Review of Medical Physiology - William F. Ganong 2002

Blood Circulation
Regional Blood Flow
Coronary Circulation

Anatomical Features

Both coronary Arteries, which supply Blood to the myocardium, originate from the sinuses behind two cusps of the aortic valve at the aortic ROOT (Fig. 32-11). Vortex currents keep the Valves away from the arterial openings, ensuring they remain patent throughout the cardiac cycle. In 50% of individuals, blood flow is greater in the right coronary artery, in 20% in the left, and in 30% it is equal in both vessels. The majority of venous blood drains into The Heart via the coronary sinus and anterior cardiac Veins (Fig. 32-12), which empty into the right atrium. In addition, there are other vessels that empty directly into the heart chambers. This group includes arteriosinusoidal vessels, sinusoidal capillary-like vessels connecting arterioles to the chambers, Thebesian veins connecting capillaries and chambers, and several arterioluminal vessels, which are small arteries draining directly into the chambers. Numerous anastomoses exist between coronary and extracardiac arterioles, particularly near the origins of the major arteries. Human coronary anastomoses commonly permit the passage of particles up to 40 µm in diameter, although evidence suggests these channels dilate in patients with coronary artery disease.

Pressure Gradient and BLOOD FLOW IN Coronary Vessels

In The cardiac Muscle, as in Skeletal Muscle, vascular compression occurs during contraction. Left ventricular pressure slightly exceeds aortic pressure during systole (Table 32-4). Consequently, blood flow in the arteries supplying the subendocardial Regions of the left ventricle occurs only during diastole, whereas in the superficial myocardial regions of the left ventricle, the compressive force is sufficiently attenuated to allow blood to pass through this zone throughout the cardiac cycle. Because diastole shortens at higher heart rates, coronary Blood flow through the left ventricle is compromised during tachycardia. On the other hand, the pressure gradients between the aorta and the right ventricle, as well as between the aorta and the atria, are slightly greater during systole than during diastole. Therefore, coronary blood flow in these PARTS OF THE heart is not significantly reduced during systole. Blood flow in the right and left coronary arteries is illustrated in Fig. 32-13. The lack of blood flow in the subendocardial layers of the left ventricle during systole renders them particularly vulnerable to ischemic injury, making this region the most common site for myocardial infarction. Blood flow to the left ventricle is impaired in patients with aortic valve stenosis because this condition requires the left ventricle to generate a much higher pressure than the aorta to eject blood, leading to significant compression of the coronary vessels during systole. Such patients are highly susceptible to symptoms of myocardial ischemia, partly due to this compression and partly because the myocardium requires more energy to force blood through a narrowed aortic valve. Coronary blood flow is also reduced when aortic diastolic pressure falls. Elevated venous pressure in conditions such as congestive Heart Failure impairs coronary blood flow by decreasing the effective coronary perfusion pressure.

Class="center">Table 32-4. Aortic, left ventricular, and right ventricular pressures during systole and diastole

¹ LV - left ventricle, RV - right ventricle.

Fig. 32-11. Human CORONARY ARTERIES AND their major branches (reproduced with permission from Ross G: The Cardiovascular system. In: Essentials of Human Physiology. Ross G [editor]. Year Book Medical Publishers, 1978).

Fig. 32-12. Schematic diagram of coronary Circulation.

Fig. 32-13. Blood flow in the left and right coronary arteries during different Phases of the cardiac cycle. Systole is indicated between the two dashed lines (reproduced with permission from Berne RM, Levy MN: Physiology. Mosby, 1983).

Coronary blood flow is measured by introducing a catheter into the coronary sinus and applying the Kety method to the heart, assuming that the N₂O content of coronary venous blood is representative of all blood passing through the myocardium. In resting humans, it averages 250 mL/min (5% of Cardiac Output). Various radionuclide techniques utilizing radioactive tracers detectable by scintillation counters placed over the chest are used to study regional cardiac blood flow, detect areas of ischemia and infarction, and assess ventricular function. Radionuclides such as thallium-201 (²⁰¹Tl) enter the myocardial Cells via Na⁺-K⁺-ATPase and equilibrate with the intracellular K⁺ pool. During the first 10-15 min following intravenous administration, the distribution of ²⁰¹Tl is directly proportional to myocardial blood flow, allowing ischemic regions to be identified by their low uptake. Isotope uptake is frequently assessed immediately after exercise and several hours later to reveal areas where stress caused the most pronounced changes in blood flow. In contrast, radiopharmaceuticals such as technetium-99m stannous pyrophosphate (^99mTc-PYP) are selectively taken up in infarcted tissue through mechanisms that are not fully understood, making infarctions identifiable as "hot spots" on chest scintigrams. Coronary angiography can be combined with ¹³³Xe washout measurements (see above) for a detailed analysis of coronary blood flow. A radiopaque contrast medium is first injected into the coronary arteries, and X-ray imaging is used to visualize its distribution. The angiographic camera can be replaced with a multicrystal scintillation camera to subsequently measure ¹³³Xe washout. An example of normal blood distribution following injection into the left coronary artery is shown in Fig. 32-14.

Variations in Coronary Blood Flow

At rest, the heart extracts 70–80% of the oxygen from each unit of incoming blood (see Table 32-1). Oxygen consumption can therefore be significantly increased only by elevating blood flow. Consequently, it is not surprising that blood flow rises alongside increases in myocardial metabolic rate. The lumen size of coronary vessels and the resulting coronary blood flow are governed not only by changes in aortic pressure but also by chemical and neural factors. Furthermore, coronary blood flow is heavily influenced by autoregulation.

Fig. 32-14. Diagram of normal human myocardial perfusion following injection of ¹³³Xe into the left main coronary artery. Arterial branches are color-coded, and their number and area correspond to blood flow rates (mL/100 g/min) in the regions beneath each scintillation detector; LC - circumflex branch; LAD - left anterior descending artery; LV - left ventricle (reproduced with permission from Cannon PJ, et al: Evaluation of myocardial circulation with radionuclides. Cardiovasc Med 1978;2:371).

Chemical factors

The close correlation between coronary blood flow and myocardial O₂ consumption suggests that one or more metabolic products mediate coronary vasodilation. Factors likely implicated include O₂ deficiency, elevated local concentrations of CO₂, H⁺, K⁺, lactate, Prostaglandins, adenine NUCLEOTIDES, and adenosine. Multiple vasodilator metabolites may be involved. Asphyxia, Hypoxia, and intracoronary administration of cyanides increase coronary blood flow by 200–300% in both denervated and intact hearts. A common feature of all three conditions is hypoxia of the cardiac muscle fibers. A similar increase in blood flow is observed in myocardial regions where the lumen of the corresponding coronary artery has been temporarily occluded and then released. This reactive hyperemia resembles the cutaneous response (see below). In the heart, this phenomenon is believed to be related to the release of adenosine. Adenosine is additionally released to ameliorate injury caused by the restoration of blood flow (see Chapter 33).

Neural Factors

Coronary arterioles contain α-adrenergic receptors, which mediate vasoconstriction, and β-adrenergic receptors, which mediate vasodilation. Activation of cardiac noradrenergic nerves and administration of norepinephrine induce coronary vasodilation. However, norepinephrine increases heart rate and contractility, and vasodilation develops secondarily due to The production of vasodilator metabolites in the myocardium in response to increased activity. After the inotropic and chronotropic effects of noradrenergic nerve stimulation are blocked by β-adrenergic blockers, stimulation of noradrenergic nerves or administration of norepinephrine in unanesthetized animals causes coronary vasoconstriction. Thus, the direct effect of noradrenergic stimulation is vasoconstriction rather than vasodilation of the coronary vessels. Vagal nerve stimulation leads to coronary vasodilation.

When systemic blood pressure drops, the overall effect of reflexly enhanced noradrenergic firing is an increase in coronary blood flow driven by myocardial metabolic changes, while cutaneous, renal, and visceral Blood Vessels constrict. Thus, Blood supply to The Heart and Brain is preserved while being reduced in other Organs.

Coronary Artery Disease

When coronary blood flow decreases to the point where myocardial hypoxia develops, P factor accumulates, leading to angina pectoris (see Chapter 7). If myocardial ischemia is severe and prolonged, irreversible changes occur in the cardiac muscle, resulting in myocardial infarction. Myocardial infarction is a frequent cause of death, particularly in developed countries, largely due to atherosclerosis and hypercholesterolemia. These relationships are described in Chapter 17. Angina pectoris is typically caused by the occlusion of at least 75% of the coronary artery lumen. Resting blood flow remains normal, but the capacity to increase flow during exertion is limited. If stenosis reaches 85%, resting blood pressure also drops, and there is an increased tendency for thrombosis at the site of narrowing. Thrombosis involves processes such as coronary vasospasm, transient platelet aggregation at the site of vascular sclerosis, and plaque rupture or Hemorrhage into an atherosclerotic plaque. Notably, acetylcholine administration causes constriction rather than dilation in stenotic coronary artery segments, because endothelial damage in these narrowed areas prevents NO production, unmasking the direct constrictor effect of acetylcholine on vascular smooth muscle.

In addition to high blood Cholesterol levels, a positive correlation has been established between coronary atherosclerosis and circulating lipoprotein (a) (Lp(a)). Lipoprotein Lp(a) interferes with Fibrinolysis by inhibiting plasmin formation (see Chapter 27). Clear correlations have also been found with circulating homocysteine levels. This compound damages endothelial cells and is converted into non-toxic Methionine in the presence of folate and vitamin B₁₂. Clinical trials are currently underway to investigate The Effect of folate and vitamin B₁₂ status on the incidence of CORONARY HEART DISEASE.

Recently, significant attention has been paid to the potential role of an inflammatory component in The Development of atherosclerosis. Inflammatory infiltrates are found in areas of atherosclerotic lesions, and an interesting correlation exists between circulating Antibodies to Chlamydia pneumoniae and atherosclerotic plaques. Cell/30.html">The Plasma Membrane of this microorganism contains Amino Acids whose sequence resembles that of the cardiac α-Myosin heavy chains. Administration of these sequences induces autoimmune inflammation and coronary artery fibrosis in mice, an example of molecular mimicry (see Chapter 27).

The electrical changes that occur during ischemia or myocardial infarction, along with their characteristic ECG manifestations, are discussed in Chapter 28. Before dying, ischemic cells cease contraction—a cessation that has a homeostatic effect, delaying irreversible damage. The exact cause of this loss of contractile activity remains unclear. In dogs whose myocardial blood flow was interrupted, necrosis began after 20 minutes, yet it remained incomplete even after 3 to 6 hours.

Damaged cells release Enzymes into the bloodstream. Detecting elevated levels of enzymes and Isoenzymes released by cells during a myocardial infarction plays a crucial role in diagnosing this condition. The enzymes most commonly measured today include the MB isoenzyme of creatine kinase (CK-MB), troponin T, and troponin I.

Nitrates, such as nitroglycerin, often help relieve anginal pain. These compounds lead to the production of NO and dilate normal arterial vessels. As noted above, NO release is impaired As a result of atherosclerotic vascular changes. However, the primary effect of nitrates is the dilation of peripheral capacitance vessels, resulting in decreased venous return to the heart. This reduces cardiac output and, consequently, lowers myocardial O₂ consumption.

Specific focal stenoses of the coronary arteries can be identified via arteriography, and their impact on blood flow can be alleviated through graft implantation (coronary artery bypass grafting). This Procedure frequently leads to the sustained relief of stable angina. Recent studies indicate that such revascularization improves cell survival, partly by restoring contraction in stunned myocardium. This term is used to describe myocardial areas with chronic ischemic changes that are not dead yet fail to contract normally until blood flow is restored. These changes must be distinguished from myocardial stunning—a brief, transient postischemic myocardial dysfunction occurring despite normal blood flow.

The mainstay of Treatment for myocardial infarction today is the prompt cessation of obstruction and/or lysis of the thrombus as soon as possible after the onset of pain, in order to achieve reperfusion and prevent irreversible damage. One approach involves advancing a catheter into the affected artery to dilate the constricted segment and disrupt the thrombus (coronary angioplasty). However, this method carries a high rate of long-term re-occlusion (exceeding 30% within a year), which is attributed to a tendency toward thrombosis and smooth muscle hyperplasia at the site of endothelial injury.

Another approach is the lysis of intracoronary thrombi via intravenous or intracoronary administration of plasmin-generating compounds (see Chapter 27). One commonly used agent is streptokinase, a protein derived from hemolytic streptococci that converts plasminogen into plasmin (see Chapter 27). Another lytic factor that converts plasminogen to plasmin within the thrombus is tissue-type plasminogen activator (t-PA), a natural protease produced for medical use via Recombinant DNA technology. The advantage of t-PA is that it preferentially activates fibrin-bound plasminogen, thereby inducing localized thrombolysis while limiting systemic plasminogen activation. Nevertheless, it remains unresolved whether t-PA is more effective than streptokinase, and streptokinase is significantly less expensive. In any case, if a lytic agent is administered within the first few hours following the onset of chest pain during a myocardial infarction, coronary perfusion can be successfully restored in the majority of patients. For the remaining patients, condition stabilization is maintained through the administration of antithrombotic and other medications.