When Exercise Is Unhealthy: Study Sheds New Light on Sudden Cardiac Death

The findings may inform development of early diagnostics, drug treatments, and personalized exercise programs.

AVC is the most common heart condition that causes sudden cardiac death during intense exercise. Using various analyses of cardiac function and morphology, a team led by Jeffrey A. Towbin, MD, of the University of Tennessee Health Science Center (Memphis, TN, USA), in collaboration with researchers from Cincinnati Children’s Hospital Medical Center (Cincinnati, OH, USA) and others has found that in mice with a known mutated version of desmoplakin, a protein that helps maintain the structure of the heart wall, exercise made the heart walls come apart sooner, leading to earlier development of AVC.

Heart wall cells are stacked in interlocking layers attached to each other by desmosomes that dot the surface of the cells. Exercise can overstretch the heart wall, but these intercellular links keep the cells from disconnecting from each other and prevent the heart wall from coming apart. Desmosomes are made up of several proteins, including desmoplakin. Defects can weaken the cell-cell links, as in AVC, such that the cells do not withstand the extra stretch from exercise and so detach from each other. Scar tissue fills the gaps between the disconnected cells, further reducing the wall’s ability to withstand increased workload as in exercise.

Several studies observed that mice with a mutated form of desmoplakin developed the same heart problems seen in patients with AVC. In this new study, in addition to finding that endurance exercise led to earlier onset of AVC symptoms in the mice with the mutated desmoplakin, the researchers also discovered that the desmosomes started coming apart before changes in heart function were detected and that exercise perturbed AKT1 and GSK3-β signaling in the Wnt-β-catenin pathway, which promotes growth of new cells and prevents deposition of fat, offering an explanation for the accelerated development of AVC.

The study suggests that changes in the cell-cell links can be detected before alterations in heart function occur. This could help identify individuals with the mutation before they develop AVC symptoms, said Dr. Towbin, opening the possibility of better strategies to prevent exercise-induced complications and of developing drugs targeting the Wnt-β-catenin pathway to potentially help AVC patients.

The study, by Martherus R et al., was published online ahead of print November 6, 2015, in the American Journal of Physiology — Heart & Circulatory Physiology.

Related Links:
University of Tennessee Health Science Center
Cincinnati Children’s Hospital Medical Center