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 for the response to CRT. Methods 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 using gas chromatography–mass spectrometry and nuclear magnetic resonance. Results 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 metabolic 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 the nonresponders to CRT, the 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). Conclusion CRT improves plasma metabolomic profile of HF patients indicating harmonization of myocardial energy substrate metabolism. CRT responders may have a favorable metabolic profile as a potential biomarker for predicting CRT outcome.

Metabolomic Analysis in Heart Failure

“…27 Furthermore, examination of plasma metabolomic profiles showed that patients with HF who respond to cardiac resynchronization therapy have higher baseline levels of BCAAs (including valine, leucine, isoleucine, and phenylalanine) and lower glutamate levels than non-responders. 52 Although BCAAs appear to have therapeutic potential against HF, there is also evidence of a pathological role in cardiac metabolic dysfunction. It was recently reported that Krüppel-like factor 15 suppressed BCAA catabolism in a murine HF model, with impairment of BCAA catabolism reducing cardiac function and promoting HF in the setting of LV pressure overload, together with elevated superoxide production and cardiac metabolic remodeling.…”

ECG-Derived Spatial QRS-T Angle Is Associated with ICD Implantation, Mortality and Heart Failure Admissions in Patients with LV Systolic Dysfunction

“…Other sources of data such as genomic, metabolomic or other biomarker information may also be additive to a global model of risk. For example, recent studies have demonstrated that metabolomics may not only be diagnostic for heart failure, but also predictive of responses to cardiac resynchronization and ICD therapies [49][50][51][52]. Integrating electrobiochemical 'omic information may yield further predictive information, which cannot be yielded by any individual method separately [53,54].…”

Metabolomics — A wide-open door to personalized treatment in chronic heart failure?

“…Systolic heart failure is also associated with inter-and intraventricular conduction disturbances and dyssynchrony, which are responsible for further impairment in systolic function. Nemutlu et al [100] indicated that resynchronization therapy (CRT) may improve plasma metabolic profile within the most important metabolites, including fatty acids, amino acids, lipids and Krebs cycle intermediates. Nevertheless, there were still some metabolites the level of which did not restore to the normal range, suggesting an existence of CRT-independent metabolic disturbances or pathways [100].…”