Gender difference in the impact of coexisting diabetes mellitus on long-term clinical outcome in people with heart failure: a report from the Korean Heart Failure Registry.

AIM: Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure. METHODS: A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission. RESULTS: People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P < 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P > 0.05). CONCLUSIONS: In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.

Gender differences in clinical and angiographic findings of patients with Takayasu arteritis.

OBJECTIVES: Because Takayasu arteritis (TA) predominantly affects females, few data regarding gender differences have been reported. The aim of the present study is to describe clinical features and angiographic findings of patients with TA according to gender. METHODS: According to the 1990 American College of Rheumatology criteria, 294 patients were diagnosed with TA between September 1994 and April 2014 at a single tertiary hospital. We reviewed clinical, laboratory, and radiologic data at the time of diagnosis. RESULTS: Among the 294 patients studied, 257 (87.4%) were female (male:female ratio=1:6.9). Female patients had a higher tendency to exhibit blood pressure differences between arms (p=0.595) and a weak pulse at the brachial artery (p=0.063). In male patients, we observed higher serum creatinine levels (p=0.038) and hypertension more frequently (p=0.061) than in females. Females exhibited more common lesions in the thoracic aorta and its branches, while males had more frequent lesions in the abdominal aorta and its branches. An analysis of angiographic classification according to the International TA Conference in Tokyo 1994 classification revealed that male patients had a higher incidence of type IV and females showed a higher incidence of types I, IIa, and IIb. CONCLUSIONS: Female patients with TA have more frequent involvement of the thoracic aorta and its branches, whereas involvement of the abdominal aorta and its branches is more common in males. Considering these gender-specific differences, adjustment of diagnostic criteria for TA according to gender may be necessary.

Usefulness of high-sensitivity troponin I for the monitoring of subclinical acute cellular rejection after cardiac transplantation.

BACKGROUND: There are conflicting data about the role of cardiac troponin I (cTnI) as determined by means of conventional methods for the prediction of acute rejection after heart transplantation (HT). The purpose of this study was to evaluate whether cTnI as measured by means of the early prototype high-sensitivity assay (hs-cTnI) can predict acute rejection episode after HT compared with grade of rejection in endomyocardial biopsy (EMB). METHODS: This was a single-center cross-sectional study evaluating cTnI levels with the use of both hs-cTnI and current less sensitive conventional cTnI (conv-cTnI) assays measured at the time of EMB after HT. We calculated an index ratio of observed cTnI to expected mean cTnI for each individual patient defined as the mean cTnI measurements at EMB 60 days after HT. RESULTS: A total of 252 biopsies from 47 patients were included in this study. In the multivariable mixed model analysis in relation to the presence of acute rejection 60 days after HT, hs-cTnI level was significantly related to the presence of rejection (P = .010). The hs-cTnI ratio index was significantly higher at the time of rejection (median, 1.37; interquartile range [IQR], 1.23-2.88) compared with those without rejection (median, 0.90; IQR, 0.51-1.16; P < .001). In receiver operating characteristic curve analysis, an hs-cTnI ratio index of ≥1.17 could predict the acute rejection with a sensitivity of 82.4% and a specificity of 77.1%. CONCLUSIONS: An increased hs-cTnI ratio index was significantly related to rejection episodes. Serial monitoring of hs-cTnI and comparing it with the values without rejection might be useful for the detection of acute rejection after HT.

Preoperative NT-proBNP and CRP predict perioperative major cardiovascular events in non-cardiac surgery.

OBJECTIVE: To investigate whether simple and non-invasive measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) and/or C-reactive protein (CRP) can predict perioperative major cardiovascular event (PMCE). DESIGN: Prospective, single-centre, cohort study. SETTING: A 1900-bed tertiary-care university hospital in Seoul, Korea Design and PATIENTS: The predictive power of NT-proBNP, CRP and Revised Cardiac Risk Index (RCRI) for the risk of PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) were evaluated from a prospective cohort of 2054 elective major non-cardiac surgery patients. Optimal cut-off values were derived from receiver operating characteristic curve (ROC) analysis. MAIN OUTCOME MEASUREMENT: PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) within postoperative 30 days. RESULTS: PMCE developed in a total of 290 patients (14.1%). Each increasing quartile of NT-proBNP or CRP level was associated with a greater risk of PMCE after adjustment for traditional clinical risk factors. The relative risk (RR) of highest versus lowest quartile was 5.2 for NT-proBNP (p<0.001) and 3.7 for CRP (p<0.001). Both NT-proBNP (cut-off = 301 ng/l) and CRP (cut-off = 3.4 mg/l) predicted PMCE better than RCRI (cut-off = 2) by ROC analysis (p<0.001). Moreover, the predictive power of RCRI (adjusted RR = 1.5) could be improved significantly by addition of CRP and NT-proBNP to RCRI (adjusted RR 4.6) (p<0.001). CONCLUSIONS: High preoperative NT-proBNP or CRP is a strong and independent predictor of perioperative major cardiovascular event in non-cardiac surgery. The predictive power of current clinical risk evaluation system would be strengthened by these biomarkers.

A novel chimeric promoter that is highly responsive to hypoxia and metals.

To develop a potent hypoxia-inducible promoter, we evaluated the usefulness of chimeric combinations of the (Egr-1)-binding site (EBS) from the Egr-1 gene, the metal-response element (MRE) from the metallothionein gene, and the hypoxia-response element (HRE) from the phosphoglycerate kinase 1 gene. In transient transfection assays, combining three copies of HRE (3 x HRE) with either EBS or MRE significantly increased hypoxia responsiveness. When a three-enhancer combination was tested, the EBS-MRE-3 x HRE (E-M-H) gave a hypoxia induction ratio of 69. The expression induced from E-M-H-pGL3 was 2.4-fold higher than that induced from H-pGL3 and even surpassed the expression from a human cytomegalovirus promoter-driven vector. The high inducibility of E-M-H was confirmed by validation studies in different cells and by expressing other cDNAs. Gel shift assays together with functional overexpression studies suggested that increased levels of hypoxia-inducible factor 1alpha, metal transcription factor-1 and Egr-1 may be associated with the high inducibility of the E-M-H chimeric promoter. E-M-H was also induced by hypoxia mimetics such as Co2+ and deferoxamine (DFX) and by hydrogen peroxide. Gene expression from the E-M-H was reversible as shown by the reduced expression of the transgene upon removal of inducers such as hypoxia and DFX. In vivo evaluation of the E-M-H in ischemic muscle revealed that erythropoietin secretion and luciferase and LacZ expression were significantly higher in the E-M-H group than in a control or H group. With its high induction capacity and versatile means of modulation, this novel chimeric promoter should find wide application in the treatment of ischemic diseases and cancer.

Postnatal development of detergent-insoluble properties of NMDA and AMPA receptor subunits in the rat brain synaptic membrane.

We investigated the developmental changes of detergent-insoluble characteristics of NMDA and AMPA receptor subunits in the synaptic membranes prepared from the rat cerebral cortex. At postnatal day (PND) 1, the majority of NMDAR1 and NMDAR2B subunits of NMDA receptors in the synaptic membranes were insoluble to the treatment of 1% Triton X-100. The detergent-insoluble properties of both subunits were not significantly changed during postnatal development. At PND 1, about 45% of GluR1 and 10% of GluR2/3 subunits of AMPA receptors in the synaptic membrane were insoluble to Triton X-100, whereas 70% of GluR1 and 56% of GluR2/3 subunits were insoluble at PND 22. These findings indicate that the postsynaptic clustering of NMDA and AMPA receptors during development seems to be differentially regulated in vivo.

The Brevibacterium albidum gene encoding the arginine tRNACCG complements the growth defect of an Escherichia coli strain carrying a thermosensitive mutation in the rnpA gene at the nonpermissive temperature.

The Escherichia coli rnpA gene encodes C5 protein, the protein component of RNase P. The rnpA49 mutation renders the C5 protein thermosensitive, which results in thermosensitivity of RNase P function. The chromosomal DNA region from Brevibacterium albidum that complements the rnpA49 mutation was analysed. The gene capable of complementing the growth defect of an rnpA49 mutant strain at nonpermissive temperature was identified as the gene for an arginine tRNA with anticodon CCG by a deletion analysis combined with complementation assays. Transcription of the arginine tRNA gene carried on a multicopy plasmid was correlated with the complementation of the rnpA49 mutation, indicating that the gene product is indeed responsible for complementation of the rnpA49 mutation.

A mutation in the puff region of VP2 attenuates the myocarditic phenotype of an infectious cDNA of the Woodruff variant of coxsackievirus B3.

Coxsackievirus B3 (CVB3) infections induce myocarditis in humans and mice. Little is known about the molecular characteristics of CVB3 that activate the cellular immunity responsible for cardiac inflammation. Previous experiments have identified an antibody escape mutant (H310A1) of a myocarditic variant of CVB3 (H3) that attenuates the myocarditic potential of the virus in mice in spite of ongoing viral replication in the heart. We have cloned full-length infectious cDNA copies of the viral genome of both the wild-type myocarditic H3 variant of CVB3 and the antibody escape mutant H310A1. Progeny viruses maintained the myocarditic and attenuated myocarditic potential of the parent viruses, H3 and H310A1. The full sequence of the H3 viral cDNA is reported and compared with those of previously published CVB3 variants. Comparison of the full sequences of H3 and H310A1 viruses identified a single nonconserved mutation (A to G) in the P1 polyprotein region at nucleotide 1442 resulting in an asparagine-to-aspartate mutation in amino acid 165 of VP2. This mutation is in a region that corresponds to the puff region of VP2. Nucleotide 1442 of the H3 and H310A1 cDNA copies of the viral genome was mutated to change amino acid 165 of VP2 to aspartate and asparagine, respectively. The presence of asparagine at amino acid 165 of VP2 is associated with the myocarditic phenotype, while an aspartate at the same site reduces the myocarditic potential of the virus. In addition, high-level production of tumor necrosis factor alpha by infected BALB/c monocytes is associated with asparagine at amino acid 165 of VP2 as has been previously demonstrated for the H3 virus. These findings identify potentially important differences between the H3 variant of CVB3 and other previously published CVB3 variants. In addition, the data demonstrate that a point mutation in the puff region of VP2 can markedly alter the ability of CVB3 to induce myocarditis in mice and tumor necrosis factor alpha secretion from infected BALB/c monocytes.