Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.

BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).

Photodynamic therapy for tracheal thyroid metastasis.

We report the case of a patient with recurrence of follicular carcinoma of the thyroid 8 years after surgical resection followed by external beam radiotherapy and radio-iodine treatment. The patient was treated by endoscopic photodynamic therapy (PDT) with complete endoscopic response after 12 months with good symptom relief.

Post-coronary artery bypass grafting left internal mammary artery to pulmonary artery fistula: a 6 year follow-up following successful surgical division.

We report a case of young male patient who developed left internal mammary artery to pulmonary artery fistula 9 years following the coronary artery bypass grafting operation. The clinical signs and symptoms were very subtle including recurrence of angina and heart murmur. Surgical division of the fistula and re-grafting of blocked coronary arteries resulted in satisfactory long term outcome.

Tumor necrosis factor-alpha gene polymorphism and death due to acute cellular rejection in a subgroup of heart transplant recipients.

Irreversible acute rejection of the transplanted heart usually has a fatal outcome. Predicting which recipients are most likely to reject might allow closer monitoring and modification of treatment protocols to prevent graft loss. Recipients genetically predisposed to produce more TNF-alpha are those who suffer the most acute rejection episodes. Here we show that TNF-alpha genotype is strongly associated with death due to acute cell-mediated heart transplant rejection (Chi-square = 28.57, p < 0.0001). This subgroup of recipients should be given optimally tissue matched transplants and should be treated with the most effective immunosuppressive regimens.

The development of a quantitative PCR ELISA to determine HCMV DNAaemia levels in heart, heart/lung and lung transplant recipients.

The adaptation of the polymerase chain reaction (PCR) enzyme-linked immunosorbent assay (ELISA) using a co-amplified DNA standard to quantitate the human cytomegalovirus (HCMV) glycoprotein B (gB) gene in clinical samples is described. The PCR ELISA is a solution hybridisation system with colorimetric end stage detection of amplicons. A DNA internal standard (IS) was designed by replacing a probe sequence used currently within the gB region with a heterogeneous sequence, allowing co-amplification with the same oligonucleotide primer sets and differentiation by probe hybridisation. Two DNA fragments homologous to the gB and IS sequences were generated and used for co-amplification studies to construct a standard curve. From this the copy number of the gB gene present in clinical samples could be interpolated. Co-amplification with 1000 IS copies allowed quantitation of 10-1000000 gB DNA copies in a single PCR. This assay was validated subsequently using blood samples tested by the HCMV antigenaemia assay and showed a trend of increasing HCMV DNAaemia with increasing antigenaemia levels. This rapid assay avoids using gel electrophoresis and cumbersome quantitative systems. It has the potential for early identification of patients at high risk of developing HCMV disease, and for therapeutic monitoring.

Orthotopic cardiac transplantation technique: a survey of current practice.

BACKGROUND: The Lower and Shumway technique has been the gold standard for orthotopic heart transplantation (OHT) for the past 35 years. In the last decade the bicaval and total techniques have been introduced but it is unclear how these alternative techniques have influenced the current surgical practice of OHT. METHODS: A worldwide survey of 210 International Society of Heart and Lung Transplantation centers was conducted by questionnaire: 169 replies were received; a response rate of 80%. RESULTS: Seventy-four centers (44%) use a combination of more than one technique with the remaining centers (n = 95 centers) employing one technique exclusively. The bicaval technique is the most frequently used technique in the majority of transplant procedures in 92 (54%) centers. In only 38 centers (22%), the standard technique was the most frequently employed technique. The total technique was the choice in 8 centers (5%). The maximum acceptable ischemic time varied from 3 to 9 hours with a median of 5.7 hours. Only 92 centers (54%) do not use cardioplegia during implantation. CONCLUSIONS: Since its introduction, the bicaval technique has become the most commonly used procedure for OHT. The long-term advantage of right atrial preservation with the bicaval technique will require further studies.

Risk factors for tricuspid valve regurgitation after orthotopic heart transplantation.

BACKGROUND: Tricuspid regurgitation (TR) may occur following orthotopic heart transplantation (OHT) and although a number of etiological factors have been suggested, the relative contribution of each of these remains to be elucidated. We aimed to assess the risk factors for TR in our 10-year experience of orthotopic heart transplantation (OHT). METHODS: OHT was performed in 249 patients (161 by the standard technique and 88 by the bicaval technique). TR was assessed using transthoracic color Doppler echocardiography. RESULTS: Recipients who underwent operation by the standard technique displayed higher incidence of moderate and severe TR than did bicaval-technique recipients. The development of early TR was also correlated to rejection greater than or equal to grade 2, preoperative raised transpulmonary gradient, and raised pulmonary vascular resistance. Risk factors for late TR were standard technique (p < 0.0001), number of rejection greater than or equal to grade 2 (p < 0.004), and the total number of heart biopsies (p < 0.02). Recipients with moderate and severe TR revealed elevated right-side pressures and advanced New York Heart Association statues compared to those with no, trivial, or mild TR. CONCLUSIONS: Various factors contribute to TR after OHT, the prevalence of which might be lowered by adopting the bicaval technique, early treatment of rejection, and reduction of the number of biopsies performed.

Heart transplantation for peripartum cardiomyopathy: a report of three cases and a literature review.

Peripartum cardiomyopathy is a devastating medical condition and carries a mortality of up to 60% with medical treatment. The authors describe their experience of successful outcome of three cases with heart transplantation and review the literature. The importance of performance of endomyocardial biopsy for all peripartum cardiomyopathy patients is emphasized. It is recommended that heart transplantation should only be offered to myocarditis negative patients.

The influence of histocompatibility on graft rejection and graft survival within a single center population of heart transplant recipients.

BACKGROUND: We report a consecutive single center series of 261 patients who received first orthotopic heart transplants from 1986 to 1997. The 1- and 5-year graft survivals were 78 and 68%. The influence of histocompatibility was investigated by comparing graft survival and numbers of treated rejection episodes with HLA-A, -B, and -DR mismatches over different time periods. FINDINGS: Recipients with six mismatches for HLA-A+-B+-DR combined (13.4%) had reduced survival at 7 years (47%) when compared with other recipients (64%). In the first year of transplant, recipients with four HLA-A+-B mismatches had significantly reduced actuarial graft survival (P=0.03) with the greatest influence apparent at 6 months [0-3 mismatches (n=193) 85% versus 4 mismatches (n=68) 69%; P=0.005, OR=2.1]. For 182 recipients with functioning hearts at 1 year, the number of rejection episodes treated within this time was strongly influenced by HLA-DR mismatch [0 DR mismatch (n=15) mean 1.2 rejection episodes versus 1 DR mismatch (n=76) mean 2.7 rejection episodes versus 2 DR mismatches (n=91) mean 3.8 rejection episodes: P=0.0002]. Of these 182 transplants, recipients who had more than four treated rejection episodes during the first year had a significantly reduced 7- year survival [<5 rejection episodes (n=133) 85% versus more than four rejection episodes (n=49) 66%; P=0.02, OR=3.4], as did those with two HLA-DR mismatches [0+1 mismatch (n=91) 87% versus 2 mismatches (n=91) 70%; P<0.05, OR=2.4]. INTERPRETATION: We show that graft loss in the first 6 months of transplant is significantly influenced by four HLA-A+-B mismatches. HLA-DR mismatch significantly increases the number of rejection episodes within the first year, without influencing graft survival. After 12 months both >4 rejection episodes in the first year and two HLA-DR mismatches are markers for late graft loss. We postulate that immunological graft loss in the first 6 months is dominated by the direct allorecognition pathway driven by HLA-DR mismatch. This mechanism is later lost or suppressed. Our data highlight HLA-DR mismatch as a marker for late graft loss and we show an advantage to avoiding transplanting hearts with six HLA-A+-B+-DR mismatches and to minimizing HLA-DR mismatches whenever possible.

The effect of 'renal-dose' dopamine on renal tubular function following cardiac surgery: assessed by measuring retinol binding protein (RBP).

OBJECTIVE: Acute renal failure complicating open heart surgery is not uncommon. Dopamine infusion (2.5-4.0 microg/kg per min) has often been advocated for prophylactic 'renal protection' in this setting despite little objective evidence of real benefit. We aimed to investigate whether dopamine offers any 'renal protection' in patients with normal heart and kidney functions undergoing routine coronary artery bypass grafting (CABG). Urinary excretion of retinol-binding protein (RBP), previously validated as a sensitive and accurate marker of early renal tubular injury, was used to assess the renal effects of dopamine during the first postoperative week. METHODS: Forty consecutive patients from the elective waiting list were prospectively randomized into two equal groups: those in Group A received dopamine infusion at 'renal dose' (2.5-4.0 microg/kg per min) starting from induction of anaesthesia for 48 h, whereas those in Group B served as untreated controls. Daily measurements were made of weight-adjusted urine output (ml/kg), fluid balance (input/output), serum creatinine, blood urea and urinary RBP. Statistical comparisons were made using Mann-Whitney U-test. RESULTS: The two groups matched in terms of age, time and temperature on cardiopulmonary bypass, number of grafts performed and perioperative haemodynamic status. No differences were detected in the weight-adjusted urine output, fluid balance, serum creatinine and blood urea between the groups. Control subjects (Group B) showed an increase in urinary RBP during the first and second postoperative days (323+/-4 microg/ mmolCr and 50+/-3 microg/mmolCr; mean+/-SD). However, patients treated with dopamine (Group A) demonstrated much greater urinary excretion of RBP over the same period (1257+/-15 microg/mmolCr and 449+/-21 microg/mmolCr; P = 0.0006 and 0.03) than those in Group B. CONCLUSIONS: Dopamine given at 'renal-dose' appears to offer no renal protection in patients with normal heart and kidney functions undergoing elective coronary surgery. On the contrary, it exacerbates the severity of renal tubular injury during the early postoperative period. Based on these findings we do not recommend the use of dopamine for routine renal prophylaxis in this group of patients.

Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis.

BACKGROUND: TGF-beta1 is a prosclerotic cytokine implicated in fibrotic processes. Fibrosis of the pulmonary parenchyma and airways is a frequent presentation in lung transplant recipients before and after transplantation. There are two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located at codon 10 (either leucine or proline) and at codon 25 (either arginine or proline). The codon 25 arginine allele is associated with higher TGF-beta1 production by cells activated in vitro. We tested the hypothesis that inheritance of alleles of the TGF-beta1 gene conferring higher production of TGF-beta1 may be responsible for over-expression of TGF-beta1 in transplant recipients resulting in lung allograft fibrosis. METHODS: We extracted DNA from leukocytes collected from 91 pulmonary transplants performed at our centre and 96 normal healthy volunteers between May 1990 and September 1995. Part of the first exon was amplified by PCR. Samples were genotyped by using sequence specific oligonucleotide probes. RESULT: The distribution of codon 10 alleles was similar in a normal healthy control group and in lung transplant recipients, regardless of their pretransplant lung pathology. By contrast, there was a significant difference in the frequency of codon 25 alleles between the control and transplant groups. In the normal control group 81% were codon 25 arginine/arginine (A/A) homozygotes, 19% were arginine/proline (A/P) heterozygotes and none were proline/proline (P/P) homozygotes. The distribution of codon 25 alleles was similar in lung transplant recipients who did not have a significant fibrosis in pretransplant pathology, but in transplant recipients who came to transplantation with lung fibrosis 98% (41 of 42 patients) were homozygous for the codon 25 A/A allele (p < .05). After lung transplantation 39 of 91 patients developed lung allograft fibrosis, and of these 92.3% (36 of 39 recipients) were of homozygous codon 25 A/A high TGF-beta1 producer genotype (p < .001). Lung transplant recipients who were homozygous for both codon 10 L/L and codon 25 A/A showed poor survival compared with all other TGF-beta1 genotypes (p < .03). CONCLUSION: Homozygosity for arginine at codon 25 of the leader sequence of TGF-beta1 that correlates with higher TGF-b production in vitro, is associated with fibrotic lung pathology before lung transplantation and with the development of fibrosis in the graft. In combination with the codon 10 leucine allele, homozygosity for the codon 25arginine allele is a marker for poor post-transplant prognosis and recipient survival.

RANTES chemokine expression is related to acute cardiac cellular rejection and infiltration by CD45RO T-lymphocytes and macrophages.

BACKGROUND: Despite the advances made in immunosuppression therapy, episodes of acute cellular rejection may affect graft function and survival. We investigated the role of RANTES in cellular recruitment and in cardiac allograft rejection. METHODS: Endomyocardial biopsies (n = 65) from 30 patients were taken at various times after transplantation. In 4 subjects who died of acute cellular rejection, the profile of RANTES expression was monitored in all biopsy specimens and in postmortem tissue. Myocardial tissue from 10 other transplants was also analyzed. Sections were stained with an anti-human RANTES antibody with the streptavidin-biotin technique. RANTES-positive cells were related to macrophage, CD45RO "memory" T-cell, and eosinophil infiltration. RESULTS: RANTES-positive cells were identified within the cellular infiltrate in 95% of biopsies with moderate/severe rejection and 28% with mild rejection. RANTES-positive, CD45RO-positive, and macrophage cell numbers were higher in subjects who died of acute cellular rejection than of other causes. A highly significant difference in RANTES-positive cell number was observed between moderate/severe, mild, and nonrejection groups (p = .0001) and correlated significantly with macrophage number in both right and left ventricles (r = .693, p < .01; r = .599, p < .05, respectively) and with the number of "memory" T cells (r = .829, p < .001; r = .779, p < .01, respectively). CONCLUSIONS: These findings suggest that local release of RANTES is important in the recruitment of both macrophages and CD45RO T cells in cardiac allograft rejection. RANTES may be an important chemokine to target for therapeutic intervention in heart rejection.

Preemptive treatment for the prevention of cytomegalovirus disease: in lung and heart transplant recipients.

BACKGROUND: Rapid quantifiable diagnostic techniques for the diagnosis of cytomegalovirus (CMV) infection may predict patients at risk of CMV pneumonitis and allow preemptive antiviral treatment. METHODS: Using CMV antigenemia as a prospective surveillance technique for CMV infection, we compared the outcome of preemptive treatment (PT) with ganciclovir, 10 mg/kg/day for 21 days directed by "high levels" of CMV antigenemia (PT group, n= 19), with the outcome in a group of historical controls (n=18) treated with ganciclovir when CMV illness occurred. Greater than 50 antigen-positive cells per 2 x 10(5) polymorphonuclear leukocytes was considered to be high-level antigenemia. RESULTS: Nine of the 18 controls developed high-level CMV antigenemia at a median of 33 days (range: 13-65 days) and 5 of the 9 developed CMV disease. Ten of the 19 PT group had high levels of CMV antigenemia detected at a median of 47 days (range: 20-63 days) and were given ganciclovir; none developed CMV disease. There was a significantly lower incidence of CMV disease in the PT group in comparison to controls (0 of 19 vs. 5 of 18: P=0.019). CONCLUSION: We have reduced the incidence of CMV disease using preemptive treatment, and because of a 100% negative predictive value, we omitted unnecessary antiviral prophylaxis for many at-risk patients.

Single lung transplantation for emphysema: predictors for native lung hyperinflation.

BACKGROUND: Single lung transplantation is an established procedure for the treatment of respiratory failure resulting from emphysema. Initial concerns suggested that ventilation/perfusion mismatch may result in an unsatisfactory outcome, but good clinical results proved those concerns to be unfounded. However, a proportion of patients have had development of native lung hyperinflation (NLH), with increased morbidity and mortality rates. This study was undertaken to evaluate the factors that might predict those patients with emphysema who are at greatest risk for development of NLH. METHODS: We retrospectively analyzed data from 27 patients who underwent 31 single lung transplantations for emphysema. The patients were divided into two groups: group A, 12 patients with development of acute or chronic NLH, and group B, 15 patients without development of hyperinflation. NLH was defined as radiologic mediastinal shift with flattening of the ipsilateral diaphragm associated with respiratory dysfunction or hemodynamic instability. All preoperative and postoperative data from recipients and data from donors were analyzed. RESULTS: There were no differences between the two groups regarding age, preoperative partial pressure of oxygen, partial pressure of carbon dioxide, acid-base status, donor lung size and physiological structure, side of transplantation, primary pathologic condition, rejection score, infection episodes and obliterative bronchiolitis in the transplanted lung after operation. Patients with NLH had a significantly higher preoperative mean pulmonary artery pressure of 31.6 mm Hg (confidence interval [CI] 26.7 to 35.7), transpulmonary gradient of 20.5 mm Hg (CI 17.4 to 23.5), a lower mean forced expiratory volume in 1 second of 427 ml (CI 352 to 502), and higher mean residual volume of 4450 ml (CI 3769 to 5132). The duration of ventilation, 168 hours (CI 45 to 290), and the postoperative mean pulmonary artery pressure of 26 mm Hg (CI 23 to 28.7) are significantly higher in the hyperinflation group. Early death in group A (n = 5) was higher than in group B (no deaths) (p = 0.02). Six patients in group A required surgical treatment (two early native lung volume reductions, two early ipsilateral retransplantations, and two late contralateral transplantations). Group A patients tended to have poorer long-term lung function after transplantation, with reduced forced expiratory volume in 1 second, forced vital capacity, and higher residual volume (p = NS). CONCLUSION: Patients with end-stage emphysema and relative pulmonary hypertension, severe airway obstruction, and air trapping are at greatest risk for development of early and late NLH. In this subgroup of patients, an alternative treatment strategy may be considered.

Treatment of mediastinitis: early modified Robicsek closure and pectoralis major advancement flaps.

BACKGROUND: The treatment of sternal wound complications is controversial. It is our practice to combine early aggressive debridement, a modified Robicsek sternal closure, and bilateral pectoralis major advancement flaps with or without closed irrigation in a single procedure. We reviewed our experience to determine the efficacy of this approach. METHODS: Grade II to IV mediastinitis (dehiscence and infection) developed in 47 patients 3 to 14 days after routine open heart operations between 1990 and 1995. Culture-positive infection was identified in 60% (n = 28); 62% (n = 29) had septicemia. Thirty patients underwent incision, drainage, and surgical assessment of the wound. Once systemic signs of infection were under control (no pyrexia, normal white blood cell count), formal single-stage debridement of all infected soft tissues and bones was performed. Sternal stability was achieved using a modified Robicsek closure and bilateral pectoralis major advancement flaps. Seventeen patients were treated with staged procedures. RESULTS: Early sternal closure and coverage with pectoralis major advancement flaps can be associated with a low mortality (0%), low morbidity (13%; n = 4: three superficial wound infections, one seroma), and shortened hospital stay (median, 22 days, compared with a median of 82 days in patients managed with conservative staged treatment; p < 0.05). Sternal stability with excellent functional and aesthetic results has been achieved in all patients. CONCLUSIONS: The combination of aggressive early surgical debridement, sternal closure, and the placement of bilateral pectoralis major advancement flaps is a simple procedure associated with a low mortality and morbidity and a short hospital stay.

Significance of raised natriuretic peptides after bicaval and standard cardiac transplantation.

BACKGROUND: High levels of plasma atrial natriuretic peptide (ANP) and ventricular natriuretic peptide (BNP) have been identified after standard orthotopic cardiac transplantation. It has been postulated that the high ANP levels are a result of persistent secretion from the large residual atrial mass after transplantation. This study was undertaken to investigate the significance of raised ANP and BNP levels after standard and bicaval orthotopic heart transplantation. METHODS: Plasma ANP and BNP levels were measured in 40 ambulatory, randomly selected cardiac transplant patients (group A, n = 20 had bicaval transplantation; group B, n = 20 had standard transplantation) and 10 healthy volunteers (group C). Cardiac transplant patients underwent endomyocardial biopsy and hemodynamic evaluation. RESULTS: Plasma levels of ANP and BNP were elevated in the transplant recipients in comparison with normal volunteers (p = 0.0001 and p < 0.0001, respectively). There was no significant difference in the ANP levels between group A and group B, whereas BNP levels were higher in group B compared with group A (p = 0.03). Linear regression analysis showed that a faster heart rate, high mean pulmonary artery pressure, high pulmonary capillary wedge pressure, and high transpulmonary gradient were associated with higher levels of BNP (p < 0.05). Lower mean systemic pressure was associated with higher levels of ANP (p < 0.05). CONCLUSIONS: High levels of ANP and BNP are synthesized and secreted by the transplanted denervated human heart regardless of the surgical technique. The level of BNP correlates with ventricular performance and afterload. The bicaval technique seems to be associated with better left ventricular and right ventricular diastolic performance.