The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy. (TEMPO)

The Effect of Metoprolol on Myocardial Function, Perfusion, Hemodynamics and Heart Failure Symptoms in Patients With Hypertrophic Obstructive Cardiomyopathy.

Hypertrophic obstructive cardiomyopathy (HOCM) patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical benefit in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs.

Background Hypertrophic cardiomyopathy (HCM) is characterized by an increase in left-ventricular wall thickness, typically localized at the interventricular septum. The hypertrophy can increase to an extend that causes a dynamic obstruction of the left ventricular outflow tract (LVOTO); these patients have hypertrophic obstructive cardiomyopathy (HOCM). Due to the obstruction, patients develop high interventricular pressure gradients, which may overtime become detrimental to the left ventricular function. HOCM patients often develop disabling symptoms of heart failure. Current treatment strategies are predicated on the empirical use of long-standing drugs, such as beta-adrenergics, although with little evidence supporting their clinical benefit in this disease. Metoprolol is currently the most widely used beta-blocker in symptomatic HOCM patients, but a randomized, placebo-controlled trial, that looks at the effect in HOCM patients has never been conducted. No studies of HOCM combine invasive pressure measurement with exercise and echocardiography. All previous studies, both invasive and echocardiographic, have been conducted during rest, and not during exercise. Symptoms of HOCM patients are function-related, and exercise testing is essential to assess the condition and the effect of drugs. Objective The investigators wants to quantify the effects of metoprolol on myocardial function and perfusion, hemodynamics and heart failure symptoms in patients with HOCM. Hypotheses Primary • Metoprolol treatment reduces ∆ pulmonary capillary wedge pressure (PCWP) (rest-exercise) Secondary Metoprolol treatment reduces PCWP at rest Metoprolol treatment increases maximal oxygen consumption (VO2-max) . Metoprolol treatment reduces LVOT gradient during exercise Metoprolol treatment increases the coronary flow reserve Metoprolol treatment decrease External Work Metoprolol treatment reduces heart failure symptoms, estimated by the Kansas City Cardiomyopathy Questionnaire Design and methods A randomized, double-blinded, placebo-controlled, crossover study, anticipated to examine 32 patients with HOCM both during treatment with metoprolol and placebo. Patients will be examined in a set-up of simultaneous 1) right heart catheterization 2) cardiopulmonary exercise test and 3) transthoracic echocardiography. The set-up allows the investigators to evaluate the hemodynamic values during rest and maximum exercise.

week: uptitration with 50 mg capsules per day, until maximum dosage of 150 mg´s/day. week: steady state treatment with the maximum tolerated dose of the 1.week.

week: uptitration with 1 capsule per day, until maximum tolerated dosage of 3 capsules/day. week: steady state treatment with the maximum tolerated dose of the 1. week

Changes in pulmonary capillary wedge pressure in mmHg from rest to exercise, measured during right heart catheterization

Changes in pulmonary capillary wedge pressure in mmHg during rest, measured during right heart catheterization

Changes in the ratio of maximum coronary blood flow (induced by infusion of adenosin) to resting coronary blood flow, estimated by 2D doppler echocardiography

Changes of symptoms and quality of life with Kansas City Cardiomyopathy Questionnaire assessed by clinical evaluation

Inclusion Criteria: Wall thickness ≥ 15 mm in one or more myocardial segments that is not explained by loading conditions. LVOT gradient > 30 mmHg at rest and/or > 50 mmHg at Valsalva's maneuver or exercise New York Heart Association Functional class (NYHA) ≥ II Exclusion Criteria: Age < 18 years Known allergy to trial medicine Contraindications to beta-blocker treatment Contraindications to Magnetic resonans scan, including contraindication to the contrast agent gadolinium. Female patients who are pregnant (positive plasma-HCG), breastfeeding or of child-bearing potential while not practicing effective chemical contraceptive hormones. In case of patients having a pacemaker, they may not be pace-dependent. Treatment with Amiodarone Atrial fibrillation/flutter at the time of examination Bradycardia < 49 beats/min Systolic blood pressure < 100 mmHg Trifascicular block Previous transcoronary ablation of septum hypertrophy (TASH) or myectomy Current abuse of alcohol and/or drugs Significant co-morbidity or issues that makes the patient unsuitable for participation, judged by the investigator Patients who cannot give valid consent (e.g. mental illness or dementia) Patients who do not understand danish

Dybro AM, Rasmussen TB, Nielsen RR, Ladefoged BT, Andersen MJ, Jensen MK, Poulsen SH. Effects of Metoprolol on Exercise Hemodynamics in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2022 Apr 26;79(16):1565-1575. doi: 10.1016/j.jacc.2022.02.024.

Dybro AM, Rasmussen TB, Nielsen RR, Andersen MJ, Jensen MK, Poulsen SH. Randomized Trial of Metoprolol in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2021 Dec 21;78(25):2505-2517. doi: 10.1016/j.jacc.2021.07.065.