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.

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.

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.

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.

Patient and professional partnership in diabetic nephropathy.

Diabetes mellitus (DM) is a complex multifaceted metabolic disorder characterised by chronic disease processes of hyperglycaemia and changes in the metabolism of carbohydrates, fats and proteins. It holds no boundaries with age, gender, culture or social strata. It is a life long disease process, which belongs to the individual, impacting on physical, social, psychosocial and spiritual life experiences. Diabetes is a worldwide burden to healthcare providers. In the United Kingdom (UK) 1.4 million people are affected with a suspected million people undiagnosed. A significant subgroup of patients with DM are predisposed to developing diabetic nephropathy, and it is now the single commonest cause of end-stage renal failure, accounting for 16% of new patients taken on to renal replacement therapy each year. It is in this subgroup that other diabetes related complications such as retinopathy, neuropathy and peripheral vascular disease are also concentrated. Microalbuminuria is an early indicator of renal disease in diabetes, and also predictive of total mortality, cardiovascular mortality and cardiovascular morbidity. These associated macro and microvascular complications can result in high personal, social and financial costs of managing complications associated with diabetic nephropathy and end-stage renal disease (ESRD). Some ethnic groups are particularly vulnerable--in the UK, the incidence of ESRD in South Asians and African Caribbean's is three times higher than in White Caucasians, in part due to the high prevalence of diabetic nephropathy.

Relation between heart rate, heart rhythm, and reverse left ventricular remodelling in response to carvedilol in patients with chronic heart failure: a single centre, observational study.

OBJECTIVE: To determine whether the process of reverse left ventricular remodelling in response to carvedilol is dependent on baseline heart rate (BHR), heart rhythm, or heart rate reduction (HRR) in response to carvedilol. DESIGN: Retrospective analysis of serial echocardiograms in 257 patients with chronic systolic heart failure at baseline and at 12-18 months after starting carvedilol. Reverse left ventricular remodelling was determined by changes in left ventricular end diastolic dimension (LVEDD), end systolic dimension (LVESD), and fractional shortening (LVFS). SETTING: Heart failure clinic within a university teaching hospital. MAIN OUTCOME MEASURES: Changes in LVEDD, LVESD, and LVFS. RESULTS: LVEDD and LVESD decreased by 2.6 (0.4) mm and 4.9 (0.5) mm, respectively (mean (SEM)), and LVFS increased by 4.3 (0.5)% (all p < 0.0001 v baseline). Simple regression revealed no significant relation between BHR or HRR and the changes in LVEDD, LVESD, or LVFS. Stratification of patients into high and low BHR groups (above and below the mean) or according to the baseline heart rhythm (sinus rhythm v atrial fibrillation) showed no differences between groups in the extent of reverse left ventricular remodelling. Improvements in left ventricular function and dimensions were associated with significant improvements in New York Heart Association functional class. CONCLUSIONS: The benefits of carvedilol in terms of reverse left ventricular remodelling and symptomatic improvement in patients with chronic heart failure are independent of BHR, heart rhythm, and the HRR that occurs in response to carvedilol.

A randomized trial of tacrolimus (FK506) versus total lymphoid irradiation for the control of repetitive rejection after cardiac transplantation.

Recurrent cardiac rejection is a major cause of morbidity during the initial 6 months following transplantation. We compared treatment with tacrolimus versus total lymphoid irradiation in 13 heart transplant recipients on a cyclosporine, azathioprine, and prednisolone regimen, who experienced repetitive rejection. The mean number of episodes of rejection significantly decreased in both groups, with no deaths and no increase in the incidence of infection, hypertension, diabetes, or renal impairment following either treatment at 12-month follow-up. Conversion to tacrolimus or a course of lymphoid irradiation are equipotent strategies, of comparable cost, for the prevention of further rejection in patients with recurrent rejection.

Optimization of left ventricular function with carvedilol before high-risk cardiac surgery.

Patients with severe left ventricular dysfunction and symptomatic heart failure caused by ischemic or valvular heart disease face a high morbidity and mortality risk from cardiac surgery. We present data showing that excellent surgical outcome can be achieved after pre-treatment of such patients with carvedilol.

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.

The potential role of xenotransplantation in treating endstage cardiac disease: a summary of the report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation.

There is an increasing shortage of human donor hearts for transplantation. One potential solution is using hearts from a suitable animal source, such as the pig. A committee of the International Society for Heart and Lung Transplantation has reviewed the current status of research into xenotransplantation. Furthermore, the committee considered what results in the pig-to-nonhuman primate experimental model would justify a clinical trial of xenotransplantation, and the criteria for selecting patients to be entered in the trial. This review emphasizes initial patient selection issues, although the committee's overall conclusions and recommendations are summarized. Although the current experimental results do not presently justify initiating a clinical trial, the committee concluded that xenotransplantation theoretically has immense potential, and that research in this field should be encouraged and supported. Human cadaveric organ donation will still be of the highest priority for the foreseeable future.

Peritoneal dialysis fill volume: can the patient tell the difference?

OBJECTIVE: Patients on continuous ambulatory peritoneal dialysis (CAPD) must receive an increased dialysis dose as they lose residual renal function so that total clearances are optimized. The dialysis dose may be increased by increasing the exchange volume. Patients on CAPD are often reluctant to use a greater exchange volume, fearing increased pain and discomfort and an altered body image. To assess patient perception of various fill volumes, we studied 12 stable patients currently treated with 2-L exchanges who had no surgical contraindication to larger fill volumes. METHOD: After an overnight dwell, patients received a 2-L, 2.5-L, or 3-L exchange of Baxter PD4 (Baxter Healthcare SA, Castlebar, Ireland) for 3 hours in a randomized crossover design. Patients and staff were both blinded to the fill volume. At the beginning and end of the exchange, intraperitoneal hydrostatic pressure (IPP) in the supine position was measured, and the patient's perception of the exchange was evaluated using the validated McGill Pain Questionnaire (MPG). RESULTS: Initial IPP increased with increasing fill volume (12.5 +/- 3.7 cmH2O vs 16.1 +/- 4.2 cmH2O vs 18.7 +/- 3.6 cmH2O for 2, 2.5 L, and 3L, respectively). For all fill volumes, IPP had fallen by the end of the 3-hour dwell, at which time it was similar to that after an overnight 2-L exchange. The pain rating index by was generally low for all exchange volumes and did not correlate with IPP. Minor degrees of discomfort were reported by 4, 2, and 1 patients with 3-L, 2.5-L, and 2-L exchanges respectively. CONCLUSION: Our study suggests that, despite an increased IPP, larger exchange volumes are generally well tolerated by patients, with only a minority of patients feeling mild discomfort.

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.

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.

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.

Interleukin-2-producing helper T lymphocyte precursor frequency and rejection: a longitudinal cellular study after cardiac transplantation.

Interleukin-2-producing helper T lymphocyte precursors (HTLp) in the recipient recognize donor alloantigen expressed by the transplanted organ. The frequency of these reactive cells in the peripheral blood was determined and correlated with rejection episodes. Endomyocardial biopsy is generally used to quantify cardiac allograft rejection and guide immunotherapy. While non-invasive techniques have been investigated, none of these has demonstrated sufficient sensitivity or specificity to replace myocardial biopsy. Twelve cardiac transplant recipients were assessed over a 1 year period using limiting dilution analysis, to determine the frequency of HTLp in response to cadaver donor splenocytes. The IL-2-dependent mouse cell line CTLL-2 was used to measure the IL-2 present and the precursor frequency was calculated using maximum likelihood estimation. In the months immediately post transplantation, six of the 12 recipients displayed an association with increases in HTLp frequency, which preceded histologically detectable rejection. The second six recipients had fewer rejection episodes and achieved 'acceptance' of their graft sooner. Once 'acceptance' was achieved, the association between IL-2 HTLp frequency and rejection was no longer apparent. The ability to identify two groups of patients on the basis of IL-2 HTLp frequency clearly highlights the heterogenous nature of the response to the graft and this emphasizes the need to monitor other cytokines, which may influence the functioning of effector T cells.

Impact of concurrent amiodarone treatment on the tolerability and efficacy of carvedilol in patients with chronic heart failure.

OBJECTIVE: To assess the safety and efficacy of carvedilol when administered to heart failure patients already receiving amiodarone. DESIGN: Retrospective analysis of the clinical outcome of 230 patients treated with carvedilol for chronic heart failure, stratified according to whether they were already receiving amiodarone (amiodarone group, 80 patients) or not (non-amiodarone group, 130 patients) at baseline. SETTING: Heart failure clinic at a university affiliated public teaching hospital. MAIN OUTCOME MEASURES: Incidence of adverse events; changes in functional status and echocardiographic dimensions at three months. RESULTS: Adverse reactions to carvedilol occurred in 33 (41%) of the amiodarone group and 43 (29%) of the non-amiodarone group (p = 0.049). Carvedilol was discontinued in 21 (26%) of the amiodarone group and 37 (25%) of the non-amiodarone group (NS). The clinical outcome at three months did not differ significantly between the two groups; 31 (39%) of the amiodarone group improved their New York Heart Association status, 28 (35%) were unchanged, and 21 (26%) deteriorated compared with 67 (45%), 51 (34%), and 32 (21%), respectively, for the non-amiodarone group (NS). Both groups had highly significant decreases in heart rate and left ventricular end systolic dimension, and a significant increase in left ventricular ejection fraction after three months of carvedilol treatment, with no significant differences between the groups. CONCLUSIONS: The beneficial effects of carvedilol on left ventricular remodelling, systolic function, and symptomatic status are not affected by concurrent treatment with amiodarone. Adverse reactions necessitating cessation of carvedilol are no more frequent in patients receiving amiodarone.

Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience.

BACKGROUND: The development of malignancies in recipients of a cardiothoracic transplant (CTT)--that is, heart, lung, or heart and lung recipients-is of concern. Cutaneous and lymphoproliferative malignancies comprise the two major groups of malignancies encountered. A small subgroup of patients will develop potentially life-threatening aggressive cutaneous malignancies (ACM); these are poorly defined and documented in the literature. The authors report the results for 619 CTT recipients from a single institution. METHODS: Between 1984 and 1995, 619 recipients received a CTT. With a minimum follow-up of 2 years, 66 patients (10.7%) were diagnosed with a major malignancy, and 27 of these 66 patients developed ACM. ACM were defined as having one or more of the following characteristics: local invasion and/or regional metastases at diagnosis, poor differentiation, and locoregional and/or systemic relapse following therapy. All malignant melanomas were considered ACM. Data on malignancy occurrence were documented in the clinical notes of the heart and lung transplant unit. A retrospective analysis was undertaken from these notes. RESULTS: Tumor histology was predominantly poorly differentiated squamous cell carcinoma (55%) (SCC) and malignant melanoma (30%) (MM). No patient developed Kaposi sarcoma (KS). The median time from transplant to diagnosis of ACM was 52 months (range, 8-127 months). Thirteen of 27 patients have died; 10 of them died of metastatic disease. The mean time to death was 20 months (range, 8-54 months). Of 14 patients alive, 5 have disease. All but one of the 19 patients diagnosed with nonmelanoma ACM received radiotherapy, either as part of initial treatment or on relapse. Eight patients have subsequently suffered an infield relapse. CONCLUSIONS: The development of ACM in CTT recipients resulted in substantial morbidity and mortality. Poor results were obtained with standard surgery and radiotherapy. Treatment modalities for and the underlying pathobiology of ACM in organ transplant recipients require detailed research if improved outcomes are to be achieved.