cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2012-3-93-101cardiovascular-1836Research ArticleМНЕНИЕ ПО ПРОБЛЕМЕOPINION ON A PROBLEMДолгосрочная терапия сульфгидрильным ингибитором ангиотензин-превращающего фермента замедляет утолщение комплекса «интима-медия» сонных артерий, улучшает показатели обмена оксида азота и окислительного стресса у пациентов с впервые диагностированной первичной мягкой артериальной гипертониейLong-term treatment with sulfhydryl angiotensin-converting enzyme inhibition reduces carotid intima-media thickening and improves the nitric oxide/oxidative stress pathways in newly diagnosed patients with mild to moderate primary hypertensionНаполиК.NapoliC.БруцессеДж.BruzzeseG.ИгнарроЛ. Дж.IgnarroL. J.КримиЭ.CrimiE.де НигрисФ.De NigrisF.Вильямс-ИгнарроШ.Williams-IgnarroS.ЛибардиС.LibardiS.СоммесеЛ.SommeseL.ФиоритоК.FioritoC.МанчиниФ. П.ManciniF. P.КаччиатореФ.CacciatoreF.ЛигуориА.LiguoriA.1 Школа медицины, II Университет Неаполя, Неаполь; Мультимедика, МиланItalyГоспиталь Пеллегрини, НеапольItalyУниверситет Калифорнии, Лос-АнжелесUnited StatesГарвардская Медицинская школа, БостонUnited States1 Школа медицины, II Университет Неаполя, НеапольItalyДавид Геффен, медицинская школа, Лос-АнжелесUnited StatesМультимедика, МиланItalyУниверситет Саннио, БеневентоItalyОбщество Сальваторе Маугери, Телесе ТермеItaly20122006201211393101Copyright © Наполи К., Бруцессе Д., Игнарро Л.Д., Крими Э., де Нигрис Ф., Вильямс-Игнарро Ш., Либарди С., Соммесе Л., Фиорито К., Манчини Ф.П., Каччиаторе Ф., Лигуори А., 20122012Наполи К., Бруцессе Д., Игнарро Л.Д., Крими Э., де Нигрис Ф., Вильямс-Игнарро Ш., Либарди С., Соммесе Л., Фиорито К., Манчини Ф.П., Каччиаторе Ф., Лигуори А.Napoli C., Bruzzese G., Ignarro L.J., Crimi E., de Nigris F., Williams-Ignarro S., Libardi S., Sommese L., Fiorito C., Mancini F.P., Cacciatore F., Liguori A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/1836

Введение. Сульфгидрильные ингибиторы ангиотензин-превращающего фермента (ИАПФ) обладают подтвержденным в экспериментальных исследованиях антиатерогенным эффектом, а также отмеченным в клинических условиях антиокислительным действием. Тем не менее, остается открытым вопрос о наличии у ИАПФ клинически значимых антиатеросклеротических свойств. Цель. У пациентов с мягкой артериальной гипертонией (АГ) был изучен эффект сульфгидрильного ИАПФ зофеноприла, в сравнении с действием карбоксильного ИАПФ эналаприла, на выраженность атеросклероза сонных артерий (СА) – толщину комплекса «интима-медия» (ТКИМ) и диаметр (D) просвета сосудов, а также на показатели системного окислительного стресса (ОС) – уровни нитритов/нитратов, асимметричного диметил-L-аргинина и изопростана. Материал и методы. В 2001г было начато проспективное, рандомизированное, клиническое исследование, в которое вошли 48 пациентов с впервые диагностированной мягкой АГ и без дополнительных факторов риска (ФР) атеросклероза (например, гиперлипидемии, курения, атеросклероза в семейном анамнезе или сахарного диабета). Пациенты рандомизированно получали либо эналаприл 20 мг/сут (n=24), либо зофеноприл (n=24) 30 мг/сут. Запланированная продолжительность исследования составила 5 лет. У всех участников показатели ТКИМ и D просвета сосудов определялись при ультразвуковом исследовании (УЗИ) СА исходно, через 1, 3 и 5 лет. Оценивались уровни нитритов/нитратов, асимметричного диметил-L-аргинина и изопростанов. Результаты. Исходные показатели TКИМ правой и левой общих СА достоверно не различались в обеих группах вмешательства. На протяжении 5 лет наблюдения значения ТКИМ продолжала достоверно снижаться в группе зофеноприла, но не в группе эналаприла (р<0,05 для сравнения между группами). У принимавших зофеноприл больных такой положительный эффект сопровождался улучшением показателей обмена NO и ОС. Заключение. Долгосрочная терапия сульфгидрильным ИАПФ зофеноприлом оказывает не только антигипертензивное действие, но и препятствует увеличению показателей ТКИМ СА у пациентов с впервые диагностированной мягкой АГ.

Aim. Sulfhydryl angiotensin-converting enzyme (ACE) inhibitors exert antiatherosclerotic effects in preclinical models and antioxidant effects in patients. However, whether ACE inhibitors have any clinically significant antiatherogenic effects remains still debated. Objectives. In mildly hypertensive patients, we evaluated the effect of the sulfhydryl ACE inhibitor zofenopril in comparison with the carboxylic ACE inhibitor enalapril on carotid atherosclerosis (intima-media thickness [IMT] and vascular lumen diameter) and systemic oxidative stress (nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostanes). Material and methods. In 2001, we started a small prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors for atherosclerosis (eg, hyperlipidemia, smoke habit, familiar history of atherosclerosisrelated diseases or diabetes). Patients were randomly assigned either to the enalapril (20 mg/d, n = 24) or the zofenopril group (30 mg/d, n = 24); the planned duration of the trial was 5 years. Carotid IMT and vascular lumen diameter were determined by ultrasonography for all patients at baseline and at 1, 3, and 5 years. Furthermore, nitrite/nitrate, asymmetrical dimethyl-L-arginine, and isoprostane levels were measured. Results. In our conditions, IMT of the right and left common carotid arteries was similar at baseline in both groups (P = NS). Intima-media thickness measurements until 5 years revealed a significant reduction in the zofenopril group but not in the enalapril group (P b .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group. Conclusion. Long-term treatment with the sulfhydryl ACE inhibitor zofenopril besides its blood pressure–lowering effects may slow the progression of IMT of the carotid artery in newly diagnosed mildly hypertensive patients. (Am Heart J 2008;156:1154.e1-1154.e8.)

ReferencesAmbrosioni E. Defining the role of zofenopril in the management of hypertension and ischemic heart disorders. Am J Cardiovasc Drugs 2007; 7: 17-24.Ambrosioni E. Defining the role of zofenopril in the management of hypertension and ischemic heart disorders. Am J Cardiovasc Drugs 2007; 7: 17-24.Napoli C, Loscalzo J. New challenges for ACE-inhibitors in vascular diseases. Drug Design Rev 2005; 2: 485-93.Napoli C, Loscalzo J. New challenges for ACE-inhibitors in vascular diseases. Drug Design Rev 2005; 2: 485-93.Napoli C, Sica V, Pignalosa O, et al. New trends in antiatherosclerotic agents. Curr Med Chem 2005; 12: 1755-72.Napoli C, Sica V, Pignalosa O, et al. New trends in antiatherosclerotic agents. Curr Med Chem 2005; 12: 1755-72.Pasini AF, Garbin U, Nava MC, et al. Effect of sulfhydryl and non-sulfhydryl angiotensin-converting enzyme inhibitors on endothelial function in essential hypertensive patients. Am J Hypertens 2007; 20: 443-50.Pasini AF, Garbin U, Nava MC, et al. Effect of sulfhydryl and non-sulfhydryl angiotensin-converting enzyme inhibitors on endothelial function in essential hypertensive patients. Am J Hypertens 2007; 20: 443-50.Powell JS, Clozel JP, Móller RK, et al. Inhibitors of angiotensinconverting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245: 186-8.Powell JS, Clozel JP, Móller RK, et al. Inhibitors of angiotensinconverting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245: 186-8.Janiak P, Libert O, Vilaine JP. Role of the renin-angiotensin system in neointima formation after injury in rabbits. Hypertension 1994; 24: 671-8.Janiak P, Libert O, Vilaine JP. Role of the renin-angiotensin system in neointima formation after injury in rabbits. Hypertension 1994; 24: 671-8.Fennessy PA, Campbell JH, Campbell GR. Perindopril inhibits both the development of atherosclerosis in the cholesterol-fed rabbit and lipoprotein binding to smooth muscle cells in culture. Atherosclerosis 1994; 106: 29-41.Fennessy PA, Campbell JH, Campbell GR. Perindopril inhibits both the development of atherosclerosis in the cholesterol-fed rabbit and lipoprotein binding to smooth muscle cells in culture. Atherosclerosis 1994; 106: 29-41.Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006; 113: 2363-72.Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006; 113: 2363-72.Napoli C, Cicala C, D’Armiento FP, et al. Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in Watanabe heritable hyperlipidemic rabbits. Gen Pharmacol 1999; 33: 467-77.Napoli C, Cicala C, D’Armiento FP, et al. Beneficial effects of ACE-inhibition with zofenopril on plaque formation and low-density lipoprotein oxidation in Watanabe heritable hyperlipidemic rabbits. Gen Pharmacol 1999; 33: 467-77.Chobanian AV, Haudenschild CC, Nickerson C, et al. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1990; 15: 327-31.Chobanian AV, Haudenschild CC, Nickerson C, et al. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1990; 15: 327-31.Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol 1990; 15: S65-72.Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol 1990; 15: S65-72.Hayek T, Attias J, Smith J, et al. Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 1998; 31: 540-4.Hayek T, Attias J, Smith J, et al. Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 1998; 31: 540-4.de Nigris F, D’Armiento FP, Somma P, et al. Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice. Int J Cardiol 2001; 81: 107-15.de Nigris F, D’Armiento FP, Somma P, et al. Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice. Int J Cardiol 2001; 81: 107-15.Sun YP, Zhu BQ, Browne AE, et al. Comparative effects of ACE inhibitors and an angiotensin receptor blocker on atherosclerosis and vascular function. J Cardiovasc Pharmacol Ther 2001; 6: 175-81.Sun YP, Zhu BQ, Browne AE, et al. Comparative effects of ACE inhibitors and an angiotensin receptor blocker on atherosclerosis and vascular function. J Cardiovasc Pharmacol Ther 2001; 6: 175-81.Charpiot P, Rolland PH, Friggi A, et al. ACE inhibition with perindopril and atherogenesis-induced structural and functional changes in minipig arteries. Arterioscler Thromb 1993; 13: 1125-38.Charpiot P, Rolland PH, Friggi A, et al. ACE inhibition with perindopril and atherogenesis-induced structural and functional changes in minipig arteries. Arterioscler Thromb 1993; 13: 1125-38.Candido R, Jandeleit-Dahm KA, Cao Z, et al. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation 2002; 106: 246-53.Candido R, Jandeleit-Dahm KA, Cao Z, et al. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation 2002; 106: 246-53.Kowala MC, Grove RI, Aberg G. Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophagefoam cell accumulation independently of blood pressure and plasma lipids. Atherosclerosis 1994; 108: 61-72.Kowala MC, Grove RI, Aberg G. Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophagefoam cell accumulation independently of blood pressure and plasma lipids. Atherosclerosis 1994; 108: 61-72.Hayek T, Attias J, Coleman R, et al. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res 1999; 44: 579-87.Hayek T, Attias J, Coleman R, et al. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res 1999; 44: 579-87.Li J, Hirose N, Kawamura M, et al. Antiatherogenic effect of angiotensin converting enzyme inhibitor (benazepril) and angiotensin II receptor antagonist (valsartan) in the cholesterol-fed rabbits. Atherosclerosis 1999; 143: 315-26.Li J, Hirose N, Kawamura M, et al. Antiatherogenic effect of angiotensin converting enzyme inhibitor (benazepril) and angiotensin II receptor antagonist (valsartan) in the cholesterol-fed rabbits. Atherosclerosis 1999; 143: 315-26.Keidar S, Attias J, Coleman R, et al. Attenuation of atherosclerosis in apolipoprotein E-deficient mice by ramipril is dissociated from its antihypertensive effect and from potentiation of bradykinin. J Cardiovasc Pharmacol 2000; 35: 64-72.Keidar S, Attias J, Coleman R, et al. Attenuation of atherosclerosis in apolipoprotein E-deficient mice by ramipril is dissociated from its antihypertensive effect and from potentiation of bradykinin. J Cardiovasc Pharmacol 2000; 35: 64-72.Hayek T, Kaplan M, Raz A, et al. Ramipril administration to atherosclerotic mice reduces oxidized low-density lipoprotein uptake by their macrophages and blocks the progression of atherosclerosis. Atherosclerosis 2002; 161: 65-74.Hayek T, Kaplan M, Raz A, et al. Ramipril administration to atherosclerotic mice reduces oxidized low-density lipoprotein uptake by their macrophages and blocks the progression of atherosclerosis. Atherosclerosis 2002; 161: 65-74.Bonithon-Kopp C, Ducimetióre P, Touboul PJ, et al. Plasma angiotensinconverting enzyme activity and carotid wall thickening. Circulation 1994; 89: 952-4.Bonithon-Kopp C, Ducimetióre P, Touboul PJ, et al. Plasma angiotensinconverting enzyme activity and carotid wall thickening. Circulation 1994; 89: 952-4.MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebocontrolled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease: PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. JACC 2000; 36: 438-43.MacMahon S, Sharpe N, Gamble G, et al. Randomized, placebocontrolled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease: PART-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. JACC 2000; 36: 438-43.Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering, and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the simvastatin/enalapril coronary atherosclerosis trial. Circulation 2000; 102: 1748-54.Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering, and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the simvastatin/enalapril coronary atherosclerosis trial. Circulation 2000; 102: 1748-54.Asselbergs FW, van Roon AM, Hillege HL, et al. Effects of fosinopril and pravastatin on carotid intima-media thickness in subjects with increased albuminuria. Stroke 2005; 36: 649-53.Asselbergs FW, van Roon AM, Hillege HL, et al. Effects of fosinopril and pravastatin on carotid intima-media thickness in subjects with increased albuminuria. Stroke 2005; 36: 649-53.Zanchetti A, Crepaldi G, Bond MG, et al, on behalf of PHYLLIS Investigators. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS—a randomized double-blind trial. Stroke 2004; 35: 2807-12.Zanchetti A, Crepaldi G, Bond MG, et al, on behalf of PHYLLIS Investigators. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS—a randomized double-blind trial. Stroke 2004; 35: 2807-12.Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE). Circulation 2001; 103: 919-25.Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE). Circulation 2001; 103: 919-25.Unger T. the role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89: 3A-10.Unger T. the role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002; 89: 3A-10.Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med 2003; 163: 1155-64.Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: from genes to treatment. Arch Intern Med 2003; 163: 1155-64.Scribner AW, Loscalzo J, Napoli C. The effect of angiotensin converting enzyme inhibition on endothelial function and oxidant stress. Eur J Pharmacol 2003; 482: 95-9.Scribner AW, Loscalzo J, Napoli C. The effect of angiotensin converting enzyme inhibition on endothelial function and oxidant stress. Eur J Pharmacol 2003; 482: 95-9.Napoli C, Sica V, de Nigris F, et al. Sulfhydryl ACE inhibition induces a sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension. Am Heart J 2004; 148: e5-13.Napoli C, Sica V, de Nigris F, et al. Sulfhydryl ACE inhibition induces a sustained reduction of systemic oxidative stress and improves the nitric oxide pathway in patients with essential hypertension. Am Heart J 2004; 148: e5-13.Evangelista S, Manzini S. Antioxidant and cardioprotective properties of the sulphydryl angiotensin-converting enzyme inhibitor zofenopril. J Int Med Res 2005; 33: 42-54.Evangelista S, Manzini S. Antioxidant and cardioprotective properties of the sulphydryl angiotensin-converting enzyme inhibitor zofenopril. J Int Med Res 2005; 33: 42-54.Cominacini L, Pasini A, Garbin U, et al. Zofenopril inhibits the expression of adhesion molecules on endothelial cells by reducing reactive oxygen species. Am J Hypertens 2002; 15: 891-5.Cominacini L, Pasini A, Garbin U, et al. Zofenopril inhibits the expression of adhesion molecules on endothelial cells by reducing reactive oxygen species. Am J Hypertens 2002; 15: 891-5.Grobbee DE, Bots ML. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis. J Intern Med 1994; 263: 567-73.Grobbee DE, Bots ML. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis. J Intern Med 1994; 263: 567-73.O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Eng J Med 1999; 340: 14-22.O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Eng J Med 1999; 340: 14-22.Napoli C, Lerman LO, de Nigris F, et al. Rethinking primary prevention of atherosclerosis-related diseases. Circulation 2006; 114: 2517-27.Napoli C, Lerman LO, de Nigris F, et al. Rethinking primary prevention of atherosclerosis-related diseases. Circulation 2006; 114: 2517-27.Napoli C, Liguori A, Sorice P, et al. Relations between vasoactive hormonal factors and left ventricular diastolic function in normotensive and hypertensive uremics. J Intern Med 1996; 240: 389-94.Napoli C, Liguori A, Sorice P, et al. Relations between vasoactive hormonal factors and left ventricular diastolic function in normotensive and hypertensive uremics. J Intern Med 1996; 240: 389-94.Persson J, Stavenow L, Wikstrand J, et al. Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurements of arterial wall thickness and plaque size. Arterioscler Thromb 1992; 12: 261-6.Persson J, Stavenow L, Wikstrand J, et al. Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurements of arterial wall thickness and plaque size. Arterioscler Thromb 1992; 12: 261-6.Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995; 26: 386-91.Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995; 26: 386-91.Allan PL, Mowbray PI, Lee AJ, et al. Relationship between carotid intimamedia thickness and symptomatic and asymptomatic peripheral arterial disease: the Edinburgh Artery Study. Stroke 1997; 28: 348-53.Allan PL, Mowbray PI, Lee AJ, et al. Relationship between carotid intimamedia thickness and symptomatic and asymptomatic peripheral arterial disease: the Edinburgh Artery Study. Stroke 1997; 28: 348-53.Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.Wang JG, Staessen JA, Li Y, et al. Carotid intima-media thickness and antihypertensive treatment. A meta-analysis of randomized controlled trials. Stroke 2006; 37: 1933-40.Wang JG, Staessen JA, Li Y, et al. Carotid intima-media thickness and antihypertensive treatment. A meta-analysis of randomized controlled trials. Stroke 2006; 37: 1933-40.Hosomi N, Mizushige K, Ohyama H, et al. Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non–insulindependent diabetes mellitus. Stroke 2001; 32: 1539-45.Hosomi N, Mizushige K, Ohyama H, et al. Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non–insulindependent diabetes mellitus. Stroke 2001; 32: 1539-45.Espeland MA, Craven TE, Riley WA, et al, for the Asymptomatic Carotid Artery Progression Study Research Group. Reliability of longitudinal ultrasonographic measurements of carotid intimalmedial thicknesses. Stroke 1996; 27: 480-5.Espeland MA, Craven TE, Riley WA, et al, for the Asymptomatic Carotid Artery Progression Study Research Group. Reliability of longitudinal ultrasonographic measurements of carotid intimalmedial thicknesses. Stroke 1996; 27: 480-5.Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: 1371-5.Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: 1371-5.Cashin-Hemphill L, Holmvang G, Chan RC, et al. for the QUIET Investigators (Quinapril Ischemic Event Trial). Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. Am J Cardiol 1999; 83: 43-7.Cashin-Hemphill L, Holmvang G, Chan RC, et al. for the QUIET Investigators (Quinapril Ischemic Event Trial). Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. Am J Cardiol 1999; 83: 43-7.Hornig B, Arakawa N, Haussmann D, et al. Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 98: 2842-8.Hornig B, Arakawa N, Haussmann D, et al. Differential effects of quinaprilat and enalaprilat on endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998; 98: 2842-8.Burnier M, Zanchi A. Blockade of renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 2006; 24: 11-25.Burnier M, Zanchi A. Blockade of renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 2006; 24: 11-25.Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens 2004; 22: 2253-61.Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens 2004; 22: 2253-61.Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669-85.Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669-85.Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115-22.Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994; 343: 1115-22.Mak IT, Freedman AM, Dickens BF, et al. Protective effects of sulfhydrylcontaining angiotensin-converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol 1990; 40: 2169-75.Mak IT, Freedman AM, Dickens BF, et al. Protective effects of sulfhydrylcontaining angiotensin-converting enzyme inhibitors against free radical injury in endothelial cells. Biochem Pharmacol 1990; 40: 2169-75.Ambrosioni E, Borghi C, Magnani B. The effect of angiotensinconverting–enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995; 332: 80-5.Ambrosioni E, Borghi C, Magnani B. The effect of angiotensinconverting–enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995; 332: 80-5.Borghi C, Bacchelli S, Esposti DD, et al. Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation. Am J Hypertens 1999; 12: 665-72.Borghi C, Bacchelli S, Esposti DD, et al. Effects of the administration of an angiotensin-converting enzyme inhibitor during the acute phase of myocardial infarction in patients with arterial hypertension. SMILE Study Investigators. Survival of Myocardial Infarction Long-term Evaluation. Am J Hypertens 1999; 12: 665-72.Borghi C, Ambrosioni E. Double-blind comparison between zofenopril and lisinopril in patients with acute myocardial infarction: results of the Survival of Myocardial Infarction Long-Term Evaluation-2 (SMILE-2) study. Am Heart J 2003; 145: 80-7.Borghi C, Ambrosioni E. Double-blind comparison between zofenopril and lisinopril in patients with acute myocardial infarction: results of the Survival of Myocardial Infarction Long-Term Evaluation-2 (SMILE-2) study. Am Heart J 2003; 145: 80-7.Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric Oxide 2001; 5: 88-97.Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric Oxide 2001; 5: 88-97.Furuki K, Adachi H, Matsuoka H, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery. An epidemiological study. Atherosclerosis 2007; 191: 206-10.Furuki K, Adachi H, Matsuoka H, et al. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery. An epidemiological study. Atherosclerosis 2007; 191: 206-10.

The authors declare that there are no conflicts of interest present.