Yidong Wei

Methylation of p15INK4b and Expression of ANRIL on Chromosome 9p21 Are Associated with Coronary Artery Disease

Background Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. Methodology/Principal Findings The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14ARF, p15INK4b and p16INK4a) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15INK4b significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15INK4b, pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15INK4b hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1–5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15INK4b and p16INK4a methylation as ANRIL exon 1–5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype. Conclusions/Significance p15INK4b methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15INK4b methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development.

Diagnostic Value of Ankle-Brachial Index in Peripheral Arterial Disease: A Meta-analysis

BACKGROUND In a previous review, we reported that ankle brachial index (ABI) ≤ 0.90 could reliably identify patients with peripheral artery disease (PAD). Since then, more studies have been published which may extend the power of a meta-analysis of studies of diagnostic accuracy of the ABI. MEDLINE and several other databases were searched for studies on sensitivity and specificity of using ABI ≤ 0.90 for PAD diagnosis compared with angiography. METHODS Quality of each study was assessed by standards for reporting diagnostic accuracy initiative and quality assessment for studies of diagnostic accuracy tool. Heterogeneity was assessed using the Cochran Q statistic, χ(2), and inconsistency index. The area under the curve and Q* were estimated using summary receiver operator curve. The pooled diagnostic odds ratio (DOR), sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) of ABI ≤ 0.90 to diagnose PAD were estimated using Meta-DiSc software (Meta-DiSc, Madrid, Spain). RESULTS Four studies comprising 569 patients (922 limbs) met inclusion criteria. Significant heterogeneity among these studies was not detected in DOR but was evident in pooled sensitivity, specificity, PLR, and NLR. The area under the curve under the summary receiver operator curve is 0.87 (standard error = 0.02) and diagnostic accuracy (Q*) is 0.80 (standard error = 0.02). Additionally, DOR was 15.33 with corresponding 95% confidence intervals of 9.39-25.02. The pooled sensitivity and specificity of ABI ≤ 0.90 for PAD diagnosis were 75% and 86% and the pooled PLR and NLR were 4.18 and 0.29, respectively. CONCLUSIONS We conclude that test of ABI ≤ 0.90 can be a useful tool to identify PAD with serious stenosis in clinical practice.

Prevalence of dyslipidaemia in patients treated with lipid-lowering agents in China: Results of the DYSlipidemia International Study (DYSIS)

BACKGROUND Despite clear guideline recommendations, there is a paucity of data regarding the prevalence and type of persistent lipid profile abnormalities in patients on stable lipid-lowering therapy in China. METHODS This cross-sectional trial included 25,697 patients treated with lipid-lowering agents from 122 centres between April 2012 and October 2012; all underwent clinical examination and had their latest fasting lipid profiles while on lipid-lowering therapy recorded. Logistic regression was performed to assess predictors for lipid abnormalities classified according to current Chinese guidelines. FINDINGS Overall, 29.1% of patients had no lipid abnormalities, and 38.5% of patients did not achieve the therapeutic goal for low-density lipoprotein cholesterol (LDL-C), either as a single lipid anomaly or associated with low high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, or both. Subjects with low risk were more likely than those with very high and high risk to be at target LDL-C levels. Furthermore, 10.4% of very high-risk patients and 11.1% of high-risk patients who attained the LDL-C goal failed to attain non-HDL-C goals. Diabetes was shown to be a strong predictor of failure in attaining non-HDL-C and both goals (OR 3.03; 3.22, 95% CI 2.58-3.55; 2.73-3.79, respectively). CONCLUSION Although great improvements have been made over the past decade, the large majority of very high-risk and high-risk patients treated with lipid-lowing agents still had one or more manifestations of dyslipidaemia. Further clinical evidence is needed to clarify whether adding other lipid-lowering agents to a statin will be associated with additional cardiovascular risk reduction.

Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R–like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2&agr;, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice. Under unstressed conditions, cardiac PERK knockout had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK knockout mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis, and exacerbated lung remodeling in comparison with wild-type mice. PERK knockout also dramatically attenuated cardiac sarcoplasmic reticulum Ca2+-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload–induced congestive heart failure.Studies have reported that development of congestive heart failure (CHF) is associated with increased endoplasmic reticulum (ER) stress. Double stranded RNA activated protein kinase-like endoplasmic reticulum kinase (PERK) is a major transducer of the ER stress response and directly phosphorylates eIF2α, resulting in translational attenuation. However, the physiological effect of PERK on CHF development is unknown. In order to study the effect of PERK on ventricular structure and function, we generated inducible cardiac specific PERK knockout (KO) mice. Under unstressed conditions, cardiac PERK KO had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK KO mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis and exacerbated lung remodeling in comparison to wild type mice. PERK KO also dramatically attenuated cardiac sarcoplasmic reticulum Ca++-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced CHF.

The Developing Cardiac Myocyte Maturation of Excitability and Excitation-Contraction Coupling

Abstract:  The study of cardiac myocyte (CM) differentiation, development, and maturation is of interest for several compelling reasons. First, mechanisms of development are of fundamental biological interest. Second, congenital malformation of the heart may be related to CM dysfunction during embryonic/fetal development. Third, adult myocardium in a variety of diseased states re‐expresses a fetal‐like gene program. Fourth, the mature heart cannot readily regenerate itself. Thus, cell replacement therapy is an emerging treatment paradigm. Among the obstacles for the realization of cell replacement therapy is our incomplete understanding of the function during CM maturation. This is crucial in the potential use of embryonic stem (ES) cell‐derived CMs as a cell source. Although much progress has been realized with mouse ES‐CMs, our understanding of human counterparts is scant. Here we discuss key molecular underpinnings of excitability and excitation–contraction coupling in developing mouse heart. We focus on the Ca channel multimeric complex and Ca handling. We compare mouse embryonic physiology to that previously described in mouse ES‐CMs and draw parallels and highlight distinctions to human ES‐CMs. During mouse embryonic and fetal maturation, the L‐type Ca channel current (ICa,L) predominates, but embryonic/fetal ICa,L has distinct properties from mature ICa,L. In addition T‐type Ca current (ICa,T) present in the fetus is not present in the adult. It is neither ethical nor practical to experiment with live human embryonic/fetal CMs for ICa and Ca handling studies, but we can draw inferences from human heart cell function based on studies of human ES‐CMs, using the parallels noted between mouse embryonic heart cells and mouse ES‐CMs.

Different β-Blockers and Initiation Time in Patients Undergoing Noncardiac Surgery: A Meta-analysis

Abstract:The effects of differences among &bgr;-blockers and initiation times in patients undergoing noncardiac surgery (NCS) remain unknown. On June 1, 2012, the authors searched PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to identify all trials of perioperative &bgr;-blockers in patients undergoing NCS published between January 1960 and June 2012. The authors included only randomized, double-blind and placebo-controlled trials of perioperatively administered &bgr;-blockers (ie, during the pre-, intra- and/or postoperative period) in patients with at least 1 risk factor for coronary artery disease undergoing NCS. The endpoints of these trials had to include all-cause mortality, myocardial infarction (MI) and/or stroke. The authors identified 8 English-language publications, involving 11,180 patients, which fulfilled our inclusion criteria. Perioperative &bgr;-blocker therapy was associated with a significant decrease in patient risk of developing MI (relative risk [RR] = 0.73; 95% confidence interval [CI], 0.61–0.86) but a significant increase in risk of developing stroke (RR = 2.17; 95% CI, 1.35–3.50) versus placebo, resulting in a nonsignificant decrease in overall mortality (RR = 0.91; 95% CI, 0.60–1.36). Indirect comparisons demonstrated that perioperative atenolol therapy was associated with lower mortality and incidence of MI. &bgr;-blocker therapy initiated >1 week before surgery was associated with improved postoperative mortality. Perioperative &bgr;-blocker treatment of patients undergoing NCS increases the incidence of stroke but decreases the incidence of MI, leading to a nonsignificant decrease in mortality. The authors also observed that atenolol treatment or &bgr;-blocker therapy initiated >1 week before NCS was associated with improved outcomes.

Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways

Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation.

Trimetazidine Prevention of Contrast-Induced Nephropathy in Coronary Angiography

Background:Contrast-induced nephropathy (CIN) after coronary angiography is frequently observed in patients with chronic renal insufficiency and no effective measures have been developed for prevention of CIN. There is evidence showing that trimetazidine (TMZ) has renoprotective effect on CIN. This study was to evaluate the role of TMZ in the prevention of CIN in renal dysfunction patients undergoing coronary angiography. Methods:A total of 132 patients with renal dysfunction who underwent coronary angiography were enrolled in our study and divided into control group (n = 70) and TMZ group (n = 62). Standard hydration was administered in all the patients. In TMZ group, patients were administered TMZ orally for 48 hours before and 24 hours after coronary angiography. Serum creatinine (SCr) and cystatin (CysC) were detected before and after contrast media injection, and the incidence of CIN was evaluated according to the elevation of SCr. Adverse events were observed in 12 months. Results:In both groups, CysC and SCr increased significantly after coronary angiography and peaked at 24 and 48 hours, respectively. CysC and SCr were significantly lower in TMZ group than in control group after coronary angiography. The incidence of CIN and adverse events was reduced in TMZ group when compared with control group (P = 0.034 and P = 0.043, respectively). Conclusions:TMZ in combination with standard hydration is more effective than isotonic saline alone in protecting renal function in patients with renal dysfunction who undergo coronary angiography and can reduce the adverse events within 12 months.

A comparison of 2 devices for radial artery hemostasis after transradial coronary intervention.

Background and Objective:Transradial access is an attractive approach for angiography or percutaneous coronary intervention. Different devices have been used to apply pressure locally at the site of arterial entry for achieving hemostasis. The aim of this study was to evaluate the effect of 2 different hemostatic devices on radial artery outcomes after transradial coronary intervention. Subjects and Methods:This study included 600 patients who had undergone transradial coronary intervention who were randomized into 2 groups after the procedure: 300 were treated with a radial compression device (TR Band, Terumo Medical, Tokyo, Japan) (CD group) and the other 300 patients were treated using a chitosan-based pad (Anscare, Daxon, Taoyuan, Taiwan) (CS group). Compression time, major and minor access site bleeding complications, and incidence of radial artery occlusion were recorded. Results:There were no statistical differences in the baseline clinical characteristics of the patients between the 2 groups. Compression time in the CS group was significantly shorter than that in the CD group (P < .001). Although no major access site bleeding complications were observed in either group, 6 patients in each group experienced minor access site bleeding complications. At the same time, 61 patients in the CD group and 21 patients in the CS group experienced errhysis (20% vs 7%, respectively; P < .001). Early radial artery occlusion (24 hours) occurred in 11.7% of the patients in the CD group and 5.4% of the patients in the CS group (P < .05). Chronic radial artery occlusion (30 days) occurred in 10% of the patients in the CD group and 5% of the patients in the CS group (P < .05). Conclusion:The application of the chitosan-based pad showed better hemostatic efficacy and a lower incidence of radial artery occlusion after transradial coronary intervention compared with the compression device.

Increased serum N-terminal pro-B-type natriuretic peptide and left ventricle diastolic dysfunction in patients with hepatitis C virus infection

Summary.  Prior studies demonstrated that patients with hepatitis C virus (HCV) infection had higher plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels, which may indicate the presence of a subclinical cardiac dysfunction. However, there are few data regarding the echocardiographic assessment in HCV‐infected patients. The objectives of this study were to investigate changes in the left ventricle (LV) with echocardiography and to identify echocardiographic correlates of serum NT‐proBNP levels in HCV‐infected patients. Ninety HCV‐infected patients and 90 age and gender‐matched healthy controls were included. The level of serum NT‐proBNP was higher in the patient group (P < 0.001). The proportion of patients whose serum NT‐proBNP levels were higher than 125 pg/mL was greater than that of controls (15.56%vs 3.33%, P = 0.011). Echocardiography did not show any significant difference of cardiac structural abnormalities between groups. In the patient group, E, E′ and E/A were lower, and E/E′ was higher. The proportion of patients (13, 14.44%) with impaired diastolic filling (E/A ≤ 0.75; 0.75 < E/A < 1.5 and E/E′ ≥ 10) was greater than that of the control group (3, 3.33%; P = 0.018). Simple regression analysis demonstrated a statistically significant linear correlation between NT‐proBNP levels and left ventricular diastolic diameter (LVDd) (r = 0.178, P = 0.013), left ventricular posterior wall diastolic thickness (LVPWd) (r = 0.147, P = 0.023) and mitral E/E’ (r = 0.414, P = 0.027). Independent correlates of NT‐proBNP levels (R2 = 0.34) were older age (β′ = 0.034, P = 0.011) and E/E’ ratio (β′ = 0.026, P = 0.018). In conclusion, the combined analysis of NT‐proBNP and echocardiography showed a possible subclinical left ventricular diastolic dysfunction as evidence of a pathogenic link between HCV and CVD.