To test the authors' hypothesis that cellular antioxidant enzymes constitute a cellular defense against acute stress, myocardial ischemia reperfusion injury in transgenic mice overexpressing the cellular glutathione peroxidase (GSHPx-1) was studied. Transgenic mice were generated using the entire mouse GSHPx-1 gene including approximately 2.0 kb 5'flanking sequence. A 400% increase of GSHPx activity was found in the hearts of transgenic mice compared with non-transgenic controls. Isolated perfused hearts were prepared from two groups of mice: transgenic overexpressed; non-transgenic controls. Hearts were perfused by Langendorff mode, and after 10 min of stabilization subjected to 30 min of ischemia followed by 20 min of reperfusion. In addition, a group of hearts were perfused for 50 min without subjecting them to ischemia and reperfusion to demonstrate the stability of heart preparation. Transgenic mouse hearts demonstrated significantly improved recovery of contractile force and the rate of contraction, compared to non-transgenic control mouse hearts. The infarct size was also lower in transgenic mouse hearts compared to those of non-transgenic controls. In concert, following ischemia, release of creatine kinase from the transgenic hearts was significantly lower than the control group. The results of this study indicate that increased GSHPx-1 expression renders the heart more resistant to myocardial ischemia reperfusion injury.

Analysis of Variance↗

PubMed1996

Mechanisms to reduce hospital stays.

BACKGROUND: The present era of medicine is concerned to a large measure with cost containment and the advent of managed care. For these reasons the concept of reducing hospital stays with a concomitant reduction in hospital cost is very attractive. The role of fast track is to ensure that we are not placing the patient at any additional risk and in fact are improving recovery and patient well-being. METHODS: Fast track is based on a specific protocol that is followed for each patient. Intensive preoperative education of patient and family familarize them with early discharge. Anesthetic technique is modified to effect early (4 to 8 hours) postoperative extubation. Steroids are administered perioperatively to improve myocardial function and reduce the release of inflammatory mediators. Digoxin is given prophylactically as are the bowel-mediating drugs metoclopramide, docusate, and ranitidine. The fast-track protocol is associated with aggressive ambulation of the patients and cardiac rehabilitation, so that the patient is out of bed the first day after operation, walking in the hall the second day, and up a flight of stairs the third day. RESULTS: A shift to fast track in 1992 permitted comparison between 282 non-fast-track patients and 280 fast-track patients undergoing coronary artery bypass grafting. The results showed no adverse consequences of fast track. Forty-eight percent of fast-track patients were discharged at 3 to 5 days compared with 26% of non-fast-track patients. No significant differences were found between the two groups with respect to infection (1%), operative mortality (approximately 4%), and 30-day hospital readmission (7% non-fast-track and 8% fast-track). A postdischarge questionnaire addressed issues of patient and family satisfaction. The early discharge patient had a 77% comfort level, whereas their family members felt satisfied with a 3- to 5-day hospital stay in only 54% of cases. These data suggest the need for better communication, education, and additional postdischarge support systems. CONCLUSIONS: A fast-track protocol allows faster recovery and earlier discharge from both the intensive care unit and the hospital without apparent increased risk. Complicated patients can also be fast tracked, and the desire to do so may actually expedite recovery.

Aged↗

PubMed1996

What is the best perfusion temperature for coronary revascularization?

BACKGROUND: [corrected] A National Institutes of Health-funded clinical trial of patients undergoing coronary artery bypass randomized perfusate and myocardial preservation to cold, tepid, or warm temperatures. The goal of the trial was to evaluate neurologic function before and after operation (4 days and 1 month after operation) and to measure hematologic data for fibrinolytic potential. METHODS: The three groups comprised 116 patients who completed neurologic evaluation by means of the Mathew scale out of 130 entered into the trial (37 cold group, 50 tepid, and 43 warm). Twenty-five patients had complete hematologic studies done. All three groups were comparable before operation. The myocardial preservation protocol used blood cardioplegic solution at cold (8 degrees to 10 degrees C), tepid (32 degrees C), or warm (37 degrees C) temperature and the systemic perfusate temperature during cardiopulmonary bypass was 20 degrees (cold), 32 degrees C (tepid), or 37 degrees (warm). RESULTS: Patients in the cold group had a longer duration of intubation and postoperative hospitalization and a slightly but significantly higher peak postoperative creatine kinase MB level than patients in the warm group. There were no deaths. There was deterioration in Mathew scale findings in all three groups, and no distinction could be made between groups. However, a significantly higher number in the cold group had an abnormal postoperative neurologic examination result that prompted computed tomographic scanning (18.9% cold, 2% tepid, 9.3% warm). A cerebrovascular accident was documented by computed tomographic scanning in 8.1%, 0%, and 4.7% of patients in the cold, tepid, and warm groups, respectively (not significant). Hematologic data documented significantly increased fibrinolytic potential in the warm group. CONCLUSIONS: Perfusion temperature is a factor in recovery from cardiopulmonary bypass. Cold has more adverse neurologic sequelae that prompt computed tomographic scanning whereas warm has more activation of fibrinolytic potential. Tepid is the best temperature for optimizing recovery from cardiopulmonary bypass.

Adult↗

PubMed1996

The role of protein kinase in C ischemic/reperfused preconditioned isolated rat hearts.

Protein kinase C (PKC) has been implicated in the preconditioning-induced cardiac protection in ischemic/reperfused myocardium. We studied the effect of PKC inhibition with calphostin C (25, 50, 100, 200, 400, and 800 nM), a potent and specific inhibitor of PKC, in isolated working nonpreconditioned and preconditioned ischemic/reperfused hearts. In the nonpreconditioned groups, all hearts underwent 30 min of normothermic global ischemia followed by 30 min of reperfusion. In the preconditioned groups, hearts were subjected to four cycles of ischemic preconditioning by using 5 min of ischemia followed by 10 min reperfusion, before the induction of 30 min ischemia and reperfusion. At low concentrations of calphostin C (25, 50, and 100 nM), the PKC inhibitor had no effect on the incidence or arrhythmias or postischemic cardiac function in the nonpreconditioned ischemic/reperfused groups. With 200 and 400 nM of calphostin C, a significant increase in postischemic function and a reduction in the incidence of arrhythmias were observed in the nonpreconditioned ischemic/reperfused groups. Increasing the concentration of calphostin C to 800 NM, the recovery of postischemic cardiac function was similar to that of the drug-free control group. In preconditioned hearts, lower concentrations (< 100 nM) of calphostin C did not change the response of the myocardium to ischemia and reperfusion in comparison to the preconditioned drug-free myocardium. Two hundred and 400 nM of the PKC inhibitor further reduced the incidence of ventricular fibrillation (VF) from the preconditioned drug-free value of 50% to 0 (p < 0.05) and 0 (p < 0.05), respectively, indicating that the combination of the two, preconditioning and calphostin C, affords significant additional protection. Increasing the concentration of calphostin C to 800 nM blocked the cardioprotective effect of preconditioning (100% incidence of VF). The recovery of cardiac function was similarly improved at calphostin C doses of 200 and 400 nM and was reduced at 800 nM (p < 0.05). With 200 and 400 nM of calphostin C, both cytosolic and particulate PKC activity were reduced by approximately 40 and 60%, respectively, in both preconditioned and preconditioned/ischemic/reperfused hearts. The highest concentration of calphostin C (800 nM) resulted in almost a complete inhibition of cytosolic (100%) and particulate (85%) PKC activity correlated with the abolition of preconditioning-induced cardiac protection. In conclusion, calphostin C protects the ischemic myocardium obtained from intact animals, provides significant additional protection to preconditioning at moderate doses, and blocks the protective effect of preconditioning at high concentrations. The dual effects of calphostin C appear to be strictly dose and "enzyme inhibition" related.

Animals↗

PubMed1996

The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts.

OBJECTIVE: Studies have shown that the diabetic heart exhibits abnormalities in cellular ion transport, which can affect susceptibility to reperfusion-induced ventricular fibrillation (VF), tachycardia (VT) and functional derangements. It has been shown that "preconditioning" renders the heart very resistant to a subsequent prolonged ischemic episode. This phenomenon has been extensively studied in healthy myocardium, but such a study has not been previously done in diseased (hypertrophic or myopathic) hearts. METHODS: We studied the incidence of reperfusion-induced VF, VT, cardiac function, and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia/reperfusion in isolated hearts from rats with streptozotocin-induced diabetes. Following 2, 4, 6, and 8 weeks of diabetes, hearts were isolated and subjected to 30 min global ischemia followed by reperfusion. RESULTS: In the 2-week diabetic group the total incidence of VF and VT was reduced from their non-diabetic age-matched control value of 100 and 100% to 42 (P < 0.05) and 42% (P < 0.05), respectively. Such a reduction in the incidence of VF and VT was not observed with progressive diabetes (4, 6, and 8 weeks). In the 2-week diabetics, the reduction in the VF and VT was reflected in the improvement of postischemic function, the reduction of ischemia and reperfusion-induced Na+ and Ca2+ gains, and the prevention in K+ and Mg2+ loss. This diabetes-induced initial protection was not seen in the 4- and 6-week diabetics, and a deterioration of postischemic function was observed in the 8-week diabetics. Four cycles of preconditioning, each consisting of 5 min ischemia followed by 10 min reperfusion, failed to reduce the incidence of VF and VT, improve cardiac function, and prevent ion shifts induced by 30 min ischemia followed by 30 min reperfusion in 4- and 8-week diabetics. CONCLUSIONS: In the early phase of diabetes the heart is more resistant to ischemia/reperfusion than the non-diabetic heart. Preconditioning does not afford protection against a prolonged period of ischemia in diabetics, indicating that preconditioning may be a "healthy heart phenomenon".

Animals↗

PubMed1996

"Diverticula" of anterior mitral valve leaflet as a cause of subvalvular aortic stenosis.

A 77-year-old male patient presented with symptoms of shortness of breath, fatigue, chest pain on exertion and dizziness. Transthoracic echocardiography suggested the presence of a diaphragmatic type of obstruction in the subaortic area of the left ventricular outflow tract. The systolic peak gradient at rest was 34 mmHg with a mean of 23 mmHg. Cardiac catheterization demonstrated rounded radiolucencies in the left ventricular outflow tract in the form of two "pouches" that moved back and forth causing subaortic stenosis. There was also a 70% stenosis of the left anterior descending coronary artery. Left ventricular function was normal. At surgery, a transesophageal echocardiogram demonstrated two distinct pouches arising from the anterior leaflet of the mitral valve. The larger of the two originated near the free edge of the leaflet and was attached via a chord to the membranous septum traversing the subaortic area of the left ventricular outflow tract. The patient underwent a left internal mammary to left anterior descending bypass graft, excision of the larger pouch and over-sewing of the smaller pouch. The excision and repair were performed through the aortic root and aortic valve. The patient made an uncomplicated recovery and on follow up his symptoms disappeared. This case shows the excellent results that can be obtained by surgery of diverticula of the mitral valve causing intermittent subaortic stenosis, a rare pathologic entity, morphologically different from the classical diaphragmatic subaortic stenosis.

Aged↗

PubMed1995

Drug-induced heat-shock preconditioning improves postischemic ventricular recovery after cardiopulmonary bypass.

BACKGROUND: Heat-stress preconditioning of mammalian heart has been found to confer protection against ischemic reperfusion injury. Heat shock is generally provided by warming the animal by mechanical means, which is often impractical in a clinical setting. Amphetamine, a sympathomimetic drug, can elevate the body temperature as a result of enhanced endogenous lipolysis. In this study, we examined the effects of heat shock induced by amphetamine on postischemic myocardial recovery in a setting of coronary revascularization for acute myocardial infarction. METHODS AND RESULTS: Adult Yorkshire swine were injected with amphetamine (3 mg/kg IM) (n = 12), and body temperature was continuously monitored. For control studies, the pigs were injected with saline (n = 12). Five swine in each group were killed after 3 hours to obtain biopsies of vital organs to measure heat-shock protein (HSP) mRNAs. After 40 hours, the remaining 7 pigs in each group were placed on cardiopulmonary bypass, and the isolated, in situ heart preparations were subjected to 1 hour of occlusion of the left anterior descending coronary artery followed by 1 hour of global hypothermic cardioplegic arrest and 1 hour of reperfusion. Postischemic myocardial performance was monitored by measuring left ventricular (LV) pressure, its dP/dt, myocardial segment shortening, and coronary blood flow. Cellular injury was examined by measurement of creatine kinase release. The antioxidant enzymes superoxide dismutase and catalase were also assayed. Amphetamine treatment was associated with the induction of mRNAs for HSP 27, HSP 70, and HSP 89 in all the vital organs, including heart, lung, liver, kidney, and brain. Amphetamine also enhanced superoxide dismutase and catalase activities in the heart. Significantly greater recovery of LV contractile functions was noticed, as demonstrated by improved recovery of LV developed pressure (61% versus 52%), LV dP/dtmax (52% versus 44%), and segment shortening (46.2% versus 10%) and reduced creatine kinase release in the amphetamine group. CONCLUSIONS: The results demonstrate that amphetamine can induce whole-body heat shock that can precondition the heart, enhancing cellular tolerance to ischemia-reperfusion injury. Amphetamine is a sympathomimetic drug that may be used for preconditioning.

Amphetamine↗

PubMed1995

Improved 4- and 6-hour myocardial preservation by hypoxic preconditioning.

BACKGROUND: A brief hypoxic episode can precondition myocardium against a subsequent ischemic-reperfusion injury. The present study sought to determine whether intracellular ionic alterations, induced expression of heat-shock proteins (hsps), and/or catalase are involved in the cellular mechanisms by which hypoxic preconditioning can preserve postischemic function in a model of prolonged hypothermic storage. METHODS AND RESULTS: Two groups of isolated working rat hearts were studied: control (CON) and hypoxically preconditioned (HP) hearts. Hearts were arrested at 4 degrees C with St Thomas' cardioplegic solution and immersion-stored for either a 4- or 6-hour period. Myocardial function (ie, heart rate, aortic flow, coronary flow, developed pressure, and its first derivative dP/dtmax) was determined at baseline, after preconditioning, and during reperfusion. At similar time points, myocardial [Na+]i, [K+]i, [Mg2+]i, and [Ca2+]i were measured using an atomic absorption spectrophotometer, and the induction of hsp 70 and catalase mRNAs was assayed using Northern blot analysis. After 4 and 6 hours of hypothermic storage, aortic flow, dP/dtmax, and [K+]i were increased, whereas [Na+]i and [Ca2+]i were decreased significantly in the HP group compared with the CON group. Steady state mRNA levels of catalase and hsp 70 were increased from baseline levels only in the HP group, with a peak (2.8- and 2.4-fold versus baseline) after 4 hours of storage. CONCLUSIONS: Our results indicate that intracellular ionic alterations and upregulation of catalase and hsp 70 gene expression may contribute to the mechanisms underlying hypoxic preconditioning, leading to improved postischemic function during prolonged hypothermic storage of hearts.

Animals↗

PubMed1995

Prazosin reduces myocardial ischemia/reperfusion-induced Ca2+ overloading in rat heart by inhibiting phosphoinositide signaling.

The aim of this study was to establish whether or not alpha 1-adrenergic receptors are implicated in triggering phosphoinositide hydrolysis and intracellular Ca2+ accumulation during myocardial ischemia and reperfusion. In isolated perfused rat hearts, the selective alpha 1-receptor antagonist prazosin abolished the increase in radioactivity incorporation into cellular inositol phosphates induced by 30 min ischemia followed by 30 min reperfusion, and selectively blocked the degradation of phosphoinositides; only minor changes in the ischemia/reperfusion-induced loss of other classes of phospholipids were seen. In addition, a prazosin-induced decrease of ischemia/reperfusion Ca2+ overloading was documented in real-time recordings of epicardial cytosolic free Ca2+ in fura 2-loaded hearts. An inhibition of early ischemic Ca2+ rise was observed, as well as a lower peak of cytosolic free Ca2+ and a more rapid reversal to normal values during reperfusion. Moreover, alpha 1-adrenergic blockade resulted in a significant improvement in the recovery of myocardial function during reperfusion: an increased left ventricular developed pressure and maximum rate of rise of systolic pressure paralleled the decrease in time-averaged cytosolic Ca2+ and the increase in amplitude of Ca2+ transients, respectively. It is concluded that myocardial Ca2+ overloading during ischemia and reperfusion may be triggered by alpha 1-adrenergic receptor-induced polyphosphoinositide hydrolysis.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1995

Oxidative stress adaptation improves postischemic ventricular recovery.

Adaptation to various forms of stress has been found to be associated with increased cellular tolerance to myocardial ischemia. In this study, the effects of myocardial adaptation to oxidative stress was examined by injecting rats with endotoxin (0.5 mg/kg) and its non-toxic derivative, lipid A (0.5 mg/kg). Both compounds exerted oxidative stress within 1 h of treatment as evidenced by enhanced malonaldehyde formation. The oxidative stress disappeared steadily and progressively with time in concert with the appearance of the induction of glutathione and antioxidative enzymes that included superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. After 24 h of endotoxin or lipid A treatment, the amount of oxidative stress and antioxidant enzyme levels were significantly lower and higher, respectively, compared to those at the baseline levels. Corroborating these results, both endotoxin and lipid A provided protection against myocardial ischemia and reperfusion injury as evidenced by a significantly improved postischemic recovery of left ventricular functions. The data presented here demonstrates that a controlled amount of oxidative stress induces the expression of intracellular antioxidants that can result in enhanced myocardial tolerance to ischemia. This suggests that myocardial adaptation to oxidative stress may be a potential tool for reduction of ischemic/reperfusion injury.

Adaptation, Physiological↗

PubMed1995

Hypoxic preconditioning enhances functional recovery after prolonged cardioplegic arrest.

The purpose of this study was to assess the ability of hypoxic preconditioning to improve myocardial salvage after prolonged hypothermic cardioplegic arrest. Isolated working rat hearts were arrested at 4 degrees C with St. Thomas' Hospital cardioplegic solution and immersion stored for 4 or 6 hours. Two groups were studied, control and hypoxically preconditioned (HP) hearts. After 4 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 8.7 +/- 1.6 mL/min, 17.8 +/- 1.6 mL/min, and 2,064 +/- 123 mm Hg/s, respectively, in control hearts (n = 11) and 25.7 +/- 2.5 mL/min, 27.1 +/- 2.5 mL/min, and 2,655 +/- 93 mm Hg/s, respectively, in HP hearts (n = 11) (p < 0.05). After 6 hours' preservation, aortic flow, coronary flow, and the first derivative of aortic pressure were 3.5 +/- 1.2 mL/min, 18.8 +/- 0.4 mL/min, and 1,622 +/- 226 mm Hg/s, respectively, in control hearts (n = 6) and 21.5 +/- 3.2 mL/min, 25.5 +/- 2.3 mL/min, and 2,439 +/- 239 mm Hg/s, respectively, in HP hearts (n = 6) (p < 0.05). After 6 hours' preservation, adenine nucleotides and creatine phosphate levels were not significantly different between the two groups, but lactate dehydrogenase release was significantly increased (p < 0.05) in control versus HP hearts (4.66 +/- 0.58 IU/L versus 1.98 +/- 0.28 IU/L). We conclude that hypoxic preconditioning reduces cellular necrosis and preserves myocardial function after prolonged hypothermic cardioplegic arrest.

Adenine Nucleotides↗

PubMed1995

Tranexamic acid significantly reduces blood loss associated with coronary revascularization.

Four hundred fifteen patients undergoing coronary revascularization over a 12-month period were divided into two groups: 209 controls in the first 6 months received no tranexamic acid (TA) before cardiopulmonary bypass and 206 patients in the second 6 months received TA as a hemostatic agent. The demographics and the surgical techniques used were similar in the two groups. With TA there was a significant decrease in blood loss postoperatively, from 1,114.1 mL in the controls to 803.7 mL in those given TA (p < 0.001); in red blood cell use, from 1.7 units/patient in the controls to 0.69 units/patient in those given TA (p < 0.001); in fresh frozen plasma requirements, from 0.23 units/patient in the controls to 0.024 units/patient in those given TA (p < 0.01); and in platelet transfusion, from 1.06 units/patient in the controls to 0.30 units/patients in those given TA (p < 0.01). The percentages of patients not receiving any blood products were 65% in those given TA versus 49% in the controls (p < 0.01). There was no significant difference between the two groups in the incidence of perioperative myocardial infarction, cerebrovascular accidents, pulmonary embolism, or venous thrombosis to clearly suggest hypercoagulability. In this study, TA profoundly affected the coagulopathy associated with bypass in patients undergoing coronary revascularization. It significantly reduced blood loss and blood product transfusions. Any potential increased thrombotic complications could not be clearly demonstrated in this study, but should not be ignored.

Aged↗

PubMed1995

Influence of steroids on complement and cytokine generation after cardiopulmonary bypass.

BACKGROUND: It is recognized that the inflammatory mediators complement and cytokines are generated during cardiopulmonary bypass as an endogenous response to extracorporeal circulation. METHODS: Nineteen randomized patients (10 steroid/9 nonsteroid) entered an institutional review board-approved protocol to measure complement and interleukin level generation before and after elective coronary revascularization. The steroid regimen involved 1 g of methylprednisolone sodium succinate intravenously before bypass and 4 mg of dexamethasone every 6 hours for four doses during the first 24 hours of recovery. Complement and interleukin levels were measured before bypass, immediately after bypass, and at 24, 48 and 72 hours of recovery. RESULTS: In the nonsteroid group, there was a significant elevation in all inflammatory mediators relative to the steroid group. The predominant changes occurred at 24 hours after operation. CONCLUSIONS: Steroids produced a dramatic reduction in complement and interleukin levels. The number of patients was clearly too small to document a clinical consequence of steroid administration.

Aged↗

PubMed1995

L-arginine reduces endothelial inflammation and myocardial stunning during ischemia/reperfusion.

BACKGROUND: This study evaluated whether the nitric oxide precursor L-arginine could reduce ischemia/reperfusion injury by preventing leukocyte-endothelial interactions. METHODS: Normothermic regional ischemia was induced in the open-chest working pig heart for 30 minutes followed by 90 minutes of reperfusion. A preischemic 10-minute intravenous infusion of 4 mg.kg-1.min-1 of L-arginine (n = 12) was compared with 12 control pigs. Nitric oxide release was measured from the coronary sinus using an amperometric probe. Left ventricular function, malonaldehyde, creatine kinase, myocardial oxygen extraction, and the soluble adhesion molecules (intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) were measured. RESULTS: Nitric oxide release was significantly reduced from baseline throughout ischemia/reperfusion only in the control group. Systolic and diastolic function, and myocardial oxygen extraction were also significantly decreased during early reperfusion in the control compared with the L-arginine group. Peak creatine kinase release was not significantly different between groups. The incidence of ventricular fibrillation, malonaldehyde release, and soluble intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 were each significantly decreased during reperfusion in the L-arginine group. CONCLUSIONS: L-Arginine reduced lipid peroxidation, plasma levels of soluble adhesion molecules, myocardial stunning, and arrhythmias. These results support an excessive endothelial injury/inflammatory response after regional ischemia/reperfusion that can be ameliorated through augmented nitric oxide.

Animals↗