Impact of low high-density lipoprotein-cholesterol level on 2-year clinical outcomes after acute myocardial infarction in patients with diabetes mellitus.

BACKGROUND: It is still unclear whether low high-density lipoprotein cholesterol (HDL-C) affects cardiovascular outcomes after acute myocardial infarction (AMI), especially in patients with diabetes mellitus. METHODS: A total of 984 AMI patients with diabetes mellitus from the DIabetic Acute Myocardial InfarctiON Disease (DIAMOND) Korean multicenter registry were divided into two groups based on HDL-C level on admission: normal HDL-C group (HDL-C ≥ 40 mg/dL, n = 519) and low HDL-C group (HDL-C < 40 mg/dL, n = 465). The primary endpoint was 2-year major adverse cardiovascular events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), and target vessel revascularization (TVR). RESULTS: The median follow-up duration was 730 days. The 2-year MACE rates were significantly higher in the low HDL-C group than in the normal HDL-C group (MACE, 7.44% vs. 3.49%, p = 0.006; cardiac death, 3.72% vs. 0.97%, p = 0.004; non-fatal MI, 1.75% vs. 1.55%, p = 0.806; TVR, 3.50% vs. 0.97%, p = 0.007). Kaplan-Meier analysis revealed that the low HDL-C group had a significantly higher incidence of MACE compared to the normal HDL-C group (log-rank p = 0.013). After adjusting for conventional risk factors, Cox proportional hazards analysis suggested that low HDL-C was an independent risk predictor for MACE (hazard ratio [HR] 3.075, 95% confidence interval [CI] 1.034-9.144, p = 0.043). CONCLUSIONS: In patients with diabetes mellitus, low HDL-C remained an independent risk predictor for MACE after adjusting for multiple risk factors during 2-year follow-up of AMI. TRIAL REGISTRATION: This study was the sub-analysis of the prospective multi-center registry of DIAMOND (Diabetic acute myocardial infarction Disease) in Korea. This is the observational study supported by Bayer HealthCare, Korea. Study number is 15614. First patient first visit was 02 April 2010 and last patient last visit was 09 December 2013.

Comparison of 2-year mortality according to obesity in stabilized patients with type 2 diabetes mellitus after acute myocardial infarction: results from the DIAMOND prospective cohort registry.

BACKGROUND: After acute myocardial infarction (AMI), the replicated phenomenon of obesity paradox, i.e., obesity appearing to be associated with increased survival, has not been evaluated in stabilized (i.e., without clinical events within 1 month post AMI) Asian patients with diabetes mellitus (DM). METHODS: Among 1192 patients in the DIabetic Acute Myocardial InfarctiON Disease (DIAMOND) Korean multicenter registry between April 2010 and June 2012, 2-year cardiac and all-cause death were compared according to obesity (body mass index ≥25 kg/m(2)) in 1125 stabilized DM patients. RESULTS: Compared with non-obese DM patients (62% of AMI patients), obese DM patients had: higher incidence of dyslipidemia (31 vs. 24%, P < 0.01); lower incidence of chronic kidney disease (26 vs. 33%) (P < 0.01); higher left ventricular ejection fraction after AMI (53 ± 11 vs. 50 ± 12%, P < 0.001); and lower 2-year cardiac and all-cause death occurrence (0.7 vs. 3.6% and 1.9 vs. 5.2%, both P < 0.01) and cumulative incidence in Kaplan-Meier analysis (P < 0.005, respectively). Likewise, both univariate and multivariate Cox hazard regression analyses adjusted for the respective confounders showed that obesity was associated with decreased risk of both cardiac [HR, 0.18 (95% CI 0.06-0.60), P = 0.005; and 0.24 (0.07-0.78), P = 0.018, respectively] and all-cause death [0.34 (0.16-0.73), P = 0.005; and 0.44 (0.20-0.95), P = 0.038]. CONCLUSIONS: In a Korean population of stabilized DM patients after AMI, non-obese patients appear to have higher cardiac and all-cause mortality compared with obese patients after adjusting for confounding factors.

Chemokine stromal cell-derived factor-1 induction by C/EBPbeta activation is associated with all-trans-retinoic acid-induced leukemic cell differentiation.

Stromal cell-derived factor-1 (SDF-1/CXCL12) is one of the essential chemokines, which mediates hematopoietic differentiations. However, the mechanism by which SDF-1 expression is regulated in granulocyte differentiation is poorly understood. Here, we suggest a novel mechanism by which all-trans-retinoic acid (ATRA) induces the expression of SDF-1 during the differentiation of promyelomonocytic leukemic U937 cells. Moreover, we also demonstrate that activation of transcription factor C/EBPbeta by ATRA regulates SDF-1 expression in U937 cells. In addition, we show that the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and Pyk2 are up-regulated by SDF-1 and increased markedly by the costimulation of ATRA and SDF-1. Furthermore, ATRA and SDF-1alpha additively induce U937 cell differentiation. Indeed, silencing the expression of SDF-1 inhibits ATRA-induced granulocyte differentiation significantly. Taken together, these results indicate that SDF-1alpha is involved in granulocyte differentiation in response to ATRA, mediated by the activation of the transcription factor C/EBPbeta.

Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPalpha.

SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761-49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158-23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; -99 to -76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPalpha activation.

Mirtazapine for patients with alcohol dependence and comorbid depressive disorders: a multicentre, open label study.

Major depressive disorder and alcohol dependence are common and serious mental illnesses. There is a great interest in discovering useful treatments for both mood symptoms and alcohol abuse in those patients with depressive disorders and comorbid alcohol dependence. The primary purpose of this study was to evaluate the effectiveness and tolerability of mirtazapine for the treatment of patients with alcohol dependence comorbid with a depressive disorder in an open label, naturalistic multicentre treatment setting. The 17-item Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS) and the Clinical Global Impression-Severity (CGI-S) scale were measured at baseline and at weeks 4 and 8 for the assessment of treatment effectiveness. Alcohol craving was measured using the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analog Scale for Craving (VAS). This study showed a statistically significant reduction of the scores on the HDRS (13.9+/-7.3, p<0.0001), HARS (10.8+/-7.2, p<0.0001) and the CGI-S (1.7+/-1.0, p<0.0001) from baseline to the endpoint (week 8). The OCDS and VAS scores were also decreased significantly by 42.3% and 53.2% (9.0+/-10.0, p<0.0001; 2.5+/-2.4, p<0.0001, respectively). The number of patients with a 50% reduction or more in the HDRS and HARS scores was 103 (72.0%) and 106 (74.1%) at the endpoint, respectively. Adverse events related to mirtazapine were observed in 10% or more of the patients in this study. In conclusion, the results from this naturalistic study suggest that the use of mirtazapine for the patients with alcohol dependence comorbid with depressive disorder is accompanied by clinical improvement in their mood and alcohol craving.

Comparison of 2-year clinical outcomes between diabetic versus nondiabetic patients with acute myocardial infarction after 1-month stabilization: Analysis of the prospective registry of DIAMOND (DIabetic acute myocardial infarctiON Disease) in Korea: an observational registry study.

This study assessed the 2-year clinical outcomes of patients with diabetes mellitus (DM) after acute myocardial infarction (AMI) in a cohort of the DIAMOND (DIabetic Acute Myocardial infarctiON Disease) registry. Clinical outcomes were compared between 1088 diabetic AMI patients in the DIAMOND registry after stabilization of MI and 1088 nondiabetic AMI patients from the KORMI (Korean AMI) registry after 1 : 1 propensity score matching using traditional cardiovascular risk factors. Stabilized patients were defined as patients who did not have any clinical events within 1 month after AMI. Primary outcomes were the 2-year rate of major adverse cardiac events (MACEs), a composite of all-cause death, recurrent MI (re-MI), and target vessel revascularization (TVR). Matched comparisons revealed that diabetic patients exhibited significantly lower left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate and smaller stent size. Diabetic patients exhibited significantly higher 2-year rates of MACE (8.0% vs 3.7%), all-cause death (3.9% vs 1.4%), re-MI (2.8% vs 1.2%), and TVR (3.5% vs 1.3%) than nondiabetic patients (all P < 0.01), and higher cumulative rates in Kaplan-Meier analyses of MACE, all-cause death, and TVR (all P < 0.05). A multivariate Cox regression analysis revealed that chronic kidney disease, LVEF < 35%, and long stent were independent predictors of MACE, and large stent diameter and the use of drug-eluting stents were protective factors against MACE. The 2-year MACE rate beyond 1 month after AMI was significantly higher in DM patients than non-DM patients, and this rate was associated with higher comorbidities, coronary lesions, and procedural characteristics in DM.

Effects of postconditioning with N,N,N'N'-tetrakis-[2-pyridylmethyl]-ethylenediamine in isolated rat hearts.

BACKGROUND: It was reported that N,N,N'N'-tetrakis-[2-pyridylmethyl]-ethylenediamine (TPEN), a transition metal chelator, confers cardioprotection against myocardial ischemic injury. In this study, we investigated the effect of TPEN targeting reperfusion period in isolated rat hearts. METHODS: Langendorff perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Hearts were randomly assigned to either control (n = 9) or 10 microM of TPEN (n = 8) groups. TPEN was perfused for a period of 5 min before and 30 min after reperfusion. RESULTS: The ratio of infarct area/ischemic area (AN/AR) was significantly reduced in TPEN treated hearts (6.9 +/- 1.7%, P < 0.001) compared to control hearts (29.5 +/- 3.2%). Recovery of left ventricular developed pressure (LVDP), rate-pressure product (RPP), +dP/dt(max), and -dP/dt(min) in the control group after reperfusion were 53.8 +/- 6.2%, 51.0 +/- 6.3%, 51.9 +/- 5.7%, and 51.4 +/- 5.7%, respectively, of the baseline levels. In the TPEN group, LVDP, RPP, +dP/dt(max), and -dP/dt(min) returned to 58.5 +/- 4.6%, 54.8 +/- 6.4%, 61.7 +/- 4.9%, and 53.4 +/- 3.9%, respectively, of the baseline levels. There were no significant differences in the cardiodynamic variables between the two groups (P > 0.05). CONCLUSIONS: Pharmacological postconditioning with TPEN reduces myocardial infarction however, TPEN does not modify post-ischemic systolic dysfunction in isolated rat hearts.

Chemokine stromal cell-derived factor-1 induction by C/EBPß activation is associated with all-trans-retinoic acid-induced leukemic cell differentiation.

Stromal cell-derived factor-1 (SDF-1/CXCL12) is one of the essential chemokines, which mediates hematopoietic differentiations. However, the mechanism by which SDF-1 expression is regulated in granulocyte differentiation is poorly understood. Here, we suggest a novel mechanism by which all-trans-retinoic acid (ATRA) induces the expression of SDF-1 during the differentiation of promyelomonocytic leukemic U937 cells. Moreover, we also demonstrate that activation of transcription factor C/EBPß by ATRA regulates SDF-1 expression in U937 cells. In addition, we show that the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and Pyk2 are up-regulated by SDF-1 and increased markedly by the costimulation of ATRA and SDF-1. Furthermore, ATRA and SDF-1α additively induce U937 cell differentiation. Indeed, silencing the expression of SDF-1 inhibits ATRA-induced granulocyte differentiation significantly. Taken together, these results indicate that SDF-1α is involved in granulocyte differentiation in response to ATRA, mediated by the activation of the transcription factor C/EBPß.