Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-23T07:33:31.518Z Has data issue: false hasContentIssue false
  • English
  • Français

Age-related change in endothelial and microvessel function and therapeutic consequences

Part of: Bespoke shallow archive Weizmann

Published online by Cambridge University Press:  11 May 2010

W David Strain ,
Salim Elyas ,
Phillip E Gates  and
Angela C Shore
W David Strain*
Affiliation:
Diabetes and Vascular Medicine, Peninsula Medical School, University of Exeter, Exeter
Salim Elyas
Affiliation:
Diabetes and Vascular Medicine, Peninsula Medical School, University of Exeter, Exeter
Phillip E Gates
Affiliation:
Diabetes and Vascular Medicine, Peninsula Medical School, University of Exeter, Exeter
Angela C Shore
Affiliation:
Diabetes and Vascular Medicine, Peninsula Medical School, University of Exeter, Exeter
*
Address for correspondence: Dr David Strain, Diabetes and Vascular Research Centre, Peninsula NIHR Clinical Research Facility and Institute of Biomedical and Clinical Sciences, Peninsula Medical School, University of Exeter, Royal Devon and Exeter Hospital (Wonford), Barrack Road, Exeter, Devon EX2 5AX. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

As the absolute numbers and proportion of older adults increases across most of the developed world, a greater understanding of the aetiopathogenic mechanisms of the increased vascular risk and their therapeutic implications becomes essential to all clinicians assessing and managing the geriatric patient. The role of endothelial function and the microcirculation is increasingly recognized in the maintenance of adequate perfusion, and their dysfunction is thought to be an early and potentially reversible mechanism by which age acts to increase cardiovascular risk.

Here we review evidence that altered microvascular function appears before other recognized predictors of vascular disease, and progresses from childhood to late adult life, preceding fulminant atherosclerotic or arteriosclerotic disease. Low birth-weight babies have reduced endothelial function in skin microvessels at 3 months, and by age ten brachial artery endothelial function is reduced in comparison with normal birth-weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is lower compared with normal weight children and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure, independent of brachial artery blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity.

Exploration of the therapeutic implications for management of endothelial dysfunction remains in embryonic state. The use of ACE-inhibitors, angiotensin receptor blockers and direct renin inhibitors in patients with evidence of microvascular damage such as retinopathy and microalbuminuria has been established; however, in the general older population the benefit has yet to be established. Therefore current recommendations are to screen for microvascular damage and if present target treatments after control of other vascular risk factors such as hypertension.

Keywords

microcirculationendothelial functionageing
Type
Biological gerontology
Information
Reviews in Clinical Gerontology , Volume 20 , Issue 3 , August 2010 , pp. 161 - 170
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Najjar, SS, Scuteri, A, Lakatta, EG.Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005; 46: 454–62.CrossRefGoogle ScholarPubMed
2Moncada, S, Palmer, RM, Higgs, EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109–42.Google ScholarPubMed
3Deanfield, JE, Halcox, JP, Rabelink, TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115: 1285–95.CrossRefGoogle ScholarPubMed
4Corson, MA, James, NL, Latta, SE, Nerem, RM, Berk, BC, Harrison, DG. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res 1996; 79: 984–91.CrossRefGoogle ScholarPubMed
5Higgs, EA, Higgs, GA, Moncada, S, Vane, JR. Prostacyclin (PGI2) inhibits the formation of platelet thrombi in arterioles and venules of the hamster cheek pouch. Br J Pharmacol 1997; 120: 439–43; discussion 437–38.CrossRefGoogle ScholarPubMed
6Busse, R, Edwards, G, Félétou, M, Fleming, I, Vanhoutte, PM, Weston, AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002; 23: 374–80.CrossRefGoogle ScholarPubMed
7Halcox, JP, Narayanan, S, Cramer-Joyce, L, Mincemoyer, R, Quyyumi, AA. Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation. Am J Physiol Heart Circ Physiol 2001; 280: H2470–77.CrossRefGoogle ScholarPubMed
8Wang, M, Lakatta, EG. Central arterial aging: humans to molecules. FASEB J 2009; 23 (1_MeetingAbstracts): 414.4.Google Scholar
9Celermajer, DS, Sorensen, KE, Spiegelhalter, DJ, Georgakopoulos, D, Robinson, J, Deanfield, JE. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994; 24: 471–76.CrossRefGoogle ScholarPubMed
10Taddei, S, Virdis, A, Mattei, P, Ghiadoni, L, Gennari, A, Fasolo, CB, Sudano, I, Salvetti, A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91: 1981–87.CrossRefGoogle ScholarPubMed
11Kinlay, S, Behrendt, D, Wainstein, M, Beltrame, J, Fang, JC, Creager, MA, Selwyn, AP, Ganz, P. Role of endothelin-1 in the active constriction of human atherosclerotic coronary arteries. Circulation 2001; 104: 1114–18.CrossRefGoogle ScholarPubMed
12Saye, JA, Singer, HA, Peach, MJ. Role of endothelium in conversion of angiotensin I to angiotensin II in rabbit aorta. Hypertension 1984; 6: 216–21.CrossRefGoogle ScholarPubMed
13Donato, AJ, Eskurza, I, Silver, AE, Levy, AS, Pierce, GL, Gates, PE, Seals, DR. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappa B. Circ Res 2007; 100: 1659–66.CrossRefGoogle Scholar
14Taddei, S, Virdis, A, Ghiadoni, L, Salvetti, G, Bernini, G, Magagna, A, Salvetti, A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension 2001; 38: 274–79.CrossRefGoogle ScholarPubMed
15Davignon, J, Ganz, P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109: III27–32.CrossRefGoogle ScholarPubMed
16Luscher, TF, Barton, M. Biology of the endothelium. Clin Cardiol 1997; 20: II3–10.CrossRefGoogle ScholarPubMed
17Vita, JA, Keaney, JF Jr.Endothelial function: a barometer for cardiovascular risk? Circulation 2002; 106: 640–42.CrossRefGoogle ScholarPubMed
18Halcox, JP, Schenke, WH, Zalos, G, Mincemoyer, R, Prasad, A, Waclawiw, MA, Nour, KR, Quyyumi, AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002; 106: 653–58.CrossRefGoogle ScholarPubMed
19Schachinger, V, Britten, MB, Zeiher, AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101: 1899–906.CrossRefGoogle ScholarPubMed
20Suwaidi, JA, Hamasaki, S, Higano, ST, Nishimura, RA, Holmes, DR Jr, Lerman, A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948–54.CrossRefGoogle ScholarPubMed
21Levy, BI, Ambrosio, G, Pries, AR, Struijker-Boudier, HA. Microcirculation in hypertension: a new target for treatment? Circulation 2001; 104: 735–40.CrossRefGoogle ScholarPubMed
22Shore, A. Vascular biology and physiology. In Tooke, J, Lowe, D (eds). A Textbook of Vascular Medicine, 1996, Arnold: Bath.Google Scholar
23Levick, J.An Introduction to Cardiovascular Physiology, 4th edn. 2003, London: Hodder Arnold.Google Scholar
24Serné, EH, de Jongh, RT, Eringa, EC, IJzerman, RG, Stehouwer, CD. Microvascular dysfunction: a potential pathophysiological role in the metabolic syndrome. Hypertension 2007; 50: 204–11.CrossRefGoogle ScholarPubMed
25Feihl, F, Liaudet, L, Waeber, B, Levy, BI. Hypertension: a disease of the microcirculation? Hypertension 2006; 48: 1012–17.CrossRefGoogle ScholarPubMed
26Tooke, JE, Sandeman, DD, Shore, AC. Microvascular hemodynamics in hypertension and diabetes. J Cardiovasc Pharmacol 1991; 18: S51–53.CrossRefGoogle ScholarPubMed
27Tooke, JE, Morris, SJ, Shore, AC. Microvascular functional abnormalities in diabetes: the role of the endothelium. Diabetes Res Clin Pract 1996; 31: S127–32.CrossRefGoogle ScholarPubMed
28Ijzerman, RG, de Jongh, RT, Beijk, MA, van Weissenbruch, MM, Delemarre-van de Waal, HA, Serné, EH, Stehouwer, CD. Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin. Eur J Clin Invest 2003; 33: 536–42.CrossRefGoogle ScholarPubMed
29Mattock, MB, Barnes, DJ, Viberti, G, Keen, H, Burt, D, Hughes, JM, Fitzgerald, AP, Sandhu, B, Jackson, PG. Microalbuminuria and coronary heart disease in NIDDM: an incidence study. Diabetes 1998; 47: 1786.CrossRefGoogle ScholarPubMed
30Ljungman, S, Wikstrand, J, Hartford, M, Berglund, G. Urinary albumin excretion – a predictor of risk of cardiovascular disease. A prospective 10-year follow-up of middle-aged non-diabetic normal and hypertensive men. Am J Hypertens 1996; 9: 770–78.CrossRefGoogle Scholar
31Roest, M, Banga, JD, Janssen, WM, Grobbee, DE, Sixma, JJ, de Jong, PE, de Zeeuw, D, van der Schouw, YT. Excessive urinary albumin levels are associated with future cardiovascular mortality in postmenopausal women. Circulation 2001; 103: 3057–61.CrossRefGoogle ScholarPubMed
32Damsgaard, EM, Frøland, A, Jørgensen, OD, Mogensen, CE. Microalbuminuria as predictor of increased mortality in elderly people. Br Med J 1990; 300: 297–300.CrossRefGoogle ScholarPubMed
33Yudkin, JS, Forrest, RD, Jackson, CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet 1988; 2: 530–33.CrossRefGoogle ScholarPubMed
34Borch-Johnsen, K, Feldt-Rasmussen, B, Strandgaard, S, Schroll, M, Jensen, JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 1999; 19: 1992–97.CrossRefGoogle ScholarPubMed
35Gerstein, HC, Mann, JF, Yi, Q, Zinman, B, Dinneen, SF, Hoogwerf, B, Hallé, JP, Young, J, Rashkow, A, Joyce, C, Nawaz, S, Yusuf, S; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and non-diabetic individuals. JAMA 2001; 286: 421–26.CrossRefGoogle Scholar
36Wong, TY, Rosamond, W, Chang, PP, Couper, DJ, Sharrett, AR, Hubbard, LD, Folsom, AR, Klein, R. Retinopathy and risk of congestive heart failure. JAMA 2005; 293: 63–69.CrossRefGoogle ScholarPubMed
37Pantoni, L, Garcia, JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997; 28: 652–59.CrossRefGoogle ScholarPubMed
38Wong, TY, Klein, R, Sharrett, AR, Couper, DJ, Klein, BE, Liao, DP, Hubbard, LD, Mosley, TH; ARIC Investigators. Atheroslerosis Risk in Communities Study. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002; 288: 67–74.CrossRefGoogle ScholarPubMed
39Noon, JP, Walker, BR, Webb, DJ, Shore, AC, Holton, DW, Edwards, HV, Watt, GC. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997; 99: 1873–79.CrossRefGoogle ScholarPubMed
40Strain, WD, Chaturvedi, N, Shore, A. Ethnic differences in microvascular structure and function. J Hypertens 2005; 23: 1434–35; author reply 1435–36.CrossRefGoogle ScholarPubMed
41Strain, WD, Chaturvedi, N, Leggetter, S, Nihoyannopoulos, P, Rajkumar, C, Bulpitt, CJ, Shore, AC. Ethnic differences in skin microvascular function and their relation to cardiac target-organ damage. J Hypertens 2005; 23: 133–40.CrossRefGoogle ScholarPubMed
42Lee, BC, Shore, AC, Humphreys, JM, Lowe, GD, Rumley, A, Clark, PM, Hattersley, AT, Tooke, JE. Skin microvascular vasodilatory capacity in offspring of two parents with Type 2 diabetes. Diabet Med 2001; 18: 541–45.CrossRefGoogle ScholarPubMed
43Goh, KL, Shore, AC, Quinn, M, Tooke, JE. Impaired microvascular vasodilatory function in 3-month-old infants of low birth weight. Diabetes Care 2001; 24: 1102–7.CrossRefGoogle ScholarPubMed
44Martin, H, Hu, J, Gennser, G, Norman, M. Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight. Circulation 2000; 102: 2739–44.CrossRefGoogle ScholarPubMed
45Leon, DA, Lithell, HO, Vâgerö, D, Koupilová, I, Mohsen, R, Berglund, L, Lithell, UB, McKeigue, PM. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15,000 Swedish men and women born 1915–29. BMJ 1998; 317: 241–45.CrossRefGoogle ScholarPubMed
46Goodfellow, J, Bellamy, MF, Gorman, ST, Brownlee, M, Ramsey, MW, Lewis, MJ, Davies, DP, Henderson, AH. Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res 1998; 40: 600–6.CrossRefGoogle ScholarPubMed
47Shore, AC, Price, KJ, Sandeman, DD, Tripp, JH, Tooke, JE. Posturally induced vasoconstriction in diabetes mellitus. Arch Dis Child 1994; 70: 22–26.CrossRefGoogle ScholarPubMed
48Rayman, G, Hassan, A, Tooke, J. Blood flow in the skin of the foot related to posture in diabetes mellitus. Br Med J (Clin Res Ed) 1986; 292: 87–90.CrossRefGoogle ScholarPubMed
49James, MA, Tullett, J, Hemsley, AG, Shore, AC. Effects of aging and hypertension on the microcirculation. Hypertension 2006; 47: 968–74.CrossRefGoogle ScholarPubMed
50Kenney, WL, Morgan, AL, Farquhar, WB, Brooks, EM, Pierzga, JM, Derr, JA. Decreased active vasodilator sensitivity in aged skin. Am J Physiol 1997; 272: H1609–14.Google ScholarPubMed
51Minson, CT, Holowatz, LA, Wong, BJ, Kenney, WL, Wilkins, BW. Decreased nitric oxide- and axon reflex-mediated cutaneous vasodilation with age during local heating. J Appl Physiol 2002; 93: 1644–49.CrossRefGoogle ScholarPubMed
52Seals, DR, Gates, PE. Stiffening our resolve against adult weight gain. Hypertension 2005; 45: 175–77.CrossRefGoogle ScholarPubMed
53de Jongh, RT, Serné, EH, Ijzerman, RG, de Vries, G, Stehouwer, CD. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 2004; 109: 2529–35.CrossRefGoogle ScholarPubMed
54Serné, EH, Gans, RO, ter Maaten, JC, ter Wee, PM, Donker, AJ, Stehouwer, CD. Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions. Cardiovasc Res 2001; 49: 161–68.CrossRefGoogle ScholarPubMed
55de Jongh, RT, Ijzerman, RG, Serné, EH, Voordouw, JJ, Yudkin, JS, de Waal, HA, Stehouwer, CD, van Weissenbruch, MM. Visceral and truncal subcutaneous adipose tissue are associated with impaired capillary recruitment in healthy individuals. J Clin Endocrinol Metab 2006; 91: 5100–6.CrossRefGoogle ScholarPubMed
56de Jongh, RT, Serné, EH, Ijzerman, RG, de Vries, G, Stehouwer, CD. Free fatty acid levels modulate microvascular function: relevance for obesity-associated insulin resistance, hypertension, and microangiopathy. Diabetes 2004; 53: 2873–82.CrossRefGoogle ScholarPubMed
57de Jongh, RT, Serné, EH, Ijzerman, RG, Stehouwer, CD. Microvascular function: a potential link between salt sensitivity, insulin resistance and hypertension. J Hypertens 2007; 25: 1887–93.CrossRefGoogle ScholarPubMed
58Feletou, M, Vanhoutte, PM. Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 2006; 291: H985–1002.CrossRefGoogle ScholarPubMed
59DeSouza, CA, Shapiro, LF, Clevenger, CM, Dinenno, FA, Monahan, KD, Tanaka, H, Seals, DR. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation 2000; 102: 1351–57.CrossRefGoogle ScholarPubMed
60Black, MA, Green, DJ, Cable, NT. Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels. J Physiol 2008; 586: 3511–24.CrossRefGoogle ScholarPubMed
61Shore, AC, Sandeman, DD, Tooke, JE. Capillary pressure, pulse pressure amplitude, and pressure waveform in healthy volunteers. Am J Physiol 1995; 268: H147–54.Google ScholarPubMed
62Gooding, KM, MacLeod, KM, Spyer, G, Ewings, P, Tooke, JE, Shore, AC. Impact of hormone replacement therapy on microvascular function in healthy and Type 2 diabetic postmenopausal women. Diabet Med 2005; 22: 536–42.CrossRefGoogle ScholarPubMed
63Vuilleumier, P, Decosterd, D, Maillard, M, Burnier, M, Hayoz, D. Post-ischemic forearm skin reactive hyperemia is related to cardiovascular risk factors in a healthy female population. J Hypertens 2002; 20: 1753–57.CrossRefGoogle Scholar
64Zandbergen, AA, Sijbrands, EJ, Lamberts, SW, Bootsma, AH. Normotensive women with type 2 diabetes and microalbuminuria are at high risk for macrovascular disease. Diabetes Care 2006; 29: 1851–55.CrossRefGoogle ScholarPubMed
65de Zeeuw, D, Remuzzi, G, Parving, HH, Keane, WF, Zhang, Z, Shahinfar, S, Snapinn, S, Cooper, ME, Mitch, WE, Brenner, BM. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004; 110: 921–27.CrossRefGoogle ScholarPubMed
66Goto, I, Katsuki, S, Ikui, H, Kimoto, K, Mimatsu, T. Pathological studies on the intracerebral and retinal arteries in cerebrovascular and noncerebrovascular diseases. Stroke 1975; 6: 263–69.CrossRefGoogle ScholarPubMed
67Wong, TY, Klein, R, Couper, DJ, Cooper, LS, Shahar, E, Hubbard, LD, Wofford, MR, Sharrett, AR. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 2001; 358: 1134–40.CrossRefGoogle ScholarPubMed
68Hambrecht, R, Wolf, A, Gielen, S, Linke, A, Hofer, J, Erbs, S, Schoene, N, Schuler, G. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454–60.CrossRefGoogle ScholarPubMed
69Hamdy, O, Ledbury, S, Mullooly, C, Jarema, C, Porter, S, Ovalle, K, Moussa, A, Caselli, A, Caballero, AE, Economides, PA, Veves, A, Horton, ES. Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 2003; 26: 2119–25.CrossRefGoogle ScholarPubMed
70Raitakari, M, Ilvonen, T, Ahotupa, M, Lehtimäki, T, Harmoinen, A, Suominen, P, Elo, J, Hartiala, J, Raitakari, OT. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol 2004; 24: 124–28.CrossRefGoogle ScholarPubMed
71Ibsen, H, Olsen, MH, Wachtell, K, Borch-Johnsen, K, Lindholm, LH, Mogensen, CE, Dahlöf, B, Devereux, RB, de Faire, U, Fyhrquist, F, Julius, S, Kjeldsen, SE, Lederballe-Pedersen, O, Nieminen, MS, Omvik, P, Oparil, S, Wan, Y. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 2005; 45: 198–202.CrossRefGoogle ScholarPubMed
72Wachtell, K, Ibsen, H, Olsen, MH, Borch-Johnsen, K, Lindholm, LH, Mogensen, CE, Dahlöf, B, Devereux, RB, Beevers, G, de Faire, U, Fyhrquist, F, Julius, S, Kjeldsen, SE, Kristianson, K, Lederballe-Pedersen, O, Nieminen, MS, Okin, PM, Omvik, P, Oparil, S, Wedel, H, Snapinn, SM, Aurup, P. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med 2003; 139: 901–6.CrossRefGoogle ScholarPubMed
73de Zeeuw, D. Albuminuria: a target for treatment of type 2 diabetic nephropathy. Semin Nephrol 2007; 27: 172–81.CrossRefGoogle ScholarPubMed
74Duprez, DA, Munger, MA, Botha, J, Keefe, DL, Charney, AN. Aliskiren for Geriatric Lowering of Systolic Hypertension: a randomized controlled trial. J Hum Hypertens 2009; Epub ahead of print (Dec 24).CrossRefGoogle Scholar
75Persson, F, Rossing, P, Reinhard, H, Juhl, T, Stehouwer, CD, Schalkwijk, C, Danser, AH, Boomsma, F, Frandsen, E, Parving, HH. Renal effects of aliskiren compared to and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria. Diabetes Care 2009; 32:1873–79.CrossRefGoogle ScholarPubMed
76Parving, HH, Persson, F, Lewis, JB, Lewis, EJ, Hollenberg, NK; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433–46.CrossRefGoogle Scholar
77Bakris, GL, Copley, JB, Vicknair, N, Sadler, R, Leurgans, S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996; 50: 1641–50.CrossRefGoogle ScholarPubMed
78ALLHAT Officers and Co-ordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981.CrossRefGoogle Scholar
79Parving, HH, Lehnert, H, Bröchner-Mortensen, J, Gomis, R, Andersen, S, Arner, P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870–78.CrossRefGoogle Scholar
80Muldoon, MF, Manuck, SB, Matthews, KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990; 301: 309–14.CrossRefGoogle ScholarPubMed
81Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandiniavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–89.Google Scholar
82Colhoun, HM, Betteridge, DJ, Durrington, PN, Hitman, GA, Neil, HA, Livingstone, SJ, Thomason, MJ, Mackness, MI, Charlton-Menys, V, Fuller, JH; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685–96.CrossRefGoogle Scholar
83Sever, PS, Dahlöf, B, Poulter, NR, Wedel, H, Beevers, G, Caulfield, M, Collins, R, Kjeldsen, SE, Kristinsson, A, McInnes, GT, Mehlsen, J, Nieminen, M, O'Brien, E, Ostergren, J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149–58.CrossRefGoogle ScholarPubMed
84Rosenberg, PB, Mielke, MM, Tschanz, J, Cook, L, Corcoran, C, Hayden, KM, Norton, M, Rabins, PV, Green, RC, Welsh-Bohmer, KA, Breitner, JC, Munger, R, Lyketsos, CG. Effects of cardiovascular medications on rate of functional decline in Alzheimer disease. Am J Geriatr Psychiatry 2008; 16: 883–92.CrossRefGoogle ScholarPubMed
85Ridker, PM, Danielson, E, Fonseca, FA, Genest, J, Gotto, AM Jr, Kastelein, JJ, Koenig, W, Libby, P, Lorenzatti, AJ, MacFadyen, JG, Nordestgaard, BG, Shepherd, J, Willerson, JT, Glynn, RJ; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207.CrossRefGoogle ScholarPubMed
86Sidhu, JS, Cowan, D, Kaski, JC. The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. J Am Coll Cardiol 2003; 42: 1757–63.CrossRefGoogle ScholarPubMed
87Nyström, T, Gutniak, MK, Zhang, Q, Zhang, F, Holst, JJ, Ahrén, B, Sjöholm, A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004; 287: E1209–15.CrossRefGoogle ScholarPubMed
88Ban, K, Noyan-Ashraf, MH, Hoefer, J, Bolz, SS, Drucker, DJ, Husain, M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and independent pathways. Circulation 2008; 117: 2340–50.CrossRefGoogle ScholarPubMed
89Pratley, RE, Rosenstock, J, Pi-Sunyer, FX, Banerji, MA, Schweizer, A, Couturier, A, Dejager, S. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care 2007; 30: 3017–22.CrossRefGoogle ScholarPubMed
90Ferrannini, E, Fonseca, V, Zinman, B, Matthews, D, Ahrén, B, Byiers, S, Shao, Q, Dejager, S. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009; 11: 157–66.CrossRefGoogle ScholarPubMed
91Bose, AK, Mocanu, MM, Carr, RD, Brand, CL, Yellon, DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 2005; 54: 146–51.CrossRefGoogle ScholarPubMed
92Bose, AK, Mocanu, MM, Carr, RD, Yellon, DM. Myocardial ischaemia-reperfusion injury is attenuated by intact glucagon like peptide-1 (GLP-1) in the in vitro rat heart and may involve the p70s6K pathway. Cardiovasc Drugs Ther 2007; 21: 253–56.CrossRefGoogle ScholarPubMed