Myocarditis-like Episodes in Patients with Arrhythmogenic Cardiomyopathy: Comparison
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Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients has been reported, suggesting a possible role of inflammation in the pathophysiology of the disease. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release have been observed and defined as the “hot-phase” phenomenon.

  • arrhythmogenic cardiomyopathy
  • myocarditis
  • troponin

1. Introduction

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease that is characterized by myocyte necrosis with fibrofatty substitution and the presence of ventricular arrhythmias, which can even lead to sudden cardiac death (SCD), especially in the young [1][2]. In approximately 50% of cases, a causative genetic variant can be found, which in most cases involves genes encoding for desmosomal proteins, although in recent years, some non-desmosomal disease genes have been identified [3].
After the first descriptions that considered the disease to be confined to the right ventricle (RV) [1][2], contrast-enhanced cardiac magnetic resonance (CE-CMR) studies demonstrated that the left ventricle (LV) is frequently involved [4]. Moreover, in 2008, Sen-Chowdhry et al. [5] described a clinical entity named “Arrhythmogenic left ventricular cardiomyopathy” (ALVC), characterized by a predominant LV involvement, with no or minor RV abnormalities. Thus, phenotypic expression of ACM has then been recognized as being wider than previously thought, including the “classical” right dominant form with exclusive RV involvement (Arrhythmogenic right ventricular cardiomyopathy: ARVC), the above-cited ALVC form and the biventricular form (BIV), diagnosed when both ventricles resulted as being involved in the disease [6].
Since the first disease descriptions, inflammatory cell infiltrates have been reported in endomyocardial biopsies or an autoptic specimens of ACM patients [1][2]. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release in keeping with acute myocarditis have been described and defined as “hot-phase” [1][2][7]. These episodes can in some cases be the initial presentation of ACM, and enter into differential diagnosis with acute myocarditis [8]. Currently, their role in disease progression, as well as in arrhythmic risk stratification, remains to be clarified.

2. Hot-Phase in ACM Patients: An Historical Perspective

The presence of inflammatory infiltrates in myocardial samples of patients affected by ACM has been reported since the first disease descriptions. In 1990, Hisaoka et al. described two patients with clinical diagnosis of ACM, whose autopsies were in keeping with chronic myocarditis [9]. In the same year, Sabel et al. reported a 12-year-old girl with a familial form of ACM in whom electrocardiographics (ECGs) and serum enzymes indicated the development of LV infarction [10]. The authors suggested that myocarditis could be a precipitating factor in patients showing an ACM form. A few years later, Hoffmann et al. described a 47-year-old man who was diagnosed with acute myocarditis, and later had an aborted SCD. The patient was later diagnosed with ACM, which was considered to be mimicked by chronic myocarditis [11]. In 1996 Basso et al. performed a pathological study in 30 hearts with ACM, and found scattered foci of lymphocytes with myocardial death in 67% of cases [12]. One of the interpretations of these findings was that the disappearance of the RV myocardium, which constitutes the diagnostic hallmark of ACM, could be interpreted as the consequence of an inflammatory necrotic injury followed by fibrofatty repair, and thus an infectious and/or immune myocardial reaction might intervene in the etiology and pathogenesis of the disease [12]. After the identification of defects in desmosomes components as the genetic basis of the disease, it was hypothesized that the gene defect could predispose to myocyte detachment and death, and that a significant myocyte loss may be accompanied by an inflammatory response [13]. In 2007, these periodic exacerbations of an otherwise-quiescent disease, clinically characterized by chest pain and myocardial enzyme release, were defined for the first time as “hot-phases” [13].

3. Hot-Phase in ACM Patients: General Considerations on Available Clinical Studies

While in the last few years the possible role of inflammation in ACM onset and progression led to a significant number of publications, few detailed clinical studies on a large cohort of patients with “hot-phases” can be found [14][15][16][17]. Here are only 9 studies describing cohorts of patients affected with ACM who showed myocarditis-like episodes [5][8][18][19][20][21][22][23][24]. This is probably due to the low prevalence of these episodes in the overall ACM population, and on the other hand, to the problem of differential diagnosis with acute myocarditis. It is noteworthy that diagnostic assessment in patients with chest pain and troponin release changed importantly with the wider use of CE-CMR, and with the identification of ALVC forms in 2008 [5].

4. Hot-Phase Episodes in ACM Patients: Clinical Features

Patients reported with hot-phase episodes were usually young, with a mean age of 26 ± 14 years; the pediatric population was highly represented [8][19][20]. Martins et al. reported six cases of ACM in children (mean age 9 years, min 2–max 15 years) carrying desmosomal gene mutations with evidence of myocardial inflammation at CE-CMR. Interestingly, hot-phase episodes were likely exercise-induced in 50% of cases [19]. De Witt et al. reported 32 children and adolescents with ACM diagnosis, and found troponin release and CE-CMR features compatible with myocardial inflammation in 6 cases (min age 6 years) [20]. Finally, Bariani et al. evaluated 23 patients with hot-phase episodes, of whom 12 were younger than 18 years (min 10 years) [8]. It can be speculated that inclusion of studies that evaluate only pediatric patients could induce bias; however, the two selected cohorts of pediatric patients represent a small number of the total amount of patients analyzed (11/103, 11%) [19][20]. Furthermore, analysis of the 92 patients described in the remaining 7 studies showed that in 16 cases (40%), the age at the time of hot-phase was below the age of 18. In addition, during chest-pain episodes, ECG can show ST segment abnormalities that could lead to the diagnosis of acute coronary syndrome or acute myocarditis. The above data suggest that in young patients presenting with myocarditis-like syndrome, a careful familial anamnesis searching for family history of SCD, myocarditis, or cardiomyopathy is mandatory. In this setting, a complete family screening, with a genetic study, should be indicated.

5. Hot-Phase and ALVC Forms

About two-thirds of patients who experienced hot-phase episodes were finally diagnosed with ALVC, often after a previous diagnosis of myocarditis. This is not surprising, as a clinical overlap exists between ALVC and myocarditis, considering that chest pain with ECG abnormalities, troponin release and LV LGE are present in both conditions. At the same time, a diagnosis of ARVC and BIV forms was achieved in one-fourth of patients. Differently from the other studies, Bariani et al., among 23 patients reporting hot-phase episodes, found 82% of ARVC and BIV forms, while ALVC forms accounted for 17% of cases [8]. Similarly, De Witt et al. [20] identified 6 pediatric patients with hot-phases and diagnosed an ARVC/BIV form in 4 of them. This difference from the other studies could be explained by the different selection of patients. Nonetheless, these data demonstrate that hot-phase episodes can characterize the whole ACM clinical spectrum, even if ALVC forms are more commonly found.

6. Hot-Phase in ACM Patients: Genetic Background

In the last few years, genetic studies allowed the identification of several ACM disease genes [25]. With the development of next-generation sequencing, molecular genetic testing for multiple genes using a multigene panel has become the standard of practice for cardiovascular genetic medicine, allowing a cascade screening of family members [26]. This led to increasing knowledge on genotype-phenotype correlation in ACM and genetic variants of genes encoding for desmosomal proteins, Phospholamban and Filamin-C, have been proven to be significantly present in ALVC forms [27]. Considering the presence of a clinical overlap between chronic myocarditis and ALVC, genetic testing has been proposed as an effective tool facilitating the differential diagnosis [28]. It can be found that in ACM patients who showed hot-phase episodes, DesmoplakinDSP (DSP) was the most common disease gene, accounting for 69% of cases. It should be emphasized that in two of selected studies, one of the inclusion criteria was the presence of pathogenic variant of the DSP gene, and this may have resulted in an overestimation of the incidence of hot-phase episodes in this genotype [22][23]. Despite this, even excluding these two studies, DSP remains the gene most frequently found associated with hot-phase [8][18][19][20][21][22][24]. On the other hand, genetic variants of PKP2 and DSG2 were detected in 17% of cases. These data confirm the key role of a genetic test in diagnostic work-up of cardiomyopathies, even if it is important to consider that gene-elusive cases are not rare, and consequently, in these patients, further investigations must be carried out to rule out phenocopies [29].

7. Arrhythmic Burden in ACM Patients with Hot-Phase of the Disease

It can be believed this to be one of the most important issues when analyzing patients with hot-phases, given that this phenomenon can sometimes be long-lasting, and that recurrences are common. Unfortunately, data on degree of electrical instability during the hot-phases are limited, and studies are difficult to compare due to the different selection of patients. Overall, 9% of patients showed SCD during the acute phase of the disease, and 9% had sVT episodes, even if data were available only in 54% of cohort. The only study that demonstrated a possible prognostic role of hot-phase episodes is that of Wang et al. [23], which identified 91 individuals (34% male, median age 27.5) carrying a pathogenic or likely pathogenic DSP  variant, and found that proband status and myocardial injury were prognostic for heart failure (HF)HF in univariate analysis, while in multivariate analysis these two variables did not reach statistical significance. Thus, data seem to indicate the presence of a significant degree of electrical instability during hot-phase episodes, requiring a continuous ECG monitoring in a hospital until the end of the acute episode. However, data on arrhythmic risk during follow-up are lacking. Future studies on a sufficiently large cohort of ACM patients are needed in order to reach definitive conclusions on arrhythmic risk and possible indication for ICD implantation in patients with hot-phase episodes.

8. Role of Inflammation in the Pathogenesis of ACM

Since the first reports of the disease, inflammatory cell infiltrates have been described in patients affected with ACM at postmortem and at endomyocardial biopsies, with the highest prevalence in people with more diffuse diseases [30]. Several studies suggested that inflammation, either reactive to internal influences or triggered by exogenous factors, has a role in the pathogenesis of ACM. In addition, most of the evidence on the role of inflammation and autoimmunity in this disease derives from studies on desmosomal forms of disease, while non-desmosomal, as well gene-elusive forms, require further studies to assess the role of inflammation and of possible modifier factors [14][15][16][17][31]. Studies on murine models supported the evidence that ACM inflammation can precede the onset of overt histological and electrical abnormalities [32]. However, the mechanistic link between cell death and inflammation remains to be fully explained [33]. Cardiomyocyte death could be a primary event due to genetically determined desmosomal disruption, enhanced by a secondary immune reaction, leading to amplified cell death [14][15][16][17]. In addition, circulating anti-DSG2 autoantibodies, anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) were identified in patients with ACM, suggesting that autoimmune response against intercalated disk components and myosin could play a role in the pathogenesis of the disease [34][35]. In humans, the level of anti-DSG2 antibodies has been found to correlate with the arrhythmic burden, AHAs to be associated with lower LV systolic function and ICD indication, and AIDAs with lower biventricular systolic function [35]. Remarkably, anti-DSG2 antibodies have been detected in ACM regardless of the presence or type of the underlying pathogenic variant, thus suggesting that a final common pathway can underlie gene-elusive ACM patients [14][34]. It is noteworthy that, regardless of evidence of inflammation in ACM pathophysiology, studies of inflammatory pathways in this disease are not fully explained, and moreover, they have not so far been translated to human diseases [34]. Current therapeutic strategies are limited to the prevention of SCD through lifestyle changes, use of antiarrhythmic drugs, ICD placement, catheter ablation and treatment of HF symptoms. In overt forms with refractory HF, heart transplants represent the ultimate therapeutic strategy [15]. Thus, understanding the role of inflammation and autoimmunity could introduce new targets, potentially leading to new therapeutic strategies [14][15][36].

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