PATHOPHYSIOLOGY OF MYOCARDIAL ISCHEMIA/REPERFUSION
The major cause of acute myocardial infarction (MI) is coronary atherosclerosis with superimposed luminal thrombus, which accounts for more than 80% of all infarcts. MIs resulting from nonatherosclerotic diseases of the coronary arteries are rare. In past decades, there have been several trends regarding the epidemiology and outcome of patients hospitalized with acute MI. Over the time span from 1975 to 2009, patients became significantly older, were more likely to be women, and were more likely to receive effective cardiac medications. Despite a greater prevalence of comorbidities, hospital survival rates have globally improved over time.1 However, mortality has remained unchanged for patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI,2 mostly because of secular trends as a result of changing population.3 Reperfusion (blood flow restoration into the ischemic territory) is the only available treatment to stop the progression of ischemic damage during an MI but comes at a price, inducing additional harm to the myocardium.4 Reperfusion injury, which accounts for up to 40% of total infarct size, is thus considered “a necessary evil.”5
Mechanisms of Myocardial Injury
The normal function of the heart muscle is supported by high rates of myocardial blood flow, oxygen consumption, and combustion of fat and carbohydrates (glucose and lactate). Under normal aerobic conditions, cardiac energy is derived from fatty acids, supplying 60% to 90% of the energy for adenosine triphosphate (ATP) synthesis (Fig. 37–1). The rest of the energy (10%-40%) comes from oxidation of pyruvate formed from glycolysis and lactate oxidation. Almost all of the ATP formed comes from oxidative phosphorylation in the mitochondria; only a small amount of ATP (< 2%) is synthesized by glycolysis. Approximately two-thirds of the ATP used by the heart goes to contractile shortening, and the remaining third is used by sarcoplasmic reticulum Ca2+ ATPase and other ion pumps.
Cardiac energy metabolism under normal aerobic conditions. Fatty acids are the primary source of energy for the heart, supplying 60% to 90% of the energy for adenosine triphosphate (ATP) synthesis. The balance (10%-40%) comes from the oxidation of pyruvate formed from glycolysis and lactate oxidation. Almost all of the ATP formation comes from oxidative phosphorylation in the mitochondria; only a trivial amount of ATP (< 2% of the total) is synthesized by glycolysis. ADP, adenosine diphosphate; SR, sarcoplasmic reticulum. Reproduced with permission from Stanley WC. Changes in cardiac metabolism: a critical step from stable angina to ischemic cardiomyopathy. Eur Heart J Suppl. 2001;3(suppl O):O2-07.
Sudden occlusion of a major branch of a coronary artery shifts aerobic or mitochondrial metabolism to anaerobic glycolysis within seconds of reduced arterial flow. Myocardial ischemia primarily affects mitochondrial metabolism, resulting in a decrease in ATP formation by shutting off oxidative phosphorylation. The reduced aerobic ATP formation stimulates glycolysis and an increase in myocardial glucose uptake and glycogen breakdown (Fig. 37–2). Decreased ATP inhibits Na+/K+-ATPase, increasing intracellular Na+ and Cl, leading to cell swelling. Derangements in transport systems in the sarcolemma and sarcoplasmic reticulum increase cytosolic Ca2+, inducing activation of proteases and alterations in contractile proteins. Pyruvate is not readily oxidized ...