Medicine: search for molecular patterns

8 Aug 2022

How pathogenic gene mutations lead to heart failure – new findings about mechanisms

Cardiomyopathy is not a uniform disease of the cardiac muscle – rather, genetic defects lead to heart failure in different ways. These are the findings, just published in the journal Science, of an international scientific consortium. The research results are based on the first comprehensive single-cell analysis of cells from healthy and diseased hearts and show that the cellular and molecular mechanisms that lead to heart failure in people with a cardiomyopathy differ according to genetic defect.

Genetic mutations identified

An international team including LMU physician Daniel Reichart, one of the three lead authors of the study, investigated the gene expression of 880,000 individual cells, taken from 61 diseased and 18 healthy hearts. Even collecting the samples was a complex undertaking that required an interdisciplinary team acting worldwide. In their gene analyses, the doctors concentrated first of all on dilated cardiomyopathy (DCM), which is one of the most common causes of heart failure leaving patients in need of a heart transplant. The dilation here is an enlargement of the left ventricle, the main pumping chamber of the heart. In this context, the team identified genetic mutations that lead to cardiomyopathies with disproportionate frequency. Next, the researchers characterized the molecular map of the various mutations of each heart and compared them both with healthy hearts and with hearts for which the causes of dilation and dysfunction were unknown.

Goal: Therapies for heart muscle diseases

As their ultimate goal, the researchers cite the development of individualized (that is, specifically tailored to the patient) therapies for myocardial diseases, as genotype-specific treatment is thought to be more effective and associated with fewer side effects. According to the scientists, the freshly published study will help advance this targeted medicine in the cardiovascular domain. “The heart tissue we studied comes from people in the final stage of this myocardial disease,” says Daniel Reichart. “We’re excited to see what changes we discover in earlier disease stages – with material from endomyocardial biopsies, for instance.”

Daniel Reichart, Eric L. Lindberg, Henrike Maatz et al.: Pathogenic variants damage cell compositions and single cell transcription in cardiomyopathies. Science, 2022.
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