Published Online
on October 13, 2008

A more recent version of this article appeared on October 28, 2008

This Article Full Text (PDF) Data Supplement All Versions of this Article: 118/18/1802    most recent CIRCULATIONAHA.108.785881v1 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 Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jaffer, F. A. Articles by Weissleder, R. Search for Related Content PubMed PubMed Citation Articles by Jaffer, F. A. Articles by Weissleder, R. Related Collections Cardiovascular imaging agents/Techniques Pathophysiology Imaging Catheter-based coronary and valvular interventions: other Related Article

Submitted on April 14, 2008
Accepted on August 8, 2008

Real-Time Catheter Molecular Sensing of Inflammation in Proteolytically Active Atherosclerosis

Farouc A. Jaffer MD, PhD^*, Claudio Vinegoni PhD, Michael C. John MPH, Elena Aikawa MD, PhD, Herman K. Gold MD, Aloke V. Finn MD, Vasilis Ntziachristos PhD, Peter Libby MD, and Ralph Weissleder MD, PhD

From the Center for Molecular Imaging Research (F.A.J., C.V., E.A., V.N., R.W.) and Cardiovascular Research Center and Cardiology Division (F.A.J., M.C.J., H.K.G., A.V.F., R.W.), Massachusetts General Hospital; Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School (F.A.J., P.L.); and Cardiovascular Division, Brigham and Women's Hospital (P.L.), Boston, Mass.

^* To whom correspondence should be addressed. E-mail: fjaffer{at}mgh.harvard.edu.

Background—To enable intravascular detection of inflammation in atherosclerosis, we developed a near-infrared fluorescence (NIRF) catheter–based strategy to sense cysteine protease activity during vascular catheterization.

Methods and Results—The NIRF catheter design was based on a clinical coronary artery guidewire. In phantom studies of NIRF plaques, blood produced only a mild (<30%) attenuation of the fluorescence signal compared with saline, affirming the favorable optical properties of the NIR window. Catheter evaluation in vivo used atherosclerotic rabbits (n=11). Rabbits received an injection of a cysteine protease–activatable NIRF imaging agent (Prosense750; excitation/emission, 750/770 nm) or saline. Catheter pullbacks through the blood-filled iliac artery detected NIRF signals 24 hours after injection of the probe. In the protease agent group, the in vivo peak plaque target-to-background ratio was 558% greater than controls (6.8±1.9 versus 1.3±0.3, mean±SEM; P<0.05). Ex vivo fluorescence reflectance imaging corroborated these results (target-to-background ratio, 10.3±1.8 for agent versus 1.8±0.3 for saline group; P<0.01). In the protease group only, saline flush–modulated NIRF signal profiles further distinguished atheromata from normal segments in vivo (P<0.01). Good correlation between the in vivo and ex vivo plaque target-to-background ratio was present (r=0.82, P<0.01). Histopathological analyses demonstrated strong NIRF signal in plaques only from the protease agent group. NIRF signals colocalized with immunoreactive macrophages and the cysteine protease cathepsin B.

Conclusions—An intravascular fluorescence catheter can detect cysteine protease activity in vessels the size of human coronary arteries in real time with an activatable NIRF agent. This strategy could aid in the detection of inflammation and high-risk plaques in small arteries.

Key words: atherosclerosis • catheters • fluorescence • imaging • inflammation • cathepsins

Related Article:

Clinical Summaries
Circulation 2008 118: 1777-1778. [Extract] [Full Text]

This article has been cited by other articles:

				P. Libby, P. M. Ridker, G. K. Hansson, and for the Leducq Transatlantic Network on Atherothro Inflammation in Atherosclerosis From Pathophysiology to Practice. J. Am. Coll. Cardiol., December 1, 2009; 54(23): 2129 - 2138. [Abstract] [Full Text] [PDF]

				C. M. Matter, M. Stuber, and M. Nahrendorf Imaging of the unstable plaque: how far have we got? Eur. Heart J., November 1, 2009; 30(21): 2566 - 2574. [Abstract] [Full Text] [PDF]

				F. K. Swirski, R. Weissleder, and M. J. Pittet Heterogeneous In Vivo Behavior of Monocyte Subsets in Atherosclerosis Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1424 - 1432. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, P. Waterman, G. Thurber, K. Groves, M. Rajopadhye, P. Panizzi, B. Marinelli, E. Aikawa, M. J. Pittet, F. K. Swirski, et al. Hybrid In Vivo FMT-CT Imaging of Protease Activity in Atherosclerosis With Customized Nanosensors Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1444 - 1451. [Abstract] [Full Text] [PDF]

				R. P. Choudhury and E. A. Fisher Molecular Imaging in Atherosclerosis, Thrombosis, and Vascular Inflammation Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 983 - 991. [Abstract] [Full Text] [PDF]

				J. H.F. Rudd, F. Hyafil, and Z. A. Fayad Inflammation Imaging in Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1009 - 1016. [Abstract] [Full Text] [PDF]

				F. A. Jaffer, P. Libby, and R. Weissleder Optical and Multimodality Molecular Imaging: Insights Into Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1017 - 1024. [Abstract] [Full Text] [PDF]

				T. Christen, M. Nahrendorf, M. Wildgruber, F. K. Swirski, E. Aikawa, P. Waterman, K. Shimizu, R. Weissleder, and P. Libby Molecular Imaging of Innate Immune Cell Function in Transplant Rejection Circulation, April 14, 2009; 119(14): 1925 - 1932. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, D. E. Sosnovik, B. A. French, F. K. Swirski, F. Bengel, M. M. Sadeghi, J. R. Lindner, J. C. Wu, D. L. Kraitchman, Z. A. Fayad, et al. Multimodality Cardiovascular Molecular Imaging, Part II Circ Cardiovasc Imaging, January 1, 2009; 2(1): 56 - 70. [Full Text] [PDF]