Pathophysiology
Summary
In the coronary circulation, cardiac myocytes generate energy primarily through oxidative phosphorylation and use more extract more oxygen from blood than any other tissue, to the extent that the coronary sinus contains the most deoxygenated blood in the body. The coronary endothelial cells produce nitric oxide (NO), a gaseous molecule that promotes coronary vasodilation by increasing cyclic GMP in arteriolar smooth muscle cells. In parallel, adenosine acts as another important vasodilator of coronary arteries. Both NO and adenosine help in autoregulation of coronary blood flow, keeping it constant across a range of blood pressures by regulating coronary vasodilation. However, coronary atherosclerosis can obstruct luminal flow and impair autoregulation by inhibiting the release of NO and other vasodilators, thereby interfering with the mechanism and ability to maximally vasodilate. This obstruction and impaired vasodilation leads to a mismatch between myocardial oxygen demand and coronary oxygen supply, culminating in ischemic heart disease. The subendocardium, which is typically well-oxygenated oxygen, becomes ischemic first when autoregulation is disrupted.
Factors like increased afterload—often arising from aortic stenosis, hypertension, or cocaine—can increase myocardial oxygen demand and exacerbate ischemic heart disease. This increased afterload results in concentric myocardial hypertrophy which further decreases coronary oxygen supply. The left ventricle receives coronary blood flow during diastole—conditions that decrease time in diastole, such as tachycardia and increased contractility, lead to reduced coronary flow to the left ventricle that can cause MI. Exercise and cocaine not only elevate myocardial oxygen demand through tachycardia and increased contractility but also decrease coronary oxygen supply. Cocaine and vasospastic angina can cause coronary artery vasoconstriction, further decreasing the coronary oxygen supply. Diminished coronary oxygen supply can also arise from coronary embolism, dissection, arteritis, myocardial fibrosis, or in systemic hypoxia due to conditions like hypotension, shock, anemia, and carbon monoxide poisoning.
In ischemic conditions, myocardial cells switch to anaerobic glycolysis within seconds, leading to ATP depletion and myofibril relaxation. Reversible ischemic myocyte damage like cellular and mitochondrial swelling, glycogen depletion, and clumping of chromatin can be improved with early reperfusion. However, after 30 minutes, the damage becomes irreversible and is indicated by signs like mitochondrial vacuolization, and myocyte cell membrane breakdown which leads to the release of troponin & creatine kinase, indicating irreversible cell damage.
Reperfusion injury can occur during the restoration of blood flow, leading to further cellular damage through the buildup of intracellular calcium during ischemia, which causes hypercontracture and cytoskeletal damage upon reperfusion. Reperfusion injury also cause the local release of free radicals, influx of inflammation, and further irreversible mitochondrial damage.
Chronic ischemic heart disease, also known as ischemic cardiomyopathy, manifests as progressive heart failure. Chronically ischemic hearts typically exhibit patchy fibrosis from previous healed infarcts. Chronic severe CAD without infarction can also cause chronic ischemic heart disease. Chronic cardiac ischemia leads to systolic heart failure with eccentric hypertrophy and may contain both nonviable and ‘hibernating' myocardial cells. Revascularization can reactivate these hibernating cells, reversing systolic dysfunction, and improving the condition of a chronically ischemic heart.
Lesson Outline
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FAQs
Cardiac myocytes generate energy almost exclusively via oxidative phosphorylation. In an ischemic event, oxygen levels are depleted and oxidative phosphorylation cannot occur efficiently. This leads to a switch from aerobic metabolism to anaerobic glycolysis, resulting in diminished ATP production and impaired function of the affected myocytes.
Increased afterload on the heart, often due to aortic stenosis or hypertension, elevates the demand for oxygen in the myocardium. This happens because the heart needs to exert more effort to pump blood against the heightened resistance. Over time, this increased workload can lead to concentric myocardial hypertrophy. This hypertrophy can further compromise the coronary oxygen supply, exacerbating the risk of ischemic heart disease.
In tachycardia, the duration of diastole is shortened, which impacts coronary blood flow to the left ventricle. This reduction in flow contributes to myocardial ischemia, a condition where the heart muscle is deprived of adequate oxygen supply. Simultaneously, the elevated heart rate intensifies the myocardium's oxygen requirements, potentially worsening the ischemic state.
In the setting of ischemia, myocytes quickly transition from aerobic to anaerobic metabolism due to oxygen scarcity, leading to ATP depletion. Myofibril relaxations is seen within seconds of oxygen depletion. Early indicators of ischemic damage in myocytes consist of cellular and mitochondrial enlargement, glycogen exhaustion, and chromatin aggregation. If oxygen supply is promptly restored through reperfusion, these alterations can be reversible. However, if ischemia persists for ~30 minutes or longer, cellular damage becomes irreversible, resulting in cell membrane disintegration and the subsequent release of cardiac markers like troponin and creatine kinase.
Following an ischemic episode, reperfusion can paradoxically exacerbate myocardial injury. During the ischemic period, intracellular calcium accumulates, which may cause hypercontracture and damage to the cytoskeleton upon reperfusion. In addition, reperfusion can trigger the local release of free radicals, provoke inflammatory responses, and induce irreversible mitochondrial damage. Another noteworthy consequence is the phenomenon of "stunned myocardium," where myocytes remain functionally impaired for a variable period, potentially lasting days, even after re-establishment of blood flow.
