Significantly Increased Risk of Cardiovascular Disease among Patients with Gallstone Disease: A Population-Based Cohort Study

<div><p>Objective</p><p>To investigate whether gallstone disease (GD) increases the risk of developing cardiovascular disease (CVD) in a large population-based cohort.</p> <p>Methods</p><p>A study population including 6,981 patients with GD was identified from The Taiwan National Health Insurance Research Database between 2004 and 2005. GD patients were defined as patients with principal discharge diagnoses of cholelithiasis using the ICD-9-CM code 574. 27,924 patients without GD were randomly selected and matched for age and gender. All patients were followed for 6 years or until diagnosis for CVD. Cox proportional hazards regression model was used to assess the risk of developing CVD with adjustment for age, gender and co-morbid conditions.</p> <p>Results</p><p>During the six years follow-up period, 935 patients with GD and 2,758 patients without GD developed CVD. Patients with GD had an elevated risk of CVD (HR, 1.32; 95% CI, 1.22-1.43) when compared with those without GD. Similar relationship was observed when CVD was categorized i.e. stroke (HR, 1.15; 95% CI, 1.01-1.32), coronary heart disease (HR, 1.42; 95% CI, 1.28-1.58) and heart failure (HR, 1.31; 95% CI, 1.00-1.73). When GD was classified according to the level of severity, using patients without GD as reference, the risks of CVD were elevated in patients with non-severe GD (HR, 1.34; 95% CI, 1.24-1.46) as well as those with severe GD (HR, 1.20, 95% CI, 1.02-1.40), after adjusting for age, gender and comorbidities. In age-stratified analysis, patients aged 18-40 years with GD were at higher risk of developing CVD (HR, 1.42; 95% CI, 1.09-1.84) than older GD patients.</p> <p>Conclusion</p><p>This study found an increased risk of CVD in patients diagnosed with GD. The excess risk was particularly high in younger GD patients. Prevention of GD could help reduce the risk of developing CVD, and the better effect could be achieved for the younger age groups.</p> </div

Immunohistochemical staining of left ventricular myocardium after induction of aorta-caval (AV) shunt with or without overexpression of mir499 or antagomir 499 treatments.

<p>There are significantly increased immunoreactive signals for CnA after AV shunt for 14 days. Overexpression of miR499 significantly decreased the immunoreactive signal induced by AV shunt. Rare CnA signals were seen in the sham group.</p

Kaplan-Meier 6-year CVD event free probability curves for gallstone and non-gallstone disease groups.

<p>Kaplan-Meier 6-year CVD event free probability curves for gallstone and non-gallstone disease groups.</p

Effects of hypoxia on tube formation by HCAECs.

<p>(A) A representative image of a tube formed by HCAECs. (B) Quantitative branching points analysis (n = 4 per group); *p < 0.01 compared to control, ^§p < 0.01 compared to hypoxia.</p

Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

<div><p>Background</p><p>Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia.</p><p>Methods and Results</p><p>Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O₂, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects.</p><p>Conclusion</p><p>Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment.</p></div

Binding of chemerin promoter with the SP1 transcription factor and transcriptional activity of the SP1-binding site of the chemerin promoter are increased in hypoxic HCAECs.

<p>(A) The electrophoretic mobility shift assay (EMSA) showed an increase in binding of chemerin promoter and SP1 in HCAECs during 2.5% O₂ hypoxia. (B and C) The luciferase reporter assay revealed that hypoxia at 2.5% O₂ increased the transcriptional activity of SP1 on the chemerin promoter as compared to the chemerin mutant. Transcriptional activity was suppressed by PD98059 and an anti-TNF-alpha antibody (Ab; n = 3 per group); *p < 0.01 compared to control, ^§p < 0.01 compared to time point 1 h.</p

Phosphorylation of ERK was responsible for the hypoxia-induced chemerin expression in HCAECs, which was blocked by PD98059 or ERK siRNA.

<p>(A and B) HCAECs were subjected to normoxia or hypoxia for different periods in the presence or absence of the inhibitors. Cell lysates were collected for western blot analysis with an antibody for total ERK and phospho-ERK. T-ERK = total ERK, P-ERK = phosphorylated ERK (n = 4 per group); *p < 0.01 compared to control.</p

Hypoxia increases proliferation of HCAECs.

<p>Incorporation of [³H]thymidine into HCAECs increased during 2.5% O₂ hypoxia and after addition of exogenous chemerin or TNF-alpha during normoxia for 2 to 4 h. Hypoxia-induced incorporation of [³H]thymidine into HCAECs was suppressed by chemerin siRNA, PD98059, or by the anti-TNF-alpha antibody (Ab; n = 4 per group); *p < 0.01 compared to control, ^§p < 0.01 compared to hypoxia. Cpm: counts per minute.</p

The ERK pathway mediates the hypoxia-induced increase in chemerin expression in HCAECs.

<p>(A and B) The hypoxia-induced increase in chemerin expression was blocked by an ERK inhibitor (PD98059), ERK siRNA, or an anti-TNF antibody. Addition of exogenous TNF—alpha during normoxia increased chemerin expression (n = 4 per group); *p < 0.01 compared to control.</p

Quarterly Composite Performance Measures of 24 Hospitals Participating in BTS-Stroke.

<p>Quarterly Composite Performance Measures of 24 Hospitals Participating in BTS-Stroke.</p