Te Rijdt W P, Hoorntje E T, de Brouwer R, Oomen A, Amin A, van der Heijden J F, Karper J C, Westenbrink B D, Silljé H H W, Te Riele A S J M, Wiesfeld A C P, van Gelder I C, Willems T P, van der Zwaag P A, van Tintelen J P, Hillege J H, Tan H L, van Veldhuisen D J, Asselbergs F W, de Boer R A, Wilde A A M, van den Berg M P
Department of Genetics, University of Groningen, Groningen UMC, Groningen, The Netherlands.
Netherlands Heart Institute, Utrecht, The Netherlands.
Neth Heart J. 2022 Feb;30(2):84-95. doi: 10.1007/s12471-021-01584-5. Epub 2021 Jun 18.
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.
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.
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.
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.
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).
p.Arg14del（c.40_42delAGA）磷酸受磷蛋白（PLN）致病变体是一种奠基者突变，可导致扩张型心肌病（DCM）和致心律失常性心肌病（ACM）。携带者发生恶性室性心律失常和心力衰竭的风险增加，这被认为与心脏纤维化有关。重要的是，心脏纤维化似乎是该疾病的早期特征，在许多无症状携带者中，在明显疾病发作之前就已出现。与大多数单基因心肌病一样，对于无症状携带者尚无循证治疗方法。
磷酸受磷蛋白相关心肌病干预研究（iPHORECAST）旨在证明，使用具有既定抗纤维化作用的盐皮质激素受体拮抗剂依普利酮对无症状PLN p.Arg14del携带者进行抢先治疗，可减少疾病进展并推迟明显疾病的发作。
iPHORECAST采用多中心、前瞻性、随机、开放标签、盲终点（PROBE）设计。无症状PLN p.Arg14del携带者被随机分配接受每日一次50毫克依普利酮治疗或不接受治疗。该研究的主要终点是对疾病进展的多参数评估，包括心脏磁共振参数（左、右心室容积、收缩功能和纤维化）、心电图参数（QRS电压、室性早搏）、与DCM和ACM相关的体征和/或症状以及心血管死亡。随访期设定为3年。
共纳入84例无症状PLN p.Arg14del携带者（每组n = 42例）。按照设计，在基线时，所有参与者均处于纽约心脏协会（NHYA）I级，左心室射血分数> 45%，24小时动态心电图监测期间室性早搏< 2500次。两组在任何基线特征方面均无统计学显著差异。该研究目前进展顺利，预计最后一名参与者将于2021年完成。
iPHORECAST是一项多中心、前瞻性随机对照试验，旨在探讨用依普利酮对PLN p.Arg14del携带者进行抢先治疗是否可预防或延迟心肌病的发作。iPHORECAST已在clinicaltrials.gov注册（编号：NCT01857856）。
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