Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts.

OBJECTIVES: Neointima formation and wall thickening caused by smooth muscle cell proliferation compromise long-term patency of human aorto-coronary vein-grafts. We investigated short- and long-term effects of anti-proliferative pharmacological agents on experimental pig vein-grafts with similar dimensions and kinetics to human coronary grafts. METHODS AND RESULTS: Saphenous veins were treated for 1 h ex vivo with vehicle or concentrations of cytochalasin D, paclitaxel or rapamycin found to be anti-proliferative in preliminary studies. Vehicle and treated veins were implanted contralaterally, end-to-end into the carotid arteries of pigs. Cytochalasin D 2.5 mug/ml non-significantly reduced neointima formation in 4-week vein-grafts (mean+/-standard error, 2.5+/-0.6 vs. 3.3+/-0.6 mm2, n = 10, p = NS), whilst paclitaxel 10 microM produced significant inhibition (1.7+/-0.2 vs. 3.0+/-0.3 mm2, n = 8, p < 0.01) as did rapamycin 0.1 mg/ml (0.6+/-0.3 vs. 1.7+/-0.5 mm(2), n = 8, p < 0.02). Similar effects were found on total wall cross-sectional area but medial area was unaffected. PCNA staining of 1-week vein grafts confirmed in vivo anti-proliferative effects of paclitaxel (21+/-2 vs. 36+/-3%, n = 5, p < 0.01) and rapamycin (32+/-1 vs. 57+/-6%, n = 6, p < 0.005); neither agent stimulated loss of endothelium at these concentrations. Neointima and total wall area increased significantly between 4- and 12-weeks in all vein-grafts such that there was no longer a significant effect on neointima formation of either paclitaxel (7.5+/-1.3 vs. 8.9+/-1.9 mm2 in control, n = 5, p = NS) or rapamycin (6.0+/-0.9 vs. 7.9+/-1.1 mm2 in control, n = 9, p = NS) or on total wall area in 12-week grafts. CONCLUSIONS: Pre-treatment of saphenous vein with anti-proliferative agents paclitaxel or rapamycin reduced neointima and total wall area after 4 weeks but continued growth abolished differences by 12 weeks. These results may help to understand the failure of clinical studies using anti-proliferative treatments in vein-grafts.

Stent-based delivery of tissue inhibitor of metalloproteinase-3 adenovirus inhibits neointimal formation in porcine coronary arteries.

BACKGROUND: Stent-based antiproliferative therapy appears to decrease in-stent restenosis. However, alternative approaches might produce equivalent efficacy with better long-term safety. In previous work, an adenovirus capable of expressing the tissue inhibitor of metalloproteinase-3 (RAdTIMP-3) inhibited neointima formation in cell cultures and porcine saphenous vein grafts. RAdTIMP-3 decreased smooth muscle cell migration, stabilized the extracellular matrix, and uniquely promoted apoptosis. The current study developed eluting stent technology to deliver RAdTIMP-3 during stenting of pig coronary arteries. METHODS AND RESULTS: Binding of virus to and elution from stents and transduction of pig coronary arteries were confirmed using beta-galactosidase as a reporter gene in vitro and in vivo. Deployment of RAdTIMP-3-coated stents increased apoptosis and reduced neointimal cell density, but did not increase inflammation or proliferation compared with beta-galactosidase-expressing adenovirus (RAdlacZ). Neointimal area after 28 days was significantly reduced to 1.27+/-0.19 mm2 with RAdTIMP-3 versus 2.61+/-0.31 mm2 with RAdlacZ stents (P<0.001) and 2.12+/-0.20 mm2 with bare stents (P<0.005). CONCLUSIONS: Our results demonstrate for the first time to our knowledge the feasibility of adenovirus-coated stent technology and highlight the potential of TIMP-3 to produce significant inhibition of in-stent neointima formation.

Effects of local all-trans-retinoic acid delivery on experimental atherosclerosis in the rabbit carotid artery.

BACKGROUND: Retinoids regulate a variety of biological processes and play an important role in cell differentiation and proliferation. All-trans retinoid acid (atRA) is known to inhibit smooth muscle cell growth and thus is supposed to have favorable effects on the incidence of restenosis after percutaneous coronary interventions. The broad biological spectrum, however, leads to numerous severe side effects which limit the clinical use of a systemic application of atRA. In order to avoid systemic side effects, local delivery of atRA is preferable. The aim of this study was to evaluate the effects of atRA on the response to injury in a second-injury model of experimental balloon angioplasty. METHODS: After induction of a fibromuscular plaque in the right carotid artery of 40 New Zealand rabbits, 35 animals underwent balloon angioplasty of the preformed plaque formation. Subsequent local atRA delivery (10 ml, 10 microM) with the double-balloon catheter was performed in 15 animals. Five animals received vehicle only as sham controls, and five animals were solely electrostimulated, 15 animals served as control group with balloon angioplasty only. Vessels were excised 7 days (n=15) and 28 days (n=30) after intervention. Immunocytochemistry with antibodies against smooth muscle alpha-actin and myosin, bromodeoxyuridine, macrophages, collagen I and III and von Willebrand factor was performed. Quantitative analysis was done by computerized morphometry. RESULTS: After local atRA delivery in vivo, the extent of stenosis was markedly reduced with 21.7+/-8.3% (mean+/-S.D.) 4 weeks after intervention compared to 31.8+/-13.4% in balloon-dilated animals (P=0.0937). Both a reduced early neointimal proliferation (P=0.0002) and an increase in overall vessel diameter (4 weeks after intervention, P=0.0264) contributed to a limitation of restenosis in atRA-treated animals. Immunocytochemistry revealed a more intense alpha-actin staining pattern after local atRA therapy indicating redifferentiating effects of atRA on vascular smooth muscle cells. CONCLUSIONS: Local delivery of atRA led to limitation of restenosis formation in this animal model. The concept of a local atRA therapy might be a promising way to exploit the potential of atRA for vascular indications while minimizing the severe side effects of systemic retinoid therapy.

Low-molecular-weight heparin therapy for non-ST-elevation acute coronary syndromes and during percutaneous coronary intervention: an expert consensus.

BACKGROUND: Therapy with either low-molecular-weight heparin (LMWH) or glycoprotein (GP) IIb/IIIa receptor antagonists is of benefit to patients with acute coronary syndromes (ACSs). However, algorithms that define how LMWH may be used in patients, proceeding from medical management to intervention and in conjunction with GP IIb/IIIa inhibitors, are lacking. The objectives of this task force were to formulate recommendations based on all available data for the use of LMWH, both with and without GP IIb/IIIa receptor antagonists, and to provide seamless integration of care during the transition from medical to interventional management. METHODS AND RESULTS: An international task force of 14 cardiologists with extensive experience in clinical trials was convened in New York in February 2001 to address issues related to the use of LMWH in patients with non-ST-elevation ACS. Evidence from randomized trials, observational studies, and other reports was discussed, and consensus recommendations were formulated. CONCLUSIONS: Substantial evidence exists that patients receiving LMWH for an ACS can safely undergo cardiac catheterization and percutaneous coronary intervention. Concerns regarding the transition of these patients from the medical service to the cardiac catheterization laboratory should therefore not impede the upstream use of LMWH. Furthermore, LMWH and GP IIb/IIIa receptor antagonists can be used safely in combination, with no apparent increase in the risk of major bleeding. Consensus algorithms for therapy are presented.

Occlusion versus shunting during MIDCAB: effects on left ventricular function and quality of anastomosis.

BACKGROUND: Minimally invasive direct coronary artery bypass is an established clinical procedure for revascularization of the left anterior descending coronary artery. Mechanical stabilization and temporary occlusion is currently used to perform the anastomosis of the internal thoracic artery to the left anterior descending coronary artery. However, critical reduction of cardiac function can occur as a result of temporary ischemia. The purpose of this study was to evaluate whether ischemic sequelae can be avoided by using temporary intraluminal shunts and whether this alters early outcome. METHODS: Thirty-five patients underwent minimally invasive direct coronary artery bypass revascularization using a mechanical stabilizer. In group A (n = 20), the anastomotic site was temporarily occluded by tourniquets. In group B (n = 15), temporary intraluminal shunts were inserted into the anastomotic site without any occlusion of the left anterior descending coronary artery. Anastomosis of the internal thoracic artery to the left anterior descending coronary artery was performed in an identical fashion. A Swan-Ganz catheter was inserted, and transesophageal echocardiographic measurements were obtained for analysis of left ventricular (LV) function. Regional wall motion, cardiac index, stroke volume index, systolic and diastolic LV diameters, and fractional area change were measured during four periods: at the start of the operation (baseline), placement of the stabilizer (stabilization), left anterior descending coronary artery occlusion (occlusion) or insertion of temporary intraluminal shunts (shunt), and 30 minutes after reperfusion (reperfusion). Angiograms were obtained 4 to 6 days postoperatively. RESULTS: In group A, LV performance, cardiac index, stroke volume index, and fractional area change decreased during occlusion whereas systolic diameters increased. Almost two myocardial segments per patient developed severe hypokinesia in the perfusion area. These changes disappeared after 30 minutes of reperfusion, with increased LV function. In group B, LV function remained stable whereas hypokinetic wall motion was only detected in 2 patients. Early angiograms revealed 90% of the grafts were patent in group A versus 100% in group B. The need for percutaneous intervention during the first 6 months was 20% in group A versus 6.7% in group B. CONCLUSIONS: The use of temporary intraluminal shunts resulted in reduced acute ischemia and revealed wall motion abnormalities and maintained LV function. Furthermore, this technique suggests an improvement of early graft patency and a lower reintervention rate within the first 6 postoperative months. Thus, use of temporary intraluminal shunts appears to be superior to the occlusion technique early after minimally invasive direct coronary artery bypass procedures.

Effects of atorvastatin on in-stent stenosis in normo- and hypercholesterolemic rabbits.

BACKGROUND: In-stent stenosis is characterized by a prolonged proliferation and inflammatory reactions around the stent struts. Potentially the antiproliferative and lipid-lowering effects of atorvastatin can synergistically limit neointima formation after stenting. METHODS: Palmaz-Schatz stents were placed in the iliac arteries of white New Zealand rabbits. One half of the animals was fed an 0.5% hypercholesterolemic diet, the other half was normocholesterolemic. Both groups received either atorvastatin (3 mg/kg bodyweight) daily or placebo (n=10 each in the four groups). After 28 days the segments were excised. RESULTS: Injury scores as a result of vessel trauma induced by stent-overstretch injury differed significantly between the four groups (median 1.0-1.9) and the stent-induced injury outweighed the beneficial effects of statin therapy on neointima formation by far. Smooth-muscle-cell proliferation was significantly increased in both hypercholesterolemic groups. Intimal and medial proliferation as well as inflammatory infiltrates around the stent strut were reduced by 20-40% in animals that received statin therapy although the injury score in both statin groups was 19 and 60% higher than in control animals. CONCLUSION: Thus, the data of this study indicate that smooth muscle cell proliferation and inflammation in stented vessels can be reduced by atorvastatin both in hypercholesterolemic rabbits and in animals with normal lipid levels.

Influence of heart rate on vessel visibility in noninvasive coronary angiography using new multislice computed tomography: experience in 94 patients.

OBJECTIVES: Initial reports indicate that coronary artery lesions might be visualized with high sensitivity and specificity by the use of recently introduced multislice computed tomography (MSCT). Current CT technology offers a temporal resolution of 250 ms. In case of heart rates (HRs) >65 beats/min (bpm), however, the reconstruction software switches from a single-phase algorithm (using data from one heart cycle only) to a biphase algorithm using image data of two consecutive heart cycles, improving temporal resolution to down to 125 ms. Thus, it was the aim of the present study to evaluate the influence of the patients' (pts) HR on image quality expressed by vessel segment visibility. METHODS AND RESULTS: MSCT scans (Somatom VZ) were performed in 94 pts. Ten coronary segments were analyzed in each patient with regard to image quality (RCA: segments [sgts] 1-4, LMS: sgt 5, LAD: sgts 5-8, LCX: sgts 11, 12). A total of 697 of 940 (74.1%) sgts were accurately visualizable (RCA: 244/376 [64.9%], LMS: 94/94 [100%], LAD: 232/283 (82.3%), LCX: 146/188 [77.7%]). Beta-blocker therapy had a significant influence on mean HR (65 pts on beta-blocker, HR 65.1+/-10.7 bpm vs. 29 pts, HR 71.6+/-12.2 bpm, P=.01). A significant inverse correlation between HR and segmental visibility was found (r=-.48, P<.0001), with best visibility in pts with lower HRs (n=14 pts with 10 analyzable sgts, HR 60+/-10.1 vs. n=8 pts with 4 analyzable sgts, HR 79.9+/-6.9, P<.0001). CONCLUSIONS: Our results indicate that vessel visibility is highly dependent on the pts HR. Best vessel visibility was found in pts with HR <65 bpm with single-phase image reconstruction. Thus, it appears to be advisable to evaluate, and if needed, to lower the pts HRs before undergoing MSCT coronary angiography in order to achieve best image quality.

Effect of a dihydropyridine-type calcium channel blocker on vascular remodeling after experimental balloon angioplasty.

OBJECTIVE: Aim of the study was to evaluate the influence of the dihydropyridine derivative BW 9798 on intimal hyperplasia in a carotid artery injury model of New Zealand White rabbits on a high cholesterol diet. METHODS: In carotid arteries of 50 New Zealand White rabbits atherosclerotic lesions were induced by cholesterol diet and electrostimulation of the artery. In 40 animals the resulting primary lesion was subjected to balloon angioplasty (BA). Three days prior to BA animals received BW 9798 or placebo per os until sacrifice three days or 28 days after BA. RESULTS: BW 9798 lead to increased cross sectional area by 128.3% and an increased luminal area by 157% after 28 days after BA compared with placebo. However the degree of stenosis did not significantly decrease. The cell count of the different layers of the arteries decreased by 64.5% in the intima and by 62.6% compared with placebo treated animals after BA. Additionally the number of smooth muscle cell (SMC) layers in the neointima was significantly lower in BW 9798 treated animals than in placebo animals (8±3 vs 14±9, p<0.05) although the proliferation was not changed by BW 9798 treatment 3 days after BA. CONCLUSION: BW 9798 leads to significant changes in vessel wall geometry although the influence on vascular remodeling of this compound is unclear. It can be speculated that the compound affects the homeostasis of extracellular matrix, invasion of inflammatory cells into the vessel wall and the expression of cytokines. However, further investigation needs to clarify the role of BW 9798 on remodelling after BA.

Coronary collateral circulation: effect on early and midterm outcomes after off-pump coronary artery bypass surgery.

BACKGROUND: The purpose of this study was to assess the prognostic effect of coronary collaterals on early and midterm clinical outcomes in patients undergoing first time isolated off-pump coronary artery bypass (OPCAB) surgery. METHODS: Preoperative angiograms from 861 patients were evaluated to assess the presence and extent of coronary collaterals (Rentrop classification). Coronary collaterals (CC) were present in 485 (56.3%) patients (CC group). Patients with coronary collaterals had a higher incidence of preoperative myocardial infarction, lower ejection fraction, and higher Parsonnet scores compared with patients without coronary collaterals (no-CC group). RESULTS: Coronary collaterals were associated with myocardial protection during OPCAB surgery, as evidenced by a significantly lower incidence of intraoperative ST-segment changes (propensity matched cohort, p = 0.008). No other statistically significant differences in in-hospital outcomes were detected between the two groups. Five years after surgery patient survival was 84.8% (95% confidence interval [CI] 79.4 to 88.8) in the CC group compared with 89.2% (95% CI 84.4 to 92.6) in the no-CC group (p = 0.48). Cardiac-related event-free survival after 5 years was 50.6% (95% CI 43.5 to 57.3) in the CC group and 54.5% (95% CI 47.1 to 61.4) in the no-CC group (p = 0.96), with no significant differences between both groups, before or after risk adjustment, or when comparing propensity-matched cohort. CONCLUSIONS: Although patients with coronary collaterals had more extensive coronary artery disease, poor left ventricular function, and more cardiac risk factors than patients without collaterals, the early and midterm clinical outcome after OPCAB surgery was comparable between the two groups.

Multislice computed tomography coronary angiography in patients admitted with a suspected acute coronary syndrome.

OBJECTIVES: The aim of this prospective clinical study was to assess the accuracy and clinical relevance of multislice computed tomography coronary angiography (MSCTCA) in patients presenting with acute chest pain. BACKGROUND: Multislice computed tomography coronary angiography has shown ability to detect accurately coronary artery disease (CAD) in selected elective patient groups. METHODS: One hundred and twenty patients presenting with acute chest pain (<24 h) underwent MSCTCA (Siemens Sensation 16) before a scheduled inpatient conventional coronary angiogram (CCA). Exclusion criteria included patients with STEMI, non-sinus rhythm, contraindication to beta blockers and renal impairment. Blinded visual assessment of MSCTCA to detect CAD was performed on an 11-segment model. The accuracy of MSCTCA was compared to CCA to detect significant stenoses (> or =50%). RESULTS: One hundred and thirteen patients underwent both investigations. The prevalence of significant CAD was 74%. 1,243 native segments were assessed by MSCTCA. The overall ability of MSCTCA to detect the presence of > or =1 significant stenosis in all native segments had a sensitivity of 92% (95%CI 83-97%), specificity of 55% (95%CI 35-74%), positive predictive value of 86% (95%CI 76-93%) and negative predictive value of 70% (95%CI 47-87%). 22% of all segments (mostly distal) were non-analyzable. Coronary calcification was a major cause of false positivity. CONCLUSION: In a prospective study of unselected patients presenting with acute chest pain, the diagnostic accuracy of 16-slice CT coronary angiography was moderate and less than reported from studies in elective patients. The clinical relevance of this technology to screen patients with acute chest pain is limited.

An update on clinical and pharmacological aspects of drug-eluting stents.

The introduction of stents to clinical practice was the major breakthrough in the field of percutaneous coronary intervention. The introduction of stents was associated with two serious complications, the first was increase in subacute thrombosis within the first 30 days of stent implantation later controlled with the use of high pressure inflation and dual antiplatelet therapy, the second was the phenomenon of in-stent restenosis that was primarily caused by smooth muscle proliferation. While coronary stenting eliminates elastic recoil, it is unable to inhibit excessive neointimal formation. Stents were associated with an increase of neointimal formation compared to balloon angioplasty as a result of excessive injury to the vessel wall and the inflammatory process from interaction of metal with vessel wall. Local delivery of the potential agents for inhibition of neointimal formation to the site of the lesion was considered the desired approach. Several compounds have been tested for stent coating, primarily with the aim of the inhibition of SMC proliferation. Recently, new stents have emerged which are loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs. In this review article the results of clinical studies investigating drug-eluting stents are discussed from pharmacological and clinical points of view, reviewing the current literature and the future prospective.

Comparison of radiation doses from multislice computed tomography coronary angiography and conventional diagnostic angiography.

OBJECTIVES: The aim of this study was to quantify and compare effective doses from conventional angiography and multislice computed tomography (MSCT) coronary angiography using a 16-slice scanner. BACKGROUND: Multislice computed tomography is now a viable modality for cardiac imaging. However, for any diagnostic use of ionizing radiation, the risk to the patient must be considered and justified. METHODS: Multislice computed tomography angiography and conventional angiography were used to assess 180 patients with suspected coronary artery disease. Estimates of effective dose were derived from exposure data recorded for each patient examination. For each modality, a comparable calculation technique was used, based on Monte Carlo modeling of the standard Cristy phantom. RESULTS: In a subset of 91 directly comparable patients the mean effective dose for MSCT coronary angiography was 14.7 mSv (SD 2.2) and that for conventional angiography was 5.6 mSv (SD 3.6). A significant difference in effective dose was seen between the two protocols. CONCLUSIONS: The mean effective dose for MSCT coronary angiography was significantly higher than that for conventional angiography. As MSCT cardiac scanners become increasingly available, operators must be aware of the radiation dose and the factors that affect it.

Ultrasound guidance: technique and results of aggressive ultrasound-guided PTCA. The UPSIZE Pilot Trial.

Stenting results in a larger lumen than conventional balloon angioplasty. This is the major determinant of a good acute and long-term result. In this non-randomised, single centre trial, intravascular ultrasound was used preinterventionally to guide the choice of the balloon size. The aim was to achieve a maximum lumen area with balloon angioplasty only. We included 346 patients with 360 lesions. The diameter of the external elastic lamina by intravascular ultrasound was 4.67 mm. A mean balloon size of 4.0 mm was chosen. The initial luminal gain was 1.82 mm, the lumen area post intervention was 6.6 mm(2). Dissections occurred frequently but the incidence of major adverse events was not increased. At one year follow-up, the overall event free survival was 81%. Target lesion revascularisation was performed in 34 patients (10%). An angiographic follow-up was available for 261 patients (76%). Restenosis (> 50% diameter Stenosis) was found in 21%. The results show, that ultrasound guidance of balloon angioplasty provides a means to achieve a large initial luminal gain without the routine use of stents. The acute and long-term results suggest that the approach is safe and efficient. The data compare favorably with similar studies using advanced intravascular diagnostic tools to guide the angioplasty procedure.