Metabolic Signatures of Cardiac Dysfunction, Multimorbidity, and Post–Transcatheter Aortic Valve Implantation Death

Abstract

Background Studies in mice and small patient subsets implicate metabolic dysfunction in cardiac remodeling in aortic stenosis, but no large comprehensive studies of human metabolism in aortic stenosis with long‐term follow‐up and characterization currently exist. Methods and Results Within a multicenter prospective cohort study, we used principal components analysis to summarize 12 echocardiographic measures of left ventricular structure and function pre–transcatheter aortic valve implantation in 519 subjects (derivation). We used least absolute shrinkage and selection operator regression across 221 metabolites to define metabolic signatures for each structural pattern and measured their relation to death and multimorbidity in the original cohort and up to 2 validation cohorts (N=543 for overall validation). In the derivation cohort (519 individuals; median age, 84 years, 45% women, 95% White individuals), we identified 3 axes of left ventricular remodeling, broadly specifying systolic function, diastolic function, and chamber volumes. Metabolite signatures of each axis specified both known and novel pathways in hypertrophy and cardiac dysfunction. Over a median of 3.1 years (205 deaths), a metabolite score for diastolic function was independently associated with post–transcatheter aortic valve implantation death (adjusted hazard ratio per 1 SD increase in score, 1.54 [95% CI, 1.25–1.90]; P <0.001), with similar effects in each validation cohort. This metabolite score of diastolic function was simultaneously associated with measures of multimorbidity, suggesting a metabolic link between cardiac and noncardiac state in aortic stenosis. Conclusions Metabolite profiles of cardiac structure identify individuals at high risk for death following transcatheter aortic valve implantation and concurrent multimorbidity. These results call for efforts to address potentially reversible metabolic biology associated with risk to optimize post–transcatheter aortic valve implantation recovery, rehabilitation, and survival.

Metabolic Dysfunction in Aortic Stenosis: A Key Piece of the Pathophysiological Puzzle

“…These hypotheses will then be able to be tested at scale by biomarker and/or metabolomic profiling of the serum, which is feasible in large multicenter studies. 8,9 As the authors highlight, pressure overload and heart failure have been associated with a metabolic shift away from fatty acid oxidation and with mitochondrial dysfunction. 10 We and others have demonstrated circulating metabolic derangements, presumed to indicate altered fatty acid oxidation that develops early in the disease course of AS and reverses with alleviation of LV unloading with transcatheter aortic valve replacement (AVR).…”

“…4 Moreover, distinct circulating metabolomic signatures associate with indices of LV volume, systolic and diastolic function, and LV hypertrophy. 8 Although these associations and the reversal of signatures of myocardial energetics with alleviation of LV afterload suggest a cardiac source for identified circulating metabolite signatures, Monga et al 6 leverage MR spectroscopy to extend these observations and clearly demonstrate in vivo altered myocardial energetics in early stages of severe AS. 6 For many years, the management of AS was purely reactive, with surgical AVR being triggered by the development of symptoms.…”