R.M.A. Henry

Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease

Increased arterial stiffness associated with diabetes and the metabolic syndrome may in part explain the increased cardiovascular disease risk observed in these conditions. Arterial stiffness can be estimated by quantifying pulse pressure but is better described by distensibility and compliance coefficients, pulse wave velocity and wave reflection. The most common non-invasive methodologies used to quantify these estimates of arterial stiffness (e.g. ultrasonography and applanation tonometry) are also described. We then review and summarise the current data on the associations between diabetes, the metabolic syndrome and insulin resistance on the one hand and greater arterial stiffness on the other, and identify and discuss some unresolved issues such as differential stiffening of central vs peripheral arterial segments, the impact of sex, and the pathobiology of increased arterial stiffness in diabetes and the metabolic syndrome. Finally, some considerations with regard to treatment options are presented. At present the most powerful therapy available for reducing arterial stiffness is to vigorously treat hypertension using pharmacological agents. New pharmacological strategies to reduce arterial stiffness are likely to be especially relevant to individuals with diabetes.

Increased Central Artery Stiffness in Impaired Glucose Metabolism and Type 2 Diabetes. The Hoorn Study

Abstract—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 systemic arterial 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.

Are retinal microvascular abnormalities associated with large artery endothelial dysfunction and intima-media thickness? The Hoorn Study

It has been hypothesized that microvascular dysfunction affects endothelial dysfunction of the large arteries, which may explain the relationship of microvascular disease with macrovascular disease. The aim of the present study was to investigate the relationship of retinal microvascular disorders with endothelium-dependent FMD (flow-mediated vasodilatation) and carotid IMT (intima-media thickness). A total of 256 participants, aged 60-85 years, 70 with normal glucose metabolism, 69 with impaired glucose metabolism and 109 with Type II diabetes, were included in this study. All participants were ophthalmologically examined, including funduscopy and two field 45 degrees fundus photography, and were graded for retinal sclerotic vessel abnormalities and retinopathy. Retinal arteriolar and venular diameters were measured with a computer-assisted method. Brachial artery, endothelium-dependent FMD and carotid IMT were assessed ultrasonically as measurements of endothelial function and early atherosclerosis respectively. After adjustment for age, sex and glucose tolerance status, retinal vessel diameters, retinal sclerotic vessel abnormalities and retinopathy were not significantly associated with FMD. In contrast with other retinal microvascular abnormalities, retinal venular dilatation was associated with increased IMT [standardized beta value (95% confidence interval), 0.14 (0.005-0.25)]. This association was attenuated and lost statistical significance after adjustment for cardiovascular risk factors, in particular after correction for fasting insulin. In the present study, retinal microvascular disorders are not independently associated with impaired FMD. In addition, retinal venular dilatation is associated with increased IMT, although non-significantly after multivariable adjustment for cardiovascular risk factors. Therefore our data provide evidence that retinal microvascular disease is of limited value in risk stratification for future cardiovascular events.

Fish Consumption in Healthy Adults Is Associated with Decreased Circulating Biomarkers of Endothelial Dysfunction and Inflammation during a 6-Year Follow-Up

A healthy diet rich in fish, fruit, and vegetables, moderate in alcoholic beverages, and low in dairy products has been associated with lower circulating concentrations of biomarkers of endothelial dysfunction (ED) and low-grade inflammation (LGI). It is, however, unknown how consumption of these food groups affects ED and/or LGI over time. We measured diet by the computer-assisted crosscheck dietary history method at 36 ± 0.63 y of age (n = 301, women = 161). At 36 and 42 y of age, we measured von Willebrand factor, soluble intercellular adhesion molecule 1 (sICAM-1), soluble endothelial selectin, soluble vascular cell adhesion molecule 1 and soluble thrombomodulin (circulating biomarkers of ED); and C-reactive protein, serum amyloid A, IL-6, IL-8, TNFα, and sICAM-1 (circulating biomarkers of LGI). We investigated the associations between food groups and changes in combined biomarker Z-scores of ED and LGI [higher scores associated with greater risk of (incident) cardiovascular disease]. After adjustment for sex, energy intake, BMI, physical activity, alcohol consumption, smoking behavior, and other food groups, consumption of fish (per 100 g/wk), but none of the other food groups, was inversely associated with changes in ED [β (95%CI) = -0.06 (-0.10; -0.02); P = 0.003] and LGI [-0.05 (-0.09; -0.003); P = 0.036]. Additionally, EPA+DHA intake was inversely associated with changes in ED [β (95%CI) = -0.13 (-0.19; -0.07); P ≤ 0.001] and LGI [-0.09 (-0.16; -0.02); P = 0.013] and explained 83 and 40% of the association between fish and changes in ED and LGI. In conclusion, fish consumption, but not fruit, vegetable, alcoholic beverage, or dairy product consumption, was associated with decreased ED and LGI in healthy adults.

Prevalence of macrovascular disease amongst type 2 diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the Hoorn Screening Study

Objectives.  Screening for type 2 diabetes has been recommended and targeted screening might be an efficient way to screen. The aim was to investigate whether diabetic patients identified by a targeted screening procedure differ from newly diagnosed diabetic patients in general practice with regard to the prevalence of macrovascular complications.

Plasma homocysteine and S-adenosylmethionine in erythrocytes as determinants of carotid intima-media thickness: different effects in diabetic and non-diabetic individuals The Hoorn Study

OBJECTIVE Hyperhomocysteinemia is a risk factor for atherothrombosis. Through unknown mechanisms, individuals with type 2 diabetes appear particularly susceptible. We determined whether components of homocysteine metabolism are associated with intima-media thickness in individuals with and without type 2 diabetes. METHODS AND RESULTS In a cross-sectional design, we studied 231 Caucasian individuals, 60.6% having type 2 diabetes. We measured fasting homocysteine, vitamin B6 and vitamin B12 in plasma, and folate, S-adenosylmethionine and S-adenosylhomocysteine in plasma and erythrocytes. A homocysteine concentration >12 micromol/l was associated with a greater intima-media thickness of +0.07 mm (95% CI, +0.01 to +0.13; P=0.03) among diabetic individuals and of -0.004 mm (95%CI, -0.08 to +0.07; P=0.92) among non-diabetic individuals. An erythrocyte S-adenosylmethionine concentration above >4000 nmol/l was associated with a smaller intima-media thickness of -0.04 mm (95%CI, -0.10 to +0.02; P=0.17) for diabetic individuals versus -0.12 mm (95%CI, -0.20 to -0.36; P=0.005) for non-diabetic individuals. CONCLUSIONS With regard to carotid intima-media thickness, individuals with diabetes appear more susceptible to the detrimental effects of homocysteine than non-diabetic individuals. In addition, diabetic individuals may lack the protective effect on the vascular wall conferred by high concentrations of S-adenosylmethionine. These findings may help explain why hyperhomocysteinemia is an especially strong risk factor for atherothrombosis among individuals with type 2 diabetes.

S-Adenosylmethionine and 5-Methyltetrahydrofolate Are Associated With Endothelial Function After Controlling for Confounding by Homocysteine The Hoorn Study

Objective—To explore to what extent homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine, total folate, 5-methyltetrahydrofolate (5-MTHF), vitamin B12, and vitamin B6 are associated with endothelium-dependent, flow-mediated vasodilation (FMD), and whether these associations are stronger in individuals with diabetes or other cardiovascular risk factors. Methods and Results—In this population-based study of 608 elderly people, FMD and endothelium-independent nitroglycerin-mediated dilation (NMD) were ultrasonically estimated from the brachial artery (absolute change in diameter [&mgr;m]). High SAM and low 5-MTHF were significantly associated with high and low FMD, respectively (linear regression coefficient, [95% confidence interval]): 48.57 &mgr;m (21.16; 75.98) and −32.15 &mgr;m (−59.09; −5.20), but high homocysteine was not (−15.11 &mgr;m (−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.

Low-grade inflammation, but not endothelial dysfunction, is associated with greater carotid stiffness in the elderly: the Hoorn Study

Objective: Biomarkers of low-grade inflammation and endothelial dysfunction are associated with cardiovascular disease. Arterial stiffening may be a mechanism through which low-grade inflammation and (or) endothelial dysfunction lead to cardiovascular disease. Therefore, we investigated whether low-grade inflammation and endothelial dysfunction were associated with greater carotid stiffness in a population-based cohort of elderly individuals. Methods: We determined biomarkers of low-grade inflammation (C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumour necrosis factor &agr; and soluble intercellular adhesion molecule 1), and of endothelial dysfunction (von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 and flow-mediated dilation), and combined these into mean z-scores (n = 572; women = 286; age 67.5 ± 6.6 years). Additionally, we determined by ultrasonography carotid diameter, distension, pulse pressure and intima–media thickness. Carotid stiffness indices were determined by calculation of the distensibility and compliance coefficient, Youngs elastic modulus and &bgr; stiffness index. Results: The study population was characterized by a high prevalence of cardiovascular disease (46%), hypertension (66%) and the use of lipid-lowering (16%) and antihypertensive (34%) medication. After adjustment for the above in addition to sex, age, glucose tolerance status and current smoking, the low-grade inflammation z-score was positively associated with Youngs elastic modulus [&bgr; (95% confidence interval) 0.080 (0.021–0.139), P = 0.008]. This association was primarily driven through greater diameter. After adjustment for the variables above, the endothelial dysfunction z-score was not associated with carotid stiffness. Conclusion: These data suggest that low-grade inflammation, in the elderly, plays an important role in carotid artery remodelling and stiffening.

Vitamin D deficiency and myocardial structure and function in older men and women: the hoorn study.

Background: Vitamin D deficiency is frequently observed in heart failure patients and it has been shown that vitamin D exerts various effects on the heart that may be relevant for the pathogenesis of myocardial diseases. Aims: We aimed to elucidate the largely unknown association of 25-hydroxyvitamin D [25(OH)D] serum levels with echocardiography measures of left ventricular (LV) structure and function. Material/Subjects and methods: We measured 25(OH)D serum levels and performed standardized LV echocardiograms in 614 persons from a population-based cohort of older men and women. Echocardiographic data were used to calculate LV mass and geometry and for classification of systolic and diastolic dysfunction. To consider the seasonal variations of 25(OH)D levels we categorized our study participants according to season-specific 25(OH)D quartiles. Results: LV systolic function, mass and geometry were not significantly associated with 25(OH)D serum levels. In binary logistic regression analyses, the prevalence of LV diastolic dysfunction was significantly higher in the first season-specific 25(OH)D quartile when compared to the fourth quartile [odds ratio 2.32 (95% CI: 1.42–3.80); p=0.001] but significance was lost after adjustments for age [odds ratio 1.51 (0.89–2.57); p=0.123] and established risk factors for heart failure [odds ratio 1.47 (0.84–2.59); p=0.178]. Conclusions: Serum levels of 25(OH)D are not significantly associated with LV structure and function but a non-significant trend towards increased risk of diastolic dysfunction in persons with vitamin D deficiency warrants further studies.

25-Hydroxyvitamin D is not Associated with Carotid Intima-Media Thickness in Older Men and Women

Recent prospective studies highlighted vitamin D deficiency as a significant risk factor for cardiovascular events, but the underlying mechanisms remain unclear [1]. In their recent work among 650 Old Order Amish persons, Michos et al. have demonstrated that 25-hydroxyvitamin D (25[OH]D) levels are not associated with carotid intimamedia thickness (cIMT) and coronary artery calcification [2]. These important findings suggest that the increased cardiovascular risk observed in persons with a poor vitamin D status is unlikely to be mediated by subclinical vascular disease. Considering, however, that 25(OH)D levels were significantly and inversely correlated with cIMT in another study among 390 patients with type 2 diabetes [3], there still exists a need to address further the issue of 25(OH)D levels and cIMT. We therefore evaluated the latter research question in the Hoorn Study, a population-based study among older men and women [4, 5]. 25(OH)D levels were measured in 614 persons during a follow-up visit in 2000–2001 which included ultrasonographic evaluations of the common cIMT [4], and we have recently published that low 25(OH)D serum levels were significantly associated with an increased risk of all-cause and cardiovascular mortality in that study cohort [5]. Consistent with the statistical analyses used by Michos et al. [2] and in order to consider the seasonal variations of 25(OH)D levels, we calculated the residual of each subject’s 25(OH)D level (nmol/l) from the mean of each season and formed quartiles of these residuals. Regression analysis adjusted for age and gender showed no significant association of these seasonally adjusted 25(OH)D levels with cIMT (in mm) (b-coefficient = -0.011, p = 0.794). Regression analysis with multivariable adjustment according to Michos et al. [2], including age (years), gender (female/male), body mass index (kg/m), current smoking (yes/no), hypertension