Abstract Body: Introduction
Arrhythmogenic cardiomyopathy (ACM) is a leading cause of sudden cardiac death in children, and exercise worsens effects of mutations in the desmosomal protein Plakophilin-2 (PKP2). Noninvasive cardiac radiotherapy has shown to reduce premature ventricular contractions (PVCs) and ventricular tachycardia in ischemic and nonischemic cardiomyopathy patients. However, efficacy has not been tested in the setting of a genetic cardiomyopathy.
Hypothesis
We hypothesized that whole-heart 25 Gray radiation would reduce PVCs, rescue cardiac function, and improve survival in a murine genetic PKP2 cardiomyopathy model.
Aims
We investigated whether exercise exacerbates pathogenesis in a PKP2 mutant mouse model, and whether whole-heart irradiation can prevent disease progression.
Methods
Homozygous mice carrying a prevalent PKP2 human RNA splice-site mutation received 25 Gray radiation at 4 weeks, followed by serial electrocardiograms. Heterozygous mutants and wild-type controls underwent a 5-week treadmill exercise regimen. PVC inducibility was assessed using caffeine/epinephrine injection pre- and post-exercise. Exercised cohorts received sham or 25 Gray, followed by measures of PVC inducibility and echocardiography at 2 and 6 weeks after irradiation. Conduction velocity was evaluated by optical mapping at the 6-week timepoint.
Results
Radiation did not prolong survival or reduce PVCs in PKP2 homozygous mutants (n=10).
In heterozygotes, the number of inducible mice significantly increased from 7/21 (33%) pre-exercise to 18/21 (86%) post-exercise, while wild-type mice remained non-inducible (0/8). Exercise reduced end systolic and diastolic volumes without altering ejection fraction.
Unexpectedly, we observed no reduction in PVC inducibility and increased mortality in exercised irradiated heterozygotes (8/13 deaths vs. 0/6 sham; p=0.0181) between 2 and 6 weeks after radiation, without a reduction in cardiac function. In contrast to conduction increases observed in wild type mice, the slowed conduction velocity in exercised heterozygotes did not significantly improve after irradiation (sham n=6; irradiated n=5). The lack of cardiac findings suggests additional mechanisms involving non-cardiac tissues may contribute to the synergistic lethality.
Conclusions
Intense exercise exacerbates ACM progression in PKP2 heterozygous mice and mortality when combined with radiation. These findings may caution against extending radiotherapy to ACM, a stress-modified genetic disease.