Form Of Heart Muscle Disease Research Articles

The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy.

The SCN5A gene encodes the alpha subunit of the cardiac sodium channel, which plays a fundamental role in the generation and propagation of the action potential in the heart muscle. During the past years our knowledge concerning the function of the cardiac sodium channel and the diseases caused by mutations of the SCN5A gene has grown. Although initially SCN5A pathogenic variants were mainly associated with channelopathies, increasing recent evidence suggests an association with structural heart disease in the form of heart muscle disease. The pathways leading to a cardiomyopathic phenotype remain unclear and require further elucidation. The aim of the present review is to provide a concise summary regarding the mechanisms through which SCN5A pathogenic variants result in heart disease, focusing in cardiomyopathy, highlighting along the way the complex role of the SCN5A gene at the intersection of cardiac excitability and contraction networks.

Genetics of BAG3: A Paradigm for Developing Precision Therapies for Dilated Cardiomyopathies.

Nonischemic dilated cardiomyopathy is a common form of heart muscle disease in which genetic factors play a critical etiological role. In this regard, both rare disease-causing mutations and common disease-susceptible variants, in the Bcl-2-associated athanogene 3 (BAG3) gene have been reported, highlighting the critical role of BAG3 in cardiomyocytes and in the development of dilated cardiomyopathy. The phenotypic effects of the BAG3 mutations help investigators understand the structure and function of the BAG3 gene. Indeed, we report herein that all of the known pathogenic/likely pathogenic variants affect at least 1 of 3 protein functional domains, ie, the WW domain, the second IPV (Ile-Pro-Val) domain, or the BAG domain, whereas none of the missense nontruncating pathogenic/likely pathogenic variants affect the proline-rich repeat (PXXP) domain. A common variant, p.Cys151Arg, associated with reduced susceptibility to dilated cardiomyopathy demonstrated a significant difference in allele frequencies among diverse human populations, suggesting evolutionary selective pressure. As BAG3-related therapies for heart failure move from the laboratory to the clinic, the ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins. The current review article provides a roadmap that investigators can utilize to determine the potential interactions between a patient's genotype, their phenotype, and their response to therapeutic interventions with both gene delivery and small molecules.

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy

Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. The ARISE-HF Trial is fully enrolled. This report describes the rationale and study design of ARISE-HF.

Assessment of Right Ventricular Function and Structure in Children with Idiopathic Dilated Cardiomyopathy

Background: Dilated cardiomyopathy (DCM) refers to dilating the ventricles and dysfunction of their systolic functions (predominantly the left ventricle) with or without congestive heart failure. In children, it is the most common form of heart muscle disease. We aimed to evaluate the right ventricular functions and structure using speckling tracking echocardiography in children with dilated cardiomyopathy and correlate this parameter with other echocardiographic findings.
 Methods: This observational Case-Control Study was carried out on 75 subjects. They were subdivided into two groups: Group 1: 50 patients with dilated cardiomyopathy Group 2: 25 healthy children matched for age and sex. Patients were evaluated by M-mode echocardiography, Transthoracic 2DE Examination (TTE), Tissue Doppler Examination (TDE) and Speckling Tracking Technique.
 Results: Left ventricle (LV) and right ventricle (RV) systolic dysfunction was evidenced by a significant decrease of mitral and tricuspid annular systolic velocities and a significant decrease of LV and RV global systolic strain and a significant decrease of LV and RV Ejection fraction (EF). LV and RV diastolic dysfunction were evidenced by a significant decrease of mitral and tricuspid annular diastolic velocities (E’/A’) and a significant increase of LV and RV Myocardial Perfusion Imaging (MPI). LV and RV global strains were significantly reduced in comparison to controls, suggesting that the dilated cardiomyopathy is a diffuse disease.
 Conclusion: In DCM patients, RV had significant systolic and diastolic dysfunction mainly elicited by the Tissue Doppler imaging (TDI) beside LV affection secondary to the interventricular interaction. TDI and 2D-STE add value to interpreting the findings and the dependency of RV systolic and diastolic functions on each other in DCM patients.

Dilated cardiomyopathy: room for (cautious) optimism?

<h2>Abstract</h2> Dilated cardiomyopathy is an uncommon but serious form of heart muscle disease affecting children and young people. The aetiology and clinical presentation are heterogenous, and a structured approach to identification, classification and management is warranted. Comprehensive initial workup is aimed at identifying potentially reversible causes, as well as identifying children where cardiomyopathy is the initial presenting feature of a multi-systemic condition. Commoner causes of primary myocarditis include infection, and heritable, familial conditions including mitochondrial disease and muscular dystrophies. It may also be secondary to arrhythmias, ischaemia, toxins, nutritional deficiencies or metabolic disturbance. Genetic testing has not yet yielded as illuminating results as in adults, or in children with hypertrophic cardiomyopathy; however, progress in this field is likely to be rapid. Understanding the key underlying pathophysiologic mechanisms, along with extrapolation from adult literature, directs pharmacologic management, which has remained largely unchanged over the past few decades. Novel pharmacologic agents, improvements in mechanical support and innovative surgical techniques, permit cautious optimism for improvement in morbidity, mortality and quality of life. Transplantation remains the gold standard for end-stage disease, with slow but continued prolongation of median survival. Although the overall prognosis remains guarded, the above advances in combination with multi-disciplinary collaboration, are gradually turning the tide in the management of children with this complex condition. In this short review we present a rational approach to diagnosis and management of this complex and challenging illness, and describe recent progress, as well as some cause for optimism.

Prognostic factors in paediatric restrictive cardiomyopathy

Restrictive cardiomyopathy (RCM) is the rarest and most serious form of heart muscle disease, accounting for 2–5% of pediatric cardiomyopathies. Identification of prognostic factors to identify high-risk patients that need to be addressed for early heart transplantation. We enrolled 47 patients that had a diagnosis of RCM between 1996 and 2017 in our center. The clinical, ultrasonography, and hemodynamic data were collected at the time of diagnosis, as well as genetic analysis in order to identify early predictors of poor prognosis (transplantation or death). The mean age at diagnosis was 5.9 years with a gender ratio of 1.76 (F/M). 57.5% had a pure RCM and 42.5% an hypertrophic cardiomyopathy with restrictive phenotype (HRCM). The median follow-up was 10.2 months. Overall survival at 1, 2 and 5 years was 43% 35% and 15% respectively. There was no statistically significant difference in terms of survival between RCM and HRCM (P = 0.651) and between age groups (P = 0.582). Clinical findings at diagnosis were dominated by congestive signs (63.9%), which were related to a poor outcome (P = 0/041). The relationship between a mildly altered left ventricular ejection fraction (LVEF 45-55%) and mortality was statistically significant (P = 0.01). Imaging findings didn’t show a late gadolinium enhancement. Regarding catheterism data, neither cardiac output nor pulmonary vascular resistance nor pulmonary capillary pressure were related to a poor outcome. The rentability of family screening was 60%: we identified 1 homozygous and 4 heterozygous mutations on TNNI3 gene including a neomutation, and 1 on MYH7 gene. Adverse prognostic factors were dominated by congestive signs at diagnosis and left ventricular dysfunction. Patient with these factors should be addressed early for Heart transplantation. Autosomic dominant mutation in TNNI3 was the most frequent genetic finding. Family screening and genetic counseling is thus important.

Update on restrictive cardiomyopathy

Abstract Restrictive cardiomyopathy (RCM) is a rare form of heart muscle disease accounting for just 2 to 5% of paediatric cardiomyopathies. It is characterised by increased myocardial stiffness and restrictive filling pattern in to the left ventricle. Idiopathic RCM with no obvious identifiable cause is the most common form of the disease. RCM can also be a secondary manifestation of miscellaneous systemic conditions. Typical examples include infiltrative and storage disorders, systemic inflammatory diseases, tumors and drug toxicity. RCM-specific mutations have been identified in several genes encoding sarcomeric proteins. Patients with RCM have heart failure symptoms related to diastolic dysfunction. Unfortunately, there is no curative treatment for RCM and the prognosis is generally very poor. Cardiac transplantation is the only effective treatment. High risk of sudden cardiac death justifies early listing especially in symptomatic children. When making the diagnosis of RCM, it is crucial to rule out constrictive pericarditis which presents with a similar clinical and haemodynamic picture. Unlike RCM it can often be cured surgically.

Abstract 9671: Molecular Dynamics and Calcium Binding Studies on Troponin Mutations Causing Dilated Cardiomyopathy

Troponin (Tn), part of the thin filament in cardiomyocytes, plays an important role in calcium signaling events in cardiac muscle contraction. It acts as a Ca2+-dependent switch, activating and deactivating the myofilament leading to contraction and relaxation of the muscle cell. The most common form of heart muscle disease, dilated cardiomyopathy (DCM), is characterized by dilatation of the heart and impaired systolic function of the left or both ventricles. Several Tn mutations that cause DCM have been reported. We used microsecond timescale molecular dynamics (MD) simulations to elucidate the molecular action of three troponin C (TnC) DCM mutations - D75Y, E59D and G159D - with particular focus on calculating the free energy difference between the open and closed states of the TnC as well as average times between opening events. We found free energy differences between the open and closed states of ~8 kcal/mol for the wildtype system. While G159D causes a significant increase in the free energy difference (by ~4 kcal/mol), D75Y does not change the free energy difference significantly, and E59D even causes a ~2 kcal/mol drop in the free energy difference. This finding illustrates nicely that the opening propensity of the TnC hydrophobic patch is only one possible mechanism by which DCM mutations can influence the contractility in cardiomyocytes. Both G159D and E59D use this mechanism. D75Y, however, does not influence TnI binding but rather impacts Ca2+-binding affinity, which can also be observed in our Brownian Dynamics simulations of calcium association.

Analysis of IL-17 gene polymorphisms in Chinese patients with dilated cardiomyopathy

Cardiomyopathy is one of the major causes of sudden death and/or progressive heart failure. Dilated cardiomyopathy (DCM), comprising 60% of the cases of identified cardiomyopathy, is the most common form of heart muscle disease. Interleukin 17 (IL-17) is a proinflammatory cytokine that has been implicated in the pathogenesis of various diseases. To evaluate the influence of IL-17A and IL-17F gene polymorphisms on the risk of DCM, a case-control study was conducted in a Chinese Han population. The TaqMan® SNP Genotyping Assay was used to genotype the SNP rs2275913 of IL-17A and SNP rs763780 of IL-17F in 288 DCM patients and 421 ethnicity-matched controls. No significant difference in genotypic and allelic frequencies between DCM patients and control subjects was observed. However, Results of stratified analysis revealed that rs763780 was associated with male DCM patients in a dominant genetic model (p=0.031, OR=1.83, 95% CI=1.04-3.22). Our results suggest that the tested two IL-17 SNPs, rs2275913 and rs763780, are not found to be associated with DCM in the Chinese population studied.

Idiopathic Restrictive Cardiomyopathy - Perspectives from Genetics Studies. Is It Time to Redefine These Disorders?

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in 33-66% of cases. Among these, the mutations most commonly involve TNNI3 and MYH7. There is a disproportionately high incidence of TNNI3 mutations in patients with restrictive physiology. De novo mutations are also frequently seen in this group of patients. IRC and hypertrophic cardiomyopathy (HCM) with restrictive phenotype reflect the same or very similar disorders with different names due to arbitrary cut offs in the left ventricular wall thickness rather than two separate distinct diseases. HCM with restrictive physiology should be considered part of a continuous spectrum with IRC. This is because patients with HCM with restrictive phenotype bear far greater clinical and genetic resemblance to IRC than to rest of the HCM cohort.

Epidermal growth factor receptor gene polymorphisms, R497K, but not (CA) n repeat, is associated with dilated cardiomyopathy

Background Epidermal growth factor receptor (EGFR) has been recently implicated in pathological tissue remodelling and sustained remodelling processes can lead to pathological outcomes, such as cardiac hypertrophy in heart failure. Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease, comprising 60% of the cases of identified cardiomyopathy. This study aimed to evaluate the association between the EGFR gene polymorphisms and DCM in a Chinese population. Methods Genomic DNA was extracted from whole blood samples in 163 DCM patients and 185 control subjects. EGFR R497K ( Arg497 Lys) and (CA)n polymorphisms were genotyped, and the difference of their allele and genotype frequencies distribution between DCM patients and controls were analyzed. Results No significant difference was observed in the frequency distribution of genotype and allele in (CA)n repeat between DCM patients and control subjects. The frequency of Lys allele in DCM patients was significantly higher than that in controls (64.4% and 53.8%, in DCM patients and controls, respectively p = 0.005, OR = 1.556, 95% CI = 1.146–2.111). The frequency for Lys/ Lys genotype was significantly overrepresented in DCM patients ( p = 0.020, OR = 2.105, 95% CI = 1.134–3.905, for Lys/ Lys vs. Arg/ Arg). Conclusion This study suggests that the R497K polymorphism may be associated with DCM in a Chinese population.

Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect

Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. The mutations in lamin A/C gene have been linked to dilated cardiomyopathy. We screened genetic mutations in a large Chinese family of 50 members including members with dilated cardiomyopathy and found a Glu82Lys substitution mutation in the rod domain of the lamin A/C protein in eight family members, three of them have been diagnosed as dilated cardiomyopathy, one presented with heart dilation. The pathogenic mechanism of lamin A/C gene defect is poorly understood. Glu82Lys mutated lamin A/C and wild type protein was transfected into HEK293 cells. The mutated protein was not properly localized at the inner nuclear membrane and the emerin protein, which interacts with lamin A/C, was also aberrantly distributed. The nuclear membrane structure was disrupted and heterochromatin was aggregated aberrantly in the nucleus of the HEK293 cells stably transfected with mutated lamin A/C gene as determined by transmission electron microscopy.

Epidemiology and Etiology of Cardiomyopathy in Africa

Cardiomyopathy, an often irreversible form of heart muscle disease that is associated with a dismal outcome, is endemic in Africa. The primary objective of this review was to summarize the current state of knowledge on the epidemiology and etiology of cardiomyopathy in people living in Africa and to identify new avenues for research. We searched MEDLINE (January 1, 1966, through February 12, 2005) and reference lists of articles for relevant references. Unlike other parts of the world in which cardiomyopathy is rare, dilated cardiomyopathy is a major cause of heart failure throughout Africa. Similarly, peripartum cardiomyopathy is ubiquitous on the continent, with an incidence ranging from 1 in 100 to 1 in 1000 deliveries. There is an apparent marked regional variation in the pathogenesis of dilated cardiomyopathy and peripartum cardiomyopathy, underlining the heterogeneity of causative factors in these conditions. By contrast, endomyocardial fibrosis is restricted to the tropical regions of East, Central, and West Africa. Although the pathogenesis of endomyocardial fibrosis is not fully understood, it seems that the conditioning factors are geography and diet, the triggering factor may be an as yet unidentified infective agent, and the perpetuating factor is eosinophilia. Although epidemiological studies are lacking, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy seem to have characteristics similar to those of other populations elsewhere in the world. There is a need for large-scale epidemiological studies of the incidence, prevalence, determinants, and outcome of cardiomyopathy in Africa to inform strategies for the treatment and prevention of heart muscle disease on the continent.

Lamin A/C Gene Mutation Associated With Dilated Cardiomyopathy With Variable Skeletal Muscle Involvement

Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. Familial transmission of the disease is frequently observed, and genetic heterogeneity is indicated by clinical and morphological variability in the disease phenotype. In the family MDDC1 reported here, the disease phenotype is severe and characterized by an autosomal dominant pattern of transmission. In addition, the majority of affected family members show signs of mild skeletal muscle involvement. On the basis of the clinical observation of both cardiac and skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was examined in this kindred. Coding regions were polymerase chain reaction-amplified from genomic DNA and sequenced. A single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion. Heterozygosity for a single nucleotide deletion in exon 6 of lamin A/C segregates with both the cardiac and skeletal abnormalities observed in the MDDC1 family.

Unexpected myocardial disease in patients with life threatening arrhythmias.

It is not unusual for an individual without recognisable clinical heart disease to have a life threatening arrhythmia. This report describes the results of endomyocardial biopsy in twelve patients who presented with life threatening arrhythmias and normal or near normal cardiac function. The eight men and four women (mean age 35) presented with ventricular tachycardia or fibrillation (nine cases), high grade heart block with inadequate ventricular escape (two cases), and dangerous ventricular extrasystoles (Lown grade 4, one case). In ten of the twelve patients symptoms had been present for less than or equal to 6 months at presentation. No patient had a normal electrocardiogram. Electrophysiological testing confirmed the clinical arrhythmia in all but three patients. Endomyocardial biopsy demonstrated lymphocytic myocarditis in two patients, granulomatous myocarditis in two patients, small vessel vasculitis in one patient, and cardiomyopathic changes in six patients. In one patient the biopsy specimen was normal. Endomyocardial biopsy is a valuable diagnostic tool in patients with unexplained life threatening arrhythmias. In this study half the patients had a treatable form of heart muscle disease.