Biomedical subjects

Basel Ramlawi

Publications and source records attributed to Basel Ramlawi.

13 recordsLinked to original sources

PubMed2006

Inhaled carbon monoxide prevents graft-induced intimal hyperplasia in swine.

BACKGROUND: Arteriovenous grafts often fail due to stenosis caused by venous anastomotic intimal hyperplasia (IH) and vascular smooth muscle cell (VSMC) proliferation. We examined the effects of inhaled carbon monoxide (CO), a product of heme-oxygenase-1 degradation of heme, on IH in a porcine arteriovenous graft model. MATERIALS AND METHODS: Eighteen Yorkshire pigs were divided into three groups (N = 6/group): (1) CO 100 ppm preoperatively for 1 h; (2) CO 250 ppm preoperatively for 1 h and intraoperatively; and (3) air-treated controls. Animals underwent end-to-side placement of polytetrafluoroethylene grafts connecting the common femoral artery and vein in both groins. Intimal thickness of the venous anastomosis at 30 days was measured blinded. The effect of CO on pig VSMC proliferation was studied in cell culture using [(3)H]thymidine incorporation. RESULTS: Pigs in the group receiving CO 250 ppm showed significantly less IH compared to animals in the group receiving 100 ppm and the air-treated group (267.5 +/- 21.4, 824 +/- 145.8, and 914.8 +/- 133.7 pixels, respectively, P < 0.0001). This effect was not observed when comparing the 100 ppm group to the air-treated group. COHb levels were significantly elevated in the 100 ppm and 250 ppm compared to air-treated pigs (5.8 +/- 0.47, 13.2 +/- 1.0 versus 2.3 +/- 0.11%, respectively, P < 0.001). Oxygen saturation, respiratory rate, and hemodynamics were not significantly different between the groups. CO induced VSMC growth arrest compared to air in vitro (11.9 +/- 4 versus 20.3 +/- 5 10(3) counts/min/well, P < 0.01). CONCLUSION: A single exposure to a low concentration of inhaled CO (250 ppm) confers protection against intimal proliferation of VSMCs when given perioperatively in a clinically relevant model of arteriovenous grafts. These data are the first to suggest, in a clinically relevant model, the potential role for CO in clinical applications.

Administration, Inhalation↗

PubMed2006

Aging is associated with an impaired coronary microvascular response to vascular endothelial growth factor in patients.

OBJECTIVE: If growth factor and cell-based therapy are to become therapeutic strategies, a better understanding of their physiologic effects in various patient populations will need to be gained. In this study, we examined age-dependent differences in vascular endothelial growth factor signaling before and after cardioplegia/cardiopulmonary bypass. METHODS: Atrial tissue and peripheral blood of patients undergoing surgery were examined before and after cardioplegia/cardiopulmonary bypass. Patients were divided into younger (age < 70) and older (age > or = 70) groups. Coronary microvascular responses, expression of vascular endothelial growth factor and its downstream signaling molecules, and the number of CD34+ progenitor cells before and after cardioplegia/cardiopulmonary bypass were compared between groups. RESULTS: Advanced age was associated with impaired basal coronary microvascular response to vascular endothelial growth factor (-13% +/- 5% at 10(-10) mol/L vascular endothelial growth factor; P = .04), whereas basal relaxation response to substance P and sodium nitroprusside were similar between groups. After cardioplegia/cardiopulmonary bypass, the microvascular response to vascular endothelial growth factor significantly worsened in both groups (both P < or = .05), and response to substance P (P = .05) was significantly impaired only in older patients. Vascular endothelial growth factor expression increased after cardioplegia/cardiopulmonary bypass in older (P = .01 vs before cardioplegia/cardiopulmonary bypass), but not younger (P = .20) patients. Expression of other signaling molecules was unaffected by age or surgery. Circulating CD34+ cells increased after cardioplegia/cardiopulmonary bypass in all patients but to a greater extent in younger patients (P = .01). CONCLUSIONS: The coronary microvascular response to vascular endothelial growth factor is impaired in older patients. Combined with reduced progenitor cell mobilization, these results suggest new mechanisms for reduced angiogenic response in older patients.

Aged↗

PubMed2006

High-dose atorvastatin improves hypercholesterolemic coronary endothelial dysfunction without improving the angiogenic response.

BACKGROUND: Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine. METHODS AND RESULTS: Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29+/-3% versus 61+/-6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67+/-2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (-0.27+/-0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (-0.35+/-0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (-68+/-8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210+/-48%; P=0.004 versus NORM). CONCLUSIONS: Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2006

Indices of apoptosis activation after blood cardioplegia and cardiopulmonary bypass.

BACKGROUND: Cardioplegic arrest (CA) using cold blood cardioplegia (CBC) has been reported to reduce ischemia-reperfusion (IR)-induced myocardial injury via apoptosis. We studied key apoptotic mediators via the caspase-dependent and intrinsic pathways as well as poly(ADP)-ribosylating protein (PARP) activity in myocardial and peripheral tissues after CA and cardiopulmonary bypass (CBP). METHODS AND RESULTS: Right atrial (RA) and skeletal muscle(SM) was harvested from cardiac surgical patients with similar baseline characteristics (N =6) before and after CPB and CBC. Total and modified caspase-3, Bcl-2, Bad, apoptosis-inducing factor (AIF), and PARP were quantified by immunoblotting. Terminal caspase-3 activity was assessed and immunohistochemistry was performed for PARP and AIF. TUNEL staining was used for identification of apoptotic cells. Microarray gene expression analysis was performed using Affymetrix U95 GeneChip. In RA tissue, CA with CBC significantly increased phosphorylation of Bcl-2 (Ser70), Bad (Ser112) (2.63+/-0.4 and 1.77+/-0.3-fold respectively; P<0.05), and cleavage of the downstream caspase 3 (1.45+/-0.1-fold; P<0.05). There was no significant change in total protein levels. Also, there was an increase in mature AIF (57 kDa) levels (1.22+/-0.01-fold; P<0.05) and a trend toward nuclear translocation on histological staining. Caspase 3 activity was increased 1.5+/-0.14-fold (P<0.05). The number of apoptotic cells in atrial tissue increased after compared with before CPB/CA using TUNEL staining (1.55+/-0.66 versus 0.325+/-0.05%, respectively; P=0.03). In contrast, SM samples did not show any of the changes observed in RA tissue after CPB. CONCLUSIONS: Despite optimal current surgical myocardial protection, we found that CA with CBC induced both programmed cell death and survival signaling in myocardial tissue.

Aged↗

PubMed2006

Role of stromal-derived factor-1alpha in the induction of circulating CD34+CXCR4+ progenitor cells after cardiac surgery.

BACKGROUND: Cardioplegia and cardiopulmonary bypass (CP/CPB) leads to an increase in circulating progenitor cells. The role of stromal-derived factor-1alpha (SDF-1alpha), a key regulator of progenitor cell mobilization, and other cytokines in this process is not clear. METHODS AND RESULTS: Peripheral blood (n=24), atrial and skeletal tissue (n=6) samples were taken from patients undergoing CP/CPB before (pre-CP/CPB), 4 hours (post-CP/CPB), and 4 days (POD4) after CP/CPB. The number of circulating CD34+CXCR4+ cells increased post-CP/CPB (442+/-53 versus 286+/-27; P=0.04 versus pre-CP/CPB), but not at POD4 (382+/-50; P=0.28 versus pre-CP/CPB). Plasma levels of SDF-1alpha increased post-CP/CPB as compared with pre-CP/CPB (3325+/-325 versus 2911+/-165 pg/mL; P=0.046) but returned to baseline at POD4 (2838+/-224 pg/mL; P=0.90). Plasma levels of vascular endothelial growth factor were similar post-CP/CPB (P=0.90 versus pre-CP/CPB) but increased at POD4 (220+/-40 pg/mL versus 134+/-26 pg/mL; P=0.04 versus pre-CP/CPB). Serum levels of granulocyte-colony stimulating factor (G-CSF) increased early after CP/CPB as compared with pre-CP/CPB (265.0+/-41.7 versus 11.1+/-1.1 pg/mL; P<0.001) and returned to baseline at POD4 (P=0.84 versus pre-CP/CPB). The circulating CD34+CXCR4+ cells were positively correlated with plasma levels of SDF-1alpha early after CP/CPB (r=0.56, P<0.01), but not at other times. Protein expression of SDF-1alpha was elevated in the atrial myocardium after CP/CPB (9.4-fold; P=0.03). CONCLUSIONS: Exposure to CP/CPB leads to an increase in circulating CD34+CXCR4+ progenitor cells, which is associated with increased myocardial SDF-1alpha expression. The numbers of CD34+CXCR4+ progenitor cells positively correlate with the plasma levels of SDF-1alpha post-CP/CPB, suggesting an important role of SDF-1alpha in progenitor cell mobilization.

Aged↗

PubMed2006

Effects of purified poloxamer 407 gel on vascular occlusion and the coronary endothelium.

OBJECTIVE: Vascular occlusion during off-pump coronary surgery often results in sub-optimal visualization and endothelial damage of the target vessel. We have previously reported the safety of purified poloxamer 407, a gel with reverse thermosensitive properties, in a model of off-pump coronary occlusion. The aim of this study was to evaluate different gel concentrations and their effects on coronary occlusion time, myocardial contractility, endothelial function, and markers of myocardial injury and apoptosis. METHODS: Yorkshire swine (30-35 kg) underwent sternotomy and mid-LAD occlusion using either microvascular clamps (n=6) or varying quantities of three different concentrations (20%; n=6, 22.5%; n=3, and 25%; n=3) of purified poloxamer 407 gel. Distal LAD flow, left ventricular pressure, and in vitro microvascular reactivity were assessed. Molecular markers of myocardial injury and apoptosis were assessed using Western blotting. RESULTS: Duration of ischemia correlated significantly with the amount of injected gel for the 20% and 22.5% formulations (Spearman r=0.64, p=0.02 and r=0.85, p=0.03, respectively) but not for the 25% gel (r=0.22, p=0.66). There were no significant differences in LV contractility (maximum+dp/dt) (p=0.86) as well as LAD flow (p=0.25) during reperfusion in the four groups. Microvessel relaxation to adenosine diphosphate in the ischemic territory was impaired with higher concentrations of the gel, 22.5% (-14.8+/-7.5% vs control at 10(-5)mol/L, p<0.05) and 25% gel (-24.0+/-7.6% vs control at 10(-5)mol/L, p<0.001) but not with the 20% gel. Endothelium-independent relaxation to sodium nitroprusside was preserved in all groups. Cleaved poly(ADP-ribose) polymerase, a marker of myocardial injury and apoptosis, was elevated in the ischemic myocardium in all groups (p=0.02 vs non-ischemic myocardium) with no significant differences between the groups (p=0.70). Phosphorylation of Bad, an anti-apoptotic protein, was significantly reduced in the ischemic territory (p=0.04). No changes were observed in other markers of myocardial apoptosis. CONCLUSIONS: Purified poloxamer 407 gel is effective for temporary coronary vascular occlusion. Coronary artery occlusion time is related to gel concentration and the quantity of gel injected. The higher gel concentrations may cause endothelial dysfunction of the distal vasculature and therefore should be avoided.

Animals↗

PubMed2006

Human coronary microvascular effects of cardioplegia-induced stromal-derived factor-1alpha.

BACKGROUND: Stromal-derived factor-1alpha (SDF-1alpha) binds to its specific receptor, CXCR4, and plays an important role in ischemia-induced angiogenesis. Some of the effects of SDF-1alpha are likely due to effects on the microcirculation. Cardioplegia and cardiopulmonary bypass (CP/CPB) activate mitogen-activated protein kinase (MAPK) signaling pathways including p38, ERK1/2, and JNK. The purpose of the present study was to evaluate SDF-1alpha expression, and relationships between SDF-1alpha-mediated coronary microvessel response and MAPKs. METHODS: The atrial tissue of patients undergoing cardiac surgery was harvested before and after CP/CPB. Protein levels of SDF-1alpha and CXCR4 were measured by Western blot and immunohistochemistry, and plasma levels of SDF-1alpha were measured by enzyme-linked immunosorbent assay. Coronary microvessel responses to SDF-1alpha were assessed by videomicroscopy. To further elucidate SDF-1alpha/CXCR4 signaling, microvessel responses were evaluated in the presence of CXCR4 antagonist (AMD3100) and MAPK inhibitors, ERK1/2 inhibitor (UO126), p38 inhibitor (SB203580), and JNK inhibitor (ALX-159-600). RESULTS: Myocardial protein expression of SDF-1alpha was elevated after CP/CPB (9.5 +/- 3.5-fold, p = 0.03 versus before CP/CPB). Increases in SDF-1alpha spatially localized to endothelial cells, smooth muscle cells, and myocytes. Plasma levels of SDF-1alpha were increased after CP/CPB (3.2 +/- 2.8 versus 2.8 +/- 1.7 ng /mL, p = 0.03 versus before CP/CPB). Stromal-derived factor-1alpha induced coronary microvessel contraction after CP/CPB (p = 0.046 versus before CP/CPB), which was blocked by the CXCR4 antagonist. Furthermore, SDF-1alpha induced microvessel contraction was inhibited by MAPK inhibitors, ERK-1/2 (p = 0.046), p38 (p = 0.049), and JNK inhibition (p = 0.06). CONCLUSIONS: These results suggest that CP/CPB induces myocardial expression of SDF-1alpha and results in coronary microvessel contraction through MAPK signaling pathways.

Aged↗

PubMed2006

C-Reactive protein and inflammatory response associated to neurocognitive decline following cardiac surgery.

BACKGROUND: It has been recognized that neurocognitive decline (NCD) often occurs as a complication in cardiac surgery. The early inflammatory response and C-reactive protein (CRP) was examined in relation to NCD and to a marker of axonal central nervous system (CNS) injury after cardiopulmonary bypass. METHODS: A cohort of patients undergoing coronary artery bypass grafting and/or valve procedures using cardiopulmonary bypass were administered a neurocognitive battery preoperatively and postoperatively at 6 hours and day 4. CRP, interleukin 1 beta, and interleukin 10 were quantified from serum. Increase of serum tau protein after surgery was used as a marker of axonal CNS damage. RESULTS: The rate of NCD was found to be 40.5% in this group. Surprisingly, known predictors of NCD did not differ significantly between patients with/without NCD. Patients with NCD had an early increase of CRP of a significantly higher magnitude than those without NCD (38.01 +/- 11.4 vs 16.49 +/- 3.5 mg/L, P = .042), interleukin 1ss (2.35 +/- 0.3 vs 1.20 +/- 0.2 pg/mL, P = .002), and interleukin 10 (29.77 +/- 4.7 vs 12.94 +/- 2.2 pg/mL, P < .001). Increase in serum Tau protein was significantly correlated to NCD (r = 0.50, P = .02). CONCLUSION: Perioperative increases in CRP and inflammatory cytokines are associated with NCD in patients after cardiopulmonary bypass. Thus, it appears that inflammation plays a key role in NCD pathophysiology, likely via axonal CNS injury, and could become a target for prevention.

Aged↗

PubMed2006

Bradykinin induces microvascular preconditioning through the opening of calcium-activated potassium channels.

BACKGROUND: This study was designed to investigate whether the activation of calcium-activated potassium (K(Ca)) or adenosine triphosphate sensitive potassium (K(ATP)) channels are required for bradykinin-induced microvascular preconditioning. METHODS: Isolated rabbit hearts underwent retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 60 minutes of ischemic arrest with cold crystalloid cardioplegia (CCCP). Eight CCCP hearts received no pretreatment. Six bradykinin-preconditioned hearts received a 10-minute coronary infusion of 10(-8) mol/L bradykinin-enriched KHB followed by a 5-minute recovery period before CCCP. Six hearts received both 10(-8) mol/L charybdotoxin (a K(Ca) channel blocker) and bradykinin preconditioning. Finally, 6 other hearts received 10(-5 degrees ) mol/L glibenclamide (a K(ATP) channel blocker) to bradykinin-enriched KHB. All hearts were reperfused for 30 minutes with KHB. RESULTS: Bradykinin preconditioning significantly improved the recovery of left ventricular and microvascular function, as compared with control. On the other hand, bradykinin preconditioning significantly reduced the contractile responses to U46619, a thromboxane A2 analogue. Charybdotoxin significantly inhibited the improved recovery of bradykinin-induced left ventricular and microvascular function. Glibenclamide tended to diminish the bradykinin preconditioning-enhanced recovery of left ventricular function, but failed to affect bradykinin preconditioning-improved recovery of microvascular function. CONCLUSION: Both K(Ca) and K(ATP) channels were involved partially in bradykinin-induced myocardial preconditioning. However, bradykinin induces microvascular preconditioning through the opening of K(Ca) channels rather than K(ATP) channels.

Adenosine Triphosphate↗

PubMed2006

Serologic markers of brain injury and cognitive function after cardiopulmonary bypass.

OBJECTIVE: To examine the association between biochemical markers of brain injury (MBI) and the inflammatory response in relation to neurocognitive deficiency (NCD) after cardiopulmonary bypass (CPB). SUMMARY BACKGROUND DATA: In cardiac surgery, NCD is a common but underdiagnosed complication with an unclear pathophysiology leading to significant morbidity. Despite extensive investigation, identification of a MBI for clinical use and clarifying the pathophysiology of NCD have not been achieved. METHODS: Forty patients undergoing CABG and/or valve procedures using CPB were administered a validated neurocognitive battery preoperatively and postoperatively at day 4 and 3 months. S-100b, neuron specific enolase (NSE), and tau protein were assayed as MBIs preoperatively and postoperatively at 6 hours and day 4. C-reactive protein (CRP), interleukin (IL)-6, C3a, and total peroxide levels were also quantified from serum. Impact of cardiotomy suction and antifibrinolytics on markers of brain injury was assessed. RESULTS: The incidence of early NCD was 40% (16 of 40). NSE and tau protein at the 6-hour time point were both significantly elevated in the presence of NCD (NCD group) compared with those without NCD (NORM group) (8.69 +/- 0.82 vs. 5.98 +/- 0.61; P = 0.018 and 68.8 vs. 29.2%; P = 0.015; respectively). S-100b increase was not different between the NCD and NORM groups. Cardiotomy suction significantly elevated S-100b levels, whereas NSE and tau were not significantly influenced. Aprotinin did not have an effect on NCD or levels of MBIs. Also, the NCD group had significantly elevated CRP and peroxide levels compared with the NORM group at postoperative day 4 while C3a was significantly elevated at 6 hours. CONCLUSION: NSE and tau are better associated with NCD and less influenced by cardiotomy suction compared with S-100beta. Inflammatory and oxidative stress is associated with NCD post-CPB.

Aged↗

PubMed2006

Targeting vascular endothelial growth factor in angina therapy.

Despite tremendous success of growth factor therapy in animal models, clinical trials have demonstrated minimal success. Vascular endothelial growth factors are perhaps the most potent inducers of angiogenesis in these animal models. This review outlines the biology of vascular endothelial growth factors in the context of myocardial angiogenesis with an emphasis on its effects on the endothelium. It also provides an overview of delivery strategies and summarises the preclinical and clinical evidence relating to exogenous growth factor delivery for myocardial angiogenesis with an emphasis on the key future challenges.

Angina Pectoris↗

PubMed2006

Aprotinin in cardiac surgery.

Aprotinin is a naturally occurring serine protease inhibitor that is being used with increasing frequency in cardiac surgery and beyond to reduce blood loss and the need for perioperative blood transfusion. Through inhibition of serine proteases such as plasmin, aprotinin significantly reduces fibrinolysis, thereby aiding hemostasis during surgical procedures. In addition, aprotinin interacts with other factors in the coagulation and fibrinolytic cascade, creating a hemostatic balance, without increasing the risk of thrombosis. These proven benefits are supplemented by the anti-inflammatory properties of aprotinin, which may help curb some of the deleterious effects of cardiopulmonary bypass. This article will review the discovery of aprotinin, its mechanism of action, dosing and adverse effects, and highlight the major recent trials demonstrating its efficacy.

Animals↗

PubMed2005

Safety and efficacy of a novel gel for vascular occlusion in off-pump surgery.

PURPOSE: Coronary occlusion techniques used during off-pump coronary artery bypass surgery often provide suboptimal visualization and can damage the endothelium. We evaluated a novel gel with reverse thermosensitive properties for internal vessel occlusion during off-pump coronary artery bypass surgery. DESCRIPTION: Yorkshire pigs (n = 6 per group) underwent two cycles of mid-left anterior descending coronary artery (LAD) occlusion using the gel (injected into the artery) or microvascular clamps (control group) followed by 30 minutes of reperfusion. Regional wall motion and LAD flow were monitored, microvessel relaxation responses were evaluated, and myocardial tissue was analyzed histologically. EVALUATION: Complete left anterior descending coronary artery occlusion was successfully achieved using the gel (median ischemic time, 14 minutes; range, 4.5 to 24 minutes). Anterior wall motion abnormalities as well as flow patterns in the reperfused left anterior descending coronary artery were similar in both groups. Microvessel relaxation to substance P was mildly impaired (-11.7 +/- 2.8% vs control; p < 0.001) in the left anterior descending coronary artery territory, but response to adenosine diphosphate and sodium nitroprusside was unaffected. Mild contraction band necrosis was present in both groups, consistent with mild ischemia-reperfusion injury. CONCLUSIONS: The gel represents a safe and effective method of vessel occlusion with a potentially important role in off-pump coronary artery bypass surgery.

Animals↗