Joseph B. Borman

The protective role of neocuproine against cardiac damage in isolated perfused rat hearts

The effect of neocuproine on cardiac injury was studied using retrogradely perfused isolated rat hearts in two experimental systems. In the first system, where hydrogen peroxide-induced damage was studied, neocuproine at the range of 40-175 microM provided protection at the level of 70-85%, as demonstrated by the reduced loss in the peak systolic pressure (P), in +dP/dt and in -dP/dt. In the second system, where ischemia/reperfusion-induced arrhythmias were studied, neocuproine (42 microM) provided a marked protection against cardiac injury as demonstrated by the lowering of the incidence in irreversible ventricular fibrillation, by decreasing the duration of ventricular fibrillation and by the concomitant increase of the duration of normal sinus rhythm, and by improving the post-ischemic recovery of P, +dP/dt and -dP/dt. Free radicals have already been implicated as causative agents in cardiac injury resulting from either hydrogen peroxide or ischemia followed by reperfusion. Additionally, iron and copper have already been shown to drastically exacerbate the injurious effects of free radicals. Thus, the results reported here with neocuproine, a highly effective chelator for both iron and copper, as well as with adventitious copper and with the combination of neocuproine and copper, are in accord with the mediatory role of transition metals in enhancing the deleterious effects induced by free radicals.

Protection of myocardium by cyclosporin A and insulin: In vitro simulated ischemia study in human myocardium

BACKGROUND The efficacy of myocardial protection by cyclosporin A (CSA) and insulin was tested in human right atrial myocardial slices subjected to simulated ischemia and reoxygenation. METHODS Slices of right atrial trabeculae were obtained from patients undergoing elective cardiac surgery. Trabeculae were incubated with oxygenated glucose containing phosphate buffered saline (O(2), G-PBS). After 30 minutes of stabilization the sections were exposed to 90 minutes of simulated ischemia (N(2), PBS without glucose) followed by 90 minutes reoxygenation (O(2), G-PBS). Cyclosporin A (0.2 micromol/L) or insulin (5 mU/mL) was added during the stabilization period prior the ischemia. Cell viability was measured by using 3-[4.5 dimethylthiazol 2-yl]-2,5-diphenyltetrazolium bromide (MTT), which is cleaved by active mitochondrial dehydrogenases of living cells. RESULTS The viability of untreated slices (control) was 30.45% +/- 2.5% versus 52.65% +/- 4.4% in the CSA treated slices, p less than 0.001. The extent of protection by CSA was affected by oral antiglycemic drugs (glibenclamide). The effect obtained by CSA was inhibited by 5-hydroxydecanoate (5HD), a specific blocker of mitochondrial K(ATP) channels. Protection of the myocardial slices with insulin appears to be superior and not affected by the medication before surgery. This protection was maximal when insulin was present during both preischemic equilibration and reoxygenation periods (68.9% +/- 9.3% viability with insulin versus 33.2% +/- 6.9% in the control, p < 0.001). CONCLUSIONS Protection of right atrial trabeculae slices with insulin is superior to that obtained with CSA and is independent of preoperative medication.

Interaction between allopurinol and copper: possible role in myocardial protection.

Allopurinol, a potent inhibitor of xanthine oxidase, is known to effectively protect the heart against damage in patients undergoing cardiac bypass surgery. There is still an ambiguity concerning the presence of xanthine oxidase in the human heart. Thus, the mechanism underlying the protective effect of allopurinol is unclear. Transition metal ions, such as iron and copper, can participate in single-electron reactions and mediate the formation of oxygen-derived free radicals. In this study the interaction between allopurinol and Cu(II) was investigated. Spectrophotometric investigation shows that allopurinol (0-0.8 mM) form a 1:1 complex with Cu(II) ions (0-0.8 mM) with a specific absorbance peak at 364 nm. Also, the rate constant (k) for the copper-catalyzed aerobic oxidation of ascorbate was markedly decreased in the presence of allopurinol (from 0.068 min-1 to 0.014 min-1). Allopurinol substantially reduced the copper-mediated and ascorbate-driven DNA breakage. Spectrophotometric measurements did not indicate a specific interaction between iron ions and allopurinol. It is suggested that the beneficial effects of allopurinol during reperfusion of the heart could stem from its chelation of copper, yielding a complex with low redox activity.

Effect of nitric oxide and nitroxide SOD-mimic on the recovery of isolated rat heart following ischemia and reperfusion.

Nitric oxide synthesized from L-arginine in cells has important salutary physiological roles, but can also exert deleterious effects. Nitric oxide (NO) can ameliorate post-ischemic reperfusion myocardial injury, yet formation from NO and O(2)z*(-) of peroxynitrite and its downstream toxic products, such as *OH, *NO(2) and CO(3)*(-), can ultimately exacerbate reperfusion damage. Nitroxide stable radicals, such as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TPL), unlike SOD, readily penetrate cells and catalytically remove intracellular O(2)*(-). Hence, nitroxides by virtue of catalytic removal of O(2)*(-) would be expected to diminish the adverse effect of NO and lower post-ischemic reperfusion cardiac damage. We show that post-ischemic recovery of hemodynamic functions of isolated perfused rat hearts treated with L-arginine or TPL alone did not differ from that of the control hearts. However, the recovery of hearts treated with the combined regimen of L-arginine and TPL was significantly improved, e.g. the Work Index=(left ventricular developed pressure x heart rate) recovered to 92+/-1.6% (L-arginine and TPL) vs. 59.4+/-5.4% (Control), 60+/-2.9% (L-arginine) and 53.3+/-4.3% (TPL) of the pre-ischemic value; mean+/-SEM, N=10, P<0.001. The enhanced recovery of hemodynamic function of hearts treated with L-arginine and TPL was accompanied by an increased recovery of oxygen consumption during the reperfusion. The combined regimen of L-arginine and TPL reduces the negative effects of NO by either inhibiting the production of ONOO(-) or through reaction with CO(3)z.rad;(-) and *NO(2) radicals formed during the decomposition of peroxynitrite in the presence of bicarbonate, thus promoting cardioprotection following post-ischemic reperfusion.

Analysis of microembolic particles originating in extracorporeal circuits

Silicone tubing is utilised increasingly in extracorporeal circulation (ECC), particularly for prolonged bypass in cases of left ventricular failure following open heart surgery. We compared the spectrum of particle formation in the EC circuit, due to roller pump damage, resulting from wear of silicone tubing with that of polyvinyl chloride (PVC) tubing. The EC circuit was primed with plasmalyte solution for pump runs of up to 24 hours. Samples of the perfusate were taken from either system at prefixed times. Number and size of the particles were determined by means of a Coulter counter, while their chemical composition was analysed by X-ray dispersion (EDXA). The tubing was examined by scanning electron microscopy. When using PVC tubing, the amount of particles of all sizes rose above acceptable standards shortly after activating the roller pump. Following this early upsurge, the number of particles continued to increase for the remainder of the pump run, albeit at a more moderate rate. The silicone tubing continuously generated a marked quantity of particular matter at a steadily increasing rate. Electron microscopic examination of the silicone tubing revealed multiple particles emanating from the inner surface of the tube. The results suggest that filtration of the initial priming fluid may be advisable before connecting the patient to an EC circuit using PVC tubing. The multitude of particles liberated by the silicone tubing implies that its usage in ECC should be curtailed. Utilisation of noncrushing head pumps is recommended in ECC.

Nicorandil decreases postischemic actin oxidation.

This study examined the hypothesis that preconditioning can decrease postischemic oxidative protein damage. Isolated rat hearts were subjected to 25 min of normothermic global ischemia followed by 45 min of reperfusion. These were compared with hearts pretreated with 20 microM nicorandil or preconditioned with two cycles of ischemia. Changes in the high energy phosphates, ATP and phosphocreatine, were followed using (31)P-NMR spectroscopy. Protein carbonyls were assessed using an immunoblot technique. Postischemic hemodynamic function and high energy phosphates recovered to significantly (p <.05) higher levels in nicorandil-treated and ischemic preconditioned hearts as compared to controls. Postischemic protein carbonyl formation was highest in control reperfused hearts but reduced to intermediate between control and preischemic hearts by ischemic preconditioning and virtually prevented by nicorandil pretreatment, with a prominent band at 43 kDa significantly affected (p <.05). Based on immunoshift and immunoprecipitation studies, this band was identified as a mixture of actin isoforms. These studies support the conclusion that nicorandil diminishes protein oxidative damage in general, and specifically actin oxidation, which in the presence of improved supply of high energy phosphates, leads to enhanced postischemic contractile function.

Occult Cardiotoxicity: Subtoxic Dosage of Bis(2-chloroethoxy)methane Impairs Cardiac Response to Simulated Ischemic Injury

The effect of Bis(2-chloroethoxy)methane (CEM) on myocardial response to ischemia was tested in rats. CEM was dermally applied for 3 days to F344/N male rats, at 0, 100, 400, or 600 mg/kg/d. Subsequently, left ventricular sections were prepared from each rat heart. Part of the sections from each heart were exposed to 90 minutes of simulated ischemia, followed by 90 minutes of reoxygenation. The rest of the sections were continuously oxygenated. Mitochondrial activity was assessed in the sections by the MTT colorimetric assay, reflecting dehydrogenases redox activity. Myocardial toxicity occurred in response to 400 and 600 mg/kg, characterized by myofiber vacuoles, necrosis, and mononuclear infiltrates. The latter dose was lethal. In sections from rats treated with 400 mg/kg CEM, redox activity was decreased by 21% (p < 0.01) in oxygenated conditions and by 45% (p < 0.01) in ischemia-reoxygenation, compared to controls. Hearts of rats treated with 100 mg/kg/d CEM showed normal histology. Their mitochondrial activity did not differ from that of untreated rat hearts in oxygenated conditions. However, in ischemia-reoxygenation, their redox activity was significantly lower (by 46%, p < 0.01) than that of untreated rat hearts. These results demonstrate that subtoxic dosage of a cardiotoxic agent may cause occult cardiotoxicity, reflected by impaired response to ischemia.

The Hemodynamic Effects of Dopamine Following Cardiopulmonary Bypass

The hemodynamic effects of dopamine were studied in 19 patients following intracardiac operation or myocardial revascularization using extracorporeal circulation. The heart rate, mean blood pressure, central venous pressure, left atrial and pulmonary artery pressures, cardiac output, and urine output were recorded before and at the end of one-hour infusions of dopamine at 5, 10, and 15 mug/kg/min. Infusion of 5 mug/kg/min of dopamine resulted in the highest gain in cardiac output and stroke work without an increase in myocardial oxygen consumption, as evidenced by lack of significant rise in heart rate. In addition, this dosage was not accompanied by an increase in pulmonary or systemic vascular resistance, nor were other untoward effects observed after administration of 5 mug/kg/min of dopamine.

Rheumatic Valvular Disease in Children

Epidemiology and Prevention of Rheumatic Heart Disease.- Acute Rheumatic Carditis.- Pathology of Rheumatic Heart Disease.- Natural History of Rheumatic Heart Disease in Childhood.- Preoperative Assessment of the Child with Chronic Rheumatic Heart Disease.- Anesthesia and Respiratory Support.- Closed Mitral Commissurotomy in Children.- Reconstructive Surgery of Rheumatic Valvular Disease in Children Under 12 Years of Age.- Mitral Valve Replacement in Children.- Aortic Valve Replacement in Children with Rheumatic Heart Disease.- Surgery for Multivalvular Disease in Children.- Prosthetic Cardiac Valves- A Comparison of the Four Basic Designs.- Long-Term Management of the Child After Surgery for Rheumatic Heart Disease.

Double aortic arch associated with coarctation, ventricular septal defect and right ventricular outflow tract obstruction: Successful surgical repair

Abstract A case of complex congenital heart disease is presented with an unusual combination of extracardiac and intracardiac anomalies. Preoperative catheterization and angiographic studies demonstrated infundibular pulmonic stenosis, ventricular septal defect and coarctation of the aorta. A double aortic arch was subsequently detected during operation. Total repair necessitated staging of the surgical procedure. The coarctation was bypassed by interposing a synthetic graft between the anterior and posterior aortic arches. The second stage consisted of direct vision intracardiac correction of the pulmonic obstruction and the ventricular septal defect.