Atherosclerosis 177 (2004) 269–274 Low flow promotes instent intimal hyperplasia Comparison with lumen loss in balloon-injured and uninjured vessels and the effects of the antioxidant pyrrolidine dithiocarbamate Colm G. Hanratty a , Melanie Murrell a , Levon M. Khachigian b , Philip S. Tsao c , Michael R. Ward a,∗ a Vascular Biology Laboratory, Cardiology Department, Royal North Shore Hospital, Sydney, Australia b Centre for Vascular Research University of New South Wales, Sydney, Australia c Department of Cardiovascular Medicine, Stanford University, Stanford, CA, USA Received 30 December 2003; received in revised form 7 July 2004; accepted 8 July 2004 Available online 11 September 2004 Abstract Low flow (LF) promotes late lumen loss after angioplasty by exacerbating inward remodelling through redox-sensitive mechanisms. Stents eliminate inward remodelling and the effect of LF on in-stent restenosis is uncertain. We performed over-sized (1.3–1.5:1) stenting (S) and balloon injury (in the same vessel, B) to the carotid arteries of cholesterol-fed rabbits and compared 28-day late lumen loss with that in an uninjured segment in the same vessel (U). Vessels (n = 5 animals per group) were subjected to high (H), normal (N) and low (L) flow in animals fed either vehicle (V) or the antioxidant pyrrolidine dithiocarbamate, PDTC (P). LF significantly increased in-stent neointima formation relative to normal and high flow (SLV 0.72 ± 0.07 mm 2 versus SNV 0.43 ± 0.08 mm 2 versus SHV 0.28 ± 0.04 mm 2 , P < 0.05). However, LF resulted in greater lumen loss in segments from the same vessel subject to balloon injury (lumen SLV 5.18 ± 0.40 mm 2 and SNV 5.32 ± 0.40 mm 2 versus BLV 1.28 ± 0.33 mm 2 and BNV 2.19 ± 0.28 mm 2 ), by greater enhancement of inward remodelling. In addition, inward remodelling and lumen loss due to LF were greater in balloon-injured segments than in adjacent uninjured segments where shear homeostatic remodelling occurs (lumen BLV 1.28 ± 0.33 mm 2 versus ULV 1.52 ± 0.22 mm 2 ). Lastly, while PDTC effectively reduced intima formation and inward remodelling due to LF in balloon-injured vessels there was no effect on flow-dependent neointima formation in stented vessels. We conclude that LF accentuates in-stent neointima formation, but that flow-dependent lumen loss after stenting is less than that after balloon injury. When LF is present lumen loss can be minimised by antioxidants or stenting. © 2004 Published by Elsevier Ireland Ltd. Keywords: Neointima formation; Balloon-injured; Stenting; Flow; Antioxidant 1. Introduction Recent studies have shown that low flow after human coronary angioplasty predicts subsequent restenosis [1,2]. Animal studies have shown that despite the flow-sensitivity of neointima formation after angioplasty [3], excess lumen loss in balloon-injured vessels subject to low flow is largely due to enhanced inward remodeling [4–6]. The effect of ∗ Corresponding author. Tel.: +61 2 9926 6182; fax: +61 2 9901 4097. E-mail address: mrward@doh.health.nsw.gov.au (M.R. Ward). low flow on remodelling after angioplasty in animals is pre- vented by concomitant administration of antioxidants [7], compounds which also effectively prevent inward remod- elling and restenosis after human coronary angioplasty [8]. However, the effect of flow on remodeling in injured ves- sels, and its prevention with antioxidants may be irrelevant if the vessel is stented, as stenting effectively eliminates in- ward remodeling [9]. Presently, stents are used in over 90% of coronary interventional procedures, and in-stent restenosis is distinct from that seen after angioplasty. Two observational human studies have had conflicting results on the relationship 0021-9150/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2004.07.016