Coronary Physiology and Atherosclerosis

Normal Artery Wall

The arterial lumen is lined by a monolayer of endothelial cells that overlies smooth muscle cells). The inner layer of smooth muscle cells, known as the intima, is circumscribed by the internal elastic lamina. Between the internal elastic lamina and external elastic lamina is another layer of smooth muscle cells, the media. Outside the external elastic lamina is an adventitia that is sparsely populated by cells but consists of complex extracellular matrix (primarily collagen and elastin fibers) and the microvessels that comprise the vasa vasorum.

Endothelium

Although the vascular endothelium was once thought of as an inert lining for blood vessels, it is more accurately characterized as a very active, distributed organ with many biologic functions. It has synthetic and metabolic capabilities and contains receptors for a variety of vasoactive substances.

Endothelium-Derived Relaxing Factors

The first vasoactive endothelial substance to be discovered was prostacyclin (PGI ₂ ), a product of the cyclooxygenase pathway of arachidonic acid metabolism ( Fig. 5.1 and Box 5.1 ). The production of PGI ₂ is activated by shear stress, pulsatility of flow, hypoxia, and a variety of vasoactive mediators. On production it leaves the endothelial cell and acts in the local environment to cause relaxation of the underlying smooth muscle or to inhibit platelet aggregation. Both actions are mediated by the stimulation of adenylyl cyclase in the target cell to produce cyclic adenosine monophosphate (cAMP).

Box 5.1

Endothelium-Derived Relaxing and Contracting Factors

Healthy endothelial cells have an important role in modulating coronary tone by producing:

• vascular muscle-relaxing factors

  • prostacyclin

  • nitric oxide

  • hyperpolarizing factor

• vascular muscle-contracting factors

  • prostaglandin H ₂

  • thromboxane A ₂

  • endothelin

It has been shown that many physiologic stimuli cause vasodilation by stimulating the release of a labile, diffusible, nonprostanoid molecule termed endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO). NO is a very small lipophilic molecule that can readily diffuse across biologic membranes and into the cytosol of nearby cells. The half-life of the molecule is less than 5 seconds so that only the local environment can be affected. NO is synthesized from the amino acid l -arginine by NO synthase (NOS). When NO diffuses into the cytosol of the target cell, it binds with the heme group of soluble guanylate cyclase; the result is a 50- to 200-fold increase in production of cyclic guanosine monophosphate (cGMP), its secondary messenger. If the target cells are vascular smooth muscle cells, vasodilation occurs; if the target cells are platelets, adhesion and aggregation are inhibited. NO is probably the final common effector molecule of nitrovasodilators. The cardiovascular system is in a constant state of active vasodilation that depends on the generation of NO. The molecule is more important in controlling vascular tone in veins and arteries compared with arterioles. Abnormalities in the ability of the endothelium to produce NO likely play a role in diseases such as diabetes, atherosclerosis, and hypertension. The venous circulation of humans seems to have a lower basal release of NO and an increased sensitivity to nitrovasodilators compared with the arterial side of the circulation.

Endothelial Inhibition of Platelets

A primary function of endothelium is to maintain the fluidity of blood. This is achieved by the synthesis and release of anticoagulant (eg, thrombomodulin, protein C), fibrinolytic (eg, tissue-type plasminogen activator), and platelet inhibitory (eg, PGI ₂ , NO) substances ( Box 5.2 ). Mediators released from aggregating platelets stimulate the release from intact endothelium of NO and PGI ₂ , which act together to increase blood flow and decrease platelet adhesion and aggregation ( Fig. 5.2 ).

Box 5.2

Endothelial Inhibition of Platelets

Healthy endothelial cells have a role in maintaining the fluidity of blood by producing:

• anticoagulant factors: protein C and thrombomodulin

• fibrinolytic factor: tissue-type plasminogen activator

• platelet inhibitory substances: prostacyclin and nitric oxide

Perfusion Pressure and Myocardial Compression

Coronary blood flow is proportional to the pressure gradient across the coronary circulation ( Box 5.3 ). This gradient is calculated by subtracting downstream coronary pressure from the pressure in the root of the aorta.

Box 5.3

Determinants of Coronary Blood Flow

The primary determinants of coronary blood flow are:

• perfusion pressure

• myocardial extravascular compression

• myocardial metabolism

• neurohumoral control

During systole, the heart throttles its own blood supply. The force of systolic myocardial compression is greatest in the subendocardial layers, where it approximates intraventricular pressure. Resistance resulting from extravascular compression increases with blood pressure, heart rate, contractility, and preload.

The most appropriate measure of the driving pressure for flow is the average pressure in the aortic root during diastole. This value can be approximated by aortic diastolic or mean pressure.

Although the true downstream pressure of the coronary circulation is likely close to the coronary sinus pressure, other choices may be more appropriate in clinical circumstances. The true downstream pressure of the left ventricular subendocardium is the left ventricular end-diastolic pressure, which can be estimated by pulmonary artery occlusion pressure. When the right ventricle is at risk of ischemia (eg, severe pulmonary hypertension), right ventricular diastolic pressure or central venous pressure may be a more appropriate choice for measuring downstream pressure.

Myocardial Metabolism

Myocardial blood flow is primarily under metabolic control. Even when the heart is cut off from external control mechanisms (neural and humoral factors), its ability to match blood flow to its metabolic requirements is almost unaffected. Because coronary venous oxygen tension is normally 15 to 20 mm Hg, only a small amount of oxygen is available through increased extraction. A major increase in myocardial oxygen consumption (M v̇o ₂ ), beyond the normal resting value of 80 to 100 mL O ₂ /100 g of myocardium, can occur only if oxygen delivery is increased by augmentation of coronary blood flow. Normally, flow and metabolism are closely matched, so that over a wide range of oxygen consumption coronary sinus oxygen saturation changes little. Flow and metabolism could be coupled either through feedback or feedforward control or a combination of both. Feedback control requires myocardial oxygen tension to fall and provide a signal that can then increase flow. That would require vascular tone to be linked either to a substrate that is depleted, such as oxygen or adenosine triphosphate (ATP), or to the accumulation of a metabolite such as carbon dioxide or hydrogen ion. The mediator or mediators linking myocardial metabolism so effectively to myocardial blood flow are still unknown ( Box 5.4 ).

Box 5.4

Myocardial Metabolism

Several molecules have been proposed as the link between myocardial metabolism and myocardial blood flow, including:

• oxygen

• reactive oxygen species

• carbon dioxide

• adenosine

Current evidence suggests that a combination of local factors, each with differing importance during rest, exercise, and ischemia, acts together to match myocardial oxygen delivery to demand.