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Original Research |

Long-Term Effect of Sirolimus on Serum VEGF-D Levels in Patients with Lymphangioleiomyomatosis

Angelo M. Taveira-DaSilva, M.D., Ph.D.; Amanda M. Jones, C.R.N.P.; Patricia Julien-Williams, C.R.N.P.; Mario Stylianou, Ph.D.; Joel Moss, M.D., Ph.D.
Author and Funding Information

Authors contributions:

Angelo M. Taveira-DaSilva and Joel Moss are responsible for study design, data analysis and writing of the manuscript.

Amanda M. Jones and Patricia Julien-Williams collected and reviewed clinical data.

Mario Stylianou performed the statistical analysis.

This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH grant 95-H-0186.

This is an original manuscript that has never been published nor is it being considered for publication elsewhere. The manuscript has been seen and approved by all authors. All authors take responsibility for the integrity of the data and the data analysis, and for the integrity of the submission. The objectives and procedures undertaken are honestly disclosed. None of the authors has any financial conflicts of interest.

1Cardiovascular and Pulmonary Branch, NHLBI, NIH, Building 10, Room 6D03, MSC 1590, Bethesda, Maryland 20892-1590, USA

2Office of Biostatistics Research, NHLBI, NIH, Rockledge 2/Room 9198, MSC 7938, Bethesda, Maryland 20892-7938, USA

Corresponding author: Angelo M. Taveira-DaSilva, M.D., Ph.D. Cardiovascular and Pulmonary Branch, NHLBI, NIH, Building 10, Room 6D03, MSC 1590, Bethesda, Maryland 20892-1590, USA


Copyright 2017, . All Rights Reserved.


Chest. 2017. doi:10.1016/j.chest.2017.05.012
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Abstract

Background  Sirolimus reduces serum levels of VEGF-D, size of chylous effusions, lymphangioleiomyomas, and angiomyolipomas, and stabilizes lung function in patients with lymphangioleiomyomatosis.

Methods  To determine whether reductions in VEGF-D levels are sustained over time, and parallel changes in lung function and lymphatic disease, we evaluated 25 patients with lymphangioleiomyomatosis and measured VEGF-D levels, lung function and extent of lymphatic disease before and during sirolimus therapy

Results  Treatment with sirolimus stabilized FEV1 and DLCO over a period of 4.5±1.6 years, caused resolution of lymphatic disease, and reduced angiomyolipomas size and VEGF-D levels (3,720±3,020 to 945±591 pg/ml, p<0.0001).. Yearly changes in % predicted FEV1 and DLCO were reduced from -7.4±1.4 to -0.3±0.5 % (p<0.001) and -6.4±0.9 to -0.4±0.5 % (p<0.001), respectively. Lower VEGF-D levels correlated with sirolimus therapy (p<0.001), but no significant relationship was observed between reduction in VEGF-D levels and FEV1 and DLCO during sirolimus therapy. The magnitude of VEGF-D decline was not related to the effect on lung function. Patients with lymphatic disease had higher serum VEGF-D levels, greater reduction in VEGF-D levels, and better long-term sustained improvement in lung function during sirolimus therapy, than those without lymphatic disease.

Conclusions  Sirolimus therapy stabilizes lung function over many years of therapy while producing a sustained reduction in VEGF-D levels in patients with elevated pre-therapy levels. An association was not demonstrated between the magnitude of VEGF-D decline and the beneficial effect of sirolimus on lung function. Persistent improvement in lung function was observed in patients with lymphatic disease.


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