Combined heart-liver transplantation with extended cardiopulmonary bypass.

We report a case of combined heart and liver transplantation for familial amyloid polyneuropathy. This is the first such combined transplant performed in Asia, and differs from previously described cases, in that cardiopulmonary bypass was continued at partial flow during liver transplantation in our case. This was done in order to provide haemodynamic support to the cardiac graft and to protect it from the impending reperfusion insult that frequently accompanies liver transplantation. The utility of this management course is discussed, along with its actual and potential complications. We also describe the impact of a lung-protective ventilation strategy employed during cardiac transplantation.

Experience with cyclosporine in heart transplantation.

The introduction of cyclosporine as an immunosuppressant in early 1980s dramatically improved the outcome of organ transplantation. The adverse effects of nephrotoxicity and increased incidence of lymphomas were recognized with high doses of cyclosporine during the early part of that decade. This led to lower doses of cyclosporine and combination with prednisolone and azathioprine as the basis of immunosuppression in transplantation. During the second half of the 1990s, the microemulsion formulation of cyclosporine was introduced that gave superior and predictable drug absorption profiles. Therapeutic drug monitoring is considered as a tool to optimize transplantation results and minimize side effects. The nephrotoxicity associated with long-term cyclosporine therapy is recognized; we are learning to take measures to minimize it. As we enter the third decade of cyclosporine use, cyclosporine-based immunosuppressive protocols remain the most popular method in heart transplantation. Newer agents in combination with cyclosporine as the core immunosuppressant are being explored.

Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic-genotypic correlates.

AIMS: To investigate the frequency of the single nucleotide polymorphism C3435T in exon 26 of the MDR1 gene in Asians and to determine the functional significance of this SNP with the clinical pharmacokinetics of oral cyclosporin (Neoral) in 10 stable heart transplant patients. METHODS: The MDR1 C3435T polymorphism was investigated in 290 healthy Asian subjects (98 Chinese, 99 Malays and 93 Indians). We also compared the MDR1 polymorphism between the Asian population studied here and the published data on Africans and Caucasians. The clinical relevance of this SNP on oral bioavailability of a known P-gp substrate, cyclosporin, was assessed in 10 stable Chinese heart transplant patients. RESULTS: The homozygous TT genotype was observed in 32%, 28% and 43% of Chinese, Malays and Indians. The homozygous CC genotype was found in 25% of Chinese and Malays compared with 18% of Indians. The Indians had a lower frequency of the C allele [0.38 (0.31-0.45)] compared with the Chinese [0.46 (0.39-0.53)] and Malays [0.48 (0.42-0.55)]. Chi-squared test showed that the distribution of allele frequencies between the Malays and Indians differed significantly (P = 0.04). In this Asian population, the overall distribution of genotypes (CC, CT and TT) and allele frequencies were significantly different from those in Africans (P < 0.001). The results were also significant when the Chinese, Malays and Indians were compared separately with the African group (P < 0.001). Compared with the Caucasian data, the overall distribution of genotype and allele frequencies in the Asian population were also significantly different (P < or = 0.05). However, when each Asian ethnic group was compared separately with the Caucasians, only the Indians were found to be significantly different (P < or = 0.004). Genotypic-phenotypic correlations of this SNP were assessed in 10 stable Chinese heart transplant patients. The median AUC(0,4 h) was 11% lower in patients with CC genotype compared with subjects with TT genotype. However, the interpatient variability in AUC(0,4 h) was high in patients, especially in those with CC genotype. CONCLUSIONS: The distribution of the SNP C3435T in exon 26 in the Chinese and Malay population was found to be similar to the Caucasians whereas the Indians were different. The Asian population also differed significantly from the African and Caucasian population in the distribution of the C3435T SNP. The low frequency of the T allele in the Indian population implies lower expression of P-gp and may have important therapeutic and prognostic implications for use of P-gp dependent drugs in individuals of Indian origin.

A limited sampling strategy for the estimation of 12-hour Neoral systemic drug exposure in heart transplant recipients.

BACKGROUND: Therapeutic drug monitoring of cyclosporine in heart transplant patients is used to monitor therapy and prevent rejection. Of the various methods available for performing therapeutic drug monitoring of cyclosporine, the method of limited sampling strategy for area under the concentration-time curve profiling has been used most widely recently. The process of identifying sparse data points to predict area under the concentration-time curve is essentially a variable selection problem, with the variables being the drug concentrations at the various timepoints. Although fitting more variables into a model will typically allow for a better prediction of area under the concentration-time curve, improving the prediction has to be traded-off against the desirability of using as few timepoints as possible. The objective of this study was thus to formulate a model that would provide a good prediction of area under the concentration-time curve based on a limited number of sampling points. METHODS: We studied 15 stable heart transplant patients (11 Chinese and 4 Indians). All patients were receiving Neoral-based immunosuppression. Whole blood samples for area under the concentration-time curve analysis were obtained at the following timepoints: pre-dose (C(0h)) and at 1, 2, 3, 4, 6 and 12 hours (C(1h), C(2h), C(3h), C(4h), C(6h), C(12h), respectively) post-dose during the first dosing interval. The linear trapezoidal rule was used to calculate the area under the concentration-time curve (AUC) from time 0 h to 12 h. Various limited sampling strategies, as well as Keown's formula, which was derived in renal transplant patients and used C(0h) and C(2h), were compared based on their capacity for reducing total error squared. RESULTS: C(4h) was found to be the single most predictive timepoint and explained 95.3% of AUC(0-12) variation. C(0h) and C(12h) explained 60% and 75.7% of the variation in AUC(0-12), respectively. The best 2-variable model identified by stepwise selection procedures included C(1h) and C(4h) as predictors, explaining 97.3% of the variation in total area under the concentration-time curve from time 0 h to 12 h. Using Keown's algorithm, the R(2) was only 80.9%. CONCLUSION: We recommend using C(1h) and C(4h) as surrogate markers of area under the concentration-time curve from time 0 h to 12 h in our heart transplant patients. Because C(1h) and C(4h) represent timepoints within the zone of highest variability for Neoral's absorption phase, a model incorporating these timepoints would be able to explain a greater degree of variability associated with the Neoral absorption profile.

Mycotic aneurysm of a coronary artery in SLE--a rare complication of salmonella infection.

We describe a 27y old female systemic lupus erythematosus (SLE) patient with salmonella bacteraemia who presented with fever, back pain and an enlarging heart size. A two dimensional echocardiogram (2D Echo) showed a mass in the right atrium. Subsequent computer tomographic (CT) and magnetic resonance imaging (MRI) studies showed that this had become a ring shaped lesion at the posterior end of the interventricular septum with an area communicating with the right atrial cavity. At operation a ruptured mycotic aneurysm of the right coronary artery was found. This is the first report of an SLE patient with a coronary artery mycotic aneurysm due to salmonella and the first reported case of survival following rupture of such aneurysm.

An unusual case of acute onset of cardiac failure.

Rupture of the aortic sinus of Valsalva is one of the rare causes of acute dyspnoea. Modern advances have enabled diagnosis to be made easily with echocardiography as illustrated in this case. The treatment of choice is surgery with excellent prognosis if detected early. Therefore a high index of suspicion is required to diagnose this potentially threatening but yet treatable condition.

Vascular assessment in the neuropathic diabetic foot.

Diabetic foot infections, a common source of morbidity and mortality, often have been related to vasculopathy and neuropathy in its etiopathogenesis, especially in the elderly person with diabetes. However, blood flow in the neuropathic diabetic foot has not been evaluated extensively, and there is evidence of abnormal blood flow patterns in the neuropathic diabetic foot unrelated to ischemia. The authors studied young persons with diabetes, with varying degrees of neuropathy, to assess the extent of vasculopathy in their lower limbs. Twelve young persons with insulin-dependent (Type I) diabetes (mean age, 36.1 +/- 1.975 years) and peripheral neuropathy, all of whom had previous surgery for diabetic foot infections, were identified. Confirmatory evidence of neuropathy was made using electromyographic studies and clinical tests that showed severe peripheral neuropathy. The results of vascular assessment of both lower limbs did not reveal any change in the pulse wave velocities from the popliteal to the digital vessels of the big toe as compared with correspondingly matched controls. There also was no significant stenosis in any of the vessels studied as far as the level of the dorsalis pedis and posterior tibial vessels. The normal triphasic pattern of arterial blood flow was lost. A monophasic pattern was present in all patients with prolonged diastolic flow at the level of the dorsalis pedis and posterior tibial arteries and distally. The pulsatility index was 3.14 +/- 0.81 as compared with 9.85 +/- 4.2. Mean toe pressures in the patient with diabetes was 64.17 +/- 20.87 mm Hg as compared with 98.23 +/- 10.12 mm Hg in controls. A linear correlation of decreasing toe pressures with increasing severity of neuropathy was seen (R = 0.7). The data suggest that changes exist in the blood flow patterns in young patients with diabetes and neuropathy, even in the absence of lower limb ischemia.

Surgical management of intrathoracic aortic aneurysm.

The pathology, clinical features, indications for surgery and the results of intrathoracic aneurysm are analysed in thirty-nine consecutive patients who underwent surgery at Singapore General Hospital from January 1986 through December 1990. There were twenty cases of non-dissecting aneurysm and nineteen cases of dissecting aneurysm or aortic dissection. The 30 day survival for the twenty patients with non-dissecting aneurysm was sixteen patients (80%). The best results were obtained in patients with aortic root aneurysms. The overall 30-day survival for the nineteen patients with aortic dissection was twelve patients (64%). The mortality was especially high in patients with acute aortic dissection (46%). Recent advances in the management of these aneurysms make early recognition and diagnosis mandatory to achieve the best results.

Role of routine endomyocardial biopsy to monitor late rejection after heart transplantation.

Endomycardial biopsy remains the standard used to monitor rejection after heart transplantation. There is, however, no consensus as to how often surveillance endomyocardial biopsy should be carried out after heart transplantation. We have analyzed 131 patients undergoing orthotopic heart transplantation during the first 4 years of the transplant program at St. Vincent's Hospital. The majority of endomyocardial biopsies that showed acute rejection occurred in the first 3 months after transplantation; after 9 months only 2.5% of endomyocardial biopsies performed showed rejection. Of those patients with rejection, 47% had symptoms. Seven patients experienced late rejection and all made a good recovery with normal cardiac function. We conclude that the incidence of acute rejection decreases significantly more than 3 months after-transplantation; after 9 months only 2.5% of endomyocardial biopsies will show rejection. Of these, 47% will be associated with symptoms. On the basis of experience, we believe that in our own unit, endomyocardial biopsy more than 9 months after transplantation seems unwarranted unless clinically indicated.

Atrial overdrive pacing for reversion of atrial flutter after heart transplantation.

Atrial overdrive pacing is an effective treatment to terminate classic (type 1) atrial flutter. After heart transplantation, the appearance of atrial flutter may be an indication of acute allograft rejection, and in patients who have this arrhythmia we routinely perform endomyocardial biopsy. In this study we examined the efficacy of atrial overdrive pacing performed at the time of endomyocardial biopsy in the termination of atrial flutter. Endomyocardial biopsy was performed with a Caves-Scholten bioptome via a right internal jugular venous sheath. After completion of the biopsy, a J-shaped 5F bipolar pacing lead was inserted via the sheath and positioned with the lead tip directed medially against the interatrial septum or right atrial appendage. Atrial pacing was performed with stimulation rates up to 450 beats/min at 20 mA for 15 seconds. Since July 1989, 16 episodes of atrial flutter have occurred in nine patients. Twelve episodes (75%) were associated with acute rejection, which was moderate or severe in nine cases. Atrial overdrive pacing was successful in restoring sinus rhythm in 13 of 14 episodes during which it was attempted (success rate, 93%). The procedure was uncomplicated and produced minimal patient discomfort. In comparison, of eight episodes of atrial flutter (in six patients) that occurred before the routine use of atrial overdrive pacing, seven were associated with rejection. With treatment of rejection, two episodes reverted spontaneously, but on six occasions cardioversion with patients under general anesthesia was necessary to restore sinus rhythm. In conclusion, atrial flutter occurring after heart transplantation is usually associated with acute allograft rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of chronic amiodarone therapy before transplantation on early cardiac allograft function.

Because of its long half-life, there has been concern that chronic amiodarone therapy before heart transplantation may adversely affect early cardiac allograft function and delay patient recovery. We retrospectively analyzed the outcome of the last 50 patients undergoing heart transplantation at our institution (between September 1988 and September 1989). Nineteen patients had been taking amiodarone at the time of transplantation (mean daily dose, 247 +/- 31 mg; mean duration of treatment, 9.0 +/- 2.2 months). These patients did not differ from the remaining 31 patients with respect to age, sex, or cause of disease. Donor organ ischemic time was also similar in the two groups (158 +/- 11 vs 153 +/- 10 minutes, NS). Patients who had received amiodarone before transplantation had significantly lower heart rates at 1 and 4 weeks after transplantation. They required atrial pacing for a longer time after transplantation compared with the remaining patients (7.3 +/- 1.4 vs 3.4 +/- 0.8 days, p less than 0.02). There was, however, no detectable effect of prior amiodarone therapy either on early allograft inotropic function or on clinical outcome. The mean time to hospital discharge was similar in the two groups. We believe that acceptance for heart transplantation should not be regarded as a contraindication to amiodarone therapy.

Myocardial preservation in heart transplantation.

The current techniques of donor procurement and transplantation provide a very low incidence "of non rejection graft failure", following cardiac transplantation. Attention needs to be paid to the preservation of organ function in the potential donor, in order to maximise the donor availability in an environment of perpetual donor shortage. The strategies aimed at myocardial preservation in the donor will be methods of protection from the pathophysiological changes associated with onset of cerebral injury and brain death. The role of various types of cardioplegia, additives and preservation fluids need to be investigated to minimise the effects of cardiac ischaemia and reperfusion injury. There is evidence to suggest the improvement in long term survival with tissue matching in cardiac transplantation. This will need methods of prolonging safe ischaemic time for the donor heart so that tissue matching and organ sharing can be carried out.

Thromboembolism and problems of anti-coagulation after prosthetic valve replacement.

104 patients who had prosthetic valve replacements were followed up for a period from 5 months to 63 months. The incidence of minor and major thromboembolism for aortic valve replacement was 1.2%/Pt.yr respectively, while the incidence for mitral valve replacement was 3.8%/Pt.yr. respectively. The haemorrhagic complication rate due to anticoagulation was 3.7%/Pt.yr. and the fatality rate due to it was 1.4%/Pt.yr. 75% of the patients who had haemorrhagic complications had a thrombotest of less than 4%. Anticoagulation related morbidity and mortality are significant in this series. Elimination of anticoagulation related complications could have improved the long term mortality rate from 2.95%/Pt.yr. to 1.4%/Pt.yr.

Acute thrombosis of Starr-Edwards aortic prosthesis.

A case of acute valve thrombosis occurring in a Starr-Edwards aortic prosthesis during the immediate postoperative period is reported. This appears to be the first such case to be reported.

Mediastinal benign teratoma in Singapore.

The purpose of this study was to analyse the pattern of benign mediastinal teratoma, in this region. The paper is based on a retrospective analysis of 16 consecutive patients who were admitted to the Cardiothoracic Surgical unit in Singapore from 1967 through 1984. The disease pattern appears to be similar to those reported from the west. Complete surgical excision offers a cure and it can be carried out safely.

Spontaneous haemothorax in a mild haemophiliac.

Spontaneous haemothoraxis is a very rare presenting manifestation in haemophilia, only four previous cases being recorded in the English literature. The clinical features and management of such a case by intercostal tube drainage in a previously unrecognized haemophiliac are described.