Background: Environmental stress, such as exercise, increases risk of sudden death and arrhythmias in patients with arrhythmogenic cardiomyopathy (ACM). Moreover, ACM patients with a defibrillator experience elevated levels of anxiety. It remains to be determined if psychosocial stress (PS) contributes to cardiac function and/or mortality in ACM subjects, and whether PS alters cardiac-neural BDNF/TrkB signaling, a pathway that regulates myocardial function.
Objective: Determine if PS contributes to cardiac dysfunction and sudden death in a mouse model of ACM harboring a loss-of-function mutation in desmoglein-2 (Dsg2).
Methods: Wild-type (WT) and homozygous Dsg2 mutant (Dsg2^mut/mut) mice were subjected to a PS paradigm (Resident-Intruder; aggressive CD1 vs WT/Dsg2^mut/mut mice, respectively) for 14 days. Light-dark box test and echocardiographic and ECG analyses were performed prior to and 14 days post-PS. Circulating corticosterone and myocardial BDNF/TrkB expression were measured via ELISA and western blot, respectively.
Results: Ten minutes of resident-intruder interactions increased mean heart rate and decreased heart rate variability, both in time and frequency domain parameters (SDRR, RMSSD and vagal activity). Moreover, PS dramatically increased anxiety-like behavior, assessed via light-dark box transitions, as well as cardiac dysfunction (reduced % ejection fraction and % fractional shortening) in Dsg2^mut/mut mice compared to WT controls. Stressed Dsg2^mut/mut mice showed elevated corticosterone levels and decreased cardiac BDNF/TrkB levels compared to stressed WT mice. Of note, 14 days of PS increased mortality rate in Dsg2^mut/mut mice by 40% compared to WT controls. Furthermore, 29 ACM patients were evaluated using standardized perceived stress scale (PSS) exams. ACM patients (PSS = 19.4) showed significantly higher levels of PS compared to the general population (PSS = 13.1, P<0.001).
Conclusion: Psychosocial distress triggers anxiety-like behavior, worsens cardiac function, and increases mortality in ACM mice. Considering ACM patients display elevated PSS scores, interventions to prevent PS should be monitored in ACM patients to avoid progression of cardiac dysfunction and potentially reduce occurrence of sudden death.