Search

Patients with nonischemic dilated cardiomyopathy (DCM), severe left ventricular (LV) dysfunction, and complete left bundle branch block benefit from cardiac resynchronization therapy (CRT). However, a large heterogeneity of response to CRT is described. Several predictors of response to CRT have been identified, but the role of the underlying genetic background is still poorly explored.

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.

IMPORTANCE: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. OBJECTIVE: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E′ velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. INTERVENTIONS: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E′ velocity and S′ velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). RESULTS: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: −0.01 [95% CI, −0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. CONCLUSIONS AND RELEVANCE: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01912534

In the wide phenotypic spectrum of cardiomyopathies, sudden cardiac death (SCD) has always been the most visible and devastating disease complication. The introduction of implantable cardioverter-defibrillators for SCD prevention by the late 1980s has moved the question from how to whom we should protect from SCD, leaving clinicians with a measure of uncertainty regarding the most reliable option to guide identification of the highest-risk patients. In this review, we will go through all the available evidence in the field of arrhythmic expression and arrhythmic risk stratification in the different phenotypes of cardiomyopathies to provide practical suggestions in daily clinical management.

Supplemental Digital Content is available in the text.

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years (NCT01912534). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n= 88) improved cardiac structure and function compared to placebo (n= 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P= 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.

The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease that affects predominantly the right ventricle and is part of the spectrum of arrythmogenic cardiomyopathies (ACMs). ARVC is a genetic condition; however, a pathogenic gene variant is found in only half of patients.ObjectiveFilamin C gene truncations (FLNCtv) have recently been identified in dilated cardiomyopathy with ventricular arrhythmia and sudden cardiac death, a phenotype partially overlapping with ARVC and part of the ACM spectrum. We hypothesised that FLNCtvcould be a novel gene associated with ARVC.MethodsOne hundred fifty-six patients meeting 2010 ARVC Task Force Criteria and lacking variants in known ARVC genes were evaluated for FLNCvariants. Available family members were tested for cosegregation.ResultsWe identified two unique FLNCtvvariants in two families (c.6565 G>T, p.Glu2189Ter and c.8107delG, p.Asp2703ThrfsTer69), with phenotypes of dominant RV disease fulfilling ‘definite’ diagnosis of ARVC according to the 2010 Task Force Criteria. Variants in other cardiomyopathy genes were excluded in both kindreds, and segregation analysis revealed that p.Asp2703ThrfsTer69 was a de novo variant. In both families, the disease phenotype was characterised by prominent ventricular arrhythmias and sudden cardiac arrest.ConclusionThe identification of FLNCtvas a novel cause of ARVC in two unrelated families expands the spectrum of ARVC non-desmosomedisease genes for this disorder. Our findings should prompt inclusion of FLNCgenetic testing in ARVC to improve diagnostic yield and testing of at-risk relatives in ARVC.

Utilizing polymers in cardiac tissue engineering holds promise for restoring function to the heart following myocardial infarction, which is associated with grave morbidity and mortality. To properly mimic native cardiac tissue, materials must not only support cardiac cell growth but also have inherent conductive properties. Here, we present an injectable reverse thermal gel (RTG)-based cardiac cell scaffold system that is both biocompatible and conductive. Following the synthesis of a highly functionalizable, biomimetic RTG backbone, gold nanoparticles (AuNPs) were chemically conjugated to the backbone to enhance the system’s conductivity. The resulting RTG–AuNP hydrogel supported targeted survival of neonatal rat ventricular myocytes (NRVMs) for up to 21 days when cocultured with cardiac fibroblasts, leading to an increase in connexin 43 (Cx43) relative to control cultures (NRVMs cultured on traditional gelatin-coated dishes and RTG hydrogel without AuNPs). This biomimetic and conductive RTG–AuNP hydrogel holds promise for future cardiac tissue engineering applications.

Nanoscale manipulations of the extracellular microenvironment are increasingly attracting attention in tissue engineering. Here, combining microscopy, biological, and single-cell electrophysiological methodologies, we demonstrate that neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes interact with carbon nanotubes by forming tight contacts and show increased viability and proliferation. Furthermore, we observed changes in the electrophysiological properties of cardiomyocytes, suggesting that carbon nanotubes are able to promote cardiomyocyte maturation.

•We identified 7 new genetic regions for factor VIII levels, 1 for von Willebrand factor levels, and 3 in a combined analysis.•Silencing B3GNT2and CD36reduced factor VIII release in vitro.Silencing B3GNT2, CD36, and PDIA3reduced von Willebrand factor release.

Supplemental Digital Content is available in the text.

Infiltrative cardiomyopathies are characterized by abnormal accumulation or deposition of substances in cardiac tissue leading to cardiac dysfunction. These can be inherited, resulting from mutations in specific genes, which engender a diverse array of extracardiac features but overlapping cardiac phenotypes. This article provides an overview of each inherited infiltrative cardiomyopathy, describing the causative genes, the pathologic mechanisms involved, the resulting cardiac manifestations, and the therapies currently offered or being developed.

The purpose of this study was to assess the phenotype of Filamin C(FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype.

The ability of the adult heart to regenerate cardiomyocytes (CMs) lost after injury is limited, generating interest in developing efficient cell-based transplantation therapies. Rigid carbon nanotubes (CNTs) scaffolds have been used to improve CMs viability, proliferation, and maturation, but they require undesirable invasive surgeries for implantation. To overcome this limitation, we developed an injectable reverse thermal gel (RTG) functionalized with CNTs (RTG-CNT) that transitions from a solution at room temperature to a three-dimensional (3D) gel-based matrix shortly after reaching body temperature. Here we show experimental evidence that this 3D RTG-CNT system supports long-term CMs survival, promotes CMs alignment and proliferation, and improves CMs function when compared with traditional two-dimensional gelatin controls and 3D plain RTG system without CNTs. Therefore, our injectable RTG-CNT system could potentially be used as a minimally invasive tool for cardiac tissue engineering efforts.

IMPORTANCE: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. OBJECTIVES: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH−), and healthy related control individuals (G−/LVH−) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016. EXPOSURES: The primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT. MAIN OUTCOMES AND MEASURES: Variables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts. RESULTS: Analyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH− (20 [10] years), and 42 G−/LVH− (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E′ velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH−, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than −1.85 or the combination of an LV end-diastolic dimension z score of −1.85 or higher and a septal E′ velocity z score less than −0.52 as having 74% accuracy in discriminating G+/LVH− participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition. CONCLUSIONS AND RELEVANCE: G+/LVH− individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G− controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree–based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

ObjectiveTo explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR).MethodsA cohort of 152 patients with DCM from the Heart Muscle Disease Registry of Trieste has been studied by next-generation sequencing (NGS). Patients were grouped into different ‘gene-clusters’ with functionally homogeneous genetic backgrounds. LVRR was defined by left ventricular ejection fraction normalisation or increase ≥10% associated with normalisation in indexed left ventricular end-diastolic diameter or relative decrease ≥10% at 24 months follow-up.ResultsA pathogenic disease-related gene variant was identified in 57% of patients: 28 (18%) TTN; 7 (5%) LMNA; 16 (11%) structural cytoskeleton Z-disk genes; 9 (6%) desmosomal genes; 18 (12%) motor sarcomeric genes and 9 (6%) other genes. Baseline clinical features were similar throughout the different genotypes. A significant relationship was found between gene cluster subgroups and LVRR, with a lower rate of LVRR in structural cytoskeleton Z-disk gene mutation carriers (1/16 patients, 6%, p<0.05 vsthe other subgroups). Of note, structural cytoskeleton Z-disk gene rare variants were independently and inversely associated with LVRR when adjusted for clinical predictors of LVRR (OR 0.065; 95% CI 0.008 to 0.535, p=0.011).ConclusionsNGS confirmed a high genetic diagnostic yield in DCM. A specific ‘gene-clusters’ classification based on functional similarities in different genes might be helpful in the clinical management of genetically determined DCM. In this study, structural cytoskeleton Z-disk gene rare variants were independently associated with a lower rate of LVRR at follow-up.

The primary objective of this study is risk stratification of patients with arrhythmic right ventricular cardiomyopathy (ARVC).

The study sought to provide an insight into the prevalence, characterization and possible reliable indicators of early sudden cardiac death/malignant ventricular arrhythmias (SCD/MVAs) in a large cohort of dilated cardiomyopathy (DCM).

NFκB signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing CCR2-expressing macrophages which promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with arrhythmogenic cardiomyopathy.

Previous investigations suggested that lamin A/C gene (LMNA) mutations, which cause a variety of human diseases including muscular dystrophies and cardiomyopathies, alter the nuclear mechanical properties. We hypothesized that biomechanical changes may extend beyond the nucleus.

Novel medical approaches and personalized medicine seek to use genetic information to ‘individualize’ and improve diagnosis, prevention, and therapy. The personalized management of cardiovascular disease involves a large spectrum of potential applications, from diagnostics of monogenic disorders, to prevention and management strategies based on modifier genes, to pharmacogenetics, in which individual genetic information is used to optimize the pharmacological treatments.

Myocardial tissue engineering currently represents one of the most realistic strategies for cardiac repair. We have recently discovered the ability of carbon nanotube scaffolds to promote cell division and maturation in cardiomyocytes. Here, we test the hypothesis that carbon nanotube scaffolds promote cardiomyocyte growth and maturation by altering the gene expression program, implementing the cell electrophysiological properties and improving networking and maturation of functional syncytia. In our study, we combine microscopy, biological and electrophysiological methodologies, and calcium imaging, to verify whether neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes acquire a physiologically more mature phenotype compared to control (gelatin). We show that the carbon nanotube substrate stimulates the induction of a gene expression profile characteristic of terminal differentiation and physiological growth, with a 2-fold increase of α-myosin heavy chain (P< 0.001) and upregulation of sarcoplasmic reticulum Ca2+ATPase 2a. In contrast, markers of pathological hypertrophy remain unchanged (β-myosin heavy chain, skeletal α-actin, atrial natriuretic peptide). These modifications are paralleled by an increase of connexin-43 gene expression, gap junctions and functional syncytia. Moreover, carbon nanotubes appear to exert a protective effect against the pathologic stimulus of phenylephrine. Finally, cardiomyocytes on carbon nanotubes demonstrate a more mature electrophysiological phenotype of syncytia and intracellular calcium signaling. Thus, carbon nanotubes interacting with cardiomyocytes have the ability to promote physiological growth and functional maturation. These properties are unique in the current vexing field of tissue engineering, and offer unprecedented perspectives in the development of innovative therapies for cardiac repair.

Hypertrophic cardiomyopathy (HCM) is the most frequent autosomal dominant genetic heart muscle disease and the most common cause of sudden cardiac death in young people (under 30 y of age), who are often unaware of their underlying condition. Genetic screening is now considered a fundamental tool for clinical management of HCM families. However, the high genetic heterogeneity of HCM makes genetic screening very expensive. Here, we propose a new high-throughput genotyping method based on a HCM 96-well sequencing plate for the analysis of 8 of the most frequent HCM-causing sarcomeric genes by automating several processes required for direct sequencing, using a commercially available robotic systems and routinely used instruments. To assess the efficiency of the robot-assisted method, we have analyzed the entire coding sequence and flanking intronic sequences of the 8 sarcomeric genes in samples from 18 patients affected by HCM and their relatives, which revealed 9 different mutations, 3 of which were novel. The automated, robot-assisted assembling of polymerase chain reaction, purification of polymerase chain reaction products, and assembly of sequencing reactions resulted in a substantial saving of time, reagent costs, and reduction of human errors, and can therefore be proposed as a primary strategy for mutation identification in HCM genetic screening in many medical genetic laboratories.

Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to -blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to -blockers in heart failure.

The human LMNAgene, when mutated, has been shown to cause at least 7 human diseases: dilated cardiomyopathy, Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, familial partial lipodystrophy, Charcot Marie tooth disease type II, mandibuloacral dysplasia, and Hutchinson-Gilford Progeria (OMIM #176670). This article describes a high-throughput method for screening the human lamin A/C (LMNA) gene for genetic mutations and sequence variation using denaturing high-performance liquid chromatography (DHPLC). In the present study, 76 patients with dilated cardiomyopathy were screened for mutations using DHPLC and sequence analysis. Abnormal elution profiles were identified and sequenced on an ABI 377 automatic sequencer. Heterozygous LMNAmutations were detected in 8% of the affected patients. In addition, a number of intronic and exonic single nucleotide polymorphisms were identified. LMNAmutations are clinically relevant in at least 6 human diseases. This study provides a protocol for high-throughput LMNAanalysis applicable both in the research and in the clinical diagnostic setting.

The human LMNAgene, when mutated, has been shown to cause at least 7 human diseases: dilated cardiomyopathy, Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, familial partial lipodystrophy, Charcot Marie tooth disease type II, mandibuloacral dysplasia, and Hutchinson-Gilford Progeria (OMIM #176670). This article describes a high-throughput method for screening the human lamin A/C (LMNA) gene for genetic mutations and sequence variation using denaturing high-performance liquid chromatography (DHPLC). In the present study, 76 patients with dilated cardiomyopathy were screened for mutations using DHPLC and sequence analysis. Abnormal elution profiles were identified and sequenced on an ABI 377 automatic sequencer. Heterozygous LMNAmutations were detected in 8% of the affected patients. In addition, a number of intronic and exonic single nucleotide polymorphisms were identified. LMNAmutations are clinically relevant in at least 6 human diseases. This study provides a protocol for high-throughput LMNAanalysis applicable both in the research and in the clinical diagnostic setting. (Journal of Biomolecular Screening2004:625-628)