Anti-inflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation

Background: Experimental studies revealed pro-inflammatory properties of angiotensin II. We evaluated antiinflammatory effects of the angiotensin II subtype 1 receptor antagonist olmesartan medoxomil alone and in cotherapy with the HMG-CoA reductase inhibitor pravastatin, in patients with essential hypertension and microinflammation. Methods and results: We measured a panel of vascular inflammation markers, including high-sensitivity C-reactive protein (hsCRP), and lipid levels during 12 weeks of therapy with olmesartan (n=100) or placebo (n=99) in a prospective double-blind multicenter study. Pravastatin was added to the double-blind therapy at week 6 in both treatment arms. Blood pressure (BP) control was achieved with addition of hydrochlorothiazide. Olmesartan treatment had already significantly reduced serum levels of hsCRP (-15,1%; p<0,05), high-sensitivity tumor necrosis factor-alpha, hsTNF-alpha (-8,9%; p<0,02), interleukin-6, IL-6 (-14,0%; p<0,05), and monocyte chemotactic protein-1, MCP-1 (-6,5%; p<0,01) after 6 weeks of therapy, whereas placebo treatment (ie, BP reduction) had no major effect on inflammation markers. After 12 weeks of therapy, hsCRP (-21,1%; p<0,02), hsTNF-alpha (-13,6%; p<0,01), and IL-6 (-18,0%; p<0,01) decreased further with olmesartan and pravastatin co-therapy, but treatment with pravastatin alone (ie, co-therapy with placebo) did not significantly alter inflammation markers. In contrast, addition of pravastatin led to a significant (p<0,001) reduction in LDL cholesterol serum concentrations in the olmesartan and placebo treatment groups (-15,1% and -12,1%, respectively). Conclusions: Angiotensin II receptor blockade significantly reduces vascular microinflammation in patients with essential hypertension by as early as week 6 of therapy. This anti-inflammatory action of angiotensin II receptor antagonists may contribute to their beneficial cardiovascular effects.

1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340:115-26.

2. Pearson TA, Mensah GA, Alexander RW, et al, for the Centers for Disease Control and Prevention and American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499 -511.

3. Espinola-Klein C, Rupprecht HJ, Blankenberg S, et al, for the AtheroGene Investigators. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation. 2002;105:15-21.

4. Magyar MT, Szikszai Z, Balla J, et al. Early-onset carotid atherosclerosis is associated with increased intima-media thickness and elevated serum levels of inflammatory markers. Stroke. 2003;34:58-63.

5. Saito M, Ishimitsu T, Minami J, et al. Relations of plasma highsensitivity C-reactive protein to traditional cardiovascular risk factors. Atherosclerosis. 2003;167:73-9.

6. Sesso HD, Buring JE, Rifai N, et al. C-reactive protein and the risk of developing hypertension. JAMA. 2003;290:2945-51.

7. Blake GJ, Rifai N, Buring JE, et al. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 2003;108: 2993-9.

8. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-54.

9. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003;107:363-9.

10. Yeh ET, Willerson JT. Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation. 2003;107:370 -1.

11. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-65.

12. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-43.

13. Esposito K, Pontillo A, Di Palo C, et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA. 2003;289:1799 -804.

14. Tchernof A, Nolan A, Sites CK, et al. Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation. 2002;105: 564-9.

15. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-99.

16. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein: the Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100:230-5.

17. Albert MA, Danielson E, Rifai N, et al, for the PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation CRP Evaluation (PRINCE). JAMA. 2001;286:64 -70.

18. Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation. 2002;106:1447-152.

19. Mervaala EM, Muller DN, Park JK, et al. Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. Hypertension. 1999;33:389 -95.

20. Brasier AR, Recinos A, Eledrisi MS. Vascular inflammation and the renin-angiotensin system. Arterioscler Thromb Vasc Biol. 2002;22: 1257-66.

21. Dandona P, Kumar V, Aljada A, et al. Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an anti-inflammatory action. J Clin Endocrinol Metab. 2003;88: 4496-501.

22. Roberts WL, Moulton L, Law TC, et al. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications, part 2. Clin Chem. 2001;47:418-25.

23. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: 145-53.

24. Dahlof B, Devereux RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.

25. Khan BV, Navalkar S, Khan QA, et al. Irbesartan, an angiotensin type 1 receptor inhibitor, regulates the vascular oxidative state in patients with coronary artery disease. JACC. 2001;38:1662-7.

26. Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. JACC. 2003;42: 905-10.

27. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102: 2165-8.

28. Pasceri V, Cheng JS, Willerson JT, et al. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103:2531-4.

29. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105:1890 -6.

30. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002;106:913-9.

31. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106:1439 -41.

32. Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103:1933-5.

33. Ridker PM, for the JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292-7.