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ANATOMIC CONSIDERATIONS
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The two coronary arteries that supply the myocardium arise from the sinuses behind two of the cusps of the aortic valve at the root of the aorta (Figure 33–11). Eddy currents keep the valves away from the orifices of the arteries, and they are patent throughout the cardiac cycle. Most of the venous blood returns to the heart through the coronary sinus and anterior cardiac veins (Figure 33–12), which drain into the right atrium. In addition, there are other vessels that empty directly into the heart chambers. These include arteriosinusoidal vessels, sinusoidal capillary-like vessels that connect arterioles to the chambers; thebesian veins that connect capillaries to the chambers; and a few arterioluminal vessels that are small arteries draining directly into the chambers. A few anastomoses occur between the coronary arterioles and extracardiac arterioles, especially around the mouths of the great veins. Anastomoses between coronary arterioles in humans only pass particles less than 40 μm in diameter, but evidence indicates that these channels enlarge and increase in number in patients with coronary artery disease.
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PRESSURE GRADIENTS & FLOW IN THE CORONARY VESSELS
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The heart is a muscle that, like skeletal muscle, compresses its blood vessels when it contracts. The pressure inside the left ventricle is slightly higher than in the aorta during systole (Table 33–4). Consequently, flow occurs in the arteries supplying the subendocardial portion of the left ventricle only during diastole, although the force is sufficiently dissipated in the more superficial portions of the left ventricular myocardium to permit some flow in this region throughout the cardiac cycle. Because diastole is shorter when the heart rate is high, left ventricular coronary flow is reduced during tachycardia. On the other hand, the pressure differential between the aorta and the right ventricle, and the differential between the aorta and the atria, are somewhat greater during systole than during diastole. Consequently, coronary flow in those parts of the heart is not appreciably reduced during systole. Flow in the right and left coronary arteries is shown in Figure 33–13. Because no blood flow occurs during systole in the subendocardial portion of the left ventricle, this region is prone to ischemic damage and is the most common site of myocardial infarction. Blood flow to the left ventricle is decreased in patients with stenotic aortic valves because the pressure in the left ventricle must be much higher than that in the aorta to eject the blood. Consequently, the coronary vessels are severely compressed during systole. Patients with aortic stenosis are particularly prone to develop symptoms of myocardial ischemia, in part because of this compression and in part because the myocardium requires more O2 to expel blood through the stenotic aortic valve. Coronary flow is also decreased when the aortic diastolic pressure is low. The rise in venous pressure in conditions such as heart failure reduces coronary flow because it decreases effective coronary perfusion pressure (Clinical Box 33–4).
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Coronary blood flow has been measured by inserting a catheter into the coronary sinus and applying the Kety method to the heart on the assumption that the N2O content of coronary venous blood is typical of the entire myocardial effluent. Coronary flow at rest in humans is about 250 mL/min (5% of the cardiac output). A number of techniques utilizing radionuclides, radioactive tracers that can be detected with radiation detectors over the chest, have been used to study regional blood flow in the heart and to detect areas of ischemia and infarct as well as to evaluate ventricular function. Radionuclides such as thallium-201 (201Tl) are pumped into cardiac muscle cells by Na+, K+ ATPase and equilibrate with the intracellular K+ pool. For the first 10–15 min after intravenous injection, 201Tl distribution is directly proportional to myocardial blood flow, and areas of ischemia can be detected by their low uptake. The uptake of this isotope is often determined soon after exercise and again several hours later to bring out areas in which exertion leads to compromised flow. Conversely, radiopharmaceuticals such as technetium-99m stannous pyrophosphate (99mTc-PYP) are selectively taken up by infarcted tissue by an incompletely understood mechanism and make infarcts stand out as “hot spots” on scintigrams of the chest. Coronary angiography can be combined with measurement of 133Xe washout (see above) to provide detailed analysis of coronary blood flow. Radiopaque contrast medium is first injected into the coronary arteries, and radiographs are used to outline their distribution. The angiographic camera is then replaced with a scintillation camera, and 133Xe washout is measured.
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VARIATIONS IN CORONARY FLOW
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At rest, the heart extracts 70–80% of the O2 from each unit of blood delivered to it (Table 33–1). O2 consumption can only be increased significantly by increasing blood flow. Therefore, it is not surprising that blood flow increases when the metabolism of the myocardium is increased. The caliber of the coronary vessels, and consequently the rate of coronary blood flow, is influenced not only by pressure changes in the aorta but also by chemical and neural factors. The coronary circulation also shows considerable autoregulation.
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CLINICAL BOX 33–4 Coronary Artery Disease
When flow through a coronary artery is reduced to the point that the myocardium it supplies becomes hypoxic, angina pectoris develops (see Chapter 30). If the myocardial ischemia is severe and prolonged, irreversible changes occur in the muscle, and the result is myocardial infarction. Many individuals have angina only on exertion, and blood flow is normal at rest. Others have more severe restriction of blood flow and have anginal pain at rest as well. Partially occluded coronary arteries can be constricted further by vasospasm, producing myocardial infarction. However, it is now clear that the most common cause of myocardial infarction is rupture of an atherosclerotic plaque, or hemorrhage into it, which triggers the formation of a coronary-occluding clot at the site of the plaque. The electrocardiographic changes in myocardial infarction are discussed in Chapter 29. When myocardial cells actually die, they leak enzymes into the circulation, and measuring the rise in serum enzymes and isoenzymes produced by infarcted myocardial cells also plays an important role in the diagnosis of myocardial infarction. The enzymes most commonly measured are the MB isomer of creatine kinase (CK-MB), troponin T, and troponin I. Myocardial infarction is a very common cause of death in developed countries because of the widespread occurrence of atherosclerosis. In addition, there is a relation between atherosclerosis and circulating levels of lipoprotein(a) (Lp[a]). Lp(a) has an outer coat consisting of apo(a). It interferes with fibrinolysis by down-regulating plasmin generation (see Chapter 31). It now appears that atherosclerosis has an important inflammatory component as well. The lesions of the disease contain inflammatory cells, and there is a positive correlation between increased levels of C-reactive protein and other inflammatory markers in the circulation with subsequent myocardial infarction.
THERAPEUTIC HIGHLIGHTS Treatment of myocardial infarction aims to restore flow to the affected area as rapidly as possible while minimizing reperfusion injury. Needless to say, it should be started as promptly as possible to avoid irreversible changes in heart function. In acute disease, antithrombotic agents are often given, but these can be problematic, leading to increased mortality due to bleeding if cardiac surgery is subsequently needed. Mechanical/surgical approaches to coronary artery disease include balloon angioplasty and/or implantation of stents to hold the vessels open, or coronary artery bypass grafting (CABG).
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The close relationship between coronary blood flow and myocardial O2 consumption indicates that one or more of the products of metabolism cause coronary vasodilation. Factors suspected of playing this role include a lack of O2 and increased local concentrations of CO2, H+, K+, lactate, prostaglandins, adenine nucleotides, and adenosine. Likely several or all of these vasodilator metabolites act in an integrated manner, redundant manner, or both. Asphyxia, hypoxia, and intracoronary injections of cyanide all increase coronary blood flow 200–300% in denervated as well as intact hearts, and the feature common to these three stimuli is hypoxia of the myocardial fibers. A similar increase in flow is produced in the area supplied by a coronary artery if the artery is occluded and then released. This reactive hyperemia is similar to that seen in the skin (see below). Evidence suggests that in the heart it is due to release of adenosine.
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The coronary arterioles contain α-adrenergic receptors, which mediate vasoconstriction, and β-adrenergic receptors, which mediate vasodilation. Activity in the noradrenergic nerves to the heart and injections of norepinephrine cause coronary vasodilation. However, norepinephrine increases the heart rate and the force of cardiac contraction, and the vasodilation is due to production of vasodilator metabolites in the myocardium secondary to the increase in its activity. When the inotropic and chronotropic effects of noradrenergic discharge are blocked by a β-adrenergic blocking drug, stimulation of the noradrenergic nerves or injection of norepinephrine in unanesthetized animals elicits coronary vasoconstriction. Thus, the direct effect of noradrenergic stimulation is constriction rather than dilation of the coronary vessels. On the other hand, stimulation of vagal fibers to the heart dilates the coronaries.
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When the systemic blood pressure falls, the overall effect of the reflex increase in noradrenergic discharge is increased coronary blood flow secondary to the metabolic changes in the myocardium at a time when the cutaneous, renal, and splanchnic vessels are constricted. In this way the circulation of the heart, like that of the brain, is preserved when flow to other organs is compromised.