Arrhythmogenic cardiomyopathy in children, on the link between injurious mutations and inflammation: Two case reports and review of the literature

Abstract

BACKGROUND

In this case report, we aimed to raise awareness regarding arrhythmogenic cardiomyopathy (ACM) with inflammatory “hot phase” episodes in pediatric patients, which is often misdiagnosed as myocarditis. This condition, caused by aseptic intracellular inflammation, can be misdiagnosed as acute coronary syndrome or myocardial viral infection, with the latter being particularly common in children. Here, we report two pediatric cases of ACM with “hot phase” episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage.

CASE SUMMARY

The first patient (aged 13 years) was hospitalized after experiencing a single episode of syncope, chest pain, and palpitation. Clinical examination revealed elevated troponin levels, complete right bundle branch block, right ventricular dilation, and normal coronary arteries. Cardiac magnetic resonance imaging (MRI) revealed extensive fibrotic changes in the right ventricle, which was consistent with ACM, and a pathogenic variant in DSG2 confirmed the diagnosis. The second patient (aged 4 years) presented with chest pain and elevated troponin levels. Electrocardiography revealed a left bundle branch block, while echocardiography showed reduced left ventricular contractility. Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis. The phenotypic features, such as curly-wool hair, hyperkeratosis, and onychodystrophy, suggested a genetic nature of the disease. Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent “hot phase” episodes.

CONCLUSION

ACM in children can present with nonspecific inflammatory symptoms, which may be misdiagnosed as myocarditis or coronary artery pathology.

Key Words: Arrhythmogenic cardiomyopathy; Hot phase; Aseptic inflammation; Desmosomal mutations; Cytoskeletal derangements; Case report

Core Tip: Arrhythmogenic cardiomyopathy (ACM) is characterized by intercalated disc remodeling and cardiomyocytes death, which can lead to fibro-fatty replacement and severe heart failure. In some children, ACM presents with a “hot phase” and may be mistaken for acute myocarditis or coronary artery pathology. In this report, we describe two cases of the “hot phase” presentation and discuss the molecular mechanisms of this phenomenon.

INTRODUCTION

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by malignant ventricular arrhythmias due to myocardial fibro-fatty replacement[1]. The disease phenotype is highly variable, ranging from an early “latent phase” with only slight conduction defects and atrial arrhythmias in structurally normal heart to malignant ventricular arrhythmias and even biventricular heart failure. In most cases, the disease progresses slowly over 10-15 years. However, the intermittent occurrence of “hot phases” that mimics acute myocarditis can be observed in some patients; it represents episodes of active aseptic inflammation response to cellular damage and death, leading to reactive cellular infiltration and life-threatening arrhythmias.

The genetic nature of ACM is diverse and mainly linked to desmosomal structures, which are the tight intercellular contacts between adjacent cells typical of cardiomyocytes and dermal epithelium. Approximately 30%-40% of all ACM cases are caused by mutations in the PKP2 gene encoding the desmosome protein plakophilin-2[2]. Other genes associated with ACM include the desmosomal proteins DSC2, DSG2, DSP, and JUP; area composita component CTNNA3; desmosome-associated intermediate filament DES; intercalated disc-associated kinase ILK; and cardiac sodium channel SCN5A[3]. Desmosomal protein defects result in damage and remodeling of cardiomyocyte intercalated discs, triggering cardiomyocyte death, inflammation, and reactive fibrosis[4-6]. In addition, mutations in genes encoding nuclear lamina proteins, LMNA and TMEM43; components of the circulating calcium system, RYR2 and PLN; growth factor TGFB3; and giant intrasarcomeric protein TTN have been described in association with ACM[3].

Several genotype-phenotype correlations are described for ACM. Thus, mutations in DSP are often associated with left ventricular involvement, heart failure progression, and cardiac transplantation[7], while rare cases linked to TMEM43 are mainly characterized by early and malignant arrhythmias[8]. However, although several clinical case descriptions have been documented, only a few genotype-phenotype correlations have been described for ACM with “hot phases” mimicking acute myocarditis. Here, we report two pediatric cases of “hot phase” ACM episodes, which, along with previously reported cases, underscores the importance of ACM awareness in pediatric patients with signs of myocardial injury and myocarditis.

CASE PRESENTATION

Chief complaints

Case 1: A 13-year-old boy was admitted to the hospital with a single episode of syncope and ventricular tachycardia. During hospitalization, the patient also experienced recurrent chest pain attacks.

Case 2: A 4-year-old boy was hospitalized in the pediatric cardiac department with dyspnea, fatigue, periodic chest pain, and elevated troponin I level.

History of present illness

Case 1: The differential diagnosis initially focused on acute myocarditis and acute coronary syndrome. General inflammatory markers were not elevated; polymerase chain reaction testing for cardiotropic viruses was negative; and typical signs of myocarditis, including early gadolinium enhancement, were absent on magnetic resonance imaging (MRI). However, MRI revealed decreased contractility and extensive fibrotic areas in the right ventricle (RV).

Case 2: The differential diagnosis included myocarditis, dilated cardiomyopathy, and left-dominant ACM. Given the anamnesis data from a previous viral infection, the patient was initially diagnosed with myocarditis and initiated with antiarrhythmic therapy (beta-blocker metoprolol 2 mg/kg/day) and angiotensin-converting enzyme (ACE) for chronic heart failure (CHF). However, over a year of surveillance, the patient demonstrated progressive clinical deterioration, indicating the genetic nature of the disease.

History of past illness

Case 1: About 6 months prior to admission, the patient had experienced a syncopal episode, with heart rate exceeding 250 beats per minute and ventricular tachycardia with wide QRS complexes, which was terminated by electrical cardioversion (Figure 1A). At that time, Holter electrocardiography (ECG) monitoring recorded occasional ventricular extrasystoles, while echocardiography showed no abnormalities. The patient was recommended for propafenone treatment and referred to our center for further examination.

Figure 1 Electrocardiography, echocardiography, angiography, and cardiac magnetic resonance imaging of a 13-year-old boy with a single episode of syncope and ventricular tachycardia. A: Electrocardiography (ECG) fragment with wide complex QRS tachycardia and a heart rate of 250 per minute; B: ECG during chest pain, sinus rhythm with a heart rate of 64 bpm, and right bundle branch block; C: Echocardiography—right ventricle dilation in the four-chamber position and parasternal position in the long and short axes; D: Type of coronary blood supply—right, coronary arteries with no angiographic signs of atherosclerotic lesions, no local stenosis, and satisfactory blood flow; E: Cardiac magnetic resonance imaging—right ventricular (RV) dilation and late gadolinium enhancement in the RV myocardium. RA: Right atrial; RV: Right ventricular; LGE: Late gadolinium enhancement.

Case 2: The patient had coronavirus infection 2 months prior to hospitalization.

Personal and family history

Case 1 and Case 2: No family history of ACM or sudden cardiac death was noted.

Physical examination

Case 1: The physical examination did not reveal notable abnormalities.

Case 2: Physical examination revealed remarkable phenotypic features such as curly-wool hair, pronounced hyperkeratosis, deep creases on the palms and soles, and onychodystrophy (Figure 2A).

Figure 2 Phenotypic characteristics, electrocardiography, echocardiography, and cardiac magnetic resonance imaging of a 4-year-old child with Carvajal syndrome. A: Child’s phenotypic characteristics: Curly-wool hair and palmoplantar keratoderma; B: Electrocardiography (ECG) fragment with polymorphic ventricular tachycardia and a heart rate ranging from 128 to 165 per minute; C: Echocardiography: Global longitudinal strain decreased by 8% due to hypokinesis in the left ventricular (LV) posterolateral segment; D: Cardiac magnetic resonance imaging: LV dilation and late gadolinium enhancement in the ventricular myocardium. RA: Right atrial; RV: Right ventricular; LGE: Late gadolinium enhancement.

Laboratory examinations

Case 1: The troponin I level increased to 232.744 ng/mL, and NT-proBNP level increased to 16308.5 pg/mL. Routine blood tests revealed no other abnormalities.

Case 2: The troponin I level was elevated to 0.0510 ng/mL, while the NT-proBNP level increased to 786.5 pg/mL. Routine blood tests revealed no other abnormalities.

Imaging examinations

Case 1: The ECG recording showed a complete right bundle branch block (Figure 1B), and Holter ECG monitoring registered monomorphic ventricular extrasystoles and episodes of monomorphic ventricular tachycardia originating from the RV outlet—a minor criterion of ACM according to the 2010 Task Force Criteria. Echocardiography revealed RV dilation without impaired contractility (Figure 1C). Selective coronary angiography showed no pathological changes (Figure 1D), thereby ruling out any acute coronary events, while MRI demonstrated decreased RV contractility and widespread subepicardial fibrotic changes, in alignment with the major MRI criterion (Figure 1E).

Case 2: ECG revealed left bundle branch block, while the Holter ECG monitoring recorded episodes of unstable mono- and polymorphic ventricular tachycardia and polymorphic ventricular extrasystoles (7682 per day) (Figure 2B). Echocardiography revealed slightly reduced myocardial contractility along with hypokinesis of the posterolateral left ventricle (LV) wall (Figure 2C). Cardiac MRI showed LV dilation and multiple subepicardial fibrotic areas in the anterior, lateral, posterior, and inferior LV walls, as well as interventricular septum fibrosis (Figure 2D).

FINAL DIAGNOSIS

Case 1

The presence of two minor and one major MRI criteria according to the 2010 Task Force Criteria allowed us to assume the diagnosis of ACM. Genetic testing revealed a mutation in DSG2 classified as pathogenic (Table 1). Based on the myocardial phenotype, genetic findings, and signs of acute myocardial damage, the patient was diagnosed with ACM “hot phase” episode.

Table 1 Genetic variants identified in patients with arrhythmogenic cardiomyopathy.

Patients	Gene	Variants	ACMG classification	CADD
Patient 1	DSG2	Сhr18:31519867, rs121913006, NM_001943.5: C.146G>A: p.R49H	P (PP5, PP3, PM1, PM5, PM2)	26
Patient 2	DSP	Chr6:7559251, NM_004415.4: C.448C>T: p.R150*	P (PVS1, PP5, PM2)	37
	DSP	Chr6:7580877-7580878, NM_004415.4: C.4687_4688del: p.L1563Efs*63	P (PVS1, PP5, PM2)	No data

ACMG: American College of Medical Genetics and Genomics; CADD: Combined Annotation Dependent Depletion.

Case 2

Genetic testing revealed two pathogenic variants in DSP (Table 1), supporting the diagnosis of Carvajal syndrome, which in this case comprised ACM with a prevalent left-dominant form along with skin derivative lesions, such as wooly hair and palmoplantar keratoderma.

TREATMENT

Case 1

Considering several previous episodes of syncope, malignant ventricular arrhythmias, and signs of myocardial damage and fibrosis, a cardioverter-defibrillator (ICD) was implanted along with the prescribed sotalol antiarrhythmic therapy (4 mg/kg/day). Additionally, diuretics, ACE inhibitors, and eplerenone were used to manage CHF symptoms.

Case 2

Despite the patient’s young age (5 years), the decision of ICD implantation was made based on the recurrent ventricular arrhythmias, decreased contractility, and progressive nature of the disease. Sotalol therapy was initiated (6 mg/kg/day), while the CHF symptoms were managed with diuretics, ACE inhibitors, and eplerenone.

OUTCOME AND FOLLOW-UP

Case 1

During the 2-year follow-up, the patient did not experience any relapses of the “hot phase”. No ICD discharge was reported, and the CHF symptoms remained stable.

Case 2

Clinical improvement was observed 6 months after ICD implantation, and no adequate ICD discharges were recorded. During the 3-year follow-up, the patient experienced five additional “hot phase” episodes confirmed by myocardial damage markers and slow progressive worsening of CHF symptoms. The patient is currently on the waiting list for heart transplantation.

DISCUSSION

The diagnosis of ACM in pediatric patients might be challenging due to its clinical ambiguity and rare occurrence in children. While the typical initial manifestation of ventricular arrhythmias is the most common, patients may also present with chest pain, elevated troponin levels, and inflammatory markers[9]. This condition, referred to as the “hot phase”, may be misdiagnosed as myocarditis or acute coronary syndrome[10]. Only a few publications have described the ACM “hot phase” in pediatric patients, demonstrating that chest pain and myocardial enzyme release at presentation can be a part of the ACM phenotype, especially in children with DSP mutations[10,11]. In addition, ACM in pediatric patients has been reported to present as recurrent myocarditis confirmed by cardiac MRI in the absence of a clear viral infection[12]. Along with our cases, this further underscores the need for ACM diagnostic workup in children with suspected myocarditis.

Since the Padua criteria were proposed in 2020, the definition of ACM—originally focused on the right ventricular form—has expanded to include left-dominant and biventricular forms as well[13], leading to the renaming of the condition from arrhythmogenic right ventricular cardiomyopathy to the broader term ACM. Patients with left-dominant and biventricular subtypes often have similarities to those with dilated cardiomyopathy or myocarditis, leading to the misinterpretation of the diagnosis and even the type of cardiomyopathy[14]. Of note, the last classification of cardiomyopathies by the European Society of Cardiology in 2023 did not specify the left ventricular or biventricular ACM forms, further leading to difficulties in interpreting terms and criteria[15]. However, although the left-dominant or biventricular ACM forms still require precise identification and common acceptance, their existence as distinct clinical forms is beyond doubt. This is further important in light of recent publications focused on genotype-phenotype correlations in ACM[16]; this is especially interesting with regard to left-dominant forms and the “hot phase” phenomenon linked to non-PKP2-associated and DSP-related cases. The cases linked to DSP variants often include LV involvement and “myocarditis-like” episodes of chest pain with laboratory signs of myocardial injury[10]. Consequently, myocardial injury is associated with worse outcomes in DSP-related cases[17]. Similarly, Scheel et al[18] reported several female patients with the left ventricular ACM subtype and genetic variants in DSP and DSG2 to be initially diagnosed with myocarditis. In addition, 10 pediatric cases with DSP causative variants reported by Choi et al[19] emphasized the unfavorable clinical trajectory of such patients with adequate ICD shocks, decrease of contractility, and left ventricular involvement. In line with these correlations, our patients also had “hot phase” manifestations with chest pain, elevated troponin I levels, and LV involvement. In such myocarditis-like cases, the unavailability of precise viral diagnostics due to the risk of cardiac biopsy underscores the importance of advanced visualization methods such as cardiac MRI along with genetic testing and application of the Padua diagnostic criteria in improving diagnostic accuracy[9].

Increasing evidence suggests that inflammation plays a significant role in the pathogenesis of ACM. Moreover, fibrous replacement as a criterion of ACM is considered to be a consequence of inflammation and cardiomyocyte degeneration[20]. In a study of 36 cardiac autopsies from patients with ACM, 39% showed myocardial inflammatory cells[21]. In our cases, we were not able to confirm the tissue signs of inflammation due to the high risk of myocardial perforation during cardiac biopsy in children. However, we could observe the laboratory and functional signs of myocardial damage, namely, increased troponin I level and transient decrease in contractility, which were most likely the consequences of myocardial inflammation. Aseptic inflammation, a molecular process unrelated to infectious pathogens but induced by intracellular damage, is mainly observed in desmosomal forms of ACM. Desmosomal disruption can be a reason for inflammatory cell recruitment through lymphokine secretion and leukocyte attraction, which results in the intensification of myocardium damage[22]. For example, desmocollin-2 overexpression results in necrosis, acute inflammation, and fibrotic remodeling in the heart[23]. In addition, Lubos et al[24] proved that inflammation triggered by cardiomyocyte necrosis is involved in the formation of fibrous scars in the DSG2-mutant mice. These findings demonstrate the importance of adequate cellular junctions (particularly desmosomes) for proper heart muscle organization and function. A major pathway for the realization of inflammation is the NLRP3-dependent inflammasome assembly and its activation[25], which is triggered by NF-κB in response to external Toll-like receptor ligands. This activation leads to the expression of the NLRP3 inflammasome components, including NLRP3, pro-IL-1β, pro-IL-18, and Pycard. Further pharmacologic targeting with an IL-1βR antagonist or inhibition of NLRP3 has been shown to reduce the signs of myocardial inflammation in a mouse model[26]. In addition, Selgrade et al[27] showed that engineered heart tissue containing induced pluripotent stem cells with homozygous mutations in DSP demonstrates transcriptomic molecular signatures of the innate system activation through cytokine release and acquired hypersensitivity to the stimulation of Toll-like receptors. In this model, treatment with colchicine and NF-κB inhibitors improved the force deficit in the DSP-deficient engineered heart tissue. Thus, targeting receptors and pathways involved in the innate immune response along with anti-inflammatory drug discovery might be a prospective approach to ACM treatment.

Genetic defects of desmosomal components could result in the weakening of cell-to-cell junctions and cellular integrity, which is accompanied by cell death, NF-kB pathway activation, and intracellular inflammation[28-30]. The NF-kB signaling pathway can also be activated in response to mechanical stimuli, including changes in the extracellular matrix stiffness and the cell’s internal cytoskeleton[31,32]. Other components of the cellular cytoskeleton, specifically actin microfilaments, may play an additional role in the modulation of intracellular inflammation in cardiomyocytes. Thus, actin filaments modulate the sequestration of NF-κB in cytosol, underlining the importance of the actin polymerization/depolymerization balance in NF-κB activation[32-34].

CONCLUSION

Cellular inflammation plays a crucial role in ACM pathogenesis, which occurs at least in part via the NF-κB signaling pathway. This pathway can be activated through different mechanisms, such as cytoskeletal or intercalated disc abnormalities and derangements. Genetic mutations associated with these structures result in cell death, inflammation, and fibrosis. Clinically, ACM can present with nonspecific inflammatory signs and symptoms, such as chest pain and elevated troponin I level and may therefore be misdiagnosed as acute coronary syndrome or myocarditis. Recognizing the ACM “hot phase” is essential for timely and accurate diagnosis. This case report presented two clinical cases of the ACM “hot phase” in children, exploring phenotypic disease heterogenicity, underscoring common pathophysiological mechanisms, and focusing on sterile myocardial inflammation. The molecular bases of ACM “hot phase” include cytoskeletal and desmosomal disruption triggering noninfectious intracellular inflammation, which points to the potential benefits of an antiinflammatory pharmacological approach in ACM patients.