Genetic Hypertrophic Cardiomyopathy Research Articles

Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including ECG abnormalities, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.

Viral myocarditis in combination with genetic cardiomyopathy as a cause of sudden death. An autopsy series

Sudden cardiac death (SCD) is a major public health issue worldwide. In the young (< 40 years of age), genetic cardiomyopathies and viral myocarditis, sometimes in combination, are the most frequent, but underestimated, causes of SCD. Molecular autopsy is essential for prevention. Several studies have shown an association between genetic cardiomyopathies and viral myocarditis, which is probably underestimated due to insufficient post-mortem investigations. We report on four autopsy cases illustrating the pathogenesis of these combined pathologies. In two cases, a genetic hypertrophic cardiomyopathy was diagnosed in combination with Herpes Virus Type 6 (HHV6) and/or Parvovirus-B19 (PVB19) in the heart. In the third case, autopsy revealed a dilated cardiomyopathy and virological analyses revealed acute myocarditis caused by three viruses: PVB19, HHV6 and Epstein-Barr virus. Genetic analyses revealed a mutation in the gene coding for desmin. The fourth case illustrated a channelopathy and a PVB19/HHV6 coinfection. Our four cases illustrate the highly probable deleterious role of cardiotropic viruses in the occurrence of SCD in subjects with genetic cardiomyopathies. We discuss the pathogenetic link between viral myocarditis and genetic cardiomyopathy. Molecular autopsy is essential in prevention of these SCD, and a close collaboration between cardiologists, pathologists, microbiologists and geneticians is mandatory.

Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration.

Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce. Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration. Mitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.

Asymptomatic obstructive asymmetric hypertrophic cardiomyopathy in late adolescence

An 18-years-old adolescent with asymmetric mid-ventricular hypertrophic cardiomyopathy, undiagnosed because he did not present symptoms. The electrocardiogram indicated an increase in the QT interval, without arrhythmias; the transthoracic echocardiogram revealed asymmetric mid-ventricular hypertrophy, with mild obstruction of the left ventricular outflow tract; the mitral valve was thickened and calcified. Symptoms were not found because the outflow tract obstruction was not noticeable; as hypertrophy increased, the symptoms appeared. The thickening and calcification of the mitral valve, uncommon for the patient's age, could cause mitral regurgitation or heart failure. Key Words: Genetic hypertrophic cardiomyopathy, mild outflow tract obstruction, calcification and thickening of the mitral valve.

Specific alterations of regional myocardial work in strength-trained athletes using anabolic androgenic steroids compared to athletes with genetic hypertrophic cardiomyopathy

BackgroundStrength-trained athletes using anabolic androgenic steroids (AAS) have left ventricular (LV) hypertrophy and myocardial fibrosis that can lead to sudden cardiac death. A similar feature was described in athletes with hypertrophic cardiomyopathy (HCM), which complicates the diagnosis for clinicians. In this context, we aimed to compare the LV function of the 2 populations by measuring global and regional strain and myocardial work using speckle-tracking imaging. MethodsTwenty-four strength-trained asymptomatic athletes using AAS (AAS-Athletes), 22 athletes diagnosed with HCM (HCM-Athletes), and 20 healthy control athletes (Ctrl-Athletes) underwent a resting echocardiography to assess LV function. We evaluated LV global and regional strains and myocardial work, with an evaluation of the constructive work (CW), wasted work, and work efficiency (WE). ResultsCompared to Ctrl-Athletes, both AAS-Athletes and HCM-Athletes had a thicker interventricular septum, with majored values in HCM-Athletes. LV strain was reduced in AAS-Athletes and even more in HCM-Athletes. Consequently, global WE was significantly diminished in both AAS and HCM-Athletes (93% ± 2% in Ctrl-Athletes, 90% ± 4% in AAS-Athletes, and 90% ± 5% in HCM-Athletes (mean ± SD); p < 0.05). Constructive work and WE regional analysis showed specific alterations, with the basal septal segments preferentially affected in AAS-Athletes, and both septal and apical segments affected in HCM-Athletes. ConclusionThe regional evaluation of myocardial work reported specific alterations of the major LV hypertrophy induced by the regular use of AAS compared to the LV hypertrophy due to HCM. This finding could help clinicians to differentiate between these 2 forms of pathological hypertrophy.

Effects of Sarcomere Activators and Inhibitors Targeting Myosin Cross-Bridges on Ca2+-Activation of Mature and Immature Mouse Cardiac Myofilaments.

We tested the hypothesis that isoform shifts in sarcomeres of the immature heart modify the effect of cardiac myosin-directed sarcomere inhibitors and activators. Omecamtiv mecarbil (OM) activates tension and is in clinical trials for the treatment of adult acute and chronic heart failure. Mavacamten (Mava) inhibits tension and is in clinical trials to relieve hypercontractility and outflow obstruction in advanced genetic hypertrophic cardiomyopathy (HCM), which is often linked to mutations in sarcomeric proteins. To address the effect of these agents in developing sarcomeres, we isolated heart fiber bundles, extracted membranes with Triton X-100, and measured tension developed over a range of Ca2+ concentrations with and without OM or Mava treatment. We made measurements in fiber bundles from hearts of adult nontransgenic (NTG) controls expressing cardiac troponin I (cTnI), and from hearts of transgenic (TG-ssTnI) mice expressing the fetal/neonatal form, slow skeletal troponin I (ssTnI). We also compared fibers from 7- and 14-day-old NTG mice expressing ssTnI and cTnI. These studies were repeated with 7- and 14-day-old transgenic mice (TG-cTnT-R92Q) expressing a mutant form of cardiac troponin T (cTnT) linked to HCM. OM increased Ca2+-sensitivity and decreased cooperative activation in both ssTnI- and cTnI-regulated myofilaments with a similar effect: reducing submaximal tension in immature and mature myofilaments. Although Mava decreased tension similarly in cTnI- and ssTnI-regulated myofilaments controlled either by cTnT or cTnT-R92Q, its effect involved a depressed Ca2+-sensitivity in the mature cTnT-R92 myofilaments. Our data demonstrate an influence of myosin and thin-filament associated proteins on the actions of myosin-directed agents such as OM and Mava. SIGNIFICANCE STATEMENT: The effects of myosin-targeted activators and inhibitors on Ca2+-activated tension in developing cardiac sarcomeres presented here provide novel, ex vivo evidence as to their actions in early-stage cardiac disorders. These studies advance understanding of the molecular mechanisms of these agents, which are important in preclinical studies employing sarcomere Ca2+-response as a screening approach. The data also inform the use of commonly immature cardiac myocytes generated from human-inducible pluripotent stem cells in screening for sarcomere activators and inhibitors.

Abstract 11792: Low Penetrance Sarcomere Variants Indicate an Additive Genetic Risk Model in Hypertrophic Cardiomyopathy

Introduction: Genetic hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited condition primarily due to pathogenic variants in sarcomere genes, often with marked clinical variability. We hypothesized that this variability may, in part, be due to additive effects from low penetrance sarcomere variants that would otherwise be dismissed due to high population prevalence. Methods: Low-penetrance HCM-associated sarcomere gene variants were identified by meeting a threshold for enrichment in HCM (ascertained from the Sarcomeric Human Cardiomyopathy Registry, SHaRe) versus the general population (ascertained from the Genome Aggregation Database, gnomAD), defined by an odds ratio (OR) &gt;5, and a population prevalence greater than the most common autosomal dominant pathogenic HCM variant, MYBPC3 R502W (4x10 -5 ). Clinical variables and time-event analyses were performed from SHaRe . Results: A total of 507 unique sarcomere gene variants were present in 6384 individuals with genetic testing. Ten putative low-penetrance variants were identified in the genes MYBPC3 (N=2), TNNT2 (N=1), TNNI3 (N=2), and MYH7 (N=5) with a combined OR of 12.7 (range 5.8 - 28.4). These variants had a population prevalence of 4.02x10 -5 to 3.5x10 -4 . Family members of low-penetrance variant carriers were less likely to have HCM (35/171, 20%) than those of MYBPC3 R502W carriers (44/113, 39%, p&lt;0.005). Age of diagnosis was older in patients with isolated low-penetrance variants than those with pathogenic variants (42 ± 19 vs 37 ± 18, p=0.005). Composite adverse events were less likely in patients with isolated low-penetrance variants than typical pathogenic sarcomere variants, but the risk was additive with both present (see Figure). Conclusions: A subset of low-penetrance sarcomere gene variants are tolerated in the general population at higher than expected proportions for HCM and may exert an additive pathogenic effect. These findings support an oligogenic risk model of HCM.

Metabolic changes in hypertrophic cardiomyopathies: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.

Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy.

Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study.

Cardiac Selective Modulator of Human Myosin for the Treatment of Genetic Hypertrophic Cardiomyopathy

Genetic hypertrophic cardiomyopathy (HCM) results from mutations in the cardiac sarcomere, including β-cardiac myosin, with HCM afflicting about 1 out of every 500 people in the United States. HCM is characterized by hyper-contractility and myocyte hypertrophy. Current agents used to treat HCM include β-blockers and Ca2+ channel blockers to decrease the hyper-contractility and improve cardiac relaxation. A novel and more direct approach to decreasing hyper-contractility and improving diastolic relaxation in HCM patients is by modulating β-cardiac myosin to produce less force. We believe modulation at the sarcomere level provides a focused strategy while lowering the potential for adverse drug events. In this study we examined the effects of MY461, a cardiac myosin selective inhibitor, on adult rat cardiomyocytes to fully understand the mechanism of action on excitation-contraction (E-C) coupling. Cellular contractility was assessed using edge detection and the calcium transient was measured using fura-2 loaded myocytes. MY461 decreased contractility in a dose dependent manner with an IC50 of 250nM without altering the calcium transient. This inhibitory effect can be reversed by stimulation of the β-adrenergic pathway with the known agonist isoproterenol. We hypothesize that modulation of mutant β-cardiac myosin activity with a small molecule agent such as MY461 could potentially treat disorders resulting from hyper-contractility such as HCM.

The Role of MEKK1 in Hypertrophic Cardiomyopathy

MEKK1 is a ubiquitously expressed mitogen activated protein kinase that is involved in tissue remodeling in a variety of settings including carotid artery blood flow cessation, wound healing, and breast adenocarcinoma intravasation. Here, we have tested the function of MEKK1 in genetic hypertrophic cardiomyopathy (HCM). MEKK1 was genetically deleted in C57Bl6/J mice expressing a mutant alpha-myosin heavy chain (HCM-MEKK1(-/-)). The absence of MEKK1 in HCM resulted in a more pronounced hypertrophy when compared to HCM mice with the MEKK1 gene intact without further increases in atrial natriuretic factor and beta-myosin heavy chain (MyHC) expression and fibrosis. Since MEKK1 is required for the induction of several tissue proteases, we tested the hypothesis that cardiac enlargement of HCM- MEKK1(-/-) mice was due to altered expression of urokinase-type plasminogen activator (uPA), JunB, matrix-metalloproteinase (MMP), and tissue inhibitors of MMPs (TIMPs). Because of its role in preventing apoptosis, we also tested the loss of MEKK1 on apoptotic mediators Bcl-2, cytochrome C, caspase-9, and caspase-3. uPA expression was decreased while JunB, MMP-9, caspase-9, and caspase-3 activities were elevated in HCM- MEKK1(-/-) hearts when compared to MEKK1(-/-), wild-type (WT), and HCM mice. Bcl-2 and Cyt C expression was elevated only in HCM mice. We conclude that the absence of MEKK1 induces a more pronounced cardiac hypertrophy to HCM through altered expression of proteases implicated in cardiac remodeling and increased apoptosis.

Combined Effects of Low-Dose Spironolactone and Captopril Therapy in a Rat Model of Genetic Hypertrophic Cardiomyopathy

For several years, the severe side effects associated with the use of high doses of the aldosterone antagonist, spironolactone, limited its clinical use. Studies have recently shown efficacy and minimal side effects of low-dose spironolactone combined with standard therapy in the treatment of heart failure and hypertensive patients. The authors evaluated the effects of low-dose spironolactone alone or in combination with angiotensin-converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy. The congenic SS-16/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high-salt diet. SS-16/Mcwi and SS/Mcwi rats were fed a low-salt (0.4% NaCl) diet and were treated with vehicle (CON), spironolactone (20 mg/kg/d subcutaneously), captopril (100 mg/kg/d drinking water), or both spironolactone and captopril for 4 weeks. Blood pressure, plasma peptides, cardiac fibrosis, and echocardiography measurements were evaluated. Spironolactone at a low dose had no effect on blood pressure, cardiac hypertrophy, and fibrosis in either strain. However, in combination with captopril, spironolactone decreased the cardiac hypertrophy more than captopril treatment alone. In the SS-16/Mcwi rats, the combined therapy significantly preserved the cardiac index when compared with control. These data indicate that the addition of low-dose spironolactone to captopril treatment was more effective in preventing the progression of heart hypertrophy and ventricular dysfunction in the SS-16/Mcwi than captopril alone. This study suggests that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy.

Left Ventricular Outflow Obstruction

Left ventricular outflow tract obstructions (LVOTOs) encompass a series of stenotic lesions starting in the anatomic left ventricular outflow tract (LVOT) and stretching to the descending portion of the aortic arch (Figure 1). Obstruction may be subvalvar, valvar, or supravalvar. These obstructions to forward flow may present alone or in concert, as in the frequent association of a bicuspid aortic valve with coarctation of the aorta. All of these lesions impose increased afterload on the left ventricle and, if severe and untreated, result in hypertrophy and eventual dilatation and failure of the left ventricle. LVOTOs are congenital in the vast majority of individuals younger than 50 years in the United States; some variants of subaortic obstruction are the exception. It is imperative to consider all patients with LVOTO at a high risk for developing infective endocarditis, and one should always institute appropriate measures for prophylaxis. The present article is intended as a contemporary review of the causes, manifestations, treatments, and outcomes of LVOTO; it will not address LVOTO in the pediatric population or genetic hypertrophic cardiomyopathy but will focus strictly on congenital malformations in the adult. Figure 1. Artist’s rendering of the LVOTO lesions in sequence as viewed from a superolateral orientation. A, Gradient echo cardiac MR image as viewed from the frontal projection demonstrating flow acceleration at a site of supravalvar aortic stenosis (white arrow) in a patient with Williams syndrome. The black arrow identifies the level of the unrestricted aortic valve. B, Classic radiological signs of coarctation of the aorta: rib notching (white arrows) as seen on a posteroanterior chest x-ray in a patient with coarctation of the aorta. The rib notching is caused by erosion of the inferior rib margins by dilated pulsatile posterior intercostals collateral arteries. The black arrow points to the Figure 3 silhouette that …

Combined Effects of Low‐Dose Spironolactone and Captopril Therapy in a Rat Model of Genetic Hypertrophic Cardiomyopathy

The aim of this study was to evaluate the effects of low dose aldosterone antagonist alone or in combination with angiotensin converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy. Congenic SS-16BN/Mcwi rats were produced by transfer of chromosome 16 from the BN rat into the salt-sensitive hypertensive (SS/Mcwi) genetic background. The SS-16BN/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high salt diet. SS-16BN/Mcwi and SS/Mcwi rats were fed a low salt (0.4% NaCl) diet and treated with either vehicle (CON), spironolactone (20mg/kg per d s.c), captopril (100 mg/kg per d drinking water), or both for four weeks. Echocardiography was performed weekly. Plasma peptide measurements, blood pressure, cardiac fibrosis and heart weight were evaluated at the end of the experimental period. Spironolactone at a low dose had no affect on blood pressure, cardiac fibrosis, heart/body weight ratio and left ventricular wall thickness in either strain. Spironolactone in combination with captopril, decreased the cardiac hypertrophy more than captopril alone. In the SS-16BN/Mcwi rats the combined therapy significantly preserved the cardiac index when compared to control. The study suggests that the addition of low-dose spironolactone to ACE inhibitor treatment prevents the progression of heart hypertrophy independently of blood pressure effects and that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy (Support NIH HL29587, U01 HL66579).