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CLINICAL RESEARCH

Cellular Immunostaining of Angiotensin-Converting Enzyme in Human Coronary Atherosclerotic Plaques

Flavio Ribichini, MD^_*,_*, Francesco Pugno, MD, Valeria Ferrero, MD^_*, Gianni Bussolati, MD, FRCPath, Mauro Feola, MD, Paolo Russo, MD, Carlo Di Mario, MD^||, Antonio Colombo, MD^|| and Corrado Vassanelli, MD^_*

^_* Catheterization Laboratory, Ospedale Maggiore della Carità, Universita' del Piemonte Orientale, Novara, Italy
Ospedale Santa Croce e Carle, Cuneo, Italy
Dipartimento di Scienze Biomediche dell'Universita' di Torino, Torino, Italy
Clinica Villa Maria Pia, Torino, Italy
^|| Centro Cuore Columbus, Ospedale San Raffaele, Milano, Italy

Manuscript received May 31, 2005; revised manuscript received August 30, 2005, accepted September 8, 2005.

^_* Reprint requests and correspondence: Dr. Flavio Ribichini, Director Catheterization Laboratory, Università del Piemonte Orientale, Ospedale Maggiore della Carità, Corso Mazzini 18, 28100 Novara, Italy (Email: flavio.ribichini{at}med.unipmn.it).

OBJECTIVES: The aim of this study was to determine the cellular localization of angiotensin I-converting enzyme (ACE) in the atherosclerotic plaque and its correlation with inflammation and cellular proliferation.

BACKGROUND: Angiotensin I-converting enzyme inhibitors reduce the incidence of vascular events; therefore, tissue ACE may play a determinant role in the pathophysiology of the atherosclerotic plaque.

METHODS: Histology and immunocytochemistry of de novo coronary plaques retrieved with directional coronary atherectomy from 141 patients were analyzed: 87 with stable angina, 39 with subacute unstable angina, and 15 with acute unstable angina.

RESULTS: Compared with stable patients, unstable patients showed more thrombotic lesions (72% vs. 27%, p < 0.0001), smaller areas of fibrous plaque (2.3 ± 1.2 mm² vs. 2.8 ± 1.1 mm², p = 0.02), higher cellular proliferative score (0.78 ± 0.9 vs. 0.27 ± 0.6, p = 0.003), larger content of ACE-stained cells (26.3 ± 23% vs. 12.6 ± 15%, p = 0.005) and larger areas of inflammation as identified by CD68 immunostaining (29.5 ± 22% vs. 20.2 ± 19%, p = 0.02). A significant linear correlation was found between CD68- and ACE-stained areas (mm²) among unstable patients (r = 0.6, p = 0.0001), but it was absent among stable patients (r = 0.006, p = 0.9). Co-localization of ACE, CD68, and alpha-actin was confirmed by double immunostaining. Patients with Ki-67–positive staining as an index of cell proliferation showed also significantly larger areas of ACE immunoactivity (p = 0.004).

CONCLUSIONS: Our data demonstrate ACE immunoactivity in inflammatory and proliferative cells of coronary atherosclerotic plaques. In particular, patients with unstable angina showed larger areas of ACE immunoactive tissue and proliferating cells compared with stable patients. These observations support a role of the enzyme in the pathophysiology of coronary unstable plaques and suggest potentially different effects of ACE inhibitors according to clinical presentation.

Abbreviations and Acronyms   ACE = angiotensin I-converting enzyme   ACS = acute coronary syndromes   DCA = directional coronary atherectomy   HPF = high-power fields   ID = insertion/deletion   MI = myocardial infarction   SMC = smooth muscle cells

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