Key result
Psychosocial stress causes ~30% mortality in arrhythmogenic cardiomyopathy mice vs wildtype.
Why the study?
Whether and to what extent psychosocial stress can increase arrhythmogenic cardiomyopathy disease progression was unexplored.
Does psychosocial stress increase mortality and worsen cardiac function in arrhythmogenic cardiomyopathy?
Does psychosocial stress increase mortality and worsen cardiac function in arrhythmogenic cardiomyopathy?
Absolute Event Rate: 30% vs 0%
This study provides foundational preclinical evidence that psychosocial stress can act as an independent, potent environmental risk factor that precipitates sudden death and exacerbates cardiac dysfunction in arrhythmogenic cardiomyopathy.
Psychosocial stress may exacerbate arrhythmogenic cardiomyopathy; leaves open whether stress-reduction strategies improve patient outcomes.
Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm-upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance.
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Agrimi et al. (2020) studied Arrhythmogenic Cardiomyopathy (n=40). Psychosocial stress (Resident-Intruder paradigm) vs. Unstressed baseline state or wildtype mice was evaluated on In-trial mortality during 14 days of psychosocial stress (Resident-Intruder paradigm) in Dsg2 mut/mut mice vs WT mice. In a mouse model of arrhythmogenic cardiomyopathy, 14 days of psychosocial stress via the resident-intruder paradigm resulted in 30% mortality compared to 0% in wildtype mice, alongside significantly worsened cardiac function.
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