Russell S. Ronson

The cardiovascular effects and implications of peroxynitrite

Nitric oxide is an endogenous autacoid produced primarily by the vascular endothelium. Under basal conditions, nitric oxide undergoes a rapid biradical reaction with superoxide anions to form peroxynitrite. This reaction, and hence the formation of peroxynitrite is augmented in inflammatory-like conditions such as ischemia-reperfusion injury when both substrates are present in high concentrations. Peroxynitrite has been implicated as a physiologically active toxic metabolite of nitric oxide leading to vascular and myocardial dysfunction. Recent evidence, however, has suggested that peroxynitrite may actually have beneficial properties under in vivo biological conditions when thiol-containing agents (glutathione, albumin, cysteine) agents are available to convert the peroxynitrite anion to nitrosothiols and related products demonstrating antineutrophil and cardioprotective properties. The dichotomy of physiologically relevant properties of peroxynitrite has important clinical applications with respect to nitric oxide therapy for cardiac, vascular, cerebral and pulmonary disease states. This review summarizes the biological properties of peroxynitrite relevant to the cardiovascular system.

Off-pump multivessel coronary bypass via sternotomy is safe and effective

BACKGROUND In an attempt to avoid the deleterious effects of cardiopulmonary bypass, off-pump coronary artery bypass grafting has been rediscovered and refined. The purpose of this study was to compare clinical outcomes, length of stay, and hospital costs with coronary artery bypass grafting on cardiopulmonary bypass. METHODS Coronary artery bypass was performed on 51 patients without cardiopulmonary bypass. Patients were selected on the basis of coronary anatomy, with significant stenoses in the left anterior descending, ramus intermedius, diagonal, right coronary, acute marginal, or posterior descending territories. Outcomes were compared with those of a computer-generated matched control group having coronary artery bypass grafting on cardiopulmonary bypass (n = 248) during the same time period. RESULTS No preoperative differences were noted between groups. There were no deaths in the off-pump group and a mortality rate of 1.6% (4/248) in the control group. There was no incidence of stroke, myocardial infarction, or reentry for bleeding among patients in the off-pump group. There was a reduction in length of stay by 3 days (p = 0.01), blood transfusions by 50% (p = 0.0001), and hospital charges by one third (p = 0.05) in the off-pump group. Twenty-six patients had repeat coronary angiography before discharge; 41/43 grafts were widely patent, 1/43 was totally occluded, and 1/43 was narrowed by more than 50%. All internal mammary artery grafts were widely patent. CONCLUSIONS Off-pump multivessel cardiopulmonary bypass grafting is a safe and effective means of revascularization for patients with coronary stenoses in the anterior or inferior regions, with excellent short-term patency rates and minimal morbidity.

Broad-spectrum cardioprotection with adenosine

Ischemia-reperfusion results in contractile dysfunction, necrosis, and vascular injury. This postischemic injury is mediated in part by superoxide radical production, neutrophils, dysfunction to ionic pumps, and edema formation. Adenosine is an autacoid released tonically by myocytes, endothelium, and neutrophils; the release of adenosine from the myocyte compartment into the interstitium is increased during ischemia. The major effects of adenosine are mediated by specific receptors identified as A1, A2a, A2b, and A3. Each receptor subtype contributes to physiological responses that influence ischemia-reperfusion injury. Adenosine has potent cardioprotective properties exerted during three major windows of opportunity: pretreatment, ischemia, and reperfusion. The cardioprotective effects exerted during pretreatment and ischemia may involve metabolic changes and hyperpolarization via K(ATP)-channel activation, mediated through A1 receptor mechanisms. The cardioprotective mechanisms exerted during reperfusion involve inhibition of neutrophils directly (superoxide anion generation, expression of adhesion molecules), and by inhibiting activation of the endothelium through A2 receptor-mediated mechanisms, thereby preventing neutrophil-endothelial cell interactions, which initiate the inflammatory-like component of reperfusion injury. Activation of the newly identified A3 receptor has been shown to be cardioprotective partially by inhibition of neutrophil adherence to endothelium and by neutrophil-independent mechanisms. These mechanisms of cardioprotection have been suggested to play major roles in the reduction of infarction and apoptosis after myocardial ischemia, cardioplegic arrest, and subsequent reperfusion. Adenosine has been used as an adjunct to both crystalloid and blood cardioplegia, but its potential as a cardioprotective agent has not been fully explored.

Nitric Oxide and the Vascular Endothelium in Myocardial Ischemia‐Reperfusion Injurya

Abstract: The normal coronary vascular endothelium (VE) tonically releases nitric oxide (NO) by converting L‐arginine to citrulline by a constitutive NO synthase. Reperfusion after myocardial ischemia reduces basal and stimulated release of NO. This “vascular reperfusion injury” is mediated largely by neutrophils (PMN) through specific interactions between adhesion molecules on the endothelium and the PMN, an interaction that precedes myocyte injury. NO inhibits the PMN‐mediated reperfusion injury by direct effects on both the PMN and the vascular endothelium. Cardioprotective strategies include augmentation of endogenous NO by the precursor L‐arginine and the administration of exogenous NO donors at the time of perfusion, which (1) attenuates PMN adherence to the coronary artery and venous endothelium, (2) reduces PMN‐mediated endothelial dysfunction, (3) reduces PMN accumulation in the area at risk, and (4) reduces infarct size. Hence, NO represents a powerful therapeutic tool with which to attenuate the consequences of ischemia‐reperfusion injury on vascular injury and infarction.

Adenosine A3 pretreatment before cardioplegic arrest attenuates postischemic cardiac dysfunction

BACKGROUND The cardioprotective effects of the adenosine A3 receptor in a cardioplegia model have not been described. We tested the hypothesis that infusion of the A3 receptor agonist, Cl-IB-MECA (100 nM), as a pretreatment (PTx) and/or as a cardioplegic (CP) additive reduces postischemic myocardial injury. METHODS Isolated perfused rat hearts underwent 30 minutes of normothermic ischemia, 60 minutes of intermittent hypothermic cardioplegia (10 degrees C), followed by 2 hours of reperfusion. Hearts were divided into four groups: (1) no pretreatment (PTx) and unsupplemented cardioplegia (CP) (control), (2) Cl-IB-MECA PTx and unsupplemented CP (A3-PTx), (3) no PTx and Cl-IB-MECA CP (A3-CP), or (4) Cl-IB-MECA PTx and Cl-IB-MECA CP (A3-[PTx+CP]). RESULTS Coronary flow was not increased after A3 pretreatment when compared to baseline values. After 2 hours of reperfusion, left ventricular developed pressure in control and A3-CP groups was depressed to 43% +/- 3% and 47% +/- 2% of baseline; while A3-PTx and A3-[PTx+CP] significantly increased left ventricular developed pressure (65% +/- 3% and 61% +/- 5%) from baseline relative to control and A3-CP. Effluent creatine kinase activity was significantly decreased by A3-PTx (1520 +/- 32 IU/L), A3-[PTx+CP] (1481 +/- 41 IU/L) from control (1734 +/- 54 IU/L) and A3-CP (1750 +/- 43 IU/L). Myocardial edema (% tissue water) was significantly less in A3-PTx (78 +/- 0.6%) and A3-[PTx+CP] (76% +/- 2%) compared with control (85% +/- 0.4%) and A3-CP (83% +/- 2%). CONCLUSIONS Adenosine A3 receptor stimulation as a pretreatment attenuates postischemic cardiodynamic dysfunction and creatine kinase release but has no cardioprotection as an adjunct to cold cardioplegia.

Embryology and surgical anatomy of the mediastinum with clinical implications.

This article discusses general mediastinal embryology, and provides anatomy and algorithms for the investigation of mediastinal masses. The superior, anterior, middle, and posterior mediastina also are detailed.

Recombinant human megakaryocyte growth and development factor attenuates postbypass thrombocytopenia

BACKGROUND Cardiopulmonary bypass contributes to platelet loss and dysfunction by exposure to shear stresses, foreign surfaces, and hypothermia. This study tested the hypothesis that pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) accelerates recovery of the platelet population after hypothermic extracorporeal circulation (HEC). METHODS In a blinded study, subcutaneous injections of drug or placebo were given to dogs daily for 3 days preoperatively (day 0, 1, and 2) with no drug on day 3. On day 4, the animal was prepared for arteriovenous HEC. After heparinization, HEC was initiated at 30 to 40 mL x kg(-1) x min(-1). Hypothermic extracorporeal circulation (25 degrees C) was continued for 90 minutes. RESULTS Preoperative platelet count (x10(3) platelets/microL) did not differ from predrug count in placebo (256+/-27 versus 255+/-20) or PEG-rHuMGDF (271+/-30 versus 291+/-38). During 60 minutes of HEC, the platelet count decreased to approximately 10% of baseline in placebo (29+/-5) and PEG-rHuMGDF (46+/-8), and recovered to approximately 70% of baseline after rewarming (90 minutes of HEC: placebo, 185+/-17, versus PEG-rHuMGDF, 169+/-22). After HEC, platelet count was greater in PEG-rHuMGDF-treated animals (p < 0.05) without altering function (aggregation responses). Within the first 6 hours after HEC, platelet count in PEG-rHuMGDF-treated animals was rising and increased to 260+/-29 (p < 0.01), but was unchanged in placebo animals (186+/-21). Thereafter, platelet count in placebo animals declined to a nadir of 124+/-15 (72 hours after HEC), whereas platelet count in PEG-rHuMGDF animals approximated the preoperative value (>200) at all times. CONCLUSIONS Appropriately timed presurgical administration of PEG-rHuMGDF counteracts post-HEC relative thrombocytopenia without increasing platelet population and enhancing aggregation preoperatively or during extracorporeal circulation.