The alterations in myocardial energy substrate metabolism that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest th...

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Myocardial Substrate Metabolism in the Normal and Failing Heart

There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the β-oxidation of long-chain fatty acids. The control of fatty acid β-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via β-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and β-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid β-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid β-oxidation and how alterations in fatty acid β-oxidation can contribute to heart disease. The implications of inhibiting fatty acid β-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.

Myocardial Fatty Acid Metabolism in Health and Disease

Utilization of carbohydrate and fatty acids is strongly influenced by rates of con­ sumption and production of high energy compounds in cardiac muscle. In well­ oxygenated hearts, fatty acid has been identified as the preferred substrate by both in vivo and in vitro studies (for review see 146). Availability of fatty acid suppresses glucose utilization by inhibition of several steps in the glycolytic pathway. Since a variety of longand short-chained fatty substrates are inhibitory and since the effect is abolished in hearts perfused under anaerobic conditions, oxidation of the fatty acid appears to be required for this effect. When energy utilization of well­ oxygenated hearts is increased, consumption of fatty acids and/or glucose is ac­ celerated. Under these conditions, fatty acids remain the preferred oxidative substrate. Availability of oxygen to the heart can be restricted either by lowering or reducing to zero the oxygen tension of the perfusate, thereby inducing hypoxia or anoxia, or by restricting the flow of perfusate containing high oxygen tensions to induce ischemia. In hypoxic or anoxic hearts, fatty acid oxidation is suppressed and glycol­ ysis is stimulated. The acceleration of flux through glycolysis may be as much as 10to 20-fold. On the other hand, ischemia results in only a transient increase in glycolytic flux that is followed within 3-4 min by inhibition. Fatty acid oxidation is suppressed in ischemic hearts leading to accumulation of long-chained CoA derivatives and increase in triglyceride levels.

Relationship Between Carbohydrate and Lipid Metabolism and the Energy Balance of Heart Muscle

In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 ± 1 years). Insulin sensitivity at physiological ( M ) and supraphysiological ( MZ ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 ± 1%, range 14–44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 ± 0.3 μmol/g, range 1.3–1.9 μmol/g) and log10 M ( r = −0.53, P ≤ 0.001), MZ ( r = −0.44, P = 0.006), and nonoxidative glucose disposal ( r = −0.48 and −0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10 M , MZ , log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.

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Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action

High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (ω-9), or polyunsaturated (ω-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at ∼1000 pM insulin were 6.2 ± 0.9, 8.9 ± 0.9, and 9.7 ± 0.4 mg · kg −1 · min −1 , respectively, versus 16.1 ± 1.0 mg · kg −1 · min −1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain ω-3 fatty acids from fish oils normalized insulin action (GIR 15.0 ± 1.3 mg · kg −1 · min −1 ). Similar replacement with short-chain ω-3 (α-linolenic acid, 18:3ω3) was ineffective in the polyunsaturated diet (GIR 9.9 ± 0.5 mg · kg −1 · min −1 ) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 ± 1.5 mg · kg −1 · min −1 ) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation ( r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P = 0.01). Furthermore, percentage of long-chain ω-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle ( r = 0.97). We conclude that 1 ) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2 ) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose–fatty acid cycle involvement; and 3 ) long-chain ω-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.

Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid.

1. Methods are described for the extraction of lipid and assay of mono-, di- and tri-glyceride glycerol and phospholipid phosphorus in rat heart and gastrocnemius muscles. 2. In hearts from normal animals, concentrations found were: monoglyceride, 0·6; diglyceride, 0·1; triglyceride, 12·6μmoles of glyceride glycerol/g. of dry muscle; phospholipid, 171μg.atoms of phospholipid phosphorus/g. of dry muscle. Concentrations of glycerides in gastrocnemius muscle were similar to heart muscle but those of phospholipids were lower (64μg.atoms of phospholipid phosphorus/g. of dry muscle). 3. Alloxan-diabetes increased the concentration of triglyceride in the muscles twofold. This increase was shown to be dependent in the heart on the availability of growth hormone and cortisol but not on the availability of dietary lipid. Total glyceride in the heart was increased after 48 and 72hr. starvation but not after 96hr. Changes in glyceride concentration seen in starvation and diabetes were not associated with significant changes in phospholipid concentration. It is suggested that mobilization of free fatty acids in diabetes leads to the synthesis of additional glyceride in muscle. 4. The possible contribution of glyceride fatty acid in the heart to respiration during perfusion has been calculated from the net loss of glyceride during perfusion, and also from the relative rates of lipolysis and esterification and compared with oxidation of fatty acid required for the balance of oxygen consumption (oxygen not utilized in the oxidation of glucose or glycogen glucose). In the normal or diabetic heart perfused with glucose and insulin the breakdown of glyceride can account for the balance of oxygen consumption. In the normal heart perfused without substrate the balance of oxygen consumption is not entirely accounted for by the breakdown of glyceride.

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Papers

Concentrations of glycerides and phospholipids in rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and perfusion.