Cardiac resynchronization therapy induces adaptive metabolic transitions in the metabolomic profile of heart failure

Abstract

Background: Heart failure (HF) is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT). The aim of this study was to determine the metabolomic signature in HF and its prognostic value regarding the response to CRT.

Methods and results: This prospective study consisted of 24 patients undergoing CRT for advanced HF and 10 control patients who underwent catheter ablation for supraventricular arrhythmia but not CRT. Blood samples were collected before and 3 months after CRT. Metabolomic profiling of plasma samples was performed with the use of gas chromatography-mass spectrometry and nuclear magnetic resonance. The plasma metabolomic profile was altered in the HF patients, with a distinct panel of metabolites, including Krebs cycle and lipid, amino acid, and nucleotide metabolism. CRT improved the metabolomic profile. The succinate-glutamate ratio, an index of Krebs cycle activity, improved from 0.58 ± 0.13 to 2.84 ± 0.60 (P < .05). The glucose-palmitate ratio, an indicator of the balance between glycolytic and fatty acid metabolism, increased from 0.96 ± 0.05 to 1.54 ± 0.09 (P < .01). Compared with nonresponders to CRT, responders had a distinct baseline plasma metabolomic profile, including higher isoleucine, phenylalanine, leucine, glucose, and valine levels and lower glutamate levels at baseline (P < .05).

Conclusions: CRT improves the plasma metabolomic profile of HF patients, indicating harmonization of myocardial energy substrate metabolism. CRT responders may have a favorable metabolomic profile as a potential biomarker for predicting CRT outcome.

Keywords: Heart failure; cardiac resynchronization therapy; metabolism.

Figure 1

Metabolomic signature of heart failure (HF). A, Changes in plasma metabolomic profile of HF patients by orthogonal partial least squares discriminant analysis (OPLS-DA). B, Most important metabolites in the metabolomic signature of HF by variable importance in the projection (VIP). C, Pattern of plasma metabolite changes in HF patients (N=24, * P<.05; ** P<.001). D, Metabolic pathways most affected in HF as deduced from an altered plasma metabolomic profile.

Figure 2

Metabolomic signature of cardiac resynchronization therapy (CRT). A, Changes in plasma metabolomic profiles of patients with heart failure (HF) after CRT by orthogonal partial least squares discriminant analysis (OPLS-DA). 3M indicates 3-month follow-up. B, Most important metabolites in metabolomic signature of CRT by variable importance in the projection (VIP). C, Pattern of plasma metabolite changes in HF patients after CRT (N=19, **P<.001). D, Metabolic pathways most affected after CRT as deduced from an altered plasma metabolomic profile.

Figure 3

Improvement of indicator metabolite ratios and correlations between plasma metabolites and cardiac performance (left ventricle ejection fraction [LVEF]) after cardiac resynchronization therapy (CRT). A, Changes in indicator metabolite ratios in HF pre-CRT and HF post-CRT. B, A panel of metabolites that correlate positively and negatively with LVEF in HF pre-CRT group (*P<.05; ** P<.001). C, A panel of metabolites that correlate positively and negatively with LVEF in HF post-CRT group (*P<.05; ** P<.001). D, A panel of metabolites that correlate positively and negatively with delta LVEF in HF post-CRT group (*P<.05). Cit/Glut indicates citrate/glutamate; Glu/Palm, glucose/palmitate; Glutin/Glut, glutamine/glutamate; HF, heart failure; Succ/Glut, succinate/glutamate.

Figure 4

Metabolomic profiles of 9 responders and 13 nonresponders to cardiac resynchronization therapy (CRT). A, Distinction of basal plasma metabolomic profiles of responders and nonresponders to CRT by orthogonal partial least squares discriminant analysis (OPLS-DA). B, An integral panel of the most important metabolites permitting prediction of responders by variable importance in the projection (VIP). C, A panel of the most important metabolite differences between responders and nonresponders (* P<.05).