The function of the coronary circulation is to supply the myocardium with O2. Contractile cardiac function relies an aerobic metabolism. Basal O2 extraction is about 60 per cent and an adequate increase of coronary blood flow is required to meet increased myocardial O2 consumption (MO2).
Regulation of Coronary Blood flow
During diastole when the aortic valve (AV) is closed, aortic diastolic pressure is transmitted through the dilated sinuses of Valsalva to the coronary ostia. The epicardial arteries serve as conductance vessels and offer little resistance to coronary flow. These vessels give rise to smaller penetrating vessels approximately at right angles which are called “ resistance vessels”.Blood flow in the coronary bed depends on the driving pressure and the resistance offered by this bed coronary vascular resistance is regulated by several factors.
Metabolic Regulation
Myocardium depends almost completely on aerobic metabolism. Occlusion of a coronary artery even briefly produces an increase in coronary blood flow above baseline, immediately following release of the occlusion. This response is called coronary reactive hyperemia. The potential mediators of this are adenosine, other nucleotides, NO, PG, CO2 and H+. Adenosine plays a significant role in the regulation of coronary blood flow during reactive hyperemia, hypoxia,inotropic stimulation with isoproterenol, dobutamine and mental stress. Other vasodilators involved in metabolic regulation of coronary flow are NO and prostanoids.
Endothelial Control
Vasoactive substances such as Endothelium Derived Relaxing Factors (EDRF). Prostacyclin and Endothelin can be formed in the vascular endothelium. Endothelial dysfunction can lead to disturbances in coronary blood flow, contribute to the pathogenesis of myocardial ischaemia and is a central feature in the evolution of atherosclerosis, thrombosis, inflammation and atherogenesis (EDRF).
Intact endothelium is a prerequisite for acetylcholine-induced vasodilation. In the presence of endothelium, acetylcholine produces dose dependent vasodilation. When the endothelium is removed, only constriction is induced by acetylcholine. EDRF has been identified to be NO radical, or a sulfhydryl complex containing it. Only a few vasodilators can act independently of the endothelium and directly on vascular smooth muscle. These include the nitrovasodilators (e.g.Nitroglycerin, nitroprusside), prostacyclin and adenosine.In patients with dysfunctional endothelium, the loss of flow mediated and catecholamine stimulated EDRF release allows the constrictor effects of the catecholamines to act unopposed. In vessels damaged by the atherosclerotic process and by plaque fissuring there is coronary constriction in response to a variety of substances that would normally elicit vasodilation.
Endothelium Derived Constricting Factor
Endothelium is a source of vasoconstrictor factor also. The best characterized of these are the endothelins. Endothelium produces only ET1. Unlike NO, which is released rapidly in response to vasodilator stimuli and then inactivated in a few seconds, ET1 has actions that lasts minutes to hours. ET1 contributes to the regulation of vascular tone primarily by exerting a tonic vasoconstrictor influence. ET1 is also produced by activated human macrophages.
Autoregulation of Coronary Blood flow
The ability to maintain myocardial perfusion at constant levels in the face of changing driving presence is termed autoregulation. In normal cases, autoregulation is maintained at mean arterial pressures as low as 60 mms of Hg and as high as 130 mm of Hg. Autoregulation plays an important role. In arteries, reduction in perfusion pressure distal to the stenosis are compensated by autoregulatory dilation of resistance vessels. Coronary collaterals do not exhibit autoregulation.
Extravascular Compression
Most of the coronary blood flow to the left ventricular myocardium occurs during diastole. Thus the contracting heart obstructs its own blood supply. The systolic compressive force has 2 components. There is LV systolic intracavitary pressure and vascular narrowing caused by contraction of the heart.
Because compressive forces exerted by the RV are ordinarily far smaller than those of LV,ventricular perfusion is reduced, but not interrupted during systole.
Diastolic Compressive Forces
Coronary perfusion pressure equal to pressure gradient between the coronary arteries and the pressure in LV in diastole. When coronary perfusion pressure is lowered, diastolic blood flow decreases.
Extravascular compressive forces are greater in subendocardial than in subepicardial zones. So systolic flow is more reduced in the subendocardium than subepicardium. But there is preferential dilatation of the subendocardial vessels causing a large increase in diastolic flow in the subendocardium. This is due to increased wall stress which is 20 per cent greater than that of the subepicardial muscle. Average endocardial to epicardial flow ratio is 1.25:1 throughout the cardiac cycle.
A low subendocardial to epicardial flow occurs in epicardial coronary stenosis and heart failure.A low endocardial to epicardial flow ratio can be increased by elevation of aortic pressure.
Neural and Neurotransmitter Control
Coronary arteries are richly innervated by adrenergic and parasympathetic nerves. Both alpha 1 and alpha 2 adrenergic receptors are present in coronary arteries and when activated by circulating norepinephine causes vasoconstriction, which appears to be mediated by an increased concentration of Ca++ in coronary vascular smooth muscle. Beta 2 adrenoceptors in the large and small coronary arteries mediate vasodilation.
Reflex Control
Baroreceptor activity affects coronary vascular resistance reflexly. With carotid occlusion,baroreceptor hypotension leads to reflex adrenergic stimulation, increased metabolic activity and secondary vasodilation. When this is prevented by beta blockade, reflex coronary vasoconstriction secondary to carotid hypotension is unmasked. Alpha1 adrenoreceptor stimulation is capable of causing epicardial vasoconstriction in ischaemic myocardium, thereby influencing favourably the transmural distribution of blood flow to the subendocardium during exercise. Activation of chemoreceptors initially causes coronary dilation, a reflex that is mediated by vagi and can be abolished by atropine e.g. Bezold Jarisch reflex.
Effects of Flow Limiting Stenosis on Blood Flow
1) The presence of epicardial coronary artery stenosis caused by artherosclerotic plaques is by far the most frequent angiographic finding in any cardiac ischaemic syndrome.
2) Experimental studies in dogs showed that the acute reduction of coronary diameter by more than 50 per cent causes a measurable basal transstenotic pressure gradient. Further decreases in diameter cause an exponential increase of transstenotic pressure gradient and reduction of maximal coronary blood flow.
3) The stenosis resistance is linearly related to the length of the stenosis and to the flow turbulence caused by the stenosis irregularities.
4) The greater the basal transstenotic pressure gradient, the greater the reduction of coronary myocardial ischaemia appears during effort.
5) In presence of a decreased poststenotic pressure ischaemia initially occurs in subendocardial layers, because the subendocardium is more vulnerable to ischaemia than the subepicardium.
Coronary Vasoconstriction
1) Coronary flow limiting stenoses are caused by concentric or eccentric artherosclerotic plaques, with or without potential for local vasomotor changes. Fixed flow limiting stenoses present smooth muscle cell atrophy and/or plaque rigidity and are associated with the
predictable ischaemic threshold and a stable pattern of effort related myocardial ischaemia.Dynamic stenoses are usually eccentric, with compliant segments of the wall and preserved muscular media, and are associated with a variable ishaemic threshold.
2) Vasoconstriction at the site of stenoses may result from (1) neural vasoconstrictor stimuli,(2) impairment of vasodilator mechanisms, (3) increased response of dysfunctional vascular smooth muscle cells to vasoconstrictor stimuli, or (4) variable combination of these mechanisms.
3) In animal models, and possibly in unstable patients, the severity of stenosis may also be modulated by platelet aggregates.
Coronary Spasm
Usually spasm develops at the site of subcritical or critical stenoses, but it may also occur in angiographically normal coronary arteries, the so called variant form of angina. Occlusive spasm causes transmural ischaemia with ST-segment elevation, but when spasm is subocclusive, it may cause subendocardial ischaemia and ST-segment depression.
Coronary Collateral Circulation
1) The drop in poststenotic pressure caused by flow-limiting stenoses stimulates the development of collateral circulation from other coronary artery beds. The supply of collateral blood flow increases poststenotic pressure, thus improving coronary flow reserve
and raising the ischaemic threshold.
2) Collateral vessels develop from the progressive enlargement of preexisting intercoronary arterial anastomoses.
3) Blood flow through these anastomeses begins as a consequence of the flow-limiting stenosis when a pressure gradient develops between their origin and termination.
4) In unanesthetized dogs, a pressure gradient of about 10mm Hg, caused by a lumen reduction of 70 to 80 per cent has been shown to elicit the development of collateral flow.
5) Preexisiting anastomoses progressively transform to vessels with a final diameter of 20 to 200 um.
6) Blood flow through collaterals is determined by the driving pressure and by their resistance,which is influenced by neural and humoral stimuli and by local vasoactive autacoids.
7) In patients, heparin and fibroblastic growth factor 1 (FGF-1) have been suggested to promote collateral growth.
Coronary Steal Distal to Stenotic Lesions
In the presence of flow-limiting stenoses, myocardial ischaemia may develop as a result of a diversion of blood flow from a myocardial region with a very severe impairment of coronary flow reserve, determining an almost maximal arteriolar dilatation in basal conditions, towards a myocardial region with sufficiently preserved coronary flow reserve.
Regulation of Coronary Blood flow
During diastole when the aortic valve (AV) is closed, aortic diastolic pressure is transmitted through the dilated sinuses of Valsalva to the coronary ostia. The epicardial arteries serve as conductance vessels and offer little resistance to coronary flow. These vessels give rise to smaller penetrating vessels approximately at right angles which are called “ resistance vessels”.Blood flow in the coronary bed depends on the driving pressure and the resistance offered by this bed coronary vascular resistance is regulated by several factors.
Metabolic Regulation
Myocardium depends almost completely on aerobic metabolism. Occlusion of a coronary artery even briefly produces an increase in coronary blood flow above baseline, immediately following release of the occlusion. This response is called coronary reactive hyperemia. The potential mediators of this are adenosine, other nucleotides, NO, PG, CO2 and H+. Adenosine plays a significant role in the regulation of coronary blood flow during reactive hyperemia, hypoxia,inotropic stimulation with isoproterenol, dobutamine and mental stress. Other vasodilators involved in metabolic regulation of coronary flow are NO and prostanoids.
Endothelial Control
Vasoactive substances such as Endothelium Derived Relaxing Factors (EDRF). Prostacyclin and Endothelin can be formed in the vascular endothelium. Endothelial dysfunction can lead to disturbances in coronary blood flow, contribute to the pathogenesis of myocardial ischaemia and is a central feature in the evolution of atherosclerosis, thrombosis, inflammation and atherogenesis (EDRF).
Intact endothelium is a prerequisite for acetylcholine-induced vasodilation. In the presence of endothelium, acetylcholine produces dose dependent vasodilation. When the endothelium is removed, only constriction is induced by acetylcholine. EDRF has been identified to be NO radical, or a sulfhydryl complex containing it. Only a few vasodilators can act independently of the endothelium and directly on vascular smooth muscle. These include the nitrovasodilators (e.g.Nitroglycerin, nitroprusside), prostacyclin and adenosine.In patients with dysfunctional endothelium, the loss of flow mediated and catecholamine stimulated EDRF release allows the constrictor effects of the catecholamines to act unopposed. In vessels damaged by the atherosclerotic process and by plaque fissuring there is coronary constriction in response to a variety of substances that would normally elicit vasodilation.
Endothelium Derived Constricting Factor
Endothelium is a source of vasoconstrictor factor also. The best characterized of these are the endothelins. Endothelium produces only ET1. Unlike NO, which is released rapidly in response to vasodilator stimuli and then inactivated in a few seconds, ET1 has actions that lasts minutes to hours. ET1 contributes to the regulation of vascular tone primarily by exerting a tonic vasoconstrictor influence. ET1 is also produced by activated human macrophages.
Autoregulation of Coronary Blood flow
The ability to maintain myocardial perfusion at constant levels in the face of changing driving presence is termed autoregulation. In normal cases, autoregulation is maintained at mean arterial pressures as low as 60 mms of Hg and as high as 130 mm of Hg. Autoregulation plays an important role. In arteries, reduction in perfusion pressure distal to the stenosis are compensated by autoregulatory dilation of resistance vessels. Coronary collaterals do not exhibit autoregulation.
Extravascular Compression
Most of the coronary blood flow to the left ventricular myocardium occurs during diastole. Thus the contracting heart obstructs its own blood supply. The systolic compressive force has 2 components. There is LV systolic intracavitary pressure and vascular narrowing caused by contraction of the heart.
Because compressive forces exerted by the RV are ordinarily far smaller than those of LV,ventricular perfusion is reduced, but not interrupted during systole.
Diastolic Compressive Forces
Coronary perfusion pressure equal to pressure gradient between the coronary arteries and the pressure in LV in diastole. When coronary perfusion pressure is lowered, diastolic blood flow decreases.
Extravascular compressive forces are greater in subendocardial than in subepicardial zones. So systolic flow is more reduced in the subendocardium than subepicardium. But there is preferential dilatation of the subendocardial vessels causing a large increase in diastolic flow in the subendocardium. This is due to increased wall stress which is 20 per cent greater than that of the subepicardial muscle. Average endocardial to epicardial flow ratio is 1.25:1 throughout the cardiac cycle.
A low subendocardial to epicardial flow occurs in epicardial coronary stenosis and heart failure.A low endocardial to epicardial flow ratio can be increased by elevation of aortic pressure.
Neural and Neurotransmitter Control
Coronary arteries are richly innervated by adrenergic and parasympathetic nerves. Both alpha 1 and alpha 2 adrenergic receptors are present in coronary arteries and when activated by circulating norepinephine causes vasoconstriction, which appears to be mediated by an increased concentration of Ca++ in coronary vascular smooth muscle. Beta 2 adrenoceptors in the large and small coronary arteries mediate vasodilation.
Reflex Control
Baroreceptor activity affects coronary vascular resistance reflexly. With carotid occlusion,baroreceptor hypotension leads to reflex adrenergic stimulation, increased metabolic activity and secondary vasodilation. When this is prevented by beta blockade, reflex coronary vasoconstriction secondary to carotid hypotension is unmasked. Alpha1 adrenoreceptor stimulation is capable of causing epicardial vasoconstriction in ischaemic myocardium, thereby influencing favourably the transmural distribution of blood flow to the subendocardium during exercise. Activation of chemoreceptors initially causes coronary dilation, a reflex that is mediated by vagi and can be abolished by atropine e.g. Bezold Jarisch reflex.
Effects of Flow Limiting Stenosis on Blood Flow
1) The presence of epicardial coronary artery stenosis caused by artherosclerotic plaques is by far the most frequent angiographic finding in any cardiac ischaemic syndrome.
2) Experimental studies in dogs showed that the acute reduction of coronary diameter by more than 50 per cent causes a measurable basal transstenotic pressure gradient. Further decreases in diameter cause an exponential increase of transstenotic pressure gradient and reduction of maximal coronary blood flow.
3) The stenosis resistance is linearly related to the length of the stenosis and to the flow turbulence caused by the stenosis irregularities.
4) The greater the basal transstenotic pressure gradient, the greater the reduction of coronary myocardial ischaemia appears during effort.
5) In presence of a decreased poststenotic pressure ischaemia initially occurs in subendocardial layers, because the subendocardium is more vulnerable to ischaemia than the subepicardium.
Coronary Vasoconstriction
1) Coronary flow limiting stenoses are caused by concentric or eccentric artherosclerotic plaques, with or without potential for local vasomotor changes. Fixed flow limiting stenoses present smooth muscle cell atrophy and/or plaque rigidity and are associated with the
predictable ischaemic threshold and a stable pattern of effort related myocardial ischaemia.Dynamic stenoses are usually eccentric, with compliant segments of the wall and preserved muscular media, and are associated with a variable ishaemic threshold.
2) Vasoconstriction at the site of stenoses may result from (1) neural vasoconstrictor stimuli,(2) impairment of vasodilator mechanisms, (3) increased response of dysfunctional vascular smooth muscle cells to vasoconstrictor stimuli, or (4) variable combination of these mechanisms.
3) In animal models, and possibly in unstable patients, the severity of stenosis may also be modulated by platelet aggregates.
Coronary Spasm
Usually spasm develops at the site of subcritical or critical stenoses, but it may also occur in angiographically normal coronary arteries, the so called variant form of angina. Occlusive spasm causes transmural ischaemia with ST-segment elevation, but when spasm is subocclusive, it may cause subendocardial ischaemia and ST-segment depression.
Coronary Collateral Circulation
1) The drop in poststenotic pressure caused by flow-limiting stenoses stimulates the development of collateral circulation from other coronary artery beds. The supply of collateral blood flow increases poststenotic pressure, thus improving coronary flow reserve
and raising the ischaemic threshold.
2) Collateral vessels develop from the progressive enlargement of preexisting intercoronary arterial anastomoses.
3) Blood flow through these anastomeses begins as a consequence of the flow-limiting stenosis when a pressure gradient develops between their origin and termination.
4) In unanesthetized dogs, a pressure gradient of about 10mm Hg, caused by a lumen reduction of 70 to 80 per cent has been shown to elicit the development of collateral flow.
5) Preexisiting anastomoses progressively transform to vessels with a final diameter of 20 to 200 um.
6) Blood flow through collaterals is determined by the driving pressure and by their resistance,which is influenced by neural and humoral stimuli and by local vasoactive autacoids.
7) In patients, heparin and fibroblastic growth factor 1 (FGF-1) have been suggested to promote collateral growth.
Coronary Steal Distal to Stenotic Lesions
In the presence of flow-limiting stenoses, myocardial ischaemia may develop as a result of a diversion of blood flow from a myocardial region with a very severe impairment of coronary flow reserve, determining an almost maximal arteriolar dilatation in basal conditions, towards a myocardial region with sufficiently preserved coronary flow reserve.
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