CABG from zero to hero Physiology introduction.

physiology of coronary circulation.

1. CORONARY ARTERY BYPASS GRAFTING From Zero To Hero Mahmoud Alhussaini

2. PHYSIOLOGY OF CORONARY CIRCULATION

3. Regulation of coronary flow The coronary circulation is unique among regional vascular beds in that its perfusion is impeded during the systolic phase of the cardiac cycle by the surrounding contracting cardiac muscle. Systolic contraction increases LV wall tension and compresses the intramyocardial micro vessels, thereby impeding coronary arterial inflow. This compression is not uniformly distributed across the LV wall, resulting in a redistribution of blood flow from the subendocardium to subepicardium

4. Regulation of coronary flow LV myocardial oxygen extraction averages 60– 80% of arterially supplied oxygen at rest. Increases in myocardial oxygen consumption (e.g., during exercise) are predominantly met by proportional increases in CBF. The increase in CBF is principally the result of a reduction in coronary vascular resistance, due to dilation of coronary small arteries and arterioles, the so-called resistance vessels.

5. Regulation of coronary flow local coronary blood flow is precisely controlled by a balance of vasodilator and vasoconstrictor mechanisms, including: (1) a metabolic vasodilator system; (2) a neurogenic control system (3) the vascular endothelium.

6. Regulation of coronary flow The metabolic vasodilator mechanism responds rapidly when local blood flow is insufficient to meet metabolic demand. The primary mediator is adenosine generated within the myocyte and released into the interstitial compartment. Adenosine relaxes arteriolar smooth muscle cells by activation of A2 receptors. Adenosine is formed when the oxygen supply cannot sustain the rapid rephosphorylation of ADP to ATP. Once sufficient oxygen is supplied to the myocardium, less adenosine is formed. Adenosine is therefore the coupling agent between oxygen demand and supply.

7. Regulation of coronary flow The sympathetic nervous system acts through alpha receptors (vasoconstriction) and beta receptors (vasodilation). There are direct innervations of the large conductance vessels and lesser direct innervations of the smaller resistance vessels. Sympathetic receptors on the smooth muscle cells of the resistance vessels respond to humoral catecholamines. Alpha receptors predominate over beta receptors such that when norepinephrine is released from the sympathetic nerve endings, vasoconstriction ordinarily occurs.

8. Regulation of coronary flow CBF remains fairly constant over a wide range of coronary perfusion pressures, owing to adjustments in the diameter of coronary resistance vessels mediated by both myogenic and metabolic mechanisms. This autoregulation of blood flow is particularly important to maintain CBF when coronary perfusion pressure is decreased by an upstream coronary artery stenosis. The pressure at which the coronary resistance vessels become maximally dilated is the lowest pressure at which normal myocardial blood flow can be maintained and is referred to as the lower limit of autoregulation.

9. Regulation of coronary flow Below this coronary pressure, CBF decreases in a pressure- dependent manner, leading to myocardial ischaemia . Under normal haemodynamic conditions, resting LV myocardial blood flow averages 0.7– 1.0 mL/ min/ g of myocardium and can increase four- to fivefold during maximal vasodilation. The ability to increase CBF above resting levels in response to pharmacological vasodilation is termed coronary flow reserve.

10. CORONARY ENDOTHELIAL FUNCTION The vascular endothelial cell layer functions under basal conditions to maintain the vessel tone, while mitigating inflammation, oxidative stress, and thrombogenicity. The coronary endothelium regulates blood flow to meet the demands of myocardial oxygen consumption (VO2) by favoring a relatively neutral state in the balance between dilatation and constriction mainly through the action of: nitric oxide (NO) (guanylate cyclase → cyclic guanosine monophosphate) prostacyclin (PGI2, cyclic adenosine monophosphate, platelet aggregation) shear stress (the drag force per unit area imposed by a fluid in motion on a solid boundary in parallel to the direction of the fluid in motion).

11. CORONARY ENDOTHELIAL FUNCTION The principal vasoconstrictor is the endothelially derived constricting peptide endothelin-1. Other vasoconstrictors include angiotensin II and superoxide free radical. NO is released by the coronary vascular endothelium by both soluble factors (acetylcholine, adenosine, and ATP) and mechanical signals (shear stress and pulsatile stress secondary to increased intraluminal blood flow).

12. CORONARY ENDOTHELIAL FUNCTION If the endothelium is intact, acetylcholine from the sympathetic nerves causes vasodilation through generation of NO. If the endothelium is not functionally intact, acetylcholine causes vasoconstriction by direct stimulation of the vascular smooth muscle. NO is a potent inhibitor of platelet aggregation and neutrophil function (superoxide generation, adherence, and migration), which has implications in the anti-inflammatory response to ischemia-reperfusion and cardiopulmonary bypass.

13. CORONARY ENDOTHELIAL FUNCTION Endothelin-1 interacts principally with specific endothelin receptors, ETA, on vascular smooth muscle, and causes smooth muscle vasoconstriction. Endothelin-1 counteracts the vasodilator effects of endogenous adenosine, NO, and prostacyclin (PGI2). Endothelin-1 is rapidly synthesized in the vascular endothelium, particularly during ischemia, hypoxia, and other stress conditions, where it acts in a paracrine fashion. Human coronary arteries demonstrate abundant endothelin-1 binding sites, suggesting that ET-1 has an important role in the control of coronary blood flow in humans The levels of ET-1 have been observed to increase with myocardial ischemia-reperfusion and after cardiac surgery.

14. CORONARY ENDOTHELIAL FUNCTION Under ordinary circumstances the metabolic vasodilator system is the dominant force acting on the resistance vessels. For example, the increased metabolic activity caused by sympathetic stimulation leads to vasodilation of the coronary arterioles through the metabolic system, despite a direct vasoconstriction effect of norepinephrine.

15. Hemodynamic Effect of Coronary Artery Stenosis Surgically treatable atherosclerotic disease primarily affects the large conductance vessels of the heart. The hemodynamic effect of a stenosis is determined by Poiseuille’s law, which describes the resistance of a viscous fluid to laminar flow through a cylindrical tube; specifically:

16. Hemodynamic Effect of Coronary Artery Stenosis Resistance (pressure change/flow) is inversely proportional to the fourth power of the radius and directly proportional to the length of the narrowing. Therefore, a small change in diameter has a magnified effect on vascular resistance

17. Hemodynamic Effect of Coronary Artery Stenosis Conductance vessels are sufficiently large that a 50% reduction in the diameter of the vessel has minimal hemodynamic effect. A 60% reduction in the diameter of the vessel has only a very small hemodynamic effect. As the stenosis progresses beyond 60%, small decreases in diameter have significant effects on blood flow. For a given segment length, an 80% stenosis has a resistance that is 16 times greater a 60% stenosis. For a 90% stenosis, the resistance is 256 times greater than for a 60% stenosis. Furthermore, for successive stenoses in the same vessel the resistance is additive.

18. Hemodynamic Effect of Coronary Artery Stenosis lesions can cause conversion from laminar to turbulent flow. With laminar flow the pressure drop is proportional to flow rate Q; with turbulent flow pressure drop is proportional to Q 2 . For all these reasons, patients who have had a small progression in the degree of coronary stenosis may experience a rapid acceleration of symptoms. Atherosclerosis also alters normal vascular regulatory mechanisms. The endothelium is often destroyed or damaged, so vasoconstrictor mechanisms are relatively unopposed by the impaired vasodilator mechanism; constriction is exaggerated and responses to stimuli that require dilatation are blunted

19. Hemodynamic Effect of Coronary Artery Stenosis As noted, when a stenosis is less than 60%, little change is flow is noted. This is due to compensation by the coronary flow reserve of the resistance vessels distal to the stenotic conductance vessel. As resistance to flow is additive, a decrease in distal resistance will balance an increase in proximal resistance and flow will be unchanged. As flow reserve decreases, any stimulus that increases myocardial oxygen demand (such a tachycardia, hypertension, or exercise) cannot be met by dilation of the distal vasculature, and myocardial ischemia results.

20. Hemodynamic Effect of Coronary Artery Stenosis With sudden coronary occlusion, although there is usually modest collateral flow through very small vessels (20 to 200 μ m in size), this flow is generally insufficient to maintain cellular viability. Collateral flow gradually begins to increase over the next 8 to 24 hours, doubling by about the third day after total occlusion. Collateral blood flow development appears to be nearly complete after 1 month, restoring normal or nearly normal resting flow to the surviving myocardium in the ischemic region. Previous ischemic events or gradually developing stenoses can lead to larger preexisting collaterals in the human heart. The presence of these pre-existing collaterals has been shown to be important in the prevention of ischemic damage if coronary occlusion should occur.

21. Endothelial Dysfunction Ischemia- reperfusion, hypertension, diabetes, and hypercholesterolemia can impair generation of NO and vasoconstriction may predominate, mediated by the relative overexpression of endothelin-1. Reperfusion after temporary myocardial ischemia is one situation in which NO production may be impaired, leading to a vicious cycle in which the vasodilator reserve of the resistance vessels is reduced with a consequent and progressive “low-flow” or “no-flow” phenomenon. The coronary vascular NO system may also be impaired in some cases after coronary artery bypass surgery.

22. Endothelial Dysfunction The endothelium helps prevent cell-cell interactions between blood-borne inflammatory cells ( ie , leukocytes and platelets) that initiate a local or systemic inflammatory reaction. Inflammatory cascades occur with sepsis, ischemia-reperfusion, and cardiopulmonary bypass. Under normal conditions, the vascular endothelium resists interaction with neutrophils and platelets by tonically releasing adenosine and NO, which have potent antineutrophil and platelet inhibitory effects.

23. Endothelial Dysfunction Damage to the endothelium lowers the resistance to neutrophil adhesion. Neutrophils can damage the endothelium by adhesion to its surface, and subsequent release of oxygen radicals and proteases. This amplifies the inflammatory response and decreases the tonic generation and release of adenosine and NO, which then permits further interaction with activated inflammatory cells. The products released by activated neutrophils have downstream physiologic consequences on other tissues, notably the heart, including increasing vascular permeability, creating blood flow defects (no-reflow phenomenon), and promoting the pathogenesis of necrosis and apoptosis.

24. Endothelial Dysfunction The release of cytokines and complement fragments during cardiopulmonary bypass activates the vascular endothelium on a systemic basis, which contributes to the inflammatory response to cardiopulmonary bypass. Both adenosine and NO have been used therapeutically to reduce the inflammatory responses to cardiopulmonary bypass, and to reduce ischemic-reperfusion injury and endothelial damage

25. Biology of the Bypass Vessels First, the endothelium activates, thanks to the expression of angiotensin- converting enzyme on its surface, angiotensin I into angiotensin II and breaks down bradykinin, a process that is more pronounced in the saphenous vein than it is in the internal mammary artery. Inhibition of angiotensin- converting enzyme, therefore, increases endothelium- dependent relaxation to bradykinin in the saphenous vein, but not in the mammary artery.

26. Biology of the Bypass Vessels The endothelial l- arginine pathway is an important local regulator of platelet vessel wall interactions as well as of vascular tone The end product of the pathway, NO, is formed from l- arginine, and activates soluble guanylyl cyclase (leading to increased cyclic guanosine monophosphate (cGMP)) and eventually reduces intracellular calcium concentration and in turn induces vasodilation and platelet inhibition, respectively.

27. Biology of the Bypass Vessels The saphenous vein, when used as a coronary bypass graft, is prone to bypass graft disease and eventual occlusion; indeed, intimal hyperplasia and plaque formation develops continuously over time in venous bypass vessels after implantation and after 10 years most venous bypass grafts are occluded. In contrast, the internal mammary artery shows the highest patency rate, while the radial artery and the gastroepiploic artery give less satisfactory results, due to their propensity towards spasm especially when patients require catecholamines after operation. These remarkable differences in the function of bypass vessels are of great interest from a biological point of view, as it must reflect the different biological properties of these blood vessels.

28. Biology of the Bypass Vessels Of note, the release of NO in response to receptor- operated agonists such as bradykinin, acetylcholine, adenosine diphosphate (ADP), or thrombin is much less pronounced or absent in the saphenous vein than it is in the internal mammary artery. The gastroepiploic artery, however, has an endothelial function that is similar to that of the internal mammary artery.

29. Biology of the Bypass Vessels Importantly, all bypass vessels respond with vasodilation when exposed to nitrovasodilators indicating that the vascular smooth muscle cells are capable of forming cGMP. In the gastroepiploic artery, the accumulation of cGMP after stimulation with nitrovasodilators is even more pronounced than with other bypass vessels, as are contractions to vasoconstrictor substances such as norepinephrine. .

30. Biology of the Bypass Vessels Regulation of platelet/ vessel wall interactions is of particular importance in graft functioning and may prevent graft occlusion. In this context, it is of interest that the platelet- derived mediator ADP binds specific receptors on endothelial cells and induces NO release, thereby inhibiting platelet function via accumulation of cGMP and induction of vasodilation in the mammary artery, a response that is conversely weak or absent in the saphenous vein

31. Biology of the Bypass Vessels Thus, the internal mammary artery exhibits endothelium- dependent relaxation and inhibition of platelet function at sites where platelets are activated and thereby is protected from thrombus formation. Interestingly, the gastroepiploic artery also exhibits marked contractions to aggregating platelets similar to the saphenous vein. This, together with its marked contractile responses to catecholamines, may explain the less favourable results seen when it is used as a bypass graft.

32. Biology of the Bypass Vessels Shear stress exerted by the circulating blood also induces the release of NO which is an important mechanism of flow- mediated vasodilation during exercise or under other conditions of increased demand. This response is crucial for the function of mammary artery grafts when they are implanted into the coronary circulation and exposed to marked increases in flow. When arterial grafts are implanted into coronary segments with haemodynamically insignificant stenoses, they tend to shrink or even occlude (angiographically described as the ‘string sign’).

33. Biology of the Bypass Vessels Histological analysis shows that the internal mammary artery exhibits little structural changes and in particular rarely develops plaques. This is obviously in sharp contrast to the saphenous vein when implanted into the coronary circulation where it exhibits marked intimal hyperplasia and develops atherosclerotic changes

34. Biology of the Bypass Vessels The remarkable clinical differences of mammary artery and venous grafts can be explained by their different biological properties. Besides endothelial cells, vascular smooth muscle cells of both blood vessels markedly differ. Explants of the media of the saphenous vein exhibit an extensive outgrowth of smooth muscle cells, while this is hardly the case with explants of the mammary artery.

35. Biology of the Bypass Vessels Furthermore, when stimulated with platelet- derived growth factor (PDGF), saphenous vein vascular smooth muscle cells rapidly and markedly grow, while this is again hardly the case with mammary artery cells. Finally, and this might be of utmost importance for venous bypass graft disease, saphenous vein smooth muscle cells grow rapidly when exposed to pulsatile stretch, while mammary cells are protected from this physical stimulus. Thus, when implanted into the coronary circulation, the saphenous vein, which physiologically is exposed to laminar flow and low shear stress in the venous circulation, will develop a marked intimal hyperplasia leading in part to narrowing of the lumen and eventually graft attrition.

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