Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.

PITX2 induction leads to impaired cardiomyocyte function in arrhythmogenic cardiomyopathy

“…We further showed that mutant DSP p.Tyr1188His/WT cardiomyocytes exhibit lower levels of the gap junction protein CX43 and NaV1.5, which in turn may be causal for the observed prolongation of the action potential. These observations are in line with previous studies that demonstrated diminished CX43 and NaV1.5 levels in explanted cardiac material isolated from patients diagnosed with ACM ( Asimaki et al., 2009 ; Bueno-Beti and Asimaki, 2021 ; Jansen et al., 2012 ). In addition, studies revealed redistribution of CX43 to the long axis of cardiomyocytes upon desmosomal protein deficiency, which in turn may act as an arrhythmogenic substrate ( Bueno-Beti and Asimaki, 2021 ; Oxford et al., 2007 ; Zhang et al., 2013 ).…”

“…Molecular analyses of DSP p.Tyr1188His/WT hiPSC-derived cardiomyocytes revealed a reduction in desmosomal proteins, an observation previously reported in ventricular tissue obtained from patients with ACM ( Asimaki et al., 2009 ). Interestingly, this pathomolecular characteristic seems to be a hallmark of ACM, as it is not evident in other forms of cardiac disease ( Asimaki et al., 2009 ; Bueno-Beti and Asimaki, 2021 ). Besides reduced protein levels, we also observed lower mRNA levels for several components of the intercalated disc.…”

Activation of PPARα Ameliorates Cardiac Fibrosis in Dsg2-Deficient Arrhythmogenic Cardiomyopathy

“…Pathological features of ACM include loss of myocytes and progressive fibro-fatty replacement. These pathological features tend to occur in the right ventricle (RV), with left ventricular (LV) or bilateral ventricular involvement [ 2 , 3 ]. Previous studies found that one or more mutations in genes encoding desmosomal proteins led to about 50% of ACM cases [ 4 ], including desmoglein2 (DSG2) [ 5 ], desmocollin2 [ 6 ], plakoglobin [ 7 ], desmoplakin [ 8 ], and plakophilin-2 [ 9 ].…”

Non Coding RNAs as Regulators of Wnt/β-Catenin and Hippo Pathways in Arrhythmogenic Cardiomyopathy

“…Historically, ACM caused by mutations in desmosomal genes was associated with isolated or predominantly right ventricular disease (RV-ACM). However, recent studies have highlighted a high prevalence of left ventricular involvement along with isolated and left-dominant ACM forms (LV-ACM) in patients carrying FLNC , DSP , or DSG2 mutations, for instance [ 3 , 8 , 9 , 10 ].…”

“…ACM is characterized by the fibrofatty replacement of the myocardium, typically progressing from the epicardium to the endocardium, and transmural fibrofatty infiltration can also be observed in advanced stages of the disease [ 1 , 4 , 5 , 6 , 10 , 18 ].…”