Aim: to compare the treatment effects of Bisoprolol (beta 1 receptor specific beta blocker (BB)) and Verapamil (cardio-specific calcium channel blockers (CCB)) in patients with non-obstructive hypertrophic cardiomyopathy (HCM).

Background: Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricular wall and a hypercontracted state of the sarcomeres. This narrows the left ventricular cavity, but though the left ejection fraction is increased the stroke volume and the cardiac output cannot be fully compensated. The disease manifestations can be mild or develop into severe functional limitations and devastating complications at early age. Dyspnea, chest pain, palpitations and syncope are the most common symptoms, and patients are at risk of supraventricular and ventricular arrhythmias. Arrhythmias and sudden cardiac deaths may precede heart failure symptoms. Patients with symptomatic HCM are treated initially with beta blockers and calcium channel blockers. However, there is limited evidence supporting the effectiveness of this guideline-recommended treatment in HCM.

Methods: The study is a multicenter, double-blinded, randomized, placebo-controlled cross-over trial. Patients are randomized in to three 35-days treatment periods with Bisoprolol, Verapamil and Placebo. Each treatment period includes a 7-days up titration period, a 21-days target dose period and a 7-days down titration period. Between treatment periods 45 days treatment pause is allowed. End point will be evaluated at day 21 (- 4 days). Patients will be evaluated by cardiopulmonary exercise test, echocardiography, 7 day Holter-monitoring, biomarkers and the Kansas City Cardiomyopathy Questionnaire (KCCQ). A subgroup of patients will also be evaluated with cardiac magnetic resonance imaging.

Hypotheses: Three separate phases each with one primary effect parameters will be analyzed between treatment with Bisoprolol and Verapamil:

Phase 1: The maximal oxygen consumption (VO2 max) is different (ΔVO2 max ≥1 ml/kg/min) between treatments in non-obstructive HCM patients Phase 2: The left ventricular enddiastolic volume (LVvol) is different (ΔLVvol ≥3 ml) between treatments in non-obstructive HCM patients.

Phase 3: The incidence of non-sustained ventricular tachycardia (NSVT) is different (Hazard ratio ≥ 0.5) between treatments in non-obstructive HCM patients.

The trial will be performed and analyzed in three phases, and each phase may be unblinded and analyzed separately.

Inclusion Criteria:

• Age ≥ 18 years

• Maximal wall thickness ≥ 15 mm unrelated to hypertension, valve diseases or storage diseases. And one of the following:

  1. New York Heart Association - functional class (NYHA) ≥ II
  2. A history of NYHA class ≥ II before treatment with BB or CCB
  3. Pro-BNP>300 ng/l/35>nmol/l or BNP >100ng/l/>29nmol/l
  4. Non-sustained VT (>120 min-1, ≥3 cycles) documented within the last 2 years of screening

Exclusion Criteria:

• Left ventricular ejection fraction < 50%
• LVOT gradient >30 mmHg at rest or during Valsalva maneuver after discontinuation of BB or CCB respectively
• History of LVOT gradient >30 mmHg at rest, during exercise or during Valsalva maneuver.
• Permanent atrial fibrillation
• Permanent right ventricular pacing
• Previous intolerance for Bisoprolol (BB) or Verapamil (CCB)
• Known present obstructive coronary disease (previous percutaneous coronary intervention is accepted)
• eGFR < 40 ml/min
• Fertile women (<50 years) who are pregnant (Positive Plasma-HCG), breastfeeding or not using anticonception.
• Significant liver failure
• Severe valvular disease
• Bradycardia (40bpm)
• Hypotension (systolic <100mmHg)
• Other significant comorbidity or risks associated with discontinuation of BB or CCB after individual judgement by the investigators.
• Unable to understand patient information intellectually or linguistically
• Unable to perform exercise test.
• Unable to speak and/or understand Danish.

Additional exclusion criteria for CMR sub study:

• Implantable cardioverter defibrillator (any kind)
• Pacemaker (any kind)
• Metal implants like to affect image quality
• Metal implants that poses a risk during CMR
• Inability to cope with being in the scanner.