The primary process of ATP resynthesis occurs in mitochondria through oxidative phosphorylation (>98%) and, to a lesser extent, through glycolysis (<2%). Oxidative phosphorylation relies on the presence of O2 and H2. O2 is delivered to the myocardium and used in the mitochondria to produce H2O, while H2 is derived from the breakdown of carbon fuels (mainly fatty acids, glucose, and lactate) and the generation of NADH. The oxidation of glucose and lactate is regulated by pyruvate dehydrogenase (PDH). PDH activity is hindered by acetyl-coenzyme A and NADH through product inhibition. Additionally, PDH is inhibited when phosphorylated by PDH kinase and activated when dephosphorylated by PDH phosphatase. ATP is formed from ADP and inorganic phosphate with the assistance of H+ ions. It is crucial to ensure an adequate supply of O2 to the myocardium for the rates of ATP production and breakdown. The supply of O2 depends on myocardial blood flow and arterial blood oxygenation. When there is an increase in ATP breakdown in the myocardium, such as during exercise when heart rate, systolic blood pressure, and contractility are heightened, there is a need for increased O2 delivery to the myocardium. This allows the mitochondria to generate enough ATP through oxidative phosphorylation to meet the demand. Hence, the rate of myocardial O2 consumption is closely linked to the work rate of the myocardium.
The heart demonstrates versatility in its use of substrates. Within certain limits, the uptake of a particular substrate is directly proportional to its concentration in the arteries. The presence or absence of other substrates also influences the utilization of a specific substrate. For instance, if lactate is added to the blood supplying a heart that metabolizes glucose, the uptake of glucose decreases, and vice versa. At normal blood concentrations, glucose and lactate are consumed at roughly equal rates.
In contrast, the uptake of pyruvate is minimal due to its low arterial concentration. The threshold concentration for glucose is approximately 4 mmol/L. Below this level, the myocardium does not uptake glucose. Insulin lowers the glucose threshold and enhances glucose uptake by the heart. The myocardium generally utilizes lactate in most circumstances, and its uptake is unaffected by insulin. Under hypoxic conditions, glucose utilization is facilitated by an increased rate of transport across the myocardial cell wall. However, the hypoxic heart cannot metabolize lactate and produces it anaerobically. The production of lactate by the hypoxic heart is accompanied by the breakdown of cardiac glycogen.
Only 35% to 40% of the total cardiac O2 consumption can be attributed to carbohydrate oxidation. Therefore, the heart predominantly derives its energy from the oxidation of noncarbohydrate sources, particularly esterified and nonesterified fatty acids, which account for approximately 60% of myocardial O2 consumption in individuals in the postabsorptive state. Different fatty acids have varying thresholds for myocardial uptake, but their utilization generally corresponds to their arterial concentration. Ketone bodies, especially acetoacetate, are readily oxidized by the heart and serve as a significant energy source during diabetic acidosis. Similar to carbohydrate substrates, the utilization of a specific noncarbohydrate substrate is influenced by the presence of other substrates, whether carbohydrate or noncarbohydrate. Thus, within certain limits, the heart favors the substrate that is available in the highest concentration. The oxidation of amino acids contributes minimally to myocardial energy expenditure.
ATP resynthesis occurs primarily through oxidative phosphorylation in mitochondria (>98%) and, to a small degree, through glycolysis (<2%). Oxidative phosphorylation requires O2 and H2. The O2 is delivered to the myocardium and consumed in the mitochondria to make H2O, and the H2 is from the metabolism of carbon fuels (mainly fatty acids, glucose, and lactate) and the generation of the reduced form of nicotinamide adenine dinucleotide (NADH). Pyruvate dehydrogenase (PDH) regulates the oxidation of glucose and lactate. The activity of PDH is inhibited by product inhibition from acetyl–coenzyme A and NADH. Also, PDH activity is inhibited when phosphorylated by PDH kinase and activated when dephosphorylated by PDH phosphatase. ATP is formed from ADP and inorganic phosphate with the use of H+ . Of importance is that the rates of ATP formation and breakdown depend on an adequate delivery of O2 to the myocardium, which is a function of myocardial blood flow and oxygenation of arterial blood. An increase in ATP breakdown in the myocardium, such as occurs when heart rate, systolic blood pressure, and contractility are increased (as during exercise), necessitates an increase in O2 delivery to the myocardium so that the mitochondria can generate sufficient ATP by oxidative phosphorylation to meet the demand for ATP. Thus the rate of myocardial O2 consumption is tightly linked to the work rate (or power) of the myocardium.
The heart is versatile in its use of substrates, and within certain limits, uptake of a particular substrate is directly proportional to its arterial concentration. The use of one substrate by the heart is also influenced by the presence or absence of other substrates. For example, the addition of lactate to the blood that perfuses a heart metabolizing glucose leads to a reduction in glucose uptake and vice versa. At normal blood concentrations, glucose and lactate are consumed at approximately equal rates.
In contrast, uptake of pyruvate is very low, as is its arterial concentration. For glucose, the threshold concentration is approximately 4 mmol/L. Below this blood level, no glucose is taken up by the myocardium. Insulin reduces the glucose threshold and increases the rate of glucose uptake by the heart. Cardiac utilization of lactate occurs in most circumstances; insulin does not affect its uptake by the myocardium. Under hypoxic conditions, glucose utilization is facilitated by an increase in the rate of transport across the myocardial cell wall. However, lactate cannot be metabolized by the hypoxic heart and is produced by the heart under anaerobic conditions. Associated with lactate production by the hypoxic heart is the breakdown of cardiac glycogen.
Of the total cardiac O2 consumption, only 35% to 40% can be accounted for by the oxidation of carbohydrate. Thus the heart derives the major part of its energy from the oxidation of noncarbohydrate sources: namely, esterified and nonesterified fatty acids, which account for approximately 60% of the myocardial O2 consumption in people in the postabsorptive state. Various fatty acids have different thresholds for myocardial uptake, but these
CHAPTER 16 Elements of Cardiac Function acids are generally used in direct proportion to their arterial concentration. Ketone bodies, especially acetoacetate, are readily oxidized by the heart, and they are a major source of energy in diabetic acidosis. As is true of carbohydrate substrates, use of a specific noncarbohydrate is influenced by the presence of other substrates, whether noncarbohydrate or carbohydrate. Therefore, within certain limits, the heart preferentially uses the substrate that is available in the largest concentration. The oxidation of amino acids makes a small contribution to myocardial energy expenditure.