Constrictive Remodeling Research Articles

RHAMM alters smooth muscle cell (SMC) remodeling of collagen‐hyaluronan (HA) matrix

HA is prominent in ECM at sites of artery injury and alters SMC proliferation and migration by binding receptors CD44 and RHAMM, respectively. HA also enhances contraction of collagen by SMC in vitro but the molecular regulation of this effect is ill defined. Given HA binding of RHAMM induces migration we hypothesize RHAMM also mediates HA‐induced collagen remodeling. To test this hypothesis, rat SMC were pre‐treated with blocking antibody and effects on adhesion, migration, collagen gel contraction determined. Consistent with the literature, HA promoted migration via RHAMM, as blocking antibody inhibited healing of a scratch assay by 84% compared to IgG control (%healing, 48 hr: 8±2 vs 92±2 %, respectively, p=0.008) but without significant effect on initial SMC adhesion to collagen‐coated plates(p=0.08). HA enhanced contraction of collagen‐I gels and contraction was further increased by RHAMM blockade (gel diam, 18hr: 8.5±0.15 vs 5.5±0.1, p=0.01). Gel histology showed increased pericellular collagen with RHAMM blockade (156±7% of control, p<0.05) and reduced cell speading (p=0.015). In summary, RHAMM promoted SMC migration with little effect on initial adhesion. Blocking RHAMM enhanced HA‐induced collagen gel contraction, suggesting RHAMM plays an inhibitory role in collagen remodeling, making RHAMM a potential target for treating constrictive remodeling in vivo.Research Support: NIH R01HL57557

Peripheral Arterial Disease and Progression of Coronary Atherosclerosis

The purpose of this analysis was to characterize the progression of coronary atherosclerosis in patients with concomitant peripheral arterial disease (PAD). Peripheral arterial disease is associated with adverse cardiovascular outcomes. The impact of concomitant PAD on coronary atherosclerosis progression in patients with coronary artery disease has not been well established. The burden and progression of coronary atherosclerosis was investigated in 3,479 patients with coronary artery disease with (n = 216) and without (n = 3,263) concomitant PAD who participated in 7 clinical trials that employed serial intravascular ultrasound imaging. Patients with PAD had a greater percent atheroma volume (40.4 ± 9.2% vs. 38.5 ± 9.1%, p = 0.002) and percentage of images containing calcium (35.1 ± 26.2% vs. 29.6 ± 24.2%, p = 0.002), in association with smaller lumen volume (275.7 ± 101.6 mm(3) vs. 301.4 ± 110.3 mm(3), p < 0.001) and vessel wall volume (467.7 ± 166.8 mm(3) vs. 492.9 ± 169.8 mm(3), p = 0.01). On serial evaluation, patients with PAD demonstrated greater progression of percent atheroma volume (+0.58 ± 0.38 vs. +0.23 ± 0.3%, p = 0.009) and total atheroma volume (-0.17 ± 2.69 mm(3) vs. -2.05 ± 2.15 mm(3), p = 0.03) and experienced more cardiovascular events (26.3% vs. 19.8%, p = 0.03). In patients with PAD and without PAD, respectively, achieving levels of low-density lipoprotein cholesterol <70 mg/dl was associated with less progression of percent atheroma volume (+0.16 ± 0.27% vs. +0.76 ± 0.20%, p = 0.04; and +0.05 ± 0.14% vs. +0.29 ± 0.13%, p < 0.001) and total atheroma volume (-3.0 ± 1.9 mm(3) vs. +1.0 ± 1.4 mm(3), p = 0.04; and -3.3 ± 1.1 mm(3) vs. -1.6 ± 1.0 mm(3), p < 0.001). Patients with concomitant PAD harbor more extensive and calcified coronary atherosclerosis, constrictive arterial remodeling, and greater disease progression. These changes are likely to contribute to adverse cardiovascular outcomes. The benefit for all patients achieving low levels of low-density lipoprotein cholesterol supports the need for intensive lipid lowering in patients with PAD.

In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis

Objective Recently, the technique of high-resolution magnetic resonance imaging (HR-MRI) has been developed to depict intracranial artery wall. We aimed to compare the vessel wall properties between symptomatic and asymptomatic atherosclerotic middle cerebral arteries (MCA) using HR-MRI. Methods We studied 26 patients with symptomatic and 35 patients with asymptomatic MCA stenosis. Routine cranial MRI, magnetic resonance angiography and HR-MRI were performed on each patient. The cross-sectional images of MCA wall on HR-MRI were compared between the two groups. Results The degree of MCA stenosis was similar between the two groups (67.9% vs 63.9%, P = 0.327). On HR-MRI, eccentric plaques were observed in 26 (100%) symptomatic and 28 (80%) asymptomatic stenosis. In the remaining seven (20%) asymptomatic stenosis, only constrictive remodeling (vessel shrinkage) was observed. Compared with the asymptomatic group, symptomatic MCA stenosis had a larger wall area ( P < 0.001), greater remodeling ratio ( P < 0.001), higher prevalence of expansive remodeling (outward expansion of the vessel wall) ( P = 0.003) and lower prevalence of constrictive remodeling ( P = 0.008). Conclusions Different vessel wall properties on HR-MRI were observed between symptomatic and asymptomatic MCA stenosis. Further prospective studies are required to investigate whether HR-MRI is a helpful tool in stratifying stroke risk in patients with MCA atherosclerotic disease.

International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010

The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

Comparison of Rates of Progression of Coronary Atherosclerosis in Patients With Diabetes Mellitus Versus Those With the Metabolic Syndrome

Diabetes mellitus (DM) and metabolic syndrome (MS) are associated with adverse cardiovascular outcomes. However, the extent and progression of coronary atherosclerosis for these conditions have not been directly compared. Three thousand four hundred fifty-nine patients with coronary artery disease underwent serial evaluation of atheroma burden by intravascular ultrasound. Patients with DM, MS, or neither diagnosis were compared with regard to plaque burden, progression, and arterial remodeling. Among the 3 groups, patients with MS had the largest number of individual cardiovascular risk factors. Patients with DM demonstrated more extensive atherosclerosis burden with a greater percent atheroma volume compared to patients with MS or those with neither diagnosis (40.3 +/- 9.0%, 37.6 +/- 8.9%, and 38.1 +/- 9.1%, p <0.001) and total atheroma volume (198.3 +/- 85.9, 190.7 +/- 85.0, and 186.3 +/- 79.1 mm(3), p = 0.05). MS compared to neither diagnosis was accompanied by expansion of the external elastic membrane (501.3 +/- 174.3 vs 484.4 +/- 160.7 mm(3), p = 0.02), whereas DM was associated with lumen constriction (290.6 +/- 111.7 vs 298.1 +/- 105.5 mm(3), p <0.0001). On serial evaluation, DM, but not MS, was associated with greater progression of percent atheroma volume compared to neither diagnosis (+0.8 +/- 0.3, +0.3 +/- 0.2, and +0.1 +/- 0.2%, p <0.0001) and total atheroma volume (-1.0 +/- 1.8, -3.3 +/- 1.8, and -4.0 +/- 1.8 mm(3), p = 0.001). Meeting criteria for MS was not associated with greater disease progression in patients with DM. In conclusion, despite having fewer individual risk factors, DM is associated with greater plaque progression and more constrictive remodeling than MS. This finding highlights the deleterious effects of DM on the arterial wall independent of its associated metabolic abnormalities.

Influence of drug-eluting stent on inflammation during restenosis in a porcine coronary model

Objective — The aim of this study is to compare anti-inflammatory and intimal hyperplasia inhibiting efficacy between the Firebird rapamycin drug-eluting stent and a bare metal stent in a porcine coronary injury model.Methods — Twelve rapamycin drug-eluting stents (Firebird), and 12 bare metal stents (BMS) were deployed with the oversizing method into porcine coronary arteries. Coronary angiography, histopathological and immunocytochemistry analysis were carried out at week 4 after stenting.Results — The distribution of stented vessels, diameter of reference vessels, and post-procedural minimal lumen diameter were compared between the two groups. At week 4 of follow-up, quantitative coronary angiography (QCA) showed that the minimal lumen diameter and late lumen loss were greater, and percent stenosis was less in the Firebird stent group than in the bare metal stent group. In the histopathological analysis, compared to the BMS group, injury score in the Firebird stent group (1.87 ± 0.16 vs. 1.32 ± 0.13) and inflammation score (1.86 ± 0.55 vs.1.12 ± 0.35) decreased, P < 0.05.There are significant differences for neointimal area (4.60 ± 1.39 mm2 in the BMS group vs. 1.51 ± 0.45 mm2 in the TCS group, P < 0.05). The lumen area in the Firebird stent group enlarged (3.24 ± 0.93 mm2 in the BMS group vs. 4.34 ± 0.93 mm2 in the Firebird stent group, P < 0.05). Immunohistochemistry revealed that the Firebird stent suppressed cell proliferation (Ki67) and expression of nuclear factor-kappaB (NF-κB) in the arterial wall.Conclusion — The Firebird stent showed suppression of constrictive remodelling, inhibition of neointimal hyperplasia through antiproliferation, and anti-inflammation acts via attenuated NF-kκ activation, which has proved to be a feasible method for preventing restenosis after coronary angioplasty in pigs.

Protein kinase C delta: a master regulator of apoptosis in neointimal thickening?

Smooth muscle cell (SMC)-driven neointimal hyperplasia is a key mechanism that reduces the long-term benefit of vascular interventions such as stenting, balloon angioplasty, and by-pass grafting. Furthermore, neointimal hyperplasia contributes significantly to the progression of atherosclerotic lesions. In response to arterial injury, neointimal hyperplasia develops rapidly—within a couple of months—as opposed to atherosclerotic lesions, which progress over decades. In general, the contribution of SMC to neointimal thickening can be attributed to increased SMC migration, proliferation, reduced apoptosis, and increased extracellular matrix accumulation. In addition, the recruitment of vascular progenitor cells and constrictive remodelling contribute to lesion formation and luminal narrowing.1,2 All of these mechanisms hold promise for the development of therapeutic interventions, and an impressive body of work has identified numerous potential targets. Unfortunately, many of these interventions were effective in rodent models but failed in human disease. However, in the recent past extensive clinical experience has been collected using drug-eluting stents (DES) for local delivery of antiproliferative drugs. Although highly efficient in inhibiting stent restenosis, sirolimus- and paclitaxel-eluting stents reduce endothelial re-growth and require long-term dual anti-platelet therapy.3 Therefore, new strategies that efficiently inhibit restenosis may still be of clinical … *Corresponding author. Tel: +49 201 723 3460; Fax: +49 201 723 5968. E-mail address : j.fischer{at}uk-essen.de

Vascular Restoration Therapy: the fourth revolution in interventional cardiology and the ultimate “Rosy” prophecy

The invention of balloon angioplasty as a treatment of obstructive coronary disease by Andreas Gruntzig in 1977 was a huge leap forward in technology, and undoubtedly will always remain the first revolution in interventional cardiology. However, this technique was plagued by multiple problems including the risk of acute occlusion of the vessel due to extensive dissection requiring emergency bypass surgery 1 . While late luminal enlargement and vascular remodelling could occur, more often constrictive vascular remodelling was the case instead, with consequent restenosis. The advent of bare metal stenting and the landmark BENESTENT trial have established bare metal stenting as the second revolution in interventional cardiology 2 . This technology provided a solution to acute vessel occlusion by sealing the dissection flaps and preventing recoil. The rate of subacute occlusion was reduced to 1.5%, making emergency by-pass surgery a rare occurrence, truly a thing of the past. Restenosis rates were further reduced from 32% to 22% at seven months, but this was still high, and neointimal hyperplasia still occurred, necessitating repeat revascularisation. Since the vessel was now caged with metal, late luminal enlargement and advantageous vascular remodelling no longer occurred. Another problem, namely that of late stent thrombosis, was also first described 3 . To solve the issue of in-stent restenosis - after the failure of brachytherapy - drug eluting stents were introduced. Indeed, the followup of the first 45 patients implanted with the sirolimus eluting Bx velocity stent (Cordis, Johnson & Johnson, Warren, NJ, USA) had negligible neointimal hyperplasia. This was confirmed in the RAVEL study 4,5 . Drug eluting stents were thus dubbed the third revolution in interventional cardiology. Both large scale randomised trials and allcomer registries showed excellent results in terms of the need for repeat revascularisation. This technology brought closer the results of percutaneous coronary intervention to that of coronary bypass graft surgery. Serruys’ “rosy” prophecy came true 6 , however, it soon turned out that, as in all true “roses”, this one also has its thorns. The thorn of the first generation of drug eluting stents was an increased risk of late stent thrombosis. Registries of all comers treated with drug eluting stents showed late stent thrombosis rates of 0.53% per year, with a continued increase to 3% over four years 7,8 . In patients with complex multivessel disease (ARTS II), the rate of combined definite, probable and possible stent thrombosis was as high as 9.4% at five years, accounting for 32% of MACE events 9 . In addition, the pathology showed uncovered struts and inflammatory reaction in post-mortem specimens. Vasomotion testing showed abnormal vasoconstriction response to acetylcholine distal to the stent, suggesting that the structure and function of the endothelium remained abnormal 10 . All

A.R.T.: concept of a bioresorbable stent without drug elution

Why bioresorbable stents? More than 20 years ago, interventional cardiology was launched by Andreas Gruntzig, introducing a revolutionary innovation, i.e., percutaneous balloon angioplasty1. The 316L stainless steel stent was initially introduced to tackle acute closure secondary to dissections following balloon angioplasty. In fact, the stent not only resolved the acute complications, but also appeared to be the appropriate response to the midterm complication, i.e., restenosis2,3. Indeed, the principal mechanism of restenosis after balloon angioplasty appeared to be related to chronic constrictive remodelling as a negative component of the healing process4-6. Nevertheless, the permanent (316L stainless steel) stent was the origin of a new disease, in-stent restenosis, corresponding to a foreign body reaction. Drug eluting stents were conceived to skip this particular healing process via cell cycle-inhibiting drugs in order to prevent in-stent restenosis. However, these drugs were cytotoxic, not only against smooth muscle cells, but also endothelial cells leading to late stent thrombosis and/or restenosis7,8. So, by inhibiting this inescapable healing process, we have delayed the occurrence of complications. The approach of Arterial Remodelling Technologies (A.R.T.) is to consider that the error resides in the discrepancy between the healing duration (i.e., a few months) and the immortal half life of the metallic stent, the source of new complications when it is no longer necessary: the bioresorbable stent acts as a transitory cast, scaffolding the artery wall during the healing process. Moreover, the healing process will induce endothelial coverage, a mandatory step for the midand long-term follow-up that will simplify one of the issues of drug eluting stents, i.e., expensive and prolonged dual antiplatelet therapy reducing the quality of life. The degradation of the bioresorbable stent will result in stent fragmentation, stopping the perpetual mechanico-genic stimulus produced by the stent’s overstretching of the arterial wall after the healing process. This can then restore the remodelling capacities of the artery wall itself, thus preserving its future, avoiding a growing accumulation of metal in the arteries9,10. Last but not least, the bioresorbable stent will not impair vasomotion after healing, namely at its extremities.

Abstract 5197: Arterial Remodeling Determines the Local Hemodynamic Environment and Subsequent Progression of Coronary Atherosclerotic Plaques: A Serial, Natural History Intravascular Ultrasound Study

Background Endothelial shear stress (ESS) is a critical determinant of plaque formation and arterial remodeling. Expansive remodeling is a feature of plaque vulnerability. Our purpose was to assess the role of remodeling and ESS in plaque progression throughout the natural history of atherosclerosis. Methods Intravascular ultrasound (IVUS)-based 3D reconstruction of all major coronary arteries (n=15) was performed in vivo at weeks 4, 11, 16, 23 and 36 in five diabetic, hyperlipidemic pigs. Each artery was divided into 3mm-long segments (n=304). We calculated ESS in all segments at all time points using computational fluid dynamics. Remodeling was characterized at all time points as excessive expansive, compensatory or constrictive. Plaque progression between consecutive time points was assessed by change of plaque area (ΔPlaque). Results The remodeling response to individual plaque formation changed substantially over time. Excessive expansive remodeling persistently developed in regions of very low ESS (Fig A ), further decreased the low ESS (p&lt;0.05), and was associated with the most marked additional plaque growth (Fig B ). Compensatory and constrictive remodeling generally resulted in increase of local ESS, and in less pronounced plaque progression (Fig A, B ). Conclusions This study provides new insight into the role of remodeling as a determinant of plaque progression. Excessive expansive remodeling exacerbates the pro-atherogenic low ESS environment, and promotes subsequent plaque growth. In contrast, attenuation of the low ESS stimulus occurs in lesions that elicit a compensatory, or constrictive remodeling response, leading to relative plaque quiescence.

Differential phosphoinositide 3-kinase signaling: implications for PTCA?

coronary revascularization by percutaneous transluminal coronary angioplasty (PTCA) has an ∼90% success rate immediately posttreatment (5). However, the procedure causes vascular injury by endothelial denudation and stretching of the vascular wall, leading to inward vascular remodeling. Endothelial cell (EC) removal exposes the underlying medial vascular smooth muscle cell (VSMC) layer to circulating growth factors and inflammatory cytokines, including platelet-derived growth factor (PDGF), thrombin, thromboxane A2, and adenosine diphosphate released from accumulating platelets (5). PDGF and thrombin are potent stimuli for VSMC proliferation and migration. Adenosine diphosphate binding to the platelet P2Y12 receptor causes enhanced platelet activation, thereby facilitating further PDGF release, as well as amplification of the response to thromboxane A2 and thrombin, thus playing a central role in thrombus formation. Balloon dilation stretches the vascular wall, resulting in activation of stretch-activated signaling pathways in medial VSMC and the adventitia, which results in further VSMC migration and proliferation. Consequently, vascular injury associated with PTCA often results in reocclusion of the artery, or restenosis, characterized by neointima formation and constrictive inward remodeling mediated by VSMC migration across the internal elastic lamina, VSMC proliferation, and extracellular matrix deposition.

Diet-induced hyperhomocysteinemia exacerbates vascular reverse remodeling of balloon-injured arteries in rat

While hyperhomocysteinemia is associated with an increased risk of cardiovascular diseases, the effect of hyperhomocysteinemia on the vascular adventitia and vessel remodeling has not been clearly demonstrated. We investigated the effect of the hyperhomocysteinemia on adventitial hyperplasia and vascular remodeling following balloon injury in rats and the underlying mechanisms. Rats were fed with diet containing methionine for 4 weeks to increase plasma homocysteine before balloon injury. Vascular geometrical changes were assessed at different time points following balloon injury. The collagen deposition was determined by picrosirius red staining and immunohistochemical staining. When compared with normal diet group, moderate hyperhomocysteinemia in methionine diet group significantly exacerbated adventitial hyperplasia at day 7 and collagen deposition mainly in the adventitia at day 28 following balloon injury. The increased plasma homocysteine level significantly increased collagen deposition in the adventitia. There was a negative correlation (r = -0.698; P < 0.01) between the luminal area and the collagen content in the adventitia on day 28 following balloon injury. In cultured adventitial fibroblasts isolated from rat aorta, 100 micromol/L L-homocysteine (L-Hcy) significantly down-regulated matrix metalloproteinase-2 activity by 43% as determined by in vitro gelatin zymography (P < 0.05) and up-regulated the expression of collagen type I by 187% (P < 0.05) assessed by Western blotting. Hyperhomocysteinemia exacerbated vascular constrictive remodeling by accelerated neointima formation and collagen accumulation in the adventitia. Increased collagen deposition may be the underlying mechanism.

Chemokines in Vascular Dysfunction and Remodeling

Vascular remodeling stands for structural changes of the vessel wall in response to various noxious stimuli, which results in reorganization of the vessel wall architecture. Luminal narrowing because of neointima formation and constrictive remodeling leading to hypoperfusion is the most relevant clinical effect. Smooth muscle cell (SMC) accumulation, inflammatory cell recruitment, and endothelial regeneration are the critical parts in obstructive vascular remodeling. Chemokines and chemokine receptors have a great impact on initiating and progressing neointimal formation by controlling each step of the remodeling process. SDF-1alpha regulates vascular repair by CXCR4-dependent smooth muscle progenitor cell recruitment, which contributes to the maladaptive response to injury. The three distinct chemokine-chemokine receptor pairs MCP-1/CCR2, RANTES/CCR5, and Fractalkine/CX(3)CR1 direct lesional leukocyte infiltration. In addition MCP-1/CCR2 and Fractalkine/CX(3)CR1 increase neointimal SMC expansion. In contrast, KC/Gro-alpha supports endothelial recovery through CXCR2, which attenuates neointima formation. These findings highlight the importance to characterize specific functions of the chemokine network to enable therapeutic intervention.

Vascular remodeling in ApoE-deficient mice: Diet dependent modulation after carotid ligation

Vascular remodeling is influenced by trauma and proatherogenic factors such as cholesterol. It has been shown that cholesterol exerts a direct effect on vessel wall structure. In this study we evaluated the effects of vascular trauma and cholesterol treatment on vascular remodeling and plaque integrity in carotid ligated ApoE-deficient mice. The right carotid artery was ligated in mice fed regular chow or cholesterol and fat containing diet. After 4 weeks left (non-ligated) and right (ligated) carotids were prepared. For studying vascular remodeling the vascular areas were evaluated morphometrically by calculating the areas from circumference measurements on Verhoff-van Gieson stains. The cellular and structural features of the plaque were analyzed by histological staining and immunohistochemistry. Under regular chow total vessel area decreased by 35% ( p < 0.001); cholesterol-rich diet led to an increase by 20% ( p < 0.05). In both feeding groups ligated carotids presented neointima development. The medial area increased only in mice fed regular chow. The luminal area was reduced by 80% (regular chow: p < 0.001) and by 90% (cholesterol-rich diet: p < 0.01). Regular chow led to structured plaques showing the typical features of stable plaques. Under cholesterol diet well defined plaque structures were missing. These lesions were characterized by numerous macrophages, few mostly PCNA positive smooth muscle cell (SMC) and less collagen particularly in the shoulder region. Our data indicate that in ApoE-deficient mice both direction of the remodeling response and lesion integrity are due to the diet applied: regular chow led to constrictive remodeling, whereas cholesterol and fat containing diet was associated with an adaptive response. Our data further indicate that the direction of response is not only related to the macrophage content but also to a proliferative intimal SMC-phenotype. Our data implicate that high serum cholesterol levels are not only inducers of plaque instability but also of the so far “positively recorded” compensatory remodeling.

CryoPlasty therapy of the superficial femoral and popliteal arteries: A reappraisal after 44 months' experience

Long-term patency remains a significant hurdle in the minimally invasive treatment of arteriosclerosis in the superficial femoral (SFA) and popliteal arteries. CryoPlasty therapy (PolarCath, Boston Scientific Corp, Natick, Mass) is a novel approach designed to significantly reduce injury, elastic recoil, neointimal hyperplasia, and constrictive remodeling. The technique combines the dilatation forces of percutaneous transluminal angioplasty (PTA) with cold thermal energy applied to the plaque and vessel wall. We previously reported a technical success rate of 96% and a 12-month freedom from restenosis rate of 82.2%. However, a review of the original cohort supplemented by experience with a further 47 lesions has demonstrated less desirable results. From December 2003 through July 2007, 92 lesions in 64 consecutive patients were treated and followed up for a median of 16 months with statistically significant follow-up at 24 months. The immediate technical success rate was 88%. Nine stents were immediately required after unsuccessful CryoPlasty (9.8%) five of which were as a result of a dissection. No unanticipated adverse events occurred, specifically, no thrombus, acute occlusions, distal embolizations, aneurysms, or groin complications. Vascular calcification was responsible for technical failure in six of the 11 immediately unsuccessful procedures. Freedom from restenosis for successfully treated lesions was 57% and 49% at 12 and 24 months, respectively. CryoPlasty of heavily calcified lesions, vein graft lesions, and in-stent stenosis faired poorly. Excluding these lesions from analysis would have resulted in an immediate success of 94% (81 of 86) and freedom from restenosis of 61% and 52% at 12 and 24 months, respectively. However, on an intention-to-treat basis, freedom from restenosis was 47% and 38% at 12 and 24 months, and CryoPlasty added approximately $1700 to the cost of each procedure. Analysis of this expanded, longer-term data suggests that our earlier, smaller study provided an overly optimistic appraisal of the benefits of CryoPlasty. It is possible that a larger analysis might have identified a subset of patients or lesions that would benefit from CryoPlasty, but considering the additional cost, we no longer use this technique in our practice.

Antiangiogenic Treatment Prevents Adventitial Constrictive Remodeling in Graft Arteriosclerosis

Lumen loss in graft arteriosclerosis is the consequence of the development of a thick neointima and constrictive arterial remodeling. The latter is due to adventitial chronic inflammation and excessive perivascular collagen deposition. We reasoned that blockade of the portal of entry of inflammatory effectors may constitute a strategy to prevent constrictive arterial remodeling. We found that an anti-angiogenic therapy (ABT-510 nonapeptide), devoid of direct immunomodulatory properties, dramatically reduced adventitial angiogenesis by 66% (P<0.0001) in the rat aortic interposition model of graft arteriosclerosis. The associated decreased entry of inflammatory cells (44%; P<0.00001) resulted in drastic reduction of collagen deposition (57%; P<0.0001) thereby preventing subsequent adventitial constrictive remodeling and reduction of lumen surface area (5.26+/-0.74 vs. 8.58+/-2.48 microm2; Control vs. ABT-510-treated rats; P<0.0001). ABT-510 had no effect on the development of the neointima. This work supports the idea that targeting angiogenesis may act synergistically with conventional immunosuppressive therapy in preventing graft arteriosclerosis, a crucial feature of chronic graft rejection.

Effect of local heating on restenosis and in-stent neointimal hyperplasia in the atherosclerotic rabbit model: a dose-ranging study

In-stent restenosis is related to neointimal hyperplasia. Heating reduces neointimal hyperplasia but promotes constrictive remodeling after balloon angioplasty. We aimed to assess the ability of local heating in inhibiting restenosis and in-stent neointimal hyperplasia and its potential side effects on arterial thrombosis. Atherosclerotic-like lesions were induced in iliac rabbit arteries. One month later, both iliac rabbit arteries were stented. In each animal, one artery was randomized to local heating at four temperatures (50, 60, 80, and 100 degrees C). The contra lateral artery was used as control. Angiographic and histomorphometric analysis were performed 42 days after angioplasty. Immunohistochemistry was performed 3, 15, and 42 days after angioplasty. Angiographic significant reduction of in-stent restenosis after moderate heating (50 degrees C) was related to in-stent neointimal hyperplasia trend to be lower after moderate local heating when compared with controls. In contrast, in-stent thrombosis was similar to controls. Higher temperatures (i.e. 80 and 100 degrees C) also reduced in-stent neointimal hyperplasia but were most frequently associated with severe in-stent thrombosis. Local heating was associated with decreased cell proliferation, collagen density, and increased smooth muscle cell apoptosis and heat shock protein expression. Moderate heating represents a promising approach to prevent in-stent restenosis via the limitation of the proliferative response without thrombosis induction.

Preventing restenosis after angioplasty: a multistage approach

Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow in atherosclerotic arteries. Restenosis of these arteries has remained a major limitation of the application of these procedures, especially in the case of balloon angioplasty. Post-angioplasty restenosis results from two major processes: neointimal formation and constrictive remodelling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to VSMC [vascular SM (smooth muscle) cell] migration from the tunica media to the intima. Migrated VSMCs contribute to the intimal thickening by the excessive synthesis of ECM (extracellular matrix) and proliferation. However, increased neointimal mass is not solely responsible for luminal narrowing. Inward constrictive remodelling is also considered as a major cause of delayed failure of angioplasty. At later stages after angioplasty, the increase in contractile forces leads to lumen narrowing. Recent studies show that SM contractile proteins are re-expressed in the neointima, concomitant with late lumen loss. Therefore one important question is whether the restoration of contractile phenotype, which can suppress VSMC migration, is favourable or detrimental. In this review, the importance of viewing restenosis as a multistage process is discussed. Different stages of restenosis occur in a sequential manner and are related to each other, but in each stage a different strategy should be taken into consideration to reduce restenosis. Defining the role of each process not only reshapes the current concept, but also helps us to target restenosis with more efficacy.

Urokinase stimulates inflammatory response in damaged vascular wall during in vivo arterial remodeling

Perivascular application of urokinase to the ballooned artery promoted the growth of neointima and constrictive remodeling of the vessel and stimulated the inflammatory response in the damaged vascular wall in vivo. Recombinant tissue plasminogen activator did not induce these changes. Our results indicate that urokinase is involved in the regulation of the inflammatory response during in vivo remodeling of the damaged vascular wall.

CryoPlasty Therapy of the Superficial Femoral and Popliteal Arteries: A Single Center Experience

Long-term patency remains a significant hurdle in the minimally invasive treatment of arteriosclerosis in the superficial femoral and popliteal arteries. New technologies designed to address the sources of restenosis have recently been introduced. CryoPlasty therapy (Boston Scientific, Natick, Mass) is a new approach designed to significantly reduce injury, elastic recoil, stent implantation, neointimal hyperplasia, and constrictive remodeling. The technique combines the dilatation forces of percutaneous transluminal angioplasty with cold thermal energy applied to the plaque and vessel wall. The cumulative effect of limiting the sources of restenosis with CryoPlasty therapy was shown to demonstrate longer term patency in a prospective, multicenter, Investigational Device Exemption study of the PolarCath Peripheral Dilatation System. The CryoPlasty therapy experience of 1 center is reported, in which 47 lesions in 32 consecutive patients (34 procedures, 33 limbs) were treated. The technical success rate was 96%. There were no type 3 flow-limiting dissections, and only 4 (8.5%) lesions were stented. There were no unanticipated adverse events, specifically no thrombus, acute occlusions, distal embolizations, aneurysms, or groin complications. With an average follow-up of 12 months, only 5 lesions have recurred, 4 requiring re-intervention. The 12-month freedom from restenosis for lesions and limbs treated was 82.2% and 84.4%, respectively. These results are similar to the findings of the Investigational Device Exemption study and are encouraging. CryoPlasty therapy appears to be a viable endovascular therapeutic option to achieve longer term patency without compromising options for future interventions. The lack of early occlusions may be due to a low rate of spiral dissection that may be a particular benefit of this form of angioplasty.