Donor heart preservation with the potassium channel opener pinacidil: comparison with University of Wisconsin and St. Thomas' solution.

BACKGROUND: Hyperpolarized arrest with the potassium channel opener pinacidil has been shown to provide effective myocardial protection during short-term global ischemia. This study tested the hypothesis that pinacidil may provide effective long-term protection for heart transplant preservation. METHODS: Four concentrations of pinacidil (50 microM, 100 microM, 0.5 mM, 1.0 mM) mixed in Krebs-Henseleit solution were compared with University of Wisconsin and St. Thomas' Hospital solutions in a Krebs-Henseleit perfused rabbit Langendorff model (n = 6 for each group). Hearts underwent 4 hours of hypothermic (4 degrees C) storage. Over a wide range of volumes, left ventricular systolic function, diastolic compliance, and coronary flow were measured prior to and following storage. Time to mechanical and electrical arrest, and post-ischemic percent tissue water were also measured. RESULTS: Pinacidil 0.5 mM provided the best preservation of post-ischemic systolic function and coronary flow compared with the other pinacidil concentrations and was statistically equivalent to St. Thomas' solution in terms of post-ischemic systolic, diastolic, and flow properties. However, hearts protected with University of Wisconsin solution had significantly better preservation of systolic function and coronary flow. CONCLUSIONS: This investigation demonstrated that pinacidil in Krebs-Henseleit solution possesses efficacy in long-term donor heart preservation. Pinacidil was equivalent to St. Thomas' solution but inferior to University of Wisconsin solution. Hyperpolarized arrest with potassium channel openers may be a novel strategy to improve donor heart preservation.

Long-term outcome after biologic versus mechanical aortic valve replacement in 841 patients.

OBJECTIVE: The purpose of this study was to optimize selection criteria of biologic versus mechanical valve prostheses for aortic valve replacement. METHODS: Retrospective analysis was performed for 841 patients undergoing isolated, first-time aortic valve replacement with Carpentier-Edwards (n = 429) or St Jude Medical (n = 412) prostheses. RESULTS: Patients with Carpentier-Edwards and St Jude Medical valves had similar characteristics. Ten-year survival was similar in each group (Carpentier-Edwards 54% 3% versus St Jude Medical 50% 6%; P =.4). Independent predictors of worse survival were older age, renal or lung disease, ejection fraction less than 40%, diabetes, and coronary disease. Carpentier-Edwards versus St Jude Medical prostheses did not affect survival (P =.4). Independent predictors of aortic valve reoperation were younger age and Carpentier-Edwards prosthesis. The linearized rates of thromboembolism were similar, but the linearized rate of hemorrhage was lower with Carpentier-Edwards prostheses (P <.01). Perivalvular leak within 6 months of operation was more likely with St Jude Medical than with Carpentier-Edwards prostheses (P =.02). Estimated 10-year survival free from valve-related morbidity was better for the St Jude Medical valve in patients aged less than 65 years and was better for the Carpentier-Edwards valve in patients aged more than 65 years. Patients with renal disease, lung disease (in patients more than age 60 years), ejection fraction less than 40%, or coronary disease had a life expectancy of less than 10 years. CONCLUSIONS: For first-time, isolated aortic valve replacement, mechanical prostheses should be considered in patients under age 65 years with a life expectancy of at least 10 years. Bioprostheses should be considered in patients over age 65 years or with lung disease (in patients over age 60 years), renal disease, coronary disease, ejection fraction less than 40%, or a life expectancy less than 10 years.

Right ventricular function in the donor heart.

OBJECTIVES: Early morbidity and mortality post cardiac transplantation is frequently caused by right ventricular failure; this is usually attributed to an elevated pulmonary vascular resistance in the recipient. Brain death in the donor is recognised as causing left ventricular dysfunction, but its effects on the right ventricle have not previously been studied. The aim of this study was to investigate right ventricular function following brain death, using a canine model. METHODS: The hearts of 33 dogs were instrumented with micromanometers, flow probes and dimension transducers to measure minor/major axes, and right and left ventricular free wall to septal distances. Left ventricular volume was calculated according to the prolate ellipsoid model and right ventricular volume was calculated according to the shell subtraction method. Systolic function for left and right ventricles was analysed by plotting ventricular stroke work vs. end-diastolic volume during a caval occlusion (preload-independent recruitable stroke work PRSW). Brain death was instigated by inflation of a subdurally placed intracranial balloon; subsequently blood pressure was maintained with intravenous fluid whilst no inotropic medications were given. Data were collected at baseline, and at 2 and 4 h thereafter. A two-tailed paired Student's t-test was applied to compare post-brain death data with baseline measurements. RESULTS: All animals had an initial hyperdynamic response post brain death ensued by the development of diabetes insipidus. Brain stem death was validated by neuropathological examination at the termination of the experiments. Right and left ventricular systolic function had deteriorated significantly 2 h post brain death by 34.4% (+/- 5.1%, P < 0.001) and 20.4% (+/- 3.4%, P < 0.001), respectively, from baseline PRSW [RV = 23.6 erg.10(3) (+/- 1.5), LV = 76.2 erg.10(3) (+/- 3.5)]. This deterioration remained at 4 h post brain death (29.4% (+/- 4.9%, P < 0.001) and 21.2% (+/- 4.3%, P < 0.001), respectively). (The results are expressed as mean and S.E.M.). CONCLUSIONS: Brain death causes a significant decrease in left and right ventricular function. The injury to the right ventricle is more prominent than the left ventricle, and at 2 h post brain death it is significantly greater. Failure of the right ventricle post transplantation in clinical practice may be related to this brain death induced injury. Further studies are required to investigate the mechanisms of this injury.

A work-performing heart preparation for myocardial performance analysis in murine hearts.

UNLABELLED: The mouse has become the animal of choice for genetic manipulations resulting in altered myocardial function, but assessment of cardiac function is extremely difficult due to the animal's size. This study was designed to establish a work-performing isolated mouse heart preparation to objectively investigate myocardial performance in murine hearts. Isolated work-performing cardiac functional studies were performed on a modified Langendorff apparatus using 15 mice [25 to 28 g, +/-0.4 (SEM)]. The hearts were instrumented with a transonic flow meter and micromanometers to measure on-line aortic flow (AF), aortic pressure, and left atrial pressure (preload). A VAX cardiac function analyzing system was used to determine cardiac parameters including heart rate, contractility (max dP/dt), stroke volume (SV), and stroke work (SW) at various preload levels compared to a baseline preload of 5 mm Hg before and after 7 min of warm ischemia. AF increased from 1.01 ml/min (+/- 0.26) at 5 mm Hg of preload to 4.15 ml/min (+/- 1.03, P < 0.05) at 20 mm Hg of preload and decreased to 3.64 ml/min (+/- 0.62) at 25 mm Hg. SV, dP/dt, and SW increased with higher preload levels. There was a significant decrease in cardiac function postischemia. CONCLUSIONS: A valid isolated work-performing preload-dependent murine heart preparation involving minimal instrumentation of the heart is established to measure cardiac function and myocardial performance. Significant ischemia-reperfusion injury occurred after 7 min of ischemia. This model is a reliable and objective tool by which to evaluate murine cardiac function and to study ischemia-reperfusion injury.

Low insertion of hepatic segmental duct VII-VIII is an important cause of major biliary injury or misdiagnosis.

BACKGROUND: The importance of variant anatomy is only mentioned generally in most articles in this era of laparoscopic cholecystectomy. We report a series of 14 patients in whom a seemingly low insertion of hepatic segmental duct VII-VIII was clinically important. METHODS: The patients were managed at Duke University Medical Center. Two intraoperative videotapes of injury were reviewed. RESULTS: Three categories of patients were identified: 6 patients who had injury in association with another major injury to the biliary system, 7 patients who had an isolated VII-VIII system injury, and 1 patient with a Klatskin tumor in whom the unobstructed variant duct was stented. After appropriate evaluation, all patients were successfully treated. Several lawsuits resulted, even when the injury was seemingly minor. Symptoms developed in all patients who filed lawsuits, but none in those who did not. CONCLUSION: Appreciation of the VII-VIII biliary variant can lead to avoidance of injury or to a successful repair. The injury can easily occur despite "normal" cholangiography. Successful clinical outcome does not necessarily correlate with freedom from lawsuits.

Desensitization of myocardial beta-adrenergic receptors and deterioration of left ventricular function after brain death.

Brain death often results in a series of hemodynamic alterations that complicate the treatment of potential organ donors before transplantation. The deterioration of myocardial performance after brain death has been described; however, the pathophysiologic process of the myocardial dysfunction that occurs after brain death has not been elucidated. This study was designed to analyze the function of the myocardial beta-adrenergic receptor and the development of left ventricular dysfunction in a porcine model of experimental brain death. Analysis of the beta-receptor included determination of receptor density and adenylate cyclase activity after stimulation independently at the receptor protein, the G protein, and the adenylate cyclase moiety. Myocardial beta-receptor density did not change after the induction of brain death. A decrease in stimulated adenylate cyclase activity was observed within the first hour after brain death at the level of the beta-receptor, the G protein, and the adenylate cyclase moiety, which suggests the occurrence of rapid desensitization of beta-receptor function. Significant deterioration of myocardial performance also occurred within the first hour after brain death, represented by a decrease in preload-recruitable stroke work compared with the baseline value. The deterioration of myocardial performance after brain death correlates temporally with desensitization of the myocardial beta-receptor signal transduction system. The mechanism of impairment appears to be localized to the adenylate cyclase moiety itself.

Management of biliary complications after heart transplantation.

BACKGROUND: Immunosuppression increases the risk of biliary complications in heart transplant recipients. METHODS: Patients undergoing heart transplantation since 1986 who were at risk for cholelithiasis (n = 60) were retrospectively studied. RESULTS: Cholestatic jaundice developed in all patients after the operation because of biliary obstruction from cholelithiasis, cyclosporine toxicity, Imuran toxicity, or Gilbert's disease. The incidence of cholelithiasis or sludge was 42% (n = 25 of 60). Gallstones developed within 1.8 +/- 1.1 years in 17% of patients (n = 8 of 48) with a normal pretransplantation ultrasonogram. Biliary colic or gallstone pancreatitis developed 2 +/- 1.2 years after transplantation in 58% of patients (n = 7 of 12) with asymptomatic gallstones diagnosed before transplantation. The overall incidence of cholecystectomy or cholecystectomy with Roux-en-Y cystojejunostomy was 40% (n = 24). Both open cholecystectomy (n = 5) and laparoscopic cholecystectomy (n = 19) were performed without significant complications. Recovery is significantly more rapid (p < 0.05) after laparoscopic cholecystectomy versus open cholecystectomy (1 week versus 3 weeks). CONCLUSIONS: This analysis indicates that transplant candidates who have gallstones on pretransplantation evaluation or in whom gallstones develop after transplantation should undergo laparoscopic cholecystectomy at the earliest time in their posttransplantation course (i.e., 3 months) regardless of their symptomatic status. Removal of the diseased gallbladder not only simplifies the evaluation of cholestatic jaundice by eliminating the need for multiple ultrasonograms to exclude acute cholecystitis or choledocholithiasis but also safely minimizes the risk of the development of severe biliary complications.

Load-independent analysis of a pulsatile right ventricular assist device.

BACKGROUND: Right ventricular assist devices are becoming increasingly used as both a bridge to heart transplantation and as a means of temporary support after cardiopulmonary bypass. There has also been a resurgence of interest in pulsatile devices fueled by anecdotal, clinical reports. However, a load-independent analysis of biventricular function after right ventricular assistance comparing a pulsatile versus a continuous-flow right ventricular assist device has not been performed, and we hypothesize that a pulsatile device is less detrimental to cardiac function than a conventional, nonpulsatile pump. METHODS: Sixteen dogs (20 to 25 kg) were instrumented through a median sternotomy for placement of left ventricular and right ventricular epicardial dimension transducers in the major, minor, and septal-free wall axes. Intracavitary micromanometers were placed in both ventricles as well. Baseline pressure-dimension data were collected, and the right atrium and pulmonary artery were cannulated. Right ventricular bypass with the use of a pneumatically driven pulsatile right ventricular assist device (SV = 60 ml; n = 7) or a conventional continuous-flow centrifugal right ventricular assist device (n = 9) was instituted for a 4-hour duration. Animals were then weaned from right ventricular support and decannulated. After bypass, biventricular function data were then collected. The load-insensitive stroke work-end diastolic volume relationship known as preload recruitable stroke work was derived and expressed as a fraction of baseline function along with conventional hemodynamic indexes, cardiac output, and pulmonary vascular resistance. RESULTS: Results of this analysis show no significant benefit to either right ventricular or left ventricular function (right ventricular preload recruitable stroke work index: 0.863 +/- 0.3 [pulsatile] versus 0.849 +/- 0.2 [continuous], left ventricular preload recruitable stroke work index: 0.880 +/- 0.4 [pulsatile] versus 0.821 +/- 0.3 [continuous] after pulsatile right ventricular support. Likewise, cardiac output (1.4 +/- 0.1 [pulsatile] versus 1.5 +/- 0.2 [continuous] L/min) and pulmonary vascular resistance (4.8 +/- 1.0 [pulsatile] versus 3.2 +/- 1.1 [continuous] Wood Units) were not significantly different in either study group. CONCLUSIONS: We conclude from these data that pneumatically driven pulsatile right ventricular assist devices provide no additional benefit to myocardial performance beyond that of conventional, nonpulsatile pumps. Further studies investigating a speculative benefit from pulsatile circulatory support are necessary to further define a potential role for these novel devices.

Stability of the beta-adrenergic receptor/adenylyl cyclase pathway of pediatric myocardium after brain death.

Our previous work in the adult porcine model shows that brain death results in a rapid decline in left ventricular systolic function as measured by the preload recruitable stroke work method to 8% of the baseline slope within 6 hours; this process is accompanied by functional uncoupling of the beta-adrenergic receptor at the level of the adenylyl cyclase moiety within 1 hour. In contrast, the pediatric porcine myocardium displays no change in left ventricular systolic function from baseline within 6 hours of brain death. This work investigates whether the beta-adrenergic receptor/adenylyl cyclase pathway remains intact after induction of brain death in the pediatric porcine model. Thirteen 1-month-old swine (7 to 10 kg) were anesthetized and underwent median sternotomy, and baseline transmural left ventricular biopsy specimens were obtained before ligation of head vessels to induce brain death in six piglets, with the remaining seven serving as controls. Baseline left ventricular biopsy specimens were obtained just before and 1 and 3 hours after brain death or at matched time points without brain death in the control group. Myocardial tissue was then analyzed for beta-adrenergic receptor density with the use of saturation [125I]-iodocyanopindolol binding in the absence and presence of propranolol 1 mumol/L. Coupling of the beta-adrenergic receptor to its signal transduction system (stimulation of adenylyl cyclase) was tested at three levels: beta-adrenergic receptor (isoproterenol 100 mumol/L), stimulatory G protein Gs (sodium fluoride 10 mmol/L), and the adenylyl cyclase moiety itself (forskolin 100 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced cardiac preservation with oxygenated University of Wisconsin solution.

The purpose of this study was to determine if oxygen delivery to rabbit cardiac allografts arrested and stored in University of Wisconsin solution (UWS) at 4 degrees C would affect preservation. Nineteen isolated rabbit hearts were rapidly excised and perfused at 80 mm Hg on an isovolumic modified Langendorff apparatus. A micromanometer was placed within a balloon and inserted into the left ventricle through the mitral valve orifice. Digitized pressure waveforms were collected at 11 known balloon volumes from 0.8 to 1.2 ml. Baseline data were obtained for all hearts while perfused with Krebs-Henseleit solution equilibrated with 95% O2:5% CO2 at 37 degrees C. All hearts were arrested with 30 ml of UWS (290 mOsm). The control group (N = 10) was stored in UWS at 4 degrees C for 8 hr, and the experimental group (N = 9) was perfused with oxygenated UWS (O2 content = 5.6 ml O2) at 4 degrees C for 8 hr at a pressure of 60 mm Hg (5-10 ml/min). Both groups were then reperfused with Krebs-Henseleit buffer at 80 mm Hg for 15 min at for postpreservation data acquisition. Left ventricular developed pressures over a physiologic range (pressure-volume area) and maximum positive and negative dP/dt were calculated. Recovery of left ventricular parameters as a percentage of the baseline values was determined. Mean pressure-volume area recovery in the nonperfused group was 40 +/- 7.9% versus the perfused group (71 +/- 7.0%, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Improved tolerance of the pediatric myocardium to brain death.

The occurrence of brain death has been shown to significantly diminish left ventricular function in the adult porcine model. This study examined whether the pediatric myocardium is as sensitive as the adult myocardium to the detrimental effects of brain death in the porcine model. Left ventricular intracavitary pressure and major and minor axis epicardial dimensions were measured in eleven 1-month old pigs (7.5 to 10 kg) during a vena caval occlusion. Brain death was induced in six pigs by acutely ligating the brachiocephalic and left subclavian arteries. The remaining five pigs served as controls. Data were then collected every hour for 6 hours. The plot of the stroke work versus the end diastolic volume, called the preload recruitable stroke work relationship, was determined from the measured pressure and calculated intracavitary volume data. The slope of this linear relationship is an index of contractility, and the x intercept (Vo) is an index of diastolic mechanics. At each hour after instrumentation two vena caval occlusions were performed, and the mean slope of the preload recruitable stroke work line was calculated as a percentage of the baseline slope in both the brain-dead and control group. The mean values from the brain-dead pigs were 118%, 138%, 126%, 154%, 123%, and 87% of the baseline value for the 6 hours after brain death. The mean control values were 128%, 117%, 133%, 123%, 114%, and 111% of baseline for the 6 hours after instrumentation alone.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficiency of pulmonary blood transport following single lung transplantation.

Perioperative right ventricular (RV) dysfunction remains a significant problem following single lung transplantation (SLT), especially in patients with pulmonary hypertension. Total RV power (Wt), a determinant of RV function, is the sum of the mean component (Wm) which contributes to actual blood flow and the oscillatory component (Wo) which is the energy expended on arterial pulsation. Calculation of Wo is possible only through harmonic analysis of pulmonary arterial (PA) pressure and flow waveforms, and as much as 33% of RV power is attributed to it. The purpose of this study was to precisely quantify changes in RV power output using Fourier analysis of PA pressure and flow waveforms after SLT. Fourteen dogs (donors) were instrumented with a PA ultrasonic flow probe, PA and left atrial (LA) micromanometers, and LA epicardial pacing leads. Control (Pre-Tx) pressure-flow data were acquired during transient occlusion of the right PA at a heart rate of 140. The PA was cannulated, the lungs were flushed with 1 liter of modified Euro-Collins solution at 4 degrees C, and the left lung was harvested and transplanted to 14 recipient dogs in a standard manner. After 1 hr of reperfusion, PA (Post-Tx) pressure-flow data were acquired as above. All recipient animals survived SLT with a mean ischemic time of 183 +/- 3 min. Following SLT, both the mean, Wm, (69 +/- 9 to 161 +/- 23 mW) and oscillatory, Wo, (23 +/- 3 to 46 +/- 10 mW) components of RV power output increased significantly after SLT (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of triiodothyronine and vasopressin on cardiac function and myocardial blood flow after brain death.

Previous studies have documented decreases in serum-free triiodothyronine (T3) after brain death and improved hemodynamics with its replacement, suggesting its controversial, but promising, clinical utility for managing potential organ donors. Vasopressin is also commonly used clinically as a pressor agent after brain death. A load-independent analysis of cardiac function and an assessment of myocardial blood flow (MBF) with these agents have not been reported, however. Eighteen pigs were instrumented with left ventricular epicardial dimension transducers and a left ventricular micromanometer. MBF was assessed by standard microsphere techniques. Baseline left ventricular pressure-dimension data were collected, and brain death was induced by ligating the innominate and left subclavian arteries. Left ventricular function data were collected every 30 minutes after brain death to 6 hours or until the animal died. Microsphere injections were performed before brain death and hourly thereafter to 4 hours. At 90 minutes after brain death, animals were assigned to a vasopressin (2 units/hr, intravenously, n = 6), T3 (0.05 microgram/kg/hr, intravenously, n = 6), or control (n = 6) treatment group. Preload recruitable stroke work (PRSW), a load-independent index of left ventricular function, was derived from the pressure-dimension data. MBF was calculated by conventional methods. At 4 hours after brain death, PRSW and MBF decreased significantly in the control, vasopressin, and T3 groups relative to the baseline, pre-brain dead state (PRSW: -36% +/- 12%, -48 +/- 7%, -52% +/- 5%; MBF: -27% +/- 15%, -38% +/- 5%, -78% +/- 2%, respectively). Neither vasopressin nor T3, however, showed any advantage over the control group in terms of preserving left ventricular function or prolonging survival. Furthermore, these data show a marked decrease in MBF in the T3 group (p < 0.01 versus control and vasopressin groups) without a significant change in cardiac function. Analysis of endocardial to epicardial flow ratios disclosed no significant differences between groups at any time. In summary, animals treated with T3 had a greater decline in MBF than the control group at 4 hours, without any benefit to cardiac function. Further studies examining the mechanism responsible for the deterioration of MBF and cardiac dysfunction will be necessary to optimally manage the brain dead patient before organ harvest, especially regarding the precise role of T3.

Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity.

Tissue injury by Aspergillus niger infection is associated with the deposition of calcium oxalate crystals. Oxalate is recognized to function as a ligand for numerous metal cations and will react with ferric ion to form a coordination complex. We describe oxalate deposition in the lung of a patient with A. niger infection and quantify surface-complexed Fe3+. Crystals collected from lung tissue demonstrated considerable concentrations of surface iron. In addition, we tested the hypothesis that this surface coordination of Fe3+ by oxalate is associated with increased in vitro oxidant generation. Calcium oxalate crystals (1.0 mg/ml) complexed all available Fe3+ from solutions of ferric chloride to concentrations of as much as 1.0 mM. Oxidant generation in both a chemical and a cellular system, measured as thiobarbituric-acid-reactive products of deoxyribose and chemiluminescence, respectively, increased with coordination of higher concentrations of inorganic iron. We conclude that calcium oxalate associated with A. niger infection complexes iron cations onto the crystalline surfaces and may generate oxidants at the solid-solution interface, which could result in tissue injury.