Development Of Myointimal Hyperplasia Research Articles

TGF-beta, A Cytokine Stimulating Restenosis: An Animal Model in the Mouse

Anastomotic restenosis remains a frequent factor of failure of the procedures of revascularization. TGF-beta is fully implied in the development of myointimal hyperplasia through its interaction with the vascular smooth muscular cells (SMC). Its role remains however discussed. On the assumption that TGF-beta stimulates restenosis, we developed an experimental model of restenosis in knock-out mice for TGF-beta, with the objectives of evaluating the patency of an arterial restoration as well as the degree of myointimal hyperplasia.

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

Immunotherapy for the Prevention of Myointimal Hyperplasia After Experimental Balloon Injury of the Rat Carotid Artery

We assessed the effect of novel immunotherapeutic heat-killed bacterial (Actinomycetales) preparations on the development of myointimal hyperplasia (MIH) in a rat carotid balloon trauma model and the effect on the immune response by measuring the expression of interferon gamma (IFN-gamma; (Th1) and interleukin 4 (IL-4; Th2). There was a significant reduction (P < .001) in intima/media ratios (mean +/- SEM) in the rats treated by immunomodulation (0.52 +/- 0.03 Gordonia bronchialis, 0.60 +/- 0.03 Rhodococcus coprophilus, 0.43 +/- 0.03 Tsukamurella inchonensis, 0.37 +/- 0.03 Mycobacterium vaccae), in comparison with untreated controls (0.91 +/- 0.05). Postballoon trauma G bronchialis increased messenger RNA (mRNA) IFN-gamma (P < .02) and reduced mRNA IL-4 (P < .05). R coprophilus, T inchonensis, and M vaccae significantly increased production of mRNA IFN-gamma (P < .001). R coprophilus and M vaccae also decreased production of mRNA IL-4 (P < .05, P < .01). Treatment with heat-killed Actinomycetales inhibits MIH through a combination of enhanced Th1 and attenuated Th2 response. Immunomodulation may provide a novel therapeutic option to prevent restenosis.

Low wall shear stress predicts subsequent development of wall hypertrophy in lower limb bypass grafts

Venous grafts commonly develop myointimal hyperplasia, which can lead to stenoses and, ultimately, with expression of adhesion molecules, lumenal occlusion. The aim of the present study was to investigate whether wall shear stress measured post-operatively would predict subsequent myointimal hypertrophy in lower limb venous bypass grafts. Magnetic resonance imaging and ultrasound were performed in a cohort of patients following lower limb venous bypass graft surgery for peripheral arterial disease at baseline (1-2 weeks) and at follow-up (9-12 months). Wall shear stress was determined at baseline using computational fluid dynamics techniques and intima-media thickness along the length of the graft was measured by ultrasound at baseline and follow up. Complete follow-up was possible in eight patients, in whom low wall shear stress at baseline predicted high intima-media thickness. The relationship between wall shear stress (WSS) and intima-media thickness (IMT) was curvilinear with IMT increasing sharply at lower levels of WSS (IMT >1.0 mm at <0.3 Pa). Low wall shear stress is associated with subsequent increase in myointimal thickness in lower limb venous bypass grafts. This is believed to be the first prospective study in humans to demonstrate the relationship between low wall shear stress and myointimal thickening and indicates a likely causative role for low wall shear stress in the development of myointimal hyperplasia.

Expression of C-reactive protein in myointimal hyperplasia in a porcine arteriovenous graft model

The migration and proliferation of myofibroblasts are prominent features of myointimal hyperplasia associated with haemodialysis polytetrafluoroethylene (PTFE) grafts. Since C-reactive protein (CRP) possesses functional activities on vascular smooth muscle cells (SMCs), we examined the expression of this protein in PTFE grafts early in the course of myointimal hyperplasia development in a porcine model. Bilateral carotid-jugular PTFE loop grafts were placed in pigs. After euthanasia at 2-4 weeks, the graft-venous and graft-arterial anastomoses and the adjacent blood vessels were excised en bloc and subjected to immunohistochemical analyses and in situ hybridization for CRP. The ability of CRP to stimulate proliferation was examined in cultured porcine venous SMCs using the bromodeoxyuridine assay after incubation for 48 h. Severe myointimal hyperplasia was found at 3 weeks after graft placement at both graft-venous and graft-arterial anastomoses. Compared to normal tissues, staining for CRP was far more intense in cells in the hyperplastic lesions at both anastomoses, which also stained positive for smooth muscle alpha-actin. In situ hybridization showed that these cells also expressed mRNA for CRP. At 1 microg/ml, CRP increased the proliferation of cultured porcine venous SMCs by 45.9+/-5.8%. CRP was produced in venous and arterial SMCs and its expression was enhanced in the hyperplastic lesions associated with arteriovenous PTFE grafts in a porcine model. Together with the ability of CRP to promote SMC proliferation, these data suggest that CRP might play a pathogenic role in the development of myointimal hyperplasia in PTFE grafts.

Differential effects of imatinib on PDGF‐induced proliferation and PDGF receptor signaling in human arterial and venous smooth muscle cells

Platelet-derived growth factor (PDGF) has been implicated in smooth muscle cell (SMC) proliferation, a key event in the development of myointimal hyperplasia in vascular grafts. Recent evidence suggests that the PDGF receptor (PDGFR) tyrosine kinase inhibitor, imatinib, can prevent arterial proliferative diseases. Because hyperplasia is far more common at the venous anastomosis than the arterial anastomosis in vascular grafts, we investigated whether imatinib also inhibited venous SMC (VSMC) proliferation, and examined possible differences in its mechanism of action between VSMC and arterial SMC (ASMC). Human ASMC and VSMC were stimulated with PDGF-AB, in the presence or absence of imatinib (0.1-10 microM). Proliferation was assayed using the 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, while PDGFR, Akt and ERK1/2-mitogen activated protein kinase (MAPK) signaling pathways were investigated by immunoblotting. The proliferative response to PDGF at 50 and 100 ng/ml was 32 and 43% greater, respectively, in VSMC than in ASMC. Similarly, PDGF-stimulated proliferation was more sensitive to inhibition by imatinib in VSMC than ASMC (IC(50) = 0.05 microM vs. 0.4 microM; P < 0.01). Imatinib also more effectively inhibited PDGF-induced phosphorylation of PDGFRbeta and Akt in VSMC, compared to ASMC. These data highlight inherent pharmacodynamic differences between VSMC and ASMC in receptor and cell signaling functions and suggest that imatinib therapy may be useful for the prevention of venous stenosis in vascular grafts.

In Vivo Attenuation of Myointimal Hyperplasia Using Transforming Growth Factor-Beta3 in an Interposition Graft Model

To examine if transforming growth factor-beta3 (TGFbeta3) can attenuate the development of para-anastomotic myointimal hyperplasia in an animal model of small-diameter vascular graft failure. Under general anesthesia, 10 adult goats underwent bilateral polyurethane interposition graft insertion in the carotid position. Following completion of the anastomoses, each artery received adventitial infiltration of 50 ng of TGFbeta3 around the anastomoses; a placebo was administered to the other side. Postoperatively, each animal received 150 mg of aspirin daily. The arteries were explanted, half at 6 weeks and the remaining 5 at 3 months, for histological examination. Vessel wall thickness surrounding the anastomosis was reduced by 37% in TGFbeta3-treated arteries compared to placebo at 6 weeks and 3 months, principally due to reduced smooth muscle cell proliferation. There was decreased overall luminal loss on angiography. Total collagen content was not significantly different between TGFbeta3 and placebo sides. Further analysis for the subendothelial matrix component collagen type VIII showed decreased levels on the treated side. Total elastin content was reduced on the TGFbeta3-treated side. Direct single-dose subadventitial infiltration of TGFbeta3 following insertion of an interposition graft reduces SMC proliferation and elastin content. It would appear that TGFbeta3 holds promise as a prophylaxis against the development of myointimal hyperplasia, the predominant cause of graft failure in peripheral bypass surgery.

Improving the patency of vascular bypass grafts: The role of suture materials and surgical techniques on reducing anastomotic compliance mismatch

Background: compliance mismatch is an important factor in the development of myointimal hyperplasia in both coronary and vascular anastomoses. This mismatch may be reduced by the use of newer suture materials and techniques. This review discusses the current techniques and materials used to date in generating anastomoses in both coronary and vascular applications and to correlate these with the degree of inherent compliance achieved. Methods: PubMed, ISIS, CAS and PAS database searches were performed. Other articles were cross-referenced. Results and Conclusion: continuous suture is still the most used technique in both cardiac and vascular surgery for the generation of anastomoses due to the reduced time and improved haemostasis. However, continuous suture results in a greater compliance mismatch than the interrupted technique. Vein cuffs and patches improve compliance and transmission of pulsatile blood flow and offer improvement of graft patency. Alternative to sutures are biological glue, clips and laser generated solders all of which have shown promising results, but further work is required before they become applicable for routine use.Eur J Vasc Endovasc Surg 25, 287-295 (2003)

Effect of endovascular stent strut geometry on vascular injury, myointimal hyperplasia, and restenosis

Purpose: Early restenosis and the development of myointimal hyperplasia in stented blood vessels have been attributed to deep vascular injury with fracture of the internal elastic lamina (IEL). The purpose of this study was the evaluation of the vascular wall response to superficial injury (without IEL rupture) after balloon angioplasty and intravascular stent placement in porcine arteries and the determination of the effect of stent strut geometry on the degree of vessel injury and early restenosis. Methods: Balloon-expandable stainless-steel stents were placed into the iliac arteries of 10 Sinclair miniature swine that had been fed an atherogenic diet. A Palmaz stent, with rectangular struts and smooth corners, was randomly assigned to one iliac artery (group 1), and a novel stent, which was designed and manufactured in the laboratory with thicker struts and sharper corners specifically to induce large wall stress concentrations, was placed in the contralateral iliac artery (group 2). Intravascular ultrasound scan was used in all deployments to ensure accurate balloon sizing and to avoid stent overexpansion and deep vascular injury. At 90 days after implantation, the animals were killed, the stented vessels harvested, and histomorphometric analysis performed. Results: Deployment of novel stents in group 2 resulted in a statistically higher incidence rate of deep vascular injury (fracture of the IEL) compared with group 1, despite identical balloon size used for deployment (with Student t test, P < .05). Vessels with deep injury showed a 10-fold increase in myointimal thickening compared with those vessels in which the IEL remained intact. A statistically higher restenosis rate was observed for group 2 (33.5% ± 19.90%) compared with group 1 (20.39% ± 14.70%). For both stent designs, there was a trend toward lower degrees of restenosis within the mid-portion of the stent. For superficially injured arteries in both groups, no correlation was observed between the amount of vessel wall/medial layer compression and the development of restenosis from myointimal hyperplasia. Conclusion: Maintenance of an intact IEL is an important factor in the prevention of myointimal hyperplasia and restenosis in stented porcine iliac arteries. The alteration of stent strut height and geometry does not significantly affect restenosis and the development of myointimal hyperplasia in vessels with superficial injury. Superficial injury elicits a response that is independent of stent strut geometry and vessel wall compression. Stent strut profile may, however, increase local vessel wall stress concentrations, leading to IEL rupture and an exaggerated response to injury. (J Vasc Surg 2002;36:143-9.)

Intraoperative flow predicts the development of stenosis in infrainguinal vein grafts

Objective: There are data to suggest that the development of myointimal hyperplasia is affected by long-term alterations in blood flow. However, the clinical relevance of these findings has not been demonstrated. Methods: In this retrospective clinical study, intraoperative volume flow measurement with transit time flowmeter was performed in 257 infrainguinal vein grafts carried out in 241 patients. The patients were enrolled in an intensive duplex scanning–based surveillance program. The relationship between the intraoperative graft flow and subsequent occlusion or development of stenosis was evaluated and controlled for other pertinent risk factors. Results: The median follow-up time was 13.6 months. A graft stenosis was found in 58 grafts. The mean graft flow for event-free grafts was 98 mL/min, which was significantly higher compared with 78 mL/min for stenosed or 69 mL/min for occluded grafts. The patients were divided into four groups according to quartiles of the sample distribution of graft flow measurements. The respective 2-year primary and assisted primary patency rates in the lowest to the highest graft flow groups were 39%, 49%, 47%, and 72% (P =.003) and 55%, 67%, 71%, and 84% (P =.01). Analogous significant differences were observed for maximal flow capacity measurements. Female sex (P =.009) and low graft flow in maximal flow capacity measurements (P =.003) were independent predictors of stenosis development in the multiple regression model. Conclusion: Intraoperative graft volume flow is a predictor of bypass occlusion after infrainguinal bypass. In addition, this study verifies an association between the development of clinically evident graft stenoses and low graft flow. (J Vasc Surg 2001;34:269-76.)

Interposition vein cuff anastomosis alters wall shear stress distribution in the recipient artery.

Interposition of a vein cuff between a prosthetic infrainguinal bypass graft and a recipient infrageniculate artery can improve graft patency. There is evidence that the improved performance may be explained by a redistribution of myointimal hyperplasia (MIH) away from the critical areas at the heel and toe of the cuff-artery anastomosis. It is widely accepted that there is an association between hemodynamic forces, more specifically, low wall shear stress (WSS), and the development of MIH. The aim of this study was to determine whether the reported redistribution of MIH in the interposition vein cuff (IVC) may be explained by differences in magnitude and distribution of WSS. Design of Study and Method: Detailed flow velocity measurements were made in life-size models of conventional end-to-side (ETS) and IVC anastomoses using a two-component laser Doppler anemometer under pulsatile flow conditions. Velocity vectors were determined in the plane of symmetry of the anastomosis, and the variation of WSS was estimated from near-wall velocity measurements on the floor and upper wall of the artery. The main flow features in the ETS anastomosis were flow separation at the graft hood, strong radial velocity at the heel, and a stagnation point on the floor of the artery that moved slightly during the flow cycle. In the IVC anastomosis, a coherent vortex that occupied most of the cuff volume was present from the systolic deceleration phase to end diastole. A stagnation point on the anastomosis floor was found to oscillate by about 4 mm. Critical regions of low mean WSS (ie, below 0.5 N/m(2)) were identified. In the ETS anastomosis, they were found at the heel and along the floor. In the IVC anastomosis, low mean WSS was found only on the floor, and it was generally less extensive than in the ETS anastomosis. The vein cuff anastomosis alters the mean WSS distribution within the recipient artery and removes the area of low WSS at the heel. This may explain the redistribution of MIH away from important sites in the recipient artery.

Healing after arterial dilatation with radiofrequency thermal and nonthermal balloon angioplasty systems.

Thermal balloon angioplasty has been proposed as a means of reducing acute and delayed reclosure of arteries after percutaneous transluminal balloon angioplasty. A radiofrequency (rf) balloon catheter was used to perform thermal balloon angioplasty on canine arteries in vivo. The histologic appearance of rf-treated sites was compared with that of control sites treated by conventional percutaneous transluminal angioplasty. Acutely, rf-treated sites showed a reduced medial cellularity with preservation of internal elastic lamina except at the transitional zone between thermal injury and normal artery, where localized internal elastic lamina disruption was found. Nonthermal sites showed generalized disruption of internal elastic lamina and normal medial cellularity. Both thermal and nonthermal sites displayed a return of intimal cover commencing at 1 to 2 weeks and completed by 4 weeks. Diffuse myointimal hyperplasia appeared by 2 weeks after injury at breaks in the internal elastic lamina along the nonthermal vessels but was localized to the transitional zone in thermal injury sites. In rf-treated vessels, repopulation of the acellular thermally modified media had commenced by 4 weeks, and by 8 weeks the media was diffusely repopulated by spindle-shaped cells resembling smooth muscle cells lying between and aligned with preserved connective tissue laminae. Overall, the distribution and extent of the proliferative response after rf thermal balloon angioplasty were less than those seen after nonthermal balloon angioplasty. Thermal sites, which underwent reintimalization before medial cells returned, were considerably less prone to the development of myointimal hyperplasia. These results suggest that this modality may have beneficial effects on arterial healing after angioplasty.

Dose responsive suppression of myointimal hyperplasia by dexamethasone.

The effect of increasing doses of dexamethasone on the development of myointimal hyperplasia in the rabbit carotid artery was studied by use of a balloon catheter injury model. Seventy New Zealand white rabbits underwent a standardized 2F balloon catheter stripping of the left carotid intima. The animals were randomly assigned to one of seven groups, each receiving daily injections of either saline (group I, N = 10) or graded doses of dexamethasone: 0.025 mg/kg (group II, N = 10); 0.050 mg/kg (group III, N = 10); 0.075 mg/kg (group IV, N = 10); 0.100 mg/kg (group V, N = 10); 0.125 mg/kg (group VI, N = 10); 0.150 mg/kg (group VII, N = 10). Injections were started 2 days before the intimal injury and continued daily, five times a week, for 8 weeks. The vessels were harvested 12 weeks after injury, and the ratio of the absolute area of intimal hyperplasia to the normalized area enclosed by the internal elastic lamina was measured as an index of myointimal hyperplasia. Also, at the time of harvest, blood flow (ml/min) was measured and the resistance delta P/flow (mm Hg/ml/min) calculated for each vessel in vivo. Twelve-week patency rates were 60% in the control group I, 90% in groups II and III, and 100% in groups IV, V, VI, and VII. The value for the intimal hyperplasia/internal elastic lamina index, expressed as a percent, was 22.2 +/- 3.7 for control group I, 17.7 +/- 2.1 group II, 14.8 +/- 3.0 group III, 12.8 +/- 2.4 group IV, 11.5 +/- 1.8 group V, 5.4 +/- 1.3 group VI, and 3.9 +/- 1.1 for group VII.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose responsive suppression of myointimal hyperplasia by dexamethasone

The effect of increasing doses of dexamethasone on the development of myointimal hyperplasia in the rabbit carotid artery was studied by use of a balloon catheter injury model. Seventy New Zealand white rabbits underwent a standardized 2F balloon catheter stripping of the left carotid intima. The animals were randomly assigned to one of seven groups, each receiving daily injections of either saline (group I, N = 10) or graded doses of dexamethasone: 0.025 mg/kg (group II, N = 10); 0.050 mg/kg (group II, N = 10); 0.075 mg/kg (group IV, N = 10); 0.100 mg/kg (group V, N = 10); 0.125 mg/kg (group VI, N = 10); 0.150 mg/kg (group VII, N = 10). Injections were started 2 days before the intimal injury and continued daily, five times a week, for 8 weeks. The vessels were harvested 12 weeks after injury, and the ratio of the absolute area of intimal hyperplasia to the normalized area enclosed by the internal elastic lamina was measured as an index of myointimal hyperplasia. Also, at the time of harvest, blood flow (ml/min) was measured and the resistance ΔP/flow (mm Hg/ml/min) calculated for each vessel in vivo. Twelve-week patency rates were 60% in the control group I, 90% in groups II and III, and 100% in groups IV, V, VI, and VII. The value for the intimal hyperplasia/internal elastic lamina index, expressed as a percent, was 22.2 ± 3.7 for control group I, 17.7 ± 2.1 group II, 14.8 ± 3.0 group III, 12.8 ± 2.4 group IV, 11.5 ± 1.8 group V, 5.4 ± 1.3 group VI, and 3.9 ± 1.1 for group VII. The calculated values for the ΔP/flow in mm Hg/ml/min were 51.6 ± 3.7, 47.4 ± 4.5, 19.3 ± 6.7, 20.2 ± 7.4, 6.2 ± 4.1, 5.1 ± 1.9, and 8.3 ± 6.5 for groups I to VII, respectively. The observed decrease in the intimal hyperplasia/interval elastic lamina index by dexamethasone is dose related. The lowest dose at which this decrease reaches statistical significance, compared with control, is group III (0.050 mg/kg,p < 0.05). In addition, this observed reduction in myointimal hyperplasia, by histologic criteria, is reflected by an improvement in the measured hemodynamic parameters. Again, the studied dose at which the measured in vivo parameters reach statistical significance is 0.050 mg/kg. We conclude that in the rabbit, dexamethasone is effective in suppressing the hyperplastic myointimal reaction to an intimal injury and that this response is dose dependent. In addition, the minimal effective dose required to achieve this effect is 0.050 mg/kg, and no further significant improvement is noted above 0.125 mg/kg.

Myointimal Hyperplasia: Pathogenesis and Implications. 2. Animal Injury Models and Mechanical Factors

Arterial wall injury either by balloon catheter, drying, or scraping results in a denudation of endothelial cells (EC) and a subsequent proliferation of smooth-muscle cells (SMC). The degree of SMC proliferation appears to be dependent on the degree of initial injury and not to the loss of the overlying endothelium. Successful reendothelialization of denuded areas depends on the size of the denuded segment as well as SMC-EC interactions. Prolonged exposure of SMC to serum substances results in inhibition of EC regrowth, the production of prostacyclin by SMC, and the development of a thromboresistant surface. Heparin appears to inhibit SMC proliferation in vivo (as well as in vitro), an effect that is independent of platelet SMC interaction. EC-derived heparin in vivo may also result in inhibition of SMC proliferation. Platelets may play an important role in the early response to arterial injury and development of myointimal hyperplasia (MIH), but their long-term role appears to be minor. Antiplatelet agents have widely varying species-dependent effects on platelets and platelet-vessel wall interactions, but in specific circumstances they may inhibit MIH. The precise role of steroid drugs and immunosuppression on MIH in arterial injury models awaits further study. The role of lipoproteins in MIH is unclear; however, the inhibition of MIH by omega-3 fatty acids in vivo as well as their inhibition of platelet-derived growth factor production by EC in vitro implies a regulatory role. Acute hypertension results in a marked proliferation of EC and SMC in vivo and enhances the proliferative response to injury as well. Low wall shear stress, turbulence, and boundary layer separation all increase EC turnover, a likely influence on EC growth factor production. The compliance mismatch resulting from graft-artery anastomoses, injury, and endarterectomy results in locally increased cyclical stretch, which may predispose to SMC proliferation.

The early and late responses of the arterial wall to graft placement

The relationship between the early smooth muscle cell proliferative response (SMC-PR) to injury and the later development of myointimal hyperplasia (MIH) complicating arterial bypass grafts remains unclear. In the present study, the early SMC-PR and the later MIH induced by a 2-mm-diameter PTFE graft placed in a rabbit carotid were compared with the response induced by an autogenous artery (AA) graft in the contralateral carotid. The early SMC-PR was measured in the proximal and distal arterial segments 5 days after graft placement by in vivo labeling with [ 3H]thymidine to determine the DNA specific activity (DNA-SA). The later anastomotic MIH was measured 16 and 32 weeks postgrafting by calculating the intimal/medial ratio. There was a marked and similar increase in the early SMC-PR noted with both the AA and the polytetrafluoroethylene (PTFE) grafts. The distal segments demonstrated a significantly higher DNA-SA when compared to the proximal in both AA- and PTFE-grafted arteries. There was a moderate degree of anastomotic MIH noted in chronic grafts; however, a regression in intimal thickening was observed over time in the AA-grafted arteries, while the distal anastomosis of the PTFE-grafted vessels demonstrated a continuous progression of the MIH process. The early SMC-PR may abate in arteries grafted with autogenous grafts, but there is a persistent proliferative response at the distal anastomosis associated with synthetic grafts.

Early myointimal hyperplasia after balloon catheter embolectomy: effect of shear forces and multiple withdrawals.

Arterial stenosis occurring after balloon catheter embolectomy may be caused by myointimal hyperplasia (MIH). This study investigated the effects of shear force and repeated catheter withdrawals on the development of MIH after embolectomy. The procedures were performed in the common carotid and common femoral arteries of 18 anesthetized dogs. During catheter withdrawal, the balloons were filled gradually to produce shear forces rising smoothly from 50 to 200 gm. Four weeks after embolectomy, the vessels were perfusion-fixed in situ with 2% glutaraldehyde and were excised. The thickness and circumferential extent of MIH were measured in cross sections from segments of the vessels exposed to shear forces of 50, 100, and 200 gm. Sixty-nine of 72 arteries remained patent. Low shear force (50 gm) consistently elicited less MIH than did higher shear forces (p less than 0.05). At each level of shear force, repeated withdrawals resulted in greater circumferential extent of MIH than did single withdrawals (p less than 0.005). Although clinically it usually is necessary to perform multiple passes during balloon embolectomy, these data suggest that, in humans, attempts should be made to perform a minimal number of catheter withdrawals at low shear force to minimize the subsequent development of MIH.

Aging and arteriosclerosis. I. Development of myointimal hyperplasia after endothelial injury.

Old Fischer 344 rats are more susceptible to vascular lesions after arterial endothelial injury than are young animals. Thus, 20-26-mo-old Fischer 344 rats developed greater and more persistent intimal proliferative lesions than did 2-5-mo-old rats after aortic endothelial denudation. 3 d after deendothelialization, intimal thickness was increased two-fold in both old and young animals. However, 14 d after endothelial injury, intimal thickness had increased nearly five times in old animals, but had regressed to normal in young animals. Intimal thickness of young aortic grafts transplanted into young recipients did not differ significantly from adjacent host aorta or autotransplanted aortic segments 6 wk after surgery. In contrast, intimal thickness of old grafts transplanted into young recipients was eight times greater than adjacent young host aorta 6 wk after surgery. The density of cell nuclei in the intima of old grafts was also much greater than that in young grafts. Thus, in two experimental models of vascular injury, old rats have consistently had greater myointimal hyperplasia than young rats. The increased proliferative response of aortic smooth muscle cells after vascular injury of old animals may contribute to the increased prevalence of vascular disease with age.