Genetic factors in sudden cardiac death victims with myocardial fibrosis

Sudden cardiac death accounts for 15–20% of all deaths, and in many cases the underlying heart disease has not been diagnosed beforehand. A common finding in these individuals is myocardial fibrosis – the accumulation of scar-like, connective tissue–resembling material in the heart muscle. Fibrosis can disrupt the heart’s electrical activity, which may lead to dangerous arrhythmias and sudden cardiac death.

This doctoral thesis aimed to identify the genetic factors underlying myocardial fibrosis and sudden cardiac death, and to investigate how these genes affect cellular function.

Genetic analysis was performed on two case groups: in the first sub study, we examined individuals diagnosed with primary myocardial fibrosis, and in the third sub study, individuals who had both myocardial fibrosis and cardiac hypertrophy, which is enlargement of the heart.

The study identified 57 candidate genes, many of which are involved in regulating the function of heart muscle cells or extracellular matrix formation. RNA sequencing of heart tissue showed that primary myocardial fibrosis is associated with changes in gene expression related to actin cytoskeleton organization and muscle tissue development. Expression of the UNC45A gene was increased in fibrotic hearts, and silencing this gene in a cell model reduced key events in the development of fibrosis: fibroblast proliferation and collagen production. Cell experiments also showed that silencing the OMA1 gene in cardiac fibroblasts increased cell growth and collagen production.

In summary, this research identifies new genetic factors underlying myocardial fibrosis and provides new insight into how these genes may contribute to harmful structural changes in the heart. In the future, these findings may support earlier diagnostics, improved risk assessment, and potentially new preventive strategies for individuals at increased risk of sudden cardiac death, as well as for their family members.