Epicardial and intra-thoracic adipose tissue and cardiovascular calcifications in type 1 diabetes (T1D) in epidemiology of diabetes Interventions and Complications (EDIC): A pilot study.

Objective: Coronary artery, aortic valve, and descending aorta calcification (CAC, AVC, DAC) are manifestations of atherosclerosis, and cardiac epicardial adipose tissue (EAT) indicates heart adiposity. This study explored the association between cardiac adipose tissue and cardiovascular calcification in participants with long-standing T1D. Methods: EAT and intra-thoracic adipose tissue (IAT) were measured in 100 T1D subjects with cardiac computed tomography (CT) scans in the EDIC study. Volume analysis software was used to measure fat volumes. Spearman correlations were calculated between CAC, AVC, DAC with EAT, and IAT. Associations were evaluated using multiple linear and logistic regression models. Results: Participants ranged in age from 32 to 57. Mean EAT, and IAT were 38.5 and 50.8 mm3, respectively, and the prevalence of CAC, AVC, and DAC was 43.6 %, 4.7 %, and 26.8 %, respectively. CAC was positively correlated with age (p-value = 0.0001) and EAT (p-value = 0.0149) but not with AVC and DAC; IAT was not associated with calcified lesions. In models adjusted for age and sex, higher levels of EAT and IAT were associated with higher CAC (p-value < 0.0001 for both) and higher AVC (p-values of 0.0111 and 0.0053, respectively), but not with DAC. The associations with CAC remained significant (p-value < 0.0001) after further adjustment for smoking, systolic blood pressure, BMI, and LDL, while the associations with AVC did not remain significant. Conclusion: In participants with T1D, higher EAT and IAT levels are correlated with higher CAC scores. EAT and IAT were not independently correlated with DAC or AVC.

Importance of Spatial Arrangement of Cardiomyocyte Network for Precise and Stable On-Chip Predictive Cardiotoxicity Measurement.

One of the advantages of human stem cell-derived cell-based preclinical screening is the reduction of the false negative/positive misjudgment of lead compounds for predicting their effectiveness and risks during the early stage of development. However, as the community effect of cells was neglected in the conventional single cell-based in vitro screening, the potential difference in results caused by the cell number and their spatial arrangement differences has not yet been sufficiently evaluated. Here, we have investigated the effect of the community size and spatial arrangement difference for cardiomyocyte network response against the proarrhythmic compounds from the viewpoint of in vitro cardiotoxicity. Using three different typical types of cell networks of cardiomyocytes, small cluster, large square sheet, and large closed-loop sheet were formed in shaped agarose microchambers fabricated on a multielectrode array chip simultaneously, and their responses were compared against the proarrhythmic compound, E-4031. The interspike intervals (ISIs) in large square sheets and closed-loop sheets were durable and maintained stable against E-4031 even at a high dose of 100 nM. In contrast, those in the small cluster, which fluctuated even without E-4031, acquired stable beating reflecting the antiarrhythmic efficacy of E-4031 from a 10 nM medium dose administration. The repolarization index, field potential duration (FPD), was prolonged in closed-loop sheets with 10 nM E-4031, even though small clusters and large sheets remained normal at this concentration. Moreover, FPDs of large sheets were the most durable against E-4031 among the three geometries of cardiomyocyte networks. The results showed the apparent spatial arrangement dependence on the stability of their interspike intervals, and FPD prolongation, indicating the importance of the geometry control of cell networks for representing the appropriate response of cardiomyocytes against the adequate amount of compounds for in vitro ion channel measurement.

Enhancement of polar nature of domain boundaries in ferroelastic Pb3(PO4)2 by doping divalent-metal ions.

The effect of doping metal ions in ferroelastic Pb3(PO4)2 (PPO) on the polar nature of domain boundaries (DBs) was investigated using a second harmonic generation (SHG) microscope. It has been already reported that (DBs) of non-doped PPO is SH active and polar. The present study reveals that DBs of Ca-doped and Mg-doped PPO show greatly enhanced SH activity. This indicates that doping by metal ions enhances the polar nature of the DBs of PPO. This is important for future applications of DB nanotechnology. The enhancement of SH intensity is explained by a larger displacement of Ca2+ and Mg2+ ions in DBs due to smaller ionic radii. Analyses of the SH anisotropy experiments reveal that the symmetry-adapted W-wall belongs to monoclinic m and the non-adapted W'-wall to monoclinic 2. Both point groups are classified as the polar classes, which coincides with the case of pure PPO.

Short-term impact of aged garlic extract on endothelial function in diabetes: A randomized, double-blind, placebo-controlled trial.

Impaired endothelial function portends an increased risk of cardiovascular disease. Vascular oxidative stress and systemic inflammation play a critical role in the pathogenesis and progression of vascular disease. Aged garlic extract (AGE) may improve impaired vascular endothelial function, while decreasing the progression of atherosclerotic plaque. We hypothesized that AGE may improve endothelial function, and in this study, we examined this hypothesis to determine whether this can be achieved over a period of 3 months, measured by the cardio-ankle vascular index (CAVI), by reducing intracellular oxidant stress and stimulating nitric oxide generation in endothelial cells. We conducted a double-blinded placebo controlled, randomized clinical trial to investigate the effects of AGE on CAVI in subjects with type 2 diabetes mellitus. A total of 65 individuals (38 men and 27 women) with a mean age of 58.8±11.1 years were enrolled and randomized to the AGE or placebo group in a double-blind placebo controlled trial. An ANOVA model with treatment as the main effect was used to compare changes in CAVI from baseline to follow-up between groups. The primary objective of this study was reduction in CAVI over a 3-month period. In the AGE group, CAVI was reduced on average by 0.71±1.27 vs. a mean reduction of 0.13±0.94 in the placebo group (P=0.04). On the whole, this study demonstrates that AGE has a positive impact on endothelial function in patients with T2DM and may play a role in the primary prevention of cardiovascular disease.

Changes in Coronary Plaque Volume: Comparison of Serial Measurements on Intravascular Ultrasound and Coronary Computed Tomographic Angiography.

Serial measurements of coronary plaque volume have been used to evaluate drug efficacy in atherosclerotic progression. However, the usefulness of computed tomography for this purpose is unknown. We investigated whether the change in total plaque volume on coronary computed tomographic angiography is associated with the change in segment plaque volume on intravascular ultrasound. We prospectively enrolled 11 consecutive patients (mean age, 56.3 ± 5 yr; 6 men) who were to undergo serial invasive coronary angiographic examinations with use of grayscale intravascular ultrasound and coronary computed tomography, performed <180 days apart at baseline and from 1 to 2 years later. Subjects underwent 186 serial measurements of total plaque volume on coronary computed tomography and 22 of segmental plaque volume on intravascular ultrasound. We used semiautomated software to examine percentage relationships and changes between total plaque and segmental plaque volumes. No significant correlations were found between percentages of total coronary and segment coronary plaque volume, nor between normalized coronary plaque volume. However, in the per-patient analysis, there were strong correlations between the imaging methods for changes in total coronary and segment coronary plaque volume (r=0.62; P=0.04), as well as normalized plaque volume (r=0.82; P=0.002). Per-patient change in plaque volume on coronary computed tomography is significantly associated with that on intravascular ultrasound. Computed tomographic angiography may be safer and more widely available than intravascular ultrasound for evaluating atherosclerotic progression in coronary arteries. Larger studies are warranted.

Coronary artery-positive remodeling in current smokers.

BACKGROUND: This study aims to evaluate the association of the coronary artery-positive remodeling (CAPR) observed on cardiac computed tomography angiography (CCTA) with cigarette smoking. PATIENTS AND METHODS: This retrospective case-control study enrolled 178 consecutive patients with CAPR plaque (case group) and 180 consecutive patients with coronary artery plaque, but no positive remodeling (control group). CAPR was evaluated in CCTA images and defined as at least 10% larger vessel diameter at the plaque site compared with a normal reference segment. RESULTS: The average age of this population was 61.8±11.5 years (30.4% women). In the case group, the prevalences of current smokers, former smokers, and nonsmokers were 15.7, 26.4, and 57.9%, respectively. In the control group, the prevalences were 6.1, 20.6, and 73.3%, respectively, which were significantly different from the control group (P=0.002 for all). In a subanalysis of the CAPR location in the CAPR group, CAPR was more prevalent in the proximal than the distal segments of the major coronary arteries. Most of the patients in the case group had only one segment involvement with CAPR (71.35%). Logistic regression analyses showed that a history of current smoking has a significant correlation with CAPR in both unadjusted and adjusted models after controlling for risk factors. Current smokers have a 3.5-fold higher risk of having CAPR compared with nonsmokers (P<0.01). CONCLUSION: There is a significant independent association between a history of cigarette smoking and CAPR evaluated by CCTA. Current cigarette smokers have a 3.5 times higher risk of having CAPR.

Differences in protein expression among five species of stream stonefly (Plecoptera) along a latitudinal gradient in Japan.

Proteome variation among natural populations along an environmental gradient may provide insights into how the biological functions of species are related to their local adaptation. We investigated protein expression in five stream stonefly species from four geographic regions along a latitudinal gradient in Japan with varying climatic conditions. The extracted proteins were separated by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption/ionization of time-of-flight (MALDI TOF/TOF), yielding 446 proteins. Low interspecies variation in the proteome profiles was observed among five species within geographical regions, presumably due to the co-occurring species sharing the environments. However, large spatial variations in protein expression were found among four geographic regions, suggesting strong regulation of protein expression in heterogeneous environments, where the spatial variations were positively correlated with water temperature. We identified 21 unique proteins expressed specifically in a geographical region and six common proteins expressed throughout all regions. In warmer regions, metabolic proteins were upregulated, whereas proteins related to cold stress, the photoperiod, and mating were downregulated. Oxygen-related and energy-production proteins were upregulated in colder regions with higher altitudes. Thus, our proteomic approach is useful for identifying and understanding important biological functions related to local adaptations by populations of stoneflies.

The relationship between cardio-ankle vascular index and subclinical atherosclerosis evaluated by cardiac computed tomographic angiography.

BACKGROUND: The cardio-ankle vascular index (CAVI) is a new noninvasive index to evaluate arterial stiffness. We investigated whether CAVI can predict severity, extent, and burden of coronary artery disease by comparing results with cardiac computed tomographic angiography (CCTA). HYPOTHESIS: CAVI may predict the presence of subclinical atherosclerosis. METHODS: We prospectively enrolled 95 patients (66% male; mean age, 50 ± 16 years) who underwent both CCTA and CAVI consecutively. We evaluated if CAVI correlated with (1) severe stenosis (≥50%); (2) plaque extent, determined by a segment-involvement score (SIS), defined by the total number of coronary artery segments containing any plaque; and (3) plaque burden, determined by a segment-stenosis score (SSS), defined by the extent of obstruction of coronary luminal diameter in individual coronary artery segments. RESULTS: Bivariate analysis showed a statistically significant relationship not only between CAVI and SIS, but also between CAVI and SSS (r2 = 0.4, P < 0.0001 for SIS; r2 = 0.36, P < 0.0001 for SSS). Multivariable logistic analysis demonstrated that CAVI is significantly associated with SSS >5 (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-7.8, P = 0.03) and SIS >5 (OR: 2.3, 95% CI: 1.1-5.8, P = 0.02), but not severe stenosis (OR: 1.7, 95% CI: 0.9-4.3, P = 0.13), after adjusting for age, sex, chest pain, hypertension, dyslipidemia, family history, diabetes, and current smoking. CONCLUSIONS: We demonstrated that CAVI had a significant relationship with subclinical coronary atherosclerosis evaluated by CCTA, especially in relation to plaque burden and plaque extent, but not severe stenosis. Thus, CAVI may reflect coronary atherosclerosis burden more than severity.

Presence, Characteristics, and Volumes of Coronary Plaque Determined by Computed Tomography Angiography in Young Type 2 Diabetes Mellitus.

Prevention and management of coronary artery disease (CAD) is of great concern in patients with diabetes mellitus. Although the impact of coronary atherosclerosis is described well for subjects older than 40 years, the prevalence and types of coronary atherosclerosis in young patients are not well known. The aim of this study was to evaluate the prevalence, extent, severity, and volumes of coronary plaque in type 2 diabetes mellitus (T2DM) population younger than of 40 years. This prospective study enrolled 181 subjects (25-40 year old) undergoing coronary computed tomography angiography, with 86 T2DM and 95 nondiabetic age/gender-matched subjects. Coronary artery calcium (CAC), plaque assessment including total segment stenosis (sum of individual segmental stenosis), total plaque scores (sum of semiquantitative segmental plaque burden), segment involvement scores (number of segments with plaque) were evaluated. In addition, we quantitatively measured plaque volumes in total, fibrous, fibrous fatty, dense calcified, and low-attenuation plaque using novel plaque software. Compared with nondiabetic patients, the prevalence of CAD, calcified, and noncalcified plaques was higher in patients with T2DM (19% vs 58%; p <0.001). In patients with a zero CAC, T2DM had a higher prevalence (46%) of noncalcified plaque (p <0.0001). In multivariate linear regression models after adjusting for traditional cardiovascular risk factors, increased total segmental stenosis, total plaque scores, and segment involvement scores were associated with T2DM. Regarding quantitative plaque assessment, all volumes in noncalcified plaque type were approximately threefold higher in patients with T2DM. In conclusion, young patients with T2DM are susceptible to premature CAD with more calcified and noncalcified plaques. Early prevention program using computed tomography angiography might be helpful in identifying young diabetic patients with subclinical atherosclerosis.

Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone.

Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Effect of treatment with 5-lipoxygenase inhibitor VIA-2291 (atreleuton) on coronary plaque progression: a serial CT angiography study.

BACKGROUND: Inflammation has a key role in the process of atherosclerosis. Production of leukotrienes by 5-lipoxygenase has been linked to atherosclerotic plaques and cardiovascular events. HYPOTHESIS: In this study, a selective 5-LO inhibitor will slow plaque progression using serial cardiac computed tomographic angiography (CCTA). METHODS: Patients with recent acute coronary syndrome (ACS) were prospectively assigned to one of 3 VIA-2291 doses (25 mg, 50 mg, 100 mg) or placebo by oral administration. All groups underwent CCTA at baseline and at 6 months' follow-up. Plaque types such as low-attenuation plaque (LAP), fibro-fatty tissue (FF), fibro-calcified plaque (FC), and dense calcium plaque (DC) were measured based upon predefined density threshold, and changes from baseline CCTA were analyzed. RESULTS: The final analysis included 54 patients (age, 56 ± 9 years; 85.1% male) with CCTA at baseline and 24 weeks. Evaluating on treatment VIA-2291 (all 3 doses, n = 37) demonstrated significant reductions in plaque progression compared with placebo (n = 17). VIA-2291 significantly reduced LAP (5.9 ± 20.7 mm3 vs -9.7 ± 33.3 mm3 ), FF (11.1 mm3 ± 13.3 mm3 vs -0.9 ± 2.7 mm3 ), and FC (-0.1 ± 6.22 mm3 vs -14.3 ± 6.2 mm3 ; all P < 0.05) and retarded the progression of DC (3.9 ± 3.2 mm3 vs 0.2 ± 0.4 mm3 ) compared with placebo. CONCLUSIONS: VIA-2291 resulted in slowed plaque progression compared with placebo across different plaque subtypes in patients with recent ACS (http://ClinicalTrials.gov NCT00358826).

Extra-coronary calcification (aortic valve calcification, mitral annular calcification, aortic valve ring calcification and thoracic aortic calcification) in HIV seropositive and seronegative men: Multicenter AIDS Cohort Study.

INTRODUCTION: Previous studies have demonstrated an association between HIV infection and coronary artery disease (CAD); little is known about potential associations between HIV infection and extra-coronary calcification (ECC). METHODS: We analyzed 621 HIV infected (HIV+) and 384 HIV uninfected (HIV-) men from the Multicenter AIDS Cohort Study who underwent non-contrast computed tomography (CT) from 2010-2013. Agatston scores were calculated for mitral annular calcification (MAC), aortic valve calcification (AVC), aortic valve ring calcification (AVRC), and thoracic aortic calcification (TAC). The associations between HIV infection and the presence of each type of ECC (score > 0) were evaluated by multivariable logistic regression. We also evaluated the association of ECC with inflammatory biomarker levels and coronary plaque morphology. RESULTS: Among HIV+ and HIV- men, the age-standardized prevalences were 15% for TAC (HIV+ 14%/HIV- 16%), 10% for AVC (HIV+ 11%/HIV- 8%), 24% for AVRC (HIV+ 23% HIV- 24%), and 5% for MAC (HIV+ 7%/HIV- 3%). After adjustment, HIV+ men had 3-fold greater odds of MAC compared to HIV- men (OR = 3.2, 95% CI: 1.5-6.7), and almost twice the odds of AVC (1.8, 1.1-2.9). HIV serostatus was not associated with TAC or AVRC. AVRC was associated with higher Il-6 and sCD163 levels. TAC was associated with higher ICAM-1, TNF-α RII, and Il-6 levels. AVC and AVRC calcification were associated with presence of non-calcified plaque in HIV+ but not HIV- men. CONCLUSION: HIV infection is an independent predictor of MAC and AVC. Whether these calcifications predict mortality in HIV+ patients deserves further investigation.

Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study.

BACKGROUND: Although several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification, its effect on noncalcified plaque (NCP) has been unclear. OBJECTIVE: This study investigated whether AGE reduces coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with metabolic syndrome (MetS). METHODS: Fifty-five patients with MetS (mean ± SD age: 58.7 ± 6.7 y; 71% men) were prospectively assigned to consume 2400 mg AGE/d (27 patients) or placebo (28 patients) orally. Both groups underwent CCTA at baseline and follow-up 354 ± 41 d apart. Coronary plaque volume, including total plaque volume (TPV), dense calcium (DC), NCP, and low-attenuation plaque (LAP), were measured based upon predefined intensity cutoff values. Multivariable linear regression analysis, adjusted for age, gender, number of risk factors, hyperlipidemia medications, history of coronary artery disease, scan interval time, and baseline %TPV, was performed to examine whether AGE affected each plaque change. RESULTS: The %LAP change was significantly reduced in the AGE group compared with the placebo group (-1.5% ± 2.3% compared with 0.2% ± 2.0%, P = 0.0049). In contrast, no difference was observed in %TPV change (0.3% ± 3.3% compared with 1.6% ± 3.0%, P = 0.13), %NCP change (0.2% ± 3.3% compared with 1.4% ± 2.9%, P = 0.14), and %DC change (0.2% ± 1.4%, compared with 0.2% ± 1.7%, P = 0.99). Multivariable linear regression analysis found a beneficial effect of AGE on %LAP regression (ß: -1.61; 95% CI: -2.79, -0.43; P = 0.008). CONCLUSIONS: This study indicates that the %LAP change was significantly greater in the AGE group than in the placebo group. Further studies are needed to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events. This trial was registered at clinicaltrials.gov as NCT01534910.

The Cardiovascular Trial of the Testosterone Trials: rationale, design, and baseline data of a clinical trial using computed tomographic imaging to assess the progression of coronary atherosclerosis.

BACKGROUND: Data from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression. OBJECTIVE: We designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population. METHODS: The Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (<275 ng/dl). CCTA performed at baseline and after 12 months of therapy will determine the effects of testosterone on the progression of the total volume of noncalcified plaques. All scans are evaluated at a central reading center by an investigator blinded to treatment assignment. RESULTS: A total of 165 men were enrolled. The average age is 71.1 years, and the average BMI is 30.7. About 9% of men had a history of myocardial infarction, 6% angina, and 10% coronary artery revascularization. A majority reported hypertension and/or high cholesterol; 31.8% reported diabetes. Total noncalcified plaque at baseline showed a slight but nonsignificant trend toward lower plaque volume with higher serum testosterone concentrations (P=0.12). CONCLUSION: The Cardiovascular Trial will test the hypothesis that testosterone therapy inhibits coronary plaque progression, as assessed by serial CCTA.

Diagnostic performance of transluminal attenuation gradient and fractional flow reserve by coronary computed tomographic angiography (FFR(CT)) compared to invasive FFR: a sub-group analysis from the DISCOVER-FLOW and DeFACTO studies.

Although coronary computed tomographic angiography (CCTA) has been a robust diagnostic tool to identify anatomical significance of coronary artery disease (CAD), the utility of CCTA to assess hemodynamic significance of CAD remains unclear. We investigated the diagnostic performance of transluminal attenuation gradient (TAG) and fractional flow reserve derived from CCTA (FFRCT) to predict lesion-specific ischemia by invasive FFR. We identified 103 patients with suspected or known CAD enrolled from the DISCOVER-FLOW and DeFACTO studies who underwent invasive coronary angiography with FFR and high quality ≥64-slice CCTA. Diagnostic performance for predicting abnormal invasive FFR (≤0.80) was assessed for TAG [≤-1.1 HU/mm by the area under the curve (AUC) by receiver-operating characteristic curve analysis (ROC)], FFR(CT) (≤0.80), and CCTA stenosis (≥50%). On a per-vessel analysis (n = 146), 52 vessels (35.6%) had ischemia by invasive FFR. The sensitivity, specificity, positive predictive value and negative predictive value were 53.8, 45.7, 35.4, 64.2% for TAG, 82.7, 74.5, 64.2, 88.6% for FFR(CT), 84.6, 39.4, 43.6, 82.2% for CCTA stenosis, respectively. The AUC by ROC curve analysis for FFR(CT) (0.79) demonstrated greater discrimination of hemodynamic ischemia compared to TAG (0.50, p < 0.0001 vs. FFR(CT)), CCTA stenosis (0.62, p = 0.0004 vs. FFR(CT)) and the combination of the two (0.63, p = 0.004 vs. FFR(CT)). These results remained consistent regardless of the number of CCTA slices. FFR(CT) allows identification of lesion-specific ischemia using invasive FFR as a reference standard with greater diagnostic accuracy than TAG, CCTA stenosis, or the combination of the two.

The relationship between coronary artery calcium score and the long-term mortality among patients with minimal or absent coronary artery risk factors.

BACKGROUND: Coronary artery calcium (CAC) is strongly predictive of all-cause mortality in intermediate-risk groups, but this relationship is not well defined in very low-risk individuals. We investigated the relationship between CAC scoring and the long-term all-cause mortality among patients with ≤ 1 cardiovascular disease (CVD) risk factor. METHODS: We analyzed a retrospective cohort of 5584 asymptomatic patients with no known CVD (mean 56.6 ± 11.6 years, 69%men) and ≤ 1 risk factor who were physician referred for a CAC scan. Mortality was ascertained through linkage with the Social Security Death Index. We calculated the prevalence of CAC stratified by age and risk factors. We also examined the association between CAC and mortality using multivariable Cox Proportional hazards models. RESULTS: During a mean follow-up of 10.4 ± 3.1 years, 168 individuals (3.0%) died. Overall, 54.5% of patients had a CAC >0 and 9.8% had CAC ≥ 400. There was a greater risk of mortality with increasing CAC 1-99 (HR 1.9, 95% CI 1.2-3.1), 100-399 (HR 2.1, 95% CI 1.2-3.6) and ≥ 400 (HR 2.8, 95% CI 1.6-4.8) compared to CAC=0 (p<0.0001 for trend). Similar results were observed when the population was stratified by zero or one risk factor. Among patients < 45 years old, there was a 0.7% incidence of mortality compared to 8.1% for individuals ≥ 65 years old. CONCLUSIONS: During long-term follow-up, an increasing CAC was significantly associated with a higher risk of all-cause mortality among patients with a very low CVD risk factor profile. CAC scanning may be a potentially useful tool for risk stratification among low CVD risk individuals who are ≥ 45 years old.

Signaling through erbB receptors is a critical functional regulator in the mature cochlea.

Noise, ototoxic substances and various genetic factors are common causes of profound hearing loss. Cochlear implants can often restore hearing in these cases, but only if a sufficient number of responsive auditory nerve fibers remain. Over time, these nerve fibers degenerate in the damaged ear, and it is therefore important to establish factors that control neuronal survival and maintain neural excitability. Recent studies show that neuregulins and their receptors are important for survival and proper targeting of neurons in the developing inner ear. A role for neuregulins as maintainers of the neuronal population in the mature inner ear was therefore hypothesized. Here, this hypothesis was directly tested by chronic local application of substances that block neuregulin receptors. Using auditory brainstem response measurements, we demonstrate that such receptor block leads to a progressive hearing impairment that develops over the course of weeks. This impairment occurs despite a normal number of auditory neurons and preserved outer hair cell function. Real-time quantitative reverse transcriptase-polymerase chain reaction shows alterations in neurotrophin-3 expression, suggesting that this growth factor participates in regulating cochlear sensitivity. The present work demonstrates the critical importance of neuregulin/erbB signaling in long-term functional regulation in the mature guinea pig hearing organ.

A Small Ras-like protein Ray/Rab1c modulates the p53-regulating activity of PRPK.

PRPK phosphorylates serine-15 residue of p53 and enhances transcriptional activity. PRPK possesses a bipartite nuclear localization signal and localizes in nucleus when over-expressed in cells. However, intrinsic PRPK localizes mainly in the cytosol in situ. While studying the mechanisms in the distribution of intrinsic PRPK, we identified a PRPK binding protein, an ubiquitously expressed Small Ras-like GTPase, Rab1c, also named Ray or Rab35. The over-expressed Ray was distributed in the nucleus, cytosol, and cell membrane. Both Ray wild type and GTP-restrictively binding mutant Ray-Q67L, but not guanine nucleotide unstable binding mutant Ray-N120I, partially distributed the over-expressed PRPK to the cytosol and also suppressed the PRPK-induced p53-transcriptional activity profoundly. A Small Ras-like GTPase protein Ray was thus indicated to modulate p53 transcriptional activity of PRPK.

Characterization of a MAPKK-like protein kinase TOPK.

A MAPKK-like protein kinase TOPK expresses in a wide range of proliferating cells and tissues such as cancer cells and testis. However, details of this kinase are still uncovered. We investigated the intracellular distribution of TOPK and its association with cdk1/cyclin B and microtubules. In interphase cells, TOPK expresses in cytosol and nucleus without any significant association with microtubule networks. During mitosis, TOPK-Thr-9 was phosphorylated by cdk1/cyclin B and TOPK significantly associates with mitotic spindles. When TOPK expression was suppressed, formation of spindle midzone was thinned and dimmed and cytokinesis was disturbed. We propose that TOPK plays a role in the formation of spindle midzone and in cytokinesis.