Cardiac Inflammation As an Underlying Trigger for the Pathological Deficits Associated with Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Gutierrez Lara Erika Joana , Zhang Jing , Fujita Kyohei , Liang Yan , Gu Yusu , Sheikh Farah 
Published: May 2023

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that causes cardiomyocyte loss, resulting in myocardial fibro-fatty deposition leading to cardiac dysfunction and sudden cardiac death, particularly in young patients and athletes, with no available treatments. The genetics of ARVC follow an autosomal dominant pattern, although severe cases (especially in pediatric populations) have been reported as recessive. Mutations in genes encoding components of desmosomes (specialized cell-cell junction that act as mechanical anchor between cardiac muscle cells) resulting in loss of desmosomal proteins underlie approximately 40-60% genetic cases of ARVC. Studies highlight that cardiac inflammation may be a critical and early component of ARVC as patients harboring mutations in the desmosomal gene desmoplakin (DSP) present with recurrent myocardial episodes (observed as myocarditis); however, the mechanisms and whether inflammation is a driver of ARVC remain unclear. We hypothesize that desmosomal gene mutations/loss/byproducts alter the acute inflammatory response on the cardiomyocyte cell surface leading to chronic immune intolerance and triggering of ARVC disease. To test our hypothesis, we injected DSP heterozygous deficient mice (harboring 50% loss of DSP without overt signs of ARVC) with a fragment of α-myosin and pertussis toxin to stimulate the immune system to assess its impact on ARVC pathogenesis. We show that DSP heterozygous mice exposed to acute immunological challenge triggered a destructive cardiomyocyte immune response in DSP heterozygous deficient hearts, reminiscent of fulminant myocarditis. Furthermore, we show that this acute immunological challenge was sufficient to trigger classic ARVC disease features in DSP heterozygous deficient mice as exemplified by: (i) enlarged ventricular (mostly right ventricular) chambers and heart size, (ii) fibrotic remodeling, with more clearly striking effects in the right ventricle (RV), (iii) epicardial fat tissue accumulation, (iv) electrophysiological deficits, such as premature ventricular contractions and QRS prolongation as well as (v) right and left ventricular physiological deficits associated with the bi-ventricular form of ARVC, although the RV appeared to be more significantly impacted. Our studies highlight the development of a novel DSP-related model of myocarditis. Using this model, we show that immunological stress is sufficient to lead to loss of cardiomyocyte immune tolerance in DSP heterozygous deficient mice with compromised desmosomal integrity to drive ARVC pathogenesis. More broadly these studies suggest that the immune system maybe an important driver of ARVC pathogenesis in patients with underlying desmosomal gene mutations/heterozygous loss, especially in the setting of autosomal dominant genetics. Work in the laboratory of FS is supported by grants from the NIH (HL142251, HL162369) and industry (LEXEO Therapeutics Inc.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.