Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis.

Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn(2+)-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis.

Schisandra extract ameliorates arthritis pathogenesis by suppressing the NF-κB and MAPK signalling pathways.

Schisandra chinensis is a medicinal plant used to treat various diseases. Extracts from the leaves or fruits of S. chinensis and their components are used in osteoarthritis (OA). The OA inhibitory effect of schisandrol A, one of its components, has been previously confirmed. We aimed to confirm the OA inhibitory effect of Schisandra (including components like schisandrol A) to identify why the inhibitory effect of the Schisandra extract is better. First, we investigated the effects of the Schisandra extract on OA as a potential therapeutic. Experimental OA was induced in a mouse model via destabilized medial meniscus surgery. The animals were orally administered the Schisandra extract; the inhibition of cartilage destruction was confirmed using histological analysis. In vitro analysis showed that the Schisandra extract attenuated osteoarthritic cartilage destruction by regulating IL-1ß-induced MMP3 and COX-2 levels. The Schisandra extract inhibited IL-1ß-induced degradation of IκB (NF-κB pathway) and IL-1ß-induced phosphorylation of p38 and JNK (mitogen-activated protein kinase (MAPK) pathway). RNA-sequencing analysis showed that the Schisandra extract decreased the expression of IL-1ß-induced MAPK and NF-κB signalling pathway-related genes more than schisandrol A alone. Therefore, Schisandra extract may be more effective than schisandrol A in preventing OA progression by regulating MAPK and NF-κB signalling.

Effect of Smoking Cessation on the Risk of Subarachnoid Hemorrhage: A Nested Case-Control Study in Korean Men.

BACKGROUND: Smoking is a well-established risk factor for subarachnoid hemorrhage (SAH), and current smokers have an increased risk of SAH. However, there are insufficient data on whether smoking cessation in current smokers reduces the risk of SAH. METHODS: A nested case-control study was conducted based on the National Health Insurance Service-National Health Screening Cohort, which comprises nationwide health claims data and a national health screening program in Korea (2002-2019). We constructed a cohort of current male smokers without a history of stroke at the baseline health screening (2002-2003). From this cohort, cases were defined as individuals who experienced a nontraumatic SAH during the follow-up period up to 2019. Five controls were matched to each case using incidence density sampling. Smoking status (continuation or cessation) before the occurrence of SAH was evaluated using the repeated national health screening program. We conducted a multivariable conditional logistic regression analysis, adjusting for alcohol consumption, physical activity, body mass index, systolic blood pressure, and fasting blood glucose levels, to evaluate the association between SAH risk and smoking cessation. RESULTS: At baseline, there were 112 142 current male smokers. After excluding individuals with prior stroke or insufficient data, the cohort consisted of 105 223 eligible participants (mean age, 50.3±8.5 years). Among them, we identified 318 cases of SAH and 1590 matched controls. Those who quit smoking had a significantly lower risk of SAH compared with current smokers (adjusted odds ratio, 0.55 [95% CI, 0.41-0.73]). The risk of SAH decreased with a longer period of smoking cessation. The risk reduction with smoking cessation was consistent even among prior heavy smokers. CONCLUSIONS: Smoking cessation in current male smokers reduced the risk of SAH, and the risk reduction was greater as the cessation period increased. These findings warrant intensive efforts to encourage smokers, even heavy smokers, to quit.

Impact of statin treatment on cardiovascular risk in patients with type 1 diabetes: a population-based cohort study.

BACKGROUND: Cardiovascular disease (CVD) is a major complication in type 1 diabetes mellitus (T1D) patients. Previous studies have suggested that statins may be helpful for prevention of CVD in T1D, but there are limited data on the role of statins in T1D. We investigated the relationship between statin treatment and cardiovascular risk in T1D patients using a population-based cohort. METHODS: We conducted a retrospective cohort study using the Korean nationwide health insurance database from January 2007 to December 2017. This study included 11,009 T1D patients aged ≥ 20 years without a prior history of CVD. The primary outcome was a composite development of stroke or myocardial infarction. Statin use during follow-up was treated as a time-varying variable. We performed a multivariable time-dependent Cox regression analysis adjusting for sex, age, type of insurance, hypertension, renal disease, and use of antiplatelets and renin-angiotensin-aldosterone system inhibitors. RESULTS: During the mean follow-up of 9.9 ± 3.7 years of follow-up, 931 T1D patients (8.5%) suffered primary outcome. Statin treatment was associated with a reduced risk of the primary outcome (adjusted hazard ratio, 0.76; 95% confidence interval 0.66-0.88; p < 0.001). Statin use led to decreased risks of ischemic stroke and myocardial infarction, but was not related to hemorrhagic stroke. We also found that the risk of cardiovascular events decreased as the cumulative exposure duration of statins increased. CONCLUSIONS: Statin use was associated with a lower risk of cardiovascular events in T1D patients. Further prospective studies are needed to confirm the potential role of statins in prevention of CVD in patients with T1D.

Lobeglitazone, a novel thiazolidinedione, for secondary prevention in patients with ischemic stroke: a nationwide nested case-control study.

INTRODUCTION: Ischemic stroke patients with diabetes are at high risk for recurrent stroke and cardiovascular complications. Pioglitazone, a type of thiazolidinedione, has been shown to reduce cardiovascular complications in patients with ischemic stroke and type 2 diabetes (T2D) or insulin resistance. Lobeglitazone is a novel thiazolidinedione agent that improves insulin resistance and has similar glycemic efficacy to pioglitazone. Using population-based health claims data, we evaluated whether lobeglitazone has secondary cardiovascular preventive effects in patients with ischemic stroke and T2D. METHODS: This study has a nested case-control design. From nationwide health claims data in Korea, we identified patients with T2D admitted for acute ischemic stroke in 2014-2018. Cases were defined who suffered the primary outcome (a composite of recurrent stroke, myocardial infarction, and all-cause death) before December 2020. Three controls were selected by incidence density sampling for each case from those who were at risk at the time of their case occurrence with exact matching on sex, age, the presence of comorbidities, and medications. As a safety outcome, we also evaluated the risk of heart failure (HF) according to the use of lobeglitazone. RESULTS: From the cohort of 70,897 T2D patients with acute ischemic stroke, 20,869 cases and 62,607 controls were selected. In the multivariable conditional logistic regression, treatment with lobeglitazone (adjusted OR 0.74; 95% CI 0.61-0.90; p = 0.002) and pioglitazone (adjusted OR 0.71; 95% CI 0.64-0.78; p < 0.001) were significantly associated with a lower risk for the primary outcome. In a safety outcome analysis for HF, treatment with lobeglitazone did not increase the risk of HF (adjusted OR 0.90; 95% CI 0.66-1.22; p = 0.492). CONCLUSIONS: In T2D patients with ischemic stroke, lobeglitazone reduced the risk of cardiovascular complications similar to that of pioglitazone without an increased risk of HF. There is a need for further studies on the cardioprotective role of lobeglitazone, a novel thiazolidinedione.

Proton Pump Inhibitors and Risk of Cardiovascular Disease: A Self-Controlled Case Series Study.

INTRODUCTION: We investigated cardiovascular risk due to proton pump inhibitor (PPI) treatment using a self-controlled case series (SCCS) study design, a type of case-only design and an approach to overcome between-person confounding in which individuals act as their own control. METHODS: We conducted an SCCS study using the National Health Insurance Service-Health Screening cohort in Korea (2002-2015). The cohort included 303,404 adult participants without prior cardiovascular events, who were followed up until December 2015. The primary outcome was a composite of stroke or myocardial infarction. The SCCS method estimated the age-adjusted incidence rate ratio between periods with and without exposure to PPI among patients with primary outcomes. As sensitivity analysis, conventional multivariable Cox proportional regression analyses were performed, which treated the exposure to PPI and H2 blocker during follow-up as time-dependent variables. RESULTS: In the SCCS design, 10,952 (3.6%) patients with primary outcomes were included. There was no association between PPI exposure and primary outcome (incidence rate ratio 0.98, 95% confidence interval [CI] 0.89-1.09). In the time-dependent Cox regression analyses, both PPI (adjusted hazard ratio 1.36, 95% CI 1.24-1.49) and H2 blocker (adjusted hazard ratio 1.46, 95% CI 1.38-1.55) were associated with an increased risk of the primary outcome. DISCUSSION: Negative findings in the SCCS design suggest that association between increased cardiovascular risk and PPI, frequently reported in prior observational studies, is likely due to residual confounding related to conditions with PPI treatment, rather than a true relationship.

Association of atrial fibrillation with infectivity and severe complications of COVID-19: A nationwide cohort study.

Infection is associated with the occurrence, recurrence, and progression of atrial fibrillation (AF), and is also closely related to poor prognosis. However, studies of the relationship between infectivity and severe complications of coronavirus infectious disease-19  (COVID-19) with a history of AF are limited. To estimate infectivity and severity of complications in COVID-19 patients with a history of AF, this study was done. From the Korean nationwide COVID-19 dataset, 212 678 participants with at least one severe acute respiratory syndrome coronavirus 2 (COVID-19) test were included between January 1 and June 4, 2020. AF was defined according to at least two outpatient hospital visits or one admission with an ICD-10 code of "I48" before the COVID-19 test. To investigate the association of AF with infectivity and severe complications of COVID-19, 1:4 ratio propensity score matching (PSM) was performed. Severe complications of COVID-19 were defined as a composite outcome of mechanical ventilation, intensive care unit admission, and death within 2 months after COVID-19 diagnosis. Among 212 678 participants who underwent the COVID-19 test, there were 7713 COVID-19 positive patients. After PSM, COVID-19 PCR positivity did not show a significant difference according to the presence of AF (odds ratio [OR]: 0.79, 95% confidence interval [CI]: [0.60-1.04]). Of 7713 COVID-19 patients, 62 (0.8%) had a history of AF and severe complications occurred in 444 (5.7%) patients. After PSM, AF was associated with the development of severe complications (OR: 2.04, 95% CI: [1.10-3.79]) and mortality (OR: 2.09, 95% CI: [1.01-4.31]) of COVID-19. We found that AF was associated with an increased risk of severe complications in COVID-19 infected patients.

Associations of heart failure with susceptibility and severe complications of COVID-19: A nationwide cohort study.

Infection is associated with occurrence and worsening of heart failure (HF). However, studies on the association of susceptibility and severe complications of coronavirus disease 2019 (COVID-19) with HF history are limited. From the Korean nationwide COVID-19 data set, 212,678 participants with at least one severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction (RT-PCR) test were included between January 1 and June 4, 2020. To investigate the association of HF with susceptibility and severe complications of COVID-19, 1:4 ratio propensity score matching (PSM) and logistic regression analysis were performed. The primary outcome was a composite outcome of mechanical ventilation, intensive care unit (ICU) admission, and death. After PSM, COVID-19 PCR positivity did not show a significant difference according to HF history in multivariable analysis (odds ratio [OR]: 0.91, 95% confidence interval (CI) (0.79-1.04), p = 0.146). Of 7630 individuals with confirmed COVID-19 infection, 310 (4.1%) had HF history. The overall primary outcome occurred in 426 (5.6%) individuals, including 159 (2.1%) cases of mechanical ventilation, 254 (3.3%) cases of ICU admission, and 215 (2.8%) cases of death. In multivariate logistic analysis, presence of HF history was associated independently with primary outcome (OR: 1.99, 95% CI: 1.42-2.79, p < 0.001), particularly mortality (OR: 2.02, 95% CI: 1.36-3.00, p < 0.001). Our study demonstrated that HF history is associated poor prognosis, particularly mortality, in COVID-19. Patients with HF can have severe complication if infected with COVID-19; therefore, careful management are necessary.

Association between the fatty liver index and the risk of severe complications in COVID-19 patients: a nationwide retrospective cohort study.

BACKGROUND: Research on the association of non-alcoholic fatty liver disease (NAFLD) with prognosis in COVID-19 has been limited. We investigated the association between the fatty liver index (FLI), a non-invasive and simple marker of NAFLD, and the severe complications of COVID-19 patients in South Korea. METHODS: We included 3122 COVID-19-positive patients from the nationwide COVID-19 cohort dataset in South Korea between January and June 2020. The FLI was calculated using triglyceride, body mass index, glutamyl transpeptidase, and waist circumference, which were obtained from the national health screening program data. Severe complications related to COVID-19 were defined as the composite of mechanical ventilation, intensive care unit treatment, high-oxygen flow therapy, and death within 2 months after a COVID-19 infection. We performed a multivariate logistic regression analysis for the development of severe complications in COVID-19 patients. RESULTS: The mean ± standard deviation of FLI were 25.01 ± 22.64. Severe complications from COVID-19 occurred in 223 (7.14%) patients, including mechanical ventilation in 82 (2.63%) patients, ICU admission in 126 (4.04%), high-flow oxygen therapy in 75 (2.40%), and death in 94 (3.01%) patients, respectively. The multivariate analysis indicated that the highest tertile (T3) of FLI was positively associated with severe complications from COVID-19 (adjusted odds ratio (OR): 1.77, 95% confidence interval (CI) (1.11-2.82), P = 0.017) compared with the lowest tertile (T1). CONCLUSIONS: Our study demonstrated that FLI, which represents NAFLD, was positively associated with an increased risk of severe complications from COVID-19. FLI might be used as a prognostic marker for the severity of COVID-19.

Association Between the Risk for Cardiovascular Events and Antiviral Treatment for Herpes Zoster.

BACKGROUND: Cardiovascular risk increases following herpes zoster. We investigated whether treatment with antiviral agents, steroids, and common cardiovascular medications was associated with the risk of postherpetic cardiovascular events. METHODS: This was a nationwide population-based, retrospective, cohort study using the National Health Insurance Service health claims data in Korea. We included patients with a first-ever diagnosis of herpes zoster in 2003-2014 and no prior cardiovascular event. The primary outcome was the occurrence of composites of myocardial infarction (International Statistical Classification of Diseases, Tenth Revision, code I21) and stroke (codes I60-I63) since the herpes zoster. We analyzed the exposure (intravenous or oral administration) to antiviral agents, steroids, antithrombotics, and statins within ±7 days from the index date of herpes zoster diagnosis. Follow-up was performed until occurrence of the primary outcome, death, or 31 December 2015, whichever came first. RESULTS: Of 84 993 patients with herpes zoster, the proportions of patients who received the treatment with antiviral agents, steroids, antithrombotics, and statins were 90.5%, 48.0%, 9.1%, and 7.9%, respectively. During the mean (standard deviation) follow-up period of 5.4 (3.1) years, 1523 patients experienced the primary outcome. Multivariate Cox regression analysis demonstrated that treatment with antiviral agents (adjusted hazard ratio, 0.82; 95% confidence interval, .71-.95) and statins (0.71; .59-.85) were significantly associated with the lower risk of primary outcome. Use of antithrombotics and steroids were not associated with the risk. CONCLUSIONS: After herpes zoster, treatment with antiviral agents was significantly associated with lower risk of cardiovascular events. We need more information on the cardiovascular protective role of herpes zoster treatments.

Dipstick proteinuria and risk of type 2 diabetes mellitus: a nationwide population-based cohort study.

BACKGROUND: Proteinuria has been recognized as a marker of systemic inflammation and endothelial dysfunction associated with insulin resistance and ß-cell impairment, which can contribute to the development of type 2 diabetes mellitus (T2DM). However, it is unknown whether the dipstick proteinuria test has a predictive value for new-onset T2DM. METHODS: This retrospective cohort study analyzed 239,287 non-diabetic participants who participated in the Korean nationwide health screening program in 2009-2010. Proteinuria was determined by the urine dipstick test at the baseline health screening. We performed multivariate Cox proportional regression analyses for the development of new-onset T2DM. Follow-up was performed until December 2015. RESULTS: During the mean follow-up period of 5.73 years, 22,215 participants were diagnosed with new-onset T2DM. The presence of proteinuria was significantly associated with an increased risk of T2DM (adjusted hazard ratio: 1.19, 95% confidence interval: 1.10, 1.29). There was a positive dose-response relationship between the degree of dipstick proteinuria and T2DM risk. This significant association between proteinuria and T2DM risk was consistent regardless of the fasting glucose level at baseline. CONCLUSIONS: Dipstick proteinuria is a significant risk factor for new-onset T2DM. Therefore, proteinuria might be a useful biomarker to identify those at a high risk for developing T2DM.

Seomae mugwort and jaceosidin attenuate osteoarthritic cartilage damage by blocking IκB degradation in mice.

Seomae mugwort, a Korean native variety of Artemisia argyi, exhibits physiological effects against various diseases. However, its effects on osteoarthritis (OA) are unclear. In this study, a Seomae mugwort extract prevented cartilage destruction in an OA mouse model. In vitro and ex vivo analyses revealed that the extract suppressed MMP3, MMP13, ADAMTS4 and ADAMTS5 expression induced by IL-1ß, IL-6 and TNF-α and inhibited the loss of extracellular sulphated proteoglycans. In vivo analysis revealed that oral administration of the extract suppressed DMM-induced cartilage destruction. We identified jaceosidin in Seomae mugwort and showed that this compound decreased MMP3, MMP13, ADAMTS4 and ADAMTS5 expression levels, similar to the action of the Seomae mugwort extract in cultured chondrocytes. Interestingly, jaceosidin and eupatilin combined had similar effects to Seomae mugwort in the DMM-induced OA model. Induction of IκB degradation by IL-1ß was blocked by the extract and jaceosidin, whereas JNK phosphorylation was only suppressed by the extract. These results suggest that the Seomae mugwort extract and jaceosidin can attenuate cartilage destruction by suppressing MMPs, ADAMTS4/5 and the nuclear factor-κB signalling pathway by blocking IκB degradation. Thus, the findings support the potential application of Seomae mugwort, and particularly jaceosidin, as natural therapeutics for OA.

TRIM24-RIP3 axis perturbation accelerates osteoarthritis pathogenesis.

OBJECTIVES: Recently, necroptosis has attracted increasing attention in arthritis research; however, it remains unclear whether its regulation is involved in osteoarthritis (OA) pathogenesis. Since receptor-interacting protein kinase-3 (RIP3) plays a pivotal role in necroptosis and its dysregulation is involved in various pathological processes, we investigated the role of the RIP3 axis in OA pathogenesis. METHODS: Experimental OA was induced in wild-type or Rip3 knockout mice by surgery to destabilise the medial meniscus (DMM) or the intra-articular injection of adenovirus carrying a target gene (Ad-Rip3 and Ad-Trim24 shRNA). RIP3 expression was examined in OA cartilage from human patients; Trim24, a negative regulator of RIP3, was identified by microarray and in silico analysis. Connectivity map (CMap) and in silico binding approaches were used to identify RIP3 inhibitors and to examine their direct regulation of RIP3 activation in OA pathogenesis. RESULTS: RIP3 expression was markedly higher in damaged cartilage from patients with OA than in undamaged cartilage. In the mouse model, adenoviral RIP3 overexpression accelerated cartilage disruption, whereas Rip3 depletion reduced DMM-induced OA pathogenesis. Additionally, TRIM24 knockdown upregulated RIP3 expression; its downregulation promoted OA pathogenesis in knee joint tissues. The CMap approach and in silico binding assay identified AZ-628 as a potent RIP3 inhibitor and demonstrated that it abolished RIP3-mediated OA pathogenesis by inhibiting RIP3 kinase activity. CONCLUSIONS: TRIM24-RIP3 axis perturbation promotes OA chronicity by activating RIP3 kinase, suggesting that the therapeutic manipulation of this pathway could provide new avenues for treating OA.

Cirsium japonicum var. maackii and apigenin block Hif-2α-induced osteoarthritic cartilage destruction.

Although Hif-2α is a master regulator of catabolic factor expression in osteoarthritis development, Hif-2α inhibitors remain undeveloped. The aim of this study was to determine whether Cirsium japonicum var. maackii (CJM) extract and one of its constituents, apigenin, could attenuate the Hif-2α-induced cartilage destruction implicated in osteoarthritis progression. In vitro and in vivo studies demonstrated that CJM reduced the IL-1ß-, IL-6, IL-17- and TNF-α-induced up-regulation of MMP3, MMP13, ADAMTS4, ADAMTS5 and COX-2 and blocked osteoarthritis development in a destabilization of the medial meniscus mouse model. Activation of Hif-2α, which directly up-regulates MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression, is inhibited by CJM extract. Although cirsimarin, cirsimaritin and apigenin are components of CJM and can reduce inflammation, only apigenin effectively reduced Hif-2α expression and inhibited Hif-2α-induced MMP3, MMP13, ADAMTS4, IL-6 and COX-2 expression in articular chondrocytes. IL-1ß induction of JNK phosphorylation and IκB degradation, representing a critical pathway for Hif-2α expression, was completely blocked by apigenin in a concentration-dependent manner. Collectively, these effects indicate that CJM and one of its most potent constituents, apigenin, can lead to the development of therapeutic agents for blocking osteoarthritis development as novel Hif-2α inhibitors.

3'-Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis.

3'-Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3'-sialyllactose on osteoarthritic cartilage destruction. In vitro and ex vivo, biochemical and histological analysis demonstrated that 3'-sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL-1ß, IL-6, IL-17 and TNF-α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3'-sialyllactose, whereas the direct binding of NF-κB to the Mmp3, Mmp13 and Cox2 promoters was reduced by 3'-sialyllactose in IL-1ß-treated chondrocytes. Additionally, IL-1ß induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3'-sialyllactose in a dose-dependent manner. In vivo, 3'-sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3'-sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration via promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3'-sialyllactose could be attributed in part to its regulation of Sox9 or NF-κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3'-sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.

NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis.

OBJECTIVE: Hypoxia-inducible factor 2α (HIF-2α), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction. METHODS: The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1(+/-), Epas1(fl/fl);Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. RESULTS: We found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery. CONCLUSIONS: Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.

Risk of thromboembolism according to statin treatment in patients with cancer: A nationwide nested case-control study.

BACKGROUND: Thromboembolic events exhibit increased prevalence in patients with cancer and can negatively affect prognoses. We investigated whether statin treatment would reduce thromboembolic risk in patients with cancer. METHODS: We conducted a nested case-control study using a Korean nationwide health claims database. The study included patients newly diagnosed with cancer without a prior history of cardiovascular disease between 2014 and 2016. Cases who developed arterial thromboembolism (ATE) or venous thromboembolism (VTE) after cancer diagnosis and three individually matched controls were selected. Conditional logistic regression was used to assess the association between thromboembolic risk and statin therapy after cancer diagnosis. RESULTS: Among 455,805 newly diagnosed patients with cancer followed for a mean of 4.3 ± 2.0 years, 22,249 patients developed thromboembolic events (ATE: 6341, VTE: 15,908), resulting in an incidence rate of 1133 per 100,000 person-years. The nested case-control study included 21,289 cases with thromboembolic events and 63,867 controls. Statin use was less frequent in the case group (18.0 % vs. 23.7 %). Statin treatment was associated with a lower risk of thromboembolic events (adjusted odds ratio [OR] 0.70; 95 % confidence interval [CI] 0.67-0.73). This association was observed for both ATE (adjusted OR 0.68; 95 % CI 0.63-0.74) and VTE (adjusted OR 0.71; 95 % CI 0.67-0.75). Longer statin use and better adherence were also associated with lower risk for thromboembolic events. Statin treatment was significantly associated with fewer thromboembolic events in most cancer types. CONCLUSIONS: Statin use was associated with lower risk for thromboembolic events in patients newly diagnosed with cancer.

Effect of Statins for Primary Prevention of Cardiovascular Disease According to the Fatty Liver Index.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). We investigated the primary preventive effect of statins on CVD according to the level of fatty liver index (FLI), which is a marker of NAFLD. METHODS: We conducted a nested case-control study on the basis of a nationwide health screening cohort in Korea. The participants were divided into tertiles (T1, T2, and T3) according to their FLI score. Cases were defined as individuals who developed CVD (composite of myocardial infarction and stroke). Three controls were matched to each case and multivariable conditional logistic regression analysis was performed. RESULTS: Within a cohort of 206,263 participants without prior CVD, 7044 individuals suffered the primary outcome. For the nested case-control study, we selected these 7044 cases along with their corresponding 20,641 matched controls. Individuals in the T3 tertiles of FLI had a higher risk of CVD than those in the T1 tertile [adjusted odds ratio (OR) 1.30; 95% confidence interval (CI) 1.20-1.40, P < 0.001]. In sub-analyses based on FLI tertiles, statin therapy was associated with a lower risk of CVD (adjusted OR 0.72; 95% CI 0.61-0.85, P < 0.001) in the T3 tertile but not in the T1 and T2 tertiles. CONCLUSIONS: Statin therapy was associated with a reduced risk of CVD in individuals with high FLI but not in those with low FLI. Further research is needed to determine the pathophysiologic mechanism between statin and NAFLD.

Proton Pump Inhibitor for Gastrointestinal Bleeding in Patients with Myocardial Infarction on Dual-Antiplatelet Therapy: A Nationwide Cohort Study.

BACKGROUND: Guidelines provide various recommendations for the use of proton pump inhibitors (PPI) to prevent upper gastrointestinal (UGI) bleeding in acute myocardial infarction (MI) treatment with dual antiplatelet therapy (DAPT). We evaluated the effects of PPIs in reducing the risk of severe UGI bleeding in patients with MI receiving DAPT. METHODS: This retrospective cohort study included patients admitted for acute MI between 2014 and 2018, based on a nationwide health claims database in Korea. Primary outcome was admission for severe UGI bleeding requiring transfusion within 1 year of MI diagnosis. A multivariable Cox regression model was used to calculate the association between PPI use and severe UGI bleeding risk. RESULTS: Of 100,556 patients with MI on DAPT (mean age, 63.7 years; 75.4% men), 37% were prescribed PPIs. Based on risk assessment for UGI bleeding, among 6,392 (6.4%) high-risk and 94,164 (93.6%) low-risk patients, 50.5% and 35.8% received PPIs, respectively. Overall, 0.5% of the patients experienced severe UGI bleeding within 1 year after MI. The use of PPI was associated with a reduced risk of severe UGI bleeding (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.47-0.70; P < 0.001). The benefits of PPIs were consistent in high-risk (HR, 0.71; 95% CI, 0.45-1.13; P = 0.147) and low-risk (HR, 0.54; 95% CI, 0.43-0.68; P < 0.001) patients (P for interaction = 0.481). CONCLUSIONS: Among Korean patients with MI receiving DAPT, PPIs were underutilized, even among those at high risk of severe UGI bleeding. Nonetheless, PPI use reduced severe UGI bleeding in low- and high-risk groups.

Discontinuation of antiplatelet therapy after stent-assisted coil embolisation of cerebral aneurysm: a nationwide cohort study.

INTRODUCTION: Stent-assisted coil embolisation (SACE) for the treatment of unruptured cerebral aneurysms has been increasingly used. Long-term advantages of antiplatelet therapy (APT) post-SACE treatment are still not well understood. We investigated the long-term effects of APT on clinical prognosis after SACE. PATIENTS AND METHODS: We conducted a retrospective study using nationwide health insurance claims data from South Korea, including patients with cerebral aneurysm treated with SACE from January 2009 to December 2020. The study outcomes consisted of the occurrence of cerebral infarction and major haemorrhage. To evaluate the impact of APT, we employed a multivariable time-dependent Cox proportional hazards regression model for each of the three distinct periods: 1-12 months, 12-24 months and >24 months after SACE. RESULTS: This study included 17 692 unruptured cerebral aneurysm patients treated with SACE. During the mean follow-up of 4.2 years, there were 379 (2.1%) patients with cerebral infarction and 190 (1.1%) patients with major haemorrhage. The percentage of patients receiving APT was 79.5% at 1 year, which gradually decreased to 58.3% at 2 years after SACE. APT was beneficial in preventing cerebral infarction within 12 months after SACE (adjusted HR (aHR) 0.56; 95% CI, 0.35 to 0.89; p=0.014). After 12 months, this association was not evident. APT increased the risk of haemorrhage after 24 months (aHR 1.76; 95% CI 1.11 to 2.87; p=0.016). DISCUSSION AND CONCLUSION: Our findings suggest that in patients with unruptured cerebral aneurysm treated with SACE, the reasonable duration of APT for preventing cerebral infarction might be 1 year after SACE.