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. 2016 Feb 23;133(8):706-16.
doi: 10.1161/CIRCULATIONAHA.115.017545. Epub 2016 Jan 27.

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure

Kenneth C Bedi Jr  1 , Nathaniel W Snyder  1 , Jeffrey Brandimarto  1 , Moez Aziz  1 , Clementina Mesaros  1 , Andrew J Worth  1 , Linda L Wang  1 , Ali Javaheri  1 , Ian A Blair  1 , Kenneth B Margulies  1 , J Eduardo Rame  2
Affiliations

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure

Kenneth C Bedi Jr et al. Circulation. .

Abstract

Background: The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se.

Methods and results: We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate.

Conclusions: These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.

Keywords: cardiomyopathies; heart failure; ketones; lipids; metabolism.

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Figures

Figure 1
Figure 1
LC-HRMS lipidomic analysis reveals a depletion of lipid features from failing human hearts. Heatmap plot of 63 differentially abundant LC-HRMS lipid features from failing and non-failing hearts. Differential features were sorted by p-value < 0.01 using Welch’s unpaired t-test and manual curation for chromatographic peak shape and integration. Features that were differentially abundant between failing and non-failing hearts were mostly depleted in the failing hearts.
Figure 2
Figure 2
SID-LC-HRMS analysis indicates a reduction in acylcarnitine species in failing versus non-failing hearts. Significant reductions, by Mann-Whitney non-parametric testing, were seen in (A) palmitoylcarnitine, (B) the detected acylcarnitine profile for non-failing (hatched) versus failing (solid black) heart tissue.
Figure 2
Figure 2
SID-LC-HRMS analysis indicates a reduction in acylcarnitine species in failing versus non-failing hearts. Significant reductions, by Mann-Whitney non-parametric testing, were seen in (A) palmitoylcarnitine, (B) the detected acylcarnitine profile for non-failing (hatched) versus failing (solid black) heart tissue.
Figure 3
Figure 3
Acyl-CoA quantitation by SID-LC-MS/MS analysis demonstrates metabolic alterations. (A) The ratio of succinyl-CoA/acetyl-CoA is significantly decreased in failing myocardium (B) A significant change in failing hearts of short chain acyl-CoA species, including the ketogenic 3-hydroxybutanoyl-CoA (β-HB), is observed as compared to non-failing. A Mann-Whitney non-parametric test performed for each of these comparisons.
Figure 3
Figure 3
Acyl-CoA quantitation by SID-LC-MS/MS analysis demonstrates metabolic alterations. (A) The ratio of succinyl-CoA/acetyl-CoA is significantly decreased in failing myocardium (B) A significant change in failing hearts of short chain acyl-CoA species, including the ketogenic 3-hydroxybutanoyl-CoA (β-HB), is observed as compared to non-failing. A Mann-Whitney non-parametric test performed for each of these comparisons.
Figure 4
Figure 4
Non-Esterified Fatty Acids (NEFAs) in non-diabetic patients. NEFA in non-failing and non-diabetic DCM patients demonstrate significantly increased circulating free fatty acids in the advanced heart failure cohort (Mann Whitney non-parametric test).
Figure 5
Figure 5
Myocardial Gene Expression. Adjusted for the housekeeping gene RPL5, myocardial gene expression is reported as fold change in 21 failing samples relative to transcript abundance in 21 non-failing samples. The transcripts with differential gene expression by parametric (t-test with Welch’s correction) testing include Phospholipase A2 (PLA2G2A), Perilipin 2 (PLIN2), Phospholipid Transfer Protein (PLTP), peroxisome proliferator-activated receptor γ coactivator (PGC-1αFold Change 1.49, p=0.0008, Solute Carrier Family 22 (organic cation /carnitine transporter) member 5 (SLC22A5).
Figure 6
Figure 6
Paired serum and myocardial measurements of β-hydroxybutyrate. There is a marked increase in systemic blood in DCM patients whereas there is a marked decrease of β-hydroxybutyrate within the failing myocardium from the paired data, implicating a process of increased myocardial ketone utilization. The p-values reflect a Mann-Whitney non-parametric test.
Figure 7
Figure 7
Increased expression of the genes implicated in ketone oxidation was identified, including β-hydroxybutyrate dehydrogenase Type 1 and 2 (BDH1 and BDH2, p=0.01 for both) and 3-oxoacid CoA transferase 1(OXCT1) also known as succinyl-CoA:3-oxoacid CoA Transferase (SCOT, p=0.0006) in advanced heart failure (N=21 samples), relative to non-failing (N=21 samples). Note that the enzyme involved in ketogenesis, 3-hydroxy-3 methylglutaryl-CoA synthase (HMGCS2) is decreased in the myocardium of end-stage failing patients (p=0.006). The illustration in the top panel demonstrates the proposed link between the decreased pool of succinyl-CoA which is necessary for Krebs (TCA) cycling and the presence of ketone oxidation as the rate limiting enzyme OXCT1 (also known as SCOT) requires succinyl-CoA as a CoA donor for acetoacetate to yield acetoacetyl-CoA. Increased myocardial ketone oxidation could also explain the increased pool of Acetyl-CoA which was identified in end-stage failing myocardium, especially with the disruption in the Krebs cycle.
Figure 7
Figure 7
Increased expression of the genes implicated in ketone oxidation was identified, including β-hydroxybutyrate dehydrogenase Type 1 and 2 (BDH1 and BDH2, p=0.01 for both) and 3-oxoacid CoA transferase 1(OXCT1) also known as succinyl-CoA:3-oxoacid CoA Transferase (SCOT, p=0.0006) in advanced heart failure (N=21 samples), relative to non-failing (N=21 samples). Note that the enzyme involved in ketogenesis, 3-hydroxy-3 methylglutaryl-CoA synthase (HMGCS2) is decreased in the myocardium of end-stage failing patients (p=0.006). The illustration in the top panel demonstrates the proposed link between the decreased pool of succinyl-CoA which is necessary for Krebs (TCA) cycling and the presence of ketone oxidation as the rate limiting enzyme OXCT1 (also known as SCOT) requires succinyl-CoA as a CoA donor for acetoacetate to yield acetoacetyl-CoA. Increased myocardial ketone oxidation could also explain the increased pool of Acetyl-CoA which was identified in end-stage failing myocardium, especially with the disruption in the Krebs cycle.
Figure 8
Figure 8
a A positive correlation of increased OCXT1 gene expression when succinyl-CoA is abundant. Expression is reciprocal as it is reported as delta ct. p=0.0076 r2 =0.8607 n=6. A Pearson correlation was calculated and the p-value reported is calculated from an F test with the null hypothesis that the overall slope is zero. b No correlation between the expression of SCOT and the concentration of succinyl-CoA is identified in the non-failing myocardium.
Figure 8
Figure 8
a A positive correlation of increased OCXT1 gene expression when succinyl-CoA is abundant. Expression is reciprocal as it is reported as delta ct. p=0.0076 r2 =0.8607 n=6. A Pearson correlation was calculated and the p-value reported is calculated from an F test with the null hypothesis that the overall slope is zero. b No correlation between the expression of SCOT and the concentration of succinyl-CoA is identified in the non-failing myocardium.
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