Cardiac Metabolism PDF

25 Cardiac metabolism ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. Differentiate energy fuels of the heart Deduce the conditions in which each energy fuel is used Interpret importance of Randle’s cycle Predict the role of insulin in cardiac metabolism Energy supply of the he...

25 Cardiac metabolism ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. Differentiate energy fuels of the heart Deduce the conditions in which each energy fuel is used Interpret importance of Randle’s cycle Predict the role of insulin in cardiac metabolism Energy supply of the heart  The heart is one of the most active tissues in the body, requiring a high rate of energy expenditure to fuel the constant power output of the ventricles. There should always be a balance between energy requirements and supply to allow the heart to function properly.  The cardiac muscle is a highly oxidative tissue.To support high rates of cardiac power, metabolism is designed to generate large amounts of ATP by oxidative phosphorylation  The energy generated from fuel oxidation in the heart helps both Contractile work of systole, in addition to calcium uptake into the sarcoplasmic reticulum that allows for relaxation during diastole.  The concentration of ATP in the heart remains constant, even when the heart is stressed by exercise. Thus, the high rate of ATP consumption is matched by a high rate of ATP re-synthesis.  ATP is resynthesized mainly in the mitochondria by oxidative phosphorylation, and to a much smaller extent by the glycolytic pathway. Fuels of the heart Under basal aerobic conditions:  60%- 80% of energy comes from free fatty acids and triglycerides (oxidation of fatty acids is strictly aerobic)  10%-30% from carbohydrates (oxidation of carbohydrates can occur aerobically or anerobically)  10-30% by lactate uptake.  Ketone bodies (beta-hydroxybutyrate and acetoacetate) can also readily be oxidized by the heart only under certain conditions. Free Fatty acids in cardiac metabolism As stated, beta oxidation of free fatty acids (following lipolysis), is the main source of energy supply to the heart under aerobic conditions. When plasma free fatty acid 1 concentrations are high, this results in elevated rates of fatty acid uptake and oxidation in the mitochondria Carbohydrates in cardiac metabolism Carbohydrates replace fatty acid oxidation in case of ischemia There are three primary sources of carbohydrate fuel for the myocardium: 1-Extracellular glucose 2-Extracellular lactate 3-Glycogen stores N.B. Glycogen pool in the heart is relatively small (~30 mmol/g wet weight compared with ~150 mmol/g wet weight in skeletal muscles)     The uptake of extracellular glucose is regulated by transmembrane glucose gradient and the concentration of glucose transporters in the membrane. Two isoforms from the glucose transporter family have been identified in the myocardium-GLUT1 and GLUT4- with GLUT4 being predominant. They are both located in the sarcolemmal membrane and in intracellular microsomal vesicles Upon entering the cell, free glucose is rapidly phosphorylated by hexokinase to form glucose-6-phosphate, thus trapping the glucose inside the cell Both glucose and lactate are converted to pyruvate Pyruvate is transported to the mitochondria and furthur oxidized to CO2 in the citric acid cycle The Randle’S Cycle (Figure 1) Refers to the significant reduction in the uptake and utilization of glucose that occurs in muscle when fatty acid oxidation is intense. The rate of carbohydrate (pyruvate and lactate) oxidation by the heart is inversely related to plasma free fatty acid concentration. The biochemical mechanisms for this elegant interrelationship is referred to as the glucose-fatty acid cycle, or the Randle cycle High rates of fatty acid oxidation inhibit the uptake and oxidation of glucose and lactate The main effect of fatty acids and ketone bodies are to inhibit the activity of pyruvate dehydrogenase (PDH) and decrease the conversion of pyruvate to acetyl CoA. The rate of pyruvate oxidation is dependent on the degree of phosphorylation of PDH. The activity of PDH is decreased by phosphorylation by PDH kinase, and is activated by dephosphorylation by PDH phosphatase. The activity of PDH kinase is activated by increase in acetyl CoA/ CoA and NADH/NAD ratios. 2 High rates of fatty acid or ketone body oxidation results in elevated mitochondrial acetyl CoA/ CoA and NADH/NAD ratios and activated PDH kinase. This results in greater phosphorylation and inhibition of PDH and less pyruvate oxidation. Conversely, low rates of fatty acid oxidation release this inhibition and stimulates pyruvate oxidation So bottom line: Oxidation of fatty acids spares the carbohydrates from being oxidized by the heart, in order to save the carbohydrates as a source of energy to other organs highly dependent on glucose for energy production (e.g brain) Figure 1. Randle’s cycle Clinical hint A group of anti-anginal drugs exist, termed: Partial FFA Oxidation Inhibitors i.e pFOX Inhibitors. They shift cardiomyocyte metabolism to the utilization of CHO [low O2 demand] rather than FFA [high O2 demand]. Thus, by sparing O2 to the ischemic myocardium they help metabolically rather than hemodynamically to control the existing pains due to lack of O2 supply. Effects of insulin on carbohydrate metabolism in the heart Insulin causes the heart to take up and oxidize more glucose and lactate through direct and indirect mechanisms: 1- Insulin directly increases glucose uptake by cardiac muscles by stimulating the incorporation of GLUT1 and GLUT4 into the sarcolemmal membrane, and allow more glucose to enter the cells. 2. Insulin increases activity of hexokinase enzyme 3. Insulin increases activity of glycogen synthase and increases glycogen storage. 3 Effect of insulin on Fatty Acids Insulin has profound indirect effects on heart metabolism through regulation of plasma free fatty acid concentrations. Insulin lowers circulating free fatty acid levels through: 1. Insulin suppresses fatty acid release (lipolysis) from fat cells. Lower fatty acid levels result in lower rates of fatty acid oxidation by the heart and release of fatty acid inhibition on PDH, causing an increase in glucose and lactate uptake and oxidation. 2. High insulin ( such as occurs after meal) results in low fatty acid levels and low rates of fatty acid uptake and oxidation by the heart and dramatic increase in glucose and lactate uptake and oxidation 4