Study Reveals Distinct Differences Between Two Heart Conditions Linked by Genetic Mutations

Recent research has uncovered that two prevalent and potentially fatal heart diseases, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), share a genetic origin while displaying markedly different clinical symptoms. This revelation comes from a study conducted by a team of researchers utilizing engineered heart tissues, with findings published in the Journal of Clinical Investigation.

HCM is characterized by an abnormal thickening of the heart's left ventricular wall, whereas DCM involves a thinning of the same wall. The research team, led by Professor Stuart Campbell, focused on understanding the biological mechanisms differentiating these two conditions, both of which are among the leading causes of sudden cardiac death and heart failure in otherwise healthy young individuals.

By comparing mutations in the same gene, the researchers found that even minor differences in the mutations could lead to vastly different outcomes in heart function. The team engineered human-induced pluripotent stem cell (iPSC) lines to represent the two conditions by modifying specific amino acids in the protein tropomyosin, crucial for muscle contraction.

For the DCM model, they altered the 54th amino acid, while for HCM, they modified the 62nd amino acid. This allowed the team to create engineered heart tissues to observe and measure their contractile properties.

Analysis revealed that the mutation linked to HCM resulted in hypercontractility, where the heart tissue contracted excessively. In contrast, the mutation associated with DCM led to hypocontractility, indicating inadequate contraction strength. The researchers employed computational models to substantiate their findings, confirming that the differences in mutations led to these distinct phenotypes.

The study also explored potential therapeutic interventions for these conditions. The researchers administered mavacamten, a drug designed to reduce muscular activity, to samples of heart tissue affected by HCM, which successfully normalized contraction levels. Conversely, they treated DCM-affected tissues with danicamtiv, a drug that enhances contractile force, resulting in a restoration of normal tissue strength.

The implications of this study are significant, as they pave the way for improved treatment strategies tailored to the specific mechanisms driving these genetic heart diseases. The researchers emphasized the importance of their findings in elucidating how variations in gene mutations can lead to diverse cardiac afflictions.