Extracorporeal Life Support and New Therapeutic Strategies for Cardiac Arrest Caused by Acute Myocardial Infarction - a Critical Approach for a Critical Condition.

This review summarizes the most recent developments in providing advanced supportive measures for cardiopulmonary resuscitation, and the results obtained using these new therapies in patients with cardiac arrest caused by acute myocardial infarction (AMI). Also detailed are new approaches such as extracorporeal cardiopulmonary resuscitation (ECPR), intra-arrest percutaneous coronary intervention, or the regional models for systems of care aiming to reduce the critical times from cardiac arrest to initiation of ECPR and coronary revascularization.

Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents in patients with multivessel coronary artery disease compared to coronary artery bypass surgery five-years after intervention.

OBJECTIVES: Cost-effectiveness of percutaneous coronary intervention (PCI) using drug-eluting stents (DES), and coronary artery bypass surgery (CABG) was analyzed in patients with multivessel coronary artery disease over a 5-year follow-up. BACKGROUND: DES implantation reducing revascularization rate and associated costs might be attractive for health economics as compared to CABG. METHODS: Consecutive patients with multivessel DES-PCI (n = 114, 3.3 ± 1.2 DES/patient) or CABG (n = 85, 2.7 ± 0.9 grafts/patient) were included prospectively. Primary endpoint was cost-benefit of multivessel DES-PCI over CABG, and the incremental cost-effectiveness ratio (ICER) was calculated. Secondary endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE), including acute myocardial infarction (AMI), all-cause death, revascularization, and stroke. RESULTS: Despite multiple uses for DES, in-hospital costs were significantly less for PCI than CABG, with 4551 €/patient difference between the groups. At 5-years, the overall costs remained higher for CABG patients (mean difference 5400 € between groups). Cost-effectiveness planes including all patients or subgroups of elderly patients, diabetic patients, or Syntax score >32 indicated that CABG is a more effective, more costly treatment mode for multivessel disease. At the 5-year follow-up, a higher incidence of MACCE (37.7% vs. 25.8%; log rank P = 0.048) and a trend towards more AMI/death/stroke (25.4% vs. 21.2%, log rank P = 0.359) was observed in PCI as compared to CABG. ICER indicated 45615 € or 126683 € to prevent one MACCE or AMI/death/stroke if CABG is performed. CONCLUSIONS: Cost-effectiveness analysis of DES-PCI vs. CABG demonstrated that CABG is the most effective, but most costly, treatment for preventing MACCE in patients with multivessel disease.

Valvuloplasty with a paclitaxel-eluting balloon prevents restenosis in an experimental animal model of aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Restenosis occurs invariably within 12 months following balloon valvuloplasty (BAV) in calcific aortic valve disease (CAVD), and is a limiting factor of this treatment. Cellular proliferation secondary to balloon injury is thought to play a pivotal role in the mechanism of restenosis. The study aim was to investigate the potential role of a paclitaxel-eluting valvuloplasty balloon to mitigate the progression of restenosis in an animal model of CAVD. METHODS: Fifty-three rabbits were fed with an aortic stenosis (AS)-inducing diet (cholesterol 0.5% plus vitamin D3 50,000 IU/day) for three months. The surviving animals (n = 40) underwent echocardiographic and invasive assessments, followed by valvuloplasty, randomly using either a paclitaxel-coated (3 µg/mm2) or a plain balloon. At one month after BAV, the surviving animals (n = 28) underwent repeat assessments, followed by histology and micro-computed tomography (MicroCT) analysis of the aortic valve. RESULTS: The baseline and post-BAV transvalvular gradients, aortic valve area (AVA), left ventricular stroke work loss (SWL) and aortic valve resistance (AVR) were similar between the groups (14 rabbits were assigned to paclitaxel-eluting, and 14 to plain balloon). Significant differences between the groups were observed at one-month post-BAV, which was suggestive of diminished restenosis in the paclitaxel-balloon group (mean maximum transvalvular pressure gradient 7.7 ± 7.7 versus 3.6 ± 3.7 mmHg, p = 0.08; AVA 0.91 ± 0.59 versus 0.55 ± 0.22 cm2, p = 0.04; SWL 3.5 ± 4.0 versus 8.6 ± 8.0%, p = 0.047; AVR 86 ± 71 versus 177 ± 137 dynes/s/cm(-5), p = 0.039). Histology demonstrated decreased leaflet thickness (0.60 ± 0.15 versus 0.71 ± 0.17 mm, p = 0.03), proliferating cell nuclear antigen (PCNA) staining (grade 1.53 ± 0.04 versus 2.24 ± 0.55, p = 0.049), and calcification in the paclitaxel-balloon group. CONCLUSION: Use of a paclitaxel-eluting valvuloplasty balloon in an animal model of AS resulted in attenuated restenosis, secondary to decrease in valve proliferation and calcification.

Comparison of short- and long-term results of drug-eluting vs. bare metal stenting in the porcine internal carotid artery.

PURPOSE: To evaluate the development of neointimal hyperplasia after implantation of drug-eluting stents (paclitaxel) compared to bare metal stents in porcine internal carotid arteries (ICAs). METHODS: While drug-eluting stents have effectively reduced neointimal proliferation in porcine external carotid arteries, the porcine internal carotid artery (ICA) is more sensitive to shear stress and altered flow conditions. Thus, a study was conducted to evaluate bare vs. drug-eluting stents in porcine ICAs. Under general anesthesia, 18 domestic pigs were implanted with paclitaxel-eluting (n = 18) and bare (n = 18) stents in the left and right ICAs, respectively. After 1 and 3 months, control carotid angiography was performed, followed by histopathological and histomorphometric analyses of the stented ICA. RESULTS: Histopathological results (fibrin deposition, necrosis, inflammation) were similar in the groups at 1 and 3 months. Moreover, the injury score and rate of endothelialization did not differ between the groups. Histomorphometric analysis after 1 month revealed significantly (p<0.05) less neointimal hyperplasia after implantation of paclitaxel-eluting stents. The antiproliferative effect of paclitaxel-eluting stents were maintained during the 3-month follow-up: the neointimal area was 0.7 ± 0.5 vs. 1.2 ± 0.6 mm(2) (p<0.01), the area stenosis was 23.5% ± 13.9% vs. 37.8% ± 14.4% (p<0.01), the maximal neointimal thickness was 0.2 ± 0.1 vs. 0.2 ± 0.9 mm (p<0.05) in paclitaxel-eluting vs. bare stents, respectively. Implantation of paclitaxel-eluting and bare stents did not lead to edge restenosis or vessel remodeling in porcine ICAs at 1 or 3 months. CONCLUSION: Compared to bare metal stents, drug-eluting stents implanted in the porcine ICA produced significantly less neointimal hyperplasia.

Drug-eluting introducer sheath prevents local peripheral complications: pre-clinical evaluation of nitric oxide-coated sheath.

OBJECTIVES: This study evaluated the protective effect of nitric oxide-coating of introducer sheath on the local complications in juvenile porcine femoral arteries with similar size to human radial arteries. BACKGROUND: Insertion of an introducer sheath induces vasospasm and transient or permanent vessel occlusion of radial arteries. METHODS: Nitric oxide-coated or control introducer sheaths with or without spasmolytic cocktail (control + C-sheath) were inserted into porcine femoral arteries, followed by percutaneous coronary intervention (PCI). The diameter of the femoral artery at the puncture site, distally and proximally, was measured by quantitative angiography. Histopathological and histomorphometric parameters of the femoral arteries were analyzed 1 h or 1 week after PCI. RESULTS: Insertion of femoral sheath led to mild or severe spasms, with significantly higher vessel diameter at the access site (2.69 ± 0.81 mm vs. 1.77 ± 0.77 mm and 1.85 ± 0.66 mm, p < 0.001), and proximal and distal to it, during PCI in the nitric oxide-sheath group versus the control-sheath and control + C-sheath groups, respectively. Immediately following PCI, significantly less luminal thrombosis (12% vs. 33% and 31% of all analyzed segments, p < 0.001) was observed in the nitric oxide-sheath arteries. At 1 week, lower intimal inflammation score (0.43 ± 11 vs. 1.03 ± 0.35 and 1.04 ± 0.32, p < 0.05), less luminal thrombosis (8% vs. 21% and 30% p < 0.05), and smaller intimal hyperplasia (0.31 ± 0.31 mm(2) vs. 0.47 ± 1.00 mm(2) and 0.86 ± 0.82 mm(2), p < 0.05) were observed in NO-sheath arteries at the injury site. CONCLUSIONS: Nitric oxide coating on the introducer sheath prevents local complications during PCI and results in less vascular thrombosis and inflammation at the access site, contributing to patency of the access vessel with similar size to the radial artery.

A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial.

AIMS: Genes encoding vascular endothelial growth factor (VEGF) can potentially augment myocardial perfusion in patients with coronary artery disease (CAD). We conducted a randomised, double-blind, placebo-controlled gene therapy study with the adenovirus carrying VEGF121 (BIOBYPASS [AdGVVEGF121.10NH]). METHODS AND RESULTS: Seventeen patients with severe CAD were 2:1 randomised to BIOBYPASS (n=12; 61 years) or placebo (n=5; 64) as 12 intra-myocardial injections into the ischaemic area using the NOGA XP® system. The study was terminated prematurely due to a company product portfolio decision. Mean change in total exercise duration from baseline to 12, 26 and 52 weeks was 20.2, 21.4 and 16.4 sec in BIOBYPASS treated and 46.2, 31.4 and 12.4 sec in placebo (NS). Change from baseline to at least 1 mm ST depression during exercise at 12, 26 and 52 weeks did not differ between BIOBYPASS and placebo. Change in stress-induced ischaemia score was similar in the BIOBYPASS (3.4%) and placebo (2.0%) groups. An improvement in symptoms was seen in patients treated with BIOBYPASS, but no difference between the groups. CONCLUSIONS: Direct intramyocardial injection of BIOBYPASS (AdGVVEGF121.10NH) was safe but did not improve exercise capacity, time to ischaemic threshold or myocardial perfusion compared to sham injection in patients with refractory myocardial ischaemia.

Rationale and design of EXPLORE: a randomized, prospective, multicenter trial investigating the impact of recanalization of a chronic total occlusion on left ventricular function in patients after primary percutaneous coronary intervention for acute ST-elevation myocardial infarction.

BACKGROUND: In the setting of primary percutaneous coronary intervention, patients with a chronic total occlusion in a non-infarct related artery were recently identified as a high-risk subgroup. It is unclear whether ST-elevation myocardial infarction patients with a chronic total occlusion in a non-infarct related artery should undergo additional percutaneous coronary intervention of the chronic total occlusion on top of optimal medical therapy shortly after primary percutaneous coronary intervention. Possible beneficial effects include reduction in adverse left ventricular remodeling and preservation of global left ventricular function and improved clinical outcome during future coronary events. METHODS/DESIGN: The Evaluating Xience V and left ventricular function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction (EXPLORE) trial is a randomized, prospective, multicenter, two-arm trial with blinded evaluation of endpoints. Three hundred patients after primary percutaneous coronary intervention for ST-elevation myocardial infarction with a chronic total occlusion in a non-infarct related artery are randomized to either elective percutaneous coronary intervention of the chronic total occlusion within seven days or standard medical treatment. When assigned to the invasive arm, an everolimus-eluting coronary stent is used. Primary endpoints are left ventricular ejection fraction and left ventricular end-diastolic volume assessed by cardiac Magnetic Resonance Imaging at four months. Clinical follow-up will continue until five years. DISCUSSION: The ongoing EXPLORE trial is the first randomized clinical trial powered to investigate whether recanalization of a chronic total occlusion in a non-infarct related artery after primary percutaneous coronary intervention for ST-elevation myocardial infarction results in a better preserved residual left ventricular ejection fraction, reduced end-diastolic volume and enhanced clinical outcome. TRIAL REGISTRATION: trialregister.nl NTR1108.

Differential effect of ischaemic preconditioning on mobilisation and recruitment of haematopoietic and mesenchymal stem cells in porcine myocardial ischaemia-reperfusion.

Effects of ischaemic preconditioning (IP) on the mobilisation and recruitment of haematopoietic (HSCs) and mesenchymal stem (MSC) cells were determined in porcine coronary occlusion/reperfusion. Thirty-three pigs underwent percutaneous occlusion of the left anterior descending coronary artery (LAD) for 90 minutes (min), followed by 120 min reperfusion. IP was performed in 16 of the 33 pigs by two cycles of 5 min balloon occlusion/reperfusion prior to the 90 min occlusion (group IP vs. group C). Peripheral blood and myocardial tissue concentration of bone marrow origin HSCs (characterised by coexpression of CD31+, CD90+, CD45+) and MSCs (characterised by coexpression of CD44+, CD90+, CD45-) were measured by flow cytometry in the early phase of IP. Plasma/serum levels of stem cell mobilisation factors (stromal cell-derived factor-1a [SDF-1a], vascular endothelial growth factor [VEGF], tumour necrosis factor a[TNF-a] and interleukin-8 [IL-8]) were measured. IP led to a significant increase in circulating HSCs as compared with the group C (475 +/- 233 vs. 281 +/- 264 /ml, p=0.032) in the early phase of IP. In contrast, a rapid and prolonged decrease in level of circulating MSCs was observed in group IP as compared with group C (19 +/- 12 vs. 32 +/- 17 /ml, p=0.015). The recruitment of HSCs and MSCs in infarct and border zone was significantly greater in IP group, indicating a faster homing of MSCs as compared with the rate of mobilisation. Rapid increase in VEGF, TNF-a and IL-8 levels was induced by IP, which, however, was not correlated with the levels of circulating SCs. In conclusion, IP resulted in differential mobilisation and recruitment of HSCs and MSCs in the early phase of cardioprotection.

Effect of intramyocardial delivery of autologous bone marrow mononuclear stem cells on the regional myocardial perfusion. NOGA-guided subanalysis of the MYSTAR prospective randomised study.

The aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30-45% received BM-MNC by intramyocardial followed by intracoronary injection 68 +/- 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 +/- 10.7% to 24.1 +/- 11.5%, p<0.001), and global EF increased (from 38 +/- 6.1% to 41.5 +/- 8.4%, p<0.001) three months after BM-MNC delivery. Analysis of ROI resulted in a significant increase in unipolar voltage (index of myocardial viability) (from 7.9 +/- 3.0 mV to 9.9 +/- 2.7 mV at FUP, p<0.001) and local linear shortening (index of local wall motion disturbances) (from 11.0 +/- 3.9% to 12.7 +/- 3.4%, p=0.01). NOGA-guided analysis of the intramyocardially treated area revealed a significantly increased tracer uptake both at rest (from 56.7 +/- 16.1% to 62.9 +/- 14.2%, p=0.003) and at stress (from 59.3 +/- 14.2% to 62.3 +/- 14.9%, p=0.01). Patients exhibiting >or=5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.

2-year results of the AUTAX (Austrian Multivessel TAXUS-Stent) registry beyond the SYNTAX (synergy between percutaneous coronary intervention with TAXUS and cardiac surgery) study.

OBJECTIVES: The multicenter AUTAX (Austrian Multivessel TAXUS-Stent) registry investigated the 2-year clinical/angiographic outcomes of patients with multivessel coronary artery disease after implantation of TAXUS Express stents (Boston Scientific, Natick, Massachusetts), in a "real-world" setting. BACKGROUND: The AUTAX registry included patients with 2- or 3-vessel disease, with/without previous percutaneous coronary intervention (PCI) and concomitant surgery. METHODS: Patients (n = 441, 64 +/- 12 years, 78% men) (n = 1,080 lesions) with possible complete revascularization by PCI were prospectively included. Median clinical follow-up was 753 (quartiles 728 to 775) days after PCI in 95.7%, with control angiography of 78% at 6 months. The primary end point was the composite of major adverse cardiac (nonfatal acute myocardial infarction [AMI], all-cause mortality, target lesion revascularization [TLR]) and cerebrovascular events (MACCE). Potential risk factor effects on 2-year MACCE were evaluated using Cox regression. RESULTS: Complete revascularization was successful in 90.5%, with left main PCI of 6.8%. Rates of acute, subacute, and late stent thrombosis were 0.7%, 0.5%, and 0.5%. Two-year follow-up identified AMI (1.4%), death (3.6%), stroke (0.2%), and TLR (13.1%), for a composite MACCE of 18.3%. The binary restenosis rate was 10.8%. The median of cumulative SYNTAX score was 23.0 (range 12.0 to 56.5). The SYNTAX score did not predict TLR or MACCE, due to lack of scoring of restenotic or bypass stenoses (29.8%). Age (hazard ratio [HR]: 1.03, p = 0.019) and acute coronary syndrome (HR: 2.1, p = 0.001) were significant predictors of 2-year MACCE. Incomplete revascularization predicted death or AMI (HR: 3.84, p = 0.002). CONCLUSIONS: With the aim of complete revascularization, TAXUS stent implantations can be safe for patients with multivessel disease. The AUTAX registry including patients with post-PCI lesions provides additional information to the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) study. (Austrian Multivessel TAXUS-Stent Registry; NCT00738686).

Successful recanalization of a chronic occluded left anterior descending coronary artery with a modification of the retrograde proximal true lumen puncture technique: the antegrade microcatheter probing technique.

Chronic total occlusions (CTO) still remain one of the most technically challenging fields in interventional cardiology. Here we report a case of successful retrograde recanalization of an occluded proximal left anterior descending coronary artery with a modification of the "retrograde proximal true lumen puncture" technique. By combining this strategy with a novel antegrade guide wire access through a microcatheter which was placed into the antegrade guiding catheter with the "reverse anchoring balloon" technique (the "antegrade microcatheter probing" technique), the need for retrograde CTO lesion dilatations has been eliminated, making the procedure easier and faster. This modified retrograde approach might provide a feasible and safe technique for antegrade guide wire access during retrograde CTO recanalization.

Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study.

BACKGROUND: Combined intracoronary and intramyocardial administration might improve outcomes for bone-marrow-derived stem cell therapy for acute myocardial infarction (AMI). We compared the safety and feasibility of early and late delivery of stem cells with combined therapy approaches. METHODS: Patients with left ventricular ejection fraction less than 45% after AMI were randomly assigned stem cell delivery via intramyocardial injection and intracoronary infusion 3-6 weeks or 3-4 months after AMI. Primary end points were changes in infarct size and left ventricular ejection fraction 3 months after therapy. RESULTS: A total of 60 patients were treated. The mean changes in infarct size at 3 months were -3.5 +/- 5.1% (95% CI -5.5% to -1.5%, P = 0.001) in the early group and -3.9 +/- 5.6% (95% CI -6.1% to -1.6%, P = 0.002) in the late group, and changes in ejection fraction were 3.5 +/- 5.6% (95% CI 1.3-5.6%, P = 0.003) and 3.4 +/- 7.0% (95% CI 0.7-6.1%, P = 0.017), respectively. At 9-12 months after AMI, ejection fraction remained significantly higher than at baseline in both groups. In the early and late groups, a mean of 200.3 +/- 68.7 x 10(6) and 194.8 +/- 60.4 x 10(6) stem cells, respectively, were delivered to the myocardium, and 1.30 +/- 0.68 x 10(9) and 1.29 +/- 0.41 x 10(9) cells, respectively, were delivered into the artery. A high number of cells was required for significant improvements in the primary end points. CONCLUSIONS: Combined cardiac stem cell delivery induces a moderate but significant improvement in myocardial infarct size and left ventricular function.

Multicenter assessment of coronary allograft vasculopathy by intravascular ultrasound-derived analysis of plaque composition.

BACKGROUND: Coronary allograft vasculopathy is a severe complication of heart transplantation. We used virtual histology intravascular ultrasound to characterize plaque burden and tissue composition over time in heart transplant recipients. METHODS: We recruited patients undergoing heart transplantation in four centers in Europe and the US between 2004 and 2006. We used intravascular ultrasound to obtain morphological plaque measurements and to perform virtual histology in the left anterior descending coronary artery. Data were characterized according to the duration between transplantation and intravascular ultrasound assessment: 24-60, >60-120 and >120-192 months. RESULTS: We assessed vessels from 152 patients (mean age 58 +/- 12 years) a mean of 70 +/- 53 months (range 1 week to 16 years) after transplantation. Plaque burden of >40% was observed in 26% of vessels analyzed, with increases from baseline being seen in all time categories. If assessed >24 months after transplantation, necrotic core and dense calcified volumes were significantly greater than at baseline (P = 0.0005 and P = 0.01, respectively). Time since heart transplantation and donor age and recipient age were independent predictive factors of increased necrotic core content. Necrotic core volume >2.01 mm(3), diabetes mellitus, donor age older than 40 years, follow-up from transplantation longer than 5 years and recipient age older than 58 years were associated with the need for revascularization. CONCLUSIONS: In coronary allograft vasculopathy, plaque burden and composition change over time and seem to affect clinical outcome. This relationship might facilitate identification of high-risk patients in whom the value of more aggressive medical therapy should be tested.

Implantation of paclitaxel-eluting stent impairs the vascular compliance of arteries in porcine coronary stenting model.

BACKGROUND: The impaired compliance of large and medium-sized muscular arteries has been shown to correlate with the risk of adverse cardiovascular events. We assessed coronary artery distensibility using simultaneous intracoronary ultrasound and pressure wire measurements in porcine coronary arteries after implantation of paclitaxel-eluting (PES) and bare metal stents (BMS) and compared this with the histopathology of the arterial wall injury. METHODS: PES and BMS were implanted into porcine left coronary arteries under general anesthesia. At 1-month follow-up (FUP) the endothelium-dependent and endothelium-independent vascular compliances were measured after intracoronary infusion of 10(-6)M acetylcholine for 2.5min, and intracoronary bolus of 100microg nitroglycerine, respectively. The arterial stiffness index, distensibility and reflexion index were calculated in stented arteries (n=25 PES and n=25 BMS), and correlated with histopathologic and histomorphometric changes of the vessel wall. RESULTS: In spite of smaller neointimal area, the fibrin deposition, medial thickening, vascular wall inflammation scores and arterial remodeling index were elevated and endothelialization was impaired in arteries with PES. Arteries with PES exhibited significantly worse endothelium-dependent vascular compliance: the stiffness (p<0.001) and reflexion index (p<0.001) were significantly higher and the distensibility index (p<0.001) lower as compared with the arteries with BMS. The endothelium-independent vascular reaction was similarly impaired in arteries with PES, as the stiffness index (p<0.001) and the distensibility index (p<0.001) differed significantly between the PES and BMS groups. Incomplete endothelialization (r=0.617, p<0.001) was significantly associated with the endothelium-dependent increased vascular stiffness. The increased fibrin score (r=0.646, p<0.001), vessel wall inflammation (r=0.657, p<0.001) and medial thickening (r=0.672, p<0.001) correlated significantly with the endothelium-independent stiffness index. CONCLUSIONS: Implantation of PES impairs the coronary artery wall structure and the endothelium-dependent and independent vessel wall dynamics more than does the implantation of BMS.

Association between the efficacy of dual antiplatelet therapy and the development of in-stent neointimal hyperplasia in porcine coronary arteries.

OBJECTIVE: We set out to compare the effectiveness of platelet aggregation therapy in association with the development of in-stent neointimal hyperplasia in porcine coronary arteries. METHODS: Thirty-two pigs underwent coronary stenting with bare-metal stents under general anaesthesia. One hundred milligrams of aspirin and loading doses of either 300 mg clopidogrel (group C, n=13) or 2 x 500 mg ticlopidine (group T, n=19) were administered before intervention. During the follow-up, the animals received a daily dose of 100 mg aspirin and 75 mg clopidogrel or 2 x 250 mg ticlopidine, respectively. After 4 weeks, the histopathological and histomorphometric parameters of the explanted stented coronaries were assessed. Levels of circulating cytokines and platelet activation factors were measured. ADP-induced and collagen-induced aggregation was measured immediately before stenting and then every 3rd day. The aggregation profiles were calculated and correlated with the histological parameters. RESULTS: The fibrin deposition scores and inflammation scores were higher in group T than in group C, with similar injury scores. Endothelialization was complete in both groups. A significantly lower neointimal area (1.08+/-0.36 vs. 1.58+/-0.5, group C vs. T, P=0.026) and percentage of area stenosis (29.8+/-12.1 vs. 44.3+/-16.3, group C vs. T, P=0.032) were observed in group C. The loading dose of clopidogrel significantly reduced the platelet activation parameters before the first angiography as compared with ticlopidone. Clopidogrel treatment resulted in a significantly better aggregation profile relative to ticlopidine (mean ADP-induced aggregation: 28.4+/-9.1 vs. 52.5+/-12.0%, P<0.001). Significant (P<0.05) positive linear correlations were observed between the ADP-induced aggregation profile and the neointimal area (r=0.584), percentage of area stenosis (r=0.666), inflammation (r=0.476) and fibrin deposition (r=0.496). CONCLUSION: The effectiveness of dual antiplatelet therapy plays an important role in the inhibition of in-stent neointimal hyperplasia.

Clopidogrel pretreatment abolishes increase of PAI-1 after coronary stent implantation.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been shown to increase after percutaneous coronary intervention (PCI). Whether activated platelets, local trauma with activation of resident vascular cells or the acute phase response is the source of this PAI-1 increase is not well defined. Therefore we examined whether intensive platelet inhibition may modulate PAI-1 levels or whether the PAI-1 increase is associated with the acute phase protein C-reactive protein (CRP). METHODS: We included 51 patients with stable angina who underwent elective PCI with stent implantation. At the time of study, routine pretreatment with clopidogrel before PCI was not standard of care, but left to the discretion of the referring cardiologist. We matched 17 patients with stable angina that were not pretreated with clopidogrel but received a loading dose of 300 mg immediately after stent implantation according age, sex and smoking with 34 patients that received clopidogrel at least 12 to 24 hours before PCI. Blood samples for measurement of PAI-1, t-PA and CRP were taken directly before and 24 hours after the procedure. RESULTS: PAI-1 and t-PA active antigen plasma levels before PCI were not different in patients with and without clopidogrel pretreatment. Whereas PCI induced a significant increase of PAI-1 levels in patients without pretreatment (p<0.05), the procedure had no effect on PAI-1 active antigen in patients pretreated with clopidogrel. This resulted in significant lower PAI-1 plasma levels 24 hours after PCI in patients with pretreatment (p<0.05). CRP was not associated with pre- or postprocedural PAI-1 levels. CONCLUSION: Clopidogrel pretreatment completely abolishes the increase of PAI-1 active antigen after coronary stent implantation. This suggests that peri-procedural platelet activation might play a major role for the increase of PAI-1 after PCI thus increasing the risk of acute and subacute thrombus formation based on a reduced endogenous fibrinolytic system.

Attainment of local drug delivery with paclitaxel-eluting balloon in porcine coronary arteries.

OBJECTIVE: Our purpose was to confirm the local drug delivery of a paclitaxel-eluting balloon by percutaneous intervention of single arterial segments or bifurcations of porcine coronary arteries. METHODS: Eight domestic pigs were subjected to 2 x 30 s Dior balloon dilatation of the mid left anterior descending, left circumflex and proximal right coronary arteries. Bifurcation intervention was performed in six arteries. The dilated, and the distal and proximal reference segments were prepared for tissue paclitaxel concentration measurement. Tissue samples were harvested at mean 1.5, 12, 24 and 48 h after balloon dilatation and plasma samples were taken at various time points. RESULTS: The tissue paclitaxel concentration of the single dilated segment was at 1.5 h postdilatation 1.82+/-1.60 micromol/l, which decreased significantly to 0.73+/-0.27 (P=0.032), 0.62+/-0.34 and 0.44+/-0.31 micromol/l at 12, 24 and 48 h. The bifurcation intervention resulted in 5.10+/-1.80 micromol/l tissue paclitaxel amount in the main branch, which at 12 h had diminished to 1.41+/-1.23 micromol/l (P=0.004). The bifurcation side contained 7.00+/-4.80 micromol/l paclitaxel at 1.5 h postdilatation, which lowered to 2.72+/-0.40 micromol/l (P=0.034). The mean paclitaxel concentration of the reference segments decreased gradually from 0.84+/-0.99 to 0.34+/-0.36 micromol/l (P=0.09), 0.28+/-0.16 and 0.19+/-0.18 micromol/l tissue at 1.5, 12, 24 and 48 h postdilatation, respectively. No paclitaxel was found in the peripheral blood at any time point. CONCLUSION: Short exposure of the coronary artery to paclitaxel with a coated balloon is sufficient for the attainment of an adequate tissue concentration of paclitaxel, which is known to be efficient in inhibiting neointimal growth.

Time course of prothrombotic and proinflammatory substance release after intracoronary stent implantation.

We hypothesized that restenosis after coronary stenting is predicted by elevated levels of markers of thrombus formation and inflammation. Plasma levels of representative markers of inflammation, the thrombin and plasmin activation systems and adhesion molecules were measured in 59 patients with stable angina pectoris before, immediately after and 6 hours (h), 12 h, 24 h, one month and six months after elective stent implantation (radioactive phosphorus-32 stents/RSs/ n = 16, bare-metal stents/BMSs/ n = 43). All patients underwent clinical and angiographic follow-up (FUP) six months after stenting. RSs had significantly higher angiographic severity of restenosis than BMSs (47.1 +/- 20.1% vs. 27.6 +/- 22.0%, p = 0.003). Repeated measures ANOVA revealed significant differences between the BMS and RS groups as regards the increases in plasma levels of vascular cell adhesion molecule-1 (VCAM-1, p = 0.022), plasminogen activator inhibitor-1 (PAI-1, p = 0.047), tissue-type plasminogen activator (tPA, p = 0.047) and CD40 ligand (CD40L, p = 0.038). tPA levels tended to increase immediately after stenting in both groups, whereas the PAI-1 level one month after stenting was elevated significantly only in the RS group. In the RS group, the plasma levels of CD40L were increased at 24 h and six months after stenting, and the VCAM-1 level rose immediately after stenting and remained high during the FUP. Multivariate analysis on pooled laboratory data of both groups revealed elevated levels of VCAM-1 at 12 h and at six months as significant predictors of the severity of stent restenosis. In conclusion, the process of inflammation and thrombosis occurring after coronary interventions seems to be prolonged and enhanced in patients with high-grade restenosis at the follow up.

Role of adult bone marrow stem cells in the repair of ischemic myocardium: current state of the art.

OBJECTIVE: To review the milestones in stem cell therapy for ischemic heart disease from early basic science to large clinical studies and new therapeutic approaches. MATERIALS AND METHODS: Basic research and clinical trials (systematic review) were used. The heart has the ability to regenerate through activation of resident cardiac stem cells or through recruitment of a stem cell population from other tissues, such as bone marrow. Although the underlying mechanism is yet to be made clear, numerous studies in animals have documented that transplantation of bone marrow-derived stem cells or circulating progenitor cells following acute myocardial infarction and ischemic cardiomyopathy is associated with a reduction in infarct scar size and improvements in left ventricular function and myocardial perfusion. RESULTS: Cell-based cardiac therapy has expanded considerably in recent years and is on its way to becoming an established cardiovascular therapy for patients with ischemic heart disease. There have been recent insights into the understanding of mechanisms involved in the mobilization and homing of the imported cells, as well as into the paracrine effect, growth factors, and bioactive molecules. Additional information has been obtained regarding new stem cell sources, cell-based gene therapy, cell-enhancement strategies, and tissue engineering, all of which should enhance the efficacy of human cardiac stem cell therapy. CONCLUSIONS: The recently published trials using bone marrow-origin stem cells in cardiac repair reported a modest but significant benefit from this therapy. Further clinical research should aim to optimize the cell types utilized and their delivery mode, and pinpoint optimal time of cell transplantation.

Detection of high-grade stenoses with multislice computed tomography in heart transplant patients.

BACKGROUND: Post-transplant follow-up of heart transplant patients consists of repeated coronary angiography, which is associated with high costs, discomfort and risk. We sought to determine whether multislice computed tomography (MSCT) permits the exclusion or progression of coronary artery disease in heart transplant patients. METHODS: MSCT scanning (Philips CT MX 8000 IDT) and invasive coronary angiography were performed on 66 consecutive heart transplant patients. One hundred milliliters of non-ionic iodinated contrast medium was applied for CT angiography. For MSCT analysis, coronary arteries and side branches with a diameter > or =1.5 mm were assessed for the presence of luminal narrowing of >70%. MSCT results were compared with those of quantitative coronary angiography analysis. RESULTS: Ten patients (17%) had one significant stenosis, whereas 3 patients (5%) had 2-vessel disease and none had 3-vessel disease. MSCT was performed successfully on 60 patients enrolled in our analysis. Forty-two of 44 patients (95%) who were estimated to be fully evaluable for MSCT were correctly classified. On per-segment-based analysis, sensitivity, specificity and positive and negative predictive values were 59%, 94%, 91% and 99.43%, respectively. After exclusion of unevaluable segments, sensitivity and specificity increased to 71% and 99.86%, respectively. On per-patient-based analysis, sensitivity, specificity and positive and negative predictive values were 88%, 97%, 88% and 97%, respectively, in evaluable transplant recipients. CONCLUSIONS: MSCT with its high specificity and high negative predictive value allows the exclusion of significant coronary artery vasculopathy in evaluable patients. From the clinical point of view, this might spare additional invasive coronary angiography in heart transplant patients.