Lactate levels and heart failure: causal insights from Mendelian randomization and multi-cohort integrated analyses

To explore the causal link between genetic predisposition for elevated lactate levels and heart failure (HF) via Mendelian randomization (MR), and investigate lactate-related genetic mechanisms and mediating pathways.

Lactate and HF summary data were from genome-wide association studies (GWAS). MR analyses used inverse variance weighting (IVW) as the main method; cardiac imaging trait MR focused on UK Biobank data. Mediation analysis examined CD20⁺ memory B cells' role in NUP50-HF pathway.

MR showed that genetically predicted elevated lactate causally increased HF risk independent of hypoperfusion (reverse causality excluded) and reduced left ventricular ejection fraction (LVEF), implying a cardiac function-impairment pathway. NUP50, a key lactate-related gene, positively associated with HF. Its HF effect was partially mediated by CD20⁺ memory B cells; both independently linked to HF risk.

Elevated lactate may increase HF risk via impaired cardiac function. NUP50 and other lactate-related genes may regulate HF risk (NUP50 partially via CD20⁺ memory B cells), highlighting lactate and its genetic pathways as potential HF prevention/treatment targets.