Michael Del Core

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials ∗

BACKGROUND Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required. METHODS Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups. RESULTS The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab. CONCLUSIONS Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention.

AIMS The growth and differentiation of cells is regulated by cytokines by binding to cell-surface receptors and activating intracellular signal transduction cascade. Suppressor of cytokine signaling (SOCS)-3 is a negative regulator of cytokines. In this study we examined the expression of SOCS-3 in porcine coronary artery smooth muscle cells (PCASMCs) in vitro and in proliferating smooth muscle cells of neointimal lesions after coronary artery intervention in a swine model. METHODS AND RESULTS PCASMCs were cultured and stimulated with TNF-α and/or IGF-1 individually or in combination. Protein expression of SOCS-3 was examined using Western blot. For in vivo studies, six female Yucatan miniswine were fed with special high cholesterol diet for 8 months. At 4 months of high cholesterol diet, animals underwent coronary balloon angioplasty. At the end of 8 months animals were euthanized, coronary arteries were isolated and morphological and histological studies were performed. Western blot data revealed significantly high SOCS-3 expression in PCASMCs in the presence of either TNF-α or IGF-1 (5-6 fold) alone. However, in the presence of both TNF-α and IGF-1 the SOCS-3 expression was significantly decreased (4-5 fold). Results from morphological studies including, H&E and Massons trichrome stain showed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased proliferating cell nuclear antigen (PCNA) in neointimal lesion. Interestingly, there was significantly decreased expression of SOCS-3 in smooth muscle cells of neointima as compared to control. CONCLUSIONS These data suggest that SOCS-3 expression is decreased in proliferating smooth muscle cells of neointimal lesions. This leads to uncontrolled growth of vascular smooth muscle cells in injured arteries leading to restenosis. Therefore, local delivery of SOCS-3 gene at the site of injury after coronary artery intervention could regulate the proliferation of vascular smooth muscle cells and help in preventing the neointimal hyperplasia and restenosis.

Decreased expression of vitamin D receptors in neointimal lesions following coronary artery angioplasty in atherosclerotic swine

Background Inflammatory cytokines, such as TNF-α, play a key role in the pathogenesis of occlusive vascular diseases. Activation of vitamin D receptors (VDR) elicits both growth-inhibitory and anti-inflammatory effects. Here, we investigated the expression of TNF-α and VDR in post-angioplasty coronary artery neointimal lesions of hypercholesterolemic swine and examined the effect of vitamin D deficiency on the development of coronary restenosis. We also examined the effect of calcitriol on cell proliferation and effect of TNF-α on VDR activity and expression in porcine coronary artery smooth muscle cells (PCASMCs) in-vitro. Methodology/Principal Findings Expression of VDR and TNF-α and the effect of vitamin D deficiency in post-angioplasty coronary arteries were analyzed by immunohistochemistry and histomorphometry. Cell proliferation was examined by thymidine and BrdU incorporation assays in cultured PCASMCs. Effect of TNF-α-stimulation on the activity and expression of VDR was analyzed by luciferase assay, immunoblotting and immunocytochemistry. In-vivo, morphometric analysis of the tissues revealed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased expression of TNF-α in neointimal lesions. Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media. Indeed, post-balloon angioplasty restenosis was significantly higher in vitamin D-deficient hypercholesterolemic swine compared to vitamin D-sufficient group. In-vitro, calcitriol inhibited both serum- and PDGF-BB-induced proliferation in PCASMCs and TNF-α-stimulation significantly decreased the expression and activity of VDR in PCASMCs. Conclusions/Significance These data suggest that significant downregulation of VDR in proliferating smooth muscle cells in neointimal lesions could be due to atherogenic cytokines, including TNF-α. Vitamin D deficiency potentiates the development of coronary restenosis. Calcitriol has anti-proliferative properties in PCASMCs and these actions are mediated through VDR. This could be a potential mechanism for uncontrolled growth of neointimal cells in injured arteries leading to restenosis.

Successful Transfection of Genes Using AAV-2/9 Vector in Swine Coronary and Peripheral Arteries

BACKGROUND Gene therapy has attracted attention for its potential to treat several cardiovascular diseases. The use of adeno-associated viral (AAV) vectors to facilitate therapeutic gene transfer to suppress intimal hyperplasia is a promising concept. The objective of this study was to analyze the in vivo transduction of a novel recombinant AAV-2/9 vector with SM22α promoter, containing β-galactosidase gene (LacZ) or green fluorescent protein (GFP) as reporter genes, to the medial layer smooth muscle cells (SMCs) of swine coronary and peripheral arteries. METHODS The AAV-2/9 vector containing SM22α (1 × 10(13) pfu) were administered into carotid/femoral/coronary arteries of domestic swine using irrigating balloon catheter-based gene delivery. Following gene transfer, cryosections of arteries were processed for X-Gal and GFP analysis. Fluorescence microscopy and Western blotting were done to analyze the GFP expression in the SMCs. RESULTS LacZ mRNA expression was visualized in the medial layer 7 d after vector administration. The GFP expression was detected at day 7 and lasted for at least 2 mo showing the longer-lasting expression of the AAV-2/9 vector. Control arteries did not show any expression of GFP or LacZ. There was no significant effect of AAV-2/9 viral transduction on serum amylase, fibrinogen, and serum CRP levels. CONCLUSION These finding support the use of AAV-2/9 as a vector to effectively transduce a gene in SMCs of coronary and peripheral arteries without causing inflammation.

Vitamin D Supplementation Reduces Intimal Hyperplasia and Restenosis following Coronary Intervention in Atherosclerotic Swine.

Vitamin D is a fat-soluble steroid hormone that activates vitamin D receptor to regulate multiple downstream signaling pathways and transcription of various target genes. There is an association between vitamin D deficiency and increased risk for cardiovascular disease. However, most of the studies are observational and associative in nature with limited data on clinical application. Thus, there is a need for more prospective randomized controlled studies to determine whether or not vitamin D supplementation provides cardiovascular protection. In this study, we examined the effects of the deficiency and supplementation of vitamin D on coronary restenosis following coronary intervention in atherosclerotic Yucatan microswine. Twelve Yucatan microswine were fed vitamin D-deficient (n = 4) or -sufficient (n = 8) high cholesterol diet for 6-months followed by coronary intervention. Post-intervention, swine in the vitamin D-sufficient high cholesterol diet group received daily oral supplementation of either 1,000 IU (n = 4) or 3,000 IU (n = 4) vitamin D3. Six months later, optical coherence tomography (OCT) was performed to monitor the development of intimal hyperplasia and restenosis. Animals were euthanized to isolate arteries for histomorphometric and immunohistochemical studies. Animals had graded levels of serum 25(OH)D; vitamin D-deficient (15.33 ± 1.45 ng/ml), vitamin D-sufficient + 1,000 IU oral vitamin D post-intervention (32.27 ± 1.20 ng/ml), and vitamin D-sufficient + 3,000 IU oral vitamin D post-intervention (51.00 ± 3.47 ng/ml). Findings from the OCT and histomorphometric studies showed a decrease in intimal hyperplasia and restenosis in vitamin D-supplemented compared to vitamin D-deficient swine. Vitamin D supplementation significantly decreased serum levels of TNF-α and IFN-γ, upregulated serum levels of IL-10, and had no effect on serum IL-6 levels. These findings suggest that vitamin D supplementation limits neointimal formation following coronary intervention in atherosclerotic swine and provide the support for vitamin D supplementation to protect against the development of coronary restenosis.

Meta-analysis of Randomized Controlled Trials on Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Prevention of Cryptogenic Stroke

The optimal management of patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) remains controversial. We conducted a meta-analysis to assess the effect of PFO closure for secondary prevention of stroke on patients with CS. We searched the literature for randomized control trials assessing the recurrence of stroke after PFO closure compared with medical therapy (antiplatelet and/or anticoagulation). Five randomized control trials with a total of 3,440 patients were included. The mean age was 45.2 ± 9.7 years and follow-up duration ranged from 2.0 to 5.9 years. PFO closure significantly reduced the risk of stroke compared with the medical therapy (2.8% vs 5.8%; relative risk [RR] 0.48, confidence interval [CI] 0.27 to 0.87, p = 0.01, I2 = 56%). The number needed to treat for stroke prevention was 10.5. PFO closure was associated with an increased risk of atrial fibrillation compared with medical therapy (4.2% vs 0.7%; RR 4.55, CI 2.16 to 9.6, p = 0.0001, I2 = 25%). There was no significant difference in all-cause mortality (RR 1.33, CI 0.56 to 3.16, p = 0.52, I2 = 0%), as well as no difference in bleeding risk between the 2 groups (RR 0.94, CI 0.49 to 1.83, p = 0.86, I2 = 29%). In conclusion, our meta-analysis demonstrates that PFO closure is associated with significantly lower risk of recurrent stroke in patients with PFO and CS compared with medical therapy. However, atrial fibrillation was more common among closure patients.

Coronary injury score correlates with proliferating cells and alpha-smooth muscle actin expression in stented porcine coronary arteries

Neointimal formation and cell proliferation resulting into in-stent restenosis is a major pathophysiological event following the deployment of stents in the coronary arteries. In this study, we assessed the degree of injury, based on damage to internal elastic lamina, media, external elastic lamina, and adventitia following the intravascular stenting, and its relationship with the degree of smooth muscle cell proliferation. We examined the smooth muscle cell proliferation and their phenotype at different levels of stent injury in the coronary arteries of domestic swine fed a normal swine diet. Five weeks after stent implantation, swine with and without stents were euthanized and coronaries were excised. Arteries were embedded in methyl methacrylate and sections were stained with H&E, trichrome, and Movat’s pentachrome. The expression of Ki67, α-smooth muscle actin (SMA), vimentin, and HMGB1 was evaluated by immunofluorescence. There was a positive correlation between percent area stenosis and injury score. The distribution of SMA and vimentin was correlated with the degree of arterial injury such that arteries that had an injury score >2 did not have immunoreactivity to SMA in the neointimal cells near the stent struts, but these neointimal cells were positive for vimentin, suggesting a change in the smooth muscle cell phenotype. The Ki67 and HMGB1 immunoreactivity was highly correlated with the fragmentation of the IEL and injury in the tunica media. Thus, the extent of coronary arterial injury during interventional procedure will dictate the degree of neointimal hyperplasia, in-stent restenosis, and smooth muscle cell phenotype.

Antithrombotic regimens in patients with indication for long-term anticoagulation undergoing coronary interventions-systematic analysis, review of literature, and implications on management.

There is lack of consensus regarding use of antithrombotic therapy (AT) in patients with indications for long-term anticoagulation who undergo percutaneous coronary intervention. We sought to evaluate the safety and efficacy of various antithrombotic regimens in this patient population. We conducted a Medline search for all English language, full-text articles from January 2000 to June 2009 that evaluated major cardiovascular outcomes in patients with indications for anticoagulation who undergo percutaneous coronary intervention. Data were analyzed from these studies to calculate annual incidence of major bleeding, stroke, and stent thrombosis with various antithrombotic regimens. Major bleeding events were calculated at 30 days and at 1 year. Ten retrospective studies, 1 post hoc analysis of a major registry, and 2 prospective studies qualified for our analysis. Atrial fibrillation was the most common indication for anticoagulation. Risk of major bleeding was 1.5% at 30 days and 5.2% at 1 year with triple AT (aspirin + warfarin + clopidogrel/ticlopidine). Dual antiplatelet therapy (aspirin + clopidogrel/ticlopidine) was associated with 2.4% annual risk of major bleeding. The annual incidence of both ischemic stroke and stent thrombosis was 1% with triple antithrombotic regimen. Risk of major bleeding increases proportionately with incremental duration of triple AT. Triple AT is effective in the prevention of ischemic stroke and stent thrombosis. Dual antiplatelet regimen is effective in patients with low annual risk of ischemic stroke (<4%; CHADS-2 score <2) due to lower annual risk of bleeding associated with this regimen (2.4%).

THERAPEUTIC HYPOTHERMIA FOR IN-HOSPITAL CARDIAC ARREST: A META ANALYSIS

Background: Multiple randomized controlled trials have demonstrated the favorable impact of Therapeutic Hypothermia (TH) in out of hospital cardiac arrest. The benefit of TH for patients with In-Hospital Cardiac Arrest (IHCA) remains unclear. There have been no RCTs and results of observational

NATIONWIDE TRENDS IN PULMONARY ARTERY ENDARTERECTOMY FOR CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

Pulmonary artery endarterectomy (PAE) is a complex curative surgery for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and is performed in a limited number of centers across the United States. We used the nationwide inpatient sample (NIS), which is a 20% stratified sample of