Models of Ischemia and Mechanisms of Angina
Ischemia and Angina – symptoms and diagnostics
Over the past decade, an explosion of information has helped medicine move beyond the rigid supply vs. demand model of ischemia that had guided therapy of coronary disease since Heberden’s first description of angina in the mid 1800s.
Although a supply of blood that is insufficient to meet the demands of a working myocardium remains a consistent mechanism for generating ischemic pain, far more than the fixed narrowing of a coronary artery is involved in the limitation of the supply of oxygen-rich blood to the heart.
The fixed obstructions to coronary arterial flow generated by cholesterol-rich atherosclerotic plaque and organized thrombus provide a substrate for the dynamic obstruction of the coronary vessels. The generation of an acute thrombus associated with a ruptured plaque appears to be the mechanism for most fatal myocardial infarctions.
The endothelium of the coronary arteries, however, appears to be the source of several vasoactive substances mediating both constriction and relaxation of the coronary vessels.
Endothelial derived Relaxation Factor
The endothelium is the site of unique receptors detecting levels of shear stress generated by increases in coronary arterial blood flow. These receptors appear to be essential in the release of endothelial-derived relaxation factor (EDRF). It has also become apparent that the vasoactive substances secreted from the endothelium are capable of regulating certain aspects of cellular growth and smooth muscle proliferation, an important element in the generation of atherosclerotic plaque.
The discovery that EDRF may be a nitric oxide-related substance (if not nitric oxide itself) has provided a molecular basis for the observed efficacy of nitroglycerin at the inception of angina attacks and the efficacy of prophylactic nitroglycerin given in anticipation of an increase in myocardial oxygen demand.
Since nitric oxide also inhibits platelet adhesion and other substances derived from the endothelium (such as prostacyclin) inhibit platelet aggregation, the ability of the endothelium to dilate the coronary artery and inhibit thrombosis on its surface further demonstrates its importance in preventing myocardial ischemia.
Once the endothelium is afflicted with the atherosclerotic process, it will behave in an abnormal manner that contributes to the development of angina pectoris. The normal endothelium responds to a high rate of blood flow by promoting dilatation of the vessel.
The abnormal endothelium will promote constriction of the coronary vessel. In addition, catecholamines, acetylcholine and serotonin may cause vasoconstriction rather than vasodilatation.
The damaged endothelium may also provide a surface for platelet aggregation and thrombus formation, whereas the normal smooth endothelial surface inhibits platelet aggregation.
The requirements of the heart for oxygen may suddenly and dramatically increase with vigorous physical activity or emotional stress as heart rate and blood pressure rise. This may produce angina, although it has also been determined that such trigger events may result in a myocardial infarction.
Coronary vasospasm may also be induced by emotional or physical stress, and the resulting disruption in laminar flow within the coronary vessel may result in a cascade of thrombotic activity.
Platelet adhesiveness may also increase under conditions that cause an increase in sympathetic neural tone, including emotional stress and vigorous physical exertion. Platelet adhesiveness and ischemic events have also been shown to vary according to the hour of day, with more frequent ischemic events occurring in the early morning hours.
A sudden increase in arterial blood pressure may also cause rupture of an endothelial plaque. The Milis study suggests that as many as 50% of all patients suffering a myocardial infarction have identifiable trigger events. Angiography has identified plaque rupture in diseased vessels as well as in vessels that had been determined to be angiographically normal prior to the infarction.
The results of several studies indicate that the culprit vessel implicated in a fresh myocardial infarction is not likely to be the vessel with the greatest degree of stenosis. Plaque rupture, however, does not always result in an acute ischemic event (either angina, myocardial infarction or sudden death).
If the consequences of plaque rupture can be limited by interference with thrombus formation, a sufficient number of collateral channels can be recruited and ischemic injury can be avoided. Vasospasm can injure the endothelial surface and result in intracoronary thrombus formation, and this may be an important factor in the rupture of endothelial plaque.
Prevention of Plaque Rupture
Most of the therapeutic interventions that have been proven to reduce the incidence of myocardial infarction and/or sudden death have been shown to have an impact on plaque rupture. beta-Blockers reduce the surge in blood pressure that may play a physical role in rupturing vulnerable plaque.
The angiotensin-converting enzyme (ACE) inhibitors have reduced the rates of subsequent myocardial infarctions in patients with left ventricular dysfunction. It is hypothesized that the inhibition of angiotensin II may reduce the likelihood of plaque rupture by several means, including a reduction in blood pressure and a possible interference with vascular smooth muscle growth factor.
An intriguing genetic observation is that the survivors of myocardial infarction are more likely to demonstrate an ACE inhibitor genotype DD, which is associated with higher levels of ACE.
Antioxidants may interfere with plaque rupture by limiting the formation of oxidized LDL cholesterol, thus slowing the progression of atherosclerosis. Vitamin E, vitamin C, beta-carotene and selenium prevent LDL oxidation, but have not been directly linked with prevention of plaque rupture (although it is likely that they play beneficial roles).
Aspirin interferes with the progress of thrombosis after a plaque has ruptured. The aggressive use of lipid-lowering agents and dietary modification may result in a very modest degree of regression of coronary atherosclerotic lesions; however, a more substantial reduction in coronary ischemic events is evident. It is hypothesized that an unstable coronary plaque (ie, one that is vulnerable to rupture) may become stabilized and far less likely to initiate the cascade of events that may lead to an episode of angina and acute myocardial infarction or sudden cardiac death.
Clinical “Pearls” Regarding Models of Ischemia and Mechanisms of Angina
The coronary endothelial surface is the site of the initiation of complex events that may lead to acute myocardial ischemia by promoting dilatation or constriction of the vessel.
EDRF may be a nitric oxide-related substance that helps explain the mechanism for the initial effect of nitroglycerin.
Vasospasm, plaque rupture and thrombus formation are important mechanisms for reducing acute myocardial ischemia.
The rupture of a lipid-laden endothelial plaque appears to be a key event in the generation of acute ischemic events, including angina, myocardial infarction and sudden cardiac death.
An angiographically normal vessel may be the site of a plaque that becomes unstable and ruptures.
Emotional and physical stress may promote plaque rupture and may provide the physiologic basis for trigger events often identified in patients with myocardial infarction.
Beta-Blockers, aspirin, ACE inhibitors, antioxidants and nitrates may all provide an anti-ischemic effect by reducing the tendency for plaque rupture.