Richard T. Lee

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)

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)

Mechanotransduction in Cardiac Myocytes

Abstract: Cardiac myocytes react to diverse mechanical demands with a multitude of transient and long‐term responses to normalize the cellular mechanical environment. Several stretch‐activated signaling pathways have been identified, most prominently guanine nucleotide binding proteins (G‐proteins), mitogen‐activated protein kinases (MAPK), Janus‐associated kinase/signal transducers and activators of transcription (JAK/STAT), protein kinase C (PKC), calcineurin, intracellular calcium regulation, and several autocrine and paracrine factors. Multiple levels of crosstalk exist between pathways. The cellular response to changes in the mechanical environment can lead to cardiac myocyte hypertrophy, cellular growth that can be accompanied by pathological myocyte dysfunction, and tissue fibrosis. Several candidates for the primary mechanosensor in cardiac myocytes have been identified, ranging from stretch‐activated ion channels in the membrane to yet‐unknown mechanosensitive mechanisms in the nucleus. New and refined experimental techniques will exploit advances in molecular biology and biological imaging to study mechanotransduction in isolated cells and genetically engineered mice to explore the function of individual proteins.

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.

Vascular mechanics for the cardiologist

Many common problems in clinical cardiology are due to disturbances in vascular mechanics. The terminology and basic principles of vascular mechanics, including fundamentals of the relation of stress and strain, are described in this review. Approaches to measuring vessel wall stiffness and the mechanical basis for vascular catastrophes are introduced.

Matrix metalloproteinase inhibition and the prevention of heart failure.

Matrix metalloproteinases (MMPs) are members of a large family of enzymes that can degrade extracellular matrix as well as other molecules. MMPs participate in a broad variety of normal and pathologic states, and recent evidence implicates the MMP family as potential mediators of cardiac dilation and progression to heart failure. This evidence is based on several lines of investigation. First, members of the MMP family are overexpressed in the myocardium in both experimental and human myocardial injury, infarction, and dilation. Second, overexpression of at least one MMP (MMP-1) in the hearts of transgenic mice can cause cardiac hypertrophy, dilation, and systolic dysfunction. Third, studies from multiple laboratories with different experimental models indicate that inhibition of MMPs through small molecules or gene transfer of endogenous inhibitors favorably affects cardiac remodeling. Fourth, targeted deletion of MMP genes in mice attenuates cardiac remodeling. These compelling results appear to fulfill Kochs Postulates as they may be applied to a non-infectious mediator of a disease, and thus current evidence supports MMP inhibition as a promising strategy for preventing heart failure. However, the crucial question of whether MMP inhibition benefits long-term left ventricular function and survival should be answered.

Engineering insulin-like growth factor-1 for local delivery

Insulin‐like growth factor‐1 (IGF‐1) is a small protein that promotes cell survival and growth, often acting over long distances. Although for decades IGF‐1 has been considered to have therapeutic poten tial, systemic side effects of IGF‐1 are significant, and local delivery of IGF‐1 for tissue repair has been a long‐standing challenge. In this study, we designed and purified a novel protein, heparin‐binding IGF‐1 (Xp‐ HB‐IGF‐1), which is a fusion protein of native IGF‐1 with the heparin‐binding domain of heparin‐binding epidermal growth factor‐like growth factor. Xp‐HB‐ IGF‐1 bound selectively to heparin as well as the cell surfaces of 3T3 fibroblasts, neonatal cardiac myocytes and differentiating ES cells. Xp‐HB‐IGF‐1 activated the IGF‐1 receptor and Akt with identical kinetics and dose response, indicating no compromise of biological activ ity due to the heparin‐binding domain. Because carti lage is a proteoglycan‐rich environment and IGF‐1 is a known stimulus for chondrocyte biosynthesis, we then studied the effectiveness of Xp‐HB‐IGF‐1 in cartilage. Xp‐HB‐IGF‐1 was selectively retained by cartilage ex plants and led to sustained chondrocyte proteoglycan biosynthesis compared to IGF‐1. These data show that the strategy of engineering a “long‐distance” growth factor like IGF‐1 for local delivery may be useful for tissue repair and minimizing systemic effects.— Tokunou, T., Miller, R., Patwari, P., Davis, M. E., Segers, V. F. M., Grodzinsky, A. J., Lee, R. T. Engineering insulin‐like growth factor‐1 for local delivery. FASEB J. 22, 1886–1893 (2008)

A model for mechanotransduction in cardiac muscle: effects of extracellular matrix deformation on autocrine signaling.

We present a computational model and analysis of the dynamic behavior of epidermal growth factor receptor (EGFR) signaling in cardiac muscle tissue, with the aim of exploring transduction of mechanical loading into cellular signaling that could lead to cardiac hypertrophy. For this purpose, we integrated recently introduced models for ligand dynamics within compliant intercellular spaces and for the spatial dynamics of intracellular signaling with a positive feedback autocrine circuit. These kinetic models are here considered in the setting of a tissue consisting of cardiomyocytes and blood capillaries as a structural model for the myocardium. We show that autocrine EGFR signaling can be induced directly by mechanical deformation of the tissue and demonstrate the possibility of self-organization of signaling that is anisotropic on the tissue level and can reflect anisotropy of the mechanical deformation. These predictions point to the potential capabilities of the EGFR autocrine signaling circuit in mechanotransduction and suggest a new perspective on the cardiac hypertrophic response.

Myocardial Tissue Characterization by Autocorrelation of Two-dimensional Ultrasonic Backscatter

To evaluate a novel method for determining the spatial distribution of echocardiographic information based on the two-dimensional autocorrelation function, echocardiographic images were obtained from specific regions of interest from 10 healthy volunteers, seven patients with genetically defined hypertrophic cardiomyopathy, and nine patients with pressure-overload hypertrophy. The wavelength of distinct peaks from the two-dimensional autocorrelation of the images was compared between groups of patients and demonstrated a significant decrease in the mean length scale associated with distinct secondary correlation peaks in patients with hypertrophic cardiomyopathy or pressure-overload hypertrophy compared with healthy volunteers (p = 0.0009). With a discriminating wavelength of 3.3 mm, the sensitivity of this technique for detecting abnormal myocardium was 84% with a specificity of 89%. This study suggests that ultrasonic tissue characterization based on the two-dimensional autocorrelation function may have potential for distinguishing normal from abnormal myocardium and provides a rationale for textural approaches to ultrasonic tissue characterization.