Arrhythmogenic Cardiomyopathy Diagnosed Late in a Master Recreational Endurance Athlete

Abstract

Background

Prompt recognition of arrhythmogenic conditions in recreational and competitive athletes is essential for clinical management and for providing appropriate exercise recommendations.

Case Summary

We report the case of a 67-year-old athletic individual with a high burden of ventricular arrhythmias and a phenotype within the dilated/nondilated left ventricular cardiomyopathy spectrum. Genetic testing identified a likely causative variant in the Filamin C (FLNC) gene. An integrative evaluation incorporating advanced cardiac imaging, genetic analysis, and invasive electrophysiology was undertaken to optimize risk stratification and customize exercise counseling.

Discussion

In arrhythmogenic cardiomyopathy with confirmed or suspected genetic etiology, a multimodal evaluation is essential for accurate patient phenotyping. The impact of exercise on disease expression in specific gene variants associated with predominantly left-sided involvement remains insufficiently understood and requires further research and shared decision-making.

Take-Home Message

A comprehensive multidisciplinary evaluation is key for diagnosis, risk stratification, and management of athletes with ventricular arrhythmias.

Visual Summary

Visual Summary.

Case Presentation and Clinical Insights

ACM = arrhythmogenic cardiomyopathy; CMR = cardiac magnetic resonance; EPS = electrophysiological study; FLNC = Filamin C; ICD = implantable cardioverter defibrillator; LGE = late gadolinium enhancement; LV = left ventricle; LVEF = left ventricular ejection fraction; PVC = premature ventricular contraction; SMVT = sustained monomorphic ventricular tachycardia.

History of Presentation

A 67-year-old man was referred for further evaluation because of a high burden of premature ventricular contractions (PVCs) detected on 24-hour electrocardiographic (ECG) monitoring in more than 1 occasion. He had been experiencing palpitations for the past 6 years, but he described no episodes of syncope or chest pain, and his functional status was NYHA functional class I. His resting ECG showed an early transition zone, a normal repolarization pattern and fairly small inferior limb lead voltages (Figure 1A). A recent transthoracic echocardiogram had revealed a mildly dilated left ventricle (left ventricular end-diastolic diameter of 57 mm and left ventricular end-diastolic volume indexed for body surface area of 77 mL/m²) with preserved systolic function (left ventricular ejection fraction [LVEF] of 55% by biplane Simpson's method), without significant valvular disease or right ventricular dysfunction. Ambulatory ECG recordings over the past 3 years had shown an increased burden of PVCs, with a documented maximum of 10,764 PVCs over 24 hours, corresponding to 11% of total beats. Several months before referral, the patient had been commenced on bisoprolol uptitrated to a maximum tolerated dose of 5 mg; this led to some symptomatic improvement, but no remarkable reduction in the PVC burden.

Figure 1.

Electrocardiographic and Imaging Data of the 67-Year-Old Athlete Presenting With Arrhythmias

Resting electrocardiogram (ECG) showed an early transition zone, normal repolarization, and fairly small inferior lead voltages (A). The updated 24-hour ECG monitoring on β-blocker therapy recorded 7,996 premature ventricular contractions with at least 2 different morphologies occurring in bigeminy, trigeminy, and couplets (B). Late gadolinium enhancement on cardiac magnetic resonance identified subepicardial and midwall fibrosis with a ring-like pattern, affecting 12% of the left ventricular mass (C).

Past Medical and Family History

The patient had a known history of arterial hypertension and dyslipidemia, both managed adequately, as well as a previous percutaneous coronary intervention to the left anterior descending artery. He had been an avid cyclist for over 20 years, with typical training volumes of approximately 8 to 10 hours per week and previous participation in several local competitive events. In the 2 years before presentation, he had modified his weekly training routine, performing an average of three 2-hour sessions of road cycling, during which his smartwatch recorded a peak heart rate (HR) of up to 130 beats/min (which would be estimated at 81% of the age-predicted maximal HR of 161 beats/min based on the widely used formula “208 – 0.7 × age”), reportedly sustained for up to one-third of his training sessions. A 3-generation pedigree did not identify any family members with a history of cardiomyopathy or unexpected cardiac death.

Differential Diagnosis

The primary differential diagnoses at this stage, based on the clinical and imaging findings and the patient's history, included an arrhythmogenic cardiomyopathy in the dilated/nondilated left ventricular cardiomyopathy spectrum,¹ PVC-induced cardiomyopathy, an expression of exercise-induced cardiomyopathy (although mostly reported with respect to right ventricular involvement, left ventricular involvement has also been speculated²), and prior myocarditis, albeit without any documented episode according to the patient.

Investigations

His laboratory workup demonstrated N-terminal pro–B-type natriuretic peptide levels of 201 pg/mL, well below the age-adjusted upper limit of normal. An updated 24-hour ECG rhythm monitoring documented 7,996 PVCs of at least 2 morphologies occurring in bigeminy, trigeminy, and some couplets (Figure 1B). The predominant PVC morphology recorded on a 12-lead ECG arose from the left ventricular outflow tract, more specifically close to the anterior interventricular sulcus. A cardiac magnetic resonance scan documented a mildly elevated indexed left ventricular volume and normal biventricular ejection fraction. The late gadolinium enhancement (LGE) imaging study showed subepicardial and midwall fibrosis predominantly in the basal inferior and basal inferolateral walls with a ring-like pattern (Figure 1C), calculated at 12% of the left ventricular (LV) mass. Repeat coronary angiography did not reveal significant coronary stenosis. Per standard of practice, cardiopulmonary exercise testing (CPET) was performed under stable β-blocker therapy. The peak oxygen uptake was 25.5 mL/kg/min (corresponding to 89% of the maximum predicted), and the first ventilatory threshold occurred at an oxygen uptake of 19 mL/kg/min and an HR of 121 beats/min. The peak HR achieved was 141 beats/min, without ST-segment changes but with persistence of PVCs during exercise.

Genetic counseling and genetic testing were offered to further investigate the patient's condition. Genetic testing identified a candidate variant in the Filamin C (FLNC) gene (NM_001127487.1: c.2092G>A p.ly698Ser) in a heterozygous state. This specific missense variant in the FLNC gene has previously been reported in public databases (ClinVar) as a variant of unknown significance. However, according to the American College of Medical Genetics criteria this missense variant fulfilled PM2 (rare in the population databases; gnomAD 0.0009%), PP3 (possibly deleterious effect on the protein produced based on in silico tools; aggregated score, 0.84), and PP4 (based on deep phenotyping of the patient). Overall, these supported reclassification of the variant to likely pathogenic status.³

Management

Based on a local protocol,⁴ although not considered standard care for all FLNC variant carriers, we decided to proceed with an electrophysiological study, including programmed ventricular stimulation. Using a standardized protocol of up to 3 extrastimuli, without inotropic infusion, presyncopal sustained monomorphic ventricular tachycardia was induced. Considering all available data, a multidisciplinary team discussion was conducted alongside shared decision-making with the patient, and it was agreed that the patient would benefit from an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death.

Given the patient's strong desire to continue cycling, exercise counseling was undertaken in the dedicated Sports Cardiology clinic within a shared decision-making framework. Current clinical recommendations5, 6, 7 as well as emerging research data⁸ were discussed. A structured program was agreed on, consisting mainly of steady-state road cycling on flat or gently undulating terrain, 3 to 5 times per week for 30 to 60 minutes per session. Exercise was to be performed at or slightly below the patient's individual first ventilatory threshold, as determined by CPET, which corresponded to a HR of approximately 121 beats/min while on β-blocker therapy, or at an intensity at which he could still converse comfortably. Each session was to include low-intensity warm-up and cool-down periods, and he consented to avoid high-intensity efforts, including maximal efforts, races, sprints, and sustained climbs, as well as to interrupt exercise in the presence of limiting symptoms or palpitations.

Outcome and Follow-Up

Up to the latest follow-up, our patient remained asymptomatic, in good functional state, on β-blocker therapy and without any ICD shocks.

Discussion

We present the case of a recreational master athlete with a late diagnosis of arrhythmogenic cardiomyopathy attributed to a variant in the gene of FLNC, a cytoskeletal protein that stabilizes the architecture of the sarcomere. Variants of the FLNC gene have been linked to a broad spectrum of cardiomyopathy phenotypes, with considerable overlap and diverse arrhythmic profiles; still much remains to be understood about their penetrance and expressivity.⁹ Truncating mutations have been primarily associated with an overtly arrhythmogenic cardiomyopathy phenotype with distinct nonischemic LV fibrosis patterns,^9,10 and their arrhythmic potential is reflected in the European Society of Cardiology guideline recommendations.^5,6 Recent efforts to more accurately stratify arrhythmic risk for truncating variant carriers have led to the development of a dedicated risk score, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF.¹¹ In contrast, the pathogenicity and natural disease course of arrhythmogenic phenotypes associated with nontruncating FLNC variants remain far less clear, with scarce clinical evidence regarding their management.⁹

Exercise counseling in arrhythmogenic cardiomyopathy poses a challenge to experts in Sports Cardiology clinics. On one hand, remaining active provides physical and psychological benefits. On the other hand, there is a potential impact of high-intensity exercise on disease expression and arrhythmic risk in FLNC variant carriers, as limited data have suggested that vigorous exercise could accelerate phenotypic features.¹² However, recent clinical data are more reassuring; a retrospective study that analyzed 45 carriers of truncating FLNC variants (probands and relatives) found that high-intensity exercise was not significantly associated with increased risk of life-threatening arrhythmias, LV systolic dysfunction, or structural cardiac disease over a mean 4.9-year follow-up.¹³ The 2020 European Society of Cardiology Sports Cardiology guidelines advise against high-intensity exercise in arrhythmogenic cardiomyopathy patients when at least 1 high-risk feature, including LVEF<45%, frequent and/or complex ventricular arrhythmias on ambulatory ECG monitoring or exercise testing, LGE on cardiac magnetic resonance, or a high-risk genotype including FLNC variants is present.⁵ The latest American Heart Association/American College of Cardiology clinical considerations for competitive sport participation also mention the link between FLNC variants and ventricular arrhythmias and advocate a cautious, shared decision-making approach, mainly extrapolating conclusions from the paradigm of typical right ventricular arrhythmogenic cardiomyopathy.⁷

Although our patient had a high burden of PVCs and extensive LGE, which generally warrant caution per current guidelines,5, 6, 7 he expressed a strong desire to continue cycling. We explicitly informed him of the potential risks and, at the same time, the limited data on specific genetic cardiomyopathies, such as filaminopathies, so that he could make an informed decision. Our proposed plan to keep his training intensity below the first ventilatory threshold as measured by CPET opted to balance the patient's wish to continue an active lifestyle with the potential risks. Importantly, the decision to implant an ICD was based on a comprehensive risk stratification process, independently of the patient's wish to keep exercising, as current guidelines do not support ICD implantation solely to facilitate sports participation; rather, they recommend carefully supervised continuation of tailored exercise in selected individuals with an ICD.^5,7

Conclusions

Current understanding of arrhythmogenic cardiomyopathies is still evolving, and further research is warranted to understand triggers of phenotypic expression and optimal arrhythmic risk stratification approaches in the setting of FLNC variants. The role of exercise in promoting disease expression is less well established, and diagnosis as well as management of cardiomyopathy in the dilated cardiomyopathy/nondilated left ventricular cardiomyopathy spectrum among endurance athletes may be particularly challenging. Shared decision-making is necessary for patients who wish to continue exercising. Our case demonstrates how we used comprehensive clinical, imaging, genetic, and sports cardiology evaluation to facilitate personalized medicine in this setting.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •Filamin C variants have been associated with arrhythmogenic cardiomyopathy; comprehensive multidisciplinary evaluation incorporating clinical history, cardiac imaging, and genetic testing is key to diagnosis, risk stratification, and management.
• •Genetic cardiomyopathies should be considered in individuals who engage in a high volume of exercise and present with ventricular arrhythmias and nonischemic left ventricular fibrosis. For those who wish to remain physically active, exercise recommendations should be individualized, guided by cardiopulmonary exercise testing and shared decision-making.