Background
This study examines the predictive value of a novel systemic immune‐inflammation index (SII, platelet × neutrophil/lymphocyte ratio) in coronary artery disease (CAD) patients.
Methods
A ...total of 5602 CAD patients who had undergone a percutaneous coronary intervention (PCI) were enrolled. They were divided into two groups by baseline SII score (high SII vs low SII) to analyse the relationship between SII groups and the long‐term outcome. The primary outcomes were major cardiovascular events (MACE) which includes nonfatal myocardial infarction (MI), nonfatal stroke and cardiac death. Secondary outcomes included a composite of MACE and hospitalization for congestive heart failure.
Results
An optimal SII cut‐off point of 694.3 × 109 was identified for MACE in the CAD training cohort (n = 373) and then verified in the second larger CAD cohort (n = 5602). Univariate and multivariate analyses showed that a higher SII score (≥694.3) was independently associated with increased risk of developing cardiac death (HR: 2.02; 95% CI: 1.43‐2.86), nonfatal MI (HR: 1.42; 95% CI: 1.09‐1.85), nonfatal stroke (HR: 1.96; 95% CI: 1.28‐2.99), MACE (HR: 1.65; 95% CI: 1.36‐2.01) and total major events (HR: 1.53; 95% CI: 1.32‐1.77). In addition, the SII significantly improved risk stratification of MI, cardiac death, heart failure, MACE and total major events than conventional risk factors in CAD patients by the significant increase in the C‐index (P < .001) and reclassification risk categories by significant NRI (P < .05) and IDI (P < .05).
Conclusions
SII had a better prediction of major cardiovascular events than traditional risk factors in CAD patients after coronary intervention.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Possible association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been controversial. This study used a nationwide population-based dataset to investigate the relationship between ...DM and subsequent AD incidence.
Data were collected from Taiwan's National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74 ± 14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD.
Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio HR, 1.76; 95% confidence interval CI, 1.50-2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10-1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06-1.46, p=0.008), hypertension (HR, 1.30; 95% CI, 1.07-1.59, p=0.01), previous stroke history (HR, 1.79; 95% CI, 1.28-2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07-1.63, p=0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04-4.52, p=0.039).
Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity. Critical limb ischemia (CLI) is the ...most severe complication of PAD. In addition to medical and interventional treatment, therapeutic angiogenesis is a novel therapy for PAD. Circulating microRNAs (miRNAs) are considered key regulators of gene expression, but their role in ischemic-induced angiogenesis is poorly-characterized. There is currently a limited understanding of the specific miRNAs associated with PAD. To determine the regulation of miRNAs, we obtained miRNA profiles using RNA isolated from patients with PAD and a control group. The effects of specific miRNAs on angiogenesis were evaluated by assessing the in vitro angiogenic function of endothelial progenitor cells (EPCs), performing an in vivo angiogenesis assay, and employing a mouse hindlimb ischemic model. Our results demonstrated that circulating miR-548j-5p was significantly reduced in patients with PAD as compared with the controls. miR-548j-5p promoted EPC angiogenesis by enhancing migration and tube formation. The endothelial nitric oxide synthase (NOS) and stromal cell-derived factor (SDF)-1 signaling pathways appeared to be potential targets of miR-548j-5p. Furthermore, the results of a directed in vivo angiogenesis assay of EPCs and a hindlimb ischemia mouse model demonstrated that miR-548j-5p enhanced the capillary density and blood flow recovery in hindlimb ischemia. In conclusion, our data indicated that up-regulation of miR-548j-5p promotes angiogenesis in ischemic tissue and may represent a novel therapeutic approach for PAD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Insulin resistance (IR) is a known risk factor for cardiovascular disease (CVD) in non-diabetic patients through the association of hyperglycemia or associated metabolic factors. The triglyceride ...glucose (TyG) index, which was defined by incorporating serum glucose and insulin concentrations, was developed as a surrogate marker of insulin resistance. We aimed to investigate the association between the TyG index and the early phase of subclinical atherosclerosis (SA) between the sexes.
The I-Lan Longitudinal Aging Study (ILAS) enrolled 1457 subjects aged 50-80 years. For each subject, demographic data and the TyG index {lnfasting triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/
} were obtained. Patients were further stratified according to sex and the 50th percentile of the TyG index (≥ 8.55 or < 8.55). SA was defined as the mean carotid intima-media thickness (cIMT) at the 75th percentile of the entire cohort. Demographic characteristics and the presence of SA were compared between the groups. Logistic regression analysis was performed to assess the relationship between TyG index and SA.
Patients with a higher TyG index (≥ 8.55) had a higher body mass index (BMI), hypertension (HTN) and diabetes mellitus (DM). They had higher lipid profiles, including total cholesterol (T-Chol) and low-density lipoprotein (LDL), compared to those with a lower TyG index (< 8.55). Gender disparity was observed in non-diabetic women who had a significantly higher prevalence of SA in the high TyG index group than in the low TyG index group. In multivariate logistic regression analysis, a high TyG index was independently associated with SA in non-diabetic women after adjusting for traditional risk factors adjusted odds ratio (OR): 1.510, 95% CI 1.010-2.257, p = 0.045 but not in non-diabetic men. The TyG index was not associated with the presence of SA in diabetic patients, irrespective of sex.
A high TyG index was significantly associated with SA and gender disparity in non-diabetic patients. This result may highlight the need for a sex-specific risk management strategy to prevent atherosclerosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on ...arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR -/- to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitro-tyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification. We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the above-mentioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H2O2 or superoxide production. These results suggest that SIM may, independent of its cholesterol-lowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Bariatric surgery is an effective therapy for morbid obesity but may reduce calcium absorption and significantly decrease the bone mineral density. This study examined the prevalence of ...secondary hyperparathyroidism (SHPT) in obese subjects during follow-up after different bariatric surgeries. We investigated predictors of SHPT.
Methods
We enrolled 1470 obese subjects undergoing bariatric/metabolic surgery with at least 1-year follow-up, including 322 patients undergoing Roux-en-Y gastric bypass (RYGB), 695 undergoing single anastomosis (mini-) gastric bypass (SAGB), 93 undergoing laparoscopic adjustable gastric banding (LAGB), and 360 undergoing sleeve gastrectomy (SG). Five years of data were available for 215 patients. Patients were instructed to supplement their diet according to the guideline. Calcium, parathyroid hormone (PTH), and vitamin D levels were measured before surgery and at 1 and 5 years after surgery. SHPT was defined as PTH > 69 pg/mL.
Results
The overall prevalence of SHPT was high, 21.0% before surgery and was not different between patients with different bariatric procedures. Pre-operative PTH correlated with age, BMI, and vitamin D levels. Multi-variate analysis confirmed that vitamin D level was the only independent predictor of SHPT before surgery. The prevalence of SHPT increased to 35.4% at 1 year after surgery and 63.3% at 5 years after surgery. SAGB had the highest prevalence of SHPT (50.6%) followed by RYGB (33.2%), LAGB (25.8%), and SG (17.8%) at 1 year after surgery. At 5 years after surgery, SAGB still had the highest prevalence of SHPT (73.6%), followed by RYGB (56.6%), LAGB (38.5%), and SG (41.7%). Serum PTH at 1 year after surgery correlated with decreased BMI and weight loss. Multi-variate analysis confirmed that age, sex, calcium level, and bypass procedure were independent predictor of SHPT after surgery.
Conclusions
The prevalence of SHPT is high in morbidly obese patients before bariatric surgery which is related to vitamin D deficiency. The prevalence of SHPT increased continually along with the time after bariatric surgery, especially in patients receiving SAGB, followed by RYGB. The supplementation of vitamin D and calcium have to be higher in bypass procedure, especially in malabsorptive procedure.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Circulating endothelial progenitor cells (EPCs), which function in vascular repair, are the markers of endothelial dysfunction and vascular health. Fibroblast growth factor 21 (FGF21), a ...liver‐secreted protein, plays a crucial role in glucose homeostasis and lipid metabolism. FGF21 has been reported to attenuate the progression of atherosclerosis, but its impact on EPCs under high oxidative stress conditions remains unclear. In vitro studies showed that the β‐klotho protein was expressed in cultured EPCs and that its expression was upregulated by FGF21 treatment. Hydrogen peroxide (H2O2)‐induced oxidative stress impaired EPC function, including cell viability, migration and tube formation. Pretreatment with FGF21 restored the functions of EPCs after the exposure to H2O2. Administration of N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME), an inhibitor of nitric oxide synthase, inhibited the effects of FGF21 in alleviating oxidative injury by suppressing endothelial nitric oxide synthase (eNOS). In an in vivo study, the administration of FGF21 significantly reduced total cholesterol (TC) and blood glucose levels in apolipoprotein E (ApoE)‐deficient mice that were fed a high‐fat diet (HFD). Endothelial function, as reflected by acetylcholine‐stimulated aortic relaxation, was improved after FGF21 treatment in ApoE‐deficient mice. Analysis of mRNA levels in the aorta indicated that FGF21 increased the mRNA expression of eNOS and upregulated the expression of the antioxidant genes superoxide dismutase (SOD)1 and SOD2 in ApoE‐deficient mice. These data suggest that FGF21 improves EPC functions via the Akt/eNOS/nitric oxide (NO) pathway and reverses endothelial dysfunction under oxidative stress. Therefore, administration of FGF21 may ameliorate a HFD‐induced vascular injury in ApoE‐deficient mice.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Trimethylamine N-oxide (TMAO) is a metabolite originated from bacterial metabolism of choline-rich foods. Evidence suggests an association between TMAO and atherosclerosis, but the relationship ...between TMAO and endothelial progenitor cells (EPCs) remains unclear. This study aimed to identify the relationship between TMAO concentrations, circulating EPCs, and endothelial function in patients with stable angina. Eighty-one stable angina subjects who underwent coronary angiography were enrolled. The circulating EPCs and flow-mediated vasodilation (FMD) were measured to evaluate endothelial function. Plasma TMAO and inflammatory markers, such as hsCRP and IL-1β, were determined. Furthermore, the effect of TMAO on EPCs was assessed in vitro. Patients with lower FMD had significantly decreased circulating EPCs, elevated TMAO, hsCRP, and IL-1β concentrations. Plasma TMAO levels were negatively correlated with circulating EPC numbers and the FMD, and positively correlated with hsCRP, IL-1β concentrations. In in vitro studies, incubation of TMAO in cultured EPCs promoted cellular inflammation, elevated oxidative stress, and suppressed EPC functions. Enhanced plasma TMAO levels were associated with reduced circulating EPCs numbers, endothelial dysfunction, and more adverse cardiovascular events. These findings provided evidence of TMAO's toxicity on EPCs, and delivered new insight into the mechanism of TMAO-mediated atherosclerosis, which could be derived from TMAO-downregulated EPC functions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fibroblast growth factor (FGF)-23 levels rise as kidney function declines. Whether elevated FGF-23 levels are associated with an increased risk for contrast-associated acute kidney injury (CA-AKI) ...and major adverse cardiovascular events (MACE) in patients undergoing coronary angiography remain uncertain.
In total, 492 patients receiving coronary angiography were enrolled. Their serum FGF-23 levels were measured before administration of contrast media. The occurrence of CA-AKI was defined as a rise in serum creatinine of 0.5 mg/dL or a 25% increase from the baseline value within 48 h after the procedure. All patients were followed up for at least 1 year or until the occurrence of MACE including death, nonfatal myocardial infarction (MI), and ischemic stroke.
Overall, CA-AKI occurred in 41 (8.3%) patients. During a median follow-up of 2.6 years, there were 24 deaths, 3 nonfatal MIs, and 7 ischemic strokes. Compared with those in the lowest FGF-23 tertile, individuals in the highest FGF-23 tertile had a significantly higher incidence of CA-AKI (P < 0.001) and lower incidence of MACE-free survival (P = 0.001). In multivariate regression analysis, higher FGF-23 level was found to be independently associated with a graded risk for CA-AKI (OR per doubling, 1.90; 95% CI 1.48-2.44) and MACE (HR per doubling, 1.25; 95% CI 1.02-1.52).
Elevated FGF-23 levels were associated with an increased risk for CA-AKI and future MACE among patients undergoing coronary angiography. FGF-23 may play a role in early diagnosis of CA-AKI and predicting clinical outcomes after coronary angiography.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND—Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase–derived nitric oxide bioavailability. Here, we ...postulated that oxidative stress induces sterol regulatory element–binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium.
METHODS AND RESULTS—Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II–infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell–specific SREBP2 transgenic mice, locked nucleic acid–modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II–induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell–dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β.
CONCLUSIONS—Our findings suggest that SREBP2–miR-92a–inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.
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