This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jaffe, R. Articles by Strauss, B. H. Search for Related Content PubMed Articles by Jaffe, R. Articles by Strauss, B. H. Related Collections Related Article

PRE-CLINICAL RESEARCH

Natural History of Experimental Arterial Chronic Total Occlusions

Ronen Jaffe, MD^_*,,, General Leung, MSc^,, Nigel R. Munce, MSc^,, Amandeep S. Thind, BSc^,, Howard Leong-Poi, MD^,, Kevan J.T. Anderson, BSc^,, Xiuling Qi, PhD, MD, Judy Trogadis, BSc, Ariella Nadler, BA^_*, Davida Shiff^_*, Jamie Saperia^_*, Julia Lockwood^_*, Chaim Jacobs^_*, Beiping Qiang, MD^_*,, Aaron Teitelbaum, MD, MSc^_*, Alexander J. Dick, MD^_*,, John D. Sparkes, MSc^_*, Jagdish Butany, MD^,||, Graham A. Wright, PhD^_*,, and Bradley H. Strauss, MD, PhD^_*,,_*

^_* Schulich Heart Programme, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
St. Michael's Hospital, Toronto, Ontario, Canada
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada
^|| Department of Pathology, University Health Network, Toronto, Ontario, Canada

Manuscript received February 21, 2008; revised manuscript received August 26, 2008, accepted September 4, 2008.

^_* Reprint requests and correspondence: Dr. Bradley H. Strauss, Reichmann Chair in Cardiovascular Sciences, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room A-253, Toronto, Ontario, Canada M4N 3M5 (Email: bradley.strauss{at}sunnybrook.ca).

Objectives: We sought to perform the first systematic study of the natural history of chronic total arterial occlusions (CTOs) in an experimental model.

Background: Angioplasty of CTOs has low success rates. The structural and perfusion changes during CTO maturation, which may adversely affect angioplasty outcome, have not been systematically studied.

Methods: Occlusions were created in 63 rabbit femoral arteries by thrombin injection. Histology, contrast-enhanced magnetic resonance imaging, relative blood volume (RBV) index, and micro-computed tomography imaging were analyzed at 2, 6, 12, and 18 to 24 weeks.

Results: Early changes were characterized by an acute inflammatory response and negative arterial remodeling, with >70% reduction of arterial cross-sectional area (CSA) from 2 to 6 weeks. Intraluminal neovascularization of the CTO occurred with a 2-fold increase in total (media + intima) microvessel CSA from 2 to 6 weeks (0.014 ± 0.002 mm² to 0.023 ± 0.005 mm², p = 0.0008) and a 3-fold increase in RBV index (5.1 ± 1.9% to 16.9 ± 2.7%, p = 0.0008). However at later time periods, there were significant reductions in both RBV (3.5 ± 1.1%, p < 0.0001) and total microvessel CSA (0.017 ± 0.002 mm², p = 0.011). Micro-computed tomography imaging demonstrated a corkscrew-like recanalization channel at the proximal end at 6 weeks that regressed at later time points. These vascular changes were accompanied by a marked decrease in proteoglycans and accumulation of a collagen-enriched extracellular matrix, particularly at the entrance ("proximal fibrous cap").

Conclusions: This study is the first to systematically analyze compositional changes occurring during CTO maturation, which may underlie angioplasty failure. Negative remodeling, regression of intraluminal channels, and CTO perfusion, together with the accumulation of dense collagen, may represent important targets for novel therapeutic interventions.

Key Words: chronic total occlusions • magnetic resonance imaging • angioplasty • collagen

Abbreviations and Acronyms   CSA = cross-sectional area   CT = computed tomography   CTO = chronic total arterial occlusion   hpf = high power field   IEL = internal elastic lamina   MRI = magnetic resonance imaging   PCI = percutaneous coronary intervention   PSR = picrosirius red   RBV = relative blood volume

Related Article

Inside This Issue
J. Am. Coll. Cardiol. 2009 53: A24. [Full Text] [PDF]