NEFROLOGIA. Vol. XVII. Suplemento 1. 1997 Vascular and cardiac remodeling in end-stage renal disease G. M. London, S. J. Marchais, A. P. Guerin, F. Metivier and B. Pannier Manhes Hospital (France). Cardiovascular complications are the principal cause of morbidity and mortality in end-stage renal disease patients 1. Myocardial infarction and cerebrovascular events related to occlusive lesions at the site of atheromatous plaques are the most frequent underlying cause 2. The frequency of these complications led to the hypothesis of the existence of an accelerated atherosclerosis in end-stage renal disease, and research has concentrated on metabolic factors of vascular remodeling associated with atheromatous plaques. Nevertheless, atherosclerosis represents only one form of large conduit arteries remodeling. The spectrum of arterial remodeling in end-stage renal disease is much wider, including structural changes related to hemodynamic alterations whose functional consequences are different from those related to the presence of plaques. CONCEPT OF VASCULAR REMODELING Vascular remodeling is an adaptative process occuring in response to long-lasting changes in arterial pressure and/or flow, and whose ultimate effect tends to maintain the constancy of tensile and/or shear stresses 3. According to Laplace's law the tensile stress () is directly proportional to arterial transmural pressure (P) and radius (r), and inversely proportional to arterial wall thickness (h) according to the formula: = Pr/h. In response to increased blood pressure the arterial wall hypertrophies principally by thickening of the media. Luminal diameter is reduced or unchanged, leading to decrease of the ratio of the width of the lumen to the width of the wall which tends to normalise the tensile stress. (This pressure-induced rearrangement in distal resistive arteries and arterioles where the luminal diameter is reduced but medial layer is not hypertrophied-"eutrophic remodeling" 4). Another form of large conduit arteries remodeling involves primarily changes in shear stress inducing changes in luminal diameter with secondary adaptation in wall thickness 5, 6. Shear stress () is directly proportional to blood flow (Q) and blood viscosity (µ) and inversely proportional to the radius (r) of the vessel, according to the formula: = 4.Q.µ/.r3. Increase in shear stress could be the consequence of increased blood viscosity, decreased arterial diameter, or increased blood flow and blood flow gradient applied on endothelial surface. The most classical example of flow mediated remodeling include arterial dilation associated with sustained high blood flow after creation of arteriovenous fistula 7. In this condition, the luminal diameter increases to maintain a constant shear stress. Endothelium plays a prominent role in the process of vascular remodeling being strategically located at the interface between blood stream and the vessel wall 3. The exact mechanisms mediating the mechanotransduction and response of endothelium to hemodynamic stimuli are not completely elucidated. Alterations in tension activate stretch-sensitive cationic channels promoting generation of mitogenic and trophic factors 8-12. Changes in shear stress activate flow-sensitive potassium channels and hyperpolarisation of smooth muscle cells, as well as generation of nitric oxide and vasodilating prostacyclin 1318. Endothelial mechanisms are involved not only in acute changes in vascular tone and diameter, but play also a role in chronic increase in blood flow 19, 20. ARTERIAL REMODELING AND ARTERIAL FUNCTION: BASIC PRINCIPLES The arterial remodeling is associated with changes in the function of arterial tree, which are different from those related to presence of atherosclero17 Correspondence address: Dr. G. London. 8. Grande Rue. Fleury-Merogis. 91712 Ste. Geneviève des Bois. France. G. M. LONDON et al. tic plaques. Indeed, the arterial system has two distinct, interrelated functions: 1) to deliver an adequate supply of blood to body tissues - the conduit func tion; 2) to smooth out the pulsations occuring with intermittent ventricular ejection - the cushioning function 21, 22. Conduit function of arteries The efficiency of conduit function in related to the width of the arteries and the almost constancy of mean blood pressure along the arterial tree, the mean pressure drop between the ascending aorta and the arteries in the forearm or leg being 2 to 3 mmHg in supine position 23, 24. Alterations of conduit function occur through narrowing or occlusion of arteries with restriction of blood flow and resulting ischemia or infarction of tissues downstream 24. Atherosclerosis characterised by the presence of plaques is the most common disease that disturbs conduit function 24. Atherosclerosis is primarily an intimal disease, focal and patchy in its distribution, occuring preferentially in the coronaries, femoral arteries, carotid bifurcation and infrarenal aorta 24. Focal compensatory enlargement occurs at discrete sites of narrowing immediately adjacent to more or less normal areas 8, 25. Mechanisms of atherogenesis-related arterial remodeling are complex, including the action of many humoral factors and also mechanical factors such as tensible stress and shear stress 8, 25-28. The role of mechanical factors is confirmed by the high prevalence of atherosclerosis in hypertension, with a predilection of atherosclerotic plaques for certains sites characterised by disturbances of flow pattern and shear stress, like orifices, bifurcations, bending or pronounced tapering 8, 29. Atherosclerosis is a frequent cause of morbidity in patients with end-stage renal disease and myocardial infarction or cerebrovascular events occupy an important place in the mortality of these patients. This has been shown in pioneer study by Lindner et al 2 and has been extensively confirmed by numerous subsequent reports. Cushioning function of arteries The principal role of arteries as cushions is to dampen the pressure oscillations resulting from intermittent ventricular ejection («Windkessel» effect) 21, 22, 24. Indeed, large arteries can instantaneously accomodate the volume of blood ejected from the heart, storing part of the stroke volume during systolic ejection and draining this volume during diastole, thereby en18 suring a continuous perfusion of organs and tissues 21, 22. The efficiency of windkessel function is due to the viscoelastic properties of arterial walls and the «geometric» characteristic of the arteries including their diameter and length 21, 22. The principal alteration in cushioning function is due to the stiffening of arterial walls. The consequences of wall stiffening are an increased systolic and pulse pressure and a decrease in diastolic pressure 21, 22. Hence the viscoelastic properties of the arterial system influence the level of systolic as well as diastolic pressure. Through promoting an increase in mean-, peak-, and end-SBP in the ascending aorta arterial stiffening is responsible for an increase in myocardial oxygen consumption, while the decrease in mean DBP tends to impair the coronary blood supply 30-32 . Furthermore, increased SBP induces myocardial hypertrophy, impairs diastolic myocardial function and ventricular ejection 33, 34. In addition increased SBP and pulse pressure accelerates arterial damage, increasing the fatigue, degenerative changes and arterial stiffening feeding a vicious circle 24. Cushioning function is altered primarily during aging process 21, 24, 35-38 and in conditions associated with «sclerotic» remodeling of arterial walls, i.e. associated with increased collagen contain and changes in extracellular matrix (arteriosclerosis). Arteriosclerosis is primarily a medial degenerative condition that is generalized thoughout the thoracic aorta and central arteries, causing dilatation, diffuse hypertrophy and stiffening of arteries 24. Arteriosclerosis is sometimes considered as a «physiological» aging phenomenon which is accelerated by hypertension 39-41. Arteriosclerosis results in diffuse fibroelastic intima thickening, an increase in medial group substance and collagen, and fragmentation of elastic lamellae with secondary fibrosis and calcification of the media. These changes are more pronounced in the aorta and central arteries than in the limb arteries 38. ARTERIAL REMODELING IN END-STAGE RENAL DISEASE (ATHEROSCLEROSIS EXCLUDED) The arterial system is ESRD patients undergoes structural remodeling very similar to changes with aging, and is characterized by diffuse dilation, hypertrophy and stiffening of the aorta and major arteries (table I) 32. Although part of the arterial alterations in ESRD patients are associated with the aging proccess, several features of arterial remodeling observed in chronic uremia are different from those of the natural aging process 32. VASCULAR AND CARDIAC REMODELING IN END-STAGE RENAL DISEASE Table I. Arterial structure and function. Parameters Controls ESRD 58.3 ± 21.0** 157 ± 31** 17.0 6.25 777 0.25 ± 2.6*** ± 0.87*** ± 115*** ± 0.03 CCA pulse pressure (mmHg) .................. 48.0 ± 17.0 Subendocardial viability index (%) ........ 173 ± 30 Aobif diameter (mm) ............................... CCA diameter (mm) ................................ CCA intima-media thickness (µm) .......... CCA wall/lumen (ratio) ........................... CCA intima-media croos-sectional area (mm2) ........................................ CCA distensibility (KPa-1.10-3) ................ CCA compliance (m2.KPa-1.10-7) ............ CCA elastic incremental modulus (KPa.103) ........................................... Carotid-femoral PWV (cm/s) ................... 15.0 5.55 678 0.24 ± ± ± ± 1.8 0.65 105 0.03 gement observed in ESRD results in part from chronic volume and flow overload, and from this point of view differs from changes observed during normal aging. Chronic volume and flow overload are also responsible for the increased internal dimensions of the left ventricle 42. The common influence of flow overload on arterial and ventricular dimensions induces a dimensional coupling between the heart and the conduit vessels 32 (figure 2). 13.4 ± 3.3 24.0 ± 12.7 6.00 ± 2.50 0.46 ± 0.23 957 ± 180 17.5 ± 4.5*** 17.8 ± 8.8** 5.15 ± 2.00* 0.61 ± 0.35** 1055 ± 290* Abbreviations are: CCA, common carotid artery; Aobif , aorta at bifurcation level; PWV, pulse wave velocity. * P < 0.05; ** P < 0.01; *** P < 0.001. Hemodynamic factors of arterial remodeling in chronic uremia Arterial changes associated with alterations in flow. In ESRD patients, conditions such as anemia, arteriovenous shunts and overhydration induce a state of chronic volume/flow overload associated with increased systemic and regional blood flow and flow velocity, creating conditions for systemic arterial remodeling 32, 42. This has been illustrated by cross sectional studies which showed a direct relationship between the diameter of the aorta and of major arteries and blood flow velocity (figure 1) 32, as well as by studies indicating that arterial enlargement could be limited by adequate fluid removal during dialysis 43. Therefore it appears that the systemic arterial enlar- Fig. 2.--(Above panel) Scatterplot showing the correlations between common carotid artery (CCA) diameter and left ventricular diastolic diameter (LVEDD) and (below panel) between CCA intima-media thickness and left ventricular mass in ESRD patients. Fig. 1.--Scatterplot showing the correlation between common carotid artery (CCA) diameter and left ventricular outflow velocity integral in ESRD patients. Arterial changes associated with increase in tensi le stress. In comparison with non-uremic patients, the intima-media thickness of major central arteries is increased in ESRD patients 32, 44. Like in general the population, in ESRD patients arterial wall thickness increases with age, distending pressure, and arterial diameter 32. The increase in wall thickness is proportional to changes in diameter, and this is a logical consequence of Laplace's law, whereby wall tension is directly proportional to arterial radius. Nevertheless, according to the same law, when the 19 G. M. LONDON et al. blood pressure increases, and whatever the internal radius, the wall-to lumen ratio should increase in order to normalize the tensile stress. This is observed in nonuremic populations 45, 46 but not in ESRD patients 32. Conduit arteries have probably a limited capacity to respond adequately to a combined flow and pressure stimuli. This was observed in ESRD patients on radial artery supplying arteriovenous fistula, and also in experimental conditions 7, 47. Indeed, in vein grafts subjected to separate mechanical factors such as circumferential stretching and changes in blood velocity, Dobrin et al 47 demonstrated that changes in flow influence intimal thickening, whereas medial thickening responds to changes in wall stress. Intimal thickening occurs in response to low flow velocity, whereas medial thickening occurs in response to increased parietal tension. Therefore in ESRD patients increased tensile stress could induce medial hypertrophy, while increased flow would decreased the intimal thickness. As the present ultrasonographic devices are unable to differentiate intima from media this remains purely speculative. In ESRD, the increase in arterial intima-media thickness is associated with decreased arterial distensibility (figure 3). In ESRD patients decreased arterial distensibility results directly from arterial wall hypertrophy, and incremental modulus of elasticity in increased in comparison with age and pressure matched non-uremic controls 34-37, 48. The different relationship between hypertrophy and intrinsic elastic properties in nonuremic subjects and ESRD points to qualitative differences in the «hypertrophic process», being in favor of altered intrinsic elastic properties as observed in experimental uremia and in vitro in arteries of uremic patients, namely fibro- elastic intimal thickening, calcification of elastic lamellae and ground substance deposition 49, 50. CONSEQUENCES OF ARTERIAL STIFFENING IN ESRD PATIENTS The most important consequence of arteriosclerosis is arterial stiffening resulting in an increased left ventricular systolic stress and an abnormal relationship between systolic and diastolic tension-time integrals 21, 22, 31, 32. The principal consequences of these alterations are left ventricular hypertrophy (figure 2) and altered coronary perfusion with decrease in subendocardial flow (figure 4) 32, 34. Fig. 4.--Scatterplot showing the correlation between the CCA distensibility and subendocardial viability index in ESRD patients. Fig. 3.--Scatterplot showing the correlation between common carotid artery (CCA) intima-media thickness and CCA distensibility in ESRD patients. The important factors relating the pressure load to LV hypertrophy and altered LV function are the peak and end-systolic pressures in the aorta and central arteries, which are critically dependent on the physical properties of arteries 21, 22, 24. Previous studies have shown that LV hypertrophy in ESRD was correlated to increased pulsatile pressure load due to increased arterial stiffness and wave reflections 32, 34. Among ESRD patients, significant relations existed between comparable cardiac and vascular parameters 32. LV diameter and arterial diameters are correlated and significant correlations were observed between the common carotid artery intima-media thickness and intima-media cross-sectional area and LV wall thickness and/or LV mass (figure 2). These relationships are independent of other factors like age, body surface area, gender 32. Moreover, independently from the blood pressure level, the extend of left ventricular hypertrophy is 20 VASCULAR AND CARDIAC REMODELING IN END-STAGE RENAL DISEASE directly proportional to decrease in aortic distensibility. However, in ESRD patients a significant correlation was observed between arterial diameter and LV wall thickness suggesting also the existence of a direct link between arterial dilation and LV hypertrophy 32. Indeed, the inertial effects are greater in enlarged arteries since larger blood-filled arteries require the heart to produce excess work in order to accelerate blood against larger inertial forces during ejection. The second most important consequence of arterial stiffening is compromised coronary perfusion 31, 32. Canine studies have shown that aortic stiffening directly decreased subendocardial blood flow despite an increase in mean coronary flow, and that chronic aortic stiffening reduced cardiac transmural perfusion and aggravated subendocardial ischemia 21, 22, 31, 51 (figure 4). Cardiac ischemia and alterations in subendocardial perfusion are frequently observed in uremic patients despite patent coronary arteries 52, 53. This has been recently shown in ESRD patients in which the changes in large artery structure and function were associated with decreased diastolic/systolic tension-time integral (subendocardial viability index) (figure 4), an index of the propensity for myocardial ischemia when there are altered hemodynamic forces in the absence of occlusive arterial lesions 32. Besides the role of abnormal structure and function of aorta and major arteries this alterations are partly related to structural abnormalities of intramyocardial microvasculature. In uremic rats, Amann et al 50 have shown diminished myocardial capillary density and thickening of intramyocardial arterioles due to smooth muscle cells hyperplasia. CONCLUSIONS Arterial remodeling in patients with ESRD includes dilation and intima-media hypertrophy of large conduit arteries. This remodeling is principally related to chronic flow overload and increased tensile stress. The consequences of arterial remodeling are an increased ventricular afterload and development of left ventricular hypertrophy and compromised subendocardial perfusion. References 1. Raine AEG, Margreit R, Brunner FP, Ehrich JHH, Geelings W, Landais P, Loirat C, Mallick NP, Selwood NH, Tufveson G, Valderrábano F: Report on management of renal failure in Europe, XXII. Nephrol Dial Transplant 7 (suppl. 2): 7-35, 1992. 2. Lindner A, Charra B, Sherrar DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290: 697-701, 1974. 3. Gibbons GH, Dzay VJ: The emerging concept of vascular remodeling. N Engl J Med 330: 1431-1438, 1994. 4. Mulvany MJ: The structure of the resistance vasculature in essential hypertension. J Hypertens 5: 129-136, 1987. 5. Langille BL, O'Donnell F: Reductions in arterial diameters produced by chronic decrease in blood flow are endotheliumdependent. Science 231: 405-407, 1986. 6. Kamiya A, Togawa T: Adaptative regulation of wall shear stress to flow change in the canine carotid artery. Am J Phy siol 239: H14-H21, 1980. 7. Girerd X, London G, Boutouyrie P, Mourad JJ, Laurent S, Safar M: Remodeling of radial artery and chronic increase in shear stress. Hypertension 27 [part 2]: 799-803, 1996. 8. Glagov S: Hemodynamic risk factors: mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis. In: Pathogenesis of atherosclerosis, RW Wissler, JC Geer (eds). Baltimore, Williams and Wilkins, chap 6. 9. Harder DR: Pressure-induced myogenic activation of cat cerebral arteries is dependent on intact endothelium. Circ Res 60: 102-107, 1987. 10. Tozzi CA, Poiani GJ, Harangozo AM, Boyd CD, Riley DJ: Pressure-induced connective tissue synthesis in pulmonary ar tery segments is dependent on intact endothelium. J Clin In vest 84: 1005-1012, 1989. 11. Iba T, Shin T, Sonoda T, Rosales O, Sumpio BE: Stimulation o f endothelial secretion of tissue-type plasminogen activator by repetitive stretch. J Surg Res 50: 457-460, 1991. 12. Gibbons GH, Pratt RE, Dzau VJ: Vascular smooth muscle cell hypertrophy vs. hyperplasia: autocrine transforming growth factor-ß1 exp res sio n determine growth response to angiotensin II. J Clin Invest 90: 456-461, 1992. 13. Zarins CK, Zatine MA, Giddens DP, Ku DN, Glagov S: Shear stress regulation of artery lumen diameter in experimental atherogenesis. J Vasc Surg 5: 413-420, 1987. 14. Davies PF, Tripathi SC: Mechanical stress mechanisms and the stress to flow change in the canine carotid artery. Circ Res 72: 235-239, 1993. 15. Pohl U, Holtz J, Busse R, Bassenge E: Crucial role of endothelium in the vasodilatator response to increased flow in vivo. Hypertension 8: 37-44, 1986. 16. Olesen SP, Clapham DE, Davies PF: Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Na ture 331: 168-170, 1988. 17. Nakache M, Gaub HE: Hydrodynamic hyperpolarization of endothelial cells. Proc Natl Acad Sci USA 85: 1841-1843, 1988. 18. Koller A, Sun D, Huang A, Kaley G: Corelease of nitric oxyde and prostaglandins mediates flow-dependent dilatation of rat gracilis muscle arterioles. Am J Physiol 267: H326-H332, 1994. 19. Tohda K, Masuda H, Kawamura K, Shozawa T: Difference in dilatation between endothelium-preserved and desquamated segments in the flow-loaded rat common carotid artery. Ar terioscler Trom 12: 519-528, 1992. 20. Tronc F, Wassef M, Esposito B, Henrion D, Glagov S, Tedgui A: Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Tromb Vasc Biol 16: 1256-1262, 1996. 21. O'Rourke MF: Arterial function in health and disease. Churchill Livingstone, Edinburgh, 1982. 22. Nichols WW, O'Rourke MF: Vascular impedance, in McDonald's Blood Flow in Arteries: Theoretic, Experimental and Clinical Principles, London, Edward Arnold Publisher, 1991. 21 G. M. LONDON et al. 23. Krooker EJ, Wood EH: Comparison of simultaneously recorded central and peripheral arterial pressure pulses during rest, exercise and tilted position in man. Circ Res 3: 623-32, 1955. 24. O'Rourke M: Mechanical principles in arterial disease. Hy pertension 26: 2-9, 1995. 25. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ: Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316: 1371-1375, 1987. 26. Fry DL: Acute vascular endothelial changes associated with increased blood flow velocity gradients. Circ Res 22: 165-97, 1968. 27. Ca r o CC, Nerem RM: Transport of 14 C-4-cholesterol between serum and wall in the perfused dog common carotid artery. Circ Res 32: 187-205, 1973. 28. Glagov S, Zarins CK: Is intimal hyperplasia an adaptive response or a pathologic process? Observations on the nature of nonatherosclerotic intimal thickening. J Vasc Surg 10: 571573, 1989. 29. Glagov S, Zarins C, Giddens DP, Ku DN: Hemodynamics and atherosclerosis: Insights and perspectives gained from the studies of human arteries. Arch Pathol Lab Med 112: 1018-1031, 1988. 30. Nichols WW, Avolio AP, Kelly RP, O'Rourke MF: Effects of age and of hypertension on wave travel and reflections. In: Arterial vasodilatati on: mechanisms and therapy. O"Rourke M, Safar M, Dzau V eds, Edward Arnold, London, pp. 23-40, 1993. 31. Buckberg GD, Towers B, Paglia DE, Mulder DG, Malonery JV: Subendocardial ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 64: 669-687, 1972. 32. London GM, Guérin AP, Marchais SJ, Pannier B, Safar ME, Day M, Metivier F: Cardiac and arterial interactions in endstage renal disease. Kidney Int 50: 600-608, 1996. 33. London GM, Guérin AP, Pannier B, Marchais SJ, Benetos A, Safar ME: Increased systolic pressure in chronic uremia: Role of arterial wave reflections. Hypertension 20: 10-19, 1992. 34. Marchais SJ, Guérin AP, Pannier BM, Levy BI, Safar ME, London GM: Wave reflections and cardiac hypertrophy in chronic uremia: Influence of body size. Hypertension 22: 876-883, 1 993. 35. Virmani R, Avolio AP, Mergner WJ, Robinowitz R, Herderick EE, Cornhill JF, Guo SY, Liu TH, Ou DY, O'Rourke MF: Effects of aging on aortic morphology in population with high and low prevalence of hypertension and atherosclerosis. Am J Pathol 139: 1119-1129, 1991. 36. Guyton JR, Lindsay KL, Dao DT: Comparison of aortic intima and inner media in young adults versus aging rats. Am J Pathol III: 234-236, 1983. 37. Feldman SA, Glagov S: Transmedial collagen and elastin gradient in human aortas: reversal with age. Atherosclerosis 13: 385-394, 1971. 38. Avolio AP, Chen S, Wang R, Zhang C, Li M, O'Rourke MF: Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban population. Circu lation 68: 50-58, 1983. 39. Fischer GM: Effects of spontaneous hypertension and age on arterial connective tissue in the rat. Exp Geront II: 209-215, 1976. 40. Wo lin sky H: Long-term effects of hypertension on the rat a ortic wall and their relation to concurrent aging changes. M or pho lo gi cal and chemical studies. Circ Res 30: 301-309, 1972. 41. Ow e ns GK, Reidy MA: Hyperplastic growth response of vascular smooth muscle cells following induction of acute hypertension in rats by aortic coarctation. Circ Res 57: 695705, 1985. 42. London GM, Marchais SJ, Guérin AP, Fabiani F, Métivier F: Cardiovascular function in hemodialysis patients. In: Advan ces in nephrology (vol. 20), edited by Grünfeld JP, Bach JF, Funck-Brentano JL, Maxwell MH: St Louis, Mosby Year Book, pp. 249-273, 1991. 43. Barenbrock M, Spieker C, Laske V, Rahn K-H: Studies of the vessel wall properties in hemodialysis patients. Kidney Int 45: 1397-1400, 1994. 44. Kawagishi T, Nishizawa Y, Konishi T, Kawasaki K, Emoto M, Shoji T, Tabata T, Inoue T, Morii H: High-resolution B-mode ultrasonography in evaluation of atherosclerosis in uremia. Kidney Int 48: 820-826, 1995. 45. Roman MJ, Saba PS, Pini R, Spitzer M, Pickering TG, Rosen S, Alderman MH, Devereux RB: Parallel cardiac and vascular adaptation in hypertension. Circulation 86: 1909-1918, 1992. 46. Boutouyrie P, Laurent S, Girerd X, Benetos A, Lacolley P, Abergel E, Safar M: Common carotid artery stiffness and patterns of left ventricular hypertrophy in hypertensive patients. Hypertension 25 [part 1]: 651-659, 1995. 47. Dobrin PB, Littooy FN, Endean ED: Mechanical factors predisposing to intimal hyperplasia and medial thickening in autogeneous vein grafts. Surgery 105: 393-400, 1989. 48. London GM, Marchais SJ, Safar ME, Genest AF, Guérin AP, Métivier F, Chedid K, London AM: Aortic and large artery compliance in end-stage renal failure. Kidney Int 37: 137142, 1990. 49. Ibels LS, Alfrey AL, Huffer WE, Craswell PW, Anderson JT, Weil R: Arterial calcification and pathology in uremic patients undergoing dialysis. Am J Med 66: 790-796, 1979. 50. Amann K, Neusüß R, Ritz E, Irzyniec T, Wiest G, Mall G: Changes of vascular architecture independent of blood pressure in experimental uremia. Am J Hypertens 8: 409-417, 1995. 51. Watanabe H, Ohtsuka S, Kakihana M, Sugishita Y: Coronary circulation in dogs with an experimental decrease in aortic compliance. J Am Coll Cardiol 21: 1497-1506, 1993. 52. Rostand SG, Gretes JC, Kirk KA, Rutsky EA, Andreoli TE: Ischemic heart disease in patients with uremia undergoing maintenance hemodialysis. Kidney Int 16: 600-611, 1979. 53. Rostand SG, Kirk KA, Rutsky EA: Relationship of coronary risk factors to hemodialysis-associated ischemic heart disease. Kidney Int 22: 304-308, 1982. 22