Arrythmogenic cardiomyopathy Indian ReGistry(AIG)

Arrythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by frequent ventricular arrhythmias and an increased risk of sudden cardiac death (SCD)1 The disease is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity2. Diagnosis of ACM is made by a complex set of Task Force criteria (TFC), which include electrocardiographic, arrhythmia, imaging, histological, and family history criteria 3. The revision of ACM diagnostic criteria in 2010 increased the specificity of the diagnosis, but it still lacks sensitivity, especially in the early stages of the disease (3,4). Genotype/phenotype studies have shown that ACM, which was initially described as an isolated or predominant RV disease, exhibits frequent left ventricular (LV) involvement. This involvement may be present or predominant at early stages in some mutation carriers, expanding the clinical spectrum of the disease to a larger group of scar-related cardiomyopathies or arrhythmic cardiomyopathies according to the suggestion of some authors (5).

Limitations of the 2010 Task force criteria include the absence of specific criteria for left ventricle (LV) involvement and the limited role of cardiac magnetic resonance (CMR) as the use of the late gadolinium enhancement technique for tissue characterization was not considered. In 2020, new diagnostic criteria (“the Padua criteria”) were proposed. The main element of novelty compared to the 2010 Task force criteria is the central role of CMR, which has become mandatory to characterize the ACM phenotype and to exclude other diagnoses The traditional organization in six categories of major/minor criteria was maintained. The criteria for identifying the right ventricular involvement were modified and a specific set of criteria for identifying LV involvement was created. Depending on the combination of criteria for right and LV involvement, a diagnosis of classic (right dominant) ACM, biventricular ACM or left dominant ACM is then made (6,7)

 The main anatomopathological feature of ACM is the replacement of myocytes by fibrous or fibro adipose tissue in the RV free wall. Lesions extend from the epicardium to the endocardium and predominantly involve the area between the anterior part of the pulmonary infundibulum, the apex, and the infero-posterior wall (the so-called “triangle of dysplasia”). Myocyte loss and fibrous replacement are most often segmental and usually do not involve the interventricular septum. LV histological involvement is frequently reported in autopsy cases or explanted hearts, even in the absence of macroscopic LV involvement (8).

The diagnostic yield of endo myocardial biopsies is relatively low and largely depends on the location and number of targeted sites because of the patchy nature of fibrous replacement and the subepicardial location of lesions. Endo myocardial biopsies are generally non-contributively on the right side of the interventricular septum (4).

Mutations in the genes encoding desmosomal proteins play a key role in the pathogenesis of fibro fatty replacement of the myocardium and the development of the disease phenotype (9, 10). Pooled data from major studies on molecular genetic screening for desmosomal gene mutations showed that the overall rate of successful genotyping in patients meeting the ITF diagnostic criteria is approximately 50%(11). The most common mutant gene is PKP2 (10–45%), followed by DSP (10–15%), DSG2 (7–10%), and DSC2 (2%).Screening for non-desmosomal genes marginally increases the rate of detection of gene mutations, even though some mutations in specific genes such as TMEM43 p. P358L22 and PLN p. R14del23 can be highly prevalent in certain populations because of a founder effect (11