Abdul K. Deiraniya

Transforming growth factor beta (TGF-β) and obliterative bronchiolitis following pulmonary transplantation

BACKGROUND Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. RESULTS Procedures were heart and lung (n = 32), bilateral sequential lung (n = 18), and single lung transplantation (n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-beta was immunolocalized in the airways and lung parenchyma. TGF-beta expression was greater in OB patients (median score 8, range 5-12) in comparison to patients without OB (median score 4, range 1-13), p < .0001. Positive TGF-beta staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus (p = .02); recurrent acute rejection episodes (p < .0005); lymphocytic bronchiolitis (p = .0001); and tissue eosinophilia, regardless of the rejection grade (p < .0001). CONCLUSIONS Increased expression of TGF-beta is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.

Transforming growth factor-beta (TGF-β1) 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.

An alternative surgical technique in orthotopic cardiac transplantation.

Abstract 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.

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)

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.

Bicaval and standard techniques in orthotopic heart transplantation: Medium-term experience in cardiac performance and survival

OBJECTIVE The aim of this study was to compare the medium-term results of right heart pressures, tricuspid valve dysfunction, overall cardiac performance, and survival between the bicaval and standard techniques. METHOD Between 1991 and 1997, 201 heart transplantations were performed in our center. Right heart catheterization was performed up to 12 months after transplantation. Echocardiography was used to assess left ventricular and tricuspid valve function. RESULT The standard technique was used in 105 cases, and the bicaval technique was used in 96 cases. There was no difference in the age, preoperative parameters, pulmonary hemodynamics, or ischemic time between the 2 groups. Right atrial pressure (4.3 +/- 4.0 mm Hg for the bicaval vs 10.9 +/- 4.8 mm Hg for standard technique) and mean pulmonary artery pressure (17.5 +/- 5.3 mm Hg and 22.5 +/- 5.2 mm Hg, respectively) were lower for the bicaval recipients up to 12 months after the operation (P =.001 and. 01, respectively). Left ventricular ejection fraction was higher for the recipients of the bicaval technique up to the most recent measurement (P =.005). The prevalence of moderate or severe tricuspid regurgitation was higher in the recipients of the standard technique up to the most recent measurement (28% vs 7%; P =.02). The actuarial survival at 1, 3, and 5 years was 74%, 70%, and 62% for the recipients of the standard technique versus 87%, 82%, and 81% for the recipients of the bicaval technique (P <.03, <.04, and <.02, respectively). CONCLUSION The bicaval technique maintains good left ventricular function, lower incidence and severity of tricuspid valve dysfunction, and improved survival compared with the standard technique.

Transforming growth factor-β1 and lung allograft fibrosis

OBJECTIVES: Transforming growth factor beta1 (TGF-beta1) is a potent immunosuppressive cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components. The repair process following lung allograft injury is due to rejection or infection replaces lung parenchyma by fibrotic tissue, leading to pulmonary dysfunction. The role of TGF-beta1 in this excessive healing process and increasing the risk of infection is unknown. METHODS: We analysed our patient data to investigate the relevance of different factors on allograft fibrosis and its correlation with TGF-beta1. Fibrosis was graded in H and E stained sections. TGF-beta1 genotype was determined in all patients. RESULTS: Patients were aged between 16 and 62 years (mean age of 39.6 years). Procedures were heart/lung (n = 32), double lung (n = 18), and SLT (n = 41). A total of 46 patients had lung allograft fibrosis diagnosed in transbronchial biopsies sections. Patients who had developed interstitial fibrosis had significantly more acute rejection episodes (mean 3.4 +/- 2.8) compared with patients without fibrosis (mean 2.1 +/- 2.2) (P = 0.024). The presence of eosinophils in the interstitium preceded and were associated with the development of fibrosis regardless of the rejection grade (P = 0.0001). TGF-beta1 was heavily expressed in sections with fibrosis with a mean score of 6.8 +/- 2.9 compared with 2.4 +/- 0.6 in sections with no fibrosis (P 6 is 892.4 +/- 73 days compared with mean survival 427 +/- 78 in patients with scores < 6 (P = 0.0001). Patients who developed fibrosis had homozygous TGF-beta1 genotype that correlates with excessive TGF-beta1 expression (P = 0.01). The use of cardiopulmonary bypass was associated with the development of excessive fibrosis (P = 0.02), and 7 patients who had severe fibrosis died of septicaemia (17.5%). FEV1 (forced expiratory volume) was significantly higher in patients without fibrosis (1870 +/- 111 ml versus 1590 +/- 160; P = 0.02). CONCLUSIONS: The risks of lung allograft fibrosis increases with recurrent rejection, tissue eosinophilia, homozygous TGF-beta1 genotype and the use of bypass machine. Fibrosis was associated with higher mortality and morbidity might be explained by the TGF-beta1 immunosuppressive and fibrotic properties. Immunological strategies to down-regulate TGF-beta1 production might improve survival and function of lung allografts.

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.

Transforming growth factor β in relation to cardiac allograft vasculopathy after heart transplantation

Background: Cardiac allograft vasculopathy is a frequent sequel to cardiac transplantation, but the role of cytokines on the subsequent development of vasculopathy is still largely unknown. Methods: We retrospectively studied 172 heart transplant recipients to investigate the relationship between the development of vasculopathy and various factors including the presence of transforming growth factor (TGF-β) in the graft. Endomyocardial biopsy specimens were stained with antibodies for TGF-β and CD+68, and a TGF-β staining score was derived. Vasculopathy was diagnosed by angiography and rejection was graded according to the International Society of Heart and Lung Transplantation classification. TGF-β1 genotype was determined by polymerase chain reaction analysis of DNA. Results: After a mean follow-up period of 68 ± 32 months, the prevalence of significant vasculopathy was 52%. The TGF-β staining score was higher in patients with more severe vasculopathy (95% confidence interval = 8.9-12.1) than in those who showed minimal or mild vasculopathy score changes of more than 7 (95% confidence interval = 3.4-5.1), P = .0001. TGF-β expression correlated with the degree of vasculopathy (r = 0.73, P < .0007) during the study period. Risks for vasculopathy were recipient homozygous TGF-β genotype, recurrent rejection, recipient history of ischemic heart disease, donor male sex, old donor age (years), and donor history of subarachnoid hemorrhage. Conclusion: A strong association exists between the expression of TGF-β in cardiac biopsy specimens and the development of vasculopathy. TGF-β in the cardiac allograft is related to its genotype and to the number of rejection episodes. Strategies to down-regulate TGF-β production might improve the outcome of cardiac allografts. (J Thorac Cardiovasc Surg 2000;119:700-8)

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.