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Markers of endothelial dysfunction and severity of hypoxaemia in the Eisenmenger syndrome

Published online by Cambridge University Press:  16 September 2005

Rosangela de P. S. Soares ,
Nair Y. Maeda ,
Sérgio P. Bydlowski  and
Antonio Augusto Lopes
Rosangela de P. S. Soares
Affiliation:
Pro-Sangue Foundation, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil
Nair Y. Maeda
Affiliation:
Pro-Sangue Foundation, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil
Sérgio P. Bydlowski
Affiliation:
Pro-Sangue Foundation, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil
Antonio Augusto Lopes
Affiliation:
Department of Pediatric Cardiology and Adult Congenital Heart Disease, Heart Institute, School of Medicine, University of São Paulo, São Paulo, Brazil
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Abstract

Endothelial dysfunction has been reported in hypoxaemic patients with the Eisenmenger syndrome, but a direct correlation between levels of endothelial markers and the severity of hypoxaemia has not been explored. With this in mind, we compared the levels in the plasma of tissue-type plasminogen activator, thrombomodulin, and von Willebrand factor in 25 patients with the Eisenmenger syndrome. They had a median age of 31 years, and were divided into 2 groups according to their recent clinical history. Thus, 18 patients were stable, being in functional class II or III, seen as outpatients, and having peripheral saturations of oxygen of 89 plus or minus 5 percent. In contrast, 7 patients were unstable, showing episodes of symptoms placing them in functional class IV, requiring care in hospital, and manifesting saturations of oxygen of 77 plus or minus 5 percent. We were able to follow 12 patients, 8 who were stable and 4 unstable, for 24 months. At baseline, levels of von Willebrand factor were higher in the unstable patients when compared to those who were stable, at 142 plus or minus 29 and 110 plus or minus 25 units per decilitre, respectively (p equal to 0.013). This correlated positively with oxygen desaturation (p less than 0.020). The structural abnormalities also correlated positively with the magnitude of hypoxaemia (p less than 0.020). Levels remained higher in the unstable patients throughout the period of follow-up (p equal to 0.006). Tissue-type plasminogen activator was also increased, at 14.3 plus or minus 8.4 versus 6.5 plus or minus 2.7 nanograms per millilitre in controls (p less than 0.001), whereas thrombomodulin was decreased, with values of 14.4 versus 34.6 nanograms per millilitre in controls (p for median values of less than 0.001). There was no correlation with saturations of oxygen. We conclude that measurement of von Willebrand factor, as compared with tissue-type plasminogen activator and thrombomodulin, will prove a better marker of endothelial response to hypoxaemia in patients with the Eisenmenger syndrome.

Keywords

Endotheliumpulmonary hypertensionvon Willebrand factorthrombomodulintissue-type plasminogen activator
Type
Original Article
Information
Cardiology in the Young , Volume 15 , Issue 5 , October 2005 , pp. 504 - 513
Copyright
© 2005 Cambridge University Press

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References

Michiels C, Arnould T, Remacle J. Endothelial cell responses to hypoxia: initiation of a cascade of cellular interactions. Biochim Biophys Acta 2000; 1497: 1–10.Google Scholar
Ginis I, Mentzer SJ, Faller DV. Oxygen tension regulates neutrophil adhesion to human endothelial cells via an LFA-1-dependent mechanism. J Cell Physiol 1993; 157: 569–578.Google Scholar
Karakurum M, Shreeniwas R, Chen J, et al. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest 1994; 93: 1564–1570.Google Scholar
Ferreiro CR, Chagas AC, Carvalho MH, et al. Influence of hypoxia on nitric oxide synthase activity and gene expression in children with congenital heart disease: a novel pathophysiological adaptive mechanism. Circulation 2001; 103: 2272–2276.Google Scholar
Horigome H, Murakami T, Isobe T, Nagasawa T, Matsui A. Soluble P-selectin and thrombomodulin-protein C – protein S pathway in cyanotic congenital heart disease with secondary erythrocytosis. Thromb Res 2003; 112: 223–227.Google Scholar
Perloff JK, Hart EM, Greaves SM, Miner PD, Child JS. Proximal pulmonary arterial and intrapulmonary radiologic features of Eisenmenger syndrome and primary pulmonary hypertension. Am J Cardiol 2003; 92: 182–187.Google Scholar
Silversides CK, Granton JT, Konen E, Hart MA, Webb GD, Therrien J. Pulmonary thrombosis in adults with Eisenmenger syndrome. J Am Coll Cardiol 2003; 42: 1982–1987.Google Scholar
Caramurú LH, Maeda NY, Bydlowski SP, Lopes AA. Age-dependent likelihood of in situ thrombosis in secondary pulmonary hypertension. Clin Appl Thromb Hemost 2004; 10: 217–223.Google Scholar
Droste DW, Ritter MA, Monning G, Kemeny V, Breithhardt G, Ringelstein EB. Abundance of microembolic signals detected by transcranial doppler ultrasound in a patient with Eisenmenger's syndrome. Cerebrovasc Dis 1999; 9: 334–336.Google Scholar
Lopes AA, Soares RPS, Maeda NY. A mathematical framework for group analysis of von Willebrand factor multimeric composition following luminography. Braz J Med Biol Res 2002; 35: 1259–1263.Google Scholar
Takahashi H, Ito S, Hanano M, et al. Circulating thrombomodulin as a novel endothelial cell marker: comparison of its behavior with von Willebrand factor and tissue-type plasminogen activator. Am J Hematol 1992; 41: 32–39.Google Scholar
Weir EK, Archer SL. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 1995; 9: 183–189.Google Scholar
Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 13S–24S.Google Scholar
Mandegar M, Fung Y-CB, Huang W, Remillard CV, Rubin LJ, Yuan JX-J. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 2004; 68: 75–103.Google Scholar
Droma Y, Hanaoka M, Ota M, et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 2002; 106: 826–830.Google Scholar
Cacoub P, Dorent R, Maistre G, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993; 71: 448–450.Google Scholar
Cacoub P, Karmochkine M, Dorent R, et al. Plasma levels of thrombomodulin in pulmonary hypertension. Am J Med 1996; 101: 160–164.Google Scholar
Goerge T, Niemeyer A, Rogge P, Ossig R, Oberleithner H, Schneider SW. Secretion pores in human endothelial cells during acute hypoxia. J Membr Biol 2002; 187: 203–211.Google Scholar
Pinsky DJ, Naka Y, Liao H, et al. Hypoxia-induced exocytosis of endothelial cell Weibel–Palade bodies: a mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97: 493–500.Google Scholar
Dong J-F, Moake JL, Nolasco L, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100: 4033–4039.Google Scholar
Pimanda J, Hogg P. Control of von Willebrand factor multimer size and implications for disease. Blood Rev 2002; 16: 185–192.Google Scholar
Pareti FI, Lattuada A, Bressi C, et al. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation 2000; 102: 1290–1295.Google Scholar
Padilla A, Moake JL, Bernardo A, et al. P-selectin anchors newly released ultra-large von Willebrand factor multimers to the endothelial cell surface. Blood 2004; 103: 2150–2156.Google Scholar
Pepper MS, Rosnoblet C, Di Sanza C, Kruithof EK. Synergistic induction of t-PA by vascular endothelial growth factor and basic fibroblast growth factor and localization of t-PA to Weibel–Palade bodies in bovine microvascular endothelial cells. Thromb Haemost 2001; 86: 702–709.Google Scholar
Shreeniwas R, Ogawa S, Cozzolino F, et al. Macrovascular and microvascular endothelium during long-term hypoxia: alterations in cell growth, monolayer permeability, and cell surface coagulant properties. J Cell Physiol 1991; 146: 8–17.Google Scholar
Esmon CT. The roles of protein C and TM in the regulation of blood coagulation. J Biol Chem 1989; 56: 151–157.Google Scholar
Ogawa S, Gerlach H, Esposito C, Pasagin-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. J Clin Invest 1990; 85: 1090–1098.Google Scholar
Healy AM, Hancok WW, Christie PD, Rayburn HB, Rosenberg RD. Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood 1998; 92: 4188–4197.Google Scholar