Geoffrey Berg

NAD(P)H Oxidase Inhibition Improves Endothelial Function in Rat and Human Blood Vessels

Abstract—The NO/superoxide (O2−) balance is a key regulator of endothelial function. O2− levels are elevated in many forms of cardiovascular disease; therefore, decreasing O2− should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2− dismutase or NAD(P)H oxidase inhibitors. O2− levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O2− production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O2− generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor NG-nitro-l-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O2− dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O2− and mRNA expression of p22phox, gp91phox, and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.

Impact of Off-Pump Coronary Artery Bypass Surgery on Systemic Inflammation: Current Best Available Evidence

Abstract  The systemic inflammatory response after coronary artery bypass grafting using cardiopulmonary bypass (CPB) contributes substantially to postoperative organ dysfunction and coagulation disorders. Important features of this inflammatory reaction include the activation of complement and leukocytes, the release of proinflammatory cytokines, alterations in the metabolism of nitric oxide, and an increase in the production of oxygen‐free radicals, which in some cases may lead to oxidant stress injury. Several strategies including the use of steroids, use of aprotinin, heparin‐coated CPB circuits, and hemofiltration have been reported to reduce the inflammatory reaction induced by CPB and its consequences. A more radical and effective way of counteracting the effects of the inflammatory reaction and oxidative stress may be the omission of CPB itself. The development and application of off‐pump coronary artery bypass (OPCAB) technology has largely been driven by this theme of avoiding systemic inflammatory reaction to decrease the incidence and/or severity of adverse outcomes. This review article discusses the influence of cardiopulmonary bypass on systemic inflammation and attempts to evaluate the current best available evidence on the impact of OPCAB on systemic inflammation.

Effects of nitric oxide and superoxide on relaxation in human artery and vein

Endothelium-derived relaxing and contracting factors play an important role in atherosclerosis, re-stenosis and graft survival. Internal thoracic artery (ITA) and saphenous vein (SV) are used as conduit vessels in coronary artery bypass graft surgery (CABG). The long-term graft patency rate is higher with ITA than SV. Effects of nitric oxide and superoxide on vascular relaxation in isolated rings of ITA and SV from patients undergoing CABG were investigated. NG-nitro-L-Argenine methylester (L-NAME) was used to block nitric oxide synthesis and superoxide dismutase (SOD) and tiron to scavenge superoxide. Responses to carbachol were taken as a measure of stimulated nitric oxide release and increased responses to phenylephrine after addition of L-NAME as a measure of basal nitric oxide release. Immunocytochemical demonstration of endothelial nitric oxide synthase was performed using anti-endothelial nitric oxide synthetase (anti-eNOS) NOS antibody. Stimulated nitric oxide release was observed in ITA and SV but basal release was reduced or absent in SV. Treatment with SOD and tiron potentiated carbachol stimulated relaxation in ITA and SV. Tiron treatment resulted in a significant increase in basal nitric oxide in veins. eNOS immunoreactivity was more intense in ITA than SV, compatible with reduced nitric oxide production in veins. This may contribute to the reduced patency of venous grafts.

Comparison of survival following coronary artery bypass grafting vs. percutaneous coronary intervention in diabetic and non-diabetic patients: retrospective cohort study of 6320 procedures.

Aim  To determine whether mortality following percutaneous coronary intervention vs. coronary bypass grafting varies according to whether or not patients have diabetes.

Low-Density Lipoprotein Cholesterol Determines Oxidative Stress and Endothelial Dysfunction in Saphenous Veins From Patients With Coronary Artery Disease

Objective—There is evidence for a relationship between endothelial dysfunction and cardiovascular disease, but a causative role for oxidative stress remains to be determined. Methods and Results—We studied 188 patients with severe coronary artery disease (CAD), of whom 51 were age and sex matched with 51 healthy controls undergoing varicose vein surgery. Relaxation of saphenous vein to calcium ionophore, apocynin, and allopurinol was studied together with the markers of oxidative stress, total antioxidant capacity and reduced/oxidized glutathione ratio. Vascular superoxide levels were measured using lucigenin chemiluminescence and hydroethidine. Relaxation to calcium ionophore was decreased in CAD compared with control patients (maximum relaxation 26±2% versus 60±1%; P<0.001). Total superoxide production was increased (0.89±0.09 versus 0.56±0.06 nmol/mg per min; P=0.008), whereas superoxide inhibition with apocynin or allopurinol had a greater effect on vasorelaxation in CAD patients. Low-density lipoprotein (LDL) cholesterol predicted relaxation to calcium ionophore (P<0.001) and oxidative stress markers (P<0.001) in CAD patients. Conclusions—Endothelial dysfunction is associated with raised levels of superoxide and biomarkers of oxidative stress in saphenous veins from CAD patients. LDL cholesterol is a major determinant of endothelial dysfunction and oxidative stress in these patients. These results support intensive LDL cholesterol-lowering therapy as suggested by recent clinical trials.

Vasorelaxant properties of isolated human radial arteries: comparison with internal mammary arteries

Radial arteries, used in revascularisation surgery, are prone to spasm. We have examined the ability of nitrovasodilators, calcium channel blockers, and K(ATP) channel openers to cause vasodilation, and to attenuate contractions due to depolarisation and receptor activation in radial and mammary arteries used in coronary artery bypass graft surgery. Two to three millimetre rings of artery obtained from patients at surgery were studied in organ baths in vitro. Constriction to KC1 and phenylephrine was examined before and again after treatment of the rings with drug or vehicle. Calcium channel blockers were the only compounds to inhibit contractions to both KC1 and phenylephrine. Sodium nitroprusside attenuated constriction to phenylephrine but not KC1 in both vessels. K(ATP) channel openers similarly attenuated constriction to phenylephrine in radial arteries but were much less effective in mammary arteries. These studies support the continued use of calcium blockers after revascularisation with radial artery but suggest that other classes of drug may be as effective at minimising spasm due to receptor mediated constriction.

Reduced LDL-cholesterol levels in patients with coronary artery disease are paralelled by improved endothelial function: An observational study in patients from 2003 and 2007

Objective Recent guidelines recommend more aggressive lipid-lowering in secondary prevention protocols. We examined whether this resulted in improved endothelial function. Methods We studied saphenous vein specimens of patients undergoing surgical coronary revascularisation in 2007 and compared results with those of patients examined in 2003. Endothelium-dependent vasodilation was assessed by relaxation to calcium ionophore A23187, and vascular superoxide production by lucigenin enhanced chemiluminescence. Results Statin dose increased from 26 ± 16 mg/d in 2003 to 37 ± 17 mg/d in 2007 (P < 0.001), and total (4.0 ± 0.9 mmol/L vs 4.8 ± 1.0 mmol/L) and LDL-cholesterol levels (2.0 ± 0.7 mmol/L vs 3.0 ± 0.9 mmol/L) were lower in 2007 compared to 2003 (P < 0.001; n = 90 each). Endothelium-dependent vasodilation was greater in 2007 (44 ± 15%) compared to 2003 (28 ± 12%; n = 36 each; P < 0.001). Vascular superoxide derived from endothelial NO synthase (eNOS) was lower in 2007 than in 2003 (reduction by NG-nitro-l-arginine-methyl ester, 0.29 ± 0.21 nmol/(mg min) vs 0.09 ± 0.20 nmol/(mg min); P = 0.002). In linear regression analysis, LDL-cholesterol levels have been shown to be the major determinant of endothelial function in the combined 2003 and 2007 cohort. Conclusion Intensive lipid-lowering is associated with improved endothelial function and reduced superoxide production from eNOS. Further improvement in vascular function could be achieved by targeting other sources of superoxide including xanthine oxidase.

Moderate Ischemic Mitral Regurgitation: to Treat or not to Treat?

Abstract  There is consensus of opinion that patients with moderately severe to severe (grade 3+ or 4+) ischemic mitral regurgitation (IMR) should undergo mitral valve surgery at the time of coronary artery bypass grafting (CABG), while trace to mild (grade 1+) IMR can probably be left alone. However, the management of moderate (grade 2+) IMR continues to be a subject of constant debate and controversy. In particular, as techniques of valvular repair continue to be refined; many surgeons have advocated mitral valve repair and concomitant CABG for these patients. Others, however, have continued to treat these patients with revascularization alone and close postoperative observation of the mitral valve. In their opinion, degree of concomitant mitral valve dysfunction in this group of patients does not justify the increased operative risks associated with simultaneous mitral valve correction. We are currently practicing in an era of evidence‐based medicine (EBM) in which clinical decision‐making has to be guided by current best available evidence from scientific, clinical studies. This review article attempts to tackle this controversial issue and find the best approach of dealing with moderate IMR at the time of CABG by evaluating current best available evidence.

Duroflo II heparin bonding does not attenuate cytokine release or improve pulmonary function.

BACKGROUND Comparison of the cytokine generation and leukocyte activation properties of Duroflo II heparin bonded bypass circuit (Baxter Healthcare Corp, Compton, UK) and the conventional cardiopulmonary bypass circuit. Attempt to correlate these to pulmonary dysfunction postoperatively. METHODS Forty patients undergoing elective, isolated coronary artery bypass grafting were randomly allocated to have either plain extracorporeal circuits (group C) or heparin bonded extracorporeal circuits (group H). Full systemic heparinization was used in all patients. The inflammatory response was assessed by measuring plasma levels of interleukin-6, interleukin-8, interleukin-10, and polymorphonuclear elastase. Gas exchange was assessed by measuring the PaO2/FIO2 ratio. RESULTS Significant impairment of oxygenation was seen in both groups with the lowest values at the end of the operation before a gradual return to normal during the next 6 hours. There were no differences between the groups in gas exchange or times to extubation. There were significant elevations in all the cytokines, with interleukin-6 levels peaking at 4 hours in group H and 24 hours in group C, before starting to return to normal at 48 hours. The patterns of interleukin-8 and interleukin-10 rise were identical in the two groups. Polymorphonuclear elastase reached a peak at the end of the operation in group H and remained elevated up to 24 hours, whereas levels continued to rise in group C up to 4 hours. There were no significant differences in levels between groups at any time. There were no differences between the groups in blood loss or blood product usage. CONCLUSIONS Cardiopulmonary bypass induces a systemic inflammatory response with release of cytokines and activation of leukocytes. This correlates with the severe deterioration in pulmonary gas exchange from preoperative levels up to 6 hours postoperatively (p < 0.05). In the presence of systemic heparinization, Duroflo II heparin bondingtf the circuits has minor effects on the pattern of evolution of this inflammatory response.

Safety of Drug Eluting Stents: Current Concerns and Controversies

Coronary artery stenting is currently the most frequently performed percutaneous coronary intervention for the treatment of coronary artery disease. Recently, drug- eluting stents, loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs, have revolutionized the management of coronary artery disease by markedly reducing in-stent restenosis. Despite the excellent short- and mid-term results of randomized controlled trials observed with drug-eluting stents, there remain a number of unresolved issues and valid concerns about long-term safety and efficacy of this revolutionary technology. Important safety issues such as thrombosis, late stent malapposition, aneurysm formation, edge effect, late inflammation due to choice of polymer used to bind the drug, the release of toxins, and potential interactions with brachytherapy and drugs have not been completely addressed. This review article evaluates current available scientific evidence on the various safety issues related to the use of drug-eluting stents.