Journal of the American College of Cardiology

ImportanceThere have been over 759 million confirmed cases of COVID-19 worldwide. A significant portion of these infections will lead to long COVID and its attendant morbidities and costs. ObjectiveTo empirically derive a long COVID case definition consisting of significantly increased signs, symptoms, and diagnoses to support clinical, public health, research, and policy initiatives related to the pandemic. DesignCase-Crossover Population-based study. SettingVeterans Affairs (VA) medical centers across the United States between January 1, 2020 and August 18, 2022. Participants367,148 individuals with positive COVID-19 tests and preexisting ICD-10-CM codes recorded in the VA electronic health record were enrolled. TriggerSARS-CoV-2 infection documented by positive laboratory test. Case WindowOne to seven months following positive COVID testing. Main Outcomes and MeasuresWe defined signs, symptoms, and diagnoses as being associated with long COVID if they had a novel case frequency of >= 1:1000 and they were significantly increased in our entire cohort after a positive COVID test when compared to case frequencies before COVID testing. We present odds ratios with confidence intervals for long COVID signs, symptoms, and diagnoses, organized by ICD-10-CM functional groups and medical specialty. We used our definition to assess long COVID risk based upon a patients demographics, Elixhauser score, vaccination status, and COVID disease severity. ResultsWe developed a long COVID definition consisting of 323 ICD-10-CM diagnosis codes grouped into 143 ICD-10-CM functional groups that were significantly increased in our 367,148 patient post-COVID population. We define seventeen medical-specialty long COVID subtypes such as cardiology long COVID. COVID-19 positive patients developed signs, symptoms, or diagnoses included in our long COVID definition at a proportion of at least 59.7% (based on all COVID positive patients). Patients with more severe cases of COVID-19 and multiple comorbidities were more likely to develop long COVID. Conclusions and RelevanceAn actionable, empirical definition for long COVID can help clinicians screen for and diagnose long COVID, allowing identified patients to be admitted into appropriate monitoring and treatment programs. An actionable long COVID definition can also support public health, research and policy initiatives. COVID patients with low oxygen saturation levels or multiple co-morbidities should be preferentially watched for the development of long COVID.

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.

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

During the process of open peer review on MedRxiv we quickly received a number of messages from reviewers concerned that there was a problem with our reported incidence of myocarditis post mRNA vaccination. Our reported incidence appeared vastly inflated by an incorrectly small denominator (ie number of doses administered over the time period of the study). We reviewed the data available at Open Ottawa and found that there had indeed been a major underestimation, with the actual number of administered doses being more than 800,000 (much higher than quoted in the paper). In order to avoid misleading either colleagues or the general public and press, we the authors unanimously wish to withdraw this paper on the grounds of incorrect incidence data. We thank the many peer reviewers who went out of their way to contact us and point out our error. We apologize to anyone who may have been upset or disturbed by our report. In summary, the authors have withdrawn this manuscript because of a major error pertaining to the quoted incidence data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

BackgroundRare variant genetics have been associated with peripartum cardiomyopathy (PPCM) but the role of genetics remains unsettled. ObjectiveThe study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients with DCM or PPCM (probands), and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls. MethodsClinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where pDCM was defined as left ventricular (LV) enlargement or a LV ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant, of which 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic or uncertain significance variants (P/LP/VUS) was estimated among probands. ResultsThe risk of DCM/pDCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (HR, 0.77; 95% CI, 0.47 - 1.28). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic EA probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a P/LP/VUS among AA and EA probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of P/LP variants among EA PPCM probands (26.6%; 95% CI, 12.6%-40.6%) exceeded a population estimate from a UK Biobank study (0.6%). ConclusionThe risk of DCM/pDCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls suggesting a shared genetic basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all PPCM patients. Condensed AbstractThis is the first study to assess and compare dilated cardiomyopathy (DCM) risk in first-degree relatives (FDRs) of females with peripartum cardiomyopathy (PPCM) and (DCM). The similar risk of DCM or a partial phenotype of DCM in FDRs of females with PPCM and DCM suggests a common genetic contribution to PPCM and DCM. Also, the prevalence of DCM-relevant rare genetic variants was similar between FDRs of females probands diagnosed with PPCM and DCM within European and African ancestry groups and much higher than in population controls. These findings underscore the need of a genetics evaluation for all females with PPCM. Clinical Trialclinicaltrials.gov, NCT03037632

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.

BackgroundInherited cardiomyopathies can present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with putative pathogenic variants (PuPV) in cardiomyopathy-associated genes in the general population. ObjectiveWe aimed to determine the risk of mortality and cardiomyopathy-related outcomes associated with PuPV in cardiomyopathy-associated genes in UK Biobank. MethodsUsing whole exome sequencing data, variants in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes with at least limited evidence of disease causality according to ClinGen Expert Panel curations, were annotated using REVEL ([&ge;]0.65) and ANNOVAR (predicted loss of function) to identify PuPVs. Individuals with PuPV comprised the genotype-positive (G+) and those without PuPV the genotype-negative (G-) cohorts. Group comparisons were made using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). ResultsAmong 200,619 participants, 22,401 (11.2%) were found to host [&ge;]1 PuPV in cardiomyopathy-associated genes (G+). After adjusting for age and sex, G+ individuals had increased all-cause mortality [HR 1.07 (95%CI 1.02-1.13; p=0.011)] and increased rates of diagnosis of cardiomyopathy later in life [HR 2.37 (95%CI 1.98-2.85; p<0.0001)], which further increased in those with PuPV in definitive/strong evidence ClinGen genes [3.25 (95%CI 2.63-4.00; p<0.0001)]. G+ individuals had a higher risk of developing the composite outcome [HR 1.11 (95%CI 1.06-1.15; p<0.0001)]. ConclusionsAdults with PuPV in cardiomyopathy-associated genes have higher all-cause mortality and increased risk of developing cardiomyopathy-associated features and complications, compared to genotype-negative controls. Condensed AbstractLeveraging the UK Biobank prospective cohort, we analyzed whole exome sequencing data in dilated, hypertrophic and arrhythmogenic cardiomyopathy-associated genes using a population screening genotype-first approach. Individuals with putative pathogenic variants in genes implicated in cardiomyopathies showed an increased risk of all-cause mortality, higher risk of developing clinical cardiomyopathy later in life, and higher risk of a composite outcome (cardiomyopathy, heart failure, arrhythmia, stroke, and death) compared to genotype-negative controls. These findings highlight the potential role of genotype-first approach in elevating personalized medicine into population level precision health in the future.

BackgroundMyocardial 18fluorodeoxyglucose (18FDG)-avidity is frequently seen in patients with genetic cardiomyopathy (CMP), as well as a growing "idiopathic 18FDG-avidity" group of genotype-negative patients who do not clearly have cardiac sarcoidosis (CS). ObjectivesTo determine the prognostic implications of 18FDG-avidity in patients with and without genetic CMP, and the effects of immunosuppression in the latter. MethodsThis multicenter, retrospective study included all patients who were referred for both 18FDG-PET and CMP genetic testing. Patients with acute myocarditis, biopsy-proven sarcoidosis or extracardiac 18FDG-avidity were excluded. We investigated heart failure (HF) composite (left ventricular assist device, heart transplant, HF hospitalization, death) and arrhythmia composite (sustained ventricular arrhythmias (VT/VF), atrio-ventricular block, death) outcomes using survival analysis including Cox proportional hazards modeling and inverse probability of treatment weighting (IPWT). ResultsAmong 372 patients, 142 (38%) were 18FDG-avid. Prevalence of genetic CMP among 18FDG-avid patients (12%) was similar to that of 18FDG-negative patients (19%, p=0.07). 18FDG-avidity was associated with increased risk of HF composite (HR 1.69 (1.04-2.75), p=0.034) and arrhythmia composite (HR 1.63 (1.1-2.4), p=0.014) outcomes compared to 18FDG-negative patients. However, these associations were present only in genotype-negative patients, and not in genetic CMP. After IPWT, immunosuppression of 18FDG-avid patients (n=49) was not associated with a reduction in HF (HR 3.31 (1.25, 8.77), p=0.016) or arrhythmia composite outcomes (HR 1.61 (0.79, 3.25), p=0.19) compared with those who were not immunosuppressed (n=93). ConclusionsMyocardial-only 18FDG-avidity is only associated with adverse HF and arrhythmia outcomes in genotype-negative patients who do not clearly have CS. IST does not seem to modify the disease course, suggesting that not all myocardial 18FDG uptake reflects clinically significant inflammation.

BackgroundMitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease (HTAD) gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium (MAC) registry. MethodsMAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using chi-squared or Fisher exact tests. ResultsMR and MVP were enriched in MAC participants (672) with pathogenic variants (PV) in TGF-{beta} pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched in SMAD3 PV compared to other TGF-{beta} PV (PR 1.8 [1.1-2.8], P< 0.02). Severe disjunction (>10 mm) was only observed in the TGF-{beta} subgroup and was further enriched in participants with SMAD3 PV (PR 3.1 [1.1-8.6]). MVP (PR 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events. ConclusionsMitral phenotypes are more prevalent in individuals with PV in TGF-{beta} pathway genes, particularly SMAD3, and are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD. Clinical/Research PerspectiveO_ST_ABSWhat Is New?C_ST_ABS1) Mitral regurgitation, mitral valve prolapse, and mitral annular disjunction (MAD) are common in heritable thoracic aortic disease (HTAD) caused by pathogenic variants (PV) in TGF-{beta} pathway genes (SMAD3, TGFBR1, TGFBR2, TGFB2, or TGFB3) and are associated with adverse cardiac events. 2) Pathological mitral phenotypes are particularly prominent in people with SMAD3 PV and may be the presenting feature of HTAD in some cases. What Are the Clinical Implications?3) Pathological mitral valve phenotypes may identify a high-risk subgroup of HTAD cases with more frequent adverse cardiovascular events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD.

BackgroundImmune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. MethodsA multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. ResultsIn 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for [&le;]0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score[&ge;]4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. ConclusionsICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527 Structured Graphical AbstractKey Question: What predicts poor prognosis in ICI-associated myocarditis? Key Finding: Troponin, thymoma, cardio-muscular symptoms, low QRS-voltage, and LVEF predicted negative outcomes. A risk score containing these features performed well. Take-Home Message: ICI-myocarditis is part of a generalized myotoxicity and early risk-stratified early is possible. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/24308336v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ef7b2corg.highwire.dtl.DTLVardef@17f9822org.highwire.dtl.DTLVardef@1dd00bforg.highwire.dtl.DTLVardef@5c2596_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundCardiac diastolic function and blood pressure are physiologically tightly interconnected. While diastolic function is regulated by post-translational modifications of sarcomeric genes, including titin (TTN), isolating its genetic determinants from those influencing blood pressure is challenging due to variable in vivo loading conditions. We aimed to genetically map diastolic function to the rat genome to prioritise human gene orthologs for genotype-phenotype studies of cardiac function and clinical outcomes. MethodsHigh-fidelity cardiac phenotyping using ex vivo Langendorff preparation in an F2 cross of inbred rat strains included evaluation of left ventricular contractility (LV) (dP / dtmax) and relaxation (dP/dtmin), while controlling loading conditions. In UK Biobank, whole exome sequencing was performed and cardiovascular image-derived phenotypes and outcomes were compared in adult rare variant carriers and genotype-negative participants. ResultsIn rats, quantitative trait locus analysis identified a single locus on chromosome 3 that reached genome-wide significance for LV relaxation (dP/dtmin), which was also associated with variation in LV contractility (dP/dtmax) but not blood pressure. The Ttn gene, which encodes varied non-synonymous single-nucleotide polymorphisms of parental strains, is encoded at the peak of linkage. In humans, the prevalence of rare titin truncating variants (TTNtv) (allele frequency < 0.00004) in 454,756 UK Biobank participants was 0.37% (n = 1,672). Carrying a TTNtv was associated with an increased risk of death or major adverse cardiac events compared to genotype negative controls (hazard ratio: 1.94; 95% confidence interval [CI]: 1.78-2.12; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 3.76; 95% CI: 3.30-4.29; P < 0.001). In 33,988 participants with both cardiac magnetic resonance imaging and whole exome sequencing, TTNtvs were associated with reduced diastolic function, even in participants with normal systolic function and no ventricular dilatation. ConclusionsThese studies demonstrate for the first time in rats, that naturally occurring variations in Ttn are associated with diastolic function, independently of blood pressure, and in humans TTNtv cause impaired cardiac relaxation and adverse outcomes before overt cardiomyopathy develops.

BackgroundDespite currently available state-of-the art therapies, a substantial proportion of patients with inflammatory cardiomyopathy progresses to advanced heart failure. There is an urgent need for novel therapies to improve outcomes. We hypothesized that elevated cyto-kine levels in inflammatory cardiomyopathy may lead to cardiac injury and that specific cyto-kines are associated with severely decreased left ventricular function consequently, thereby suggesting their potential as therapeutic targets. Methods and ResultsBlood samples collected from 529 patients at 2 registries were inves-tigated. First, in a derivation cohort of inflammatory cardiomyopathy from our medical center (n=63), we discovered cytokines that correlate inversely with severely decreased left ventricu-lar ejection fraction (LVEF). We confirmed reproducibility of our results in an independent cohort from a national registry (n=425) and to some degree generalizability in a small cohort of idiopathic dilated cardiomyopathy (IDCM, n=41). In total, we identified 82 cytokines asso-ciated with severely decreased LVEF (FDR < 0.05); a small portion had been previously pro-posed as therapeutic targets, while others emerged as novel discoveries. Finally, real-world data from electronic medical records further indicated the potential of inhibitors targeting cy-tokines of interest to confer a cardioprotective effect. ConclusionsWe identified 82 cytokines associated with severe inflammatory cardiomyopa-thy. Our data were highly significant, reproducible, and generalizable to IDCM. The fact that some of the cytokines had been suggested as potential targets in prior literature supports va-lidity and plausibility of our data. Given that inhibition of cytokines is technically feasible, the identified proteins are compelling potential novel therapeutic targets. Trial registration number: ClinicalTrials.gov Identifier: NCT04265040, NCT02187263 VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/23293253v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1dbe69aorg.highwire.dtl.DTLVardef@c0cforg.highwire.dtl.DTLVardef@1725609org.highwire.dtl.DTLVardef@16e823b_HPS_FORMAT_FIGEXP M_FIG C_FIG

AimsAmong genetically at-risk first-degree relatives (FDRs) of probands with dilated cardiomyopathy (DCM), the ability to detect changes in left ventricular (LV) mechanics with normal LV size and ejection fraction (LVEF) remains incompletely explored. We sought to define a pre-DCM phenotype among at-risk FDRs, including those with variants of uncertain significance (VUSs), using echocardiographic measures of cardiac mechanics. Methods and ResultsLV structure and function, including speckle-tracking analysis for LV global longitudinal strain (GLS), were evaluated in 124 FDRs (65% female; median age 44.9 [IQR: 30.6-60.3] years) of 66 DCM probands of European ancestry sequenced for rare variants in 35 DCM genes. FDRs had normal LV size and LVEF. Negative FDRs of probands with pathogenic or likely pathogenic (P/LP) variants (n=28) were a reference group to which negative FDRs of probands without P/LP variants (n=30), FDRs with only VUSs (n=27), and FDRs with P/LP variants (n=39) were compared. In an analysis accounting for age-dependent penetrance, FDRs below the median age showed minimal differences in LV GLS across groups while those above it with P/LP variants or VUSs had lower absolute values than the reference group (-3.9 [95% CI: -5.7, -2.1] or -3.1 [-4.8, -1.4] %-units) and negative FDRs of probands without P/LP variants (-2.6 [-4.0, -1.2] or -1.8 [-3.1, -0.6]). ConclusionsOlder FDRs with normal LV size and LVEF who harbored P/LP variants or VUSs had lower absolute LV GLS values, indicating that some DCM-related VUSs are clinically relevant. LV GLS may have utility for defining a pre-DCM phenotype. Clinical Trial Registrationclinicaltrials.gov, NCT03037632 Graphical AbstractDifferences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study. DCM = dilated cardiomyopathy, FDR = first-degree relative, GLS = global longitudinal strain, HF = heart failure, LP = likely pathogenic, LV = left ventricular, LVEF = left ventricular ejection fraction, P = pathogenic, VUS = variant of uncertain significance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/23290123v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1a1a86aorg.highwire.dtl.DTLVardef@37eadcorg.highwire.dtl.DTLVardef@11c4f2dorg.highwire.dtl.DTLVardef@192234f_HPS_FORMAT_FIGEXP M_FIG C_FIG

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

BackgroundThe Global Burden of Disease study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with single study design exists for hundreds of rare diseases. Consequently, many rare conditions lack population-level evidence including prevalence and clinical vulnerability. This has led to the absence of evidence-based care for rare diseases, prominently in the COVID-19 pandemic. MethodThis study used electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning healthcare settings for people alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet, we quality assured and filtered down to analyse 331 conditions with ICD-10 or SNOMED-CT mappings clinically validated in our dataset. We report 1) population prevalence, clinical and demographic details of rare diseases, and 2) investigate differences in mortality with SARs-CoV-2. FindingsAmong 58,162,316 individuals, we identified 894,396 with at least one rare disease. Prevalence data in Orphanet originates from various sources with varying degrees of precision. Here we present reproducible age and gender-adjusted estimates for all 331 rare diseases, including first estimates for 186 (56.2%) without any reported prevalence estimate in Orphanet. We identified 49 rare diseases significantly more frequent in females and 62 in males. Similarly we identified 47 rare diseases more frequent in Asian as compared to White ethnicity and 22 with higher Black to white ratios as compared to similar ratios in population controls. 37 rare diseases were overrepresented in the white population as compared to both Black and Asian ethnicities. In total, 7,965 of 894,396 (0.9%) of rare-disease patients died from COVID-19, as compared to 141,287 of 58,162,316 (0.2%) in the full study population. Eight rare diseases had significantly increased risks for COVID-19-related mortality in fully vaccinated individuals, with bullous pemphigoid (8.07[3.01-21.62]) being worst affected. InterpretationOur study highlights that National-scale EHRs provide a unique resource to estimate detailed prevalence, clinical and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision-making for these often neglected patient populations. FundingBritish Heart Foundation Data Science Centre, led by Health Data Research UK. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSWe have previously published the largest study looking at COVID-19 across rare diseases, but with a sample size of 158 COVID-19 infected rare disease patients and 125 unaffected relatives, from Genomics England, the power of that study was limited. We searched PubMed from database inception to Apr 21, 2023, for publications using the search terms "COVID-19" or "SARS-CoV-2" and "rare disease" or "ORPHANET", without language restrictions. There are many studies examining the severity of COVID-19 in rare disease patients. However, to date, most studies have focused on a single or a few rare diseases associated with severity of COVID-19, and not taken a comprehensive rare disease wide approach. So far no studies have examined the impact of vaccination on mortality in rare disease patients. Moreover, the sample size used to examine rare diseases is limited in most studies. The largest study we identified included 168,680 individuals but only focused on autoimmune rheumatic disease. Added value of this studyIn this study we use national scale EHR data from England to report age and gender adjusted point prevalence for 331 rare diseases, with clinically-validated ICD-10 and/or SNOMED-CT code lists. Among these, 186 (56.2%) diseases did not have existing point prevalence data available in Orphanet. To our knowledge, this is the first time that rare diseases have been examined on a national scale, encompassing a population of over 58 million people. The large sample size provides sufficient statistical power to detect and describe enough carriers of even very rare conditions <1 case per million. Our analysis of COVID-related mortality has demonstrated the clinical relevance of national data for rare diseases. Specifically, we identified eight rare conditions that are associated with a significantly increased risk of mortality from COVID-19, even among fully vaccinated individuals. Implication of all the available evidenceThese findings provide robust reproducible prevalence, gender, and ethnicity estimates for disease that may often have been under prioritised, and where such information in most cases was not previously available. Our COVID-19 mortality findings highlight the need for targeted policy and support addressing the high level of vulnerability of these patients to COVID-19.

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5-20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50-200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 ({Delta}) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTSAt week 24, {Delta}pVO2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were -0.05 (95% CI, -0.58 to 0.48), +0.35 (95% CI, -0.22 to 0.91), and -0.61 (95% CI, -1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO2) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, -0.59 to 0.90), -1.15 (95% CI, - 1.89 to -0.42), and 0.88 (95% CI, -0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO2, 60% of patients receiving aficamten achieved a {Delta}pVO2 [&ge;]0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P<0.001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONSChanges in pVO2 of +0.35 and -0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial RegistrationSEQUOIA-HCM (NCT05186818; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1); MAPLE-HCM (NCT05767346; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1) Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUsing pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2) using patient-anchored and distribution-based methodologies. C_LIO_LIA change in pVO2 of +0.35 mL/kg/min and a change in VE/VCO2 of -1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. C_LIO_LIResponder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO2. C_LI What Are the Clinical Implications?O_LIThese newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. C_LIO_LIClinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. C_LIO_LIThese data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials. C_LI

ImportanceThe effect of high percentage spliced in (hiPSI) TTN truncating variants (TTNtvs) on risk of dilated cardiomyopathy (DCM) has historically been studied among population subgroups defined by genetic similarity to European reference populations. This has raised questions about the effect of TTNtvs in diverse populations, especially among individuals genetically similar to African reference populations. ObjectiveTo determine the effect of TTNtvs on risk of DCM in diverse population as measured by genetic distance (GD) in principal component (PC) space. DesignCohort study SettingPenn Medicine Biobank (PMBB) is a large, diverse biobank. ParticipantsParticipants were recruited from across the Penn Medicine healthcare system and volunteered to have their electronic health records linked to biospecimen data including DNA which has undergone whole exome sequencing. Main Outcomes and MeasuresRisk of DCM among individuals carrying a hiPSI TTNtv. ResultsCarrying a hiPSI TTNtv was associated with DCM among PMBB participants across a range of GD deciles from the 1000G European centroid; the effect estimates ranged from odds ratio (OR) = 3.29 (95% confidence interval [CI] 1.26 to 8.56) to OR = 9.39 (95% CI 3.82 to 23.13). When individuals were assigned to population subgroups based on genetic similarity to the 1000G reference populations, hiPSI TTNtvs conferred significant risk of DCM among those genetically similar to the 1000G European reference population (OR = 7.55, 95% CI 4.99 to 11.42, P<0.001) and individuals genetically similar to the 1000G African reference population (OR 3.50, 95% CI 1.48 to 8.24, P=0.004). Conclusions and RelevanceTTNtvs are associated with increased risk of DCM among a diverse cohort. There is no significant difference in effect of TTNtvs on DCM risk across deciles of GD from the 1000G European centroid, suggesting genetic background should not be considered when screening individuals for titin-related DCM. Key Points QuestionDo high percentage spliced in (hiPSI) titin truncating variants (TTNtvs) confer similar levels of risk for dilated cardiomyopathy (DCM) across diverse populations? FindingsIn a cohort study that comprised 43,731 individuals of diverse genetic background with electronic health records linked to whole exome sequencing data, hiPSI TTNtvs conferred increased risk of DCM across all individuals irrespective of genetic background as measured by genetic distance from the 1000 Genomes Project European centroid. MeaningThe findings of this study suggest that TTNtvs increase risk of DCM among individuals independent of genetic background and that genetic similarity to a reference population should not play a role in screening for genetic causes of dilated cardiomyopathy.

BackgroundAcute myocarditis (AM) is an inflammatory cardiac condition with variable prognosis, ranging from complete recovery to progressive heart failure (HF) or death. While advances in diagnostics, such as high-sensitivity troponins and cardiac magnetic resonance imaging (CMR), have facilitated detection of milder cases, prognostic insights across unselected, real-world populations remain limited. MethodsIn this retrospective cohort study, we analyzed 471 consecutive patients hospitalized with a discharge diagnosis of AM between 2009 and 2019. Inclusion was based on clinical diagnosis. Baseline clinical features, laboratory data, and imaging results were extracted and systematically reviewed. The primary composite outcome comprised all-cause mortality, heart transplantation, use of mechanical circulatory support, new-onset HF, ventricular arrhythmias, and cardiac device implantation. ResultsThe median age was 34 years, 32% were female. Chest pain was the predominant presenting symptom (87%), while ST-segment elevation was observed in 48% of cases. At admission, 24.2% of patients had hypokinesia on echocardiography, and 11.6% had a left ventricular ejection fraction (LVEF) <50%. Within the first year of follow-up, 41 patients (8.7%) experienced the composite outcome. Older age, dyspnea at presentation, and elevated biomarkers were associated with adverse events in the first year. Over a median follow-up of 8.2 years, multivariable analysis revealed age (HR 1.05 per year, 95% CI: 1.03-1.07, p<0.001), signs of HF (HR 3.27, 95% CI: 1.25-8.52, p=0.015), and hypokinesia on echocardiography (HR 19.77, 95% CI: 4.10-95.36, p<0.001) as independent predictors of poor outcomes. No sex-based difference in the primary outcome was observed (HR 0.78, 95% CI: 0.31-1.96, p=0.592) despite different clinical presentation. ConclusionsIn this real-world, decade-long cohort, the majority of patients had favorable outcomes. However, a small subset experienced poor outcomes in both the short and long term, highlighting the need for early risk stratification and targeted management of high-risk individuals. What is new?O_LIThis is one of the largest real-world cohorts (n = 471) of patients hospitalized with acute myocarditis (AM) diagnosed through clinical judgment, CMR, or EMB over a 10-year period. C_LIO_LIUnlike prior studies, inclusion was not limited to CMR-or biopsy-confirmed cases, offering a more representative clinical picture. C_LIO_LIMost patients (87.9%) had favorable long-term outcomes; early adverse events were significantly associated with: older age; heart failure signs at admission and regional hypokinesia. C_LI What are the clinical implications?O_LIBedside clinical features, particularly heart failure symptoms and echocardiographic hypokinesia are powerful early predictors of poor prognosis and can guide triage and monitoring decisions. C_LIO_LIPatients without chest pain, or presenting with dyspnea, elevated NT-proBNP, and regional wall motion abnormalities, are at higher risk and may require closer follow-up. C_LIO_LIThis study offers a more inclusive and practical understanding of AM prognosis and supports risk-adapted strategies in real-world cardiology. C_LI

BackgroundPredicting ascending aortic (AsAo) growth is challenging. Conventional paradigms often assume a linear and monotonic relationship between baseline size and future growth that occurs continuously-assumptions that may oversimplify biology-driven disease progression. We first evaluated whether body size-indexed baseline AsAo diameter shows a non-linear association with subsequent growth at the population-level, and second whether patient-level growth trajectories are predominantly continuous or episodic. MethodsWe performed a single-center, retrospective study (2012-2024). The Primary Cohort (n=3,315; [&ge;]2 CT/MR scans) was used to model the relationship between baseline indexed AsAo size (Z-score) and subsequent annualized growth using multivariable linear regression and generalized additive models (GAMs), adjusting for clinical covariates. A Sub-Cohort (n=1,055; [&ge;]4 scans) was used to classify longitudinal phenotypes as: Stable (Total Growth <2.0 mm), Stable-with-Noise (Total Growth <2.0 mm with alternating small changes), Continuous Growth (Total Growth [&ge;]2.0 mm without a qualifying event), or Discontinuous/Episodic Growth (Total Growth [&ge;]2.0 mm with [&ge;]1 "growth event"). A growth event was defined as a diameter increase [&ge;]2.0 mm within a single imaging interval or across two adjacent intervals (combined 0.5-5 years). ResultsIn the Primary Cohort, baseline Z-score demonstrated a significant non-linear (U-shaped) association with subsequent growth in the GAM (p<0.001), with higher growth at both small (Z<0) and severely dilated (Z>5) sizes. In the Sub-Cohort examining growth trajectory, the distribution was: Stable: 50.4% (532/1,055), Stable-with-Noise: 21.6% (228/1,055), Continuous: 5.4% (57/1,055), and Discontinuous/Episodic 22.6% (238/1,055). Among patients with measurable growth (Total Growth [&ge;]2.0 mm, n=295), 81%(n=238) exhibited episodic growth and 58.3% (172/295) had a non-dilated baseline aorta (Z<2). Group differences (e.g., younger age and smaller baseline Z-scores in the Growth vs. Stable groups) were consistent across sensitivity analyses. ConclusionsAsAo growth is not well described by linear, continuous assumptions. Baseline size relates to future growth in a non-linear (U-shaped) manner, and nearly one-quarter of patients exhibit discrete growth bursts separated by periods of quiescence, with episodic behavior dominating among those who enlarge. These findings support a punctuated growth paradigm and argue for re-examining surveillance intervals, risk communication, and threshold-based decision pathways in thoracic aortic disease.

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.