Carotid arterial remodeling - A maladaptive phenomenon in type 2 diabetes but not in impaired glucose metabolism: The Hoorn Study

Background and Purpose-Deteriorating glucose tolerance is associated with an increased cardiovascular disease (CVD) risk. The underlying mechanisms remain unclear. Arterial remodeling is the change in structural properties through time in response to atherogenic and/or hemodynamic alterations and aims to maintain circumferential wall stress constant (

Deteriorating glucose tolerance status is associated with left ventricular dysfunction - the Hoorn Study

Background: Type 2 diabetes (DM2) is associated with a greater risk of heart failure. The mechanisms underlying this association remain controversial and include diabetes-associated hypertension and obesity, impaired small and large artery function, and a distinct metabolic cardiomyopathy related to hyperglycaemia/hyperinsulinaemia. The proximate causes of heart failure are left ventricular (LV) systolic dysfunction (SDF) and diastolic dysfunction (DDF). We investigated, in a population-based cohort (n=746), the association between glucose tolerance status and SDF and DDF. Methods and results: The study population consisted of 274 individuals with normal glucose metabolism (NGM), 174 with impaired glucose metabolism (IGM) and 298 with DM2 (mean age 68.5 years). All participants underwent an LV echocardiogram. SDF was defined as ejection fraction <55%. DDF was determined by a sum score of peak A velocity (abnormal, ≥97 cm/s), the difference between Apv and Amv duration (≥41 ms), and left atrial volume (≥57 ml), where cut-off values were based upon the 90th percentile in NGM. In addition, we analysed the ratio of early to late diastolic filling (E/A ratio) on a continuous scale using linear regression analyses. The age- and sex-standardised prevalences in NGM, IGM and DM2 were 13, 14 and 30% for SDF, and 26, 36 and 47% for DDF (P(trend) for both <0.001). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria, DM2 was significantly associated with both SDF (odds ratio (95% CI) 2.04 (1.24 to 3.36)) and DDF (2.42 (1.63 to 3.60)) (90th percentile definition). This was also true for the analyses with the E/A ratio on a continuous scale (regression coefficient β (95% CI) -0.05 (-0.09 to -0.01). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria IGM was not significantly associated with SDF (odds ratio (95% CI) 1.04 (0.58 to 1.88)) or DDF (1.33 (0.86 to 2.06)) using the definition based upon the 90th percentile. However, IGM was significantly associated with DDF if the E/A ratio was analysed on a continuous scale (regression coefficient β (95% CI) -0.05 (-0.10 to -0.01). Additional adjustment for brachial artery flow-mediated vasodilation or arterial stiffness, as measures of large artery function, did not materially alter the results. Hyperglycaemia and hyperinsulinaemia together explained ∼30% of the association of DM2 with SDF and ∼40% of that with DDF. Conclusion: DM2 is independently associated with a 2.0-fold greater risk of SDF and a 2.4-fold greater risk of DDF. IGM was not associated with SDF, and the association with DDF was limited to the E/A ratio. These observations may therefore explain the increased risk of systolic and diastolic heart failure in elderly individuals with DM2

Arterial stiffness increases with deteriorating glucose tolerance status - The Hoorn Study

Background - Type 2 diabetes (DM-2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. In nondiabetic individuals, increased arterial stiffness is an important cause of cardiovascular disease. Associations between DM-2 and IGM and arterial stiffness have not been systematically investigated. Methods and Results - In a population-based cohort (n=747; 278 with normal glucose metabolism, 168 with IGM, and 301 with DM-2; mean age, 68.5 years), arterial stiffness was ultrasonically estimated by distensibility and compliance of the carotid, femoral, and brachial arteries and by the carotid elastic modulus. After adjustment for age, sex, and mean arterial pressure, DM-2 was associated with increased carotid, femoral, and brachial stiffness, whereas IGM was associated only with increased femoral and brachial stiffness. Carotid but not femoral or brachial stiffness increased from IGM to DM-2. Standardized βs (95% CI) for IGM and DM-2, compared with normal glucose metabolism, were -0.06 (-0.23 to 0.10) and -0.37 (-0.51 to -0.23) for carotid distensibility; -0.02 (-0.18 to 0.18) and -0.25 (-0.40 to -0.09) for carotid compliance; -0.05 (-0.23 to 0.13) and 0.25 (0.10 to 0.40) for carotid elastic modulus; -0.70 (-0.89 to -0.51) and -0.67 (-0.83 to -0.52) for femoral distensibility; and -0.62 (-0.80 to -0.44) and -0.79 (-0.94 to -0.63) for femoral compliance. The brachial artery followed a pattern similar to that of the femoral artery. Increases in stiffness indices were explained by decreases in distension, increases in pulse pressure, an increase in carotid intima-media thickness, and, for the femoral artery, a decrease in diameter. Hyperglycemia or hyperinsulinemia explained only 30% of the arterial changes associated with glucose tolerance. Adjustment for conventional cardiovascular risk factors did not affect these findings. Conclusions - IGM and DM-2 are associated with increased arterial stiffness. An important part of the increased stiffness occurs before the onset of DM-2 and is explained neither by conventional cardiovascular risk factors nor by hyperglycemia or hyperinsulinemia

Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes - The Hoorn study

Impaired glucose metabolism (IGM) and type 2 diabetes (DM-2) are associated with high cardiovascular disease risk. Increases in peripheral and central artery stiffness may represent pathophysiologic pathways through which glucose tolerance status leads to cardiovascular disease. Peripheral artery stiffness increases with deteriorating glucose tolerance status, whereas this trend remains unclear for central artery stiffness. Therefore, we investigated the associations between glucose tolerance status and estimates of central arterial stiffness. We performed a population-based study of 619 individuals (normal glucose metabolism, n=261; IGM, n=170; and DM-2, n=188) and assessed central artery stiffness by measuring total systemic arterial compliance, aortic pressure augmentation index, and carotid-femoral transit time. After adjustment for sex, age, heart rate, height, body mass index, and mean arterial pressure, DM-2 was associated with decreased total systemic arterial compliance, increased aortic augmentation index, and decreased carotid-femoral transit time. IGM was borderline significantly associated with decreased total systemic arterial compliance. Respective regression coefficients (95% confidence intervals) for IGM and DM-2 compared with normal glucose metabolism were -0.05 (-0.11 to 0.01) and -0.13 (-0.19 to -0.07) mL/mm Hg for total system carterial compliance; 1.1 (-0.2 to 2.5) and 1.6 (0.2 to 3.0) percentage points for aortic augmentation index; and -0.85 (-5.20 to 3.49) and -4.95 (-9.41 to -0.48) ms for carotid-femoral transit time. IGM and DM-2 are associated with increased central artery stiffness, which is more pronounced in DM-2. Deteriorating glucose tolerance is associated with increased central and peripheral arterial stiffness, which may partly explain why both DM-2 and IGM are associated with increased cardiovascular risk

S-Adenosylmethionine and 5-Methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn study

): 48.57 microm (21.16; 75.98) and -32.15 microm (-59.09; -5.20), but high homocysteine was not (-15.11 microm (-42.99; 12.78). High SAM and low 5-MTHF were also significantly associated with high and low NMD, respectively. NMD explained the association of 5-MTHF with FMD but not of SAM. No interactions were observed for diabetes or cardiovascular risk factors. CONCLUSIONS: In this elderly population, both SAM and 5-MTHF are associated with endothelial and smooth muscle cell function. The effect of homocysteine on endothelial function is relatively small compared with SAM and 5-MTHF. The relative impact of SAM, 5-MTHF, and homocysteine, and the mechanisms through which these moieties may affect endothelial and smooth muscle cell function need clarification. Both SAM and 5-MTHF are associated with endothelial and smooth muscle cell function whereas the effect of homocysteine is relatively small compared with SAM and 5-MTH

Association between serum uric acid, aortic, carotid and femoral stiffness among adults aged 40-75 years without and with type 2 diabetes mellitus: The Maastricht Study

Objective: Arterial stiffness may be a mechanism to explain the association between uric acid and cardiovascular disease. We aimed to analyse associations between serum uric acid and regional and local arterial stiffness, and assess potential differences related to sex and glucose metabolism status. Methods: A cross-sectional study was performed in 614 adults [52.6% men; mean age 58.7 +/- 8.5 years; 23.2% type 2 diabetes mellitus (by design)] from The Maastricht Study. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), distensibility, and compliance coefficient of the carotid and femoral artery, and carotid artery Young's elastic modulus. Results: Higher uric acid (per SD of 74 mu mol/l) was associated with greater stiffness indicated by a significantly higher cfPWV [beta = 0.216 (95% confidence interval 0.061, 0.372); P = 0.006] and lower carotid distensibility coefficient [beta = -0.633 (95% confidence interval -1.099, -0.166); P = 0.008] after adjustment for sex, age, and glucose metabolism status. Associations lost significance after adjusting for mean arterial pressure, BMI, waist, smoking status, heart rate, total : high-density lipoprotein cholesterol ratio, triglycerides, estimated glomerular filtration rate, use of lipid-lowering, antihypertensive, and diabetes medication, and use of secondary uricosurics. No associations were found between uric acid and carotid compliance coefficient, carotid Young's elastic modulus, or stiffness of the femoral artery. A significant interaction (P <0.10) with glucose metabolism status was found for cfPWV. However, none of the stratified associations were significant. There was no interaction with sex. Conclusion: Uric acid was not significantly associated with stiffness of the aorta, or the carotid or femoral artery among adults aged 40-75 years without and with type 2 diabetes mellitus

Exercise SBP response and incident depressive symptoms: The Maastricht Study

Objective : An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time. Methods : We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 +/- 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10. Results : After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness. Conclusion : A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms

Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and electrochemiluminescense-based multi-array platform

Background - In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods - We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects’ cardiovascular risk factors by ANOVA. Results - Despite that both methods ranked individuals’ levels of biomarkers very similarly (Pearson’s r all=0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. Conclusions - Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies