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Open AccessFeature PaperArticle

Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC

by Sunil K. Vasireddi, Prasongchai Sattayaprasert, Dandan Yang, Adrienne T. Dennis, Emre Bektik, Ji-dong Fu, Judith A. Mackall and Kenneth R. Laurita

J. Pers. Med. 2022, 12(10), 1680; https://doi.org/10.3390/jpm12101680 - 9 Oct 2022

Cited by 10 | Viewed by 2803

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin–dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2–4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2–4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations. Full article

(This article belongs to the Special Issue The Challenges and Prospects in Cardiology)

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13 pages, 3781 KiB

Open AccessCase Report

Sudden Death without a Clear Cause after Comprehensive Investigation: An Example of Forensic Approach to Atypical/Uncertain Findings

by Simone Grassi, Mònica Coll Vidal, Oscar Campuzano, Vincenzo Arena, Alessandro Alfonsetti, Sabina Strano Rossi, Francesca Scarnicci, Anna Iglesias, Ramon Brugada and Antonio Oliva

Diagnostics 2021, 11(5), 886; https://doi.org/10.3390/diagnostics11050886 - 17 May 2021

Cited by 17 | Viewed by 4333

Abstract

Sudden death (SD) is defined as the unexpected natural death occurred within an hour after the onset of symptoms or from the last moment the subject has been seen in a healthy condition. Brugada syndrome (BrS) is one of the most remarkable cardiac causes of SD among young people. We report the case of a 20-year-old man who suddenly died after reportedly having smoked cannabis. Autopsy, toxicology, and genetic testing were performed. Autopsy found a long and thick myocardial bridging (MB) at 2 cm from the beginning of the left anterior descending coronary artery. Furthermore, at the histopathological examination, fibrosis and disarray in myocardial area above the MB, fatty tissue in the right ventricle and fibrosis of the sino-atrial node area were found. Toxicology testing was inconclusive, while genetic testing found a rare missense variant of the TTN gene, classified as likely benign, and a variant of unknown significance in the SLMAP gene (a gene that can be associated with BrS). Hence, despite several atypical features were found, no inference on the cause of the death could be made under current evidence. Full article

(This article belongs to the Section Pathology and Molecular Diagnostics)

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