Int Immunopharmacol. 2025 May 26;159:114946. doi: 10.1016/j.intimp.2025.114946. Online ahead of print.
ABSTRACT
BACKGROUND: The role of various antihypertensive drug classes in myocarditis remains unclear. We aimed to investigate the causal effects of antihypertensive medications on myocarditis and identify potential metabolic pathways.
METHODS: We extracted single-nucleotide polymorphisms for systolic blood pressure (SBP) and diastolic BP (DBP) from a genome-wide association study (N = 757,601) and screened single-nucleotide polymorphisms associated with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers (BB), calcium channel blockers (CCB), and thiazides as instrumental variables. Summary-level statistics of myocarditis were sourced from the FinnGen study, encompassing 1847 cases and 231,952 controls. We subsequently performed a drug-targeted Mendelian randomization (MR) and a two-step network MR approach to investigate the causal impact of antihypertensive medications on myocarditis and to uncover metabolic mediators.
RESULTS: Our study revealed that elevated SBP (odds ratio [OR] = 1.05, 95 % confidence interval [CI] = 1.04-1.06, p = 4.75 × 10-14) and DBP (OR = 1.07, 95 % CI = 1.05-1.10, p = 1.54 × 10-10) significantly increased myocarditis risk. Conversely, the use of BB (OR = 0.86, 95 % CI = 0.82-0.90, p = 5.14 × 10-10) and CCB (OR = 0.95, 95 % CI = 0.92-0.99, p = 0.005) to lower BP was associated with a reduced risk of myocarditis. Network MR analyses identified four and seven metabolites mediating BB and CCB associations with myocarditis, respectively. Methyl indole-3-acetate mediated a significant portion of the relationships between BB and myocarditis (mediation proportion = 6.82 %), while phenylalanine to tyrosine ratio was the predominant mediator (mediation proportion = 11.35 %) linking CCB to myocarditis.
CONCLUSIONS: Our findings suggest that reducing BP through antihypertensive drugs, specifically BB and CCB, may hold potential for preventing myocarditis and have identified several metabolic pathways linking these associations.
PMID:40424652 | DOI:10.1016/j.intimp.2025.114946
