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. 2019 Mar 15:221:212-223.
doi: 10.1016/j.lfs.2019.01.040. Epub 2019 Feb 5.

Metabolomic analysis of serum and myocardium in compensated heart failure after myocardial infarction

M Dan McKirnan  1 , Yasuhiro Ichikawa  2 , Zheng Zhang  2 , Alice E Zemljic-Harpf  2 , Sili Fan  3 , Dinesh Kumar Barupal  3 , Hemal H Patel  2 , H Kirk Hammond  4 , David M Roth  5
Affiliations

Metabolomic analysis of serum and myocardium in compensated heart failure after myocardial infarction

M Dan McKirnan et al. Life Sci. .

Abstract

Aims: To determine the metabolic adaptations to compensated heart failure using a reproducible model of myocardial infarction and an unbiased metabolic screen. To address the limitations in sample availability and model variability observed in preclinical and clinical metabolic investigations of heart failure.

Main methods: Metabolomic analysis was performed on serum and myocardial tissue from rabbits after myocardial infarction (MI) was induced by cryo-injury of the left ventricular free wall. Rabbits followed for 12 weeks after MI exhibited left ventricular dilation and depressed systolic function as determined by echocardiography. Serum and tissue from the viable left ventricular free wall, interventricular septum and right ventricle were analyzed using a gas chromatography time of flight mass spectrometry-based untargeted metabolomics assay for primary metabolites.

Key findings: Unique results included: a two- three-fold increase in taurine levels in all three ventricular regions of MI rabbits and similarly, the three regions had increased inosine levels compared to sham controls. Reduced myocardial levels of myo-inositol in the myocardium of MI animals point to altered phospholipid metabolism and membrane receptor function in heart failure. Metabolite profiles also provide evidence for responses to oxidative stress and an impairment in TCA cycle energy production in the failing heart.

Significance: Our results revealed metabolic changes during compensated cardiac dysfunction and suggest potential targets for altering the progression of heart failure.

Keywords: BCAA; Heart failure; Inosine; Metabolomics; Myo-inositol; Myocardial infarction; Taurine.

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Conflict of interest statement

Conflict of interest

DMR and HHP are scientific founders of CavoGene LifeSciences LLC and hold equity interest in the company. HKH is a scientific founder and non-paid consultant of Renova Therapeutics.

CavoGene LifeSciences LLC and Renova Therapeutics were not involved with experimental design, analysis, discussions or in the writing of the manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. DMR and HHP are scientific founders of Cavogene. HKH is a scientific founder of Renova Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Fig. 1
Fig. 1
Cryo-probe freezing the myocardium and the effected region immediately post the 3-minute freeze.
Fig. 2
Fig. 2
Volcano plot (a) of serum metabolites wherein red dots indicate significantly different signals between MI and Sham rabbits. (p<.05: log transformed data); Network regions (b) and metabolite comparisons within the regions for serum. Red dot indicates that the compound signal for MI rabbits was greater than Sham rabbits while blue dot indicates that the signal for MI rabbits was less than Sham rabbits (p < .05, log data analysis). Size of the dot indicates the relative difference.
Fig. 3
Fig. 3
Venn Diagram of compound signals present in the Interventricular Septum (IVS), Left Ventricle (LV) and Right Ventricle (RV) that were significantly different between Mi and Sham rabbits. Log transformed data analysis.
Fig. 4
Fig. 4
Volcano plots of compounds present in the Left Ventricle (LV), Intraventricular Septum (IVS) and Right Ventricle (RV) of myocardial infarction (MI) and sham rabbits. Red dots indicate that compound levels are significantly different between MI and Sham rabbits (p< .05; log data analysis).
Fig. 5
Fig. 5
Network regions (a) and compound comparisons for the three myocardial regions: (b) Interventricular Septum - IVS, (c) Left Ventricle – LV, (d) Right Ventricle – RV. Red dot indicates that the compound signal for MI rabbits was greater than Sham rabbits while blue dot indicates that the signal for MI rabbits was less than Sham rabbits (p < .05, log data analysis). Size of the dot indicates the relative difference.
See this image and copyright information in PMC

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