Novel Frontiers in Sarcomeric Cardiomyopathies: Biomarkers, Early Detection and Prognosis

This thesis describes new insights in sarcomeric cardiomyopathies, focusing on biomarkers, early detection and prognosis. The sarcomere constitutes the basic contractile unit of cardiomyocytes. Variants in genes that encode sarcomeric proteins can cause cardiomyopathies. Cardiomyopathies may lead to heart failure or cardiac arrhythmia. However, severity is highly variable and penetrance among carriers of pathogenic genetic variants is incomplete. These aspects remain poorly understood, and our ability to predict the disease course of individual patients remains limited.

Part I of this thesis assesses circulating biomarkers in patients with sarcomeric variants that cause hypertrophic cardiomyopathy (HCM). A systematic review and meta-analysis was performed to provide an overview of and appraise prognostic circulating biomarkers reported by previous cohort studies. A cohort of carriers of Dutch founder variants in MYBPC3 was established and blood samples were obtained. Untargeted metabolomics was used in a case-control study to identify potential biomarkers for HCM severity, and associations of acylcarnitines to HCM severity and echocardiographic markers of HCM were evaluated in a cross-sectional study.

Part II evaluated new methods to leverage routinely collected clinical data for early detection of patients with HCM. As sudden cardiac death may be the first clinical manifestation of otherwise asymptomatic individuals with HCM, it is important to detect asymptomatic cases to allow preventative treatment with an implantable defibrillator. To this aim, I helped establish the UNRAVEL research data platform, which integrates data from electronic health records of patients with inheritable cardiac diseases and carriers of pathogenic variants with a biobank. Within UNRAVEL, we used text mining and machine learning to detect subjects with HCM. Additionally, the ethical and legal considerations for different kinds of informed consent and opt-out were assessed for the use of routinely collected clinical data in observational studies on inherited cardiac diseases.

In part III, the prognosis of carriers of variants in specific sarcomeric genes was studied. Penetrance and major cardiomyopathy-related events (MCE) were assessed in a cohort of MYH7 variant carriers. Penetrance and MCE were common before the age of 12 years in variants linked to non-compaction cardiomyopathy and dilated cardiomyopathy. Additionally, patients with a family history of MCE were at increased risk of penetrance before the age of 1 year and MCE before the age of 5 years, and patients with a HCM-causing variant in the converter region were at an increased risk of penetrance. Furthermore, the family tree mortality ratio method was used to study the prognosis of carriers of truncating TTN variants. This method reduces ascertainment bias by including previously unidentified carriers and relatives at 50% risk of carrying the variant from extensive pedigrees. This revealed a relatively mild disease course with excess mortality among individuals aged ≥60 years compared to the general population.

Finally, future perspectives on personalised medicine in sarcomeric cardiomyopathies are discussed, with a focus on improvements that can be made to cohort studies in order to obtain this goal, including potential concerns and biases that should be addressed and the role of data governance.