bluuebunny/crossref_metadata_2025_split huggingface dataset:
407-P: Cardiac and Retinal Imaging Studies Suggest Comparable Protective Factors between Cardiovascular Disease and Retinopathy in Long Duration Type 1 Diabetes
Authors: YU MARC GREGORY , SHAH HETAL , WOLFSON EMILY , BAHNAM VANESSA , GAUTHIER JOHN , CAI QIZHE , JHA VIBHAV , TSAO CONNIE , KING GEORGE L. 
Published: June 2020

In the Joslin Medalist Study (“Medalists”), which enrolled people with ≥50 years of type 1 diabetes (T1D), factors have been shown to individually protect against vascular complications, such as proliferative retinopathy (PDR), and possibly, cardiovascular disease (CVD). However, shared protective factors against these disease outcomes have not been demonstrated. Recently, Medalists underwent cardiac computed tomography (CT; n=67) and cardiac magnetic resonance imaging (CMR; n=54) for assessment of coronary artery calcification (CAC) and myocardial and aortic structure and function, respectively; as well as optical coherence tomography angiography for assessment of superficial (SCP) and deep (DCP) retinal capillary plexus density (n=28 eyes). In this cohort, CAC severity was associated with self-reported CVD history (p=0.04). CAC&gt;200 was associated with PDR (p=0.03) and with lower density of both SCP (p=0.002) and DCP (p=0.047). Among the CMR parameters, lower ascending aortic distensibility, indicating higher stiffness, was found among participants with PDR (p=0.009), and was also associated with lower SCP density (p=0.037). Meanwhile, measures of myocardial strain (longitudinal, circumferential, and radial) were significantly lower in women and in those with CAC&gt;200 (all p&lt;0.05); likewise, Medalists with CAC&gt;200 were also less likely to be female (p=0.02). The common association of CAC and aortic stiffness with PDR and SCP density suggests that protective markers of progression to angiogenesis (PDR) may have similarities with those protecting against coronary calcification and aortic dysfunction. Furthermore, the results highlight the important relationship between CAC, gender, and myocardial biomechanics in Medalists. Future proteomic and metabolomic studies using circulatory and retinal biosamples could be helpful in identifying common factors that can delay the onset of CVD and PDR.

Disclosure
M. Yu: None. H. Shah: None. E. Wolfson: None. V. Bahnam: None. J. Gauthier: None. Q. Cai: None. V. Jha: None. C. Tsao: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

Funding
American Diabetes Association (9-18-CVD1-005 to M.G.Y.); Thomas J. Beatson, Jr. Foundation (2185, 20008, 2800200)
415-P: Remnant Cholesterol in Patients with Established Coronary Artery Disease Predicts Cardiovascular Events Both among Patients with Type 2 Diabetes and among Nondiabetic Subjects
Authors: SAELY CHRISTOPH H. , MAECHLER MAXIMILIAN , MADER ARTHUR , LARCHER BARBARA , SPRENGER LUKAS , KLEMENT MARGARETHA , PURIN DANIELA , LEIHERER ANDREAS , MUENDLEIN AXEL , VONBANK ALEXANDER , DREXEL HEINZ 
Published: June 2020

Remnant cholesterol, which is calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol has attracted interest as a marker of cardiovascular event risk. The power of remnant cholesterol to predict cardiovascular events in patients with established coronary artery disease (CAD) is unclear and is addressed in the present study. We enrolled 1350 consecutive patients with angiographically proven stable CAD. Prospectively, cardiovascular events were recorded over a mean follow-up period of 10.4±4.8 years. At baseline, remnant cholesterol was significantly higher in patients with T2DM (n=428) than in nondiabetic subjects (29±24 vs. 24±22 mg/dl; p&lt;;0.001). During follow-up, 651 of our patients suffered cardiovascular events; the event rate was significantly higher in patients with T2DM than in nondiabetic subjects (56.9 vs. 44.9%; p&lt;;0.001). Remnant cholesterol in Cox regression models adjusting for age, sex, hypertension, smoking, body mass index and LDL cholesterol independently predicted cardiovascular events in the total study population (standardized adjusted HR 1.15 [1.07-1.23]; p&lt;;0.001), and in patients with T2DM as well as in nondiabetic subjects (standardized adjusted HRs 1.19 [1.05-1.35]; p=0.006 and 1.12 [1.02-1.23]; p=0.010, respectively). From our data we conclude that remnant cholesterol in patients with established CAD predicts cardiovascular events both among patients with T2DM and among nondiabetic subjects.

Disclosure
C.H. Saely: None. M. Maechler: None. A. Mader: None. B. Larcher: None. L. Sprenger: None. M. Klement: None. D. Purin: None. A. Leiherer: None. A. Muendlein: None. A. Vonbank: None. H. Drexel: None.
419-P: Type 2 Diabetes, Congestive Heart Failure, and Nonalcoholic Fatty Liver Disease
Authors: MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , SPRENGER LUKAS , LEIHERER ANDREAS , PURIN DANIELA , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) is associated with both type 2 diabetes (T2DM) and congestive heart failure (CHF). T2DM is highly prevalent in CHF patients; however, the single and joint associations of T2DM and CHF with NAFLD have not been investigated yet. This issue therefore is addressed in the present study. We investigated 202 patients with CHF and 670 controls who did not have signs or symptoms of CHF and in whom significant coronary artery disease was ruled out angiographically. The presence of NAFLD was determined using the validated fatty liver index (FLI). The prevalence of T2DM was 47.0% in CHF patients and 22.1% in controls (p&lt;0.001). FLI and prevalence of NAFLD (FLI≥60) in non-CHF subjects without T2DM were 49±28 and 38.6%, respectively. They were significantly higher in non-CHF T2DM patients (70±25, p&lt;0.001 and 68.5%, p&lt;0.001, respectively), in CHF patients without T2DM (63±23, p&lt;0.001 and 58.6%, p&lt;0.001, respectively) and in CHF patients with T2DM (73±24, p&lt;0.001 and 78.0%, p&lt;0.001, respectively). In multivariate analysis of covariance, T2DM and CHF proved to be mutually independent predictors of FLI after adjustment for age, sex, BMI, LDL-C, history of smoking and hypertension (F=21.47; p&lt;0.001 and F=53.92; 0&lt;0.001, respectively); concordantly, T2DM and CHF independently predicted the presence of NAFLD in logistic regression analyses, with adjusted odds ratios of 2.49 [1.55-3.99]; p&lt;0.001 and 6.97 [3.95-12.29]; p&lt;0.001, respectively.
We conclude that T2DM and CHF are mutually independent predictors of NAFLD.

Disclosure
M. Maechler: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. L. Sprenger: None. A. Leiherer: None. D. Purin: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
427-P: Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Are Mutually Independent Predictors of Cardiovascular Events in Patients with Established Cardiovascular Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , MAECHLER MAXIMILIAN , LARCHER BARBARA , SPRENGER LUKAS , MADER ARTHUR , PURIN DANIELA , KLEMENT MARGARETHA , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2020

Nonalcoholic Fatty Liver Disease (NAFLD) is associated with insulin resistance, type 2 diabetes (T2DM) and cardiovascular disease. However, data on NAFLD in patients with established cardiovascular disease (CVD) are scarce. We therefore aimed at investigating its association with T2DM as well as its impact on cardiovascular event risk in a large series of 1518 patients with established CVD (1274 patients with angiographically proven coronary artery disease and 244 patients with sonographically proven peripheral artery disease), using the validated fatty liver index for the diagnosis of NAFLD. At baseline, the prevalence of NAFLD was significantly higher in patients with T2DM than in nondiabetic subjects (61.3 vs. 39.8%; p&lt;0.001) respectively. Prospectively, we recorded 738 cardiovascular events over a mean follow-up period of 9.7±4.6 years. Cardiovascular event risk was significantly higher in NAFLD patients than in those who did not have NAFLD (52.0 vs. 46.4%; p=0.040) and in patients with T2DM than in nondiabetic subjects (58.2 vs. 44.8%; p&lt;0.001). Cox regression models adjusting for conventional cardiovascular risk factors proved NAFLD and T2DM to be mutually independent predictors of cardiovascular events, with adjusted hazard ratios of 1.44 [1.19-1.74]; p&lt;0.001 and 1.45 [1.24-1.9]; p&lt;0.001, respectively. We conclude that NAFLD and T2DM are mutually independent predictors of cardiovascular events in patients with established CVD.

Disclosure
C.H. Saely: None. A. Vonbank: None. M. Maechler: None. B. Larcher: None. L. Sprenger: None. A. Mader: None. D. Purin: None. M. Klement: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
433-P: Type 2 Diabetes and Risk of Cardiovascular Events in Peripheral Artery Disease vs. Coronary Artery Disease Patients
Authors: SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , KLEMENT MARGARETHA , PURIN DANIELA , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2020

The prevalence of type 2 diabetes (T2DM) is higher in peripheral artery disease (PAD) than in coronary artery disease (CAD) patients, and PAD overall confers higher cardiovascular risk than CAD. How cardiovascular risk compares between PAD and CAD patients when analyses are stratified by the presence of T2DM is unclear and is addressed in the present study. We prospectively recorded cardiovascular events over 7.6±5.0 years in 253 patients with PAD, of whom 41.9% had T2DM and in 923 patients with stable CAD, of whom 26.7% had T2DM. Four groups were analyzed: CAD patients without diabetes (CAD/T2DM-; n=677), CAD patients with T2DM (CAD/T2DM+; n=246), PAD patients without diabetes (PAD/T2DM-; n=147) and PAD patients with T2DM (PAD/T2DM+; n=106). The cardiovascular event rate was lowest in CAD/T2DM- patients (40.5%). It was significantly higher in CAD/T2DM+ patients (50.2%; p=0.007), in PAD/T2DM- patients (55.2%; p&lt;0.001), and in PAD/T2DM+ patients (67.6%; p&lt;0,001), who in turn were at a higher risk than CAD/T2DM+ or PAD/T2DM- patients (p&lt;0.001 and p=0.013, respectively). Further, cardiovascular risk was significantly higher in PAD/T2DM- than in CAD/T2DM+ patients (p&lt;0.001). Cox regression analysis after multivariate adjustment confirmed that PAD versus CAD (HR=2.58 [2.12-3.15]; p&lt;0.001) more strongly than the presence of T2DM (HR=1.55 [1.30- 1.85]; p&lt;0.001) predicted cardiovascular events. We conclude that even when compared to CAD PAD confers a higher risk than T2DM. PAD patients without diabetes are at a higher risk than the extremely high risk patients with the combination of CAD and T2DM; risk is exceedingly high in PAD patients with T2DM.

Disclosure
L. Sprenger: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. M. Klement: None. D. Purin: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
435-P: Novel Approach to the Detection and the Treatment of Vulnerable Coronary Plaques Using Color Mapped Coronary CT Angiography and Optimal Medical Therapy Including Anti-PCSK9 Antibody
Authors: HIRAI AIZAN , KONDO SEIYA , GOTO TOSHIO , HIRAI KEIJI , KAMIYA NORIFUMI , TANABE YUKI , KOMESU ISAO , MOROMIZATO HIDEKAZU , NAKAZATO JUN , IKEJIMA SHIN , SUNAGAWA HIROSHI , KIDO TERUHITO 
Published: June 2020

Background: Coronary CT angiography (CCTA) has been applied to detect vulnerable plaques having low attenuation of CT value and positive remodeling which have been associated with acute coronary syndrome. The present study was performed to establish a novel approach to qualitative and quantitative analysis of coronary plaque, especially early detection of high-risk plaque by visualizing intra-plaque localization of necrotic core and the evaluation of plaque stabilizing effect of optimal medical therapy (OMT) including anti-PCSK9 antibody.
Methods: We developed color mapped CCTA. The vulnerable plaques are identified by red color (CT attenuation: 0-30) and yellow color (CT attenuation: 30-60). The effect of OMT including anti-PCSK9 antibody on the vulnerable plaques in diabetic patients was studied.
Results: Color mapped CCTA clearly demonstrated the presence of necrotic core (red in yellow sign) in vulnerable plaque. After 12 months administration of anti-PCSK9 antibody, an improvement of vulnerable plaque e.g., disappearance of necrotic core in vulnerable plaque was observed.
Conclusion: Color mapped CCTA provides a new insight into early detection of high-risk plaque by visualizing intra-plaque localization of necrotic core, also contributes to the evaluation of drugs which may improve vulnerable plaques.

Disclosure
A. Hirai: None. S. Kondo: None. T. Goto: None. K. Hirai: None. N. Kamiya: None. Y. Tanabe: None. I. Komesu: None. H. Moromizato: None. J. Nakazato: None. S. Ikejima: None. H. Sunagawa: None. T. Kido: None.
438-P: Prediction of Heart Failures for Diabetics Only Using Major Longitudinal Lab Test Results
Authors: KOSEKI AKIRA , OHKO TAKUYA , KUDO MICHIHARU , MAKINO MASAKI , SUZUKI ATSUSHI 
Published: June 2020

Background: In the presence of a large data set of electronic health records (EHRs), predicting the future diabetic complications is of importance for decision making in the medical treatments. Using modern machine learning techniques, it is generally becoming easier to build complex models to predict the future. While complex models are giving good prediction performance, simple models should be more useful in terms of interpretability and practicality in the real medical fields. For example the less the explanatory variables such as lab tests are used for the model, the more useful it is. Our interests thus lie in whether accurate prediction is possible when using less and major explanatory variables to make a model to predict the future diabetic complications.
Method: In this paper, we make a prediction model of heart failures for diabetics in half, 1, 3, 5 years using 13 longitudinal lab tests records including hemoglobin A1c, fasting blood glucose, low-density cholesterol, high-density cholesterol, triglycerides, uric acid, serum creatinine, estimated glomerular filtration rate, proteinuria, albuminuria, gamma-glutamyl transpeptidase, alanine transaminase, aspartate transaminase, from which we extracted several longitudinal statistics for input variables. We also compared the prediction performance using several major machine learning algorithms.
Results: In prediction of future heart failures in half, 1, 3, 5 years, AUC of 0.77, 0.79, 0.79, and 0.80 were marked when using Logistic Regression. Comparing algorithms for half year prediction, ensemble algorithms outperformed Logistic Regression. The AdaBoost algorithm marked AUC of 0.82.
Conclusion: We observed that when using only 13 longitudinal lab tests records, future heart failure prediction is successfully made by using modern machine learning algorithms.

Disclosure
A. Koseki: Employee; Self; IBM. T. Ohko: Employee; Self; IBM. M. Kudo: Employee; Self; IBM. M. Makino: None. A. Suzuki: Research Support; Self; Chugai Pharmaceutical Co., Ltd., Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.
44-OR: PAR2-Regulated MIF Secretion from Non-Immune Cells in Adipose Tissue Is a Key Mechanism Involved in the Development of Metabolic Dysfunction
Authors: HUANG YIHENG , CHEN LIUJUN , QI YADAN , QI DAKE 
Published: June 2020

Macrophage migration inhibitory factor (MIF) is a cytokine that is increased in obesity and contributes to metabolic dysfunction. Our present study describes a novel mechanism by which fatty acids activate non-immune cells to increase MIF secretion in adipose tissue, initiating cross-talk between preadipocytes and adipocytes. High fatty acids specifically induce protease-activated receptor 2 (PAR2) activation in preadipocytes, which downregulates pref-1 expression and release. Preadipocyte factor 1 (Pref-1) has an autocrine-paracrine action to inhibit the release of MIF from both preadipocytes and adipocytes. Thus, the loss of Pref-1 secretion during high fat feeding is responsible in part for both increased MIF secretion in adipose tissue and the rise in plasma MIF levels that ensues. The physiological consequences are most evident in adipose tissue. Genetic deletion of Par2 confirms the importance of this mechanism in mice, protecting against high fat diet-induced metabolic dysfunction. Importantly, this novel mechanism is also operative in adipose tissue from obese human subjects. These results provide the scientific rationale to consider whether strategies to either block Par2 expression or augment Pref-1 secretion might improve metabolic health in obesity or type 2 diabetes.

Disclosure
Y. Huang: None. L. Chen: None. Y. Qi: None. D. Qi: None.
448-P: Secondary Analyses to Assess the Profound Effect of Empagliflozin on Endothelial Function in Patients with Type 2 Diabetes and Established Cardiovascular Diseases: The Placebo-Controlled Double-Blind Randomized EMBLEM Trial
Authors: TANAKA ATSUSHI , NODE KOICHI , INVESTIGATORS EMBLEM TRIAL 
Published: June 2020

Background: Recent clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors reported improved cardiovascular outcomes in patients with type 2 diabetes (T2D) with a high risk of cardiovascular events. However, the mechanisms of these clinical effects on endothelial function are not fully understood.
Methods: The EMBLEM trial in patients with T2DM and cardiovascular disease (CVD) demonstrated no effects of 24 weeks of empagliflozin treatment on endothelial function assessed by reactive hyperemia peripheral arterial tonometry. This secondary analysis of the EMBLEM trial included a detailed evaluation of the effect of empagliflozin treatment on endothelial function, its association with clinical variables, and the clinical characteristics of responders or non-responder to treatment.
Results: Among 47 patients randomized into the empagliflozin group, 21 (44.7%) patients showed increases in reactive hyperemia index (RHI) after 24 weeks of intervention, and no significant difference in clinical characteristics between patients whose RHI increased (at least &gt;0) or did not increase. There was also no significant difference between the treatment groups in the proportion of patients who had a clinically meaningful change (≥15%) in log-transformed RHI. No correlation was observed between changes in RHI and clinical variables, such as vital signs and laboratory parameters.
Conclusions: 24 weeks of empagliflozin treatment in patients with T2DM and established CVD did not affect peripheral endothelial function, and that was not associated with changes in clinical variables, including glycemic parameters. These findings emphasize that the improved cardiovascular outcomes observed in the recent trials on SGLT2 inhibitors are attributable, at least in the early phase, to mechanisms other than direct amelioration of endothelial function.

Disclosure
A. Tanaka: Consultant; Self; Kowa Company, Ltd. Research Support; Self; GlaxoSmithKline plc. Speaker’s Bureau; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. K. Node: None.

Funding
Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance
453-P: Cell-Specific Role of Insulin in an In Vivo Model of Restenosis
Authors: GONZALEZ MAREL , MORI YUSAKU , GUO JUNE , DINGWELL LUKE S. , GIACCA ADRIA 
Published: June 2020

The effects of insulin on the vasculature remains a hotly debated and controversial topic. Its role on endothelial cells (ECs) is thought to be vasculoprotective, whereas its effects on vascular smooth muscle cells (SMCs) are mainly mitogenic according to in vitro data. We have previously demonstrated a suppressive effect of insulin treatment on neointimal growth in rodent models of restenosis under conditions of normal insulin sensitivity that was abolished in insulin resistant conditions. The objective of this study was to determine the endothelial-and SMC-specific effects of insulin treatment on neointimal growth in a murine model of restenosis. Mice were generated by crossing loxP-flanked insulin receptor (IR) mice with mice overexpressing tamoxifen-inducible Cre recombinase under the control of Tie2 (endothelial-specific receptor tyrosine kinase) or SMMHC (smooth muscle myosin heavy chain) promoters. Mice were fed with standard chow and implanted with insulin pellet (0.1 U/day) or sham (control) three days prior to undergoing femoral artery wire injury. Lastly, femoral arteries were collected for morphological analysis 28 days after wire injury. Tamoxifen-induced Tie2-Cre+ mice showed decreased IR expression in ECs compared with Tie2-Cre-, with no change in IR expression in SMCs. Neointimal area in Tie2-Cre- mice was reduced following insulin treatment, whereas it was unaffected in Tie2-Cre+ mice. Similarly, tamoxifen-induced SMMHC-Cre+ mice showed a reduction in IR expression in SMCs, but not in the ECs, compared to SMMHC-Cre- mice. In SMMHC-Cre- mice, neointimal area was decreased with insulin treatment; however, insulin surprisingly failed to have the same effects in SMMHC-Cre+ mice. These data demonstrate that insulin action in both ECs and SMCs is required for the antirestenotic effect of insulin in insulin sensitive conditions.

Disclosure
M. Gonzalez: None. Y. Mori: Research Support; Self; Taisho Pharmaceutical Co., Ltd. J. Guo: None. L.S. Dingwell: None. A. Giacca: None.
46-LB: Exercise Improves Endothelial Function Associated with Alleviated Inflammation and Oxidative Stress of Perivascular Adipose Tissue in Type 2 Diabetic Mice
Authors: WANG JINJU , POLAKI VENKATA , CHEN SHUZHEN , BIHL JI 
Published: June 2020

Perivascular adipose tissue (PVAT), a type of adipose tissue which surrounds blood vessels, has been considered as an active component of blood vessel walls and involved in vascular homeostasis. Recent evidence shows that increased inflammation and oxidative stress in PVAT contribute to endothelial dysfunction in type 2 diabetes (T2D). Exercise is an important non-pharmacological approach for vascular diseases. However, there is limited information regarding whether the beneficial effects of exercise on vascular function is related to PVAT status. In this study, we investigated whether exercise can decrease oxidative stress and inflammation of PVAT and promote the improvement of endothelial function in a T2D mouse model. Diabetic db/db (5-wk old) mice performed treadmill exercise (10 m/min) or keep sedentary for 8 wks. Body weight, fasting blood glucose levels, glucose and insulin tolerance were determined. The cytokines (IL-6, IL-10, IFN-r, TNF-a) and adiponectin levels, macrophage polarization in PVAT, and oxidative stress and nitric oxide expression in vascular wall were evaluated. The leukocyte adhesion ability of aorta endothelial cells isolated from the db/db mice was analyzed. Our data showed that: 1) Exercise decreased body weight and the fasting blood glucose level as well as improved glucose tolerance and insulin sensitivity in T2D mice. 2) Exercise increased adiponectin and IL-10 levels, decreased IFN-r, IL-6, TNF-a levels and promoted M1 to M2 polarization in PVAT. 3) Exercise decreased superoxide production in the vascular wall of diabetic mice, accompanied with increased nitric oxide bioavailability. 4) Exercise decreased the adhesion of diabetic aorta endothelial cells to leukocytes, accompanying with decreased ICAM-1 and VCAM-1 expression.
In conclusion, our data suggest that exercise improved endothelial function by attenuating the oxidative stress and inflammation in PVAT.

Disclosure
J. Wang: None. V. Polaki: None. S. Chen: None. J. Bihl: None.

Funding
American Diabetes Association (1-17-IBS-187 to J.B.)