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• W4254052732 abstract "These abstracts were presented at the 3rd International Symposium on “Myocardial Protection From Surgical Ischemic–Reperfusion Injury” as a moderated poster session. They represent cutting-edge investigations into a wide range of areas related to the pathophysiology of myocardial ischemic-reperfusion injury and myocardial protection. It is the purpose of this portion of our supplement to use these superb investigations to stimulate further ideas and discussion of the topics presented here. Perhaps the novel information presented in these abstracts will provide stimulus for further research leading to innovative changes in the clinical practice of myocardial protection. PV Ching, HB Bittner. Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, MN Background: It is shown that coronary artery bypass grafting (CABG) without cardiopulmonary bypass or CPB (off-pump or OPCABG) preserves better cerebro-cognitive, pulmonary, hepato-renal, and blood cell function compared to on-pump surgery due to an attenuated inflammatory response. The degree of ischemia/reperusion injury, myocardial protection as well as quantitative changes in myocardial contractile performance following OPCABG are not well documented. Methods: A canine myocardial ischemic injury model (60 minutes LAD occlusion,n = 30,27 to 35 kg) was used to assess postoperative regional left ventricular function (sonomicrometry, micromanometry, preload-recruitable stroke work=PRSW) quantitatively,oxygenation, and inflammatory response(cytokines/adhesion molecules). The left internal thoracic artery (LITA) to distal LAD was anastomosed in off-pump/on-pump CABG with antegrade/retrograde cold blood cardioplegic arrest (CPB-time 58 minutes ± 2; cross clamp time 28 minutes ± 3). (ANOVA, t-test, *=p < 0.05 vs base line). Results: LAD occlusion resulted in ischemia/infarction (CK-MB on-pump/off-pump vs base line 17.5 ± 1.4*/19.5 ± 1.8* mg/L vs 1.5 ± 0.3/2.1 ± 0.4) and a significant decrease in regional myocardial function in both groups (PRSW decrease by 50%, see Fig 1). Revascularization led to reestablishment of myocardial function to base line (on-pump/off-pump PRSW = 57 to 196 ergcm-2×103, mean 127 ± 25/81 to 98, mean 90 ± 15. There was significantly elevated postoperative cytokine/adhe sion molecule activation in the on-pump cases. On 100% inspired FIO2 oxygen tension decreased significantly more in the on-pump group (from 489 mm Hg to 180 mm Hg vs 418 mm Hg to 345 mm Hg) post bypass surgery. All anastomoses were widely patent 14 days after surgery in all animals. Conclusions: Compared most commonly applied myocardial preservation techniques (CPB, hypothermic blood cardioplegic arrest), OP CABG provides at least equal myocardial protection since there were no significant quantitative differences in myocardial contractile performance following LITA to LAD revascularization in off/on-pump CABG. The inflammatory response to cardiopulmonary bypass does not change contractility but decreases significantly pulmonary function. Grant Support: Minnesota Medical Foundation, AO-168 to 00. GP Dobson, MW Jones. Department of Physiology and Pharmacology, James Cook University, Townsville, Queensland, Australia 4811 Background: Currently 99% of cardioplegic solutions contain high depolarising potassium which is typically present at or above 16 mmol/L. Over the past ten years, prolonged potassium arrest has been linked to ionic and metabolic imbalances, myocardial stunning, ventricular arrhythmias, ischemic injury, tissue edema, free radical production and functional loss during the reperfusion period. The major damage is thought to arise from oxidative stress and accelerated intracellular Ca2+ overload, which can lead to mitochondrial dysfunction, apoptosis and cell death. A new cardioplegia was developed employing ‘hyperpolarizing’ adenosine and ‘polarising’ lignocaine (AL) as the arresting agents in a normokalemic Krebs-Henseleit buffer (5.9 mmol/L K+) delivered under normothermic conditions. Methods and Results: Hearts were rapidly excised from anesthetized male Sprague-Dawley rats (323 ± 6 g) and perfused in the Langendorff and working mode (preload 10 cm H2O: afterload 100 cm H2O). After 30 minutes stabilization, hearts were switched back to Langendorff mode and subjected to intermittent perfusion with either 200 uM adenosine and 0.5 mmol/L lignocaine in air-equilibrated Krebs-Henseleit (10 mmol/L glucose, pH 7.7 @ 37°C) or modified St. Thomas No 2 Hospital solution (16 mmol/L K+) delivered at a constant pressure head of 70 mm Hg and 37°C. Hearts receiving AL cardioplegia achieved mechanical arrest in less than half the time (25 ± 2 seconds, n = 23) compared to St. Thomas solution (70 ± 5 seconds n = 24). Following 30 minutes arrest (2 minutes induction and a 2 minutes pulse at 15 minutes), there were no significant functional differences between working hearts arrested with either cardioplegia. However, after 2 and 4 hours of arrest (cardioplegia pulsed every 20 minutes for 2 minutes at 37°C), only 50% (4 out of 8) and 14% (1 out of 7) of the St. Thomas’ hearts recovered aortic flow respectively. All hearts arrested with AL cardioplegia recovered 70 to 85% aortic flow after 2 hours (n = 7) and 4 hours arrest (n = 9) and coronary flows were 70 to 80% prearrest values. Heart rate, systolic and diastolic pressures, and rate-pressure product returned to 85 to 100%. Conclusions: AL normokalemic cardioplegia provides greater myocardial and presumably endothelial protection during arrest and recovery than hyperkalemic St. Thomas’s solution in the isolated rat heart model. Future studies will investigate the efficacy of AL crystalloid and blood cardioplegia in larger animal models undergoing cardio-pulmonary bypass. Partially supported by JCU Small grants 6215.93766.004 (GPD) and 6215.94591.2828 (GPD) and Australian Heart Foundation Grant G00B O547 (GPD). DV Jayakar, U Williams, E Bacha, V Jeevanandam. Department of Cardiac Surgery, University of Chicago Hospitals, Chicago, Illinois Background: Reperfusion injury contributes significantly to myocardial dysfunction following ischemia. We have examined the effect of tepid (30°C) blood reperfusion and its effect of myocardial function following ischemic injury. This is a simple and novel method to decrease I/R injury and improve allograft donor heart function following heart transplant. Methods: 48 Male Sprague-Dawley rat hearts were perfused with modified Krebs-Henseleit buffer (KHB) on working heart model with adjustable independent preload and afterload. After stabilization, the hearts were subjected to no-flow ischemia for 15 minutes and then reperfused 5-minutes with diluted whole blood or KHB at 20°C, 30°C or 36°C. The heart function was analyzed on working heart mode for 60 minutes. Preand after-load were normalized. ABGs, and aortic and coronary flows were measured at base line and every 15 minutes after ischemia under both 8 and 12 mm Hg preload. Results: All hearts recovered function. The table below summarizes the data. At 8 & 12 mm Hg preload, when compared to warm or cold blood reperfusion, hearts reperfused with tepid blood had the best function. Also, the tepid blood group did better than the acellular Krebs group at similar temperature. Conclusions: This is the first time that reperfusion with tepid blood has shown to decrease myocardial I/R injury even after a severe no- flow ischemic insult. Previous reports demonstrate superiority of acelluar solutions compared to blood due to presence of leukocytes and plaelets during reperfusion. We have shown that alteration in temperature makes blood superior to Krebs solution. Since working heart function model is a true myocardial function model, it has clinical implications as reperfusion with tepid blood before release of cross-clamp during heart transplant should improve immediate postsurgical myocardial function. Tabled 1% Recovery of Cardiac Flow compared to Pre.15 mins30 mins45 mins60 minsno ischemia100%100%100%100%Blood at 20 deg C56%56%68%64%Blood at 30 deg C75%88%86%79% (p<.05)Blood at 36 deg C71%67%73%72%Krebs at 20 deg C75%78%74%70%Krebs at 30 deg C69%72%67%57%Krebs at 36 deg C73%76%74%67% Open table in a new tab DV Jayakar, U Williams, E Bacha, V Jeevanandam. Department of Cardiac Surgery, University of Chicago Hospital, Chicago, Illinois Background: Ischemia/reperfusion (I/R) injury is a major cause of donor allograft dysfunction after heart transplant. Glutamine (GLN) administration to chick myocytes increases production of heat shock protein 72 (HSP 72) and attenuates I/R injury. Pretreating hearts with glutamine would be a novel method to improve heart function after I/R injury. We tested the effect of GLN preconditioning on myocardial performance using a rat working heart model. Methods: Male rats were injected IP with either 0.52 g/kg GLN in 15% RL (n = 10, GLN group) or RL alone (n = 10, control). 18 hours later their hearts were removed and immediately connected to the perfusion apparatus. Hearts were initially perfused via the aorta (Langendorff mode) and then switched to left atrial perfusion (working heart mode). After stabilization, the hearts were subjected to no-flow ischemia for 15 minutes and then reperfused on working heart mode for 60 minutes. Preand after-load were normalized. ABGs, and aortic and coronary flows were measured at base line and every 15 minutes after ischemia under both 8 and 12 mm Hg preload. Results: All hearts recovered some function. The table below summarizes the data. At end-diastolic pressure of 8 mm Hg, both groups had similar preischemic aortic flow, but after ischemia the GLN group demonstrated higher percentage of recovered flow. 12 mm Hg preload results were similar. ABG’s and perfusates were similar in both groups. Conclusions: GLN can induce HSP 72, help clear lactate, and increase the antioxidant glutathione. This is the first time preconditioning whole body administration of GLN has shown to decrease myocardial I/R injury even after a severe no- flow ischemic insult. Administration of this nonessential and nontoxic amino acid to donors several hours before cross clamping would improve post transplant heart function and thus enlarge the donor pool by increasing the period of safe ischemic, and allowing use of marginal heart donors. Tabled 1% of Recovery of Cardiac Output After I/R Injury (Compared to Pre-Level)15 min30 min45 min60 minKrebs 8 mmHg Preload61%67%62%51%Krebs 12 mmHg Preload55%62%57%48%Glutamine 8 mmHg Preload80%79%77%72%Glutamine 12 mmHg Preload71%74%70%67%*Glutamine vs Krebs = difference statistically significant. Open table in a new tab *Glutamine vs Krebs = difference statistically significant. Bothe, T Doenst, F Beyersdorf. Department of Cardiovascular Surgery, University of Freiburg, 79106, Freiburg, Germany Background: Metabolic therapy with high-dose glucose-insulin-potassium (GIK)-infusion improves postoperative recovery of myocardial contractile function after cardioplegic arrest. GIK may act through insulin or through a reduction in serum free fatty acids. However, the application of high doses of insulin may cause profound disturbances in glucose and potassium homeostasis. We set out to establish a high-dose insulin therapy for patients with impaired left ventricular function undergoing cardiac surgery with cardioplegic arrest. Methods: Insulin therapy was started immediately after arrival in the ICU in 4 patients with a preoperative ejection fraction less than 40% and a creatinine level less than 2.0 mg/dL. We infused insulin for 8 hours at a constant rate of 2.5IU · kg−1 · h−1. We started glucose and potassium infusion at a rate of 0.25 g · kg−1 · h−1 and 0.5 mval · kg−1 · h−1, adjusting the rates hourly to keep blood glucose levels between 150 to 250 mg/dL and serum potassium levels between 4.5 and 5.0 mval/L. We measured serum levels of glucose, insulin, c-peptide and free fatty acids. Results: Glucose levels were 235 ± 81 mg/dL before, 170 ± 51 mg/dL during, and 151 ± 57 mg/dL after treatment. Insulin levels were 3.91 ± 2.99 μU/ml before and increased to 11129 ± 7671 μU/ml and 24582 ± 12759 μU/ml 1 hour and 7 hours after start of insulin, respectively. After insulin infusion, we noted a long-lasting elevation in insulin levels with a rise in elimination-half-life from approx. 5 minutes to 1°,51 ± 0°,57 hours, requiring a continuation of glucose infusion. C-peptide levels did not change during the study period. Serum-free fatty acids were 0.65 ± 0.30 mmol/L before and 0.51 ± 0.28 mmol/L and 0.28 ± 0.08 mmol/L 1 hour and 3 hours after start of insulin, respectively. Insulin therapy did not disturb potassium homeostasis and there were no adverse events. Conclusions: High-dose insulin therapy a.) does not disturb glucose or potassium hemostasis, b.) increases the elimination half life of insulin, and c.) causes a delayed reduction of free fatty acids, suggesting that a reduction of free fatty acids may not be a major mechanism of insulin action. SD Herman, R Sahni, MF Aliasghapour, J Haft, D Bregman. St. Michael’s Medical Center, Newark, New Jersey Background: A protocol has been designed to improve heart surgery outcomes by managing the inflammatory response and reperfusion injury of cardiopulmonary bypass. The goal was to decrease complications and length of stay (LOS). Recently others have attempted to achieve this by discarding the pump. However, benefits of cardiopulmonary bypass (CPB), which made surgical coronary revascularization the gold standard, have been lost. Our method retains the pump, but overcomes many deficiencies of CPB, allowing patients to recover and be discharged in 1 or 2 days. Method: Our medication and technical based protocol addressed postoperative cardiac and cerebral function, reperfusion injuries, and the inflammatory response to CPB. It sought to reduce weight gain, arrhythmias, and pulmonary dysfunction. A unique technique of mammary artery preparation and testing maximized immediate cardiac reperfusion in CABG. Results: 35 of 178 (20%) consecutive unselected patients managed by the protocol were discharged home in 1 or 2 days. Median LOS of the entire group was 3 days. 30/35 (85%) had CABG (3.23 grafts/pt), while 5/35 (15%) under-went valve replacement, including one reop MVR. Ages of patients discharged within 2 days were 32 to 87 years (average 64.1). EF’s ranged 20 to 70% (average 46%). Complications were minimal. 3/35 (8.5%) patients developed atrial fibrillation. All were converted to NSR by discharge using a medication protocol designed specifically to not retard recovery. No patient required hospital readmission and all returned expeditiously to full activity. Conclusions: If specific techniques and protocols are followed, traditional CPB can achieve recoveries equal to and surpassing nonpump based techniques without sacrificing benefits of pump-supported surgery. T Acuff, D Cheng, J Kelley, C Otero, V Kshettry. Denton Regional Medical Center, 333 Colorado Blvd. Denton, Texas 76210 Background: Theoretically the best approach for myocardial protection is to prevent ischemia altogether. Beating heart surgery transforms the global ischemia of aortic occlusion into regional ischemia of coronary occlusion or manipulation. However, both experimentally and clinically, beating heart techniques cause alterations of systemic hemodynamics that may compromise coronary artery perfusion, prevent optimal exposure and offset the theoretical benefits of avoiding global ischemia. Right ventricular support has been suggested as a means of restoring hemodynamic compromise during beating heart surgery while decompressing the RV for better exposure and enabling the surgeon to perform beating heart techniques. Method: The hemodynamics of 147 primary multi-vessel CABG patients were prospectively recorded interoperatively at base line, three minutes into each distal anastomosis and after each anastamosis. Right ventricular support was used with each patient during each anastamosis then momentarily stopped after each anastamosis to measure the effect of RV support after each distal graft was completed. RV support was performed with right atrial to pulmonary artery bypass (Paraflow, AMed). 470 grafts were performed for an average of 3.2 grafts per patient. Average patient age was 67.3 (40 to 91) and average EF was 51.4 (11 to 81). 34% had previous MI, 29% had DM and 40% were urgent cases. Results: No patients died. Two (1.4%) required conversion to CPB. No patient required new IABP. There appeared to be less need for pharmacological support in this group of patients. Only 20.8% of patients required more pressors than base line to main hemodynamics. 44% of patients required no pressor support at all during this study. The following table shows the effect of RV support on hemodynamics during the anastamosis on different coronary distributions. Conclusions: RV support is an effective method of maintaining hemodynamics during Beating Heart surgery. Maintenance of systemic pressure and perfusion are significantly improved during the exposure of inferior, lateral and even anterior vessels for CABG by use of RV support. The lesser effect of RV support to improve hemodynamics with exposure of the main RCA in contradistinction to other coronary distribution lends credence to the theory of distortion of the RV outflow tract as a mechanism of impaired hemodynamics during OPCAB. RV support can safely minimize hemodynamic compromises in a large group of patients and may be the most appropriate method of restoring systemic perfusion during Beating Heart surgery. Study supported by Amed. Tabled 1DistributionMap On supportMAP Off supportp valueSVO2 On supportSVO2 Off supportp valueCircumflex or obtuse marginal73.061.7<10−2374.870.9<10−9PDA (L or R)74.761.8<10−1476.370.5<10−7LAD72.564.8<10−1576.273.4<10−10RCA (main)74.767.2<.00177.175.6<.15 (NS) Open table in a new tab U Sunderdiek, B Korbmacher, P Feindt, JD Schipke, E Gams. Department of Thoracic and Cardiovascular Surgery; Heinrich-Heine University Dusseldorf, Germany Background: Intermittend, hypothermic aortic crossclamping (IAC) with myocardial fibrillation has been established as an effective cardioprotective method in coronary artery surgery (CABG). Compared to cardioplegic arrest (CA) there exsists controversy about the more beneficial cardioprotective method in CABG-patients. Methods: This prospective study was designed to compare the clinical outcome, ischemic serum-markers (CK-MB, troponin I), ECG-changes, hemodynamic data on 112 patients. Randomization (n = 61) was done on routine, consequetive patients. For cardioplegic arrest the Bretschneider-HTK solution was used. Data were collected before ischemic arrest, 5 and 60 minutes after reperfusion, 1 and 6 hrs. after operation, 1, 2 and 10 days postoperatively. Results: Both groups were age-matched (IAC 68,3 yrs vs 66,1 yrs CA), no differences were found in LV-function data (i.e. EF IAC 54,2% vs CA 58,6%). The amount of bypass vessels were similar (IAC 3.4 vs CA 3.6). Total operation time was comparable IAC 214 minutes versus CA 231 minute, where as total time of ischemia was significant less in IAC 37 minutes versus CA 53 minutes. In the IAC-group, a higher mortality was noticed (7.7% vs 3.9%; NS), incidents of cerebral stroke were seen in 2 IAC-pts, none for CA-pts. CK-MB increases more than 40 U/l and troponin I more than 50 ng/ml were seen in 17 IAC-pts and 9 in CA-pts. Ischemic ECG-changes: 22 IAC versus 16 CA. Persistant ECG-changes in 7 IAC versus 5 CA-pts. Conclusions: Both cardioprotective methods, IAC and HTK-cardioplegia, seem to offer sufficient myocardial protection in routine CABG-procedures. Although neurologic disorders and mortality rates were slightly higher in patients with intermittent aortic crossclamping, the differences to the cardioplegia group were not significant. According to the analysis of increased ECG-changes, higher CK-MB and troponin I values which occurred especially in patients with myocardial ischemia time longer than 50 minutes we conclude that cardioplegic arrest with HTK seems to offer more beneficial effects in procedures with prolonged ischemia. M Marzban, K Abbasif, NG Movahedi, B Hanafi, MH Mndegar, AA Karimi, D Javidi. Shariati Hospital, Department of Cardiovascular Surgery, Tehran, Iran Background: Oxygen derived free radicals play a crucial role in myocardial damage during cardiopulmonary bypass (CPB) and global myocardial ischemia. In this study we evaluated the effect of allopurinol, vitamin E and vitamin C on clinical and paraclinical indices oc coronary patients undergoing CABG using CPB and cross clamp of aorta. Method: Between Sep.2000 and Aug.2000, 96 consecutive patients underwent elective CABG operation using CPB, mild hypothermia and cold blood cardioplegia in our institution, patients were randomized to two groups: group A (N = 48) received allopurinol (1200 mg/d) vit.C (3gm/d)and vit. E(600 mg/d)orally for two days before operation, group B as control received placebo in a double blind study. In hospital mortality and morbidity, ICU and hospital stay, duration of ventilatory support postoperative hemodynamic parameters ECG abnormalities, cardiac enzymes arterial oxygen pressure and saturation alveolo-arterial o2 difference and ionotropic need are measured in two groups and compared using statistical analysis by K-2 test and P-value. Results: Two groups were matched for risk factors, demographic, CPB and operative variables. Mean LVEF was similar (A:45.1%, B45.5%, p-val = 0.84).There was no mortality in either group. Two cases in gp. A and one case in gp. B needed intraaortic balloon pump. NO reoperation for bleeding and no major wound infection occurred in either group. ICU stay was shorter in gp. A (26.7 hours vs30.5 hours) The need for ionotropic support was less in gp A.(10.1% vs23.8%)Ischemic ECG changes and enzyme rising were more in gp B (23.9% vs25%)There was no difference in arterial o2 saturation, pressure and alveolo-arterial o2 gradient hospital stay were similar (8.6 vs 8.5 days)Evident adverse drug reaction was not recorded in any of our patients . Conclusions: Combination pretreatment of coronary patients with allopurinol vit. E and vit.C, can reduce the damaging effect of CPB and ischemia on myocardium but have not any demonstrable effect on pulmonary function .These drugs are safe and are recommended at least for poor risk patients routinely. B Korbmacher, KK Klein, U Sunderdiek, U Mohan, JD Schipke, E Gams. Department of Thoracic and Cardiovascular Surgery, University Hospital Dusseldorf, Dusseldorf, Germany Background: Endogenous myocardial protection during CABG can be achieved with intermittent aortic cross-clamping. To test whether exogenous adenosine can additionally protect the myocardium, a clinical, prospective, randomized, double-blind study was performed. Methods: Two groups: placebo (Pla; n = 18; age 67.2 ± 7.7 ys) and adenosine (ADO; n = 15; 62.3 ± 9.7 ys). Male pts; EF more than 50%; three-vessel disease; elective operation. During the first aortic cross-clamping, 5 mg/min adenosine infused together with sufficient blood at systemic perfusion pressure via the aortic root for 10 minutes. Pts in the Pla group received the same dose of physiologic solution. Blood samples were collected before onset of anesthesia, before the onset of ECC, 1 hour after end of surgery, on the first and second day post surgery to assess: CK-MB, LDH, GOT, GPT, troponin I, Hb, Hct and leukocytes. Following hemodynamic variables were assessed: HR, CVP, LVPmax, LVPed, dP/dtmax, and dP/dtmin. Results: ECC time between the Pla and ADO group was comparable: 115 versus 130 minutes, as well as the total aortic clamping 37 versus 40 minutes. LVPmax before ECC (115 ± 20 vs 113 ± 19 mm Hg) and after ECC (109 ± 17 vs 117 ± 23 mm Hg) did not differ between both groups. LVPed before ECC was not different between Pla and ADO (11 ± 6 vs 10 ± 4 mm Hg) and was moderately elevated in both groups after ECC (14 ± 5 vs 19 ± 7 mm Hg). Troponin I, as very sensitive marker of myocardial damage, was comparable before ECC, had a maximum at day 1 after surgery (77 ± 59 vs 107 ± 92 ng/ml) and was already decreased at day 2 (52 ± 30 vs 51 ± 33 ng/ml). Conclusions: According to these results, there is no significant difference between the two groups. Apparently, sufficient myocardial protection is achieved via intermittent cross-clamping and low temperature during surgery. Thus, pharmacological preconditioning using exogenous adenosine did not exert the expected, beneficial effect. JD Schipke, S Schmitz-Spanke, V Pomblum, N Amaral, E Gams. Department of Thoracic and Cardiovascular Surgery, University Hospital Dusseldorf, D-40225 Dusseldorf, Germany Background: Heart rate (HR) is a major factor determining myocardial oxygen consumption. Thus, HR reduction would improve the energy balance in various heart diseases. In addition, specific bradycardic agents could be helpful to reduce HR during off-pump surgery and to prevent unwanted tachycardia after thoracic surgery. Since HR considerably contributes to the severity of myocardial ischemia, HR reduction may also be an effective therapy for dysfunctional myocardium. In this study, different aspects of bradycardia produced by either a sinus node inhibitor cilobradine (DK-AH 269, CL) or a Ca2+-channel antagonist verapamil (VP) were tested in in vitro and in vivo rabbit hearts. Methods: In a first series, isolated, blood-perfused rabbit hearts were subjected to a 60 minutes, global, low-flow ischemia that was followed by a 60 minutes reperfusion. In a second series, rabbit hearts were subjected to 60 minutes occlusion of a coronary artery and 180 minutes reperfusion. In both series, experiments were performed on placebo-, cilobradine- and verapamil-treated hearts. The infarct area was assessed via TTC staining. Results: In the isolated hearts, HR was significantly reduced by both CL and VP. Whereas stroke volume (SV) remained unchanged in the CL group (n = 10), SV decreased in the VP group (n = 10). Myocardial oxygen consumption was reduced by both CL and VP (14 vs 24%). After 60 minutes reperfusion, ventricular function was better preserved in the CL group than in the placebo and the VP group. Infarct size was significantly reduced by CL and VP. In the anesthetized rabbits, VP, at a dose to reduce HR by about 30%, impaired ventricular function so drastically that it ceased during ischemia (n = 4). At a lower dose (n = 10), VP still impaired ventricular function but prevented the ischemia-induced increase in HR. During reperfusion, ventricular function started to recover. CL (n = 7) reduced HR (−28%) and increased both length of diastole (+54%) and SV (+33%). During reperfusion, ventricular function remained deteriorated. Infarct size in the CL group was significantly smaller compared with the placebo and the VP groups. Conclusions: Cilobradine reduces HR both in vitro and in situ and has no direct inotropic and vasoactive effects. Reduction in HR effectively reduces infarct size. The specific bradycardic agent seems to outmatch the Ca2+ antagonist in protecting the myocardium in vivo and in vitro by reducing HR. S Verma, PWM Fedak, RD Weisel, R-K Li, DAG Mickle. Division of Cardiac Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada Background: Pharmacological interventions may restore ischemic hearts to full functional integrity during cardioplegic arrest. Contemporary cardioprotective strategies to prevent perioperative ischemia-reperfusion (I/R) injury have focused on the L-arginine NO pathway. Tetrahydrobiopterin (BH4) is an absolute cofactor required for the enzyme nitric oxide synthase (NOS) and is thus a critical determinant of nitric oxide (NO) production. We hypothesized that diminished levels of BH4 represents a key cellular defect underlying endothelial and myocyte dysfunction following I/R. To this aim, we examined the effects of BH4 supplementation in (i) an in vivo experimental model of global I/R and (ii) an in vitro human ventricular heart cell model of simulated I/R. Measures of endothelial function, oxidant production, cell survival and cardiac function were used to assess outcome. Methods Study 1: Wistar rats were divided into 2 groups (n = 10 per group). One group received BH4 (25 mg/kg/d, 7 days) while the other group served as the control group. Hearts were subjected to 30 minutes of ischemia followed by 30 minutes of reperfusion and LVDP, LVSP and LVEDP were determined using the modified Langendorff technique. Study 2: In a separate study, we quantitated myocardial malondialdehyde (MDA), a marker of lipid peroxidation, in ventricular tissues from both groups of animals using butanol phase extraction and spectrophotometric analysis. Study 3: Coronary vascular responses were determined in vascular segments of the left anterior descending coronary artery in both groups of animals before and after reperfusion. Endothelium-dependent and –independent vasodilatation to acetylcholine (Ach) and sodium nitroprusside (SNP) respectively were compared between groups. Study 4: Using a human ventricular heart cell model of simulated I/R, we studied the effects of BH4 (20 μmol/L) on cellular injury (assessed by trypan blue uptake). Results: Following I/R, myocardial dysfunction was evidenced by a decrease in LVDP and an increase in LVEDP (p < 0.01). Hearts from BH4 treated rats exhibited protection against I/R injury (LVDP 74 ± 4 vs control 42 ± 8 mm Hg, p < 0.01; LVEDP 12 ± 3 vs 34 ± 7, p < 0.001). Futhermore, BH4 treatment attenuated the rise in MDA following I/R (p < 0.01). Following reperfusion, coronar" @default.
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