Neuregulin-1 promotes mitochondrial biogenesis, attenuates mitochondrial dysfunction, and prevents hypoxia/reoxygenation injury in neonatal cardiomyocytes.

Neuregulin-1 (NRG-1)/erythroblastic leukaemia viral oncogene homologues (ErbB) pathway activation plays a crucial role in regulating the adaptation of the adult heart to physiological and pathological stress. In the present study, we investigate the effect of recombined human NRG-1 (rhNRG-1) on mitochondrial biogenesis, mitochondrial function, and cell survival in neonatal rat cardiac myocytes (NRCMs) exposed to hypoxia/reoxygenation (H/R). The results of this study showed that, in the H/R-exposed NRCMs, mitochondrial biogenesis was impaired, as manifested by the decrease of the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and mitochondrial membrane proteins, the inner membrane (Tim23), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2). RhNRG-1 pretreatment effectively restored the expression of PGC-1α and these membrane proteins, upregulated the expression of the anti-apoptosis proteins Bcl-2 and Bcl-xL, preserved the mitochondrial membrane potential, and attenuated H/R-induced cell apoptosis. Blocking PGC-1 expression with siRNA abolished the beneficial role of rhNRG-1 on mitochondrial function and cell survival. The results of the present study strongly suggest that NRG-1/ErbB activation enhances the adaption of cardiomyocytes to H/R injury via promoted mitochondrial biogenesis and improved mitochondrial homeostasis. SIGNIFICANCE OF THE STUDY: The results of this research revealed for the first time the relationship between neuregulin-1 (NRG-1)/erythroblastic leukaemia viral oncogene homologues (ErbB) activation and mitochondrial biogenesis in neonatal cardiomyocytes and verified the significance of this promoted mitochondrial biogenesis in attenuating hypoxia/reoxygenation injury. This finding may open a new field to further understand the biological role of NRG-1/ErbB signalling pathway in cardiomyocyte.

Association Between Blood Glucose Variability and the Characteristics of Vulnerable Plaque in Elderly Non-ST Segment Elevation Acute Coronary Syndrome Patients.

Blood glucose variability is considered to be one of the risk factors for coronary heart disease, and there is growing evidence that blood glucose fluctuation is closely related to the characteristics of plaques. The aim of the study was to investigate the influence of blood glucose variability on the vulnerability of culprit plaques in elderly non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients.Coronary angiography and VH-IVUS were applied to evaluate the components of culprit plaque in NSTE-ACS patients. CGMS monitoring was performed for 72 hours and blood glucose variability was assessed by glycemic excursions (MAGE), absolute means of daily differences (MODD), postprandial glycemic excursions (PPGE), and the largest amplitude of glycemic excursions (LAGE). An oxidative stress indicator (urinary 8-iso-PGF2α) was also tested.Eighty two elderly NSTE-ACS patients were enrolled in this study. Higher glucose variability was associated with the increased culprit plaque instability. MODD was positively correlated with urinary 8-iso-PGF2α. PPGE and urinary 8-iso-PGF2α were independent risk factors for percent fibrous and necrotic volume in culprit plaques (PPGE: ß = -0.340, P = 0.024; urinary 8-iso-PGF2α: ß = -0.294, P = 0.013).Blood glucose variability is positively related to oxidative stress. With an increase in blood glucose variability, the instability of criminal plaques in elderly NSTE-ACS patients increased.

Association of Isoprostanes-Related Oxidative Stress with Vulnerability of Culprit Lesions in Diabetic Patients with Acute Coronary Syndrome.

Urinary excretion of 8-iso-prostaglandin F2α (8-iso-PGF2α), a reliable biomarker for enhanced oxidant stress in vivo, has been described in association with diabetes and coronary heart disease. The aim of this study was to evaluate the relationship between urinary 8-iso-PGF2α levels and the characteristics of coronary culprit lesion in diabetic patients with acute coronary syndrome (ACS). A total of 79 diabetic patients with ACS were included. iMAP intravascular ultrasound (iMAP-IVUS) was performed to evaluate the characteristics of culprit plaques. Fasting urinary 8-iso-PGF2α level was measured and corrected by creatinine clearance. iMAP-IVUS data showed culprit plaques in high urinary 8-iso-PGF2α level patients had a greater percentage of necrotic core and less fibrous components. High urinary 8-iso-PGF2α levels were correlated with increased necrotic plaque components (r = 0.325, P = 0.003). Meanwhile, the presence of thin-capped fibroatheroma (50.0% versus 11.5%, P = 0.003), ruptured plaques (30.8% versus 7.7%, P = 0.035), and thrombus (38.5% versus 7.7%, P = 0.008) were significantly more frequent in the upper tertile of urinary 8-iso-PGF2α levels than in the low tertile. Multivariate analysis showed high levels of urinary 8-iso-PGF2α (OR 4.240, P = 0.007) was independently associated with the presence of vulnerable culprit plaque in diabetic ACS patients. Urinary 8-iso-PGF2α also displayed a significant value in predicting vulnerable plaques in diabetic patients with ACS by constructing the receiver-operating characteristic (ROC) curve (Area under the ROC curve: 0.713, P = 0.001). Urinary 8-iso-PGF2α levels are associated with the vulnerability of the coronary culprit lesion in diabetic patients with ACS and may provide additional information for risk assessment in suspected vulnerable patients.

Orthostatic hypotension and the risk of incidental cardiovascular diseases: A meta-analysis of prospective cohort studies.

OBJECTIVE: To quantitatively estimate the prospective associations between orthostatic hypotension (OH) and cardiovascular diseases, including coronary heart disease (CHD) and stroke. METHODS: Relevant prospective cohort studies were identified by searching of Medline and Embase databases. We applied fixed or random effect model to estimate the overall effects depending on the heterogeneity among the included studies. RESULTS: Eight published articles from 7 cohorts, consisting of 64,782 participants, were included. During a mean follow-up of 15.2years, 5719 CHD events and 3657 stroke events occurred. The overall results of the meta-analysis indicated that OH was associated with significant increased risk for incident CHD (adjusted hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.12-1.56) and stroke (HR: 1.19, 95% CI 1.08-1.30), which were independent of conventional risk factors. Stratified analyses by ages suggested that the associations between OH and CHD and stroke were significant for both the middle-aged and the old participants. CONCLUSION: Presence of OH was independently related to significantly increased risk for incidence of CHD and stroke. Further, studies regarding the mechanisms and potential treatments for OH may be important for understanding whether the associations between OH and cardiovascular diseases are causative.

Does B-type natriuretic peptide-guided therapy improve outcomes in patients with chronic heart failure? A systematic review and meta-analysis of randomized controlled trials.

The role of B-type natriuretic peptide (BNP) in the management of patients with chronic heart failure (CHF) was uncertain. The aim of this meta-analysis was to comprehensively evaluate the effect of BNP-guided therapy in CHF. Relevant randomized controlled trials were identified by searching of Pubmed, Embase and the Cochrane Library databases. Fixed or randomized effect models were applied to combine the data according to the heterogeneity of the included studies. Fourteen studies with 3,004 CHF patients were included. Results of our meta-analyses suggested that compared with clinical group, BNP-guided treatment significantly decreased the risk of heart failure-related hospitalization (RR 0.79, 95 % CI 0.63-0.98, p = 0.03), although did not significantly affect the risk of all-cause mortality (RR 0.94, 95 % CI 0.81-1.08, p = 0.39) or all-cause hospitalization (RR 0.97, 95 % CI 0.89-1.07, p = 0.56). Furthermore, between-group BNP changes seemed to be a significant modifier to the effects of BNP-guided therapy on clinical outcomes, and BNP-guided therapy may improve the clinical outcomes of CHF patients if substantial reduction of BNP can be achieved. In addition, BNP-guided therapy was not associated with increased risk for serious adverse events. BNP-guided therapy may improve the clinical outcomes of CHF patients if substantial reduction of BNP can be achieved. BNP-guided therapy seemed to be safe and promising for CHF patients, and future studies with well-designed BNP-guided medication up-titration strategies are needed to confirm these results.

Prognostic value of early in-hospital glycemic excursion in elderly patients with acute myocardial infarction.

BACKGROUND: Acute phase hyperglycemia has been associated with increased mortality in patients with acute myocardial infarction (AMI). However, the predictive value of glycemic excursion for adverse outcome in elderly AMI patients is not clear. The aim of this study is to investigate the prognostic value of early in-hospital glycemic excursion and hemoglobin A1c (HbA1c) for one-year major adverse cardiac event (MACE) in elderly patients with AMI. METHODS: We studied 186 elderly AMI patients, whose clinical data were collected and the Global Registry of Acute Coronary Events (GRACE) risk score were calculated on admission. The fluctuations of blood glucose in patients were measured by a continuous glucose monitoring system (CGMS) for 72 hours. Participants were grouped into tertiles of mean amplitude of glycemic excursions (MAGE) and grouped into HbA1c levels (as ≥6.5% or <6.5%). The MACE of patients, including new-onset myocardial infarction, acute heart failure and cardiac death, was documented during one year follow-up. The relationship of MAGE and HbA1c to the incidence of MACE in elderly AMI patients was analyzed. RESULTS: In all participants, a higher MAGE level was associated with the higher GRACE score (r = 0.335, p < 0.001). The rate of MACE by MAGE tertiles (>3.94 mmol/L, 2.55-3.94 mmol/L or <2.55 mmol/L) was 30.2% vs. 14.8% vs. 8.1%, respectively (p = 0.004); by HbA1c category (≥6.5% vs. <6.5%) was 22.7% vs. 14.4%, respectively (p = 0.148). Elderly AMI patients with a higher MAGE level had a significantly higher cardiac mortality. In multivariable analysis, high MAGE level was significantly associated with incidence of MACE (HR 3.107, 95% CI 1.190-8.117, p = 0.021) even after adjusting for GRACE risk score, but HbA1c was not. CONCLUSIONS: The early in-hospital intraday glycemic excursion may be an important predictor of mortality and MACE even stronger than HbA1c in elderly patients after AMI.

[Impact of anemia on long-term outcome in elderly patients with acute coronary syndrome undergoing percutaneous coronary interventions].

OBJECTIVE: To assess the impact of pre-procedure anemia on the long-term mortality in elderly patients with acute coronary syndrome (ACS) after percutaneous coronary interventions. METHODS: A total of 1014 ACS patients (≥ 60 years of age) with hemoglobin data and without previous treatment with thrombolytic agents and without end-stage renal failure before the interventional procedure were included. Patients were classified as anemia using the definition of World Health Organization: hemoglobin < 130 g/L in men, and < 120 g/L in women. A total of 253 patients were anemia. The clinical features of patients with and without anemia and association of pre-procedure anemia with long-term mortality were analyzed. RESULTS: Incidence of diabetes and serum creatinine level were significantly higher in anemia patients than in non-anemia patients while systolic blood pressure and low-density lipoprotein cholesterol were significantly lower in anemia patients than in non-anemia patients (P < 0.05 or P < 0.01). The patients were followed up for 528 (178 - 675) days. After adjustment for potential co-variants in Cox regression analysis, pre-procedure anemia was associated with a significantly higher long-term mortality (RR: 3.293, 95%CI: 1.431 - 7.578, P < 0.01). CONCLUSION: Pre-procedure anemia is an independent predictor of long-term mortality in elderly patients with acute coronary syndrome after percutaneous coronary interventions.

Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes.

BACKGROUND: Glucose variability is one of components of the dysglycemia in diabetes and may play an important role in development of diabetic vascular complications. The objective of this study was to assess the relationship between glycemic variability determined by a continuous glucose monitoring (CGM) system and the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS: In 344 T2DM patients with chest pain, coronary angiography revealed CAD (coronary stenosis ≥ 50% luminal diameter narrowing) in 252 patients and 92 patients without CAD. Gensini score was used to assess the severity of CAD. All participants' CGM parameters and biochemical characteristics were measured at baseline. RESULTS: Diabetic patients with CAD were older, and more were male and cigarette smokers compared with the controls. Levels of the mean amplitude of glycemic excursions (MAGE) (3.7 ± 1.4 mmol/L vs. 3.2 ± 1.2 mmol/L, p < 0.001), postprandial glucose excursion (PPGE) (3.9 ± 1.6 mmol/L vs. 3.6 ± 1.4 mmol/L, p = 0.036), serum high-sensitive C-reactive protein (hs-CRP) (10.7 ± 12.4 mg/L vs. 5.8 ± 6.7 mg/L, p < 0.001) and creatinine (Cr) (87 ± 23 mmol/L vs. 77 ± 14 mmol/L, p < 0.001) were significantly higher in patients with CAD than in patients without CAD. Gensini score closely correlated with age, MAGE, PPGE, hemoglobin A1c (HbA1c), hs-CRP and total cholesterol (TC). Multivariate analysis indicated that age (p < 0.001), MAGE (p < 0.001), serum levels of HbA1c (p = 0.022) and hs-CRP (p = 0.005) were independent determinants for Gensini score. Logistic regression analysis revealed that MAGE ≥ 3.4 mmol/L was an independent predictor for CAD. The area under the receiver-operating characteristic curve for MAGE (0.618, p = 0.001) was superior to that for HbA1c (0.554, p = 0.129). CONCLUSIONS: The intraday glycemic variability is associated with the presence and severity of CAD in patients with T2DM. Effects of glycemic excursions on vascular complications should not be neglected in diabetes.

Association of chemerin mRNA expression in human epicardial adipose tissue with coronary atherosclerosis.

BACKGROUND: Growing evidence suggests that epicardial adipose tissue (EAT) may play a key role in the pathogenesis and development of coronary artery disease (CAD) by producing several inflammatory adipokines. Chemerin, a novel adipokine, has been reported to be involved in regulating immune responses and glucolipid metabolism. Given these properties, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis. In this study, we sought to determine the relationship of chemerin expression in EAT and the severity of coronary atherosclerosis in Han Chinese patients. METHODS: Serums and adipose tissue biopsies (epicardial and thoracic subcutaneous) were obtained from CAD (n = 37) and NCAD (n = 16) patients undergoing elective cardiac surgery. Gensini score was used to assess the severity of CAD. Serum levels of chemerin, adiponectin and insulin were measured by ELISA. Chemerin protein expression in adipose tissue was detected by immunohistochemistry. The mRNA levels of chemerin, chemR23, adiponectin and TNF-alpha in adipose tissue were detected by RT-PCR. RESULTS: We found that EAT of CAD group showed significantly higher levels of chemerin and TNF-alpha mRNA, and significantly lower level of adiponectin mRNA than that of NCAD patients. In CAD group, significantly higher levels of chemerin mRNA and protein were observed in EAT than in paired subcutaneous adipose tissue (SAT), whereas such significant difference was not found in NCAD group. Chemerin mRNA expression in EAT was positively correlated with Gensini score (r = 0.365, P < 0.05), moreover, this correlation remained statistically significant (r = 0.357, P < 0.05) after adjusting for age, gender, BMI and waist circumference. Chemerin mRNA expression in EAT was also positively correlated with BMI (r = 0.305, P < 0.05), waist circumference (r = 0.384, P < 0.01), fasting blood glucose (r = 0.334, P < 0.05) and negatively correlated with adiponectin mRNA expression in EAT (r = -0.322, P < 0.05). However, there were no significant differences in the serum levels of chemerin or adiponectin between the two groups. Likewise, neither serum chemerin nor serum adiponectin was associated with Gensini score (P > 0.05). CONCLUSIONS: The expressions of chemerin mRNA and protein are significantly higher in EAT from patients with CAD in Han Chinese patients. Furthermore, the severity of coronary atherosclerosis is positive correlated with the level of chemerin mRNA in EAT rather than its circulating level.

Urinary 8-iso-prostaglandin F2α as a risk marker for the vulnerability of culprit plaque in diabetic patients with stable coronary artery disease.

We evaluated the association of urinary excretion of 8-iso-prostaglandin F2α (8-iso-PGF2α) with the vulnerability of culprit lesions in 156 age- and sex-matched diabetic stable coronary artery disease (CAD) patients with or without thin-capped fibroatheroma (TCFA) identified by iMAP intravascular ultrasound. Fasting urinary 8-iso-PGF2α level was measured and corrected by creatinine clearance. Compared to non-TCFA group, patients with TCFA had higher urinary 8-iso-PGF2α levels [114.6 (71.1, 181.5) vs. 83.0 (63.2, 138.2) pmol/mmolCr, P = 0.012]. Urinary 8-iso-PGF2α level was positively correlated with percent necrotic volume of culprit lesion (r = 0.218, P = 0.006). High urinary 8-iso-PGF2α level (OR 2.941, P = 0.009) was independently associated with the presence of TCFA and displayed a significant value in predicting TCFA plaques in study patients. The current study indicated that urinary 8-iso-PGF2α may be an important surrogate marker for the vulnerability of culprit lesion in diabetic patients with CAD.

Regulation of adiponectin and leptin secretion and expression by insulin through a PI3K-PDE3B dependent mechanism in rat primary adipocytes.

Adiponectin is intimately involved in the regulation of insulin sensitivity, carbohydrate and lipid metabolism, and cardiovascular functions. The circulating concentration of adiponectin is decreased in obesity and Type 2 diabetes. The present study attempts to elucidate the mechanisms underlying the regulation of adiponectin secretion and expression in rat primary adipocytes. The beta-agonist, isoprenaline, decreased adiponectin secretion and expression in a dose-dependent manner in primary adipocytes. Importantly, such an inhibitory effect could be blocked by insulin. The opposing effects of isoprenaline and insulin could be explained by differential regulation of intracellular cAMP levels, since cAMP analogues suppressed adiponectin secretion and expression in a fashion similar to isoprenaline, and insulin blocked the inhibitory effects of the cAMP analogue hydrolysable by PDE (phosphodiesterase). A specific PDE3 inhibitor, milrinone, and PI3K (phosphoinositide 3-kinase) inhibitors abolished the effects of insulin on adiponectin secretion and expression. In the same studies, leptin secretion and expression displayed a similar pattern of regulation to adiponectin. We conclude that insulin and beta-agonists act directly at the adipocytes in opposing fashions to regulate the production of adiponectin and leptin, and that a PI3K-PDE3B-cAMP pathway mediates the effects of insulin to restore beta-agonist/cAMP-suppressed secretion and expression of these two adipokines.

Admission glycemic variability correlates with in-hospital outcomes in diabetic patients with non-ST segment elevation acute coronary syndrome undergoing percutaneous coronary intervention.

OBJECTIVE: The aim of this study is to evaluate the effects of admission glycemic variability (AGV) on in-hospital outcomes in diabetic patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). METHODS: We studied 759 diabetic patients with NSTE-ACS undergoing PCI. AGV was accessed based on the mean amplitude of glycemic excursions (MAGEs) in the first 24 hours after admission. Primary outcome was a composite of in-hospital events, all-cause mortality, new-onset myocardial infarction, acute heart failure, and stroke. Secondary outcomes were each of these considered separately. Predictive effects of AGV on the in-hospital outcomes in patients were analyzed. RESULTS: Patients with high MAGE levels had significantly higher incidence of total outcomes (9.9% vs. 4.8%, p=0.009) and all-cause mortality (2.3% vs. 0.4%, p=0.023) than those with low MAGE levels during hospitalization. Multivariable analysis revealed that AGV was significantly associated with incidence of in-hospital outcomes (Odds ratio=2.024, 95% CI 1.105-3.704, p=0.022) but hemoglobin A1c (HbA1c) was not. In the receiver-operating characteristic curve analysis for MAGE and HbA1c in predicting in-hospital outcomes, the area under the curve for MAGE (0.608, p=0.012) was superior to that for HbA1c (0.556, p=0.193). CONCLUSION: High AGV levels may be closely correlated with increased in-hospital poor outcomes in diabetic patients with NSTE-ACS following PCI.

[New compound heterozygous mutation causes partial combined 17 alpha-hydroxylase/17,20-lyase deficiency].

OBJECTIVE: To investigate the CYP17A1 gene mutations in a Chinese 46,XX patient with partial combined 17 alpha-hydroxylase/17,20-lyase deficiency. METHODS: Clinical data were retrospectively analyzed. The genomic DNA of the patient and her parents was isolated from whole blood. Seven pairs of primers were used to amplify eight exons and exon-intron boundaries of the CYP17A1 gene. The amplified PCR products were purified by agarose gel and then directly sequenced. In order to confirm the DNA sequences of different alleles, some fragments were inserted into pMD 18-T vector and then subclone sequenced. Sequencing results were compared to the established human CYP17A1 sequence. RESULTS: The patient was new compound heterozygous of 5994-5995 delAT/7541 C>T. The mutation 5994-5995 del AT, causing amino acid I259H, 274X, was proposed to result early truncated protein which was lack of the activity center site of P450C17, whereas missense mutation 7541 C>T causing A398V did not lie in the active site of the enzyme according to the computer model of human P450C17. The 46, XX case had irregular menstruation and slightly hypertension and hypokalemia. The ACTH stimulating test as well as the result of the sex hormones suggested that there was partial 17 alpha-hydroxylase/17, 20-lyase enzyme activities in the adrenal and sexual gland. We speculate that A398V might conserve partial of the enzyme's activities. The genotype was coincident with phenotype. CONCLUSION: More study should be done to have better understanding of the function of the mutated P450C17 enzymes.

Comparison of in-hospital glycemic variability and admission blood glucose in predicting short-term outcomes in non-diabetes patients with ST elevation myocardial infarction underwent percutaneous coronary intervention.

AIMS: Admission hyperglycemia is associated with increased mortality and major adverse cardiac events (MACE) in patients with or without diabetes mellitus after acute myocardial infarction (AMI). However, effects of glycemic variability (GV) on outcomes of non-diabetes patients with AMI still remains unclear. The aim of this study is to compare the prognostic value of in-hospital GV with admission blood glucose (ABG) for 3-month MACE in non-diabetes patients with ST elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI). METHODS: We analyzed 256 non-diabetes patients with STEMI in study. The GV accessed by mean amplitude of glycemic excursions (MAGE) was calculated from blood glucose profiles of continuous glucose monitoring system (CGMS) during hospitalization. ABG was measured on admission. Main endpoints were 3-month MACE; secondary endpoints were GRACE scores and enzymatic infarct size. Predictive effects of MAGE and ABG on the MACE in patients were analyzed. RESULTS: In all participants, MAGE level was associated with ABG level (r = 0.242, p < 0.001). Both elevated MAGE levels (p = 0.001) and elevated ABG (p = 0.046) were associated with incidences of short-term MACE. Patients with a higher MAGE level had a significantly higher cardiac mortality (5.8 vs. 0.6%, p = 0.017) and incidence of acute heart failure (12.8 vs. 2.4%, p = 0.001) during 3 months follow-up. In multivariable analysis, high MAGE level (HR 2.165, p = 0.023) was significantly associated with incidence of short-term MACE, but ABG (HR 1.632, p = 0.184) was not. The area under the receiver-operating characteristic curve for MAGE (0.690, p < 0.001) was superior to that for ABG (0.581, p = 0.076). CONCLUSIONS: To compare with ABG, in-hospital GV may be a more important predictor of short-term MACE and mortality in non-diabetes patients with STEMI treated with PCI.

Study on the genetic mutations of 17 alpha-hydroxylase/17,20-lyase deficiency in Chinese patients.

OBJECTIVE: To investigate the CYP17A1 gene mutations in Chinese patients with 17 alpha-hydroxylase/17, 20-lyase deficiency. METHODS: Clinical data were retrospectively analyzed. The CYP17A1 gene mutations were detected in 5 cases with 17 alpha-hydroxylase/17, 20-lyase deficiency and their relatives. The genomic DNA of the patients was isolated from whole blood. Seven pairs of primers were used to amplify eight exons and exon-intron boundaries of the CYP17A1 gene. The amplified PCR products were purified by agarose gel and then directly sequenced. In order to confirm the DNA sequences of different alleles, some fragments were inserted into pMD 18-T vector and then sequenced. Sequencing results were compared to the established human CYP17A1 sequence. RESULTS: Briefly, we found 2 kinds of compound mutations, of which were: (1) 6436-6438(TAC-->AA), causing amino acid Y329K, 418X; (2) 6531-6532(GC-->A), causing amino acid L361F, 418X. Among the five cases, four were homozygous for 6436-6438(TAC-->AA), whereas one was compound heterozygous for 6436-6438(TAC-->AA)/6531-6532(GC-->A). The clinical characteristics of 5 cases were all completely combined defects of 17 alpha-hydroxylase/17, 20-lyase, and they all carried two alleles of CYP17A1 gene mutations that all shifted the reading frame and resulted in truncated protein which lack of the activity center site of P450C17, of which corresponding with their clinical feature. CONCLUSION: Nine alleles have the mutation of 6436-6438(TAC-->AA), accounting for 90% of total alleles (9/10). That suggests this kind of mutation may have racial specificity. More study should be done to have better understanding of the function of the truncated P450C17 enzymes.

Allopurinol therapy improves vascular endothelial function in subjects at risk for cardiovascular diseases: a meta-analysis of randomized controlled trials.

AIMS: The effect of allopurinol on flow-mediated dilation (FMD), an index of endothelial function in humans, remains inconsistent. We performed a meta-analysis to determine whether allopurinol therapy could improve FMD. METHODS: Human intervention studies were identified by systematic searches of Medline, Embase, Cochrane's library, and references of related reviews and studies. A random-effect model was applied to estimate the pooled results. RESULTS: Ten randomized controlled trials with 594 subjects at risk of cardiovascular risks were included. Results of the meta-analysis indicated that allopurinol therapy significantly improved FMD in these subjects as compared with control groups (WMD=1.67%, 95% CI: 0.83% ~ 2.50%, P<.001; I2 =86%), with no evidence of significant heterogeneity if only double-blinded studies were included (WMD=1.36%, 95% CI: 0.89% ~ 1.83%, P<.001; I2 =21%). Results of metaregression and subgroup analyses suggested that the benefit of allopurinol to FMD seemed to be not related to its uric acid (UA)-lowering action. Moreover, allopurinol therapy may be associated with more remarkable improvement of FMD in subjects with lower serum UA (<7 mg/dL: WMD=2.62%, 95% CI: 1.10% ~ 4.14%), compared to those with higher UA (≥7 mg/dL: WMD=0.87%, 95% CI: 0.37% ~ 1.38%; P for subgroup difference=.03). CONCLUSIONS: Allopurinol therapy is associated with significantly improved endothelial function in subjects at risk of CVD risks, and the beneficial effects of allopurinol seemed to be more remarkable in patients with normal UA at baseline.

Short-term Prognosis of Fragmented QRS Complex in Patients with Non-ST Elevated Acute Myocardial Infarction.

BACKGROUND: There remains significant debate as to the relationship between fragmented QRS (fQRS) complexes on electrocardiogram (ECG) and acute myocardial infarction (AMI). Few studies have reported on this relationship in non-ST elevated AMI (NSTEMI), and thus, we attempt to assess this relationship and its potential short-term prognostic value. METHODS: This was a single-center, observational, retrospective cohort study. A total of 513 consecutive patients (399 men, 114 women) with NSTEMI within 24 h who underwent coronary angiography at our department, between January 1, 2014, and December 31, 2014. Patients were divided into 2 groups according to the presence or absence of fQRS complex on the admission ECG. fQRS complexes were defined as the existence of an additional R' or crochetage wave, notching in the nadir of the S wave, RS fragmentation, or QS complexes on 2 contiguous leads. All patients were followed up for 6 months, and all major adverse cardiac events (MACE) were recorded. RESULTS: In this study, there were 285 patients with fQRS ECG in the 513 patients with NSTEMI. The number of patients with 0-2 coronary arteries narrowed by ≥50% in fQRS group were less while patients with 3 narrowed arteries were more than in the non-fQRS group (P = 0.042). There were fewer Killip Class I patients in the fQRS group (P = 0.019), while Killip Class II, III, and IV patients were more in the fQRS group than in the non-fQRS group (P = 0.019). Left ventricular ejection fraction levels were significantly lower in the fQRS group (P = 0.021). Baseline total cholesterol, low-density lipoprotein, creatinine, creatine kinase, homocysteine, high-sensitivity C-reactive protein (CRP), and red blood cells distribution width levels were significantly higher in the fQRS group. Total MACE (MACE, P = 0.028), revascularization (P = 0.005), and recurrent angina (P = 0.005) were also significantly greater in the fQRS group. On final logistic regression analysis, after adjusting for baseline variables, the following variables were independent predictors of fQRS: Coronary artery narrowing (P = 0.035), Killip classification (P = 0.026), and total cholesterol (P = 0.002). The following variables were found to be independent predictors of preoperative MACE: Hemoglobin (P = 0.000), gender (P = 0.026), fQRS (P = 0.016), and time from myocardial infarction to balloon or coronary artery bypasses grafting (P = 0.013). CONCLUSIONS: The fQRS complexes are commonly present in NSTEMI and the fQRS complexes are an independent predictor of MACE in NSTEMI patients. The number of narrowed coronary arteries, Killip classification, and total cholesterol are all independent predictors of the fQRS complexes.

[Rosiglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice].

OBJECTIVE: To study the effect of rosiglitazone on atherosclerosis and potential mechanism in ApoE-knockout mice. METHODS: Thirty-two 6-week-old ApoE-knockout mice were used as atherosclerosis model in two groups: rosiglitazone group (n = 18) and control group (n = 14). Each group contained equal numbers of male and female mice. All mice were fed with normal chow diet. In addition to normal diet, rosiglitazone group received rosiglitazone 17 mg/kg of body weight/day. Venous bloods were collected for plasma glucose and lipid analysis, and aorta were prepared for morphologic and immunohistochemical analysis after 14 weeks. Aortic root (1 cm) was cut and prepared for paraffin slice. The histomorphometric analysis of atherosclerotic lesion was performed by means of HE; positive percentage of macrophage cell and tumor necrosis factor-alpha were measured by means of immunohistochemistry in cross section. The ratio of lesion/aortic wall surface in the rest aorta was measured by means of Sudan IV staining in longitudinal section. RESULTS: The amount of fatty streak in rosiglitazone group was significantly greater than that of control group; the gross number of lesions and the number of fibrous plaque and atheromatous plaque were similar in two groups. There were no differences in percentage of lesions in cross section in two groups. Rosiglitazone could significantly reduce the extend of atherosclerosis of longitudinal section, decrease the amount of macrophage cell and the level of tumor necrosis factor-alpha in lesions. The plasma glucose was normal and similar in two groups, and total cholesterol, LDL-cholesterol and triglyceride were significantly higher in rosiglitazone group. CONCLUSION: Rosiglitazone suppresses the expression of tumor necrosis factor-alpha, reduces the number of macrophage cell in lesion, and inhibits the development of atherosclerosis.

Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies.

CONTEXT: Orthostatic hypotension (OH) has been found to be related to increased risk of mortality, although results of previous cohort studies were not always consistent. OBJECTIVE: The aim of this meta-analysis was to investigate the association between OH and mortality risk. DATA SOURCE: Medline, Embase and references cited in related reviews and studies. STUDY SELECTION: Cohort studies evaluating the association between OH and mortality risk were identified. DATA EXTRACTION: Two investigators read all papers and extracted all relevant information. RESULTS: A total of 56 125 subjects with 11 580 mortality cases from nine cohorts were included in the meta-analysis. Pooled results indicated that the presence of OH at baseline was significantly associated with an increased risk of all-cause mortality (adjusted risk ratio (RR) = 1.40, p<0.001). Subgroup analysis suggested that the association between OH and all-cause mortality was less strong for the studies in which classic risk factors were adequately adjusted compared with those in which they were not adequately controlled. In addition, although our meta-analysis failed to reveal a significant association between OH and cardiovascular (CV) mortality (RR=1.20, p=0.47), we did find that subjects with OH had an increased risk of non-CV mortality (RR=1.18, p=0.05). CONCLUSIONS: The presence of OH is associated with a significantly increased risk of all-cause mortality, which may partially be mediated by classic risk factors. Further research is needed to determine whether the association between OH and mortality risk is causal.

Impact of admission glycemic variability, glucose, and glycosylated hemoglobin on major adverse cardiac events after acute myocardial infarction.

OBJECTIVE: Dysglycemia is associated with poorer prognosis in patients with acute myocardial infarction (AMI). Whether admission glycemic variability (GV) has important value in prognosis of AMI patients is still unknown. The aim of the study is to investigate the prognostic value of admission GV, glucose, and glycosylated hemoglobin (HbA(1c)) in AMI patients. RESEARCH DESIGN AND METHODS: We measured blood glucose, HbA(1c), and GV on admission in 222 consecutive patients with diagnosed AMI. GV, indicated as the mean amplitude of glycemic excursions (MAGE), was determined by a continuous glucose monitoring system. MAGE was categorized as ≥3.9 or <3.9 mmol/L, admission glucose as ≥8.61 or <8.61 mmol/L, and HbA(1c) as ≥6.5 or <6.5%. Participants were followed up prospectively for 12 months. The relationship of admission MAGE, glucose, and HbA(1c) to the major adverse cardiac event (MACE) of AMI patients was analyzed. RESULTS: In 222 enrolled patients with AMI, the rate of MACE by MAGE category (<3.9 or ≥3.9 mmol/L) was 8.4 and 24.1%, respectively (P = 0.001), by admission glucose category (<8.61 or ≥8.61 mmol/L) was 10.1 and 21.6%, respectively (P = 0.020), and by HbA(1c) category (<6.5 vs. ≥6.5%) was 10.7 versus 18.7%, respectively (P = 0.091). In multivariate analysis, high MAGE level was significantly associated with incidence of MACE (hazard ratio 2.419 [95% CI 1.273-9.100]; P = 0.017) even after adjusting for Global Registry of Acute Coronary Events risk score, but admission glucose and HbA(1c) was not. CONCLUSIONS: Elevated admission GV appears more important than admission glucose and prior long-term abnormal glycometabolic status in predicting 1-year MACE in patients with AMI.