- Email: [email protected]
Origin of neointimal smooth muscle cells in human cardiac allograft coronary artery vasculopathy
The Journal of Heart and Lung Transplantation Volume 21, Number 1
Abstracts
11 EFFECT OF PERFADEX威 IN CLINICAL LUNG PRESERVATION C.T. Mueller,1 F. Kur,2 H. Fuerst,1 B. Reichart,2 1Department of Surgery, Ludwig-Maximilians University, Munich, Germany; 2 Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany In experimental lung transplantation, the superiority of low potassium dextrane (LPD, Perfadex威) over Euro Collins威 solution (EC) was demonstrated. In clinical lung transplantation, there is ongoing discussion about the superiority of LPD. Method: Patients undergoing single- (SLTx: EC n⫽31; LPD n⫽37) or double- (DLTx: EC n⫽17; LPD n⫽39) lung transplantation were investigated. Following iv infusion of PgI2, donor lungs were flushed with EC (n⫽48) or LPD (n⫽76), insufflated with O2 (FiO2⫽1,0) and stored in a hypothermic state. Duration of ischemia of the first and second organ and duration of ventilation were analized. Graft function was evaluated according to AaDO2 after transplantation (day 0) and at day 1 and 3 post Tx. 30 - day-mortality rate is given in % of transplanted patients for each group. Results: (*⫽p⬍0,05 vs EC; see table) Conclusion: In clinical lung preservation, low potassium dextrane solution is superior to Euro Collins威 solution. (mean ⴞ SEM)
EC
LPD
Ischemia (h) 1st lung Ischemia (h) 2nd lung Ventilation (days) Stay on ICU (days)
4.2 ⫾ 0.2 6.0 ⫾ 0.4 22 ⫾ 7 30 ⫾ 46
5.0 ⫾ 0.3* 7.0 ⫾ 0.3* 10 ⫾ 2 20 ⫾ 21
AaDO2 (day 0) AaDO2 (day 1) AaDO2 (day 3) 30-d-mortality (%)
EC
LPD
276 ⫾ 25 143 ⫾ 20 101 ⫹ 18 12.5
172 ⫹ 16* 118 ⫹ 14 73 ⫹ 7 7.9
12 ORIGIN OF NEOINTIMAL SMOOTH MUSCLE CELLS IN HUMAN CARDIAC ALLOGRAFT CORONARY ARTERY VASCULOPATHY C. Atkinson, J. Horsley, M. Southwood, C. Phillpotts, J. Wallwork, M.J. Goddard, Pathology, Papworth Hospital, Cambridge, United Kingdom Background-Transplant coronary artery vasculopathy (CAV) is an obliterative process that leads to lumen occlusion and cardiac failure. Current theories suggest that the process evolves over time in response to inflammation and proliferation of donor derived medial vascular smooth muscle cells (VSMC). Animal models of cardiac transplantation have suggested the origin of VSMC’s within the neointima to be derived from recipient circulating progenitor cells. By using sex mis-matched recipients and donors, and a Y specific chromosome probe, the aim of this investigation was to determine the origin of the neointimal VSMC’s within a human cardiac allograft model. Method-Post mortem coronary arteries from 14 patients previously assessed histologically to have CAV were analysed. 8 male recipients of female donor organs, 2 female to female, and 4 male to male transplants. A double immunocytochemistry and in-situ hybridisation technique using a Y chromosome DNA probe and either antibodies to smooth muscle actin, macrophages (CD68), or T cells (CD3) were employed. Results-No Y chromosome bodies could be identified in the cases of the female to female allografts. In the 4 male donor and male recipients cases all cells were positive for the Y chromosome probe. In the sex mis-matched transplants, the inflammatory cells marked with CD3 or CD68 were dual positive for Y chromosome
59
DNA probe. Flattened cells positive for Y chromosome were observed just beneath the endothelial surface. When double stained these were identified as infiltrating macrophages. No double staining smooth muscle cells and Y chromosome positive cells could be identified within the neointima. Conclusion-This study confirms the source of smooth muscle cells of the neointima of CAV lesions to be of donor origin. Circulating progenitor cells do not appear to play a role within the neointima as suggested in animal model studies. 13 INTERLEUKIN-1 AND RISK OF CORONARY ARTERY DISEASE IN HEART TRANSPLANT PATIENTS C.A. Labarrere,1 R.W. Benner,1 D.R. Nelson,2 M.H. Al-Hassani,1 S.J. Miller,4 H.J. Eisen,3 1Division of Experimental Pathology, Methodist Research Institute at Clarian Health, Indianapolis, IN; 2 Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, OH; 3Department of Cardiology, Temple University, Philadelphia, PA; 4Methodist Research Institute at Clarian Health, Indianapolis, IN Purpose: The expression of intercellular adhesion molecule-1 (ICAM-1) on arterial endothelium and increased levels of ICAM-1 in circulation have been implicated in the development of transplant coronary artery disease (CAD). We studied whether interleukin-1 (IL-1), known to stimulate ICAM-1, was associated with increased ICAM-1 levels and subsequent CAD. Procedure: Soluble IL-1 and ICAM-1 levels were measured in serial serum samples (4.5 ⫾ 1.2/patient) using a sandwich ELISA. Serum samples were obtained in the first 3 months post-transplantation from 120 patients. Matching endomyocardial biopsies were studied immunohistochemically for arterial ICAM-1 expression and endomyocardial IL-1 levels. Serial coronary angiograms (3.7 ⫾ 0.2/patient) were assessed for CAD. We used Cox and logistic regression for data analyses. Results: We found a significant correlation (p⫽0.003) between elevated soluble IL-1 levels and increased arterial and arteriolar endothelial ICAM-1 expression within endomyocardial biopsies. We also found a significant relationship between soluble IL-1 and soluble ICAM-1 levels during the follow-up period (p⫽0.01). Moreover, endomyocardial biopsies from patients with elevated arterial and arteriolar endothelial ICAM-1 and soluble IL-1 showed higher IL-1 expression on macrophages. Early elevated soluble IL-1 levels were significantly associated (p⫽0.02) with subsequent development of transplant CAD. Conclusions: Elevated IL-1 levels in endomyocardial biopsies and circulation during the first 3 months post-transplantation are associated with elevated soluble ICAM-1 levels, arterial and arteriolar endothelial ICAM-1 expression, and subsequent development of transplant CAD. Soluble IL-1 can be used to identify patients at risk of developing transplant CAD. 14 THE LOSS OF FUNCTION OF FAS-L MAY CONTRIBUTE TO THE ACCELERATED NATURE OF TRANSPLANT CORONARY ARTERY VASCULOPATHY C. Atkinson, N. Dennett, R. Barcia, M. Southwood, J. Wallwork, J. McLeod, M. Goddard, Pathology, Papworth Hospital, Cambridge, United Kingdom Background-Recent insights into immunomodulatory mechanisms by which monocyte/macrophages and T cells, central to the
Abstracts
11 EFFECT OF PERFADEX威 IN CLINICAL LUNG PRESERVATION C.T. Mueller,1 F. Kur,2 H. Fuerst,1 B. Reichart,2 1Department of Surgery, Ludwig-Maximilians University, Munich, Germany; 2 Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany In experimental lung transplantation, the superiority of low potassium dextrane (LPD, Perfadex威) over Euro Collins威 solution (EC) was demonstrated. In clinical lung transplantation, there is ongoing discussion about the superiority of LPD. Method: Patients undergoing single- (SLTx: EC n⫽31; LPD n⫽37) or double- (DLTx: EC n⫽17; LPD n⫽39) lung transplantation were investigated. Following iv infusion of PgI2, donor lungs were flushed with EC (n⫽48) or LPD (n⫽76), insufflated with O2 (FiO2⫽1,0) and stored in a hypothermic state. Duration of ischemia of the first and second organ and duration of ventilation were analized. Graft function was evaluated according to AaDO2 after transplantation (day 0) and at day 1 and 3 post Tx. 30 - day-mortality rate is given in % of transplanted patients for each group. Results: (*⫽p⬍0,05 vs EC; see table) Conclusion: In clinical lung preservation, low potassium dextrane solution is superior to Euro Collins威 solution. (mean ⴞ SEM)
EC
LPD
Ischemia (h) 1st lung Ischemia (h) 2nd lung Ventilation (days) Stay on ICU (days)
4.2 ⫾ 0.2 6.0 ⫾ 0.4 22 ⫾ 7 30 ⫾ 46
5.0 ⫾ 0.3* 7.0 ⫾ 0.3* 10 ⫾ 2 20 ⫾ 21
AaDO2 (day 0) AaDO2 (day 1) AaDO2 (day 3) 30-d-mortality (%)
EC
LPD
276 ⫾ 25 143 ⫾ 20 101 ⫹ 18 12.5
172 ⫹ 16* 118 ⫹ 14 73 ⫹ 7 7.9
12 ORIGIN OF NEOINTIMAL SMOOTH MUSCLE CELLS IN HUMAN CARDIAC ALLOGRAFT CORONARY ARTERY VASCULOPATHY C. Atkinson, J. Horsley, M. Southwood, C. Phillpotts, J. Wallwork, M.J. Goddard, Pathology, Papworth Hospital, Cambridge, United Kingdom Background-Transplant coronary artery vasculopathy (CAV) is an obliterative process that leads to lumen occlusion and cardiac failure. Current theories suggest that the process evolves over time in response to inflammation and proliferation of donor derived medial vascular smooth muscle cells (VSMC). Animal models of cardiac transplantation have suggested the origin of VSMC’s within the neointima to be derived from recipient circulating progenitor cells. By using sex mis-matched recipients and donors, and a Y specific chromosome probe, the aim of this investigation was to determine the origin of the neointimal VSMC’s within a human cardiac allograft model. Method-Post mortem coronary arteries from 14 patients previously assessed histologically to have CAV were analysed. 8 male recipients of female donor organs, 2 female to female, and 4 male to male transplants. A double immunocytochemistry and in-situ hybridisation technique using a Y chromosome DNA probe and either antibodies to smooth muscle actin, macrophages (CD68), or T cells (CD3) were employed. Results-No Y chromosome bodies could be identified in the cases of the female to female allografts. In the 4 male donor and male recipients cases all cells were positive for the Y chromosome probe. In the sex mis-matched transplants, the inflammatory cells marked with CD3 or CD68 were dual positive for Y chromosome
59
DNA probe. Flattened cells positive for Y chromosome were observed just beneath the endothelial surface. When double stained these were identified as infiltrating macrophages. No double staining smooth muscle cells and Y chromosome positive cells could be identified within the neointima. Conclusion-This study confirms the source of smooth muscle cells of the neointima of CAV lesions to be of donor origin. Circulating progenitor cells do not appear to play a role within the neointima as suggested in animal model studies. 13 INTERLEUKIN-1 AND RISK OF CORONARY ARTERY DISEASE IN HEART TRANSPLANT PATIENTS C.A. Labarrere,1 R.W. Benner,1 D.R. Nelson,2 M.H. Al-Hassani,1 S.J. Miller,4 H.J. Eisen,3 1Division of Experimental Pathology, Methodist Research Institute at Clarian Health, Indianapolis, IN; 2 Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, OH; 3Department of Cardiology, Temple University, Philadelphia, PA; 4Methodist Research Institute at Clarian Health, Indianapolis, IN Purpose: The expression of intercellular adhesion molecule-1 (ICAM-1) on arterial endothelium and increased levels of ICAM-1 in circulation have been implicated in the development of transplant coronary artery disease (CAD). We studied whether interleukin-1 (IL-1), known to stimulate ICAM-1, was associated with increased ICAM-1 levels and subsequent CAD. Procedure: Soluble IL-1 and ICAM-1 levels were measured in serial serum samples (4.5 ⫾ 1.2/patient) using a sandwich ELISA. Serum samples were obtained in the first 3 months post-transplantation from 120 patients. Matching endomyocardial biopsies were studied immunohistochemically for arterial ICAM-1 expression and endomyocardial IL-1 levels. Serial coronary angiograms (3.7 ⫾ 0.2/patient) were assessed for CAD. We used Cox and logistic regression for data analyses. Results: We found a significant correlation (p⫽0.003) between elevated soluble IL-1 levels and increased arterial and arteriolar endothelial ICAM-1 expression within endomyocardial biopsies. We also found a significant relationship between soluble IL-1 and soluble ICAM-1 levels during the follow-up period (p⫽0.01). Moreover, endomyocardial biopsies from patients with elevated arterial and arteriolar endothelial ICAM-1 and soluble IL-1 showed higher IL-1 expression on macrophages. Early elevated soluble IL-1 levels were significantly associated (p⫽0.02) with subsequent development of transplant CAD. Conclusions: Elevated IL-1 levels in endomyocardial biopsies and circulation during the first 3 months post-transplantation are associated with elevated soluble ICAM-1 levels, arterial and arteriolar endothelial ICAM-1 expression, and subsequent development of transplant CAD. Soluble IL-1 can be used to identify patients at risk of developing transplant CAD. 14 THE LOSS OF FUNCTION OF FAS-L MAY CONTRIBUTE TO THE ACCELERATED NATURE OF TRANSPLANT CORONARY ARTERY VASCULOPATHY C. Atkinson, N. Dennett, R. Barcia, M. Southwood, J. Wallwork, J. McLeod, M. Goddard, Pathology, Papworth Hospital, Cambridge, United Kingdom Background-Recent insights into immunomodulatory mechanisms by which monocyte/macrophages and T cells, central to the