Are Disease-Modifying Treatments on the Horizon for Patients With Arrhythmogenic Right Ventricular Cardiomyopathy?

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EP LAB DIGEST. 2024;24(7):6.

Dear Readers,

A 47-year-old previously healthy man presented with a wide QRS complex tachycardia consistent with ventricular tachycardia (VT) at 200 beats per

minute. The VT had a right bundle branch block (RBBB) morphology with a late QRS transition and an inferior axis (Figure 1). He underwent electrical cardioversion. His electrocardiogram (ECG) during sinus rhythm showed a RBBB and a PR interval of 210 msec (Figure 2). Further evaluation included a cardiac MR that showed a low normal left ventricular ejection fraction (LVEF) of 52%, mildly dilated right ventricle (RV), and a mildly reduced RVEF. Imaging criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were not met. An electrophysiology study was performed. Four different monomorphic VTs were induced with programmed electrical stimulation during isoproterenol infusion. The VTs had both right and left bundle morphologies and were pace terminated. The patient underwent implantation of a transvenous dual-chamber defibrillator. He has no family history of cardiac disorders or premature sudden death, and genetic testing results are pending.

ARVC is a genetic condition that is particularly common in Germany and Italy, and is one of the most common causes of sudden cardiac arrest. There are international major and minor criteria for the diagnosis of ARVC based on electrocardiographic and imaging abnormalities.¹ This patient does not meet the diagnostic criteria for ARVC, but his clinical presentation is consistent with some form of an arrhythmogenic cardiomyopathy. Patients who do have ARVC have gene mutations encoding for desmosomal proteins that are located at the intercalated disk involved in cardiac cell-to-cell adhesion. The most common mutation is in plakophilin-2 (PKP2). The mechanism for VT in these patients is the fibrofatty infiltration of the RV myocardium creating substrate for reentry. The RV is usually involved, but the left can also be affected. Although many patients first present with VT, the disease can eventually result in advanced heart failure. An interesting aspect of the disease is that endurance training exacerbates the phenotype both clinically and in animal experiments. For this reason, patients are advised to strictly limit aerobic activities. 

Beyond beta-blockers, antiarrhythmic drugs, catheter ablation, implantable cardioverter-defibrillators, and heart transplantation, there are currently no disease-modifying therapies for patients with ARVC. But just like the recent development of disease-specific therapy for patients with hypertrophic cardiomyopathy with mavacamten,² a drug which reduces myocyte contractility by directly effecting the cardiac myosin heavy chain protein, there appears to be some new developments for the treatment of ARVC. A logical target for ARVC is the PKP2 gene because it is the most common genetic defect in these patients. Earlier this year, van Opbergen and colleagues published their study on the effects of vector-mediated delivery of the human PKP2 gene using an adeno-associated virus to tamoxifen-activated PKP2 knockout mice and found the gene therapy can arrest disease progression and significantly prolong survival.³ The results were dramatic—all of the untreated PKP2 knockout mice died within 50 days, but all of the treated mice survived until the study ended at over 150 days. 

A limitation of gene-specific therapy for ARVC is that there are many mutations that can cause the disease. A more generic approach might be to target the end result of the mutations, which is the formation of myocardial fibrosis. Fibroblast growth factor 21 (FGF21) is a secreted protein that acts as a metabolic regulator for glucose homeostasis, insulin sensitivity, and ketogenesis. It is also produced by cardiac cells and acts in an autocrine manner on the heart itself. FGF21 has been demonstrated to protect against cardiac hypertrophy, cardiac inflammation, and oxidative stress. Prior studies have shown that FGF21 administration effectively suppresses atrial remodeling by reducing oxidative stress.⁴ Companies are now developing antibodies that agonize FGF21 signaling pathways for the treatment of ARVC and are expected to start human clinical trials in the next few months.

ARVC is a devastating inherited disease that tends to affect young adults in the prime of their life, causing life-threatening ventricular arrhythmias with little warning. Fortunately, gene therapy targeting the underlying desmosomal mutation and approaches to prevent myocardial fibrosis independent of the specific genetic defect by increasing cardiac levels of FGF21 may be on the horizon for these patients.

Bradley P Knight, MD, FACC, FHRS

Editor-in-Chief, EP Lab Digest

Disclosures: Dr Knight has served as a paid consultant to Medtronic and was an investigator in the PULSED AF trial. In addition, he has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AltaThera, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Philips, and Sanofi; he has no equity or ownership in any of these companies.

References

1. Corrado D, Zorzi A, Cipriani A, et al. Evolving diagnostic criteria for arrhythmogenic cardiomyopathy. J Am Heart Assoc. 2021;10(18):e021987. doi:10.1161/JAHA.121.021987
2. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977. doi:10.1001/jamacardio.2023.3342
3. van Opbergen CJM, Narayanan B, Sacramento CB, et al. AAV-mediated delivery of plakophilin-2a arrests progression of arrhythmogenic right ventricular cardiomyopathy in murine hearts: preclinical evidence supporting gene therapy in humans. Circ Genom Precis Med. 2024;17(1):e004305. doi:10.1161/CIRCGEN.123.004305
4. Chen M, Zhong J, Wang Z, et al. Fibroblast growth factor 21 protects against atrial remodeling via reducing oxidative stress. Front Cardiovasc Med. 2021;8:720581. doi:10.3389/fcvm.2021.720581