Mechanistic Clinical Trial Comparing the Pharmacokinetics/Pharmacodynamics of Metoprolol in Heart Failure With Reduced Ejection Fraction Patients With Low vs. High Polygenic Score

Inclusion criteria

• Heart Failure with Reduced Ejection Fraction (HFrEF)
• Has not taken a beta-blocker within the past 6 months (preferred), or if needed to meet enrollment target, patients that have not taken a beta-blocker in the past 3 months, or only taken a low dose of beta-blocker within the past 6 months (i.e., < 50% of the guideline-recommended HFrEF target dose, or for beta-blockers that are not approved for HFrEF, <50% of the maximum dose)
• Genetic data already available to calculate the polygenic score (e.g., through participation in the Michigan Genomics Initiative (MGI) or other genetic tests) or willingness to provide a deoxyribonucleic acid (DNA) sample for genetic analysis
• White race
• Has been prescribed a stable dose (including no dose) of angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), ARB-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT-2) inhibitor, or mineralocorticoid receptor antagonist (MRA) for at least the past 4 weeks
• Has been prescribed a stable dose (including no dose) of diuretic(s) for at least the past 2 weeks
• For women of child-bearing potential: the participant is willing to perform a pregnancy test and use a highly effective contraceptive method for at least 4 weeks prior to the start of metoprolol treatment, during the entire metoprolol treatment period, and for at least 5 days after the discontinuation of metoprolol treatment
• Ability to understand and willing to sign a written informed consent

Exclusion criteria

• Prior heart transplant or left ventricular assist device (LVAD) or planned within treatment period
• Planned implantation of a pacemaker or Cardiac Resynchronization Therapy (CRT) during treatment period
• Patients with a pacemaker that does not allow their heart rate to change in response to exercise per protocol
• Pregnant
• Systolic blood pressure < 95 millimeters of mercury (mmHg)
• Heart rate < 60 beats per minute
• Second (Mobitz II)- or third-degree heart block
• Cardiogenic shock
• Patients with acute decompensated heart failure requiring current hospitalization or immediate medical intervention.
• Sick sinus syndrome
• Pheochromocytoma
• Known hypersensitivity to the metoprolol succinate oral tablet used in the trial
• Hypertrophic obstructive cardiomyopathy
• Active myocarditis
• Acute coronary syndrome within the past month
• Active or uncorrected severe mitral or aortic valvular dysfunction
• Patients with known severe congenital heart disease per protocol
• Child-Pugh Class C liver disease
• Patients with end-stage renal disease (ESRD) requiring hemodialysis
• Concomitant disease that prohibits participating in Cardiopulmonary Exercise Test (CPET) per protocol
• Concomitant disease with expected survival less than the duration of the study (e.g., metastatic cancer)
• Current or planned treatment with cardiotoxic medications, including interferons and the cancer therapies per protocol
• Concurrent participation in another clinical trial that may affect participant safety or validity of data collected in this clinical trial
• Inability to take oral medication
• Unwilling or unlikely to adhere to the study procedures, as determined at the discretion of the study team, including but not limited to the following reasons:

• Psychiatric illness or other comorbidities
• Substance abuse
• Social or logistical circumstances