Coronary Physiology

Extravascular Compressive Forces and Transmural Flow Distribution

Phasic measurements of coronary blood flow indicate that flow to the LV occurs predominately during diastole ( Box 6.3 ) ( Fig. 6.3 ). The inhibition to LV blood flow during systole results from extravascular compressive forces exerted on intramural vessels located predominantly in the subendocardium. Preferential subendocardial flow occurs in the LV during diastole, compensating for its inhibition during systole, and preserving uniform transmural LV perfusion. The primary mechanism for this response is a metabolically mediated reduction in coronary vasomotor tone. Interestingly, uniform perfusion across the LV wall was also observed after coronary vasomotor tone was intentionally abolished using an intracoronary infusion of the vasodilator papaverine. This finding is consistent with a transmural gradient of vascularity that favors the subendocardium and provides a second compensatory mechanism to counteract the systolic flow limitation in that region of the LV wall. Tachycardia shortens diastole but subendocardial blood flow normally remains adequate because of recruitment of the coronary flow reserve. However, when this reserve is compromised (e.g., by a large vessel coronary stenosis or LV hypertrophy ), tachycardia may precipitate or exacerbate subendocardial ischemia. In contrast to the LV, RV systolic intramyocardial pressure is low and does not produce compressive forces that impede blood flow. Indeed, RV blood flow is appreciable throughout the entire cardiac cycle, essentially following the contour of the aortic pressure curve ( Box 6.3 , Box 6.4 ) ^, Measurements of phasic flow velocity obtained in patients using a Doppler flow probe demonstrated that the ratio of systolic to diastolic blood flow velocity in the RV branches of the right coronary artery (RCA) was threefold greater than in the left anterior descending coronary artery (LAD). RV pressure overload or compensatory hypertrophy associated with acute or chronic pulmonary artery hypertension, respectively, are accompanied by increases in RV intramyocardial pressure such that RV perfusion becomes more diastole-dominant and resembles the flow pattern observed in the LV (see the following section).

BOX 6.3

Characteristics of Coronary Blood Flow in the Left Ventricle

• High systolic pressure limits appreciable flow to diastole

• Flow low relative to oxygen consumption resulting in high oxygen extraction, low coronary venous PO ₂ , and minimal oxygen extraction reserve

• Flow tightly coupled to the oxygen demand by metabolic mechanism

• Autoregulatory mechanism maintains flow nearly constant over wide range of perfusion pressures

• Flow normally uniform across LV wall, but becomes maldistributed (subendocardium < subepicardium) in presence of an epicardial coronary stenosis

• Influence of autonomic nervous system subordinate to metabolic regulation

BOX 6.4

Major Differences in Coronary Blood Flow Characteristics in the Right Ventricle Compared with the Left Ventricle

• Lower systolic pressure results in appreciable blood flow throughout the entire cardiac cycle

• Smaller baseline myocardial oxygen uptake, blood flow, and oxygen extraction

• Significant oxygen extraction reserve

• Less effective pressure-flow autoregulation

• Ability to downregulate metabolic demand during hypoperfusion (i.e., hibernation) and maintain contractile function and energy stores

• Transmurally-uniform reduction in myocardial perfusion in presence of epicardial coronary stenosis

• Enhanced vasoconstrictor response to sympathetic nerve stimulation

Metabolic Regulation: Maintenance of Oxygen Supply/Demand Balance

The heart depends almost exclusively on aerobic metabolism to meet its energy demands. More than 95% of adenosine triphosphate (ATP) generated by the cardiac myocyte is derived from oxidative phosphorylation within the mitochondria. Free fatty acids, glucose, and lactate are the principal substrates for ATP production. The high-energy expenditure of the heart is underscored by the observation that it accounts for approximately 7% of the body’s basal oxygen use despite comprising less than 0.5% of total body weight. When oxygen availability is limited, the cardiac myocyte uses an anaerobic glycolytic pathway in the cytoplasm to convert glucose to lactate for energy production. Indeed, an elevated lactate concentration in the coronary venous effluent is an indicator of myocardial ischemia. Anaerobic glycolysis has a very limited ability to fulfill the energy requirements of the myocardium, as contraction ceases within 10 to 15 seconds after coronary blood flow is interrupted. Effective matching of coronary blood flow (oxygen supply) to myocardial oxygen demand is essential for optimal cardiac performance. This is accomplished by an intrinsic regulatory mechanism, termed “metabolic regulation,” in which the cardiac myocytes release vasodilating substances that directly modulate coronary arteriolar tone, and thereby coronary blood flow, according to their current oxygen demand.

Metabolic regulation of coronary blood flow was first postulated by Barcroft and Dixon in 1907, but it was not until 1947 that Eckenhoff et al. provided compelling evidence for its existence in a canine model. In these experiments, stroke work and oxygen demand were varied by increasing LV afterload (acute aortic occlusion), preload (volume loading), or myocardial contractility (intravenous administration of epinephrine) ( Box 6.5 ). Eckenhoff’s data demonstrated a strong parallel relationship between left coronary blood flow and myocardial oxygen consumption (calculated using the Fick equation; Fig. 6.4 ), indicating a tight coupling between these parameters. Furthermore, the findings showed that myocardial oxygen extraction is nearly maximum under baseline conditions: 75% of oxygen was extracted from the blood as it passed from the arterial to venous side of the capillary network (corresponding to a coronary sinus oxygen tension of approximately 20 mm Hg). As a result, the LV has a very limited oxygen extraction reserve, and is essentially dependent on increases in blood flow to satisfy increases in oxygen demand. Such compensatory increases in flow occur through recruitment of arteriolar vasodilator reserve by metabolites produced in the myocardium. A constant value for coronary sinus oxygen tension is a hallmark of effective metabolic control of coronary blood flow. This mechanism has been observed in all mammalian species studied, including humans. ^{, ,}

BOX 6.5

Determinants of Myocardial Oxygen Demand

• Wall tension

• Systolic ventricular pressure

• Ventricular volume

• contractility

• Heart rate

• Afterload (systolic wall stress)

• Preload (diastolic wall stress)

The earliest measurements of myocardial oxygen consumption were performed in the LV because its venous drainage into the coronary sinus is readily accessible. Several laboratories also mastered the technique required to obtain venous effluent from the small, delicate superficial veins draining the RV, which enabled measurements of myocardial oxygen consumption in both chambers simultaneously. These studies demonstrated that baseline values for myocardial oxygen consumption are much smaller in the RV compared with the LV ( Table 6.1 ), ^, which is consistent with the disparity in pressure-volume work between the chambers. The reduced oxygen consumption of the RV is the result of lower values for both blood flow and oxygen extraction. RV blood flow (per 100 g tissue) is approximately two-thirds that of the LV. Thus baseline coronary vascular resistance (the ratio of perfusion pressure to blood flow) is substantially greater in the RV compared with the LV. The RV’s smaller myocardial oxygen extraction indicates that blood flow is high relative to oxygen consumption. This relative “overperfusion” of the RV has been attributed to a blunting of right coronary vasoconstriction by NO (a coronary vasodilator) that is released tonically from the vascular endothelium. Indeed, antagonism of NO synthesis caused a reduction in resting right coronary blood flow. However, this intervention had no effect on resting blood flow in the left coronary circulation. The sustained basal release of NO in the right coronary circulation may be related to a greater vascular resistance, blood flow velocity, and shear stress. The RV’s lower oxygen extraction provides it with an oxygen extraction reserve that can be exploited, along with increases in blood flow, to meet an increased oxygen demand ( Table 6.1 ). ^, The relative importance of oxygen extraction in the RV versus LV is consistent with their respective capillary reserves, as measured using stop-motion microcinematography in rat hearts. These experiments demonstrated that the capillary reserve of the RV was approximately twice that of the LV, and was the result of a smaller number of open capillaries at baseline and a greater total capillary density.

Studies in chronically instrumented dogs shed light on the interplay between increases in RV coronary blood flow and oxygen extraction during graded treadmill exercise. These studies demonstrated that the RV relies preferentially on increases in oxygen extraction at low levels of exercise, whereas the contribution of blood flow becomes prominent during more intense exercise when the coronary venous oxygen tension falls to approximately 20 mm Hg. These observations in the RV, and those described previously for the LV, support the contention that a coronary venous oxygen tension of 20 mm Hg is the critical value for activation of a metabolically linked coronary vasodilator response.

Current concepts of metabolic regulation implicate a “feed-forward” mechanism in which vasodilating metabolites are produced by the myocardium in proportion to the level of cardiac work ( Fig. 6.5 ). The primary metabolites proposed to mediate this process are carbon dioxide (generated in citric acid cycle decarboxylation reactions) and reactive oxygen species (formed in the mitochondrial respiratory chain). NO and adenosine triphosphate-sensitive potassium (K _ATP ) channels are likely downstream mediators of this flow response. Adenosine, a breakdown product of ATP, is a potent endogenous vasodilator that was once thought to play a central role in metabolic regulation of coronary blood flow, but it is now presumed that adenosine is involved only in the presence of tissue hypoxia, which is the main stimulus for its production. Whether vasodilation occurs in response to an endogenous local metabolite or to an exogenously administered drug, it requires relaxation of vascular smooth muscle due to a decrease in intracellular Ca ²⁺ concentration and an increase in myosin light chain phosphatase activity.

Endothelial Control of Coronary Vasomotor Tone: Role of Nitric Oxide

As recently as the early 1970s, the endothelial lining of blood vessels was viewed as a “sheet of nucleated but inert cellophane.” However, it became apparent, based on new in vitro research techniques developed in that era, that the endothelium is a profoundly dynamic “biochemical machine” serving many diverse physiological roles. Most relevant to this chapter is that the vascular endothelium was demonstrated to produce a number of molecules, the most prominent of which is NO, that are integral to the regulation of coronary vasomotor tone. The discovery of NO as an endogenous mediator of vasodilation was based on the observation by Furchgott and Zawadzki in 1980 that acetylcholine-induced relaxation of isolated segments of rabbit aorta required an intact endothelium. This finding led to the conclusion that acetylcholine acted on muscarinic receptors located on the endothelial membrane to cause release of a vasodilating substance, which they termed “endothelium-derived relaxing factor.” Seven years later, this factor was definitively identified as NO. It is now recognized that NO is a ubiquitous molecule that plays many essential roles not only in the circulatory system, but also in immunological responses and as a central nervous system neurotransmitter. NO is a free radical synthesized from L-arginine in a reaction requiring the constitutive enzyme NO synthase (NOS) ( Fig. 6.6 ). An increase in intracellular Ca ²⁺ concentration, which occurs in response to activation of specific membrane receptors (eg, bradykinin, acetylcholine) or to increased wall shear stress, stimulates NOS activity. The NO that is produced then diffuses into the underlying vascular smooth muscle, where it stimulates production of cyclic guanosine monophosphate (cGMP) and causes relaxation. Investigators extended the vasorelaxing effect of endothelium-derived NO to the coronary arterioles by demonstrating that its inhibition blunted the increases in coronary blood flow caused by intracoronary infusions of acetylcholine ( Fig. 6.7 ). NO is rapidly scavenged by hemoglobin and as a result, it has an effect with limited range and short duration. The release of NO from the vascular endothelium is inhibited in several pathological states associated with increased risk of myocardial ischemia and infarction, including atherosclerosis, diabetes mellitus, and hypercholesterolemia. Vascular endothelial dysfunction resulting from abnormal NO metabolism may also promote coronary vasospasm.

Two additional endothelial-derived vasoactive factors merit discussion: the vasodilator and platelet inhibitor prostaglandin I ₂ (prostacyclin) and the vasoconstrictor endothelin-1. Prostacyclin, which was discovered in 1976, is a lipid derivative produced by the action of cyclooxygenase on arachidonic acid, a constituent of the endothelial cell membrane. The mechanism for prostacyclin-induced relaxation of coronary vascular smooth muscle involves receptor-mediated activation of adenylyl cyclase leading to increased intracellular levels of cyclic adenosine monophosphate (cAMP) and an opening of K _ATP channels. ^, Treatment with the cyclooxygenase inhibitor indomethacin did not alter increases in coronary blood flow during treadmill exercise in a canine model, suggesting that prostacyclin does not play an essential role in this local metabolic response.

Endothelin-1, which was discovered in 1987, is an endothelial cell-derived peptide that is the most powerful known endogenous vasoconstrictor. ^, Endothelin-1 acts by binding to endothelin subtype A and B receptors on the coronary vascular smooth muscle cell. Endothelin-1 release is normally modest and has no important effects in the coronary circulation under baseline conditions. However, excessive production of endothelin-1 may cause coronary vasoconstriction in a variety of pathological conditions such as hyperglycemia, systemic or pulmonary hypertension, heart failure, and during stimulation by angiotensin II, platelet-derived factors, thrombin, cytokines, reactive oxygen species, and local shear forces. NO may serve as an important counter-regulatory mechanism to limit this endothelin-related coronary vasoconstriction.

Role of K _ATP Channels in Coronary Vascular Control

Potassium channels closed by intracellular ATP were first discovered in cardiac muscle in 1983 and were subsequently identified in vascular smooth muscle 6 years later. The K _ATP channel provides a means by which the metabolic status of the cell regulates its level of activity. Opening of K _ATP channels causes hyperpolarization of the vascular smooth muscle cells by shifting the membrane potential closer to the K ⁺ reversal potential. This hyperpolarization inhibits Ca ²⁺ entry through voltage-dependent Ca ²⁺ channels, leading to vasodilation. Studies using glibenclamide (now known as glyburide) to inhibit K _ATP channel function have demonstrated involvement of these channels in fundamental processes of coronary vascular control, including maintenance of basal coronary vascular tone. Coronary vasodilation associated with increased myocardial oxygen consumption or reduced perfusion pressure is also mediated by K _ATP channels.