Coronary Physiology and Atherosclerosis




Key Points




  • 1.

    To care for patients with coronary artery disease in the perioperative period safely, the clinician must understand how the coronary circulation functions in health and disease.


  • 2.

    Coronary endothelium modulates myocardial blood flow by producing factors that relax or contract the underlying vascular smooth muscle.


  • 3.

    Vascular endothelial cells help maintain the fluidity of blood by elaborating anticoagulant, fibrinolytic, and antiplatelet substances.


  • 4.

    One of the earliest changes in coronary artery disease, preceding the appearance of stenoses, is the loss of the vasoregulatory and antithrombotic functions of the endothelium.


  • 5.

    Although sympathetic activation increases myocardial oxygen demand, activation of α-adrenergic receptors causes coronary vasoconstriction.


  • 6.

    It is unlikely that one substance alone (eg, adenosine) provides the link between myocardial metabolism and myocardial blood flow under a variety of conditions.


  • 7.

    As coronary perfusion pressure decreases, the inner layers of myocardium nearest the left ventricular cavity are the first to become ischemic and display impaired relaxation and contraction.


  • 8.

    The progression of an atherosclerotic lesion is similar to the process of wound healing.


  • 9.

    Lipid-lowering therapy can help restore endothelial function and prevent coronary events.



When caring for patients with coronary artery disease (CAD), the anesthesiologist must prevent or minimize myocardial ischemia by maintaining optimal conditions for perfusion of the heart. This goal can be achieved only with an understanding of the many factors that determine myocardial blood flow in both health and disease.




Anatomy and Physiology of Blood Vessels


The coronary vasculature has been traditionally divided into three functional groups: (1) large conductance vessels visible on coronary angiography, which offer little resistance to blood flow; (2) small resistance vessels ranging in size from approximately 250 nm to 10 µm in diameter; and (3) veins. Although it has been taught that arterioles (precapillary vessels <50 µm in size) account for most coronary resistance, studies indicate that, under resting conditions, 45% to 50% of total coronary vascular resistance resides in vessels larger than 100 µm in diameter. The reason may be, in part, the relatively great length of the small arteries.


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).




Fig. 5.1


The production of endothelium-derived vasodilator substances. Prostacyclin (PGI 2 ) is produced by the cyclooxygenase pathway of arachidonic acid (AA) metabolism, which can be blocked by indomethacin (Indo) and aspirin. PGI 2 stimulates smooth muscle adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) production, actions that cause relaxation. Endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO), is produced by the action of NO synthase on L-arginine in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), oxygen (O 2 ), and calcium (Ca 2+ ) and calmodulin. This process can be blocked by arginine analogs such as N G -monomethyl- l -arginine (LNMMA). NO combines with guanylate cyclase in the smooth muscle cell to stimulate production of cyclic guanosine monophosphate (cGMP), which results in relaxation. Less well characterized is an endothelium-derived hyperpolarizing factor (EDHF), which hyperpolarizes the smooth muscle membrane and probably acts by activation of potassium (K + ) channels. ACh, Acetylcholine; ADP, adenosine diphosphate; [Ca 2+ ] i , intracellular calcium; 5-HT, serotonin; M, muscarinic receptor; P, purinergic receptor; T, thrombin receptor.

(From Rubanyi GM. Endothelium, platelets, and coronary vasospasm. Coron Artery Dis. 1990;1:645.)


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.


Endothelium-Derived Contracting Factors


Contracting factors produced by the endothelium include prostaglandin H 2 , thromboxane A 2 (generated by cyclooxygenase), and the peptide endothelin. Endothelin is a potent vasoconstrictor peptide (100-fold more potent than norepinephrine). In vascular smooth muscle cells, endothelin 1 (ET-1) binds to specific membrane receptors (ET A ) and, through phospholipase C, induces an increase in intracellular calcium resulting in long-lasting contractions. It is also linked by a guanosine triphosphate (GTP)-binding protein (G i ) to voltage-operated calcium channels. This peptide has greater vasoconstricting potency than any other cardiovascular hormone, and in pharmacologic doses it can abolish coronary flow, thereby leading to ventricular fibrillation and death.


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





Fig. 5.2


Inhibition of platelet adhesion and aggregation by intact endothelium. Aggregating platelets release adenosine diphosphate (ADP) and serotonin (5-HT), which stimulate the synthesis and release of prostacyclin ( PGI 2 ) and endothelium-derived relaxing factor ( EDRF; nitric oxide [NO] ), which diffuse back to the platelets and inhibit further adhesion and aggregation and can cause disaggregation. PGI 2 and EDRF act synergistically by increasing platelet cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively. By inhibiting platelets and also increasing blood flow by causing vasodilation, PGI 2 and EDRF can flush away microthrombi and prevent thrombosis of intact vessels. P 2y , Purinergic receptor.

(From Rubanyi GM. Endothelium, platelets, and coronary vasospasm. Coron Artery Dis. 1990;1:645.)




Anatomy and Physiology of Blood Vessels


The coronary vasculature has been traditionally divided into three functional groups: (1) large conductance vessels visible on coronary angiography, which offer little resistance to blood flow; (2) small resistance vessels ranging in size from approximately 250 nm to 10 µm in diameter; and (3) veins. Although it has been taught that arterioles (precapillary vessels <50 µm in size) account for most coronary resistance, studies indicate that, under resting conditions, 45% to 50% of total coronary vascular resistance resides in vessels larger than 100 µm in diameter. The reason may be, in part, the relatively great length of the small arteries.


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).




Fig. 5.1


The production of endothelium-derived vasodilator substances. Prostacyclin (PGI 2 ) is produced by the cyclooxygenase pathway of arachidonic acid (AA) metabolism, which can be blocked by indomethacin (Indo) and aspirin. PGI 2 stimulates smooth muscle adenylyl cyclase and increases cyclic adenosine monophosphate (cAMP) production, actions that cause relaxation. Endothelium-derived relaxing factor (EDRF), now known to be nitric oxide (NO), is produced by the action of NO synthase on L-arginine in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH), oxygen (O 2 ), and calcium (Ca 2+ ) and calmodulin. This process can be blocked by arginine analogs such as N G -monomethyl- l -arginine (LNMMA). NO combines with guanylate cyclase in the smooth muscle cell to stimulate production of cyclic guanosine monophosphate (cGMP), which results in relaxation. Less well characterized is an endothelium-derived hyperpolarizing factor (EDHF), which hyperpolarizes the smooth muscle membrane and probably acts by activation of potassium (K + ) channels. ACh, Acetylcholine; ADP, adenosine diphosphate; [Ca 2+ ] i , intracellular calcium; 5-HT, serotonin; M, muscarinic receptor; P, purinergic receptor; T, thrombin receptor.

(From Rubanyi GM. Endothelium, platelets, and coronary vasospasm. Coron Artery Dis. 1990;1:645.)


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.


Endothelium-Derived Contracting Factors


Contracting factors produced by the endothelium include prostaglandin H 2 , thromboxane A 2 (generated by cyclooxygenase), and the peptide endothelin. Endothelin is a potent vasoconstrictor peptide (100-fold more potent than norepinephrine). In vascular smooth muscle cells, endothelin 1 (ET-1) binds to specific membrane receptors (ET A ) and, through phospholipase C, induces an increase in intracellular calcium resulting in long-lasting contractions. It is also linked by a guanosine triphosphate (GTP)-binding protein (G i ) to voltage-operated calcium channels. This peptide has greater vasoconstricting potency than any other cardiovascular hormone, and in pharmacologic doses it can abolish coronary flow, thereby leading to ventricular fibrillation and death.


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 ).


Sep 1, 2018 | Posted by in PAIN MEDICINE | Comments Off on Coronary Physiology and Atherosclerosis
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