ORIGINAL ARTICLE Effect of angiotensin-converting enzyme inhibitors on systemic inflammation and myocardial sympathetic innervation in normotensive patients with type 2 diabetes mellitus ME Marketou 1 , EA Zacharis 1 , S Koukouraki 2 , MI Stathaki 2 , DA Arfanakis 1 , GE Kochiadakis 1 , G Chlouverakis 3 , NS Karkavitsas 2 and PE Vardas 1 1 Department of Cardiology, Heraklion University Hospital, Crete, Greece; 2 Department of Nuclear Medicine, Heraklion University Hospital, Crete, Greece and 3 Department of Biostatistics, University of Crete, Crete, Greece Diabetes mellitus (DM) may cause an increase in the inflammatory status and oxidative stress as well as sympathetic nervous system overactivity, even in the absence of any other organic heart disease. We investigated the effect of perindopril, an angiotensin- converting enzyme inhibitor (ACE-i), on indexes of systemic inflammation and oxidative stress in normo- tensive patients with type 2 DM. We also examined the effect of the drug on the disturbances of left ventricular myocardial adrenergic innervation that may be seen in these patients. We studied 62 normotensive patients with type 2 DM, who were randomized to receive perindopril (n ¼ 32) or placebo (n ¼ 30). At the start of the study and after 6 months’ therapy blood samples were taken to evaluate total peroxides (TP), interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a), and the patients underwent a 123 I-metaiodobenzylguanidine myocardial scintigraphy study. ACE-i caused a significant reduction in levels of cytokines and TP (Po0.001 for IL-6 and TNF-a, P ¼ 0.001 for TP). There was also a reduction in total defect score (Po0.001) and the heart to mediastinum ratio at 10 min and 4 h was improved (Po0.001 for both). No significant alterations were observed in the placebo group. Our data indicate that the addition of ACE-i to the medication of normotensive diabetic type 2 patients may improve the disturbed myocardial adrenergic innerva- tion, the systemic inflammatory status and oxidative stress. Our findings indicate the cardioprotective action of ACE-i and suggest that earlier treatment might be appropriate in those patients. Journal of Human Hypertension (2008) 22, 191–196; doi:10.1038/sj.jhh.1002310; published online 29 November 2007 Keywords: angiotensin-converting enzyme inhibitor; cytokines; myocardial adrenergic innervation Introduction Cardiovascular diseases are the principal causes of death and disability in diabetics. The increased proinflammatory status and oxidative stress seem to play a major role in the initiation and progression of cardiovascular dysfunction in diabetes mellitus (DM). Hyperglycaemia has been shown to lead to a series of cellular events that increase the production of reactive oxygen species 1 and induce proinflam- matory effects 2 that promote the migration of monocytes and vascular smooth muscle cells into the intima and formation of the initial atherosclero- tic lesions. 3 On the other hand, neurohumoral factors, such as the renin angiotensin and sympa- thetic nervous system, are activated in patients with DM and cardiovascular autonomic neuropathy is frequently observed. In addition, angiotensin II and sympathetic nervous system overactivity are factors that regulate cytokine production and oxidative stress, at least in part, 4,5 thus contributing to the development of atheromatosis and cardiovascular complications. The renin angiotensin aldosterone system (RAAS) has been recognized as an important therapeutic target for the prevention of cardiovascular complica- tions in patients with type 2 DM. Its inhibition with angiotensin-converting enzyme inhibitors (ACE-i) has been shown to improve prognosis and to have multiple beneficial effects in diabetic patients with hypertension. 6 However, it has been demonstrated Received 27 June 2007; revised 11 September 2007; accepted 21 October 2007; published online 29 November 2007 Correspondence: Professor PE Vardas, Department of Cardiology, Heraklion University Hospital, PO Box 1352, Heraklion, Crete 71110, Greece. E-mail: cardio@med.uoc.gr Journal of Human Hypertension (2008) 22, 191–196 & 2008 Nature Publishing Group All rights reserved 0950-9240/08 $30.00 www.nature.com/jhh