Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin.

We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single-ATP turnover kinetics. A two-headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.

A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice.

Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

Intrauterine Treatment of a Fetus with Familial Hypertrophic Cardiomyopathy Secondary to MYH7 Mutation.

There is no clear consensus on optimal management of fetuses affected by familial hypertrophic cardiomyopathy (HCM). Intrauterine treatment of the condition has not been attempted in any standardized fashion. We report the case of a fetus treated by maternal propranolol during the third trimester after septal hypertrophy and diastolic dysfunction was diagnosed on fetal echocardiogram. The pregnancy went successfully to term, and fetal septal hypertrophy was noted to improve prior to delivery.

Effects of lifestyle changes and high-dose ß-blocker therapy on exercise capacity in children, adolescents, and young adults with hypertrophic cardiomyopathy.

AIM: The use of ß-blocker therapy in asymptomatic patients with hypertrophic cardiomyopathy is controversial. This study evaluates the effect of lifestyle changes and high-dose ß-blocker therapy on their exercise capacity. METHODS AND RESULTS: A total of 29 consecutive newly diagnosed asymptomatic patients with familial hypertrophic cardiomyopathy, median age 15 years (range 7-25), were recruited. In all, 16 patients with risk factors for sudden death were treated with propranolol if no contraindications, or equivalent doses of metoprolol; 13 with no risk factors were randomised to metoprolol or no active treatment. Thus, there were three treatment groups, non-selective ß-blockade (n=10, propranolol 4.0-11.6 mg/kg/day), selective ß-blockade (n=9, metoprolol 2.7-5.9 mg/kg/day), and randomised controls (n=10). All were given recommendations for lifestyle modifications, and reduced energetic exercise significantly (p=0.002). Before study entry, and after 1 year, all underwent bicycle exercise tests with a ramp protocol. There were no differences in exercise capacity between the groups at entry, or follow-up, when median exercise capacity in the groups were virtually identical (2.4, 2.3, and 2.3 watt/kg and 55, 55, and 55 watt/(height in metre) 2 in control, selective, and non-selective groups, respectively. Maximum heart rate decreased in the selective (-29%, p=0.04) and non-selective (-24%, p=0.002) groups. No patient developed a pathological blood-pressure response to exercise because of ß-blocker therapy. Boys were more frequently risk-factor positive than girls (75% versus 33%, p=0.048) and had higher physical activity scores than girls at study-entry (p=0.011). CONCLUSIONS: Neither selective nor non-selective ß-blockade causes significant reductions in exercise capacity in patients with hypertrophic cardiomyopathy above that induced by lifestyle changes.

Advances in medical treatment of hypertrophic cardiomyopathy.

We reviewed the natural history of patients with hypertrophic cardiomyopathy (HCM). The effect of medical treatments on natural history, left ventricular (LV) functions and LV remodeling was also evaluated. Sudden cardiac death and end-stage heart failure are the most serious complications of HCM. Age <30 years and a family history of sudden premature death are risk factors for sudden cardiac death in HCM patients. End-stage heart failure is not a specific additional phenomenon observed in patients with HCM, but is the natural course of the disease in most of those patients. After the occurrence of heart failure, the progression to cardiac death is very rapid. Young age at diagnosis, a family history of HCM, and greater wall thickness are associated with a greater likelihood of developing end-stage heart failure. Neither beta-blockers nor calcium antagonists can prevent this transition. The class Ia antiarrhythmic drugs, disopyramide and cibenzoline are useful for the reduction of LV pressure gradient. Unlike disopyramide, cibenzoline has little anticholinergic activity; therefore, this drug can be easily adapted to long-term use. In addition to the reduction in LV pressure gradient, cibenzoline can improve LV diastolic dysfunction, and induce regression of LV hypertrophy in patients with HCM. A decrease in intracellular Ca(2+) concentration through the activation of the Na(+)/Ca(2+) exchanger associated with cibenzoline therapy is likely to be closely related with the improvement in HCM-related disorders. It is possible that cibenzoline can prevent the progression from typical HCM to end-stage heart failure.

Human-induced pluripotent stem cell models of inherited cardiomyopathies.

PURPOSE OF REVIEW: This article provides an overview of the latest advances in in-vitro modeling of inherited cardiomyopathies using human-induced pluripotent stem cells (iPSCs). RECENT FINDINGS: Inherited cardiomyopathies have been recently modeled by generating iPSCs from patients harboring mutations in genes associated with the pathogenesis of hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. SUMMARY: Patient-specific iPSCs and their differentiated cardiomyocytes (induced pluripotent stem cell-derived cardiomyocytes) now provide a novel model to study the underlying molecular mechanism of the pathogenesis of familial cardiomyopathies as well as for in-vitro drug screening and drug discovery.

Pharmacological treatment options for hypertrophic cardiomyopathy: high time for evidence.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, affecting over one million individuals in Europe. Hypertrophic cardiomyopathy patients often require pharmacological intervention for control of symptoms, dynamic left ventricular outflow obstruction, supraventricular and ventricular arrhythmias, and microvascular ischaemia. Current treatment strategies in HCM are predicated on the empirical use of long-standing drugs, such as beta-adrenergic and calcium blockers, although with little evidence supporting their clinical benefit in this disease. In the six decades since the original description of the disease, <50 pharmacological studies enrolling little over 2000 HCM patients have been performed, the majority of which were small, non-randomized cohorts. As our understanding of the genetic basis and pathophysiology of HCM improves, the availability of transgenic and preclinical models uncovers clues to novel and promising treatment modalities. Furthermore, the number of patients identified and followed at international referral centres has grown steadily over the decades. As a result, the opportunity now exists to implement adequately designed pharmacological trials in HCM, using established as well as novel drug therapies, to potentially intervene on the complex pathophysiology of the disease and alter its natural course. Therefore, it is timely to review the available evidence for pharmacological therapy of HCM patients, highlight the most relevant gaps in knowledge, and address some of the most promising areas for future pharmacological research, in an effort to move HCM into the era of evidence-based management.

Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N.

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e., α-Tm D175N TG, or Tm175). For acute effects, intravenously injected NIC increased heart rate, left ventricular (LV) pressure, and the maximal rate of LV pressure increase (+dP/dt) in non-TG (NTG) and Tm175 mice; however, Tm175 showed a significantly smaller increase in the maximal rate of LV pressure decrease (-dP/dt) compared with NTGs. Western blots revealed phosphorylation of phospholamban Ser16 and Thr17 residue increased in NTG mice following NIC injection but not in Tm175 mice. In contrast, phosphorylation of troponin I at serine residues 23 and 24 increased equally in both NTG and Tm175. Thus the attenuated increase in relaxation in Tm175 mice following acute NIC appears to result primarily from attenuated phospholamban phosphorylation. Chronic NIC administration (equivalent to smoking 2 packs of cigarettes/day for 4 mo) also increased +dP/dt in NTG and Tm175 mice compared with chronic saline. However, chronic NIC had little effect on heart rate, LV pressure, -dP/dt, LV wall and chamber dimensions, or collagen content for either group of mice.

Negative ionotropic agents for the treatment of left ventricular outflow tract obstruction due to sigmoid septum and concentric left ventricular hypertrophy.

BACKGROUND: Negative ionotropic agents are established treatments for left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM). However, their benefit in those with LVOTO without typical HCM is unclear. We evaluated if negative ionotropic agents are beneficial in treatment of LVOTO in patients without typical HCM. METHOD: In this retrospective cohort study, we evaluated echocardiograms and reviewed records of 15 patients with resting LVOT obstruction due to sigmoid septum (SS, n=9) and mild concentric left ventricular hypertrophy (LVH, n=6). Patients received treatment with sequential negative ionotropic agents (ß-blockers and disopyramide). Initial symptoms, presentation characteristics and echocardiographic characteristics pre and post treatment were evaluated. RESULTS: Fifteen patients (mean age 66.2 years, 46.7% male) were included. Dyspnoea (NYHA Class II/III) was reported as the initial symptom in all patients with four patients reporting chest pain. All patients had hypercontractile LV function at baseline (fractional shortening 46.29±8.77%) but had normal LVS/PW ratio (1.03±0.10). The mean resting LVOT gradient was 74.4±55.2 mmHg. Fourteen patients received initial ß-blocker therapy with a mean reduction in peak LVOT gradient of 40.9 mmHg seen in 11 patients that responded to therapy (p=0.02). Nine patients received disopyramide with a further 24.2±25.8 mmHg reduction in peak LVOT gradient observed in eight patients who tolerated treatment (p=0.04). Symptomatic improvement occurred in 80% of treated patients. CONCLUSIONS: In patients with LVOTO without typical HCM, sequential treatment with negative ionotropes is associated with a significant reduction in the degree of LVOTO and leads to symptomatic improvement.

Rescue of familial cardiomyopathies by modifications at the level of sarcomere and Ca2+ fluxes.

Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that frequently show inappropriate ventricular hypertrophy or dilation. Current data suggest that numerous mutations in several genes can cause cardiomyopathies, and the severity of their phenotypes is also influenced by modifier genes. Two major types of inherited cardiomyopathies include familial hypertrophic cardiomyopathy (FHC) and dilated cardiomyopathy (DCM). FHC typically involves increased myofilament Ca(2+) sensitivity associated with diastolic dysfunction, whereas DCM often results in decreased myofilament Ca(2+) sensitivity and systolic dysfunction. Besides alterations in myofilament Ca(2+) sensitivity, alterations in the levels of Ca(2+)-handling proteins have also been described in both diseases. Recent work in animal models has attempted to rescue FHC and DCM via modifications at the myofilament level, altering Ca(2+) homeostasis by targeting Ca(2+)-handling proteins, such as the sarcoplasmic reticulum ATPase and phospholamban, or by interfering with the products of different modifiers genes. Although attempts to rescue cardiomyopathies in animal models have shown great promise, further studies are needed to validate these strategies in order to provide more effective and specific treatments.

Medical management of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetically transmitted cardiomyopathy. The underlying cause of HCM has been attributed to a number of mutations within genes encoding primarily for sarcomeric proteins, which lead to a heterogeneous phenotype of left ventricular hypertrophy in the absence of other causes (eg, hypertension, aortic stenosis, or a discrete membranous subaortic stenosis). Symptoms may range from mild to severely limiting and consist of dyspnea and chest pain with exertion or at rest, syncope, or even sudden cardiac death (SCD). The majority of patients with HCM are treated medically. The primary aim of therapy is to reduce symptoms, but it should also address the risk of SCD. Throughout the years, numerous medical treatments have been used to achieve symptom control in these patients, and include medications such as ß-blockers, calcium channel blockers, amiodarone, disopyramide, and angiotensin receptor blockers. This review provides an overview of the current medical treatment of HCM.

Myopathy, apical hypertrophic cardiomyopathy and left ventricular noncompaction within the same family.

OBJECTIVE: Familial occurrence of left ventricular hypertrabeculation/noncompaction (LVHT) comprises a wide spectrum. Detection of asymptomatic LVHT is a challenge, since the assumed poor prognosis of LVHT may induce anxiety and over-reaction. The different echocardiographic diagnostic criteria render the situation still more difficult. METHODS AND RESULTS: Among 3 brothers, the 24-year-old index patient suffered from heart failure. He fulfilled both echocardiographic criteria for LVHT. The 35-year-old brother suffered from palpitations and showed echocardiographically an apical-type hypertrophic cardiomyopathy. The 17-year-old asymptomatic brother showed LVHT fulfilling only one echocardiographic criterion. Two brothers suffered from muscle weakness since childhood, the third was investigated neurologically and showed weakness of the lower limbs. Most likely, the 3 brothers suffered from the same neuromuscular disorder. CONCLUSION: Apical-type hypertrophic cardiomyopathy may occur together with LVHT in the same family and may represent an abortive form of LVHT. Neuromuscular disorders are associated with familial LVHT, thus representing cardiac involvement of the underlying neurological disease.

Effect of spironolactone on diastolic function and left ventricular mass in Maine Coon cats with familial hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis occurs in cats with hypertrophic cardiomyopathy (HCM), and is one factor that leads to diastolic dysfunction. Spironolactone (SPIR) reduces myocardial fibrosis in several models of HCM and in humans with cardiac disease. HYPOTHESIS: SPIR will improve diastolic function and reduce left ventricular (LV) mass in Maine Coon cats with HCM. METHODS: Maine Coon cats with familial HCM were included if there was concentric hypertrophy (> or =6 mm end diastolic wall thickness) and decreased early lateral mitral annular velocity (Em) or summated early and late mitral annular velocity (EAsum) measured by pulsed wave tissue Doppler imaging echocardiography. Cats were paired by Em-EAsum and randomized to receive 2 mg/kg SPIR (n = 13) or placebo (n = 13) PO q12 h for 4 months. Em-EAsum, systolic velocity, LV mass, and the ratio of left atrial to aortic diameter were measured at baseline, 2 months, and 4 months. Statistical analysis included 2-way repeated measures analysis of variance and the Student's t-test. RESULTS: Plasma aldosterone concentration increased in cats treated with SPIR (235 ng/mL, baseline; 935 ng/mL, 2 months; 1,077 ng/mL, 4 months; P < .001 at 2 and 4 months). No significant treatment effect was identified for early or early-late summated diastolic mitral annular velocity or any other variable except plasma aldosterone concentration. Severe facial ulcerative dermatitis developed in 4 of 13 cats treated with SPIR, requiring discontinuation of the drug. CONCLUSION: SPIR did not improve Em or EAsum of the lateral mitral annulus or alter LV mass over 4 months. One third of cats treated with SPIR developed severe ulcerative facial dermatitis.

The effect of ramipril on left ventricular mass, myocardial fibrosis, diastolic function, and plasma neurohormones in Maine Coon cats with familial hypertrophic cardiomyopathy without heart failure.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common heart disease of cats, resulting in left ventricular (LV) hypertrophy, myocardial fibrosis, and diastolic dysfunction. HYPOTHESIS: Ramipril will reduce LV mass, improve diastolic function, and reduce myocardial fibrosis in cats with HCM without congestive heart failure (CHF). ANIMALS: This prospective, blinded, placebo-controlled study included 26 Maine Coon and Maine Coon cross-bred cats with familial HCM but without CHF. METHODS: Cats were matched for LV mass index (LVMI) and were randomized to receive ramipril (0.5 mg/kg) or placebo q24h for 1 year, with investigators blinded. Plasma brain natriuretic peptide (BNP) concentration, plasma aldosterone concentration, Doppler tissue imaging (DTI), and systolic blood pressure were measured at baseline and every 3 months for 1 year. Cardiac magnetic resonance imaging (cMRI) was performed to quantify LV mass and myocardial fibrosis by delayed enhancement (DE) cMRI at baseline and 6 and 12 months. Plasma angiotensin-converting enzyme (ACE) activity was measured on 16 cats 1 hour after PO administration. RESULTS: Plasma ACE activity was adequately suppressed (97%) in cats treated with ramipril. LV mass, LVMI, DTI, DE, blood pressure, plasma BNP, and plasma aldosterone were not different in cats treated with ramipril compared with placebo (P = .85, P = .94, P = .91, P = .89, P = .28, P = .18, and P = .25, respectively). CONCLUSION: Treatment of Maine Coon cats with HCM without CHF with ramipril did not change LV mass, improve diastolic function, alter DE, or alter plasma BNP or aldosterone concentrations in a relevant manner.

Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy.

BACKGROUND: The cardiac troponin T I79N mutation, linked to familial hypertrophic cardiomyopathy, carries a high risk of sudden cardiac death even in the absence of significant cardiac hypertrophy. The pathology underlying this mechanism has not yet been identified. AIMS: To study the underlying mechanism of this phenomenon we characterized the left ventricular (LV) performance of transgenic mice carrying the human troponin T mutation I79N under basal and isoproterenol-induced stress conditions. METHODS AND RESULTS: LV function was analyzed by recording pressure-volume loops using a microconductance catheter. Despite a hypercontractile systolic function under basal conditions TnT-I79N mice showed a diastolic dysfunction indicated by an increase in end-diastolic pressure-volume relationship (EDPVR), a load-independent factor of LV stiffness (0.06+/-0.01 vs. 0.02+/-0.01; P<0.05), when compared to mice expressing human wild-type troponin T (TnT-WT). TnT-I79N mutants developed severe diastolic heart failure and cardiac sudden death under isoproterenol stress. This was prevented after pretreatment with the L-type Ca2+ channel inhibitor diltiazem. CONCLUSIONS: Diastolic dysfunction due to increased LV stiffness in TnT-I79N mice leads to severe primary diastolic heart failure and finally to cardiac sudden death, which can be prevented by diltiazem.

Management of pediatric hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: As the underlying genetic basis of hypertrophic cardiomyopathy is being characterized, there has been increasing recognition of the wide spectrum and variable evolution of this disease within the pediatric age range. This review outlines recent evidence relevant to the diagnosis, management, and prognosis of hypertrophic cardiomyopathy specific to children and adolescents. RECENT FINDINGS: Studies of putative causal genes are leading to the discovery of factors affecting the variability of phenotypic expression and possible avenues for new therapies. Nonetheless, the use of genetic testing currently remains for research purposes only. Echocardiography is the primary means for evaluation, with an increasing focus on diastolic performance. Useful prognostic information can be obtained from the safe performance of cardiopulmonary stress testing. Sudden death can occur in children, although the risk factors are likely different than in adults. The role and mechanisms for possible ischemia remain controversial, and likely differ between individuals. Activity restrictions are recommended, with medical therapy reserved for those who are symptomatic. For those with important left ventricular outflow obstruction, surgical myectomy may be indicated, with little current role for alcohol septal ablation. Advances in implantable defibrillators now make this therapy feasible in younger children. SUMMARY: There are important differences from adults in the approach to the diagnosis and management of hypertrophic cardiomyopathy in children and adolescents. Care regarding prognostication and therapy must be taken given the potential life-long implications.

Coexistence of familial hypertrophic cardiomyopathy and vasospastic angina pectoris in two brothers.

Two brothers had familial hypertrophic cardiomyopathy and vasospastic angina pectoris concurrently. Their family history showed that one of their sisters had hypertrophic cardiomyopathy and another brother died suddenly at age 52. The clinical diagnosis of hypertrophic cardiomyopathy was confirmed by an echocardiogram and left ventriculography. They had typical chest pain at rest, and a significant vasospasm of coronary arteries with chest pain and obvious ST-T changes in the electrocardiograms was provoked by intracoronary injection of acetylcholine in both patients. The administration of a calcium antagonist and nitrate was effective for ameliorating chest pain with no cardiovascular events during the follow up period of more than 3 years. Although underlying pathophysiologic abnormalities of familial hypertrophic cardiomyopathy and vasospastic angina pectoris are considered to be transmitted genetically, the genetic backgrounds of these cases remain to be clarified.