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BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM. RESULTS: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics. CONCLUSIONS: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN.

Background: Primary cardiomyopathies are major causes of heart failure, placing a substantial burden on both individuals and society. Revealing its genetic profiles can lead to a better understanding of the mechanism and is critical for disease prevention and treatment. Method: Primary cardiomyopathy patients were enrolled and whole exome sequence was conducted to analyze their genetic profiles. Retrospective clinical information extraction and analysis of sequence data were implemented. Results: A total of 77 primary cardiomyopathy patients were enrolled, comprising 65 patients with dilated cardiomyopathy (DCM) and 12 with hypertrophic cardiomyopathy (HCM). Among the DCM patients, 13 variants classified as pathogenic (P) or likely pathogenic (LP) were identified in 12 patients (18.46%), predominantly in genes associated with the nuclear envelope and sarcomere. Among HCM patients, 6 P/LP variants were discovered in 6 (50%) patients. Taking variants of uncertain significance (VUS) into consideration, an analysis of the association between the number of variants carried by patients and their clinical characteristics revealed that DCM patients with more than one variant had a higher proportion of hyperuricemia. Conclusions: We map a comprehensive profile of primary cardiomyopathy in Chinese population and, for the first time, identify a possible association between hyperuricemia and the number of genetic variants carried by DCM patients. [ABSTRACT FROM AUTHOR]

Duchenne Muscular Dystrophy (DMD) is a severe X-linked recessive disorder characterized by progressive muscle degeneration due to dystrophin deficiency. Cardiac involvement, particularly dilated cardiomyopathy, significantly impacts morbidity and mortality, typically manifesting after age 10. This case report presents a rare instance of early-onset cardiac involvement in a 3-year-old male with a confirmed deletion in exon 55 of the dystrophin gene. The patient developed dilated cardiomyopathy at 3 years and 8 months, with progressive left ventricular dysfunction despite early treatment with corticosteroids, ACE inhibitors, and beta-blockers. Genetic mechanisms and genotype–phenotype correlations related to cardiac involvement were reviewed, highlighting emerging therapies such as exon skipping, vamorolone, ifetroban, and rimeporide. Studies indicate that variants in exons 12, 14–17, 31–42, 45, and 48–49 are associated with more severe cardiac impairment. This case emphasizes the need for early, ongoing cardiac assessment and personalized treatment to address disease heterogeneity. While current DMD care standards improve survival, optimizing management through early intervention and novel therapies remains essential. Further research is needed to better understand genotype–phenotype correlations and improve cardiac outcomes for patients with DMD. [ABSTRACT FROM AUTHOR]

Background: TGF-β-activated kinase 1 binding protein 2 (TAB2) is an intermediary protein that links Tumor necrosis factor receptor 1 (TNFR1) and other receptor signals to the TGF-β-activated kinase 1 (TAK1) signaling complex. TAB2 frameshift mutations have been linked to dilated cardiomyopathy (DCM), while the exact mechanism needs further investigation. Methods: In this study, we generated a TAB2 compound heterozygous knockout cell line in induced pluripotent stem cells (iPSCs) derived from a healthy individual using CRISPR/Cas9 technology. IPSCs are not species-dependent, are readily accessible, and raise fewer ethical concerns. Results: TAB2 disruption had no impact on the cardiac differentiation of iPSCs and led to confirmed TAB2 deficiency in human iPSC-derived cardiomyocytes (hiPSC-CMs). TAB2-deficient hiPSC-CMs were found to develop phenotypic features of DCM, such as distorted sarcomeric ultrastructure, decreased contractility and energy production, and mitochondrial damage at day 30 post differentiation. Paradoxically, TAB2 knockout cell lines showed abnormal calcium handling after 40 days, later than reduced contractility, suggesting that the main cause of impaired contractility was abnormal energy production due to mitochondrial damage. As early as day 25, TAB2 knockout cardiomyocytes showed significant mitochondrial calcium overload, which can lead to mitochondrial damage. Furthermore, TAB2 knockout activated receptor-interacting protein kinase 1 (RIPK1), leading to an increase in mitochondrial calcium uniporter (MCU) expression, thereby augmenting the uptake of mitochondrial calcium ions. Finally, the application of the RIPK1 inhibitor Nec-1s prevents the progression of these phenotypes. Conclusions: In summary, TAB2 abatement cardiomyocytes mimic dilated cardiomyopathy in vitro. This finding emphasizes the importance of using a human model to study the underlying mechanisms of this specific disease. More importantly, the discovery of a unique pathogenic pathway introduces a new notion for the future management of dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

There is increasing evidence that β1-adrenoreceptor autoantibody (β1AR-AAb) elimination can break the vicious circle induced by certain pathological conditions associated with alteration of the physiological self-tolerance, followed by generation of such AAbs and activation of cell-mediated immune processes directed against the myocardium. Concerning this, the present narrative review article provides an updated overview of the state of knowledge about the role of auto-immunity in the etiopathogenesis of cardiomyopathies, with a particular focus on immunoadsorption (IA) therapy for β1AR-AAb-positive adult patients with a dilated cardiomyopathy (DCM)-associated refractory heart failure (HF). Among many relevant findings, the increasing prevalence (up to 97%) of β1AR-AAb-positive patients related to the aggravation of HF, the high prevalence (between 84% and 91%) of HF patients in which IA can reduce to a minimum any increased β1AR-AAb level, as well as the high prevalence (about 80%) of responders to the IA-induced normalization of β1AR-AAb levels by long-term improvement in LV ejection fraction with increase in LV stroke volume and cardiac output, are of particular relevance. Given that after the elimination of β1AR-AAbs in potential candidates for heart transplantation (HTx), the post-IA 3- and 5-year HTx-/mechanical support-free survival probability reached 80% and 63-69%, respectively, the good tolerability of IA and the possibility to repeat that therapy also in elderly persons strongly suggest that in appropriately selected patients, this therapy deserves much more attention in the future. [ABSTRACT FROM AUTHOR]

Background/Objectives: Late gadolinium enhancement (LGE)-MRI has proven utility in prognosticating outcomes in patients with non-ischemic cardiomyopathy (NICM). However, evidence regarding its ability to predict responsiveness to optimal medical therapy remains insufficient. This study conducted a meta-analysis to evaluate the predictive utility of LGE-MRI for left ventricular reverse remodeling (LVRR) in response to pharmacological therapy. Methods: Data from 1092 NICM patients across 13 studies were included in the analysis. To assess the predictive ability of LGE-MRI for LVRR following optimal medical therapy, a pooled odds ratio was calculated using an inverse variance random-effects meta-analysis. Subgroup analyses were performed by stratifying patients based on the presence or absence of left ventricular dilation and by LVEF (<30% vs. ≥30%). Results: The pooled odds ratio of the absence of LGE for predicting LVRR in NICM was 3.72 (95% CI: 2.83–4.90, I2 = 0, P for heterogeneity = 0.54). A comparison of pooled odds ratios between dilated cardiomyopathy (DCM) and NICM showed no significant difference (p = 0.16). A subgroup analysis in NICM based on the left ventricular ejection fraction (LVEF) demonstrated no significant difference in odds ratios between patients with LVEF <30% (OR: 2.96, 95% CI: 1.80–4.87) and those with LVEF ≥30% (OR: 3.97, 95% CI: 2.97–5.31), (p = 0.13). Conclusions: This meta-analysis suggested that LGE-MRI serves as a reliable predictor of LVRR in patients with NICM, regardless of left ventricular dilation or baseline LVEF classification. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) can be an inherited condition related to premature sudden cardiac death (SCD). Pathogenic variants in some genes, like LMNA, SCN5A, FLNC or RBM20, have been linked to an increased risk of SCD. Although genetic study can help to stratify the arrhythmic risk, there are no specific guidelines for RBM20 carriers' management. We aimed to evaluate the genetic profile and clinical features of all DCM patients with pathogenic variants in RBM20.Methods: We identified all carriers of pathogenic variants in RBM20 in a single national center that specializes in inherited cardiac conditions. Forensic and molecular autopsies provided crucial information. Results: We identified a large family with inherited DCM due to RBM20 p.Arg636Cy and several SCDs. The proband was a 37-year-old male who suffered an unexpected SCD despite presenting a mild DCM phenotype with normal left ventricular ejection fraction. Family screening identified four other carriers, who were asymptomatic, but presented concealed mild DCM phenotypes. Family history revealed that six other relatives (two of them obligate carriers) had also suffered sudden deaths at young ages. Conclusions: We present an informative family with DCM, due to RBM20 p.Arg636Cys, and high rates of SCD, even in members with mild DCM phenotypes. ICD implantation to prevent SCD should be carefully evaluated in all RBM20 p.Arg636Cys carriers. Moreover, the frequent development of AF and HF progression requires specific awareness. [ABSTRACT FROM AUTHOR]

In one of the earliest reports from China during COVID-19, it was noted that over 20% of patients hospitalized with the disease had significant elevations of troponin, a marker of myocardial tissue damage, that put them at a higher risk. In a hypothesis-independent whole exome sequencing (WES) study in hospitalized COVID-19 patients of diverse ancestry, we observed putative enrichment in pathogenic variants in genes known to be involved in the pathogenesis of cardiomyopathy. This observation led us to hypothesize that the observed high morbidity and mortality in these patients might be due to the presence of rare genetic factors that had previously been silent but became relevant as a consequence of the severe stress inflicted by an infection with SARS-CoV-2. To test this hypothesis, we analyzed our WES data generated from a cohort of 325 patients sequentially admitted for COVID-19 infection. In this predominantly minority population (53.9% African ancestry and 37.9% Hispanic/Latin ancestry), our initial analysis screen identified 263 variants that were identified as highly deleterious (HD) from a total of 26,661 variants of interest that represented 215 genes. Of those, we identified 46 genes (in 58 patients) harboring rare HD coding variants that were previously implicated in dilated cardiomyopathy and were considered as disease initiators for the severe COVID-19 in this study. These findings offer valuable insights into the molecular mechanisms and genetic susceptibility to heart injury in severe COVID-19. Key messages: COVID-19 may cause cardiac damage in some affected patients without a plausible biological explanation. Our study reveals an enrichment of highly deleterious variants linked to cardiomyopathy in severe COVID-19 patients. Genetic profiling unveils the molecular basis of severe COVID-19-related heart injury, potentially aiding in patient stratification. [ABSTRACT FROM AUTHOR]

Introduction: Current family screening approaches in dilated cardiomyopathy (DCM) depend on the presence or absence of a familial genetic variant, in which variant pathogenicity (i.e. benign or pathogenic) classification drives screening recommendations. However, this approach has never been systematically evaluated. Methods: To describe the yield of DCM family screening stratified by variant classification in the Netherlands, we included 358 relatives (mean age ± standard deviation: 44.4 ± 15.9 years at baseline; 52% female; 41% (likely) pathogenic (LP/P) variant carriers from 210 families). Demographics, symptoms and genetic/cardiac test results were obtained. Endpoints were the development of DCM (left ventricular ejection fraction < 50% of non-ischaemic aetiology) or occurrence of major adverse cardiovascular events (MACE) (i.e. heart failure hospitalisation, ventricular arrhythmia or death). Probability of DCM or MACE was assessed with the Kaplan-Meier method. Results: DCM was present in 32 relatives (9%) (25/32 (78%) with LP/P variant) at baseline and in an additional 10/97 relatives (10%) (9/10 (90%) with LP/P variant) who were re-evaluated during a median follow-up time of 5.0 years (interquartile range: 3.2–7.4). Of the 128 relatives without the familial LP/P variant, none developed DCM. MACE was experienced by 5 relatives (1%) (4/5 (80%) with LP/P variant), all of whom had DCM at the time of the event. Conclusion: The yield of DCM family screening was ~10% at baseline and another ~10% during 5‑year follow-up. Relatives without the familial LP/P variant could be safely discharged. These results reinforce the use of a genetics-first screening approach in relatives from families with an LP/P variant. This will lower the burden on resources in Dutch hospitals and help allocate resources to those who are most likely to benefit. [ABSTRACT FROM AUTHOR]

Doxorubicin-induced cardiomyopathy (DOX-IC) is a significant and common complication in patients undergoing chemotherapy, leading to cardiac remodeling and reduced heart function. We hypothesized that the intrapericardial injection of hydrogels derived from the cardiac decellularized extracellular matrix (dECM) loaded with adipose tissue-derived stromal cells (ASC) and their secretome dampens or reverses the progression of DOX-IC. DOX-IC was induced in Wistar male rats through ten weekly intra-peritoneal injections of doxorubicin (cumulative dose: 18 mg/kg). We performed intrapericardial treatment in week five with dECM hydrogel loaded with ASC and their conditioned medium (CMed). The volume of intrapericardial injection was 2 ml/kg, the ASC density was 20 million/mL, while the hydrogel contained 100-fold concentrated CMed. Interstitial myocardial fibrosis was assessed by PicroSirius Red staining and hemodynamics parameters in pressure-volume loops. Compared to saline controls, interstitial myocardial fibrosis was reduced in ASC/CMed-loaded hydrogels treated animals (p = 0.0139). Ejection fraction and cardiac work efficiency improved in the ASC/CMed-treated rats compared to saline treatment (p = 0.0151 and p = 0.0655, respectively). The intrapericardial injection of dECM hydrogels loaded with ASC and their secretome warrants a novel therapeutic modality to improve ventricular hemodynamics and reduce cardiac remodeling in DOX-IC. [ABSTRACT FROM AUTHOR]

Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs. [ABSTRACT FROM AUTHOR]

Background: Dilated cardiomyopathy (DCM) stands as one of the most prevalent and severe causes of heart failure. Inflammation plays a pivotal role throughout the progression of DCM to heart failure, while age acts as a natural predisposing factor for all cardiovascular diseases. These two factors often interact, contributing to cardiac fibrosis, which is both a common manifestation and a pathogenic driver of adverse remodeling in DCM-induced heart failure. Method: Bulk RNA-seq, single-cell RNA-seq, Mendelian randomization analysis, animal model construction, and BMP6 knockdown were utilized to identify and validate potential specific markers and targets for intervention in DCM heart failure. Results: We found that DCM hearts exhibit pronounced inflammatory cell infiltration and fibrosis. Both bulk RNA-seq and single-cell RNA-seq analyses revealed aberrant BMP6 expression specifically in fibroblasts. The ROC curve underscores the high specificity of BMP6 in relation to DCM, while Mendelian randomization analysis further confirms BMP6 as a protective factor against DCM. Notably, BMP6 knockdown led to a decrease in SMAD6 expression and a marked elevation in COL1A1 expression levels, indicating its antifibrotic role. Conclusion: BMP6 emerges as a promising biomarker for DCM, and its functional role in exerting an antifibrotic effect underscores its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Nondilated left ventricular cardiomyopathy (NDLVC) is a newly defined category of cardiomyopathy. We sought to evaluate and compare the phenotype of NDLVC with DCM using cardiac magnetic resonance (CMR) imaging and to investigate the prognostic significance of these conditions. Methods: One hundred and fifty patients suspected of having cardiomyopathy referred for CMR were recruited. We considered 3 groups; Group 1: NDLVC‐reduced EF, (NDLVC‐REF), LVEF ≤ 40%, Group 2: NDLVC‐mildly reduced EF(NDLVC‐MREF), 40 < LVEF < 50, Group 3: Dilated cardiomyopathy (DCM). All selected patients were followed up for a median of 24 months to determine the composite cardiac endpoint consisting of mortality and/or hospitalization for cardiovascular reasons (composite cardiac event (CCE)) as the primary endpoint. Results: The mean age (SD) was 42.6 (13.7) years (range: 18–77 years). There was no association between the presence of myocardial LGE and the development of atrial and/or ventricular arrhythmias. Atrial fibrillation was most common in the NDLVC groups during the follow‐up period. Myocardial late gadolinium enhancement (LGE) was also more pronounced in the DCM group. Most patients in the NDLVC groups had no LGE. LGE in the midwall was the most common LGE pattern in all three groups and the septal wall was the most commonly affected area of the LV. There was no significant difference between the CMR findings of patients with and without CCE in each subgroup. However, the presence of myocardial replacement fibrosis was higher in patients with a CCE in total study population, (n = 144, 68% versus 32%, p = 0.03), but the difference was not significant in subgroup analyzes. Conclusion: NDLVC has a relatively good prognosis in recent times. The consideration of NDLVC in a spectrum with DCM can be reasonable. However, the prognostic risk factors need to be investigated in more detail. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to know the clinical, demographic, diagnostic, and treatments characteristics in patients with cardiomyopathies in Mexico. Methods: The Mexican Registry of Cardiomyopathies (REMEMI) is an observational, prospective and national study of patients with cardiomyopathies, which includes: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM) and arrhythmogenic cardiomyopathy of the right ventricle (ARVC). Results: A total of 1026 patients from most states of the Mexican Republic (19) were included, with 494 corresponding to DCM, 490 to HCM, 35 to RCM, and seven to ARVC. We found significant differences between the various cardiomyopathy phenotypes (p < 0.05) in the coexistence with diabetes, use of implantable defibrillator, presence of ventricular tachycardia, and NYHA functional class ≥ 1. There were no significant differences in age and predominant gender between each one. When analyzing by phenotype, we found that patients with HCM have limited use of diagnostic methods considered indispensable, such as cardiac magnetic resonance, Holter monitoring, and genetic testing in patients and their relatives. Conclusion: Seeking contemporary information through observational registries in Mexico is a valuable opportunity to understand the characteristics of the methods used in the study and treatment of diseases such as cardiomyopathies by Mexican physicians. It can provide information for the implementation of management guidelines and strategies to disseminate findings to improve healthcare in our country. Objetivo: Conocer las características clínicas y demográficas, así como las herramientas diagnósticas y tratamientos utilizados en pacientes con miocardiopatías en México. Métodos: El Registro Mexicano de Miocardiopatías (REMEMI) es un estudio observacional, prospectivo y nacional de pacientes con diagnóstico de miocardiopatía, que incluye: miocardiopatía dilatada (MCD), miocardiopatía hipertrófica (MCH), miocardiopatía restrictiva (MCR) y miocardiopatía arritmogénica del ventrículo derecho (MAVD). Resultados: Se incluyó un total de 1026 pacientes provenientes de la mayoría de los estados de la República Mexicana (19), de los cuales 494 corresponden a MCD, 490 a MCH, 35 a MCR y 7 a MAVD. Encontramos diferencias significativas entre los diversos fenotipos de miocardiopatías (p < 0.05) en la coexistencia con diabetes, empleo de desfibrilador implantable, presencia de taquicardia ventricular y la clase funcional de la NYHA ≥ 1. No hubo diferencias significativas en la edad y sexo predominante entre cada uno. Al analizar por fenotipo encontramos que la MCH tienen poco empleo de métodos diagnósticos considerados como indispensables como la resonancia magnética cardiaca, el monitoreo Holter y el estudio genético en los pacientes y sus familiares. Conclusión: La búsqueda de información contemporánea a través de registros observacionales en México es una buena oportunidad para conocer las características de los métodos empleados en el estudio y tratamiento de enfermedades como las miocardiopatías por médicos mexicanos, y puede ofrecernos información para la implementación de guías de manejo y estrategias de difusión de los hallazgos para así mejorar el cuidado de la salud en nuestro país. [ABSTRACT FROM AUTHOR]

Necroptosis, a type of programmed cell death, has been increasingly linked to cardiovascular disease development, yet its role in dilated cardiomyopathy (DCM) remains unclear. In this study, we analyzed the GSE5406 dataset from the GEO database to explore necroptosis-related prognostic signatures in DCM using LASSO regression. We identified five necroptosis-related genes (BID, CAMK2B, GLUL, HSP90AB1, CHMP5) that define a necroptosis-related signature with strong predictive value, evidenced by ROC curve areas of 0.852 and 0.957 in training and test sets, respectively. Our analyses, including GO and GSEA enrichment, focused on pathways associated with high necroptosis-related scores (NRS) and revealed significant immune cell infiltration. Notably, nTreg and iTreg cells were enriched in the high NRS group, while CD8 naive T cells and CD8 T cells positively correlated with NRS. Small molecule drugs fenofibrate, procyclidine, and tienilic acid emerged as potential therapeutic agents for high-risk patients, with fenofibrate showing efficacy in inhibiting DCM progression in an inflammatory animal model. These findings underscore the clinical relevance of necroptosis-related genes in assessing DCM progression and prognosis and highlight their potential for targeted therapeutic development. [ABSTRACT FROM AUTHOR]

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type-specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In BAG3-/- CFs, we observed an increased sensitivity to TGF-β signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 variants. BAG3 pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type-specific aspects of cardiac disease. [ABSTRACT FROM AUTHOR]

In dogs with diet-associated dilated cardiomyopathy (DCM), we have identified electron microscopic changes suggestive of abnormal lysosomal accumulation of phospholipids and consistent with the appearance of drug-induced phospholipidosis in people and other animals. The objective of this study was to compare concentrations of urine di-docosahexaenoyl (22:6)-bis(monoacylglycerol)phosphate (BMP), a biomarker of drug-induced phospholipidosis, in dogs with DCM eating high-pulse (HP) diets, dogs with DCM eating low-pulse (LP) diets, and healthy controls (control-HP and control-LP). METHODS In this cross-sectional study, voided urine was collected from client-owned dogs with DCM from September 2018 through March 2020. Urine di-22:6-BMP was measured by LC-MS-MS and normalized to urine creatinine. Normalized di-22:6-BMP concentrations were compared among groups using mixed-effects-model analysis. RESULTS 53 dogs were included: DCM-HP (n = 25), DCM-LP (n = 4), control-HP (n = 10), and control-LP (n = 14). Mixed-effects models adjusted for age and sex showed that HP diet was significantly associated with higher normalized urine di22:6-BMP concentrations. A 1-way ANOVA identified a significant difference among the 4 groups, with Tukey post hoc analysis showing that the DCM-HP group had significantly higher normalized urine di-22:6-BMP concentrations compared to the control-LP group. Normalized di-22:6-BMP concentrations were significantly positively correlated with diet pulse scores (r = 0.52). CONCLUSIONS High-pulse diets were significantly associated with higher normalized urine di-22:6-BMP concentrations. CLINICAL RELEVANCE These results support the possible presence of primary or secondary phospholipidosis in dogs with diet-associated DCM and provide a plausible mechanism for further investigation. [ABSTRACT FROM AUTHOR]

Background: Myocardial disease is an important component of the wide field of cardiovascular disease. However, the phenomenon of multiple myocardial diseases in a single patient remains understudied. Aim: To investigate the prevalence and impact of myocarditis in patients with genetic cardiomyopathies and to evaluate the outcomes of myocarditis treatment in the context of cardiomyopathies. Methods: A total of 342 patients with primary cardiomyopathies were enrolled. The study cohort included 125 patients with left ventricular non-compaction (LVNC), 100 with primary myocardial hypertrophy syndrome, 70 with arrhythmogenic right ventricular cardiomyopathy (ARVC), 60 with dilated cardiomyopathy (DCM), and 30 with restrictive cardiomyopathy (RCM). The diagnosis of myocarditis was based on data from myocardial morphological examination or a non-invasive diagnostic algorithm consisting of an analysis of clinical presentation, anti-cardiac antibody (Ab) titres, and cardiac MRI. Results: The prevalence of myocarditis was 74.3% in ARVC, 56.7% in DCM, 54.4% in LVNC, 37.5% in RCM, and 30.9% in HCM. Myocarditis had a primary viral or secondary autoimmune nature and manifested with the onset or worsening of chronic heart failure (CHF) and arrhythmias. Treatment of myocarditis in cardiomyopathies has been shown to stabilise or improve patient condition and reduce the risk of adverse outcomes. Conclusions: In cardiomyopathies, the genetic basis and inflammation are components of a single continuum, which forms a complex phenotype. In genetic cardiomyopathies, myocarditis should be actively diagnosed and treated as it is an important therapeutic target. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is the ultimate manifestation of the myocardial response to various genetic and environmental changes and is characterized mainly by impaired left ventricular systolic and diastolic function. DCM can ultimately lead to heart failure, ventricular arrhythmia (VA), and sudden cardiac death (SCD), making it a primary indication for heart transplantation. With advancements in modern medicine, several novel techniques for evaluating myocardial involvement and disease severity from diverse perspectives have been developed. Myocardial fibrosis is a significant contributor to VA events and SCD. Based on different pathological mechanisms, myocardial fibrosis can be categorized into replacement and interstitial forms. Late gadolinium enhancement (LGE) derived from cardiovascular magnetic resonance is the clinical gold standard for evaluating replacement myocardial fibrosis and exhibits high concordance with histological replacement fibrosis. However, because of the absence of normal tissue as a control, the LGE technique often fails to effectively visualize diffuse interstitial fibrosis. In such cases, T1 mapping and extracellular volume fraction mapping can be complementary or alternative methods to the LGE technique for detecting interstitial fibrosis. This review aimed to provide a comprehensive and precise assessment of myocardial fibrosis and to determine the use of cardiac magnetic resonance imaging for prognostic evaluation and risk stratification of patients with DCM. [ABSTRACT FROM AUTHOR]

Background Left bundle branch block (LBBB) is a rare conduction disorder in athletes associated with ventricular dyssynchrony, which can lead to left ventricular systolic dysfunction and exercise intolerance. Inappropriate sinus tachycardia (IST) is characterized by an excessive heart rate (HR) that is not related to physiological needs, often resulting in reduced exercise capacity. Managing these conditions in athletes can be challenging, as standard treatments like beta-blockers and ivabradine, while effective in controlling HR, are described to be associated with a reduction in maximal exercise performance. Case summary A 50-year-old amateur athlete presented with exercise intolerance, LBBB, and mild dilated cardiomyopathy due to ventricular dyssynchrony. Resting electrocardiogram and 24-h monitoring confirmed IST. Initial cardiopulmonary exercise testing (CPET) off-therapy showed rapid HR increase during exertion, an early plateau in oxygen pulse, and reduced peak oxygen consumption (VO2, 22.1 mL/kg/min, 76% of the predicted value). After 1 month of ivabradine 5 mg b.i.d. there was some improvement in these parameters. At the third follow-up, with combined therapy of ivabradine (5 mg b.i.d.) and metoprolol (50 mg b.i.d.), the HR response during exercise normalized, and CPET parameters significantly improved, with peak VO2 reaching 29.2 mL/kg/min (101% of the predicted value). Discussion This case highlights a paradoxical improvement in exercise tolerance and peak VO2 with combined ivabradine and beta-blocker therapy in a patient with IST. The treatment optimized the HR response during exercise, suggesting that individualized strategies can enhance exercise performance in patients with IST and mild cardiomyopathy, despite the expected limitations of these medications. [ABSTRACT FROM AUTHOR]

Cardiomyopathy represents the most important life-limiting condition of Duchenne muscular dystrophy (DMD) patients after the age of 20. Genetic alterations in the DMD gene result in the absence of functional dystrophin protein, leading to skeletal/cardiac muscle impairment. The DMD incidence is one in 5000 live male births. Identifying the genetic background, in addition to DMD disease-causing variants, is one of the unmet needs in understanding the cardiac disease's pathogenetic mechanisms and its prognostic implications. The clinical scenario is made even more intricate by the difficulty in predicting the onset and progression of cardiomyopathy, as no clear genotype/phenotype correspondence has been found thus far. The evaluation of genes involved in the onset of primary cardiomyopathies could explore the hypothesis that changes in cytoskeletal and sarcomeric protein function are the modulators of ventricular dysfunction in DMD patients. In the last decade, with the advent of next-generation sequencing (NGS) technology, many disease-causing genes and modifiers have been identified. Assessing the genetic origin of the phenotypic variability of the disease in both the onset and progression of cardiomyopathy in DMD would be extremely helpful in managing these patients. This review article aims to spotlight the genetic background associated with Cardiomyopathy in DMD patients toward a more predictive personalized model of care. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study aimed to evaluate layer-specific strain according to etiology and assess whether subtle changes in longitudinal and circumferential layer strain are involved in predicting cardiac mortality during a two-year follow-up in patients with dilated cardiomyopathy admitted with heart failure decompensation. Methods: 97 patients with dilated cardiomyopathy and a left ventricle ejection fraction ≤ 40% were recruited, 51 with ischemic and 46 with nonischemic etiologies. Conventional and two-dimensional speckle-tracking echocardiography (2D-STE) were conducted in dilated cardiomyopathy patients with a compensated phase of heart failure before discharge. Layer-specific longitudinal and circumferential strain was assessed from the endocardium, mid-myocardium, and epicardium by two-dimensional (2D) speckle-tracking echocardiography. The gradient between the endocardium and epicardium was calculated. Results: Patients with nonischemic etiology of dilated cardiomyopathy presented smaller values of global and layer strain than patients in the ischemic group. GLS, GLSend, GLSend-GLSepi, CSPMend, CSPMend-CSPMepi, CSAP, CSAPend, and CSAPend-CSAPepi were the parameters with statistically significant decreased values in non-survivors compared with survivors. In multivariate analysis, only CSPMend showed an independent value in predicting mortality at two-year follow-up. Receiver operator curve analysis provided CSPMend of −10.8% as a cut-off value with a sensitivity of 80% and specificity of 61.05% in identifying the dilated cardiomyopathy and heart failure patients with a risk of death at two-year follow-up. Conclusions: GLS, GCS, and layer-specific strain analysis showed decreased values in nonischemic compared with ischemic dilated cardiomyopathy and also in non-survivors compared with survivors. CSPMend was the most sensitive strain parameter to identify patients with increased mortality risk at two-year follow-up. [ABSTRACT FROM AUTHOR]

Macrophage accumulation found in biopsy specimens of patients with dilated cardiomyopathy (DCM) has been thought to reflect chronic myocarditis. However, it is unsettled whether they are responsible for the active or persistent phase of the disease.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. METHODS AND RESULTS: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p =

Abstract Background Epicardial adipose tissue (EAT) has been suggested to play paradoxical roles in patients with heart failure. The role of EAT in dilated cardiomyopathy (DCM) patients remains unclear. We aimed to assess the associations between the dynamic changes EAT and left ventricular reverse remodeling (LVRR) in DCM patients based on baseline and follow-up CMR. Methods In this prospective study, we consecutive enrolled DCM patients with baseline and follow-up cardiac magnetic resonance (CMR) examinations. All participating patients underwent 1–2 years of guideline-directed medical therapy (GDMT) at follow-up. The EAT was measured as pericardial and epicardial fat thickness, and paracardial fat volume, while the abdominal adiposity was measured in terms of subcutaneous and visceral fat thickness. The univariable and multivariable logistic regression analyses were performed to evaluate the associations of changes in abdominal and epicardial adiposities with the presence of LVRR. Results A total of 232 patients (mean age, 45.7 ± 15.1 years, 157 male) at baseline were enrolled. After a period of GDMT with a median duration of 15.5 months (interquartile range, 12.5–19.1 months) all participants underwent follow-up CMR with the same standardized protocol. Patients who reached LVRR showed a significant increment in EAT parameters compared to those who did not. After adjusting for age, sex, and delta changes of body mass index (BMI), the increment of pericardial fat thickness (odds ratio [OR]: 1.53; 95% confidence interval [CI]: 1.27 to 1.83; p

Abstract Dilated cardiomyopathy (DCM) is a progressive myocardial disorder characterized by impaired cardiac contraction and ventricular dilation. However, some patients with DCM improve when experiencing left ventricular reverse remodeling (LVRR). Currently, the detailed association between genotypes and clinical outcomes, including LVRR, particularly among children, remains uncertain. Pediatric patients with DCM from multiple Japanese institutions recorded between 2014 and 2023 were enrolled. We identified their DCM-related genes and explored the association between gene variants and clinical outcomes, including LVRR. We included 123 pediatric patients (62 males; median age: 8 [1–51] months) and found 50 pathogenic variants in 45 (35.0%) of them. The most identified gene was MYH7 (14.0%), followed by RYR2 (12.0%) and TPM1 (8.0%). LVRR was achieved in 47.5% of these patients. The left ventricular ejection fraction remained unchanged (31.4% to 39.8%, P = 0.1913) in patients with sarcomere gene variants and in those with non-sarcomere gene variants (33.4% to 47.8%, P = 0.0522) but significantly increased in those without gene variants (33.6% to 54.1%, P

Introduction: Since the introduction of mandatory infant screening for 26 hereditary metabolic diseases from a drop of blood, many rare diseases – including phenylketonuria (PKU) – have been recognized in time. As a result, the affected population is getting older and due to the higher survival rate, the risk factors associated with the disease and their correlation with cardiovascular diseases can be investigated more widely. Case report: Our case illustrates the cardiovascular manifestations of PKU in adulthood. Our 55-year-old male patient receiving long-term supplementation due to confirmed PKU was diagnosed with heart failure with reduced ejection fraction (HFrEF) during a cardiological control examination, and an intact coronary system was described during the subsequent coronary angiography. In 2023, he was admitted to our department due to cardiac decompensation. Hypertension, elevated LDL-cholesterol level, male gender, obesity and PKU were identified as cardiovascular risk factors. Strategic drug therapy for HFrEF was introduced, with sequential nephron blockade (furosemide, hydrochlorothiazide, eplerenone), his cardiac status was compensated, and his effort dyspnoea and chest discomfort were reduced. During a cardiac MR (magnetic resonance) examination, dilated cardiomyopathy was confirmed. During the control echocardio­graphy performed 3 months after the introduction of the optimal drug therapy and its increase to the maximum tolerable dose, the ejection fraction did not exceed 35%, so the patient received primary prophylactic VVI-ICD implantation. During his cardiological control examinations, the patient's ejection fraction increased compared to the time of the first hospitalization, his complaints decreased, and there was no hospitalization due to repeated cardiac decompensation. Conclusion: PKU is a rare inherited amino acid metabolic disease with widespread complications affecting multiple organ systems. It is associated with several cardiovascular risk factors (hyperlipidemia, hypertension, increased oxidative stress), and has a high rate of cardiovascular complications. In addition, literature data also describe its forms associated with cardiomyopathy. Therefore, close cardiological control examination of these patients, as part of this, echocardiographic follow-up, is essential for timely recognition of complications and their subsequent mitigation.

Graves’ disease commonly presents with thyroid and extrathyroid manifestations. Cardiovascular manifestations are present in 6% of patients. Only 1% of patients has dilated cardiomyopathy and acute heart failure, which is an unusual presentation of Graves’ disease. An elderly male patient presented with acute heart failure, atrial fibrillation, renal impairment, and secondary to hypotension, diagnosed with dilated cardiomyopathy and significant left ventricular (LV) dysfunction. His test results revealed an increase in T3 and T4 levels with a low thyroid-stimulating hormone (TSH), as well as positive antithyroid antibodies and TSH receptor antibodies, confirming Graves’ disease. The patient improved symptomatically with antiheart failure treatment and antithyroid drugs. On follow-up, his LV dysfunction completely recovered. This instance emphasizes the need of screening heart failure patients to identify reversible causes of heart failure and provide suitable treatment.

Abstract Aims Heritable dilated cardiomyopathy (DCM) or DCM associated with congenital or acquired left ventricular diseases carries a significant mortality risk. Pulmonary artery banding (PAB) has been proposed as an alternative to heart transplantation. This study aimed to delineate the clinical development, ventricular reverse remodelling, and functional regeneration of the dilated left ventricle, presenting as a pioneering approach in China. Methods and results This prospective study was initiated in November 2021, involving paediatric patients with a significant dilated left ventricle and preserved right ventricle who underwent surgical PAB. The baseline characteristics and clinical information during follow‐up were collected. Seven patients (five boys) with a median age of 240 (148, 1028) days have been included thus far. No procedural or follow‐up mortality was observed. The modified Ross functional class improved from treatment to follow‐up of 348 (200, 629) days, and the median left ventricular ejection fraction increased from 27.0 (15.0, 34.0) % before surgery to 61.0 (52.0, 68.0) % (P

Abstract Aims LMNA‐related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM‐DCM trial evaluated a potential disease‐modifying therapy for LMNA‐related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM‐DCM to descriptively characterize the phenotype and progression of LMNA‐related DCM in a contemporary cohort of patients using common heart failure (HF) measures. Methods REALM‐DCM enrolled patients with stable LMNA‐related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. Results Between 2018 and 2022, 77 patients took part in REALM‐DCM. The median patient age was 53 years (range: 23–72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ‐OS) score and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentration at baseline were 42% (23–62), 403 m (173–481), 67 (18–97) and 866 pg/mL (57–5248), respectively. LVEF, 6MWT distance and KCCQ‐OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ‐OS score: 43 vs. 70), whereas NT‐proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow‐up was 73 weeks (range: 0.4–218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ‐OS and NT‐proBNP values during follow‐up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF‐related hospitalization or urgent care visit) or all‐cause death; six had NYHA Class II and four had NYHA Class III at baseline. All‐cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. Conclusions Findings confirm the significant morbidity and mortality associated with LMNA‐related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ‐OS score and NT‐proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA‐related DCM. NCT03439514.

Abstract Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. Study Design The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow‐up. Three hundred patients, aged 18–75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I–III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and high‐sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high‐density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. Discussion The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.