UPBEAT: Using Polygenic Scores to Guide BB Therapy in HF With Mildly Reduced EF (UPBEAT)

Using Polygenic Scores to Guide Beta-blocker Therapy for Heart Failure With Mildly Reduced Ejection Fraction

This study will use polygenic scores, a tool which describes differences in genetics, to examine effectiveness of beta blocker medication in heart failure patients with ejection fraction of 41-50 percent. The study will also assess beta blockers' effect on the changes in left ventricular end-systolic volume index by MRI.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Polygenic Score
• Intervention / Treatment: Other: Beta blocker

Detailed Description

Heart failure (HF) is a major public health problem that displays wide variation in progression and response to therapy. Beta-blockers (BB) are the cornerstone of treatment for HF reduced ejection fraction (HFrEF) but only ~25% of patients experience a marked and sustained ejection fraction (EF) response, and they can have unwanted side effects (fatigue, depression, erectile dysfunction, others). The potential for Precision Medicine to improve HF care is great, but despite proof of concept, actionable ways are still lacking to use genomic or biomarker strategies to predict response to typical treatment. An important limitation of pharmacogenetics to date is that most studies used candidate gene approaches, assuming other loci are not meaningful. Unbiased approaches (e.g. genome-wide [GW] association) overcome this, but the typical analysis requires stringent significance levels which result in missing potentially important sources of variation. Common complex disease and drug responses are unlikely to be under strong single-loci influence (e.g., Mendelian disease), and instead are likely influenced by many loci that have relatively weak effects (i.e., polygenicity); such phenotypes are better tackled with approaches like polygenic risk scores. The PI has developed and validated a polygenic score for BB drug-response (in terms of mortality benefit) in HF for European ancestry patients and is currently developing a new score for diverse ancestries, particular African ancestry and admixed populations. To move this new paradigm for precision medicine forward to clinical utility, a randomized trial of BB by genomic (polygenic score) subgroups is needed. Moreover, pivotal trials of BB in HF excluded patients with mildly reduced EF (HFmEF, 40-50%), representing a public health issue of significant size (an estimated prevalence of 1.6M Americans) where currently BB may or may not be used and with limited data to guide who should or should not receive this key therapy. HFmEF patients have abnormal systolic function, high event rates, share many characteristics with HFrEF, and the polygenic response score correctly differentiates responders from non-responders in this group, making them the ideal group of patients in which to test genomically targeted BB treatment in a clinical trial. This pilot study will demonstrate feasibility of a future phase 2 study. That study, if successful would potentially revolutionize HF care by demonstrating signs of efficacy in terms of polygenic drug targeting.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Whitney Cabral, MS; Phone Number: 313-949-6616; Email: wcabral1@hfhs.org

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Health
      • Contact: Whitney Cabral; Phone Number: 313-949-6616; Email: WCABRAL1@hfhs.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-89 years
• Ejection Fraction (EF) >40% and =<50% by any modality within 1 year (must be most recent)
• Clinical diagnosis of HF within 1 year, evidenced by any one: Hospital discharge with primary or secondary HF diagnosis, ER discharge with primary diagnosis of HF, ambulatory diagnostic code for HF and diuretic use, BNP>35 ng/L or NTproBNP >125 ng/L at any time
• Expected ability to fully participate in study (can tolerate study processes, no long travel)

Exclusion Criteria:

• Unable to provide informed consent
• Previous documented EF =< 35%
• Currently on BB =>25% target dose
• Uncontrolled hypertension (systolic BP > 180 at enrollment)
• Has contraindications to all BB or intolerance to metoprolol
• Systolic BP < 100 or heart rate <70
• Current cancer requiring active treatment
• Heart transplant or LVAD or expected in the next year
• Life expectancy < 1 year for any reason
• Dialysis dependence or ESRD
• MI/ PCI or other cardiac surgery within 90 days prior to enrollment or planned in the future
• Absolute indication for BB other than heart failure (e.g. tachyarrhythmia required BB for rate control, angina)
• If PI decides for any reason participation in trial is not in best interest of the patient
• Has a contraindication to completing MRI procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Beta Blocker; This group will be dispensed and titrated on beta blocker according to study protocol.	Other: Beta blocker; Participants randomized to intervention will be dosed and titrated on beta blocker according to study protocol.
No Intervention: Placebo; This group will be dispensed and titrated on placebo according to study protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricle end systolic volume index	LVESVi, measured in mL per square meter; assessed by cardiac MRI	Within 6 months of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other MRI ventricular performance characteristics: Left ventricular EF	Left ventricular EF, measured in percentage	Baseline and within 6 months of randomization
Other MRI ventricular performance characteristics: Left ventricular end-diastolic volume index	Left ventricular end-diastolic volume index (LVEDVi) as assessed by cardiac MRI, measured in mL per square meter	Baseline and within 6 months of randomization
Clinical effects: blood pressure	Change in Blood pressure, measured in mmHg	Baseline through exit visit, an interval of approximately 6 months
Clinical effects: Heart rate	Change in Heart rate, measured in beats per minute	Baseline through exit visit, an interval of approximately 6 months
Change in NT-proBNP levels	Blood test for biomarker level of N-terminal pro Brain natriuretic protein, measured in ng/L	Baseline and within 6 months of randomization
Quality of life status	Summary score of KCCQ	Baseline and monthly for duration of approximately 6 months
Functional status	Change in 6-minute-walk-test, measured in meters	Baseline through exit visit, an interval of approximately 6 months
Clinical safety events	Measured in all-cause mortality	Baseline through 30 days following completion of exit visit
Clinical safety events	Measured in heart failure hospitalizations and emergency room visits	Baseline through 30 days following completion of exit visit
Clinical safety events	Measured in symptomatic hypotension or syncope	Baseline through 30 days following completion of exit visit

Collaborators and Investigators

• Sponsor: David Lanfear
• Investigators: Principal Investigator: David Lanfear, MD, Henry Ford Health

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: March 24, 2025
• First Submitted That Met QC Criteria: June 27, 2025
• First Posted (Actual): July 8, 2025

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Metoprolol; Beta blocker
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Adrenergic Agents; Adrenergic Antagonists; Pharmacologic Actions; Chemical Actions and Uses; Adrenergic beta-Antagonists
• Other Study ID Numbers: 17427

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No