Howard M. Loree

Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation

Background. Although rupture of an atherosclerotic plaque is considered to be the cause of most acute coronary syndromes, the mechanism of plaque rupture is controversial. Methods and Results. To test the hypothesis that plaque rupture occurs at sites of high circumferential stress in the diseased vessel, the distribution of stress was analyzed in 24 coronary artery lesions. Histological specimens from 12 coronary artery lesions that caused lethal myocardial infarction were compared with those from 12 stable control lesions. A finite element model was used to calculate the stress distributions at a mean intraluminal pressure of 110 mm Hg. The maximum circumferential stress in plaques that ruptured was significantly higher than maximum stress in stable specimens (4,091±1,199 versus 1,444±485 mm Hg, p<0.0001). Twelve of 12 ruptured lesions had a total of 31 regions of stress concentration of more than 2,250 mm Hg (mean, 2.6±1.4 high stress regions per lesion); only one of 12 control lesions had a single stress concentration region of more than 2,250 mm Hg. In seven of 12 lethal lesions (58%), rupture occurred in the region of maximum circumferential stress; in 10 of the 12 lethal lesions (83%), rupture occurred in a region where computed stress was more than 2,250 mm Hg. Conclusions. These data suggest that concentrations of circumferential tensile stress in the atherosclerotic plaque may play an important role in plaque rupture and myocardial infarction. However, plaque rupture may not always occur at the region of highest stress, suggesting that local variations in plaque material properties contribute to plaque rupture. (Circulation 1993;87:1179‐1187)

Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels.

It is likely that factors other than stenosis severity predispose some atherosclerotic plaques to rupture. Because focal increases in circumferential stress may be an important mechanism of plaque rupture, we examined peak circumferential stress of atherosclerotic lesions by using finite element analysis based on idealized two-dimensional cross sections of diseased vessels similar to intravascular ultrasound images. The study was designed to test the hypothesis that subintimal plaque structural features such as thickness of the fibrous cap are more important factors in the distribution of stress in the plaque than stenosis severity. The analysis incorporated equilibrium biomechanical parameters from normal and diseased vessels and determined the stress distribution within the plaque at a mean luminal internal pressure of 110 mm Hg. With a constant luminal area reduction of 70%, maximum circumferential stress (sigma max) normalized to luminal pressure (sigma max/P) increased from 6.0 to 24.8 as the thickness of the lipid pool was increased from 38% to 54% of the plaque thickness because of the thinner fibrous cap over the lipid pool. When the lipid pool thickness was constant, increasing the stenosis severity from 70% to 91% by increasing the fibrous cap thickness decreased sigma max/P from 24.8 to 4.7. When no lipid pool was present and the stenosis severity was increased from 70% to 99%, sigma max/P decreased from 5.3 to 4.7. Thus, reducing the fibrous cap thickness dramatically increases peak circumferential stress in the plaque, whereas increasing the stenosis severity actually decreases peak stress in the plaque.(ABSTRACT TRUNCATED AT 250 WORDS)

Circumferential Stress and Matrix Metalloproteinase 1 in Human Coronary Atherosclerosis Implications for Plaque Rupture

Atherosclerotic plaque rupture may occur when regions of weakened extracellular matrix are subjected to increased mechanical stresses. Since collagen is a major determinant of extracellular matrix strength, enzymes that degrade collagen may play an important role in destabilizing the atherosclerotic lesion. To test the hypothesis that matrix metalloproteinase 1 (interstitial collagenase, or MMP-1), which initiates degradation of fibrillar collagens, colocalizes with increased stress in the fibrous cap of the atherosclerotic lesion, 12 unruptured human coronary lesions were studied. Finite-element analysis was used to determine the distribution of stress in the lesion, with estimates of material properties from previous measurements of human tissues. A computerized image analysis system was used to determine the distribution of immunoreactive MMP-1 within the fibrous tissue of the lesion. There was a significant correlation between immunoreactive MMP-1 and circumferential tensile stress in the fibrous cap within a given lesion (median Spearman rank correlation coefficient, .36; interquartile range, -.02 to .81; P < .02). Within a given lesion, the highest-stress region had twofold greater MMP-1 expression than the lowest-stress regions. In unruptured human atherosclerotic coronary lesions, overexpression of MMP-1 is associated with increased circumferential stress in the fibrous plaque. Degradation and weakening of the collagenous extracellular matrix at these critical high-stress regions may play a role in the pathogenesis of plaque rupture and acute ischemic syndromes.

Mechanical properties of model atherosclerotic lesion lipid pools.

Structural analysis of atherosclerotic coronary arteries has suggested that stress concentrations are associated with plaque rupture and that these stress concentrations are critically dependent on the geometry and mechanical properties of the fibrous cap and lipid pool. Recent clinical trials of lipid-lowering therapy have shown a significant reduction in cardiac events associated with plaque rupture perhaps because of the changing composition of subintimal lipid pools. To test the hypothesis that changes in lipid composition can change the mechanical properties of lipid pools, we measured the dynamic shear moduli of combinations of cholesterol monohydrate crystals, phospholipids, and triglycerides similar to those found in atherosclerotic lesions. Increasing the cholesterol monohydrate concentration from 0% to 50% increased the real component of the dynamic shear modulus (storage modulus or stiffness) by 4.5 times at a frequency of 1 Hz (P < .001). All specimens demonstrated an increase in stiffness with increasing frequencies of stress ranging from 0.1 to 3 Hz. We conclude that the stiffness of model atherosclerotic plaque lipid pools is related to the concentration of cholesterol monohydrate crystals. Because the relative concentration of cholesterol monohydrate increases during early regression of experimental atherosclerosis, the resultant stiffening of the lipid pool may reduce stresses in plaque caps. However, the magnitude of the contribution of changing lipid stiffness to the reduction of cardiac events seen in clinical studies is unclear.

Static circumferential tangential modulus of human atherosclerotic tissue

The mechanical properties of atherosclerotic plaque may be of critical importance to the processes of plaque rupture, the most common antecedent of myocardial infarction. To investigate the effects of plaque structure and applied tensile stress on the static circumferential tangential modulus of atherosclerotic plaque, the stress-strain behavior of 26 human aortic intimal plaques was studied. Intimal plaques were collected during routine autopsies of 21 patients from the abdominal (n = 19) and thoracic (n = 2) aorta and were classified by histological analysis as cellular (n = 12), hypocellular (n = 9), and calcified (n = 5). At a physiologic applied circumferential tensile stress of 25 kPa, the tangential moduli of cellular, hypocellular, and calcified specimens were 927 +/- 468 kPa, 2312 +/- 2180 kPa, and 1466 +/- 1284 kPa, respectively. There was a nonsignificant difference in tangential modulus at 25 kPa stress between specimens classified as cellular and hypocellular (p = 0.098), cellular and calcified (p = 0.410), and hypocellular and calcified (p = 0.380). This is in marked contrast to the previously measured radial compressive behavior of plaque tissue, which showed that cellular, hypocellular, and calcified plaques were significantly different in their modulus. In tension, all 26 plaques tested demonstrated a statistically significant increase in tangential modulus with increasing applied circumferential stress. We conclude that the static circumferential tangential modulus of atherosclerotic plaque, unlike its radial compressive modulus, is not significantly affected by the degree of cellularity and calcification determined by histological characterization.(ABSTRACT TRUNCATED AT 250 WORDS)

Computational structural analysis based on intravascular ultrasound imaging before in vitro angioplasty: Prediction of plaque fracture locations

OBJECTIVES This in vitro study was designed to test the hypothesis that a structural analysis based on intravascular ultrasound images of atherosclerotic vessels obtained before angioplasty can be used to predict plaque fracture locations and balloon pressures required to cause fracture. BACKGROUND Intravascular ultrasound imaging performed before interventional procedures has potential for providing information useful for guiding therapeutic strategies. METHODS Intravascular imaging was performed on 16 atherosclerotic human iliac vessel segments obtained freshly at autopsy; balloon angioplasty was then performed with 1-min inflations at 2 atm, increasing in 2-atm increments until fracture of the lumen surface occurred. Fracture locations were confirmed by histopathologic examination. Structural analysis of these images was performed with a large strain finite element analysis of the image that calculated the distribution of stress in the vessel with 2 atm of lumen pressure. RESULTS Structural analysis demonstrated a total of 30 high circumferential stress regions in the vessels (mean 1.9 high stress regions/vessel). A total of 18 plaque fractures occurred in the 16 vessel segments. Of the 17 fractures that occurred in the 15 specimens with regions of high circumferential stress, 14 (82%) occurred at a high stress region (p < 0.0001). However, there was no significant relation between the peak stresses estimated by structural analysis and the ultimate balloon inflation pressure required to cause fracture. CONCLUSIONS Structural analysis based on intravascular ultrasound imaging performed before in vitro balloon angioplasty can predict the locations of plaque fracture that usually accompany angioplasty. However, these data suggest that intravascular ultrasound may not be useful for predicting the ultimate balloon inflation pressure necessary to cause fracture, possibly because of the variable fracture properties and microscopic structure of atherosclerotic tissues.

Prediction of mechanical properties of human atherosclerotic tissue by high-frequency intravascular ultrasound imaging. An in vitro study.

Intravascular ultrasound may be useful for studying the natural history of atherosclerotic lesions of different morphologies and for guiding interventional strategies. This study was designed to test the hypothesis that tissue appearance by intravascular ultrasound is related to the biomechanical properties of atheroma components. Forty-three atheroma caps were obtained from the abdominal aortas of 22 patients at autopsy and studied with an ultrasensitive, servo-controlled spectrometer. By measuring the static strain caused by increasing levels of compressive stress from 30 to 90 mm Hg, the uniaxial unconfined compression stiffness (ratio of stress to strain) was determined. After mechanical testing, specimens were imaged with a 6F, 20-MHz intravascular ultrasound transducer, and images were interpreted by an investigator who was unaware of the mechanical measurements. Specimens were classified as nonfibrous (n = 14), fibrous (n = 18), or calcified (n = 11) based on intravascular ultrasound appearance. The static stiffnesses of the nonfibrous, fibrous, and calcified ultrasound classes were 41.2 +/- 18.8 kPa, 81.7 +/- 33.2 kPa, and 354.5 +/- 245.4 kPa, respectively (p = 0.0002 by analysis of variance). The times to reach static equilibrium (creep time) for the nonfibrous, fibrous, and calcified classes were 79.6 +/- 26.5 minutes, 50.2 +/- 20.0 minutes, and 19.4 +/- 8.1 minutes, respectively (p = 0.0007). Intravascular ultrasound appearance was most significantly related to biomechanical behavior when calcium deposits were noted; the differences in biomechanical behavior between nonfibrous and fibrous tissue appearances were less apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of mechanical properties of human atherosclerotic tissue by high-frequency intravascular ultrasound imaging

Intravascular ultrasound may be useful for studying the natural history of atherosclerotic lesions of different morphologies and for guiding interventional strategies. This study was designed to test the hypothesis that tissue appearance by intravascular ultrasound is related to the biomechanical properties of atheroma components. Forty-three atheroma caps were obtained from the abdominal aortas of 22 patients at autopsy and studied with an ultrasensitive, servo-controlled spectrometer. By measuring the static strain caused by increasing levels of compressive stress from 30 to 90 mm Hg, the uniaxial unconfined compression stiffness (ratio of stress to strain) was determined. After mechanical testing, specimens were imaged with a 6F, 20-MHz intravascular ultrasound transducer, and images were interpreted by an investigator who was unaware of the mechanical measurements. Specimens were classified as nonfibrous (n = 14), fibrous (n = 18), or calcified (n = 11) based on intravascular ultrasound appearance. The static stiffnesses of the nonfibrous, fibrous, and calcified ultrasound classes were 41.2 +/- 18.8 kPa, 81.7 +/- 33.2 kPa, and 354.5 +/- 245.4 kPa, respectively (p = 0.0002 by analysis of variance). The times to reach static equilibrium (creep time) for the nonfibrous, fibrous, and calcified classes were 79.6 +/- 26.5 minutes, 50.2 +/- 20.0 minutes, and 19.4 +/- 8.1 minutes, respectively (p = 0.0007). Intravascular ultrasound appearance was most significantly related to biomechanical behavior when calcium deposits were noted; the differences in biomechanical behavior between nonfibrous and fibrous tissue appearances were less apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological Study of Recovery of Peripheral Nerves Regenerated by a Collagen-Glycosaminoglycan Copolymer Matrix

We have studied the effects of variations in the structure of a collagen-glycosaminoglycan (CG) copolymer matrix on the regeneration of transected rat sciatic nerves. Silicone tubes ensheathing 10-mm lengths of CG copolymer were grafted between the transected sciatic nerve stumps. Empty and saline-filled silicone tubes, as well as autografts, were studied as controls. The mean pore diameter and the degradation rate of the copolymer in collagenase were independently varied to investigate how each affects regeneration. Electrophysiological properties of the regenerating motor nerve fibers innervating the plantar flexor muscles, were serially monitored over about 40 weeks following surgery. Rapidly degrading CG copolymers with pore channels oriented predominantly along the axes of the tubes induced regeneration with a success rate of 100% (n = 35). Although CG copolymers with axially-oriented pore channels that degraded slowly had a success rate as high as 96% (n = 23), the long-term electrophysiological results were markedly inferior to those obtained with the rapidly degrading grafts. In another study of axially-oriented pore structures, the level of recovery of long-term electrophysiological results was observed to increase monotonously as preliminary results showed that CG copolymers with pore channels predominantly oriented along the radial direction of the tubes had a success rate of only 50% (n = 6). Control groups of empty and saline-filled tubes had an aggregated success rate of 29% (n = 21). The ongoing study has shown that systematic physiochemical manipulation of simple chemical analogs of the extracellular matrix can be used to define substrate features which encourage regeneration.

High stress regions in saphenous vein bypass graft atherosclerotic lesions

OBJECTIVES Our aim was to test the hypothesis that maximal stresses in saphenous vein atherosclerotic stenoses are greater than those in native coronary artery stenoses. BACKGROUND The patency of coronary artery saphenous vein bypass grafts decreases with time, usually because of thrombosis. Plaque rupture has been described as one mechanism of vein graft thrombosis. METHODS Twenty-six nonruptured human lesions were studied. Fourteen lesions were from native coronary arteries, and 12 were from saphenous vein bypass grafts placed a mean +/- SD of 9.8 +/- 3.3 years before pathologic study. The finite element method was used to determine the distribution of stress in the lesion, using estimates of material properties from previous measurements of human tissues. RESULTS Maximal circumferential stresses were significantly higher in the saphenous vein lesions (median 352 kPa [interquartile range 161 to 475]) than in the coronary artery lesions (median 104 kPa [interquartile range 75 to 185]) (p = 0.05). Thin-walled cylinder formulations predict that stresses are proportional to the radius of the vessel and inversely proportional to the minimal wall thickness. In this study, there was a good correlation between the maximal stress in the 26 lesions and the ratio of the square root of lumen area to minimal fibrous cap thickness (r = 0.83, p < 0.001). CONCLUSIONS Maximal circumferential tensile stresses in saphenous vein bypass graft stenoses are higher than in native coronary artery atherosclerotic stenoses. These data suggest that strategies that decrease stresses in bypass graft atherosclerotic lesions, such as prevention of lipid accumulation, could reduce the probability of plaque rupture in bypass grafts.