ClinicalHeart FailureEffect of preload reducing therapy on right ventricular size and function in patients with arrhythmogenic right ventricular cardiomyopathy
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)
- et al.
Arrhythmogenic right ventricular cardiomyopathy
Lancet
(2009) - et al.
Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice
J Am Coll Cardiol
(2011) - et al.
Abnormal regulation of renin angiotensin aldosterone system is associated with right ventricular dysfunction in hypertension
Can J Cardiol
(2014) - et al.
Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography
J Am Soc Echocardiogr
(2010) - et al.
Evaluation of structural progression in arrhythmogenic right ventricular dysplasia/cardiomyopathy
JAMA Cardiol
(2017) - et al.
Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members
Circ Cardiovasc Genet
(2015) - et al.
Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice
Circulation
(2006)
Cited by (4)
Selection of the best of 2021 in familial heart disease and cardiovascular genetics
2022, REC: CardioClinics
Funding sources: The authors have no funding sources to disclose. Disclosures: The authors have no conflicts of interest to disclose.