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1.  Impact of obesity and epicardial fat on early left atrial dysfunction assessed by cardiac MRI strain analysis 
Background
Diastolic dysfunction is a major cause of morbidity in obese individuals. We aimed to assess the ability of magnetic resonance imaging (MRI) derived left atrial (LA) strain to detect early diastolic dysfunction in individuals with obesity and type 2 diabetes, and to explore the association between cardiac adipose tissue and LA function.
Methods
Twenty patients with obesity and T2D (55 ± 8 years) and nineteen healthy controls (48 ± 13 years) were imaged using cine steady state free precession and 2-point Dixon cardiovascular magnetic resonance. LA function was quantified using a feature tracking technique with definition of phasic longitudinal strain and strain rates, as well as radial motion fraction and radial velocities.
Results
Systolic left ventricular size and function were similar between the obesity and type 2 diabetes and control groups by MRI. All patients except four had normal diastolic assessment by echocardiography. In contrast, measures of LA function using magnetic resonance feature tracking were uniformly altered in the obesity and type 2 diabetes group only. Although there was no significant difference in intra-myocardial fat fraction, Dixon 3D epicardial fat volume(EFV) was significantly elevated in the obesity and type 2 diabetes versus control group (135 ± 31 vs. 90 ± 30 mL/m2, p < 0.001). There were significant correlations between LA functional indices and both BMI and EFV (p ≤ 0.007).
Conclusions
LA MRI-strain may be a sensitive tool for the detection of early diastolic dysfunction in individuals with obesity and type 2 diabetes and correlated with BMI and epicardial fat supporting a possible association between adiposity and LA strain.
Trials Registration Australian New Zealand Clinical Trials Registry No. ACTRN12613001069741
doi:10.1186/s12933-016-0481-7
PMCID: PMC5178096  PMID: 28007022
Diastolic dysfunction; Cardiac dysfunction; Magnetic resonance studies; Fat distribution; Obesity and type 2
2.  Ankle-brachial index and incident diabetes mellitus: the atherosclerosis risk in communities (ARIC) study 
Background
Individuals with peripheral artery disease (PAD) often have reduced physical activity, which may increase the future risk of diabetes mellitus. Although diabetes is a risk factor for PAD, whether low ankle-brachial index (ABI) predates diabetes has not been studied.
Methods
We examined the association of ABI with incident diabetes using Cox proportional hazards models in the ARIC Study. ABI was measured in 12,247 black and white participants without prevalent diabetes at baseline (1987–1989). Incident diabetes cases were identified by blood glucose levels at three subsequent visits (1990–92, 1993–95, and 1996–98) or self-reported physician diagnosis or medication use at those visits or during annual phone interview afterward through 2011.
Results
A total of 3305 participants developed diabetes during a median of 21 years of follow-up. Participants with low (≤0.90) and borderline low (0.91–1.00) ABI had 30–40% higher risk of future diabetes as compared to those with ABI of 1.10–1.20 in the demographically adjusted model. The associations were attenuated after further adjustment for other potential confounders but remained significant for ABI 0.91–1.00 (HR = 1.17, 95% CI 1.04–1.31) and marginally significant for ABI ≤ 0.90 (HR = 1.19, 0.99–1.43). Although the association was largely consistent across subgroups, a stronger association was seen in participants without hypertension, those with normal fasting glucose, and those with a history of stroke compared to their counterparts.
Conclusions
Low ABI was modestly but independently associated with increased risk of incident diabetes in the general population. Clinical attention should be paid to the glucose trajectory among people with low ABI but without diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0476-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0476-4
PMCID: PMC5142100  PMID: 27923363
Ankle-brachial index; Peripheral artery disease; Diabetes mellitus; Community-based study; Prospective cohort study
3.  Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study 
Background
Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM.
Methods
We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naïve to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500–3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter.
Results
There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months.
Conclusions
Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study.
Trial Registration ClinicalTrials.gov: NCT01715428.
doi:10.1186/s12933-016-0480-8
PMCID: PMC5135832  PMID: 27912784
Liraglutide; Cardiovascular risk; Carotid intima-media thickness; Metabolic syndrome
4.  Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis 
Background
Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is a major contributor to the development of atherosclerotic process. In a previous work, we demonstrated that the insulin receptor isoform A (IRA) and its association with the insulin-like growth factor-I receptor (IGF-IR) confer a proliferative advantage to VSMCs. However, the role of IR and IGF-IR in VSMC migration remains poorly understood.
Methods
Wound healing assays were performed in VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs). To study the role of IR isoforms and IGF-IR in experimental atherosclerosis, we used ApoE−/− mice at 8, 12, 18 and 24 weeks of age. Finally, we analyzed the mRNA expression of total IR, IRB isoform, IGF-IR and IGFs by qRT-PCR in the medial layer of human aortas.
Results
IGF-I strongly induced migration of the four cell lines through IGF-IR. In contrast, insulin and IGF-II only caused a significant increase of IRA VSMC migration which might be favored by the formation of IRA/IGF-IR receptors. Additionally, a specific IGF-IR inhibitor, picropodophyllin, completely abolished insulin- and IGF-II-induced migration in IRB, but not in IRA VSMCs. A significant increase of IRA and IGF-IR, and VSMC migration were observed in fibrous plaques from 24-week-old ApoE−/− mice. Finally, we observed a marked increase of IGF-IR, IGF-I and IGF-II in media from fatty streaks as compared with both healthy aortas and fibrolipidic lesions, favoring the ability of medial VSMCs to migrate into the intima.
Conclusions
Our data suggest that overexpression of IGF-IR or IRA isoform, as homodimers or as part of IRA/IGF-IR hybrid receptors, confers a stronger migratory capability to VSMCs as might occur in early stages of atherosclerotic process.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0477-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0477-3
PMCID: PMC5134076  PMID: 27905925
Atherosclerosis; Insulin receptor; Migration; Vascular smooth muscle cells
5.  Characteristics and outcomes of diabetic patients with an implantable cardioverter defibrillator in a real world setting: results from the Israeli ICD registry 
Aims
There are limited data regarding the effect of diabetes mellitus (DM) on the risks of both appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy. The present study was designed to compare the outcome of appropriate and inappropriate ICD therapy in patients with or without DM.
Methods and results
The risk of a first appropriate ICD therapy for ventricular tachyarrhythmias (including anti tachycardia pacing and shock) was compared between 764 DM and 1346 non-DM patients enrolled in the national Israeli ICD registry. We also compared the risks of inappropriate ICD therapy, and death or cardiac hospitalization between diabetic and non-diabetic patients. Diabetic patients were older, were more likely to have ischemic cardiomyopathy, lower ejection fraction, atrial fibrillation, and other co-morbidities. The 3-year cumulative incidence of appropriate ICD therapy was similar in the DM and non-DM groups (12 and 13%, respectively, p = 0.983). Multivariate analysis showed that DM did not affect the risk of appropriate ICD therapy (HR = 1.07, 95% CI 0.78–1.47, p = 0.694) or inappropriate therapy (HR = 0.72, 95% CI 0.42–1.23, p = 0.232). However, DM was associated with a 31% increased risk for death or cardiac hospitalization (p = 0.005). Results were similar in subgroup analyses including ICD and defibrillators with cardiac resynchronization therapy function recipients, primary or secondary prevention indication for an ICD.
Conclusions
Despite a significant excess of cardiac hospitalizations and mortality in the diabetic population, there was no difference in the rate of ICD treatments, suggesting that the outcome difference is not related to arrhythmias.
doi:10.1186/s12933-016-0478-2
PMCID: PMC5134232  PMID: 27905927
Implantable cardioverter defibrillator; Diabetes mellitus; Heart failure; Outcomes
6.  Impact of visceral fat on gene expression profile in peripheral blood cells in obese Japanese subjects 
Background
Visceral fat plays a central role in the development of metabolic syndrome and atherosclerotic cardiovascular diseases. The association of visceral fat accumulation with cardio-metabolic diseases has been reported, but the impact of visceral fat on the gene expression profile in peripheral blood cells remains to be determined. The aim of this study was to determine the effects of visceral fat area (VFA) and subcutaneous fat area (SFA) on the gene expression profile in peripheral blood cells of obese subjects.
Methods
All 17 enrolled subjects were hospitalized to receive diet therapy for obesity (defined as body mass index, BMI, greater than 25 kg/m2). VFA and SFA were measured at the umbilical level by computed tomography (CT). Blood samples were subjected to gene expression profile analysis by using SurePrint G3 Human GE Microarray 8 × 60 k ver. 2.0. The correlation between various clinical parameters, including VFA and SFA, and peripheral blood gene expression levels was analyzed.
Results
Among the 17 subjects, 12 had normal glucose tolerance or borderline diabetes, and 5 were diagnosed with type 2 diabetes without medications [glycated hemoglobin (HbA1c); 6.3 ± 1.3%]. The mean BMI, VFA, and SFA were 30.0 ± 5.5 kg/m2, 177 ± 67 and 245 ± 131 cm2, respectively. Interestingly, VFA altered the expression of 1354 genes, including up-regulation of 307 and down-regulation of 1047, under the statistical environment that the parametric false discovery rate (FDR) was less than 0.1. However, no significant effects were noted for SFA or BMI. Gene ontology analysis showed higher prevalence of VFA-associated genes than that of SFA-associated genes, among the genes associated with inflammation, oxidative stress, immune response, lipid metabolism, and glucose metabolism.
Conclusions
Accumulation of visceral fat, but not subcutaneous fat, has a significant impact on the gene expression profile in peripheral blood cells in obese Japanese subjects.
doi:10.1186/s12933-016-0479-1
PMCID: PMC5129204  PMID: 27899146
Obesity; Visceral fat; Subcutaneous fat; Fat distribution; Gene expression; Microarray; Metabolic syndrome; Diabetes; Adiponectin; KLF
7.  Relationship of cardiometabolic parameters in non-smokers, current smokers, and quitters in diabetes: a systematic review and meta-analysis 
Background
Smoking is associated with increased macrovascular and microvascular complications in people with diabetes. In addition to other concomitant vascular perturbations, it also seems to influence the cardiometabolic parameters, which may partly explain the accelerated rate of vascular complications in smokers with diabetes. While smoking cessation is advocated as a universal component of the management of diabetes, there is some anecdotal evidence that HbA1c could increase following smoking cessation. The aim of this review is to explore the relationship between smoking and its cessation on cardiometabolic parameters in diabetes.
Methods
Searches were conducted on Medline, EMBASE and CINAHL up to March 2016. After screening 6866 studies (Additional file 1), 14 observational studies with a total of 98,978 participants’ with either type 1 or type 2 diabetes were selected for review. Narrative synthesis and meta-analyses were carried out to explore the relationship between smoking and its cessation.
Results
Meta-analysis showed that the pooled mean difference of HbA1c between non-smokers and smokers was −0.61% (95% CI −0.88 to −0.33, p < 0.0001). The difference in LDL cholesterol between non-smokers and smokers was −0.11 mmol/l (95% CI −0.21 to −0.01, p = 0.04). The difference in HDL cholesterol between non-smokers and smokers was 0.12 mmol/l (95% CI 0.08–0.15, p < 0.001). However, there was no statistically significant difference in blood pressure between the two groups. The difference in HbA1c between quitters and continued smokers was not statistically significant −0.10% (95% CI −0.42 to 0.21, p = 0.53). However, a narrative synthesis revealed that over a period of 10 years, the HbA1c was comparable between non-smokers and quitters.
Conclusion
Non-smokers have a statistically significant lower HbA1c and more favourable lipid profile compared to smokers. Smoking cessation does not lead to an increase in HbA1c in long-term and may reduce vascular complications in diabetes by its favourable impact on lipid profile.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0475-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0475-5
PMCID: PMC5121966  PMID: 27881170
Smoking; Smoking cessation; Glycosylated haemoglobin (HbA1c); Diabetes; Low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol: blood pressure (systolic and diastolic—SBP and DBP)
8.  Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome 
Background
The potential benefit of SGLT2 inhibitors in metabolic syndrome is with prediabetic stage unclear. This work was undertaken to investigate the non-glycemic effect of empagliflozin on metabolic syndrome rats with prediabetes.
Methods
SHR/NDmcr-cp(+/+) rats (SHRcp), a model of metabolic syndrome with prediabetes, were given empagliflozin for 10 weeks to examine the effects on urinary sodium and water balance, visceral and subcutaneous adipocyte, and cardiac injury. Further, the effect of empagliflozin on blood pressure and autonomic nervous system was continuously investigated by using radiotelemetry system.
Results
Empagliflozin significantly reduced urinary sodium and water balance of SHRcp only within 1 week of the treatment, but later than 1 week did not alter them throughout the treatment. Empagliflozin significantly reduced body weight of SHRcp, which was mainly attributed to the significant reduction of subcutaneous fat mass. Empagliflozin significantly reduced the size of visceral adipocytes and increased the number of smaller size of adipocytes, which was associated with the attenuation of oxidative stress. Empagliflozin ameliorated cardiac hypertrophy and fibrosis of SHRcp, in association with the attenuation of cardiac oxidative stress and inflammation. However, empagliflozin did not significantly change blood pressure, heart rate, sympathetic activity, or baroreceptor function, as evidenced by radiotelemetry analysis.
Conclusions
Our present work provided the evidence that SGLT2 inhibition reduced visceral adipocytes hypertrophy and ameliorated cardiac injury in prediabetic metabolic syndrome rat, independently of diuretic effect or blood pressure lowering effect. Thus, SGLT2 inhibition seems to be a promising therapeutic strategy for prediabetic metabolic syndrome.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0473-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0473-7
PMCID: PMC5106779  PMID: 27835975
Cardiac protection; Oxidative stress; Inflammation; Metabolic syndrome; Prediabetes; Natriuresis; Adipose tissue
9.  Correlation between insulin-induced estrogen receptor methylation and atherosclerosis 
Background
Hyperinsulinemia and insulin resistance have been recently recognized as an important cause of atherosclerosis. Clinical studies have also found that expression of the estrogen receptor is closely related to the incidence of atherosclerosis. This study investigate the effects of insulin and estrogen receptor α (ER-α) in atherosclerosis.
Methods
Double knockout ApoE/Lepr mice were given intraperitoneal injections of insulin, and their aortae were harvested for hematoxylin-eosin staining and immunohistochemical analysis. In addition, vascular smooth muscle cells (VSMCs) were treated with insulin or infected with a lentivirus encoding exogenous ER-α, and changes in gene expression were detected by real-time polymerase chain reaction and western blotting. The methylation levels of the ER-α gene were tested using bisulfite sequencing PCR, and flow cytometry and EdU assay were used to measure VSMCs proliferation.
Results
Our results showed that insulin can induce the formation of atherosclerosis. Gene expression analysis revealed that insulin promotes the expression of DNA methyltransferases and inhibits ER-α expression, while 5-aza-2′-deoxycytidine can inhibit this effect of insulin. Bisulfite sequencing PCR analysis showed that methylation of the ER-α second exon region increased in VSMCs treated with insulin. The results also showed that ER-α can inhibit VSMCs proliferation.
Conclusions
Our data suggest that insulin promotes the expression of DNA methyltransferases, induces methylation of ER-α second exon region and decreases the expression of ER-α, thereby interfering with estrogen regulation of VSMCs proliferation, resulting in atherosclerosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0471-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0471-9
PMCID: PMC5105242  PMID: 27832775
VSMC; Insulin; Estrogen receptor (ER); DNA methylation; Epigenetics
10.  Obesity-induced cardiac lipid accumulation in adult mice is modulated by G protein-coupled receptor kinase 2 levels 
Background
The leading cause of death among the obese population is heart failure and stroke prompted by structural and functional changes in the heart. The molecular mechanisms that underlie obesity-related cardiac remodeling are complex, and include hemodynamic and metabolic alterations that ultimately affect the functionality of the myocardium. G protein-coupled receptor kinase 2 (GRK2) is an ubiquitous kinase able to desensitize the active form of several G protein-coupled receptors (GPCR) and is known to play an important role in cardiac GPCR modulation. GRK2 has also been recently identified as a negative modulator of insulin signaling and systemic insulin resistance.
Methods
We investigated the effects elicited by GRK2 downregulation in obesity-related cardiac remodeling. For this aim, we used  9 month-old wild type (WT) and GRK2+/− mice, which display circa 50% lower levels of this kinase, fed with either a standard or a high fat diet (HFD) for 30 weeks. In these mice we studied different parameters related to cardiac growth and lipid accumulation.
Results
We find that GRK2+/− mice are protected from obesity-promoted cardiac and cardiomyocyte hypertrophy and fibrosis. Moreover, the marked intracellular lipid accumulation caused by a HFD in the heart is not observed in these mice. Interestingly, HFD significantly increases cardiac GRK2 levels in WT but not in GRK2+/− mice, suggesting that the beneficial phenotype observed in hemizygous animals correlates with the maintenance of GRK2 levels below a pathological threshold. Low GRK2 protein levels are able to keep the PKA/CREB pathway active and to prevent HFD-induced downregulation of key fatty acid metabolism modulators such as Peroxisome proliferator-activated receptor gamma co-activators (PGC1), thus preserving the expression of cardioprotective proteins such as mitochondrial fusion markers mitofusin MFN1 and OPA1.
Conclusions
Our data further define the cellular processes and molecular mechanisms by which GRK2 down-regulation is cardioprotective during diet-induced obesity, reinforcing the protective effect of maintaining low levels of GRK2 under nutritional stress, and showing a role for this kinase in obesity-induced cardiac remodeling and steatosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0474-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0474-6
PMCID: PMC5105284  PMID: 27832814
Cardiac steatosis; Obesity; Insulin resistance; G protein-coupled receptor kinase 2; Cardiac hypertrophy; Mitochondria
11.  Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study 
Background
Trelagliptin, an oral DPP-4 inhibitor, which is administered once per week and characterized by a long half-life in blood. The effects of trelagliptin on vascular endothelial functions have not been clarified to date. The objective of the present study was to examine the effects of trelagliptin on vascular endothelial functions in patients with type 2 diabetes mellitus (DM) using flow-mediated dilatation (FMD), adiponectin, and asymmetric dimethylarginine (ADMA) as evaluation indicators.
Methods
This study was a preliminary single-arm prospective pilot study. The subjects of this study were type 2 DM patients aged 20–74 years, who visited our outpatient department. The patients were treated with trelagliptin, and their FMD, adiponectin, and ADMA levels were measured at baseline and at 12 weeks after initial treatment to determine the changes during the study period.
Results
A total of 27 patients, excluding three dropouts, were included in the population for analysis. Trelagliptin treatment showed no significant changes in FMD (2.42 ± 2.7% at baseline vs. 2.66 ± 3.8% post-treatment, P = 0.785) and ADMA (0.41 ± 0.0 µg/mL at baseline vs. 0.40 ± 0.0 µg/mL post-treatment, P = 0.402). Trelagliptin treatment resulted in a significant increase of serum adiponectin level (7.72 ± 6.9 µg/mL at baseline vs. 8.82 ± 8.3 µg/mL post-treatment, P < 0.002).
Conclusions
In this pilot study, trelagliptin treatment showed no significant changes in FMD. On the other hand, it was believed that trelagliptin treatment may increase serum adiponectin level.
Trial Registration http://www.umin.ac.jp (Trial ID UMIN000018311)
doi:10.1186/s12933-016-0468-4
PMCID: PMC5096292  PMID: 27809903
Type 2 diabetes mellitus; Dipeptidyl peptidase-4 inhibitor; Trelagliptin; Vascular endothelial functions
12.  Changes in triglycerides and high-density lipoprotein cholesterol may precede peripheral insulin resistance, with 2-h insulin partially mediating this unidirectional relationship: a prospective cohort study 
Background
Results of longitudinal researches regarding the temporal relationship between dyslipidemia and insulin resistance (IR) are inconsistent. This study assessed temporal relationships of blood lipids with IR and determined whether there are any mediating effects existed in these temporal relationships.
Methods
This study examined a longitudinal cohort of 3325 subjects aged 20–74 years from China with an average of 4.2 years follow-up. Measurements of fasting blood lipids, as well as fasting and 2-h serum glucose and insulin, were obtained at two time points. The Gutt index and HOMA-IR were calculated as indicators of peripheral IR and hepatic IR. A cross-lagged path analysis was performed to examine the temporal relationships between blood lipids and IR. A mediation analysis was used to examine mediating effect.
Results
After adjusting for covariates, the cross-lagged path coefficients from baseline TG and HDL-C to follow-up Gutt index were significantly greater than those from baseline Gutt index to follow-up TG and HDL-C (β1 = −0.131 vs β2 = −0.047, P < 0.001 for TG; β1 = 0.134 vs β2 = 0.023, P < 0.001 for HDL-C). The path coefficients from baseline TG and HDL-C to follow-up 2-h insulin were significantly greater than those from baseline 2-h insulin to follow-up TG and HDL-C (β1 = 0.125 vs β2 = 0.040, P < 0.001 for TG; β1 = −0.112 vs β2 = −0.026, P < 0.001 for HDL-C). 2-h insulin partially mediated the effect of TG/HDL-C on Gutt index with a 59.3% mediating effect for TG and 61.0% for HDL-C.
Conclusions
These findings provide strong evidence that dyslipidemia probably precede peripheral IR and that 2-h insulin partially mediates this unidirectional temporal relationship.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0469-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0469-3
PMCID: PMC5095985  PMID: 27814764
Blood lipids; 2-h insulin; Insulin resistance; Temporal relationship; Mediating effect
13.  Impact of diabetes on the predictive value of heart failure biomarkers 
Background
Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF.
Methods
We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death.
Results
During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p < 0.001). NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), and cystatin-C (p = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower (p = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16–1.40, p < 0.001) and 1.23 (95% CI 1.09–1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35–1.73, p < 0.001) and 1.64 (95% CI 1.31–2.05, p < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve.
Conclusions
Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality.
doi:10.1186/s12933-016-0470-x
PMCID: PMC5093972  PMID: 27809845
Diabetes mellitus; Heart failure; Biomarkers; ST2; Prognostic
14.  Impact of glycemic control with sitagliptin on the 2-year progression of arterial stiffness: a sub-analysis of the PROLOGUE study 
Background
No conclusive evidence has been obtained yet on the significance of the effects of dipeptidyl peptidase-4 (DPP-4 inhibitor) treatment on the arterial stiffness in clinical settings. In addition, the effects of good glycemic control on the arterial stiffness have also not been clarified yet. As a sub-analysis of the PROLOGUE study, we examined the effect of a DPP-4 inhibitor (sitagliptin) on the 2-year progression of the arterial stiffness and also to determine the effect of good glycemic control on the rate of progression of the arterial stiffness.
Methods
In the PROLOGUE study, the study participants were either allocated to add-on sitagliptin treatment or to continued treatment with conventional anti-diabetic agents. Among the 463 participants of the PROLOGUE study, we succeeded in measuring the brachial-ankle pulse wave velocity (baPWV) at least two times during the 2-year study period in 96 subjects.
Results
The changes in the baPWV during the study period were similar between the both groups (i.e., with/without staglipitin), overall. On the other hand, when the study subjects were divided into two groups according to the glycemic control status during the study period {good glycemic control group (GC) = hemoglobin (Hb)A1c <7.0 at both 12 and 24 months after the treatment randomization; poor glycemic control group (PC) = HbA1c ≥7.0 at either 12 months, 24 months, or both}, the 2-year increase of the baPWV was marginally significantly larger in the PC group (144 ± 235 cm/s) as compared to that the GC group (−10 ± 282 cm/s) (p = 0.036).
Conclusion
While the present study could not confirm the beneficial effect of sitagliptin per se on the arterial stiffness, the results suggested that good glycemic control appears to be beneficial for delaying the annual progression of the arterial stiffness.
Trial registration University Hospital Medical Information Network Clinical Trials Registry UMIN000004490
doi:10.1186/s12933-016-0472-8
PMCID: PMC5094002  PMID: 27809848
Arterial stiffness; Dipeptidyl peptidase 4 inhibitor; Glycemic control
15.  Cyclophilin A enhances macrophage differentiation and lipid uptake in high glucose conditions: a cellular mechanism for accelerated macro vascular disease in diabetes mellitus 
Background
Vascular disease in diabetes is initiated by monocyte adhesion to vascular endothelium, transmigration and formation of foam cells. Increasing clinical evidence supports a role for the secretory protein, cyclophilin A in diabetic vascular disease. The means by which cyclophilin A contributes to vascular lesion development in diabetes is however largely unknown.
Methods
In this study we investigated using THP1 cells and human monocytes whether cyclophilin A under hyperglycemic conditions, functions in the inflammatory cascade as a chemoattractant and increases lipid uptake by formation of foam cells invitro. We developed an invitro model of monocytes cultured in 20 mm glucose (high glucose) equivalent to 360 mg/dL of plasma glucose levels. These monocytes were then differentiated into macrophages using PMA and subsequently transformed to lipid laden foam cells using oxidized low density lipoproteins in the presence and absence of cyclophilin A. This cellular model was used to study monocyte to macrophage differentiation, transmigration and foam cell formation. A similar cellular model using siRNA mediated transient elimination of the cyclophilin A gene as well as chemical inhibitors were used to further confirm the role of cyclophilin A in the differentiation and foam cell formation process.
Results
Cyclophilin A effectively increased migration of high glucose treated monocytes to the endothelial cell monolayer (p < 0.0001). In the presence of cyclophilin A, differentiated macrophages, when treated with oxLDL had a 36 percent increase in intracellular lipid accumulation (p = 0.01) when compared to cells treated with oxLDL alone. An increased flux of reactive oxygen species was also observed (p = 0.01). Inflammatory cytokines such as TNF-α, MCP-1 and cyclophilin A were significantly increased. Silencing cyclophilin A in THP-1 cells and human monocytes using siRNA or chemical inhibitor, TMN355 resulted in decrease in lipid uptake by 65–75% even after exposure to oxidized LDL. The expression of scavenger receptors expressed during differentiation process, CD36 and LOX-1 were decreased (p < 0.0001). Levels of extracellular cyclophilin A and other inflammatory cytokines such as TNF-α and MCP-1also significantly reduced.
Conclusions
Taken together, we describe here a possible cellular basis by which cyclophilin A may accelerate atherogenesis in diabetes mellitus.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0467-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0467-5
PMCID: PMC5094075  PMID: 27809851
Atherosclerosis; Macrovascular complications; Diabetes mellitus; Macrophages; Cyclophilin A; Monocyte adhesion; Transmigration; Foam cell formation; Hyperglycemia; THP 1
16.  Metabolic syndrome is independently associated with increased 20-year mortality in patients with stable coronary artery disease 
Background
Data regarding long-term association of metabolic syndrome (MetS) with adverse outcomes are conflicting. We aim to determine the independent association of MetS (based on its different definitions) with 20 year all-cause mortality among patients with stable coronary artery disease (CAD).
Methods
Our study comprised 15,524 patients who were enrolled in the Bezafibrate Infarction Prevention registry between February 1, 1990, and October 31, 1992, and subsequently followed-up for the long-term mortality through December 31, 2014. MetS was defined according to two definitions: The International Diabetes Federation (IDF); and the National Cholesterol Education Program–Third Adult Treatment Panel (NCEP).
Results
According to the IDF criteria 2122 (14%) patients had MetS, whereas according to the NCEP definition 7446 (48%) patients had MetS. Kaplan–Meier survival analysis showed that all-cause mortality was significantly higher among patients with MetS defined by both the IDF (67 vs. 61%; log rank-p < 0.001) as well as NCEP (67 vs. 54%; log rank-p < 0.001) criteria. Multivariate adjusted mortality risk was 17% greater [Hazard Ratio (HR) 1.17; 95% Confidence Interval (CI) 1.07–1.28] in patients with MetS according to IDF and 21% (HR 1.21; 95% CI 1.13–1.29) using the NCEP definition. Subgroup analysis demonstrated that long-term increased mortality risk associated with MetS was consistent among most clinical subgroups excepted patients with renal failure (p value for interaction < 0.05).
Conclusions
Metabolic syndrome is independently associated with an increased 20-year all-cause mortality risk among patients with stable CAD. This association was consistent when either the IDF or NCEP definitions were used.
Trial registration retrospective registered
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0466-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0466-6
PMCID: PMC5084328  PMID: 27793156
Metabolic syndrome; Stable coronary artery disease; Prognosis; All-cause mortality; Long term outcomes
17.  Association of metabolic syndrome and its components with arterial stiffness in Caucasian subjects of the MARK study: a cross-sectional trial 
Background
The cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV) can reflect both central and peripheral arterial stiffness. Metabolic syndrome (MetS) and its components may increase arterial stiffness and the risk of cardiovascular diseases. However, the correlation of MetS and its components with arterial stiffness is still not clear. The primary aim of this study is thus the relationship using baPWV and CAVI in Caucasian adults with intermediate cardiovascular risk. The secondary aim is to analyze sex differences.
Methods
This study analyzed 2351 subjects aged 35–74 years (mean, 61.4 ± 7.7 years) comprising 61.7 % males and enrolled in the improving interMediAte Risk management (MARK) study. CAVI was measured using a VaSera VS-1500 ® device, and baPWV was calculated using a validated equation. MetS was defined based on the Joint Scientific Statement National Cholesterol Education Program III. Waist circumference, blood pressure, fasting plasma glucose, and lipid profile were measured.
Results
MetS was found in 51.9 % of the subjects. All MetS components except reduced HDL-cholesterol (p = 0.578) were associated with CAVI. High density lipoprotein cholesterol (p = 0.075) and waist circumference (p = 0.315) were associated with baPWV. The different MetS components that assess dyslipidemia using the stiffness measures show different associations according to patient sex. The high blood pressure component had a greater odds ratio (OR) for both baPWV ≥ 17.5 m/sec (OR = 6.90, 95 % CI 3.52–13.519) and CAVI ≥ 9 (OR = 2.20, 95 % CI 1.63–1.90).
Conclusions
MetS and all its components (except HDL-cholesterol with baPWV and CAVI and WC with baPWV) were associated with baPWV and CAVI. However, there were sex differences in the association of MetS and its components with baPWV and CAVI. Data from this study suggest a greater association of CAVI and baPWV values with MetS components in males than in females and indicate greater arterial stiffness in the event of simultaneously elevated blood pressure, fasting plasma glucose, and waist circumference.
Trial Registration Clinical Trials.gov Identifier: https://clinicaltrials.gov/ct2/show/ NCT01428934. Registered 2 September 2011. Last updated September 8, 2016
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0465-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0465-7
PMCID: PMC5078926  PMID: 27776526
Metabolic syndrome; Brachial-ankle pulse wave velocity; Cardio-ankle vascular index; Arterial stiffness
18.  Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study 
Background
Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention.
Methods
We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B).
Results
Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan–Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041–1.387, p 0.012).
Conclusions
These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy.
Trial registration ClinicalTrials.gov Identifier NCT00535925. Date of registration: September 24, 2007, retrospectively registered
doi:10.1186/s12933-016-0463-9
PMCID: PMC5062846  PMID: 27733159
CVD; Primary prevention; Statin; Diabetes; Nephropathy
19.  N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats 
Background
Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia–reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes.
Methods
Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5 g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30 min of left anterior descending artery ligation followed by 2 h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5 mmol/L) or high glucose (HG, 25 mmol/L) for 36 h before being subjected to 4 h of hypoxia followed by 4 h of reoxygenation (H/R).
Results
NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2 −, nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-β-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA.
Conclusions
Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.
doi:10.1186/s12933-016-0460-z
PMCID: PMC5062884  PMID: 27733157
N-acetylcysteine; Diabetic cardiomyopathy; Myocardial ischemia–reperfusion injury; Caveolin-3; Diabetes
20.  Low and exacerbated levels of 1,5-anhydroglucitol are associated with cardiovascular events in patients after first-time elective percutaneous coronary intervention 
Background
Postprandial hyperglycemia plays an important role in the pathogenesis of coronary artery disease and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia. However, the impact of 1,5-AG level on cardiovascular events has not been fully investigated.
Methods
We enrolled 240 consecutive patients who had undergone first-time elective percutaneous coronary intervention (PCI) with follow-up angiography within 1 year. We excluded patients with a history of acute coronary syndrome, advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2), or uncontrolled diabetes mellitus (HbA1c ≥7.0 %). Fasting blood glucose (FBS), HbA1c, and 1,5-AG levels were measured prior to PCI and at the time of follow-up angiography. Clinical events, including target lesion revascularization, target vessel revascularization, and revascularization of new lesions, were evaluated.
Results
Subjects were divided into two groups according to clinical outcomes: the Event (+) group (n = 40) and the Event (−) group (n = 200). No significant differences were observed, except for the number of diseased vessels and the prevalence of statin use, in baseline clinical characteristics between the two groups. Serum levels of 1,5-AG at follow-up were significantly lower in the Event (+) group than in the Event (−) group (P = 0.02). A significant reduction in 1,5-AG level from baseline to follow-up was observed in the Event (+) group compared with the Event (−) group (P = 0.04). The association between 1,5-AG levels at follow-up and clinical events remained significant after adjustment for independent variables, including FBS and HbA1c levels (P = 0.04).
Conclusions
Low and exacerbated levels of 1,5-AG were associated with cardiovascular events in the present study, indicating that postprandial hyperglycemia is an important risk factor for adverse clinical events even in patients with HbA1c < 7.0 %, following first-time elective PCI.
doi:10.1186/s12933-016-0459-5
PMCID: PMC5057449  PMID: 27729086
Postprandial hyperglycemia; 1,5-Anhydroglucitol; Coronary artery disease; Cardiovascular events
21.  Combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT–FFR) prospective study. Rationale and design 
Background
Fractional flow reserve (FFR) is a widely used tool for the identification of ischaemia-generating stenoses and to guide decisions on coronary revascularisation. However, the safety of FFR-based decisions in high-risk subsets, such as patients with Diabetes Mellitus (DM) or vulnerable stenoses presenting thin-cap fibro-atheroma (TCFA), is unknown. This study will examine the impact of optical coherence tomography (OCT) plaque morphological assessment and the identification of TCFA, in combination with FFR to better predict clinical outcomes in DM patients.
Methods
COMBINE (OCT–FFR) is a prospective, multi-centre study investigating the natural history of DM patients with ≥1 angiographically intermediate target lesion in three subgroups of patients; patients with FFR negative lesions without TCFA (group A) and patients with FFR negative lesions with TCFA (group B) as detected by OCT and to compare these two groups with each other, as well as to a third group with FFR-positive, PCI-treated intermediate lesions (group C). The study hypothesis is that DM patients with TCFA (group B) have a worse outcome than those without TCFA (group A) and also when compared to those patients with lesions FFR ≤0.80 who underwent complete revascularisation. The primary endpoint is the incidence of target lesion major adverse cardiac events (MACE); a composite of cardiac death, myocardial infarction or rehospitalisation for unstable/progressive angina in group B vs. group A.
Conclusion
COMBINE (OCT–FFR) is the first prospective study to examine whether the addition of OCT plaque morphological evaluation to FFR haemodynamic assessment of intermediate lesions in DM patients will better predict MACE and possibly lead to new revascularisation strategies.
Trial Registration Netherlands Trial Register: NTR5376
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0464-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0464-8
PMCID: PMC5057218  PMID: 27724869
Diabetes mellitus; Fractional flow reserve; Major adverse cardiac event
22.  Vitamin D modifies the associations between circulating betatrophin and cardiometabolic risk factors among youths at risk for metabolic syndrome 
Background
Betatrophin has been recently reported to play a role in glucose homeostasis by inducing beta-cell proliferation in mice. However, studies in human are inconsistent. As a nutritionally-regulated liver-enriched factor, we hypothesize that betatrophin might be regulated by vitamin D, and ignorance of vitamin D status may explain the discrepancy in previous human studies. The aims of this study were to assess the association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youths at risk for metabolic syndrome and test the possible influence of vitamin D status on the association.
Methods
559 subjects aged 14–28 years were recruited from Beijing children and adolescents metabolic syndrome study. All underwent a 2 h-oral glucose tolerance test. Serum levels of betatrophin, 25-hydroxy-vitamin D as well as adipokines including adiponectin and fibroblast growth factor 21 (FGF21) were measured by immunoassays. The relationships between betatrophin and insulin resistance, beta-cell function, other cardiometabolic variables and vitamin D status were evaluated.
Results
Participants in the highest quartile of betatrophin levels had the highest levels of total cholesterol (P < 0.001), triglyceride (P < 0.001) and low-density lipoprotein cholesterol (P < 0.001) and the lowest levels of vitamin D (P = 0.003). After stratification by vitamin D status, betatrophin in subjects with vitamin D deficiency were positively correlated with unfavorable metabolic profiles including high blood pressures, dyslipidemia and hyperglycemia, whereas betatrophin in those with higher vitamin D levels only showed negative association with fasting insulin, 2 h-insulin, and insulin resistance. In addition, adiponectin and FGF21 demonstrated the expected associations with metabolic parameters.
Conclusions
Elevated betatrophin levels were associated with cardiometabolic risk factors in this young population, but the association was largely dependent on vitamin D status. These findings may provide valuable insights in the regulation of betatrophin and help explain the observed discrepancies in literature.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0461-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0461-y
PMCID: PMC5054537  PMID: 27716289
Betatrophin; Vitamin D; Metabolic syndrome; Adolescents
23.  Serum bicarbonate concentration and the risk of cardiovascular disease and death in type 2 diabetes: the Fremantle Diabetes Study 
Background
Serum bicarbonate is associated with mortality, heart failure (HF) and progression of renal failure in studies of healthy people and patients with chronic kidney disease, but the significance of these observations in unselected patients with diabetes in the general population is unknown. The aim of this study was to determine whether serum bicarbonate was associated with mortality and cardiovascular disease risk in type 2 diabetes.
Methods
Baseline serum bicarbonate was available for 1283 well-characterized community-based patients (mean ± SD age 64.1 ± 11.3 years, 48.7 % males) from the longitudinal observational Fremantle Diabetes Study followed for a mean of 12 years. Associations between serum bicarbonate and mortality, coronary heart disease (CHD) and incident HF were analysed using Cox proportional hazards regression.
Results
Serum bicarbonate was independently and negatively associated with incident CHD. For each 1 mmol/L increase in bicarbonate, the hazard ratio for CHD was 0.95 (95 % confidence interval 0.92–0.99) after adjustment for age as time scale, age at baseline, sex, English fluency, diabetes duration, loge(serum triglycerides), loge(urinary albumin: creatinine ratio), peripheral sensory neuropathy and peripheral arterial disease. There were no independent associations between serum bicarbonate and all-cause mortality [0.98 (0.95–1.004)] or incident HF [0.99 (0.95–1.03)].
Conclusions
Serum bicarbonate was a significant independent predictor of incident CHD but not death or HF in community-based patients with type 2 diabetes. This supports intervention trials of bicarbonate replacement in type 2 patients at risk of CHD and who have a low serum bicarbonate concentration.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0462-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0462-x
PMCID: PMC5054557  PMID: 27716263
Bicarbonate; Coronary artery disease; Type 2 diabetes; Mortality
24.  A 19-SNP coronary heart disease gene score profile in subjects with type 2 diabetes: the coronary heart disease risk in type 2 diabetes (CoRDia study) study baseline characteristics 
Background
The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits.
Methods
Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox’s Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185).
Results
Overall, 10-year CHD risk ranged from 2–72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plus risk group (n = 66) (p = 0.80) and a sample of UK healthy men (n = 1360). The GS was also associated with LDL-cholesterol (p = 0.05) and family history (p = 0.03) in a sample of UK healthy men (n = 1360).
Conclusions
CHD risk is high in this group of T2D subjects. The risk array is an accurate genotyping assay, and is suitable for estimating an individual’s genetic CHD risk.
Trial registration This study has been registered at ClinicalTrials.gov; registration identifier NCT01891786
doi:10.1186/s12933-016-0457-7
PMCID: PMC5048451  PMID: 27716211
Type 2 diabetes; Coronary heart disease; Gene score; UKPDS score; Risk prediction
25.  Association of serum calcium and heart failure with preserved ejection fraction in patients with type 2 diabetes 
Background
Type 2 diabetes mellitus (T2DM) is a recognized trigger factor for heart failure with preserved ejection fraction (HFpEF). Recent studies show that higher serum calcium level is associated with greater risk of both T2DM and heart failure. We speculate that increased serum calcium is related to HFpEF prevalence in patients with T2DM.
Methods
In this cross-sectional echocardiographic study, 807 normocalcemia and normophosphatemia patients with T2DM participated, of whom 106 had HFpEF. Multinomial logistic regression was carried out to determine the variables associated with HFpEF. The associations between serum calcium and metabolic parameters, as well as the rate of HFpEF were examined using bivariate linear correlation and binary logistic regression, respectively. The predictive performance of serum calcium for HFpEF was evaluated using the area under the receiver operating characteristic curve (AUC).
Results
Patients with HFpEF have significantly higher serum calcium than those without HFpEF. Serum calcium was positively associated with total cholesterol, triglycerides, low-density lipoprotein cholesterol, serum uric acid, HOMA-IR and fasting plasma glucose. Compared with patients in the lowest serum calcium quartile, the odds ratio (OR) for HFpEF in patients in the highest quartile was 2.331 (95 % CI 1.088–4.994, p = 0.029). When calcium was analyzed as a continuous variable, per 1 mg/dL increase, the OR (95 % CI) for HFpEF was [2.712 (1.471–5.002), p = 0.001]. Serum calcium can predict HFpEF [AUC = 0.673, 95 % CI (0.620–0.726), p < 0.001].
Conclusions
An increase in serum calcium level is associated with an increased risk of HFpEF in patients with T2DM.
doi:10.1186/s12933-016-0458-6
PMCID: PMC5048602  PMID: 27716206
Calcium; Heart failure with preserved ejection fraction; Type 2 diabetes mellitus

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