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Biomedical subjects

Munir Boodhwani

Publications and source records attributed to Munir Boodhwani.

At least 19 recordsLinked to original sources
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

Ultrafiltration reduces blood transfusions following cardiac surgery: A meta-analysis.

BACKGROUND: Although used routinely in pediatric patients, ultrafiltration techniques that reverse hemodilution are infrequently used in adults. Data from small, unblinded clinical trials suggest that the use of ultrafiltration can reduce inflammatory mediators, improve cardiac function, and reduce hemodilution. We conducted a meta-analysis of randomized trials to evaluate the effects of ultrafiltration on blood transfusions and blood loss following adult cardiac surgery. METHODS: Medline, EMBASE, and Cochrane databases were searched and randomized controlled trials evaluating modified and/or conventional ultrafiltration, meeting pre-determined selection criteria, were obtained. Quality evaluation and data extraction were performed by two independent observers blinded to study source. Random effects models were used to determine pooled effect estimates and sources of heterogeneity were explored using meta-regression. RESULTS: One hundred and thirty two studies were screened and 10 randomized trials evaluating 1004 patients (control, n = 495; ultrafiltration, n = 509) were identified of which only two were double-blinded. The use of ultrafiltration was associated with a reduction in postoperative blood transfusions (weighted mean difference [95% CI] of -0.73 units [-1.16, -0.31]; p = 0.001). This reduction was greater in studies evaluating modified ultrafiltration. Use of ultrafiltration was also associated with reduced postoperative bleeding (-70 ml, [-118, -21]; p = 0.005), which was driven primarily by trials evaluating modified rather than conventional ultrafiltration. CONCLUSIONS: Use of ultrafiltration is associated with a significant reduction in postoperative blood transfusions as well as reduced bleeding in adults undergoing cardiac surgery. The efficacy and cost-effectiveness of ultrafiltration as a blood conservations strategy should be evaluated in a large, randomized, double-blinded study.

Adult↗
PubMed2006

Skeletonized internal thoracic artery harvest reduces pain and dysesthesia and improves sternal perfusion after coronary artery bypass surgery: a randomized, double-blind, within-patient comparison.

BACKGROUND: Observational studies suggest that skeletonization of the internal thoracic artery (ITA) can improve conduit flow and length and reduce deep sternal infections and postoperative pain. We performed a randomized, double-blind, within-patient comparison of skeletonized and nonskeletonized ITAs in patients undergoing coronary surgery. METHODS AND RESULTS: Patients (n = 48) undergoing bilateral ITA harvest were randomized to receive 1 skeletonized and 1 nonskeletonized ITA. Intraoperatively, ITA flow was assessed directly and with a Doppler flow probe before and after topical application of papaverine. ITA harvest time and conduit length were recorded. A blinded assessment of pain (visual analog scale) and dysesthesia (physical examination) was performed at discharge, at 2 weeks, and at a 3-month follow-up. Sternal perfusion was assessed with nuclear imaging (n = 7). Skeletonization required longer ITA harvest times (27 +/- 1 versus 24 +/- 1 minutes; P = 0.04). There was a trend toward increased ITA length in the skeletonized group (18.2 +/- 0.3 versus 17.7 +/- 0.3 cm; P = 0.09). In situ ITA flow was lower in skeletonized arteries (7.4 +/- 0.9 versus 10.1 +/- 1.0 mL/min; P = 0.01) and increased significantly after ITA division and papaverine application. Postanastomotic flows were similar between groups. Skeletonization was associated with decreased pain at the 3-month follow-up and a reduction in major sensory deficits at the 4-week and 3-month (17% versus 50%; P = 0.002) follow-ups. Baseline adjusted sternal perfusion was significantly greater by 17 +/- 6% (P = 0.03) on the skeletonized side. CONCLUSIONS: Skeletonization results in reduced postoperative pain and dysesthesia and increased sternal perfusion at follow-up but does not produce increased conduit flow. ITA skeletonization may be a strategy for reducing morbidity after CABG.

Coronary Artery Bypass↗
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

Predictors of early neurocognitive deficits in low-risk patients undergoing on-pump coronary artery bypass surgery.

BACKGROUND: Postoperative cognitive deficits (POCDs) are a source of morbidity and occur frequently even in low-risk patients undergoing cardiac surgery. Predictors of neurocognitive deficits can identify potentially modifiable risk factors as well as high-risk patients in whom alternate revascularization strategies may be considered. METHODS AND RESULTS: 448 patients undergoing coronary surgery (coronary artery bypass graft [CABG]) underwent standardized preoperative and postoperative neurocognitive testing as part of 2 randomized trials evaluating the effects of mild hypothermia during coronary surgery. Prospectively collected data were used to identify univariate predictors of POCDs and multivariable logistic regression models were constructed. Models were bootstrapped 1000 times. POCDs occurred in 59% of patients. Significant univariate predictors included intraoperative normothermia, impaired left ventricular (LV) function, higher educational level, elevated serum creatinine and reduced creatinine clearance, prolonged intubation time, intensive care unit (ICU) stay, and hospital stay. Advanced age, presence of carotid disease, and cardiopulmonary bypass time were not associated with increased POCDs in this cohort. Multivariable modeling identified intraoperative normothermia (odds ratio [95% confidence interval] -1.15 [1.01, 1.31]), poor LV function (1.53 [1.02, 2.30]), and elevated preoperative creatinine (1.01 [1.00 to 1.03] for every 1 mmol/L increase), prolonged (>24 hours) ICU stay (1.88 [1.27 to 2.79]), and higher educational level (1.52 [1.01 to 2.28]) as independent predictors of POCD occurrence. CONCLUSIONS: Mild hypothermia, in the intraoperative and perioperative period, may be a protective strategy for the prevention of POCDs. Patients with elevated pre-operative creatinine and poor LV function carry a higher risk of POCDs and may benefit from revascularization strategies other than conventional on-pump CABG.

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

The internal thoracic artery skeletonization study: a paired, within-patient comparison [NCT00265499].

BACKGROUND: Traditional harvesting of the internal thoracic artery (ITA) for use as a conduit in coronary bypass surgery involves the dissection of a rim of tissue surrounding the artery on either side. Recent studies, primarily observational, have suggested that skeletonization of the ITA can improve conduit flow, increase length, and reduce the risk of deep sternal infection in high risk patients. Furthermore, skeletonization of the ITA can potentially preserve intercostal nerves and reduce post-operative pain and dysesthesias associated with ITA harvesting. In order to assess the effects of ITA skeletonization, we report a prospective, randomized, within-patient study design that shares many features of a cross-over study. METHODS: Patients undergoing bilateral internal thoracic artery harvest will be randomized to having one side skeletonized and the other harvested in a non-skeletonized manner. Outcome measures include ITA flow and length measured intra-operatively, post-operative pain and dysesthesia, evaluated at discharge, four weeks, and three months post-operatively, and sternal perfusion assessed using single photon emission computed tomography. Harvest times as well as safety endpoints of ITA injury will be recorded. DISCUSSION: This study design, using within-patient comparisons and paired analyses, minimizes the variability of the outcome measures, which is seldom possible in the evaluation of surgical techniques, with minimal chance of carryover effects that can hamper the interpretation of traditional cross-over studies. This study will provide a valid evaluation of clinically relevant effects of internal thoracic artery skeletonization in improving outcomes following coronary artery bypass surgery.

Journal Article↗
PubMed2006

Hypercholesterolemia impairs the myocardial angiogenic response in a swine model of chronic ischemia: role of endostatin and oxidative stress.

BACKGROUND: Recent studies have shown that angiogenesis is regulated by a balance between activators and inhibitors. We investigated the effects of hypercholesterolemia on the functional angiogenic response and collateral formation induced by chronic myocardial ischemia and the expression of angiogenic mediators. METHODS: Twelve Yucatan miniswine, fed either a normal (NORM, n = 6) or high cholesterol (HCHO, n = 6) diet for 13 weeks, underwent ameroid constrictor placement around the circumflex artery. Three weeks later, myocardial perfusion was quantified using isotope-labeled microspheres. Seven weeks after ameroid placement, coronary microvascular responses and myocardial perfusion were assessed. Vascular density was evaluated by PECAM-1 (CD-31) staining, and vascular endothelial growth factor, endothelial nitric oxide synthase, endostatin, and angiostatin protein levels were determined. Myocardial protein oxidation was quantified. RESULTS: Coronary microvessels from HCHO pigs showed significant endothelial dysfunction. Baseline-adjusted myocardial flow at 7 weeks was significantly reduced in the HCHO animals (-0.002 +/- 0.06 versus +0.23 +/- 0.09 mL/min/g, HCHO versus NORM, p = 0.04). Endostatin expression was significantly increased in the HCHO pigs (2.2-fold, p = 0.001 versus NORM). There was a mild reduction in myocardial vascular endothelial growth factor expression (-29% +/- 14%, p = 0.09) in HCHO animals, but no difference in expression of endothelial nitric oxide synthase and angiostatin. The HCHO animals demonstrated increased myocardial protein oxidation compared with the NORM group (+155% +/- 21%, p = 0.03 versus NORM). CONCLUSIONS: Ischemia-induced angiogenesis is inhibited in hypercholesterolemic pigs with a concomitant increase in endostatin expression and oxidative stress. These findings suggest that under conditions of hypercholesterolemia, coronary collateral development may be regulated by endogenous angiogenesis inhibitors such as endostatin as well as reactive oxygen species.

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

High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine.

OBJECTIVES: The disappointing results of myocardial angiogenic therapy have been attributed, in part, to endothelial dysfunction present in patients with coronary disease. Statins have established proendothelial properties but seem to have dose-dependent effects on angiogenesis. We investigated the functional and molecular effects of high-dose atorvastatin on vascular endothelial growth factor-induced myocardial angiogenesis in hypercholesterolemic swine. METHODS: Yucatan miniswine (20-30 kg) were fed either a normal (ND group, n = 8) or high-cholesterol diet, with (HC-ATOR group, n = 8) or without (HC group, n = 8) atorvastatin (3 mg x kg(-1) x d(-1)), for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery, followed 3 weeks later by perivascular vascular endothelial growth factor administration (2 microg over 4 weeks) with a sustained release osmotic pump. Microvessel relaxation responses, myocardial perfusion, and myocardial expression of angiogenic mediators were assessed 4 weeks later. RESULTS: Hypercholesterolemic swine demonstrated impaired microvessel relaxation to vascular endothelial growth factor (P < .01 vs ND group) and adenosine diphosphate (P < .001 vs ND group), which was normalized in the HC-ATOR group. After perivascular vascular endothelial growth factor administration, collateral-dependent myocardial perfusion was significantly increased in the ND group but decreased in both the HC and HC-ATOR groups (both P < .01 vs the ND group). The animals in the HC-ATOR group demonstrated increased myocardial expression of the antiangiogenic protein endostatin and increased Akt phosphorylation without significant changes in Akt and endothelial nitric oxide synthase expression. CONCLUSIONS: Atorvastatin treatment reverses hypercholesterolemia-induced endothelial dysfunction without appreciable improvements in collateral-dependent myocardial perfusion in response to vascular endothelial growth factor treatment. Increased myocardial endostatin expression and chronic Akt activation, associated with atorvastatin therapy, might account for the lack of improvement in the angiogenic response to vascular endothelial growth factor therapy.

Animals↗
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

Biologically based myocardial regeneration: is there a role for the surgeon?

PURPOSE OF REVIEW: Despite advances in medical, percutaneous, and surgical treatment, there is an increasing burden of ischemic cardiovascular disease and heart failure. Over the past decade, a large number of preclinical and clinical studies have evaluated various biologic agents to treat these diseases. RECENT FINDINGS: Although the safety and feasibility of growth factor therapy, using vascular endothelial growth factors and fibroblast growth factors, for myocardial angiogenesis has been well established in a number of clinical trials, their ability to induce clinically significant improvements in symptoms remains uncertain. Numerous candidates have been proposed for cell-based therapies to improve myocardial perfusion and function and have demonstrated efficacy in preclinical studies. These cell types include skeletal myoblasts, bone-marrow derived cells, endothelial progenitors, and mesenchymal stem cells. Early clinical trials have demonstrated feasibility of cell harvest and implantation. SUMMARY: Biologic myocardial regeneration is a new and rapidly evolving area for the treatment of cardiovascular disease. Translation of these biologic entities into clinically useful therapeutic agents will require a better mechanistic understanding of their effects on the myocardium and the coronary circulation, optimization of delivery techniques, and systematic evaluation in large, randomized, placebo-controlled studies.

Biological Therapy↗
PubMed2006

The future of therapeutic myocardial angiogenesis.

Despite improvements in its medical and surgical management, ischemic coronary disease remains responsible for significant morbidity, mortality, and economic burden in developed nations. Therapeutic myocardial angiogenesis is an attractive treatment option for patients with end-stage coronary disease who have failed percutaneous and surgical methods of revascularization. Over the past decade, our understanding of the biology of new blood vessel formation has improved significantly, and consequently, the use of growth factors to induce myocardial angiogenesis has been attempted in preclinical and clinical trials. Although growth factor therapy had demonstrated tremendous success in animal models, clinical trials have shown limited benefit in patients with coronary disease. Vascular endothelial growth factors and fibroblast growth factors are perhaps the most potent inducers of angiogenesis that have been used in animal models, and the only ones that have been used in clinical trials. This review outlines the biology of new vessel formation and the effects of these growth factors in the context of myocardial angiogenesis with an emphasis on the effects on the endothelium. It also provides a brief overview of delivery strategies and summarizes the preclinical and clinical evidence relating to exogenous growth factor delivery for myocardial angiogenesis. Lastly, we discuss the limitations and future challenges of angiogenic therapy.

Angiogenesis Inducing Agents↗