reverse-transcription polymerase chain reaction and sequencing. NoxA1/p47phox interaction after thrombin treatment was observed by immunoprecipitation/Western analysis of lysates from p47phox(-/-) VSMCs transfected with adenoviral HA-NoxA1 and Myc-p47phox. Infection with adenoviral NoxA1 significantly enhanced thrombin-induced reactive oxygen species generation in wild-type but not in p47phox(-/-) and Nox1(-/-) VSMCs. Thrombin-induced reactive oxygen species production and VSMC proliferation were significantly reduced after downregulation of NoxA1 with shRNA. Infection with NoxA1 shRNA but not scrambled shRNA significantly decreased thrombin-induced activation of the redox-sensitive protein kinases (Janus kinase 2, Akt, and p38 mitogen-activated protein kinase) in VSMCs. Adenovirus-mediated overexpression of NoxA1 in guidewire-injured mouse carotid arteries significantly increased superoxide production in medial VSMCs and enhanced neointimal hyperplasia. NoxA1 expression was significantly increased in aortas and atherosclerotic lesions of ApoE(-/-) mice compared with age-matched wild-type mice. Furthermore, in contrast to p67phox, immunoreactive NoxA1 is present in intimal and medial SMCs of human early carotid atherosclerotic lesions. CONCLUSIONS: NoxA1 is the functional homolog of p67phox in VSMCs that regulates redox signaling and VSMC phenotype. These findings support the potential for modulation of NoxA1 expression as a viable approach for the treatment of vascular diseases.

Atherosclerosis is attenuated by limiting superoxide generation in both macrophages and vessel wall cells.

OBJECTIVE: We previously showed that NAD(P)H oxidase deficiency significantly reduces atherosclerosis in apoE(-/-) mice. The present study was designed to determine the relative contribution of monocyte/macrophage versus vascular wall cell NAD(P)H oxidase to atherogenesis in this model. METHODS AND RESULTS: Cell-specific NAD(P)H oxidase inhibition was achieved via allogenic, sex-mismatched bone marrow transplantation. Aortic atherosclerosis and superoxide production in apoE(-/-) mice (Control) with functional NAD(P)H oxidase in both monocytes/macrophages and vascular wall cells was compared with that in apoE(-/-) mice with nonfunctional monocyte/macrophage NAD(P)H oxidase (BMO) or nonfunctional vessel wall NAD(P)H oxidase (VWO). A significant decrease in superoxide production and atherosclerotic lesions was observed in BMO and VWO mice compared with control mice. Interestingly, BMO mice had significantly lower plasma oxidized LDL levels compared with control and VWO mice, whereas aortic sections of VWO mice showed decreased expression of cellular adhesion molecules compared with control and BMO mice. NAD(P)H oxidase deficiency also attenuated neointimal hyperplasia and mitogenic protein activation in apoE(-/-) mice after arterial injury. CONCLUSIONS: We conclude that (1) both monocyte/macrophages and vessel wall cells play critical roles in atherogenesis; (2) decrease in atherosclerosis results from attenuated superoxide generation in monocyte/macrophages or vessel wall cells; and (3) superoxide generation may impact atherosclerosis, in part, by activating smooth muscle cell mitogenic signaling pathways.