phospholamban related cardiomyopathy study - intervention

Conditions: Phospholamban R14del Mutation-related Cardiomyopathy

Summary: phospholamban (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.

Eligibility criteria:
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

Keywords: phospholamban cardiomyopathy eplerenone presymptomatic