Jun-Bean Park

PhoB-dependent transcriptional activation of the iciA gene during starvation for phosphate in Escherichia coli

Abstract The IciA protein from Escherichia coli has been shown specifically to inhibit the in vitro initiation of chromosomal DNA replication. However, the in vivo role of IciA has not yet been established. In order to investigate the in vivo function of this protein, expression of the iciA gene was studied by monitoring the β-galactosidase activity specified by an iciA promoter-lacZ fusion inserted into the chromosome. Among the conditions tested (carbon starvation, the stringent response, phosphate starvation, and the SOS response), only phosphate depletion increased iciA expression. Supplementation of phosphate-depleted cultures with inorganic phosphate reduced the β-galactosidase activity to basal levels. Enhanced expression of iciA-lacZ was dependent upon the PhoB protein. PhoB is known to be a transcriptional activator of the Pho regulon, expression of which is activated during phosphate starvation. It was also found that the iciA promoter contains a PhoB protein-binding sequence, termed the Pho box, which is necessary for the activation of genes of the Pho regulon. These results suggest that the iciA gene is a member of the Pho regulon.

SYSTEMIC INFLAMMATION IS ASSOCIATED WITH CORONARY ARTERY CALCIFICATION AND ALL-CAUSE MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Systemic inflammation in chronic kidney disease (CKD) is associated with advanced coronary artery calcification (CAC). However, the prognostic significance of such association is unknown. We assessed if the associations between CAC, estimated glomerular filtration rate (eGFR) and all-cause mortality

Global Longitudinal Strain to Predict Mortality in Patients With Acute Heart Failure

BACKGROUNDnHeart failure (HF) is currently classified according to left ventricular ejection fraction (LVEF); however, the prognostic value of LVEF is controversial. Myocardial strain is a prognostic factor independently of LVEF.nnnOBJECTIVESnThe authors sought to evaluate the prognostic value of global longitudinal strain (GLS) in patients withxa0HF.nnnMETHODSnGLS was measured in 4,172 consecutive patients with acute HF. Patients were categorized as either HF with reduced (LVEFxa0<40%), midrange (LVEF 40% to 49%), or preserved ejection fraction (LVEFxa0≥50%) and were also classified as having mildly (GLS >12.6%), moderately (8.1%xa0< GLSxa0<12.5%), or severely (GLSxa0≤8.0%) reduced strain. The primary endpoint was 5-year all-cause mortality.nnnRESULTSnMean GLS was 10.8%, and mean LVEF was 40%. Overall, 1,740 (40.4%) patients had died at 5 years. Patients with reduced ejection fraction had slightly higher mortality than those with midrange or preserved ejection fraction (41%, 38%, and 39%, respectively; log-rank pxa0=xa00.031), whereas patients with reduced strain had significantly higher mortality (severely reduced GLS, 49%; moderately reduced GLS, 38%; mildly reduced GLS, 34%; log-rank pxa0< 0.001). In multivariable analysis, each 1% increase in GLS was associated with a 5% decreased risk for mortality (pxa0< 0.001). Patients with moderate (hazard ratio: 1.31; 95% confidence interval: 1.13 to 1.53) and severe GLS reductions (hazard ratio: 1.61; 95% confidence interval: 1.36 to 1.91) had higher mortality, but LVEF was not associated with mortality.nnnCONCLUSIONSnIn patients with acute HF, GLS has greater prognostic value than LVEF. Therefore, the authors suggest that GLS should be considered as the standard measurement in all patients with HF. This new concept needs validation in further studies.

Systemic Inflammation Is Associated With Coronary Artery Calcification and All-Cause Mortality in Chronic Kidney Disease

BACKGROUNDnPresence of systemic inflammation in chronic kidney disease (CKD) is associated with advanced coronary artery calcification (CAC). The prognostic significance of this association, however, is unknown. We evaluated the associations between CAC, estimated glomerular filtration rate (eGFR) and all-cause mortality, to determine whether the associations differ according to the presence of systemic inflammation.nnnMETHODSANDRESULTSnWe followed 30,703 consecutive individuals who underwent CAC measurement for a median of 79 months (IQR, 65-96 months). Patients were categorized according to baseline CAC score (0, 1-99, 100-399 and ≥400), eGFR (<45, 45-59, 60-74, 75-89, 90-104, and ≥105 ml/min/1.73 m(2)) and high-sensitivity C-reactive protein (hsCRP; <2.0, and ≥2.0 mg/L). Prevalence and extent of CAC were greater in those with lower eGFR and higher hsCRP accordingly, even after adjustment. Lower eGFR was strongly associated with higher CAC score (≥400), and the association was more significant in patients with higher hsCRP. The greater CAC burden was associated with worse outcome in the CKD patients (eGFR <60 ml/min/1.73 m(2)) only in those with higher hsCRP.nnnCONCLUSIONSnPatients with low eGFR and more extensive CAC had greater risk of mortality, and associations differed according to the presence of systemic inflammation. Among the CKD patients, coronary evaluation may be considered for those with elevated hsCRP. (Circ J 2016; 80: 1644-1652).

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using 68Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized 68Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with 68Ga. The efficacy of 68Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. 68Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). 68Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. 68Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with 68Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.

Noncontrast Myocardial T1 Mapping by Cardiac Magnetic Resonance Predicts Outcome in Patients With Aortic Stenosis

OBJECTIVESnThe aim of this study was to evaluate whether native T1 value of the myocardium on cardiac magnetic resonance (CMR) could predict clinical events in patients with significant aortic stenosis (AS).nnnBACKGROUNDnAlthough previous studies have demonstrated the prognostic value of focal fibrosis using late gadolinium enhancement (LGE) by CMR in AS patients, the prognostic implication of diffuse myocardial fibrosis by noninvasive imaging remains unknown.nnnMETHODSnA prospective observational longitudinal study was performed in 127 consecutive patients with moderate or severe AS (68.8 ± 9.2 years of age, 49.6% male) and 33 age- and sex-matched controls who underwent 3-T CMR. The degree of diffuse myocardial fibrosis was assessed by noncontrast mapping of T1 relaxation time using modified Look-Locker inversion-recovery sequence, and the presence and extent of LGE were also evaluated. The AS patients were divided into 3 groups by the native T1 value. Primary endpoint was a composite of all-cause death and hospitalization for heart failure.nnnRESULTSnNative T1 value was higher in AS patients, compared with control subjects (1,232 ± 53 ms vs. 1,185 ± 37 ms; pxa0=xa00.008). During follow-up (median 27.9 months), there were 24 clinical events including 9 deaths (6 pre-operative and 3 post-operative), the majority of which occurred in the patients in the highest T1 tertile group (2.4% vs. 11.6% vs.xa042.9% for lowest, mid-, and highest tertile groups; pxa0< 0.001 by log-rank test). The total number of events for both pre- and post-operative events also occurred more frequently in patients in the highest T1 tertile group. EuroSCORE II, the presence and/or extent of LGE, and the native T1 value were predictors of poor prognosis (adjusted hazard ratio forxa0every 20-ms increase of native T1: 1.28; pxa0= 0.003). In particular, the highest native T1 value provided further risk stratification regardless of the presence of LGE.nnnCONCLUSIONSnHigh native T1 value on noncontrast T1 mapping CMR is a novel, independent predictor of adverse outcome in patients with significant AS.

Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM): study protocol for a randomized controlled trial

BackgroundThe diabetogenic action of statins remains a concern, particularly in patients at high risk for diabetes receiving intensive statin therapy. Despite the risk of diabetes with statin use being considered a potential class effect, recent studies have suggested that pitavastatin exerts neutral or favorable effects on diabetogenicity. However, no randomized trial has compared the long-term effects of pitavastatin with those of other statins on glycemic control in populations at high risk for diabetes. Hence, we aim to assess the long-term effects of pitavastatin in comparison with atorvastatin on glucose metabolism in patients with metabolic syndrome (MetS).Methods/designThe Long-term Effects of high-doSe pitavaStatin on Diabetogenicity in comparison with atorvastatin in patients with Metabolic syndrome (LESS-DM) trial is a prospective, randomized, open-label, active control clinical trial of patients with MetS. We plan to randomize 500 patients with MetS (1:1) to receive high-dose pitavastatin (4xa0mg) or atorvastatin (20xa0mg) daily for 24xa0months. The primary endpoint will be the change in hemoglobin A1c after statin treatment. Secondary endpoints will include the following: (1) changes in biochemical markers, including insulin, C-peptide, homeostasis model assessment of insulin resistance and insulin secretion, and adiponectin; (2) changes in imaging parameters, including carotid elasticity metrics and indices of cardiac function; and (3) the incidence of clinical events, including new-onset diabetes and cardiovascular disease.DiscussionIn this trial, we will explore whether pitavastatin 4xa0mg does not disturb glucose metabolism in patients with MetS. It will also provide mechanistic information on statin type-dependent diabetogenic effects and surrogate data regarding vascular and cardiac changes achieved by intensive statin therapy.Trial registrationClinicalTrials.gov, NCT02940366. Registered on 19 October 2016.

Prognostic Value of Cardiac MR Imaging for Preoperative Assessment of Patients with Severe Functional Tricuspid Regurgitation

Purpose To explore the prognostic value of cardiac magnetic resonance (MR) imaging in predicting postoperative cardiac death in patients with severe functional tricuspid regurgitation (TR). Materials and Methods This study was approved by the institutional review board, and written informed consent was obtained from all patients. Prospectively collected data included cardiac MR images, New York Heart Association (NYHA) functional class, a comprehensive laboratory test, and clinical events over the follow-up period in 75 consecutive patients (61 women and 14 men; mean age ± standard deviation, 59 years ± 9) undergoing corrective surgery for severe functional TR. Cox proportional hazards models were used to assess the association between cardiac MR parameters and outcomes. Results During a median follow-up period of 57 months (range, 21-82 months), cardiac mortality and all-cause mortality were 17.3% and 26.7%, respectively, with a surgical mortality of 6.7%. Cardiac death risk was lower with a higher right ventricular (RV) ejection fraction (EF) on cardiac MR images (hazard ratio per 5% higher EF = 0.790, P = .048). By adjusting for confounding variables, RV EF remained a significant predictor for cardiac death (P < .05) and major postoperative cardiac events (P < .05). The area under the receiver operating characteristic curve (AUC) confirmed the incremental role of RV EF on cardiac MR images in the prediction of postoperative cardiac death (AUC, 0.681-0.771; P = .041) and major postoperative cardiac events (AUC, 0.660-0.745; P = .044) on top of NYHA class. RV end-systolic volume index was also independently associated with these outcomes but failed to increase the AUC significantly. Conclusion Preoperative assessment of cardiac MR imaging-based RV EF provides independent and incremental prognostic information in patients undergoing corrective surgery for severe functional TR. (©) RSNA, 2016 Online supplemental material is available for this article.

The Incremental Prognostic Value of Cardiac Computed Tomography in Comparison with Single-Photon Emission Computed Tomography in Patients with Suspected Coronary Artery Disease.

Background Coronary computed tomographic angiography (CCTA) facilitates comprehensive evaluation of coronary artery disease (CAD), including plaque characterization, and can provide additive diagnostic value to single-photon emission computed tomography (SPECT). However, data regarding the incremental prognostic value of CCTA to SPECT remain sparse. We evaluated the independent and incremental prognostic value of CCTA, as compared with clinical risk factors and SPECT. Materials and methods A total of 1,077 patients with suspected CAD who underwent both SPECT and cardiac CT between 2004 and 2012 were enrolled retrospectively. Presence of reversible or fixed perfusion defect (PD) and summed stress score were evaluated on SPECT. Presence, extent of coronary atherosclerosis and diameter stenosis (DS) were evaluated on CCTA. Plaque composition was categorized as non-calcified, mixed, or calcified according to the volume of calcified component (>130 Hounsfield Units). Patients were followed up for the occurrence of adverse cardiac events including cardiac death, non-fatal myocardial infarction, unstable angina, and late revascularization (>90 days after imaging studies). Results During follow-up (median 23 months), adverse cardiac events were observed in 71 patients (6.6%). When adjusted for clinical risk factors and SPECT findings, the presence of any coronary plaque, any plaque in ≥3 segments, coronary artery calcium score (CACS) ≥400, a plaque ≥50% DS, presence of non-calcified plaque (NCP) or mixed plaque (MP), and NCP/MP in ≥2 segments were independent predictors of adverse cardiac events; however, the presence of calcified plaque (CP) was not. Conventional CCTA findings, including CACS ≥400 and a plaque ≥50% DS, demonstrated incremental prognostic value over clinical risk factors and SPECT (χ² 54.19 to 101.03; p <0.001). Addition of NCP/MP in ≥2 segments resulted in further significantly improved prediction (χ² 101.03 to 113.29; p <0.001). Conclusion Comprehensive CCTA evaluation of coronary atherosclerosis provides independent and incremental prognostic value in relation to SPECT evaluation of myocardial ischemia. Specifically, segmentally-analyzed plaque composition with CCTA provides further risk stratification in addition to CACS and DS.

Diastolic Dysfunction and Outcome in Acute Ischemic Stroke

Background: Left ventricular diastolic dysfunction (DD) is associated with an increased mortality in general population and patients with myocardial infarct. In the present study, we investigated whether DD is associated with outcomes after ischemic stroke. Methods: Five hundred and three acute ischemic stroke patients with normal left ventricular ejection fraction (≥50%) were retrospectively included. Echocardiography and tissue Doppler imaging were used to evaluate and grade diastolic function. Ordinal logistic and Cox regression analyses were used to examine relations between DD and modified Rankin Scale (mRS) score at 3 months and mortality after stroke, respectively. Results: Mean age was 67.2 ± 11.8 years and 63% were men. Among parameters of diastolic function, early mitral inflow velocity/early diastolic mitral annulus velocity (E/e) was independently related with higher mRS score at 3 months and mortality after ischemic stroke. The highest quartile of E/e (>14) was independently associated with higher mRS score (adjusted OR 3.86, 95% CI 2.27-6.54) as well as with mortality (hazards ratio [HR] 2.87, 95% CI 1.17-7.04) as compared to the lowest quartile of E/e (<8.8). In addition, moderate-to-severe DD grade was related to higher mRS score (adjusted OR 2.41, 95% CI 1.15-5.06) and mortality (HR 6.63, 95% CI 1.80-24.43) compared to the normal diastolic function. Conclusion: In patients with ischemic stroke, DD is associated with functional outcome at 3 months and mortality. Our data suggest that more attention should be given to DD in patients with ischemic stroke.