Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.ope

Oral health and longitudinal changes in fasting glucose levels: A nationwide cohort study

We investigated the association between oral hygiene indicators of periodontitis, tooth loss, and tooth brushing on the longitudinal fasting glucose level in non-diabetic subjects. Using a nationwide health screening database in Korea, we included non-diabetic individuals who received a health screening program with oral health check in 2009-2010. We constructed a linear mixed model for the longitudinal data of fasting glucose from the baseline to 2015. During the 4.84-year of median follow-up, 91,963 individuals (mean age 56.2 at baseline) underwent 392,780 health examinations with fasting glucose level (mmol/L). The presence of periodontitis was 39.3%. In the multivariate linear mixed analysis, periodontitis was related with increased fasting glucose levels (β = 0.0084, standard error = 0.0035, p = 0.018). Similarly, tooth loss was associated with increased level of fasting glucose (β = 0.0246, standard error = 0.0038, p < 0.001). Compared with tooth brushing ≤2 times/day, tooth brushing ≥3 times/day was associated with decreased fasting glucose levels (β = -0.0207, standard error = 0.0033, p < 0.001). Our data showed that periodontitis and tooth loss were associated with increased fasting glucose levels in non-diabetic individuals. The study findings imply that frequent tooth brushing may reduce fasting glucose levels. Further research is needed to determine the effect of periodontal intervention on glycemic control.ope

Plasma Fibroblast Growth Factor 23 Concentration Is Associated With Intracranial Cerebral Atherosclerosis in Acute Ischemic Stroke Patients

Background and purpose: Fibroblast growth factor 23 (FGF23) is associated with atherosclerosis via nitric-oxide-associated endothelial dysfunction and calcium-phosphate-related bone mineralization. This study aimed to determine the association of the plasma FGF23 concentration with intracranial cerebral atherosclerosis (ICAS) and extracranial cerebral atherosclerosis (ECAS). Methods: We prospectively enrolled 262 first-ever ischemic stroke patients in whom brain magnetic resonance was performed and a blood sample acquired within 24 h after admission. Plasma FGF23 concentrations were measured using an enzyme-linked immunosorbent assay. The presence of ICAS or ECAS was defined as a ≥50% decrease in arterial diameter in magnetic resonance angiography. The burden of cerebral atherosclerosis was calculated by adding the total number of vessels defined as ICAS or ECAS. Results: Our study population included 152 (58.0%) males. The mean age was 64.7 years, and the plasma FGF23 concentration was 347.5±549.6 pg/mL (mean±SD). ICAS only, ECAS only, and both ICAS and ECAS were present in 31.2% (n=82), 4.9% (n=13), and 6.8% (n=18) of the subjects, respectively. In multivariate binary and ordinal logistic analyses, after adjusting for sex, age, and variables for which p<0.1 in the univariate analysis, the plasma FGF23 concentration (per 100 pg/mL) was positively correlated with the presence of ICAS [odds ratio (OR)=1.07, 95% CI=1.00-1.15, p=0.039], burden of ICAS (OR=1.09, 95% CI=1.04-1.15, p=0.001), and burden of ECAS (OR=1.06, 95% CI=1.00-1.12, p=0.038), but it was not significantly related to the presence of ECAS (OR=1.05, 95% CI=0.99-1.12, p=0.073). Conclusions: The plasma FGF23 may be a potential biomarker for cerebral atherosclerosis, particularly the presence and burden of ICAS in stroke patients.ope

Long-Term Benefit and Withdrawal Effect of Statins After Percutaneous Coronary Intervention: A Nationwide Population-Based Cohort Study

Purpose: Despite indubitable evidence for the cardiovascular benefits of statins, there have been concerns that statin discontinuation may cause negative effects known as "statin withdrawal syndrome." This study aimed to assess the benefit and the withdrawal effect of statins after percutaneous coronary intervention (PCI). Patients and methods: We conducted a retrospective cohort study on 5218 patients who underwent PCI between 2002 and 2013 using the nationwide health insurance claim data in Korea. Based on the prescription data, the use of statins during follow-up was classified into three risk periods: "statin period" (period with statin cover), "statin withdrawal period" (withdrawal of statin within 30 days), and "no statin period" (no exposure to statin for longer than 30 days). The primary outcome was the composite outcome of myocardial infarction, coronary revascularization, stroke, and all-cause death. We performed multivariate Cox proportional regression analyses which treated the use of statins as a time-dependent variable. Results: During the follow-up period of 3.54 ± 2.91 years (mean ± standard deviation), 1515 (29.0%) patients sustained a primary outcome. Compared with the "no statin period," the "statin period" was associated with lower risk of the primary outcome (adjusted hazard ratio [HR] 0.72, 95% confidence interval [CI, 0.63-0.81]). While the "statin withdrawal period" posed a significantly increased risk (adjusted HR 1.87, 95% CI [1.52-2.29]). With respect to the intensity of statins associated with withdrawal, dose-dependent increased risk was observed for withdrawal of low-, moderate-, and high-intensity statins; adjusted HR [95% CI] were 1.45 [0.74-2.86], 1.86 [1.49-2.32], and 2.61 [1.41-4.81], respectively. Conclusion: After PCI, there was an increased cardiovascular risk during the statin withdrawal period, especially with the use of high-intensity statins. To maximize the beneficial effect and to avoid the withdrawal effect of statins, high-risk patients need to adhere to taking statins without discontinuation.ope

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.ope

Clopidogrel preventive effect based on cytochrome P450 2C19 genotype in ischaemic stroke: protocol for multicentre observational study

Introduction: Clopidogrel is an antiplatelet agent that is widely used for the secondary prevention of cardiovascular and cerebrovascular events. The genotype of cytochrome P450 2C19 (CYP2C19) differentially affects the liver's metabolism of clopidogrel, which may influence the drug's response and efficacy for cardiovascular event prevention. In contrast to prior studies of patients with coronary artery diseases, little is known about whether the CYP2C19 genotype influences the preventive efficacy of clopidogrel in patients who had a stroke. We hypothesise that, among patients who had an acute ischaemic stroke who are prescribed clopidogrel, the patients with a loss-of-function CYP2C19 genotype (poor and intermediate metabolisers) may be at a higher risk of composite cardiovascular events than those who are non-carriers (extensive metabolisers). Methods and analysis: This prospective observational multicentre study was designed to determine whether composite cardiovascular events would differ among patients who had an ischaemic stroke prescribed clopidogrel according to CYP2C19 genotype (poor or intermediate vs extensive metabolisers). Inclusion criteria were patients who had an acute ischaemic stroke who underwent CYP2C19 genotype evaluation and received clopidogrel within 72 hours of stroke onset. The primary outcome is composite cardiovascular events (stroke, myocardial infarction, or cardiovascular death) within 6 months after acute ischaemic stroke between patients categorised as poor or intermediate metabolisers and those categorised as extensive metabolisers according to their CYP2C19 genotype. Ethics and dissemination: The Institutional Review Board of Severance Hospital, Yonsei University College of Medicine approved this study (3-2019-0195). We received study approval from the institutional review board of each participating hospital. We plan to disseminate our findings at relevant conferences and meetings and through peer-reviewed journals. Trial registration number: NCT04072705.ope

Association of triglyceride-glucose index with prognosis of COVID-19: A population-based study

Background: Triglyceride-glucose (TyG) index is a simple and reliable surrogate marker for insulin resistance. Epidemiology studies have shown that insulin resistance is a risk factor for various infectious diseases. We evaluated the prognostic value of TyG index measured before the COVID-19 infection in COVID-19 infected patients. Methods: From a nationwide COVID-19 cohort dataset in Korea, we included COVID-19 patients diagnosed between Jan and Jun 2020. Based on the nationwide health screening data between 2015 and 2018, TyG index was calculated as ln [triglyceride (mg/dL) × fasting glucose level (mg/dL)/2]. Primary outcome is development of severe complications of COVID-19 defined as composite of mechanical ventilation, intensive care unit care, high-flow oxygen therapy, and mortality within two months after the diagnosis of COVID-19. Results: This study included 3887 patients with COVID-19 confirmed by reverse transcription polymerase chain reaction. Mean ± standard deviation of TyG index was 8.54 ± 0.61. Severe complications of COVID-19 were noted in 289 (7.44%) patients. In the multivariate logistic regression, TyG index was positively associated with severe complications of COVID-19 (adjusted odds ratio: 1.42, 95% confidence interval [1.12-1.79]). Conclusions: In COVID-19 infected patients, high TyG index was associated with increased risk for severe complications. TyG index might be useful predictor for the severity of COVID-19 infection.ope

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.ope

Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study

BACKGROUND: Pioglitazone is an oral antidiabetic drug with multiple pleiotropic actions. Recent clinical trials have demonstrated that treatment with pioglitazone reduces cardiovascular risk in patients who have had an ischemic stroke. We examined the secondary preventive effects of pioglitazone in acute ischemic stroke patients with diabetes mellitus (DM) based on nationwide real-world data. METHODS: A nested case-control study was conducted with data from the National Health Insurance Service-National Sample Cohort in Korea. Study subjects were diabetic patients admitted for acute ischemic stroke (ICD-10 code; I63) between 2002 and 2013. Cases were defined as patients who suffered from composites of recurrent stroke (I60-63), myocardial infarction (I21), or all-cause mortality after ischemic stroke. Controls were selected by incidence density sampling. Three controls were matched to each case for sex, age, treatment with insulin, and oral antidiabetic medications, with the exception of pioglitazone. Medication history after ischemic stroke was obtained by accessing the prescription records. In the matched dataset, conditional logistic regression analysis was performed with adjustments for hypertension, atrial fibrillation, prior myocardial infarction, and treatment with oral antithrombotics and statins. RESULTS: From the patients with acute ischemic stroke and DM, 1150 cases with primary outcomes were matched to 3450 controls. In the matched analysis, treatment with pioglitazone was significantly associated with a lower cardiovascular risk (adjusted OR [95% CI], 0.43 [0.23-0.83]). CONCLUSIONS: In this nested case-control study using real-world data, treatment with pioglitazone exhibited significant cardiovascular preventive effect in diabetic patients with acute ischemic stroke.ope

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 β-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.ope