Recurrent acute myocarditis: An under-recognized clinical entity associated with the later diagnosis of a genetic arrhythmogenic cardiomyopathy

Abstract

BackgroundMyocardial inflammation has been consistently associated with genetic arrhythmogenic cardiomyopathy (ACM) and it has been hypothesized that episodes mimicking acute myocarditis (AM) could represent early inflammatory phases of the disease.ObjectiveWe evaluated the temporal association between recurrent acute myocarditis (RAM) episodes and the later diagnosis of a genetic ACM.Materials and methodsBetween January 2012 and December 2021, patients with RAM and no previous cardiomyopathy were included (Recurrent Acute Myocarditis Registry, NCT04589156). A follow-up visit including clinical evaluation, resting and stress electrocardiogram, cardiac magnetic resonance imaging, and genetic testing was carried out. Endpoints of the study was the incidence of both ACM diagnosis criteria and ACM genetic mutation at the end of follow-up.ResultsTwenty-one patients with RAM were included and follow-up was completed in 19/21 patients (90%). At the end of follow-up, 3.3 ± 2.9 years after the last AM episode, 14/21 (67%) patients with an ACM phenotype (biventricular: 10/14, 71%; left ventricular: 4/14, 29%) underwent genetic testing. A pathogenic or likely pathogenic mutation was found in 8/14 patients (57%), 5/8 in the Desmoplakin gene, 2/8 in the Plakophillin-2 gene, and 1/8 in the Titin gene. Family history of cardiomyopathy or early sudden cardiac death had a positive predictive value of 88% for the presence of an underlying genetic mutation in patients with RAM.ConclusionRAM is a rare entity associated with the latter diagnosis of an ACM genetic mutation in more than a third of the cases. In those patients, RAM episodes represent early inflammatory phases of the disease. Including RAM episodes in ACM diagnosis criteria might allow early diagnosis and potential therapeutic interventions.

Pathogenic truncating filamin C mutations presenting as acute myocarditis: a case series with insights from cardiac magnetic resonance and histological analysis

“… 12 In a cohort of 21 cases of recurrent myocarditis, it was found that approximately one-third of patients had a previously unknown pathogenic or likely pathogenic mutation, mostly affecting the DSP gene. 13 Additionally, Piriou et al 14 found that in patients with acute myocarditis and a family history of cardiomyopathy or sudden cardiac death, genetic testing revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that may evade the ARVC Task Force Criteria. An inflammatory insult may uncover increased genetic susceptibility to develop significant LV dysfunction or an arrhythmogenic phenotype in cases of acute myocarditis.…”

The Many Faces of Arrhythmogenic Cardiomyopathy: An Overview

“… 110 Underlying genetic variants were most often found in DSP, PKP2 and DSG2 . 110 , 111 The majority of these patients had LV LGE on CMR and endomyocardial biopsies with virus negative myocarditis. 103 , 112 A family history of cardiomyopathy or SCD was common in these cohorts, and carried a high positive predictive value for an underlying genetic variant, again highlighting the importance of a comprehensive family history of at least 3 generations.…”

Case Illustration of the Natural History of Left Dominant Arrhythmogenic Cardiomyopathy

“…Arrhythmogenic cardiomyopathy manifests as a spectrum of myocardial disorders characterized by progressive myocardial damage caused by fibrofatty replacement of the myocardium and resulting malignant ventricular arrhythmias. 1 , 2 Arrhythmogenic cardiomyopathy can present with heart failure, arrhythmias, and sudden cardiac death. 2 Previously believed to be isolated to right ventricular involvement, arrhythmogenic cardiomyopathy is now understood to involve the right, left, or both ventricles.…”

“… 1 , 2 Arrhythmogenic cardiomyopathy can present with heart failure, arrhythmias, and sudden cardiac death. 2 Previously believed to be isolated to right ventricular involvement, arrhythmogenic cardiomyopathy is now understood to involve the right, left, or both ventricles. 1 …”

“…Arrhythmogenic left ventricular cardiomyopathy is a rare, genetically inheritable disease associated with a desmoplakin mutation that alters the protein that determines the structural integrity of the myocardium. 1 , 2 Clinical presentation is highly variable and often includes ventricular arrhythmias, myocardial injury with left ventricular dysfunction, or recurrent myocarditis. 1 , 3 Patients are often misdiagnosed as having recurrent myocarditis because of alternating periods of the hot and cold phases of the disease.…”