The myocardial contractile response to physiological stress improves with high saturated fat feeding in heart failure

Abstract

Impaired myocardial contractile function is a hallmark of heart failure (HF), which may present under resting conditions and/or during physiological stress. Previous studies have reported that high fat feeding in mild to moderate HF/left ventricular (LV) dysfunction is associated with improved contractile function at baseline. The goal of this study was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat after infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal chow (NC; 10% kcal fat; Sham + NC and HF + NC groups) or high-fat chow (SAT; 60% kcal saturated fat; Sham + SAT and HF + SAT groups) for 8 wk. Myocardial contractile function was assessed using a Millar pressure-volume conductance catheter at baseline and during inferior vena caval occlusions and dobutamine stress. Steady-state indexes of systolic function, LV +dP/dt(max), stroke work, and maximal power were increased in the HF + SAT group versus the HF + NC group and reduced in the HF + NC group versus the Sham + NC group. Preload recruitable measures of contractility were decreased in HF + NC group but not in the HF + SAT group. beta-Adrenergic responsiveness [change in LV +dP/dt(max) and change in cardiac output with dobutamine (0-10 microg x kg(-1) x min(-1))] was reduced in HF, but high fat feeding did not further impact the contractile reserve in HF. The contractile reserve was reduced by the high-fat diet in the Sham + SAT group. Microarray gene expression analysis revealed that the majority of significantly altered pathways identified contained multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts but may negatively impact the contractile reserve under nonpathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways revealed promising targets through which high saturated fat potentially mediates cardioprotection in mild to moderate HF/LV dysfunction.

Fig. 1.

Inferior vena caval occlusion parameters: A: slope of the end-systolic pressure-volume relationship (ESPVR). B: maximal elastance, which was obtained from a series of pressure-volume regression curves at varying preloads. C: preload recruitable stroke work (PRSW), which was generated with varying left ventricular (LV) end-diastolic volumes. Animals were divided into the following four groups: sham operation (Sham) with a normal chow (NC) diet (Sham + NC), Sham with a high saturated fat (SAT) diet (Sham + SAT), heart failure (HF) with a NC diet (HF + NC), and HF with SAT diet (HF + SAT). n = 6–8 animals/group. *P < 0.05 Sham vs. HF within diet; † P < 0.05, diet within treatment.

Fig. 2.

A: preload adjusted peak +dP/dt_max (in mmHg/s)-end-diastolic volume (EDV; in μl) in representative Sham + NC, Sham + SAT, HF + NC, and HF + SAT animals. B: slope of the peak LV +dP/dt_max-EDV relationship. n = 6–8 animals/group. *P < 0.05, Sham vs. HF within diet; †P < 0.05, diet within treatment.

Fig. 3.

Change in LV +dP/dt_max (A) and change in cardiac output (B) during dobutamine stress (change from 0 to 10 μg·kg⁻¹·min⁻¹ dobutamine). n = 5 animals/group. *P < 0.05, main effect of Sham vs. HF; †P < 0.05, Sham + NC group vs. Sham + SAT group.

Fig. 4.

Venn diagram and ontological assignments for gene probes with altered expression in rats subjected to infarction followed by high fat feeding. A: Venn diagram of gene probes altered across model variables of HF or SAT from the 1,848 whole model analysis probe list (P < 0.05). Gene probes altered by HF and SAT were determined in the subset analysis (P < 0.05 by t-test). B: ontology terms associated with the cellular location of the 1,848 gene probes found to be statistically altered in the model. ECM, extracellular matrix. C: ontological breakdown of the gene probes by biological process.

Fig. 5.

Ontological assignments of the genes altered between the HF + NC and HF + SAT groups (324 gene probes). A: ontology terms associated with the cellular location of the gene probes found to be statistically significant (P < 0.05) when the HF + SAT and HF + NC groups were compared within the whole model list (1,848 gene probes). B: ontological breakdown of the gene probes by biological process (P < 0.05). The “undefined” designation was used for probes with multiple localization terms. “Other” was used for ontology categories containing fewer than two gene probes. “Unknown” designates gene probes with no annotative information available.