Prevention of bone loss and fracture after lung transplantation: a pilot study.

BACKGROUND: Osteoporotic fracture is a significant source of morbidity after lung transplantation. Therapies to prevent posttransplant fracture are largely untested among lung transplant recipients. METHODS: In this prospective uncontrolled study, lung transplant referrals were assessed for bone health with metabolic, radiographic, and bone mineral density measurements. Transplant recipients were treated with an antiresorptive regimen that included a bisphosphonate starting before or after transplantation. One year after transplantation, the fracture rate and bone density of patients in each group were reassessed and compared to historical controls. Between January 1996 and August 1999, 45/50 (90%) lung transplant referrals underwent bone health assessment. Transplant candidates received calcium, vitamin D, and hormone replacement therapy as indicated for hypogonadism. After July 1998, bisphosphonate therapy was added for candidates with osteopenia or osteoporosis (T score <1). After transplantation, all patients received 90 mg of pamidronate i.v. every 12 weeks, regardless of pretransplant bone density. Radiologic evaluation was performed for clinical suspicion of fracture. Bone density was remeasured 1 year after transplantation. RESULTS: Most transplant referrals suffered from osteopenia or osteoporosis, and 29% of transplant referrals had prevalent vertebral compression fractures. Hypogonadism was untreated in 50% of men and 20% of women, and 15% of patients had hypovitaminosis D. Of the 21 patients assessed 1 year after transplantation, new fractures occurred in 4% of these patients. Lateral lumbar spine and hip bone density remained stable or improved in 65% and 86% of patients, respectively. Most of those who lost bone density had started bisphosphonate therapy after transplantation. CONCLUSIONS: Antiresorptive therapy with a bisphosphonate decreases the fracture rate and preserves bone mass 1 year after lung transplantation. In end-stage lung disease patients with osteopenia or osteoporosis, bisphosphonate therapy should be initiated before transplant surgery is contemplated.

Effect of a resident self-study and presentation program on performance on the thoracic surgery in-training examination.

BACKGROUND: In this study we examine whether conversion from a didactic lecture format to a resident self-study and presentation program can improve performance on the Thoracic Surgery In-Training Examination (TSITE). METHODS: During the first 5 years, educational conferences were didactic lectures delivered by the attending thoracic surgery staff (group 1, n = 9 residents). During the second 5 years, residents prepared and delivered reviews from major textbook sources (group 2, n = 9 residents). Scores on the American Board of Surgery In-Training Examination (ABSITE) as a chief resident in general surgery were analyzed using one-way analysis of variance to assess fund of knowledge and test-taking skills prior to thoracic surgery training for the two groups. Scores on the TSITE during the first and second years of thoracic surgery training were recorded for each resident and analyzed using a paired t test. The data are expressed as the mean +/- standard deviation. RESULTS: Eighteen thoracic surgery residents over a 10-year period were involved in the study. ABSITE scores as a chief resident in general surgery did not differ between the two groups. Residents in group 1 improved their percentile rank from the first to the second year by a mean of 11%+/-12%, whereas those in group 2 improved their scores by a mean of 31%+/-21% (P < 0.05). CONCLUSIONS: When compared with a didactic lecture format, a resident self study and presentation program improves performance on the Thoracic Surgery In-Training Examination. This improvement in performance typically manifests during the second year of thoracic surgery training.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts.

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Esophageal laceration and charcoal mediastinum complicating gastric lavage.

A 19-year-old woman underwent multiple attempts at orogastric lavage before success 5 h after ingesting approximately 24 grams of ibuprofen in a suicide attempt. Activated charcoal was administered via the lavage tube. She vomited charcoal shortly after administration and began experiencing difficulty breathing and an increase in the pitch of her voice. A chest X-ray study showed a widened mediastinum, pneumopericardium, and subcutaneous emphysema consistent with esophageal perforation that was confirmed by computed tomography scan. Surgical exploration revealed a tear in the proximal posterior esophagus with charcoal in the posterior mediastinum. She remained intubated for 7 days and was discharged 14 days after admission. This is a report of esophageal perforation with activated charcoal contamination of the mediastinum after gastric lavage. The risks and benefits of this procedure should be carefully considered in each patient prior to its use. Awake patients should be cooperative with the procedure to minimize any risk of trauma to the oropharynx or esophagus.

Coronary artery bypass grafting with cardiopulmonary bypass versus off-pump cardiopulmonary bypass grafting: does eliminating the pump reduce morbidity and cost?

BACKGROUND: Cardiopulmonary bypass (CPB) may contribute to the complications and cost of coronary artery bypass grafting (CABG). Off-pump CABG (OPCAB) allows coronary revascularization without CPB. We hypothesized that OPCAB provides satisfactory graft patency while reducing complications and cost compared with CABG with CPB. METHODS: We prospectively followed 80 patients undergoing CABG: 40 patients undergoing OPCAB and 40 patients undergoing CABG with CPB. OPCAB patients underwent angiography within 48 hours of surgery to determine early graft patency. Incidence of complications, length of stay, and costs were recorded for each patient. The influence of the number of vessels bypassed was analyzed. RESULTS: OPCAB patients (n = 40) underwent grafting of 2.7 +/- 0.7 vessels per patient compared with 3.6 +/- 0.8 vessels per patient in the CABG with CPB group (n = 40) (p < 0.0001). Angiography demonstrated 105 of 108 (97%) of grafts were patent in the OPCAB group. Incidence of complications, length of stay, and costs did not differ between the OPCAB and CABG with CPB groups. Number of vessels grafted showed a positive correlation to total costs in both groups. CONCLUSIONS: While OPCAB provided satisfactory early graft patency, there was no significant difference between OPCAB and CABG with CPB with regard to cost, length of stay, or incidence of complications. In this study, eliminating CPB did not reduce morbidity or cost after CABG.

Improved biochemical preservation of lung slices during cold storage.

BACKGROUND: Development of lung preservation solutions typically requires whole-organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that lung slices could be used to assess preservation of biochemical function during cold storage. MATERIALS AND METHODS: Whole rat lungs were precision cut into slices with a thickness of 500 microm and preserved at 4 degrees C in the following solutions: University of Wisconsin (UW), Euro-Collins (EC), low-potassium-dextran (LPD), Kyoto (K), normal saline (NS), or a novel lung preservation solution (NPS) developed using this model. Lung biochemical function was assessed by ATP content (etamol ATP/mg wet wt) and capacity for protein synthesis (cpm/mg protein) immediately following slicing (0 h) and at 6, 12, 18, and 24 h of cold storage. Six slices were assayed at each time point for each solution. The data were analyzed using analysis of variance and are presented as means +/- SD. RESULTS: ATP content was significantly higher in the lung slices stored in NPS compared with all other solutions at each time point (P < 0.0001). Protein synthesis was significantly higher in the lung slices stored in NPS compared with all other solutions at 6, 12, and 18 h of preservation (P < 0.05). CONCLUSIONS: This lung slice model allows the rapid and efficient screening of lung preservation solutions and their components using quantifiable biochemical endpoints. Using this model, we have developed a novel solution that improves the biochemical preservation of lung slices during cold storage.

Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor.

OBJECTIVE: Inflammatory cytokines, particularly tumor necrosis factor, contribute to myocardial dysfunction after ischemia-reperfusion injury. Aprotinin may improve outcomes in cardiac surgery through suppression of inflammatory mediators. We hypothesized that aprotinin may exert its beneficial effects through suppression of tumor necrosis factor alpha. METHODS: Adult rat hearts were precision cut into slices with a thickness of 200 microm and stored in crystalloid cardioplegic solution alone or with one of the following additions: aprotinin or tumor necrosis factor alpha, aprotinin plus tumor necrosis factor alpha, a monoclonal antibody to tumor necrosis factor alpha, or a polyclonal antibody to the tumor necrosis factor alpha receptor. Myocardial biochemical function was assessed by adenosine triphosphate content and capacity for protein synthesis immediately after slicing (0 hours) and after 2, 4, and 6 hours of storage at 4 degrees C. The content of tumor necrosis factor alpha was measured by an enzyme-linked immunosorbent assay. Six slices were assayed at each time point for each solution. The data were analyzed by analysis of variance and are expressed as the mean +/- standard deviation. RESULTS: When stored in cardioplegic solution containing aprotinin, the heart slices demonstrated (1) an increase in adenosine triphosphate content and protein synthesis (P <.0001), (2) a decrease in intramyocardial generation of tumor necrosis factor alpha (P

Functional outcome and survival after pharyngolaryngoesophagectomy for cancer.

BACKGROUND: Surgical resection of the larynx, hypopharynx and cervical esophagus, or pharyngolaryngoesophagectomy (PLE), with pharyngogastric anastomosis (PGA) offers a means of controlling local and regional carcinoma of the upper aerodigestive tract (UADT). We reviewed our experience with PLE for carcinoma of the UADT to evaluate functional outcome and survival. METHODS: Patients undergoing PLE from 1986 through 1999 were reviewed. Survivors completed questionnaires which graded their level of function and voice rehabilitation. Gastric emptying studies were performed with rates compared with normal controls. Survival curves were generated using the Kaplan-Meier method. RESULTS: Thirty-one patients underwent PLE during the study period. Twenty-nine patients had squamous cell carcinoma. Operative mortality was 0%. Thirty-day mortality was 9.6%. There were 2 anastomotic leaks (6.4%). All survivors reported normal ability to complete activities of daily living. Voice rehabilitation was acceptable in 7 of 10 survivors. Positive surgical margins resulted in decreased survival (P = 0.03). No other patient demographic or management variable altered survival. One-year, 5-year, and 10-year survival rates were 67%, 40%, and 18%, respectively. CONCLUSION: PLE with PGA for carcinoma of the UADT may be performed with low morbidity and mortality. Functional patient outcomes including gastric emptying, activities of daily living, and voice rehabilitation are acceptable.

Improved biochemical preservation of heart slices during cold storage.

BACKGROUND: Development of myocardial preservation solutions requires the use of whole organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that myocardial slices could be used to assess preservation of biochemical function during cold storage. MATERIALS AND METHODS: Whole rat hearts were precision cut into slices with a thickness of 200 microm and preserved at 4 degrees C in one of the following solutions: Columbia University (CU), University of Wisconsin (UW), D5 0.2% normal saline with 20 meq/l KCL (QNS), normal saline (NS), or a novel cardiac preservation solution (NPS) developed using this model. Myocardial biochemical function was assessed by ATP content (etamoles ATP/mg wet weight) and capacity for protein synthesis (counts per minute (cpm)/mg protein) immediately following slicing (0 hours), and at 6, 12, 18, and 24 hours of cold storage. Six slices were assayed at each time point for each solution. The data were analyzed using analysis of variance and are presented as the mean +/- standard deviation. RESULTS: ATP content was higher in the heart slices stored in the NPS compared to all other solutions at 6, 12, 18 and 24 hours of cold storage (p < 0.05). Capacity for protein synthesis was higher in the heart slices stored in the NPS compared to all other solutions at 6, 12, and 18 hours of cold storage (p < 0.05). CONCLUSIONS This myocardial slice model allows the rapid and efficient screening of cardiac preservation solutions and their components using quantifiable biochemical endpoints. Using this model, we have developed a novel preservation solution which improves the biochemical function of myocardial slices during cold storage.

Does University of Wisconsin solution harm the transplanted heart?

BACKGROUND: University of Wisconsin solution (UW) has been shown to be an effective preservative for the cardiac allograft. Recently, the high potassium content of UW has been implicated in causing coronary endothelial damage, allegedly contributing to development of cardiac allograft vasculopathy (CAV) and eventually to poorer survival. METHODS: We examined our experience using UW for preservation of cardiac allografts between 1990 and 1994 (n = 94), and compared these to hearts preserved with the lower potassium-containing Stanford solution used at our center between 1986 and 1990 (n = 65). Indices of graft function, ischemic injury, CAV incidence, CAV severity, and survival were evaluated. RESULTS: The 2 groups were similar in age, gender, diagnosis, donor inotropic support, donor-recipient weight ratio, incidence of acute graft failure, and cytomegalovirus seroconversion. UW-preserved hearts came from older donors (30.5 vs 24.1 years, p < .001), and were transplanted into more status 1 recipients (56% vs 22%, p < .001), consistent with current trends. Mean ischemic time of UW-preserved hearts was significantly longer (184 vs 155 minutes, p < .005) although time required to wean from bypass was less (45.5 vs 73.8 minutes, p < .001) and there was a trend towards less inotropic requirement. CPK-MB release was less with UW preservation (63 vs 87 microg/ dL, p = .001). Three years after transplantation, both groups were similar in the incidence of CAV (UW, 27.3%; STNF, 37.5%; p = 0.27), and also the severity of CAV (p = 0.78). Deaths attributed to CAV were equal in each group (UW, 11.4% vs STNF, 10.7%; p = 0.79). Kaplan-Meier survival analysis revealed equivalent survival curves (p = 0.26). CONCLUSIONS: We conclude that UW is a safe and effective myocardial preservative, allowing longer ischemic times with equivalent graft function. Our data suggest that when UW is used for cardiac allograft preservation, both CAV and survival are comparable to the experience with other preservatives containing lower concentrations of potassium.

Avoidance of cellular blood product transfusions in LVAD recipients does not prevent HLA allosensitization.

BACKGROUND: Transfusion of cellular blood products during left ventricular assist device (LVAD) implantation has been associated with HLA allosensitization, resulting in the need for a negative prospective cross-match and prolonged transplant waiting times. In order to prevent this risk, we developed a protocol to avoid transfusion of cellular blood products. METHODS: The protocol included preoperative patient stabilization, perioperative recombinant erythropoietin and blood conservation strategies, and postoperative monitoring of mixed venous oxygen saturation (SVO2) to assure adequate peripheral oxygen delivery. Panel reactive antibody (PRA) was measured in all patients pre and post LVAD placement to assess HLA sensitization. RESULTS: Seven consecutive patients underwent LVAD implantation without transfusion of blood or platelets, one of whom expired perioperatively. Mean hematocrit was 35.2% preoperatively, and 21.8% postoperatively, reaching a nadir of 20.2%. Postoperative SVO2 was >60% in all patients. In the six survivors, mean hematocrit reach 24.3%, 27.3%, and 33.0% by postoperative day seven, fourteen, and thirty, respectively. PRA in three patients was 0% preoperatively and remained 0% until transplantation after 33, 34, and 50 days of support. In two patients, preoperative PRA was 7% and 17%, dropped to 3% and 0% after thirty days, then progressively rose to 96% and 100% after 60 and 90 days, respectively. In one other patient, preoperative PRA was 0%, remained at 0% after thirty days, then rose to 96% by 60 days. CONCLUSIONS: Avoiding transfusion of cellular blood products in LVAD recipients is safe and well tolerated, but does not universally protect from HLA allosensitization. Other factors may also produce sensitization, such as immunogenic components of the LVAD, soluble antigen in fresh frozen plasma, or latent sensitization which is not initially evident in critically ill and possibly anergic patients.

Impact of University of Wisconsin solution on clinical heart transplantation. A comparison with Stanford solution for extended preservation.

BACKGROUND: The University of Wisconsin Solution (UW) has extended preservation of abdominal organs but has not allowed equally extended preservation of the heart. Therefore, the impact of UW on clinical heart transplantation has remained unclear. METHODS AND RESULTS: Between June 1986 and March 1994, 161 orthotopic heart transplants were performed at our center. Of these, 66 were preserved for > or = 3 hours. Of these, 17 hearts were preserved with Stanford solution (STNF), which was used before 1990, and 49 were preserved with UW. These groups were compared for indexes of ischemic injury, ventricular function, and survival. The UW group contained more status-1 recipients (57% versus 29%, P < 0.05) and a higher mean donor age (30.7 versus 22.1 years, P = 0.008). Mean ischemic time was slightly but not significantly higher with UW (228 versus 205 minutes for UW versus STNF, respectively; P = 0.085). The time to wean from bypass after cross-clamp removal was nearly twice as long with STNF than with UW (80.6 versus 44.3 minutes, P < 0.001). There was no difference in the incidence of primary graft failure (2% for UW versus 6% for STNF, P = 0.43). The average need for inotropic support over the first 8 posttransplant hours was significantly higher with STNF than UW. Neither hospital stay nor survival differed. Nevertheless, the ability to use donor organs from more distant sites was increased. Of all hearts preserved with STNF, 26% were stored for > or = 3 hours, whereas 51% of all hearts preserved in UW were stored for this length of time. Donor use of hearts increased from 20% in 1989 to 63% in 1993, largely because of greater use of more distant donors. CONCLUSIONS: We conclude that heart preservation with UW limits ischemic damage from prolonged storage and improves myocardial function in the early posttransplant period, thus allowing greater use of available donors from distant sites to patients awaiting heart transplantation.

Adjuvant intrapleural amphotericin B therapy for pulmonary mucormycosis in a cardiac allograft recipient.

Infectious complications after heart transplantation remain a major cause of morbidity and mortality. While many viral, bacterial, and protozoal infections can be successfully treated, fungal infections continue to be challenging. Mucormycosis is a rare infection in heart transplant recipients; however, mortality is exceedingly high. We report a case of cavitary Rhizopus lung infection 2 months after cardiac transplantation. The infection was complicated by inadvertent exposure of the pleural cavity to the fungus during surgical resection. Therapy consisted of standard systemic amphotericin B, surgical excision, and for the first time, the use of adjuvant intrapleural amphotericin B. Cure was achieved with no clinical or radiological evidence of disease at 3 months follow-up. Rhizopus pulmonary infection is a rare complication of cardiac transplantation. Treatment consists of the triad of systemic anti-fungal therapy, surgical resection, and control of any underlying predisposing diseases. Adjuvant intrapleural amphotericin B use could also be considered in patients with fungal pneumonias and evidence of chest wall and/or pleural cavity involvement.

Forty-hour preservation of the rabbit heart: optimal osmolarity, [Mg2+], and pH of a modified UW solution.

The University of Wisconsin solution modified with 2,3-butanedione monoxime and calcium experimentally extends the limits of ischemic preservation of the heart. This study evaluates other characteristics of this modified solution that may further enhance preservation: osmolarity, Mg2+ concentration ([Mg2+]), and pH. Rabbit hearts were flushed with the modified University of Wisconsin solution and stored for 40 hours at 4 degrees C. Maximal left ventricular developed pressure (LVDP), left ventricular end-diastolic volume (LVEDV), maximum rate of increase of left ventricular pressure (dP/dt), heart rate, and coronary flow were measured during 60 minutes of isolated crystalloid reperfusion with an isovolumic left ventricular balloon at constant end-diastolic pressure. Creatine kinase release and myocardial adenine nucleotide content were measured at completion of reperfusion. Solution osmolarity was tested at 357, 327, 297, and 277 mOsm/L by reducing K+, Na+, and lactobionate concentrations. [Mg2+] was assessed at 5 and 16 mmol/L. Solution pH was studied at 7.0, 7.4, and 7.8. A control group of hearts was flushed and immediately reperfused to establish baseline function. Hearts stored in either hypertonic (357 mOsm/L) or hypotonic (277 mOsm/L) solutions functioned poorly, reaching 58% and 50% of control LVDP (p < 0.001), 49% (p < 0.01), and 58% (p = not significant) of LVEDV, 56% and 49% of +dP/dt (p < 0.001), respectively, and released substantially more creatine kinase (p < 0.001 versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Improved myocardial ischemic tolerance by contractile inhibition with 2,3-butanedione monoxime.

Contracture of the arrested myocardium during prolonged storage of the heart results in both systolic and diastolic dysfunction, and is a major limitation to extended preservation. We studied the effects of a reversible contractile inhibitor, 2,3-butanedione monoxime (BDM), on myocardial ischemic tolerance. Isolated rabbit hearts were flushed with University of Wisconsin (UW) solution with and without 30 mmol/L BDM and 1 mmol/L CaCl, stored at 4 degrees C for 24 hours, and subsequently reperfused for 60 minutes. Left ventricular pressure-volume relationships and adenine nucleotide content were determined before reperfusion. Left ventricular systolic pressure, diastolic volume, and adenine nucleotide content were measured after reperfusion. Hearts stored in UW solution underwent contracture and adenosine triphosphate (ATP) depletion during storage, and exhibited systolic dysfunction, impaired diastolic relaxation, and poor ATP regeneration upon reperfusion. The addition of calcium worsened contracture and ATP depletion (p < 0.005) and slightly improved function and ATP regeneration (p = not significant). Hearts stored in the presence of BDM experience no contracture during storage; ATP was preserved (10.7 versus 15.7 nmol/mg; p < 0.05), and left ventricular systolic pressure and ATP content recovered to 74% and 93% of control on reperfusion, respectively (p < 0.005). Left ventricular diastolic volume remained depressed, however, although less than with UW solution (0.87 versus 0.45 mL; p < 0.001). When both BDM and calcium were included in the UW solution, calcium-stimulated ATP hydrolysis and contracture were prevented, left ventricular systolic pressure returned to 87% of control, and left ventricular diastolic volume and ATP content returned to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Limitations of heart preservation by cold storage.

Clinical heart preservation is currently limited to only 4-6 hr, while the kidney, liver, and pancreas can tolerate 24-48 hr of cold ischemia. A fundamental difference between these organs is that the heart is contractile, containing large quantities of actin and myosin, and is susceptible to contracture-induced injury caused by energy deprivation. We have quantified and correlated the onset of contracture with levels of ATP and glycogen during cold storage in rabbit hearts flushed with UW solution, with and without 1 mM calcium (Ca), or 3 mM iodoacetate (IAA). A fluid-filled left ventricular balloon was used to generate pressure-volume curves (compliance) at 1, 6, 12, 18, and 24 hr of cold storage. Onset of contracture occurred in UW stored hearts at 18 hr, contracture in hearts exposed to Ca occurred between 6 and 12 hr. Compliance was significantly less in hearts exposed to Ca at 12, 18, and 24 hr (P less than .01) than in hearts without Ca. ATP levels were well maintained for up to 18 hr in the hearts preserved in UW solution (78%), but fell more rapidly in the presence of Ca at 12 hr (P less than .005), 18 hr (P less than .005), and 24 hr (P less than .05). In comparison, the ATP supply of the liver and kidney was exhausted by only 4 hr of cold storage. Onset of myocardial contracture correlated with a decrease in ATP to less than 80% of control, and contracture accelerated ATP decline 3-6-fold. IAA caused nearly complete myocardial contracture and ATP depletion within 2 hr. Isolated heart function was 77% and 73% at 6 and 12 hr of storage, but fell to 54% and 42% at 18 and 24 hr, respectively, coinciding with development of contracture. We conclude that ischemic contracture in this model is a major cause of myocardial damage during cold storage, and is accelerated by the presence of Ca. Other organs can be successfully stored despite exhaustion of ATP reserves. Thus successful cold-storage of the heart is highly ATP-dependent. Since cold storage inevitably leads to ATP depletion, extension of myocardial ischemic tolerance will depend on either reversible inhibition of ATP hydrolysis during storage, reversible uncoupling of contracture development from ATP depletion, or maintaining ATP production by continuous hypothermic perfusion.