Elsevier

Heart Rhythm

Volume 18, Issue 7, July 2021, Pages 1186-1191
Heart Rhythm

Clinical
Heart Failure
Effect of preload reducing therapy on right ventricular size and function in patients with arrhythmogenic right ventricular cardiomyopathy

https://doi.org/10.1016/j.hrthm.2021.03.018Get rights and content

Background

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death in young people and athletes. To date, no treatment has proven to slow the progression of the disease. Preload reducing agents such as nitrates and diuretics have shown promising results in preventing training-induced development of ARVC in a murine model.

Objective

The purpose of this study was to describe our experience with preload reducing therapy in patients with ARVC and symptomatic right ventricular (RV) dysfunction.

Methods

We performed retrospective chart review of prospectively collected registry data and included 20 patients with definite ARVC who had serial echocardiographic measurements and an implantable cardioverter-defibrillator. Six of the 20 patients with RV end-diastolic area (RVEDA) above median (>25 cm2) and New York Heart Association functional class II–IV symptoms were successfully treated with long-term isosorbide dinitrate 5–40 mg tid (at maximum tolerated dose) and hydrochlorothiazide-spironolactone 25–25 mg daily. The main outcomes of interest were RVEDA, RV fractional area change (FAC), and RV outflow tract measurements. Generalized estimating equations with repeated measures were used to identify the association between preload reducing agents and echocardiographic structural progression.

Results

Patients who received preload reducing agents (n = 6) were older and had larger RVs with lower FAC at baseline. However, treatment with preload reducing agents was associated with less RVEDA enlargement during mean 3.3 (range 1–6.7) years of treatment in multivariate analysis (% change in RVEDA associated with treatment –7.71; 95% confidence interval –13.29 to –2.13; P = .007).

Conclusion

Preload reducing agents show promising results in slowing RV enlargement in patients with ARVC and show possible disease-modifying potential.

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder that results in fibrofatty tissue replacement of right ventricular (RV) muscle.1 Genetic mutations related to desmosomes (eg, plakophilin-2, plakoglobin, desmocollin-2, desmoglein-2, desmoplakin) are identified in >60% of these patients.2,3 Mouse models with heterozygous deletion of plakoglobin show progressive RV enlargement and dysfunction as well as inducible ventricular tachycardia (VT) before fibrofatty infiltration. In this murine model, endurance training can accelerate ARVC development and progression, likely by chronically increasing RV load.4 Increased RV load then leads to RV dilation and reduced connexin43 content (gap junctional main protein that allows for electrical coupling between cardiomyocytes) and therefore reduced mechanical connection between cells, which promotes conduction slowing. Interestingly, treatment with preload reducing agents (eg, furosemide, isosorbide dinitrate [ISDN]) in these mice prevented training-induced RV enlargement and was associated with less inducible VT and less RV conduction delay.5 We hypothesized that preload reducing agents in humans may prevent or slow progression of RV dysfunction through the same mechanism.

Section snippets

Study population and design

This was a single-center observational study performed at the University of California San Francisco (UCSF) using prospectively collected data from the UCSF ARVC registry.

All patients were prospectively enrolled into the UCSF ARVC registry. Patients provided consent for genetic study and review of their medical records. As part of this registry, patients are followed regularly with clinic visits, serial electrocardiograms, echocardiograms, and device interrogations at an interval that is

Results

Of the 54 patients included in the UCSF ARVC registry, 27 with an ICD had definite ARVC based on 2010 Task Force Criteria, with at least 2 serial echocardiograms performed at least 6 months apart. Ten patients with RVEDA above the UCSF cohort median (>25 cm2) and at least New York Heart Association functional class II symptoms were offered preload reducing therapy. All patients had normal left ventricular ejection fraction at the time of treatment eligibility (Figure 1). Seven patients chose to

Discussion

We found that preload reducing agents showed promise in slowing RV structural changes in patients with ARVC, particularly in patients with no significant comorbidities. To our knowledge, this is the first study in humans that describes the effect of preload reduction on ARVC progression. ARVC is known to be a progressive disease associated with enlargement of RVEDA, RV dysfunction, and heart failure. 2,12,13 Abnormal RV function and symptomatic RV failure in patients with ARVC have shown to be

Conclusion

Treatment with preload reducing agents in 6 patients with ARVC and symptomatic RV dysfunction was associated with slowing RV enlargement over mean 3.3 (range 1–6.7) years of treatment. A multicenter, multinational randomized trial is required to definitively characterize the relationship between preload reducing agents and ARVC progression.

Acknowledgements

We would like to acknowledge Jana Svetlichnaya, MD, MS, and Dwight Bibby, RDCS, for their help in collecting data.

References (15)

There are more references available in the full text version of this article.

Cited by (4)

Funding sources: The authors have no funding sources to disclose. Disclosures: The authors have no conflicts of interest to disclose.

View full text