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Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a very common inherited cardiovascular disease (CAD) and the incidence is about 1/500 of the common population. It is caused by more than 1,400 mutations in 11 or more genes encoding the proteins of the cardiac sarcomere. HCM presents a heterogeneous clinical profile and complex pathophysiology and HCM is the most important cause of sudden cardiac death (SCD) in young people. HCM also contributes to functional disability from heart failure and stroke (caused by atrial fibrillation). Current treatments for HCM (medication, myectomy, and alcohol septal ablation) are geared toward slowing down the disease progression and symptom relief and implanted cardiac defibrillator (ICD) to prevent SCD. HCM is, however, entering a period of tight translational research that holds promise for the major advances in disease-specific therapy. Main insights into the genetic landscape of HCM have improved our understanding of molecular pathogenesis and pointed the potential targets for the development of therapeutic agents. We reviewed the critical discoveries about the treatments, mechanism of HCM, and their implications for future research.

SUBMITTER: Cheng Z

PROVIDER: S-EPMC8572854 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment.

Cheng Zeyi Z Fang Tingting T Huang Jinglei J Guo Yingqiang Y Alam Mahboob M Qian Hong H

Frontiers in cardiovascular medicine 20211025

Hypertrophic cardiomyopathy (HCM) is a very common inherited cardiovascular disease (CAD) and the incidence is about 1/500 of the common population. It is caused by more than 1,400 mutations in 11 or more genes encoding the proteins of the cardiac sarcomere. HCM presents a heterogeneous clinical profile and complex pathophysiology and HCM is the most important cause of sudden cardiac death (SCD) in young people. HCM also contributes to functional disability from heart failure and stroke (caused ...[more]

PMID: 34760939

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Project description:AimsTo describe the phenotype, genetics, and events associated with the development of hypertrophic cardiomyopathy (HCM) with reduced ventricular function (HCMr). Heart failure in HCM is usually associated with preserved ejection fraction, yet some HCM patients develop impaired systolic function that is associated with worse outcomes.Methods and resultsOur registry included 1328 HCM patients from two centres in Spain and Israel. Patients with normal baseline ventricular function were matched, and a competing-risk analysis was performed to find factors associated with HCMr development. Patient records were reviewed to recognize clinically significant events that occurred closely before the development of HCMr. Genetic data were collected in patients with HCMr. A composite of all-cause mortality or ventricular assist device (VAD)/heart transplantation was assessed according to ventricular function. Median age was 56, and 34% were female patients. HCMr at evaluation was seen in 37 (2.8%) patients, and 46 (3.5%) developed HCMr during median follow up of 9 years. HCMr was associated with younger age of diagnosis, poor functional class, and ventricular arrhythmia. Atrial fibrillation, pacemaker implantation, and baseline left ventricular ejection fraction (LVEF) of ≤55% were significant predictors of future HCMr development, while LV obstruction predicted a lower risk. Genetic testing performed in 53 HCMr patients, identifying one or more pathogenic variant in 38 (72%): most commonly in myosin binding protein C (n = 20). Six of these patients had an additional pathogenic variant in one of the sarcomere genes. Patients with baseline HCMr had a higher risk (hazard ratio 6.4, 4.1-10.1) for the composite outcome and for the individual components. Patients who developed HCMr in the course of the study had similar mortality but a higher rate of VAD/heart transplantation compared with HCM with normal LVEF.ConclusionsHypertrophic cardiomyopathy with reduced ejection fraction is associated with heart failure and poor outcome. Arrhythmia, cardiac surgery, and device implantation were commonly documented prior to HCMr development, suggesting they may be either a trigger or the result of adverse remodelling. Future studies should focus on prediction and prevention of HCMr.

Project description:BackgroundHypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.MethodsAs a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.ResultsThe most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p = 0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p = 0.085). Laboratory analyses revealed normal levels of creatinine (85.5 ± 18.3 vs. 81.3 ± 16.4 µmol/l; p = 0.487) and blood urea nitrogen (10.2 ± 15.6 vs. 6.9 ± 3.9 mmol/l; p = 0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p = 0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p = 0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p = 0.001). The difference in diastolic function, i.e. E/e' ratio between the two groups was also noted (MYBPC3 8.8 ± 3.3, MYH7 13.9 ± 6.9, p = 0.079).ConclusionsMajor findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

Project description:Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na+ current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic [Ca2+] and Ca2+ waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na+ current and reduced intracellular [Na+] and diastolic [Ca2+], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. Owing to the sustained reduction of intracellular Ca2+ and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na+ current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.

Dataset Information

Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment.

Publications

Hypertrophic Cardiomyopathy: From Phenotype and Pathogenesis to Treatment.

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