Pathological healing response of explanted MitraClip devices.

BACKGROUND: The safety and effectiveness of the MitraClip device (Abbott Vascular, Menlo Park, CA) is being evaluated in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) clinical studies. The healing response after device implantation has not previously been characterized in humans. METHODS AND RESULTS: A total of 67 explanted devices (implantation duration, 1 to 1878 days) from 50 patients were submitted for histological evaluation. Explants were analyzed in 4 implantation intervals: acute (≤30 days; n=7), subacute (31 to 90 days; n=23), chronic (91 to 300 days; n=18), and long term (>300 days; n=19). The acute healing response consisted of platelet/fibrin deposition. The subacute response exhibited granulation tissue with early fibrous encapsulation (pannus). The chronic response was characterized by various degrees of tissue bridging between the device arms. The long-term healing response demonstrated collagen-rich matrix (by type I collagen), incorporating the device components with complete encapsulation by organized, fibrous growth. In long-term devices with minimal surgical disruption, a fibrous tissue bridge (mean area, 7.39±4.3 mm(2)) was observed over and between the device arms, resulting in atrial tissue continuity between the 2 valve leaflets. Devices demonstrated no evidence of endocarditis, mechanical wear, component fracture, or corrosion up to the time of explantation (median, 119 days; first and third quartiles, 42 and 365 days). CONCLUSIONS: In all patients, device mechanical integrity was maintained up to the time of explantation. Four phases of physiological healing were observed: platelet and fibrin deposition, inflammation, granulation tissue, and finally, fibrous encapsulation. Long-term device fibrous encapsulation with extension over adjacent mitral leaflets and tissue bridge formation adds structural stability. Clinical Trial Registration- URL: http://clinicaltrials.gov/show/NCT00209274. Unique identifiers: NCT00209339 and NCT00209274.

Left atrial appendage obliteration: mechanisms of healing and intracardiac integration.

OBJECTIVES: The objectives of this study were: 1) to delineate the temporal course of histopathologic healing as the left atrial appendage (LAA) is obliterated by a mechanical device; and 2) to compare this process with other intravascular and intracardiac implanted technologies. BACKGROUND: Intracardiac device healing is incompletely understood. We thus studied the histopathology of device-based LAA obliteration. METHODS: Nine dog hearts were examined over time after LAA device placement and results were compared with human hearts with prior LAA obliteration using the same device. RESULTS: At 3 days in dogs, atrial surfaces were covered by fibrin, which sealed gaps between the LA wall and the device and filled the LA appendage cavity. At 45 days, endothelial cells covered the endocardial surface with underlying smooth muscle cells that sealed the device-LA interface. Regions with prior thrombus were replaced by endocardium surrounding the device membrane. Disorganized thrombus remained in the LAA body and at the periphery near the appendage walls. Mild inflammation was observed as thrombus resorbed. By 90 days, a complete endocardial lining covered the former LAA ostium. Organizing thrombus had become connective tissue, with no residual inflammation. The human necropsy hearts had similar findings. In these 4 hearts (139, 200, 480, and 852 days after implant), the ostial fabric membrane was covered with endocardium. The appendage surface contained organizing thrombus with minimal inflammation. Organizing fibrous tissue was inside the LAA cavity, prominent near the atrial wall. The LAA interior contained organizing thrombus. CONCLUSIONS: This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices.

A comparison of experimental aneurysm occlusion determination by angiography, scanning electron microscopy, MICROFIL perfusion, and histology.

In clinical practice, occlusion of embolized, intracerebral aneurysms is evaluated using angiography. Standard, two-dimensional digital subtract angiography (DSA) is unable to quantify irregular aneurysm remnants, and even three-dimensional rotational angiography cannot quantify the degree of occlusion. To better understand occlusion at the aneurysm neck, we compared angiographic results with MICROFIL perfusion, histology, and scanning electron microscopy (SEM) results in 20 elastase-induced saccular aneurysms in rabbits. Aneurysms were embolized with HydroCoil devices (n = 12) or platinum coils (n = 8). Aneurysm follow-up occurred at 2 (n = 10) and 6 (n = 10) weeks. Aneurysm occlusion was evaluated using DSA, MICROFIL perfusion, histological ground sections, and SEM. Groups were compared statistically using ANOVA and chi(2) tests. The MICROFIL perfusion results were not concordant with the angiographic results for the HydroCoil and platinum coil groups. Both increased and decreased occlusion was observed on the MICROFIL-perfused aneurysms when compared with angiography. The histologic occlusion results of the HydroCoil group were concordant with the angiographic results; however, unoccluded areas not visible on angiography were routinely observed on the ground sections in the platinum coil group. SEM imaging of the aneurysm neck consistently showed decreased occlusion than angiographic results for both the HydroCoil and platinum coil groups. Although histology and MICROFIL-perfusion analyses provided additional details of aneurysm occlusion when compared with angiography, complete visualization of the entire neck of the aneurysm and accurate assessment of aneurysm occlusion was possible only with SEM.

Toremifene metabolism in rat, mouse and human liver microsomes: identification of alpha-hydroxytoremifene by LC-MS.

The in vitro metabolism of toremifene has been studied in liver microsomal preparations from rat, mouse and human sources using high-performance liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESIMS). The metabolites detected were N-desmethyltoremifene (m/z 392), 4-hydroxytoremifene (m/z 422), 4'-hydroxytoremifene (m/z 422) and toremifene N-oxide m/z 422). In addition, a new polar metabolite with a protonated molecule at m/z 422 has been detected in all three species. The compound was identified by tandem MS-MS as alpha-hydroxytoremifene, an analogue of alpha-hydroxytamoxifen. The results showed that alpha-hydroxylation is a common feature of tamoxifen and toremifene metabolism and that alpha-hydroxytamoxifen is unlikely to be the reactive metabolite responsible for the hepatocarcinogenesis in rat, as widely believed.