Long-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 hypertension

Received 24 June 2008; accepted 10 September 2008.

Background

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).

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 atherosclerosis-related 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 < .05 vs enalapril-treated group). This effect was coupled with a favorable nitric oxide/oxidative stress profile in the zofenopril group.

Conclusions

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.

a Department of General Pathology and Excellence Research Center on Cardiovascular Diseases, and Microbiology Section, 1st School of Medicine, II University of Naples, Naples, Italy

b IRCCS, Multimedica, Milan, Italy

c Division of Cardiology-UTIC, Pellegrini Hospital, ASLNA1, Naples, Italy

d Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA

e Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA

f Division of Anesthesiology and, David Geffen School of Medicine, University of California, Los Angeles, CA

g Department of Biological and Environmental Sciences, University of Sannio, Benevento, Italy

h Fondazione Salvatore Maugeri, IRCCS, Telese Terme (BN), Italy

Reprint requests: Professor Claudio Napoli, MD, PhD, MBEth, FACA, Department of General Pathology and Excellence Research Center on Cardiovascular Diseases, 1st School of Medicine, II University of Naples; Complesso S. Andrea delle Dame; Via L. de Crecchio 7, Naples, 80138, Italy.

Presented in abstract form at the Symposium “Current role of angiotensin converting enzyme-inhibitors in high-risk patients,” European Society of Cardiology, September 1, 2003, Wien (Austria); at the Plenary Session on ACE-Inhibition, 65° National Congress of the Italian Society of Cardiology, December 13, 2004, Rome, Italy; at the Plenary Session on “The renin angiotensin system and oxidative stress,” 4° International Forum on Angiotensin II Receptor Antagonism, January 28, 2005, Monte Carlo, Monaco; and at the Annual Meeting of European Society of Atherosclerosis, June 10, 2007, Helsinki, Finland.

PII: S0002-8703(08)00791-6

doi:10.1016/j.ahj.2008.09.006

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