Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Keywords: arrhythmias, cardiac; arrhythmogenic right ventricular dysplasia; autoimmunity; death, sudden, cardiac; genetics; inflammation; myocarditis.

Figure 1.. Schematic diagram illustrating mechanistic pathways involved in the pathogenesis of myocyte damage and replacement-type myocardial fibrosis in different genetic forms of arrhythmogenic cardiomyopathy.

Please see text for details regarding the pathogenic cascade. Note, mechanisms involved in cardiac electrical susceptibility in the context of alterations in cardiac ion channels and intercalated discs, are not shown.

Figure 2.. Histological evidence of myocardial inflammation in arrhythmogenic right ventricular cardiomyopathy.

Histological specimen from the right ventricular myocardium of a 32-year old male patient with sudden cardiac death and post-mortem diagnosis of typical arrhythmogenic right ventricular cardiomyopathy showing extensive fibrosis, very few adipocytes and areas of focal inflammation in the, hematoxylin and eosin magnified 40 x. Given sudden death was the sentinel event, no in vivo ECG or CMR data were available. Two family members were subsequently diagnosed with ARVC. Genetic testing revealed a truncation pathogenic variant in the PKP2 gene, which segregated with phenotype in the family and was confirmed in the index patient.

Figure 3.. Arrhythmogenic left ventricular cardiomyopathy and inflammation: case presentations.

A 49-year-old male with a history of chest pain, troponin elevation, normal epicardial coronary arteries presented several weeks dyspnea, NTproBNP 1500 pg/ml. A 12-lead ECG showed sinus rhythm with T-wave inversion in the lateral leads (I, aVL, V5, V6) and poor R wave progression across the precordial leads (panel A). A CMR showed extensive left ventricular late gadolinium enhancement with near circumferential ring-like pattern of the basal, mid and apical segments (panels B-F). T2 STIR imaging also showed edema (panel G). An arrhythmogenic cardiomyopathy and dilated cardiomyopathy panel was sent revealing a pathogenic DSP variant c.478C>T (p.Arg160Ter). An unrelated patient who had died of a sudden cardiac death event on histological analysis showed lymphocytic infiltrates of the left ventricular myocardium (negative for viral PCR), hematoxylin and eosin 10 × panel (H) and magnified 20 × (I). This patient tested positive for a truncating pathogenic DSP variant.

Figure 4.. Genes associated with arrhythmogenic cardiomyopathy (ACM).

Pathogenic variants in desmosomal genes (shown in yellow) are very frequent among patients with ACM. Less frequently, pathogenic variants in ACM patients are found in genes encoding proteins that interact with the desmosome (CDH2, CTNNA3, and DES), in the genes potentially involved in expression of proteins (LMNA, TFGB3, and TMEM43), in the genes related to sarcoplasmic reticulum calcium homeostasis (PLN), or in the sarcomeric gene TTN (less frequently involved genes are shown in blue). Pathogenic variants in the SCN5A gene have been associated with defects in cadherin 2 (encoded by CDH2) at the intercalated disc, which might underlie the mechanism of ACM (although a direct interaction between these molecules has yet to be demonstrated). SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; TGFβ, transforming growth factor-β.