Phospholamban R14del Mutation-related Cardiomyopathy
Conditions
Keywords
Phospholamban, cardiomyopathy, Eplerenone, presymptomatic
Brief 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.
Detailed description
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.
Interventions
DRUGEplerenone
eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day
Sponsors
M.p. van den Berg, MD, PhD, professor in Cardiology
University Medical Center Groningen
The Interuniversity Cardiology Institute of the Netherlands
ZonMw: The Netherlands Organisation for Health Research and Development
Netherlands: CVON, CardioVascular Research Netherlands
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| (Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy | yearly at 0,1,2 and 3 years, and possibly in between at referral |
| Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI | three years |
| LV ejection fraction, absolute decrease >5%, as measured by MRI | three years |
| Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI | three years |
| RV ejection fraction, absolute decrease >5%, as measured by MRI | three years |
| late gadolinium enhancement, absolute increase >5%, as measured by MRI | three years |
| Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring) | yearly at 0, 1, 2 and 3 years |
| Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing) | yearly at 0, 1, 2 and 3 years |
| Change in QRS voltage, decrease >25% (ECG) | 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 | yearly at 0,1,2 and 3 years, and possibly in between at referral |
Secondary
| Measure | Time frame |
|---|---|
| Change in QRS-axis on 12-lead ECG | yearly at 0,1, 2 and 3 years |
| Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG | yearly at 0,1, 2 and 3 years |
| Change in STT-segment on 12-lead ECG | yearly at 0,1, 2 and 3 years |
| Development of global or regional dysfunction and structural alterations on MRI | three years |
| (Change in) Diagnosis of ARVC (according to task force criteria) | yearly at 0,1,2 and 3 years, and possibly in between at referral |
| (Change in) Diagnosis of DCM | yearly at 0,1,2 and 3 years, and possibly in between at referral |
| Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation | yearly at 0,1,2 and 3 years, and possibly in between at referral |
| (Change in) hospitalization for a cardiovascular reason | yearly at 0,1,2 and 3 years, and possibly in between at referral |
| Change in biomarkers | yearly at 0, 1, 2 and 3 years |
Countries
Netherlands
Outcome results
None listed