Constrictive Remodeling Research Articles

Volumetric intravascular ultrasound imaging to illustrate the extent of coronary plaque burden in type 2 diabetic patients

Background Although angiography is the gold standard for coronary imaging, its efficacy in outlining diffuse coronary atherosclerosis in diabetic patients remains questionable. We aimed to compare quantitative cineangiographic analysis (QCA) with three-dimensional intravascular ultrasound (IVUS) imaging in type 2 diabetic patients with coronary artery disease. Methods IVUS runs of 104 significant coronary lesions in 88 diabetic patients were performed. Arterial remodeling index was calculated as vessel area at minimal lumen area divided by mean reference vessel area. Results No difference between the two analysis modes was shown for lesion length and minimal lumen diameter, whereas a significant discrepancy between QCA and IVUS was found for diameter stenosis (10±9% vs. 41±8%; P<.001) and vessel diameter (3.01±0.66 vs. 4.53±0.70 mm; P<.001). A significant difference on arterial remodeling at lesion site was found between insulin-treated diabetic patients and non-insulin-treated diabetic patients (remodeling index: 0.98±0.16 vs. 1.07±0.21; P=.04). Conclusions Coronary angiographic diagnosis in diabetic patients may be distorted due to a large plaque burden over longer vessel segments and the resulting absence of plaque-free reference segments. This distortion was found to be more pronounced in QCA analysis requiring a reference diameter, whereas volumetric IVUS imaging illustrated coronary artery dimensions more accurately according to anatomic structures. Constrictive arterial remodeling was observed more frequently in type 2 diabetic patients treated with insulin.

Histomorphological observation in arterial remodeling following New Zealand rabbit auto-extremity artery transplantation

Objective To investigate the histomorphological change in auto-extremity artery following transplantation. Methods 50 New Zealand rabbits were randomly divided into 5 groups(postoperative 1 d, 3 d, 7 d, 14 d, 56 d, n = 10). Femoral artery was harvested and end-to-side anastomosed with carotid in order to build the auto-extremity arterialgraft animalmodel. On thepostoperative 1st, 3rd, 7th, 14th and 56th days, grafts for morphometric analysis under the Image analysis system were obtained; and electron microscope was scanned to observe endothelial cells. In addition, Immunostaining of sections were performed with the mouse monoclonal antibody of the a-smooth muscle isoform of actin and proliferating cell nuclear antigen antibody. Results Overall patency rate for all conduits was 86%.The intimal hyperplasia was first observed in the 7th day group, and continued to increase in the 56th day group(183.21 ±111.74)μm, P < 0.01. Additionally, the luminal narrowed(32.43±18.28)% in the 56th day group. Smooth muscle cells were the mainly hyperplastic components. The most active proliferation of cells was detected in the 14th day group, where the extracellular matrix gradually deposited in the intima. Conclusion Moderate intimal hyperplasia occurred in arterial conduits and vascular structure experienced constrictive remodeling after auto-transplantation.

Comparison of Clinical Characteristics and Arterial Remodeling by Intravascular Ultrasonic Imaging in Three Age Groups (≤55, 56 to 69 and ≥70 Years) of Japanese Patients With Acute Myocardial Infarction

Recent epidemiologic, pathologic, and intravascular ultrasound (IVUS) studies have shown that there are differences in coronary risk factors or plaque morphology between younger and older patients with acute myocardial infarctions (AMIs). This study examined clinical background and plaque morphology using IVUS in younger and older adults with AMIs in Japan. The study population consisted of 96 patients with AMIs, for whom preinterventional IVUS images were obtained. Patients were classified into 3 groups: a young group (aged < or =55 years), a middle-aged group (aged 56 to 69 years), and an old group (aged > or =70 years). The remodeling index was defined as the ratio of the external elastic membrane area at the culprit lesion to the external elastic membrane area at the proximal reference site. Expansive remodeling was defined as a remodeling index >1.05 and constrictive remodeling as a remodeling index <0.95. The frequency of hypercholesterolemia was significantly different among the 3 age groups. Total cholesterol (p <0.001), low-density lipoprotein cholesterol (p <0.005), and triglyceride (p <0.05) levels and body mass index (p <0.001) in the young group were significantly higher than in the old group. On IVUS images, constrictive remodeling was most common in the young group, whereas expansive remodeling occurred most commonly in the middle-aged and old groups. In conclusion, this study demonstrated that patients with AMIs in the young group had higher levels of hypercholesterolemia, obesity, and constrictive remodeling compared with those in the old group. The differences in arterial remodeling of the culprit lesions between younger and older patients with AMIs may reflect different biologic mechanisms of plaque activation and destabilization.

Effect of perindopril on coronary remodelling: insights from a multicentre, randomized study

This study sought to evaluate the effect of perindopril in coronary remodelling. In this sub-study of a double-blind, multicentre trial, patients without clinical evidence of heart failure were randomized to perindopril 8 mg/day or placebo for at least 3 years and IVUS investigation was performed at both time-points. Positive and negative remodelling were defined as a relative increase (positive remodelling) or decrease (negative remodelling) of the mean vessel cross-sectional area (CSA)>2 SD of the mean intra-observer difference. A total of 118 matched evaluable IVUS (711 matched 5 mm segments) were available at follow-up. After a median follow-up of 3.0 (inter-quartile range 1.9, 4.1) years, there was no significant difference in the change of plaque CSA between perindopril (360 segments) and placebo (351 segments) groups, P=0.27. Conversely, the change in vessel CSA was significantly different between groups (perindopril -0.18+/-2.4 mm2 vs. placebo 0.19+/-2.4, P = 0.04). Negative remodelling occurred more frequently in the perindopril than in the placebo group (34 vs. 25%, P=0.01). In addition, the placebo group showed a larger, although not significant, mean remodelling index (RI) than the perindopril group (1.03+/-0.2 vs. 1.00+/-0.2, P=0.06). The temporal change in vessel dimensions assessed by the RI was significantly correlated with the change in plaque dimensions (r=0.48, P<0.0001). In this sub-analysis of a multicentre, controlled study, long-term administration of perindopril was associated with a constrictive remodelling pattern without affecting the lumen.

Arterial remodelling: an independent pathophysiological component of atherosclerotic disease progression and regression. Insights from serial pharmacological intervention trials

Rodriguez-Granillo et al. 1 report arterial remodelling data from the ‘PERSPECTIVE’ study,2 an imaging substudy of the ‘EUROPA’ study.3 ‘EUROPA’ is a randomized, placebo-controlled, multicentre trial, which demonstrated that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced adverse clinical events in 12 218 patients with stable coronary artery disease (CAD). The EUROPA investigators suggested that the clinical benefit is related to anti-atherosclerotic effects of ACE inhibitors. However, the ‘PERSPECTIVE’ substudy, which examined the impact of perindopril on atherosclerosis in a subset of 118 patients, found neither an effect on plaque burden assessed by intravascular ultrasound (IVUS) nor an effect on angiographic luminal diameter. The lack of change in these imaging end-points could indicate that the clinical benefit of ACE inhibition is not mediated by changes of atherosclerotic plaque anatomy. However, an alternative explanation is that ACE inhibition exerts other plaque-stabilizing effects including modification of plaque composition and arterial remodelling. This hypothesis is examined in the current, serial IVUS study, which investigates the effect of perindopril on arterial remodelling and plaque composition. Remodelling was defined as a relative increase (expansive remodelling) or decrease (constrictive remodelling) of the mean vessel cross-sectional area (CSA) between baseline and follow-up. A total of 711 matched 5 mm segments from 118 IVUS examinations were available at baseline and after 3-year follow-up. There was no significant difference in the change of plaque burden between the perindopril and placebo groups. However, the … *Corresponding author. Tel: +1-216-445-7579. E-mail address: schoenp1{at}ccf.org

Mechanisms of Reduced Human Vascular Cell Migration After Photodynamic Therapy¶

Restenosis results from intimal hyperplasia and constrictive remodeling following cardiovascular interventions. Photodynamic therapy (PDT) has been shown to inhibit intimal hyperplasia in vivo by preventing neointimal repopulation of the treated vessel. This study was undertaken in an attempt to further dissect the mechanisms by which PDT acts on secreted and extracellular matrix proteins to inhibit migration of cultured human vascular cells. PDT of three-dimensional collagen gels inhibited invasive human smooth muscle cell (SMC) migration, whereas cell-derived matrix metalloproteinase production remained unaltered. Additionally, PDT generated cross-links in the collagen gels, a result substantiated in an ex vivo model whereby PDT rendered the treated vessels resistant to pepsin digestion and inhibited invasive migration of SMC and fibroblasts. These data support the premise that by inducing matrix protein cross-links, rendering the vessel resistant to degradation, in vivo PDT inhibits repopulation of the vessel and therefore intimal hyperplasia.

UVB-activated Psoralen Reduces Luminal Narrowing After Balloon Dilation Because of Inhibition of Constrictive Remodeling¶

UVB-activated Psoralen Reduces Luminal Narrowing After Balloon Dilation Because of Inhibition of Constrictive Remodeling¶

α8β1 Integrin is up-regulated in the neointima concomitant with late luminal loss after balloon injury

Constrictive remodeling of the neointima results in the late lumen loss and restenosis after balloon angioplasty. Intense expression of alpha8beta1 integrin in the contractile state of vascular smooth muscle cells (VSMCs) and in myofibroblasts led us to hypothesize that it might be involved in the process of late constrictive remodeling. Balloon injury was used to induce neointima formation in the rat carotid artery. Immunohistochemical analysis and immunoconfocal studies showed that late lumen narrowing was concomitant with the up-regulation of smooth muscle alpha-actin and alpha8 integrin in the neointima. The transforming growth factor-beta (TGF-beta)-induced contractile properties of fibroblasts and VSMCs populated in a three-dimensional collagen matrix was associated with up-regulation of alpha8 integrin. TGF-beta-induced myofibroblastic features in Rat1 fibroblasts were impaired in cells pretreated with a small interference RNA silencing the alpha8 integrin gene. The close correlation between alpha8 integrin up-regulation in the neointima and late luminal loss and alpha8 integrin being required for contractile properties induced by TGF-beta highlight a possible role for alpha8 integrin in postangioplasty restenosis.

Determinants of arterial wall remodeling during lipid-lowering therapy: Serial intravascular ultrasound observations from the reversal of atherosclerosis with aggressive lipid Lowering therapy (REVERSAL) trial

Conclusion: Plaque stabilization therapy with statin medications results in constrictive remodeling of the arterial wall and appears related to the anti-inflammatory effects of statin medications. Summary: The authors sought to study remodeling of coronary arteries during plaque-stabilizing therapy and to relate this remodeling to markers of lipid metabolism and inflammation. The Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial examined reversal of coronary artery atherosclerosis during 18 months of intensive vs moderate lipid-lowering therapy. The authors identified 210 patients with mild luminal narrowing coronary lesions. External elastic membrane (EEM) area, lumen area, and plaque area were determined at the site of the coronary lesions and at a reference site proximal to the lesions. Measurements were taken at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing EEM area of the lesion by EEM reference area. Changes in remodeling and changes in plaque area were correlated with lipid profile and inflammatory markers. The lesions examined showed a progression in plaque area (8.9% ± 25.7%) and a decrease in RR (−3.0% ± 11.2%) during follow-up. Direct effects with RR were correlated with percentage change in plaque area (P < .0001), baseline RR (P < .0001), and baseline lesion lumen area (P = .019) as well as change in high sensitivity C-reactive protein levels (P = .027) and baseline hypertension (P = .014). Age (P = .037) and percentage change in triglyceride levels (P = .049) demonstrated significant inverse relationships with RR during follow-up. There were no associations between changes in treatment group (moderate vs high-intensity statin therapy) levels of low-density (LDL) or high-density lipoprotein (HDL) cholesterol. Comment: Plaque regression and stabilization appears to be accompanied by a reduction in vessel size. Correlation of these effects with C-reactive protein, but not serum levels of HDL or LDL cholesterol, suggest drugs targeting arterial inflammation may be more effective than those targeting simple measures of lipid metabolism. The anti-inflammatory effects of statins may turn out to be more important than their cholesterol-lowering effects.

Topological Determinants and Consequences of Adventitial Responses to Arterial Wall Injury

Arteries are composed of 3 concentric tissue layers which exhibit different structures and properties. Because arterial injury is generally initiated at the interface with circulating blood, most studies performed to unravel the mechanisms involved in injury-induced arterial responses have focused on the innermost layer (intima) rather than on the outermost adventitial layer. In the present review, we focus on the involvement of the adventitia in response to various types of arterial injury leading to vascular remodeling. Physiologically, soluble vascular mediators are centrifugally conveyed by mass transport toward the adventitia. Moreover, in pathological conditions, neomediators and antigens can be generated within the arterial wall, whose outward conveyance triggers different patterns of local adventitial response. Adventitial angiogenesis, immunoinflammation, and fibrosis sequentially interact and their net balance defines the participation of the adventitial response in arterial pathology. In the present review we discuss 4 pathological entities in which the adventitial response to arterial wall injury participates in arterial wall remodeling. Hence, the adventitial adaptive immune response predominates in chronic rejection. Inflammatory phagocytic cell recruitment and initiation of a shift from innate to adaptive immunity characterize the adventitial response to products of proteolysis in abdominal aortic aneurysm. Adventitial sprouting of neovessels, leading to intraplaque hemorrhages, predominates in atherothrombosis. Adventitial fibrosis characterizes the response to mechanical stress and is responsible for the constrictive remodeling of arterial segments and initiating interstitial fibrosis in perivascular tissues. These adventitial events, therefore, have an impact not only on the vessel wall biology but also on the surrounding tissue.

Regions of low endothelial shear stress are the sites where coronary plaque progresses and vascular remodelling occurs in humans: an in vivo serial study

We performed serial intracoronary studies of patients with stable coronary artery disease (CAD) to investigate the relationships among baseline endothelial shear stress (ESS), CAD progression, and vascular remodelling. Local haemodynamic factors are critical determinants of plaque progression, vascular remodelling, and clinical CAD manifestations. The 3-D anatomy of coronary arteries with lumen obstruction <50% was determined by fusing intracoronary ultrasound and angiographic images in 13 patients at baseline and 8 +/- 2 months later. Cross-sectional area of plaque, lumen, and external elastic membrane (EEM), and coronary flow were measured. Local ESS was calculated. Subsegments with similar ESS were categorized based on low (<12 dynes/cm(2)) and moderate/higher ESS (> or =12 dynes/cm(2)). There were 47 subsegments of similar baseline ESS: nine with low ESS and 38 with moderate/higher ESS. Median subsegment length was 6.9 mm (25th-75th percentiles = 4.2-12.0), and median area of similar ESS of 52.6 mm(2) (25th-75th percentiles = 26.9-88.0). Subsegments with low ESS exhibited plaque progression when compared with subsegments with moderate/higher ESS (33.3% vs. 7.9%, respectively, P = 0.009 adjusted for clustering of lesions within patients) and constrictive remodelling (44.0% vs. 5.3%, respectively, P = 0.16 adjusted for clustering of lesions within patients). Expansive remodelling occurred with similar frequency in subsegments with low vs. moderate/higher baseline ESS. Plaque progresses in subsegments with low ESS, associated with either constrictive or expansive remodelling. Different mechanisms are likely responsible for expansive remodelling in different local vascular environments. Early in vivo identification of arterial subsegments likely to develop high-risk plaque characteristics may allow for selective interventions to avoid adverse cardiac outcomes.

Vascular Remodeling 1 Year After Cardiac Transplantation

The belief that vascular remodeling and intimal hyperplasia are causes of luminal narrowing in cardiac allograft vasculopathy (CAV) is controversial. This study evaluated the relationship of vascular remodeling and intimal hyperplasia to luminal narrowing 1 year after orthotopic heart transplantation. Intravascular ultrasound imaging was performed on 190 cardiac transplant recipients at baseline and again 1 year after transplantation as part of a randomized trial of mycophenolate mofetil (MMF) and azathioprine (Aza). Studies 1 year apart were matched at 625 sites. All sites were classified into positive, non-significant and negative remodeling patterns, depending on a change of +/-10% in external elastic membrane area. Of the 190 patients, 99 were randomized to receive MMF, and 91 to receive Aza. A total of 625 sites were observed. Of these, 52% had no remodeling, 25% exhibited vessel dilation, and 23% had vessel shrinkage in the presence of variable intimal growth (Delta intimal area: 0.73 +/- 1.70 mm2, p < 0.0001; 1.23 +/- 2.02 mm2, p < 0.0001; and 0.20 +/- 1.40 mm2, p = 0.09, respectively). Sixty percent of the lumen loss was due to a decrease in external elastic membrane area and 40% to an increase in intimal area (p = 0.005). Compared with Aza-treated patients, the MMF-treated patients had a lower incidence of vessel shrinkage (17% vs 28%, p = 0.001), and a trend for smaller maximum intimal thickness (0.21 +/- 0.25 mm vs 0.29 +/- 0.31 mm, p = 0.052). Positive remodeling is associated with intimal growth, but negative remodeling does not correlate with any specific change in intimal hyperplasia. Constrictive remodeling is more responsible than intimal hyperplasia for the luminal narrowing that occurs. MMF is more efficacious than azathioprine in preventing the development of CAV at 1 year, by reducing the degree and incidence of vessel shrinkage and the progression of intimal hyperplasia.

Neointimal Cracks (Plaque Rupture?) and Thrombosis in Wrapped Arteries Without Flow

The Editor’s pick for the June 2006 issue of Arteriosclerosis, Thrombosis, and Vascular Biology was the article by Sasaki et al1 entitled “A Simple Method of Plaque Rupture Induction in Apolipoprotein E–Deficient Mice.” The key term in this title is “plaque rupture.” The article was accompanied by a supportive editorial by Jackson.2 We would like to suggest that the enthusiasm for this experiment as a model for plaque rupture needs to be moderated by a better understanding of the model itself and of human plaque rupture. In 1997, Lindner and coworkers described that flow cessation induced by ligation of the common carotid artery (CCA) near its bifurcation led to constrictive vascular remodeling and neointima formation in mice within 4 weeks.3,4 Flow cessation was followed by loss of medial smooth muscle cells and early recruitment of leukocytes that infiltrated the developing neointima, media, and adventitia during the first week. Focal …

Opposite effects of vascular irradiation on inflammatory response and apoptosis induction in the vessel wall layers via the peroxynitrite-poly(ADP-ribose) polymerase pathway

We investigated in a surgical rat model of vascular injury the potential role of the peroxynitrite - poly(ADPribose) polymerase (PARP) pathway in inflammatory response and apoptosis induction after vascular gamma irradiation. Male Sprague-Dawley rats underwent left carotid endarterectomy with removal of intima: control (n = 10) and were irradiated with 15 Gray (n = 13) or 20 Gray (n = 10) postoperatively and compared with sham-operated rats (n = 10). Additional animals were solely irradiated with 15 Gy (n = 10) and with 20 Gy (n = 10) to distinguish between primary effects of vascular injury and secondary effects due to irradiation. After 21 days, neointima formation was significantly suppressed after irradiation (control: 0.07 mm(2) +/- 0.04 mm(2), 15 Gy: 0.003 mm(2) +/- 0.004 mm(2), 20 Gy: 0.001 mm(2) +/- 0.0006 mm(2), P< 0.0001). However, a significant inflammation of the vessel wall with focal wall necrosis was detected (control: 0.2 +/- 0.15, 15 Gy: 0.82 +/- 1.2, 20 Gy: 1.25 +/- 0.86, P= 0.003). Immunohistochemistry showed significant staining for nitrotyrosine, poly(ADP-ribose) and nuclear translocation of apoptosis-inducing factor in the neointima of the control group. In the irradiated groups these stainings were significantly higher in the media and adventitia compared to the non-irradiated groups. Activation of the peroxynitrite-PARP pathway was demonstrated during neointima proliferation in a rat model of surgical vascular injury. Vascular irradiation suppressed neointima formation, but induced significant activation of the peroxynitrite - PARP pathway in the outer vessel wall layers concomitant to inflammation and focal wall necrosis. This may contribute to adverse effects of vascular irradiation such as fibrosis and constrictive remodeling.

Static and serial assessments of coronary arterial remodeling are discordant: An intravascular ultrasound analysis from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial

Arterial remodeling is a major determinant of the clinical manifestations of coronary artery disease. Assessment of arterial remodeling with intravascular ultrasound (IVUS) used to rely on comparing the external elastic membrane (EEM) areas of lesion and reference sites at a single time point (static assessment). Recently, performance of serial IVUS provided the opportunity for direct assessment of remodeling. Our aim was to study the concordance of the static and serial methods. We identified 210 focal coronary lesions on the baseline IVUS interrogations of the REVERSAL trial. A follow-up IVUS was performed at 18 months. Static assessment was performed by calculating the remodeling index (RI) (lesion EEM area / reference EEM area) and serial assessment by comparing the changes in atheroma and EEM areas at follow-up. Using the serial method, there was a 1.24 mm2 increase in EEM area for every 1 mm2 increase in atheroma area at the lesion site, which was indicative of expansive (overcompensatory) remodeling. By using the static method, the RI was paradoxically lower at follow-up (1.062 +/- 0.15 at baseline vs 1.027 +/- 0.14 at follow-up, P < .001), indicating a trend toward constrictive remodeling. The reason for decreased RI at follow-up was the relatively larger expansion of the EEM areas at the reference sites. Static and serial assessments of arterial remodeling are discordant. This is due to concomitant remodeling of the reference sites used in the static assessment. Intravascular ultrasound performed at a single point in time does not reflect the dynamic remodeling response.

Intravascular Ultrasound in Cardiovascular Medicine

Case presentation: A 38-year-old man underwent angiography 2 weeks after a non–ST-segment myocardial infarction. He was overweight and prehypertensive, with a blood pressure of 134/86 mm Hg. His biochemical parameters included low-density lipoprotein cholesterol (LDL-C) 127 mg/dL, high-density lipoprotein cholesterol (HDL-C) 38 mg/dL, and C-reactive protein (CRP) 3.2 mg/L. Angiography revealed mild disease throughout the coronary arteries and a hazy appearance that involved the proximal left anterior descending coronary artery. Intravascular ultrasound (IVUS) imaging revealed diffuse and extensive atherosclerosis with evidence of plaque rupture at multiple sites (Figure 1). In the presence of no significant luminal stenoses, the patient was treated medically with aspirin and low-dose statin therapy. Figure 1. Illustrative example of coronary angiography of the left anterior descending artery that appears to be free of irregularities, apart from a hazy appearance in the proximal segment. A representative cross-sectional tomographic image obtained by IVUS examination (top right) within the proximal segment (white arrow on angiogram) revealed substantial atheroma within the arterial wall. The bottom right segment illustrates a tomographic image of atheroma containing significant ulceration (5 o’clock) at the site of the gold arrow on the angiogram. The application of IVUS in this case highlights a number of important points with regard to the natural history of atherosclerosis and its modification by use of established medical therapies. The ability to image the entire arterial wall represents a significant advantage over coronary angiography. In the presence of minimal luminal stenoses, IVUS imaging in patients with coronary symptoms typically reveals extensive and diffuse atherosclerosis.1 Application of serial IVUS imaging in prospective clinical trials has enabled a greater understanding of the impact of antiatherosclerotic interventions on patients with established coronary artery disease (CAD). Ultrasonic coronary imaging has revealed essential details about the natural history of atherosclerosis. Atheroma formation begins at a …

Shear Stress–Mediated Arterial Remodeling in Atherosclerosis

Under physiological conditions, chronic changes in blood flow stimulate compensatory changes in arterial size. This arterial remodeling process occurs during normal growth and development and contributes to the adaptive response to a variety of clinical situations. For example, repetitive increases in blood flow during exercise may stimulate expansive remodeling of conduit arteries in the limbs and heart,1 whereas chronic disuse of the lower extremities as a result of spinal cord injury is associated with constrictive remodeling of the femoral arteries.2 Uterine arteries display expansive remodeling during pregnancy and then undergo constrictive remodeling after delivery. Thus, dynamic remodeling of the arterial tree plays a critical role in maintaining the appropriate balance between tissue demand and blood supply throughout life. Article p 2826 A primary signal for arterial remodeling is shear stress, which is the frictional force at the endothelial surface produced by flowing blood.3,4 Shear stress relates directly to flow and blood viscosity and inversely to the third power of arterial radius.3 A macroscopic increase in blood flow increases local shear stress and stimulates arterial expansion until shear stress has been restored to baseline. Conversely, low shear stress leads to constrictive remodeling. This important homeostatic mechanism maintains shear stress in an appropriate range. When exposed to physiological levels of shear stress (15 to 40 dyne/cm2), endothelial cells appropriately elongate, align in the direction of flow, and maintain barrier function.4 Furthermore, normal shear stress promotes expression of vasodilator and antithrombotic factors, suppresses growth and proinflammatory factors, and generally maintains a state of vascular health. In contrast, low, oscillating, and disordered shear stress promotes the development of atherosclerosis. Expansive remodeling in response to chronic or repetitive increases in flow involves a coordinated sequence of events in the arterial wall, as has been extensively reviewed.3,5,6 Over a …

Determinants of Arterial Wall Remodeling During Lipid-Lowering Therapy

Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9+/-25.7%) and a decrease in the RR (-3.0+/-11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area (P<0.0001), baseline RR (P<0.0001), baseline lesion lumen area (0.019), logarithmic value of the change in high-sensitivity C-reactive protein (P=0.027), and hypertension at baseline (P=0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery (P=0.006), percentage change in triglyceride levels (P=0.049), and age (P=0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.

Doxycycline Alters Vascular Smooth Muscle Cell Adhesion, Migration, and Reorganization of Fibrillar Collagen Matrices

Remodeling of injured blood vessels is dependent on smooth muscle cells and matrix metalloproteinase activity. Doxycycline is a broad spectrum matrix metalloproteinase inhibitor that is under investigation for the treatment of acute coronary syndromes and aneurysms. In the present study, we examine the mechanisms by which doxycycline inhibits smooth muscle cell responses using a series of in vitro assays that mimic critical steps in pathological vascular remodeling. Doxycycline treatment dramatically increased smooth muscle cell adhesion to the substrate, as evidenced by interference reflection microscopy and immunostaining for paxillin and phosphotyrosine. Cell aggregation was also potentiated after treatment with doxycycline. Treatment with 104 mumol/L doxycycline reduced thymidine uptake by 58% compared with untreated cells (P < 0.05) and inhibited closure of a scrape wound made in a smooth muscle cell monolayer by 20% (P < 0.05). Contraction of a three-dimensional collagen gel was used as an in vitro model for constrictive vessel remodeling, demonstrating that treatment with 416 mumol/L doxycycline for 12 hours inhibited collagen gel remodeling by 37% relative to control (P < 0.05). In conclusion, we have shown that doxycycline treatment leads to dramatically increased smooth muscle cell adhesion, which in turn might limit responses in pathological vascular remodeling.

Adaptive-Outward and Maladaptive-Inward Arterial Remodeling Measured by Intravascular Ultrasound in Hyperhomocysteinemia and Diabetes

Coronary artery remodeling implies structural changes in the vessel wall in response to various pathophysiologic conditions. However, the classification of remodeling is unclear. We hypothesized that the adaptive, positive-outward remodeling is a reactive and compensatory response to the stress. The maladaptive negative-inward constrictive remodeling is a passive atherosclerotic condition in which the vessel becomes stiffer. Patients with atherosclerotic lesions underwent intravascular ultrasound (IVUS) scans. The size of the vessels distal to and proximal to plaques were analyzed by IVUS. Diabetes was created in mice by an intraperitoneal injection of alloxan (65 mg/kg). To reduce remodeling, mice received ciglitazone, an agonist of peroxisome proliferators activated receptor-gamma (PPARgamma) in drinking water. After 8 weeks, atherosclerotic vessels were analyzed for collagen and elastin. IVUS data suggest an adaptive coronary arterial remodeling was a positive compensatory response to various pathologic stimuli; for example, with the deposition of atherosclerotic plaque, coronary arterial segments enlarged to maintain luminal area. This phenomenon was commonly observed during the initial phases of the development of atherosclerosis. However, negative coronary artery remodeling, or a decrease in vessel area with the formation of atherosclerotic plaque, was maladaptive and was associated with smoking, hypertension, hyperhomocysteinemia, diabetes mellitus, and also after percutaneous coronary interventions (restenosis). In diabetic mice, there was increased collagen and decreased elastin contents; however, treatment with ciglitazone ameliorated the decrease in elastin contents. Global enlargement of the coronary vascular tree occurs during pressure and volume overload associated with ventricular hypertrophic states such as athletic conditioning, hypertensive heart disease, and dilated cardiomyopathy. On the other hand, maladaptive coronary arterial remodeling occurs in patients with severe deconditioning, diabetes mellitus, after coronary artery bypass surgery, and in some instances, postintervention.