Telomere shortening is a hallmark of genetic cardiomyopathies

Area of Science:

• Cardiovascular Biology
• Cellular Aging
• Genetics

Background:

• Telomeres protect chromosome ends and shorten with cell division, typically indicating aging.
• Cardiomyocytes (CMs) in healthy individuals usually maintain stable telomere length.
• Genetic mutations in cardiac contractile proteins are linked to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).

Purpose of the Study:

• To investigate telomere length in cardiomyocytes from patients with genetic HCM and DCM.
• To determine if telomere shortening is a characteristic feature of these cardiomyopathies.
• To establish a human-induced pluripotent stem cell (hiPSC) model for studying telomere dynamics in HCM and DCM.

Main Methods:

• Quantitative Fluorescence In Situ Hybridization (Q-FISH) was used to measure telomere length in single cardiomyocytes from patient tissues and hiPSC-derived CMs.
• Comparison of telomere length in cardiomyocytes versus vascular smooth muscle cells from the same patients.
• Telomere length assessment in hiPSC-derived cardiomyocytes from HCM and DCM patients.

Main Results:

• Cardiomyocytes from individuals with end-stage HCM and DCM showed significantly shortened telomeres compared to healthy controls (26% reduction in HCM, 40% in DCM).
• Telomere shortening was specific to cardiomyocytes and not observed in vascular smooth muscle cells from the same patients.
• Telomere shortening was successfully recapitulated in hiPSC-derived cardiomyocytes from HCM and DCM patients.

Conclusions:

• Significantly shortened telomeres are a hallmark of genetic HCM and DCM, linked to mutations in cardiac contractile proteins.
• Telomere shortening in these cardiomyopathies can be modeled using patient-derived hiPSCs, providing a platform for drug discovery.
• This study highlights a novel cellular aging aspect in genetic cardiomyopathies.