Strength of patient cohorts and biobanks for cardiomyopathy research

Abstract

In 2011 the Netherlands Heart Foundation allocated funding (CVON, Cardiovasculair Onderzoek Nederland) to stimulate collaboration between clinical and preclinical researchers on specific areas of research. One of those areas involves genetic heart diseases, which are frequently caused by pathogenic variants in genes that encode sarcomere proteins. In 2014, the DOSIS (Determinants of susceptibility in inherited cardiomyopathy: towards novel therapeutic approaches) consortium was initiated, focusing their research on secondary disease hits involved in the onset and progression of cardiomyopathies. Here we highlight several recent observations from our consortium and collaborators which may ultimately be relevant for clinical practice.

Keywords: Cardiomyopathies; Gene variants; Patient cohorts.

Fig. 1

Activation of a cardiomyocyte triggers calcium entry and release of calcium from the sarcomplasmic reticulum (SR), which results in contraction of the cardiac myofibrils. To relax the cardiomyocyte, calcium is pumped back into the SR, and out of the cell via the sodium-calcium exchanger (NCX). Myofibrils consist of sarcomeres composed of the thin actin and thick myosin filament, and the third filament titin. Sarcomeres consist of sub-regions (depicted by the different bands), which underlie the striated pattern of cardiac muscle. Gene variants that cause cardiomyopathies are frequently found in myosin heavy chain, troponin T, cardiac myosin-binding protein‑C (located in the Z‑zone) and titin. (Figure is adapted from Sequeira at al. [34])

Fig. 2

Disease modifiers in inherited cardiomyopathies (PQC protein quality control)

Fig. 3

By combining cellular, genetic and clinical data from well-phenotyped national patient cohorts, DOSIS strives to define disease factors that in addition to the pathogenic gene variant cause and aggravate cardiac disease in cardiomyopathy patients