Metformin Inhibits Abdominal Aortic Aneurysm Formation through the Activation of the AMPK/mTOR Signaling Pathway.

BACKGROUND AND OBJECTIVE: Epidemiological evidence suggests that the antidiabetic drug metformin (MET) can also inhibit abdominal aortic aneurysm (AAA) formation. However, the underlying protective mechanism remains unknown. It has been reported that phosphorylated AMP-activated protein kinase (AMPK) levels are significantly lower in AAA tissues than control aortic tissues. AMPK activation can inhibit the downstream signaling molecule called mechanistic target of rapamycin (mTOR), which has also been reported be upregulated in thoracic aneurysms. Thus, blocking mTOR signaling could attenuate AAA progression. MET is a known agonist of AMPK. Therefore, in this study, we investigated if MET could inhibit formation of AAA by activating the AMPK/mTOR signaling pathway. MATERIALS AND METHODS: The AAA animal model was induced by intraluminal porcine pancreatic elastase (PPE) perfusion in male Sprague Dawley rats. The rats were treated with MET or compound C (C.C), which is an AMPK inhibitor. AAA formation was monitored by serial ultrasound. Aortas were collected 4 weeks after surgery and subjected to immunohistochemistry, Western blot, and transmission electron microscopy analyses. RESULTS: MET treatment dramatically inhibited the formation of AAA 4 weeks after PPE perfusion. MET reduced the aortic diameter, downregulated both macrophage infiltration and matrix metalloproteinase expression, decreased neovascularization, and preserved the contractile phenotype of the aortic vascular smooth muscle cells. Furthermore, we detected an increase in autophagy after MET treatment. All of these effects were reversed by the AMPK inhibitor C.C. CONCLUSION: This study demonstrated that MET activates AMPK and suppresses AAA formation. Our study provides a novel mechanism for MET and suggests that MET could be potentially used as a therapeutic candidate for preventing AAA.

Excessive Methionine Supplementation Exacerbates the Development of Abdominal Aortic Aneurysm in Rats.

OBJECTIVE: The relationship between methionine (Met) and abdominal aortic aneurysm (AAA) has been previously demonstrated, but the mechanisms controlling this association remain unclear. This study investigated the potential contribution of hypermethioninemia (HMet) to the development of AAA. METHODS: A model of AAA was induced by intraluminal porcine pancreatic elastase (PPE) infusion in 60 male Sprague-Dawley rats divided into 4 groups (n = 15 per group). Met was supplied by intragastric administration (1 g/kg body weight/day) from 1 week before surgery until 4 weeks after surgery. The aortic diameter was measured by ultrasound. Aortas were collected 4 weeks after surgery and subjected to biochemical analysis, histological assays, and transmission electron microscopy. RESULTS: After 5 weeks of Met supplementation, HMet increased the dilation ratio of the HMet + PPE group, and hyperhomocysteinemia was also induced in HMet and HMet + PPE rats. Increased matrix metalloproteinase-2 (MMP-2), osteopontin, and interleukin-6 expression was detected in HMet + PPE rats. Furthermore, increased autophagy was detected in the HMet + PPE group. CONCLUSION: This study demonstrates that HMet may exacerbate the formation of AAA due to the increased dilation ratio partially via enhancing MMP-2 and inflammatory responses.

Sex differences in the correlation between white matter hyperintensity and 3-month outcome in acute stroke patients.

Background: The severity of white matter hyperintensities (WMH) has been shown to be an independent predictor of poor stroke outcome, but the effect of sex on this correlation has not been investigated further. Therefore, the purpose of our study was to assess whether there was a sex difference between the severity of WMH and poor stroke outcome. Methods: This retrospective study included 449 patients with acute ischemic stroke (AIS) who received intravenous thrombolysis. WMH severity was graded based on the Fazekas scale. The association between WMH severity and stroke outcome was explored through multivariable regression analyses in men and women. Results: Among women, when dividing WMH severity into tertiles, T3 (Fazekas scale >3) had a 5.334 times higher risk for unfavorable outcomes than T1 (Fazekas scale <2) (p-trend = 0.026) in the adjusted model. In addition, moderate-severe WMH (Fazekas scale 3-6) had a 3.391 (1.151-9.991) times higher risk than none-mild WMH (Fazekas scale 0-2) (p = 0.027). Conclusions: The risk of unfavorable outcomes increased proportionally with the enlargement of the WMH severity in females, suggesting the sex-specific value of the WMH severity in optimizing the risk stratification of stroke.

Cardiac troponin and adverse outcomes in atrial fibrillation: A meta-analysis.

BACKGROUND: The prognostic value of cardiac troponin elevation in atrial fibrillation (AF) is unclear. OBJECTIVE: To investigate the association of cardiac troponin elevation with adverse outcomes in AF by conducting a meta-analysis. METHODS: We systematically searched the PubMed and Embase databases until April 2017 for studies assessing the association of cardiac troponin-T (cTnT) or troponin-I (cTnI) elevation with adverse outcomes in AF. The outcome measures were all-cause mortality and major adverse cardiac events (MACEs: death, stroke, myocardial infarction, pulmonary embolism, major bleeding, or revascularization). RESULTS: Six studies involving 22,697 AF patients were identified. Meta-analysis showed that AF with elevated cardiac troponin was independently associated with increased risk of all-cause mortality (HR 2.04; 95% CI 1.56-2.67) and MACEs (HR 1.93; 95% CI 1.61-2.30). Furthermore, the prognostic value of cardiac troponin elevation was consistently found irrespective of method determination, type of troponin measured, sample size, and study quality subgroup. CONCLUSIONS: AF with cardiac troponin elevation was independently associated with increased risk of all-cause mortality and MACEs. Therefore, determination of troponin should be considered for risk stratification in AF.

Early growth response factor-1 DNA enzyme 1 inhibits the formation of abdominal aortic aneurysm in rats.

The aim of the present study was to characterize the effects of early growth response factor-1 DNA enzyme (EDRz) in a rat abdominal aortic aneurysm (AAA) model to determine the mechanism by which EDRz inhibits AAA and affects the formation of AAA by regulating the activity of matrix metalloproteinase (MMP)-2 and MMP-9. EDRz was transfected into the abdominal aorta of rats using the jetPRIME transfection reagent following infusion with elastase. Fluorescent microscopy, hematoxylin and eosin staining, ultrastructural analysis, reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical analysis were performed to characterize the response to EDRz. The EDRz group showed minimal aneurysm formation when compared with the control group, with significantly lower aortic diameter expansion (2.5±0.1 vs. 3.5±0.1 mm; P<0.05). Early growth response factor 1 (Egr-1) mRNA and protein levels were significantly decreased in the EDRz group, as expected. The decrease in Egr-1 was accompanied by decreases in the mRNA and protein levels of MMP-2 and MMP-9 (P<0.05). Transfection of the Egr-1 specific synthetic DNA enzyme EDRz significantly reduced AAA following elastase infusion in rats, at least in part due to the decreased expression of downstream MMP-2 and MMP-9.

Uric acid in aortic dissection: A meta-analysis.

BACKGROUND: Studies on the serum uric acid levels in patients with aortic dissection have yielded conflicting results. OBJECTIVE: To compare the difference in serum uric acid (SUA) levels between aortic dissection patients and controls by meta-analysis. METHODS: Electronic literature search was conducted in PubMed, Embase, CKNI, CBM, Wanfang, and VIP databases until January 31, 2018. All observational studies that investigated SUA levels in aortic dissection patients and controls were included. Weighted mean difference (WMD) with 95% confidence intervals (CI) was used to summarize the difference in SUA levels between aortic dissection and control group. RESULTS: A total of seven case-control studies involving 1197 patients and 1193 controls were included. Pooled analysis showed that SUA levels were significantly higher in aortic dissection patients compared with those in the controls (WMD 58.22 µmol/L; 95% CI 26.71-89.73) in a random effect model. No significant difference (WMD 9.94 µmol/L; 95% CI -17.89-37.76) was observed in SUA levels between Stanford type A and Stanford type B aortic dissection. CONCLUSIONS: This meta-analysis provides evidence that SUA levels are significantly higher among patients with aortic dissection than those in controls. Elevated SUA levels may contribute to the pathogenesis of aortic dissection. Further large clinical studies to investigate whether SUA levels are an independently risk factor for aortic dissection are warranted.

Usual walking speed and all-cause mortality risk in older people: A systematic review and meta-analysis.

The purpose of this study was to investigate the relationship between slow usual walking speed and all-cause mortality risk in older people by conducting a meta-analysis. We searched through the Pubmed, Embase and Cochrane Library database up to March 2015. Only prospective observational studies that investigating the usual walking speed and all-cause mortality risk in older adulthood approaching age 65 years or more were included. Walking speed should be specifically assessed as a single-item tool over a short distance. Pooled adjusted risk ratio (RR) and 95% confidence interval (CI) were computed for the lowest versus the highest usual walking speed category. A total of 9 studies involving 12,901 participants were included. Meta-analysis with random effect model showed that the pooled adjusted RR of all-cause mortality was 1.89 (95% CI 1.46-2.46) comparing the lowest to the highest usual walk speed. Subgroup analyses indicated that risk of all-cause mortality for slow usual walking speed appeared to be not significant among women (RR 1.45; 95% CI 0.95-2.20). Slow usual walking speed is an independent predictor of all-cause mortality in men but not in women among older adulthood approaching age 65 years or more.