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Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon
Atherosclerosis 149 (2000) 1 – 3 www.elsevier.com/locate/atherosclerosis
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Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon Allen M. Scher * Department of Physiology and Biophysics, Uni6ersity of Washington, Room G415, Box 357290, Seattle, WA 98195 7290, USA Received 16 July 1999; accepted 4 October 1999
Abstract Atherosclerosis is absent in human intramyocardial (buried) coronary arteries but atherosclerosis may be severe in superficial segments of the same vessels. The development of atherosclerosis has three phases: a plasma phase, a transfer phase and an intramural phase. The transfer phase involves the transfer of low-density lipoproteins and macrophages from the plasma into the arterial wall. Efficiency of transfer is low where plasma flow near the wall is rapid. Eddy currents caused by arterial branches produce low flow near the arterial wall. Plasma recalculates and moves slowly in these eddy currents and thus prolongs contact of LDL and macrophages with the wall, increasing the occurrence of atherosclerosis. Absence of atherosclerosis in buried vessels appears due to the effects of myocardial contraction on the transfer phase. Contraction of the myocardium surrounding buried arterial vessel compresses these vessels and moves the plasma, LDL and macrophages away from the wall. This will decrease transfer into the wall and act to prevent the development of atherosclerosis. Similar but less striking effects occur where bridges of myocardium cross arterial vessels. Possible applications to human disease are discussed briefly. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Intramyocardial coronary arteries; Myocardial contraction; Transfer; Low density lipoproteins; Macrophages
Several studies show that in the human heart, atherosclerosis is virtually non-existent in intramyocardial (buried) coronary arteries [1 – 3]. In a recent study [3], 26 arterial segments which were being replaced by bypass vessels were examined. These segments were superficial near their origins and then became buried in the myocardium. When they were superficial all segments were grossly atherosclerotic. In contrast 24 of these segments were completely free of atherosclerosis in their distal, intramyocardial regions. This ‘natural prevention’ of atherosclerosis in intramyocardial vessels is rarely discussed. This paper considers the cause of this prevention and speculates about further studies. Concerning cause, we consider three stages in the development of atherosclerosis. * Tel.: +1-206-543-0986; fax: + 1-206-685-0619. E-mail address: [email protected] (A.M. Scher)
1. Stages in the development of atherosclerosis The concentration of LDL cholesterol and monocytes in the plasma, determined by diet and metabolism, set the stage for atherosclerosis. We do not believe that these concentrations are important in the difference between superficial and intramyocardial vessels.
2. The transfer stage LDL and monocytes adhere to and then move through the endothelium. LDL moves by diffusion and by active transport. Monocytes move actively. Adherence is increased by adhesion molecules and is facilitated by slow movement or stasis of plasma (less mixing) at the plasma/endothelial boundary. The flow
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 9 9 ) 0 0 4 6 4 - 5
2
A.M. Scher / Atherosclerosis 149 (2000) 1–3
velocity profile in unbranched blood vessels is approximately flat where flow enters the vessel and becomes laminar or streamlined in straight unbranched segments of sufficient length [4]. A flat profile shows nearly invariant velocity across the central stream, a streamlined flow profile is parabolic with the highest velocity in the center of the stream, and a smooth decrease in velocity with distance from the center. With either flow profile, arterial flow moves forward smoothly. With laminar flow, plasma and its contents move more rapidly in the higher central layers. The contents have less contact with the wall and tend to remain in the bloodstream. At higher rates of flow with either profile, increased movement of plasma near the blood vessel wall impedes transfer of LDL and monocytes into the wall, and transfer is promoted by slow flow or flow stasis. Smooth flow is interrupted at arterial branches where flow encounters Y- or T-shaped flow dividers and impinges on vessel orifices and opposing walls [4]. At these sites there are regions of backflow and eddy currents near the walls. Plasma moves to and fro and recirculates. With the resultant slow movement of plasma, LDL and monocytes will have more prolonged contact with the wall and will pass through it more easily. They are less likely to be washed away by the slowly recirculating stream. Such regions of eddies and low shear stress are preferred sites for development of atherosclerosis throughout the arterial circulation [5]. Myocardial contraction further alters flow patterns in buried intramyocardial vessels. These vessels are completely surrounded by contracting myocardium. During systole, as the intramyocardial pressure increases, these vessels will be compressed and their diameter will decrease. The contained plasma and its contents will be stirred, moved off the vessel wall and perhaps pushed into adjacent coronary segments. If the vessel closes completely, the walls may be wiped clean by movement of opposite sides of the vessel. Thus contraction of the myocardium and compression of the vessel will lessen the duration of contact between plasma contents and the vessel wall. This will decrease transfer of LDL and monocytes into the intima. In contrast, superficial vessels are only partly surrounded by contracting myocardium. Contraction may shorten the inner myocardial surfaces but the vessels will not be compressed and can expand freely on their outer aspect. The vessel diameter changes will be smaller than in buried vessels, and there will be less mixing of the plasma and its constituents. In superficial vessels, the passage of LDL and monocytes across the wall will be less disturbed by myocardial contraction. The difference in susceptibility to atherosclerosis between superficial and intramyocardial coronary arteries appears due to the effects of contraction on the transfer of
LDL and monocytes. The transmural pressure differences which appear responsible have been documented [3].
3. The intramural stage Monocytes which have entered the cell become macrophages and incorporate (scavenge) LDL, initiating atherosclerosis. Initiation and growth may be aided by oxidizing compounds, adherence molecules etc. Although the cellular contents may differ it seems unlikely that this phase differs between superficial and intramyocardial arteries. Cellular contents may be moved by myocardial contraction but LDL and macrophages will not leave the wall, and atherosclerosis will progress. In the study cited above [3], superficial epicardial wall segments of the removed vessels showed severe signs of atherosclerosis including discoloration, elevated and non-elevated plaques calcification and ulcers. The intramyocardial segments of the same vessels had thin and pliable walls without the above signs of atherosclerosis. There were two exceptions to this in 26 segments examined. One had a thin myocardial cover; the other was totally occluded proximally and possibly included a recanalized thrombotic segment.
Discussion Other evidence supports the importance of myocardial contraction flow stasis and hemodynamic factors in the location and development of atherosclerosis. Atherosclerosis is rare beneath myocardial bridges in superficial arteries [6]. Effects of myocardial bridges are not as marked as the effects of intramyocardial location of vessels. The difference is probably due to the facts that vessels under bridges are only partially intramyocardial and that bridges vary widely in size and thickness, and therefore in effect. Atherosclerosis is common in venous bypass grafts [7]. Increased flow stasis would be expected in these grafts due to their large size. Also there may be turbulence and eddy currents at the union between vessels of different size. Some large straight coronary arterial segments, which have rapid flow and in which flow is probably laminar rarely become atherosclerotic [8]. It is surprising that the absence of atherosclerosis in buried intramyocardial arterial segments is rarely discussed. Whatever the mechanism, it shows that atherosclerosis can be prevented. What can be done to make this observation more applicable to human disease? Laboratory research might further investigate the
A.M. Scher / Atherosclerosis 149 (2000) 1–3
transfer phase and detail the mechanism of prevention. Studies in animals or human subjects might indicate if external manipulation such as vibration can interfere with development of atherosclerosis. There are hints in the literature. Whole body vibration (30 min per day) in the cholesterol fed rabbit lowered the size of aortic atherosclerotic plaques [9].. Also cyclists (cycling is a vibratory activity) have less atherosclerosis than control accident victims (matched only by sex, age, and year of death) [10].. This last suggests the remote possibility that re-investigation of available clinical data bases might indicate if individuals subjected to high vibration (jackhammer operators?) are protected against atherosclerosis. Trial studies of particular physical activities could be initiated perhaps based on such analysis. Although these possibilities seem remote, the potential reward is high. In defense of this speculation, recent history shows that ‘unlikely’ hypotheses about atherosclerosis and coronary disease often produce unexpected discoveries and benefits. The following is from Geiringer [1]. ‘‘It is a melancholy reflection that a shift of a few millimeters in the anatomical course of the main coronary branches would have resulted in practical immunity from the most common form of coronary vascular accident, that is atherogenic thrombosis. This reflection gains piquancy through the investigations of Chase and Gars who found that while the gorilla and gibbon have an epicardial network of main coronaries, the coronary arteries of the chimpanzee and to a lesser extent of the orangutan tend to run a mural course. Using an outmoded form of expression, it would seem that in this respect at any rate we are descended from the wrong type of ape’’.
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3
Acknowledgements Generous support for the preparation of this manuscript and related research was provided by the Department of Physiology and Biophysics at the University of Washington, The G. Edgar Folk Jr Fund of the American Physiological Society and especially by Dr Michael Rosenfeld. References [1] Geiringer E. The mural coronary. Am Heart J 1951;41:359–68. [2] Roberts WC, Buja LM. The frequency and significance of coronary artery thrombi and other observations on fatal acute myocardial infarction. A study of 107 necropsy specimens. Am J Med 1972;52:425 – 43. [3] Robicsek F, Thubrikar MJ. The freedom from atherosclerosis of intramyocardial coronary arteries: reduction of mural stress — a key factor. Eur J Cardiothorac Surg 1994;8:228 – 35. [4] Vogel S. Life in moving fluids. Princeton: Princeton University Press, 1994. [5] Glacov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988;112:1018 –31. [6] Ishii T, Hosoda Y, Osaka T, Imai T, Shimada H, Takami A, et al. The significance of myocardial bridge upon atherosclerosis in the left anterior descending coronary artery. J Pathol 1986;148:279 – 91. [7] Davies MG, Hagen PO. Pathophysiology of vein graft failure: a review. Eur J Vasc Endovasc Surg 1995;9:7 – 18. [8] Velican C, Velican D. Natural resistance to atherosclerosis exhibited by the first centimeter of left and right coronary arteries. Atherosclerosis 1984;50:173 – 81. [9] Oki M, Ishitake T, Ohkubo A, Tsunetaka M. Frequency dependence of the suppressive effects of vibration on atherosclerosis in the rabbit. Kurume Med J 1989;36:161 – 6. [10] Kennedy A. Exercise and heart disease: cardiac findings in fatal cycle accidents. Br J Sports Med 1997;31:328 – 31.
Viewpoint
Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon Allen M. Scher * Department of Physiology and Biophysics, Uni6ersity of Washington, Room G415, Box 357290, Seattle, WA 98195 7290, USA Received 16 July 1999; accepted 4 October 1999
Abstract Atherosclerosis is absent in human intramyocardial (buried) coronary arteries but atherosclerosis may be severe in superficial segments of the same vessels. The development of atherosclerosis has three phases: a plasma phase, a transfer phase and an intramural phase. The transfer phase involves the transfer of low-density lipoproteins and macrophages from the plasma into the arterial wall. Efficiency of transfer is low where plasma flow near the wall is rapid. Eddy currents caused by arterial branches produce low flow near the arterial wall. Plasma recalculates and moves slowly in these eddy currents and thus prolongs contact of LDL and macrophages with the wall, increasing the occurrence of atherosclerosis. Absence of atherosclerosis in buried vessels appears due to the effects of myocardial contraction on the transfer phase. Contraction of the myocardium surrounding buried arterial vessel compresses these vessels and moves the plasma, LDL and macrophages away from the wall. This will decrease transfer into the wall and act to prevent the development of atherosclerosis. Similar but less striking effects occur where bridges of myocardium cross arterial vessels. Possible applications to human disease are discussed briefly. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Intramyocardial coronary arteries; Myocardial contraction; Transfer; Low density lipoproteins; Macrophages
Several studies show that in the human heart, atherosclerosis is virtually non-existent in intramyocardial (buried) coronary arteries [1 – 3]. In a recent study [3], 26 arterial segments which were being replaced by bypass vessels were examined. These segments were superficial near their origins and then became buried in the myocardium. When they were superficial all segments were grossly atherosclerotic. In contrast 24 of these segments were completely free of atherosclerosis in their distal, intramyocardial regions. This ‘natural prevention’ of atherosclerosis in intramyocardial vessels is rarely discussed. This paper considers the cause of this prevention and speculates about further studies. Concerning cause, we consider three stages in the development of atherosclerosis. * Tel.: +1-206-543-0986; fax: + 1-206-685-0619. E-mail address: [email protected] (A.M. Scher)
1. Stages in the development of atherosclerosis The concentration of LDL cholesterol and monocytes in the plasma, determined by diet and metabolism, set the stage for atherosclerosis. We do not believe that these concentrations are important in the difference between superficial and intramyocardial vessels.
2. The transfer stage LDL and monocytes adhere to and then move through the endothelium. LDL moves by diffusion and by active transport. Monocytes move actively. Adherence is increased by adhesion molecules and is facilitated by slow movement or stasis of plasma (less mixing) at the plasma/endothelial boundary. The flow
0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 9 9 ) 0 0 4 6 4 - 5
2
A.M. Scher / Atherosclerosis 149 (2000) 1–3
velocity profile in unbranched blood vessels is approximately flat where flow enters the vessel and becomes laminar or streamlined in straight unbranched segments of sufficient length [4]. A flat profile shows nearly invariant velocity across the central stream, a streamlined flow profile is parabolic with the highest velocity in the center of the stream, and a smooth decrease in velocity with distance from the center. With either flow profile, arterial flow moves forward smoothly. With laminar flow, plasma and its contents move more rapidly in the higher central layers. The contents have less contact with the wall and tend to remain in the bloodstream. At higher rates of flow with either profile, increased movement of plasma near the blood vessel wall impedes transfer of LDL and monocytes into the wall, and transfer is promoted by slow flow or flow stasis. Smooth flow is interrupted at arterial branches where flow encounters Y- or T-shaped flow dividers and impinges on vessel orifices and opposing walls [4]. At these sites there are regions of backflow and eddy currents near the walls. Plasma moves to and fro and recirculates. With the resultant slow movement of plasma, LDL and monocytes will have more prolonged contact with the wall and will pass through it more easily. They are less likely to be washed away by the slowly recirculating stream. Such regions of eddies and low shear stress are preferred sites for development of atherosclerosis throughout the arterial circulation [5]. Myocardial contraction further alters flow patterns in buried intramyocardial vessels. These vessels are completely surrounded by contracting myocardium. During systole, as the intramyocardial pressure increases, these vessels will be compressed and their diameter will decrease. The contained plasma and its contents will be stirred, moved off the vessel wall and perhaps pushed into adjacent coronary segments. If the vessel closes completely, the walls may be wiped clean by movement of opposite sides of the vessel. Thus contraction of the myocardium and compression of the vessel will lessen the duration of contact between plasma contents and the vessel wall. This will decrease transfer of LDL and monocytes into the intima. In contrast, superficial vessels are only partly surrounded by contracting myocardium. Contraction may shorten the inner myocardial surfaces but the vessels will not be compressed and can expand freely on their outer aspect. The vessel diameter changes will be smaller than in buried vessels, and there will be less mixing of the plasma and its constituents. In superficial vessels, the passage of LDL and monocytes across the wall will be less disturbed by myocardial contraction. The difference in susceptibility to atherosclerosis between superficial and intramyocardial coronary arteries appears due to the effects of contraction on the transfer of
LDL and monocytes. The transmural pressure differences which appear responsible have been documented [3].
3. The intramural stage Monocytes which have entered the cell become macrophages and incorporate (scavenge) LDL, initiating atherosclerosis. Initiation and growth may be aided by oxidizing compounds, adherence molecules etc. Although the cellular contents may differ it seems unlikely that this phase differs between superficial and intramyocardial arteries. Cellular contents may be moved by myocardial contraction but LDL and macrophages will not leave the wall, and atherosclerosis will progress. In the study cited above [3], superficial epicardial wall segments of the removed vessels showed severe signs of atherosclerosis including discoloration, elevated and non-elevated plaques calcification and ulcers. The intramyocardial segments of the same vessels had thin and pliable walls without the above signs of atherosclerosis. There were two exceptions to this in 26 segments examined. One had a thin myocardial cover; the other was totally occluded proximally and possibly included a recanalized thrombotic segment.
Discussion Other evidence supports the importance of myocardial contraction flow stasis and hemodynamic factors in the location and development of atherosclerosis. Atherosclerosis is rare beneath myocardial bridges in superficial arteries [6]. Effects of myocardial bridges are not as marked as the effects of intramyocardial location of vessels. The difference is probably due to the facts that vessels under bridges are only partially intramyocardial and that bridges vary widely in size and thickness, and therefore in effect. Atherosclerosis is common in venous bypass grafts [7]. Increased flow stasis would be expected in these grafts due to their large size. Also there may be turbulence and eddy currents at the union between vessels of different size. Some large straight coronary arterial segments, which have rapid flow and in which flow is probably laminar rarely become atherosclerotic [8]. It is surprising that the absence of atherosclerosis in buried intramyocardial arterial segments is rarely discussed. Whatever the mechanism, it shows that atherosclerosis can be prevented. What can be done to make this observation more applicable to human disease? Laboratory research might further investigate the
A.M. Scher / Atherosclerosis 149 (2000) 1–3
transfer phase and detail the mechanism of prevention. Studies in animals or human subjects might indicate if external manipulation such as vibration can interfere with development of atherosclerosis. There are hints in the literature. Whole body vibration (30 min per day) in the cholesterol fed rabbit lowered the size of aortic atherosclerotic plaques [9].. Also cyclists (cycling is a vibratory activity) have less atherosclerosis than control accident victims (matched only by sex, age, and year of death) [10].. This last suggests the remote possibility that re-investigation of available clinical data bases might indicate if individuals subjected to high vibration (jackhammer operators?) are protected against atherosclerosis. Trial studies of particular physical activities could be initiated perhaps based on such analysis. Although these possibilities seem remote, the potential reward is high. In defense of this speculation, recent history shows that ‘unlikely’ hypotheses about atherosclerosis and coronary disease often produce unexpected discoveries and benefits. The following is from Geiringer [1]. ‘‘It is a melancholy reflection that a shift of a few millimeters in the anatomical course of the main coronary branches would have resulted in practical immunity from the most common form of coronary vascular accident, that is atherogenic thrombosis. This reflection gains piquancy through the investigations of Chase and Gars who found that while the gorilla and gibbon have an epicardial network of main coronaries, the coronary arteries of the chimpanzee and to a lesser extent of the orangutan tend to run a mural course. Using an outmoded form of expression, it would seem that in this respect at any rate we are descended from the wrong type of ape’’.
.
3
Acknowledgements Generous support for the preparation of this manuscript and related research was provided by the Department of Physiology and Biophysics at the University of Washington, The G. Edgar Folk Jr Fund of the American Physiological Society and especially by Dr Michael Rosenfeld. References [1] Geiringer E. The mural coronary. Am Heart J 1951;41:359–68. [2] Roberts WC, Buja LM. The frequency and significance of coronary artery thrombi and other observations on fatal acute myocardial infarction. A study of 107 necropsy specimens. Am J Med 1972;52:425 – 43. [3] Robicsek F, Thubrikar MJ. The freedom from atherosclerosis of intramyocardial coronary arteries: reduction of mural stress — a key factor. Eur J Cardiothorac Surg 1994;8:228 – 35. [4] Vogel S. Life in moving fluids. Princeton: Princeton University Press, 1994. [5] Glacov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988;112:1018 –31. [6] Ishii T, Hosoda Y, Osaka T, Imai T, Shimada H, Takami A, et al. The significance of myocardial bridge upon atherosclerosis in the left anterior descending coronary artery. J Pathol 1986;148:279 – 91. [7] Davies MG, Hagen PO. Pathophysiology of vein graft failure: a review. Eur J Vasc Endovasc Surg 1995;9:7 – 18. [8] Velican C, Velican D. Natural resistance to atherosclerosis exhibited by the first centimeter of left and right coronary arteries. Atherosclerosis 1984;50:173 – 81. [9] Oki M, Ishitake T, Ohkubo A, Tsunetaka M. Frequency dependence of the suppressive effects of vibration on atherosclerosis in the rabbit. Kurume Med J 1989;36:161 – 6. [10] Kennedy A. Exercise and heart disease: cardiac findings in fatal cycle accidents. Br J Sports Med 1997;31:328 – 31.