Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Comparison of de novo cancer incidence in Australian liver, heart and lung transplant recipients.

Population-based evidence on the relative risk of de novo cancer in liver and cardiothoracic transplant recipients is limited. A cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized incidence ratios (SIRs) were computed by cancer type, transplanted organ and recipient age. Cox regression models were used to compare cancer incidence by transplanted organ. During a median 5-year follow-up, the risk of any cancer in liver and cardiothoracic recipients was significantly elevated compared to the general population (n = 499; SIR = 2.62, 95%CI 2.40-2.86). An excess risk was observed for 16 cancer types, predominantly cancers with a viral etiology. The pattern of risk by cancer type was broadly similar for heart, lung and liver recipients, except for Merkel cell carcinoma (cardiothoracic only). Seventeen cancers (10 non-Hodgkin lymphomas), were observed in 415 pediatric recipients (SIR = 23.8, 95%CI 13.8-38.0). The adjusted hazard ratio for any cancer in all recipients was higher in heart compared to liver (1.29, 95%CI 1.03-1.63) and lung compared to liver (1.65, 95%CI 1.26-2.16). Understanding the factors responsible for the higher cancer incidence in cardiothoracic compared to liver recipients has the potential to lead to targeted cancer prevention strategies in this high-risk population.

De novo cancer-related death in Australian liver and cardiothoracic transplant recipients.

Evidence is sparse on the relative mortality risk posed by de novo cancers in liver and cardiothoracic transplant recipients. A retrospective cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized mortality ratios (SMRs) were computed by cancer type, transplanted organ, recipient age and sex. During a median 5-year follow-up, de novo cancer-related mortality risk in liver and cardiothoracic recipients was significantly elevated compared to the matched general population (n = 171; SMR = 2.83; 95% confidence interval [95%CI], 2.43-3.27). Excess risk was observed regardless of transplanted organ, recipient age group or sex. Non-Hodgkin lymphoma was the most common cancer-related death (n = 38; SMR = 16.6; 95%CI, 11.87-22.8). The highest relative risk was for nonmelanocytic skin cancer (n = 23; SMR = 49.6, 95%CI, 31.5-74.5), predominantly in males and in recipients of heart and lung transplants. Risk of death from de novo cancer was high in pediatric recipients (n = 5; SMR = 41.3; 95%CI, 13.4-96.5), four of the five deaths were non-Hodgkin lymphoma. De novo cancer was a leading cause of late death, particularly in heart and liver transplantation. These findings support tailored cancer prevention strategies, surveillance to promote early detection, and guidelines for managing immunosuppression once cancer occurs.

Overweight and obesity among older adults on admission to hospital.

Poor nutritional status, which includesboth under- a nd over-nutrition, i s associated w it h poor health outcomes. T his cross-sectional study assessed the nutritional status of older patients admitted to an acute geriatric ward of a Dublin hospital. Anthropometric and clinical measurements were made. Thirty patients, mean (sd) age 79 (7) y and body mass index 26.6 (4.7) kg/m2, participated. More patients were overweight (n = 12) or obese (n = 9) than underweight (n= 1) or healthy weight (n = 8) which indicates that this age-group may be part of the Irish obesity epidemic.

Comparison and validation of three measures of quality of life in patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension, when advanced, markedly limits exercise capacity, activities of daily living and quality of life (QoL). No measure of QoL has yet been validated for the assessment of pulmonary hypertension. The aim of the study was to compare the validity of the Minnesota Living with Heart Failure (MLwHF) questionnaire, the Short Form-36 (SF-36) questionnaire and the Australian Quality of Life (AQoL) measure for assessing pulmonary hypertension treatment. METHODS: Eighty-three patients were enrolled in three studies of pulmonary hypertension treatment (treprostinil, bosentan and sildenafil). They were assessed at baseline and 3 months with the MLwHF questionnaire. Treprostinil and bosentan groups also had 6 and 12 months' data. Twenty-one patients in the sildenafil trial completed concurrently, the SF-36 and AQoL measures at baseline and 3 months. QoL scores were correlated with the 6-min walk test distance, New York Heart Association functional class and right heart catheter-derived haemodynamic parameters of the disease for all matching time points and for changes in scores and clinical measurements over time. RESULTS: The MLwHF and SF-36 scores correlated well with the 6-min walk test distance and New York Heart Association functional class, but did not correlate with haemodynamic measurements. MLwHF and SF-36 scores also correlated with the rate of change of the 6-min walk test distance and New York Heart Association functional class over time. CONCLUSION: The MLwHF questionnaire and SF-36 are useful tools for the assessment of QoL in pulmonary hypertension and may be useful in the ongoing evaluation of QoL in the treatment and study of pulmonary hypertension.

Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension.

BACKGROUND: Few treatments are available for isolated pulmonary hypertension (PHT), which has a high morbidity and mortality. This trial was designed to assess the hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with PHT, in which local overproduction of endothelin-1 (ET-1) is thought to play a pathogenic role. METHODS AND RESULTS: An open-label, dose-ranging study was performed in 7 female patients with primary PHT (n=5) or isolated PHT associated with limited scleroderma (n=2). Infusions of 50, 150, and 300 mg were administered at 2-hour intervals, and the hemodynamic responses were measured. Bosentan caused a dose-dependent fall in total pulmonary resistance (-20.0+/-11.0%, P=0.01) and mean pulmonary artery pressure (-10.6+/-11.0%, P>0.05). However, there was also a fall in the systemic vascular resistance (-26.2+/-12.8%, P<0.005) and mean arterial pressure (-19.8+/-14.4%, P<0.001). There was a slight increase in cardiac index (15+/-12%, P>0.05) and a dose-dependent rise in ET-1 but no significant change in other hemodynamic variables, gas exchange, or other vasoactive mediators. CONCLUSIONS: Intravenous bosentan is a potent but nonselective pulmonary vasodilator at the doses tested, even in patients resistant to inhaled nitric oxide. Transient increases in plasma ET-1 were observed, consistent with a blockade of endothelial ET(B) receptors. Systemic hypotension and other significant events during the study indicate that its intravenous use in patients with severe PHT may be limited. Implications for future trial design and studies of chronic oral treatment are discussed.

Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure.

OBJECTIVES: The purpose of this study was to assess the tolerability and efficacy of carvedilol in patients with New York Heart Association (NYHA) functional class IV symptoms. BACKGROUND: Carvedilol, a nonselective beta-adrenergic blocking drug with alpha-adrenergic blocking and antioxidant properties, has been shown to improve left ventricular function and clinical outcome in patients with mild to moderate chronic heart failure. METHODS: We retrospectively analyzed the outcomes of 230 patients with heart failure treated with carvedilol who were stratified according to baseline functional class: 63 patients were NYHA class IV and 167 were NYHA class I, II or III. Carvedilol was commenced at 3.125 mg b.i.d. and titrated to 25 mg b.i.d. as tolerated. Patients with class IV symptoms were older (p = 0.03), had lower left ventricular fractional shortening (p < 0.001), had lower six-min walk distance (p < 0.001) and were receiving more heart failure medications at baseline compared with less symptomatic patients. RESULTS: Nonfatal adverse events while taking carvedilol occurred more frequently in class IV patients (43% vs. 24%, p < 0.0001), and more often resulted in permanent withdrawal of the drug (25% vs. 13%, p < 0.01). Thirty-seven (59%) patients who were NYHA class IV at baseline had improved by one or more functional class at 3 months, 8 (13%) were unchanged and 18 (29%) had deteriorated or died. Among the less symptomatic group, 62 (37%) patients had improved their NYHA status at 3 months, 73 (44%) were unchanged and 32 (19%) had deteriorated or died. The differences in symptomatic outcome at three months between the two groups were statistically significant (p = 0.001, chi-square analysis). Both groups demonstrated similar significant improvements in left ventricular dimensions and systolic function. CONCLUSIONS: Patients with chronic NYHA class IV heart failure are more likely to develop adverse events during initiation and dose titration when compared with less symptomatic patients but are more likely to show symptomatic improvement in the long term. We conclude that carvedilol is a useful adjunctive therapy for patients with NYHA class IV heart failure; however, they require close observation during initiation and titration of the drug.

Unbound cyclosporine and allograft rejection after heart transplantation.

BACKGROUND: To determine the impact of cyclosporine plasma protein binding on organ rejection after cardiac transplantation, the incidence of cardiac rejection episodes was compared among patients who had differing levels of cyclosporine plasma fraction unbound (fU). METHODS: Forty-six consecutive cardiac transplant recipients were sampled at 1, 3, 6, and 12 months after transplantation, and cyclosporine plasma fU was determined, using a specially developed equilibrium dialysis method. At the completion of the study, incidences of cardiac rejection episodes were compared among patients having mean cyclosporine fU (Csfu) that were low (LCsfu; mean+/-SD, 1.33+/-0.10%, n=15), intermediate (ICsfu; 1.60+/-0.07%, n= 16), and high (HCsfu; 1.99+/-0.30%, n=15). RESULTS: Percentage of endomyocardial biopsies (grade 3a, 3b, and 4) with respect to the total number of biopsies performed in the first 3 months after transplant was significantly higher in the LCsfu group than the other groups (40.9% in LCsfu vs. 28.5% for ICsfu and 32.1% for HCsfu groups, P=0.02). The linearized rate of rejection (episodes of rejection/100 patient-days) in the first month after transplant was 6.5+/-1.7 for LCsfu, 3.5+/-0.8 for ICsfu and 4.3+/-0.9 for the HCsfu group (P<0.05, low vs. intermediate-high). The mean (95% confidence interval) of time interval between the first and second episodes of rejections was 10.7 (5.6-16.0) days for LCsfu, 18.0 (8.6-29.0) days for the ICsfu, and 26.0 (15.1-36.9) days for the HCsfu group (P<0.01). The total number of rejections requiring treatment per patient in the first 3 months after transplant was higher in the LCsfu group compared with the others (4.0+/-1.7 episodes for LCsfu vs. 2.9+/-1.1 for ICsfu and 3.2+/-1.2 episodes for HCsfu; P<0.05). Four patients in the low group, one patient in the intermediate group, and no patients in the high group required treatment with total lymphoid irradiation (P<0.02). CONCLUSIONS: This finding suggests that patients with lower levels of cyclosporine fU are more prone to cardiac rejection and that the level of cyclosporine fraction unbound may be clinically important for determination of response to cyclosporine therapy.

A prospective randomized study of prophylactic OKT3 versus equine antithymocyte globulin after heart transplantation--increased morbidity with OKT3.

The aim of this study was to compare the efficacy and toxicity of prophylactic OKT3 and equine antithymocyte globulin when each drug was administered for a similar duration after heart transplantation. Forty-one patients (35 males, 6 females; mean age 46 +/- 2 years) were randomized to receive either OKT3 for 10 days (20 patients) commencing within 24-48 hr of transplantation or ATGAM for 8 days (21 patients) commencing on the day of transplantation. All patients were maintained on triple-agent immunosuppression with prednisolone, azathioprine, and cyclosporine. The two groups were well matched with respect to age, sex distribution, pretransplant cardiac diagnosis, and donor heart ischemic time. Mean duration of follow-up was 14 months (range 9-19 months): Actuarial survival at 12 months was 83 +/- 9 in the OKT3 group and 81 +/- 9 in the ATG group (P = NS). Mean time to first cardiac rejection was 33 +/- 8 days in the OKT3 group compared with 27 +/- 5 days in the ATG group (P = NS). Linearized rejection rate did not differ between the two groups at any time point up to 12 months posttransplant. Viral infections were significantly more common in the OKT3 group: 1.6 +/- 0.3 vs. 0.8 +/- 0.2 infections per patient (P < 0.05). Adverse reactions were more common in patients who received OKT3 prophylaxis and included three patients who developed acute respiratory distress, two of whom required assisted ventilation. In conclusion, prophylactic OKT3 and ATGAM result in comparable rejection rates and survival when administered for a similar duration after cardiac transplantation. OKT3, however, is associated with increased morbidity due to a higher incidence of adverse reactions and of viral infections. These findings suggest that ATGAM is the more suitable cytolytic agent for rejection prophylaxis after heart transplantation.

Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.

Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.

Urinary nitrate excretion is a noninvasive indicator of acute cardiac allograft rejection and nitric oxide production in the rat.

Cytokine induction of calcium-independent nitric oxide synthase is associated with production of large amounts of nitric oxide (NO). NO is a free radical that is rapidly degraded to nitrite and nitrate. Measurement of plasma and urinary nitrate is an indirect marker of NO production and previous studies have demonstrated that plasma nitrate rises with allograft rejection. The purpose of this study was to examine the temporal relationship between the rise in urinary nitrate excretion and the onset of graft rejection, and to determine the effect of conventional immunosuppression on nitrate excretion. The heterotropic model of cardiac transplantation in the rat was used, with Brown-Norway to Lewis allografts and Lewis to Lewis isograft controls. Twenty-four-hour urine specimens were collected before and after transplantation. Urinary nitrate excretion was measured by gas chromatography/mass spectrometry. Each group was treated with (1) no immunosuppression, (2) dexamethasone (3 mg/kg), or (3) CsA (10 mg/kg) on days 0, 1, and 2. Time to rejection for untreated allografts was 5.1 +/- 0.1 days, extending to 8.4 +/- 0.5 and 9.6 +/- 0.4 days with dexamethasone and CsA treatment, respectively. There was a significant rise in nitrate excretion on days 4, 7, and 9 for control, dexamethasone-treated, and CsA-treated allografts, respectively, preceding evidence of rejection. Untreated allograft rejection was associated with a peak in nitrate excretion 8 times that of basal excretion by isografts. Treatment of the allografts with dexamethasone and CsA significantly attenuated peak nitrate excretion compared with untreated allografts with a only a 2- to 3-fold rise preceding rejection. Results indicate that allograft rejection is associated with a dramatic increase in peak urinary nitrate excretion that is attenuated by standard immunosuppressive therapy. An increase in nitrate excretion precedes evidence of graft rejection, and may serve as a noninvasive marker of graft rejection.

Timing of cardiac transplantation in idiopathic dilated cardiomyopathy.

Seventy-nine patients with idiopathic dilated cardiomyopathy were assessed and followed up to evaluate 9 variables that might predict duration of survival after assessment for cardiac transplantation. Patients with ischemic heart disease, alcoholic and peripartum cardiomyopathy were excluded. There were 38 deaths (48%) during the 18-month (mean) follow-up. Patients underwent determination of left ventricular ejection fraction by radionuclide scan, echocardiography, cardiac catheterization and myocardial biopsy. Only left ventricular ejection fraction determined by radionuclide study correlated significantly with time to death in nonsurvivors (r = 0.38, p less than 0.05). Multivariant analysis and Cox multivariate regression analysis revealed that the single consistent determinant of prognosis was radionuclide-determined ejection fraction. It was an excellent predictor of survival to 3 months (p less than 0.0001) and a reasonable predictor of survival to 6 months (p less than 0.05). There was no variable that efficiently predicted survival for any period greater than 6 months. In 15 of 70 patients (21% of the entire group), clinical status and radionuclide ejection fraction improved after assessment but only one of these had an ejection fraction less than or equal to 0.10. No patient with a radionuclide ejection fraction greater than or equal to 0.20 died within 6 months of assessment. For those with ejection fraction between 0.11 and 0.19, survival after cardiac transplantation exceeded that of the natural history of their disease; this suggests that transplantation should be undertaken within 6 to 12 months of assessment. Left ventricular ejection fraction less than or equal to 0.10 predicts an extremely poor prognosis (6-month survival was 17%) and such patients should be transplanted with minimal delay.

Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation.

In an attempt to identify which parameters predict survival in advanced dilated cardiomyopathy, 232 patients presenting for assessment for cardiac transplantation were investigated and followed for 10 +/- 12 months (range 2 weeks to 5 years). Etiology of dilated cardiomyopathy included ischemic heart disease (33%), idiopathic (42%) and miscellaneous (25%). In each patient, 26 parameters were recorded. Whole group survival was 68% at 1 year, 56% at 2 years, 41% at 3 years and 25% at 4 years. On Cox multivariate regression analysis, 3 parameters predicted survival: New York Heart Association symptom class (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.008) and plasma atrial natriuretic factor level (p less than 0.002). On paired testing of actuarial survival curves, plasma noradrenaline also held predictive value (p less than 0.002), as did left ventricular ejection fraction less than or equal to 20% on radionuclide ventriculography (p = 0.007) and presence of greater than or equal to 4 beats of ventricular tachycardia on Holter monitoring (p = 0.007). Treatment with amiodarone did not appear to influence survival. Conventional determinants of prognosis in cardiomyopathy (symptom class, wedge pressure, nonsustained ventricular tachycardia and ejection fraction) do not alone always adequately differentiate survival in this group of high risk patients. More attention to plasma noradrenaline and to atrial natriuretic factor levels may give important additional information in the context of assessment of patients for transplantation.

Inhaled nitric oxide in cardiology.

Inhaled nitric oxide (INO) allows selective pulmonary vasodilatation with rapidity of action. It is effective in the acute management of reversible pulmonary hypertension in cardiac medical and surgical patients and is also useful in assessing the pulmonary vasodilator capacity in patients with chronic pulmonary hypertension. This review will examine the role of INO in the management of cardiac patients, compared to alternatives where available. The use of INO in cardiac failure, post-operative cardiac patients, patients with congestive cardiac failure or congenital heart disease will also be reviewed. Newer alternatives with prolonged pulmonary activity and simpler administration are also discussed.

Pharmacokinetics of cyclosporine in heart transplant recipients receiving metabolic inhibitors.

BACKGROUND: Inhibitors of cyclosporine metabolism are commonly co-administered with cyclosporine in transplant recipients. The aim of this study was to compare cyclosporine pharmacokinetics using the conventional formulation (Sandimmune) and after switching to the microemulsion (Neoral) formulation, in stable heart transplant recipients receiving various cyclosporine metabolic inhibitors. METHODS: Steady-state blood concentration-time profiles of Sandimmune were studied in 47 transplant recipients receiving either cyclosporine alone (Group A, n = 11) or in combination with diltiazem (120 mg/day, Group B, n = 11), ketoconazole (200 mg/day, Group C, n = 13), or both ketoconazole and diltiazem (200 and 120 mg/day, respectively, Group D, n = 12), and restudied 1 week after switching to Neoral. RESULTS: Neoral resulted in more rapid cyclosporine absorption as judged by the shorter absorption half-lives in all groups (p < 0.05). The mean percentage increase in the values of area-under-the-concentration-time curve was 42% and 37.5% higher for Neoral compared with Sandimmune for Groups A and B, respectively, but only 5.4% higher for Group C and 9.5% higher for Group D. The mean morning trough concentration of cyclosporine was not significantly different after administration of Neoral compared with Sandimmune in any of the groups studied (179 vs. 167 microg/liter for Group A; 171 vs. 147 microg/liter for Group B; 189 vs. 194 microg/liter for Group C; and 181 vs 201 microg/liter for Group D). Neoral did not alter serum concentrations of sodium, potassium, creatinine, and urea in any of the study groups. CONCLUSIONS: The faster absorption and improved bioavailability of cyclosporine (around 40%) with Neoral compared with Sandimmune was not seen in patients receiving ketoconazole, where in fact cyclosporine bioavailability was already maximal. Mean morning trough levels of cyclosporine did not reflect the improvement in bioavailability seen in patients switching from Sandimmune to Neoral. Cyclosporine dose adjustment may be needed when switching from Sandimmune to Neoral for patients not receiving sparing agents or who receive diltiazem, but trough levels cannot necessarily be relied upon to determine the degree of adjustment needed. For patientson ketoconazole, the absorption profile is already optimized and no dosage alteration seems necessary.

Increased rejection in gender-mismatched grafts: amelioration by triple therapy.

Increased rejection incidence in female heart transplant recipients receiving immunosuppressive therapy with cyclosporine and azathioprine has been reported and a possible role for gender-mismatched grafting (male donor into female recipient) has been suggested. To test the hypothesis that rejection is more frequent in female patients receiving male hearts, we analyzed the results of heart transplantation in gender-matched and -mismatched grafts in 313 recipients maintained with either double therapy with cyclosporine and prednisone (group 1, n = 104) or triple therapy with cyclosporine, azathioprine, and prednisone (group 2, n = 209). There were 21 female recipients in group 1 and 41 in group 2. The variables studied were 90-day total methylprednisolone sodium succinate requirements, 90-day linearized rejection rate, 90-day event-free actuarial rejection, 6-month actuarial infection-free survival, overall actuarial survival, and median day to first rejection. Statistical analyses included two-tailed t or Cox-Mantel testing as appropriate. In group 1, transplantation of a male heart into a female recipient (M/F grafting) was associated with a 40% higher 90-day cumulative steroid requirement (5008 +/- 3400 mg for M/F vs 3600 +/- 2977 mg for F/F), reflecting a higher rate of rejection in M/F recipients. Linearized rejection rates (90-day) were higher (1.6 +/- 0.4 vs 1.3 +/- 0.5 episodes per patient), and consequent 6-month event-free infection rates were lowest in these patients, although not significantly so. Actuarial survival did not differ significantly between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases.

An urgent and steadily increasing need exists world-wide for a greater supply of donor thoracic organs. Xenotransplantation offers the possibility of an unlimited supply of hearts and lungs that could be available electively when required. However, anti-body- mediated mechanisms cause the rejection of pig organs transplanted into non-human primates, and these mechanisms provide major immunologic barriers that have not yet been overcome. Having reviewed the literature on xenotransplantation, we present a number of conclusions on its present status with regard to thoracic organs, and we make a number of recommendations relating to eventual clinical trials. Although pig hearts have functioned in heterotopic sites in non-human primates for periods of several weeks, median survival of orthotopically transplanted hearts is currently ,1 month. No transplanted pig lung has functioned for even 24 hours. Current experimental results indicate that a clinical trial would be premature. A potential risk exists, hitherto undetermined, of transferring infectious organisms along with the donor pig organ to the recipient, and possibly to other members of the community. A clinical trial of xeno-transplantation should not be undertaken until experts in microbiology and the relevant regulatory authorities consider this risk to be minimal. A clinical trial should be considered when approximately 60% survival of life-supporting pig organs in non-human primates has been achieved for a minimum of 3 months, with at least 10 animals surviving for this minimum period. Furthermore, evidence should suggest that longer survival (.6 months) can be achieved. These results should be achieved in the absence of life-threatening complications caused by the immunosuppressive regimen used. The relationship between the presence of anti-HLA antibody and anti-pig antibody and their cross-reactivity, and the outcome of pig-organ xenotransplantation in recipients previously sensitized to HLA antigens require further investigation. We recommend that the patients who initially enter into a clinical trial of cardiac xenotransplantation be unacceptable for allotransplantation, or acceptable for allotransplantation but unlikely to survive until a human cadaveric organ becomes available, and in whom mechanical assist-device bridging is not possible. National bodies that have wide-reaching government-backed control over all aspects of the trials should regulate the initial clinical trial and all subsequent clinical xenotransplantation procedures for the foreseeable future. We recommend coordination and monitoring of these trials through an international body, such as the International Society for Heart and Lung Transplantation, and setting up a registry to record and widely disperse the results of these trials. Xenotransplantation has the potential to solve the problem of donor-organ supply, and therefore research in this field should be actively encouraged and supported.

A double-blind placebo-controlled trial of low-dose ganciclovir to prevent cytomegalovirus disease after heart transplantation.

BACKGROUND: The aim of this double-blind, placebo-controlled study was to determine whether a prolonged course of low-dose ganciclovir prevented the development of clinical cytomegalovirus disease after heart transplantation. METHODS: Fifty-six consecutive patients were stratified into two groups: cytomegalovirus-positive recipients (n = 40) and cytomegalovirus-negative recipients of organs from cytomegalovirus-positive donors (n = 16). All patients received equine antithymocyte globulin induction for 7 days and maintenance doses of cyclosporine, azathioprine, and prednisolone. Ganciclovir (5 mg/kg intravenously) or matching placebo was given with the premedication, three times weekly for the first 6 weeks after transplantation and for another 2 weeks for each treated rejection episode between 6 and 12 weeks. RESULTS: Ganciclovir prophylaxis reduced the actuarial incidence of cytomegalovirus disease from 71% to 11% in cytomegalovirus-mismatched patients (p < 0.01). Ganciclovir prophylaxis did not reduce the incidence of cytomegalovirus disease in cytomegalovirus-positive recipients (25% in both placebo and ganciclovir groups) but did delay its onset and reduce its morbidity. There were no adverse reactions during ganciclovir administration. Gastritis was the most common clinical manifestation of cytomegalovirus disease. Pneumonitis and myocarditis were seen only in placebo-treated cytomegalovirus-mismatched patients. All patients with clinical cytomegalovirus disease responded to ganciclovir, 10 mg/kg/day for 2 weeks. CONCLUSIONS: Prolonged low-dose ganciclovir prophylaxis after heart transplantation reduces the incidence of cytomegalovirus disease in cytomegalovirus-mismatched patients and reduces the morbidity of cytomegalovirus disease in cytomegalovirus-positive recipients.

Impact of proximal or midvessel discrete coronary artery stenoses on survival after heart transplantation.

To assess survival after the development of transplant coronary artery disease, annual angiography reports from 353 heart transplant recipients were reviewed. Fifty-four patients who survived beyond 1 year and in whom moderate-to-severe proximal or midvessel coronary artery disease developed were identified. Moderate-to-severe proximal or midvessel coronary disease was defined for this study as a 40% or more stenosis in 1 or more primary or secondary epicardial arteries. Actuarial survival (Kaplan-Meier) from the time of disease detection in those 54 patients was 67% at 1 year, 44% at 2 years, and 17% at 5 years. Actuarial survival was reduced proportionate to disease severity. Survival for single-vessel disease (> or = 40% stenosis) was 64% at 1 year, 36% at 2 years, and 22% at 5 years. Survival was significantly worse with triple-vessel disease (13% at 2 years; p = 0.01) and intermediate for double-vessel disease (41% at 2 years; p = 0.01). Of 19 patients who underwent retransplantation for coronary artery disease, 13 patients (68%) died at a mean of 24 +/- 20 months (range, 1 to 59), and of 15 patients from whom postmortem or angiographic data were available, 11 patients (73%) showed recurrence of significant coronary artery disease in the new graft. Identification of moderate or severe proximal or midvessel coronary disease at angiography predicts an overall mortality rate of more than 50% at 2 years. The poor survival rate in those who underwent retransplantation (around 50% at 4 years) and the high rate of redevelopment of coronary disease suggest that retransplantation should be reserved for selected candidates with angiographically severe disease, if used at all.

Bone loss after heart transplantation: a prospective study.

Osteoporotic fractures result in substantial morbidity after heart transplantation. To measure the acute effects of corticosteroids on bone after heart transplantation, we measured bone mineral density by dual energy x-ray absorptiometry and biochemical indexes of bone turnover in 25 patients (21 male, 4 female) at baseline, 6 months, and 12 months after transplantation. Two patients sustained vertebral fractures. Bone loss was rapid in the first 6 months, occurred in 24 of 25 (96%) patients, and was most marked from the lumbar spine (mean +/- SD, -7.4% +/- 4.5%). In the second 6 months little further bone loss was evident (lumbar spine, -7.8% total over 12 months) despite continuing moderate maintenance doses of corticosteroids. Serum osteocalcin and testosterone levels rose and urinary hydroxyproline:creatinine level ratio fell significantly by 6 months. Bone loss from the lumbar spine correlated inversely with serum osteocalcin level at 6 months. Serum osteocalcin level was the only significant predictor of lumbar spine bone loss by multiple regression analysis that included age, corticosteroid dose, cyclosporine dose, lean body mass, and body mass index. These data suggest that prophylactic therapy to prevent bone loss may only be necessary in the first 6 to 12 months after heart transplantation.