Ronald M. A. Henry

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 &bgr;s (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.

Estimated Glomerular Filtration Rate and Urinary Albumin Excretion Are Independently Associated with Greater Arterial Stiffness: The Hoorn Study

Mild renal insufficiency is a risk factor for cardiovascular disease (CVD). Both a decline in GFR and (micro)albuminuria are associated with greater cardiovascular mortality. In ESRD, arterial stiffness, an important cause of CVD, is known to be greater, but few data exist in individuals with mild renal insufficiency or microalbuminuria. This study investigated the association of impaired renal function expressed as lower GFR or greater urinary albumin excretion with arterial stiffness. In a population-based study in 806 individuals (402 men), mean age 68 yr (range 50 to 87), peripheral arterial stiffness (by compliance and distensibility of the carotid, brachial, and femoral arteries and by the carotid elastic modulus [E(inc)]) and central arterial stiffness (by total systemic arterial compliance, carotid-femoral transit time, and aortic augmentation index) were measured ultrasonically. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. Urinary albumin excretion was expressed as urinary albumin/creatinine ratio (UACR). eGFR was 60.6 +/- 11.1 ml/min per 1.73 m(2). Median UACR was 0.57 mg/mmol (range 0.1 to 26.6). After adjustment for age, mean arterial pressure (MAP), gender, and glucose tolerance status (GTS), each 5-ml/min per 1.73 m(2) lower eGFR was associated with a lower distensibility coefficient of the carotid (regression coefficient beta -0.20 10(-3)/kPa; 95% confidence interval [CI] -0.34 to -0.07 10(-3)/kPa) and brachial artery (-0.15 10(-3)/kPa; 95% CI -0.28 to -0.03 10(-3)/kPa) and a greater carotid E(inc) (0.02 kPa; 95% CI 0.0004 to 0.04 kPa). No statistically significant association was found of eGFR with other arterial stiffness indices. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was associated with a greater E(inc) (0.03 kPa; 95% CI 0.001 to 0.07 kPa) and a trend to a lower distensibility coefficient (-0.24 10(-3)/kPa; 95% CI -0.49 to 0.02 10(-3)/kPa) of the carotid artery. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was in addition associated with a shorter carotid-femoral transit time (-1.67 ms; 95% CI -3.24 to -0.10 ms). These associations were not substantially changed by mutual adjustment for eGFR and UACR. In individuals with mild renal insufficiency, both a lower eGFR and a greater albumin excretion, even below levels that are considered to reflect microalbuminuria, are independently associated with greater arterial stiffness. Moreover, these associations were mutually independent. These findings may explain, in part, why eGFR and microalbuminuria are associated with greater risk for CVD and suggest that amelioration of arterial stiffness could be a target of intervention.

Local stiffness of the carotid and femoral artery is associated with incident cardiovascular events and all-cause mortality: the Hoorn study.

OBJECTIVES This study sought to investigate the association of local and segmental arterial stiffness with incident cardiovascular events and all-cause mortality. BACKGROUND The association of different stiffness indices, in particular of carotid, brachial, and femoral stiffness, with cardiovascular disease and mortality is currently unknown. METHODS In a population-based cohort (n = 579, mean age 67 years, 50% women, 23% with type 2 diabetes [by design]), we assessed local stiffness of carotid, femoral, and brachial arteries (by ultrasonography), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index, and systemic arterial compliance. RESULTS After a median follow-up of 7.6 years, 130 participants had a cardiovascular event and 96 had died. The hazard ratios (HRs) (95% confidence intervals [CIs]) per 1 SD for cardiovascular events and all-cause mortality, respectively, were HR: 1.22 (95% CI: 0.95 to 1.56) and 1.51 (95% CI: 1.11 to 2.06) for lower carotid distensibility; HR: 1.19 (95% CI: 1.00 to 1.41) and 1.28 (95% CI: 1.07 to 1.53) for higher carotid elastic modulus; HR: 1.08 (95% CI: 0.88 to 1.31) and 1.43 (95% CI: 1.10 to 1.86) for lower carotid compliance; HR: 1.39 (95% CI: 1.06 to 1.83) and 1.27 (95% CI: 0.90 to 1.79) for lower femoral distensibility; HR: 1.25 (95% CI: 0.96 to 1.63) and 1.47 (95% CI: 1.01 to 2.13) for lower femoral compliance; and HR: 1.56 (95% CI: 1.23 to 1.98) and 1.13 (95% CI: 0.83 to 1.54) for higher cfPWV. These results were adjusted for age, sex, mean arterial pressure, and cardiovascular risk factors. Mutual adjustments for each of the other stiffness indices did not materially change these results. Brachial stiffness, augmentation index, and systemic arterial compliance were not associated with cardiovascular events or mortality. CONCLUSIONS Carotid and femoral stiffness indices are independently associated with incident cardiovascular events and all-cause mortality. The strength of these associations with events may differ per stiffness parameter.

Regional body composition as a determinant of arterial stiffness in the elderly: The Hoorn Study.

Objective To estimate the relation of precisely measured regional body composition with peripheral and central arterial stiffness in the elderly. Methods We investigated 648 participants (mean age 69.0 ± 6.0 years) of the Hoorn Study, a population-based cohort study. Trunk fat, leg fat, trunk lean and leg lean mass were distinguished by dual-energy X-ray absorptiometry. We used ultrasound to measure the distensibility and compliance of the carotid, femoral and brachial arteries, and carotid Youngs elastic modulus, as estimates of peripheral stiffness. As estimates of central stiffness we measured carotid–femoral transit time, aortic augmentation index and systemic arterial compliance. Results After adjustment for sex, age, height, mean arterial pressure, leg lean and leg fat mass, a larger trunk fat mass was consistently associated with higher peripheral arterial stiffness (standardized beta (β) of mean Z-scores of all three large arteries −0.24, P < 0.001). In contrast, larger leg fat mass (β = 0.15, P = 0.009) and leg lean mass (β = 0.09, P = 0.20) were associated with lower peripheral arterial stiffness. Trunk or leg fat mass were not associated with central arterial stiffness. Leg lean mass, however, was consistently associated with lower central arterial stiffness (β = 0.29, P < 0.001). Conclusions Trunk fat mass may have adverse effects on peripheral, but not on central arterial stiffness, while leg fat was not harmful and may have a slight protective effect. Larger leg lean mass was the most important determinant of lower central arterial stiffness. These results provide a pathophysiological framework to explain not only the higher cardiovascular risk in individuals with larger trunk fat mass, but also the reduced cardiovascular risk in individuals with larger leg lean and fat mass.

Endothelial Dysfunction and Low-Grade Inflammation Are Associated With Greater Arterial Stiffness Over a 6-Year Period

Endothelial dysfunction and low-grade inflammation are associated with cardiovascular disease. Arterial stiffening plays an important role in cardiovascular disease and, thus, may be a mechanism through which endothelial dysfunction and/or low-grade inflammation lead to cardiovascular disease. We investigated the associations between, on the one hand, biomarkers of endothelial dysfunction (soluble endothelial selectin, thrombomodulin, and both vascular and intercellular adhesion molecules 1 and von Willebrand factor) and of low-grade inflammation (C-reactive protein, serum amyloid A, interleukin 6, interleukin 8, tumor necrosis factor-&agr; and, soluble intercellular adhesion molecule 1) and, on the other hand, arterial stiffness over a 6-year period, in 293 healthy adults (155 women). Biomarkers were combined into mean z scores. Carotid, femoral, and brachial arterial stiffness and carotid-femoral pulse wave velocity were determined by ultrasonography. Measurements were obtained when individuals were 36 and 42 years of age. Associations were analyzed with generalized estimating equation and adjusted for sex, height, and mean arterial pressure. The endothelial dysfunction z score was inversely associated with femoral distensibility (&bgr;: −0.51 [95% CI: −0.95 to −0.06]) and compliance coefficients (&bgr;: −0.041 [95% CI: −0.076 to −0.006]) but not with carotid or brachial stiffness or carotid-femoral pulse wave velocity. The low-grade inflammation z score was inversely associated with femoral distensibility (&bgr;: −0.51 [95% CI: −0.95 to −0.07]) and compliance coefficients (&bgr;: −0.050 [95% CI: −0.084 to −0.016]) and with carotid distensibility coefficient (&bgr;: −0.910 [95% CI: −1.810 to −0.008]) but not with brachial stiffness or carotid-femoral pulse wave velocity. Biomarkers of endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness. This provides evidence that arterial stiffening may be a mechanism through which endothelial dysfunction and low-grade inflammation lead to cardiovascular disease.

Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: A systematic review and meta-analysis.

Arterial stiffness may be a cause of cerebral small vessel disease and cognitive impairment. We therefore performed a systematic review and meta-analysis of studies on the association between stiffness, cerebral small vessel disease and cognitive impairment. For the associations between stiffness (i.e. carotid-femoral pulse wave velocity (cfPWV), brachial-ankle PWV (baPWV), carotid stiffness and pulse pressure) on the one hand and cerebral small vessel disease and cognitive impairment on the other, we identified 23 (n=15,666/20 cross-sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal) and 41 studies (n=57,671/26 cross-sectional; 11 longitudinal; 4 combined cross-sectional/longitudinal), respectively. Pooled analyses of cross-sectional studies showed that greater stiffness was associated with markers of cerebral small vessel disease with odds ratios, per +1 SD, of 1.29-1.32 (P<.001). Studies on cognitive impairment could not be pooled due to large heterogeneity. Some (but not all) studies showed an association between greater stiffness and cognitive impairment, and the strength of this association was relatively weak. The present study supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease.

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 (&sfgr;C). Arterial remodeling has not been studied in relation to glucose tolerance. Methods— The study population consisted of 278 people with normal glucose metabolism, 168 with impaired glucose metabolism, and 301 with type 2 diabetes (DM-2); their mean age was 67.8 years. We assessed carotid intima-media thickness (IMT), interadventitial diameter (IAD), lumen diameter (LD), and &sfgr;C. Results— After adjustment for age, sex, height, body mass index, and prior CVD, DM-2 was associated with increased IAD, IMT, and &sfgr;C but not LD (regression coefficients: 0.24 mm; 95% confidence interval [CI], 0.07 to 0.41; 0.050 mm; 95% CI, 0.024 to 0.077; 5.00 kPa; 95% CI, 0.92 to 9.08; and 0.13 mm; 95% CI, −0.03 to 0.29, respectively). After additional adjustment for pulse pressure, the association between DM-2 and IAD disappeared, whereas the association with IMT remained. After adjustment, impaired glucose metabolism was not significantly associated with LD (0.12 mm; 95% CI, −0.06 to 0.33), &sfgr;C (0.25 kPa; 95% CI, −4.49 to 4.98), IAD (0.08 mm; 95% CI, −0.11 to 0.27), or IMT (0.029 mm; 95% CI, −0.002 to 0.060). However, the IMT regression coefficient was half that of DM-2. Conclusions— DM-2 is associated with preserved LD at increased IMT, which, however, does not normalize the increased &sfgr;C. In contrast, impaired glucose metabolism is not associated with changes in LD or IAD, whereas IMT is moderately increased but &sfgr;C remains constant. Carotid remodeling in DM-2 thus appears maladaptive, which may explain the increased CVD risk, especially stroke, in DM-2.

Use of dipeptidyl peptidase-4 inhibitors for type 2 diabetes mellitus and risk of fracture

INTRODUCTION Although patients with type 2 diabetes mellitus have an increased bone mineral density as compared to healthy patients, their risk of fracture is elevated. Incretins, new anti-diabetic drugs, may have a protective effect on bone mineral density. However, data on the effect of incretins on fracture risk are limited. Therefore the aim of this study was to investigate the association between the use of DPP4-I and the risk of fracture. METHODS A retrospective population based cohort study, using data from the Clinical Practice Research Datalink (CPRD) database (2007-2012), was conducted. Patients (N=216,816) with at least one prescription for a non-insulin anti-diabetic drug (NIAD), aged 18+ during data collection, were matched to one control patient. Cox proportional hazards models were used to estimate the hazard ratio of any fracture in DPP4 inhibitor (DPP4-I) users versus controls and versus other NIAD patients. Time-dependent adjustments were made for age, sex, life style, comorbidity and drug use. RESULTS The actual duration of DPP4-I use was 1.3years. There was no different risk of fracture comparing current DPP4-I users to controls (adjusted hazard ratio (adj. HR) 0.89, 95% confidence interval (CI) 0.71-1.13). There was also no increased risk comparing current DPP4-I users to other NIAD users, adj. HR 1.03 (95% CI 0.92-1.15). CONCLUSIONS DPP4-I use was not associated with fracture risk compared to controls and to other NIAD users. However, the duration of DPP4-I use in our database might have been too short to show an association with fracture risk.

Albuminuria, but not estimated glomerular filtration rate, is associated with maladaptive arterial remodeling: the Hoorn Study.

Objective Arterial remodeling aims to maintain a constant circumferential wall stress (σc). A failing remodeling process is associated with stroke. Data on the relationship between chronic kidney disease and arterial remodeling are scarce. Methods We investigated the association between a lower glomerular filtration rate (GFR) and microalbuminuria with arterial remodeling of the common carotid artery (CCA) in a population-based study of 806 patients. CCA properties including intima-media thickness and interadventitial diameter (IAD) were assessed. Lumen diameter, circumferential wall tension (CWT), and circumferential wall stress (σc) were calculated. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease formula. Albuminuria was expressed as urinary albumin/creatinine ratio. Results Mean eGFR was 60.3 (±10.8) ml/min/1.73 m2; median urinary albumin/creatinine ratio was 0.57 (range 0.10–26.6 mg/mmol). After adjustment for age, sex, glucose tolerance status, and prevalent cardiovascular disease, eGFR was not independently associated with CCA properties. A greater urinary albumin/creatinine ratio (per quartile) was associated with a greater lumen diameter [regression coefficient β with 95% confidence interval, 0.14 (0.08–0.20; P < 0.01)], IAD [0.15 (0.09–0.21; P < 0.01)], CWT [0.95 (0.52–1.38; P < 0.01)], and σc [1.7 (0.5–2.9; P < 0.01)] but not with a greater IMT [0.01 (−0.002–0.02; P = 0.12)]. Additional adjustments for mean arterial pressure, pulse pressure, and eGFR did not change the results. Conclusion Greater albuminuria is independently associated with an increase in lumen diameter and IAD of the CCA. In addition, greater albuminuria is associated with a maladaptive carotid remodeling process as shown by an increase in CWT and σc. These findings may explain, why microalbuminuria is associated with a greater risk of cardiovascular disease and especially stroke.

Endothelial Dysfunction Plays a Key Role in Increasing Cardiovascular Risk in Type 2 Diabetes: The Hoorn Study

In the pathogenesis of cardiovascular events, interaction between risk factors has seldom been identified. However, endothelial dysfunction on the one hand and type 2 diabetes mellitus, impaired glucose metabolism (IGM), and insulin resistance on the other may act synergistically (ie, interact) in the development of cardiovascular disease. We therefore investigated the interaction between endothelial dysfunction and type 2 diabetes mellitus, IGM, and insulin resistance with regard to risk of cardiovascular events. In a prospective population-based cohort (n=445; 69 years; 55% women; 23% type 2 diabetes mellitus, 28% IGM [by design]), endothelial dysfunction (brachial artery flow-mediated dilatation), glucose tolerance (oral glucose tolerance test), and insulin sensitivity (homeostasis model assessment for insulin resistance [HOMA2-IR]) were determined. After a median follow-up of 7.6 years, 106 participants had had a cardiovascular event. After adjustments, 1 SD less flow-mediated dilatation was associated with cardiovascular events in type 2 diabetes mellitus (hazard ratio 1.69 [95% confidence interval, 1.14–2.52]) and IGM (1.50 [0.95–2.37]) and among those in the highest HOMA2-IR tertile (1.92 [1.42–2.60]), but not in normal glucose metabolism (0.85 [0.63–1.16]) or among those in the lower 2 HOMA2-IR tertiles combined (0.85 [0.65–1.12]). Interaction between flow-mediated dilatation and type 2 diabetes mellitus, IGM, or insulin resistance was present on an additive (relative excess risk caused by interaction >0) and on a multiplicative scale (P interaction <0.05). Endothelial dysfunction and type 2 diabetes mellitus, IGM, or insulin resistance synergistically increase cardiovascular event risk. This identifies endothelial dysfunction as a key therapeutic target in these individuals.