With the development and advancement of next-generation sequencing (NGS), genetic analysis is becoming more accessible. High-throughput genetic studies using NGS have contributed to unraveling the association between cardiomyopathy and genetic background, as is the case with many other diseases. Rare variants have been shown to play major roles in the pathogenesis of cardiomyopathy, which was empirically recognized as a monogenic disease, and it has been elucidated that the clinical course of cardiomyopathy varies depending on the causative genes. These findings were not limited to dilated and hypertrophic cardiomyopathy; similar trends were reported one after another for peripartum cardiomyopathy (PPCM), cancer therapy-related cardiac dysfunction (CTRCD), and alcoholic cardiomyopathy (ACM). In addition, as the association between clinical phenotypes and the causative genes becomes clearer, progress is being made in elucidating the mechanisms and developing novel therapeutic agents. Recently, it has been suggested that not only rare variants but also common variants contribute to the development of cardiomyopathy. Cardiomyopathy and genetics are approaching a new era, which is summarized here in this overview.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction–induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R -LMNA– related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA -related DCM.

Background: Original apical hypertrophic cardiomyopathy was characterized by left ventricular hypertrophy confined to the apex below the papillary muscle level. In contrast, apical hypertrophic cardiomyopathy in Western countries often includes hypertrophy extending to the midventricular septum. Recognizing these phenotypic differences is essential as they may influence the clinical prognosis. The aim of this study was to delineate the clinical and genetic disparities between the pure‐apical form, according to the original definition, and the distal‐dominant form, in which hypertrophy extends to the ventricular septum without basal septal hypertrophy. Methods: A retrospective analysis was conducted for 111 consecutive patients with apical hypertrophic cardiomyopathy with assessment of hypertrophic cardiomyopathy–related adverse events including hypertrophic cardiomyopathy–related death, heart failure admission, embolic stroke admission, and sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter‐defibrillator discharge. Genetic testing for hypertrophic cardiomyopathy‐associated genes was performed in 72 patients. Results: Among the patients, 60 were classified as pure‐apical form, and 51 were classified as distal‐dominant form. The median age at diagnosis was 63 years, with a predominance of men in both groups. Over a follow‐up period of 11.0 years, the incidence of hypertrophic cardiomyopathy–related adverse events was significantly higher in the distal‐dominant group than in the pure‐apical group (log‐rank, P <0.001). The detection rate of pathogenic or likely pathogenic variants was also significantly higher in the distal‐dominant group than in the pure‐apical group (26% versus 3%; P =0.005). Conclusions: Distinct clinical and genetic profiles of the 2 apical hypertrophic cardiomyopathy phenotypes warrant their recognition and differentiation in clinical practice due to distinct prognoses and genetic backgrounds.

Background: Fulminant myocarditis is life‐threatening and often requires mechanical circulatory support. Predicting its clinical course is crucial, yet data on early recovery predictors, particularly with veno‐arterial extracorporeal membrane oxygenation, remain lacking. Methods and Results: We aimed to identify prognostic factors of early recovery in fulminant myocarditis requiring veno‐arterial extracorporeal membrane oxygenation by retrospective analysis of a nationwide registry in Japan. Early recovery was defined as successful weaning from mechanical circulatory support within 7 days and discharge without heart transplantation or long‐term mechanical circulatory support. A total of 343 patients were analyzed; 71 were classified as early recovery and 272 as nonearly recovery. The early recovery group was significantly younger, had higher white blood cell counts, and lower creatine kinase‐myocardial band level than the nonearly recovery group. To enhance clinical interpretability, we dichotomized continuous variables using optimal cutoff values derived from the Youden index. Multivariable logistic regression analysis showed the independent factors of early recovery were age ≤40 years (odds ratio [OR], 3.25), white blood cell count ≥11 000/μL (OR, 3.10), and creatine kinase‐myocardial band ≤61 U/L (OR, 2.46), and if all conditions were fulfilled, the early recovery rate increased to 61.5%. Additionally, although not statistically significant, the number of rehospitalization with cardiovascular causes, death, or heart transplantation at 1‐year follow‐up was higher in the nonearly recovery group. Conclusions: Our study suggested younger patients who have a strong inflammatory response but less myocardial damage on admission could recover earlier. Conversely, in cases where mechanical circulatory support duration is prolonged, careful monitoring is required for prolonged left ventricular dysfunction and subsequent prognosis. Registration: URL: https://www.umin.ac.jp/ ; Unique identifier: UMIN000039763.