In vivo feasibility study of ultrasound potentiated collagenase therapy of chronic total occlusions.

Arterial chronic total occlusions (CTOs) pose considerable challenges for percutaneous interventions, due primarily to the presence of stiff proximal fibrous caps (PFCs) which act as a barrier to the penetration of guide wires. A new approach under development for improving the success rate of guide wire crossing in CTOs is to employ collagenase to degrade the mechanical integrity of the PFCs. This has been shown to be feasible in preclinical work and in a Phase 1 clinical trial. In a recent study we demonstrated using ex vivo experimental CTO specimens that ultrasound-stimulated microbubbles (USMBs) could potentiate the effects of collagenase and result in increased mechanical degradation of the PFCs of CTOs. Here we report the results of the first in vivo study examining the feasibility of this approach, which demonstrates that the force required to puncture through the PFCs of CTOs is reduced with combined USMB+collagenase treatments relative to collagenase only treatments. This approach has the potential to further improve the efficacy of the emerging technique of collagenase facilitation of percutaneous interventions for CTO.

The use of ultrasound-stimulated contrast agents as an adjuvant for collagenase therapy in chronic total occlusions.

AIMS: To investigate the effectiveness of combining collagenase and ultrasound-stimulated microbubble (USMB) treatments in reducing the mechanical force required for crossing a guidewire through CTOs. METHODS AND RESULTS: Experiments were conducted on ex vivo specimens of a rabbit femoral artery CTO model (n=45 total samples). Four primary groups were employed: control (n=6), collagenase only (n=15), USMB only (1 MHz frequency) (n=5), and collagenase+USMB (n=19). In one set of experiments the force required to puncture through CTO samples was measured and it was found that the puncture force was 2.31-fold lower for the combined treatment group relative to the comparable collagenase-only group (p<0.05). In a second set of experiments, the total protein and hydroxyproline content of the supernatant solution adjacent to the CTO was analysed. Significantly higher hydroxyproline levels were measured in collagenase+USMB treated CTOs (0.065 g/mL) compared to collagenase (0.030 g/mL), USMB (0.003 g/mL) and control (0.004 g/mL) (p<0.05), indicating that the combined treatment augmented collagenase degradation. CONCLUSIONS: Ultrasound-stimulated microbubbles improved the effectiveness of collagenase in reducing the force required to cross experimental CTOs. This new approach may have the potential to reduce treatment times and improve the success rates of emerging collagenase-based treatments of CTO.

Hybrid intravascular ultrasound and optical coherence tomography catheter for imaging of coronary atherosclerosis.

OBJECTIVE: To demonstrate the feasibility of imaging human coronary atherosclerosis using a novel hybrid intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging catheter. BACKGROUND: IVUS and OCT have synergistic advantages and recent studies involving both modalities suggest the use of a hybrid imaging catheter may offer improved guidance of coronary interventions and plaque characterization. METHODS: A 1.3 m custom hybrid IVUS-OCT imaging probe was built within a 4F catheter using a 42 MHz ultrasound transducer and an OCT imaging fiber. Coplanar images were simultaneously acquired ex vivo by both modalities in 31 arterial segments from 11 cadaveric human coronaries. IVUS and OCT images were acquired at 250 µm intervals, of which 13 of the arterial segments were selected as representative of a diverse set of pathological findings. The selected segments were then imaged with either digital X-ray or micro-CT, processed for histological analysis and compared with the corresponding IVUS and OCT images. RESULTS: Images of human coronary atherosclerosis using the hybrid IVUS-OCT catheter demonstrated a range of vascular pathologies that were confirmed on histology. The anticipated synergistic advantages of each modality were qualitatively apparent, including the deeper tissue penetration of IVUS and the superior contrast, resolution and near-field image quality of OCT. CONCLUSIONS: Preliminary ex vivo images using a hybrid IVUS-OCT catheter demonstrated feasibility in using the device for intracoronary imaging of atherosclerosis. Future studies will include in vivo imaging and larger samples sizes to enable quantitative comparisons of tissue characterization and feature identification using hybrid imaging catheters versus standalone IVUS and OCT imaging techniques. © 2012 Wiley Periodicals, Inc.

Natural history of experimental arterial chronic total occlusions.

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.

Innovations in imaging for chronic total occlusions: a glimpse into the future of angiography's blind-spot.

Chronic total occlusions (CTOs) are a subset of lesions that present a considerable burden to cardiovascular patients. There exists a strong clinical desire to improve non-surgical options for CTO revascularization. While several techniques, devices, and guide wires have been developed and refined for use in CTOs, the inability of angiography to adequately visualize occluded arterial segments makes interventions in this setting technically challenging. This review describes the current status of several invasive and non-invasive imaging techniques that may facilitate improved image guidance during CTO revascularization, with the goals of improving procedure safety and efficacy while reducing the time required to complete these interventions. Cardiac imaging also has important potential roles in selecting patients most likely to benefit from revascularization as well as pre-procedural planning, post-procedural assessment of revascularized segments and long-term outcomes studies. Modalities discussed include non-invasive techniques, such as CT(computed tomography) angiography and cardiac magnetic resonance imaging (MRI), as well as invasive techniques, such as intravascular ultrasound, optical coherence tomography, intravascular MRI, and conventional angiography. While some of these techniques have some evidence to support their use at present, others are at earlier stages of development. Strategies that combine imaging techniques with the use of interventional therapies may provide significant opportunities to improve results in CTO interventions and represent an active area of investigation.

Investigation of micro-ultrasound for microvessel imaging in a model of chronic total occlusion.

The aim of the current study is to investigate the ability of micro-ultrasound (microUS) to identify microvasculature in CTOs in vivo. Results are compared with MRI studies. CTOs were developed in nine porcine superficial femoral arteries (SFA) by percutaneous insertion of a dissolvable polymer plug. This model is characterized by acute thrombosis that later organizes into a fibrotic CTO containing abundant microchannels. 3D microUS images with Power Doppler (PD) overlays from the arteries were acquired at two timepoints: one and eight weeks after placement ofthe polymerplug. Phase contrast MRI and contrast enhanced MRI was also performed. Imaging was performed transcutaneously. Microvessels were identified in vivo in six of eight CTOs using microUS, and in three of seven CTO vessels with MRI, compared with five of seven seen histologically. PW Doppler profiles showed pulsatile blood velocities of approximately 2 cm/s. Intraluminal microvessels within CTOs can be consistently identified by 3D microUS. This technique appears to be more sensitive than MRI. MicroUS may play a role in guiding CTO interventions.