Seymour Glagov

Compensatory Enlargement of Human Atherosclerotic Coronary Arteries

Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histologic sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement preserves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r = 0.44, P less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area = 9.26 + 0.88 (lesion area) + 0.026 (age) + 0.005 (heart weight). The correlation coefficient for the lesion area was significant (P less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of stenosis (lesion area/internal elastic lamina area X 100) for values between zero and 40 percent but did diminish markedly and in close relation to the percentage of stenosis for values above 40 percent (r = -0.73, P less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40 percent of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography.

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesion progression. The initial (type 1) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress.

The distribution of nonstenosing, asymptomatic intimal plaques in 12 adult human carotid bifurcations obtained at autopsy was compared with the distribution of flow streamline patterns, flow velocity profiles, and shear stresses in corresponding scale models. The postmortem specimens were fixed while distended to restore normal in vivo length, diameter, and configura- tion. Angiograms were used to measure branch angles and diameters, and transverse histological sections were studied at five standard sampling levels. Intimal thickness was determined at 15° intervals around the circumference of the vessel sections from contour tracings of images projected onto a digitizing plate. In the models, laser-Doppler anemometry was used to determine flow velocity profiles and shear stresses at levels corresponding to the standard specimen sampling sites under conditions of steady flow at Reynolds numbers of 400, 800, and 1200, and flow patterns were visualized by hydrogen bubble and dye-washout techniques. Intimal thickening was greatest and consistently eccentric in the carotid sinus. With the center of the flow divider as the 0° index point, mid-sinus sections showed minimum intimal thickness (0.05 ± 0.02 mm) within 15° of the index point, while maximum thickness (0.9 ± 0.1 mm) occurred at 161 ± 16°, i.e., on the outer wall opposite the flow divider. Where the intima was thinnest, along the inner wall, flow streamlines in the model remain axially aligned and unidirectional, with velocity maxima shifted toward the flow divider apex. Wall shear stress along the inner wall ranged from 31 to 600 dynes/cm2 depending on the Reynolds number. Where the intima was thickest, along the outer wall opposite the flow divider apex, the pattern of flow was complex and included a region of separation and reversal of axial flow as well as the development of counter-rotating helical trajectories. Wall shear stress along the outer wall ranged from 0 to —6 dynes/cm2. Intimal thickening at the common carotid and distal internal carotid levels of section was minimal and was distributed uniformly about the circumference. We conclude that in the human carotid bifurcation, regions of moderate to high shear stress, where flow remains unidirectional and axially aligned, are relatively spared of intimal thickening. Intimal thickening and atherosclerosis develop largely in regions of relatively low wall shear stress, flow separation, and departure from axially aligned, unidirectional flow. Similar quantitative evaluations of other atherosclerosis-prone locations and corresponding flow profile studies in geometrically accurate models may reveal which of these hemodynamic conditions are most consistently associated with the development of intimal disease.

A Lamellar Unit of Aortic Medial Structure and Function in Mammals

The close association of elastin, collagen, and smooth muscle in the mammalian aortic media results in viscoelastic properties that account for many of its static and dynamic mechanical features. The structural components of the media are precisely oriented in concentric layers, or lamellar units, of fairly uniform composition. A comparative study of the adult thoracic aorta in 10 mammalian species, including 15 canine breeds, showed that the number of lamellar units in the media of adult mammalian aortas is very nearly proportional to aortic radius regardless of species or variations in measured wall thickness. Estimated wall tensions ranged from 7,820 dynes/cm in a 28-g mouse to 203,000 dynes/cm in a 200,000-g sow, but the average tension per lamellar unit of an aortic media was remarkably constant regardless of species, ranging from 1,090 to 3,010 dynes/cm. The findings suggest that the elastin lamella and the contents of its adjacent interlamellar zone represent the unit of structure and function of the mammalian aortic wall.

Shear stress regulation of artery lumen diameter in experimental atherogenesis

We studied the adaptive response of the arterial wall and intimal thickening under conditions of increased flow in an atherogenic model. Blood flow was increased by construction of an arteriovenous fistula between the right iliac artery and vein in six cynomolgus monkeys fed a diet containing 2% cholesterol and 25% peanut oil. The left iliac artery served as the control. Serum cholesterol increased from 135 +/- 22 mg/dl to 880 +/- 129 mg/dl during the experiment. After 6 months, blood flow in the right iliac artery (420 +/- 95 ml/min) was 10 times greater than in the left iliac artery (44 +/- 9 ml/min, p less than 0.005). Flow velocity in the right iliac artery (31 +/- 6 cm/sec) was more than twofold greater than in the left (12 +/- 1 cm/sec, p less than 0.05). Despite the marked difference in blood flow and flow velocity, calculated wall shear stress was the same in both the right (16 +/- 4 dynes/cm2) and left iliac vessels (15 +/- 2 dynes/cm2) because of a twofold increase in lumen diameter (p less than 0.001) of the right iliac artery. Shear stress in the aorta was also normal (12 +/- 2 dynes/cm2). There was no difference in plaque deposition or mean intimal thickness between the right and left iliac arteries. In the right iliac artery there was a twofold increase in media cross-sectional area (p less than 0.001) but no change in media thickness or total wall thickness. Tangential wall tension and tangential wall stress were two times greater on the right than on the left (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Structural Basis for the Static Mechanical Properties of the Aortic Media

The arrangement and interrelation of the structural components of the rabbit aorta were studied by light and electron microscopy. Segments of abdominal aorta were restored to in vivo length and fixed in formalin or osmic acid while intraluminal pressures ranging from 0 to 200 mm Hg were maintained by a constant pressure perfusion apparatus. Transverse, longitudinal, and tangential sections of vessels fixed at various distending pressures were examined. Micrometric measurements included vessel diameters and wall thickness, thickness and waviness of elastin lamellae and interlamellar distances. With increasing pressures below the diastolic value, aortic radius increased and wall thickness decreased rapidly. Waviness of the tubular elastin lamellae decreased uniformly throughout the wall. Interlamellar distances decreased uniformly and markedly. Lamellar thicknesses decreased uniformly but much less than interlamellar distances. A fine fibrillary elastin network connected the thick lamellae. Collagen fibers showed no definite pattern of orientation. At and above diastolic pressure radius and wall thickness changed little with increasing pressures. Elastin lamellae were straight and interlamellar distances were uniform; the fibrils of the interlamellar elastin net were arranged obliquely. Collagen fibers were arranged nearly circumferentially. Collagen and elastin fibers were closely intermingled in the narrow interlamellar space but no collagen-elastin connections were obserevd. The mechanical properties and organization of the collagen and elastin components of the aortic media indicate that the wall normally functions as a “two-phase” material. At and above physiological pressures, circumferentially aligned collagen fibers of high tensile strength and relatively high modulus of elasticity bear most of the stressing force. Elastin lamellae and fibrils of relatively low modulus of elasticity distribute stressing forces uniformly. Attempts to assess the role of medial pressure and tension gradients in the pathogenesis of aortic disease must take into account the special mechanical properties of this “two-phase” material.

The Role of Fluid Mechanics in the Localization and Detection of Atherosclerosis

Fluid dynamics research over the past twenty years has contributed immensely to our knowledge of atherosclerosis. The ability to detect localized atherosclerotic plaques using noninvasive ultrasonic methods was advanced significantly by investigations into the nature and occurrence of velocity disturbances created by arterial stenoses, and diagnosis of carotid bifurcation disease using a combination of ultrasonic imaging and Doppler measurement of blood velocity is now quite routine. Since atherosclerotic plaques tend to be localized at sites of branching and artery curvature and since these locations would be expected to harbor complex flow patterns, investigators postulated that fluid dynamics might play an initiating role in atherogenesis. Several fluid dynamic variables were proposed as initiating factors. Investigations were undertaken during the 1980s in which fluid dynamic model experiments with physiologic geometries and flow conditions were employed to simulate arterial flows and in which morphometric mapping of intimal thickness was performed in human arteries. Correlations between fluid dynamic variables and intimal thickness revealed that atherosclerotic plaques tended to occur at sites of low and oscillating wall shear stress; and these observations were reinforced by studies in a monkey model of atherosclerosis. Concomitantly, it was realized that arteries adapt their diameters so as to maintain wall shear stress in a narrow range of values around 15 dynes/cm2, findings which were based both on observations of normal arteries and on animal studies in which flow rates were manipulated and arterial diameter adaptation was measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomotic intimal hyperplasia: Mechanical injury or flow induced

All anastomotic intimal thickening may not be the same, and the underlying mechanism(s) regulating the different types may vary. We investigated the localization of experimental anastomotic intimal thickening in relation to known biomechanical and hemodynamic factors. Bilateral iliofemoral saphenous vein and polytetrafluoroethylene grafts were implanted in 13 mongrel dogs. The distal end-to-side anastomotic geometry was standardized, and the flow parameters were measured. After 8 weeks, seven of 10 animals (group I) with patent grafts were killed and the anastomoses fixed by perfusion. Histologic sections from each anastomosis were studied with light microscopy, and regions of intimal thickening were identified and quantitated with use of oculomicrometry. To characterize the anastomotic flow patterns, transparent silicone models were constructed from castings of the distal anastomosis of three animals (group II), and flow was visualized with use of helium-neon laser-illuminated particles under conditions simulating the in vivo pulsatile flow parameters. Histologic sections revealed two separate and distinct regions of anastomotic intimal thickening. The first, suture line intimal thickening, was greater in polytetrafluoroethylene anastomoses (0.35 +/- 0.23 microns) than in vein anastomoses (0.15 +/- 0.03 microns, p less than 0.05). The second distinct type of intimal thickening developed on the arterial floor and was the same in polytetrafluoroethylene (0.11 +/- 0.11 microns) and vein anastomoses (0.12 +/- 0.03 microns). Model flow visualization studies revealed a flow stagnation point along the arterial floor resulting in a region of low and oscillating shear where the second type of intimal thickening developed. High shear and short particle residence time were observed along the hood of the graft, an area devoid of intimal thickening.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis

Clinically significant atherosclerosis in the human aorta is most common in the infrarenal segment. This study was initiated to test the hypothesis that flowfield properties are closely related to the localization of plaques in this segment of the arterial system. Wall shear stress was calculated from magnetic resonance velocity measurements of pulsatile flow in an anatomically accurate model of the human abdominal aorta. The wall shear stress values were compared with intimal thickening from 15 post-mortem aortas measured by quantitative morphometry of histological cross sections obtained at standard locations. Wall shear stress oscillated in direction throughout most of the infrarenal aorta, most prominently in the distal region. The time-averaged mean wall shear stress (-1.7 to 1.4 dyn/cm2) was lowest near the posterior wall in this region. These hemodynamic parameters coincided with the locations of maximal intimal thickening. Statistical correlation between oscillatory shear and intimal thickness yielded r = 0.79, P < 0.00001. Low mean shear stresses correlated nearly as well (r = -0.75, P < 0.00005). Comparison of our data with surface maps of Sudan Red staining and early lesions as reported by others revealed similar conclusions. In contrast, pulse and maximum shear stresses did not correlate with plaque localization as has been shown for other sites of selective involvement by atherosclerosis (r < 0.345). Simulated exercise conditions markedly changed the magnitude and pattern of wall shear stress in the distal abdominal aorta. These results demonstrate that in the infrarenal aorta, regions of low mean and oscillating wall shear stresses are predisposed to the development of plaque while regions of relatively high wall shear stress tend to be spared.

Nature of Species Differences in the Medial Distribution of Aortic Vasa Vasorum in Mammals

Thoracic aortic segments of 12 mammalian species were fixed while distended at normal physiological pressures after the vasa vasorum were filled by a perfusion mixture containing gelatin and carbon. Mammals whose aortas had 29 or fewer medial lamellar units had no demonstrable intramural vascular channels; those whose aortas had more than 29 medial lamellar units, had medial vasa. Aortas with medial vasa vasorum always had a subintimal medial zone devoid of vasa vasorum. In growing animals the width of this avascular zone increased with age; in adults, the width increased slightly with increasing species body weight. However, the number of lamellar units in the avascular zone was independent of both age and species and equal to 29.0 ± 2.5. All of the species with intramural aortic vasa vasorum as adults had 29 or more aortic medial lamellar units at birth; none of the species which had 29 or fewer lamellar units at birth had more than 29 lamellar units at maturity. In aortas with medial vasa vasorum, widening of the avascular zone during growth appeared to be due only to the uniform thickening of each of the approximately 29 lamellar units already present at birth; the vascularized outer zone widened both by enlargement of its lamellar units and the addition of new lamellar units. Species differences in medial distribution of vasa vasorum are due primarily to differences in thickness of the vascularized outer zone.