Diabetes Mellitus Coronary Artery Disease Research Articles

Evaluating dyNamic myocardial blood flow qUantitation as a Cost-effective care modeL for diabEtic patients with coronary artery diSease (NUCLEuS): A randomized controlled trial – Rationale and Design

BackgroundRecent advancements in quantifying myocardial blood flow (MBF) and coronary flow reserve using dynamic SPECT MPI have demonstrated comparable hemodynamic correlations with invasive angiography and PET. Implementation into routine practice, however, imposes attendant demands on resources. Diabetes mellitus is a rising pandemic associated with accelerated atherosclerosis, yet there is potential for under-detection of significant ischemia. ObjectivesWe postulate that quantifying myocardial blood flow (MBF) by dynamic SPECT reduces post-test resource utilization and improve economic efficiency over conventional SPECT. MethodsNUCLEuS is an ongoing prospective open-label randomized clinical trial that will enroll 300 diabetic patients without known coronary artery disease (CAD) referred clinically for SPECT MPI from March 2022 to March 2025. The aim is to determine the incremental prognostic value and post-test resource utilization of dynamic MBF over conventional SPECT in diabetic patients with suspected CAD. The primary endpoint is diagnostic failure, defined as unnecessary coronary angiography (absence of ≥50% stenosis in ≥1 coronary artery) or additional anatomical testing (e.g., coronary computed tomography angiography) within 90 days. Secondary endpoints are referrals for angiography or revascularization, escalation of anti-anginal medications, and quality-of-life scores at 12 months. Long-term endpoints are major adverse cardiovascular events (cardiac mortality, myocardial infarction, unstable angina, revascularization) within 36 months. The incremental cost-effectiveness ratio will be estimated based on cost and clinical effectiveness. ConclusionsNUCLEuS will be an imaging-directed clinical trial that will compare differences in outcomes and resource utilization of dynamic MBF over conventional SPECT MPI in the routine clinical management of CAD in diabetes mellitus.

Key Therapeutic Targets to Treat Hyperglycemia-Induced Atherosclerosis Analyzed Using a Petri Net-Based Model.

Chronic superphysiological glucose concentration is a hallmark of diabetes mellitus (DM) and a cause of damage to many types of cells. Atherosclerosis coexists with glucose metabolism disturbances, constituting a significant problem and exacerbating its complications. Atherosclerosis in DM is accelerated, so it is vital to slow its progression. However, from the complex network of interdependencies, molecules, and processes involved, choosing which ones should be inhibited without blocking the pathways crucial for the organism's functioning is challenging. To conduct this type of analysis, in silicotesting comes in handy. In our study, to identify sites in the network that need to be blocked to have an inhibitory effect on atherosclerosis in hyperglycemia, which is toxic for the human organism, we created a model using Petri net theory and performed analyses. We have found that blocking isoforms of protein kinase C (PKC)-PKCβ and PKCγ-in diabetic patients can contribute to the inhibition of atherosclerosis progression. In addition, we have discovered that aldose reductase inhibition can slow down atherosclerosis progression, and this has been shown to reduce PKC (β and γ) expression in DM. It has also been observed that diminishing oxidative stress through the inhibitory effect on the AGE-RAGE axis may be a promising therapeutic approach in treating hyperglycemia-induced atherosclerosis. Moreover, the blockade of NADPH oxidase, the key enzyme responsible for the formation of reactive oxygen species (ROS) in blood vessels, only moderately slowed down atherosclerosis development. However, unlike aldose reductase blockade, or direct PKC (β and γ), the increased production of mitochondrial ROS associated with mitochondrial dysfunction effectively stopped after NADPH oxidase blockade. The results obtained may constitute the basis for further in-depth research.

Analysis of circulating ceramides and hexosylceramides in patients with coronary artery disease and type II diabetes mellitus

BackgroundCardiovascular disease (CVD) remains the leading cause of death worldwide. The main driving force behind this association is coronary artery disease (CAD), the manifestation of atherosclerosis in the coronary circulation. Cornerstones in the development of CAD are pathologies in lipid metabolism. In recent years, ongoing research has identified ceramides, a subclass of sphingolipids to be mediators of CVD. The aim of this study is to investigate the influence of type II diabetes mellitus (DM) on circulating ceramides and hexosylceramides (HexCers) in CAD patients.Methods24 patients aged 40–90 years with CAD confirmed by angiography were included into a pilot study. Patients with DM were identified by analysis of discharge letters or other medical documents available at the study center. During coronary angiography, arterial blood samples were collected and quantification of sphingolipids in patient serum was performed by mass spectrometry.ResultsStatistical analysis showed nine significantly different HexCers in CAD patients with DM compared to patients without DM. Among the nine significantly regulated HexCers, we identified seven d18:1 HexCers. This group contributes to the fourth most abundant subgroup of total ceramides and HexCers in this dataset. HexCer-d18:1–23:1(2-OH) showed the strongest downregulation in the patient group with DM.ConclusionThis study suggests that levels of circulating HexCers are downregulated in patients with CAD and concomitant DM compared to patients without DM. Further research is needed to investigate the underlying mechanisms and the suitability of HexCers as possible mediators and/or prognostic markers in CAD.

Urinary c-peptide creatinine ratio (UCPCR) as a predictor of coronary artery disease in type 1 diabetes mellitus.

Elevated C-peptide has been suggested as a risk factor for coronary artery disease (CAD). Elevated urinary C-peptide to creatinine ratio (UCPCR) as an alternative measurement is shown to be related to insulin secretion dysfunction; however, data regarding UCPCR predictive value for CAD in diabetes mellitus (DM) are scarce. Therefore, we aimed to assess the UCPCR association with CAD in type 1 DM (T1DM) patients. 279 patients previously diagnosed with T1DM included and categorized into two groups of CAD (n=84) and without-CAD (n=195). Furthermore, each group was divided into obese (body mass index (BMI) ≥ 30) and non-obese (BMI < 30) groups. Four models utilizing the binary logistic regression were designed to evaluate the role of UCPCR in CAD adjusted for well-known risk factors and mediators. Median level of UCPCR was higher in CAD group compared to non-CAD group (0.07 vs. 0.04, respectively). Also, the well-acknowledged risk factors including being active smoker, hypertension, duration of diabetes, and body mass index (BMI) as well as higher levels of haemoglobin A1C (HbA1C), total cholesterol (TC), low-density lipoprotein (LDL) and estimated glomeruli filtration rate (e-GFR) had more significant pervasiveness in CAD patients. Based on multiple adjustments by logistic regression, UCPCR was a strong risk factor of CAD among T1DM patients independent of hypertension, demographic variables (gender, age, smoking, alcohol consumption), diabetes-related factors (diabetes duration, FBS, HbA1C), lipid profile (TC, LDL, HDL, TG) and renal-related indicators (creatinine, e-GFR, albuminuria, uric acid) in both patients with BMI≥30 and BMI < 30. UCPCR is associated with clinical CAD, independent of CAD classic risk factors, glycaemic control, insulin resistance and BMI in type 1 DM patients.

Effect of piper Crocatum leaves extract on atherosclerosis in diabetic rats

Atherosclerosis is caused by an inflammatory process in the endothelium due to an imbalance between oxidant and antioxidant agents that often occurs in Diabetes mellitus (DM) patients. Antioxidants that function to neutralize superoxide can be used to prevent atherosclerosis in DM. Piper crocatum leaves shows an unknown antioxidant effect on the atherosclerosis process.The aim of this study is to determine the effect Piper crocatum leaves extract on blood MDA levels and the severity of atherosclerosis in diabetic rats. 30 Sprague Dawley rats were randomly divided into 6 groups, namely, HC (nondiabetic), NC (diabetic-no therapy), PC (metformin 45 mg/kg), PC200, PC300, PC400 (Piper crocatum leaves extract 200/300/ 400 mg/kg/day). Termination, blood sampling, and histopathological analysis were performed after 14 days of treatment. MDA was measured using the TBARS method, and read on a 532 nm wavelength UV-vis spectrophotometer. The severity of atherosclerosis of the rat carotid artery was observed from tissue stained with Haematoxylin Eosin staining at 400x microscope magnification. The mean blood MDA levels in the PC200, PC300, PC400 groups were 1.24 ± 0.26, 0.85 ± 0.35, 0.10 and ± 0.02, respectively, and a decrease in MDA levels was found in the PC200, PC300, and PC400 compared to group NC. The study showed a decrease in the severity of atherosclerosis in groups PC200, PC300, PC400 compared to groups NC. Piper crocatum leaves extract had an effect on decreasing MDA levels and severity of atherosclerosis in diabetic rats.

Associations of serum calcium/magnesium ratios with coronary artery disease in diabetes: a cross-sectional study

ABSTRACT Objective The early detection of coronary artery disease (CAD) in diabetes mellitus is a major clinical difficulty. The purpose of this paper is to find out a convenient and economical index to help to screen for patients with CAD in diabetes mellitus. Method From January 2019 to December 2019, a total of 1028 patients hospitalized in the general department of our hospital have been enrolled in our cross-sectional study, of which 190 were diagnosed with CAD and 314 with diabetes. Differences of various factors between the CAD group and the non-CAD group were analyzed. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to evaluate the efficacy of each factor in predicting CAD. The correlation between calcium/magnesium (Ca/Mg) ratio and the prevalence of CAD in diabetic and non-diabetic people was compared, and the cutoff of Ca/Mg ratio to predict the risk of CAD in diabetic patients was calculated. Results Logistic regression analysis showed that serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, calcium, magnesium, Ca/Mg ratio, hypertension, diabetes, and smoking history were all associated with CAD. Among them, the AUC value of Ca/Mg ratio was the highest of 0.70. Furthermore, in diabetes patients, the AUC value of Ca/Mg ratio to predict the risk of CAD was 0.72, the cutoff was 2.55, the sensitivity was 77.1%, and the specificity was 53.7%. The prevalence rate of CAD was 18.5% below the cutoff, 46.9% higher than the cutoff, and the prevalence rate increased by 153.5%. Conclusion The Ca/Mg ratio is a good predictor of the risk of CAD in diabetes, higher than the cutoff, the prevalence rate was significantly increased. PLA IN LANGUAGE SUMMARY CAD brings great pain and burden to patient. However, CAD is asymptomatic in quiet a few cases of type 2 diabetes until myocardial infarction or sudden cardiac death occurs. In this study, we explored the association between CAD and various serum factor. We found that the Ca/Mg ratio is of excellent value in screening CAD, especially in diabetes. Moreover, we found that the cutoff of Ca/Mg ratio was 2.55 in diabetic population and the prevalence rate of CAD was 18.5% below the cutoff, 46.9% higher than the cutoff. The Ca/Mg ratio will provide good prediction of the risk of CAD and make early detection easier in diabetes.

Sex differences in subclinical atherosclerosis

Background and Aims : There is emerging evidence demonstrating the sex dichotomy in atherosclerotic cardiovascular diseases (ASCVD) among individuals with diabetes mellitus (DM). However, the mechanisms are unclear. We aimed to evaluate the impact of sex on the associations and possible mechanisms modulating ASCVD risk factors and subclinical atherosclerosis in DM.

Negative Correlation of Serum Adiponectin Level with Aortic Stiffness in Elderly Diabetic Persons.

Adiponectin has anti-inflammatory activity against atherosclerosis. Aortic stiffness is a common manifestation of atherosclerosis in diabetes mellitus and elderly persons. This study aimed to evaluate whether low serum adiponectin levels were associated with aortic stiffness in geriatric diabetic patients. Blood samples were obtained from 130 diabetic participants aged ≥ 65 years. We defined high aortic stiffness based on a carotid–femoral pulse wave velocity (cfPWV) of >10 m/s. Circulating adiponectin concentrations were examined using enzyme-linked immunosorbent assays. Sixty-six participants (50.8%) had aortic stiffness. Patients with aortic stiffness had lower serum adiponectin concentrations than those in the control group (p < 0.001). Multivariate logistic regression analysis showed that the adiponectin level (odds ratio: 0.939, 95% confidence interval: 0.898–0.981, p = 0.005) was an independent predictor of aortic stiffness in elderly diabetic persons. Multivariate forward stepwise linear regression analysis also demonstrated that the adiponectin level (β = −0.256, adjusted R2 change = 0.100, p = 0.003) was negatively associated with cfPWV values in older diabetic patients. In conclusion, serum adiponectin is negatively correlated with cfPWV and is an independent predictor of aortic stiffness in elderly diabetic persons.

Comparison of Intravascular Ultrasound Virtual Histology Parameters in Diabetes versus Non-Diabetes with Acute Coronary Syndrome

Introduction: The progression and pattern of coronary atherosclerosis in diabetes mellitus (DM) is different from non-DM, leading to a higher rate of vascular complications in DM. Objective: This study aims to assess and compare the high-risk plaque characteristics in the culprit artery of DM and non-DM patients with acute coronary syndrome (ACS) using virtual histology intravascular ultrasound (VH-IVUS). Methods: A total of 158 ACS patients were included, 63 of whom were known to have DM. IVUS analysis was done in the de novo target vessel and culprit lesion for which percutaneous coronary intervention was planned. Culprit lesions with a visual-estimate angiographic stenosis of <70% were excluded. Results: The mean age of patients was 52.4 ± 11.6 years. The study group comprised 82% men, 31% with hypertension, and 39.87% with DM. No significant difference was observed between the DM and non-DM groups in relation to quantitative IVUS parameters like lesion length, minimal lumen area, and plaque area. However, there was a significant difference in VH-IVUS parameters like higher necrotic core and dense calcium in the DM patients than in the non-DM patients (p < 0.01). The occurrence of VH-derived thin-cap fibroatheroma (VH-TCFA) in the culprit vessel was significantly higher in the DM group than in the non-DM group (25.3 vs. 5.2%; p < 0.01). Positive vessel-wall remodeling was noted in both groups without any significant difference (p = 0.74). Conclusion: The DM patients had high-risk plaque composition features like a higher necrotic core, which is a marker of plaque vulnerability. Thus, aggressive medical therapy targeting vascular inflammation using high-dose statins would help in the stabilization of unstable plaque morphology and the reduction of major cardiovascular events.

Current Data Regarding the Relationship between Type 2 Diabetes Mellitus and Cardiovascular Risk Factors.

Reducing cardiovascular risk (CVR) is the main focus of diabetes mellitus (DM) management nowadays. Complex pathogenic mechanisms that are the subject of this review lead to early and severe atherosclerosis in DM patients. Although it is not a cardiovascular disease equivalent at the moment of diagnosis, DM subjects are affected by numerous cardiovascular complications, such as acute coronary syndrome, stroke, or peripheral artery disease, as the disease duration increases. Therefore, early therapeutic intervention is mandatory and recent guidelines focus on intensive CVR factor management: hyperglycaemia, hypertension, and dyslipidaemia. Most important, the appearance of oral or injectable antidiabetic medication such as SGLT-2 inhibitors or GLP-1 agonists has proven that an antidiabetic drug not only reduces glycaemia, but also reduces CVR by complex mechanisms. A profound understanding of intimate mechanisms that generate atherosclerosis in DM and ways to inhibit or delay them are of the utmost importance in a society where cardiovascular morbidity and mortality are predominant.

Prostaglandin E2 confers protection against diabetic coronary atherosclerosis by stimulating M2 macrophage polarization via the activation of the CREB/BDNF/TrkB signaling pathway.

It has been documented that M2 macrophage polarization plays a suppressive role in atherosclerosis in diabetes mellitus (DM). In addition, prostaglandin E2 (PGE2) is implicated in the development of M2 macrophage polarization. Therefore, the study aimed to investigate the specific mechanism of PGE2 in M2 macrophage polarization in diabetic coronary atherosclerosis (DMAS). Initially, clinical samples were obtained and DMAS mouse model was established. The expression of BDNF was determined, and M1 and M2 macrophage polarizations were evaluated. Then, the levels of BDNF and PGE2 were modified in DMAS mice and the serum indicator, atherosclerotic plaque, lipid uptake by PBMCs, as well as M1 and M2 macrophage polarization were determined. Macrophages were isolated and the effects of PGE2 and the CREB/BDNF/TrkB signaling pathway on M2 macrophage polarization were explored. BDNF was downregulated and macrophages were differentiated into M1 in DMAS patients and mice. BDNF and PGE2 were observed to promote M2 macrophage polarization, where atherosclerotic plaque and lipid uptake by PBMCs were reduced, and DMAS was alleviated in mice. Overexpression of BDNF activated the CREB/BDNF/TrkB signaling pathway and stimulated M2 macrophage polarization in macrophages. PGE2 stimulated M2 macrophage polarization by inducing KLF4 via the activation of the CREB/BDNF/TrkB signaling pathway. This study demonstrates that PGE2 promotes M2 macrophage polarization by activating the CREB/BDNF/TrkB signaling pathway, thus alleviating DMAS.

Risk of coronary artery disease according to glucose abnormality status and prior coronary artery disease in Japanese men

ObjectiveAlthough glucose abnormality status (GAS), prior coronary artery disease (CAD), and other traditional risk factors affect the incidence of subsequent CAD, their impact in the same cohort has been scantly studied. Research design and methodsWe analyzed data from a nationwide claims database in Japan that was accumulated during 2008–2016 involving 138,162 men aged 18–72 years. Participants were classified as having normoglycemia, borderline glycemia, or diabetes mellitus (DM) with prior CAD (CAD+) or without prior CAD (CAD−). Cox regression model identified variables related to the incidence of CAD. ResultsAmong CAD−, management of traditional risks differed from those with and without subsequent CAD events. On the other hand, such differences were weaker in borderline glycemia and DM CAD+, and the influence of traditional risk factors on subsequent CAD was not observed. Cox regression model showed that borderline glycemia and DM confer approximately 1.2- and 2.8-fold excess risks of CAD, respectively, compared with CAD− with normoglycemia. CAD+ confers approximately a 5- to 8-fold increased risk. The impacts of DM and prior CAD additively reached a hazard ratio (HR) of 15.74 (95% confidence interval [CI]: 11.82–21.00). However, the HR in those with borderline glycemia and CAD+ was 7.20 (95% CI: 5.01–10.34), which was not different from those with normoglycemia and CAD+. ConclusionControl status of traditional risk factors and impact on subsequent CAD differ among categories of glycemic status with and without prior CAD. Individualizing treatment strategies is needed in consideration of risk factors, such as GAS and CAD+.

Examination of Clinical and Demographic Characteristics of 14 Cases with Frontal Fibrosing Alopecia

Objective: Frontal fibrosing alopecia (FFA) is a rare type of cicatricial alopecia seen in postmenopausal women characterized with band-type frontal/frontotemporal hair traction and/or significant or complete loss of the eyebrows. We aimed to present the demographic, clinical and laboratory characteristics of female patients diagnosed and followed-up with FFA in our clinic by comparing these with the literature data. Method: A total of 14 patients who admitted to our outpatient clinic with alopecia on the frontotemporal/frontal hairline and were clinically and/or histopathologically diagnosed with FFA between 2011 and 2016 were evaluated in a retrospective manner. The patients were reviewed in terms of the age of lesion onset, localization, accompanying symptom or disease, and treatment options. Results: The ages of the patients who were followed-up in our outpatient clinic with FFA were between 52 and 73 (mean 2 years). Eight patients (57%) had total eyebrow loss,. Laboratory tests were in normal limits or negative. Comorbidities included thyroid disease, hypertension and coronary artery disease diabetes mellitus. For treatment, all patients were given systemic, intralesional and topical steroid, and topical minoxidil at various times. Four patients received hydroxychloroquine, 2 patients acitretin, 2 patients Vitamin E, 1 patient itraconazole, and 1 patient topical tacrolimus. Conclusion: FFA should be considered in middle aged and elderly postmenopausal women presenting with hair loss complaints and were detected to have frontal hairline traction and cicatricial alopecia, and the diagnosis should be supported by biopsy. Thereby, the disease progression may be prevented or delayed with early diagnosis and proper treatment..

Endothelial TNF-α induction by Hsp60 secreted from THP-1 monocytes exposed to hyperglycaemic conditions.

A non-resolving inflammation of the endothelium is recognised to be an important process leading to atherosclerosis. In diabetes, this process is thought to account for a significant number of cardiovascular disease-associated death and disability. However, the molecular mechanisms by which diabetes contributes to endothelial inflammation remain to be established. Whilst there is some evidence linking hyperglycaemia-induced reactive oxygen species (ROS) formation by the mitochondrial electron-transport chain to oxidative stress, cellular injury and apoptosis in the endothelium, a clear link to endothelium inflammation has not yet been established. The mitochondrial molecular stress protein Hsp60 is known to be secreted from mammalian cells and is capable of activating pro-inflammatory mediators on target cells expressing Toll-like receptors (TLRs). Hsp60 is also known to be elevated in serum of diabetes patients and has been shown to be upregulated by hyperglycaemic growth conditions in cultured human HeLa cells. This study shows that Hsp60 induced in human acute monocyte leukaemia cell line (THP-1) cells grown under hyperglycaemic conditions (25mM glucose) was able to be secreted into growth media. Furthermore, the secretion of Hsp60 from THP-1 cells was able to be inhibited by 5,5-(N-N-dimethyl)-amiloride hydrochloride (DMA), an exosomal inhibitor. Interestingly, the conditioned media obtained from THP-1 cells grown in the presence of 25mM glucose was able to induce the secretion of TNF-α in human vascular endothelium cell line (HUVEC). When conditioned media was immuno-depleted of Hsp60, there was a significant reduction in the release of TNF-α from the HUVEC cells. This suggests that a potential link may exist between hyperglycaemia-induced expression of Hsp60 in monocyte cells and vascular inflammation. Circulating levels of Hsp60 due to mitochondrial stress in diabetes patients could therefore be an important modulator of inflammation in endothelial cells and thus contribute to the increased incidences of atherosclerosis in diabetes mellitus.

Relation between low-density lipoprotein cholesterol/apolipoprotein B ratio and triglyceride-rich lipoproteins in patients with coronary artery disease and type 2 diabetes mellitus: a cross-sectional study

BackgroundThe low-density lipoprotein cholesterol/apolipoprotein B (LDL-C/apoB) ratio has conventionally been used as an index of the LDL-particle size. Smaller LDL-particle size is associated with triglyceride (TG) metabolism disorders, often leading to atherogenesis. We investigated the association between the LDL-C/apoB ratio and TG metabolism in coronary artery disease (CAD) patients with diabetes mellitus (DM).MethodsIn the cross-sectional study, the LDL-C/apoB ratio, which provides an estimate of the LDL-particle size, was calculated in 684 consecutive patients with one additional risk factor. The patients were classified into 4 groups based on the presence or absence of CAD and DM, as follows: CAD (−) DM (−) group, n = 416; CAD (−) DM (+) group, n = 118; CAD (+) DM (−) group, n = 90; CAD (+) DM (+) group, n = 60.ResultsA multi-logistic regression analysis after adjustments for coronary risk factors revealed that the CAD (+) DM (+) condition was an independent predictor of the smallest LDL-C/apoB ratio among the four groups. Furthermore, multivariate regression analyses identified elevated TG-rich lipoprotein (TRL)-related markers (TG, very-LDL fraction, remnant-like particle cholesterol, apolipoprotein C-II, and apolipoprotein C-III) as being independently predictive of a smaller LDL-particle size in both the overall subject population and a subset of patients with a serum LDL-C level < 100 mg/dL. In the 445 patients followed up for at least 6 months, multi-logistic regression analyses identified increased levels of TRL-related markers as being independently predictive of a decreased LDL-C/apoB ratio, which is indicative of smaller LDL-particle size.ConclusionsThe association between disorders of TG metabolism and LDL heterogeneity may account for the risk of CAD in patients with DM. Combined evaluation of TRL-related markers and the LDL-C/apoB ratio may be of increasing importance in the risk stratification of CAD patients with DM. Further studies are needed to investigate the useful clinical indices and outcomes of these patients.Clinical Trial Registration UMIN (http://www.umin.ac.jp/) Study ID: UMIN000028029 retrospectively registered 1 July 2017

AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages

Background and aimsAdvanced glycation end products (AGEs) induce cellular oxidative/endoplasmic reticulum stress and inflammation. We investigated its underlying mechanisms for atherogenesis focusing on regulation of ABCA1 protein decay in macrophages. MethodsThe ABCA1 decay rate was evaluated in macrophages after treatment with LXR agonist and by incubation with control (C) or AGE-albumin concomitant or not with cycloheximide, MG-132, ammonium chloride and calpain inhibitors were utilized to inhibit, respectively, proteasome, lysosome and ABCA1 proteolysis at cell surface. ABCA1 was determined by immunoblot and the protein decay rate calculated along time by the slope of the linear regression. Ubiquitination level was determined in ABCA1 immunoprecipitated from whole cell lysate or bulk cell membrane. AGE effect was also analyzed in THP-1 cells transfected with siRNA-RAGE. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/MS. One-way ANOVA and Student t test were utilized to compare results. ResultsCML and PYR-albumin were higher in AGE-albumin as compared to C. AGE-albumin reduced ABCA1 in J774 and THP-1 macrophages (20–30%) and induced a higher ABCA1 ubiquitination and a faster protein decay rate that was dependent on the presence of AGE during the kinetics of measurement in the presence of cycloheximide. Proteasomal inhibition restored and lysosomal inhibition partially recovered ABCA1 in cells treated with AGE-albumin. Calpain inhibition was not able to rescue ABCA1. RAGE knockdown prevented the reduction in ABCA1 elicited by AGE. ConclusionsAGE-albumin diminishes ABCA1 by accelerating its degradation through the proteasomal and lysosomal systems. This may increase lipid accumulation in macrophages by diminishing cholesterol efflux via RAGE signaling contributing to atherosclerosis in diabetes mellitus.

Association study to evaluate TFPI gene in CAD in Han Chinese

BackgroundTissue factor pathway inhibitor (TFPI) is the main physiological inhibitor of TF-induced blood coagulation process, and may play essential roles in the pathogenesis of major adverse cardiac events. This study was designed to determine whether the variation of TFPI was related with coronary artery disease (CAD) in the Han Chinese populations.MethodsA total of 1271 patients with coronary atherosclerosis and 1287 normal individuals from northern China were enrolled in the present study. Four tagging single-nucleotide polymorphisms (SNPs) (rs7586970, rs6434222, rs10153820 and rs8176528) from TFPI were selected and genotyped by direct sequencing. And the genotypes of the above SNPs were determined in all these participants.ResultsIn the populations from Beijing and Harbin, no significant case-control differences in the frequencies of TFPI polymorphism (rs10153820 and rs8176528) were observed between CAD patients and controls. Meanwhile, two SNPs of TFPI (rs7586970 and rs6434222) were found to be associated with CAD in both groups. In stratified analyses based on gender, smoking, hypertension, diabetes mellitus and hyperlipidemia, we further determined that the investigated genetic variations of the TFPI genes seemed to be related with diabetes mellitus in CAD patients.ConclusionsGenetic variations of the TFPI genes seem to be related with CAD, which likely cooperate with metabolic risk factor (diabetes mellitus) and play critical roles in the pathogenesis of coronary artery disease.

Karin Bornfeldt

Karin Bornfeldt is stubborn. Once she gets curious about something, she does not let it go—turning questions around in her head, examining the issue from varying perspectives, thinking about alternative solutions, and applying a variety of tools to the problem. The question that sparked Bornfeldt’s curiosity during her PhD research at the University of Linkoping was how diabetes mellitus accelerates atherosclerosis. She has never lost interest, and in 3 decades of research, she has worked to uncomplicate the most deadly of diabetic complications. Bornfeldt, joint professor of medicine and pathology at the University of Washington in Seattle, arrived at the university in 1991 as a postdoc to work with Russell Ross, PhD, and Edwin Krebs, MD. She joined the faculty in 1995 and is now associate director of the Diabetes and Obesity Center of Excellence, deputy director of the Diabetes Research Center, and director of the Viral Vector and Transgenic Mouse Core at the university. Karin Bornfeldt When Bornfeldt established her independent laboratory in 1997, she recognized the need for a mouse model of diabetes mellitus–accelerated atherosclerosis that could separate the effects of diabetes mellitus per se from the effects of diabetes mellitus–induced hyperlipidemia. The laboratory created a transgenic mouse that develops type 1 diabetes mellitus in a process similar to that of type 1 in humans, with viral infection inducing T-cell–mediated destruction of beta cells, and also develops atherosclerosis. Using that model, the team showed that, even with no lipid abnormalities or cholesterol in the diet, diabetes mellitus accelerates the initiation of atherosclerotic lesions by stimulating macrophage accumulation within the vascular wall. In contrast, when the mice are fed a cholesterol-rich diet and then given diabetes mellitus, they develop severe hypertriglyceridemia and advanced atherosclerotic plaques.1 Later, when the team induced type 1 diabetes mellitus in mice after they …

Stroke-free status and depression scores among Saudi dialysis patients

Background: To assess the prevalence of stroke symptoms and depression among Saudi dialysis patients and related factors. Methods: This is a cross-sectional multicentre study of Saudi dialysis patients. Demographics, clinical and laboratory’s data were collected. Freedom from stroke symptoms was assessed using the Questionnaire for Verifying Stroke-Free Status and depression using the Geriatric Depression Scale. Results: Five-hundred and forty-nine patients (77.3% response rate); 94.6% were receiving hemodialysis and 5.4% peritoneal dialysis were included in the study. Freedom from stroke was reported in 76.6% of patients, was higher in females (p = 0.07), and was not affected by the presence of diabetes mellitus coronary artery disease or peripheral vascular disease. However, it was significantly lower in hypertensive patients (p = 0.035) and was not affected by age, dialysis duration, Kt/V, albumin or hemoglobin levels. It was, however, more prevalent in the non-depressed patients compared to depressed patients (p = 0.036). Mild and major depression scores were noted in 45.2% and 6.1%, respectively; the depression score being significantly higher in HD than in PD patients (6.3 ± 3.4 vs. 5.0 ± 3.2 p = 0.049) but was not related to sex, employment, vascular access type, age, dialysis duration, Kt/V or serum albumin or hemoglobin levels. Conclusion: A quarter of the patients were not stroke symptom-free and these were more likely the depressed patients, in females, but significantly less in hypertensive patients. Almost half of the patients were depressed with 6.1% having major depression. The depression score was significantly higher in HD than in PD patients.

Risk Factors Associated with Hypercoagulability in Type 2 Diabetes Mellitus Patients at Ndola Central Hospital Zambia

Background: Thrombosis, attributed to atherosclerosis, is the leading cause of morbidity and mortality in patients with diabetes mellitus. Pathogenesis of atherosclerosis in diabetes mellitus is not entirely clear and conventional risk factors such as smoking, obesity, blood pressure and serum lipids fail to explain fully this excess risk. We set out a cross-sectional study to determine the risk factors and patient attributes that may predispose type 2 Diabetes Mellitus (T2DM) patients to be in hypercoagulable state. Methods: A structured questionnaire was used to capture Age, Sex, duration of diabetes mellitus and knowledge on T2DM of study participants. Body weight and height were also measured and BMI calculated.VWF, Cholesterol, and Glycated haemoglobin were measured in 213 T2DM patients. VWF was used as a proxy marker for hypercoagulability in T2DM patients. Participants with VWF of >2.0 IU/ml plasma concentration were regarded to be in hypercoagulable state. Results: Chi-square analysis revealed that hypercoagulability in T2DM patients was associated with Age (P=0.001), Sex (P=0.000), glycaemic control (P=0.003), duration of diabetes (P=0.000), BMI (P=0.000) and knowledge on type 2 diabetes mellitus (P=0.001). In multivariate analysis after adjusting for confounders, knowledge on T2DM was not independently associated with hypercoagulability AOR being 1.00(CI 95% 0.80-2.20). However Age, sex, glycaemic control, duration of diabetes and BMI were found to be independent r i sk f a c tor s for hypercoagulability in T2DM patients giving AOR of 1.45(95%CI[1.19-3.16]), 4.42 (95% CI [2.77-10.63]), 6.12 (95% CI 2.27-8.36) 5.28(CI 95% 3.01-8.21) and 1.05(95% CI 0.75-2.86) respectively. Conclusion: Age, Sex, poor glycaemic control, duration of diabetes and obesity should be taken into account in the management of T2DM patients as these variables are independent risk factors of hypercoagulability in T2DM patients.