N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure.

AIMS: The selection of patients for cardiac transplantation (CTx) is notoriously difficult and traditionally involves clinical assessment and an assimilation of markers of the severity of CHF such as the left ventricular ejection fraction (LVEF), maximum oxygen uptake (peak VO2) and more recently, composite scoring systems e.g. the heart failure survival score (HFSS). Brain natriuretic peptide (BNP) is well established as an independent predictor of prognosis in mild to moderate chronic heart failure (CHF). However, the prognostic ability of NT-proBNP in advanced heart failure is unknown and no studies have compared NT-proBNP to standard clinical markers used in the selection of patients for transplantation. The purpose of this study was to examine the prognostic ability of NT-proBNP in advanced heart failure and compare it to that of the LVEF, peak VO2 and the HFSS. METHODS AND RESULTS: We prospectively studied 142 consecutive patients with advanced CHF referred for consideration of CTx. Plasma for NT-proBNP analysis was sampled and patients followed up for a median of 374 days. The primary endpoint of all-cause mortality was reached in 20 (14.1%) patients and the combined secondary endpoint of all-cause mortality or urgent CTx was reached in 24 (16.9%) patients. An NT-proBNP concentration above the median was the only independent predictor of all cause mortality (chi2=6.03, P=0.01) and the combined endpoint of all cause mortality or urgent CTx (chi2 =12.68, P=0.0004). LVEF, VO2 and HFSS were not independently predictive of mortality or need for urgent cardiac transplantation in this study. CONCLUSION: A single measurement of NT-proBNP in patients with advanced CHF, can help to identify patients at highest risk of death, and is a better prognostic marker than the LVEF, VO2 or HFSS.

Intrathoracic organ transplantation in the United Kingdom 1995-99: results from the UK cardiothoracic transplant audit.

OBJECTIVE: To describe the current practice and outcomes of intrathoracic transplantation in the United Kingdom. DESIGN: Prospective observational cohort study. SETTING: Multicentre study involving all nine UK intrathoracic transplant units. PATIENTS: 2588 patients added to the national waiting list between April 1995 and March 1999 and 1737 patients who underwent heart, lung, or heart-lung transplantation in the same period. MAIN OUTCOME MEASURES: Waiting list mortality and post-transplant graft survival. RESULTS: There was a slight fall in transplant activity over the four years. Within six months of listing, 52.5% of patients on the heart transplant list had been transplanted and 11.0% had died, compared with 31.3% and 15.2% for lung, and 23.4% and 20.4% for heart-lung. The median time to transplant in days (95% confidence interval) was 133 (115 to 149) for heart, 386 (328 to 496) for lung, and 471 (377 to 577) for heart-lung. After three years, the waiting list mortality was 16.9% (6.1% to 46.8%) for heart, 33.1% (9.0% to 100%) for lung, and 36.5% (10.5% to 100%) for heart-lung. The three year graft survival after transplantation was 74.2% (71.2% to 77.0%) for heart, 53.8% (48.2% to 59.2%) for lung, and 57.2% (49.0% to 64.6%) for heart-lung. CONCLUSIONS: This validated database defines the current state of thoracic transplantation in the United Kingdom and is a useful source of data for workers involved in the field. Thoracic transplantation is still limited by donor scarcity and high mortality. Overoptimistic reports may reflect publication bias and are not supported by data from this national cohort.

Low clinical utility of routine angiographic surveillance in the detection and management of cardiac allograft vasculopathy in transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV), a form of accelerated atherosclerosis, is the major cause of late death in heart transplant recipients. Routine annual coronary angiography has been used as the standard surveillance technique for CAV in most transplant centers. HYPOTHESIS: The aim of this study was to investigate the clinical utility of routine angiographic surveillance in the detection and management of CAV in transplant recipients. METHODS: We reviewed the case notes and angiograms of 230 patients who underwent cardiac transplantation in our unit between January 1986 and January 1996 and survived beyond the first year post transplantation. RESULTS: Significant complications secondary to angiography arose in 19 patients (8.2%). Cardiac allograft vasculopathy was present on none of angiograms performed 3 weeks post transplantation, but was identified in 9 patients (4%) at the first annual angiogram and an additional 25 patients by the fifth annual angiogram. A target lesion suitable for angioplasty was only identified in two patients, and only limited procedural success was achieved in both cases. Twenty-five patients (11%) died during the study period, and the most common cause of late death was graft failure which occurred in 10 patients. All patients who died from graft failure had significant CAV at autopsy, but the most recent coronary angiogram had been normal in eight of these patients. CONCLUSIONS: These data clearly illustrate the limited clinical utility of routine angiographic surveillance for CAV in heart transplant recipients and prompted us to abandon this method of surveillance in our unit.

Assessment of quality of life in lung transplantation using a simple generic tool.

BACKGROUND: The EuroQol is a generic questionnaire developed to provide a simple method for assigning utility values to health. This study examines the applicability of the EuroQol to the measurement of quality of life in single, bilateral, and heart-lung transplantation. METHODS: A cross sectional study was performed in 87 patients awaiting lung transplantation and in 255 transplant recipients attending follow up clinics in four transplant units. RESULTS: In the waiting list group 61% reported extreme problems in at least one of the five EuroQol quality of life domains compared with 20% single lung recipients, 4% bilateral lung recipients, and 2% heart-lung recipients at 3 or more years after transplantation. The mean utility value of patients on the waiting list was 0.31. In comparison, utility values for recipients 3 years after transplantation were 0.61 for single, 0.82 for bilateral, and 0.87 for heart-lung transplants. The utility scores and health profiles of bilateral and heart-lung recipients were consistently superior to those of single lung recipients. Problems in all five domains were more frequent in single lung recipients. Subjective assessment with a visual analogue scale showed a similar trend. CONCLUSIONS: The EuroQol is a simple method of deriving a single utility value for quality of life and is responsive to changes after lung transplantation. It is worth considering as a means of monitoring quality of life after transplantation and as an index of quality of survival in research studies in solid organ transplantation. These data suggest that quality of life after transplantation of one lung is inferior to that after transplantation of two lungs.

Does splitting the lung block into two single lung grafts equate to doubling the societal benefit from bilateral lung donors? Comparisons between two single versus one bilateral lung transplant. UK Cardiothoracic Transplant Audit Steering Group.

Multi-organ thoracic transplantation, although beneficial to one recipient, has an opportunity cost of denied transplants to others. This paper compares population based outcomes of splitting lung blocks for two single lung transplants compared to doing one bilateral lung transplant, and suggests that the benefit of splitting lung blocks may not necessarily be double that of using each block for one recipient.

Human cytomegalovirus genome sequences in lymph nodes.

Human cytomegalovirus (CMV) is a major cause of morbidity in heart and lung transplant patients, resulting from immunosuppression-mediated reactivation of latent CMV originating either from the transplanted tissue, or the recipient. We showed that out of eight donor/recipient pairs, the lymph nodes (LNs) of three donors and four recipients, all CMV seropositive, harboured CMV DNA at exceeding levels compared with those of matched blood samples, as well as CMV RNA otherwise undetectable in patients' blood. On follow-up, patients positive for CMV DNA and RNA in LNs developed viraemia 4 to 5 weeks earlier than those initially polymerase chain reaction-negative for CMV. Our results indicate that LN are a significant site for sequestration and persistence of CMV and that LN may be important in seeding of CMV-infected cells into the circulation.

A simple approach to risk stratification in adult heart transplantation.

OBJECTIVE: While there are numerous reports in the literature of risk factors for graft failure after heart transplantation, simple models for risk stratification are lacking. This study describes a simple method for risk stratification in adult heart transplantation that can be applied when the size of a dataset is insufficient for formal regression modelling. METHODS: Multi-centre prospective cohort study. Fourteen risk factors documented in the literature as increasing post transplant graft failure were used to formulate a model. Risk factors included in the model were recipient age >50 years, pre-operative ventilatory support, pre-operative circulatory support, >1 previous sternotomy, pulmonary vascular resistance >2.5 wood units, male with body surface area >2.5 m2, retransplant, ischaemic time >3.5 h, donor age >45 years, donor inotropic support >10 microg/kg per min dopamine, female donor, ratio donor/recipient body surface area <0.7, donor with diabetes and history of donor drug abuse. Four risk groups were defined depending on the number of risk factors present: Low, none; moderate, 1; high, 2 or 3; very high, 4 or more. Graft survival to 30 days was chosen as the primary outcome. The model was tested on 373 adult transplants performed in the UK between April 1995 and December 1996. RESULTS: Twenty eight transplants were low risk, 82 moderate, 201 high and 62 very high. The 30-day survival (70% CI) for the risk groups was low, 97% (93-100), moderate 95% (92-98), high 87% (84-89) and very high 80% (75-83) (P = 0.02). CONCLUSIONS: This preliminary model enables some stratification of heart transplant procedures according to donor and recipient risk profile. Further work will be directed at refining and validating the model.

Variations in cardiac transplantation: comparisons between the United Kingdom and the United States.

BACKGROUND: International practice variations have been documented in various health care specialties. This study compares cardiac transplantation in the UK with practice in the US. METHODS: UK data were from an ongoing multi-center prospective study, the UK Cardiothoracic Transplant Audit. The UK population comprised 620 listings and 463 transplants. US data were obtained from UNOS and comprised 3946 listings and 4704 transplants. RESULTS: There was a mean of 14 transplants per center per year in the US compared with 34 in the UK. Notable differences in practice include rarity of listing in the UK of patients > 65 years (0.2% vs 4.1% in US) and patients with previous transplants (UK 0.9%, US 3.2%). Patients listed in the US were more likely to be on ventricular assist devices (odds ratio 8.0, 95% CI 3.0-21.7) or inotropes (odds ratio 4.9, 95% CI 3.7-6.4). Living donor (domino) transplants, although comprising 7% of transplants in the UK, are virtually non-existent in the US (1 domino in 4704 transplants). Heterotopic transplants were more common in the UK (4.4% vs 0.5%). Indications for transplant were similar (except retransplantation). The donor age was > 35 years in 43% of UK donors vs 33% of US donors. CONCLUSION: This study reveals substantial practice differences between the UK and US. Further studies are required to examine the reasons for these practice differences, the influence on transplant outcome, and their ethical and economic implications.

Regional variations in endothelin-1 and its receptor subtypes in human coronary vasculature: pathophysiological implications in coronary disease.

Endothelin-1 is a potent vasoconstrictor peptide and mitogen for vascular smooth muscle cells. Increased plasma or tissue levels of endothelin-1 have been described after myocardial infarction and in atherosclerosis, suggesting that this peptide may play a pathophysiological role in various coronary syndromes. Here, we have studied regional variations in ET-1 and its receptors in control and atherosclerotic human coronary vasculature using standard immunohistochemistry and in vitro autoradiography. ET-1 immunoreactivity was associated with luminal endothelial cells and smooth muscle cells at regions of atherosclerosis. ET(A) receptors were present on smooth muscle cells of coronary arteries and on cardiac myocytes. Medial ET(B) receptor binding at the proximal region of coronary arteries was weak, but increased significantly towards distal regions of this vessel (p<0.005 in control and p<0.0005 in ischaemic heart disease). Microvascular endothelial cells in the adventitia of coronary arteries, myocardial microvessels and the endocardial endothelium expressed the ET(B) receptor exclusively. The receptor variations revealed in this study provide supporting evidence that ET-1 is associated with (1) vascular smooth muscle and endothelial cell proliferation, including areas of intimal hyperplasia and regions of neovascularization (2) increased ET-1-induced reactivity of distal portions of the human coronary artery, (3) ET-1-mediated constriction of myocardial microvessels. These results provide new insights into different potential roles for this peptide in healthy and diseased human coronary vasculature.

Cold blood cardioplegia or intermittent cross-clamping in coronary artery bypass grafting?

BACKGROUND: We determined that cold blood cardioplegia and intermittent ventricular fibrillation with ischemia were associated with similar enzyme and myocardial protein leakage in a randomized, prospective study of 40 patients. We have continued to use both methods in our unit, according to surgeons' preference. METHODS: In our database we have reviewed 1,923 patients who have undergone first-time elective or urgent coronary artery bypass grafting from January 1992 to May 1997. RESULTS: Five hundred seventy-eight patients underwent coronary artery bypass grafting with cold blood cardioplegia and 1,345 had ventricular fibrillation and aortic cross-clamping. The preoperative factors were virtually identical. Intraoperative differences were only those inherent to the two techniques: temperature and cross-clamp time. Mortality was 2.5% for ventricular fibrillation and aortic cross-clamping arrest and 2.1% for cardioplegia (p=0.55 by chi2 test). There was a higher use of the intraaortic balloon pump in the ventricular fibrillation and aortic cross-clamping group (2.4% versus 1.0%; p=0.04), but no other differences in outcome were detected. CONCLUSIONS: A truly randomized trial to demonstrate which technique is superior is impractical at this level of difference because it would require 37,000 patients to avoid a beta error. We have to base our practice on the retrospective data available. Each technique has its merits in practice, which are discussed.

Human cytomegalovirus and acute rejection after heart transplantation are not directly associated.

Retrospective and prospective analyses of heart transplant recipients showed no significant association between acute rejection and the detection of cytomegalovirus (CMV) infection by culture or the polymerase chain reaction (PCR) for viral DNA, neither on grounds of the incidence of both conditions nor in relation to which was diagnosed first in the patient. Semiquantitative PCR of serial blood and endomyocardial biopsy specimens from individual patients revealed different patterns in the development of the viral DNA in the blood and the heart, also clear episodes of CMV infection in CMV antibody-negative recipients of hearts from CMV antibody-negative donors, none of whom went on to develop a CMV-specific antibody response. None of these findings was associated with the development of rejection in the patient. On the other hand, in those patients who did experience rejection, peak levels of CMV DNA in the blood and the heart were usually not reached until 6 weeks or more after transplantation, whereas in those in whom rejection was not detected at all during the period of observation, peak levels of CMV DNA were detected earlier, mainly within the first 6 weeks after transplantation. In several cases, the delayed increase in CMV DNA in those with rejection, albeit not the delay itself, was linked to treatment with steroids. These findings support the view that CMV infection and rejection are independent events, but that the timing of the infection, and whether or not rejection is detected, are indicative of the general status of the immune response in individual patients.