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Biomedical subjects

J Wallwork

Publications and source records attributed to J Wallwork.

At least 163 records · Page 9Linked to original sources
PubMed1992

The use of allopurinol in the inhibition of obliterative bronchiolitis of the transplanted lung.

Long-term survival following lung transplantation has been limited primarily by the development in patients' lungs of a rejection-related obliteration of terminal bronchioles by fibroblasts. It is known to result from frequent and persistent acute lung rejection and its physiological features include a progressive decline in the lung function measurement of forced expiratory volume in 1 s. We report the dramatic effect on this hitherto usually fatal condition of a specific inhibition of purine metabolism at the xanthine oxidase enzyme by the hypoxanthine analogue allopurinol. The effect of this drug in heart-lung transplant patients with deteriorating lung function in reducing the rate of rejection and in stabilizing lung function was apparent over as short a follow-up period as 3 months and in ten patients. Although the follow-up time is short, we believe the effects are so striking as to require reporting although the mechanisms of this phenomenon are not yet well understood.

Adult↗
PubMed1992

Evaluation of the International Society for Heart Transplantation (ISHT) grading of pulmonary rejection in 100 consecutive biopsies.

Heart-lung and lung transplantation are accepted treatments for patients with end-stage pulmonary vascular disease or parenchymal lung disease. Survival rates for heart-lung and lung transplantation are lower than those for heart transplantation alone. The 5-year actuarial survival for heart-lung transplantation has been 41% largely due to rejection and infection remaining as the limiting factors for long-term survival. A standardized nomenclature for the histological grading of pulmonary rejection was formulated by the International Society for Heart Transplantation (ISHT) in July 1990. Infection, however, is a major problem in the histological assessment of lung recipient biopsies, potentially limiting the usefulness of such a classification. In this study, 100 consecutive transbronchial biopsies (TBBs) from lung transplant recipients were analysed, together with microbiological and serological data, in order to evaluate the proposed ISHT grading system for pulmonary rejection and the importance of concomitant infections in the histological interpretation of TBBs.

Adolescent↗
PubMed1992

Coronary flow reserve and coronary occlusive disease.

The functional effects of coronary occlusive disease (COD) in cardiac transplant patients on small-resistance coronary vessels are unclear. We investigated the changes in coronary flow reserve (CFR) in response to the non-specific smooth muscle vasodilator papaverine. A 3F Doppler probe was inserted into the left anterior descending (LAD) coronary artery in 61 patients following orthotopic heart transplantation. Studies were performed in 57 males and 4 females with a mean age of 46 years (range 20-61 years). The median time from operation was 4 years (range 3 months to 10 years). Coronary blood velocity was measured at rest (RFV) and maximum hyperaemia (PFV) produced by intracoronary papaverine. Coronary flow reserve (CFR) was defined as the ratio of PFV to RFV. Minor lesions in epicardial vessels were found in 23 transplant patients. The mean percentage diameter of the most severe lesion in the coronary tree was 23% SD 3% including 12 lesions in the LAD coronary artery itself (mean 24% SD 4%). Patients with COD had an impaired CFR (2.6 SEM 0.2) compared with normals (3.9 SEM 0.2, P = 0.0003), adjusting for year after operation. Mean resting flow velocity was similar in both groups (minor COD, 6.8 cm/s SEM 1.2; normals, 7.1 cm/s SEM 0.6), but mean peak flow velocity response to papverine was reduced (16.5 cm/s SEM 2.5 versus 27.3 cm/s SEM 2.6; P = 0.007). In the presence of minor epicardial disease, coronary flow reserve in resistance vessels was reduced due to impairment of peak flow. This demonstrates that non-endothelial-dependent coronary resistance vessel vasodilatation is abnormal and may be caused by a defect in vascular smooth muscle function.

Blood Pressure↗
PubMed1992

Perfusion of rabbit hearts with human blood results in immediate graft thrombosis, a temporally distinct component of hyperacute rejection.

Hyperacute discordant xenograft rejection can be simulated by a blood-perfused working isolated heart. The survival of the heart is dependent on its functional integrity, and the preparation is thus sensitive to early myocardial damage. Perfusion of rabbit hearts with human blood produces immediate graft destruction by a thrombotic process which is a distinct component of hyperacute rejection.

Acute Disease↗
PubMed1992

Activation of the alternative pathway of complement is an important component of hyperacute rejection of rabbit hearts by human blood.

Hyperacute discordant xenograft rejection can be simulated by blood perfused working isolated heart. The survival of the heart is dependent on its functional integrity, and the preparation is thus sensitive to early myocardial damage. Perfusion of rabbit hearts with human blood results in immediate graft destruction by a thrombotic process. Prevention of this process results in rapid rejection at about 20 min by the alternative pathway of complement.

ABO Blood-Group System↗
PubMed1992

Inhibition of rejection of hamster-to-rat heart xenografts.

Prolonged survival of concordant organ xenografts as typified by hamster-to-rat heart transplants is difficult to produce. Studies have revealed that T cells are not primarily involved in rejecting such xenografts and that the rat recipients produce high titres of lytic anti-hamster antibodies. In this study, 200 hamster-to-rat cardiac xenografts performed in 30 different experiments revealed that cyclophosphamide (CyP) and cyclosporin A (CyA) could inhibit this antibody production. CyP alone was relatively ineffective in prolonging graft survival (the median survival time was 14 days versus 3 days in untreated controls). Combining CyP and CyA virtually abolished rejection in this model. Four critically timed doses of CyP combined with continuous CyA resulted in recipients not producing anti-hamster antibodies, despite cessation of CyP therapy, and prolonged graft survival time (median survival time was more than 100 days). Cessation of CyA at 60 and 100 days resulted in the rejection of the xenografts and the appearance of the rat anti-hamster antibodies. Xenografts in recipients given only one or two doses of CyP (and continuous CyA) had a median survival time of 7 and 12 days respectively. However xenograft rejection in rats given only 1 or 2 doses of CyP could be averted by complement depletion using a 3-week course of cobra venom factor (CoF) starting on day 4 or day 7 post-transplantation respectively. Discontinuation of CoF after 3 weeks did not result in graft rejection. These results showed that immunosuppressive therapies directed at inhibiting antibody production may be of value in preventing rejection of concordant xenografts. Short-term complement depletion could rescue xenografts from rejection such that rescued grafts appear to be accommodated.

Animals↗
PubMed1992

Perfusion of rabbit hearts with pig blood results in complement mediated hyperacute xenograft rejection.

Investigation of hyperacute rejection of discordant xenografts has been hampered by the lack of a model for the study of rapid time course events. In vivo models are unsuitable for observation of early rejection processes and, along with most ex-vivo perfusion preparations, are insensitive since no functional demand is placed on the organ which may have undergone extensive damage whilst still appearing viable. For this reason a blood perfused isolated working heart preparation has been developed. With left atrial and left ventricular loading the heart performs measurable work as it ejects into a mock circulation with both afterload and compliance components. When cardiac function is compromised the heart is no longer able to eject against the fixed afterload and both cardiac output and coronary circulation cease with resultant organ failure. The model is thus highly sensitive to minimal organ damage and has an easily identifiable endpoint. In the present study, we used this preparation to study the discordant species combination of rabbit hearts perfused with pig blood.

Animals↗
PubMed1992

Exercise increases the release of atrial natriuretic peptide in heart transplant recipients.

It is known that atrial natriuretic peptide (ANP) is synthesized, stored and released from the myocytes of mammalian heart, but the role of cardiac autonomic nerves in triggering the release of ANP has not been fully assessed. We have therefore measured plasma ANP concentrations in the right atrium and the main pulmonary artery, together with pulmonary haemodynamics in 10 heart transplant (HT) recipients who underwent graded submaximal bicycle exercise during right-heart catheterisation. Pulmonary arterial blood samples and haemodynamic measurements were obtained at rest, on peak of exercise, and after ten minutes of recovery. A radioreceptor of alpha-human ANP was used to measure ANP levels. Exercise significantly increased ANP levels in both the right atrium from 24 pM (resting values) to 48.5 pM, and the main pulmonary artery from 27.1 pM (resting values) to 58.4 pM. We conclude that HT recipients still retain the ability to increase ANP release in response to graded submaximal dynamic exercise, and that the mechanisms underlying ANP release depend on other factors than the integrity of cardiac innervation in man.

Adult↗
PubMed1992

Efficacy of pyrimethamine for the prevention of donor-acquired Toxoplasma gondii infection in heart and heart-lung transplant patients.

Seven (11%) of the first 65 patients who received heart transplants at Papworth Hospital were mismatched for Toxoplasma gondii. Of these, four (57%) experienced T. gondii infection and two died. The remaining two had severe symptoms and received anti-T-gondii chemotherapy for a year after transplantation. In an attempt to reduce the impact of donor-acquired T. gondii in our heart transplant recipients, we decided in April 1984 to give prophylactic pyrimethamine to all T. gondii-mismatched patients. In this study, 7 years later, we review the efficacy of this policy. Five of 37 (14%) patients given prophylactic pyrimethamine acquired T. gondii infection; only one was symptomatic, and none died. This compares with 100% symptomatic infection in the pre-1984 patients, who did not receive prophylactic pyrimethamine. We believe that our experience has shown that pyrimethamine is effective in reducing the incidence and severity of primary donor-acquired T. gondii infection in mismatched heart and heart-lung transplant recipients.

Adolescent↗
PubMed1992

Right atrial thrombus in constrictive pericarditis.

We describe right atrial thrombus complicated by tricuspid valve obstruction in a patient with constrictive pericarditis. This report highlights the role of surgical thrombectomy, and the investigation of constrictive pericarditis to exclude intra-cardiac thrombus.

Adult↗
PubMed1992

Late pulmonary haemodynamic changes in heart-lung transplantation.

As survival improves following heart-lung transplantation (HLT) the importance of obliterative bronchiolitis (OB) as a cause of late death increases. Whilst coronary occlusive disease (COD) may be less common in heart-lung transplant recipients than in patients receiving heart transplants, COD associated with OB can be lethal. We have studied 22 long-term survivors of heart-lung transplantation at an average of 25 months following transplantation during rest and at 50 W supine exercise and with prostacyclin induced vasodilation. Cardiac index increased less with exercise as the physiological measurement of OB using forced expiratory volume in one second (FEV1) fell (P = 0.018). Although resting pulmonary vascular resistance increased with falling FEV1, this increase was still within the normal range. We conclude that a fall in cardiac reserve on exercise accompanies the fall in FEV1 which characterizes OB and may reflect cardiac vascular disease.

Adult↗
PubMed1992

Cyclosporine in heart transplant recipients: an exercise study of vasopressor effects.

The possible vasopressor effect of cyclosporine (CS) on both the systemic and pulmonary vascular beds has been investigated during bicycle exercise in 12 heart transplant recipients (mean age, 41 years) using pulmonary artery catheter measurements. Eight patients were taking cyclosporine and six azathioprine and prednisolone (AzS) as immunosuppressive therapy. With exercise, CS recipients show a significantly larger rise in systemic pressure than AzS recipients (P less than 0.001), with persistently higher pulmonary pressures (P less than 0.001). This suggests a generalized vasopressor effect of CS on the vasculature.

Adult↗
PubMed1992

Blood cyclosporin concentrations but not doses correlate with acute changes in renal function following heart and heart-lung transplantation.

The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.

Creatinine↗
PubMed1992

Evidence that long-term survival of concordant xenografts is achieved by inhibition of antispecies antibody production.

Antibody and complement have been shown to be of primary importance in the rejection of hamster heart xenografts by rats. Very high anti-hamster antibody titers were detected at the time of rejection of hamster hearts transplanted into untreated or T cell deficient rats. This study demonstrates a method of inhibiting this antibody production by pulse therapy with cyclophosphamide (CyP) and continuous cyclosporine treatment, resulting in a median survival of the hamster heart of greater than 100 days. Controls and CsA-treated rats reject the transplanted hamster heart in a median of 3 days. CyP as a sole therapy resulted in a median survival of 14 days. Prolonged CyP therapy when combined with CsA was associated with increased death among rat recipients due to infection. Antispecies antibody production was suppressed during CyP and CsA therapy and did not recur after cessation of CyP therapy. Cessation of CsA therapy at 60 and 100 days posttransplantation resulted in subsequent rejection of the xenografts (median survival after cessation of therapy of 11 and 19.5 days, respectively) and was associated with production of rat anti-hamster antibodies.

Animals↗
PubMed1992

Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation.

1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Coronary occlusive disease and late graft failure after cardiac transplantation.

OBJECTIVE: Coronary occlusive disease is the main cause of late mortality after cardiac transplantation. It has both similarities and differences compared with conventional atherosclerotic coronary disease. The pathophysiology of late graft failure from coronary occlusive disease is unclear at present. We reviewed the experience of this disorder in our cardiac transplant programme. DESIGN: A retrospective analysis of angiographic and pathological data. SETTING: A regional cardiothoracic centre and transplant unit. PATIENTS: Of a population of 383 orthotopic cardiac transplant recipients operated upon between January 1979 and June 1990, 447 coronary angiograms were available for review in 193 patients. Thirteen of a possible 18 results of post mortem examinations from patients dying from coronary occlusive disease were available. MAIN OUTCOME MEASURE: Coronary occlusive disease was defined as any evidence of disease on coronary angiography. Post mortem examinations were performed with standard techniques. RESULTS: The angiographic prevalence of coronary occlusive disease was 3% (1/32 patients) and 40% (19/47 patients) at one and five years respectively. Twenty six grafts failed due to coronary occlusive disease compared with 132 graft failures from all causes during this period. Acute thrombosis was present in a large vessel in seven of 13 fatal cases undergoing necropsy (54%). Noticeable large vessel involvement with disease in smaller distal vessels was present in four patients (31%). The remaining two patients (15%) had small vessel disease alone. Twelve of the 13 patients had significant cardiomegaly (cardiac weight > or = 400 g) with a mean weight of 510 (range 370-740) g. CONCLUSION: Coronary occlusive disease is the main late complication after cardiac transplantation. A combination of coronary thrombosis, ischaemia from stenoses of large and small coronary vessels, and cardiomegaly contribute to the graft failure of these patients.

Adolescent↗
PubMed1992

Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease.

OBJECTIVE: Coronary occlusive disease is the major long-term complication after cardiac transplantation. The relation between minor angiographic abnormalities and myocardial perfusion has not been previously assessed in a large number of cardiac transplant patients. DESIGN: Prospective study. Coronary flow reserve was measured with an intracoronary Doppler flow probe in the proximal left anterior descending coronary artery in each patient. A dose of intracoronary papaverine producing maximal vasodilation was then administered. SETTING: A regional cardiothoracic centre and a supraregional transplant unit. PATIENTS: Seven patients with chest pain but normal coronary anatomy (controls), and 61 cardiac transplant patients between three months and 10 years after operation (median 4.5 years). Twenty one cardiac transplant patients had angiographic evidence of minor coronary occlusive disease (mean (SD) percentage stenosis diameter 23% (6%)) in a primary or secondary coronary vessel (group 1), with 12 of these in the left anterior descending coronary artery (stenosis diameter (mean (SD) 24% (8%)). The remaining 40 transplant patients had normal coronary angiograms (group 2). MAIN OUTCOME MEASURE: Coronary flow reserve was defined as the ratio of the peak flow velocity after papaverine to the resting flow velocity. RESULTS: Group 1 patients had a noticeably impaired coronary flow reserve (2.6 (1.1)) compared with control patients (3.9 (0.4), p = 0.05) and, after adjusting for year after operation, compared with group 2 patients (3.8 (1.0), p < 0.001). No other variables were associated with a reduction in coronary flow reserve. Mean resting flow velocity was similar in all three groups (controls, 7.4 (4.6) cm/s; group 1, 7.5 (5.9) cm/s; and group 2, 7.3 (3.9) cm/s). Mean peak flow velocity response to papaverine was reduced in group 1 patients (18.1 (13.5) cm/s) relative to group 2 patients (27.5 (15.4) cm/s, p = 0.05) but not controls (28.4 (15.1) cm/s, p = 0.1). CONCLUSIONS: Coronary flow reserve and the peak flow response to the coronary vascular smooth muscle relaxant papaverine are impaired in cardiac transplant patients with minor coronary occlusive disease. This disturbance of cardiac microvascular function may contribute to the late morbidity and mortality seen in cardiac transplant patients with coronary occlusive disease.

Blood Flow Velocity↗