Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

W P Te Rijdt, E T Hoorntje, R de Brouwer, A Oomen, A Amin, J F van der Heijden, J C Karper, B D Westenbrink, H H W Silljé, A S J M Te Riele, A C P Wiesfeld, I C van Gelder, T P Willems, P A van der Zwaag, J P van Tintelen, J H Hillege, H L Tan, D J van Veldhuisen, F W Asselbergs, R A de Boer, A A M Wilde, M P van den Berg, W P Te Rijdt, E T Hoorntje, R de Brouwer, A Oomen, A Amin, J F van der Heijden, J C Karper, B D Westenbrink, H H W Silljé, A S J M Te Riele, A C P Wiesfeld, I C van Gelder, T P Willems, P A van der Zwaag, J P van Tintelen, J H Hillege, H L Tan, D J van Veldhuisen, F W Asselbergs, R A de Boer, A A M Wilde, M P van den Berg

Abstract

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers.

Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease.

Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years.

Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021.

Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Keywords: Cardiomyopathy; Design; Intervention study; Phospholamban; Pre-emptive treatment; Presymptomatic carriers.

Conflict of interest statement

W.P. te Rijdt, E.T. Hoorntje, R. de Brouwer, A. Oomen, A. Amin, J.F. van der Heijden, J.C. Karper, B.D. Westenbrink, H.H.W. Silljé, A.S.J.M. te Riele, A.C.P. Wiesfeld, I.C. van Gelder, T.P. Willems, P.A. van der Zwaag, J.P. van Tintelen, J.H. Hillege, H.L. Tan, D.J. van Veldhuisen, F.W. Asselbergs, R.A. de Boer, A.A.M. Wilde and M.P. van den Berg declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Function of phospholamban. Phospholamban (PLN; blue arrow) is a reversibly phosphorylated transmembrane protein that binds to and regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) pump. From: MacLennan et al. Nat Rev Mol Cell Biol. 2003 [27]. Printed with permission from Springer Nature
Fig. 2
Fig. 2
Left ventricular delayed contrast enhancement in PLN p.Arg14del carrier. Example of left lateral delayed contrast enhancement (arrow; short axis CMR image) in the left ventricle of PLN p.Arg14del carrier. CMR cardiac magnetic resonance, PLN phospholamban

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Source: PubMed

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