Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an inherited disorder whose causal variants involve sarcomeric protein genes. One of these is myosin-binding protein C (MYBPC3), being previously associated with a favourable prognosis. Our objective is to describe the clinical characteristics and events of a molecularly homogeneous HCM cohort associated with truncating MYBPC3 variants.

Methods and results: A cohort of patients and relatives with HCM diagnosis and carrying a truncating MYBPC3 variant were retrospectively recruited. Subjects had an average follow-up of 7.77 years, with an incident HCM phenotype of 10%. They were middle-aged adult patients (47±16.8 years) without significant comorbidities or symptoms. Hypertrophy was discrete with a significative difference between probands and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001). Ejection fraction was predominantly preserved (65%±10%). Despite it being the most common clinical event, relevant heart failure (observed in 8.1% of patients) was infrequent and commonly found in the presence of a second environmental precipitating agent. ESC-HCM risk calculator and modifier factors did not correlate with the risk of major events predicting events, which were low (1.51 per 100 patients/year) and associated with the severity of HCM, abnormal QRS in the ECG and age. Genetic factors and sex were not associated with major events.

Conclusions: This is the first molecularly homogeneous, contemporary cohort, including HCM patients secondary to MYBPC3 truncating variants. Patients showed a good prognosis with a low event rate. In our cohort, major arrhythmic events were not related to measured environmental or genetic factors.

Keywords: Cardiomyopathy, Hypertrophic; Genetic Diseases, Inborn; HEART FAILURE.

Figure 1. ECG (A) and echocardiographic (B) findings in patients with hypertrophic cardiomyopathy due to truncating variants. ASH, asymmetric hypertrophy; CH, concentric hypertrophy; EH, eccentric hypertrophy; EF, ejection fraction; IVCD, interventricular conduction delay; LA, left atrial anteroposterior diameter; LBBB, left bundle branch block; LVH, left ventricular hypertrophy; LVOTO, left ventricular outflow tract obstruction; Nc: non-compacted myocardium; RBBB, right bundle branch block; RVD, right ventricular dysfunction; RVH, right ventricular hypertrophy.

Figure 2. Free major events (A) and death (B) survival curves.