Incidence and predictors of coronary stent thrombosis: evidence from an international collaborative meta-analysis including 30 studies, 221,066 patients, and 4276 thromboses.

BACKGROUND: Stent thrombosis remains among the most feared complications of percutaneous coronary intervention (PCI) with stenting. However, data on its incidence and predictors are sparse and conflicting. We thus aimed to perform a collaborative systematic review on incidence and predictors of stent thrombosis. METHODS: PubMed was systematically searched for eligible studies from the drug-eluting stent (DES) era (1/2002-12/2010). Studies were selected if including ≥ 2000 patients undergoing stenting or reporting on ≥ 25 thromboses. Study features, patient characteristics, and incidence of stent thrombosis were abstracted and pooled, when appropriate, with random-effect methods (point estimate [95% confidence intervals]), and consistency of predictors was formally appraised. RESULTS: A total of 30 studies were identified (221,066 patients, 4276 thromboses), with DES used in 87%. After a median of 22 months, definite, probable, or possible stent thrombosis had occurred in 2.4% (2.0%; 2.9%), with acute in 0.4% (0.2%; 0.6%), subacute in 1.1% (1.0%; 1.3%), late in 0.5% (0.4%; 0.6%), and very late in 0.6% (0.4%; 0.8%). Similar figures were computed for studies reporting only on DES. From a total of 47 candidate variables, definite/probable stent thrombosis was more commonly and consistently predicted by early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length, with acute coronary syndrome at admission, diabetes, smoking status, and bifurcation/ostial disease also proving frequent predictors, but less consistently. CONCLUSIONS: Despite numerous possible risk factors, the most common and consistent predictors of stent thrombosis are early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length.

Regression and shift in composition of coronary atherosclerotic plaques by pioglitazone: insight from an intravascular ultrasound analysis.

BACKGROUND: Plaque reduction with the use of pioglitazone and statin combination therapy has been observed in carotid plaque. We sought to investigate the effect of combination therapy with statins and pioglitazone on coronary plaque regression and composition with the use of intravascular ultrasound (IVUS) and intravascular ultrasound-virtual histology (IVUS-VH). METHODS: We analysed 29 plaques in 25 diabetic patients with angiographic evidence of nonsignificant coronary lesions with IVUS-VH. Patients were treated with 80 mg of atorvastatin and 30 mg of pioglitazone daily for 6 months. After 6 months of therapy, IVUS-VH of each lesion was reacquired. RESULTS: Mean elastic external membrane volume was significantly reduced between baseline and follow-up (343.9 vs. 320.5 mm; P < 0.05) as was mean total atheroma volume (179.3 vs. 166.6 mm; P < 0.05). Change in total atheroma volume showed a 6.3% mean reduction. Areas of fibrous tissue, fibrolipidic tissue and calcium decreased over the 6 months of follow-up, although not significantly. On the other hand, the necrotic core increased from 9 to 14% (P < 0.05). CONCLUSION: Our data demonstrated that atorvastatin/pioglitazone association is able to induce significant regression of coronary atherosclerosis, acting on plaque composition. Our findings are preliminary results and will be confirmed in an ongoing randomized placebo-controlled multicenter trial (PIPER; Pioglitazone for Prevention of Restenosis in Diabetics with Complex Lesion; trial registration: clinical trials.gov. Identifier: NCT 00376870).

Adiponectin isoforms are not associated with the severity of coronary atherosclerosis but with undiagnosed diabetes in patients affected by stable CAD.

BACKGROUND AND AIMS: Total adiponectin is emerging as an independent risk factor for cardiovascular diseases, but the role of adiponectin isoforms in coronary artery disease (CAD) is still unknown. We investigated the role of adiponectin isoforms with respect to the severity of coronary disease and to the presence of undiagnosed diabetes in patients with CAD. METHODS AND RESULTS: We recruited 205 CAD patients, all living in the central area of Italy, with a history of a previous myocardial infarction but apparently not affected by type 2 diabetes (DM2). We compared the CAD patients to a control population (n=100) matched for age, sex, BMI and cardiovascular risk factors, but without overt diabetes and cardiovascular disease. In all patients we measured Total Adiponectin (Tot-Ad) and its isoforms, metabolic, pro- and anti-inflammatory markers and we performed an oral glucose tolerance test (OGTT). CAD patients underwent a coronary angiography and/or coronary multi-slice computed tomography. Based on the severity of CAD they were divided into mono-vessel versus multi-vessel patients. Tot-Ad levels and its isoforms were comparable in patients with mono-vessel versus multi-vessel CAD. After the OGTT, in CAD patients, the results showed that 19% of patients were affected by unknown DM2, 36.1% by unknown impaired glucose tolerance (IGT), and only 43.9% were truly normoglycemic (NGT). Low levels of high molecular weight-adiponectin (HMW-Ad) were significantly associated with undiagnosed IGT or DM2 status (p<0.01). CONCLUSIONS: In our cohort of CAD patients, Tot-Ad and its isoforms do not correlate with severity of CAD, but with undiagnosed defects of glucose metabolism.

[Treatment of coronary bifurcation lesions]. / II trattamento delle biforcazioni coronariche.

Percutaneous treatment of coronary bifurcation lesions remains a challenge for interventional cardiology, both for technical aspects and long-term clinical results. Albeit coronary bifurcation encompasses 15-20% of all lesions treated in the cardiology laboratory, and their treatment has improved due to continuous progress in techniques and materials, such lesions are still related to a higher incidence of periprocedural complications, need for reinterventions, stent thrombosis, and adverse clinical events. In this context, drug-eluting stent introduction has reduced the incidence of restenosis compared to traditional bare-metal stents but it has not modified strategic modalities of treatment. Indeed, the incidence of restenosis at the ostium of the side branch still remains high regardless of the technique used (single or double stent strategy). Therefore, provisional stenting technique still remains the preferred treatment strategy in most cases. The introduction of dedicated stents, which have been designed to reduce most technical difficulties of treating such lesions, did not translate into an improvement in the long-term clinical results. In this review, we will summarize the anatomical characteristics of coronary bifurcations and the technical difficulties related to their treatment with the aim at discussing the best strategic approach.

A randomized trial comparing eptifibatide vs. placebo in patients with diffuse coronary artery disease undergoing drug-eluting stent implantation: design of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial.

BACKGROUND: Despite the availability of several potent antithrombotic agents, the optimal antiplatelet regimen in elective patients undergoing complex percutaneous coronary interventions is still debated. Aim of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial will be to assess the safety and efficacy of routine usage of the glycoprotein IIb/IIIa inhibitor eptifibatide in patients already treated with aspirin and clopidogrel and undergoing implantation of at least two drug-eluting stents in the same lesion, thus identifying a clinically stable but anatomically complex patient subset. DESIGN: This will be a single-blind, placebo-controlled multicenter randomized trial. METHODS: Patients with stable coronary artery disease, who are undergoing percutaneous coronary intervention by means of implantation of greater than 33 mm of drug-eluting stents (e.g. with two 23-mm drug-eluting stents or one 32-mm and one 12-mm drug-eluting stent), will be randomized, after administration of aspirin and clopidogrel (600 mg loading dose recommended), to eptifibatide and unfractioned heparin according to the ESPRIT protocol or placebo and unfractioned heparin. Blood draws for creatine kinase-MB mass, total creatine kinase, and cardiac troponin levels will be taken at baseline, 6 and 12 h postprocedurally. Patients will be followed for clinical events by direct visit or phone contact up to 6 months. The primary endpoint of the study will be the rate of abnormal values of creatine kinase-MB mass after percutaneous coronary intervention. Secondary endpoints will be the composite of cardiac death, nonfatal myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 180 days, and in-hospital, 1-month and 6-month major adverse cardiovascular events, defined as the composite of cardiac death, nonfatal myocardial infarction or urgent target vessel revascularization. IMPLICATIONS: The INtegrilin plus STenting to Avoid myocardial Necrosis Trial study will test for the first time the beneficial impact of routine glycoprotein IIb/IIIa inhibition on top of dual oral antiplatelet treatment in clinically stable yet anatomically complex patients undergoing drug-eluting stents implantation. Results of this single-blind randomized trial will provide important insights to improve the management strategy of patients and outcomes in the current drug-eluting stents era.

Revascularization strategy in patients with multivessel disease and a major vessel chronically occluded; data from the CABRI trial.

OBJECTIVE: In patients with multivessel coronary artery disease and total occlusion of major epicardial vessel, completeness of revascularization has not been investigated in specific trials comparing the surgical and the percutaneous revascularization strategy. Analyzing the database of the CABRI study, which randomized a substantial number of these patients, we investigated the long-term effects of a successful or unsuccessful revascularization of the occluded vessel and completeness of the revascularization. METHODS AND RESULTS: The CABRI study randomized 1054 patients with multivessel coronary disease to coronary bypass or to coronary angioplasty. From the database of this trial, we selected patients with a major vessel chronically occluded (103 in the bypass group and 120 in the angioplasty group). At a median follow-up of 30 months, the incidence of death or Q-wave myocardial infarction (combined end point) was significantly lower in the bypass group than in the angioplasty group (6.8% vs 17.5%, respectively; hazard ratio [HR], 0.42 [95% CI 0.17-0.98]; p=0.047). On univariate analysis, age, proximal occlusion, complete revascularization, revascularization of the occluded vessel and revascularization procedure were identified as significant predictors of combined end points. On multivariate analysis, independent predictors of combined end points resulted in completeness of revascularization (HR 0.26; 95% CI 0.09-0.76; p=0.01) and age (HR 1.07; 95% CI 1.02-1.12; p<0.01). CONCLUSION: In patients with multivessel coronary disease and chronic occlusion of a major epicardial vessel, achieving of a complete revascularization by reopening or bypassing the occluded vessel is associated with a significantly better long-term prognosis.

Gender-related differences in catheter ablation of atrial fibrillation.

AIMS: Women have an increased risk for atrial fibrillation (AF)-related complications and there is evidence towards a reduced efficacy of the rhythm control strategy than men. A catheter-based strategy is therefore widely attractive, but the impact of gender on catheter ablation (CA) of AF remains undefined. METHODS AND RESULTS: We included 221 consecutive patients (150 men) who underwent CA of drug-refractory AF. Gender differences in clinical presentation and outcomes were compared. Women were older (P = 0.002), had a longer history of AF (P = 0.04), and were more likely to have hypertension (P = 0.04). Moreover, a concomitant valvular heart disease tended to be more common in women (32.4 vs. 23.3%; P = 0.28) and left atrium dimensions were significantly larger (P = 0.003). However, acute success rate and complications rate were similar between genders. After 22.5 +/- 11.8 months of follow-up, the overall freedom from arrhythmia recurrences was similar (83.1 vs. 82.7% in men), and a similar improvement in SF-36 quality of life scores was achieved in both groups. CONCLUSION: Women are referred for AF ablation later with a more complex clinical pre-operative presentation. Despite this higher risk profile in women, no differences were detected in clinical outcomes. Our findings indicate that CA of AF appears to be safe and effective in women as in men.

Plaque vulnerability and related coronary event prediction by intravascular ultrasound with virtual histology: "it's a long way to tipperary"?

Identification of so-called "vulnerable plaque" or "high-risk" plaques have spawned manifold attempts to develop diagnostic tools capable to afford this task. This task is particularly challenging but the reward is high: local intervention on identified "vulnerable plaque" could preclude plaque thrombosis and possibly prevent acute coronary syndromes. Various imaging techniques are currently under investigation by extensive clinical testing to identify which could become the most sensible and specific modality for vulnerable plaque detection. Noninvasive techniques are fascinating for their easily applicability to a broad population but nowadays are not sufficiently powered for this task. The emerging technologies with the greatest resolution are indeed catheter-based and many intravascular modalities have been developed for identification of "vulnerable plaque". Among these, IVUS-Virtual Histology (IVUS-VH) is the most promising technique in the field. IVUS-VH offers an in vivo opportunity to assess plaque morphology and histology. IVUS-VH uses underlying frequency information along with echoes intensity, while grey-scale IVUS data are obtained from echoes of different intensity or amplitude. The major advantage of IVUS-VH is that it is based on a device that is practical for use in the clinical setting and that it generates a real-time assessment of plaque morphology. Unfortunately, numerous challenging issues still need to be overcome until the numerous "vulnerable plaques" could be identified and successfully treated. Future efforts may identify plaques that are on a trajectory of evolution toward a vulnerable state, and help us target interventions to those plaques most likely to develop plaque disruption and related complications.

Engineering aspects of stents design and their translation into clinical practice.

The implantation of coronary stents is a relevant part of interventional procedures for percutaneous revascularization. The wide acceptance of coronary stenting was based on the results of two highly significant trials which have shown the superiority of stenting over balloon angioplasty in terms of reduction of angiographic restenosis and need for repeated intervention in focal lesions and large coronary arteries. Since then, the growing use of stent market was impressive. A rapidly increasing number of different stent type with different material and designs has been introduced in the market both for bare metal stent and drug eluting stent. This review will summarize the different components of stent design that are important in term of biological response of the arterial wall and clinical outcome. In addition, new stent platforms, mainly represented by the biodegradable stent will be shortly reviewed since it may provide in the near future a more "physiological" answer to stent implantation, reducing vascular injury and accelerating vessel healing with consequent improving in clinical outcome.

Multislice computed tomography in an asymptomatic high-risk population.

Approximately 50% of all acute coronary syndromes occur in previously asymptomatic patients. This study evaluated the value of multislice computed tomography for early detection of significant coronary artery disease (CAD) in high-risk asymptomatic subjects. One hundred sixty-eight asymptomatic subjects with >or=1 major risk factor (hypertension, diabetes, hypercholesterolemia, family history, or smoking) and an inconclusive or unfeasible noninvasive stress test result (stress electrocardiography, echocardiography, or nuclear scintigraphy) were evaluated in an outpatient setting. After clinical examination and laboratory risk analysis, all patients underwent multislice computed tomographic (MSCT) coronary angiography within 1 week. In all subjects, conventional coronary angiography was also carried out. Multislice computed tomography displayed single-vessel CAD in 16% of patients, 2-vessel CAD in 7%, and 3-vessel CAD in 4%. Selective coronary angiography confirmed the results of multislice computed tomography in 99% of all patients. Sensitivity and specificity of MSCT coronary angiography were 100% and 98%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In conclusion, MSCT coronary angiography is an excellent noninvasive technique for early identification of significant CAD in high-risk asymptomatic patients with inconclusive or unfeasible noninvasive stress test results.

In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a fundamental role in the pathogenesis of atherosclerosis. LOX-1 activation is associated with apoptosis of endothelial cells, smooth muscle cells (SMCs), and macrophages. This process is an important underlying mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. Because single nucleotide polymorphisms (SNPs) linked to MI are located in intronic sequences of the gene, it remains unclear as to how they determine their biological effects. Using quantitative real-time PCR and minigene approach, we show that intronic SNPs, linked to MI, regulate the expression of a new functional splicing isoform of the OLR1 gene, LOXIN, which lacks exon 5. Macrophages from subjects carrying the "non-risk" disease haplotype at OLR1 gene have an increased expression of LOXIN at mRNA and protein level, which results in a significant reduction of apoptosis in response to oxLDL. Expression of LOXIN in different cell types results in loss of surface staining, indicating that truncation of the C-terminal portion of the protein has a profound effect on its cellular trafficking. Furthermore, the proapoptotic effect of LOX-1 receptor in cell culture is specifically rescued by the coexpression of LOXIN in a dose-dependent manner. The demonstration that increasing levels of LOXIN protect cells from LOX-1 induced apoptosis sets a groundwork for developing therapeutic approaches for prevention of plaque instability.

The protective effect of superoxide dismutase mimetic M40401 on balloon injury-related neointima formation: role of the lectin-like oxidized low-density lipoprotein receptor-1.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the principal receptor for oxidized low-density lipoprotein (ox-LDL) in vascular endothelial cells (ECs), has recently been suggested to exert a pivotal role in atherogenesis, possibly by mediating ox-LDL-evoked endothelial dysfunction. On the other hand, LOX-1 expression seems to strongly correlate with the oxidative stress occurring in the vascular wall of experimentally injured blood vessels. Here, we investigated LOX-1 expression and superoxide generation during neointima formation in a balloon injury rat carotid artery model. To test this, we used M40401 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand], a synthetic superoxide dismutase mimetic that is a selective scavenger of superoxide. The injury was performed inserting the balloon catheter through the rat common carotid artery and after 14 days a histopathological analysis revealed a significant restenosis with smooth muscle cell proliferation and neointima formation that was associated with an enhanced expression of LOX-1, nitrotyrosine (the footprint of peroxynitrite) staining, and lipid peroxidation as assessed by malondialdehyde (MDA) formation. Pretreatment of rats with M40401 (0.5-10 mg/kg i.p. daily) reduced neointima formation, MDA accumulation, nitrotyrosine staining, and LOX-1 expression. Here, we show that removal of superoxide formation occurring in injured arteries reduces both neointima formation and LOX-1 expression and that this may represent a novel therapeutical approach in the treatment of vascular disorders in which proliferation of vascular smooth muscle cells and ox-LDL-related endothelial cell dysfunction occur.