Integrative Evidence From Metabolome‐Wide Mendelian Randomization and Animal Models Implicates Tyrosine in Cardiac Hypercontractility and Arrhythmia Risk

ABSTRACT Arrhythmias account for approximately 80% of sudden cardiac deaths, posing a significant challenge to public health. Investigating the relationships between plasma metabolites and arrhythmia contributes to understanding disease etiology and informing therapeutic strategies. In this research, we accessed the causal links between 735 circulating metabolites and arrhythmias using Mendelian randomization (MR) across multiple genome‐wide association studies (GWAS) datasets and meta‐analyzed the results. Tyrosine showed the strongest putative causal association with arrhythmias and their risk factors. We further replicated this finding using independent GWAS data from FinnGen, providing additional support. Moreover, genetic loci associated with circulating tyrosine levels were significantly enriched for genes implicated in cardiovascular disease. To provide experimental support, we tested these predictions in an animal model. Transthoracic echocardiography demonstrated that tyrosine increased ejection fraction and fractional shortening, indicating enhanced cardiac systolic function. Transcriptomic analysis indicated that tyrosine activated adrenergic signaling in cardiomyocytes, which promotes cardiac conduction and muscle contraction. Consistently, tyrosine elevated serum epinephrine levels in a dose‐dependent manner. Furthermore, metabolomic profiling showed that tyrosine altered serum metabolites previously linked to arrhythmias. In conclusion, convergent evidence from genetic analyses and animal experiments suggests that excessive dietary tyrosine induces cardiac hypercontractility, and circulating tyrosine may serve as a potential target for arrhythmia prevention.