EDITORIALS
Hemodynamic Shear Force in Rupture of Coronary Arterial Atherosclerotic Plaques S. David Gertz, MD, PhD, and William C. Roberts, MD
ngiographic and necropsy studies have suggested a direct pathogenetic relation among rupture of a coronary arterial atherosclerotic plaque, coronary thrombus formation, and acute myocardial infarction (AMI).‘-” However, the local pathophysiologic factor or factors responsible for the initiation of plaque rupture have not been identified, Suggestions have included hemorrhage into a plaque after injury to vasa vasora; mechanical compression associated with coronary spasm; increased intraluminal arterial pressure; and circumferential tensile stress on the “fibrous cap” of the plaque. In this article we summarize the evidence for and against each of these theories and present the case for hemodynamic (rheologic) shear forces as a factor in the pathogenesis of plaque rupture. Rupture of vasa vasora: Damage to small vascular channels within atherosclerotic plaques has been suggested by a number of investigators to be a source of plaque hemorrhage,12-15 but none has shown how this might result in plaque rupture. Extravasation of erythrocytes from injury to intraplaque vascular channels is known to occur in large plaques, but this has been distinguished from hemorrhage associated with plaque rupture by the absence in the former of associated fibrin and platelets. I6 Moreover, Constantinides,17 in an analysis of serial sections of 17 cases of fatal coronary thrombosis, showed that the associated plaque hemorrhage could always be traced to an entry of blood from the lumen through the same crack in the plaque. Thus, although intraplaque vascular channels are seen often, it is our experience that they are not seen within lipid-rich pultaceous debris, and there is no evidence that such channels are associated with plaque hemorrhage which accompanies rupture of a coronary atherosclerotic plaque. Plaque compression by coronary vasospasm: Vasoconstriction or spasm has been proposed as a cause of rupture of an atherosclerotic plaque,18-20 but can vasospasm occur in severely narrowed coronary arteries? The dominant histopathologic component of coronary atherosclerotic plaques is fibrous tissue, and, when the luminal narrowing is severe, the underlying media is often severely attenuated. 21,22Nevertheless, angiographic
A
From the Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and The Department of Anatomy and Embryology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel. Manuscript received July 20, 1990, and accepted July 23. Address for reprints: S. David Gertz, MD, Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N258, Bethesda, Maryland 20892. 1368
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
studies, particularly those involving provocative testing with ergonovine maleate, have identified spasm in coronary arteries at, and in close proximity to, sites of severe luminal narrowing.23-27 Recent experimental studies have suggested that sites of atherosclerotic narrowing may be hypercontractile because of possible loss of endothelial-dependent arterial relaxation associated with structural or functional damage to these cells.28,2gJoris and Majno30 and Kurgan et a13’ reported endothelial desquamation after experimental vasospasm induced by periarterial application of L-epinephrine and calcium chloride. Thus, it appears that vasospasm may occur at sites of atherosclerotic stenosis and that vasospasm may be associated with damage to the arterial intima. However, that vasospasm may cause plaque rupture remains an important but still unanswered question. Sudden
increase
in intraluminal
arterial
pressure:
Constantinides reported that intravenous injection of various vasopressor amines, in combination with Russel viper venom, induced thrombus formation associated with plaque fissure and hemorrhage in arteries with advanced atherosclerosis.32,33 It was hypothesized, therefore, that plaque fissures can be produced in mammalian atherosclerotic arteries by a sudden surge of intraluminal pressure in synergy with endothelial damage.17 It can be questioned, however, whether this model provides a sufficiently convincing case for increased intraluminal pressure as a factor in the initiation of plaque rupture, and whether an agent such as Russel viper venom, which can cause endothelial damage, might not by itself contribute to plaque rupture. Increased circumferential tensile stress: Richardson et aP4 recently suggested that the eccentric “pools” of extracellular lipid within the atherosclerotic plaque are associated with increased circumferential tensile stress on the thin residuum of fibrous tissue adjacent to the lumen, particularly during ventricular systole, and that variations in the mechanical strength of the plaque cap, such as that which may result from infiltration of foam cells, might further contribute to the likelihood of rupture at such sites. This hypothesis is based on a computerized reconstruction of the distribution of tensile stress within the arterial wall in response to theoretic elevation of intraluminal pressure. Values for tensile strengths of the various components of the atherosclerotic plaque were obtained from previous studies involving micromechanical testing of samples of intima and media obtained from the coronary arteries of human cadavers. Although the applicability of this model to the biophysical forces generated in vivo in the highly pulsatile coronary arterial system may be questioned, this study pro-
vides valuable information concerning the potential for components of the atherosclerotic plaque to yield in response to increased lateral pressure forces, which are well within the realm of physiologic possibility. In the following discussion we present evidence supporting hemodynamic shear forces as a major factor in the initiation of plaque rupture.
Atherosclerotic Plaque for All Segments (5-mm Intervals) the infarct-Related Coronary Arteries of 17 Patients with
Plaque rupture involves plaques heavily laden with extracellular lipid material (pultaceous debris) covered by a thin residuum of fibrous tissue (cap) adjacent to the lumen.‘6x34m36 Morphometric analysis (performed
by a computerized technique described elsewhere22) of Movat-stained sections of the infarct-related coronary arteries of patients who died after their first acute myocardial infarction showed the atherosclerotic plaques at sites of plaque rupture to consist of about 32% pultaceous debris, whereas plaques not associated with rupture contained approximately 5% pultaceous debris (Table I). Although plaque rupture occurs at sites of luminal narrowing, the degree of narrowing is usually insufficient to reduce the rate of distal coronary blood flow.
Histologic study of Movat-stained sections from 101 five-mm-long segments at sites of plaque rupture in the infarct-related arteries of 37 patients with first and fatal acute myocardial infarction showed the lumen to be narrowed by 5 1 to 75% in cross-sectional area by plaque in 27 (27%) segments; by 76 to 95% in 66 (65%) segments; and by 96 to 100% in 5 (5%) segments37 (Figure 1). By planimetry, with the internal elastic lamina as the perimeter of the luminal circle, the mean percent reduction in luminal cross-sectional area by atherosclerotic plaque alone (of all S-mm coronary segments) at sites of plaque rupture was 81 f 9%. Although the latter is significantly greater than the mean percent crosssectional narrowing of all segments of the infarct-relat-
Fibrous Tissue
Calcifz Deposits
772~13
14f13
69f15
15i15
Pultaceous
5f5
of
Debris
12410
ed arteries that did not have plaque rupture (68 f 9%, p = 0.002), this “severe” degree of cross-sectional narrowing corresponds, if considering a perfect circle, to approximately 56% reduction in transluminal diameter by plaque alone, which is insufficient, by itself, to reduce the rate of distal coronary flow substantially. This observation is supported by the necropsy studies of Falk,5 which show that, of 103 sites of plaque rupture, the lumen was narrowed, in cross-sectional area, by 94% at only 12 (12%) sites of plaque rupture. From quantitative high-resolution angiographic studies, the “critical stenosis,” beyond which coronary flow is sufficiently reduced to cause symptoms, has been determined to range between 70 and 80% reduction in luminal diameter, which corresponds to approximately 90 to 95% reduction in cross-sectional area.3s Because angiographic images may underestimate the degree of diameter reduction, in that the most narrowed areas are compared to less narrowed and not necessarily normal areas,39 the degree of actual diameter reduction necessary to result in critical reduction in flow might be even greater (Figure 2). In contrast, techniques of specimen preparation for histopathologic study, such as fixation l____ll_l-~-~-
.
.
.
.
.
.
.
.
.
.
.
.
.
.
..^....._.._._.______...____..____._.
ANGlOGRAPHIC VIEW
. . . . . . . . . . . .. . . .._.._...__..._._.______._._........
HISTOLOGIC VIEW
RIGORS 1. Seventy-five percent area ~~~~s~~ds to approximately
reduction 50%
in ~ross-~ti~~aS diameter reduction.
MIGUEL 2. ~ompa~son between views of ~urni~al fla~owim~*
THE AMERICAN
JOURNAL
OF CARDIOLOGY
angiographic
DECEMBER
and drossy
1. 1990
and dehydration, may cause tissue shrinkage and, hence, slight overestimation of absolute values of luminal narrowing.40 Angiographic studies have suggested that the degree of stenosis of infarct-related coronary arteries is not a reliable predictor of the time or location of future myocardial infarcts, and that infarcts frequently develop in association with coronary arteries that previously were not severely narrowed.41,42 It can be argued that the hypothesis-that coronary arteries subtending a myocardial infarct frequently are not critically narrowed-is not strongly supported by the latter studies, because they were based on angiograms performed weeks to years before the infarction, and these images may underestimate the degree of diameter reduction.3g Nonetheless, we and others have found the lumen at sites of plaque rupture frequently to be narrowed by
Hemodynamic Shear Force in Rupture of Coronary Arterial Atherosclerotic Plaques S. David Gertz, MD, PhD, and William C. Roberts, MD
ngiographic and necropsy studies have suggested a direct pathogenetic relation among rupture of a coronary arterial atherosclerotic plaque, coronary thrombus formation, and acute myocardial infarction (AMI).‘-” However, the local pathophysiologic factor or factors responsible for the initiation of plaque rupture have not been identified, Suggestions have included hemorrhage into a plaque after injury to vasa vasora; mechanical compression associated with coronary spasm; increased intraluminal arterial pressure; and circumferential tensile stress on the “fibrous cap” of the plaque. In this article we summarize the evidence for and against each of these theories and present the case for hemodynamic (rheologic) shear forces as a factor in the pathogenesis of plaque rupture. Rupture of vasa vasora: Damage to small vascular channels within atherosclerotic plaques has been suggested by a number of investigators to be a source of plaque hemorrhage,12-15 but none has shown how this might result in plaque rupture. Extravasation of erythrocytes from injury to intraplaque vascular channels is known to occur in large plaques, but this has been distinguished from hemorrhage associated with plaque rupture by the absence in the former of associated fibrin and platelets. I6 Moreover, Constantinides,17 in an analysis of serial sections of 17 cases of fatal coronary thrombosis, showed that the associated plaque hemorrhage could always be traced to an entry of blood from the lumen through the same crack in the plaque. Thus, although intraplaque vascular channels are seen often, it is our experience that they are not seen within lipid-rich pultaceous debris, and there is no evidence that such channels are associated with plaque hemorrhage which accompanies rupture of a coronary atherosclerotic plaque. Plaque compression by coronary vasospasm: Vasoconstriction or spasm has been proposed as a cause of rupture of an atherosclerotic plaque,18-20 but can vasospasm occur in severely narrowed coronary arteries? The dominant histopathologic component of coronary atherosclerotic plaques is fibrous tissue, and, when the luminal narrowing is severe, the underlying media is often severely attenuated. 21,22Nevertheless, angiographic
A
From the Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and The Department of Anatomy and Embryology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel. Manuscript received July 20, 1990, and accepted July 23. Address for reprints: S. David Gertz, MD, Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N258, Bethesda, Maryland 20892. 1368
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
studies, particularly those involving provocative testing with ergonovine maleate, have identified spasm in coronary arteries at, and in close proximity to, sites of severe luminal narrowing.23-27 Recent experimental studies have suggested that sites of atherosclerotic narrowing may be hypercontractile because of possible loss of endothelial-dependent arterial relaxation associated with structural or functional damage to these cells.28,2gJoris and Majno30 and Kurgan et a13’ reported endothelial desquamation after experimental vasospasm induced by periarterial application of L-epinephrine and calcium chloride. Thus, it appears that vasospasm may occur at sites of atherosclerotic stenosis and that vasospasm may be associated with damage to the arterial intima. However, that vasospasm may cause plaque rupture remains an important but still unanswered question. Sudden
increase
in intraluminal
arterial
pressure:
Constantinides reported that intravenous injection of various vasopressor amines, in combination with Russel viper venom, induced thrombus formation associated with plaque fissure and hemorrhage in arteries with advanced atherosclerosis.32,33 It was hypothesized, therefore, that plaque fissures can be produced in mammalian atherosclerotic arteries by a sudden surge of intraluminal pressure in synergy with endothelial damage.17 It can be questioned, however, whether this model provides a sufficiently convincing case for increased intraluminal pressure as a factor in the initiation of plaque rupture, and whether an agent such as Russel viper venom, which can cause endothelial damage, might not by itself contribute to plaque rupture. Increased circumferential tensile stress: Richardson et aP4 recently suggested that the eccentric “pools” of extracellular lipid within the atherosclerotic plaque are associated with increased circumferential tensile stress on the thin residuum of fibrous tissue adjacent to the lumen, particularly during ventricular systole, and that variations in the mechanical strength of the plaque cap, such as that which may result from infiltration of foam cells, might further contribute to the likelihood of rupture at such sites. This hypothesis is based on a computerized reconstruction of the distribution of tensile stress within the arterial wall in response to theoretic elevation of intraluminal pressure. Values for tensile strengths of the various components of the atherosclerotic plaque were obtained from previous studies involving micromechanical testing of samples of intima and media obtained from the coronary arteries of human cadavers. Although the applicability of this model to the biophysical forces generated in vivo in the highly pulsatile coronary arterial system may be questioned, this study pro-
vides valuable information concerning the potential for components of the atherosclerotic plaque to yield in response to increased lateral pressure forces, which are well within the realm of physiologic possibility. In the following discussion we present evidence supporting hemodynamic shear forces as a major factor in the initiation of plaque rupture.
Atherosclerotic Plaque for All Segments (5-mm Intervals) the infarct-Related Coronary Arteries of 17 Patients with
Plaque rupture involves plaques heavily laden with extracellular lipid material (pultaceous debris) covered by a thin residuum of fibrous tissue (cap) adjacent to the lumen.‘6x34m36 Morphometric analysis (performed
by a computerized technique described elsewhere22) of Movat-stained sections of the infarct-related coronary arteries of patients who died after their first acute myocardial infarction showed the atherosclerotic plaques at sites of plaque rupture to consist of about 32% pultaceous debris, whereas plaques not associated with rupture contained approximately 5% pultaceous debris (Table I). Although plaque rupture occurs at sites of luminal narrowing, the degree of narrowing is usually insufficient to reduce the rate of distal coronary blood flow.
Histologic study of Movat-stained sections from 101 five-mm-long segments at sites of plaque rupture in the infarct-related arteries of 37 patients with first and fatal acute myocardial infarction showed the lumen to be narrowed by 5 1 to 75% in cross-sectional area by plaque in 27 (27%) segments; by 76 to 95% in 66 (65%) segments; and by 96 to 100% in 5 (5%) segments37 (Figure 1). By planimetry, with the internal elastic lamina as the perimeter of the luminal circle, the mean percent reduction in luminal cross-sectional area by atherosclerotic plaque alone (of all S-mm coronary segments) at sites of plaque rupture was 81 f 9%. Although the latter is significantly greater than the mean percent crosssectional narrowing of all segments of the infarct-relat-
Fibrous Tissue
Calcifz Deposits
772~13
14f13
69f15
15i15
Pultaceous
5f5
of
Debris
12410
ed arteries that did not have plaque rupture (68 f 9%, p = 0.002), this “severe” degree of cross-sectional narrowing corresponds, if considering a perfect circle, to approximately 56% reduction in transluminal diameter by plaque alone, which is insufficient, by itself, to reduce the rate of distal coronary flow substantially. This observation is supported by the necropsy studies of Falk,5 which show that, of 103 sites of plaque rupture, the lumen was narrowed, in cross-sectional area, by 94% at only 12 (12%) sites of plaque rupture. From quantitative high-resolution angiographic studies, the “critical stenosis,” beyond which coronary flow is sufficiently reduced to cause symptoms, has been determined to range between 70 and 80% reduction in luminal diameter, which corresponds to approximately 90 to 95% reduction in cross-sectional area.3s Because angiographic images may underestimate the degree of diameter reduction, in that the most narrowed areas are compared to less narrowed and not necessarily normal areas,39 the degree of actual diameter reduction necessary to result in critical reduction in flow might be even greater (Figure 2). In contrast, techniques of specimen preparation for histopathologic study, such as fixation l____ll_l-~-~-
.
.
.
.
.
.
.
.
.
.
.
.
.
.
..^....._.._._.______...____..____._.
ANGlOGRAPHIC VIEW
. . . . . . . . . . . .. . . .._.._...__..._._.______._._........
HISTOLOGIC VIEW
RIGORS 1. Seventy-five percent area ~~~~s~~ds to approximately
reduction 50%
in ~ross-~ti~~aS diameter reduction.
MIGUEL 2. ~ompa~son between views of ~urni~al fla~owim~*
THE AMERICAN
JOURNAL
OF CARDIOLOGY
angiographic
DECEMBER
and drossy
1. 1990
and dehydration, may cause tissue shrinkage and, hence, slight overestimation of absolute values of luminal narrowing.40 Angiographic studies have suggested that the degree of stenosis of infarct-related coronary arteries is not a reliable predictor of the time or location of future myocardial infarcts, and that infarcts frequently develop in association with coronary arteries that previously were not severely narrowed.41,42 It can be argued that the hypothesis-that coronary arteries subtending a myocardial infarct frequently are not critically narrowed-is not strongly supported by the latter studies, because they were based on angiograms performed weeks to years before the infarction, and these images may underestimate the degree of diameter reduction.3g Nonetheless, we and others have found the lumen at sites of plaque rupture frequently to be narrowed by
