TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.

BACKGROUND: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm. METHODS/DESIGN: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands. DISCUSSION: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms. TRIAL REGISTRATION: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.

Potential vascular mechanisms of ramipril induced increases in walking ability in patients with intermittent claudication.

RATIONALE: We recently reported that ramipril more than doubled maximum walking times in patients with peripheral artery disease with intermittent claudication. OBJECTIVE: Our aim was to conduct exploratory analyses of the effects of ramipril therapy on circulating biomarkers of angiogenesis/arteriogenesis, thrombosis, inflammation, and leukocyte adhesion in patients with intermittent claudication. METHODS AND RESULTS: One hundred sixty-five patients with intermittent claudication (mean, 65.3 [SD, 6.7] years) were administered ramipril 10 mg per day (n=82) or matching placebo (n=83) for 24 weeks in a randomized, double-blind study. Plasma biomarkers of angiogenesis/arteriogenesis (vascular endothelial growth factor-A, fibroblast growth factor-2), thrombosis (D-dimer, von Willebrand factor, thrombin-antithrombin III), inflammation (high-sensitivity C-reactive protein, osteopontin), and leukocyte adhesion (soluble vascular cell adhesion molecule-1, soluble intracellular adhesion molecule-1) were measured at baseline and 24 weeks. Relative to placebo, ramipril was associated with increases in vascular endothelial growth factor-A by 38% (95% confidence interval [CI], 34%-42%) and fibroblast growth factor-2 by 64% (95% CI, 44-85%; P<0.001 for both), and reductions in D-dimer by 24% (95% CI, -30% to -18%), von Willebrand factor by 22% (95% CI, -35% to -9%), thrombin-antithrombin III by 16% (95% CI, -19% to -13%), high-sensitivity C-reactive protein by 13% (95% CI, -14% to -9%), osteopontin by 12% (95% CI, -14% to -10%), soluble vascular cell adhesion molecule-1 by 14% (95% CI, -18% to -10%), and soluble intracellular adhesion molecule-1 by 15% (95% CI, -17% to -13%; all P<0.001). With the exception of von Willebrand factor, all the above changes correlated significantly with the change in maximum walking time (P=0.02-0.001) in the group treated with ramipril. CONCLUSIONS: Ramipril is associated with an increase in the biomarkers of angiogenesis/arteriogenesis and reduction in the markers of thrombosis, inflammation, and leukocyte adhesion. This study informs strategies to improve mobility in patients with intermittent claudication. CLINICAL TRIAL REGISTRATION INFORMATION URL: http://clinicaltrials.gov. Unique identifier: NCT00681226.

Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial.

IMPORTANCE: Approximately one-third of patients with peripheral artery disease experience intermittent claudication, with consequent loss of quality of life. OBJECTIVE: To determine the efficacy of ramipril for improving walking ability, patient-perceived walking performance, and quality of life in patients with claudication. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial conducted among 212 patients with peripheral artery disease (mean age, 65.5 [SD, 6.2] years), initiated in May 2008 and completed in August 2011 and conducted at 3 hospitals in Australia. INTERVENTION: Patients were randomized to receive 10 mg/d of ramipril (n = 106) or matching placebo (n = 106) for 24 weeks. MAIN OUTCOME MEASURES: Maximum and pain-free walking times were recorded during a standard treadmill test. The Walking Impairment Questionnaire (WIQ) and Short-Form 36 Health Survey (SF-36) were used to assess walking ability and quality of life, respectively. RESULTS: At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60-89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215-295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges-Lehmann 95% CI, 12.2-15.5), speed score by 13.3 (95% CI, 11.9-15.2), and stair climbing score by 25.2 (95% CI, 25.1-29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges-Lehmann 95% CI, 3.6-11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score. CONCLUSIONS AND RELEVANCE: Among patients with intermittent claudication, 24-week treatment with ramipril resulted in significant increases in pain-free and maximum treadmill walking times compared with placebo. This was associated with a significant increase in the physical functioning component of the SF-36 score. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00681226.

A meta-analysis of the outcome of endovascular and noninvasive therapies in the treatment of intermittent claudication.

PURPOSE: Intermittent claudication is a common symptom of peripheral arterial disease. Currently, there is a lack of consensus on the most effective therapies for this problem. We conducted a meta-analysis of randomized trials assessing the efficacy of endovascular therapy (EVT) compared with noninvasive therapies for the treatment of intermittent claudication. METHODS: Randomized trials comparing the efficacy of EVT and noninvasive therapies, such as medical therapy (MT) and supervised exercise (SVE) in patients with intermittent claudication were identified by a systematic search. Data were pooled, and combined overall effect sizes (standardized differences of mean values) were calculated for a random effect model in terms of ankle-brachial index (ABI) and treadmill walking for initial claudication distance (ICD) and maximum walking distance (MWD). Nine eligible trials (873 participants) were included: two compared EVT and MT alone, four compared EVT and SVE, and three trials compared EVT plus SVE vs SVE alone. RESULTS: Heterogeneity between studies was marked. Quantitative data analysis suggested that EVT improved outcomes over MT alone at early follow-up evaluations. Outcomes of EVT plus SVE were better than those of SVE alone in terms of both ABI and treadmill walking at immediate, early, and intermediate follow-up. No substantial differences in outcomes of EVT alone compared with SVE alone were found. CONCLUSION: In patients with intermittent claudication, current evidence supports improved ABI and treadmill walking when EVT is added to MT or SVE during early and intermediate follow-up. There is no evidence that EVT alone provides improved outcome over SVE alone. There is low confidence in these findings for a number of reasons, including the small number of trials, the small size of these studies, the heterogeneity in study design, and the limited use of quality of life tools in assessing outcomes. More consistent data from larger, more homogenous studies, including longer follow-up, are required.

Gender differences in artery wall biomechanical properties throughout life.

Elevated large artery stiffness and pulse pressure have emerged as important risk factors for cardiovascular disease. The genders differ in large artery biomechanical properties throughout the lifespan with females displaying higher stiffness than males during the prepubertal years and a dramatic increase after menopause. Males on the other hand experience an increase in arterial stiffness postpuberty and a linear increase thereafter, suggesting that females have intrinsically stiffer large arteries than males, but that such effects are mitigated by sex steroids during the reproductive years. This review discusses anthropometric and sex steroid influences on gender differences in large artery stiffness and pressure dynamics from childhood to senescence. In particular, the sex-specific effects of estrogen, progesterone and testosterone on vascular structure and function and how these influence arterial stiffness are explored. These factors may contribute in part to the observed gender differences in the pathophysiology and clinical manifestations of cardiovascular disease.

A role for plasma transforming growth factor-beta and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome?

BACKGROUND: We have previously shown that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced aortic diameter by 3-7mm in Marfan syndrome (MFS) patients. Excessive signalling by the transforming growth factor-beta (TGF-beta) has been implicated in the development of aortic dilatation. We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF-beta and matrix metalloproteinase (MMP) levels. METHODS: 17 MFS patients (aged 33+/-5 (mean+/-SD)) on standard beta-blocker therapy were randomised to also receive perindopril (n=10) or placebo (n=7) for 24 weeks in a double blind study. Aortic root diameters were assessed at four sites via transthoracic echocardiography. Venous blood samples were analysed for latent and active TGF-beta, MMP-2 and MMP-3 levels. RESULTS: Perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (by 1.2-3mm/m(2), p<0.001). In addition, compared to placebo perindopril significantly reduced latent TGF-beta levels by 14.0+/-4.5ng/ml (p=0.01), active TGF-beta levels by 4+/-1ng/ml (p=0.02), MMP-2 levels by 22+/-6ng/ml (p<0.001), and MMP-3 levels by 5+/-1ng/ml (p<0.001). There were moderately strong correlations between the pre/post intervention change in aortic diameters and the change in both latent (r=0.49-0.76, p=0.001-0.04) and active TGF-beta (r=0.59-0.73, p=0.002-0.02), MMP-2 (r=0.63-0.75, p=0.001-0.007), and MMP-3 plasma levels (r=0.81-0.83, p<0.0001). CONCLUSIONS: Plasma TGF-beta, MMP-2 and MMP-3 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS.

Oral nitrate therapy does not affect glucose metabolism in healthy men.

1. Previously, we demonstrated that nitric oxide (NO) may be an important mediator of peripheral glucose disposal. The aim of the present study was to determine whether acute oral nitrate therapy improves glucose metabolism in healthy individuals. 2. Healthy men (n = 10), aged between 19 and 46 years, participated in a randomized cross-over placebo-controlled study. During Visit 1, participants received a dose-graded intravenous infusion of sodium nitroprusside (SNP; titrated from a dose of 0.5 microg/kg per min to a maximum of 2 microg/kg per min and delivered at a rate of 2 mL/min over 30 min). On Visits 2, 3 and 4, participants received oral extended-release isosorbide mononitrate (120 mg), pentaerythritol tetranitrate (160 mg) and placebo in a randomized Latin square design (one treatment per visit). The main outcome measures were plasma glucose and insulin levels and glucose tolerance determined by an oral glucose tolerance test following the SNP infusion and 3 h after nitrate/placebo administration. Exhaled NO, cGMP and pulmonary blood flow were also measured for 3 h after administration of nitrate/placebo and after SNP infusion. 3. None of the nitrate interventions influenced measures of glucose metabolism. Following SNP infusion, there was no change in plasma glucose (P = 0.42) or insulin (P = 0.25) levels, and the response to a glucose load did not different from baseline (P = 0.46). Similarly, neither of the oral nitrates altered plasma glucose (P = 0.24) or insulin levels (P = 0.90) or glucose tolerance (P = 0.56) compared with placebo. 4. In conclusion, these results indicate that acute oral nitrate therapy does not influence glucose metabolism. Studies using NO donors in a chronic setting are required to clarify the role of NO in mediating peripheral glucose uptake.

Reduced arterial stiffness may contribute to angiotensin-converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients.

OBJECTIVE: Claudication is a debilitating consequence of peripheral arterial disease. Evidence is accumulating to suggest that large artery stiffness may influence peripheral perfusion and walking time through effects on peripheral hemodynamics as well as microvascular structure and function. We have previously shown that the angiotensin-converting enzyme inhibitor ramipril increased systemic arterial compliance by 64%, and increased maximum walking time by over 200% in patients with peripheral arterial disease. In the current analysis in the same patient cohort, we hypothesized that this relationship may, in part, be causal. METHODS: Forty patients with peripheral arterial disease [66 +/- 4 years (mean +/- SD); n = 20 per group] were randomized to ramipril, 10 mg once daily, or placebo for 24 weeks in a double-blind study. Maximum walking time was recorded during a standard treadmill test. Indices of arterial stiffness were assessed globally by systemic arterial compliance and augmentation index and regionally via central pulse wave velocity. RESULTS: Ramipril increased maximum walking time by 243% and improved arterial stiffness parameters by between 17 and 64% (all P < 0.001 compared with placebo). There were moderately strong correlations between the pre/post intervention change in maximum walking time and the change in indices of arterial stiffness (systemic arterial compliance, r = 0.65, P < 0.001; central pulse wave velocity, r = -0.57, P < 0.001; augmentation index, r = -0.79, P < 0.001; time to pressure augmentation, r = 0.52, P = 0.001). CONCLUSION: The present data support the hypothesis that the beneficial effects of ramipril on maximum walking time observed in our peripheral arterial disease population are, at least partly, a consequence of reduced arterial stiffness.

Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial.

CONTEXT: Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness. OBJECTIVE: To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard beta-blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia. INTERVENTION: Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks. MAIN OUTCOME MEASURES: Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography. RESULTS: Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor beta (TGF-beta), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms. CONCLUSIONS: Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard beta-blocker therapy, possibly through attenuation of TGF-beta signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00485368.

Arterial stiffness and coronary ischemic disease.

Large artery stiffening may be both a cause and a consequence of atherosclerosis and is independently related to coronary outcome. This relationship is likely to be causal given the unfavourable effect of large artery stiffening on coronary hemodynamics. There is clear experimental and clinical evidence that large artery stiffening promotes myocardial ischemia secondary to central pulse pressure elevation. Many agents commonly used to treat ischemic heart disease symptoms also reduce large artery stiffness, through both functional and structural mechanisms. Such effects likely contribute to the anti-ischemic actions of these drugs. However, it remains to be elucidated whether agents specifically targeted to reduce large artery stiffness provide ischemic protection in the setting of coronary disease.

Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial.

BACKGROUND: Peripheral arterial disease (PAD) affects up to 12% of adults older than 50 years of age. Conventional therapies have only modest effects in improving symptoms. OBJECTIVE: To examine the effects of angiotensin-converting enzyme inhibition on walking ability in patients with PAD. DESIGN: Randomized, double-blind, placebo-controlled trial initiated in March 2003 and completed in January 2005. SETTING: The Alfred Hospital, Melbourne, Australia. PARTICIPANTS: 40 older adults with symptomatic PAD and no history of diabetes or hypertension. INTERVENTION: 10 mg of ramipril (n = 20) or placebo (n = 20) once daily for 24 weeks. All patients completed the trial. MEASUREMENTS: Pain-free and maximum walking time were recorded during a standard treadmill test, and the standard Walking Impairment Questionnaire was administered. RESULTS: After adjustment for the baseline pain-free walking time, mean pain-free walking time after ramipril treatment was 227 seconds (95% CI, 175 seconds to 278 seconds; P < 0.001) longer than that after placebo treatment. Similarly, maximum walking time improved by 451 seconds in the ramipril group (CI, 367 seconds to 536 seconds; P < 0.001) but did not change in the placebo group. Ramipril improved the Walking Impairment Questionnaire median distance score from 5% (range, 1% to 39%) to 21% (range, 12% to 58%; P < 0.001), speed score from 3% (range, 3% to 39%) to 18% (range, 8% to 50%; P < 0.001), and stair-climbing score from 17% (range, 4% to 80%) to 67% (range, 38% to 88%; P < 0.001). No adverse events were reported. LIMITATIONS: The sample size is modest, and the strict inclusion criteria limit the applicability of the results to patients with claudication and infrainguinal disease and those without diabetes. CONCLUSION: Ramipril improved pain-free and maximum walking time in some adults with symptomatic PAD.

Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression.

Large artery stiffening increases cardiovascular risk and promotes isolated systolic hypertension which is more prevalent in elderly women than men. Variation in sex steroid levels between males and females and throughout life may modulate arterial stiffness. We hypothesized that sex steroids directly influence expression of important structural proteins which determine arterial biomechanical properties. Human aortic smooth muscle cells were incubated with physiological concentrations of 17beta-estradiol, progesterone, 17beta-estradiol and progesterone, or testosterone for 4 weeks. Collagen, elastin, and fibrillin-1 deposition was examined (histochemistry/immunohistochemistry). Gene and protein expression of 2 important matrix metalloproteinases (MMPs), MMPs 2 and 3, regulating matrix turnover was assessed. All sex steroids reduced collagen deposition relative to control (100%). However, the reduction was greater with female sex steroids than testosterone (control, 100%; 17beta-estradiol plus progesterone, 20+/-2%; testosterone 74+/-12%, P<0.001). Female sex steroids increased elastin deposition compared with control (control, 100%; 17beta-estradiol, 540+/-60%; progesterone, 290+/-40%; 17beta-estradiol plus progesterone, 400+/-80%, all P<0.01). The elastin/collagen ratio was >11-fold higher in the presence of 17beta-estradiol and progesterone compared with testosterone. Fibrillin-1 deposition was doubled in the presence of female sex steroids (17beta-estradiol plus progesterone) compared with testosterone (P<0.01). MMP-2 gene and protein expression was unaffected by any sex steroid. Testosterone increased both gene and protein expression of MMP-3 relative to both control and female sex steroids (P<0.01). This may contribute to degradation of elastic matrix proteins. In conclusion, female sex steroids promote an elastic matrix profile, which likely contributes to variation in large artery stiffness observed between sexes and with changes in hormonal status across the lifespan.

Ramipril reduces large-artery stiffness in peripheral arterial disease and promotes elastogenic remodeling in cell culture.

Ramipril improves cardiovascular outcome in patients with peripheral arterial disease; however, the precise mechanisms of benefit remain to be elucidated. The effect of ramipril on large-artery stiffness in patients with peripheral arterial disease was examined. In addition, we determined the effect of ramiprilat on extracellular matrix from human aortic smooth muscle cell culture. Forty patients with peripheral arterial disease were randomized to receive ramipril, 10 mg once daily or placebo for 24 weeks. Arterial stiffness was assessed globally via systemic arterial compliance and augmentation index (carotid tonometry and Doppler velocimetry), and regionally via carotid-femoral pulse wave velocity. Angiotensin-converting enzyme inhibition increased arterial compliance by 0.10+/-0.02 mL/mm Hg, (P<0.001, all probability values relative to placebo) and reduced pulse wave velocity by 1.7+/-0.2 m/s (P<0.001), augmentation index by 4.1+/-0.3% (P<0.001), and systolic blood pressure by 5+/-1 mm Hg (P<0.001). Ramipril did not reduce mean arterial pressure significantly compared with placebo (P=0.59). In cell culture, ramiprilat decreased collagen deposition by >50% and increased elastin and fibrillin-1 deposition by >3- and 4-fold respectively (histochemistry and immunohistochemistry). Fibrillin-1 gene expression was increased 5-fold (real-time reverse-transcriptase polymerase chain reaction). Ramiprilat also reduced gene and protein (Western) expression of both matrix metalloproteinase (MMP)-2 and MMP-3. In conclusion, ramipril promoted an elastogenic matrix profile that may contribute to the observed clinical reduction in large-artery stiffness and carotid pressure augmentation, which occurred independently of mean arterial blood pressure reduction in patients with peripheral arterial disease.

Gender differences in large artery stiffness pre- and post puberty.

Age-related large artery stiffening is more pronounced in women compared with men and is an important cause of isolated systolic hypertension. This study aimed to investigate whether such gender differences are inherent or the result of sex steroid influences. Healthy children prepuberty [26 female (10.3 +/- 0.1 yr), 32 male (10.3 +/- 0.1 yr), mean age +/- SD] and post puberty [30 female (15.9 +/- 0.2 yr), 22 male (15.9 +/- 0.4 yr)] were studied. Large artery stiffness was assessed globally via systemic arterial compliance and regionally via pulse wave velocity. Prepubertal males and females did not differ in body size, cardiac output, or heart rate. Prepubertal females had stiffer large arteries and higher pulse pressure than age-matched males (P < 0.05). Postpubertal males were taller and heavier and had a greater cardiac output and lower heart rate compared with similarly aged females. In relation to pubertal status, females developed more distensible large arteries post puberty whereas males developed stiffer large vessels (P < 0.05). These changes where such that central large artery stiffness was similar between genders in the postpubertal group. Together these data suggest that large artery stiffness varies intrinsically between genders but is also modulated by both male and female sex steroids.