PHOspholamban RElated CArdiomyopathy STudy - Intervention

M.p. van den Berg, MD, PhD, professor in Cardiology84 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 30 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (4)

AMC

Amsterdam, North Holland, Netherlands

Antonius ziekenhuis Sneek

Sneek, Provincie Friesland, Netherlands

UMCG

Groningen, Netherlands

UMCU

Utrecht, Netherlands

Outcomes

Primary Outcomes

Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI

Time frame: three years

LV ejection fraction, absolute decrease >5%, as measured by MRI

Time frame: three years

Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI

Time frame: three years

RV ejection fraction, absolute decrease >5%, as measured by MRI

Time frame: three years

late gadolinium enhancement, absolute increase >5%, as measured by MRI

Time frame: three years

Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring)

Time frame: yearly at 0, 1, 2 and 3 years

Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)

Time frame: yearly at 0, 1, 2 and 3 years

Change in QRS voltage, decrease >25% (ECG)

Time frame: yearly at 0,1,2 and 3 years

Change in symptoms/signs of heart failure and/or arrhythmias necessitating treatment according to the attending physician and likely due to arrhythmogenic cardiomyopathy

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

(Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

Secondary Outcomes

Change in biomarkers

Time frame: yearly at 0, 1, 2 and 3 years

Change in QRS-axis on 12-lead ECG

Time frame: yearly at 0,1, 2 and 3 years

Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG

Time frame: yearly at 0,1, 2 and 3 years

Change in STT-segment on 12-lead ECG

Time frame: yearly at 0,1, 2 and 3 years

Development of global or regional dysfunction and structural alterations on MRI

Time frame: three years

(Change in) Diagnosis of ARVC (according to task force criteria)

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

(Change in) Diagnosis of DCM

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

(Change in) hospitalization for a cardiovascular reason

Time frame: yearly at 0,1,2 and 3 years, and possibly in between at referral

PHOspholamban RElated CArdiomyopathy STudy - Intervention

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes