High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy.

Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.

Basic and translational mechanisms in inflammatory arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a familial, nonischemic heart disease typically inherited via an autosomal dominant pattern (Nava et al., [1]; Wlodarska et al., [2]). Often affecting the young and athletes, early diagnosis of ACM can be complicated as incomplete penetrance with variable expressivity are common characteristics (Wlodarska et al., [2]; Corrado et al., [3]). That said, of the five desmosomal genes implicated in ACM, pathogenic variants in desmocollin-2 (DSC2) and desmoglein-2 (DSG2) have been discovered in both an autosomal-recessive and autosomal-dominant pattern (Wong et al., [4]; Qadri et al., [5]; Chen et al., [6]). Originally known as arrhythmogenic right ventricular dysplasia (ARVD), due to its RV prevalence and manifesting in the young, the disease was first described in 1736 by Giovanni Maria Lancisi in his book "De Motu Cordis et Aneurysmatibus" (Lancisi [7]). However, the first comprehensive clinical description and recognition of this dreadful disease was by Guy Fontaine and Frank Marcus in 1982 (Marcus et al., [8]). These two esteemed pathologists evaluated twenty-two (n = 22/24) young adult patients with recurrent ventricular tachycardia (VT) and RV dysplasia (Marcus et al., [8]). Initially, ARVD was thought to be the result of partial or complete congenital absence of ventricular myocardium during embryonic development (Nava et al., [9]). However, further research into the clinical and pathological manifestations revealed acquired progressive fibrofatty replacement of the myocardium (McKenna et al., [10]); and, in 1995, ARVD was classified as a primary cardiomyopathy by the World Health Organization (Richardson et al., [11]). Thus, now classifying ACM as a cardiomyopathy (i.e., ARVC) rather than a dysplasia (i.e., ARVD). Even more recently, ARVC has shifted from its recognition as a primarily RV disease (i.e., ARVC) to include left-dominant (i.e., ALVC) and biventricular subtypes (i.e., ACM) as well (Saguner et al., [12]), prompting the use of the more general term arrhythmogenic cardiomyopathy (ACM). This review aims to discuss pathogenesis, clinical and pathological phenotypes, basic and translational research on the role of inflammation, and clinical trials aimed to prevent disease onset and progression.