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. Heart failure is a common, serious condition where the heart cannot pump blood well enough to meet the body’s needs. High levels of a substance called lactate (made when cells break down sugar without enough oxygen) are often seen in people with heart failure, but it was unclear if high lactate actually causes heart failure or just happens because of the disease. To answer this, our study used a special genetic method called Mendelian randomization—this method uses genes (which are fixed from birth) to check if high lactate levels cause heart failure, avoiding confusion from other health issues (like diabetes or kidney problems) that might affect both lactate and heart failure. We also looked at heart scans (to measure how well the heart pumps) and genes linked to lactate, plus immune cells that might connect these genes to heart failure. We found that people with genetic traits leading to higher lactate levels have a 37% higher risk of heart failure, and this is not because heart failure causes high lactate (we ruled out that reverse effect). High lactate was also linked to worse heart pumping function. We identified a gene called NUP50 (linked to lactate) that increases heart failure risk, and part of this effect happens through a type of immune cell called CD20+ memory B cells—these cells can promote inflammation that harms the heart. Our findings mean high lactate is not just a sign of heart failure but a cause, so lowering lactate levels might help prevent or treat heart failure. Targeting NUP50 or the immune cells it affects could also be new ways to fight heart failure. This helps make heart failure care more personalized, like using genetic or lactate tests to spot people at higher risk earlier. This study confirms a significant positive causal association between elevated lactate levels and an increased risk of heart failure through Mendelian randomization analysis, with reverse causality excluded.Higher lactate levels are causally linked to a reduced left ventricular ejection fraction, suggesting a potential pathway through impaired cardiac function in heart failure development.Lactate-related gene NUP50 is identified as a key player, showing a significant positive association with heart failure, and its effect on heart failure is partially mediated by CD20+ memory B cells.Integrated analyses including eQTL, pQTL, SMR, and colocalization analyses reveal other relevant lactate-related genes (such as SIRT6, VCAN, HDAC3, KAT5) and proteins (RACGAP1, PLOD2) associated with heart failure.These findings highlight lactate and its related genetic pathways, as well as immune mediators like CD20+ memory B cells, as potential targets for heart failure prevention and treatment. This study confirms a significant positive causal association between elevated lactate levels and an increased risk of heart failure through Mendelian randomization analysis, with reverse causality excluded. Higher lactate levels are causally linked to a reduced left ventricular ejection fraction, suggesting a potential pathway through impaired cardiac function in heart failure development. Lactate-related gene NUP50 is identified as a key player, showing a significant positive association with heart failure, and its effect on heart failure is partially mediated by CD20+ memory B cells. Integrated analyses including eQTL, pQTL, SMR, and colocalization analyses reveal other relevant lactate-related genes (such as SIRT6, VCAN, HDAC3, KAT5) and proteins (RACGAP1, PLOD2) associated with heart failure. These findings highlight lactate and its related genetic pathways, as well as immune mediators like CD20+ memory B cells, as potential targets for heart failure prevention and treatment.