Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 Diabetes Mellitus

Background

Aortic distensibility (AD) is a marker of the elastic properties of the aorta. Reduction of AD occurs early in subjects with type 2 diabetes mellitus (T2DM) and it is associated with subclinical generalized atherosclerosis. Metabolic syndrome (MetS) is common in subjects with T2DM and predicts cardiovascular morbidity and mortality. This study examined the potential relationship between MetS and AD in a cohort of subjects with T2DM.

Methods and results

A total of 210 subjects with T2DM were studied. MetS was diagnosed using the NCEP/ATP-III criteria. AD was assessed non-invasively by ultrasonography. The prevalence of MetS was 64.8%. AD was not significantly different between subjects with and without MetS (1.80 ± 0.54 vs. 1.84 ± 0.53 10^-6 dyn^-1 cm², p = 0.55). Univariate linear regression analysis showed that AD was associated positively with male sex (p = 0.02) as well as glomerular filtration rate (p < 0.001), and negatively with age (p = 0.04), history of hypertension (p = 0.001), as well as duration of diabetes (p < 0.001). After multivariate adjustment, AD was associated independently and significantly only with age (p = 0.02), duration of diabetes p < 0.001), and history of hypertension (p = 0.004); no significant relationship was found with MetS status, the sum of the components of the MetS or the individual components-besides hypertension-of the MetS.

Conclusion

In subjects with T2DM, MetS status per se is not associated with reduction of AD. In addition, it was shown that besides ageing, duration of glycemia was a strong predictor of AD. From the components of the MetS only hypertension was associated with reduction of the elastic properties of the aorta.     

Reconciling research and implementation in micro health insurance experiments in India: study protocol for a randomized controlled trial

Background

Recent attention has focused on strategies to combat the forecast epidemic of type-2 diabetes (T2DM) and its major vascular sequelae. Metabolic syndrome (MetS) comprises a constellation of factors that increase the risk of cardiovascular disease (CVD) and T2DM. Our study aims to develop a structured self-management education programme for people with MetS, which includes management of cardiovascular and diabetes risk factors, and to determine its impact. This paper describes the rationale and design of the TRIMS study, including intervention development, and presents baseline data.

Methods

Subjects recruited from a mixed-ethnic population with MetS were randomised to intervention or control arms. The intervention arm received structured group education based on robust psychological theories and current evidence. The control group received routine care. Follow-up data will be collected at 6 and 12 months. The primary outcome measure will be reversal of metabolic syndrome in the intervention group subjects compared to controls at 12 months follow-up.

Results

82 participants (44% male, 22% South Asian) were recruited between November 2009 and July 2010. Baseline characteristics were similar for both the intervention (n = 42) and control groups (n = 40). Median age was 63 years (IQR 57 - 67), mean waist size 106 cm (SD ± 11), and prescribing of statins and anti-hypertensives was 51% in each case.

Conclusion

Results will provide information on changes in diabetes and CVD risk factors and help to inform primary prevention strategies in people with MetS from varied ethnic backgrounds who are at high risk of developing T2DM and CVD. Information gathered in relation to the programme's acceptability and effectiveness in a multi-ethnic population would ensure that our results are widely applicable.

Trial registration

The study is registered at ClinicalTrials.gov, study identifier: NCT01043770.     

Strong interaction between T allele of endothelial nitric oxide synthase with B1 allele of cholesteryl ester transfer protein TaqIB highly elevates the risk of coronary artery disease and type 2 diabetes mellitus

Background

The present study was conducted to investigate the possible outcome of interaction between endothelial nitric oxide (NOS3) G894T and cholesteryl ester transfer TaqIB variants on the risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). The sample included a total of 207 CAD patients (102 CAD patients with T2DM and 105 CAD patients without T2DM). There were also 101 patients with T2DM and 92 age- and sex-matched healthy individuals as controls. All study participants were from Western Iran. The sample was genotyped by polymerase chain reaction-restriction fragment length polymorphism.

Results

The presence of NOS3 T allele was not associated with the risk of CAD or T2DM, and the CETP B1 allele was only significantly associated with the increased risk of CAD in total CAD patients (odds ratio (OR)?=?5.1, p?=?0.019). However, the concomitant presence of both CETP B1 and NOS3 T alleles significantly increased the risk of CAD in total CAD patients (OR?=?18.1, p?<?0.001), in CAD patients without T2DM (OR?=?27.1, p?=?0.03), and in CAD patients with T2DM (OR?=?13.5, p?=?0.002). Also, the presence of both alleles increased the risk of T2DM (OR?=?12, p?=?0.004).

Conclusions

Our findings, for the first time, indicate that NOS3 T allele strongly interacts with CETP B1 allele to augment the risk of CAD and T2DM in the population of Western Iran.     

The Incidence and Prevalence of Diabetes Mellitus and Related Atherosclerotic Complications in Korea: A National Health Insurance Database Study

Aims/Introduction

The incidence and prevalence of type 2 diabetes mellitus (T2DM) and related macrovascular complications in Korea were estimated using the Health Insurance Review and Assessment (HIRA) database from 2007–2011, which covers the claim data of 97.0% of the Korean population.

Materials and Methods

T2DM, coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral artery disease (PAD) were defined according to ICD-10 codes. We used the Healthcare Common Procedure Coding System codes provided by HIRA to identify associated procedures or surgeries. When calculating incidence, we excluded cases with preexisting T2DM within two years before the index year. A Poisson distribution was assumed when calculating 95% confidence intervals for prevalence and incidence rates.

Results

The prevalence of T2DM in Korean adults aged 20–89 years was 6.1–6.9% and the annual incidence rates of T2DM ranged from 9.5–9.8/1,000 person-year (PY) during the study period. The incidence rates of T2DM in men and women aged 20–49 years showed decreasing patterns from 2009 to 2011 (P<0.001); by contrast, the incidence in subjects aged 70–79 years showed increased patterns from 2009 to 2011 (P<0.001). The incidence rates of CAD and CVD in patients newly diagnosed with T2DM were 18.84/1,000 PY and 11.32/1,000 PY, respectively, in the year of diagnosis. Among newly diagnosed individuals with T2DM who were undergoing treatment for PAD, 14.6% underwent angioplasty for CAD during the same period.

Conclusions

Our study measured the national incidences of T2DM, CAD, CVD, and PAD, which are of great concern for public health. We also confirmed the relatively higher risk of CAD and CVD newly detected T2DM patients compared to the general population in Korea.     

Comparison of accuracy of diabetes risk score and components of the metabolic syndrome in assessing risk of incident type 2 diabetes in Inter99 cohort

Background

Given the increasing worldwide incidence of diabetes, methods to assess diabetes risk which would identify those at highest risk are needed. We compared two risk-stratification approaches for incident type 2 diabetes mellitus (T2DM); factors of metabolic syndrome (MetS) and a previously developed diabetes risk score, PreDx® Diabetes Risk Score (DRS). DRS assesses 5 yr risk of incident T2DM based on the measurement of 7 biomarkers in fasting blood.

Methodology/Principal Findings

DRS was evaluated in baseline serum samples from 4,128 non-diabetic subjects in the Inter99 cohort (Danes aged 30–60) for whom diabetes outcomes at 5 years were known. Subjects were classified as having MetS based on the presence of at least 3 MetS risk factors in baseline clinical data. The sensitivity and false positive rate for predicting diabetes using MetS was compared to DRS. When the sensitivity was fixed to match MetS, DRS had a significantly lower false positive rate. Similarly, when the false positive rate was fixed to match MetS, DRS had a significantly higher specificity. In further analyses, subjects were classified by presence of 0–2, 3 or 4–5 risk factors with matching proportions of subjects distributed among three DRS groups. Comparison between the two risk stratification schemes, MetS risk factors and DRS, were evaluated using Net Reclassification Improvement (NRI). Comparing risk stratification by DRS to MetS factors in the total population, the NRI was 0.146 (p = 0.008) demonstrating DRS provides significantly improved stratification. Additionally, the relative risk of T2DM differed by 15 fold between the low and high DRS risk groups, but only 8-fold between the low and high risk MetS groups.

Conclusions/Significance

DRS provides a more accurate assessment of risk for diabetes than MetS. This improved performance may allow clinicians to focus preventive strategies on those most in need of urgent intervention.     

Eptifibatide and abciximab inhibit insulin-induced focal adhesion formation and proliferative responses in human aortic smooth muscle cells

Aims

We examined, in a country of the African region, i) the prevalence of the metabolic syndrome (MetS) according to three definitions (ATP, WHO and IDF); ii) the distribution of the MetS criteria; iii) the level of agreement between these three definitions and iv) we also examined these issues upon exclusion of people with diabetes.

Methods

We conducted an examination survey on a sample representative of the general population aged 25–64 years in the Seychelles (Indian Ocean, African region), attended by 1255 participants (participation rate of 80.3%).

Results

The prevalence of MetS increased markedly with age. According to the ATP, WHO and IDF definitions, the prevalence of MetS was, respectively, 24.0%, 25.0%, 25.1% in men and 32.2%, 24.6%, 35.4% in women. Approximately 80% of participants with diabetes also had MetS and the prevalence of MetS was approximately 7% lower upon exclusion of diabetic individuals. High blood pressure and adiposity were the criteria found most frequently among MetS holders irrespective of the MetS definitions. Among people with MetS based on any of the three definitions, 78% met both ATP and IDF criteria, 67% both WHO and IDF criteria, 54% both WHO and ATP criteria and only 37% met all three definitions.

Conclusion

We identified a high prevalence of MetS in this population in epidemiological transition. The prevalence of MetS decreased by approximately 32% upon exclusion of persons with diabetes. Because of limited agreement between the MetS definitions, the fairly similar proportions of MetS based on any of the three MetS definitions classified, to a substantial extent, different subjects as having MetS.     

Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity

Background

Patients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function.

Methods

Patients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension.

Results

In total 31 patients with diabetes and 31 controls were included. Mean age was 58 ± 12 years, mean LVEF was 51 ± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 ± 2.9 vs. 17.7 ± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 ± 1.1 vs. 6.4 ± 1.1 cm/s, p = 0.02 and 6.1 ± 1.7 vs. 7.7 ± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively.

Conclusion

In patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis.     

Evidence of suboptimal management of cardiovascular risk in patients with type 2 diabetes mellitus and symptomatic atherosclerosis

Background

Given that most deaths among patients with diabetes mellitus are due to cardiovascular disease, we sought to determine the extent to which medications proven to reduce cardiovascular mortality are prescribed for patients with type 2 diabetes who have symptomatic atherosclerosis (i.e., coronary artery disease [CAD], cerebrovascular disease [CBVD] or peripheral arterial disease [PAD]).

Methods

Administrative records from Saskatchewan Health were used to evaluate the use of antiplatelet agents, statins and angiotensin-converting enzyme (ACE) inhibitors by people with treated type 2 diabetes with and without symptomatic atherosclerosis. CAD and CBVD were defined by International Classification of Diseases (ninth revision) codes, and PAD was defined on the basis of pentoxifylline use or lower limb amputation. Multivariate logistic regression analysis was used to compare medication use in patients with and without PAD, with adjustments for differences in age, sex and comorbidity.

Results

In this cohort of 12 106 patients with type 2 diabetes (mean age 64 years, 55% male, mean follow-up 5 years), fewer than 25% received an antiplatelet agent or statin, and fewer than 50% received an ACE inhibitor. Although patients with CAD were more likely to receive antiplatelet agents, statins or ACE inhibitors than people without CAD (p < 0.001 for all), the overall use of these medications was suboptimal (37%, 29% and 60% respectively among patients with symptomatic CAD). Similar patterns of practice were found for patients with symptomatic CBVD and PAD. All 3 proven efficacious therapies were prescribed for only 11% of patients with CAD, 22% with CBVD and 12% with PAD. Patients with PAD who had undergone lower limb amputation were no more likely to subsequently receive antiplatelet agents or statins than those without an amputation.

Interpretation

Diabetic patients with symptomatic atherosclerotic disease are undertreated with medications known to reduce cardiovascular morbidity and mortality, perhaps because of a “glucocentric” view of diabetes. Programs to improve the quality of cardiovascular risk reduction in these high-risk patients are needed.Diabetes mellitus in adults is associated with an annual rate of death of about 5%, approximately double the rate for age- and sex-matched control subjects without diabetes. Most of this excess mortality risk is attributable to macrovascular atherosclerotic disease.¹ Thus, it has been recommended that medical management to decrease cardiovascular risk should start when type 2 diabetes mellitus is diagnosed.^2,3 At the very least, medications proven to reduce cardiovascular risk should be prescribed for patients with diabetes and established atherosclerotic disease.In addition to smoking cessation and control of blood pressure, strategies proven to reduce cardiovascular risk in patients with diabetes and established atherosclerotic disease include therapy with antiplatelet agents, statins and angiotensin-converting enzyme (ACE) inhibitors.² Coronary artery disease (CAD), cerebrovascular disease (CBVD) and peripheral arterial disease (PAD) are all manifestations of established atherosclerosis.⁴ Recent epidemiologic studies have suggested that PAD may be present in one-quarter to one-half of all adults with type 2 diabetes and have confirmed that PAD is a powerful predictor of cardiovascular death.⁴ In fact, the survival rate for patients with PAD is worse than that for patients with breast cancer (72% v. 85% at 5 years).⁴ However, a recently published survey suggested that clinicians were less likely to prescribe antiplatelet therapy for patients with PAD than for patients with CAD.⁵We sought to evaluate the use of antiplatelet agents, statins and ACE inhibitors among diabetic patients with and without symptomatic atherosclerotic vascular disease. Given the high prevalence of symptomatic PAD among diabetic patients and suggestions that it is often neglected as a marker of atherosclerotic disease, we were particularly interested in examining patterns of care for overall cardiovascular risk reduction in patients with this condition.⁴     

Baseline and follow-up assessment of regional left ventricular volume using 3-dimensional echocardiography: comparison with cardiac magnetic resonance

Background

2-D Echo is often performed in patients without history of coronary artery disease (CAD). We sought to determine echo features predictive of CAD.

Methods

2-D Echo of 328 patients without known CAD performed within one year prior to stress myocardial SPECT and angiography were reviewed. Echo features examined were left ventricular and atrial enlargement, LV hypertrophy, wall motion abnormality (WMA), LV ejection fraction (EF) < 50%, mitral annular calcification (MAC) and aortic sclerosis/stenosis (AS). High risk myocardial perfusion abnormality (MPA) was defined as >15% LV perfusion defect or multivessel distribution. Severe coronary artery stenosis (CAS) was defined as left main, 3 VD or 2VD involving proximal LAD.

Results

The mean age was 62 ± 13 years, 59% men, 29% diabetic (DM) and 148 (45%) had > 2 risk factors. Pharmacologic stress was performed in 109 patients (33%). MPA was present in 200 pts (60%) of which, 137 were high risk. CAS was present in 166 pts (51%), 75 were severe. Of 87 patients with WMA, 83% had MPA and 78% had CAS. Multivariate analysis identified age >65, male, inability to exercise, DM, WMA, MAC and AS as independent predictors of MPA and CAS. Independent predictors of high risk MPA and severe CAS were age, DM, inability to exercise and WMA. 2-D echo findings offered incremental value over clinical information in predicting CAD by angiography. (Chi square: 360 vs. 320 p = 0.02).

Conclusion

2-D Echo was valuable in predicting presence of physiological and anatomical CAD in addition to clinical information.     

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

Background

Cardiomyopathy and distal symmetrical polyneuropathy (DSPN), including sensory and autonomic dysfunction, often co-occur in diabetic mellitus (DM) patients. However, the temporal relationship and progression between these two complications has not been investigated. Using a streptozotocin DM animal model that develops insensate neuropathy, our aim was to examine in parallel the development of DSPN and DM-associated changes in cardiac structure and function as well as potential mechanisms, such as autonomic dysfunction, evaluated by changes in urinary and myocardial norepinephrine content and myocardial neuronal markers.

Methods

Sensory neuropathy was measured by behavioral tests using Von Frey filaments and Hargreaves methods. Echocardiography was used to evaluate myocardial structure and function. Autonomic function was evaluated by measuring urinary and myocardial norepinephrine (NE) levels by enzyme-linked immunosorbent assay and high-performance liquid chromatography/mass spectrometry. Quantitative immunohistochemistry was used to measure the myocardial neuronal markers, calcitonin gene-related peptide (CGRP) and general neuronal protein gene product 9.5 (PGP 9.5).

Results

The DM group developed tactile and thermal insensate neuropathy 4–5 weeks after DM onset. Cardiovascular changes were found between 4 and 12 weeks after DM onset and included bradycardia, diastolic and systolic dysfunction and cardiac dilation. There was a 2.5-fold reduction in myocardial NE levels and a 5-fold increase in urinary NE levels in the DM group. Finally, there was a 2.3-fold increase in myocardial CGRP levels in the DM group and no change in PGP9.5 levels.

Conclusions

Cardiovascular structural and functional changes developed early in the course of DM and in combination with insensate neuropathy. In parallel, signs of cardiac autonomic dysfunction were also found and included decreased myocardial NE levels and altered CGRP levels. These results may indicate the need for early cardiovascular evaluation in DM patients with insensate neuropathy.     

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

Background

Although there is a growing body of evidence showing that patients with type 2 diabetes mellitus (T2DM) have poor glycemic control in general, it is not clear whether T2DM patients with pre-existing cardiovascular diseases (CVD) are more or less likely to have good glycemic control than patients without pre-existing CVD. Our aim was to examine the degree of glycemic control among T2DM patients in Europe with and without pre-existing CVD.

Methods

This is a matched cohort study based on a multi-center, observational study with retrospective medical chart reviews of T2DM patients in Spain, France, United Kingdom, Norway, Finland, Germany, and Poland. Included patients were aged >= 30 years at time of diagnosis of T2DM, had added a SU or a PPARγ agonist to failing metformin monotherapy (index date) and had pre-existing CVD (cases). A control cohort with T2DM without pre-existing CVD was identified using 1:1 propensity score matching. With difference-in-difference approach, logistic and linear regression analyses were applied to identify differences in glycemic control by CVD during the follow up period, after controlling for baseline demographics, clinical information, and concurrent anti-hyperglycemic medication use.

Results

The percentage of case patients with adequate glycemic control relative to control patients during the 1st, 2nd, 3rd, and 4th years after the index date was 19.9 vs. 26.5, 16.8 vs. 26.5, 18.8 vs. 28.3, and 16.8 vs. 23.5 respectively. Cases were significantly less likely to have adequate glycemic control (odds ratio: 0.62; 95% confidence interval: 0.46-0.82) than controls after adjusting for baseline differences, secular trend, and other potential confounding covariates.

Conclusions

T2DM patients with pre-existing CVD tended to have poorer glycemic control than those without pre-existing CVD, all other factors being equal. It suggests that clinicians may need to pay more attention to glycemic control among T2DM patients with CVD.     

Statins research unfinished saga: desirability versus feasibility

Aims

Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease.

Methods

One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean ± SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean ± SD) 8.1 Kgm² median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD).

Results

Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R² 0.045).

Conclusion

The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.     

Extremely short duration high intensity interval training substantially improves insulin action in young healthy males

Background

Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS^®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

Methods/Design

602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA_1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.

Conclusion

ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.

Trial Registration

clinical trials.gov identifier: NCT00220961     

Monocyte matrix metalloproteinase production in Type 2 diabetes and controls – a cross sectional study

Background

Even mild hyperglycemia is associated with future acute and chronic complications. Nevertheless, many cases of diabetes in the community go unrecognized. The aim of the study was to determine if national electronic patient records could be used to identify patients with diabetes in a health management organization.

Methods

The central district databases of Israel's largest health management organization were reviewed for all patients over 20 years old with a documented diagnosis of diabetes mellitus (DM) in the chronic disease register or patient file (identified diabetic patients) or a fasting serum glucose level of >126 mg/100 ml according to the central laboratory records (suspected diabetic patients). The family physicians of the patients with suspected diabetes were asked for a report on their current diabetic status.

Results

The searches yielded 1,694 suspected diabetic patients; replies from the family physicians were received for 1,486. Of these, 575 (38.7%) were confirmed to have diabetes mellitus. Their addition to the identified patient group raised the relative rate of diabetic patients in the district by 3.2%.

Conclusion

Cross-referencing existing databases is an efficient, low-cost method for identifying hyperglycemic patients with unrecognized diabetes who require preventive treatment and follow-up. This model can be used to advantage in other clinical sites in Israel and elsewhere with fully computerized databases.     

Negative predictive value of SPECT for the occurrence of MACE in a medium-sized clinic in the Netherlands

Background

Single-photon emission computed tomography (SPECT) is an important prognostic tool in evaluating coronary artery disease (CAD), with a high negative predictive value (NPV) for the occurrence of major adverse cardiac events (MACE). The prognostic value of SPECT is disputed in women, patients with atrial fibrillation (AF), diabetes, left bundle branch block (LBBB) and renal impairment.

Methods

Seven hundred sixty-two patients without prior history of CAD who had SPECT without perfusion deficits were followed for 2 years for MACE. Predictive variables for the occurrence of MACE were reviewed by Cox proportional hazard regression, considering clinical information, resting-ECG data and SPECT data.

Results

The NPV of SPECT for the occurrence of MACE within 2 years was 95.8 %. Multivariate Cox regression revealed male gender as the only significant predictor for the occurrence of MACE, besides a positive stress ECG at SPECT and a low LVEF. AF, LBBB, renal impairment and diabetes had no significant effect on the prognosis after normal SPECT.

Conclusion

SPECT with normal perfusion images has great NPV in a medium-sized clinic in the Netherlands, even in patients with LBBB, AF, diabetes and renal impairment. MACE-free survival, however, was negatively influenced by male gender; we therefore propose more caution in men.     

PAD4 is not essential for disease in the K/BxN murine autoantibody-mediated model of arthritis

Introduction

Both murine and human genome-wide association studies have implicated peptidyl arginine deiminase (PAD4) as a susceptibility gene in rheumatoid arthritis (RA). In addition, patients with RA commonly have autoantibodies which recognize PAD4 or and/or citrullinated peptides. This study aims to evaluate the role of PAD4 in the effector phase of arthritis.

Methods

PAD4 knock out (KO) and wild type (WT) C57BL/6J mice were injected with K/BxN sera to induce disease. Progression of disease was monitored by measuring paw and ankle swelling and clinical indexes of disease, and pathogenesis was assessed by indexing of clinical progression on paws collected from WT and PAD4 KO mice injected with K/BxN serum. PAD4 activity was determined by visualization of neutrophil extracellular traps (NETs) and immunohistological analysis of histone citrullination.

Results

PAD4 activity is readily detectable in the inflamed synovium of WT but not PAD4 deficient animals, as demonstrated by histone citrullination and NET formation. However, PAD4 WT and KO animals develop K/BxN serum transfer disease with comparable severity and kinetics, with no statistically significant differences noted in clinical scores, swelling, joint erosion or joint invasion.

Conclusions

PAD4 WT and KO mice develop disease in the K/BxN serum transfer model of arthritis with similar severity and kinetics, indicating that PAD4 is dispensable in this effector phase model of disease.     

The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance

Background

Type 2 diabetes mellitus (T2DM) patients are at increased risk of developing cardiovascular events. Unfortunately traditional risk assessment scores, including the Framingham Risk Score (FRS), have only modest accuracy in cardiovascular risk prediction in these patients.

Methods

We sought to determine the prognostic values of different non-invasive markers of atherosclerosis, including brachial artery endothelial function, carotid artery atheroma burden, ankle-brachial index, arterial stiffness and computed tomography coronary artery calcium score (CACS) in 151 T2DM Chinese patients that were identified low-intermediate risk from the FRS recalibrated for Chinese (<20% risk in 10?years). Patients were prospectively followed-up and presence of atherosclerotic events documented for a mean duration of 61?±?16?months.

Results

A total of 17 atherosclerotic events in 16 patients (11%) occurred during the follow-up period. The mean FRS of the study population was 5.0?±?4.6% and area under curve (AUC) from receiver operating characteristic curve analysis for prediction of atherosclerotic events was 0.59?±?0.07 (P?=?0.21). Among different vascular assessments, CACS?>?40 had the best prognostic value (AUC 0.81?±?0.06, P?<?0.01) and offered significantly better accuracy in prediction compared with FRS (P?=?0.038 for AUC comparisons). Combination of FRS with CACS or other surrogate vascular markers did not further improve the prognostic values over CACS alone. Multivariate Cox regression analysis identified CACS?>?40 as an independent predictor of atherosclerotic events in T2DM patients (Hazards Ratio 27.11, 95% Confidence Interval 3.36-218.81, P?=?0.002).

Conclusions

In T2DM patients identified as low-intermediate risk by the FRS, a raised CACS?>?40 was an independent predictor for atherosclerotic events.     

Effect of repaglinide on endothelial dysfunction during a glucose tolerance test in subjects with impaired glucose tolerance

Background

Secondary treatment of arteriosclerosis may be applicable for the primary prevention of atherosclerosis in diabetic patients. This prospective, 2-year follow-up study was designed to determine the efficacy and safety of antiplatelet therapy in the prevention of atherosclerosis of diabetic subjects.

Methods

Patients with type 2 diabetes and arteriosclerosis obliterans from the Eastern Asian countries were registered online and randomly assigned either to the aspirin group (81–100 mg/day) or the cilostazol group (100–200 mg/day) in this international, 2-year, prospective follow-up interventional study.

Results

The primary study endpoint was changes in right and left maximum intima-media thickness of the common carotid artery. Secondary endpoints include changes in right and left maximum intima-media thickness of the internal carotid artery; semiquantitative evaluation of cerebral infarction by magnetic resonance imaging; cardiovascular events including sudden death, stroke, transient cerebral ischemic attacks, acute myocardial infarction, angina, and progression of arteriosclerosis obliterans; overall death; withdrawal; and change in ankle-brachial pressure index.

Conclusion

This is the first study to use an online system that was developed in Asian countries for pooling data from an international clinical trial. These findings are expected to help in the prevention of diabetic atherosclerosis and subsequent cardiovascular and cerebrovascular disease.     

Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury

Background

Metabolic syndrome is characterized by insulin resistance, which is closely related to GLUT4 content in insulin-sensitive tissues. Thus, we evaluated the GLUT4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model.

Methods

Spontaneously hypertensive neonate rats (18/group) were treated with monosodium glutamate (MetS) during 9 days, and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Blood pressure (BP) and lipid levels, C-reactive protein (CRP), interleukin 6 (IL-6), TNF-?? and adiponectin were evaluated. GLUT4 protein was analysed in the heart, white adipose tissue and gastrocnemius. Studies were performed at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age.

Results

MetS rats were more insulin resistant (p<0.001, all ages) and had higher BP (3-mo: p<0.001, 6-mo: p?=?0.001, 9-mo: p?=?0.015) as compared to C. At 6 months, CRP, IL-6 and TNF-?? were higher (p<0.001, all comparisons) in MetS rats vs H, but adiponectin was lower in MetS at 9 months (MetS: 32?±?2, H: 42?±?2, C: 45?±?2 pg/mL; p<0.001). GLUT4 protein was reduced in MetS as compared to C rats at 3, 6 and 9-mo, respectively (Heart: 54%, 50% and 57%; Gastrocnemius: 37%, 56% and 50%; Adipose tissue: 69%, 61% and 69%).

Conclusions

MSG-treated SHR presented all metabolic syndrome characteristics, as well as reduced GLUT4 content, which must play a key role in the impaired glycemic homeostasis of the metabolic syndrome.