Editorial
Uric Acid and Coronary Collateral Circulation: To be or Not to be?
Angiology 2014, Vol. 65(7) 560-562 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319713506960 ang.sagepub.com
Yavuzer Koza, MD1
Coronary collateral (CC) artery development is usually attributed to ischemia, but these anastomotic channels are also present in individuals who do not have coronary artery disease (CAD).1,2 The CCs are present in one-fourth of the patients with normal coronary arteries or nonobstructive CAD.2 Currently, there is no noninvasive method for evaluating CC circulation in humans. The most widely used strategy is visual assessment of collateral arteries as described by Rentrop et al.3 This method involves balloon occlusion of the contralateral coronary artery, which is rarely performed. In clinical practice, this method is applied without occluding the contralateral vessels. As a result, underestimation of collateralization is inevitable. Other limitations of this visual method include observer variability, influence by the blood pressure, and the force of contrast injection as well as the duration of filming. The most accurate assessment could be obtained by measuring the pressure-derived collateral flow index.4 Several clinical and angiographic variables including the degree of coronary stenosis, proximal lesion location, longer duration of symptoms, and occlusion as well as resting bradycardia have been reported as variables that correlated with the degree of collateralization.1,5,6 Also, in patients without CAD, the baseline heart rate has been described as the main predictor of collateralization.7 The most important trigger for collateral growth is tangential (radial) fluid shear stress at the endothelial level with the recruitment of bone marrow-derived mononuclear cells.1,8 It is a remodeling process of preexisting small collateral arterioles rather than the growth of new capillary vessels, which is induced by ischemia. Collateral growth is induced by fluid shear stress in preformed collateral vessels caused by a pressure gradient between the area proximal to a coronary stenosis and the low-pressure poststenotic area.1,8,9 The CCs play a role in preserving myocardial function,10 limiting infarct size, and increasing survival.11 However, a meta-analysis showed that a well-developed collateral circulation was a risk factor for restenosis after coronary revascularization.12 In humans, uric acid (UA) is generated from purine catabolism with the conversion of hypoxanthine to xanthine and of xanthine to UA by the enzyme xanthine oxidoreductase. It is further oxidized to allantoin in most species except humans and some higher primates who lack uricase.13 Therefore, serum UA (SUA) levels in humans are appreciably higher than in other mammals.13 Because of this difference in urate metabolism, the
results of animal studies can be difficult to interpret. Also, different methods of measuring collateral flow may be applied in animal studies. Many patients with CAD use at least 1 drug that can influence SUA levels (eg, aspirin, statins, fibrates, and some antihypertensive agents).14,15 The SUA levels are higher in men than in women at all ages due to gender steroids.16 Sumino et al17 showed that hormone replacement therapy in postmenopausal women was associated with a significant reduction in SUA level. Also, dietary, environmental, and genetic factors are important determinants of SUA levels.13,18 It is important to note that UA is a potent antioxidant, but it can also be a prooxidant if the level is >6 mg/dL in women and 6.5 to 7.0 mg/dL in men.19 Therefore, elevated SUA level might be an indicator of increased burden of oxidant attack. Besides its dual oxidant effect, if UA is a harmful product, why do our kidneys recover 90% of filtered UA20 instead of eliminating it? Despite the antioxidant properties of UA, several studies have indicated that high SUA levels are associated with several disorders, including CAD, peripheral arterial disease, heart failure, metabolic syndrome, hypertension, and stroke.21-25 These associations have been mainly attributed to upregulation of renin release and the subsequent cascade-related reduction in endothelial function.19 However, instead of proven causal associations, possible explanations with small study groups could be reverse causality. For example, preclinical atherosclerosis could lead to higher levels of SUA. In contrast, experts from the Framingham Heart Study group have reported no association between the SUA and the cardiovascular disease.26 In a recently published study, Palmer et al27 investigated the association of plasma UA with CAD and hypertension using Mendelian randomization. They found no evidence of a causal effect of UA or hyperuricemia on the risk of CAD and hypertension. Recently, some studies28-31 have demonstrated an association between SUA and CC development in patients with CAD and
1
Department of Cardiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
Corresponding Author: Yavuzer Koza, Department of Cardiology, Faculty of Medicine, Ataturk University Yakutiye, Erzurum 25100, Turkey. Email: [email protected]
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
Koza
561
acute coronary syndrome. Except Hsu et al,29 other authors reported a positive association with high SUA level and poor CC development. All of these studies have important limitations and confounding factors (small study population, Rentrop score, gender and race difference, difference in enrollment criteria and baseline characteristics of patients, and medication use). In conclusion, it is hard to attribute a causative role to UA in CC development. Since, well-developed CCs have many beneficial effects, we have to research new methods to stimulate collateral growth other than exercise32 and enhanced external counterpulsation.33 Whether lowering SUA level is associated with CC development should be evaluated in large prospective studies. In this regard, accurate and quantitative CC assessment methods are needed. Lowering SUA levels by diet (sometimes impossible) or drugs should be expected to improve poor CC circulation. Or are the harmful effects of UA only due to its serum level? If so, why? Could UA be an inadequate marker to predict CC development? Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Seiler C. The human coronary collateral circulation. Eur J Clin Invest. 2010;40(5):465-476. 2. Wustmann K, Zbinden S, Windecker S, Meier B, Seiler C. Is there functional collateral flow during vascular occlusion in angiographically normal coronary arteries? Circulation. 2003;107(17): 2213-2220. 3. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985;(3):587-592. 4. Seiler C, Fleisch M, Garachemani A, Meier B. Coronary collateral quantitation in patients with coronary artery disease using intravascular flow velocity or pressure measurements. J Am Coll Cardiol. 1998;32(5):1272-1279. 5. Piek JJ, van Liebergen RA, Koch KT, Peters RJ, David GK. Clinical, angiographic and hemodynamic predictors of recruitable collateral flow assessed during balloon angioplasty coronary occlusion. J Am Coll Cardiol. 1997;29(2):275-282. 6. Werner GS, Ferrari M, Betge S, Gastmann O, Richartz BM, Figulla HR. Collateral function in chronic total coronary occlusions is related to regional myocardial function and duration of occlusion. Circulation. 2001;104(23):2784-2790 7. de Marchi SF, Gloekler S, Meier P, et al. Determinants of preformed collateral vessels in the human heart without coronary artery disease. Cardiology. 2011;118(3):198-206. 8. Schaper W. Collateral vessels reduce mortality. Eur Heart J. 2012;33(5):564-566.
9. Pipp F, Boehm S, Cai WJ, et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler Thromb Vasc Biol. 2004; 24(9):1664-1668. 10. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation. 1986;74(3):469-476. 11. Habib GB, Heibig J, Forman SA. Influence of coronary collateral vessels on myocardial infarct size in humans. results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI investigators. Circulation. 1991;83(3):739-746. 12. Meier P, Indermuehle A, Pitt B, et al. Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis. BMC Med. 2012;10:62. 13. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143(7):499-516. 14. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis. 2004;43(4):589-599. 15. Daskalopoulou SS, Mikhailidis DP, Athyros VG, Papageorgiou AA, Elisaf M. Fenofibrate and losartan. Ann Rheum Dis. 2004; 63(4):469-470. 16. Adamopoulos D, Vlassopoulos C, Seitanides B, Contoyiannis P, Vassilopoulos P. The relationship of sex steroids to uric acid levels in plasma and urine. Acta Endocrinol (Copenh). 1977;85(1):198-208. 17. Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet. 1999; 21;354(9179):650. 18. Nath SD, Voruganti VS, Arar NH, et al. Genome scan for determinants of serum uric acid variability. J Am Soc Nephrol. 2007;18(12):3156-3163. 19. Basaga HS. Biochemical aspects of free radicals. Biochem Cell Biol. 1990;68(7-8):989-998. 20. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41(6):1183-1190. 21. Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and risk for peripheral arterial disease: analysis of data from the multiple risk factor intervention trial. Angiology. 2007;58(4):450-457. 22. Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. J Card Fail. 2012;18(9):694-701. 23. Yoo TW, Sung KC, Shin HS, et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005;69(8):928-933. 24. Sundstro¨m J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension. 2005; 45(1):28-33. 25. Karagiannis A, Mikhailidis DP, Tziomalos K, et al. Serum uric acid as an independent predictor of early death after acute stroke. Circ J. 2007;71(7):1120-1127.
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
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26. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham heart study. Ann Intern Med. 1999;131(1):7-13. 27. Palmer TM, Nordestgaard BG, Benn M, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomisation analysis of two large cohorts. BMJ. 2013;347:4262. 28. Uysal OK, Sahin DY, Duran M, et al. Association between uric acid and coronary collateral circulation in patients with stable coronary artery disease. Angiology. 2014;65(3):227-231. 29. Hsu PC, Su HM, Lin TH. Association between coronary collaterals and serum uric acid level in Chinese population with acute coronary syndrome. Angiology. 2013;64(4):323-324.
30. Duran M, Ornek E, Murat SN, et al. High levels of serum uric acid impair development of coronary collaterals in patients with acute coronary syndrome. Angiology. 2012;63(6):472-475. 31. Kasapkara HA, Topsakal R, Yarlioglues M, et al. Effects of serum uric acid levels on coronary collateral circulation in patients with non-ST elevation acute coronary syndrome. Coron Artery Dis. 2012;23(7):421-425. 32. Heaps CL, Parker JL. Effects of exercise training on coronary collateralization and control of collateral resistance. J Appl Physiol. 2011;111(2):587-598. 33. Gloekler S, Meier P, de Marchi SF, et al. Coronary collateral growth by external counterpulsation: a randomised controlled trial. Heart. 2010;96(3):202-207.
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
Uric Acid and Coronary Collateral Circulation: To be or Not to be?
Angiology 2014, Vol. 65(7) 560-562 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319713506960 ang.sagepub.com
Yavuzer Koza, MD1
Coronary collateral (CC) artery development is usually attributed to ischemia, but these anastomotic channels are also present in individuals who do not have coronary artery disease (CAD).1,2 The CCs are present in one-fourth of the patients with normal coronary arteries or nonobstructive CAD.2 Currently, there is no noninvasive method for evaluating CC circulation in humans. The most widely used strategy is visual assessment of collateral arteries as described by Rentrop et al.3 This method involves balloon occlusion of the contralateral coronary artery, which is rarely performed. In clinical practice, this method is applied without occluding the contralateral vessels. As a result, underestimation of collateralization is inevitable. Other limitations of this visual method include observer variability, influence by the blood pressure, and the force of contrast injection as well as the duration of filming. The most accurate assessment could be obtained by measuring the pressure-derived collateral flow index.4 Several clinical and angiographic variables including the degree of coronary stenosis, proximal lesion location, longer duration of symptoms, and occlusion as well as resting bradycardia have been reported as variables that correlated with the degree of collateralization.1,5,6 Also, in patients without CAD, the baseline heart rate has been described as the main predictor of collateralization.7 The most important trigger for collateral growth is tangential (radial) fluid shear stress at the endothelial level with the recruitment of bone marrow-derived mononuclear cells.1,8 It is a remodeling process of preexisting small collateral arterioles rather than the growth of new capillary vessels, which is induced by ischemia. Collateral growth is induced by fluid shear stress in preformed collateral vessels caused by a pressure gradient between the area proximal to a coronary stenosis and the low-pressure poststenotic area.1,8,9 The CCs play a role in preserving myocardial function,10 limiting infarct size, and increasing survival.11 However, a meta-analysis showed that a well-developed collateral circulation was a risk factor for restenosis after coronary revascularization.12 In humans, uric acid (UA) is generated from purine catabolism with the conversion of hypoxanthine to xanthine and of xanthine to UA by the enzyme xanthine oxidoreductase. It is further oxidized to allantoin in most species except humans and some higher primates who lack uricase.13 Therefore, serum UA (SUA) levels in humans are appreciably higher than in other mammals.13 Because of this difference in urate metabolism, the
results of animal studies can be difficult to interpret. Also, different methods of measuring collateral flow may be applied in animal studies. Many patients with CAD use at least 1 drug that can influence SUA levels (eg, aspirin, statins, fibrates, and some antihypertensive agents).14,15 The SUA levels are higher in men than in women at all ages due to gender steroids.16 Sumino et al17 showed that hormone replacement therapy in postmenopausal women was associated with a significant reduction in SUA level. Also, dietary, environmental, and genetic factors are important determinants of SUA levels.13,18 It is important to note that UA is a potent antioxidant, but it can also be a prooxidant if the level is >6 mg/dL in women and 6.5 to 7.0 mg/dL in men.19 Therefore, elevated SUA level might be an indicator of increased burden of oxidant attack. Besides its dual oxidant effect, if UA is a harmful product, why do our kidneys recover 90% of filtered UA20 instead of eliminating it? Despite the antioxidant properties of UA, several studies have indicated that high SUA levels are associated with several disorders, including CAD, peripheral arterial disease, heart failure, metabolic syndrome, hypertension, and stroke.21-25 These associations have been mainly attributed to upregulation of renin release and the subsequent cascade-related reduction in endothelial function.19 However, instead of proven causal associations, possible explanations with small study groups could be reverse causality. For example, preclinical atherosclerosis could lead to higher levels of SUA. In contrast, experts from the Framingham Heart Study group have reported no association between the SUA and the cardiovascular disease.26 In a recently published study, Palmer et al27 investigated the association of plasma UA with CAD and hypertension using Mendelian randomization. They found no evidence of a causal effect of UA or hyperuricemia on the risk of CAD and hypertension. Recently, some studies28-31 have demonstrated an association between SUA and CC development in patients with CAD and
1
Department of Cardiology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
Corresponding Author: Yavuzer Koza, Department of Cardiology, Faculty of Medicine, Ataturk University Yakutiye, Erzurum 25100, Turkey. Email: [email protected]
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
Koza
561
acute coronary syndrome. Except Hsu et al,29 other authors reported a positive association with high SUA level and poor CC development. All of these studies have important limitations and confounding factors (small study population, Rentrop score, gender and race difference, difference in enrollment criteria and baseline characteristics of patients, and medication use). In conclusion, it is hard to attribute a causative role to UA in CC development. Since, well-developed CCs have many beneficial effects, we have to research new methods to stimulate collateral growth other than exercise32 and enhanced external counterpulsation.33 Whether lowering SUA level is associated with CC development should be evaluated in large prospective studies. In this regard, accurate and quantitative CC assessment methods are needed. Lowering SUA levels by diet (sometimes impossible) or drugs should be expected to improve poor CC circulation. Or are the harmful effects of UA only due to its serum level? If so, why? Could UA be an inadequate marker to predict CC development? Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Seiler C. The human coronary collateral circulation. Eur J Clin Invest. 2010;40(5):465-476. 2. Wustmann K, Zbinden S, Windecker S, Meier B, Seiler C. Is there functional collateral flow during vascular occlusion in angiographically normal coronary arteries? Circulation. 2003;107(17): 2213-2220. 3. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985;(3):587-592. 4. Seiler C, Fleisch M, Garachemani A, Meier B. Coronary collateral quantitation in patients with coronary artery disease using intravascular flow velocity or pressure measurements. J Am Coll Cardiol. 1998;32(5):1272-1279. 5. Piek JJ, van Liebergen RA, Koch KT, Peters RJ, David GK. Clinical, angiographic and hemodynamic predictors of recruitable collateral flow assessed during balloon angioplasty coronary occlusion. J Am Coll Cardiol. 1997;29(2):275-282. 6. Werner GS, Ferrari M, Betge S, Gastmann O, Richartz BM, Figulla HR. Collateral function in chronic total coronary occlusions is related to regional myocardial function and duration of occlusion. Circulation. 2001;104(23):2784-2790 7. de Marchi SF, Gloekler S, Meier P, et al. Determinants of preformed collateral vessels in the human heart without coronary artery disease. Cardiology. 2011;118(3):198-206. 8. Schaper W. Collateral vessels reduce mortality. Eur Heart J. 2012;33(5):564-566.
9. Pipp F, Boehm S, Cai WJ, et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler Thromb Vasc Biol. 2004; 24(9):1664-1668. 10. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation. 1986;74(3):469-476. 11. Habib GB, Heibig J, Forman SA. Influence of coronary collateral vessels on myocardial infarct size in humans. results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI investigators. Circulation. 1991;83(3):739-746. 12. Meier P, Indermuehle A, Pitt B, et al. Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis. BMC Med. 2012;10:62. 13. Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med. 2005;143(7):499-516. 14. Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Am J Kidney Dis. 2004;43(4):589-599. 15. Daskalopoulou SS, Mikhailidis DP, Athyros VG, Papageorgiou AA, Elisaf M. Fenofibrate and losartan. Ann Rheum Dis. 2004; 63(4):469-470. 16. Adamopoulos D, Vlassopoulos C, Seitanides B, Contoyiannis P, Vassilopoulos P. The relationship of sex steroids to uric acid levels in plasma and urine. Acta Endocrinol (Copenh). 1977;85(1):198-208. 17. Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet. 1999; 21;354(9179):650. 18. Nath SD, Voruganti VS, Arar NH, et al. Genome scan for determinants of serum uric acid variability. J Am Soc Nephrol. 2007;18(12):3156-3163. 19. Basaga HS. Biochemical aspects of free radicals. Biochem Cell Biol. 1990;68(7-8):989-998. 20. Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41(6):1183-1190. 21. Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and risk for peripheral arterial disease: analysis of data from the multiple risk factor intervention trial. Angiology. 2007;58(4):450-457. 22. Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. J Card Fail. 2012;18(9):694-701. 23. Yoo TW, Sung KC, Shin HS, et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005;69(8):928-933. 24. Sundstro¨m J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension. 2005; 45(1):28-33. 25. Karagiannis A, Mikhailidis DP, Tziomalos K, et al. Serum uric acid as an independent predictor of early death after acute stroke. Circ J. 2007;71(7):1120-1127.
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
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26. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham heart study. Ann Intern Med. 1999;131(1):7-13. 27. Palmer TM, Nordestgaard BG, Benn M, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: Mendelian randomisation analysis of two large cohorts. BMJ. 2013;347:4262. 28. Uysal OK, Sahin DY, Duran M, et al. Association between uric acid and coronary collateral circulation in patients with stable coronary artery disease. Angiology. 2014;65(3):227-231. 29. Hsu PC, Su HM, Lin TH. Association between coronary collaterals and serum uric acid level in Chinese population with acute coronary syndrome. Angiology. 2013;64(4):323-324.
30. Duran M, Ornek E, Murat SN, et al. High levels of serum uric acid impair development of coronary collaterals in patients with acute coronary syndrome. Angiology. 2012;63(6):472-475. 31. Kasapkara HA, Topsakal R, Yarlioglues M, et al. Effects of serum uric acid levels on coronary collateral circulation in patients with non-ST elevation acute coronary syndrome. Coron Artery Dis. 2012;23(7):421-425. 32. Heaps CL, Parker JL. Effects of exercise training on coronary collateralization and control of collateral resistance. J Appl Physiol. 2011;111(2):587-598. 33. Gloekler S, Meier P, de Marchi SF, et al. Coronary collateral growth by external counterpulsation: a randomised controlled trial. Heart. 2010;96(3):202-207.
Downloaded from ang.sagepub.com at Oregon Health & Science University on March 27, 2015
