Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts

Maarten A. Lijkwan, David T Cooke, Jasper M. Martens, Murray H. Kown, Seiichiro Murata, Shannon H. Peterson, E. Grant Hoyt, Robert C. Robbins

Research output: Contribution to journalArticle

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Abstract

Background: Graft coronary artery disease (GCAD) limits allograft survival after cardiac transplantation. The objective of this study was to correlate GCAD with the level of immunosuppression in an established allogeneic rodent cardiac chronic rejection model to better understand the mechanisms of GCAD in this system. Methods: Donor PVG hearts were transplanted into the abdomen of ACI rats. Six recipient groups received either 10, 7.5 or 5 mg/kg/day of oral cyclosporine (CsA), for 90 (10mg/90d, 7.5mg/90d, 5mg/90d) or 10 days (10mg/10d, 7.5mg/10d, 5mg/10d; n = 10 all groups), and grafts procured on Day 90. GCAD was assessed by histology for percent luminal narrowing (%LN), percent affected vessels (%AV) and intima/media ratio (I/M ratio). Sections were stained for ED1-positive macrophages and MHC Class II-positive cells. Results: The 10mg/90d treatment group showed significantly reduced GCAD compared with the 5mg/10d treatment group (%LN = 4.3 ± 3.1% vs 39 ± 11.9%, p < 0.05). The 7.5mg/90d group had a reduced %LN and I/M ratio compared with the 5mg/10d group (%LN = 8.0 ± 3.5% vs 39 ± 11.9%, p < 0.05; I/M ratio = 0.06 ± 0.02 vs 0.41 ± 0.14, p < 0.05). There was a trend toward reduction of GCAD with both increasing the dose of CsA as well as the duration of treatment. Continuous treatment with CsA reduced perivascular macrophage and MHC II cell infiltration. Macrophage infiltrates correlated strongly with GCAD (R2 > 0.90, p < 0.01), and MHC II infiltrates showed a weak correlation, although not statistically significant (R2 > 0.56, p = NS). Conclusions: This study further defines the effect of cyclosporine on GCAD in this cardiac transplantation model. In this system, higher dose and longer duration of treatment with CsA markedly reduces macrophage and MHC II infiltration, correlating with diminished GCAD. However, increasing dose and duration of CsA did not completely eliminate the development of GCAD. Non-immunologic factors could contribute to this occurrence.

Original languageEnglish (US)
Pages (from-to)439-445
Number of pages7
JournalJournal of Heart and Lung Transplantation
Volume24
Issue number4
DOIs
StatePublished - Apr 2005
Externally publishedYes

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Cyclosporine
Allografts
Coronary Artery Disease
Rodentia
Transplants
Therapeutics
Heart Transplantation
Inbred ACI Rats
Macrophages
Abdomen
Immunosuppression
Histology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Transplantation

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Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts. / Lijkwan, Maarten A.; Cooke, David T; Martens, Jasper M.; Kown, Murray H.; Murata, Seiichiro; Peterson, Shannon H.; Hoyt, E. Grant; Robbins, Robert C.

In: Journal of Heart and Lung Transplantation, Vol. 24, No. 4, 04.2005, p. 439-445.

Research output: Contribution to journalArticle

Lijkwan, Maarten A. ; Cooke, David T ; Martens, Jasper M. ; Kown, Murray H. ; Murata, Seiichiro ; Peterson, Shannon H. ; Hoyt, E. Grant ; Robbins, Robert C. / Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts. In: Journal of Heart and Lung Transplantation. 2005 ; Vol. 24, No. 4. pp. 439-445.
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abstract = "Background: Graft coronary artery disease (GCAD) limits allograft survival after cardiac transplantation. The objective of this study was to correlate GCAD with the level of immunosuppression in an established allogeneic rodent cardiac chronic rejection model to better understand the mechanisms of GCAD in this system. Methods: Donor PVG hearts were transplanted into the abdomen of ACI rats. Six recipient groups received either 10, 7.5 or 5 mg/kg/day of oral cyclosporine (CsA), for 90 (10mg/90d, 7.5mg/90d, 5mg/90d) or 10 days (10mg/10d, 7.5mg/10d, 5mg/10d; n = 10 all groups), and grafts procured on Day 90. GCAD was assessed by histology for percent luminal narrowing ({\%}LN), percent affected vessels ({\%}AV) and intima/media ratio (I/M ratio). Sections were stained for ED1-positive macrophages and MHC Class II-positive cells. Results: The 10mg/90d treatment group showed significantly reduced GCAD compared with the 5mg/10d treatment group ({\%}LN = 4.3 ± 3.1{\%} vs 39 ± 11.9{\%}, p < 0.05). The 7.5mg/90d group had a reduced {\%}LN and I/M ratio compared with the 5mg/10d group ({\%}LN = 8.0 ± 3.5{\%} vs 39 ± 11.9{\%}, p < 0.05; I/M ratio = 0.06 ± 0.02 vs 0.41 ± 0.14, p < 0.05). There was a trend toward reduction of GCAD with both increasing the dose of CsA as well as the duration of treatment. Continuous treatment with CsA reduced perivascular macrophage and MHC II cell infiltration. Macrophage infiltrates correlated strongly with GCAD (R2 > 0.90, p < 0.01), and MHC II infiltrates showed a weak correlation, although not statistically significant (R2 > 0.56, p = NS). Conclusions: This study further defines the effect of cyclosporine on GCAD in this cardiac transplantation model. In this system, higher dose and longer duration of treatment with CsA markedly reduces macrophage and MHC II infiltration, correlating with diminished GCAD. However, increasing dose and duration of CsA did not completely eliminate the development of GCAD. Non-immunologic factors could contribute to this occurrence.",
author = "Lijkwan, {Maarten A.} and Cooke, {David T} and Martens, {Jasper M.} and Kown, {Murray H.} and Seiichiro Murata and Peterson, {Shannon H.} and Hoyt, {E. Grant} and Robbins, {Robert C.}",
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T1 - Cyclosporine treatment of high dose and long duration reduces the severity of graft coronary artery disease in rodent cardiac allografts

AU - Lijkwan, Maarten A.

AU - Cooke, David T

AU - Martens, Jasper M.

AU - Kown, Murray H.

AU - Murata, Seiichiro

AU - Peterson, Shannon H.

AU - Hoyt, E. Grant

AU - Robbins, Robert C.

PY - 2005/4

Y1 - 2005/4

N2 - Background: Graft coronary artery disease (GCAD) limits allograft survival after cardiac transplantation. The objective of this study was to correlate GCAD with the level of immunosuppression in an established allogeneic rodent cardiac chronic rejection model to better understand the mechanisms of GCAD in this system. Methods: Donor PVG hearts were transplanted into the abdomen of ACI rats. Six recipient groups received either 10, 7.5 or 5 mg/kg/day of oral cyclosporine (CsA), for 90 (10mg/90d, 7.5mg/90d, 5mg/90d) or 10 days (10mg/10d, 7.5mg/10d, 5mg/10d; n = 10 all groups), and grafts procured on Day 90. GCAD was assessed by histology for percent luminal narrowing (%LN), percent affected vessels (%AV) and intima/media ratio (I/M ratio). Sections were stained for ED1-positive macrophages and MHC Class II-positive cells. Results: The 10mg/90d treatment group showed significantly reduced GCAD compared with the 5mg/10d treatment group (%LN = 4.3 ± 3.1% vs 39 ± 11.9%, p < 0.05). The 7.5mg/90d group had a reduced %LN and I/M ratio compared with the 5mg/10d group (%LN = 8.0 ± 3.5% vs 39 ± 11.9%, p < 0.05; I/M ratio = 0.06 ± 0.02 vs 0.41 ± 0.14, p < 0.05). There was a trend toward reduction of GCAD with both increasing the dose of CsA as well as the duration of treatment. Continuous treatment with CsA reduced perivascular macrophage and MHC II cell infiltration. Macrophage infiltrates correlated strongly with GCAD (R2 > 0.90, p < 0.01), and MHC II infiltrates showed a weak correlation, although not statistically significant (R2 > 0.56, p = NS). Conclusions: This study further defines the effect of cyclosporine on GCAD in this cardiac transplantation model. In this system, higher dose and longer duration of treatment with CsA markedly reduces macrophage and MHC II infiltration, correlating with diminished GCAD. However, increasing dose and duration of CsA did not completely eliminate the development of GCAD. Non-immunologic factors could contribute to this occurrence.

AB - Background: Graft coronary artery disease (GCAD) limits allograft survival after cardiac transplantation. The objective of this study was to correlate GCAD with the level of immunosuppression in an established allogeneic rodent cardiac chronic rejection model to better understand the mechanisms of GCAD in this system. Methods: Donor PVG hearts were transplanted into the abdomen of ACI rats. Six recipient groups received either 10, 7.5 or 5 mg/kg/day of oral cyclosporine (CsA), for 90 (10mg/90d, 7.5mg/90d, 5mg/90d) or 10 days (10mg/10d, 7.5mg/10d, 5mg/10d; n = 10 all groups), and grafts procured on Day 90. GCAD was assessed by histology for percent luminal narrowing (%LN), percent affected vessels (%AV) and intima/media ratio (I/M ratio). Sections were stained for ED1-positive macrophages and MHC Class II-positive cells. Results: The 10mg/90d treatment group showed significantly reduced GCAD compared with the 5mg/10d treatment group (%LN = 4.3 ± 3.1% vs 39 ± 11.9%, p < 0.05). The 7.5mg/90d group had a reduced %LN and I/M ratio compared with the 5mg/10d group (%LN = 8.0 ± 3.5% vs 39 ± 11.9%, p < 0.05; I/M ratio = 0.06 ± 0.02 vs 0.41 ± 0.14, p < 0.05). There was a trend toward reduction of GCAD with both increasing the dose of CsA as well as the duration of treatment. Continuous treatment with CsA reduced perivascular macrophage and MHC II cell infiltration. Macrophage infiltrates correlated strongly with GCAD (R2 > 0.90, p < 0.01), and MHC II infiltrates showed a weak correlation, although not statistically significant (R2 > 0.56, p = NS). Conclusions: This study further defines the effect of cyclosporine on GCAD in this cardiac transplantation model. In this system, higher dose and longer duration of treatment with CsA markedly reduces macrophage and MHC II infiltration, correlating with diminished GCAD. However, increasing dose and duration of CsA did not completely eliminate the development of GCAD. Non-immunologic factors could contribute to this occurrence.

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