Background

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterised by fibrofatty infiltration of the myocardium, leading to ventricular arrhythmias and an increased risk of sudden cardiac death. While it was traditionally thought to affect the right ventricle primarily, recent findings show that fibrofatty infiltration often involves the left or both ventricles. Prevention of sudden cardiac death and the control of arrhythmic and heart failure events are the main targets when dealing with patients with ACM. 

ACM is typically inherited in an autosomal dominant manner, exhibiting age-dependent onset, incomplete penetrance, and variable expressivity. The classic right-dominant form of ACM is primarily associated with mutations in genes encoding desmosomal proteins, such as plakoglobin (JUP), plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein (DSG2), and desmocollin (DSC2). Additionally, mutations in genes encoding adherens junction proteins, including α-T-catenin (CTNNA3) and N-cadherin (CDH2), have been implicated in ACM pathogenesis. Desmosomes and adherens junctions are critical for mechanical integration between cardiomyocytes, while sodium channels facilitate electrical impulse initiation and gap junctions ensure impulse propagation. These structures form intercalated discs, essential for maintaining electromechanical connections and intracellular signalling, such as the Wnt/β-catenin pathway. Disruption of desmosomal integrity leads to cardiomyocyte death and fibrotic scarring, a hallmark of ACM.

Case Description

A 22-year-old male endurance athlete and semi-professional rower presented to our sports cardiology clinic with recurrent episodes of sudden palpitations, accompanied by pre-syncopal symptoms and nausea. The patient reported that his smartwatch recorded heart rates peaking at 238 beats per minute during these episodes. His cardiovascular history is notable for a suspected episode of myocarditis several years ago, with evidence of myocardial fibrosis on MRI (documentation from that event is unavailable due to being conducted in a foreign country). His family history is significant for the sudden cardiac death of one paternal grandfather at the age of 75.

A 12-lead resting ECG (Figure 1) showed T-wave inversions in the anterior leads up to V4, which is considered abnormal based on International criteria for electrocardiographic interpretation in athletes. This finding prompted further diagnostic evaluation. 

Diagnostic Work-up:

1. Transthoracic Echocardiogram (TTE): The TTE revealed regional discrete hypokinesia in the inferoposterior midventricular region, suggesting the possibility of fibrosis.

2. Cyclo-ergometry Stress Test: A standardised protocol was implemented, beginning at 75 watts and incrementing by 30 watts per minute. During the test, seven isolated premature ventricular contractions (PVCs) with left bundle branch block (LBBB) morphology with inferior axis were observed. After 7 minutes, peak exercise was achieved at approximately 272 watts. One minute into the recovery phase, the patient experienced an arrhythmic event during exercise, as illustrated in Figure 2. This event was characterized by rapid monomorphic ventricular tachycardia with LBBB morphology, transitioning in leads V5-V6. At that time, the patient experienced nausea and dizziness but remained hemodynamically stable. The exercise test was subsequently halted, and the patient was placed on the floor to recover. During this period, a 12-lead ECG demonstrated the spontaneous termination of the ventricular tachycardia (VT).

Given these findings, the patient was admitted for further comprehensive evaluation.

3. Cardiac MRI: CMR at our institution revealed RV dysfunction, with a reduced RVEF of 43% and regional hypokinesia in the anterolateral RV wall on cine sequences. Late gadolinium enhancement (LGE) imaging identified areas of non-ischaemic myocardial fibrosis in the anterolateral RV wall and the lateral LV wall, with fibrofatty infiltration.

4. Electrophysiological Study (EPS): The EPS revealed easily inducible runs of both sustained and non-sustained ventricular tachycardia (VT). Electroanatomical mapping identified patchy scar tissue in the anterolateral RVOT. Ablation was performed by targeting the scar tissue. An Ajmaline provocation test was negative, making the presence of Brugada syndrome very unlikely.

Following the ablation, repeat exercise testing was conducted, during which sustained or non-sustained VT could no longer be induced.

Management:

Given the limited arrhythmic substrate, younger age and the nature of the ventricular tachycardia being exercise-induced, we decided against immediate implantation of an implantable cardioverter-defibrillator (ICD). Instead, an internal loop recorder (ILR) was implanted for continuous rhythm monitoring, and the patient was started on a low-dose beta-blocker (1.25 mg). We recommended competitive sports restriction, advising the patient to avoid activities that would elevate his heart rate above 110 beats per minute. While there is no universally fixed heart rate limit, the 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease (1) suggest that maintaining a heart rate below 55% of the predicted maximum (220 - age; 198 beats per minute in this case) is considered low intensity.

Follow-up:

1. Cardiopulmonary Exercise Test with Echocardiography: Follow-up testing revealed a slightly diminished right ventricular contractile reserve. Consequently, the beta-blocker dose was up-titrated.
2. Genetic Testing: Genetic analysis identified a heterozygous pathogenic mutation in the PKP2 gene (c.2489+1G>A in intron 12), which is associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). Consequently, family screening was recommended.

The patient continues to be monitored with the ILR. Given the limited residual arrhythmic substrate and the absence of non-sustained VT episodes on Holter monitoring, we are currently managing conservatively without ICD implantation. However, we maintain a low threshold for ICD placement should the patient’s condition evolve.

Figure 1: 12-lead resting ECG 

Figure 2: exercise ECG testing with sustained ventricular tachycardia

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Case report

Read the corresponding case report:

Paddling Through Palpitations: When Genes, Myocardial Inflammation and Exercise Collide – A Case Report of Arrhythmogenic Cardiomyopathy in a Young Competitive Rower

Boris Delpire, MD, Olivier Ghekiere, MD PhD, Dagmara Dilling-Boer, MD, Pieter Koopman, MD, Guido Claessen, MD PhD, European Heart Journal - Case Reports, ytaf442, https://doi.org/10.1093/ehjcr/ytaf442