Title
PHOspholamban RElated CArdiomyopathy STudy - Intervention
PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomaticphospholamban R14del Carriers)
Phase
Phase 3Lead Sponsor
University of GroningenStudy Type
InterventionalStatus
Completed No Results PostedIndication/Condition
Phospholamban R14del Mutation-related CardiomyopathyIntervention/Treatment
eplerenone ...Study Participants
84Phospholamban (PLN) R14del mutation carriers may develop dilated cardiomyopathy (DCM) and/or arrhythmmogenic cardiomyopathy (ACM). Analogous to other inherited cardiomyopathies, the natural course of the disease is age-related ("age-related penetrance"); after a presymptomatic phase of variable length many PLN R14del-carriers progress to overt disease, and are diagnosed with either DCM or ARVC. PLN is a regulator of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) pump in cardiac muscle and thereby important for maintaining Ca2+ homeostasis. Cardiac fibrosis appears to be an early manifestation of disease. The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking properties is a strong antifibrotic agent, reduces disease progression and postpones onset of overt disease.
In the Netherlands ≈15% of idiopathic dilated cardiomyopathy (DCM) and ≈10% arrhythmogenic right ventricular cardiomyopathy (ARVC) patients carry a single (founder) mutation in the gene encoding Phospholamban, PLN R14del. Analogous to other inherited cardiomyopathies, the natural course of the disease is age-related ("age-related penetrance"); after a presymptomatic phase of variable length many PLN R14del-carriers progress to overt disease, and are diagnosed with either DCM or ARVC. PLN is a regulator of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) pump in cardiac muscle and thereby important for maintaining Ca2+ homeostasis. Cardiac fibrosis appears to be an early manifestation of disease. The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking properties is a strong antifibrotic agent, reduces disease progression and postpones onset of overt disease.
eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day
no medical treatment
Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily
Inclusion Criteria: Phospholamban (PLN) R14del mutation carriers Age ≥30 and ≤ 65 years New York Heart Association functional class ≤ 1 LV ejection fraction ≥.45 (measured with MRI) Exclusion Criteria: Palpitations necessitating treatment (at the discretion of the attending physician) A diagnosis of DCM (see appendix 1). Note: regional LV wall motions abnormalities are acceptable. A diagnosis of ARVC (according to the task force criteria, see appendix 2) Global or regional RV dysfunction and/or structural alterations (according to task force criterion 1, see appendix 2). Ventricular premature complexes >1000 during 24hours Holter-monitoring Non-sustained ventricular tachycardia during Holter-monitoring or exercise-testing History of sustained ventricular tachycardia or ventricular fibrillation Hypertension requiring the use of antihypertensive drugs, or when this is anticipated within the coming 3 years Evidence of ischemic heart disease Treatment with cardioactive medication Hyperkaliemia (serum potassium >5.0 mmol/l) Severe renal dysfunction (eGFR <30 ml/min/1.73 m2) Severe hepatic impairment (Child-Pugh class C) Women who are currently pregnant or report a recent pregnancy (last 60 days) or plan on becoming pregnant. Concomitant use of CYP3A4-inhibitors (see appendix 5) Concomitant use of NSAIDs (see appendix 5) Concomitant use of potassium sparing-agents (see appendix 5) Known intolerance or contraindication to aldosterone antagonists Participation in another drug trial in which the last dose of drug was within the past 30 days. Contra-indications for MRI (claustrophobia, metal devices) Subjects unable or unwilling to provide written informed consent
