Metabolic profiling and longitudinal changes in patients with severe aortic stenosis undergoing valve replacement

AimsIn 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 characterise metabolic profiles in patients with severe AS before and after aortic valve replacement (AVR) and their association with functional status, structural remodelling and mortality. Methods and resultsPatients 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 non-fasting plasma samples underwent targeted nuclear magnetic resonance for free fatty acids (FFAs), branched chain amino acids (BCAAs), glycolysis-related metabolites, and ketones. Lower FFAs 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 FFAs and BCAAs, but not ketones were independently associated with higher mortality risk (P<0.05). At 1-year after AVR, FFAs had decreased compared to baseline. ConclusionReduced serum FFAs and BCAA concentrations are cardiac, maladaptive metabolic changes to AS, and are not reversible after AVR. Whether these markers may be used to guide the timing of AVR or may be targeted by metabolic interventions remains to be evaluated by future research. Condensed AbstractIn patients with aortic stenosis (AS) systemic metabolomics and their association with myocardial remodeling and outcome after aortic valve replacement (AVR) are largely unknown. We show that in severe AS low levels of unsaturated fatty acids and branch chain amino acids correlate with worse disease markers by cardiac magnetic resonance, biomarkers, and functional incapacity, do not increase after AVR and correlate with higher mortality. Targeted manipulation of metabolite perturbations might ameliorate myocardial energetics before and after AVR. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/25332646v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1b35853org.highwire.dtl.DTLVardef@16bbe53org.highwire.dtl.DTLVardef@9c62daorg.highwire.dtl.DTLVardef@11e05b6_HPS_FORMAT_FIGEXP M_FIG C_FIG Metabolites in severe aortic stenosis and their associations with cardiac remodeling/damage and mortality after aortic valve replacement (AVR). FFAs indicates free fatty acids; BCAA, branched chained amino acids;