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Chronic cyanosis and vascular function: implications for patients with cyanotic congenital heart disease

Published online by Cambridge University Press:  26 April 2010

Rachael L. Cordina  and
David S. Celermajer
Rachael L. Cordina
Affiliation:
Department of Cardiology, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
David S. Celermajer*
Affiliation:
Department of Cardiology, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
*
Correspondence to: Dr D. S. Celermajer, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; E-mail: [email protected]
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Abstract

In patients with cyanotic congenital heart disease, chronic hypoxaemia leads to important changes in blood vessel function and structure. Some of these alterations are maladaptive and probably contribute to impaired cardiopulmonary performance and an increased incidence of thrombotic and embolic events. Recent evidence suggests that deranged endothelial function, a sequel of chronic cyanosis, could be an important factor in the pathogenesis of cyanosis-associated cardiovascular risk. In this article, we discuss the physiological and mechanical consequences of compensatory erythrocytosis and possible pathophysiological mechanisms of vascular dysfunction in chronic cyanosis.

Keywords

Cyanosiscongenital heart diseasehaemorheologyendothelial dysfunctionerythrocytosis
Type
Review
Information
Cardiology in the Young , Volume 20 , Issue 3 , June 2010 , pp. 242 - 253
Copyright
Copyright © Cambridge University Press 2010

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References

1. Lerman, A, Zeiher, AM. Endothelial function: cardiac events. Circulation 2005; 111: 363–368.CrossRefGoogle ScholarPubMed
2. Fischer, D, Rossa, S, Landmesser, U, et al. Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J 2005; 26: 65–69.CrossRefGoogle ScholarPubMed
3. Engelfriet, P, Boersma, E, Oechslin, E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on adult congenital heart disease. Eur Heart J 2005; 26: 2325–2333.CrossRefGoogle Scholar
4. Ammash, N, Warnes, CA. Cerebrovascular events in adult patients with cyanotic congenital heart disease. J Am Coll Cardiol 1996; 28: 768–772.CrossRefGoogle ScholarPubMed
5. Daliento, L, Somerville, J, Presbitero, P, et al. Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J 1998; 19: 1845–1855.CrossRefGoogle ScholarPubMed
6. 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.CrossRefGoogle ScholarPubMed
7. 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.CrossRefGoogle ScholarPubMed
8. Niwa, K, Perloff, JK, Kaplan, S, Child, JS, Miner, PD. Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart. J Am Coll Cardiol 1999; 34: 223–232.CrossRefGoogle ScholarPubMed
9. Oechslin, EN, Harrison, DA, Connelly, MS, Webb, GD, Siu, SC. Mode of death in adults with congenital heart disease. Am J Cardiol 2000; 86: 1111–1116.CrossRefGoogle ScholarPubMed
10. Pirofsky, B. The determination of blood viscosity in man by a method based on Poiseuille’s law. J Clin Invest 1953; 32: 292–298.CrossRefGoogle Scholar
11. Stuart, J, Kenny, MW. Blood rheology. J Clin Pathol 1980; 33: 417–429.CrossRefGoogle ScholarPubMed
12. House, SD, Lipowsky, HH. Microvascular hematocrit and red cell flux in rat cremaster muscle. Am J Physiol 1987; 252 (Part 2): H211–H222.Google ScholarPubMed
13. Lipowsky, HH, Firrell, JC. Microvascular hemodynamics during systemic hemodilution and hemoconcentration. Am J Physiol 1986; 250 (Part 2): H908–H922.Google ScholarPubMed
14. Fahraeus, R. The suspension stability of blood. Physiol Rev 1929; 9: 241–274.CrossRefGoogle Scholar
15. Lipowsky, HH, Usami, S, Chien, S. In vivo measurements of “apparent viscosity” and microvessel hematocrit in the mesentery of the cat. Microvasc Res 1980; 19: 297–319.CrossRefGoogle ScholarPubMed
16. Barbee, JH, Cokelet, GR. Prediction of blood flow in tubes with diameters as small as 29 microns. Microvasc Res 1971; 3: 17–21.CrossRefGoogle Scholar
17. Pries, AR, Neuhaus, D, Gaehtgens, P. Blood viscosity in tube flow: dependence on diameter and hematocrit. Am J Physiol 1992; 263 (Part 2): H1770–H1778.Google ScholarPubMed
18. Pries, AR, Secomb, TW. Microvascular blood viscosity in vivo and the endothelial surface layer. Am J Physiol Heart Circ Physiol 2005; 289: H2657–H2664.CrossRefGoogle ScholarPubMed
19. Linderkamp, O, Klose, HJ, Betke, K, et al. Increased blood viscosity in patients with cyanotic congenital heart disease and iron deficiency. J Pediatr 1979; 95: 567–569.CrossRefGoogle ScholarPubMed
20. Hutton, RD. The effect of iron deficiency on whole blood viscosity in polycythaemic patients. Br J Haematol 1979; 43: 191–199.CrossRefGoogle ScholarPubMed
21. Milligan, DW, MacNamee, R, Roberts, BE, Davies, JA. The influence of iron-deficient indices on whole blood viscosity in polycythaemia. Br J Haematol 1982; 50: 467–471.CrossRefGoogle ScholarPubMed
22. Pearson, TC, Grimes, AJ, Slater, NG, Wetherley-Mein, G. Viscosity and iron deficiency in treated polycythaemia. Br J Haematol 1981; 49: 123–127.CrossRefGoogle ScholarPubMed
23. Van de Pette, JE, Guthrie, DL, Pearson, TC. Whole blood viscosity in polycythaemia: the effect of iron deficiency at a range of haemoglobin and packed cell volumes. Br J Haematol 1986; 63: 369–375.CrossRefGoogle Scholar
24. Broberg, CS, Bax, BE, Okonko, DO, et al. Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease. J Am Coll Cardiol 2006; 48: 356–365.CrossRefGoogle ScholarPubMed
25. Iolster, NJ. Blood coagulation in children with cyanotic congenital heart disease. Acta Paediatr Scand 1970; 59: 551–557.CrossRefGoogle ScholarPubMed
26. Martelle, RR, Linde, LM. Cerebrovascular accidents with tetralogy of Fallot. Am J Dis Child 1961; 101: 206–209.Google ScholarPubMed
27. Maguire, JL, deVeber, G, Parkin, PC. Association between iron-deficiency anemia and stroke in young children. Pediatrics 2007; 120: 1053–1057.CrossRefGoogle ScholarPubMed
28. Koller, A, Sun, D, Kaley, G. Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro. Circ Res 1993; 72: 1276–1284.CrossRefGoogle ScholarPubMed
29. Tsai, AG, Friesenecker, B, McCarthy, M, Sakai, H, Intaglietta, M. Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model. Am J Physiol 1998; 275 (Part 2): H2170–H2180.Google ScholarPubMed
30. Hudak, ML, Jones, MD Jr, Popel, AS, Koehler, RC, Traystman, RJ, Zeger, SL. Hemodilution causes size-dependent constriction of pial arterioles in the cat. Am J Physiol 1989; 257 (Part 2): H912–H917.Google ScholarPubMed
31. Cabrales, P, Tsai, AG. Plasma viscosity regulates systemic and microvascular perfusion during acute extreme anemic conditions. Am J Physiol Heart Circ Physiol 2006; 291: H2445–H2452.CrossRefGoogle ScholarPubMed
32. Tsai, AG, Acero, C, Nance, PR, et al. Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion. Am J Physiol Heart Circ Physiol 2005; 288: H1730–H1739.CrossRefGoogle ScholarPubMed
33. Cooke, JP, Stamler, J, Andon, N, Davies, PF, McKinley, G, Loscalzo, J. Flow stimulates endothelial cells to release a nitrovasodilator that is potentiated by reduced thiol. Am J Physiol 1990; 259 (Part 2): H804–H812.Google ScholarPubMed
34. Pohl, U, Herlan, K, Huang, A, Bassenge, E. EDRF-mediated shear-induced dilation opposes myogenic vasoconstriction in small rabbit arteries. Am J Physiol 1991; 261 (Part 2): H2016–H2023.Google ScholarPubMed
35. Celermajer, DS, Sorensen, KE, Gooch, VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992; 340: 1111–1115.CrossRefGoogle ScholarPubMed
36. de Wit, C, Schafer, C, von Bismarck, P, Bolz, SS, Pohl, U. Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo. Pflugers Arch 1997; 434: 354–361.CrossRefGoogle ScholarPubMed
37. Wilcox, CS, Deng, X, Doll, AH, Snellen, H, Welch, WJ. Nitric oxide mediates renal vasodilation during erythropoietin-induced polycythemia. Kidney Int 1993; 44: 430–435.CrossRefGoogle ScholarPubMed
38. Lopez Ongil, SL, Saura, M, Lamas, S, Rodriguez Puyol, M, Rodriguez Puyol, D. Recombinant human erythropoietin does not regulate the expression of endothelin-1 and constitutive nitric oxide synthase in vascular endothelial cells. Exp Nephrol 1996; 4: 37–42.Google Scholar
39. Wang, XQ, Vaziri, ND. Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension 1999; 33: 894–899.CrossRefGoogle ScholarPubMed
40. Gidding, SS, Stockman, JA 3rd. Erythropoietin in cyanotic heart disease. Am Heart J 1988; 116 (Part 1): 128–132.CrossRefGoogle ScholarPubMed
41. Tyndall, MR, Teitel, DF, Lutin, WA, Clemons, GK, Dallman, PR. Serum erythropoietin levels in patients with congenital heart disease. J Pediatr 1987; 110: 538–544.CrossRefGoogle ScholarPubMed
42. Ogunshola, OO, Djonov, V, Staudt, R, Vogel, J, Gassmann, M. Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain. Am J Physiol Regul Integr Comp Physiol 2006; 290: R678–R684.CrossRefGoogle ScholarPubMed
43. Belhassen, L, Pelle, G, Sediame, S, et al. Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation. Blood 2001; 97: 1584–1589.CrossRefGoogle ScholarPubMed
44. Gillespie, JS, Sheng, H. Influence of haemoglobin and erythrocytes on the effects of EDRF, a smooth muscle inhibitory factor, and nitric oxide on vascular and non-vascular smooth muscle. Br J Pharmacol 1988; 95: 1151–1156.CrossRefGoogle ScholarPubMed
45. Rimar, S, Gillis, CN. Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Circulation 1993; 88: 2884–2887.CrossRefGoogle ScholarPubMed
46. Rich, GF, Roos, CM, Anderson, SM, Urich, DC, Daugherty, MO, Johns, RA. Inhaled nitric oxide: dose response and the effects of blood in the isolated rat lung. J Appl Physiol 1993; 75: 1278–1284.CrossRefGoogle ScholarPubMed
47. Madsen, PL, Scheuermann Freestone, M, Neubauer, S, Channon, K, Clarke, K. Haemoglobin and flow-mediated vasodilation. Clin Sci (Lond) 2006; 110: 467–473.CrossRefGoogle ScholarPubMed
48. Anand, IS, Chandrashekhar, Y, Wander, GS, Chawla, LS. Endothelium-derived relaxing factor is important in mediating the high output state in chronic severe anemia. J Am Coll Cardiol 1995; 25: 1402–1407.CrossRefGoogle Scholar
49. Defouilloy, C, Teiger, E, Sediame, S, et al. Polycythemia impairs vasodilator response to acetylcholine in patients with chronic hypoxemic lung disease. Am J Respir Crit Care Med 1998; 157 (Part 1): 1452–1460.CrossRefGoogle ScholarPubMed
50. Giannattasio, C, Piperno, A, Failla, M, Vergani, A, Mancia, G. Effects of hematocrit changes on flow-mediated and metabolic vasodilation in humans. Hypertension 2002; 40: 74–77.CrossRefGoogle ScholarPubMed
51. Oldershaw, PJ, Sutton, MG. Haemodynamic effects of haematocrit reduction in patients with polycythaemia secondary to cyanotic congenital heart disease. Br Heart J 1980; 44: 584–588.CrossRefGoogle ScholarPubMed
52. Rosenthal, A, Nathan, DG, Marty, AT, Button, LN, Miettinen, OS, Nadas, AS. Acute hemodynamic effects of red cell volume reduction in polycythemia of cyanotic congenital heart disease. Circulation 1970; 42: 297–308.CrossRefGoogle ScholarPubMed
53. Gladwin, MT, Lancaster, JR Jr, Freeman, BA, Schechter, AN. Nitric oxide’s reactions with hemoglobin: a view through the SNO-storm. Nat Med 2003; 9: 496–500.CrossRefGoogle ScholarPubMed
54. Gross, SS, Lane, P. Physiological reactions of nitric oxide and hemoglobin: a radical rethink. Proc Natl Acad Sci USA 1999; 96: 9967–9969.CrossRefGoogle ScholarPubMed
55. Han, TH, Pelling, A, Jeon, TJ, Gimzewski, JK, Liao, JC. Erythrocyte nitric oxide transport reduced by a submembrane cytoskeletal barrier. Biochim Biophys Acta 2005; 1723: 135–142.CrossRefGoogle ScholarPubMed
56. Liu, X, Samouilov, A, Lancaster, JR Jr, Zweier, JL. Nitric oxide uptake by erythrocytes is primarily limited by extracellular diffusion not membrane resistance. J Biol Chem 2002; 277: 26194–26199.CrossRefGoogle Scholar
57. Liao, JC, Hein, TW, Vaughn, MW, Huang, KT, Kuo, L. Intravascular flow decreases erythrocyte consumption of nitric oxide. Proc Natl Acad Sci U S A 1999; 96: 8757–8761.CrossRefGoogle ScholarPubMed
58. Kim-Shapiro, DB, Schechter, AN, Gladwin, MT. Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 2006; 26: 697–705.CrossRefGoogle ScholarPubMed
59. Bonetti, PO, Pumper, GM, Higano, ST, Holmes, DR Jr, Kuvin, JT, Lerman, A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004; 44: 2137–2141.CrossRefGoogle ScholarPubMed
60. Andreassen, AK, Kvernebo, K, Jorgensen, B, Simonsen, S, Kjekshus, J, Gullestad, L. Exercise capacity in heart transplant recipients: relation to impaired endothelium-dependent vasodilation of the peripheral microcirculation. Am Heart J 1998; 136: 320–328.CrossRefGoogle ScholarPubMed
61. Katz, SD, Hryniewicz, K, Hriljac, I, et al. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 2005; 111: 310–314.CrossRefGoogle ScholarPubMed
62. Pohl, U, Holtz, J, Busse, R, Bassenge, E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 1986; 8: 37–44.CrossRefGoogle ScholarPubMed
63. Ramsey, MW, Goodfellow, J, Jones, CJ, Luddington, LA, Lewis, MJ, Henderson, AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995; 92: 3212–3219.CrossRefGoogle ScholarPubMed
64. Maiorana, A, O’Driscoll, G, Dembo, L, et al. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol Heart Circ Physiol 2000; 279: H1999–H2005.CrossRefGoogle ScholarPubMed
65. Hambrecht, R, Hilbrich, L, Erbs, S, et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 2000; 35: 706–713.CrossRefGoogle ScholarPubMed
66. Adatia, I, Kemp, GJ, Taylor, DJ, Radda, GK, Rajagopalan, B, Haworth, SG. Abnormalities in skeletal muscle metabolism in cyanotic patients with congenital heart disease: a 31P nuclear magnetic resonance spectroscopy study. Clin Sci (Lond) 1993; 85: 105–109.CrossRefGoogle ScholarPubMed
67. Miall-Allen, VM, Kemp, GJ, Rajagopalan, B, Taylor, DJ, Radda, GK, Haworth, SG. Magnetic resonance spectroscopy in congenital heart disease. Heart 1996; 75: 614–619.CrossRefGoogle ScholarPubMed
68. Oechslin, E, Kiowski, W, Schindler, R, Bernheim, A, Julius, B, Brunner-La Rocca, HP. Systemic endothelial dysfunction in adults with cyanotic congenital heart disease. Circulation 2005; 112: 1106–1112.CrossRefGoogle ScholarPubMed
69. 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.CrossRefGoogle ScholarPubMed
70. Toporsian, M, Govindaraju, K, Nagi, M, Eidelman, D, Thibault, G, Ward, ME. Downregulation of endothelial nitric oxide synthase in rat aorta after prolonged hypoxia in vivo. Circ Res 2000; 86: 671–675.CrossRefGoogle ScholarPubMed
71. Armstead, WM. Opioids and nitric oxide contribute to hypoxia-induced pial arterial vasodilation in newborn pigs. Am J Physiol 1995; 268 (Part 2): H226–H232.Google ScholarPubMed
72. Nase, GP, Tuttle, J, Bohlen, HG. Reduced perivascular PO2 increases nitric oxide release from endothelial cells. Am J Physiol Heart Circ Physiol 2003; 285: H507–H515.CrossRefGoogle ScholarPubMed
73. Pape, D, Beuchard, J, Guillo, P, Allain, H, Bellissant, E. Hypoxic contractile response in isolated rat thoracic aorta: role of endothelium, extracellular calcium and endothelin. Fundam Clin Pharmacol 1997; 11: 121–126.CrossRefGoogle ScholarPubMed
74. Wolff, B, Lodziewski, S, Bollmann, T, Opitz, CF, Ewert, R. Impaired peripheral endothelial function in severe idiopathic pulmonary hypertension correlates with the pulmonary vascular response to inhaled iloprost. Am Heart J 2007; 153: 1088 e1–7.CrossRefGoogle ScholarPubMed
75. Karakantza, M, Giannakoulas, NC, Zikos, P, et al. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera. Int J Hematol 2004; 79: 253–259.CrossRefGoogle ScholarPubMed
76. Lessiani, G, Dragani, A, Falco, A, Fioritoni, F, Santilli, F, Davi, G. Soluble CD40 ligand and endothelial dysfunction in aspirin-treated polycythaemia vera patients. Br J Haematol 2009; 145: 538–540.CrossRefGoogle ScholarPubMed
77. Neunteufl, T, Heher, S, Stefenelli, T, Pabinger, I, Gisslinger, H. Endothelial dysfunction in patients with polycythaemia vera. Br J Haematol 2001; 115: 354–359.CrossRefGoogle ScholarPubMed
78. 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.CrossRefGoogle ScholarPubMed
79. Ten, VS, Pinsky, DJ. Endothelial response to hypoxia: physiologic adaptation and pathologic dysfunction. Curr Opin Crit Care 2002; 8: 242–250.CrossRefGoogle ScholarPubMed
80. Malek, AM, Jackman, R, Rosenberg, RD, Izumo, S. Endothelial expression of thrombomodulin is reversibly regulated by fluid shear stress. Circ Res 1994; 74: 852–860.CrossRefGoogle ScholarPubMed
81. 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.CrossRefGoogle ScholarPubMed
82. Territo, MC, Perloff, JK, Rosove, MH, Moake, JL, Runge, A. Acquired Von Willebrand factor abnormalities in adults with congenital heart disease: dependence upon cardiopulmonary pathophysiological subtype. Clin Appl Thromb Hemost 1998; 4: 257–261.CrossRefGoogle Scholar
83. de PS, Soares R, Maeda, NY, Bydlowski, SP, Lopes, AA. Markers of endothelial dysfunction and severity of hypoxaemia in the Eisenmenger syndrome. Cardiol Young 2005; 15: 504–513.Google Scholar
84. Starnes, SL, Duncan, BW, Kneebone, JM, et al. Vascular endothelial growth factor and basic fibroblast growth factor in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 2000; 119: 534–539.CrossRefGoogle ScholarPubMed
85. Niwa, K, Perloff, JK, Bhuta, SM, et al. Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses. Circulation 2001; 103: 393–400.CrossRefGoogle ScholarPubMed
86. Dedkov, EI, Perloff, JK, Tomanek, RJ, Fishbein, MC, Gutterman, DD. The coronary microcirculation in cyanotic congenital heart disease. Circulation 2006; 114: 196–200.CrossRefGoogle ScholarPubMed
87. Fyfe, A, Perloff, JK, Niwa, K, Child, JS, Miner, PD. Cyanotic congenital heart disease and coronary artery atherogenesis. Am J Cardiol 2005; 96: 283–290.CrossRefGoogle ScholarPubMed
88. Perloff, JK. The coronary circulation in cyanotic congenital heart disease. Int J Cardiol 2004; 97 (Suppl 1): 79–86.CrossRefGoogle ScholarPubMed
89. Mansour, AM, Bitar, FF, Traboulsi, EI, et al. Ocular pathology in congenital heart disease. Eye 2005; 19: 29–34.CrossRefGoogle ScholarPubMed
90. Petersen, RA, Rosenthal, A. Retinopathy and papilledema in cyanotic congenital heart disease. Pediatrics 1972; 49: 243–249.CrossRefGoogle ScholarPubMed
91. Chugh, R, Perloff, JK, Fishbein, M, Child, JS. Extramural coronary arteries in adults with cyanotic congenital heart disease. Am J Cardiol 2004; 94: 1355–1357.CrossRefGoogle ScholarPubMed
92. Crowe, RJ, Kohner, EM, Owen, SJ, Robinson, DM. The retinal vessels in congenital cyanotic heart disease. Med Biol Illus 1969; 19: 95–99.Google ScholarPubMed
93. Kohner, EM, Allen, EM, Saunders, KB, Emery, VM, Pallis, C. Electroencephalogram and retinal vessels in congenital cyanotic heart disease before and after surgery. BMJ 1967; 4: 207–210.CrossRefGoogle ScholarPubMed
94. Harino, S, Motokura, M, Nishikawa, N, Fukuda, M, Sasaoka, A, Grunwald, JE. Chronic ocular ischemia associated with the Eisenmenger’s syndrome. Am J Ophthalmol 1994; 117: 302–307.CrossRefGoogle ScholarPubMed
95. Eperon, G, Johnson, M, David, NJ. The effect of arterial PO2 on relative retinal blood flow in monkeys. Invest Ophthalmol 1975; 14: 342–352.Google ScholarPubMed
96. Ames, A 3rd. Energy requirements of CNS cells as related to their function and to their vulnerability to ischemia: a commentary based on studies on retina. Can J Physiol Pharmacol 1992; 70 (Suppl): S158–S164.CrossRefGoogle ScholarPubMed
97. Ahmed, J, Pulfer, MK, Linsenmeier, RA. Measurement of blood flow through the retinal circulation of the cat during normoxia and hypoxemia using fluorescent microspheres. Microvasc Res 2001; 62: 143–153.CrossRefGoogle ScholarPubMed
98. Bosch, MM, Merz, TM, Barthelmes, D, et al. New insights into ocular blood flow at very high altitudes. J Appl Physiol 2009; 106: 454–460.CrossRefGoogle ScholarPubMed
99. Wangsa-Wirawan, ND, Linsenmeier, RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol 2003; 121: 547–557.CrossRefGoogle ScholarPubMed
100. Linsenmeier, RA, Braun, RD. Oxygen distribution and consumption in the cat retina during normoxia and hypoxemia. J Gen Physiol 1992; 99: 177–197.CrossRefGoogle ScholarPubMed
101. Bosch, MM, Barthelmes, D, Merz, TM, et al. High incidence of optic disc swelling at very high altitudes. Arch Ophthalmol 2008; 126: 644–650.CrossRefGoogle ScholarPubMed
102. Rennie, D, Morrissey, J. Retinal changes in Himalayan climbers. Arch Ophthalmol 1975; 93: 395–400.CrossRefGoogle ScholarPubMed
103. Wiedman, M. High altitude retinal hemorrhage. Arch Ophthalmol 1975; 93: 401–403.CrossRefGoogle ScholarPubMed
104. Shults, WT, Swan, KC. High altitude retinopathy in mountain climbers. Arch Ophthalmol 1975; 93: 404–408.CrossRefGoogle ScholarPubMed
105. Droma, Y, Hanaoka, M, Basnyat, B, et al. Symptoms of acute mountain sickness in Sherpas exposed to extremely high altitude. High Alt Med Biol 2006; 7: 312–314.CrossRefGoogle ScholarPubMed
106. Clarke, C, Duff, J. Mountain sickness, retinal haemorrhages, and acclimatisation on Mount Everest in 1975. BMJ 1976; 2: 495–497.CrossRefGoogle ScholarPubMed
107. Wilson, MH, Newman, S, Imray, CH. The cerebral effects of ascent to high altitudes. Lancet Neurol 2009; 8: 175–191.CrossRefGoogle ScholarPubMed
108. Hammond, CJ, Chauhan, DS, Stanford, MS. Pulmonary hypertension and diffuse macular edema responsive to acetazolamide. Arch Ophthalmol 1998; 116: 1535–1536.Google ScholarPubMed
109. Van Camp, G, Renard, M, Verougstraete, C, Bernard, R. Ophthalmologic complications in primary pulmonary hypertension. Chest 1990; 98: 1543–1544.CrossRefGoogle ScholarPubMed
110. Kety, SS, Schmidt, CF. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 1948; 27: 484–492.CrossRefGoogle ScholarPubMed
111. Lennox, WG, Gibbs, EL. The blood flow in the brain and the leg of man, and the changes induced by alteration of blood gases. J Clin Invest 1932; 11: 1155–1177.CrossRefGoogle ScholarPubMed
112. De Schweinitz, GE, Woods, AC. Concerning the ocular symptoms of erythremia (chronic polycythemia vera), with special reference to the fundus picture. Trans Am Ophthalmol Soc 1925; 23: 90–105.Google Scholar
113. Feman, SS, Stein, RS. Waldenstrom’s macroglobulinemia, a hyperviscosity manifestation of venous stasis retinopathy. Int Ophthalmol 1981; 4: 107–112.CrossRefGoogle ScholarPubMed
114. Nagy, F. Changes in the fundus caused by polycythaemia. Br J Ophthalmol 1950; 34: 380–384.CrossRefGoogle ScholarPubMed
115. Morley, MG, Heier, JS. Venous obstructive disease of the retina. In: Yanoff M, Duker JS (eds). Yanoff and Duker: Ophthalmology, 3rd edn. Mosby, St. Louis, MO, 2008; 597–601.Google Scholar
116. Tsutsumi, A. Retinopathy in cyanotic congenital heart disease. Jpn J Clin Ophthalmol 1983; 37: 933.Google Scholar
117. Michelson, G, Welzenbach, J, Pal, I, Harazny, J. Functional imaging of the retinal microvasculature by scanning laser Doppler flowmetry. Int Ophthalmol 2001; 23: 327–335.CrossRefGoogle ScholarPubMed
118. Michelson, G, Patzelt, A, Harazny, J. Flickering light increases retinal blood flow. Retina 2002; 22: 336–343.CrossRefGoogle ScholarPubMed
119. Wong, TY, Islam, FM, Klein, R, et al. Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci 2006; 47: 2341–2350.CrossRefGoogle ScholarPubMed
120. Klein, R, Klein, BE, Knudtson, MD, Wong, TY, Tsai, MY. Are inflammatory factors related to retinal vessel caliber? The Beaver Dam eye study. Arch Ophthalmol 2006; 124: 87–94.CrossRefGoogle ScholarPubMed
121. Ikram, MK, de Jong, FJ, Vingerling, JR, et al. Are retinal arteriolar or venular diameters associated with markers for cardiovascular disorders? The Rotterdam Study. Invest Ophthalmol Vis Sci 2004; 45: 2129–2134.CrossRefGoogle ScholarPubMed
122. Wong, TY, Kamineni, A, Klein, R, et al. Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. Arch Intern Med 2006; 166: 2388–2394.CrossRefGoogle ScholarPubMed
123. Wong, TY, Klein, R, Sharrett, AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The atherosclerosis risk in communities study. JAMA 2002; 287: 1153–1159.CrossRefGoogle ScholarPubMed
124. Wong, TY, Klein, R, Couper, DJ, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis risk in communities study. Lancet 2001; 358: 1134–1140.CrossRefGoogle ScholarPubMed
125. Wang, JJ, Liew, G, Wong, TY, et al. Retinal vascular calibre and the risk of coronary heart disease-related death. Heart 2006; 92: 1583–1587.CrossRefGoogle ScholarPubMed
126. Wong, TY, Klein, R, Nieto, FJ, et al. Retinal microvascular abnormalities and 10-year cardiovascular mortality: a population-based case–control study. Ophthalmology 2003; 110: 933–940.CrossRefGoogle ScholarPubMed
127. Kawagishi, T, Matsuyoshi, M, Emoto, M, et al. Impaired endothelium-dependent vascular responses of retinal and intrarenal arteries in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 1999; 19: 2509–2516.CrossRefGoogle ScholarPubMed
128. Delles, C, Michelson, G, Harazny, J, Oehmer, S, Hilgers, KF, Schmieder, RE. Impaired endothelial function of the retinal vasculature in hypertensive patients. Stroke 2004; 35: 1289–1293.CrossRefGoogle ScholarPubMed
129. Hida, K, Wada, J, Yamasaki, H, et al. Cyanotic congenital heart disease associated with glomerulomegaly and focal segmental glomerulosclerosis: remission of nephrotic syndrome with angiotensin converting enzyme inhibitor. Nephrol Dial Transplant 2002; 17: 144–147.CrossRefGoogle ScholarPubMed
130. Fujimoto, Y, Matsushima, M, Tsuzuki, K, et al. Nephropathy of cyanotic congenital heart disease: clinical characteristics and effectiveness of an angiotensin-converting enzyme inhibitor. Clin Nephrol 2002; 58: 95–102.CrossRefGoogle ScholarPubMed
131. Fujita, N, Manabe, H, Yoshida, N, et al. Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. Biofactors 2000; 11: 257–266.CrossRefGoogle ScholarPubMed
132. Walther, T, Olah, L, Harms, C, et al. Ischemic injury in experimental stroke depends on angiotensin II. FASEB J 2002; 16: 169–176.CrossRefGoogle ScholarPubMed
133. Creager, MA, Roddy, MA. Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension 1994; 24: 499–505.CrossRefGoogle ScholarPubMed
134. O’Driscoll, G, Green, D, Maiorana, A, Stanton, K, Colreavy, F, Taylor, R. Improvement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1999; 33: 1506–1511.CrossRefGoogle ScholarPubMed
135. Glynn, RJ, Danielson, E, Fonseca, FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360: 1851–1861.CrossRefGoogle ScholarPubMed
136. Phornphutkul, C, Rosenthal, A, Nadas, AS, Berenberg, W. Cerebrovascular accidents in infants and children with cyanotic congenital heart disease. Am J Cardiol 1973; 32: 329–334.CrossRefGoogle ScholarPubMed