Effects of renin-angiotensin system blockers on left ventricular hypertrophy and biochemical markers of collagen balance in patients with hypertensive hypertrophy

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Aim. To evaluate the effect of ACE inhibitor enalapril, AR blocker candesartan and their combination on left ventricular hypertrophy (LVH) and content of biochemical markers of collagen balance in patients with hypertensive LV hypertrophy.
Material and methods. A total of 66 patients with arterial hypertension with LV hypertrophy were divided into two groups. Group 1 (n = 33) received candesartan (8-16 mg/day), group 2 (n = 33) received enalapril (10-20 mg/day). In effective hypotensive response to the initial treatment, it was continued for 6 months. If in two months of monotherapy the effect was unsatisfactory, the other drug was added. At baseline and upon 6 months of treatment all the patients were examined for myocardial mass index (MMI), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (THMP-1) in the blood.
Results. In effective initial treatment with candesartan 6-month treatment lowered LV MMI by 13.9%, while in enalapril group - only by 1.5%. In addition of the second drug in ineffective initial therapy the reduction was 5.1%. THMP-1 did not change during the trial.
Conclusion. In patients with hypertensive LVH candesartan more effectively treated LVH. The addition of the second RAS blocker in insufficient efficacy of the initial one significantly reduces LV MMI. A significant antifibrotic effect was achieved only in case of simultaneous use of two RAS blockers.


  1. Koren M., Devereux R., Casale P. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann. Intern. Med. 1991; 114: 345-352.
  2. Verdecchia P., Shillaci G., Borgioni C. et al. Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation 1998; 97: 48-54.
  3. Schmieder R., Martus P., Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: meta-analysis of randomized studies. J. A. M. A. 1996; 275: 1507-1513.
  4. Urata H., Nishimura H., Ganten D. Mechanisms of angiotensin II formation in humans. Eur. Heart. J. 1995; 16 (suppl. N): 79-85.
  5. van den Meiracker A., Man in't Veld A., Admiraal P. et al. Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: Does it exist and does it affect the antihypertensive response? J. Hypertens. 1992; 10: 803-808.
  6. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ. Res. 1998; 83: 1182-1191.
  7. Ohkubo N., Matsubara H., Nozawa Y. et al. Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation 1997; 96: 3954-3962.
  8. Tsutsumi H., Matsubara H., Ohkubo N. et al. Angiotensin type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ. Res. 1998; 83: 1035-1046.
  9. Weber K., Brilla C. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991; 83: 1849-1865.
  10. Овчинников А., Габрусенко С., Сербул В. и др. Состояние диастолической функции при гипертрофии левого желудочка различной этиологии. В кн.: Сборник тезисов Ежегодной Всероссийской конф. Общества специалистов по сердечной недостаточности. Москва. - 7-9 декабря 2004 г.: 20.
  11. Овчинников А., Сербул В., Габрусенко С. и др. Содержание мозгового натрийуретического пептида у пациентов с гипертрофией левого желудочка различной этиологии. В кн.: Сборник тезисов I Конгресса (VII Ежегодной Всероссийской конф. Общества специалистов по сердечной недостаточности) "Сердечная недостаточность 2006", Москва, 6-8 дек., 2006 г.: 54.
  12. Tikkanen I., Omvik P., Jenstn H. et al. Comparison of the angiotensin II antagonist losartan with angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J. Hypertens. 1995; 13: 1343-1351.
  13. Ruff D., Gazdick L., Berman R. et al. Comparative effects of combination drug therapy regimens commencing with either losartan potassium, an angiotensin II receptor antagonist, or enalapril maleate for the treatment of severe hypertension. J. Hypertens. 1996; 14: 263-270.
  14. Laviades C., Varo N., Fernбndez J. et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998; 98: 535-540.
  15. Diez J., Laviades C., Mayor G. et al. Increased serum concentrations of procollagen peptides in essential hypertension: relation to cardiac alterations. Circulation 1995; 91: 1450-1456.
  16. Diez J., Panizo A., Gi1 M. et al. Serum markers of collagen type I metabolism in spontaneously hypertensive rates: relation to myocardial fibrosis. Circulation 1996; 93: 1026-1032.
  17. Woessner J. Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991; 131: 2145-2154.
  18. Laurent G. Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am. J. Physiol. 1987; 252: C1-C9.
  19. Feldman A., Li Y., McTiernan C. Matrix metalloproteinases in pathophysiology and treatment of heart failure. Lancet 2001; 357: 654-655.
  20. Spinale F. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ. Res. 2002; 890: 520-530.
  21. Weber K., Anversa P., Armstrong P. et al. Remodeling and reparation of the cardiovascular system. J. Am. Coll. Cardiol. 1992; 20: 3-16.
  22. The ONTARGET/TRANSCEND Investigators. Telmisartan, ramipril, or both at high risk for vascular events. N. Engl. J. Med. 2008; 358(15): 1547-1559.
  23. Yoshida J., Yamamoto K., Nishikawa N. et al. Angiotensin converting enzyme inhibitor and angiotensin II type I receptor antagonist differently modulate extracellular matrix regulatory system in diastolic heart failure. J. Hypertens. 2005; 23: 393-400.
  24. Mйnard J., Duncan J., Campbell J., Azizi M. Synergistic effects of the ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hydertensive rats. Circulation 1997; 96: 3072-3078.
  25. Nunez E., Hosoya K., Susik D., Frohlich D. Enalapril and losartan reduced mass and improved coronary hemodynamics in SHR. Hypertension 1997; 29(2): 519-524.
  26. Kim S., Zhan Yu., Izumi Ya., Iwao H. Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. Hypertension 2000; 35: 769-774.
  27. Richer C., Bruneval P., Mйnard J., Giudicelli J.-F. Additive effect of enalapril in (mREN-2)27 transgenic rats. Hypertension 1998; 31: 692-698.
  28. Avanza A., Aourar L., Mill J. Reduction in left ventricular hypertrophy in hypertensive patients treated with enalapril, losartan or the combination of enalapril and losartan. Arq. Bras. Cardiol. 2000; 252: 74-78.
  29. Anan F., Takahashi N., Ooie T. et al. Effects of valsartan and perindopril combination therapy on left ventricular hypertrophy and aortic arterial stiffness in patients with essential hypertension. Eur. J. Clin. Pharmacol. 2005; 61: 353-359.
  30. Ganau A., Deverux R., Roman M. et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J. Am. Coll. Cardiol. 1992; 19: 1550-1558.
  31. Schiller N., Shah P., Crawford M. et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J. Am. Soc. Echocardiogr. 1989; 2: 358-367.
  32. Lindsay M., Maxwell P., Dunn G. TLMP-l: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension. Hypertension 2002; 40: 136-141.
  33. Mancia G., De Backer G., Dominiczak A. et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur. Heart J. 2007; 28; 1462-1536.
  34. Linz W., Scholkens B. A specific BK2-bradykinin receptor antagonist Hoe 140 abolishes the antihypertrophic effect of ramipril. Br. J. Pharmacol. 1991; 105: 771-772.
  35. Kaplan N. Systemic hypertension: mechanism and diagnosis. In: Zippes D., Libby P., Bonow R., Braunwald E. (eds.) Braunwald's heart disease: a textbook of cardiovascular medicine. 7th ed. Philadelphia: Elsevier Saunders; 2005. 959-987.
  36. Nussberger J., Brunner D., Waeber B. et al. Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma. Hypertension 1986; 8: 476-482.
  37. Mukawa H., Toki Y., Shimauchi A. et al. Possible involvement of angiotensin II type 2 receptor in antihypertrophic effects exerted by the type 1 receptor antagonist in hypertensive rats. Eur. Heart J. 1997; 18(suppl.): 445.
  38. Villatico S., Campbell V., Rizzo F. et al. Antihypertensive therapy with losartan and fosinopril: efficacy in left ventricular hypertrophy regression. Am, J. Hypertens. 1998; 11: 125A.
  39. Cuspidi C., Muiesan M., Valagussa L. et al. Comparative effects of candesartan and enalapril on left ventricular hypertrophy in patients with essential hypertension: the Candesartan Assessment in the Treatment of Cardiac Hypertrophy (CATCH) study. 2002; 20: 2293-2300.
  40. Gosse P., Sheridan D., Zannand F. et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 ng; the LIVE study. J. Hypertens. 2000; 18: 1465-1475.
  41. Gottdiener J., Diamond J., Phillips R. Hypertension: impact of echocardiographic data on the mechanism of hypertension, treatment options, prognosis, and assessment of therapy. In: Otto C., ed. The practice of clinical echocardiography. 2-nd ed. Philadelphia: W. B. Saunders Company; 2002. 705-738.
  42. Lцpez B., Gonzalez A., Varo N. et al. Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension 2001; 38: 1222-1226.
  43. Katz A. The heart as a muscular pump. In: Katz A. Physiology of the heart. 3-rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. 398-417.
  44. Yip G., Zhang Y., Fung J. et al. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002; 87: 121-125.
  45. Freer R., Pappano A., Peach M. et al. Mechanism for the positive inotropic effect of angiotensin II on isolated cardiac muscle. Circ. Res. 1976; 39: 178-183.
  46. Giatras I., Lau J., Levey A. et al. Effect of angiotensin-converting enzyme inhibitors on the progression of non-diabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern. Med. 1997; 127: 337-345.
  47. GISEN Study Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Renal functions and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet 1998; 352: 1252-1256.
  48. Glennon P., Sugden P., Poole-Wilson P. Cellular mechanisms of cardiac hypertrophy. Br. Heart J. 1995; 73: 496-499.
  49. Lцpez B., Querejeta R., Varo N. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation 2001; 104: 286-291.
  50. Brilla C., Funck R., Rupp H. Lisinopril mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000; 102: 1388-1393.
  51. Frank J., Langer G. The myocardial interstitium: Its structure and its role in ionic exchange. J. Cell. Biol. 1974; 60: 586-601.
  52. Cheitlin M., Rubinowitz M., McAllister H. et al. The distribution of fibrosis in the left ventricle in congenital aortic stenosis and coarctation of the aorta. Circulation 1980; 62: 823-830.
  53. Oldershaw P., Brooksby I., Davies M. et al. Correlations of fibrosis in endomyocardial biopsies from patients with aortic valve disease. Br. Heart J. 1980; 44: 609-611.
  54. Chapman D., Weber K., Eghbali M. Regression of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in hypertrophied rat myocardium. Circ. Res. 1990; 67: 787-794.
  55. Brilla C., Maisch B. Regulation of the structural remodeling of the myocardium: from hypertrophy to heart failure. Eur. Heart J. 1994; 15 (suppl. D): 45-52.
  56. Weber K., Clarck W., Janicki J. et al. Physiologic versus pathologic hypertrophy and the pressure-overload myocardium. J. Cardiovasc. Pharmacol. 1987; 10: S37-S49.



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