BAG3V468M impairs proteasomal protein clearance and induces dilated cardiomyopathy in vivo.

Dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) are major non-ischemic cardiomyopathy (NICM) subtypes with heterogeneous outcomes. Conventional clinical and echocardiographic markers remain insufficient for long-term risk stratification. This study aimed to identify serum metabolites associated with adverse cardiovascular outcomes and evaluate their incremental prognostic value in NICM. Thirty-two patients with DCM or LVNC and left ventricular ejection fraction < 50% were enrolled and followed for a median of 45.5 months. The primary endpoint was a composite of cardiovascular death, heart failure-related hospitalization, or clinically indicated cardiovascular device implantation. Baseline serum samples underwent liquid chromatography-mass spectrometry-based untargeted metabolomic profiling. Differential metabolites were identified using OPLS-DA and KEGG enrichment analysis. Prognostic metabolites were screened using Cox regression, Kaplan-Meier analysis, correlation filtering, and ROC analysis. An integrated Cox model combining clinical and metabolic markers was evaluated using bootstrapping, calibration, and time-dependent ROC analysis. A total of 299 differential metabolites were identified and enriched in bile secretion, steroid hormone biosynthesis, and neuroactive ligand-receptor interaction pathways. Sphingosine-1-phosphate (S1P) and tetrahydrocortisone (THE) were selected as final prognostic metabolite biomarkers, with ROC AUCs of 0.777 and 0.793, respectively. The integrated model incorporating S1P, THE, tricuspid annular plane systolic excursion, and total protein achieved a bootstrap-corrected C-index of 0.772, with time-dependent AUCs of 0.92 and 0.86 at 3 and 5 years. Serum metabolomics may provide complementary prognostic information in NICM. S1P and THE are exploratory biomarkers linked to remodeling and stress, supporting risk stratification in NICM with reduced ejection fraction.

Plasticizer-responsive molecular axes in heart failure: a subtype-aware toxicogenomic framework relevant to environmental health.

Spatially confined β-adrenergic receptor-cAMP nanodomain signaling depends on scaffolded protein-protein interactions (PPIs), yet converting such nanointerfaces into cell-active disruptor peptides remains challenging. Here, we identify a previously unrecognized phosphodiesterase 4A (PDE4A)-filamin A complex in human cardiac tissue that is disrupted in dilated cardiomyopathy. To target this interaction, we developed a nanodomain-resolved AlphaFold3 workflow integrating interface-recurrence filtering, orthogonal docking, and peptide-binding site inference to define a tractable binding region. This approach identified a filamin A docking sequence spanning R2520-H2528, which was optimized to RLVSNHSLH and rendered cell-permeant by N-terminal polyarginine tagging. In ventricular cardiomyocytes, the peptide reduced PDE4A-filamin A proximity and selectively attenuated β-adrenergic cAMP signaling in cytosolic and sarcolemmal compartments, measured by FRET biosensors. This work establishes a potential transferable strategy for translating predicted scaffolded PPI nanointerfaces into functional disruptor peptides and highlights compartmentalized signaling complexes as actionable targets for selective cellular modulation.

Exosomal MALAT1 expression associated with the cardioprotective effects of carvacrol in acute doxorubicin-induced cardiac injury: Potential involvement of Nrf2/Keap1-related signaling.

Temporary Mechanical Support for Chagas Dilated Cardiomyopathy Related Cardiogenic Shock in Latin America

β-Arrestin-biased activation of type I angiotensin II receptors improves prognosis of murine pediatric heart failure.

Autosomal dominant kidney hypomagnesemia with RRAGD variants (ADKH-RRAGD) is a hereditary disorder characterized by kidney tubulopathy and dilated cardiomyopathy (DCM). RagD, encoded by the RRAGD gene, is a small GTPase involved in activating the mechanistic target of rapamycin complex 1 (mTORC1) by amino acids. Although several gain-of-function variants in the RRAGD gene have been identified, their contributions to DCM remain unclear. Here, we hypothesize that these RRAGD variants induce mTORC1 overactivation, thereby contributing to the manifestation of DCM. To investigate this, we established T-REx HeLa cell lines that overexpress the RRAGD p.(Ser76Leu) or the wild-type (WT) variant to assess the effects on mTORC1 signaling. Additionally, we developed the first cellular model of ADKH-RRAGD utilizing genetically edited human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express the mutated variant. Our data indicate that the RRAGD p.(Ser76Leu) variant maintains the phosphorylation of mTORC1 targets (i.e., S6K, 4E-BP1, and TFEB) during amino acid starvation, in contrast to RRAGD WT in T-REx HeLa cells. The pharmacological inhibition of mTOR with Torin1 reversed these changes. In 2D-cultured RRAGDWT/p.(Ser76Leu) hiPSC-CMs, mTORC1 remained responsive to amino acid starvation. Results from bulk RNA sequencing showed an upregulation of pathways associated with cytoskeletal organization and a downregulation of muscle development in RRAGDWT/p.(Ser76Leu) hiPSC-CMs. Moreover, a prolonged duration of Ca2+ transients was observed in the mutant cardiomyocytes. Altogether, our data demonstrate that gain-of-function variants in RRAGD cause mTORC1 activation in T-REx HeLa cells. Consequently, cardiomyocytes develop impaired intracellular Ca2+ clearance and activation of transcriptional programs, suggesting dedifferentiation.

Sex and Age Specific Genetic Risk Across the Dilated and Arrhythmogenic Cardiomyopathy Spectrum: Insights From the SHaRe Registry.

Genotype and left ventricular reverse remodelling in familial dilated cardiomyopathy with contemporary heart failure therapy - the ReaGEN study

Mutations in LMNA, which encodes the nuclear envelope protein lamin A/C, cause laminopathies that frequently present as dilated cardiomyopathy (DCM). We investigated whether re-expression of lamin A in cardiomyocytes can rescue the severe phenotype of Lmna-/- mice. An adeno-associated virus vector expressing wild-type Lmna (AAV-Lmna/DJ8) was administered intrathoracically to neonatal mice. Three weeks after injection, treated Lmna-/- mice exhibited robust cardiac Lmna mRNA induction and correct nuclear localization of lamin A protein, indicating efficient cardiotropic gene delivery. Compared with PBS treatment, AAV-Lmna/DJ8 treatment promoted body weight maintenance, improved left ventricular systolic function, and significantly prolonged survival in Lmna-/- mice. To explore the underlying mechanisms, we performed single-nucleus RNA sequencing of cardiomyocytes from wild-type mice, PBS-treated Lmna-/- mice, and AAV-Lmna/DJ8-treated Lmna-/- mice. AAV-mediated lamin A re-expression shifted the cardiomyocyte transcriptome toward the wild-type profile, and restored oxidative phosphorylation-related gene programs, which were diminished in untreated Lmna-/- mice. These findings demonstrate that targeted re-expression of Lmna partially ameliorates cardiac dysfunction in Lmna-/- mice and highlight the therapeutic potential of LMNA gene replacement for laminopathy-associated cardiomyopathy.

Cardiomyopathies frequently arise from rare, highly penetrant coding variants with variable clinical expressivity. Genome-wide association studies (GWAS) suggest significant polygenic contributions to cardiovascular diseases, including cardiomyopathy. Most GWAS loci map to poorly conserved noncoding regions, requiring human genome context for experimental validation. We created engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes and primary cardiac fibroblasts. We assayed single-cell gene expression and chromatin accessibility to generate comprehensive genome-wide regulatory maps. Open chromatin regions were integrated with chromatin contact information and used to fine-map cardiomyopathy GWAS single-nucleotide polymorphisms. Single-nucleotide polymorphisms and their associated open chromatin regions were assessed using reporter assays, genome editing, and expression profiling. EHT Single-cell RNA-seq recapitulated major cardiac cell types, with advanced cardiomyocyte maturation compared with monolayer human induced pluripotent stem cell cardiomyocytes. More than 400 000 open chromatin regions were resolved to cell types and assayed for transcription factor motifs. Functional fine-mapping of GWAS loci prioritized 5817 variants, and reporter assays validated allele-specific enhancer activity. We identified an intergenic chr3p25.1 locus harboring significant GWAS signals from both dilated cardiomyopathy and left ventricular ejection fraction. Several of these variants lie in open chromatin regions participating in long-range chromatin interactions with SLC6A6 and GRIP2. Haplotype-resolved and synthetic reporter assays confirmed enhancer activity and narrowed candidate single-nucleotide polymorphisms. CRISPR-deletion of this region reduced expression of both SLC6A6 and GRIP2, indicating the enhancer regulates the expression of multiple genes. EHTs with the enhancer deletion displayed markedly reduced contractile function, confirming that this enhancer region contributes to myocardial function. EHTs are an experimentally tractable platform for testing the function of noncoding variants as modifiers of cardiomyopathy. Variants fine-mapped from cardiomyopathies using EHT regulatory maps have functional consequences and provide a set of prioritized sites to advance the study of polygenic heart failure.

Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a heart failure-associated gene. However, the role of SYBU in regulating cardiac function remains unclear. Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes (NRVMs). SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened heart failure under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy (SIM) and analysis of mitochondria-associated endoplasmic reticulum membrane (MAM) fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with RyR2 and SERCA2, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and PKA activation, inducing phosphorylation of Drp1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy. Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signaling pathways could be a promising therapeutic strategy to restrain HF in pressure overload - induced cardiac hypertrophy.

Guideline-directed medical therapy use in adults with duchenne muscular dystrophy and heart failure with reduced ejection fraction

Mitral valve dysplasia is a rare congenital etiology of primary mitral valve regurgitation. It can cause severe chronic mitral regurgitation, which may eventually lead to left atrial and ventricular dilation and dysfunction. Left ventricular non-compaction is a relatively rare cardiomyopathy that overlaps with hypertrophic and dilated cardiomyopathy. It can also lead to left or right ventricular dysfunction and failure. Papillary muscle hypertrophy may be a subtype of, or an early expression of, hypertrophic cardiomyopathy. Herein, we present a 42-year-old woman with a rare coexistence of mitral valve dysplasia, non-compaction left ventricular cardiomyopathy, and papillary muscle hypertrophy.

Cardiovascular disease remains the leading cause of global mortality. Understanding its complexity requires dissecting the heart's cellular landscape. Here we present HeartMap, a comprehensive single-nucleus RNA sequencing atlas of the adult human heart. This resource integrates data from nine studies, encompassing over 2.4 million nuclei, 209 individuals, eight anatomical regions and seven disease and healthy states. After rigorous data harmonization and method comparison of batch correction methods, we characterized transcriptional diversity across 14 cell types. To demonstrate the utility of HeartMap, we identified robust disease-associated gene signatures in dilated cardiomyopathy by comparing multiple studies. Notably, we identified distinct activated fibroblast populations, enriched for COL22A1 or TNC, that display variable prevalence across cardiomyopathies. HeartMap provides a valuable tool for exploring cardiac disease at the single-cell level, facilitating both fundamental research and potential therapeutic development.

Objective: To evaluate the predictive value of the 2025 appropriate use criteria (AUV) for implantable cardioverter defibrillators (ICD) jointly issued by the American College of Cardiology/American Heart Association and other societies, for sudden cardiac death (SCD) in patients with dilated cardiomyopathy (DCM), and to explore the incremental value of cardiac magnetic resonance (CMR) tissue characterization in SCD risk stratification. Methods: This was a single-center, retrospective study that consecutively enrolled DCM patients who underwent CMR with late gadolinium enhancement (LGE) and T1 mapping at Fuwai Hospital, Chinese Academy of Medical Sciences from February 2012 to September 2021. According to the 2025 ICD appropriate use criteria and LGE extent, patients were divided into three groups: AUC-appropriate with LGE<7.2% (AUC-A+LGE<7.2%) group, AUC-appropriate with LGE≥7.2% (AUC-A+LGE≥7.2%) group, and AUC-maybe appropriate (AUC-M) group. Baseline data and CMR parameters were collected, and all patients were followed up. Predictors of the SCD composite endpoint were identified using Cox proportional hazards regression, and the clinical efficacy of LGE and extracellular volume fraction (ECV<31.8% or ≥31.8%) for SCD risk stratification was assessed using Kaplan-Meier survival analysis. Results: A total of 741 DCM patients were enrolled, aged (47.0±14.3) years, with 581 (78.4%) males. There were 447 patients in the AUC-A+LGE<7.2% group, 162 in the AUC-A+LGE≥7.2% group, and 132 in the AUC-M group. Over a follow-up of 53.4 (32.9, 74.8) months, the SCD composite endpoint occurred in 78 patients (10.5%). Multivariable Cox regression analysis identified left atrial volume index (HR=1.005, 95%CI 1.001-1.009, P=0.015), right ventricular ejection fraction (HR=0.976, 95%CI 0.963-0.990, P<0.001), LGE≥7.2% (HR=4.308, 95%CI 2.633-7.050, P<0.001), and ECV≥31.8% (HR=2.719, 95%CI 1.515-4.878, P<0.001) were predictors of the SCD composite endpoint. Kaplan-Meier analysis showed no significant difference in SCD risk between the AUC-A+LGE<7.2% group and AUC-M group (log-rank P=0.269). Further stratification revealed that patients with ECV<31.8% in the AUC-A+LGE<7.2% subgroup had an extremely low annual SCD event rate of 0.6%, representing a truly low-risk population accounting for 35.8% (265/741) of the total cohort. In contrast, the annual SCD event rate in the AUC-A+LGE≥7.2% group was as high as 5.5%. Conclusions: CMR myocardial tissue characterization parameters (LGE and ECV) provide significant incremental prognostic value to the 2025 ICD appropriate use criteria, enabling precise re-stratification of SCD risk in DCM patients and facilitating optimized clinical decision-making for primary prevention with ICD implantation.

Genetic testing has become an integral part of the diagnostic workup of patients with dilated cardiomyopathy (DCM). While the initial goal of genetic testing was to identify family members at risk, recent advances have now extended their relevance to clinical decision-making. Our knowledge of the genetic architecture of DCM has expanded significantly, promoting a shift from the monogenic dogma towards a broader polygenic spectrum. However, current genetic testing strategies still primarily rely on the model of monogenic inheritance with an incomplete penetrance. Large studies have shown a yield varying from 8% to 36% of genetic testing in patients with DCM, depending on aetiology or family history. Genetic testing is generally warranted for every patient with DCM where genetic results could have an impact on risk stratification, the prognosis or the treatment of the patient, or its family members with an opportunity for reassurance or early disease detection. There are various strategies for genetic testing including broad multigene panels, or more targeted panels limited to specific disease-associated genes. Identified variants are classified by genetic laboratories, where pathogenic or likely pathogenic variants often have actionable clinical implications. It is crucial to interpret these variants in the context of the individual patient considering the phenotype and other contributing factors. When the genetic results are consistent with the patients' broader phenotype, potential clinical implications may include decision for device therapy, recommendations for family screening, and reproductive options. A comprehensive approach to integrate genetic testing in the clinical care of patients with DCM is proposed.

Sacubitril/valsartan is widely used in adults with heart failure with reduced ejection fraction, but paediatric experience, especially across ventricular dysfunction phenotypes, remains limited. To evaluate the efficacy and tolerability of sacubitril/valsartan in children with cardiomyopathy and compare outcomes in patientswith predominantly right or left ventricular dysfunction. This single-centre retrospective study included 33 patients aged 1 month to 18 years who received sacubitril/valsartanbetween October 2020 and October 2024. Diagnoses included arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction, and dilated cardiomyopathy. Patients were stratified by predominant ventricular dysfunction. Echocardiographic parameters, N-terminal pro B-type natriuretic peptide, six-minute walk test, NYHA class, blood pressure, creatinine, and potassium were recorded at baseline and at 1, 3, and 6 months, and at final follow-up. Clinical outcomes included rehospitalisation, death, and heart transplantation or listing. The cohort included 21 male patients (63.6%), and the median age was 8.6 years. Arrhythmogenic right ventricular cardiomyopathy was present in 45.5%, left ventricular non-compaction in 15.2%, and dilated cardiomyopathy in 39.4%. Left ventricular ejection fraction >45% increased from 39.4% to 72.7%. Mean N-terminal pro B-type natriuretic peptide decreased from 6309 to 3137 pg/mL (p < 0.001). NYHA class improved or remained stable in 93.3% of patients, with greater improvement in left ventricular dysfunction. During a median 17.3-months follow-up, rehospitalisation occurred in 42.4%,and 5 patients died or underwent heart transplantation/listing. Hypotension occurred in 18.2% but was manageable. Sacubitril/valsartan was generally well tolerated and associated with improved ventricular function, biomarkers, and functional status in paediatric cardiomyopathy, particularly in left ventricular dysfunction.

LMNA gene-related dilated cardiomyopathy (DCM), or laminopathy, leads to severe heart failure, neuromuscular involvement and ventricular arrhythmia and has been described as the most frequent DCM genetic cause requiring heart transplantation (HTx). However, no study has specifically evaluated outcomes of HTx in patients with laminopathy. We aimed to describe and evaluate the clinical outcomes of this specific population. Data from all consecutive patients with laminopathy who underwent HTx (LMNA-HTx) between 2003 and 2024 in three French centres were retrospectively extracted. Patients in the LMNA-HTx group were compared with patients with matched non-ischaemic DCM who underwent HTx (DCM-HTx) using propensity score matching. The primary endpoints were 1 year and long-term post-HTx survival. Secondary objectives were to describe mortality risk factors and assess the progression and impact of neuromuscular symptoms after HTx. 40 patients with laminopathy underwent HTx (median age 45.4 years, 57.5% males). HTx followed electrical storm (ES) in 33% of cases. Post-HTx survival at 3 months, 1 year and 5 years was 90%, 74% and 70%, respectively, comparable to 160 matched patients in the DCM-HTx group (Kaplan-Meier survival analysis: HR: 1.01; 95% CI 0.52 to 1.95; p=0.98). The occurrence of ES in the days preceding HTx emerged as the only factor associated with mortality (Kaplan-Meier survival analysis: HR: 8.46; 95% CI 1.66 to 43.17; p=0.002). Neuromuscular and extracardiac involvement was not associated with mortality and did not worsen after HTx. In this first systematic evaluation of HTx in patients with laminopathy, we show that post-transplant survival was comparable between LMNA-HTx and matched DCM-HTx patients and was not associated with neuromuscular involvement. In contrast, ES occurred in one-third of patients prior to HTx and was associated with mortality. These findings support considering HTx early in the disease course, particularly in the setting of arrhythmogenic instability, while mild neuromuscular involvement should not be viewed as a contraindication.