Increased particle size of triglyceride remnant lipoproteins, but not their plasma concentration or lipid content, augment risk prediction of incident diabetes: prospective results from ELSA-Brasil

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L.S Carvalho ◽  
I.M Bensenor ◽  
P.A Lotufo ◽  
B.B Duncan ◽  
M.J Blaha ◽  
...  
Keyword(s):  
Particle Size ◽  
Plasma Concentration ◽  
Risk Prediction ◽  
Particle Diameter ◽  
Public Institution ◽  
Oral Glucose ◽  
Funding Source ◽  
National Council ◽  
Remnant Lipoproteins ◽  
Pancreatic Steatosis

Abstract Importance Predicting risk of Type 2 Diabetes Mellitus (T2DM) accurately allows allocation of resources to prevent its development. Fasting blood triglycerides are highly predictive for T2DM. Triglyceride remnant lipoproteins (TRL) more accurately reflect pathophysiological changes that underlie progression to T2DM, such as pancreatic steatosis and inflammation. We hypothesized TRL-related factors could improve risk prediction for development of T2DM. Methods We included individuals aged 35–74 years from the ELSA-Brasil cohort who had HbA1c and an oral glucose tolerance test at baseline. Regression models were used to predict incident T2DM, starting with medical history, metabolic syndrome traits (age, sex, hypertension, waist circumference [WC], HbA1c, triglycerides) and hsCRP, adding TRL-related measurements, including plasma concentration, particle size, as well as cholesterol and triglyceride content. TRL features were measured by NMR spectroscopy. Discrimination was assessed with area under receiver operator curves (AUROCs). Results Among 4,466 individuals at-risk, there were 353 new cases of T2DM after 3.7 (SD=0.6) years follow-up. We derived an 8-variable model with AUROC 0.891 (95% CI: 0.870–0.913). Overall TRL-related markers did not improve predictive capacity for T2DM. However, TRL particle diameter (TRLZ) increased AUROC, particularly in individuals without glucose abnormalities at baseline (Hba1c <5.7%). In this subgroup, AUROC increased from 0.761 (95% CI: 0.739–0.798 – Baseline-model) to 0.823 (95% CI: 0.783–0.862 – TRLZ model) (p-value=0.00006). Consistently, the net reclassification improvent (NRI) of the model with TRLZ improved by 10.27% (95% CI: 1.0–24.1, p=0.00041). In subjects with pre-diabetes at baseline, TRLZ is highly correlated with obesity, insulin resistance and inflammation (sum of z-scores for WC + HOMA-IR + hsPCR: R2=0.25), but this was less important in individuals with Hba1c <5.7% (R2=0.15). Sensitivity analyzes confirmed the results with different inclusion criteria (pre-diabetes defined with TTGO only) and excluding patients diagnosed with DM2 incident based only on fasting blood glucose. Conclusions TRL particle diameter improves prediction of T2DM, particularly in subjects with no glycemic abnormalities at baseline. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Brazilian Ministry of Health (Department of Science and Technology), Ministry of Science, Technology and Innovation, and the National Council for Scientific and Technological Development (CNPq)

scholarly journals Reduced NT-proBNP threshold for risk prediction in high-risk elderly with subclinical heart failure: support from cardiopulmonary exercise testing

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Potter ◽  
M Woessner ◽  
T.H Marwick
Keyword(s):  
Heart Failure ◽  
High Risk ◽  
Risk Prediction ◽  
Global Longitudinal Strain ◽  
Cardiopulmonary Exercise Testing ◽  
Left Ventricular ◽  
Public Institution ◽  
Funding Source ◽  
Cardiopulmonary Exercise ◽  
Cardiac Phenotype

Abstract Background Subclinical heart failure (HF) is divided into Stage A and B (SAHF and SBHF) depending on structural or functional cardiac abnormalities. However, risk of HF progression is not solely dependent on echocardiographic abnormalities. Data on oxygen consumption (VO2) and other prognostic cardiopulmonary exercise test (CPET) markers in subclinical HF, particularly in the elderly, is lacking. VO2 may refine risk prediction and provide pathological insight in subclinical HF. Methods Asymptomatic individuals were recruited through primary care if they were ≥65 years with ≥1 non-ischaemic risk factor for HF. Clinical evaluation determined risk profile, biometrics and NT-proBNP. Treadmill CPET was undertaken with a modified Bruce protocol. Low V02 was defined as ≤20th percentile of age and gender specific VO2 in healthy individuals. SBHF defined as systolic (global longitudinal strain, GLS ≤16%), diastolic (E/e' ≥15, E/e' >10 with left atrial enlargement or impaired relaxation with other changes or left ventricular (LV) hypertrophy (LV mass index >95 g/m2 in women or >115 g/m2 in men). Results Of the 91 included individuals (age 71±4 years, 53% female), 46 (51%) had SBHF, average NT-proBNP was 60pg/ml (26–99mg/ml) and did not differ by HF stage (59 [26–85] pg/ml vs. 60 [30–99] pg/ml for Stage A vs. B respectively, p=0.94). Average peak VO2 was 19.8 (16–22.6) ml/kg/min and was low in 71 (78%). VO2 did not differ by HF stage (19.9 [17.7–22.4] ml/kg/min vs. 19.7 [16–22.8] ml/kg/min for SAHF vs. SBHF respectively, p=0.62). NT-proBNP was significantly higher in those with abnormal VO2 (66 [34–110] pg/ml vs 31 [20–70] pg/ml, p=0.016). Within each HF stage, low VO2 was associated with higher NT-proBNP (Figure). Of those with NT-proBNP >100pg/ml, 95% (22/23) had low VO2 compared with 72% of those ≤100pg/ml, p=0.02 (non-signifcant for 125pg/ml cut-off). No associations were found between SBHF or individual echo abnormalities and VO2. In logistic regression analysis NT-proBNP was a significant univariable predictor of low VO2 and remained significant after adjustment for other significant univariables (BMI) (OR 1.02 [95% CI 1.0001–1.03], p=0.048). Conclusion Low VO2 identifies a high-risk cardiac phenotype within subclinical HF stages, but is not necessarily associated with LV dysfunction. Levels of NT-proBNP beneath the cut-off used for HF exclusion may assist risk stratification in this population. NT-proBNP by VO2 in subclinical HF Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Dr E Potter is supported by a PhD Scholarship from Monash University, Melbourne, Australia

Application of Plakett-Burman Screening Design in Optimization of Process Parameters for Formulation of Canaglifozin Nanosuspension

2020 ◽  
Vol 13 (6) ◽  
pp. 5208-5216
Author(s):  
Nisha Patel ◽  
Hitesh A Patel
Keyword(s):  
Particle Size ◽  
Particle Diameter ◽  
Spherical Shape ◽  
Water Soluble ◽  
Pareto Chart ◽  
Independent Variables ◽  
Mean Particle Size ◽  
Screening Design ◽  
Stirring Time ◽  
Response Variables

In this study, we sought to improve the dissolution characteristics of a poorly water-soluble BCS class IV drug canaglifozin, by preparing nanosuspension using media milling method. A Plackett–Burman screening design was employed to screen the significant formulation and process variables. A total of 12 experiment were generated by design expert trial version 12 for screening 5 independent variables namely the amount of stabilizer in mg (X1), stirring time in hr (X2), amt of Zirconium oxide beads in gm (X3), amount of drug in mg (X4) and stirring speed in rpm (X5) while mean particle size in nm (Y1) and drug release in 10 min. were selected as the response variables. All the regression models yielded a good fit with high determination coefficient and F value. The Pareto chart depicted that all the independent variables except the amount of canaglifozin had a significant effect (p<0.001) on the response variables. The mathematical model for mean particle size generated from the regression analysis was given by mean particle size = +636.48889 -1.28267 amt of stabilizer(X1) -4.20417 stirring time (X2) -7.58333 amt of ZrO2 beads(X3) -0.105556 amt of drug(X4) -0.245167 stirring speed(X5) (R2=0.9484, F ratio=22.07, p<0.001). Prepared canaglifozin nanosuspension exemplified a significant improvement (p<0.05) in the release as compared to pure canaglifozin and marketed tablet with the optimum formulation releasing almost 80% drug within first 10min. Optimized nanosuspension showed spherical shape with surface oriented stabilizer molecules and a mean particle diameter of 120.5 nm. There was no change in crystalline nature after formulation and it was found to be chemically stable with high drug content.

scholarly journals Ten-year all-cause death after percutaneous or surgical revascularization for men and women with multivessel or left main coronary artery disease: insights from the SYNTAX extended survival study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Hara ◽  
K Takahashi ◽  
D Klaveren ◽  
M Ono ◽  
H Kawashima ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Left Main Coronary Artery ◽  
Mortality Rates ◽  
Public Institution ◽  
Funding Source ◽  
Left Main ◽  
Main Coronary Artery Disease ◽  
Artery Disease ◽  
Extended Survival

Abstract Background In patients with complex coronary artery disease (CAD), women favored coronary artery bypass grafting surgery (CABG) compared to percutaneous coronary intervention (PCI) at 5 years in the SYNTAX trial, whereas mortality rates after PCI and CABG were not different in men. On the other hand, poor outcomes of women undergoing PCI were not observed in the PRECOMBAT and BEST trials. The long-term optimal revascularization strategy according to gender has not been fully evaluated. Purpose In the SYNTAX Extended Survival (SYNTAXES) study, no significant difference existed in all-cause death between PCI and CABG at 10 years. This study aimed to assess treatment effect of PCI and CABG for 10-year all-cause death according to gender. Methods The SYNTAXES study evaluated vital status up to 10 years in 1,800 patients with de novo three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to treatment with CABG or PCI in the SYNTAX trial, and the pre-specified primary endpoint was all-cause death at 10 years. In this prespecified analysis, all-cause death at 10 years according to gender in patients undergoing PCI or CABG was evaluated. Results Of 1800 patients, 402 (22.3%) were women and 1398 (77.7%) were men. In women, the rate of mortality was significantly higher in the PCI arm at 5 years than in the CABG arm (19.3% vs. 10.3%; Log-rank p=0.010, Figure A), but the rates of mortality were not different at 10 years between the PCI and CABG arms (33.0% vs. 32.5%; Log-rank p=0.600, Figure A). In men, the mortality rate tended to be higher in the PCI arm at 10 years than in the CABG arm (27.0% vs. 22.5%; Log-rank p=0.082, Figure B), although the mortality rates were not different at 5 years between the PCI and CABG arms (12.4% vs. 12.3%; Log-rank p=0.957, Figure B). Conclusion The efficacy of CABG observed at 5 years disappeared at 10 years in women, whereas the efficacy of CABG became apparent after 5 years in men. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Erasmus University Medical Centre, Rotterdam, Netherlands, reference: MEC-2016-716

Usefulness of collaboration between mathematical models and cell engineering for elucidating complex disease mechanisms and discover effective drugs

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Kohjitani ◽  
A Kashiwa ◽  
T Makiyama ◽  
F Toyoda ◽  
Y Yamamoto ◽  
...  
Keyword(s):  
Mathematical Model ◽  
In Silico ◽  
Complex Disease ◽  
Ion Selectivity ◽  
Public Institution ◽  
Cell Engineering ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
In Silico Model

Abstract Background A missense mutation, CACNA1C-E1115K, located in the cardiac L-type calcium channel (LTCC), was recently reported to be associated with diverse arrhythmias. Several studies reported in-vivo and in-vitro modeling of this mutation, but actual mechanism and target drug of this disease has not been clarified due to its complex ion-mechanisms. Objective To reveal the mechanism of this diverse arrhythmogenic phenotype using combination of in-vitro and in-silico model. Methods and results Cell-Engineering Phase: We generated human induced pluripotent stem cell (hiPSC) from a patient carrying heterozygous CACNA1C-E1115K and differentiated into cardiomyocytes. Spontaneous APs were recorded from spontaneously beating single cardiomyocytes by using the perforated patch-clamp technique. Mathematical-Modeling Phase: We newly developed ICaL-mutation mathematical model, fitted into experimental data, including its impaired ion selectivity. Furthermore, we installed this mathematical model into hiPSC-CM simulation model. Collaboration Phase: Mutant in-silico model showed APD prolongation and frequent early afterdepolarization (EAD), which are same as in-vitro model. In-silico model revealed this EAD was mostly related to robust late-mode of sodium current occurred by Na+ overload and suggested that mexiletine is capable of reducing arrhythmia. Afterward, we applicated mexiletine onto hiPSC-CMs mutant model and found mexiletine suppress EADs. Conclusions Precise in-silico disease model can elucidate complicated ion currents and contribute predicting result of drug-testing. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists

Coronary sinus catalase and ceruloplasmin levels predict all-cause mortality in patients with end-stage heart failure awaiting heart transplantation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Szczurek ◽  
M Gasior ◽  
M Skrzypek ◽  
G Kubiak ◽  
A Kuczaj ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Transplantation ◽  
Coronary Sinus ◽  
Public Institution ◽  
Funding Source ◽  
Organ Shortage ◽  
Number Of Patients ◽  
End Stage ◽  
Medical University

Abstract   Background, As a consequence of the worldwide increase in life expectancy and due to significant progress in the pharmacological and interventional treatment of heart failure (HF), the proportion of patients that reach an advanced phase of disease is steadily growing. Hence, more and more numerous group of patients is qualified to the heart transplantation (HT), whereas the number of potential heart donors has remained invariable since years. It contributes to deepening in disproportion between the demand for organs which can possibly be transplanted and number of patients awaiting on the HT list. Therefore, accurate identification of patients who are most likely to benefit from HT is imperative due to an organ shortage and perioperative complications. Purpose The aim of this study was to identify the factors associated with reduced survival during a 1.5-year follow-up in patients with end-stage HF awating HT. Method We propectively analysed 85 adult patients with end-stage HF, who were accepted for HT at our institution between 2015 and 2016. During right heart catheterization, 10 ml of coronary sinus blood was additionally collected to determine the panel of oxidative stress markers. Oxidative-antioxidant balance markers included glutathione reductase (GR), glutathione peroxidase (GPx), glutathione transferase (GST), superoxide dismutase (SOD) and its mitochondrial isoenzyme (MnSOD) and cytoplasmic (Cu/ZnSOD), catalase (CAT), malondialdehyde (MDA), hydroperoxides lipid (LPH), lipofuscin (LPS), sulfhydryl groups (SH-), ceruloplasmin (CR). The study protocol was approved by the ethics committee of the Medical University of Silesia in Katowice. The endpoint of the study was mortality from any cause during a 1.5 years follow-up. Results The median age of the patients was 53.0 (43.0–56.0) years and 90.6% of them were male. All included patients were treated optimally in accordance with the guidelines of the European Society of Cardiology. Mortality rate during the follow-up period was 40%. Multivariate logistic regression analysis showed that ceruloplasmin (odds ratio [OR] = 0.745 [0.565–0.981], p=0.0363), catalase (OR = 0.950 [0.915–0.98], p=0.0076), as well as high creatinine levels (OR = 1.071 [1.002–1.144], p=0.0422) were risk factors for death during 1.5 year follow-up. Conclusions Coronary sinus lower ceruloplasmin and catalase levels, as well as higher creatinine level are independently associated with death during 1.5 year follow-up. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical University of SIlesia, Katowice, POland

A chromatin signature by the methyltransferase SETD7 regulates semaphorin-3G transcription and angiogenic response in diabetes: insights for personalized epigenetic therapies

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.A Mohammed ◽  
S Costantino ◽  
A Akhmedov ◽  
G Karsai ◽  
S Ambrosini ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gastrocnemius Muscle ◽  
Tube Formation ◽  
Public Institution ◽  
Epigenetic Therapy ◽  
Great Promise ◽  
Funding Source ◽  
Rna Seq ◽  
Angiogenic Response ◽  
Pharmacological Inhibition

Abstract Background Despite advances in revascularization strategies, type 2 diabetic (T2D) patients with peripheral artery disease (PAD) continue to have a high risk of limb amputation. Modulation of blood vessel growth holds great promise for the treatment of PAD patients. Epigenetic modifications, namely histone post-translational modifications, have shown to regulate transcriptional programs implicated in the pathogenesis of cardiovascular disease. Aim To investigate the role of chromatin changes in regulating post-ischemic vascularization in experimental diabetes as well as in patients with T2D. Methods Experiments were performed in primary human aortic endothelial cells (HAECs), double-mutant leptin deficient mice (Lepdb/db) carrying a genetic deletion of the methyltransferase SETD7 (Setd7−/−Lepdb/db) as well as in gastrocnemius muscle samples from T2D patients with PAD and age-matched non-diabetic controls. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). Pharmacological blockade of SETD7 was performed by using the selective inhibitor (R)-PFI-2. Scratch and tube formation assays were performed to investigate the impact of SETD7 on angiogenic response. Results RNA-seq in high glucose-treated HAECs revealed a profound upregulation of the methyltransferase SETD7 (fold change 2.8, p&lt;0.001), an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and Chromatin Immunoprecipitation (ChIP) assays showed that SETD7-dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G). Increased SEMA-3G transcript was associated with enhanced secretion from HAECs. Co-immunofluorescence experiments showed that SEMA-3G blunts the angiogenic response by competing with VEGF receptors VEGFR/Neuropillin2. Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. SETD7 and SEMA-3G were significantly upregulated in endothelial cells from Lepdb/db mice, whereas SEMA-3G transcription was blunted in Setd7−/−Lepdb/db animals. Consistently, endothelial sprouting was defective in aortas from Lepdb/db as compared to WT mice, whereas Setd7−/−Lepdb/db mice displayed a preserved angiogenic response. Of clinical relevance, SETD7/SEMA-3G axis was upregulated in gastrocnemius muscle specimens from T2D patients with PAD as compared with non-diabetic controls. Conclusion In HAECs, genetically modified mice and T2D patients we show that SETD7-dependent chromatin changes regulate SEMA-3G transcription and angiogenic response. Pharmacological inhibition of SETD7 may represent a novel epigenetic therapy to boost neovascularization in T2D patients with PAD. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Zurich/Universitätsspital Zürich

scholarly journals Performance of the ESC 0/3-hour algorithm for rapid triage of myocardial infarction: systematic review and meta-analysis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Chiang ◽  
C.H Chiang ◽  
G.H Lee ◽  
C.C Lee
Keyword(s):  
Myocardial Infarction ◽  
Predictive Value ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Public Institution ◽  
Systematic Evaluation ◽  
Funding Source ◽  
Cochrane Central Register ◽  
Comparative Performance ◽  
Rule Out

Abstract Objective The European Society of Cardiology (ESC) 0/3-hour algorithm is one of the most widely strategies used for rule-out or rule-in of acute myocardial infarction (AMI). However, a systematic evaluation of its performance has not been conducted. Furthermore, recent studies showed that the 0/3-hour algorithm is non-superior to the 0/1-hour algorithm. Purpose This study aims to summarize the safety and efficacy of the 0/3-hour algorithm and its comparative performance with the 0/1-hour algorithm. Methods We conducted literature search on PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for studies published between 1 January 2008 and 31 May 2019. A bivariate random-effects meta-analysis was used to estimate the primary and secondary outcomes, defined as index myocardial infarction and triage efficacy, major adverse cardiac event (MACE) or mortality at 30 days, respectively. Results A total of 10,832 patients from 9 studies with a pooled AMI prevalence of 16% were analyzed. The 0/3-hour algorithm ruled out 69% of the patients with a pooled sensitivity of 94.2% [95% CI: 87.6%–97.4%] and negative predictive value of 98.6% [95% CI: 97.0%–99.4%]; 17% of the patients were ruled in with a pooled specificity of 94.9% [95% CI: 88.6%–97.8%] and positive predictive value of 72.9% [95% CI: 54.6%–85.7%]. The 30-day mortality and 30-day MACE for patients that were ruled out were 0.0% [95% CI: 0.0%–0.0%] and 1.4% [95% CI: 0.9%–2.0%], respectively. In a pooled analysis of 3 cohorts, the 0/3-hour algorithm had a non-superior sensitivity compared with the 0/1-hour algorithm (94.4% [95% CI: 87.0%–97.7%] vs. 98.4% [95% CI: 95.4%–99.7%]). The 0/3-hour algorithm also had a similar rule-out efficacy compared with the 0/1-hour algorithm (52% [95% CI: 39%–65%] vs. 53% [95% CI: 42%–64%]). Conclusion The widely used 0/3-hour algorithm has sensitivity substantially below the consensus goal of 99% and may not be sufficiently safe for triage of myocardial infarction. Furthermore, the 0/3-hour algorithm is not superior to the 0/1-hour algorithm despite the additional triage time. Performance of ESC 0/3-hour algorithm Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Taiwan National Ministry of Science and Technology Grants

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