Metabolic Markers of Mortality Risk in Patients With Severe Aortic Stenosis Undergoing Valve Replacement

In patients with aortic stenosis (AS), the relation of cardiac energetic pathways with cardiac structure and function, their changes, and their prognostic significance are not well understood. We aimed to characterize metabolic profiles in patients with severe AS before and after aortic valve replacement (AVR) and their association with functional status, structural remodeling and mortality. Patients with symptomatic, severe AS before (n = 143) and 1-year after (n = 113) AVR underwent cardiac magnetic resonance (CMR), serum cardiac biomarkers, and 6-minute walk test. Resting nonfasting plasma samples underwent targeted nuclear magnetic resonance (NMR) for fatty acids (FA), branched chain amino acids (BCAAs), glycolysis-related metabolites, and ketones. Lower FA and BCAA concentrations, but not glycolysis metabolites or ketones, correlated with greater myocardial mass and focal fibrosis, NT-proBNP, TnT and 6-minute walk distance. After 10.5 years of follow-up (66/143 deaths), lower FAs and BCAAs, but not ketones were independently associated with higher mortality risk (p <0.05). At 1-year after AVR, FAs had decreased compared to baseline. In conclusion, reduced serum FA and BCAA concentrations are cardiac, maladaptive, prognostic metabolic changes to AS, which are not reversible after AVR. Whether these markers may be used to guide the timing of AVR or provide metabolic risk stratification remains to be evaluated by future research. In patients with AS systemic metabolomics and their association with myocardial remodeling and outcome after AVR are largely unknown. We show that in severe AS low levels of unsaturated FA and BCAAs correlate with higher mortality risk, and biomarkers measured by CMR, serum, and functional incapacity, and do not increase after AVR. This may provide an alternate approach to risk stratification using blood biomarkers or guide targeted therapies to myocardial energetics before or after AVR.