Arrhythmogenic Cardiomyopathy: Exercise Pitfalls, Role of Connexin-43, and Moving beyond Antiarrhythmics.

Arrhythmogenic Cardiomyopathy (ACM), a Mendelian disorder that can affect both left and right ventricles, is most often associated with pathogenic desmosomal variants that can lead to fibrofatty replacement of the myocardium, a pathological hallmark of this disease. Current therapies are aimed to prevent the worsening of disease phenotypes and sudden cardiac death (SCD). Despite the use of implantable cardioverter defibrillators (ICDs) there is no present therapy that would mitigate the loss in electrical signal and propagation by these fibrofatty barriers. Recent studies have shown the influence of forced vs. voluntary exercise in a variety of healthy and diseased mice; more specifically, that exercised mice show increased Connexin-43 (Cx43) expression levels. Fascinatingly, increased Cx43 expression ameliorated the abnormal electrical signal conduction in the myocardium of diseased mice. These findings point to a major translational pitfall in current therapeutics for ACM patients, who are advised to completely cease exercising and already demonstrate reduced Cx43 levels at the myocyte intercalated disc. Considering cardiac dysfunction in ACM arises from the loss of cardiomyocytes and electrical signal conduction abnormalities, an increase in Cx43 expression-promoted by low to moderate intensity exercise and/or gene therapy-could very well improve cardiac function in ACM patients.

A new “single” era of biomedicine: Applications in cardiovascular disease and COVID-19 (preprint)

With the development of cellular, chemical, and molecular biology, such as, single-cell, single-molecule, single-nucleus, single-chromosome and other related biotechnologies for analysis of chromatin regions, and under the help of single-nucleus and single-cell transcriptomics of human diseases in cardiovascular system, there are many novel breakthroughs in the field of life science and medicine. It can be said that a new “single” era of biomedicine comes. As transforming medical research tools at single-cell levels, single-cell technologies including single-cell RNA sequencing (scRNA-seq) provide high-resolutions insight into complex tissues covered cardiovascular and brain systems, they can help to understand molecular mechanisms of both COVID-19 and cardiovascular disease (CVD), such as atherosclerosis (AS), acute myocardial infarction (AMI), arrhythmogenic cardiomyopathy (ACM), inherited thoracic aortic aneurysm (iTAA) or ascending thoracic aortic aneurysm (ATAA), calcific aortic valve disease, heart failure, and others as well as develop novel therapeutic targets and approaches relevant for CVD and COVID-19.

Immunosuppressive therapy in childhood-onset arrhythmogenic inflammatory cardiomyopathy.

We present, to our knowledge, the first case of immunosuppressive therapy (IST) application in a 12-year-old child with arrhythmogenic inflammatory cardiomyopathy resulting from the overlap between autoimmune myocarditis and primary arrhythmogenic cardiomyopathy. Indication to off-lable IST was compelling, because of recurrent drug-refractory ventricular arrhythmias (VAs). We show that IST was feasible, safe, and effective on multiple clinical endpoints, including symptoms, VA recurrences, and T-troponin release. Remarkably, all diagnostic and therapeutic strategies were worked out by a dedicated multidisciplinary team, including specialized pediatric immunologists.

SARS-CoV-2 protein Nsp1 alters actomyosin cytoskeleton and phenocopies arrhythmogenic cardiomyopathy-related PKP2 mutant (preprint)

Mutations in desmosomal Plakophilin-2 (PKP2) are the most prevalent drivers of arrhythmogenic-cardiomyopathy (ACM) and a common cause of sudden death in young athletes. However, partner proteins that elucidate PKP2 cellular mechanism behind cardiac dysfunction in ACM are mostly unknown. Here we identify the actin-based motor proteins Myh9 and Myh10 as key PKP2 interactors and demonstrate that expression of the ACM-related PKP2 mutant R735X alters actin fiber organization and cell mechanical stiffness. We also show that SARS-CoV-2 Nsp1 protein acts similarly to this known pathogenic R735X mutant, altering the actomyosin component distribution on cardiac cells. Our data reveal that Nsp1 hijacks PKP2 into the cytoplasm and mimics the effect of delocalized R735X mutant. These results demonstrate that cytoplasmic PKP2 drives actomyosin deregulation and structural collapse, validating a critical role of PKP2 localization in the regulation of actomyosin architecture. The fact that Nsp1 and R735X share similar phenotypes also suggests that direct SARS-CoV-2 heart infection could induce a transient ACM-like disease in COVID-19 patients, which may contribute to right ventricle dysfunction, observed in patients with poor prognosis.