Scandinavian Journal of Clinical and Laboratory Investigation
ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
Myocardial Blood Flow Distribution Jon Lekven To cite this article: Jon Lekven (1976) Myocardial Blood Flow Distribution, Scandinavian Journal of Clinical and Laboratory Investigation, 36:1, 1-6, DOI: 10.1080/00365517609068011 To link to this article: http://dx.doi.org/10.1080/00365517609068011
Published online: 14 Feb 2011.
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Date: 29 June 2016, At: 12:14
Scand. .I din. . Lab. Invest. 36, 1-6, 1976.
ED IT0 RIAL
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Myocardial Blood Flow Distribution It has been known for decades that the arterial coronary blood flow is restricted and that the coronary vein flow is promoted by ventricular contraction. These apparently contradictory observations were largely resolved by the finding that both the arterial inflow and the coronary sinus outflow increased in hearts during sudden cardiac arrest with artificially maintained coronary perfusion pressure (29). By beating, the heart thus limits its own blood supply. Normal myocardium About 80% of the coronary blood flow occurs during ventricular diastole. In addition to intrinsic vascular resistance there is a significant extravascular component. Systolic cardiac compression leading to phasic variations in blood flow resistance is not uniformly distributed across the ventricular wall (9, 14). Most authors, howewer, believe that average coronary blood flow is uniformly distributed across the left ventricular free wall of the unstressed and normally perfused heart (2, 6-8, 11, 20). Since systolic blood flow is preferentially distributed to epicardial regions (8, 9, 15), a uniform average perfusion of the entire ventricular wall implies preferential diastolic blood flow to endocardial regions. Coronary arteries, like arteries of several other organs, possess an autoregulatory capacity (21); i.e. blood flow remains constant by arterial vasodilation during reductions in coronary perfusion pressure to about 70 mm Hg. It has been proposed that autoregulatory adjustments in vascular tone are responsible for maintaining adequate subendocardial perfusion (20) to meet local tissue requirements, which actually might be greatest in this layer of the ventricle (31). Whereas it is well documented that coronary autoregulation compensates for relatively slow and stepwise reductions in coronary perfusion pressure (18, 21), it remains unclear whether this vascular process is rapid enough to work selectively in the diastolic phase of the normal cardiac cycle and thus compensate for extensive systolic vascular compression in endocardial layers. In addition to the autoregulation theory, other mechanisms have been proposed for better endocardial perfusion conditions than in epicardial regions. These include a greater capillary volume in the endocardium (15, 33), precapillary sphincters directing blood preferentially to the endocardium (25), and a greater vascular permeability in endocardial layers (1). 1 - Scand. J. din. Lab. Invest.
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Downloaded by [University of California, San Diego] at 12:14 29 June 2016
Stressed myocardium
A multitude of physiological interventions changing cardiac performance have been shown to influence coronary blood flow distribution. Tachycardia induced by atrial pacing increases epicardial blood flow more than endocardial flow (23), although signs of ischemia have not been demonstrated in healthy dogs with extreme heart rates (24). Redistribution to epicardial layers is readily explained by a relative increase in the duration of systolic vascular compression. Variations in the arterial blood pressure also influence blood flow distribution. In fibrillating hearts without systolic compressive forces, increments in the intracavitary ventricular pressure redistribute flow to the epicardium (7), as does raised aortic blood pressure induced by supravalvular aortic constriction in beating hearts (5). When a similar rise in systolic blood pressure was accomplished by distal aortic constriction, the endocardial/epicardial relationship remained equal (5, 20). Reduced diastolic driving pressure during high-output failure of the heart, induced by opening a large arteriovenous fistula, also redistributed blood to epicardial regions (5). Conversely, raised ventricular diastolic pressure induced by heavy blood infusion slightly increased the endocardial/epicardial ratio and actually increased endocardial flow in excess of myocardial metabolic needs, since the myocardial oxygen extraction was reduced (16). These experiments demonstrate the perplexing effect that coronary arteries dilate in response to elevated extravasal tissue pressure, and they also show that the endocardium relies on diastolic blood flow to a greater extent than epicardial regions. p-adrenergic stimulation of the heart with isoproterenol causes a relative decrease in subendocardial flow (lo), and frank subendocardial necrosis can be precipitated by sustained isoproterenol infusion in otherwise healthy hearts (13). The effect of isoproterenol is not readily explained by changes in perfusion or tissue pressures, since both are probably reduced (18). Conversely, pharmacological blockade of p-adrenergic receptors increases endocardial blood flow at the expense of epicardial flow (3, 10, 20). However, diastolic intraventricular and tissue pressures are elevated without compensating elevation of the arterial pressure. The mechanisms for redistribution of coronary blood flow during changes in the p-adrenergic activity therefore remain obscure at present. Coronary insufficiency
Blood flow is uneven within an acutely ischemic area; it is lowest in the center and increases towards normal in the periphery of the lesion. Although reactive hyperemia in surrounding border zones, probably effected by release of the strong coronary dilator substance adenosine (28), has been indicated in some experiments (27), this could not be confirmed in other experiments (30).
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Subendocardial regions are more susceptible to ischemic manifestations when coronary blood flow is restricted (17), as should be expected from the discussion above. Occlusive coronary disease predominantly involves the main conducting artery trunks. Because this artery segment does not possess autoregulatory properties (34), the epicardium and endocardium are presumed to be equally exposed to reductions in coronary perfusion pressure. Since a homogeneous transmural distribution of blood flow requires dilation of endocardial vessels, autoregulation is more readily exhausted in endocardial regions when the perfusion pressure falls; below a critical pressure level, flow through these arteries depends solely on the coronary perfusion pressure and the extravasal tissue pressure (11). Under such circumstances, diastolic tissue pressure - or ventricular diastolic pressure - gains far greater importance for endocardial blood flow than the coronary venous counterpressure, and increased ventricular preload by blood infusion definitely impairs underperfusion of subendocardial regions in ischemic areas (16). Isoproterenol enlarges the ischemic area following acute coronary occlusion due to raised demands for oxygen in excess of simultaneously raised supplies (18). This metabolic effect is remarkably strong in subendocardial layers (12). Furthermore, a coronary steal syndrome parallel to vessels subtotally occluded by sclerotic lesions has been proposed for the vasodilatory effect of isoproterenol (30). Improvement of coronary autoregulation may increase coronary flow during mild ischemia but has no effect in regions with total artery occlusion (18). Several reports have indicated that blockade of 0-adrenergic receptors favors subendocardial blood flow relative to subepicardial flow (3, 20). However, the precise mechanism for this effect remains obscure. The effects of nitroglycerin have been extensively studied. Although nitroglycerin does not change the endocardial/epicardial ratio of blood flow distribution in hearts with unrestricted coronary flow, it seems to be generally agreed that nitroglycerin improves endocardial blood flow in ischemic tissue (3, 19). It is doubtful that nitroglycerin dilates coronary arteries to a significant extent; its effect is most likely explained by reduction of ventricular preload through systemic peripheral vasodilation. Collaterals Following coronary artery occlusion, blood flow falls to a variable extent in the area of supply, depending on the collateral blood supply. The importance of direct cavitary channels for collateral circulation is minimal, and extracardiac collaterals arising from mediastinal structures may actually represent a coronary steal syndrome, since tissue pressure is far greater in the left ventricle. Functional collateral circulation is mediated via preformed intercoronary communications. Collateral arterial flow increases within days, and flow to the area of occlusion may approach normal
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
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levels after a few weeks (26). Acute coronary occlusion in dogs without preformed collaterals showed a closer relationship between the ischemic injury and myocardial oxygen demands than in dogs with abundant native collaterals (32). Collateral blood flow is relatively unaffected by changes in ventricular peak systolic pressure and heart rate, both major determinants for myocardial oxygen demands, suggesting that collateral flow is not metabolically regulated (4). The collateral blood flow is almost exclusively a diastolic phenomenon, mainly determined by diastolic duration and diastolic aortic blood pressure (4). This finding is compatible with the absence of autoregulatory capacity in collateral vessels (16). Furthermore, the deleterious effect of tachycardia on acute ischemic lesions (22) can be partially explained by reduced diastolic duration for collateral flow. Concluding remarks
During the last decade an increasing number of research reports on myocardial blood flow distribution have appeared. The basic concepts of coronary autoregulation, influence of systolic vascular compression, and dependence on diastolic ventricular pressure have undoubtedly enriched our present knowledge of blood flow regulation. Although the effects of most physiological interventions on blood flow distribution are now known, this review shows that many of these effects cannot be readily explained by the concepts mentioned above. Considerable discrepancies in the literature are probably due to methodological difficulties, and further research efforts are therefore needed in this field. During recent years it has become obvious that the appearance of myocardial ischemia is not solely a question of blood or oxygen shortage. Local and regional function and accompanying needs for oxygen may be equally important for development of ischemia. Detailed studies of these factors are therefore required but have hitherto been limited by lack of proper experimental methods. Jon Lekven Institute for Experimental Medical Research University of Oslo Ullevil Hospital Oslo 1, Norway REFERENCES 1. Anversa, P., Giacomelli, F. & Wiener, J. Regional variation in capillary permeability of ventricular myocardium. Microvasc. Res. 6,273, 1973. 2. Bache, R. I., Cobb, F. R. & Greenfield, J. C., Jr. Myocardial blood flow distribution during ischemia-induced coronary vasodilation in the unanesthetized dog. J . clin. Invest. 54, 1462, 1974. 3. Becker, L. C., Fortuin, N. J. & Pitt, B. Effect of ischemia and antianginal drugs on the distribution of radioactive microspheres in the canine left ventricle. Circulat. Res. 28, 263, 1971. 4. Brown, B. G., Gundel, W. D., Gott, V. L. & Covell, J. W. Coronary collateral flow following acute coronary occhsion: a diastolic phenomenon. Curdiovasc. lies. 8, 621, 1974.
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5. Buckberg, G. D., Fixler, D. E., Archie, J. P. & Hoffman, J. I. E. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circulat. Res. 30, 67, 1972. 6. Cobb, F. R., Bache, R. J. & Greenfield, J. C., Jr. Regional myocardial blood flow in awake dogs. I . clin Invest. 53, 1618, 1974. 7. Cutarelli, R. & Levy, M. N. Intraventricular pressure and the distribution of coronary blood flow. Circulat. Res. 12, 322, 1963. 8. Downey, H. F., Bashour, F. A., Boatwright, R. B., Parker, P. E. & Kechejian, S. J. Uniformity of transmural perfusion in anesthetized dogs with maximally dilated coronary circulations. Circulat. Res. 37, 111, 1975. 9. Downey, J. M. & Kirk, E. D. Distribution of the coronary blood flow across the canine heart wall during systole. Circular. Res. 34, 251, 1974. lO.Fortuin, N. J., Kaihara, S., Becker, L. C. & Pitt, B. Regional myocardial blood flow in the dog studied with radioactive microspheres. Cardiovasc. Res. 5, 331, 1971. 11. Griggs, D. M. & Nakamura, Y. Effect of coronary constriction on myocardial distribution of i~doantipyrine-l~~I. Amer. J. Physiol. 215, 1082, 1968. 12. Griggs, D. M., Tchokoev, V. V. & DeClue, J. W. Effect of beta-adrenergic receptor stimulation on regional myocardial metabolism: importance of coronary vessel patency. Amer. Heart J . 82, 492, 1971. 13. Handforth, C. P. Jsoproterenol-induced myocardial infarction in animals. Arch. Path. 73, 161, 1962. 14. Kirk, E. S. & Honig, C. R. An experimental and theoretical analysis of myocardial tissue pressure. Amer. J . Physiol. 207, 361, 1964. 15.Kirk, E. S. & Honig, C. R. Nonuniform distribution of blood flow and gradients of oxygen tension within the heart. Amer. J . Physiol. 207,661, 1964. 16. Kjekshus, J. K. Mechanism for flow distribution in normal and ischemic myocardium during increased ventricular preload in the dog. Circulat. Res. 33, 489, 1973. 17. Kjekshus, J. K., Maroko, P. R. & Sobel, B. E. Distribution of myocardial injury and its relation to epicardial ST-segment changes following acute coronary artery occlusion in the dog. Cardiovasc. Res. 6,490, 1972. lS.Lekven, J., Kjekshus, J. K. & Mjos, 0. D. Cardiac effects of isoproterenol during graded myocardial ischemia. Scand. J. clin. Lab. Invest. 33, 161, 1974. 19. Mathes, P. & Rival, J. Effect of nitroglycerin on total and regional coronary blood flow in normal and ischemic canine myocardium. Cardiovasc. Res. 5, 54, 1971. 20. Moir, T. W. & DeBra, D. W. Effect of left ventricular hypertension, ischemia and vasoactive drugs on the myocardial distribution of coronary flow. Circulat. Res. 21, 65, 1967. 21.Mosher, P., Ross, J., Jr., McFate, P. A. & Shaw, R. F. Control of coronary blood flow by an autoregulatory mechanism. Circulat. Res. 14, 250, 1964. 22. Neill, W. A., Oxendine, J., Phelps, N. & Anderson, R. P. Subendocardial ischemia provoked by tachycardia in conscious dogs with coronary stenosis. Amer. J . Cardiol. 35, 30, 1975. 23.Neil1, W. A., Phelps, N. C., Oxendine, J. M., Mahler, D. J. & Sim, D. N. Effect of heart rate on coronary blood flow distribution in dogs. Amer. J . Cardiol. 32, 306, 1973. 24. Pitt, B. & Gregg, D. E. Coronary hemodynamic effects of increasing ventricular rate in the unanesthetized dog. Circulat. Res. 22, 753, 1968. 25.Provenza, D. V. & Scherlis, S. Coronary circulation in the dog’s heart: demonstration of muscle sphincters in capillaries. Circulat. Res. 7, 318, 1959. 26.Rees, J. R. & Redding, V. J. Anastomotic blood flow in experimental myocardial infarction. A new method, using xenon133 clearance, for repeated measurements during recovery. Cardiovasc. Res. I , 169, 1967. 27.Rees, J. R. & Redding, V. J. Experimental myocardial infarction in the dog: comparison of myocardial blood flow within, near, and distant from the infarct. Circulat. Res. 25, 161, 1969. 28.Rubio, R., Berne, R. M. & Katori, M. Release of adenosine in reactive hyperemia of the dog heart. Amer. J. Physiol. 216,56, 1969.
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29.Sabiston, D. C. & Gregg, D. E. Effect of cardiac contraction on coronary blood flow. Circulation 15, 14, 1957. 30. Sharma, G. V. R. K., Kumar, R., Molokhia, F. & Messer, J. V. ‘Coronary steal’: regional myocardial blood flow studies during isoproterenol infusion in acute and healing myocardial infarction. Clin. Res. 19, 339, 1971. 31. Spotnitz, H. M., Sonnenblick, E. H. & Spiro, D. Relation of ultrastructure to function in the intact heart: sarcomere structure relative to pressure volume curves of intact left ventricles of dog and cat. Circulat. Res. 18,49, 1966. 32.Stephan, K., Meesmann, W. & Sadony, V. Oxygen demand and collateral vessels of the heart. Factors influencing the severity of myocardial ischaemic injury after experimental coronary artery occlusion. Cardiovasc. Res. 9, 640, 1975. 33. Weiss, H. R. & Winbury, M. M. Nitroglyerin and chromonar on small-vessel blood content of the ventricular walls. Amer. J . Physiol. 226, 838, 1974. 34. Winbury, M. M., Howe, B. B. & Hefner, M. A. Effect of nitrates and other coronary dilators on large and small vessels: hypothesis for the mechanism of action of nitrates. J . Pharmacol. exp. Ther. 168, 70, 1969.
ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
Myocardial Blood Flow Distribution Jon Lekven To cite this article: Jon Lekven (1976) Myocardial Blood Flow Distribution, Scandinavian Journal of Clinical and Laboratory Investigation, 36:1, 1-6, DOI: 10.1080/00365517609068011 To link to this article: http://dx.doi.org/10.1080/00365517609068011
Published online: 14 Feb 2011.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iclb20 Download by: [University of California, San Diego]
Date: 29 June 2016, At: 12:14
Scand. .I din. . Lab. Invest. 36, 1-6, 1976.
ED IT0 RIAL
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
Myocardial Blood Flow Distribution It has been known for decades that the arterial coronary blood flow is restricted and that the coronary vein flow is promoted by ventricular contraction. These apparently contradictory observations were largely resolved by the finding that both the arterial inflow and the coronary sinus outflow increased in hearts during sudden cardiac arrest with artificially maintained coronary perfusion pressure (29). By beating, the heart thus limits its own blood supply. Normal myocardium About 80% of the coronary blood flow occurs during ventricular diastole. In addition to intrinsic vascular resistance there is a significant extravascular component. Systolic cardiac compression leading to phasic variations in blood flow resistance is not uniformly distributed across the ventricular wall (9, 14). Most authors, howewer, believe that average coronary blood flow is uniformly distributed across the left ventricular free wall of the unstressed and normally perfused heart (2, 6-8, 11, 20). Since systolic blood flow is preferentially distributed to epicardial regions (8, 9, 15), a uniform average perfusion of the entire ventricular wall implies preferential diastolic blood flow to endocardial regions. Coronary arteries, like arteries of several other organs, possess an autoregulatory capacity (21); i.e. blood flow remains constant by arterial vasodilation during reductions in coronary perfusion pressure to about 70 mm Hg. It has been proposed that autoregulatory adjustments in vascular tone are responsible for maintaining adequate subendocardial perfusion (20) to meet local tissue requirements, which actually might be greatest in this layer of the ventricle (31). Whereas it is well documented that coronary autoregulation compensates for relatively slow and stepwise reductions in coronary perfusion pressure (18, 21), it remains unclear whether this vascular process is rapid enough to work selectively in the diastolic phase of the normal cardiac cycle and thus compensate for extensive systolic vascular compression in endocardial layers. In addition to the autoregulation theory, other mechanisms have been proposed for better endocardial perfusion conditions than in epicardial regions. These include a greater capillary volume in the endocardium (15, 33), precapillary sphincters directing blood preferentially to the endocardium (25), and a greater vascular permeability in endocardial layers (1). 1 - Scand. J. din. Lab. Invest.
2
Editorial
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
Stressed myocardium
A multitude of physiological interventions changing cardiac performance have been shown to influence coronary blood flow distribution. Tachycardia induced by atrial pacing increases epicardial blood flow more than endocardial flow (23), although signs of ischemia have not been demonstrated in healthy dogs with extreme heart rates (24). Redistribution to epicardial layers is readily explained by a relative increase in the duration of systolic vascular compression. Variations in the arterial blood pressure also influence blood flow distribution. In fibrillating hearts without systolic compressive forces, increments in the intracavitary ventricular pressure redistribute flow to the epicardium (7), as does raised aortic blood pressure induced by supravalvular aortic constriction in beating hearts (5). When a similar rise in systolic blood pressure was accomplished by distal aortic constriction, the endocardial/epicardial relationship remained equal (5, 20). Reduced diastolic driving pressure during high-output failure of the heart, induced by opening a large arteriovenous fistula, also redistributed blood to epicardial regions (5). Conversely, raised ventricular diastolic pressure induced by heavy blood infusion slightly increased the endocardial/epicardial ratio and actually increased endocardial flow in excess of myocardial metabolic needs, since the myocardial oxygen extraction was reduced (16). These experiments demonstrate the perplexing effect that coronary arteries dilate in response to elevated extravasal tissue pressure, and they also show that the endocardium relies on diastolic blood flow to a greater extent than epicardial regions. p-adrenergic stimulation of the heart with isoproterenol causes a relative decrease in subendocardial flow (lo), and frank subendocardial necrosis can be precipitated by sustained isoproterenol infusion in otherwise healthy hearts (13). The effect of isoproterenol is not readily explained by changes in perfusion or tissue pressures, since both are probably reduced (18). Conversely, pharmacological blockade of p-adrenergic receptors increases endocardial blood flow at the expense of epicardial flow (3, 10, 20). However, diastolic intraventricular and tissue pressures are elevated without compensating elevation of the arterial pressure. The mechanisms for redistribution of coronary blood flow during changes in the p-adrenergic activity therefore remain obscure at present. Coronary insufficiency
Blood flow is uneven within an acutely ischemic area; it is lowest in the center and increases towards normal in the periphery of the lesion. Although reactive hyperemia in surrounding border zones, probably effected by release of the strong coronary dilator substance adenosine (28), has been indicated in some experiments (27), this could not be confirmed in other experiments (30).
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
Editorial
3
Subendocardial regions are more susceptible to ischemic manifestations when coronary blood flow is restricted (17), as should be expected from the discussion above. Occlusive coronary disease predominantly involves the main conducting artery trunks. Because this artery segment does not possess autoregulatory properties (34), the epicardium and endocardium are presumed to be equally exposed to reductions in coronary perfusion pressure. Since a homogeneous transmural distribution of blood flow requires dilation of endocardial vessels, autoregulation is more readily exhausted in endocardial regions when the perfusion pressure falls; below a critical pressure level, flow through these arteries depends solely on the coronary perfusion pressure and the extravasal tissue pressure (11). Under such circumstances, diastolic tissue pressure - or ventricular diastolic pressure - gains far greater importance for endocardial blood flow than the coronary venous counterpressure, and increased ventricular preload by blood infusion definitely impairs underperfusion of subendocardial regions in ischemic areas (16). Isoproterenol enlarges the ischemic area following acute coronary occlusion due to raised demands for oxygen in excess of simultaneously raised supplies (18). This metabolic effect is remarkably strong in subendocardial layers (12). Furthermore, a coronary steal syndrome parallel to vessels subtotally occluded by sclerotic lesions has been proposed for the vasodilatory effect of isoproterenol (30). Improvement of coronary autoregulation may increase coronary flow during mild ischemia but has no effect in regions with total artery occlusion (18). Several reports have indicated that blockade of 0-adrenergic receptors favors subendocardial blood flow relative to subepicardial flow (3, 20). However, the precise mechanism for this effect remains obscure. The effects of nitroglycerin have been extensively studied. Although nitroglycerin does not change the endocardial/epicardial ratio of blood flow distribution in hearts with unrestricted coronary flow, it seems to be generally agreed that nitroglycerin improves endocardial blood flow in ischemic tissue (3, 19). It is doubtful that nitroglycerin dilates coronary arteries to a significant extent; its effect is most likely explained by reduction of ventricular preload through systemic peripheral vasodilation. Collaterals Following coronary artery occlusion, blood flow falls to a variable extent in the area of supply, depending on the collateral blood supply. The importance of direct cavitary channels for collateral circulation is minimal, and extracardiac collaterals arising from mediastinal structures may actually represent a coronary steal syndrome, since tissue pressure is far greater in the left ventricle. Functional collateral circulation is mediated via preformed intercoronary communications. Collateral arterial flow increases within days, and flow to the area of occlusion may approach normal
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
4
Editorial
levels after a few weeks (26). Acute coronary occlusion in dogs without preformed collaterals showed a closer relationship between the ischemic injury and myocardial oxygen demands than in dogs with abundant native collaterals (32). Collateral blood flow is relatively unaffected by changes in ventricular peak systolic pressure and heart rate, both major determinants for myocardial oxygen demands, suggesting that collateral flow is not metabolically regulated (4). The collateral blood flow is almost exclusively a diastolic phenomenon, mainly determined by diastolic duration and diastolic aortic blood pressure (4). This finding is compatible with the absence of autoregulatory capacity in collateral vessels (16). Furthermore, the deleterious effect of tachycardia on acute ischemic lesions (22) can be partially explained by reduced diastolic duration for collateral flow. Concluding remarks
During the last decade an increasing number of research reports on myocardial blood flow distribution have appeared. The basic concepts of coronary autoregulation, influence of systolic vascular compression, and dependence on diastolic ventricular pressure have undoubtedly enriched our present knowledge of blood flow regulation. Although the effects of most physiological interventions on blood flow distribution are now known, this review shows that many of these effects cannot be readily explained by the concepts mentioned above. Considerable discrepancies in the literature are probably due to methodological difficulties, and further research efforts are therefore needed in this field. During recent years it has become obvious that the appearance of myocardial ischemia is not solely a question of blood or oxygen shortage. Local and regional function and accompanying needs for oxygen may be equally important for development of ischemia. Detailed studies of these factors are therefore required but have hitherto been limited by lack of proper experimental methods. Jon Lekven Institute for Experimental Medical Research University of Oslo Ullevil Hospital Oslo 1, Norway REFERENCES 1. Anversa, P., Giacomelli, F. & Wiener, J. Regional variation in capillary permeability of ventricular myocardium. Microvasc. Res. 6,273, 1973. 2. Bache, R. I., Cobb, F. R. & Greenfield, J. C., Jr. Myocardial blood flow distribution during ischemia-induced coronary vasodilation in the unanesthetized dog. J . clin. Invest. 54, 1462, 1974. 3. Becker, L. C., Fortuin, N. J. & Pitt, B. Effect of ischemia and antianginal drugs on the distribution of radioactive microspheres in the canine left ventricle. Circulat. Res. 28, 263, 1971. 4. Brown, B. G., Gundel, W. D., Gott, V. L. & Covell, J. W. Coronary collateral flow following acute coronary occhsion: a diastolic phenomenon. Curdiovasc. lies. 8, 621, 1974.
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
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5. Buckberg, G. D., Fixler, D. E., Archie, J. P. & Hoffman, J. I. E. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circulat. Res. 30, 67, 1972. 6. Cobb, F. R., Bache, R. J. & Greenfield, J. C., Jr. Regional myocardial blood flow in awake dogs. I . clin Invest. 53, 1618, 1974. 7. Cutarelli, R. & Levy, M. N. Intraventricular pressure and the distribution of coronary blood flow. Circulat. Res. 12, 322, 1963. 8. Downey, H. F., Bashour, F. A., Boatwright, R. B., Parker, P. E. & Kechejian, S. J. Uniformity of transmural perfusion in anesthetized dogs with maximally dilated coronary circulations. Circulat. Res. 37, 111, 1975. 9. Downey, J. M. & Kirk, E. D. Distribution of the coronary blood flow across the canine heart wall during systole. Circular. Res. 34, 251, 1974. lO.Fortuin, N. J., Kaihara, S., Becker, L. C. & Pitt, B. Regional myocardial blood flow in the dog studied with radioactive microspheres. Cardiovasc. Res. 5, 331, 1971. 11. Griggs, D. M. & Nakamura, Y. Effect of coronary constriction on myocardial distribution of i~doantipyrine-l~~I. Amer. J. Physiol. 215, 1082, 1968. 12. Griggs, D. M., Tchokoev, V. V. & DeClue, J. W. Effect of beta-adrenergic receptor stimulation on regional myocardial metabolism: importance of coronary vessel patency. Amer. Heart J . 82, 492, 1971. 13. Handforth, C. P. Jsoproterenol-induced myocardial infarction in animals. Arch. Path. 73, 161, 1962. 14. Kirk, E. S. & Honig, C. R. An experimental and theoretical analysis of myocardial tissue pressure. Amer. J . Physiol. 207, 361, 1964. 15.Kirk, E. S. & Honig, C. R. Nonuniform distribution of blood flow and gradients of oxygen tension within the heart. Amer. J . Physiol. 207,661, 1964. 16. Kjekshus, J. K. Mechanism for flow distribution in normal and ischemic myocardium during increased ventricular preload in the dog. Circulat. Res. 33, 489, 1973. 17. Kjekshus, J. K., Maroko, P. R. & Sobel, B. E. Distribution of myocardial injury and its relation to epicardial ST-segment changes following acute coronary artery occlusion in the dog. Cardiovasc. Res. 6,490, 1972. lS.Lekven, J., Kjekshus, J. K. & Mjos, 0. D. Cardiac effects of isoproterenol during graded myocardial ischemia. Scand. J. clin. Lab. Invest. 33, 161, 1974. 19. Mathes, P. & Rival, J. Effect of nitroglycerin on total and regional coronary blood flow in normal and ischemic canine myocardium. Cardiovasc. Res. 5, 54, 1971. 20. Moir, T. W. & DeBra, D. W. Effect of left ventricular hypertension, ischemia and vasoactive drugs on the myocardial distribution of coronary flow. Circulat. Res. 21, 65, 1967. 21.Mosher, P., Ross, J., Jr., McFate, P. A. & Shaw, R. F. Control of coronary blood flow by an autoregulatory mechanism. Circulat. Res. 14, 250, 1964. 22. Neill, W. A., Oxendine, J., Phelps, N. & Anderson, R. P. Subendocardial ischemia provoked by tachycardia in conscious dogs with coronary stenosis. Amer. J . Cardiol. 35, 30, 1975. 23.Neil1, W. A., Phelps, N. C., Oxendine, J. M., Mahler, D. J. & Sim, D. N. Effect of heart rate on coronary blood flow distribution in dogs. Amer. J . Cardiol. 32, 306, 1973. 24. Pitt, B. & Gregg, D. E. Coronary hemodynamic effects of increasing ventricular rate in the unanesthetized dog. Circulat. Res. 22, 753, 1968. 25.Provenza, D. V. & Scherlis, S. Coronary circulation in the dog’s heart: demonstration of muscle sphincters in capillaries. Circulat. Res. 7, 318, 1959. 26.Rees, J. R. & Redding, V. J. Anastomotic blood flow in experimental myocardial infarction. A new method, using xenon133 clearance, for repeated measurements during recovery. Cardiovasc. Res. I , 169, 1967. 27.Rees, J. R. & Redding, V. J. Experimental myocardial infarction in the dog: comparison of myocardial blood flow within, near, and distant from the infarct. Circulat. Res. 25, 161, 1969. 28.Rubio, R., Berne, R. M. & Katori, M. Release of adenosine in reactive hyperemia of the dog heart. Amer. J. Physiol. 216,56, 1969.
Downloaded by [University of California, San Diego] at 12:14 29 June 2016
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29.Sabiston, D. C. & Gregg, D. E. Effect of cardiac contraction on coronary blood flow. Circulation 15, 14, 1957. 30. Sharma, G. V. R. K., Kumar, R., Molokhia, F. & Messer, J. V. ‘Coronary steal’: regional myocardial blood flow studies during isoproterenol infusion in acute and healing myocardial infarction. Clin. Res. 19, 339, 1971. 31. Spotnitz, H. M., Sonnenblick, E. H. & Spiro, D. Relation of ultrastructure to function in the intact heart: sarcomere structure relative to pressure volume curves of intact left ventricles of dog and cat. Circulat. Res. 18,49, 1966. 32.Stephan, K., Meesmann, W. & Sadony, V. Oxygen demand and collateral vessels of the heart. Factors influencing the severity of myocardial ischaemic injury after experimental coronary artery occlusion. Cardiovasc. Res. 9, 640, 1975. 33. Weiss, H. R. & Winbury, M. M. Nitroglyerin and chromonar on small-vessel blood content of the ventricular walls. Amer. J . Physiol. 226, 838, 1974. 34. Winbury, M. M., Howe, B. B. & Hefner, M. A. Effect of nitrates and other coronary dilators on large and small vessels: hypothesis for the mechanism of action of nitrates. J . Pharmacol. exp. Ther. 168, 70, 1969.
