Journal of the American College of Cardiology

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by variable left ventricular hypertrophy, but current diagnostic criteria rely on absolute wall thickness thresholds that may miss early or subtle phenotypic expressions, especially in sarcomere mutation carriers. ObjectivesThis study aimed to assess whether wall thickness standard deviation (WTSD), as a marker of wall thickness heterogeneity, improves the identification of HCM and mutation carriers. MethodsWe evaluated 382 healthy controls, 297 patients with guideline-based HCM diagnosis, and 82 sarcomere mutation carriers without overt hypertrophy using cardiac magnetic resonance imaging. End-diastolic wall thickness (WT) was measured across 16 myocardial segments, and WTSD was calculated. Diagnostic performance of WTSD and other wall thickness-derived parameters was assessed using age- and sex-specific thresholds. ResultsWTSD was significantly higher in HCM patients (4.3 {+/-} 1.1 mm) and mutation carriers (2.3 {+/-} 0.3 mm) compared to healthy controls (1.3 {+/-} 0.3 mm; p<0.0001). WTSD identified 97% of HCM patients and 64% of mutation carriers, with excellent specificity (99%). In females, WTSD achieved a sensitivity of 98.9% and specificity of 100% for HCM diagnosis, and identified 74% of female mutation carriers. WTSD outperformed demographic-based personalized thresholds and BSA-indexed maximal WT in all subgroups. Mutation carriers exhibited increased heterogeneity due to the coexistence of hypertrophic and thinned segments, despite normal absolute WT. ConclusionsWTSD is a robust imaging biomarker that detects early and overt manifestations of sarcomeric HCM with high accuracy. Incorporating WT heterogeneity into diagnostic algorithms may enhance early identification, particularly in women and mutation carriers. CONDENSED ABSTRACTWall thickness heterogeneity, quantified as wall thickness standard deviation (WTSD) by magnetic resonance, emerged as a powerful diagnostic marker of sarcomeric hypertrophic cardiomyopathy (HCM). In 297 HCM patients and 82 mutation carriers, WTSD identified nearly all overt cases and 64% of carriers without hypertrophy with excellent specificity (99%). Particularly in women, WTSD achieved near-perfect diagnostic accuracy and uncovered early disease otherwise missed by conventional thresholds. These findings support incorporating WT heterogeneity into diagnostic algorithms to enable earlier identification of at-risk individuals and refine risk stratification beyond absolute wall thickness criteria.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation and predisposes to thoracic aortic aneurysms. The Montalcino Aortic Consortium (MAC) registry collects genetic and phenotypic data on individuals with heritable thoracic aortic disease genes (HTAD PVs) that primarily regulate smooth muscle cell contraction or TGF-{beta} signaling (TGF-{beta} PVs, termed Loeys-Dietz Syndrome (LDS)). We evaluated associations between BAV, HTAD PVs and aortic outcomes in the MAC cohort. BAV was present in 48 (6%) of 816 MAC participants (age 38 [IQR 20-52] years, 51% female) and was not significantly increased in males or in the entire TGF-{beta} PV group (417 with TGF-{beta} PVs, p=0.14) but was enriched in participants with TGFBR1 or TGFBR2 PVs (16/168, 10% vs. 32/648, 5%, PR 1.93 [1.08, 3.43], p<0.05). BAV was associated with aortic regurgitation (AR, 17/46, 37% vs. 84/752, 11%, PR 3.3 [2.2-5.1], P<0.001), younger age at first aortic event (24 vs. 40 years, p<0.001), primarily reflecting increased proximal aortic repair (27/48, 56% vs. 227/768, 30%, PR 1.90 [1.45, 2.50], P<0.0001), but not aortic dissection (6/48, 13% vs. 134/768, 18%, P>0.5). Sinus of Valsalva dilation (Z>3, 25/48, 52% vs. 128/768, 17%, P<0.0001) and ascending aorta dilation (Z>3, 12/48, 25% vs. 26/768, 3%, P<0.0001) were more common in participants with BAV. Participants with both TGF-{beta} PV and BAV more frequently had aortic valve surgery (17/30, 57% vs. 110/387, 28%, PR 1.99 [1.40-2.83], p<0.01) and sinus of Valsalva dilation (20/29, 69% vs. 91/258, 35% PR 1.96 [1.40-2.63], p<0.001), but not ascending dilation, than participants with TGF-{beta} PV who did not have BAV. BAV is enriched in individuals with HTAD PV, most prominently in the subgroup with LDS TGFBR1 and TGFBR2, and is associated with accelerated aortic valve and aortic diseasebut does not confer an increased risk for aortic dissection. These observations highlight the potential benefits of genetic testing for BAV patients who have a family history of HTAD, a sinus of Valsalva aneurysm, or clinical features suggestive of LDS.

BackgroundAlthough the genetic backgrounds of dilated cardiomyopathy (DCM) have been intensively investigated, the clinical impact of ultra-rare genetic variants (URVs) on DCM remains underexplored. AimsThis study aimed to identify genes enriched for pathogenic coding URVs in DCM patients and elucidate their clinical and structural significance, with focus on LMNA mutations. MethodsAmong patients with DCM, the significance of pathogenic URVs (minor allele frequency [&le;]0.001%), identified based on predictions by AlphaMissense or protein truncation, was examined. ResultsAmong 245 Japanese patients with DCM (53.1 {+/-} 15.1 y.o., 18.0% female.), 43 patients (17.6%) had a total of 49 pathogenic URVs; 14 missense URVs in LMNA (10 patients), 3 missense URVs in SLC51A (3 patients), and 32 protein-truncating URVs in TTN (32 patients). Among the patients with URVs in SLC51A, one also carried URVs in LMNA, and another in TTN. Compared to those without any URVs, the LMNA URV carriers had increased risk of the composite of cardiovascular death, heart transplantation, and left ventricular assist device implantation (hazard ratio [HR] 6.44, 95% CI: 2.85-14.54; P<0.001) as well as implantable cardioverter defibrillator implantation (HR 4.49, 95%CI: 2.02-9.94; P<0.001). Among them, seven amino acid substitutions were identified, including E115M and R190W, which were found in three patients each. Six of the substitutions were localized to the 1B and 2B domains of the alpha-helical coiled-coil structure that play a role in modulating the elasticity of lamin. Histological examinations revealed abnormal nuclear morphology in cardiomyocytes of LMNA URV carriers. ConclusionPathogenic URVs were identified in 17.6% of patients with DCM. Among them, the LMNA URV carriers were characterized by histologically abnormal nuclear structure in cardiomyocytes and increased risk of adverse cardiovascular events. CLINICAL PERSPECTIVEO_ST_ABSWhats New?C_ST_ABSO_LIThis is the first comprehensive investigation to delineate both the clinical and histopathological significance of coding ultra-rare variants (URVs; allele frequency [&le;]0.001% in control populations) in dilated cardiomyopathy (DCM). C_LIO_LIUtilizing whole-genome sequencing in a Japanese cohort of 245 patients with DCM, this study identified pathogenic coding URVs in 17.6% of cases, with a predominance in LMNA and TTN. C_LIO_LICarriers of LMNA URVs--including those with a potentially population-enriched variant (E115M)--demonstrated a significantly elevated risk of severe cardiovascular events and exhibited distinctive nuclear abnormalities in cardiomyocytes. C_LI What are the clinical implications?O_LIGenetic screening for LMNA URVs in patients with DCM may enable early identification of individuals at elevated risk for adverse cardiovascular outcomes. C_LIO_LIThese findings support the need for genotype-guided clinical management, including early initiation of guideline-directed medical therapy and consideration of prophylactic implantable cardioverter-defibrillator (ICD) placement in LMNA URV carriers. C_LIO_LIIdentification of population-specific variants, such as E115M, may enhance risk stratification and contribute to improved long-term prognosis through tailored surveillance and intervention strategies. C_LI

BackgroundCross-sectional studies of various forms of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin ( TTNtv) in 7-30% of patients, but the clinical importance of identifying a TTNtv in an asymptomatic adult is largely unknown. In contrast to cross-sectional studies, prospective cohort studies allow for unbiased estimates of the disease risks associated with a genotype exposure. ObjectivesTo determine the prevalence of cardiac imaging abnormalities and risk of incident disease among middle-aged TTNtv carriers without known congestive heart failure. MethodsWe analyze exome sequencing data of 45,747 participants of the UK Biobank without known congestive heart failure to identify TTNtv carriers. Among 10,552 with cardiac magnetic resonance imaging (MRI), we determine the relationship between TTNtv carrier status and left ventricular ejection fraction. In this prospective cohort, we quantify the absolute and relative risks of incident disease in TTNtv carriers versus noncarriers. ResultsAmong 45,747 middle-aged participants without known congestive heart failure, 196 (0.43%) harbored a TTNtv. The average ejection fraction was 61% in TTNtv carriers versus 65% in noncarriers (P = 1.8 x 10-8), with a 9.3-fold increase (95% CI 3.9 - 22.2) in odds of subnormal ejection fraction (P = 5.7 x 10-5). Over a median follow-up of 6.9 years, a composite endpoint of incident dilated cardiomyopathy, congestive heart failure, or all-cause mortality was observed in 6.6% of TTNtv carriers versus 2.9% of non-carriers (adjusted hazard ratio 2.5; 95% CI 1.4 - 4.3; p = 1.1 x 10-3). ConclusionsApproximately 1 in 230 middle-aged adults without known congestive heart failure harbored a TTNtv. These carriers had a substantially increased relative risk--but modest absolute risk--of having a subnormal ejection fraction or manifesting clinical disease during prospective follow-up. Condensed AbstractCross-sectional studies of dilated cardiomyopathy have noted a truncating mutation in the gene encoding titin ( TTNtv) in up to 30% of patients--but the clinical importance of TTNtv in asymptomatic adults is largely unknown. Here, we observe a TTNtv in 0.43% of 45,747 middle-aged adults. Average ejection fraction was 61% in TTNtv carriers versus 65% in non-carriers (p<0.001). Over a median follow-up of 7 years, incident congestive heart failure or mortality was observed in 6.6% of TTTtv carriers versus 2.9% of non-carriers (hazard ratio 2.5; p = 0.001).

BackgroundCardiovascular-Kidney-Metabolic (CKM) Syndrome is a progressive multisystem construct linked to elevated cardiovascular risk. Coronary microvascular dysfunction may reflect early CKM pathophysiology, but its prevalence and prognostic relevance across CKM stages are unclear. We hypothesized that myocardial flow reserve (MFR), measured by 82Rb PET/CT, declines with advancing CKM stage and provides prognostic value across the spectrum. MethodsWe retrospectively analyzed 5,502 patients who underwent rest-stress 82Rb PET myocardial perfusion imaging between 2016 and 2022. CKM stages 0-4 were defined using a structured algorithm integrating clinical, metabolic, and imaging features. Abnormal MFR was defined as <2.0. The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure hospitalization. Associations between MFR, CKM stage, and outcomes were assessed using Cox models and Kaplan-Meier curves stratified by MFR and CKM stage. ResultsMFR declined stepwise with increasing CKM stage, from 2.65 {+/-} 0.86 in Stage 0-1 to 2.08 {+/-} 0.73 in Stage 4 (p < 0.001). Abnormal MFR prevalence rose from 21% to 50%. Over a median follow-up of 3.9 years (IQR 2.4-5.6), 1,527 composite events occurred. Both abnormal MFR (HR 2.23; 95% CI: 1.96-2.53) and higher CKM stage (Stage 4 vs. Stage 0-1: HR 2.99; 95% CI: 1.71-5.21) independently predicted events. Abnormal MFR further stratified risk within each CKM stage, with the strongest association in Stage 0-1 (HR 7.26; 95% CI: 2.36-22.4; p-interaction < 0.05). ConclusionsMFR is progressively lower across CKM syndrome stages. Abnormal MFR is independently associated with cardiovascular events and provides incremental prognostic value within each CKM stage--most notably in early-stage disease--supporting its potential role in improving risk stratification across the CKM continuum.

BackgroundCoronavirus disease 2019 (COVID-19) can lead to long-term cardiopulmonary symptoms and is associated to coronary microvascular dysfunction (CMD). However, long-term data on CMD following severe COVID-19 are lacking. ObjectiveTo determine long-term left ventricular (LV) function and presence of CMD after severe COVID-19, utilizing cardiovascular magnetic resonance (CMR) and stress perfusion mapping. MethodsHospitalized COVID-19 patients underwent CMR at 10 months follow-up (1.5T Aera, Siemens Healthineers) including cine imaging, native T1 and T2, extracellular volume, and adenosine stress perfusion mapping. Clinical data were obtained from patient records. Patients were compared to volunteers without symptomatic ischemic heart disease (IHD). ResultsCOVID-19 patients (n=37, age 56{+/-}12 years, 76% male) and volunteers (n=22, age 51{+/-}13 years, 55% male, p=ns for both) were included. COVID-19 patients demonstrated reduced stress perfusion (2.8{+/-}0.81 vs 3.4{+/-}0.69 ml/min/g, p=0.003), impaired global longitudinal strain (GLS, -17{+/-}2 vs -19{+/-}2 %, p=0.003) and global circumferential strain (GCS, -16{+/-}3 vs -19{+/-}3 %, p=0.001). There were no differences in stress perfusion or myocardial perfusion reserve between COVID-19 patients with or without cardiovascular risk factors or cardiac symptoms. ConclusionCOVID-19 patients exhibit long-term reduced stress perfusion indicating CMD, and impaired LV function by GLS and GCS. Lack of variation in stress perfusion between patients with and without cardiovascular risk factors suggests that CMD may be a consequence of severe COVID-19, warranting further investigation to elucidate mechanisms, and guide potential therapeutic interventions.

BackgroundPrimary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exists on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indians (SAI), that is necessary for minimizing disparities in interpreting ancestry-specific variants. ObjectivesThe ClinGen Hereditary Cardiovascular Disorders (HCVD) Gene Curation Expert Panel categorized HCM-causing genes into five categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI are lacking. MethodsWhole-exome sequencing was performed for 335 primary SAI-HCM patients, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. ResultsSAI-HCM exomes revealed a total of 194 P/LP and VUS across 26 clinically actionable genes in 119 (35.52%) of the 335 cases. The SAI-HCM cohort exhibited significantly fewer variants in the 12 definitive category genes compared to other global HCM cohorts (17.33% vs. 41.21%, P = 0.0003). For the five strong/moderate genes, no significant difference was observed between the SAI-HCM cohort and other global HCM cohorts (2.59% vs. 2.49%, P = 1). Among the 21 limited and disputed genes, MYH6 showed a significantly higher prevalence of variants in the SAI-HCM cohort than in the other global HCM cohorts (5.07% vs. 1.67%, P = 0.0408). ConclusionsThe clinically actionable gene variants in SAI-HCM cohort differed significantly from other global HCM cohorts, specifically MYBPC3, MYH7, and MYH6.

BackgroundSphericity is a measurement of how closely an object approximates a globe. The sphericity of the blood pool of the left ventricle (LV), is an emerging measure linked to myocardial dysfunction. MethodsVideo-based deep learning models were trained for semantic segmentation (pixel labeling) in cardiac magnetic resonance imaging in 84,327 UK Biobank participants. These labeled pixels were co-oriented in 3D and used to construct surface meshes. LV ejection fraction, mass, volume, surface area, and sphericity were calculated. Epidemiologic and genetic analyses were conducted. Polygenic score validation was performed in All of Us. Results3D LV sphericity was found to be more strongly associated (HR 10.3 per SD, 95% CI 6.1-17.3) than LV ejection fraction (HR 2.9 per SD reduction, 95% CI 2.4-3.6) with dilated cardiomyopathy (DCM). Paired with whole genome sequencing, these measurements linked LV structure and function to 366 distinct common and low-frequency genetic loci--and 17 genes with rare variant burden--spanning a 25-fold range of effect size. The discoveries included 22 out of the 26 loci that were recently associated with DCM. LV genome-wide polygenic scores were equivalent to, or outperformed, dedicated hypertrophic cardiomyopathy (HCM) and DCM polygenic scores for disease prediction. In All of Us, those in the polygenic extreme 1% had an estimated 6.6% risk of DCM by age 80, compared to 33% for carriers of rare truncating variants in the gene TTN. Conclusions3D sphericity is a distinct, heritable LV measurement that is intricately linked to risk for HCM and DCM. The genetic findings from this study raise the possibility that the majority of common genetic loci that will be discovered in future large-scale DCM analyses are present in the current results.

BackgroundDiffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate). ObjectivesTo evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing. MethodsAmong patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy. ResultsAfter a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not. ConclusionsDMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation. Condensed AbstractAnalogous to heart failure and mortality outcomes, diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a more vulnerable phenotype for life-threatening ventricular arrhythmia than focal myocardial fibrosis. In patients referred for cardiovascular magnetic resonance, we identified 215 subsequently receiving implantable cardioverter defibrillators (ICD). After a median of 2.9 (IQR 1.5-4.2) years, 25 patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV associated with ICD therapy in Cox regression models. Focal fibrosis variables or global longitudinal strain did not. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation.

BackgroundsFabry disease (FD) is an X-linked lysosomal disorder with ventricular myocardial involvement that drives morbidity and mortality. Early diagnosis of cardiac involvement can be difficult. This study explored whether abnormal left atrial (LA) strain by cardiovascular magnetic resonance (CMR) may be an early sign of ventricular involvement in FD. MethodsA multicenter, multinational cohort of FD patients was assembled with images centralized for corelab analysis. Adult gene-positive FD patients and healthy volunteers (HV) underwent CMR. LA strain analyses included manually contouring the LA in end-diastole and end-systole to calculate LA volumes and ejection fraction, then semi-automatic analysis for LA reservoir strain. ResultsThere were n=214 FD patients (mean age 45{+/-}15 years, 39% males) and n=76 HV (49{+/-}15 years, 53% males). CMR results in FD: LVEF 73% (IQR=9), LV mass indexed (LVMi) 89{+/-}39g/m2, 99 (46%) had left ventricular hypertrophy (LVH), 36% had late gadolinium enhancement. In FD, LA strain correlated with LVMi (r=-0.52, p<0.01), LV global longitudinal strain (GLS) (r=-0.61,p<0.01), and native myocardial T1 (r=0.34, p<0.01). FD had abnormal LA strain in overt disease (LVH +ve) compared to HVs (p<0.01). LVH-negative FD did not differ in LA strain compared with HV (p>0.5). FD with low T1+LVH-negative did not differ in LA strain compared with normal T1/LVH-negative FD or HV (p>0.3). ConclusionsLA strain is abnormal in FD with LVH (overt disease) and correlates with LVMi, native T1, and GLS. LA strain is normal in FD with early disease (LVH negative+low T1) and normal in FD with no myocardial disease (LVH negative + normal T1). These findings indicate that LA strain is a consequence of abnormal LV mechanics such as LVH and abnormal GLS, rather than isolated myocardial sphingolipid deposition. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSFabry disease is an X-linked lysosomal disorder with potential cardiac complications. Progressive ventricular myocardial involvement drives morbidity and mortality and can be detectable through advanced imaging techniques like cardiovascular magnetic resonance. Early diagnosis of cardiac involvement can be difficult. What this study addsLA strain is abnormal in overt Fabry disease with left ventricular hypertrophy (LVH) and correlates with left ventricular mass, native T1, and global longitudinal strain (GLS). LA strain is normal in Fabry with early disease (LVH negative+low T1) and normal in FD with no myocardial disease (LVH negative + normal T1). These findings indicate that LA strain is a consequence of abnormal LV mechanics such as LVH and abnormal GLS, rather than isolated myocardial sphingolipid deposition. How this study might affect researchThere is a need to identify markers of early cardiac involvement in Fabry disease.

BackgroundRare (monogenic) variants linked to non-ischemic dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcohol-induced (ALCM), and cancer therapy-related (CCM) cardiomyopathies, but are present in less than 15% of cases. Whether a common variant (polygenic) predisposition to DCM also pervades these secondary cardiomyopathies remains unclear. MethodsWe evaluated the association of a DCM polygenic score with PPCM, ALCM, and CCM in the Mass General Brigham (MGB) Biobank (n = 42,137), with replication in the UK Biobank (n = 295,160) and FinnGen (n = 417,950). We then assessed the proportion of cases with a monogenic variant and/or a high polygenic score (defined as > 80th percentile of the score distribution). Finally, we queried medical charts to ascertain whether cardiomyopathy onset in those at high polygenic risk might have been heralded by relevant clinical risk factors. ResultsWe identified 415 individuals with a secondary cardiomyopathy (30 with PPCM, 275 with ALCM, and 110 for CCM) across the three cohorts. The DCM polygenic score associated with PPCM (OR = 1.88 per 1 standard deviation (SD) increase in polygenic score, p= 0.001), ALCM (OR per SD = 1.38, p = 1.46E-07), and CCM (OR per SD = 1.58, p = 2.97E-06). Monogenic DCM variants were strongly associated with PPCM, ALCM, and CCM, but were present in less than 10% of cases. Roughly 40% of all secondary cardiomyopathy cases had a high polygenic score, which conferred [~]3-fold odds of cardiomyopathy (p <0.001). Most secondary cardiomyopathy cases lacked known antecedent clinical risk factors. ConclusionCases of PPCM, ALCM, and CCM are enriched for monogenic DCM variants and a high DCM polygenic score, further supporting a shared genetic susceptibility influenced by distinct environmental precipitants. Considering both monogenic and polygenic risk for DCM may improve identification of individuals predisposed to secondary cardiomyopathies, particularly among those lacking established clinical risk factors.

BackgroundMyocarditis is a leading cause of sudden cardiac death among competitive athletes and may occur without antecedent symptoms. COVID-19-associated myocarditis has been well-described, but the prevalence of myocardial inflammation and fibrosis in young athletes after COVID-19 infection is unknown. ObjectivesThis study sought to evaluate the prevalence and extent of cardiovascular involvement in collegiate athletes that had recently recovered from COVID-19. MethodsWe conducted a retrospective cohort analysis of collegiate varsity athletes with prior COVID-19 infection, all of whom underwent cardiac magnetic resonance (CMR) prior to resumption of competitive sports in August 2020. ResultsTwenty-two collegiate athletes with prior COVID-19 infection underwent CMR. The median time from SARS-CoV-2 infection to CMR was 52 days. The mean age was 20.2 years. Athletes represented 8 different varsity sports. This cohort was compared to 22 healthy controls and 22 tactical athlete controls. Most athletes experienced mild illness (N=17, 77%), while the remainder (23%) were asymptomatic. No athletes had abnormal troponin I, electrocardiograms, or LVEF < 50% on echocardiography. Late gadolinium enhancement was found in 9% of collegiate athletes and one athlete (5%) met formal criteria for myocarditis. ConclusionsOur study suggests that the prevalence of myocardial inflammation or fibrosis after an asymptomatic or mild course of ambulatory COVID-19 among competitive athletes is modest (9%), but would be missed by ECG, Ti, and strain echocardiography. Future investigation is necessary to further phenotype cardiovascular manifestations of COVID-19 in order to better counsel athletes on return to sports participation. Condensed AbstractCOVID-19-associated myocarditis has been well-described, but the prevalence of myocardial inflammation and fibrosis in athletes after COVID-19 is unknown. We conducted a retrospective cohort analysis of 22 collegiate athletes with prior COVID-19 infection who underwent electrocardiography, troponin I, echocardiography with strain, and CMR. The median time from SARS-CoV-2 infection to CMR was 52 days. All athletes experienced mild illness or were asymptomatic. Late gadolinium enhancement was found in 9%. This suggests the prevalence of myocardial inflammation or fibrosis after an asymptomatic or mild course of COVID-19 among competitive athletes is modest, but would be missed without CMR screening.

Increased left ventricular (LV) mass (LVM) and LV hypertrophy (LVH) are risk markers for adverse cardiovascular events, and may indicate an underlying cardiomyopathy. Cardiac magnetic resonance (CMR) is the gold standard for LVM estimation, but is challenging to obtain at scale, which has limited the power of prior genetic analyses. In the current study, we performed a genome-wide association study (GWAS) of CMR-derived LVM indexed to body surface area (LVMI) estimated using a deep learning algorithm within nearly 50,000 participants from the UK Biobank. We identified 12 independent associations (1 known at TTN and 11 novel) meeting genome-wide significance, implicating several candidate genes previously associated with cardiac contractility and cardiomyopathy. Greater CMR-derived LVMI was associated with higher risk of incident dilated (hazard ratio [HR] 2.58 per 1-SD increase, 95% CI 2.10-3.17) and hypertrophic (HR 2.62, 95% CI 2.09-3.30) cardiomyopathies. A polygenic risk score (PRS) for LVMI was also associated with incident hypertrophic cardiomyopathy within a separate set of UK Biobank participants (HR 1.12, 95% CI 1.01-1.12) and among individuals in an external Mass General Brigham dataset (HR 1.18, 95% CI 1.01-1.37). In summary, using CMR-derived LVM available at scale, we have identified 12 common variants associated with LVMI (11 novel) and demonstrated that both CMR-derived and genetically determined LVMI are associated with risk of incident cardiomyopathy. Journal Subject Termsmachine learning, left ventricular hypertrophy, genetics

BackgroundUsual clinical testing rarely reveals cardiac abnormalities persisting after hospitalization for COVID-19. Such testing may overlook residual changes responsible for increased adverse cardiac events post-discharge. MethodsTo further elucidate long-term status, we performed exercise stress echocardiography (ESE) in 15 patients age 30-63 without myocarditis 3 to 31 months after hospital discharge. We compared patient outcomes to published data in healthy comparisons (HC) exercising according to the same protocol. ResultsPatients treadmill exercise (Bruce protocol), averaging 8.2 min, was halted by dyspnea or fatigue. Pre-stress baselines in recovering patients (RP) matched HC except for higher heart rate: mean 81 bpm for RP and 63 for HC (p<0.0001). At peak stress, RP had significantly lower mean left ventricular (LV) ejection fraction (67% vs 73%, p<0.0017) and higher peak early mitral inflow velocity/early mitral annular velocity (E/e, 9.1 vs 6.6, p<0.006) compared with HC performing equal exercise (8.5 min). Thus, when stressed, patients without known cardiac impairment showed modest but consistently diminished systolic contractile function and diastolic LV compliance during recovery vs HC. Peak HR during stress was significantly elevated in RP vs HC; peak SBP also trended higher. Average pulmonary artery systolic pressures among RP remained normal. ConclusionsOur measurements during ESE uniquely identified residual abnormality in cardiac contractile function not evident in the unstressed condition. This finding exposes a previously-unrecognized residual influence of COVID-19, possibly related to underlying autonomic dysfunction, microvascular disease, or diffuse interstitial changes after subclinical myocarditis; it may have long-term implications for clinical management and later prognosis. CLINICAL PERSPECTIVENew Findings (relative to a historical comparison group) O_LISymptom-limited treadmill exercise 3-31 months after hospitalization with COVID-19 without overt myocarditis elicited a lesser rise in left ventricular ejection fraction than seen in similar subjects with no exposure to COVID-19. C_LIO_LIThe same symptom-limited exercise in these patients revealed evidence of diminished left ventricular diastolic function relative to subjects with no exposure to COVID-19. C_LIO_LIThese distinctive differences in left ventricular function were observed although overall exercise capacity was the same as in the uninfected comparison group. C_LI Clinical Implications O_LIPrior hospitalization with COVID-19 even in the absence of overt myocarditis was often associated with a modest but consistent decrement in left ventricular systolic contraction and diastolic relaxation; these functional abnormalities were evident after peak treadmill exercise stress despite lack of distinctive difference in contractile parameters at rest. C_LIO_LIPatients recovering after hospitalization with COVID-19 may benefit from sustained observation of their cardiovascular status and adjustment of their exercise requirements appropriate to individual cardiovascular capabilities. C_LIO_LITreadmill stress testing with echocardiography uniquely identifies potentially important differences in the cardiovascular function of patients recovering after hospitalization with COVID-19. C_LI

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSThe degree of myocardial injury, reflected by troponin elevation, and associated outcomes among hospitalized patients with Coronavirus Disease (COVID-19) in the US are unknown. ObjectivesTo describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19. MethodsPatients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27th and April 12th, 2020 with troponin-I (normal value <0.03ng/mL) measured within 24 hours of admission were included (n=2,736). Demographics, medical history, admission labs, and outcomes were captured from the hospitals EHR. ResultsThe median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. Even small amounts of myocardial injury (e.g. troponin I 0.03-0.09ng/mL, n=455, 16.6%) were associated with death (adjusted HR: 1.77, 95% CI 1.39-2.26; P<0.001) while greater amounts (e.g. troponin I>0.09 ng/dL, n=530, 19.4%) were associated with more pronounced risk (adjusted HR 3.23, 95% CI 2.59-4.02). ConclusionsMyocardial injury is prevalent among patients hospitalized with COVID-19, and is associated with higher risk of mortality. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation likely reflects non-ischemic or secondary myocardial injury. Unstructured AbstractMyocardial injury reflected as elevated troponin in Coronavirus Disease (COVID-19) is not well characterized among patients in the United States. We describe the prevalence and impact of myocardial injury among hospitalized patients with confirmed COVID-19 and troponin-I measurements within 24 hours of admission (N=2,736). Elevated troponin concentrations (normal <0.03ng/mL) were commonly observed in patients hospitalized with COVID-19, most often present at low levels, and associated with increased risk of death. Patients with cardiovascular disease (CVD) or risk factors for CVD were more likely to have myocardial injury. Troponin elevation likely reflects non-ischemic or secondary myocardial injury.

IntroductionMeasurement of the interventricular septum (IVS) is a key diagnostic and prognostic parameter in the evaluation of hypertrophic cardiomyopathy (HCM). Right ventricular muscle bundles (RVMB) that parallel the IVS complicate septal measurement on both echocardiography and magnetic resonance imaging. Current guideline statements reference left ventricular wall thickness measurements more than 15 mm as part of the diagnostic criteria for HCM. The medical literature lacks published data on the impact of including RVMB as part of the IVS measurement and its influence on diagnostic accuracy for HCM. MethodsWe measured the IVS and RVMB separately on echocardiography in 97 consecutive subjects referred for both echocardiography and magnetic resonance imaging (MRI) as part of the initial evaluation for HCM. Subjects were categorized as having or not having HCM based on current practice guidelines. Patients with HCM were sub-categorized as having septal involvement (HCM-Sep) or primarily apical hypertrophy (HCM-Ap). This was done because subjects with obvious HCM-Ap could be diagnosed with HCM irrespective of IVS thickness. ResultsCompared to subjects who did not have HCM, those with HCM-Sep had both increased IVS (15.4 {+/-} 2.7 vs 9.8 {+/-} 1.9 mm, p<0.001) and RVMB thickness (5.2 {+/-} 3.1 vs 1.9 {+/-} 1.9 mm, p<0.001). Within the group of subjects that either had HCM-Sep or did not have HCM, inclusion of the RVMB in the septal measurement increased the sensitivity for HCM from 63% to 100%, whereas specificity decreased from 100% to 87%. RVMB thickness more than 5 mm was seen in 46% of subjects with HCM-Sep but was absent in all subjects with HCM-Ap and those without HCM. The RVMB was visible on long axis imaging in 55% of subjects without HCM, 75% of subjects with HCM-Ap and 85% of subjects with HCM-Sep. ConclusionsInclusion of the RVMB in the measurement of IVS thickness on echocardiography may improve overall diagnostic accuracy for HCM. In addition, RVMB thickness is increased and is more often visible on parasternal long axis imaging in subjects with HCM, consistent with being part of the HCM pathology. This is particularly true in those with HCM-Sep. These data have implications for standardization of echocardiographic and MRI reporting in HCM.

BackgroundThere is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general, adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional and arrhythmic disease features. MethodsUK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiovascular magnetic resonance (CMR) imaging were selected for study. Three different variant calling strategies (one primary and two secondary) were used to identify subjects with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded to either 1) DCM (clinical or CMR diagnosis); 2) early DCM features, including arrhythmia and/or conduction disease, isolated ventricular dilation, and hypokinetic non-dilated cardiomyopathy; or 3) phenotype-negative. ResultsAmong 18,665 individuals included in the study, 1,463 (7.8%) subjects possessed [&ge;]1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and CMR analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in 15.9% of individuals with putative pathogenic variants. Arrhythmias and/or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic non-dilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was [&le;]30% with all three variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes, as compared to those with variants in moderate/limited evidence genes. ConclusionsIn the UK Biobank, approximately 1/6 of adults with putative pathogenic variants in DCM genes exhibited a subclinical phenotype based on ECG and/or CMR, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation/dysfunction. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIAmong individuals with putative pathogenic DCM gene variants, subclinical DCM and early DCM features, detected by ECG and/or CMR, were nearly four times more common than clinically manifest DCM or early features (23.7% vs. 6.1%). C_LIO_LIOver 90% of subjects with a putative pathogenic variant in DCM-associated genes did not have a prior history of DCM. C_LIO_LIClinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes (13.9% for clinical and subclinical), as compared to those with variants in moderate/limited evidence genes, but there was no significant difference in combined clinical/subclinical phenotype by cluster. C_LIO_LIThe overall clinical/subclinical penetrance of DCM-associated single putative pathogenic variants was highly variable between genes, ranging from 0 to 66.7%. C_LI What are the clinical implications?O_LIArrhythmias and cardiac conduction disease are the most common early manifestation of putative pathogenic variants implicated in DCM, mostly occurring prior to the development of structural/functional abnormalities. C_LIO_LIA genotype-first screening approach for DCM using a large genetic panel is currently not suitable in the general population due to incomplete understanding of DCM genetic architecture and reduced penetrance of DCM-associated putative pathogenic variants. C_LI Journal Subject TermsCardiomyopathy; Genetics; Sudden Cardiac Death

BackgroundGenetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants (RBM20tvs) is unclear. ObjectiveAssess the contribution of RBM20tvs to DCM. MethodsWe assembled an international cohort of DCM patients with RBM20 variants and used data from the genome-first UK Biobank (UKB) to assess the etiologic fraction, natural history and penetrance of RBM20tvs. ResultsThe etiologic fraction of RBM20tvs in arrhythmogenic DCM was modest (0.53[0.32,0.67], p=7.5x10-5). RBM20tv DCM patients presented to referral centers later in life than RBM20 P/LP DCM patients (53{+/-}10 vs. 34{+/-}18 years, p=4x10-3), and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%, p= 0.046) or cardiomyopathy (20% vs. 78% p=5.4x10-3). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between RBM20tv and RBM20 P/LP DCM patients, though sex-adjusted lifetime hazard was reduced in RBM20tv DCM (HR 0.15[0.03,0.66],p=0.009). In UKB, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20tvs than in those with TTNtvs (HR 0.55 [0.36,0.84], p=5.9x10-3). ConclusionsRBM20tvs contribute to arrhythmogenic DCM phenotypes, but confer milder disease severity alone than RBM20 P/LP variants, and reduced lifetime disease penetrance compared to TTNtvs. Their potential for additive interactions with other damaging variants should be considered in DCM patients and families.

ImportancePolygenic background modifies variant penetrance in hypertrophic (HCM) and dilated (DCM) cardiomyopathy, diseases with opposing morphologic characteristics and inversely related genetic pathways. Whether polygenic susceptibility for one disease protects against monogenic risk for the other remains unexplored. ObjectiveTo characterize if polygenic background bidirectionally modifies pathogenicity of established rare variants associated with HCM and DCM. DesignCross-sectional study. SettingThe Penn Medicine BioBank (PMBB). ParticipantsVolunteers enrolled in PMBB with available electronic health record and genotyping data. ExposuresNormalized polygenic scores (PGS) for HCM and DCM, as well as carrier status of pathogenic variants in established HCM or DCM genes. Main OutcomesHCM and DCM defined using electronic health record diagnosis and procedure code, as well as echocardiogram measurements derived from medical records. ResultsThis study included 49,434 PMBB participants. An increased HCM PGS was associated with significantly increased left ventricular ejection fraction (LVEF), decreased left ventricular internal diameter at end-diastole (LVIDd), and increased interventricular septal thickness (IVS) (p<0.001). An increased DCM PGS was significantly (p<0.001) associated with decreased LVEF and increased LVIDd, but was not associated with IVS. A one standard deviation increase in HCM PGS was associated with increased risk of HCM (OR 1.8; 95% CI 1.6-2.0; p=9.6x10-25) and decreased risk of DCM (OR 0.69; 95% CI 0.64-0.74; p=4.3x10-22). A one standard deviation increase in DCM PGS was associated with an increased risk of DCM (OR 1.6; 95% CI 1.5-1.7; p=1.7x10-40) and decreased risk of HCM (OR 0.69; 95% CI 0.63-0.76; p=3.0x10-13). Monogenic and polygenic risk terms had significant, independent effects when combined in models of disease status and echocardiographic measurements; the additional inclusion of either an HCM or DCM PGS improved the discrimination of models of HCM and DCM that included age, sex, and monogenic variant status (>95% probability of difference in AUROC). Conclusions and RelevanceHCM and DCM risk are markedly modified by polygenic background which exists on an overlapping spectrum. Consideration of polygenic background may offer clinical value through improving understanding and prediction of these inherited cardiomyopathies. Key PointsO_ST_ABSQuestionC_ST_ABSHow is risk for hypertrophic and dilated cardiomyopathy modified by polygenic background? FindingsPolygenic scores for HCM and DCM associate with clinical and echocardiographic measures relevant to both diseases and inversely modify the penetrance of pathogenic variants. MeaningPolygenic background contributes to HCM and DCM susceptibility, and exists on an overlapping spectrum.

BackgroundInterleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in adverse cardiac remodeling and outcomes in various cardiovascular diseases. Its role in hypertrophic cardiomyopathy (HCM), particularly in risk stratification and prognosis, remains underexplored. This study evaluates serum IL-6 levels alongside cardiac magnetic resonance (CMR) imaging parameters as predictors of major adverse cardiac events (MACE) in patients with apical HCM (ApHCM) and non-apical HCM (Non-ApHCM). MethodA cohort of 255 patients was recruited between 2013 and 2023, with blood samples collected for genetic analysis and biomarker testing. A subset of 196 patients underwent CMR imaging to assess left ventricular morphology, function, and myocardial fibrosis. MACE was defined as the composite occurrence of ventricular arrhythmias, heart failure, atrial fibrillation, stroke, or all-cause mortality. ResultsPatients with elevated IL-6 levels (above the median) demonstrated significantly higher MACE rates compared to those with lower levels (7.5 vs. 3.3 events/100 patient-years; pairwise log-rank P < 0.001). IL-6 levels correlated with adverse CMR markers, including myocardial fibrosis, increased left atrial volume, and impaired strain, regardless of HCM subtype. Combining IL-6 levels with morphological classification revealed stepwise risk stratification, with MACE rates escalating from 0.9 (ApHCM with low IL-6) to 8.8 events/100 patient-years (Non-ApHCM with high IL-6) (pairwise log-rank P < 0.001). ConclusionThis study highlights IL-6 as a critical biomarker associated with adverse outcomes in HCM. When integrated with morphological assessment, IL-6 enhances risk stratification and provides a novel approach to assessing disease severity. These findings underscore the potential for IL-6 to guide clinical decision-making and inform therapeutic strategies in HCM.