Selective Angiotensin Receptor Antagonism with Valsartan Decreases Arterial Stiffness Independently of Blood Pressure Lowering in Hypertensive Patients

Nakamura, Toshio; Fujii, Shigeki; Hoshino, Jin; Saito, Yoshiaki; Mizuno, Haruyoshi; Saito, Yuichiro; Kurabayashi, Masahiko

doi:10.1291/hypres.28.937

Cited by 37 publications

(28 citation statements)

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“…Actually, antihypertensive treatment has profound effects on PWVcf, while, as we mentioned before, the effects of such treatment on TRF length is unknown. The high percentage of the patients treated with statins and ACE inhibitors/ARBs in our study, medications with known favorable effects on arterial stiffness (32,45), may have affected the discrepancy in the association between TRF length and indexes of arterial stiffness.…”

Section: Resultsmentioning

confidence: 87%

White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria

et al. 2007

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OBJECTIVE -To examine differences in telomere (terminal restriction fragment [TRF]) length and pulse wave velocity (PWV)-an index of arterial stiffness-in patients with type 2 diabetes with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS-A total of 84 men with type 2 diabetes, 40 with MA and 44 without MA (aged 63.5 Ϯ 9.0 vs. 61.2 Ϯ 9.8 years), were studied. TRF length was determined in white blood cells. MA was defined as albumin excretion rate (AER) in the range of 30 -300 mg/24 h in at least two of three 24-h urine collections. PWV was assessed using applanation tonometry. Markers of oxidative stress were also measured.RESULTS -TRF length was shorter in patients with MA than in those without MA (6.64 Ϯ 0.74 vs. 7.23 Ϯ 1.01 kb, respectively, P ϭ 0.004). PWV was significantly higher in the patients with MA. Multivariate linear regression analysis in the total sample demonstrated an independent association between TRF length and age (P ϭ 0.02), MA status (P ϭ 0.04) or AER (P ϭ 0.002), and plasma nitrotyrosine levels (P ϭ 0.02). AER was associated significantly with PWV (P Ͻ 0.01).CONCLUSIONS -Subjects with type 2 diabetes and MA have shorter TRF length and increased arterial stiffness than those without MA. Additionally, TRF length is associated with age, AER, and nitrosative stress. As shorter TRF length indicates older biological age, the increased arterial stiffness in patients with type 2 diabetes who have MA may be due to the more pronounced "aging " of these subjects. Diabetes Care 30:2909-2915, 2007M icroalbuminuria (MA) is a common complication of diabetes, affecting almost 30 -50% of the patients with type 2 diabetes (1,2). MA is a strong predictor of cardiovascular morbidity and mortality in individuals with diabetes (3,4). Although a number of abnormalities have been described in patients with MA, including high blood pressure, dyslipidemia, increased oxidative stress, inflammation, endothelial dysfunction, left ventricular hypertrophy, and hypercoagulation (rev. in 5), they do not seem adequate to explain the increased cardiovascular risk in this group of patients.Telomeres, the tandem repeats of TTAGGG of the DNA sequence at the ends of eukaryotic chromosomes, undergo attrition with each cell division, and their length is an indicator of the replicative potential of somatic cells (6). Telomere length reflects the biological age of humans, which may differ from the chronological age (6). Inflammation and oxidative stress accelerate the rate of telomere attrition in different cell types (6 -8). Telomere attrition has been associated with hypertension, endothelial dysfunction, arterial stiffening, atherosclerosis, and cardiovascular mortality (9 -14). Diabetes is marked by increased oxidative stress and low-grade inflammation (15,16), phenomena which are further enhanced in the presence of MA (5,17,18).The hypothesis we tested herein is that the mean length of telomeres, expressed as the mean length of the terminal restriction fragments (TRFs) of white blood cells (WBCs), is shorter in s...

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Section: Resultsmentioning

confidence: 87%

White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria

et al. 2007

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“…As the most predictive index of mortality, 2 h plasma glucose following a standard 75 g oral glucose tolerance test (2-HPG) may contribute to the pathogenesis of macrovascular disease more than fasting plasma glucose values (FPG) [2]. Premature conduit vessel arteriosclerosis predicts mortality in type 2 diabetes [3] and may be attenuated by therapeutic approaches with potential to lower glucose or blood pressure directly [4][5][6][7]. The independent association of FPG and 2-HPG indices with the haemodynamic consequence of early sclerosis (aortic stiffness) implies that modifiable structural mechanisms connect hyperglycaemia with vascular complications even within prediabetes thresholds of impaired glucose tolerance (IGT) [8][9][10][11] and impaired fasting glycaemia (IFG) [12,13].…”

Section: Introductionmentioning

confidence: 99%

Impact of metabolic indices on central artery stiffness: independent association of insulin resistance and glucose with aortic pulse wave velocity

et al. 2010

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Aims/hypothesis Non-invasive measures of aortic stiffness reflect vascular senescence and predict outcome in diabetes. Glucose-mediated elastic artery sclerosis may play an integral role in the development of macrovascular complications. We used carotid-femoral pulse wave velocity ( cf PWV) to quantify independent associations of fasting glucose, post-challenge glucose and derived insulin resistance (HOMA-IR) with aortic stiffness. Methods cf PWV was measured using a 4 MHz continuous wave Doppler ultrasound probe within groups with newly identified age-and sex-matched normal glucose metabolism (NGM), impaired glucose regulation (IGR) and diabetes mellitus populations (n=570, mean age 59.1, 56% male). Results After multivariate adjustment, IGR and diabetes were associated with significant aortic stiffening compared with NGM (adjusted cf PWV±SE: NGM, 9.15±0.12 m/s; IGR 9.76±0.11 m/s, p<0.001; diabetes, 9.89±0.12 m/s, p< 0.001). IGR stratification indicated that impaired fasting glucose (IFG; 9.71±0.12 m/s) and post-challenge (impaired glucose tolerance; 9.82±0.24 m/s) categories had similar cf PWV (p=0.83). Modelled predictors of cf PWV were used to assess independent metabolic associations with arterial stiffness. Fasting glucose concentration (β=0.10; 95% CI 0.05, 0.18; p=0.003), 2 h post-challenge glucose (β=0.14; 95% CI 0.02, 0.23; p<0.001) and HOMA-IR (β=0.20, 95% CI 0.05, 0.53; p<0.001) were independently related to cf PWV after adjustment for age, sex, mean arterial pressure, heart rate, body mass index, renal function and antihypertensive medication. Conclusions/interpretation IGR characterised by fasting or post-challenge hyperglycaemia is associated with significant vascular stiffening. Post-challenge glucose and HOMA-IR are the most powerful metabolic predictors of arterial stiffness, implying hyperglycaemic excursion and insulin resistance play important roles in the pathogenesis of arteriosclerosis.

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“…In long-term controlled studies, the angiotensin-converting enzyme inhibitors (ACEIs) perindopril 7 and trandolapril, 8 the combined neutral endopeptidase/ACEI omapatrilat, 9 the angiotensin receptor blocker (ARB) valsartan, 10 and the aldosterone antagonist spironolactone 11 had the capacity to reverse aortic stiffening independently of changes in BP. However, only 1 dose was tested in these studies.…”

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confidence: 99%

Dose-Dependent Arterial Destiffening and Inward Remodeling After Olmesartan in Hypertensives With Metabolic Syndrome

Laurent

Boutouyrie

2014

Hypertension

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Whether the reduction in arterial stiffness after antihypertensive treatment is only because of the blood pressure (BP) lowering, which unloads the stiff components of the arterial wall such as collagen, or whether additional BP-independent effects are involved, has been largely debated. [1][2][3][4] An increasing body of evidence, including theoretical aspects of arterial mechanics, 4 long-term observational studies in humans, 5 and a recent meta-analysis of double-blind, randomized, controlled trials, 6 suggests that only part of aortic stiffness could be reduced through the normalization of BP by pharmacological treatment, and further reduction of aortic stiffness would require long-term arterial remodeling, including reduction in collagen density and rearrangement of the wall materials.Blockers of the renin-angiotensin-aldosterone system (RAAS) are privileged antihypertensive drugs for such a BP-independent effect on arterial stiffness, mainly through the reduction of arterial wall fibrosis and remodeling. In long-term controlled studies, the angiotensin-converting enzyme inhibitors (ACEIs) perindopril 7 and trandolapril, 8 the combined neutral endopeptidase/ACEI omapatrilat, 9 the angiotensin receptor blocker (ARB) valsartan, 10 and the aldosterone antagonist spironolactone 11 had the capacity to reverse aortic stiffening independently of changes in BP. However, only 1 dose was tested in these studies.A major argument in favor of a BP-independent reduction in aortic stiffness by a RAAS blocker would come from the demonstration of a dose-dependent reduction in aortic stiffness for a given mean BP (MBP) reduction. To our knowledge, no such pharmacodynamic data are yet available. We hypothesized that high doses of olmesartan medoxomil (OM), through various mechanisms common to RAAS blockers in general and ARBs in particular, and possible additional anti-inflammatory effects reported in subjects with hypertension and microinflammation 12 would gradually lower aortic stiffness for a given MBP reduction. This is of particular interest in patients with metabolic syndrome. Impaired glucose metabolism 13 and the clustering of risk factors known as the metabolic syndrome are associated with stiffening of the larger arteries.14-16 Metabolic syndrome is also associated with vascular inflammation, 17 andAbstact-Whether angiotensin receptor blockers can dose-dependently remodel the arterial wall during long-term treatment has been largely debated. In this phase III, multicenter, randomized, double-blind, parallel-group study, 133 subjects with hypertension and metabolic syndrome were assigned to olmesartan, either 20 mg (n=44), 40 mg (n=42), or 80 mg (n=47) once a day, according to a force titration design during a 1-year period. Office blood pressure, 24-hour blood pressure, aortic stiffness (carotid-femoral pulse wave velocity), and carotid parameters were measured at baseline, 24 weeks, and 52 weeks. Pulse wave velocity significantly decreased (P<0.001) with time in each group, with no significant time-dose inter...

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Selective Angiotensin Receptor Antagonism with Valsartan Decreases Arterial Stiffness Independently of Blood Pressure Lowering in Hypertensive Patients

Cited by 37 publications

References 31 publications

White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria

White Blood Cells Telomere Length Is Shorter in Males With Type 2 Diabetes and Microalbuminuria

Impact of metabolic indices on central artery stiffness: independent association of insulin resistance and glucose with aortic pulse wave velocity

Dose-Dependent Arterial Destiffening and Inward Remodeling After Olmesartan in Hypertensives With Metabolic Syndrome

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