Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension.
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.


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+ progenitor cells 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 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.
Diller
Gerhard-Paul
GP
Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. g.diller@imperial.ac.uk
van Eijl
Sven
S
Okonko
Darlington O
DO
Howard
Luke S
LS
Ali
Omar
O
Thum
Thomas
T
Wort
Stephen J
SJ
Bédard
Elisabeth
E
Gibbs
J Simon R
JS
Bauersachs
Johann
J
Hobbs
Adrian J
AJ
Wilkins
Martin R
MR
Gatzoulis
Michael A
MA
Wharton
John
J
D000071916:AC133 Antigen; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000097:blood; D004314:Down Syndrome / Q000473:pathology / Q000503:physiopathology; D004541:Eisenmenger Complex / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000166:cytology*; D015444:Exercise; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010455:Peptides / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D011687:Purines / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013450:Sulfones / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D006023:Glycoproteins; D018836:Inflammation Mediators; C000606023:PROM1 protein, human; D010455:Peptides; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D020097:Natriuretic Peptide, Brain; C018524:N,N-dimethylarginine; D001120:Arginine; D000068677:Sildenafil Citrate; D040301:Vascular Endothelial Growth Factor Receptor-2; D006152:Cyclic GMP