Beta-blockade versus Buckberg blood-cardioplegia in coronary bypass operation.

OBJECTIVE: Continuous perfusion of the coronary arteries with beta-blocker (esmolol)-enriched normothermic blood during cardiac surgery has been suggested as an alternative technique for myocardial protection. The aim of the present study was to compare the beta-blocker technique to Buckberg's blood cardioplegia during coronary artery bypass grafting (CABG). METHODS: Sixty patients with coronary artery disease were randomly assigned to either the esmolol group (ES, n = 30) or the blood cardioplegia group (BC, n = 30). During aortic crossclamp ES patients received continuous normothermic coronary perfusion with esmolol-enriched blood. Hearts of the BC group were protected by antegrade cold blood cardioplegia according to Buckberg. We measured left ventricular (LV) contractility using TEE (fractional area of contraction, FAC) and hemodynamic parameters prior to cannulation for cardiopulmonary bypass (CPB), after decannulation, and 4 h postoperatively. Myocardial lactate release was measured prior to aortic cross-clamp, during cross-clamp, and after decannulation. LV biopsies for determination of heat-shock protein (HSP-70), actin pattern and intercellular adhesion-molecule (ICAM-I) as indicators for structural changes were collected prior CPB, at the end of the aortic cross-clamp period, and prior to weaning off CPB. RESULTS: There was no significant difference between both groups with respect to grafts and cross-clamp time. ES hearts did not release lactate during cross-clamp. In contrast, BC hearts released significant amounts of lactate. Post CPB FAC and hemodynamics under similar inotropic stimulation showed no difference between groups, whereas at 4 h post CPB measurements showed slightly better values in the ES group: cardiac index: ES: 2.9+/-0.1 (SEM) versus BC: 2.6+/-0.1 L/min per m2 (P < 0.05); FAC: ES: 55+/-3 versus BC: 48+/-3% (P < 0.05). HSP-70 and actin pattern showed no difference between groups; however, ICAM-I showed a significantly higher degree of structural changes in BC hearts: 18+/-2 versus ES: 11+/-1% (P < 0.05). CONCLUSION: Our data demonstrate that application of the beta-blocker technique during routine CABG was associated with slightly better functional recovery and less structural myocardial alteration as compared with intermittent cold blood cardioplegia, however, both techniques provided equivalent myocardial protection in terms of patient outcome. Future studies are required to investigate if myocardial ischemia minimization by use of the beta-blocker technique may be beneficial in compromized hearts.     

Adenosine-enhanced ischemic preconditioning provides myocardial protection equal to that of cold blood cardioplegia

BACKGROUND: We recently described a novel myoprotective protocol-adenosine-enhanced ischemic preconditioning (APC)-that extends the protection of ischemic preconditioning (IPC) by both reducing myocardial infarct size and enhancing postischemic functional recovery in the isolated perfused heart. In the present report the efficacy of APC in the blood-perfused heart was investigated and compared with that of cold blood cardioplegia (CBC). METHODS: Cardiopulmonary bypass was instituted in 21 sheep hearts. The APC hearts (n = 6) received a bolus injection of adenosine through the aortic root at the immediate start of IPC (5 minutes of zero-flow global ischemia, followed by 5 minutes of reperfusion) before 30 minutes of global ischemia and 120 minutes of reperfusion. Nine other hearts received CBC. A control group (n = 6) received IPC only. RESULTS: Infarct size was significantly decreased (p<0.01) in the APC (3.0%+/-0.8%) and CBC (2.6%+/-0.2%) hearts compared with the IPC hearts (16.3%+/-1.6%). The preload recruitable stroke work relation, mean arterial pressure, and the time constant of pressure decay (tau) were significantly preserved (p<0.05) in APC and CBC hearts compared with IPC hearts. No significant differences were observed between APC and CBC hearts. CONCLUSIONS: Use of APC is as effective as CBC in significantly decreasing infarct size and enhancing post-ischemic functional recovery.     

Poly(ADP-ribose) polymerase inhibition improves postischemic myocardial function after cardioplegia-cardiopulmonary bypass

BACKGROUND: Poly(ADP-ribose) polymerase activation has been shown to contribute to the pathogenesis of myocardial ischemia-reperfusion injury. We hypothesized that a novel poly(ADP-ribose) polymerase inhibitor, INO-1001, provides myocardial protection and improves cardiac function after regional ischemia and cardioplegia-cardiopulmonary bypass (CPB). STUDY DESIGN: Pigs were subjected to 30 minutes of regional ischemia by distal left anterior descending coronary artery ligation followed by CPB (60 minutes) with hyperkalemic cardioplegia (45 minutes). The myocardium then was reperfused post-CPB for 90 minutes. After 15 minutes of ischemia, the treatment group (n = 6) received an INO-1001 bolus (1mg/kg) before a continuous infusion (1mg/kg/hour). Control pigs (n = 6) received vehicle solution. Left ventricular pressure was monitored, from which the maximum, positive first derivative of left ventricular pressure over time (+dP/dt) was calculated. Regional myocardial function in the ischemic area was determined by sonomicrometric analysis. Infarct size was measured as the percent of the ischemic area by tetrazolium staining. Myocardial sections were immunohistochemically stained for poly(ADP-ribose) as a measure of poly(ADP-ribose) polymerase activity and inhibition. RESULTS: Pigs treated with INO-1001 showed improvements in the +dP/dt at 60 and 90 minutes of post-CPB reperfusion (both p = 0.03) and percent segmental shortening at 30, 60, and 90 minutes of post-CPB reperfusion (p = 0.03, 0.009, and 0.03, respectively). Infarct size was decreased in the treatment group (18.5 +/- 5.7% versus 52.0 +/- 7.7%, INO-1001 versus control, p = 0.03). Poly(ADP-ribose) was reduced in myocardial sections from INO-1001-treated animals compared with controls. CONCLUSIONS: These results suggest that INO-1001 provides myocardial protection by reducing the extent of infarction and improves cardiac function after regional ischemia and cardioplegia-CPB.     

Does isoflurane optimize myocardial protection during cardiopulmonary bypass?

OBJECTIVE: To investigate the possible myocardial protective effect of isoflurane during aortic cross-clamp and cardioplegic cardiac arrest in patients undergoing conventional coronary artery bypass graft surgery. DESIGN: Prospective, randomized. SETTING: University medical center. PARTICIPANTS: Forty-nine patients undergoing elective coronary artery bypass graft surgery divided into 2 groups: control group (n = 21) and isoflurane group (n = 28). INTERVENTION: Isoflurane was administered in the pre-cardiopulmonary bypass (CPB) period to the isoflurane group. MEASUREMENTS AND MAIN RESULTS: Hemodynamics and ST- segment variations were monitored in the pre-CPB period and after weaning from CPB in both groups. Incidence of reperfusion arrhythmias after release of aortic cross-clamp was compared. In the isoflurane group, the mean cardiac index after CPB was significantly higher than the pre-CPB value, whereas no difference between the 2 values was found in the control group. The higher cardiac index in the isoflurane group was associated with a lesser degree of ST- segment changes than in the control group. There was no significant difference between the 2 groups in the incidence of reperfusion arrhythmias after release of aortic cross-clamp. CONCLUSION: The present report suggests that administration of isoflurane before aortic cross-clamping in patients undergoing coronary artery bypass graft surgery may optimize the myocardial protective effect of cardioplegia. Isoflurane may be particularly advantageous whenever prolonged periods of aortic cross-clamping or inadequate delivery of cardioplegia is expected.     

A double-blind randomized trial: prophylactic vasopressin reduces hypotension after cardiopulmonary bypass

BACKGROUND: Inhibition of angiotensin-converting enzyme (ACE) predisposes patients to vasodilatory hypotension after cardiopulmonary bypass (CPB). This hypotension has been correlated with arginine vasopressin deficiency and can be corrected by its replacement. In patients receiving ACE inhibition, we investigated whether initiation of vasopressin before CPB would diminish post-CPB hypotension and catecholamine use by avoiding vasopressin deficiency. METHODS: Cardiac surgical patients on ACE inhibitor therapy were randomized to receive vasopressin (0.03 U/min) (n = 13) or an equal volume of normal saline (n = 14) starting 20 minutes before CPB. RESULTS: Vasopressin did not change pre-CPB mean arterial pressure or pulmonary artery pressure. After CPB, the vasopressin group had a lower peak norepinephrine dose than the placebo group (4.6 +/- 2.5 versus 7.3 +/- 3.5 microg/min, p = 0.03), a shorter period on catecholamines (5 +/- 6 versus 11 +/- 7 hours, p = 0.03), fewer hypotensive episodes (1 +/- 1 versus 4 +/- 2, p < 0.01), and a shorter intensive care unit length of stay (1.2 +/- 0.4 versus 2.1 +/- 1.4 days, p = 0.03). CONCLUSIONS: In this cohort, prophylactic administration of vasopressin, at a dose without a vasopressor effect pre-CPB, reduced post-CPB hypotension and vasoconstrictor requirements, and was associated with a shorter intensive care unit stay.     

Effect of the Na+/H+ exchange inhibitor eniporide on cardiac performance and myocardial high energy phosphates in pigs subjected to cardioplegic arrest

BACKGROUND: Pharmacologic Na(+)/H(+) exchange inhibition has been suggested to ameliorate cardiac performance depression associated with myocardial ischemia/reperfusion. The purpose of our experimental study was to investigate the impact of the novel Na(+)/H(+) exchange inhibitor Eniporide (EMD 96785) on cardiac performance and high energy phosphate content in a clinically relevant pig model of cardioplegic arrest. METHODS: We subjected 21 pigs (47 +/- 12 [SD] kg) to cardiopulmonary bypass (CPB) and 60 minutes cold (4 degrees C) crystalloid cardioplegic arrest (Bretschneider). The pigs were randomized to receive either systemic infusion of 3 mg/kg Eniporide before cardioplegia with added 2 micromol/L Eniporide (ENI-CP+iv; n = 7); 3 mg/kg Eniporide in cardioplegia only (ENI-CP; n = 7); or no Eniporide (control; n = 7). For cardiac performance determination we measured preload recruitable stroke work and Tau, the time constant of left ventricular (LV) isovolumic relaxation using sonomicrometry and micromanometry before CPB as well as 30, 60, and 120 minutes after weaning off CPB. LV and right ventricular myocardial adenine nucleotides (ATP, ADP, and AMP), glycogen, and water content were determined at the end of the experiments. RESULTS: Neither for standard hemodynamics including vascular pressures and cardiac index nor for cardiac performance factors did we find statistically significant differences between the groups. Similarly, myocardial adenine nucleotides, glycogene, and water content did not differ significantly between the groups. CONCLUSIONS: In this acute study we did not find significant effects of the Na(+)/H(+) exchange inhibitor Eniporide on cardiac performance and high energy phosphate content in healthy pig hearts subjected to ischemia/reperfusion induced by crystalloid cardioplegic arrest.     

Is Post Cardiopulmonary Bypass Dysfunction a Special Form of Stunning?

Abstract It has been suggested that cardioplegic arrest during cardiopulmonary bypass (CPB) produces global myocardial ischemia with a risk of myocardial stunning. It has also been postulated that anesthetic technique may affect the course of post-CPB myocardial stunning via exaggerated myocardial depression. However, we have previously found that global ventricular and regional myocardial responses to halothane do not differ in post-CPB and pre-CPB dogs. Our examination of the effects of CPB on the beta-adrenergic function revealed that beta-adrenergic receptor function is only slightly decreased immediately following (i.e., 1 min) and 30 minutes post-CPB. A dose-response relationship was established for dobutamine, with decreased responsiveness noted at both times. Since other data show normal inotropic stimulation of stunned myocardium, decreases in dobutamine responsiveness cannot be explained by beta-receptor desensitization. Overall, these data indicate that CPB does not result in myocardial stunning. The differences between these data and others showing myocardial stunning following CPB may be due to several factors, such as anesthetic regimen, lack of coronary blood flow abnormalities, and a reduction in sarcoplasmic reticular damage due to the hypothermic conditions used.     

Myocardial beta-blockade as an alternative to cardioplegic arrest during coronary artery surgery.

The authors' recent experimental work has demonstrated that myocardial protection using continuous coronary perfusion with warm beta-blocker-enriched blood avoids myocardial ischaemia and minimizes myocardial oedema formation, thus completely preserving left ventricle function. The purpose of this clinical study was to compare this alternative technique in terms of structural and functional myocardial protection with the routinely used crystalloid Bretschneider cardioplegia. Sixty coronary artery surgery patients were randomized to receive either crystalloid cardioplegia or continuous coronary perfusion with warm blood enriched with the ultra-short acting beta-blocker esmolol. Cardiac function was evaluated using transoesophageal echocardiography (fractional area of contraction) and cardiac metabolism using arterial-coronary sinus lactate concentration difference (a - csD(LAC)). From left ventricular biopsies, the authors determined myocardial oedema, heat-shock-protein-70, intercellular-adhesion-molecule and actin pattern. Patients with crystalloid cardioplegia received 3.6 +/- 0.8 grafts during 64 +/- 20 min cross-clamp time (beta-blocker: 3.5 +/- 0.9 grafts during 68 +/- 22 min; NS). Following cross-clamp removal crystalloid cardioplegia hearts released significant lactate amounts (a- csD(LAC)) - 1.0 +/- 0.6 versus - 0.1 +/- 0.2 mmol/litre in beta-blocker hearts; P < 0.05). In crystalloid cardioplegia hearts, myocardial water content increased from 82.1 +/- 2.1% pre-cardiopulmonary bypass to 83.2 +/- 1.7% at the end of cardiopulmonary bypass (P < 0.05); in beta-blocker hearts myocardial water content remained unchanged (pre-cardiopulmonary bypass: 82.3 +/- 1.9%; end of cardiopulmonary bypass: 82.4 +/- 1.7%; NS). At the end of cardiopulmonary bypass, left ventricular biopsies of beta-blocker hearts showed less structural damage as determined by heat shock protein-70, intercellular adhesion molecule-I and deranged actin cross-striation pattern as compared with crystalloid cardioplegia hearts (P < 0.05). The post-cardiopulmonary bypass fractional area of contraction was similar in both groups (beta-blocker: 65 +/- 14%; crystalloid cardioplegia: 62 +/- 16%); however, beta-blocker patients required less inotropic stimulation (dopamine: beta-blocker: 2.9 +/- 2.5 versus crystalloid cardioplegia: 5.0 +/- 2.3 microg/kg per min; P < 0.05). The data suggest that continuous coronary perfusion with warm esmolol-enriched blood results in better myocardial protection compared with crystalloid cardioplegia. It is concluded that the concept of beta-blocker-induced cardiac surgical conditions may be a useful alternative for myocardial protection during coronary artery surgery.     

Beneficial effects of sevoflurane and desflurane against myocardial reperfusion injury after cardioplegic arrest

PURPOSE: To determine whether sevoflurane or desflurane offer additional protective effects against myocardial reperfusion injury after protecting the heart against the ischemic injury by cardioplegic arrest. METHODS: Isolated rat hearts in a Langendorff-preparation (n = 9) were arrested by infusion of HTK cardioplegic solution and subjected to 30 min global ischemia followed by 60 min reperfusion (controls). An additional 18 hearts were subjected to the same protocol, and sevoflurane (n = 9) or desflurane (n = 9) was added to the perfusion medium during the first 30 min of reperfusion in a concentration corresponding to 1.5 MAC in rats. Left ventricular (LV) developed pressure and creatine kinase (CK) release were determined as indices of myocardial performance and cellular injury, respectively. RESULTS: The LV developed pressure recovered to 46+/-7% of baseline in controls. Functional recovery during reperfusion was improved by inhalational anesthetics to 67+/-3% (sevoflurane, P<0.05) and 61+/-5% of baseline (desflurane, P<0.05), respectively. Peak CK release during early reperfusion was reduced from 52+/-11 U x min(-1) x g(-1) in controls to 34+/-7 and 26+/-7 U x min(-1) x g(-1) in sevoflurane and desflurane treated hearts, respectively. The CK release during the first 30 min of reperfusion was reduced from 312+/-41 U x g(-1) in control hearts to 195+/-40 and 206+/-37 U x g(-1) in sevoflurane and desflurane treated hearts. CONCLUSION: After ischemic protection by cardioplegia, sevoflurane and desflurane given during the early reperfusion period offer additional protection against myocardial reperfusion injury.     

Cardioprotective properties of sevoflurane in patients undergoing aortic valve replacement with cardiopulmonary bypass

In coronary surgery patients the use of a volatile anesthetic regimen with sevoflurane was associated with a better recovery of myocardial function and less postoperative release of troponin I. In the present study we investigated whether these cardioprotective properties were also apparent in the cardiac surgical setting of aortic valve replacement (AVR) surgery for the correction of aortic stenosis. Thirty AVR surgery patients were randomly assigned to receive either target-controlled infusion of propofol or inhaled anesthesia with sevoflurane. Cardiac function was assessed perioperatively using a pulmonary artery catheter. Perioperatively, a high-fidelity pressure catheter was positioned in the left ventricle. Postoperative concentrations of cardiac troponin I were followed for 48 h. After cardiopulmonary bypass (CPB), stroke volume and dP/dt(max) were significantly higher in the patients with sevoflurane. Post-CPB, the effects of an increase in cardiac load on dP/dt(max) were similar to pre-CPB in the sevoflurane group (1.0 % +/- 5.4% post-CPB versus 1.3% +/- 8.6% pre-CPB) but more depressed in the propofol group (-8.2% +/- 4.4% post-CPB versus 0.1% +/- 4.9% pre-CPB). The rate of relaxation was significantly slower post-CPB in the propofol group. Postoperative levels of troponin I were significantly lower in the sevoflurane group. Our data indicate that the use of a volatile anesthetic regimen in AVR surgery was associated with better preservation of myocardial function and a reduced postoperative release of troponin I.     

Evaluation of myocardial preservation using 31P NMR

The purpose of this study was (1) to monitor myocardial high-energy phosphate content and recovery of left ventricular (LV) contractile function following normothermic graded cardiac ischemia and single-dose hypothermic potassium cardioplegia, and (2) to assess the temporal limits of LV functional recovery during single-dose cardioplegia maintained at 17 degrees C. Rabbit hearts (30) were perfused, equipped with an LV balloon, paced at 240 beats/min, and placed in a nuclear magnetic resonance (NMR) magnet. Hearts underwent either graded, global normothermic ischemia or potassium cardioplegia arrest maintained at 17 degrees C for 1 hr. Myocardial high-energy phosphate level, LV contractility, and temperature were monitored continuously. Phosphocreatine (PCr) fell to 10 +/- 2, 2 +/- 1, and 0% of control and ATP to 70 +/- 3, 19 +/- 7, and 0% of control at 10, 40, and 60 min of 37 degrees C ischemia. After 1 hr of reperfusion, regression analysis of final developed pressure (DP) on end ischemic ATP (EIATP) content revealed: DP = 1.02 EIATP + 18 (r = 0.95). Following single-dose cardioplegia, maintained at 17 degrees C, PCr fell to 16 +/- 3% of control at 60 min while ATP fell only to 92 +/- 5% control. With reperfusion, recovery of DP was 100%. It was concluded that (1) PCr serves as an energy buffer for ATP, (2) EIATP predicts recovery of LV function, (3) single-dose cardioplegia maintained at 17 degrees C provides complete myocardial preservation for up to 60 min.     

Surgical reoxygenation injury of the myocardium in cyanotic patients: clinical relevance and therapeutic strategies by normoxic management during cardiopulmonary bypass

Cyanotic hearts are associated with depleted endogenous antioxidants (glutathione peroxidase, superoxide dismutase, and catalase), and thereby is more susceptible to myocardial ischemia/reperfusion injury during open heart surgery compared with acyanotic ones. Clinically, when surgery is performed on cyanotic infants, cardiopulmonary bypass (CPB) is usually initiated at high PaO(2), without consideration of possible cytotoxic effects of hyperoxia. The concept of "surgical reoxygenation injury of cyanotic myocardium" was proposed, wherein unintended abrupt reoxygenation of cyanotic myocardium at the onset of routine CPB causes oxygen-mediated injury, which may render the reoxygenated myocardium more susceptible to subsequent surgical ischemia/reperfusion injury and accentuates post-CPB myocardial dysfunction. The experimental studies using acute and chronic hypoxia models confirmed the role of reoxygenation injury mediated by reactive oxygen species in the pathogenesis of post-CPB myocardial dysfunction and addressed the importance of controlling PaO(2) at the onset of CPB. The clinical relevance of this injury was shown by subsequent clinical studies, which demonstrated depleted antioxidant reserve capacity and troponin release during the initial reoxygenation on hyperoxic CPB prior to cardioplegic arrest. Furthermore recent randomized clinical trials verified that hyperoxic CPB provokes biochemical multi-organ damage including myocardium, lung, liver, and brain after open heart surgery in cyanotic patients, which can be successfully reduce by normoxic CPB management (i.e., reducing PaO(2) at onset of CPB, gradual reoxygenation and controlled reoxygenation protocol). Based on these experimental and clinical studies, avoidance of using hyperoxic PaO(2) on routine CPB is strongly recommended in the cyanotic patients.     

Esmolol improves left ventricular function via enhanced beta-adrenergic receptor signaling in a canine model of coronary revascularization

BACKGROUND: Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of beta-adrenergic receptor (beta AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether beta AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra-short-acting beta AR antagonist) to determine whether beta AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved beta AR signaling. METHODS: Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial beta AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy. RESULTS: While beta AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 +/- 6% in the control group but increased 38 +/- 10% in the esmolol group (pre-CPB to end-CPB, mean +/- SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 +/- 23% of pre-CPB values compared to 48 +/- 12% for the control group (P = 0.0008). CONCLUSIONS: These data provide prospective evidence that esmolol administration results in improved myocardial function. Furthermore, the mechanism appears to involve enhanced myocardial beta AR signaling.     

Does cardiopulmonary bypass alter enflurane requirements for anesthesia?

This study on dogs determined whether the requirement for enflurane anesthesia was different pre- versus postcardiopulmonary bypass (CPB). Male mongrel dogs (n = 16) were anesthetized with enflurane in oxygen. Tracheal intubation was performed, monitors placed, and end-tidal enflurane concentration measured via a Puritan-Bennett Anesthesia Agent Monitor. MAC was determined by the tail-clamp method. CPB was then initiated using aortoatrial (n = 6, group 1) or femoral artery-vein (n = 4, group 2) cannulation or none (n = 6, group 3, control). CPB was maintained for 1 h using a bubble oxygenator, a crystalloid prime, and flows of approximately 70-80 ml/kg with a mean systemic pressure maintained between 50-70 mmHg. Following separation from CPB, MAC was again determined. The reduction in enflurane MAC following CPB was 30.1 +/- 21.5% (mean +/- SD; P less than 0.05 vs. pre-CPB) in group 1 but there was a wide range of reduction produced (3.8-58.8%). The degree of MAC reduction (19.8 +/- 8.6%; P less than 0.05 vs. pre-CPB) produced by CPB in group 2 was much less variable in degree (range 13.0-32.4%) but did not differ from group 1. Although pre- versus post-CPB mean systemic pressure fell from 83 +/- 13 to 69 +/- 15 mmHg (P less than 0.05), this is above the level likely to produce a reduction in MAC. No other significant hemodynamic changes were observed. Temperature pre- versus post-CPB was not different. The degree of hemodilution and acid-base disturbances are unlikely to be the explanation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injury

BACKGROUND: In skeletal muscle, dantrolene reduces free cytosolic calcium by inhibiting calcium release from the sarcoplasmic reticulum. A similar effect in ischemic-reperfused heart cells would protect myocardial tissue against reperfusion injury. We tested the hypothesis that dantrolene infusion during reperfusion protects the heart against reperfusion injury. METHODS: Isovolumetric beating rat hearts were subjected to 30 min of ischemia followed by 60 min of reperfusion. Left ventricular (LV) developed pressure (LVDP) and creatine kinase release (CKR) were determined as indices of myocardial performance and cellular injury, respectively. In the treatment groups, dantrolene (25 (DAN25) or 100 (DAN100) micromol l(-1)) was infused during the first 15 min of reperfusion; control hearts received the respective concentration of the vehicle (mannitol (CON25, CON100), each group n=7). To investigate the effects of dantrolene on reperfusion injury in vivo, 18 chloralose-anesthetized rabbits were subjected to 30 min occlusion and 180 min reperfusion of a major coronary artery. LV pressure (LVP), cardiac output (CO), and infarct size were determined. During the last 5 min of ischemia, nine rabbits received 10 mg kg(-1) dantrolene intravenously (DAN). Another nine rabbits received the vehicle (dimethylsulfoxide) and served as controls (CON). RESULTS: In isolated rat hearts, there was no recovery of LVDP in any group. Total CKR during 1 h of reperfusion was 845+/-76 (CON100) and 550+/-81 U g(-1) dry mass (DAN100, P<0.05). In rabbits in vivo, hemodynamic baseline values were similar between groups (CON vs. DAN: LVP, 99+/-6 (mean+/-SEM) vs. 91+/-6mm Hg, P=0.29; CO, 252+/-26 vs. 275+/-23 ml min(-1), P= 0.53). During coronary artery occlusion, LVP and CO were reduced in both groups (CON: LVP, 89+/-3%; CO, 90+/-5% of baseline values) and LVP did not recover to baseline values during reperfusion (51+/-5% (CON) vs. 67+/-7% (DAN) of baseline, P=0.10). Infarct size was 41+/-4% of the area at risk in controls and 37+/-6% in dantrolene treated hearts (P=0.59). CONCLUSIONS: Dantrolene reduced CKR, indicating an attenuation of lethal cellular reperfusion injury in isolated rat hearts. However, in the rabbit in vivo, there was no effect on the extent of reperfusion injury after regional myocardial ischemia.     

Effects of ischemic preconditioning in human heart

BACKGROUND: The aim of this study is to investigate the effects of ischemic preconditioning (IP) on myocardium and the level of nitric oxide (NO) in patients undergoing aorta-coronary bypass surgery. METHODS: Twenty consecutive patients with coronary artery disease were subjected into two equal groups; the IP group and the control group. Following the onset of cardiopulmonary bypass in the study group, hearts were preconditioned with two 3-minute periods of cross-clamping separated by 2 minutes of reperfusion. In the control group, cardiopulmonary bypass was continued for 10 minutes without using cross-clamp. Arterial and coronary sinus blood samples were used to determine serum NO, malondialdehyde (MDA), creatine phosphokinase-MB (CKMB), and lactate dehydrogenase (LDH) levels. Need for defibrillation after cross-clamp removal, ECG changes, postoperative arrhythmias, ejection fraction, and fractional shortening rates were recorded as hemodynamic data. RESULTS: Serum NO level was higher in the study group 5 minutes after aortic clamp removal (199.3 +/- 92.7 vs. 112.2 +/- 35.8 micromol; p = 001). Serum MDA (2.55 +/- 0.4 vs. 4.06 +/- 0.5; etamol/ml; 5 minutes after the aortic clamp removal; p = 0.0002); CK-MB (22.8 +/- 2.5 vs. 37.4 +/- 4.1; U/L 12 hours after the operation, p < 0.0001), and LDH (501.8 +/- 46.7 vs. 611.4 +/- 128.3; IU/L 48 hours after the operation, p = 0.02) levels were significantly lower in the preconditioned group when compared with the control group. Also, need for electrical defibrillation was significantly lower in the study group; Ejection fraction (64.3 +/- 6.3 vs. 57.6 +/- 7.6; p = 0.04) and fractional shortening (31.7 +/- 3.9 vs. 26.2 +/- 4.0; p = 0.04) rates were better in the study group postoperatively. CONCLUSIONS: These data may suggest that cardioprotection by ischemic preconditioning offers higher NO production, a lower myocardial ischemia, and better functional recovery of the hearts in coronary artery surgery patients.     

Postischemic infusion of 17-beta-estradiol protects myocardial function and viability

BACKGROUND: Females demonstrate improved cardiac recovery after ischemia/reperfusion injury compared with males. Attenuation of myocardial dysfunction with preischemic estradiol suggests that estrogen may be an important mediator of this cardioprotection. However, it remains unclear whether post-injury estradiol may have clinical potential in the treatment of acute myocardial infarction. We hypothesize that postischemic administration of 17beta-estradiol will decrease myocardial ischemia/reperfusion injury and improve left ventricular cardiac function. MATERIALS AND METHODS: Adult male Sprague Dawley rat hearts (n = 20) (Harlan, Indianapolis, IN) were isolated, perfused with Krebs-Henseleit solution via Langendorff model, and subjected to 15 min of equilibration, 25 min of warm ischemia, and 40 min reperfusion. Experimental hearts received postischemic 17beta-estradiol infusion, 1 nm (n = 4), 10 nm (n = 4), 25 nm (n = 4), or 50 nm (n = 4), throughout reperfusion. Control hearts (n = 4) were infused with perfusate vehicle. RESULTS: Postischemic recovery of left ventricular developed pressure was significantly greater with 1 nm (51.6% +/- 7.4%) and 10 nm estradiol (47.7% +/- 8.6%) than with vehicle (37.8% +/- 9.7%) at end reperfusion. There was also greater recovery of the end diastolic pressure with 1 nm (47.8 +/- 4.0 mmHg) and 10 nm estradiol (54.0 +/- 4.0) compared with vehicle (75.3 +/- 7.5). Further, 1 nm and 10 nm estrogen preserved coronary flow after ischemia and decreased coronary effluent lactated dehydrogenase compared with controls. Estrogen at 25 nm and 50 nm did not provide additional benefit in terms of functional recovery. Estrogen at all concentrations increased extracellular signal-regulated protein kinase phosphorylation. CONCLUSIONS: Postischemic infusion of 17beta-estradiol protects myocardial function and viability. The attractive potential for the clinical application of postischemic estrogen therapy warrants further study to elucidate the mechanistic pathways and differences between males and females.     

Unveiling gender differences in demand ischemia: a study in a rat model of genetic hypertension.

OBJECTIVE: Female gender is associated with reduced tolerance against acute ischemic events and a higher degree of left ventricular hypertrophy under chronic pressure overload. We tested whether female and male rats with left ventricular hypertrophy present the same susceptibility to demand ischemia. METHODS: Hearts from hypertrophied female and male salt-resistant and salt-sensitive Dahl rats (n=8 per group) underwent 30min of demand ischemia induced by rapid pacing (7Hz) and an 85% reduction of basal coronary blood flow, followed by 30min of reperfusion on an isovolumic red cell perfused Langendorff model. RESULTS: In female hearts, high-salt diet induced a pronounced hypertrophy of the septum (2.38+/-0.09 vs 2.17+/-0.08mm; p<0.01), whereas male hearts showed the greatest increase in the anterior/posterior wall of the left ventricle (LV) (3.19+/-0.22 vs 2.01+/-0.16mm; p<0.05) compared with salt-resistant controls. At baseline, LV-developed pressure/g LV was significantly higher in female than male hearts (200+/-13 and 196+/-14 vs 161+/-10 and 152+/-15mmHgg(-1); p<0.01), independent of hypertrophy, indicating greater contractility in females. During ischemia, LV-developed pressure decreased in all groups; at the end of reperfusion, hypertrophied female and male hearts showed higher developed pressures independent of gender (148+/-3 and 130+/-8 vs 100+/-7 and 85+/-6mmHg; p<0.01). In contrast, diastolic pressure was more pronounced in female than in male hypertrophied hearts during ischemia and reperfusion (24+/-3 vs 12+/-2mmHg; p<0.01). CONCLUSIONS: In the pressure overload model of the Dahl salt-sensitive rat, female gender is associated with a more pronounced concentric hypertrophy, whereas male hearts develop a more eccentric type of remodeling. Although present at baseline, after ischemia/reperfusion systolic function is gender-independent but more determined by hypertrophy. In contrast, diastolic function is gender-dependent and aggravated by hypertrophy, leading to pronounced diastolic dysfunction. We can conclude that in the malignant setting of demand ischemia/reperfusion gender differences in hypertrophied hearts are unmasked: female hypertrophied hearts are more susceptible to ischemia/reperfusion than males. To determine whether in female hypertensive patients with acute coronary syndromes, diastolic dysfunction could contribute to the worse clinical course, further experimental and clinical studies are needed.     

Effects of heat stress on metabolism of high-energy phosphates. Comparison of normothermic and hypothermic ischemia.

BACKGROUND: Alterations in metabolic pathways may contribute to the cardioprotective effects of heat stress (HS). We investigated the effects of HS on ATP and phosphocreatine (PCr) levels in the ischemic rat myocardium, after both normothermic and hypothermic ischemia. METHODS: Two protocols were used: (1) normothermic ischemia (20 min at 37 degrees C) with no myocardial protection (n=6 HS; n=6 control); (2) hypothermic ischemia (4 hrs at 4 degrees C) after cardioplegic arrest (n=6 HS; n=6 control). ATP and PCr levels in the heart were measured using 31P nuclear magnetic resonance spectroscopy. RESULTS: At the end of normothermic ischemia, ATP levels were better maintained in HS hearts (C vs HS: 4.51+/-0.66 vs 7.81+/-1.06 micromol/g dry wt+/-SEM, p=0.04). A trend for higher ATP content in HS hearts was observed after 40 min of reperfusion (C vs HS: 11.7+/-1.5 vs 16.9+/-2.0 micromol/g dry wt+/-SEM, p=0.09). PCr content was also higher at the end of 40 minutes of reperfusion in HS hearts (C vs HS: 46.4+/-2.9 vs 56.9+/-3.0 micromol/g dry wt+/-SEM, p=0.03). After prolonged hypothermic ischemia under cardioplegic arrest, heat stress again led to better preservation of ATP levels at the end of ischemia (C vs HS: 5.71+/-0.88 vs 9.23+/-1.38 micromol/g dry wt+/-SEM, p=0.05) and after 40 minutes of reperfusion (C vs HS: 16.8+/-1.4 vs 24.6+/-2.8 micromol/g dry wt+/-SEM, p=0.03). PCr levels were also better maintained at the end of ischemia (C vs HS: 4.87+/-0.77 vs 12.4+/-3.0 micromol/g dry wt+/-SEM, p=0.03) and after 40 minutes of reperfusion in HS hearts (C vs HS: 55.1+/-7.0.vs 79.8+/-7.3 micromol/g dry wt+/-SEM, p=0.03). CONCLUSIONS: Heat stress induces changes in the energy profile of the heart which results in better preservation of ATP and phosphocreatine levels. These changes could be observed after brief normothermic ischemia and also after prolonged hypothermic ischemia under cardioplegic arrest, mimicking conditions of preservation for cardiac transplantation.