Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients--a large European trial.

We compared efficacy and safety of tacrolimus (Tac)-based vs. cyclosporine (CyA) microemulsion-based immunosuppression in combination with azathioprine (Aza) and corticosteroids in heart transplant recipients. During antibody induction, patients were randomized (1:1) to oral treatment with Tac or CyA. Episodes of acute rejection were assessed by protocol biopsies, which underwent local and blinded central evaluation. The full analysis set comprised 157 patients per group. Patient/graft survival was 92.9% for Tac and 89.8% for CyA at 18 months. The primary end point, incidence of first biopsy proven acute rejection (BPAR) of grade >/= 1B at month 6, was 54.0% for Tac vs. 66.4% for CyA (p = 0.029) according to central assessment. Also, incidence of first BPAR of grade >/= 3A at month 6 was significantly lower for Tac vs. CyA; 28.0% vs. 42.0%, respectively (p = 0.013). Significant differences (p < 0.05) emerged between groups for these clinically relevant adverse events: new-onset diabetes mellitus (20.3% vs. 10.5%); post-transplant arterial hypertension (65.6% vs. 77.7%); and dyslipidemia (28.7% vs. 40.1%) for Tac vs. CyA, respectively. Incidence and pattern of infections over 18 months were comparable between groups, as was renal function. Primary use of Tac during antibody induction resulted in superior prevention of acute rejection without an associated increase in infections.

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.

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.

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.

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.

Orthotopic heart transplantation hemodynamics: does atrial preservation improve cardiac output after transplantation?

BACKGROUND: We have described an alternative technique for orthotopic heart transplantation (bicaval Wythenshawe technique) which maintains the right and left atrial anatomy and contractility. METHODS: Fifty patients were randomized into two groups: group A (n = 25) who had orthotopic heart transplantation using the bicaval Wythenshawe technique and group B (n = 25) who had conventional (Lower and Shumway) technique of orthotopic heart transplantation. We compared the cardiac output (measured by thermodilution technique) with atrial activation (AAI pacing) to cardiac output without atrial activity (VVI pacing) in both groups to identify any beneficial hemodynamic effects. All patients were studied the first and second weeks after transplantation. The inaccuracies of comparing cardiac output measurements caused by different loading conditions, inotropic state, and systemic vascular resistance were eliminated by using the patient as his or her own control. RESULTS: The difference between the measured cardiac output with atrial pacing and ventricular pacing was 1.42 +/- 0.44 L/min in group A in comparison with 0.32 +/- 0.4 L/min in group B (p = 0.001 Wilcoxon signed rank). The percentage of atrial contribution to the cardiac output in group A was 30% +/- 12% (standard deviation), 95% confidence interval in comparison with 7% +/- 9%, 95% confidence interval in group B. The mean stroke volume in group A was higher in sinus rhythm (65 +/- 19.2 ml) and atrial pacing (62 +/- 17.7 ml) compared with ventricular pacing (49.17 +/- 16.43 ml) p = 0.001. In group B no statistical difference was found between stroke volume measured with atrial (47.71 +/- 6.23 ml) or ventricular pacing (46.9 +/- 6.35 ml). CONCLUSIONS: We conclude that the bicaval technique of orthotopic heart transplantation preserve the atrial kick and its contribution to cardiac output early after transplantation.

Extended criteria for cardiac allograft donors: a consensus study.

BACKGROUND AND METHODS: To achieve a consensus regarding extending the current criteria for referring potential cardiac allograft donor, we sent a detailed questionnaire to all heart transplant surgeons in the United Kingdom. RESULTS: Replies representing the opinion of 16 heart transplant surgeons (88% response rate) suggest that the majority believe that donor age could be extended up to 55 years even in the absence of a coronary angiogram or echocardiogram. Family history of ischemic heart disease, history of hyperlipidemia or smoking, and brain death caused by paracetamole or barbiturates overdose were not considered prohibitive to cardiac allograft donation. Similarly, chest trauma, prolonged mechanical ventilation, pre-referral cardiac arrest or hypotension for any length of time, and nonspecific ST-segment elevation were not considered to be contraindications. By contrast, significant Q waves in a recent electrocardiogram, the presence of hepatitis C antibodies, pulmonary capillary wedge pressure more than 20 mm Hg, and dependency on multiple inotropic support were considered definite exclusion criteria. Donor hormonal resuscitation (T3-cocktail), insertion of a Swan-Ganz catheter, and direct measurement of intracavitary pressure at the time of retrieval were considered unnecessary by more than 80% of respondents. There was no consensus of opinion regarding the use of donors above the age of 55 years, brain death caused by carbon monoxide poisoning, history of diabetes mellitus, alcohol or drug abuse, systemic infections, electrocardiographic evidence of left ventricular hypertrophy, or the maximum dose of inotropic support required to maintain satisfactory hemodynamics. CONCLUSIONS: The number of potential cardiac allograft donors can be increased by extending the donor age to 55 years. Brain death caused by Paracetamole and barbiturate overdose may not prohibit organ donation.

Severe mitral valve dysfunction due to unsuspected granulomatous myocarditis: successful cardiac transplantation following attempted mitral valve repair.

Granulomatous involvement of the myocardium is a rapidly fatal disease of uncertain aetiology rarely diagnosed premorbidly. We report a patient who presented with mitral valve incompetence and congestive cardiac failure who underwent a successful mitral valve repair but could not be weaned from cardiopulmonary bypass. Urgent heart transplantation was successfully performed and histological studies of the explanted heart revealed granulomatous myocarditis involving the mitral subvalvular apparatus. Endomyocardial biopsy may be necessary in young patients presenting with mitral valve disease of unknown aetiology.

Right lower lobe herniation after domino heart-lung transplantation.

We report 2 cases of trapping and incarceration of the right lower lobe in the left hemithorax after heart-lung transplantation with bicaval anastamoses (domino donors). This occurred despite confirmation of the normal anatomy at the time of implantation, before lung inflation. In 1 case this complication resulted in a right lower lobectomy 7 days after transplantation due to infarction and infection of the right lower lobe. These cases illustrate the importance of reexamining the anatomy after lung inflation, before chest closure.

Orthotopic cardiac transplantation: a comparison of standard and bicaval Wythenshawe techniques.

We describe an alternative technique for orthotopic cardiac transplantation (bicaval Wythenshawe technique), which maintains the right and left atrial anatomy. We compared the new bicaval technique with the conventional (Lower and Shumway) technique of orthotopic cardiac transplantation to identify any beneficial physiologic and clinical outcomes resulting from maintaining the normal anatomy. Seventy-five patients were randomized on an alternate basis to two groups: group A (n = 40) had orthotopic cardiac transplantation with the bicaval technique and group B (n = 35) had conventional orthotopic heart transplantation. All patients were studied with transthoracic echocardiogram, endomyocardial biopsies, and measurement of intracardiac pressures 1, 4, and 12 weeks after transplantation. There were no statistically significant differences in the demographic profile, ischemic time, bypass time, implantation time, transpulmonary gradient, or pulmonary vascular resistance between the two groups. The hemodynamic data were collected in the absence of histologic signs of rejection. In group A right atrial pressure (mean 3.6 mm Hg) was significantly lower (p < 0.03) than in group B (mean 8.8 mm Hg). The right atrial a wave was recorded in 38 patients in group A compared with seven patients in group B (p = 0.041). Atrial tachyarrhythmias occurred in two patients in group A compared with 11 in group B (p < 0.016). Temporary pacing was required in 10 patients in group A and 16 patients in group B (p = 0.034). Four cases of mitral regurgitation (all mild) were detected in group A in comparison with 12 cases (10 mild, 2 severe) in group B (p = 0.008). The mean ejection fraction in the first week after transplantation was 58% in group A and 46% in group B (p = 0.5). In the first 3 months the need for diuretics was less in group A (mean dose 80.8 mg furosemide daily) than in group B (mean dose 134 mg furosemide daily in the first week increasing to 160 mg furosemide daily). Hospital stay was shorter in group A (mean 23 days) than in group B (mean 27 days) (p < 0.015). There were no early deaths as a result of right ventricular failure in group A (n = 0/40) compared with four (n = 4/35; 9%) in group B (p < 0.034). This difference suggests that bicaval orthotopic cardiac implantation is associated with a lower right atrial pressure, a lower likelihood of atrial tachyarrhythmias, less need for pacing, less mitral incompetence, a lower diuretic dose, and a shorter hospital stay.(ABSTRACT TRUNCATED AT 400 WORDS)

Rejection in heart transplantation strongly correlates with HLA-DR antigen mismatch.

It is well established that incompatible HLA antigens presented by donor tissue readily evoke an immune response. Prospective HLA matching policies, widespread in European kidney transplant centers have reduced the level of HLA mismatching and have significantly improved graft survival. The influence of HLA incompatibility in heart transplantation remains controversial, and prospective HLA matching is seldom achieved. We examined the role of HLA antigen mismatching on transplant rejection by analyzing 2569 endomyocardial biopsies (EMB) from 157 consecutive orthotopic heart transplants performed from April 1987 to August 1993 in our own center. Biopsies were graded according to the accepted International Classification, with grade 2 and higher indicating rejection. Among 91 patients who received a 2 HLA-DR mismatch transplant 34% of 1624 biopsies analyzed were graded as > or = 2. This frequency fell to 29% of 797 biopsies for 53 patients with a one-HLA-DR mismatch and to 18% of 148 biopsies for 13 patients in the zero-HLA-DR-mismatch group (P < 0.00005). No significant effect on EMB grade frequencies was observed using the same method of analysis with transplants mismatched at the HLA-A or HLA-B loci apart from analysis of HLA-B matched transplants at 3 months posttransplant (P = 0.02). The close linkage of the HLA-B and HLA-DR loci may account for this observation. The results of this study show that heart transplants matched at the HLA-DR locus have a significantly reduced incidence of EMB grades indicative of rejection requiring augmented immunosuppressive therapy. We propose that prospective HLA-DR matching should be adopted for allocation of donor hearts for more efficient use of this precious and limited resource.

An alternative surgical technique in orthotopic cardiac transplantation.

Forty patients underwent orthotopic cardiac transplantation at Wythenshawe Hospital between May 1991 and November 1992. Twenty patients had transplantation using an alternative technique that preserves the shape of the left atrium and leaves the right atrium intact (group A). The remaining twenty had conventional transplantation using the technique described by Lower and Shumway (group B). The patients were randomized to either the new or the conventional technique on an alternate basis. There was no mortality in group A, but two patients in group B developed right ventricular failure and died. Two patients in each group developed nodal rhythm and all four recovered sinus rhythm. Echocardiography and Doppler velocimetry at the transvalvular level confirmed normal atrial function in group A with erratic atrial contraction wave in group B. There was also slightly lower incidence of mitral and tricuspid valve regurgitation in group A than in group B. The improved atrial function in group A may play a part in the prevention of right sided failure following cardiac transplantation.