Published Online
on June 2, 2008

A more recent version of this article appeared on June 10, 2008

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Submitted on May 14, 2007
Accepted on March 7, 2008

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Gerhard-Paul Diller MD^*, Sven van Eijl PhD, Darlington O. Okonko MRCP, Luke S. Howard MRCP, Omar Ali MRCP, Thomas Thum MD, Stephen J. Wort MRCP, Elisabeth Bédard FRCPC, J. Simon R. Gibbs FRCP, Johann Bauersachs MD, Adrian J. Hobbs PhD, Martin R. Wilkins FRCP, Michael A. Gatzoulis PhD, and John Wharton PhD

From the Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, London, UK (G.-P.D., E.B., S.J.W., M.A.G.); National Heart and Lung Institute (G.-P.D., D.O.O., J.S.W., M.A.G., J.S.R.G., L.S.H) and Department of Experimental Medicine and Toxicology (S.v.E., O.A., M.R.W., J.W.), Imperial College London, London, UK; Julius-Maximilians-Universität, Medizinische Klinik I, Würzburg, Germany (T.T., J.B); National Pulmonary Hypertension Service, Hammersmith Hospital, London, UK (L.S.H., S.R.G.); and Wolfson Institute for Biomedical Research, University College London, London, UK (A.J.H).

^* To whom correspondence should be addressed. E-mail: g.diller{at}imperial.ac.uk.

Background—Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression.

Methods and Results—We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34⁺, CD34⁺/AC133⁺, CD34⁺/KDR⁺, and CD34⁺/AC133⁺/KDR⁺ EPCs was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures also was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies.

Conclusions—Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

Key words: endothelial progenitor cells • endothelium • heart defects, congenital • hypertension, pulmonary • pulmonary heart disease

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