Inflammatory Hot Phases in Arrhythmogenic Cardiomyopathy

Figures

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  Figure 1. This 4-Panel Figure Integrates Mechanistic and Clinical Aspects of the ACM Hot-Phase Paradigm Panel 1 illustrates how desmosomal vulnerability and mechanical micro-injury may promote maladaptive plakoglobin/Wnt signaling, adipogenic tendency, DAMP release, NLRP3 inflammasome activation, caspase-1 activation, and IL-1β/IL-18 release. Panel 2 depicts potential humoral immune amplification through anti-DSG2 immune reactivity, with desmosomal weakening, connexin-43 remodeling, and electrical instability shown as hypothesis-generating downstream consequences. Panel 3 highlights imaging and histologic clues across phenotypes, including classic RV-dominant disease, left-dominant inflammatory-prone patterns with T2-positive edema and ring-like LV LGE, and supportive—but not pathognomonic—histology. Panel 4 summarizes a practical phenotyping and management framework: suspect hot phase clinically; exclude ischemic and inflammatory mimics; use CMR to characterize active edema vs chronic scar; intensify rhythm monitoring; pursue genetics and family screening; and apply standard ACM management and risk modification, while recognizing that immunomodulation remains investigational and…

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  Central Illustration. Predisposing Substrate Including Desmosomal Vulnerability (e.g., DSP, PKP2, DSG2), Mechanical Stress, and Innate Immune Activation, Primes The Myocardium for Inflammatory Exacerbation During the inflammatory hot phase, patients may develop chest pain or palpitations, troponin elevation, ventricular ectopy or NSVT, CMR evidence of T2 edema with or without LGE, and dynamic electrical instability. Over time, episodes may partially resolve or recur, while repeated injury may promote progressive scar, a persistent arrhythmogenic substrate, and risk beyond fixed scar alone. The management layer emphasizes exclusion of ischemic or inflammatory mimics, CMR plus rhythm monitoring, genetics and family screening, standard ACM management and conventional risk stratification, and the continued investigational status of immunomodulation for presumed ACM hot phase. ACM = arrhythmogenic cardiomyopathy; CMR = cardiac magnetic resonance; DSG2 = desmoglein-2; DSP = desmoplakin; ECG = electrocardiography; ICD = implantable cardioverter-defibrillator; ILR = implantable loop recorder; LGE = late gadolinium enhancement; NSVT = nonsustained ventricular tachycardia; PKP2 = plakophilin-2.