AIMS: Elevated expression of cathepsins, integrins and matrix metalloproteinases (MMPs) is typically associated with atherosclerotic plaque instability. While fluorescent tagging of such molecules has been amply demonstrated, no imaging method was so far shown capable of resolving these inflammation-associated tags with high fidelity and resolution beyond microscopic depths. This study is aimed at demonstrating a new method with high potential for noninvasive clinical cardiovascular diagnostics of vulnerable plaques using high-resolution deep-tissue multispectral optoacoustic tomography (MSOT) technology. METHODS AND RESULTS: MMP-sensitive activatable fluorescent probe (MMPSense™ 680) was applied to human carotid plaques from symptomatic patients. Atherosclerotic activity was detected by tuning MSOT wavelengths to activation-dependent absorption changes of the molecules, structurally modified in the presence of enzymes. MSOT analysis simultaneously provided morphology along with heterogeneous MMP activity with better than 200 micron resolution throughout the intact plaque tissue. The results corresponded well with epi-fluorescence images made from thin cryosections. Elevated MMP activity was further confirmed by in situ zymography, accompanied by increased macrophage influx. CONCLUSIONS: We demonstrated, for the first time to our knowledge, the ability of MSOT to provide volumetric images of activatable molecular probe distribution deep within optically diffuse tissues. High-resolution mapping of MMP activity was achieved deep in the vulnerable plaque of intact human carotid specimens. This performance directly relates to pre-clinical screening applications in animal models and to clinical decision potential as it might eventually allow for highly specific visualization and staging of plaque vulnerability thus impacting therapeutic clinical decision making.
AIMS: Elevated expression of cathepsins, integrins and matrix metalloproteinases (MMPs) is typically associated with atherosclerotic plaque instability. While fluorescent tagging of such molecules has been amply demonstrated, no imaging method was so far shown capable of resolving these inflammation-associated tags with high fidelity and resolution beyond microscopic depths. This study is aimed at demonstrating a new method with high potential for noninvasive clinical cardiovascular diagnostics of vulnerable plaques using high-resolution deep-tissue multispectral optoacoustic tomography (MSOT) technology. METHODS AND RESULTS: MMP-sensitive activatable fluorescent probe (MMPSense™ 680) was applied to human carotid plaques from symptomatic patients. Atherosclerotic activity was detected by tuning MSOT wavelengths to activation-dependent absorption changes of the molecules, structurally modified in the presence of enzymes. MSOT analysis simultaneously provided morphology along with heterogeneous MMP activity with better than 200 micron resolution throughout the intact plaque tissue. The results corresponded well with epi-fluorescence images made from thin cryosections. Elevated MMP activity was further confirmed by in situ zymography, accompanied by increased macrophage influx. CONCLUSIONS: We demonstrated, for the first time to our knowledge, the ability of MSOT to provide volumetric images of activatable molecular probe distribution deep within optically diffuse tissues. High-resolution mapping of MMP activity was achieved deep in the vulnerable plaque of intact human carotid specimens. This performance directly relates to pre-clinical screening applications in animal models and to clinical decision potential as it might eventually allow for highly specific visualization and staging of plaque vulnerability thus impacting therapeutic clinical decision making.
Authors: Bastiaan M Wallis de Vries; Jan-Luuk Hillebrands; Gooitzen M van Dam; René A Tio; Johannes S de Jong; Riemer H J A Slart; Clark J Zeebregts Journal: Circulation Date: 2009-05-26 Impact factor: 29.690
Authors: Salman Choudhary; Catherine L Higgins; Iou Yih Chen; Michael Reardon; Gerald Lawrie; G Wesley Vick; Christof Karmonik; David P Via; Joel D Morrisett Journal: Arterioscler Thromb Vasc Biol Date: 2006-08-03 Impact factor: 8.311
Authors: Morteza Naghavi; Peter Libby; Erling Falk; S Ward Casscells; Silvio Litovsky; John Rumberger; Juan Jose Badimon; Christodoulos Stefanadis; Pedro Moreno; Gerard Pasterkamp; Zahi Fayad; Peter H Stone; Sergio Waxman; Paolo Raggi; Mohammad Madjid; Alireza Zarrabi; Allen Burke; Chun Yuan; Peter J Fitzgerald; David S Siscovick; Chris L de Korte; Masanori Aikawa; K E Juhani Airaksinen; Gerd Assmann; Christoph R Becker; James H Chesebro; Andrew Farb; Zorina S Galis; Chris Jackson; Ik-Kyung Jang; Wolfgang Koenig; Robert A Lodder; Keith March; Jasenka Demirovic; Mohamad Navab; Silvia G Priori; Mark D Rekhter; Raymond Bahr; Scott M Grundy; Roxana Mehran; Antonio Colombo; Eric Boerwinkle; Christie Ballantyne; William Insull; Robert S Schwartz; Robert Vogel; Patrick W Serruys; Goran K Hansson; David P Faxon; Sanjay Kaul; Helmut Drexler; Philip Greenland; James E Muller; Renu Virmani; Paul M Ridker; Douglas P Zipes; Prediman K Shah; James T Willerson Journal: Circulation Date: 2003-10-14 Impact factor: 29.690
Authors: Yusuke Nakagawa; Amir H Lebaschi; Susumu Wada; Samuel J E Green; Dean Wang; Zoe M Album; Camilla B Carballo; Xiang-Hua Deng; Scott A Rodeo Journal: J Orthop Res Date: 2018-12-13 Impact factor: 3.494