Metabolomics insights into the causal associations between antihypertensive drugs and myocarditis.

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.