Allopurinol enhanced adenine nucleotide repletion after myocardial ischemia in the isolated rat heart.

Allopurinol, a competitive inhibitor of xanthine oxidase, has been shown to have a protective effect on ischemic myocardium, but its mechanism of action remains controversial. We used an isolated rat heart preparation to test the hypothesis that allopurinol could restore adenosine triphosphate (ATP) levels and improve the recovery of left ventricular function after global myocardial ischemia. Hearts were equilibrated for 30 min, subjected to 10 min of global, normothermic (37 degrees C) ischemia, and reperfused for 15, 30, and 60 min. Hearts treated with allopurinol (100 microM) exhibited greater ATP levels and improved function during reperfusion than did untreated control hearts. Hearts treated with hypoxanthine (100 microM), the substrate for xanthine oxidase, also showed increased ATP and functional recovery compared with controls. These results suggest that allopurinol may protect the globally ischemic myocardium by enhancing the salvage of hypoxanthine for reincorporation into adenine nucleotides.

Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation.

To examine the role of alterations in myofibrillar function in human dilated cardiomyopathies, we determined isometric tension-calcium relations in permeabilized myocytesized myofibrillar preparations (n = 16) obtained from left ventricular biopsies from nine patients with dilated cardiomyopathy (DCM) during cardiac transplantation or left ventricular assist device implantation. Similar preparations (n = 10) were obtained from six normal hearts used for cardiac transplantation. Passive and maximal Ca2+-activated tensions were similar for the two groups. However, the calcium sensitivity of isometric tension was increased in DCM compared to nonfailing preparations ([Ca2+]50=2.46+/-0.49 microM vs 3.24+/-0.51 microM, P < 0.001). In vitro treatment with the catalytic subunit of protein kinase A (PKA) decreased calcium sensitivity of tension to a greater degree in failing than in normal preparations. Further, isometric tension-calcium relations in failing and normal myofibrillar preparations were similar after PKA treatment. These findings suggest that the increased calcium sensitivity of isometric tension in DCM may be due at least in part to a reduction of the beta-adrenergically mediated (PKA-dependent) phosphorylation of myofibrillar regulatory proteins such as troponin I and/or C-protein.

Left ventricular mural thrombus in a patient with thrombocytosis and agnogenic myeloid metaplasia.

The two factors responsible for the development of left ventricular mural thrombi are endocardial injury secondary to old or recent anterior myocardial infarction and left ventricular dysfunction. Endothelial damage also is thought to be the initial event in the development of arterial thrombi. However, arterial thrombi may develop in patients with thrombocytosis secondary to myeloproliferative disorders in the absence of endothelial injury. A patient had thrombocytosis secondary to agnogenic myeloid metaplasia and a left ventricular mural thrombus developed in the absence of clinical or laboratory evidence of old or coronary angiogram and left ventricular function. To our knowledge, this is the first such case reported.

Adenosine increases lactate release and delays onset of contracture during global low flow ischaemia.

OBJECTIVE: Adenosine reduces myocardial ischaemic injury and enhances postischaemic recovery of function following zero flow global and regional ischaemia. The purpose of this study was to determine the functional and metabolic effects of endogenous and exogenous adenosine during low flow ischaemia. METHODS: Isolated perfused rat hearts (n = 80), paced at 300 beats-min-1, were subjected to 45 min of low flow ischaemia (0.6 ml.min-1). The time to onset of ischaemic contracture (TOIC) was used as a marker of myocardial ischaemic injury. Coronary venous effluent samples were collected prior to and throughout ischaemia to measure lactate and purine release. Untreated hearts were compared to hearts treated with either adenosine (100 microM), adenosine plus EHNA (erythro-9-[2-hydroxy-3-nonyl]adenine HCl), an adenosine deaminase inhibitor (50 microM), or BW A1433U, an adenosine receptor blocker (5 microM). RESULTS: Adenosine and adenosine+EHNA prolonged TOIC from 11.6 (SEM 0.5) min to 13.6(0.5) and 13.5(0.3) min, respectively, and increased lactate release from 1.67(0.19) mumol.min-1.g-1 to 2.20(0.09) and 2.35(0.31) mumol.min-1.g-1, respectively, after 20 min ischaemia. Treatment with BW A1433U reduced TOIC [8.7(0.2)min] and markedly reduced lactate release. When glucose was omitted from the perfusate, adenosine+EHNA treatment had no effect on TOIC. Lactate release during glucose free perfusion was similar to that in hearts treated with the adenosine receptor blocker. CONCLUSIONS: Endogenous and exogenous adenosine may enhance myocardial tolerance to ischaemia in part via the modulation of glucose metabolism.

Changes in interstitial adenosine during hypoxia: relationship to oxygen supply:demand imbalance, and effects of adenosine deaminase.

OBJECTIVE: The aim was to determine the changes in coronary blood flow and intramyocardial interstitial fluid (ISF) adenosine and adenosine metabolites during systemic hypoxia, and to evaluate (1) whether the increase in ISF adenosine during hypoxia is augmented if the hypoxic hyperaemia is prevented, and (2) the effects of adenosine deaminase on ISF adenosine and coronary blood flow during sustained hypoxia. METHODS: Anaesthetised dogs were instrumented with a flow probe around the left anterior descending coronary artery to measure coronary blood flow and with a microdialysis probe in the myocardium perfused by this artery to sample intramyocardial ISF. Dialysate purine metabolite levels were used as indices of ISF levels. Systemic hypoxia was induced by a reduction in the FIO2. RESULTS: Acute systemic hypoxia (PaO2 approximately 3.9 kPa) resulted in a 60% increase in dialysate adenosine, along with increases in dialysate levels of the adenosine metabolites inosine (74%), hypoxanthine (33%), and xanthine (32%). If the hypoxic hyperaemia was prevented, dialysate adenosine increased by 180% during hypoxia, and the increases in adenosine metabolites were augmented as well. During sustained hypoxia, intracoronary administration of adenosine deaminase decreased dialysate adenosine below prehypoxia levels, but did not alter the hypoxic hyperaemia. CONCLUSIONS: While ISF adenosine is increased during acute systemic hypoxia and is increased in relation to the oxygen supply:demand imbalance, consistent with a role of adenosine in hypoxic hyperaemia in the heart, adenosine is not necessary for the maintenance of a sustained increase in coronary blood flow during hypoxia.

Ischaemic and hypoxic preconditioning enhance postischaemic recovery of function in the rat heart.

OBJECTIVE: The aims were (1) to determine whether ischaemic and hypoxic preconditioning enhance recovery of left ventricular function after global ischaemia in the rat, and (2) to evaluate the effects of selective adenosine A1 receptor antagonists on ischaemic and hypoxic preconditioning. METHODS: Isolated rat hearts, perfused at constant pressure, were subjected to 30 min ischaemia and 30 min reperfusion. Control hearts were compared to hearts preconditioned with 5 min ischaemia in the presence or absence of the adenosine A1 antagonist A1433U (10 microM), and hearts preconditioned with 5 min hypoxia in the presence or absence of the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 5 microM). Recovery of left ventricular function was assessed by percent recovery of preischaemic rate-pressure product. RESULTS: Control hearts recovered 64(SEM 4)% of preischaemic rate-pressure product after 30 min reperfusion, whereas ischaemic and hypoxic preconditioned hearts recovered 86(3)% and 94(5)%, respectively (p < 0.05 v control). Despite enhanced recovery of postischaemic ventricular function, ischaemic and hypoxic preconditioning reduced the time to onset of ischaemic contracture from a control value of 12.6(0.6) min to 9.3(0.7) and 9.0(0.6) min, respectively (p < 0.05). Neither adenosine receptor antagonist blocked preconditioning. Ischaemic preconditioned hearts recovered 80(5)% of preischaemic function in the presence of A1433U, and hypoxic preconditioned hearts in the presence of DPCPX recovered 85(4)%. CONCLUSIONS: Ischaemic and hypoxic preconditioning enhance recovery of function following global ischaemia in the rat. The observations that adenosine receptor antagonists do not block the salutary effects of ischaemic or hypoxic preconditioning suggest that adenosine is not the sole mediator of preconditioning.

Tacrolimus as a rescue immunosuppressant after heart and lung transplantation. The U.S. Multicenter FK506 Study Group.

BACKGROUND: Organ transplant recipients with refractory rejection or intolerance to conventional immunosuppressants may respond to rescue therapy with tacrolimus. METHODS: Tacrolimus was used as a rescue immunosuppressant for 16 heart and 15 lung recipients. Heart recipients were converted to tacrolimus therapy because of cyclosporine intolerance, acute rejection despite treatment with cyclosporine, or humoral rejection. Lung recipients were converted because of cyclosporine intolerance, chronic rejection, or acute rejection. All immunosuppressive medications except corticosteroids were discontinued before tacrolimus therapy was begun. Patients remained in the study until they were converted to commercial tacrolimus. RESULTS: The duration of follow-up after conversion varied widely (heart recipients: 183+/-65 days; lung recipients: 169+/-86 days). For the heart recipients, patient and graft survivals were 100%. Twenty percent of recipients experienced no rejection episodes after conversion to tacrolimus; 60% experienced none or only one. For the lung recipients, patient survival was 67% and graft survival was 60%. Eighty percent of recipients experienced no rejections and 13% experienced one episode of rejection each. The remaining patient experienced two biopsy-confirmed episodes of rejection. Five lung patients died within the year and one patient required retransplantation. The most common adverse events were diarrhea, headache, abnormal kidney function, depression, dyspnea, nausea, and pneumonia. CONCLUSIONS: Tacrolimus is an effective and safe immunosuppressant for the rescue of heart transplant patients. Lung transplant patients may receive more benefit if rescued earlier.

Influence of magnesium ion on human ventricular defibrillation after aortocoronary bypass surgery.

The administration of magnesium ion (Mg++) has been reported to defibrillate the ventricles and to decrease the incidence of arrhythmias after cardiopulmonary bypass. In a prospective study of 76 randomly selected patients undergoing coronary artery bypass grafting, patients received either no Mg++, 0.25 mEq/kg of Mg++ during cardiopulmonary bypass with the aorta clamped, or 0.375 mEq/kg of Mg++ before cardiopulmonary bypass. Spontaneous resumption of a cardiac rhythm or spontaneous defibrillation during reperfusion was not significantly affected by Mg++ administration. However, the number of shocks to initial and to sustained defibrillation and the energy required for the last direct-current shock was greatest in patients who received Mg++ before bypass and in those whose plasma Mg++ was greater than 2.26 mg/dl. Thus, the administration of Mg++ may have adverse effects on the heart if intraoperative plasma Mg++ exceeds 2.26 mg/dl.

Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery.

Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 microM, 500 microM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 microg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs pastoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p <0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p = 0.003) and nitroglycerine (p = 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 microM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans.

The role of adenosine in extended myocardial preservation with the University of Wisconsin solution.

The purpose of this study was to determine the role that adenosine plays in enhanced myocardial preservation during cold storage with the University of Wisconsin solution. Hearts from adult rabbits were flushed with University of Wisconsin solution with or without adenosine and stored at 4 degrees C for 24 hours. Interstitial fluid purine levels during the period of cold storage were estimated with cardiac microdialysis probes. In a second series of experiments hearts were flushed with University of Wisconsin solution with or without adenosine or St. Thomas' Hospital cardioplegic solution and stored for 18 hours (4 degrees C). Functional recovery was assessed by reperfusing the hearts on a Langendorff apparatus (100 cm H2O) for 45 minutes with Krebs-Henseleit buffer. During cold storage dialysate adenosine concentrations in hearts flushed with University of Wisconsin solution were 20- to 40-fold greater than adenosine levels in hearts flushed without adenosine. After 45 minutes of reperfusion hearts preserved with University of Wisconsin solution exhibited a rate-pressure product of 11,098 +/- 576 mm Hg/min, significantly greater than that for hearts flushed with University of Wisconsin solution minus adenosine (8106 +/- 780 mm Hg/min) and St. Thomas' Hospital solution (7317 +/- 768 mm Hg/min). These results suggest that adenosine plays a major role in enhanced myocardial preservation with the University of Wisconsin solution, possibly by maintaining elevated interstitial fluid adenosine levels during the period of cold storage.

The effects of dopamine and isoproterenol on the pulmonary circulation.

Dopamine and isoproterenol, although used primarily for their inotropic effects, are also potent vasoactive substances. To determine their effects on the pulmonary circulation, we cannulated the left lower lobe bronchus in 20 dogs to permit ventilation with either air or a mixture of 95% nitrogen and 5% carbon dioxide; systemic oxygenation was maintained by venitlating the right lung with 95% oxygen. The lobe was perfused at a controlled flow rate and left atrial pressure was held constant. Hypoxic ventilation increased the lobar vascular resistance by 52% (p less than 0.001). Dopamine infusion (20 mcg. per kilogram per minute) during air ventilation also increased lobar vascular resistance by 50% (p less than 0.001). During hypoxic ventilation, dopamine increased the resistance by an additional 19% (p less than 0.001). In contrast, isoproterenol (0.2 mcg. per kilogram per minute) abolished the hypoxic pressor response (p less than 0.001). Combined alpha- and beta-adrenergic blockade did not alter hypoxia-induced vasoconstriction, whereas phentolamine blocked the dopamine response and propranolol abolished the isoproterenol-induced vasodilation. These results indicate the following: (1) The hypoxic pressor response is independent of sympathetic innervation; (2) dopamine in dogs is a pulmonary vasoconstrictor; and (3) isoproterenol is a pulmonary vasodilator. If these findings can be extrapolated to man, isoproterenol may be the preferred inotropic agent in patients with an elevated pulmonary vascular resistance.

Salutary effects of exogenous adenosine administration on in vivo myocardial stunning.

Augmentation of endogenous adenosine levels is associated with decreased myocardial ischemic-reperfusion injury. The purpose of this study was to determine whether exogenous adenosine administered before ischemia could attenuate postischemic myocardial dysfunction. Regional myocardial stunning was induced by 15 minutes of coronary artery occlusion and 90 minutes of reperfusion in an open-chest canine preparation. Regional ventricular function was assessed by measurement of systolic wall thickening. Control untreated hearts were compared with two groups of hearts treated immediately before ischemia with intracoronary adenosine (5 micrograms/kg per minute and 50 micrograms/kg per minute). A fourth group of hearts was treated for the first 30 minutes of reperfusion with adenosine (50 micrograms/kg per minute). Preischemic adenosine administration increased coronary flow sixfold to sevenfold without altering regional function, mean arterial pressure, or left ventricular end-diastolic pressure. Both adenosine pre-treatments attenuated stunning compared with results in control animals (14.7% +/- 5.1% and 21.6% +/- 7.3% of preischemic systolic wall thickness versus -14.0% +/- 10%). Adenosine treatment during reperfusion transiently increased function in parallel with increased coronary blood flow, but after termination of the infusion regional function was not different from that in control stunned hearts (-5.0% +/- 13.1% of preischemic systemic wall thickness). These results indicate that adenosine pretreatment is associated with attenuation of stunning, an effect that can be produced at doses that do not alter systemic hemodynamics.

Ischemic preconditioning does not acutely improve load-insensitive parameters of contractility in in vivo stunned porcine myocardium.

OBJECTIVE: Ischemic preconditioning has been shown to have no beneficial effect on segment shortening in in vivo regionally stunned myocardium. The purpose of this study was to determine whether ischemic preconditioning improves the recovery of postischemic ventricular function when contractility is assessed by load-insensitive measurements including end-systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area in in vivo regionally stunned porcine myocardium. METHODS: Open chest, pentobarbital-anesthetized pigs were used. Regional ventricular function was monitored by measurements of segment shortening, stroke work, end systolic pressure length relations, preload recruitable stroke work, and preload recruitable stroke work area. The control group was submitted to 15 minutes of left anterior descending coronary artery occlusion and 3 hours of reperfusion. The preconditioned group underwent 2 cycles of 5-minute left anterior descending coronary artery occlusion and 10-minute reperfusion before 15 minutes of occlusion. RESULTS: There was no infarct in either group. The preconditioning protocol significantly depressed preischemic segment shortening but not regional stroke work. Ischemic preconditioning had no significant beneficial effect on regional stroke work, end-systolic pressure length relations, preload recruitable stroke work, or preload recruitable stroke work area. CONCLUSIONS: These results confirm that ischemic preconditioning does not ameliorate in vivo porcine myocardial stunning and indicate that ischemic preconditioning may have a limited cardioprotective role during cardiac operation.

The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function.

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37 degrees C) ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 mumol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content four-fold and sevenfold at 60 and 90 minutes, respectively (p less than 0.05), but had no effect on tissue adenosine monophosphate levels. During ischemia, there was a 50% decrease in adenosine triphosphate content in the AICAR-treated hearts and a thirteen-fold increase in adenosine monophosphate levels (p less than 0.05). After 60 minutes of reperfusion, adenosine triphosphate and monophosphate levels in the AICAR-treated hearts recovered to only 52% and 59% of preischemic values, respectively. These findings were similar to those observed in the untreated ischemic hearts. In contrast, tissue inosine monophosphate content in the AICAR-treated hearts during reperfusion remained significantly elevated and was fivefold greater than the reperfusion values in the untreated group. Concurrently, AICAR failed to enhance the recovery of postischemic left ventricular developed pressure. These results suggest that inhibition of the conversion of inosine monophosphate to adenosine monophosphate limits the usefulness of the agent in evaluating the temporal relationships between postischemic adenosine triphosphate repletion and recovery of myocardial function in the acute setting.

Functional and metabolic evidence of enhanced myocardial tolerance to ischemia and reperfusion with adenosine.

An isolated, isovolumetrically contracting rat heart preparation, perfused at constant flow, was used to test the hypothesis that adenosine treatment (100 microM) throughout the experiment could enhance the repletion of adenosine triphosphate and the recovery of ventricular function following 10 minutes of global, normothermic (37 degrees C) ischemia. Left ventricular developed pressure was measured with an intraventricular balloon, and myocardial adenine nucleotides were measured from freeze-clamped tissues in a parallel series of experiments. The adenosine triphosphate level in the adenosine-treated hearts was not different from that of the untreated control hearts at the end of 30 minutes of equilibration but was significantly (p less than 0.05) higher at the end of 10 minutes of ischemia and at 15, 30, and 60 minutes of reperfusion. Left ventricular developed pressure in the adenosine-treated group at the end of 30 minutes of equilibration (92 +/- 3 mm Hg) was not significantly different from that of the control hearts (101 +/- 10 mm Hg). During the reperfusion period the control group returned to 75% +/- 7%, 73% +/- 6%, and 73% +/- 6% of the preischemic control function at 15, 30, and 60 minutes of reperfusion, respectively. The adenosine-treated group had significantly greater return of function to 86% +/- 3%, 96% +/- 3%, and 95% +/- 3% of the preischemic control at 15, 30, and 60 minutes of reperfusion, respectively. In a protocol to assess the effect of adenosine during ischemia, we found that adenosine (100 microM) increased the time to onset of ischemic contracture by 50% from 12 +/- 3 to 18 +/- 3 minutes and decreased the rate of net adenosine triphosphate degradation. Our data suggest that under these experimental conditions, adenosine enhances myocardial preservation by reducing the net degradation of adenosine triphosphate during ischemia and facilitating the repletion of adenosine triphosphate during reperfusion.

Sex hormone receptors in non-small-cell lung cancer in human beings.

To investigate whether sex hormone receptors exist in the resected non-small-cell lung cancer in human beings and to determine a link between the pulmonary carcinogenesis and the sex receptor status of the lung cancer tissue, we reviewed the case histories of 64 patients who underwent resectional therapy for non-small-cell lung cancer between 1988 and 1990 (38 men and 26 women, mean age 65 years). Mouse monoclonal immunoglobulin G antibodies were used for immunohistochemical detection of estrogen receptors and progesterone receptors in the acetone-fixed specimen. The control group consisted of normal lung tissue from the patients with and without bronchogenic carcinoma and breast cancer tissue from the patients with estrogen and progesterone receptor immunoreactivity. No evidence of estrogen and progesterone receptor immunoreactivity was present in the normal lung tissue. All but two patients had immunoreactivity (97%) for estrogen receptors in the lung cancer tissue (p < 0.001). The differences for sex and for histologic subtypes were not statistically significant. Observed actuarial survival at 3 years was 83% for all patients with estrogen receptor immunoreactivity: 94% for women and 75% for men (p < 0.05). We found no correlation between the hormone receptor status and the type, clinical features, or prognosis of the non-small-cell lung cancer. We conclude that an abundance of estrogen receptors is hosted only in cancerous tissue, not in normal pulmonary tissue. Improved identification and definition of estrogen receptors in the nontarget lung cancer tissue offer a possibility of antiestrogen therapy for patients with advanced bronchogenic carcinoma.

Myocardial stunning: a therapeutic conundrum.

Dobutamine and pyruvate are two inotropic agents with different mechanisms of action. Although both agents alter postischemic myocardial dysfunction, their potential metabolic effects in the setting of in vivo myocardial stunning have not been addressed. In this study, the effects of dobutamine and pyruvate on systolic wall thickening, myocardial phosphorylation potential index, interstitial fluid adenosine level, and myocardial oxygen consumption in in vivo stunned porcine myocardium were assessed. Stunning was induced with a 10-minute occlusion of the left anterior descending coronary artery. After 30 minutes of reperfusion, pigs were treated with either intravenous dobutamine (10 micrograms/kg per minute) or intracoronary pyruvate (1 ml/min, 150 mmol/L solution, pH 7.4). Infusion of both agents resulted in a marked improvement in regional systolic wall thickening. The dobutamine effect, however, produced a marked increase in myocardial oxygen consumption and was associated with an increase in interstitial adenosine caused by myocardial de-energization, because the myocardial phosphorylation potential index ratio decreased from 0.17 +/- 0.02 to 0.09 +/- 0.02 (p < 0.05). In contrast, pyruvate enhanced myocardial energy status, because the myocardial phosphorylation potential index ratio increased from 0.20 +/- 0.03 to 0.55 +/- 0.08 (p < 0.01). These experimental findings suggest that under certain circumstances the use of beta-receptor agonists to treat myocardial stunning may be suboptimal, if not undesirable. Further investigation is warranted to determine the optimum therapy for the stunned heart.

Prolonging myocardial preservation with a modified University of Wisconsin solution containing 2,3-butanedione monoxime and calcium.

The University of Wisconsin solution is an effective preservative for cold storage of the cardiac allograft. In an earlier study we showed that addition of calcium and 2,3-butanedione monoxime, a reversible inhibitor of myocardial contracture, further improved preservation of the rabbit heart. In this study we investigated the following: (1) the effects of different concentrations of 2,3-butanedione monoxime and calcium on function of the preserved rabbit heart, (2) how heart preservation is affected when 2,3-butanedione monoxime and calcium are added to the St. Thomas' Hospital and Stanford solutions, and (3) how 2,3-butanedione monoxime and calcium, at optimal concentrations in University of Wisconsin solution, affect hearts preserved up to 48 hours. Rabbit hearts were flushed with preservative and stored at 4 degrees C for 24, 30, 40, or 48 hours. Myocardial function was assessed during 60 minutes of isolated reperfusion, and myocardial adenine nucleotide content was measured after completion of reperfusion. Three concentrations of 2,3-butanedione monoxime (15, 30, and 60 mmol/L) in the University of Wisconsin solution were studied in hearts preserved for 30 hours. Storage with 2,3-butanedione monoxime at 30 mmol/L resulted in significantly better left ventricular developed pressure (p < 0.01), left ventricular end-diastolic volume (p < 0.01), rate of left ventricular pressure rise (p < 0.01), coronary flow (p < 0.05), rate-pressure product (p < 0.001), and adenine nucleotide regeneration (p < 0.05) than with 60 mmol/L, although function was not significantly different when the osmolarity of the solutions was equalized. There was significant reduction in end-diastolic volume (p < 0.05) and adenine nucleotide recovery (p < 0.01) when 2,3-butanedione monoxime was lowered to 15 mmol/L. Decreasing the calcium concentration from 1.0 to 0.1 mmol/L also had a deleterious effect on myocardial function (p < 0.05). The addition of 30 mmol/L 2,3-butanedione monoxime and 1.0 mmol/L calcium to the St. Thomas' or Stanford solutions improved preservation of the heart when compared with the unmodified solutions, but to a lesser degree than with the modified University of Wisconsin solution. After 24 to 48 hours of storage in University of Wisconsin solution containing 30 mmol/L 2,3-butanedione monoxime and 1.0 mmol/L calcium, there was substantial improvement in developed pressure (p < 0.001), end-diastolic volume (p < 0.05), and rate pressure product (p < 0.001), although there was little effect on heart rate and coronary flow, when compared with the unmodified University of Wisconsin solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Combined antegrade/retrograde cardioplegia for myocardial protection: a clinical trial.

The role of retrograde coronary sinus perfusion in the preservation of ischemic myocardium is controversial. We evaluated the use of combined antegrade and retrograde cardioplegia in 59 patients undergoing coronary artery bypass surgery. Nineteen patients were administered antegrade cardioplegia, whereas 40 patients were administered antegrade plus retrograde cardioplegia. Hemodynamic data were obtained before the onset of cardiopulmonary bypass and at 1, 2, 4, 8, 16, and 24 hours after cessation of cardiopulmonary bypass. Myocardial function was assessed by measuring systemic blood pressure, heart rate, cardiac index, pulmonary artery pressure, and capillary wedge pressure. Both cohorts were similar in age, incidence of hypertension, diabetes, and previous myocardial infarction. No significant differences were noted in the need for postoperative inotropic support, the incidence of postoperative arrhythmias, myocardial infarction, heart block, or death. The two groups were similar with respect to cardiac index and systemic and pulmonary vascular resistance. However, the left ventricular stroke work index, when expressed as a function of its prebypass control value, was significantly improved (p less than 0.01) in the cohort administered combined cardioplegia. In the combined group recovery of left ventricular stroke work index occurred earlier and was more complete. These results suggest that the use of combined antegrade/retrograde cardioplegia is safe and may provide superior protection.

Chronic traumatic thoracic aneurysm. Influence of operative treatment on natural history: an analysis of reported cases, 1950-1980.

A total of 401 cases of chronic traumatic aneurysm reported during the past 30 years plus 12 cases from the University of Virginia Medical Center were analyzed. Forty-two percent of the patients developed signs or symptoms of aneurysm expansion within 5 years of injury: 85% within 20 years. Pain was the most frequently occurring sign or symptom, followed by serial enlargement on chest roentgenogram. Of the 60 patients who were followed without operative intervention, 20 died of their aortic lesions. For these patients, the combined risk of dying or developing signs or symptoms was 41% at 5 years. Over 300 patients underwent operative repair of the aneurysm. Operative mortality was 4.6%. Bleeding was the major cause of death as well as the most common major complication. When the survival probability of patients treated operatively was compared with that of patients treated nonoperatively, the operative group demonstrated a significantly higher survival probability.