Myocardial Blood Flow

Blood containing carbon substrate and oxygen is delivered to the heart by two main coronary arteries that originate from the proximal aorta and course over the surface of the heart (epi-cardium). These arteries arborize into progressively smaller branches that turn inward to penetrate the epicardium and supply blood to the myocardium (Fig. 2). In the left ventricle, the heart muscle is typically subdivided into transmural layers; these are termed the subepicardium (outer layer), the midmyo-cardium, and the subendocardium (innermost layer).

The coronary arterial tree terminates in muscular vessels 60150 ^m in diameter termed arterioles. The arterioles are the major locus of resistance to blood flow (MBF), and contraction or relaxation of the smooth muscle in the walls of the arterioles (vasomotion) provides the mechanism for control of the rate of blood flow into the myocardium.

Each arteriole supplies an array of capillaries, thin-walled tubes comprised of a single layer of endothelial cells, across which most of the exchange of nutrients, oxygen, and metabolic waste products occurs. At their terminal end, the capillaries coalesce into venules, the initial component of the cardiac venous system that conducts blood back into the venous circulation primarily through the coronary sinus, which drains into the right atrium.

2.1. Regulation of Myocardial Blood Flow

Coronary blood flow is closely regulated in response to changes in energy requirements of the myocardium. The principal work of the heart is muscle contraction, which generates the pressure that drives blood through the arterial system of the body. Elevation of cardiac ATP expenditure during exercise or other stresses increases myocardial demand for oxygen and carbon substrate. Often, there is a need to assess the effects of changes of the rate of myocardial energy expenditure on cardiac performance (e.g., during exercise stress testing). Because routine measurement of myocardial oxygen consumption (MVO2) is not practical, a rough estimate of the change in the energy demands of the heart can be obtained as the product of systolic blood pressure multiplied by the times per minute that pressure generation occurs (heart rate), termed the rate-pressure product. This measurement provides a simple estimate of changes in metabolic requirements of the heart in clinical situations.

The coronary circulation operates on the principle of "justin-time" delivery of oxygen and carbon substrate. In other words, coronary blood flow is regulated to be only minimally greater than required to meet the ambient metabolic demands of the heart. As a result, the heart extracts 70-80% of the O2 from the blood as it flows through the coronary capillaries. Because of this high level of basal oxygen extraction, there is little ability to increase oxygen uptake by increased extraction of oxygen from the blood. As a result, increases in myocardial energy requirements during exercise or other stress must be satisfied by parallel increases of coronary blood flow. Because ATP and oxygen stores in the myocardium are very low, the response time for the increase in coronary flow during an increase in cardiac work must be rapid, on the order of a few seconds. From these considerations, it is clear that highly responsive signaling systems must exist between myocardial metabolic processes and vasomotor activity in the resistance vessels that control coronary blood flow. To date, the nature of these signaling systems is not totally clear despite intense study over the last 75 years.

2.2. Biological Signals

Regulating the Coronary Circulation

The regulatory signals can be classified as having feedback or feed-forward characteristics; the final common response to these signals is relaxation of the vascular smooth muscle cells that make up the resistance vessels that control coronary blood flow (Fig. 3). Several major feedback mechanisms resulting from increased cardiomyocyte metabolism (including adenosine, nitric oxide [NO], and other less-defined signals) cause opening of ATP-sensitive potassium channels (KATP) on the sarcolemma of smooth muscle cells of the coronary arterioles. Opening of these channels allows potassium to escape from the cytosol of the smooth muscle cells, resulting in hyperpolariza-tion (increased negativity) of the cell membrane. The increased negativity of the membrane causes sarcolemmal voltage-dependent calcium channels to close; as a result, calcium entry is reduced, the muscle relaxes (vasodilation), and coronary blood flow increases. In addition to effects on the KATP channels, adenosine (a product of ATP utilization in the cardiomyocyte) has potent, direct dilator effects on arteriolar smooth muscle.

Another feedback signal is NO generated by the vascular endothelium. Mechanotransduction of flow-induced shear forces exerted on the endothelial cells augments NO synthesis. In addition to causing potassium channel opening, NO also

Intramural arteries Epicardial artery Class B Class A

Intramural arteries Epicardial artery Class B Class A

Subendocardial plexus

Fig. 2. The transmural distribution of the coronary arterial system is depicted. The large conductance arteries traversing the epicardial surface supply shallow and deep branches to the subepicardium (outer-most myocardial layers) and subendocardium (inner-most myocardial layers), respectively. These perforating vessels arborize to create the arteriolar network that supplies the myocardial capillary bed. LV, left ventricle. Reprinted from D.J. Duncker and R.J. Bache, Regulation of coronary vasomotor tone under normal conditions and during acute myocardial hypoperfusion, Pharmacol Ther., 86, 87-110, © 2000, with permission from Elsevier.

Subendocardial plexus

Fig. 2. The transmural distribution of the coronary arterial system is depicted. The large conductance arteries traversing the epicardial surface supply shallow and deep branches to the subepicardium (outer-most myocardial layers) and subendocardium (inner-most myocardial layers), respectively. These perforating vessels arborize to create the arteriolar network that supplies the myocardial capillary bed. LV, left ventricle. Reprinted from D.J. Duncker and R.J. Bache, Regulation of coronary vasomotor tone under normal conditions and during acute myocardial hypoperfusion, Pharmacol Ther., 86, 87-110, © 2000, with permission from Elsevier.

Major Mediators of Metabolic Feed-back Vasodilation

1. Katp channel

2. Adenosine

Major Mediators of Metabolic Feed-back Vasodilation

1. Katp channel

2. Adenosine

Mediator of Metabolic Feed-forward Vasodilation 1. Increased Sympathetic Nerve NE Discharge

ß-adrenergic receptor stimulation of resistance vessels

Mediator of Metabolic Feed-forward Vasodilation 1. Increased Sympathetic Nerve NE Discharge

ß-adrenergic receptor stimulation of resistance vessels

Fig. 3. Major feedback and feed-forward mechanisms underlying metabolic vasodilation of resistance vessels are depicted. See text for discussion. NO, nitric oxide; KATP channel, adenosine triphosphate-inhibited potassium channel; NE , norepinephrine.

directly relaxes vascular smooth muscle. Importantly, this brief discussion does not include all of the known feedback mechanisms involved in regulation of coronary blood flow.

Increases of cardiac sympathetic nerve activity, such as during exercise, activate a feed-forward mechanism for control of coronary blood flow that augments the local metabolic vasodilator influences. The sympathetic neurotransmitter norepinephrine activates a- and p-adrenergic receptors in vascular smooth muscle. Activation of a-adrenergic receptors causes modest constriction of the large coronary arteries; however, because these arteries function as conduit vessels that offer little resistance to blood flow, this has little effect on coronary flow. However, activation of p-adrenergic receptors on the coronary arterioles results in relaxation (vasodilation)

of these resistance vessels; the resultant decrease of coronary resistance causes an increase in blood flow that is not dependent on local metabolic mechanisms for regulation of coronary vasomotor tone.

Pharmacological studies have shown that simultaneous blockade of the coronary KATP channels, adenosine, and NO pathways significantly decreases myocardial blood flow in the resting animal. Moreover, the increase of coronary flow that normally occurs during exercise is severely blunted, resulting in a perfusion-metabolism mismatch that is accompanied by evidence of ischemia in the normal heart. Hence, activation of these three pathways appears to be the primary means by which metabolic vasodilation is achieved in the heart. However, in the normal situation, blockade of any one of these mechanisms for smooth muscle relaxation elicits compensatory activation of the other pathways to minimize changes in coronary blood flow.

2.3. Blood Flow in the Diseased Heart

Coronary blood flow in the diseased heart can be limited by: (1) partial or complete obstruction of the large coronary arteries (e.g., as in atherosclerotic disease); (2) decreased responsiveness of the signaling systems relating MBF to myocardial energy requirements; or (3) increases in extravascular forces acting to compress the small vessels in the wall of the left ventricle. In the case of obstructive coronary disease, a moderately narrowed vessel may functionally restrict blood flow only during periods of increased work (i.e., it reduces vasodilator reserve); a severely narrowed vessel may limit blood flow even when the subject is at rest. In the presence of a moderate coronary obstruction, the arteriolar bed can maintain adequate blood flow by metabolic signaling-based arteriolar vasodilation. That is, a decrease in small-vessel resistance can compensate for the resistance offered by the coronary artery stenosis. However, when the capacity for vasodilation of the arterioles has been exhausted, any further increase in cardiac work cannot result in an increase of blood flow, and the myocardium supplied by the narrowed vessel will become ischemic. There is also some evidence that malfunction of metabolic signaling pathways in the arteriolar resistance vessels can aggravate (e.g., in patients with nonobstructive atherosclerotic disease or with diabetes) or cause (syndrome X) myocardial ischemia.

In the normal heart, blood flow to the inner layers of the left ventricle occurs principally during diastole. This is because tissue pressures in the wall of the left ventricle during systole are so great that inner-layer arterioles are squeezed shut by the extravascular compressive forces. Diastolic left ventricular tissue pressures are also greatest in the subendocardium. As the heart fails and/or becomes hypertrophied, these extravascular compressive forces increase as left ventricular diastolic pressure (i.e., ventricular filling pressure) increases.

Slowing of myocyte relaxation also encroaches on the interval of diastole in the hypertrophied or failing heart. In the normal heart, autoregulatory (i.e., metabolic vasodilation) processes cause arteriolar vasodilation in the subendocardium to compensate for systolic underperfusion. However, increases of left ventricular diastolic pressure that occur in the failing heart may compress the arteriolar bed in the inner myocardial layers sufficiently to overwhelm autoregulatory mechanisms, particularly those that normally maintain adequate subendocardial blood flow. Because subendocardial blood flow occurs predominantly during diastole, tachycardia also acts to impede blood flow in the subendocardium by shortening the interval of diastole.

Thus, even in the absence of obstructive coronary artery disease, functional abnormalities can limit blood flow to the inner myocardial layers of the diseased heart. These abnormalities are often then associated with a reduction of the ATP synthetic capacity in the subendocardium. Thus, the extravascular forces that act on the small coronary vessels embedded in the myocardium cause the subendocardium to be the region of the ventricular wall that is most vulnerable to hypoperfusion and ischemia.

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