Prognostic relevance of β1-adrenergic receptor polymorphisms on cardiovascular outcome in patients treated with metoprolol after acute myocardial infarction - an observational study.
Bruun L, Andersen G, et al. • European journal of clinical pharmacology • 2026
In post-AMI patients treated with metoprolol, Gly389 homozygotes but not heterozygotes were associated with an increased risk of MACE compared with Arg389 homozygotes, and observations raise the possibility of a protective association of the Gly49 variant on cardiovascular death.
Key Findings
Results
Gly389 homozygotes had a significantly increased risk of MACE compared with Arg389 homozygotes in post-AMI patients treated with metoprolol.
When Gly49 homozygotes and heterozygotes were merged, there was a numerical but not statistically significant reduction in cardiovascular deaths compared to Ser49 homozygotes (p=0.07)
Results
The Arg389Ser49 haplotype was not associated with a primary outcome.
Haplotype copy number analysis was used in addition to dominant and codominant genetic models
No statistically significant association was found between the Arg389Ser49 haplotype and MACE or cardiovascular death
The study assessed both MACE and cardiovascular death as primary endpoints
Methods
Over three years of follow-up, MACE occurred in 105 and cardiovascular death in 47 patients among 1584 post-AMI patients treated with metoprolol.
Total study population: n=1584 patients hospitalized for AMI and treated with metoprolol at discharge
Total MACE events: 105
Total cardiovascular deaths: 47
Patients were genotyped for two ADRB1 variants: Arg389Gly and Ser49Gly
Cox proportional hazards models using dominant and codominant genetic models were applied
Discussion
The study raises the possibility of a protective association of the Gly49 variant on cardiovascular death, but this requires validation in larger studies.
The Gly49 carrier group showed a numerical trend toward fewer cardiovascular deaths (p=0.07), falling short of conventional significance thresholds
The Gly49 homozygote group was small (n=28) with zero events, limiting statistical power
Authors explicitly state 'this hypothesis requires validation in larger, future studies'
The observational study design limits causal inference
What This Means
This research examined whether genetic differences in the beta-1 adrenergic receptor (the main target of the heart medication metoprolol) affect how well patients fare after a heart attack. The study followed 1,584 patients who were prescribed metoprolol after an acute heart attack (AMI) for three years, tracking serious heart-related events (called MACE) and cardiovascular deaths. Patients were genotyped for two genetic variants: Arg389Gly and Ser49Gly.
The study found that patients who inherited two copies of the Gly389 gene variant (homozygotes) had roughly twice the risk of experiencing a major cardiovascular event compared to patients with two copies of the Arg389 variant, even though both groups were treated with metoprolol. Interestingly, patients with only one copy of Gly389 (heterozygotes) did not show this elevated risk at a statistically significant level, suggesting the effect may depend on having two copies of the variant. For the Ser49Gly variant, patients carrying the Gly49 version showed a trend toward fewer cardiovascular deaths—and none of the 28 patients with two copies of Gly49 died of cardiovascular causes during follow-up—though this finding did not reach statistical significance, likely due to the small number of such patients.
This research suggests that a person's genetic makeup at the beta-1 adrenergic receptor gene may influence how protective metoprolol is after a heart attack, potentially explaining why some patients do better than others on the same medication. However, because this was an observational study and some of the findings did not reach conventional statistical significance, the results should be interpreted cautiously. Larger studies are needed to confirm whether genetic testing for these variants could one day help personalize heart attack treatment decisions.
Bruun L, Andersen G, Myhre P, Halvorsen S, Kringen M, Hansen C, et al.. (2026). Prognostic relevance of β1-adrenergic receptor polymorphisms on cardiovascular outcome in patients treated with metoprolol after acute myocardial infarction - an observational study.. European journal of clinical pharmacology. https://doi.org/10.1007/s00228-026-04091-x