Myocarditis-like in cardiomyopathy patients and in genotype positive carriers: genetic substrate and phenotypic spectrum. A systematic review and individual patient level meta-analysis
A Constante, H Lopez-Arevalo, J Moreno-Miron, L BianchiAbstract
Background
Myocarditis-like episodes (“hot-phases”) are increasingly recognised in inherited cardiomyopathies (CMP), often representing the first clinical manifestation. Although desmosomal gene variants — particularly in desmoplakin (DSP) — have been implicated, the broader genetic basis of hot-phase CMP remains incompletely defined.
Purpose
To comprehensively characterize the genetic architecture of myocarditis-like episodes in CMP patients and genotype-positive carriers.
Methods
PubMed, Scopus, and Cochrane were systematically searched for studies reporting genotyped CMP patients or genotype-positive carriers with ≥1 non-infective myocarditis-like episode. Genetic variants, CMP phenotypes, and clinical characteristics were extracted and synthesised.
Results
the 176 unique patients had a mean age at diagnosis of 29.3 (±15.6) years, 44.9% were male. The hot-phase represented the first manifestation of CMP in 48.6%, presenting with chest pain and troponin elevation (84.1%), followed by arrhythmias (4.6%) and heart failure (2.3%). 142 patients exhibited a positive genotype and a CMP phenotype, whereas 34 were genotype-positive carriers without an overt phenotype. Likely pathogenic or pathogenic (P/LP) variants were identified in 90.9% of patients (88% in the CMP group). Desmosomal genes were the predominant genetic substrate with DSP variants accounting for 75% of all P/LP variants, followed by PKP2 (7.5%), DSG2 (5.6%). Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) was the most common phenotype (31.8%), followed by Non-dilated Left Ventricular Cardiomyopathy (NDLVC) (18.2%) and Dilated Cardiomyopathy (DCM) (8.5%); 21% of cases were unclassified or overlapping DCM/NDLVC.
Conclusions
P/LP variants in desmosomal genes represent the predominant genetic substrate for myocarditis-like episodes in CMP. Hot-phase episodes may precede overt phenotypic expression, reflecting an underlying genetic predisposition. These findings support genetic testing in young patients presenting with non-viral myocarditis and/or a family history of myocarditis or CMP.Genotype-phenotype characterization