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HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-β and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-β1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-β1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression.

BACKGROUND Watchman 2.5 (Boston Scientific Inc, Marlborough, MA) implant success approaches 95% in registries, yet many patients are not attempted because of complex left atrial appendage (LAA) anatomy. Watchman FLX can expand the range of ostium width (14-31.5 mm) and depth available for LAA closure.OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of Watchman FLX in patients with a failed Watchman 2.5 attempt or prohibitive LAA anatomy.METHODS The roll-in (n 5 58) and primary effectiveness (n 5 400) cohorts of the PINNACLE FLX trial comprised the study population. Subjects were identified who previously failed implantation of Watchman 2.5 (n 5 11) or were not attempted because of prohibitive LAA anatomy (n 5 88). Demographic characteristics, implant procedure details, and TEE follow-up data were compared to controls composed of enrollees not meeting these criteria (n 5 359).RESULTS Watchman FLX LAA closure was successfully implanted in all subjects with a prior failed Watchman 2.5 attempt (n 5 11 of 11). Subjects with previously failed Watchman 2.5 were more likely to receive a 35 mm FLX device than controls (27.3% vs 7.3%; P 5 .047). Patients with prohibitive anatomy had smaller LAA dimensions than did controls (diameter 18.0 6 4 mm vs 20.4 6 3 mm; P , .001 and length 23.7 6 5 mm vs 28.9 6 5 mm; P , .001). There was no difference in age, sex, CHA 2 DS 2 -VASc score, HAS-BLED score, or primary efficacy between cohorts. Transesophageal echocardiography (TEE) at 12 months showed zero leak in 90.9% in the failed Watchman 2.5 cohort, 91.3% in the prohibitive anatomy cohort, and 89.5% in the control cohort (P 5 .84). Overall and cardiovascular mortality was lower in the prohibitive anatomy cohort (1.2% vs 8.8% in controls; P 5 .02).CONCLUSION Watchman FLX implantation in patients with a prior failed Watchman 2.5 attempt or prohibitive LAA anatomy remained safe and highly effective. The association of reduced overall mortality with smaller LAA dimension warrants future study.

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