BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status.

M Jansen,D Dooijes,S N Van Der Crabben,J D H Jongbloed,Y M Hoedemaekers,F W Asselbergs,R H Lekanne Deprez,A F Baas,A A M Wilde,J P Van Tintelen,M Michels,R Huurman,J J M Jans,L G Boven,R A De Boer,I Christiaans,J Van Der Velden

doi:10.1007/s12471-021-01539-w

Abstract

BackgroundHypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited.AimTo create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression.MethodsIn the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death).ResultsSo far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects.ConclusionBIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.Supplementary InformationThe online version of this article (10.1007/s12471-021-01539-w) contains supplementary material, which is available to authorized users.

Highlights

Hypertrophic cardiomyopathy (HCM) is characterised by hypertrophy of the ventricular wall not explained by abnormal loading conditions [1]
HCM is an important cause of sudden cardiac death (SCD) [2] and may lead to end-stage heart failure and left ventricular outflow tract (LVOT) obstruction [3]
HCM is typically inherited as an autosomal dominant disease and a likely pathogenic/pathogenic variant is found in approximately 50% of patients [6, 7]

Summary

Introduction

Hypertrophic cardiomyopathy (HCM) is characterised by hypertrophy of the ventricular wall not explained by abnormal loading conditions [1]. HCM is an important cause of sudden cardiac death (SCD) [2] and may lead to end-stage heart failure and left ventricular outflow tract (LVOT) obstruction [3]. Despite the association with life-threatening arrhythmia and end-stage heart failure, clinical severity in HCM is highly variable, with low overall mortality [8] and incomplete, age-dependent penetrance in carriers of pathogenic variants (G+) [9]. This highlights the need for risk stratification. Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. Results So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been

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