Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Results: Median follow-up was 49 (18–105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04–3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30–2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07). Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype. Truncating variants in ALPK3 are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes. ALPK3tv, alpha-protein kinase 3-truncating variants; CK, creatine kinase; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter–defibrillator; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death. (B) Cardiac magnetic resonance imaging showing the prevalent phenotype of severe mid to apical hypertrophy and extensive late gadolinium enhancement in three patients. Left to right: 4-chamber view end-diastole cine image, 4-chamber view late gadolinium enhancement image, short axis late gadolinium enhancement image. (C) Kaplan–Meier analysis comparing incidence of an outcome of heart failure death and transplant between ALP3tv patients, sarcomere positive and sarcomere negative. SARC+: sarcomere positive; SARC−: sarcomere negative.

Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing. A cohort of 577 individuals with DCM phenotyped with genetic testing and CMR was analysed. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. LGE patterns in genetic DCM have a specific distribution. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. Abbreviations: CMR, cardiovascular magnetic resonance; DCM, dilated cardiomyopathy; HR, hazard ratio; IQR, interquartile range; LGE, late gadolinium enhancement; L.Midwall, lineal midwall; LVEF, left ventricular ejection fraction; MVA, major ventricular arrhythmias; RV, right ventricle.

Aims: Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non‐ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM. Methods and results: Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing were retrospectively analysed. The primary endpoints were end‐stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow‐up of 2.7 years (interquartile range 1.3–4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p < 0.001) while positive genotype was associated with ESHF ( p = 0.034) but not with MVA ( p = 0.102). Classification of patients according to genotype (G+/G−) and LGE presence (L+/L−) revealed progressively increasing events across L−/G−, L−/G+, L+/G− and L+/G+ groups and resulted in optimized MVA and ESHF prediction ( p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L−/G− were 4.71 (95% confidence interval: 2.11–10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86–33.78, p < 0.001), respectively. Conclusion: Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter‐defibrillator placement.

Background: Cardiac sequelae of past SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in health-care workers to report evidence of pericarditis and myocarditis after SARS-CoV-2 infection. Methods: We studied 139 health-care workers with confirmed past SARS-CoV-2 infection (103 diagnosed by RT-PCR and 36 by serology). Participants underwent clinical assessment, electrocardiography, laboratory tests including immune cell profiling and cardiac magnetic resonance (CMR). Pericarditis was diagnosed when classical criteria were present, and the diagnosis of myocarditis was based on the updated CMR Lake-Louise-Criteria. Results: Median age was 52 years (IQR 41–57), 100 (72%) were women, and 23 (16%) were previously hospitalized for Covid-19 pneumonia. At examination (10.4 [9.3–11.0] weeks after infection-like symptoms), all participants presented hemodynamic stability. Chest pain, dyspnoea or palpitations were observed in 58 (42%) participants; electrocardiographic abnormalities in 69 (50%); NT-pro-BNP was elevated in 11 (8%); troponin in 1 (1%); and CMR abnormalities in 104 (75%). Isolated pericarditis was diagnosed in 4 (3%) participants, myopericarditis in 15 (11%) and isolated myocarditis in 36 (26%). Participants diagnosed by RT-PCR were more likely to still present symptoms than participants diagnosed by serology (73 [71%] vs 18 [50%]; p=0.027); nonetheless, the prevalence of pericarditis or myocarditis was high in both groups (44 [43%] vs 11 [31%]; p=0.238). Most participants (101 [73%]) showed altered immune cell counts in blood, particularly decreased eosinophil (37 [27%]; p<0.001) and increased CD4 ^- CD8 ^-/lo Tαβ-cell numbers (24 [17%]; p<0.001). Pericarditis was associated with elevated CD4 ^- CD8 ^-/lo Tαβ-cell numbers (p=0.011), while participants diagnosed with myopericarditis or myocarditis had lower (p<0.05) plasmacytoid dendritic cell, NK-cell and plasma cell counts and lower anti-SARS-CoV-2-IgG antibody levels (p=0.027). Conclusions: Pericarditis and myocarditis with clinical stability are frequent long after SARS-CoV-2 infection, even in presently asymptomatic subjects. These observations will probably apply to the general population infected and may indicate that cardiac sequelae might occur late in association with an altered (delayed) innate and adaptative immune response. The trial is registered with ClinicalTrials.gov, number NCT04413071 Research in context: Evidence before this study: Very little evidence exists describing long cardiac sequelae after SARS-CoV-2 infection. Although pericarditis and myocarditis are the two most frequent cardiac manifestations observed after a viral infection, as of May 13, 2020, the peer-reviewed literature was limited to isolated case reports of myocarditis and pericarditis during the COVID-19 hospitalization phase and to a retrospective observation in 26 recovered patients with COVID-19 pneumonia presenting cardiac complaints during hospitalization, revealing the presence of myocardial oedema in 14 (54%) patients and late gadolinium enhancement in 8 (31%) patients. These small size case series, limited to hospitalized RT-PCR patients with COVID-19 pneumonia, are insufficient to generalize conclusions about the true prevalence of pericardial and myocardial long involvement after SARS-CoV-2 infection. In addition, no study has investigated the immunological consequences of SARS-CoV-2 infection in the settings of pericarditis and myocarditis. Added value of this study: To our knowledge, this is the largest cohort of subjects (N=139) —even for other common viruses— with clinical, electrocardiographic, laboratory and CMR imaging evaluations, to assess pericardial and myocardial involvements after SARS-CoV-2 infection. The strength of this study is the addition of non-hospitalized participants and also the inclusion of participants diagnosed of past SARS-CoV-2 infection through serology. Contrary to previous studies, women are well represented. We found a prevalence of pericarditis or myocarditis up to 40% cases; pericarditis coexisted with some degree of concurrent myocardial inflammation in 11% cases. Study participants who were previously hospitalized for COVID-19 pneumonia and patients who received antiviral (hydroxychloroquine, lopinavir-ritonavir) or anti-inflammatory (high-dose glucocorticoids and anti-interleukin treatments) treatments, and who were on chronic drug treatment with statins, were less likely to develop pericarditis or myocarditis. The clinical assessment of the participants showed clinical stability without any patient presenting severe pericardial effusion, heart failure or left ventricular dysfunction. We provide new data on seropositive subjects; although RT-PCR participants were more likely to still present symptoms than participants diagnosed by serology, the prevalence of pericarditis, myocarditis or myocarditis, almost three months after the initial viral prodrome, was high in both groups. In-depth investigation of the distribution of multiple major and minor populations of immune cells in blood showed high frequency of altered immune profiles after SARS-CoV-2 infection. The altered immune cell profiles identified partially mimic abnormalities previously reported during active infection together with others described here for the first time, with unique patterns associated with pericardial and/or myocardial injury. Nonetheless, we also described altered immune profiles in participants without pericardial and myocardial manifestations. Whether these later alterations are due to persistence of tissue damage in other organs affected by SARS-CoV-2, such as the lung, or they reflect normal post-infection immune recovery mechanisms, remains to be investigated. Implications of all the available evidence: At present, there is much interest in the long-term sequelae of COVID-19. It is intriguing that pericarditis and myocarditis were observed so long after SARS-CoV-2 infection and also in some presently asymptomatic subjects, in association with notably altered immune cell profiles in blood. These observations will probably apply to the general population infected and may indicate that cardiac sequelae might occur late, paving the way for a better understanding the immune mechanisms involved. Thus, our study may have health-care consequences given the widespread diagnosis of SARS-CoV-2 infection in population-based seroprevalence studies.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder linked primarily to rare variants in sarcomeric genes, although recently certain nonsarcomeric genes have emerged as important contributors. Nonmendelian genetic variants with reproducible moderate-effect sizes and low penetrance, intermediate-effect variants (IEVs), can play a crucial role in modulating disease expression. Understanding the clinical impact of IEVs is crucial to unravel the complex genetic architecture of HCM. METHODS: We conducted an ancestry-based enrichment analysis of 14 validated HCM genes, including the 9 core sarcomeric and 5 nonsarcomeric genes (ALPK3 , CSRP3 , FHOD3 , FLNC , and TRIM63 ). Enrichment of intermediate frequency missense variants was evaluated in 10 981 patients with HCM, 4030 internal controls of European-ancestry, and 590 000 external controls from gnomAD non-Finnish Europeans. The population-attributable fraction was calculated to assess contribution of IEVs to HCM. Age-related disease penetrance, phenotypic severity (left ventricular maximum wall thickness), and major adverse cardiac events were analyzed in 11 991 HCM cases of the whole cohort according to 5 genetic groups: genotype negative, isolated IEV, monogenic, monogenic+IEV, and double monogenic. RESULTS: Fourteen IEVs in 8 genes were identified in 731 individuals (6.1% of the cohort), of whom 570 patients (4.8%) had IEVs in isolation: 198 (34.7%) in sarcomeric genes and 372 (65.3%) in nonsarcomeric genes. The contribution of IEVs to HCM genetics according to population-attributable fraction was estimated to be 4.9% (95% CI, 3.2–6.7). A significant gradient in penetrance, phenotypic severity, and major adverse cardiac events was observed across genetic groups. Compared with genotype-negative patients, IEV carriers displayed a younger median age at diagnosis (59 years of age [95% CI, 46–69] versus 61 years [95% CI, 49–70]; P =0.0073) and a higher mean left ventricular maximum wall thickness (18.1±3.7 versus 19.0±4.3; P =0.0043). IEVs also modified disease expression in individuals with monogenic variants, causing a more aggressive phenotype than in individuals from the monogenic-only group with HCM onset at younger age and a higher left ventricular maximum wall thickness (all P <0.0001), with major adverse cardiac event–free survival being significantly lower (93.3% versus 69.3% at 70 years of age; P <0.0001). CONCLUSIONS: IEVs are present in 6.1% of HCM cases and account for 4.8% of HCM genetic burden. IEVs also influence disease severity and outcomes, particularly when combined with monogenic disease-causing variants. Evaluation of IEVs should be considered when HCM genetic testing is performed.