Protonotarios, Alexandros; (2025) The Role of Inflammation in Arrhythmogenic Right Ventricular Cardiomyopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease and a major cause of sudden cardiac death. It is characterised by the presence of fibro-fatty replacement of the myocardium that leads to the development of life-threatening ventricular arrhythmias. There has been increasing evidence pointing towards a crucial role of inflammation in the pathomechanism of ARVC, both from pathological studies showing the high prevalence of inflammatory infiltrates and studies reporting ARVC patients presenting with episodes of myocarditis. This thesis aimed to determine the role of inflammation in ARVC through a series of clinical cohort studies, immunological analyses, and experiments. One-third of symptomatic ARVC patients showed evidence of latent myocardial inflammation using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). This phenomenon was more prominent in carriers of disease-causing variants in DSP. Increased circulating cardiotropic T-cells were identified in ARVC patients and gene-positive phenotype-negative (G+P-) individuals. These cells were found in crucial effector and memory T-cell subpopulations and exhibited specific patterns of cytokine release consistent with Th1, Th17 and Treg responses. They were also identified within the inflammatory infiltrates from a case-studied post-mortem. Activated T-regulatory cells were negatively associated with disease burden and were significantly increased in G+P- individuals who have not yet developed an overt phenotype. Autoimmunity against Desmoglein-2 was identified, a key desmosomal protein of which autoantibodies have been previously described in ARVC. In conclusion, this project provides evidence to support chronic active inflammatory burden activity in ARVC patients and a key role for adaptive immunity that can be used to develop novel mechanism-based therapies for improving patients’ lives.

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