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.

Keywords: aortic stenosis; metabolomics; outcomes; remodeling.

Figure 1. Overall study design.

FEV₁ indicates forced expiratory volume in the first second; LASSO, least absolute shrinkage and selection operator; LV, left ventricular; and TAVI, transcatheter aortic valve implantation. Created with BioRender.com.

Figure 2. Interindividual heterogeneity in cardiac structure before TAVI.

A, Results of PCA of 12 echocardiographic measures. The bar plot indicates the PCA‐based loadings for each echocardiographic measure for each PC. B, Clustered heatmap demonstrating individuals across echocardiographic measures, with PC scores for each individual represented as heatbars across the top of the heatmap. Each column is a participant, and rows represent phenotypes. AV indicates aortic valve; LA Vol, left atrium volume; LV DTI, tissue Doppler S velocity of lateral mitral annulus; LV, left ventricular; LVEDDI, left ventricular end‐diastolic diameter index; LVEDVI, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; LVESDI, left ventricular end‐systolic diameter index; LVESVI, left ventricular end‐systolic volume index; LVMi, left ventricular mass index; PC, principal component; RWT, relative wall thickness; and SVI, stroke volume index.

Figure 3. Metabolite scores are associated with measures of multimorbidity.

Spearman correlation between each metabolite PC scores and available measures of multimorbidity in the multicenter derivation cohort. Exemplary echocardiographic variables are also included (LVEDVI for volumes, PC1; LVEF for systolic function, PC2; Mean E/e′ for diastolic function, PC3) to demonstrate the relation between each metabolite score with its exemplary LV phenotype. Raw data are reported in Table S2. eGFR indicates estimated glomerular filtration rate; FEV₁, forced expiratory volume in the first second; KCCQ, Kansas City Cardiomyopathy Questionnaire summary score; LVEDVI, left ventricular end‐diastolic volume index; LVEF, left ventricular ejection fraction; Mini‐Cog, Mini‐Cog score for dementia; and PC, principal component. *indicates a false discovery rate <0.05 (Benjamini–Hochberg method).

Figure 4. Association of metabolite scores and parent phenotype scores with death.

Results of Cox models are displayed with 95% CIs (model results in Table S5). A, Phenotype‐based PC scores demonstrated limited associations with death after adjustment. The metabolite score for diastolic function (PC3) was associated with all‐cause death. B, The association of each metabolite score with death in our replication cohorts, demonstrating replication of the prognostic association of our diastolic function metabolite score (PC3) with death in the multicenter and single‐center validation cohorts. The effect sizes appear in a similar range as with the derivation cohort. PC indicates principal component.