Metabolomic Analysis of Pressure-Overloaded and Infarcted Mouse Hearts

Abstract

Background Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Here, we investigated the impact of pressure overload and infarction on myocardial metabolism. Methods and Results Male C57BL/6J mice were subjected to transverse aortic constriction (TAC) or permanent coronary occlusion (myocardial infarction; MI). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both TAC and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched amino acids acids (BCAAs) were observed after 1 week of TAC and 5 days after MI. Changes in BCAAs after MI were associated with myocardial insulin resistance. Longer duration of TAC and MI led to a decrease in purines, acylcarnitines, fatty acids and several lysolipid and sphingolipid species, but a marked increase in pyrimidines as well as ascorbate, heme and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated also with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline. Conclusions These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extensive extracellular matrix remodeling, insulin resistance and perturbations in amino acid, lipid and nucleotide metabolism.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Although these metabolites represent a small portion of the human metabolome in terms of absolute numbers, they report on pathways critical for cellular and organism‐level homeostasis: fatty acid, carbohydrate, amino acid, and urea metabolism. These particular metabolites were chosen for several reasons: (1) An expanding body of evidence has implicated impairments in fatty acid and carbohydrate oxidation in HF pathophysiology, which could be reflected in acylcarnitine elevations13, 50, 73, 74, 75, 76, 77; (2) previous metabolomics investigations have identified derangements in plasma levels of these metabolites in HF patients49, 50, 78, 79, 80; and (3) acylcarnitines and their derivatives have been suggested to have intrinsic physiological effects that could contribute to the HF phenotype 66, 67, 68, 81, 82…”

Metabolomic Analysis in Heart Failure

“…Oxidation study found that only pyruvate was reduced in hearts under LV pressure overload. 27 In hamsters with dilated cardiomyopathy, it was reported that glucose-6-phosphate, fructose-6-phosphate, fructose-1, 6-bisphosphate, malate, iso-citrate, and succinate were comparable between the cardiomyopathy group and control group at 4 weeks of age, but were all reduced in the cardiomyopathy group at 16 weeks of age. 45 It is currently accepted that the alterations in glucose utilization vary according to the animal model, pathology, and stage of HF.…”

“…Levels of several sphingolipids are reported to be reduced in models of HF caused by LV pressure overload or myocardial infarction (MI). 27 Sphingosine-1-phosphate (S1P) is a bioactive cardioprotective sphingolipid that is more abundant in plasma than in the tissues and is mainly associated with high-density lipoprotein (50-60%) or albumin (30-40%). 28 S1P/S1P receptor 1 signaling was recently reported to contribute to Ca 2+ homeostasis by maintaining the Na + /H + exchanger 1 (NHE-1) in cardiomyocytes, thus having a cardioprotective effect in a myocardial ischemiareperfusion model.…”

“…15 It is also reported that cardiac tissue levels of BCAAs are increased by both LV pressure overload and MI. 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.…”

The role of stem cells in adipose tissue remodeling.

“…Prior to tissue collection, the mice were fasted for 16 h. After euthanasia, the adipose tissue was removed and immediately snap-frozen in liquid nitrogen. Relative metabolite abundance was then measured by GC/MS or LC/MS as described before (103,105).…”