The purpose of this trial is to better understand how the beta-blocker metoprolol works in people with Heart Failure with Reduced Ejection Fraction (HFrEF) according to participants genetics. Participants will have the beta-blocker (BB) polygenic score calculated from genotype data. The score will be used to stratify the patients in the low and high polygenic score groups in the study.

The hypotheses for this trial are:

• HFrEF patients with high polygenic score will have weaker cardiovascular responses to metoprolol succinate than HFrEF patients with low polygenic score.
• HFrEF patients with high polygenic score have lower steady-state plasma concentrations of metoprolol succinate than HFrEF patients with low polygenic score.
• HFrEF patients with high polygenic score require higher metoprolol succinate plasma concentrations to achieve similar cardiovascular effects as those with low 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:

  1. Psychiatric illness or other comorbidities
  2. Substance abuse
  3. Social or logistical circumstances