Patient case: 36-year-old female with Brugada syndrome; genetic feature: SCN5A

Clinical trial: PHOspholamban RElated CArdiomyopathy STudy - Intervention

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.

Eligibility: 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

Relevance to patient case: not relevant