Normalizing the metabolic phenotype after myocardial infarction: impact of subchronic high fat feeding

Abstract

The normal heart relies primarily on the oxidation of fatty acids (FA) for ATP production, whereas during heart failure (HF) glucose utilization increases, implying pathological changes to cardiac energy metabolism. Despite the noted lipotoxic effects of elevating FA, our work has demonstrated a cardioprotective effect of a high fat diet (SAT) when fed after myocardial infarction (MI), as compared to normal chow (NC) fed cohorts. This data has suggested a mechanistic link to energy metabolism. The goal of this study was to determine the impact of SAT on the metabolic phenotype of the heart after MI. Male Wistar rats underwent coronary ligation surgery (MI) and were evaluated after 8 weeks of SAT. Induction of MI was verified by echocardiography. LV function assessed by in vivo hemodynamic measurements revealed improvements in the MI-SAT group as compared to MI-NC. Perfused working hearts revealed a decrease in cardiac work in MI-NC that was improved in MI-SAT. Glucose oxidation was increased and FA oxidation decreased in MI-NC compared to shams suggesting an alteration in the metabolic profile that was ameliorated by SAT. (31)P NMR analysis of Langendorff perfused hearts revealed no differences in PCr:ATP indicating no overt energy deficit in MI groups. Phospho-PDH and PDK(4) were increased in MI-SAT, consistent with a shift towards fatty acid oxidation (FAO). Overall, these results support the hypothesis that SAT post-infarction promotes a normal metabolic phenotype that may serve a cardioprotective role in the injured heart.

Figure 1

In vivo hemodynamic parameters from anesthetized rats after 8 weeks of high fat feeding post-MI. Values represent the mean ± SEM (n = 5–6). Statistical differences were defined by a two-way ANOVA using Bonferroni post-hoc analysis (p < 0.05). *Denotes statistical difference from the respective surgical control (SH). †Denotes statistical difference with respect to the dietary control group (NC).

Figure 2

Glucose and oleate oxidation rates obtained from working perfused hearts. Values represent the mean ± SEM (n = 13–16). Statistical differences were defined by a two-way ANOVA using Bonferroni post-hoc analysis (p < 0.05). *Denotes statistical difference from the respective surgical control (SH). †Denotes statistical difference with respect to the dietary control group (NC).

Figure 3

Myocardial oxygen consumption and exogenous substrate oxidation rates presented as percent (%) of oxygen consumption in working perfused hearts (see materials and methods for additional information). Values represent the mean ± SEM (n = 13–16). *Denotes statistical difference from the respective surgical control (SH).

Figure 4

³¹P NMR analysis of PCr:ATP ratio in Langendorff perfused hearts. A. Representative ³¹P NMR spectra. B. Quantitative representation of PCr:ATP ratios from ³¹P NMR. Values represent the mean ± SEM (n = 7–8). No statistical differences were observed.

Figure 5

Western blot analysis of phosphorylated pyruvate dehydrogenase (pPDH) and PDH kinase 4 (PDK₄) protein content in LV tissue. A. Representative western blots for pPDH, PDH, and HSC70 (loading control). B. Relative content of pPDH. C. Total content of PDH. D. Representative blots for PDK₄ and HSC70. E. Total content of PDK₄. Values represent the mean ± SEM (n = 4–5). Statistical differences were defined by two-way ANOVA with Bonferroni post-hoc analysis (p < 0.05). *Denotes statistical difference from the respective surgical control (SH). †Denotes statistical difference vs. respective dietary control (NC).