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Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

ABSTRACT: Background: Hypertrophic 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 ?-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.

Methods: As 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.

Results: The 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).

Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

SUBMITTER: Velicki L

PROVIDER: S-EPMC7727200 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

Velicki Lazar L Jakovljevic Djordje G DG Preveden Andrej A Golubovic Miodrag M Bjelobrk Marija M Ilic Aleksandra A Stojsic Snezana S Barlocco Fausto F Tafelmeier Maria M Okwose Nduka N Tesic Milorad M Brennan Paul P Popovic Dejana D Ristic Arsen A MacGowan Guy A GA Filipovic Nenad N Maier Lars S LS Olivotto Iacopo I

BMC cardiovascular disorders 20201209 1

<h4>Background</h4>Hypertrophic 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.<h4>Methods</h4>As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study ...[more]

PMID: 33297970

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Project description:Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and defined by unexplained isolated progressive myocardial hypertrophy, systolic and diastolic ventricular dysfunction, arrhythmias, sudden cardiac death and histopathologic changes, such as myocyte disarray and myocardial fibrosis. Mutations in genes encoding for proteins of the contractile apparatus of the cardiomyocyte, such as ?-myosin heavy chain and myosin binding protein C, have been identified as cause of the disease. Disease is caused by altered biophysical properties of the cardiomyocyte, disturbed calcium handling, and abnormal cellular metabolism. Mutations in sarcomere genes can also activate other signaling pathways via transcriptional activation and can influence non-cardiac cells, such as fibroblasts. Additional environmental, genetic and epigenetic factors result in heterogeneous disease expression. The clinical course of the disease varies greatly with some patients presenting during childhood while others remain asymptomatic until late in life. Patients can present with either heart failure symptoms or the first symptom can be sudden death due to malignant ventricular arrhythmias. The morphological and pathological heterogeneity results in prognosis uncertainty and makes patient management challenging. Current standard therapeutic measures include the prevention of sudden death by prohibition of competitive sport participation and the implantation of cardioverter-defibrillators if indicated, as well as symptomatic heart failure therapies or cardiac transplantation. There exists no causal therapy for this monogenic autosomal-dominant inherited disorder, so that the focus of current management is on early identification of asymptomatic patients at risk through molecular diagnostic and clinical cascade screening of family members, optimal sudden death risk stratification, and timely initiation of preventative therapies to avoid disease progression to the irreversible adverse myocardial remodeling stage. Genetic diagnosis allowing identification of asymptomatic affected patients prior to clinical disease onset, new imaging technologies, and the establishment of international guidelines have optimized treatment and sudden death risk stratification lowering mortality dramatically within the last decade. However, a thorough understanding of underlying disease pathogenesis, regular clinical follow-up, family counseling, and preventative treatment is required to minimize morbidity and mortality of affected patients. This review summarizes current knowledge about molecular genetics and pathogenesis of HCM secondary to mutations in the sarcomere and provides an overview about current evidence and guidelines in clinical patient management. The overview will focus on clinical staging based on disease mechanism allowing timely initiation of preventative measures. An outlook about so far experimental treatments and potential for future therapies will be provided.

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Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

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Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy.

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