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Unformatted text preview: Coronary Circulation Coronary Artery Disease
What is the function of coronary arteries?
The coronary arteries supply blood flow to the heart, and when functioning normally, they ensure adequate oxygenation of the myocardium at all levels of cardiac activity. Constriction and dilation of the coronary arteries, governed primarily by local regulatory mechanisms, regulate the amount of blood flow to the myocardium in a manner that matches the amount of oxygen delivered to the myocardium with the myocardial demand for oxygen. What is coronary artery disease?
Coronary artery disease (CAD) causes changes in both structure and function of the blood vessels. Atherosclerotic processes cause an abnormal deposition of lipids in the vessel wall, leukocyte infiltration and vascular inflammation, plaque formation and thickening of the vessel wall. These changes lead to a narrowing of the lumen (i.e., stenosis), which restricts blood flow. There are also subtle, yet functionally important changes that can occur before overt changes in structure are observed. Early in the disease process, the endothelial cells that line the coronary arteries become dysfunctional. Because the endothelium produces important substances such as nitric oxide and prostacyclin that are required for normal coronary function, endothelial dysfunction can lead to coronary vasospasm, impaired relaxation, and formation of blood clots that can partially or completely occlude the vessel. What are the physiological and clinical consequences of coronary artery disease?
When CAD restricts blood flow to the myocardium (ischemia) there is an imbalance between oxygen supply and oxygen demand. When the oxygen supply is insufficient to meet the oxygen demand (reduced oxygen supply/demand ratio), the myocardium becomes hypoxic. This is often associated with chest pain (angina) and other clinical symptoms. Severe ischemia can lead to anoxia and infarction of the tissue. Furthermore, acute or chronic ischemia caused by CAD can impair cardiac mechanical and electrical activities leading to heart failure and arrhythmias. How common is coronary artery disease?
About 13 million Americans (~7% of population) have coronary artery disease. About half of all deaths related to cardiovascular disease result from coronary artery disease. Coronary artery disease is the leading cause of death among American men and women, and represents about 20% of all deaths. How is coronary artery disease treated? 1 Coronary Circulation As described above, CAD results in myocardial ischemia, which leads to chest pain (angina) and cardiac mechanical and electrical dysfunction. The goal in treating CAD is to restore normal coronary perfusion, or if that is not possible, then to reduce the oxygen demand by the heart (i.e., normalize the oxygen supply/demand ratio) so as to minimize myocardial hypoxia. In severe CAD in which one or more coronary arteries is very stenotic, some patients will have a stent implanted within the coronary artery to open up the lumen and restore blood flow. Other patients may undergo coronary artery bypass grafts in which the diseased segment is bypassed using an artery or vein harvested from elsewhere in their body (i.e., internal mammary artery). If the coronary is occluded by a blood clot, a thrombolytic drug may be administered to dissolve the clot. Anti-platelet drugs and anticoagulants are also given to patients with CAD. However, the vast majority of CAD patients are treated with antianginal drugs that reduce the myocardial oxygen demand by decreasing heart rate, contractility, afterload or preload (e.g., beta-blockers, calcium-channel blockers, nitrodilators), or they are treated with drugs that many prevent or reverse coronary vasospasm in patients with variant angina. Click here for more information on drug treatment for CAD and angina. 2 Coronary Circulation Oxygen Supply
Oxygen is supplied to the myocardium by the coronary circulation. Coronary blood flow is determined by hemodynamic factors such as perfusion pressure and vascular resistance. The latter is determined by vascular anatomy and structure, as well as by changes in diameter of the vascular lumen resulting from contraction and relaxation of vascular smooth muscle (local regulation of blood flow). The delivery of oxygen to the myocardium (oxygen supply) is determined by two factors: coronary blood flow (CBF) and the oxygen content of the blood (AO2). O2 Delivery = CBF x AO2, where CBF = ml/min and AO2 = ml O2/ml blood Therefore, the units for O2 delivery are ml O2/min. The normal content of oxygen in arterial blood is about 20 ml O2/100 ml blood (0.2 ml O2/ml blood), or 20 vol %. CBF, expressed per 100g of tissue weight is about 80 ml/min per 100g at resting heart rates. Therefore, the oxygen delivery to the heart under resting conditions is about 16 ml O2/ min per 100g. Ordinarily, the oxygen content of arterial blood changes relatively little. Therefore, the primary determinant of oxygen delivery in the absence of hypoxemia is coronary blood flow. In coronary artery disease, a number of factors can reduce coronary blood flow. Stenotic lesions cause a narrowing of vessel, particularly the large epicardial coronaries (e.g., left anterior descending or circumflex arteries). The stenosis may be at a specific site, or it may diffuse along the length of the vessel. In either case, the stenosis can limit maximal coronary flow (decreased coronary flow reserve. Maximal flow is reduced because the the fixed stenosis is in-series with the distal microcirculation. Diseased coronary vessels are more susceptible to vasospasm, which can lead to a temporary restriction of coronary flow at rest. This can occur during stressful conditions or during exercise in susceptible individuals. Finally, thrombus formation, particularly at the site of a ruptured atherosclerotic plaque, can partially or completely occlude a coronary vessel causing unstable angina or myocardial infarction. 3 Coronary Circulation Oxygen Demand
Oxygen demand is a concept that is closely related to the oxygen consumption of an organ. The two terms are often used interchangeably although they are not equivalent. Demand is related to need, whereas consumption is the actual amount of oxygen consumed per minute. Under some conditions, demand may exceed consumption because the latter may be limited by the delivery of oxygen to the myocardium. The following discussion focuses on the oxygen demand by the heart. Highly oxidative organs such as the heart [see cardiac metabolism] have a high demand for oxygen and therefore have a relatively high oxygen consumption. Myocardial oxygen consumption (MVO2) is required to regenerate ATP that is utilized by membrane transport mechanisms (e.g., Na+/K+-ATPase pump) and by myocyte contraction and relaxation (e.g., myosin ATPase). The following tables give MVO2 values and compares these with the oxygen consumption of other organs: Cardiac State Arrested heart Resting heart rate Heavy exercise MVO2 (ml O2/min per 100g) 2 8 70 By comparison, the oxygen consumption (ml O2/min per 100g) for other organs is: Organ Brain Kidney Skin Resting muscle Contracting muscle O2 Consumption (ml O2/min per 100g) 3 5 0.2 1 50 The above tables show that the heart has a wide range of MVO2 values that depends on the state of mechanical activity. Skeletal muscle, like the heart, has a wide range of values for oxygen consumption depending on its level of mechanical activity. The MVO2 in the arrested heart represents basal ATP utilization, primarily by membrane transport systems. The additional increase in MVO2 above this basal level is that required to support myocyte contraction and relaxation. In order to support MVO2, particularly during times of increased oxygen demand (e.g., during exercise), the heart must extract oxygen from the arterial blood supplying the myocardium (see Oxygen Supply). 4 Coronary Circulation There is a unique relationship between MVO2, coronary blood flow (CBF), and the extraction of oxygen from the blood (arterial-venous oxygen difference, AO2 -VO2). This relationship is an application of the Fick Principle: MVO2 = CBF x (AO2 VO2),
where CBF = coronary blood flow (ml/min), and (AO2 VO2) is the arterial-venous oxygen content difference (ml O2/ml blood). For example, if CBF is 80 ml/min per 100g and the A-VO2 difference is 0.1 ml O2/ml blood, then the MVO2 = 8 ml O2/min per 100g. Another way of expressing this relationship is: MVO2 = (CBF AO2 ) (CBF VO2),
where CBF AO2 is the oxygen supply (or delivery) to the myocardium and CBFVO2 is the unextracted oxygen leaving the heart via the venous circulation. The difference between the oxygen that enters the heart and that which leaves the heart per minute is the oxygen consumption of the heart. Oxygen consumption by the heart can be estimated in humans by utilizing the Fick Principle; however, that requires catheterization of the coronary sinus to measure venous oxygen saturation and coronary blood flow. Relative changes in MVO2 can be estimated by using an indirect index such as the pressure-rate product. There are different variations of this index, but one method simply multiplies the aortic systolic pressure by the heart rate. This can be useful, for example, in clinical trials to determine if a drug reduces oxygen demand. The pressure-rate product is based on the observation that MVO2 is closely related to ventricular wall tension. 5 Coronary Circulation Determinants of myocardial oxygen consumption
Myocyte contraction is the primary factor determining myocardial oxygen consumption (MVO2) above basal levels. Therefore, factors that enhance tension development by the cardiac muscle cells, the rate of tension development, or the number of tension generating cycles per unit time will increase MVO2. For example, doubling heart rate approximately doubles MVO2 because ventricular myocytes are generating twice the number of tension cycles per minute. Increasing inotropy also increases MVO2 because the rate of tension development is increased as well as the magnitude of tension, both of which result in increased ATP hydrolysis and oxygen consumption. Increasing afterload, because it increases tension development, also increases MVO2. Increasing preload (e.g., ventricular end-diastolic volume) also increases MVO2; however, the increase is much less than what might be expected because of the LaPlace relationship. The LaPlace relationship says that wall tension (T) is proportional to the product of intraventricular pressure (P) and ventricular radius (r). (Law of LaPlace) Wall tension can be thought of as the tension generated by myocytes that results in a given intraventricular pressure at a particular ventricular radius. Therefore, when the ventricle needs to generate greater pressure, for example with increased afterload or inotropic stimulation, the wall tension is increased (i.e., increased myocyte tension development). This relationship also shows us that a dilated ventricle (as occurs in dilated cardiomyopathy) has to generate increased wall tension to produce the same intraventricular pressure. We observe empirically that wall tension and MVO2 are closely related. For this reason, changes in intraventricular pressure and ventricular radius affect MVO2. As stated above, changes in ventricular preload volume do not affect MVO2 to the same extent quantitatively as changes in afterload. This is because preload is usually expressed as the ventricular end-diastolic volume, not radius. If the ventricle is assumed to be a sphere, then the ventricular volume (V) is related to radius (r) by: Therefore, 6 Coronary Circulation Substituting this relationship into the LaPlace relationship, This relationship indicates that a 100% increase in ventricular volume (V) increases wall tension (T) by only 26%. In contrast, increasing intraventricular pressure (P) by 100% increases wall tension (T) by 100%. For this reason, wall tension, and therefore MVO2, is far less sensitive to changes in ventricular volume than pressure (see figure at right). In summary, increasing heart rate (HR), aortic pressure (AP), and inotropy (Ino) increase MVO2 about 4-times more than an equivalent percent change in stroke volume (SV). These finding have implications for the treatment of patients with coronary artery disease (CAD). For example, drugs that decrease afterload, heart rate, and inotropy are particularly effective in reducing MVO2 and relieving anginal symptoms. CAD patients should avoid situations that lead to large increases in afterload such as lifting heavy weights, which causes large increases in arterial pressure. It is very important that hypertensive CAD patients are fully complying with their anti-hypertensive medications because hypertension dramatically increases MVO2 due to increased afterload. CAD patients can also be encouraged to participate in exercise programs such as walking that utilize preload changes to augment cardiac output by the Frank-Starling mechanism. It is important to minimize adrenergic activation in CAD patients because sympathetic activation of the heart and vasculature increases heart rate, inotropy, and systemic vascular resistance, all of which lead to significant increases in oxygen demand by the heart. 7 Coronary Circulation Ischemia and Hypoxia
Ischemia is insufficient blood flow to provide adequate oxygenation. This, in turn, leads to tissue hypoxia (reduced oxygen) or anoxia (absence of oxygen). Ischemia always results in hypoxia; however, hypoxia can occur without ischemia if, for example, arterial hypoxia occurs. The most common causes of ischemia are acute arterial thrombus formation, chronic narrowing (stenosis) of a supply artery that is often caused by atherosclerotic disease, and arterial vasospasm. As blood flow is reduced to an organ, oxygen extraction increases. When the tissue is unable to extract adequate oxygen, the partial pressure of oxygen within the tissue falls (hypoxia) leading to a reduction in mitochondrial respiration and oxidative metabolism. Myocardial Oxygen Balance
Myocardial oxygen balance is determined by the ratio of oxygen supply to oxygen demand as shown in the figure. Increasing oxygen supply by increasing either arterial oxygen content or coronary blood flow leads to an increase in tissue oxygen levels (usually measured as the partial pressure of oxygen, pO2). Increasing oxygen demand alone (i.e., myocardial oxygen consumption) decreases tissue oxygen levels. Normally, when oxygen demand increases there is a proportionate increase in coronary blood flow and oxygen supply so that tissue oxygen levels are maintained during times of increased oxygen demand. This increase in blood flow is performed by local regulatory mechanisms. This tight coupling between oxygen demand and coronary blood flow is impaired in coronary artery disease because oxygen supply is limited by vascular stenosis. If the oxygen supply/demand ratio is reduced either by a decrease in oxygen delivery relative to demand, or by an increase in demand relative to supply, then tissue hypoxia results. A reduced oxygen supply/demand ratio is the cause of chest pain (angina) associated with coronary artery disease. These patients are treated with antianginal drugs such as beta-blockers, calcium-channel blockers, nitrodilators that improve this ratio. 8 Coronary Circulation Angina
Angina is chest pain caused by an imbalance between oxygen supply (decreased coronary blood flow) and oxygen demand (increased myocardial oxygen consumption), which leads to a decrease in the oxygen supply/demand ratio and myocardial hypoxia. The decreased flow can result from coronary artery vasospasm, fixed stenotic lesions (chronic vessel narrowing), or from a blood clot (thrombus) that incompletely (non-occlusive thrombus) or completely occludes a coronary artery (occlusive thrombus). Oxygen consumption can be elevated by increased heart rate, contractility (inotropy), afterload and preload. Type of Angina There are three types of angina: Printzmetal's variant angina, chronic stable angina, and unstable angina. All three forms are associated with a reduction in the oxygen supply/ demand ratio. Variant (Printzmetal's) angina results from coronary vasospasm, which temporarily reduces coronary blood flow (i.e., produces ischemia by reducing oxygen supply; "supply ischemia"), thereby decreasing the oxygen supply/demand ratio. Enhanced sympathetic activity (e.g., during emotional stress), especially when coupled with a dysfunctional coronary vascular endothelium (i.e., reduced endothelial production of the vasodilators nitric oxide and prostacyclin) can precipitate vasospastic angina. This form of angina is treated with drugs that reverse or inhibit coronary vasospasm. These drugs include calcium-channel blockers and nitrodilators. These drugs also reduce oxygen demand to further improve the oxygen supply/demand ratio. Chronic stable angina is caused by a chronic narrowing of coronary arteries due to atherosclerosis. This narrowing is readily observed in the large epicardial arteries by an angiogram; however, narrowing also occurs in smaller branches that cannot be visualized angiographically. When a coronary artery is narrowed beyond a critical value 9 Coronary Circulation (critical stenosis), the myocardial tissue perfused by the artery will not receive adequate blood flow because coronary flow reserve (i.e., maximal flow capacity) is limited. This results in the tissue becomes ischemic and hypoxic, particularly during times of increased oxygen demand (e.g., during physical exertion). Therefore, in this type of angina, relative ischemia occurs when the oxygen demand increases, so this is referred to as "demand ischemia." This leads to anginal pain during physical exertion (exertional angina). The pain usually is associated with a predictable threshold of physical activity. Other conditions that cause myocardial oxygen demand to increase, such as a large meal or emotional stress, can also precipitate pain. This form of angina is most commonly treated with drugs that reduce oxygen demand. These drugs include beta-blockers, calcium-channel blockers, nitrodilators. They act by decreasing heart rate, contractility, afterload and preload. Unstable angina is caused by transient formation and dissolution of a blood clot (thrombosis) within a coronary artery. The clots often form in response to plaque rupture in atherosclerotic coronary arteries; however, the clot may also form because diseased coronary artery endothelium (endothelial dysfunction) is unable to produce nitric oxide and prostacyclin that inhibit platelet aggregation and clot formation. When the clot forms, coronary flow is reduced, leading to a reduction in the oxygen supply/demand ratio ("supply ischemia"). If the clot completely occludes the coronary artery for a sufficient period of time, the myocardium supplied by the vessel may become infarcted (acute myocardial infarction) and become irreversibly damaged. This form of angina is treated with drugs that reduce oxygen demand (i.e., beta-blockers, calcium-channel blockers, nitrodilators), but more importantly, this form of angina is treated with drugs that inhibit thrombus formation (e.g., anti-platelet drugs and aspirin). Angina may also be precipitated by a combination of supply and demand ischemia. For example, diseased, stenotic coronary segments can sometimes undergo vasoconstriction during exercise (healthy arteries dilate). This probably occurs due to the absence of sufficient production of nitric oxide and perhaps prostacyclin by the vascular endothelium to counteract normal sympathetic-mediated effects on vascular alpha-adrenoceptors. A hemodynamic condition may exist that leads to coronary vascular steal. In this condition, multiple fixed stenotic lesions can lead to a redistribution of flow within the major supply arteries of the heart under conditions of exercise or vasodilator therapy. As blood flow increases in one region of the coronary vascular network, blood flow can reciprocally decrease in another region leading to anginal pain. 10 Coronary Circulation Myocardial Oxygen Extraction
The amount of oxygen delivered to the myocardium is greater than the amount that is actually taken up (oxygen consumed) by the myocardium to support oxidative metabolism. Typically, the myocardium extracts about 50% of the oxygen supplied by the arterial blood. This oxygen extraction is determined by the ratio of oxygen consumption to coronary blood flow as described by the Fick Principle. Oxygen extraction is, by definition, the difference between the arterial and venous contents of oxygen (AO2-VO2). Compared to most organs of the body (see table below), the oxygen extraction of the heart is relatively high. The AO2-VO2 of the heart is typically 10-12 vol % (ml O2/100 ml blood). Organ heart skeletal muscle (resting) kidney intestine skin AO2-VO2 (vol %) 10-12 2-5 2-3 4-6 1-2 Theoretically, the maximal amount of oxygen that can be extracted is 20 vol %. In reality, however, the maximal oxygen extraction is around 15-16 vol % because of the kinetics of oxygen dissociation from hemoglobin. Therefore, the heart is extracting at least two-thirds of the physiologically available oxygen under normal operating conditions. Because of this, the heart must tightly couple oxygen supply and demand in order to ensure adequate tissue oxygenation. In the absence of coronary artery disease (CAD), coronary blood flow increases almost proportionately to increases in MVO2 thereby preventing tissue hypoxia and functional impairment. Local regulation of blood flow is responsible for adjusting coronary blood flow to the metabolic demands of the contracting myocardium. In the presence of CAD, coronary blood flow may not be able to supply adequate oxygen to meet metabolic demands of the contracting heart. This will increase the oxygen extraction and decrease the venous oxygen content. This leads to tissue hypoxia and angina. If the lack of blood flow is due to a fixed stenotic lesion in the coronary artery (because of atherosclerosis), blood flow can be improved within that vessel by 1) placing a stent within the vessel to expand the lumen, 2) using an intracoronary angioplasty balloon to stretch the vessel open, or 3) bypassing the diseased vessel with a vascular graft. If the insufficient blood flow is caused by a blood clot (thrombosis), a thrombolytic drug that dissolves clots may be administered. Antiplatelet drugs and aspirin are commonly used to prevent the reoccurrence of clots. If the reduced flow is due to coronary vasospasm, then coronary vasodilators can be given (e.g., nitrodilators, calcium-channel blockers) to reverse and prevent vasospasm. 11 ...
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- Fall '07