Scottish Symposium on Angina Pectoris
MYOCARDIAL METABOLISM IN ANGINA PECTORIS
A. C. Hjalmarson and A. P. Waldenstriim Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Goteborg, Sweden
of angina pectoris is described as chest discomfort, generally lasting for short periods, and is often related to physical or mental stress. The symptoms include oppression, mild to severe pain, dyspnoea, fatigue and sometimes sensations of arrhythmias. The attack is due to a temporary inadequacy of coronary blood supply to the myocardium. It was earlier thought that the primary event in this attack was a coronary artery spasm. This might be true in some patients, e.g. in Prinzmetal's angina. In most patients with angina pectoris the coronary blood flow is limited due to atherosclerosis. It seems reasonable to assume that the primary event in angina pectoris is a sudden increase in heart work and that the metabolic demand will not be met by a proportional increase in coronary flow. An imbalance between metabolic demand and coronary blood supply will occur with accumulation of metabolites, resulting in chest pain, ventricular dysfunction and arrhythmias (Hjalmarson & Waldenstrom, 1975). A more severe imbalance between myocardial metabolic demand and coronary flow will result in irreversible damage of the ischaemic myocardium. This presentation will deal with myocardial metabolism during experimental ischaemia and with the underlying factors of importance for the development of myocardial ischaemia.
THE ATTACK
Definition of myocardial hypoxia and ischaemia It is important to make a distinction between
myocardial hypoxia and ischaemia. Hypoxia is defined as deficiency of oxygen with normal coronary flow. Myocardial ischaemia is defined as inadequacy of coronary blood flow in relation to the metabolic demand. During ischaemia there is a restriction of the coronary artery supply of oxygen, substrates, ions and fluid, resulting in a deficiency of oxygen and substrates, ionic changes and accumulation of metabolic products. Oxygen deficiency is thus only one part of the metabolic changes 30
occurring in ischaemia. The metabolic and haemodynamic changes induced by hypoxia and ischaemia have been compared in isolated rat heart preparations (Rovetto et al., 1973). Data from such experiments are summarized in Table I. During hypoxia with maintained normal coronary artery perfusion there is a reduction in ventricular pressure development and in heart rate since the oxygen supply is insufficient to provide enough ATP by oxidative phosphorylation. There is a 2 to 3--fold acceleration of anaerobic glycolysis and an inhibition of fatty acid oxidation. The mechanical performance of the heart decreases until the metabolic demand equals the energy supply from the anaerobic glycolysis. During anoxia the heart stops beating, anaerobic glycolysis is maximally accelerated, and acid oxidation is inhibited. The glycolytic flux is enhanced due to an increase in glucose uptake over the cell membrane and activation of a number of glycolytic enzymes, including phosphofructokinase, which normally is ratelimiting. The lactate production is increased several times, but due to the maintained coronary perfusion lactate is not accumulated in the tissue. Therefore only small changes in the intracellular pH are seen. Ischaemia induced by a sudden restriction of coronary flow of the isolated rat heart preparation resuts in an initial acceleration of glycolysis which, however, is restrained within a few minutes (Rovetto et al., 1973). Thus, the anaerobic glycolysis as well as the fatty acid oxidation are inhibited. Lactate and hydrogen ions are accumulated in the cells, which is believed to be the cause of the inhibited anaerobic glycolysis and decreased contractile state. It has been suggested that accumulated hydrogen ions might reduce the effectiveness of calcium ions in the interaction with troponin (Katz & Hecht, 1969). The inhibition of fatty acid oxidation results in accumulation of long-chain acyl CoA. In-
Scottish Symposium on Angina Pectoris
Table I. Comparison between experimental anoxia and ischaemia. Conditions
Metabolic changes
Mechanical performance
Anoxia
-Oxygen deficiency -Glucose utilization t -Maintained coronary flow -Fatty acid oxidation ..r -Washout of lactate -Anaerobic glycolysis will produce ATP in proportion to the low metabolic demand in arrested heart -Reversible changes
Severe ischaemia (Centre of ischaemic area)
-~ 90 % Reduction
of coronary flow -Inadequate washout of metabolites
-Glucose utilization ..f -Fatty acid oxidation ..r Accumulation of lactate and hydrogen ions -ATP production lower than metabolic demand -Irreversible cell damage (autodigestion)
Mild ischaemia (border zone of ischaemia)
-
MYOCARDIAL METABOLISM IN ANGINA PECTORIS
A. C. Hjalmarson and A. P. Waldenstriim Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Goteborg, Sweden
of angina pectoris is described as chest discomfort, generally lasting for short periods, and is often related to physical or mental stress. The symptoms include oppression, mild to severe pain, dyspnoea, fatigue and sometimes sensations of arrhythmias. The attack is due to a temporary inadequacy of coronary blood supply to the myocardium. It was earlier thought that the primary event in this attack was a coronary artery spasm. This might be true in some patients, e.g. in Prinzmetal's angina. In most patients with angina pectoris the coronary blood flow is limited due to atherosclerosis. It seems reasonable to assume that the primary event in angina pectoris is a sudden increase in heart work and that the metabolic demand will not be met by a proportional increase in coronary flow. An imbalance between metabolic demand and coronary blood supply will occur with accumulation of metabolites, resulting in chest pain, ventricular dysfunction and arrhythmias (Hjalmarson & Waldenstrom, 1975). A more severe imbalance between myocardial metabolic demand and coronary flow will result in irreversible damage of the ischaemic myocardium. This presentation will deal with myocardial metabolism during experimental ischaemia and with the underlying factors of importance for the development of myocardial ischaemia.
THE ATTACK
Definition of myocardial hypoxia and ischaemia It is important to make a distinction between
myocardial hypoxia and ischaemia. Hypoxia is defined as deficiency of oxygen with normal coronary flow. Myocardial ischaemia is defined as inadequacy of coronary blood flow in relation to the metabolic demand. During ischaemia there is a restriction of the coronary artery supply of oxygen, substrates, ions and fluid, resulting in a deficiency of oxygen and substrates, ionic changes and accumulation of metabolic products. Oxygen deficiency is thus only one part of the metabolic changes 30
occurring in ischaemia. The metabolic and haemodynamic changes induced by hypoxia and ischaemia have been compared in isolated rat heart preparations (Rovetto et al., 1973). Data from such experiments are summarized in Table I. During hypoxia with maintained normal coronary artery perfusion there is a reduction in ventricular pressure development and in heart rate since the oxygen supply is insufficient to provide enough ATP by oxidative phosphorylation. There is a 2 to 3--fold acceleration of anaerobic glycolysis and an inhibition of fatty acid oxidation. The mechanical performance of the heart decreases until the metabolic demand equals the energy supply from the anaerobic glycolysis. During anoxia the heart stops beating, anaerobic glycolysis is maximally accelerated, and acid oxidation is inhibited. The glycolytic flux is enhanced due to an increase in glucose uptake over the cell membrane and activation of a number of glycolytic enzymes, including phosphofructokinase, which normally is ratelimiting. The lactate production is increased several times, but due to the maintained coronary perfusion lactate is not accumulated in the tissue. Therefore only small changes in the intracellular pH are seen. Ischaemia induced by a sudden restriction of coronary flow of the isolated rat heart preparation resuts in an initial acceleration of glycolysis which, however, is restrained within a few minutes (Rovetto et al., 1973). Thus, the anaerobic glycolysis as well as the fatty acid oxidation are inhibited. Lactate and hydrogen ions are accumulated in the cells, which is believed to be the cause of the inhibited anaerobic glycolysis and decreased contractile state. It has been suggested that accumulated hydrogen ions might reduce the effectiveness of calcium ions in the interaction with troponin (Katz & Hecht, 1969). The inhibition of fatty acid oxidation results in accumulation of long-chain acyl CoA. In-
Scottish Symposium on Angina Pectoris
Table I. Comparison between experimental anoxia and ischaemia. Conditions
Metabolic changes
Mechanical performance
Anoxia
-Oxygen deficiency -Glucose utilization t -Maintained coronary flow -Fatty acid oxidation ..r -Washout of lactate -Anaerobic glycolysis will produce ATP in proportion to the low metabolic demand in arrested heart -Reversible changes
Severe ischaemia (Centre of ischaemic area)
-~ 90 % Reduction
of coronary flow -Inadequate washout of metabolites
-Glucose utilization ..f -Fatty acid oxidation ..r Accumulation of lactate and hydrogen ions -ATP production lower than metabolic demand -Irreversible cell damage (autodigestion)
Mild ischaemia (border zone of ischaemia)
-
