Patients with cardiomyopathies are a heterogeneous group of patients who experience high morbidity and mortality. Early cardiac assessment and intervention with access to genetic counselling in a multidisciplinary Cardiomyopathy Clinic may improve outcomes and prevent progression to advanced heart failure.

Our prospective cohort study was conducted at a multidisciplinary Cardiomyopathy Clinic with 421 patients enrolled (42.5% female, median age 58 years), including 224 patients with dilated cardiomyopathy (DCM, 42.9% female, median age 57 years), 72 with hypertrophic cardiomyopathy (HCM, 43.1% female, median age 60 years), 79 with infiltrative cardiomyopathy (65.8% female, median age 70 years) and 46 who were stage A/at risk for genetic cardiomyopathy (54.3% female, median age 36 years). Patients were seen in follow-up at a median of 18 months. A pathogenic/likely pathogenic variant was identified in 28.5% of the total cohort, including 33.3% of the DCM cohort (28% TTN mutations) and 34.1% of the HCM cohort (60% MYBPC3 and 20% MYH7) who underwent genetic testing. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (48.3-69.5% of total cohort, P < 0.001), β-blockers (58.4-72.4%, P < 0.001), mineralocorticoid receptor antagonists (33.9-41.4%, P = 0.0014) and sodium/glucose cotransporter-2 inhibitors (5.3-27.9%, P < 0.001) all increased at follow-up. Precision-based therapies were also implemented, including tafamidis for transthyretin amyloidosis (n = 21), enzyme replacement therapy for Fabry disease (n = 14) and mavacamten (n = 4) for HCM. Optimization of medications and devices resulted in improvements in left ventricular ejection fraction (LVEF) from 27% to 43% at follow-up for DCM patients with reduced LVEF at baseline (P < 0.001) and reduction in left ventricular mass index (LVMI) from 156 g/m2 to 128 g/m2 at follow-up for HCM patients with abnormal LVMI at baseline (P = 0.009). Optimization of therapies was associated with stable plasma biomarkers in stage B patients while lowering levels of BNP (619-517.5 pg/mL, P = 0.048), NT-proBNP (777.5-356 ng/L, P < 0.001) and hsTropT (31-22 ng/L, P = 0.005) at follow-up relative to baseline values for stage C patients. Despite stage B patients having overt cardiomyopathy at baseline, stage A and B patients had a similarly high probability of survival (χ2 = 0.204, P = 0.652). The overall cardiovascular mortality rate was low at 1.7% for the cohort (0.5% for stage B and 3.3% for stage C) over a median of 34-month follow-up.

Our study demonstrates that a multidisciplinary cardiomyopathy clinic can improve the clinical profiles of patients with diverse genetic cardiomyopathies.

Cardiomyopathies (CMs) are a clinically heterogeneous group of cardiovascular diseases characterized by structural and functional abnormalities of the heart muscle in the absence of coronary artery disease, hypertension, valve disease, or congenital heart disease as a leading cause. The phenotypic spectrum of CMs ranges from silent heart failure to symptomatic heart failure and sudden cardiac death, and CMs are one of the leading causes of cardiovascular morbidity worldwide. CMs are highly heritable, although a clear distinction between inherited and acquired forms remains challenging, particularly due to observed incomplete penetrance and variable expressivity of inherited CMs. Based on their specific morphological phenotypes and functional characteristics, CMs can be divided into at least 5 different subgroups: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), restrictive cardiomyopathy (RCM), and (left ventricular) non-compaction cardiomyopathy (LVNC), which show both clinical as well as genetic overlap. Since the identification of pathogenic variants in MYH7 as a genetic cause of HCM in 1990, enormous progress has been made in understanding genetic factors contributing to cardiomyopathies. Currently, over 100 genes have been associated with at least one of the CM subtypes, providing a deeper understanding of the cellular basis of genetic heart failure syndromes, unveiling new insights into the molecular biology of heart function in both health and disease, and, thereby, facilitating the development of novel therapeutic strategies and personalized treatment approaches.

Inherited cardiomyopathy is a broad class of heart disease that includes pathological cardiac remodeling such as hypertrophic and dilated cardiomyopathy, affecting 1/250-1/500 people worldwide. In many cases, mutations in proteins that make up the sarcomere, the basic subcellular unit of contraction, alter thin filament regulation and are the root cause of hypertrophic and dilated cardiomyopathy. Initially, compensations can maintain cardiac function, so patients may remain asymptomatic for years before a major cardiac episode. Early therapeutic intervention could rescue the deleterious effects of mutations thereby avoiding pathological remodeling, so prediction of potential outcomes and severity of as yet uncharacterized and known mutants of uncertain significance is critical. To accomplish this goal, we begin with the structure of the thin filament containing actin, tropomyosin, and troponin in its regulatory B- and C-states, incorporate all potential single nucleotide mutations to the tropomyosin sequence (over 1700 unique mutations), and then measure the interaction energy between tropomyosin and actin after energy minimization. Analysis of the database thus generated shows the tropomyosin residues resulting in large changes in tropomyosin-actin interaction, and therefore most likely to be deleterious to function. Some of these mutants have been observed in human patients, whereas others are novel. Global analysis further refines hotspots of mutation-sensitive, coiled-coil tropomyosin residues affecting actin interactions. Altogether, the database will allow research to focus in great depth on key candidates for functional analysis, for instance, by assaying in vitro motility and engineered heart tissue mechanics and assessing outcomes in animal models.

Dilated cardiomyopathy is an important contributor to heart failure burden worldwide. With an aging population and rising multimorbidity, in this review, we describe the prevalence of metabolic syndrome and renal failure in patients with dilated cardiomyopathy and focus on common underlying mechanisms, evaluate outcomes in these patients and highlight newer therapeutic strategies.

A significant proportion of patients with dilated cardiomyopathy has concomitant metabolic syndrome and renal disease. This combination of multimorbidity portends worse prognosis and often presents unique challenges in treatment given the complex interplay and shared pathophysiological pathways. Optimization of the cardio-renal-metabolic profile should be a key consideration in the management of patients with dilated cardiomyopathy. Therapeutic strategies targeting common pathophysiological pathways are needed in order to improve overall outcomes.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic heart disease with a wide range of clinical manifestations, from asymptomatic cases to heart failure and sudden cardiac death.

To identify the disease-causing variants in patients with severe HCM by carrying on clinical examination and genetic analysis through 2 generations in a single family.

Family 'members underwent comprehensive cardiovascular examinations. Whole-exome sequencing was carried on the proband, a girl of five-years old followed by co-segregation and in silico analyses.

The proband harboured a homozygous variant, NM_022915.5: c.198_205delinsTA; p.(Trp66_His69 delinsCysAsn), in the MRPL44 gene, leading to a shorter protein. This variant is novel, being absent in ClinVar and Human Gene Mutation Database (HGMD) and classified as VUS according to American College of Medical Genetics and Genomics (ACMG) criteria. Co-segregation analyses revealed that the proband's parents and her sister were heterozygous carriers, her other sister was wild-type, and her affected brother was homozygous for the mutation. In silico analysis showed significant structural differences in the mutated mL44 protein, disrupting its interaction with ribosomal complex components and impairing translation and protein synthesis.

This study reports a novel MRPL44 variant associated with HCM in a Tunisian family. This finding expands current knowledge of genetic variations linked to mitochondrial cardiomyopathy and highlights the importance of genetic testing for diagnosis and management of cardiomyopathy.

Dilated cardiomyopathy (DCM) is a prevalent cardiac disorder affecting 1 in 250-500 individuals, characterized by ventricular dilation and impaired systolic function, leading to heart failure and increased mortality, including sudden cardiac death. DCM arises from genetic and environmental factors, such as drug-induced, inflammatory, and viral causes, resulting in diverse yet overlapping phenotypes. Advances in precision medicine are revolutionizing DCM management by leveraging genetic and molecular profiling for tailored diagnostic and therapeutic approaches. This review highlights comprehensive diagnostic evaluations, genetic discoveries, and multi-omics approaches integrating genomic, transcriptomic, proteomic, and metabolomic data to enhance understanding of DCM pathophysiology. Innovative risk stratification methods, including machine learning, are improving predictions of disease progression. Despite these advancements, the current one-size-fits-all management strategy contributes to persistently high morbidity and mortality. Emerging targeted therapies, such as CRISPR/Cas9 genome editing, aetiology-specific interventions, and pharmacogenomics, are reshaping treatment paradigms. Precision medicine holds promise for optimizing DCM diagnosis, treatment, and outcomes, aiming to reduce the burden of this debilitating condition.

Genome-wide association studies (GWASs) have recently shown that common genetic variations significantly affect the risk of developing dilated cardiomyopathy (DCM). This has enabled the development of polygenic scores (PGSs), which aim to aggregate the impact of multiple common genetic variants across the genome to provide an overall genetic risk score for disease manifestation and disease severity. In this review, we discuss the latest findings pertaining to GWASs and PGSs for DCM and various ways in which PGSs could improve the management of patients with DCM or risk of developing DCM.

In 2024 the two largest GWAS meta-analyses for DCM were published. Notably, both studies produced PGSs that were able to discriminate healthy subjects from DCM patients which brings promise for potential clinical application of the scores. Large-scale GWAS have identified common genetic variants associated with DCM, leading to the development of PGS, which show strong associations with disease risk and hold potential for clinical applications. However, before clinical implementation, further research is needed to explore their utility in real-world settings and across diverse populations.

Marfan syndrome (MFS) is an autosomal dominant disease caused by mutations in the gene (FBN1) of fibrillin-1, a major determinant of the extracellular matrix (ECM). Functional impairment in the cardiac left ventricle (LV) of these patients is usually a consequence of aortic valve disease. However, LV passive stiffness may also be affected by chronic changes in mechanical load and ECM dysfunction. Passive stiffness is determined by the giant sarcomeric protein titin that has two main cardiac splice isoforms: the shorter and stiffer N2B and the longer and more compliant N2BA. Their ratio is thought to reflect myocardial response to pathologies. Whether this ratio and titin's sarcomeric layout is altered in MFS is currently unknown. Here, we studied LV samples from MFS patients carrying FBN1 mutation, collected during aortic root replacement surgery. We found that the N2BA:N2B titin ratio was elevated, indicating a shift toward the more compliant isoform. However, there were no alterations in the total titin content compared with healthy humans based on literature data. Additionally, while the gross sarcomeric structure was unaltered, the M-band was more extended in the MFS sarcomere. We propose that the elevated N2BA:N2B titin ratio reflects a general adaptation mechanism to the increased volume overload resulting from the valvular disease and the direct ECM disturbances so as to reduce myocardial passive stiffness and maintain diastolic function in MFS.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by the presence of left ventricular dilatation and systolic dysfunction unexplained by abnormal loading conditions or coronary artery disease. However, a broad range of phenotypic manifestations, encompassing isolated scar, DCM with preserved ejection fraction, and overt DCM, should be regarded as a diagnostic classification representing a broad spectrum of underlying aetiologies, including both inherited and acquired heart muscle disorders. A multimodal non-invasive imaging approach is essential for accurate morpho-functional assessment of cardiac chambers and is key to establish the cardiac phenotype and to rule out an underlying ischaemic aetiology. Furthermore, advanced imaging techniques enable deep cardiovascular phenotyping and non-invasive tissue characterization. The aim of this review is to propose a systematic approach to the diagnosis of DCM, emphasizing the importance of genetics and clinical findings for a precise and practical clinical approach. Also, we strive to qualify the role of cardiac imaging in the diagnosis of DCM, particularly on the relevance of novel techniques and clinical utility of actionable parameters to improve current diagnostic schemes and risk stratification algorithms. We further elaborate on the role of cardiac imaging to deliver optimal guidance to aetiology-based therapeutic approaches, verification of treatment response and disease progression monitoring.

Inherited cardiomyopathies are a major cause of heart failure in all age groups, often with an onset in adolescence or early adult life. More than a thousand variants in approximately one hundred genes are associated with cardiomyopathies. Interestingly, many genetic cardiomyopathies display overlapping phenotypical defects in patients, despite the diversity of the initial pathogenic variants. Understanding how the underlying pathophysiology of genetic cardiomyopathies leads to these phenotypes will improve insights into a patient's disease course, and creates the opportunity for conceiving treatment strategies. Moreover, therapeutic strategies can be used to treat multiple cardiomyopathies based on shared phenotypes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer reliable, high-throughput models for studying molecular and cellular characteristics of hereditary cardiomyopathies. hiPSC-CMs are produced relatively easily, either by directly originating them from patients, or by introducing patient-specific genetic variants in healthy lines. This review evaluates 90 studies on 24 cardiomyopathy-associated genes and systematically summarises the morphological and functional phenotypes observed in hiPSC-CMs. Additionally, treatment strategies applied in cardiomyopathic hiPSC-CMs are compiled and scored for effectiveness. Multiple overlapping phenotypic defects were identified in cardiomyocytes with different variants, whereas certain characteristics were only associated with specific genetic variants. Based on these findings, common mechanisms, therapeutic prospects, and considerations for future research are discussed with the aim to improve clinical translation from hiPSC-CMs to patients.

Mitochondrial oxidative stress (ROS) is a crucial factor in the pathogenesis of dilated cardiomyopathy (DCM). Despite its significance, robust biomarkers for assessing its role remain scarce. This study investigates ROS mechanisms in DCM and identifies associated biomarkers, offering fresh insights into diagnosis and treatment.

We sourced transcriptomic data from the GEO database and mitochondrial oxidative stress-related genes from GeneCards. Using consensus clustering, we identified 64 genes associated with mitochondrial oxidative stress in DCM and further isolated five hub genes through protein-protein interaction and machine learning techniques. These genes were analyzed for functions related to immunity, drug sensitivity, and single-cell localization. Concurrently, we collected blood samples from DCM patients to validate the hub genes' expression.

The study identified five hub genes related to mitochondrial oxidative stress: VCL, ABCB1, JAK2, KDR, and NGF. Expression analysis revealed high levels of VCL, ABCB1, KDR, and NGF in the non-failing (NF) group, while JAK2 was elevated in the DCM group (p < 0.05). Diagnostic efficacy, measured by area under the curve (AUC), was significant for VCL (76.4), ABCB1 (80.1), JAK2 (68.2), KDR (78.1), and NGF (71.8). Moreover, several drugs were identified as potential regulators of these hub genes, including Topotecan, CDK9_5576, Acetalax, Afatinib, and GSK591. Notably, VCL showed increased expression in DCM patient blood samples, consistent with transcriptomic and single-cell findings.

This research highlights key genes associated with mitochondrial oxidative stress-VCL, ABCB1, JAK2, KDR, NGF-that show differential expression in DCM and myocardial infarction. These findings underscore their diagnostic potential and pave the way for new therapeutic strategies.

Genetics has assumed a pivotal role in clarifying the pathophysiology of cardiomyopathies, facilitating molecular diagnosis, and enabling effective family screening. The advent of next-generation sequencing has revolutionized genetic testing by enabling cost-effective, high-throughput analysis. It is imperative for cardiovascular physicians to mainstream genetic testing into their clinical decision-making. Although a definitive genotype-phenotype correlation may not always be evident, several genotypes have emerged as valuable risk predictors for disease severity and progression. European guidelines emphasize the importance of genetic tests for predicting clinical outcome in cardiomyopathies. While further research is essential to bridge existing gaps in the genetic evidence on cardiomyopathies, there is considerable potential for significant advancements.

Dilated cardiomyopathy is a myocardial condition marked by the enlargement of the heart's ventricular chambers and the gradual decline in systolic function, frequently resulting in congestive heart failure. Dilated cardiomyopathy has obvious familial characteristics, and mutations in related pathogenic genes can account for about 50% of patients with dilated cardiomyopathy. The most common genes related to dilated cardiomyopathy include TTN, LMNA, MYH7, etc. With more and more research on these genes, it will undoubtedly provide more potential targets and therapeutic pathways for the treatment of dilated cardiomyopathy. In addition, myocardial inflammation, myocardial metabolism abnormalities and cardiomyocyte apoptosis all have an important impact on the pathogenesis of dilated cardiomyopathy. Approximately half of sudden deaths among children and adolescents, along with the majority of patients undergoing heart transplantation, stem from cardiomyopathy. Therefore, precise and prompt clinical diagnosis holds paramount importance. Currently, diagnosis primarily hinges on the patient's medical background and imaging tests, with the significance of genetic testing steadily gaining prominence. The primary treatment for dilated cardiomyopathy remains heart transplantation. However, the scarcity of donors and the risk of severe immune rejection underscore the pressing need for novel therapies. Presently, research is actively exploring preclinical treatments like stem cell therapy as potential solutions.

Heart failure (HF) is a medical condition associated with high morbidity and mortality, despite ongoing advances in diagnosis and treatment. Among the various causes of HF, cardiomyopathies are particularly significant and must be thoroughly diagnosed and characterized from the outset. In this review, we aim to present a brief overview of cardiomyopathies as a driver of HF, with a specific focus on the genetic causes, particularly nexilin (NEXN) cardiomyopathy, illustrated by a clinical case. The case involves a 63-year-old male who presented with HF symptoms at moderate exertion. Six months prior, he had been asymptomatic, and a routine transthoracic echocardiography had shown a preserved left ventricular ejection fraction (LVEF). However, during the current evaluation, transthoracic echocardiography revealed a dilated left ventricle with a severely reduced LVEF of 30%. Subsequent coronary angiography ruled out ischemic heart disease, while cardiac magnetic resonance imaging indicated a non-inflammatory, non-infiltrative dilated cardiomyopathy with extensive LV fibrosis. Genetic testing identified a heterozygous in-frame deletion variant in the NEXN gene [c.1949_1951del, p.(Gly650del)], classified as likely pathogenic. State-of-the-art HF treatment was initiated, including cardiac resynchronization therapy with defibrillator support. Following treatment, the patient's symptoms resolved, and LVEF improved to 42%. Interestingly, this patient experienced the onset of symptoms and left ventricular dysfunction within just six months, a much faster progression compared to previously documented cases where the G650del NEXN variant is typically linked to a more gradual development of dilated cardiomyopathy. Current literature offers limited data on patients with NEXN mutations, and the connection between this gene and both dilated and hypertrophic cardiomyopathies remains an area of active research.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, yet therapeutic options remain limited. While traditional research has focused on mechanisms such as energy deficits and calcium dysregulation, increasing evidence suggests that mitochondria-associated membranes (MAMs) could provide new insights into understanding and treating DCM. In this narrative review, we summarize the key role of MAMs, crucial endoplasmic reticulum (ER)-mitochondria interfaces, in regulating cellular processes such as calcium homeostasis, lipid metabolism, and mitochondrial dynamics. Disruption of MAMs function may initiate pathological cascades, including ER stress, inflammation, and cell death. These disruptions in MAM function lead to further destabilization of cellular homeostasis. Identifying MAMs as key modulators of cardiac health may provide novel insights for early diagnosis and targeted therapies in DCM.

Chinese classical prescriptions (CCPs) are commonly utilized in China as an adjuvant treatment for dilated cardiomyopathy (DCM). Nevertheless, there was insufficient systematic evidence data to show the advantages of CCPs plus current conventional therapy (CT) against DCM. This network meta-analysis (NMA) sought to evaluate and prioritize the six different CCP types' respective efficacies for DCM.

A comprehensive search was conducted from the databases' inception to November 30, 2024, to extract RCTs that addressed the use of CCPs in conjunction with CT for DCM. The databases included PubMed, Embase, Web of Science Core Collection, Cochrane Library, ProQuest, China National Knowledge Infrastructure (CNKI), China Science Periodical Database (CSPD), Chinese Citation Database (CCD), Chinese Biomedical Literature Database (CBM), and ClinicalTrials.gov. The Cochrane Risk of Bias assessment tool was used to evaluate the quality of the included RCTs. Surface under the cumulative ranking curve (SUCRA) probability values was employed to rank the relative efficacy. Bayesian network meta-analysis was applied to evaluate the efficacy of various CCPs. This review was registered with PROSPERO (CRD42024586365).

Following the application of inclusion and exclusion criteria, 27 eligible RCTs involving 2019 patients were included. The evaluated outcomes included clinical effectiveness rate (CER), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), brain natriuretic peptide (BNP), cardiac output (CO), hypersensitive C-reactive protein (hs-CRP), and six-min walk test (6MWT). According to the NMA, Zhigancao decoction (ZGCD), Zhenwu decoction (ZWD), Shenfu decoction (SFD), Shengmai powder (SMP), Yangxin decoction (YXD), and Buyang Huanwu decoction (BYHW) in addition to CT considerably enhanced DCM treatment outcomes when compared to CT alone. SMP + CT (MD = 12.75, 95%CI 8.28-17.22) showed the highest probability of being the best treatment on account of the enhancement of LVEF. SFD + CT was most likely to be the optimal intervention for LVEDD decrease (MD = -4.68, 95%CI -8.73 to -0.62). YXD + CT (MD = -4.47, 95%CI -4.47 to -4.47) had the highest likelihood of being the optimal therapy for reducing LVESD. ZGCD + CT seemed to be the most promising intervention on the improvement in hs-CRP (MD = -2.82, 95%CI -3.60 to -2.04) and 6MWT (MD = 141.00, 95%CI 136.57 to 145.43). However, the optimal CCP for improving BNP and CO could not be identified based on the present studies. No significant adverse events emerged in the included studies.

This NMA indicated that adding CCPs to current CT treatment had a favorable effect on DCM. In light of the clinical efficacy and other outcomes, SMP + CT, SFD + CT, YXD + CT, and ZGCD + CT demonstrated a preferred improvement in patients with DCM when combined. Furthermore, additional larger RCTs with longer follow-up periods and standardized outcome reporting are required to give more solid evidence to support our findings due to the small sample size of the current studies and the presence of risk of bias.

Vinculin (VCL) is a key adapter protein located in force-bearing costamere complexes, which mechanically couples the sarcomere to the ECM. Heterozygous vinculin frameshift genetic variants can contribute to cardiomyopathy when external stress is applied, but the mechanosensitive pathways underpinning VCL haploinsufficiency remain elusive. Here, we show that in response to extracellular matrix stiffening, heterozygous loss of VCL disrupts force-mediated costamere protein recruitment, thereby impairing cardiomyocyte contractility and sarcomere organization. Analyses of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) harboring either VCL c.659dupA or VCL c.74del7 heterozygous VCL frameshift variants revealed that these VCL mutant hPSC-CMs exhibited heightened contractile strain energy, morphological maladaptation, and sarcomere disarray on stiffened matrix. Mechanosensitive recruitment of costameric talin 2, paxillin, focal adhesion kinase, and α-actinin was significantly reduced in vinculin variant cardiomyocytes. Despite poorly formed costamere complexes and sarcomeres, elevated expression of integrin β1 and cortical actin on stiff substrates may rescue force transmission on stiff substrates, an effect that is recapitulated in WT CMs by ligating integrin receptors and blocking mechanosensation. Together, these data support that heterozygous loss of VCL contributes to adverse cardiomyocyte remodeling by impairing adhesion-mediated force transmission from the costamere to the cytoskeleton. (191 words).

Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. Despite improvements in the prognosis of patients with DCM in the past decade, this condition remains a leading cause of heart failure and premature death. Conventional treatment for DCM is based on the foundational therapies for heart failure with reduced ejection fraction. However, increasingly, attention is being directed towards individualized treatments and precision medicine. The ability to confirm genetic causality is gradually being complemented by an increased understanding of genotype-phenotype correlations. Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the 'two-hit' hypothesis). The roles of common genetic variants in the general population and of gene modifiers in disease onset and progression are also discussed. Finally, areas for future research are highlighted, particularly novel therapies, such as small molecules, RNA and gene therapy, and measures for the prevention of arrhythmic death.

TTN (titin) is the third myofilament type of the cardiac sarcomere and performs important functions that include generating passive tension. Changes in TTN expression are associated with cardiac dysfunction, and TTN is one of the main genes linked to dilated cardiomyopathy (DCM). DCM is frequently associated with changes in the expression of N2BA (compliant cardiac TTN isoform), 1 of the 2 major TTN isoforms found in the heart (the other isoform being the N2B [stiff cardiac TTN isoform]). Whether altered expression of N2BA TTN causes DCM or is a secondary change remains unclear.

Here, we present a mouse model, the TtnΔ112-158 model, which specifically shortens the proline, glutamate, valine, lysine region of the N2BA isoform.

Echocardiography and pressure-volume analysis revealed a DCM phenotype characterized by systolic dysfunction and dilation. RNA sequencing studies showed the absence of proline, glutamate, valine, lysine exons, as expected, but also reduced expressions of exons specific to the N2BA isoform of TTN. Protein studies revealed a reduction in the overall expression level of the N2BA isoform with a concomitant increase in N2B TTN, with preserved TT (total TTN) levels. Passive tension was modestly increased in the TtnΔ112-158 model. Western blotting revealed that the N2BA TTN-associated protein MARP1 (muscle ankyrin repeat protein 1) is downregulated during both the pre-DCM and DCM phase. Downregulation of MARP1 coincided with the downregulation of the transcription factor Gata-4 (GATA binding protein 4), an MARP1-regulating and interacting protein, which is associated with DCM development.

Thus, N2BA TTN is essential for maintaining cardiac health, and perturbed N2BA-MARP1 signaling contributes to DCM development.

Atrial myopathy is the underlying pathophysiological substrate of atrial fibrillation and contributes to the risk of heart failure as well. Atrial myopathy is caused by classic risk factors such as obesity, inflammation, diabetes, hypertension, and frequent alcohol use, in addition to structural heart and lung diseases that cause atrial pressure or volume overload. An optimal management of atrial fibrillation includes careful assessment of contributors to atrial myopathy, which can be treated by guideline-recommended medical therapies for heart failure, adequate control of congestion, and treatment of comorbid conditions such as sleep apnea syndrome. This approach works synergistically with rhythm control.

The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2025 AHA Statistical Update is the product of a full year's worth of effort in 2024 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. This year's edition includes a continued focus on health equity across several key domains and enhanced global data that reflect improved methods and incorporation of ≈3000 new data sources since last year's Statistical Update.

Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Acute heart failure (AHF) is a complex clinical syndrome characterized by the rapid or gradual onset of symptoms and/or signs of heart failure (HF), leading to an unplanned hospital admission or an emergency department visit. AHF is the leading cause of hospitalization in patients over 65 years, thus significantly impacting public health care. However, its prognosis remains poor with high rates of mortality and rehospitalization. Many pre-existing cardiac conditions can lead to AHF, but it can also arise de novo due to acute events. Therefore, understanding AHF etiology could improve patient management and outcomes. Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), non-dilated cardiomyopathy (NDLVC), and arrhythmogenic right ventricular cardiomyopathy (ARVC), that frequently present with HF. Patients with CMPs are under-represented in AHF studies compared to other etiologies, and therefore therapeutic responses and prognoses remain unknown. In DCM, AHF represents the most frequent cause of death despite treatment improvements. Additionally, DCM is the first indication for heart transplant (HT) among young and middle-aged adults. In HCM, the progression to AHF is rare and more frequent in patients with concomitant severe left ventricle (LV) obstruction and hypertrophy or severe LV systolic dysfunction. HF is the natural evolution of patients with RCM and HF is associated with poor outcomes irrespective of RCM etiology. Furthermore, while the occurrence of AHF is rare among patients with ARVC, this condition in NDLVC patients is currently unknown. In this manuscript, we assessed the available evidence on AHF in patients with CMPs. Data on clinical presentation, therapeutic management, and clinical outcomes according to specific CMPs are limited. Future HF studies assessing the clinical presentation, treatment, and prognosis of specific CMPs are warranted.

Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.

A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (TTN and LMNA), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios.

A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28-0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26-0.36]; M:F 2.22:1; P=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24-0.37]; M:F 2.29:1; P=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22-0.36]; M:F 2.51:1; P=0.82) or LMNA (0.35 [95% CI, 0.27-0.44]; M:F 1.84:1; P=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28-0.40]; M:F 1.98:1; P=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively.

This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance.

URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42023451944.

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.

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.

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.

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.

Cardiomyopathies, among the leading causes of heart failure and sudden cardiac death, are often driven by genetic mutations affecting the heart's structural proteins. Despite significant advancements in understanding the genetic basis of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), effective long-term therapies remain limited. The advent of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) gene editing offers a promising therapeutic strategy to address these genetic disorders at their root. CRISPR-Cas9 enables precise modification of pathogenic variants (PVs) in genes encoding sarcomeric and desmosomal proteins, which are frequently implicated in cardiomyopathies. By inducing site-specific double-stranded breaks in DNA, followed by repair through nonhomologous end joining (NHEJ) or homology-directed repair (HDR), this system allows for targeted correction of mutations. In preclinical models, CRISPR-Cas9 has shown promise in correcting HCM-associated mutations in β-myosin heavy chain 7 (MYH7), preventing disease phenotypes such as ventricular hypertrophy and myocardial fibrosis. Similarly, gene editing has successfully rectified DCM-linked mutations in Titin (TTN) and LMNA, resulting in improved heart function and reduced pathological remodeling. For ARVC, CRISPR-Cas9 has demonstrated the ability to repair mutations in desmosomal genes such as plakophilin 2 (PKP2), thereby restoring normal cardiac function and cellular adhesion. Despite these successes, challenges remain, including mosaicism, delivery efficiency, and off-target effects. Nevertheless, CRISPR-Cas9 represents a transformative approach to treating genetic cardiomyopathies, potentially offering long-lasting cures by directly addressing their underlying genetic causes.

Cardiovascular diseases (CVDs) remain a significant global health challenge, with many current treatments addressing symptoms rather than the genetic roots of these conditions. The advent of CRISPR-Cas9 technology has revolutionized genome editing, offering a transformative approach to targeting disease-causing mutations directly. This article examines the potential of CRISPR-Cas9 in the treatment of various CVDs, including atherosclerosis, arrhythmias, cardiomyopathies, hypertension, and Duchenne muscular dystrophy (DMD). The technology's ability to correct single-gene mutations with high precision and efficiency positions it as a groundbreaking tool in cardiovascular therapy. Recent developments have extended the capabilities of CRISPR-Cas9 to include mitochondrial genome editing, a critical advancement for addressing mitochondrial dysfunctions often linked to cardiovascular disorders. Despite its promise, significant challenges remain, including off-target effects, ethical concerns, and limitations in delivery methods, which hinder its translation into clinical practice. This article also explores the ethical and regulatory considerations surrounding gene editing technologies, emphasizing the implications of somatic versus germline modifications. Future research efforts should aim to enhance the accuracy of CRISPR-Cas9, improve delivery systems for targeted tissues, and ensure the safety and efficacy of treatments in the long term. Overcoming these obstacles could enable CRISPR-Cas9 to not only treat but also potentially cure genetically driven cardiovascular diseases, heralding a new era in precision medicine for cardiovascular health.

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in adult hearts compared with control animals. However, only the early embryonic deletion of FKBP12 (αMHC-Cre) resulted in an early-onset and progressive DCM, increased cardiac oxidative stress, altered expression of proteins associated with cardiac remodeling and disease, and sarcoplasmic reticulum Ca2+ leak. Our findings indicate that FKBP12 deficiency during early development results in cardiac remodeling and altered expression of DCM-associated proteins that lead to progressive DCM in adult hearts, thus suggesting a major role for FKBP12 in embryonic cardiac muscle.

Gene therapy has emerged as a possible treatment for progressive, debilitating Mendelian cardiomyopathies with limited therapeutic options. This paper arises from discussions at the 2023 Cardiovascular Clinical Trialists Forum and highlights several challenges relevant to gene therapy clinical trials, including low prevalence and high phenotypic heterogeneity of Mendelian cardiomyopathies, outcome selection complexities and resulting regulatory uncertainty, and immune responses to the adeno-associated viral vectors that are being used in ongoing studies. Avenues to address these challenges such as natural history studies, external controls, novel regulatory pathways, and immunosuppression are discussed. Relevant cases of recent therapy approvals are highlighted. Ultimately, this work aims to broadly frame discussions on and provide potential future avenues for clinical trial design for rare cardiomyopathy gene therapies.

Early precise identification of high-risk dilated cardiomyopathy (DCM) phenotype is essential for clinical decision-making and patient surveillance. The aim of the study was to assess the prognostic value of enhanced cine cardiac magnetic resonance (CMR)-based radiomics in DCM.

We prospectively enrolled 401 (training set: 281; test set: 120) DCM patients. Radiomic features were extracted from enhanced cine images of entire left ventricular wall and selected by the least absolute shrinkage and selection operator. Different predictive models were built using logistic regression classifier to predict all-cause mortality and heart transplantation. Model performances were compared with the area under the receiver operating characteristic curves (AUCs). Kaplan-Meier curves, log-rank test, and Cox regression were used for survival analysis.

Endpoint events occurred in 65 patients over a median follow-up period of 25.4 months. 13 radiomic features were finally selected. The Rad_Combined model integrating clinical characteristics, CMR parameters and radiomics features achieved the best performance with an AUC of 0.836 and 0.835 in the training and test sets, respectively. High-risk groups with endpoint events defined by the Rad_Combined model had significantly shorter survival time than low-risk group in both the training [Hazard Ratio (HR) = 7.74, P < 0.001] and test sets (HR = 4.84, P < 0.001).

The Rad_Combined model might serve as an effective tool to help risk stratification and clinical decision-making for patients with DCM.

Chinese Clinical Trial Registry, ChiCTR1800017058 by the ethics committee of West China hospital,Sichuan University.

Structural or electrophysiologic cardiac anomalies may compromise cardiac function, leading to sudden cardiac death (SCD). Genetic screening of families with severe cardiomyopathies underlines the role of genetic variations in cardiac-specific genes. The present study details the clinical and genetic characterization of a malignant dilated cardiomyopathy (DCM) case in a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD. A total of 132 genes (48 structure- and 84 electrical-related genes) were examined by next generation sequencing to identify potential causative mutations in comparison to control population. In silico analysis identified only two deleterious heterozygous mutations within an evolutionarily well-conserved region of the sarcomeric genes ACTC1/cardiac actin (c.664G > A/p.Ala222Thr) and TTN/titin (c.33250G > A/p.Glu11084Lys). Further pedigree analysis revealed the father of the index case to carry with the TTN mutation. Surprisingly, the ACTC1 mutation was not harbored by any first-degree family member. Computational 3D modeling of the mutated proteins showed electrostatic and conformational shifts of cardiac actin compared to wild-type version, as well as changes in the stability of the compact/folded states of titin that normally contributes to avoid mechanic damage. In conclusion, our findings suggest a likely pathogenic de novo mutation in ACTC1 in coexpression of a TTN variant as possible causes of an early onset of a severe DCM and premature death. These results may increase the known clinical pathogenic variations that may critically alter the structure of the heart, whose fatality could be prevented when rapidly detected.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure (HF) characterized by left ventricular dilatation and systolic dysfunction not explained by abnormal loading conditions. Despite its prevalence, DCM's epidemiology and prognosis remain poorly studied in our country.

A retrospective observational study encompassed patients discharged from all Spanish public hospitals between 2016 and 2021 diagnosed with DCM. Data were extracted from the Minimum Basic Data Set. The study focused on hospital admissions, comorbidities, in-hospital mortality, and readmission rates for circulatory system diseases at 30 and 365 days.

Among 27,402 index episodes, DCM was the primary diagnosis in 12.4%, predominantly affecting men (72.5%). In-hospital mortality was 8.7%, with significant predictors including cardiogenic shock (OR: 12.4, 95% CI: 9.6-15.9), advanced or metastatic cancer (OR: 4.3, 95% CI: 3.8-5.0), renal failure (OR: 2.4, 95% CI: 2.2-2.7), and chronic liver disease (OR: 2.4, 95% CI: 2.1-2.8). Readmission rates were 7.9% at 30 days and 25.5% at 365 days, predominantly due to HF. Multivariate analysis identified age (IRR: 1.02, 95% CI: 1.01-1.02), female sex (IRR: 0.87, 95% CI: 0.79-0.96), severe hematological diseases (IRR: 2.12, 95% CI: 1.45-3.10), and metastatic cancer (IRR: 1.65, 95% CI: 1.31-2.07) as predictors of 30-day readmissions. At 365 days, predictors included age (IRR: 1.02, 95% CI: 1.01-1.02), female sex (IRR: 0.80, 95% CI: 0.74-0.86), severe hematological diseases (IRR: 2.43, 95% CI: 1.66-3.56), and renal failure (IRR: 1.42, 95% CI: 1.31-1.55).

This study highlights the substantial hospitalization burden and mortality risk among DCM patients, emphasizing the necessity for advanced management strategies and specialized cardiac care.

Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and poor systolic function. Approximately half of idiopathic DCM cases are assigned to genetic causes in familial or apparently sporadic cases, and more than 50 genes are reported to cause DCM. However, genetic basis of most DCM patients still keeps unknown and require further study. Clinical data, family histories, and blood samples were collected from the proband and family members in a Chinese family presenting with DCM and conduction system disease. A genetic analysis was performed using next generation sequencing (NGS). Bioinformatic analysis was performed to predict the pathogenic consequence of gene mutation. A missense heterozygous mutation c.652G > A (p.G218R) in Laminin Subunit Alpha-4 (LAMA4) gene was identified in proband and his 2 brothers with relevant clinical symptoms. Individuals without carrying this mutation in this family had no symptoms or cardiac structural abnormality related to DCM or conduction system disease. The p.G218R mutation is located in a conservative area within the laminin epidermal growth factor (EGF)-like domain of LAMA4 with uncertain significance in ClinVar archive. Bioinformatic analysis predicted p.G218R mutation as deleterious and pathogenic damaging in DCM patients. Our results reported a potential pathogenic mutation associated with DCM, which may provide further insight into genetic contributions of LAMA4 gene mutations to DCM phenotypes.

This review aims to provide a comprehensive overview of the current understanding of genetic markers associated with heart failure (HF) and its underlying causative diseases, such as cardiomyopathies. It highlights the relevance of genetic biomarkers in diagnosing HF, predicting prognosis, potentially identifying its preclinical stages and identifying targets to enable the implementation of individualized medicine approaches.

The prevalence of HF is increasing due to an aging population but with greater access to disease-modifying therapies. Advanced diagnostic tools such as cardiac magnetic resonance, nuclear imaging, and AI-enabled diagnostic testing are now being utilized to further characterize HF patients. Additionally, the importance of genetic testing in HF diagnosis and management is increasingly being recognized. Genetic biomarkers, including single nucleotide polymorphisms (SNPs) and rare genetic variants, are emerging as crucial tools for diagnosing HF substrates, determining prognosis and increasingly directing therapy. These genetic insights are key to optimizing HF management and delivering personalized treatment tailored to individual patients. HF is a complex syndrome affecting millions globally, characterized by high mortality and significant economic burden. Understanding the underlying etiologies of HF is essential for improving management and clinical outcomes. Recent advances highlight the use of multimodal assessments, including AI-enabled diagnostics and genetic testing, to better characterize and manage HF. Genetic biomarkers are particularly promising in identifying preclinical HF stages and providing personalized treatment options. The genetic contribution to HF is heterogeneous, with both monogenic and polygenic bases playing a role. These developments underscore the shift towards personalized medicine in HF management.