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.

improved patency of transjugular intrahepatic portosystemic shunt: the efficacy of cilostazol for the prevention of pseudointimal hyperplasia in swine TIPS models.

PURPOSE: To investigate the efficacy of oral administration of cilostazol to inhibit pseudointimal/intimal hyperplasia in swine TIPS models. METHODS: Successful TIPS creation was carried out in 11 of 12 healthy young pigs (20-25 kg). In the treatment group (n = 6), both cilostazol and aspirin were administered daily, from the first day of TIPS creation. The control group (n = 5) was administered only aspirin. The animals were followed-up for 2 weeks and then killed. The specimen (including portal vein, hepatic parenchymal tract, hepatic vein, and inferior vena cava) and stents were carefully bisected in a longitudinal fashion. The control group was compared with the treatment group by means of a gross and histologic evaluation of the degree of pseudointimal/intimal hyperplasia in the shunt. RESULTS: At the gross evaluation, the control group showed considerably more pseudointimal/intimal hyperplasia than the treatment group. Using microscopic evaluation, there was a statistically significant difference (p < 0.05) in the mean maximum pseudointimal/intimal hyperplasia thickness between the control group (2.97 +/- 0.33 mm) and treatment group (0.73 +/- 0.27 mm). CONCLUSION: Oral administration of cilostazol may have been effective in reducing pseudointimal/intimal hyperplasia in swine TIPS models.

Cardiac allograft vasculopathy: pathology, prevention and treatment.

PURPOSE OF REVIEW: Cardiac transplantation is a recognized therapy for end-stage heart failure. Graft coronary artery disease is a chief determinant of long-term survival following cardiac transplantation. There are multiple purported etiologies for graft coronary artery disease including both immunologic and nonimmunologic factors. Immunologic factors include human leukocyte antigen mismatching, cytokine production, and activation of the cellular immune system. Nonimmunologic factors include diabetes, hypertension, hyperlipidemia, and cytomegalovirus infection, just to name a few. There are also donor and recipient factors including age, prior coronary artery disease in the donor heart, and mode of donor brain death. RECENT FINDINGS: The diagnosis of graft coronary artery disease is especially difficult, partially due to the de-innervated allograft, as well as to its inherent predilection to affect the medium-sized and smaller arteries in a concentric and diffuse nature. Conventional angiography can overlook this condition because of the lack of eccentric plaques in larger epicardial arteries. Intravascular ultrasonography, by contrast, is more sensitive in detecting graft coronary artery disease but is unable to visualize the entire arterial system. Treatment is challenging and often unrewarding, leading to re-transplantation. Prevention is therefore ideal and involves protection against endothelial injury before and during transplantation as well as after transplantation, with decreased ischemic time, aggressive attention to early rejection, risk factor modification, and close follow-up. SUMMARY: This review will look at the pathophysiology of graft coronary artery disease, current diagnostic and therapeutic choices, as well as existing and future directions.

Does a carbon ion-implanted surface reduce the restenosis rate of coronary stents?

BACKGROUND: Neointimal hyperplasia and resulting restenosis limit the long-term success of coronary stenting. Heavy metal ions induce an inflammatory and allergic reaction, and result in in-stent restenosis. However, a carbon ion-implanted surface might prevent heavy metal ions from diffusing into surrounding tissue. METHODS: 140 lesions in 140 patients with coronary lesions underwent implantation of carbon-implanted surface stents (Arthos(inert) stent group, n=70) or control stents (Arthos stent group, n=70). The primary end point was the in-stent restenosis and the secondary end point was the value of hs-CRP at 48 h and 6 months after coronary stenting. Clinical and angiographic follow-ups were performed at 6 months. RESULTS: The rate of in-stent restenosis was lower in the Arthos(inert) stent group (15.9%, 10/63) than in the Arthos stent group (20.9%, 13/62), but there were no significant differences between both groups (p=0.56). The value of hs-CRP at 48 h was lower in the Arthos(inert) stent group (13.9+/-13.4 mg/dl) than in the Arthos stent group (24.5+/-26.0 mg/dl) with significant differences (p=0.04). However, the differences between two groups were not statistically significant at 6 months (p=0.76). CONCLUSIONS: As compared with a standard coronary stent, a carbon ion-implanted stent shows no considerable benefit for the prevention of in-stent restenosis within the range of this study. Despite all the limitations of this study, a positive effect of a carbon ion-implanted stent in reducing inflammatory reaction after coronary revascularization seems likely.

Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry.

OBJECTIVES: This study was designed to evaluate whether rapid endothelialization of stainless steel stents with a functional endothelium prevents stent thrombosis and reduces the restenotic process. BACKGROUND: A "pro-healing" approach for prevention of post-stenting restenosis is theoretically favored over the use of cytotoxic or cytostatic local pharmacologic therapies. It is believed that the central role of the vascular endothelium is to maintain quiescence of the underlying media and adventitia. METHODS: Sixteen patients with de novo coronary artery disease were successfully treated with implantation of endothelial progenitor cell (EPC) capture stents. RESULTS: Complete procedural and angiographic success was achieved in all 16 patients. The nine-month composite major adverse cardiac and cerebrovascular events (MACCE) rate was 6.3% as a result of a symptom-driven target vessel revascularization in a single patient. There were no other MACCE despite only one month of clopidogrel treatment. At six-month follow-up, mean angiographic late luminal loss was 0.63 +/- 0.52 mm, and percent stent volume obstruction by intravascular ultrasound analysis was 27.2 +/- 20.9%. CONCLUSIONS: This first human clinical investigation of this technology demonstrates that the EPC capture coronary stent is safe and feasible for the treatment of de novo coronary artery disease. Further developments in this technology are warranted to evaluate the efficacy of this device for the treatment of coronary artery disease.

Elimination of vascular fibrointimal hyperplasia by somatostatin receptor 1,4-selective agonist.

The somatostatin analogs octreotide and lanreotide, selective to receptor subtypes 2 and 5, failed clinical efficacy for the prevention of restenosis after percutaneous transluminal angioplasty. These findings might have been the result of targeting a wrong subset of receptors. In rat arteries, subtypes 1 and 4 are expressed 3-4 times more prominently than 2 and 5, and subtype 1 is the nearly exclusive subtype in atherosclerotic human vessels. Here, we demonstrate that daily s.c. injections (50-500 microg/kg/d) of CH275 (DesAA1,2,5(D-W8,IAmp9)Somatostatine-14), selective to subtypes 1 and 4, dose-dependently inhibited intimal hyperplasia 14 days after rat carotid denudation injury (for intimal area P=0.0002 across the dose range). CH275 was more effective than somatostatin-14 (equal affinity to all five subtypes, P=0.03), or octreotide (selective to subtypes 2 and 5, P=0.098). When rats were given the peptides for 14 days with end-point at 28 days, CH275 still significantly inhibited intimal area expansion. Both CH275 and octreotide inhibited the outgrowth of cells from postinjury aortic tissue punch-explants and the distance migrated in vitro, but not cell replication, which indicated that the effects of somatostatin analogs were directed on the migration of intimal cell progenitors rather than on their proliferation.

Infusion of an antialpha4 integrin antibody is associated with less neoadventitial formation after balloon injury of porcine coronary arteries.

BACKGROUND: The alpha4beta1 (or very late antigen-4 [VLA-4]) integrin is thought to play a role in inflammatory processes, mediating mononuclear leukocyte infiltration. The adventitial response to balloon injury is an important determinant of neointimal formation and arterial remodelling. OBJECTIVES: To determine whether the monoclonal antibody hHP1/2 directed against the human alpha4-integrin subunit decreases neoadventitial formation and subsequent luminal narrowing following balloon injury. DESIGN: Randomized, double-blind, placebo controlled study. SETTING: Tertiary care, Canadian university hospital vascular biology laboratory. ANIMALS AND METHODS: In 16 pigs, two coronary arteries were injured with an oversized balloon, while a third coronary artery was designated as an uninjured control vessel. One hour before balloon injury, 5 mg/kg of hHP1/2 was administered to eight animals, while another eight animals received an infusion of a saline placebo. Animals were killed three and 14 days following balloon injury. MAIN RESULTS: Administration of hHP1/2 resulted in an immediate decrease in circulating monocyte and lymphocyte counts. These parameters returned to normal within three days. There was a decrease in neoadventitial formation 14 days after arterial injury in pigs treated with hHP1/2 compared with controls (2.26+/-0.77 versus 3.42+/-1.01 mm, respectively, P=0.04). There was a loss of lumen area between days 3 (4.33+/-1.09 mm2) and 14 (3.09+/-0.38 mm2, P=0.02) after balloon injury in pigs treated with saline, but not in the pigs treated with hHP1/2. CONCLUSIONS: Administration of an antibody to the alpha4-integrin subunit is associated with less neoadventitial formation and less lumenal narrowing after balloon injury. This novel therapy may play an important role in modulating arterial remodelling and thereby may reduce restenosis following percutaneous coronary interventions in humans.

A rationale for targeting antithrombotic therapy at the vessel wall: improved antithrombotic effect and decreased risk of bleeding.

Intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) or vascular surgical procedures remains a significant problem despite current antithrombotic therapy. The use of the current antithrombotic drugs, namely heparin + chronic aspirin (ASA) +/- oral anticoagulants, is based upon the assumptions that: i) heparin blocks thrombin generation and/or accelerates thrombin inhibition by antithrombin III (ATIII); ii) aspirin acetylates platelet cyclooxygenase, thereby preventing thromboxane A2 (TxA2) synthesis; and iii) oral anticoagulants reduce the availability of vitamin K-dependent procoagulants, thereby reducing the risk of thrombus formation. Albeit beneficial, this approach has a number of shortcomings and limitations: i) when thrombin binds to an injured vessel wall, it becomes resistant to inhibition by heparin/ATIII; thus, surface-bound thrombin remains active, stimulating further thrombus formation, smooth muscle cell proliferation and subsequent hyperplasia; ii) while TxA2 inhibition reduces platelet reactivity, platelets are able to respond to multiple stimuli generated at the time of, or after, vessel wall injury; and iii) heparin, aspirin and the oral anticoagulants all render the patient hemostatically defective and at risk of bleeding. Recent studies suggest that alternate therapeutic approaches can inhibit thrombogenesis more effectively at the time of injury, thereby not only inhibiting hyperplasia more effectively than the currently used drugs, but also reducing (or eliminating) the need for long-term therapy. For example, we suggest that the heparin cofactor II (HCII) catalysts, dermatan sulfate and Intimatan, inhibit surface-bound thrombin more effectively than heparin/ATIII, thereby inhibiting intimal hyperplasia effectively. Their effects are achieved when the drug is given only at the time of injury; i.e. with no further antithrombotic therapy. Other studies indicate that injured vessel wall thrombogenicity can be reduced by pretreatment with Persantine (dipyridamole) or with certain fatty acid supplements which either increase vessel wall cAMP and/or 13HODE synthesis. These increases are associated with decreased vessel wall thrombogenicity, which, in turn, is associated with decreased intimal hyperplasia. Such results suggest that vessel wall repair is achieved more effectively by targeting antithrombotic drugs directly at the vessel wall thrombogenicity per se rather than indirectly by altering the circulating blood cells and systemic coagulant system.

Chronic estrogen replacement inhibits aortic intimal hyperplasia independent of serum lipids.

The role of estrogens in providing atheroprotection has been well documented in both epidemiologic and experimental studies. This phenomenon has traditionally been attributed to the beneficial lipid-modifying effects of estrogens. Yet lipid alterations may not be the sole mechanism of estrogen-mediated cardiovascular protection. Previous studies have utilized models of either diet- or injury-induced atherosclerosis. As such, the interrelationship between estrogens, lipids, and atherosclerosis remains unclear. The purpose of this study was to determine the effect of ovariectomy with or without estrogen replacement on the development of aortic intimal hyperplasia. Although we acknowledge the influence of estrogens on the lipid profile, we hypothesized that estrogens are atheroprotective independent of changes in serum lipids. Twelve Warhill ewes (7-11 years old) were randomized to sham (2 sheep) operation, ovariectomy (OVx-5 sheep), or ovariectomy with 17 beta-estradiol replacement (OVxE-5 sheep). Serum cholesterol and triglyceride levels were measured at 0, 6, and 12 months. Necropsy was performed at 6 and 12 months with histologic morphometric analysis of the aortoiliac bifurcation. Ovariectomy resulted in intimal thickening in comparison to the sham (p < 0.0001) and hormone replacement group (p < 0.0001). Serum cholesterol and triglyceride levels were similar and normal (40-60 mg/dl) among all groups. Estradiol abrogates aortic intimal hyperplasia following ovariectomy independent of the hormone's effects on lipid metabolism.