Stella-Maria G. Kyvelou, MD, Hypertension Unit, First Department of Cardiology, Athens Medical School, Hippokration Hospital, First Cardiology Department of Onassis Cardiosurgery Center, 108, Vasilisis Sofia Avenue, PO 11526, Athens, Greece E-mail: firstname.lastname@example.org
The purpose of the present study was to assess angiotensin receptor blocker (ARB) treatment on arterial stiffness in select hypertensive patients and define possible differences between smokers and nonsmokers. The authors evaluated 81 consecutive, nondiabetic patients (mean age, 52 years; 47 men) with uncomplicated essential hypertension with high plasma renin activity who were administered monotherapy with irbesartan, an ARB, at maximal dose. Patients were divided into smokers (n=24) and nonsmokers (n=57). Carotid-radial pulse wave velocity (PWVc-r), carotid-femoral pulse wave velocity (PWVc-f), and augmentation index (AIx) were measured before and 6 months after ARB antihypertensive treatment. All mean values of elastic effect indices were decreased after irbesartan monotherapy (AIx, from 26.3%to 21.2% [P<.01]; PWVc-f, from 7.7 m/s to 7.3 m/s [P<.05], and PWVc-r, from 8.9 m/s to 8.3 m/s [P<.001]). When comparing smokers vs nonsmokers, no difference was noted in AIx and PWVc-f change (P=not significant), while PWVc-r change was greater in smokers compared with nonsmokers (P<.05). Chronic ARB treatment may favorably affect arterial stiffness and wave reflections in hypertensive chronic smokers with elevated plasma renin levels.
During recent years, interest in the evaluation of arterial elastic effects and the assessment of arterial stiffness indices, especially in hypertensive patients, has increased.
Arterial stiffness depends on structure and function of arteries,1 progresses with age,2 and is considered an independent prognostic factor of mortality in hypertension.3 Furthermore, aortic stiffness, increased wave reflections, and their pathophysiologic manifestations such as increased systolic pressure, pulse pressure, and especially central pulse pressure with reduced diastolic pressure, have been identified as independent factors of cardiovascular risk.4,5
Smoking is a major risk factor in the development and progression of cardiovascular disease.6 Despite extensive research, the pathophysiologic mechanisms that are responsible for smoking-related vascular damage have not been elucidated. McVeigh and colleagues,7 using invasive methods, demonstrated abnormalities in the brachial artery pressure waveforms of chronic smokers, while in older patients, smoking was associated with increased carotid artery stiffness.7 The effect of smoking on arterial stiffness in hypertensive patients on chronic angiotensin receptor blocker (ARB) treatment has not been investigated.
The role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension is well established. Clinical and experimental studies have shown that over the long-term, the RAS may act on the geometry and stiffness of the large artery wall independent of blood pressure (BP) levels through alterations of the extracellular matrix of vascular smooth muscle cells.8,9 Many of the complications seen with angiotensin II excess—an increased event rate, left ventricular hypertrophy, endothelial dysfunction, and target organ damage—are also associated with increased arterial stiffness.10 Thus, it is possible that reduced arterial compliance may be one mechanism whereby increased activity of the RAS produces adverse vascular effects. Yet the role of the RAS in modulating arterial compliance in essential hypertension and in normotensive patients is less clear cut.
Based on this approach to the RAS system, and to the possible alterations due to smoking status, the purpose of the present study was to assess the long-term effect of a selective ARB, irbesartan, on arterial stiffness indices in patients with essential hypertension and high renin levels and with different current smoking habits.
MATERIALS AND METHODS
In the present study we recruited 100 consecutive patients with uncomplicated essential hypertension after informed consent was obtained. At drug-free baseline, full clinical and laboratory evaluation (routine examination of blood and urine, liver, kidney, thyroid function, lipid, and glucose profile) was carried out to exclude patients with low plasma renin activity (<1 ng/mL/h) (Table I), acute and chronic inflammatory disease, endocrine disorders, chronic obstructive pulmonary disease, malignancy, renal insufficiency (serum creatinine >1.3 mg/dL), heart failure, recent (<6 months) cerebrovascular event, coronary artery disease (history of stable, unstable angina, or past myocardial infraction), ventricular arrhythmia, sinus bradycardia (<55 beats per minute), sinus tachycardia (>100 beats per minute) or atrioventricular conduction disturbances, and secondary hypertension.
Table I. Blood Pressure, Heart Rate, and PRA Alterations According to Smoking Status
Systolic BP, mm Hg
Diastolic BP, mm Hg
Heart rate, beats per min
Abbreviations: BP, blood pressure; NS, not significant; Post, after irbesartan therapy; PRA, plasma renin activity; Pre, before irbesartan therapy.
The diagnosis of arterial hypertension was based on elevations of either systolic (>140 mm Hg) or diastolic (>90 mm Hg) BP on 3 visits 1 week apart, and mean values were calculated. An at least 2-week washout period proceeded to measurements for every patient taking antihypertensive treatment (37%, 30 patients). Patients already on angiotensin-converting enzyme inhibitors (ACEIs), aldosterone receptors antagonists, or thiazide diuretic treatment were not eligible for the study. At each visit, BP was measured 3 times with 1-minute intervals and with the patient resting comfortably, back supported in the sitting position after a 10- to 15-minute relaxation period. A mercury sphygmomanometer was used for all measurements with a medium or large cuff, according to the patient's arm circumference.
All patients were initially treated with irbesartan at a maximal dose (300 mg once daily). BP response to monotherapy was evaluated 4 weeks later, and only patients who had reached BP target values (<140/90 mm Hg) continued irbesartan monotherapy for 6 months (responders).
Thus, from a total of 100 patients, the final cohort comprised 81 hypertensive patients (mean age, 52.2 years; 47 men) with elevated renin levels treated with irbesartan, all responders to monotherapy (from 164.9/101.8 to 129.4/82.4 mm Hg; P<.001, Table I). All patients were asked about their current smoking habits and thus the study population was further divided into 2 subgroups: 57 nonsmokers and 24 smokers.
Aortic Stiffness Measurements
In each patient, arterial stiffness measurements were performed at drug-free baseline and after 6 months of ARB monotherapy, 24 hours after last drug ingestion. Patients were requested to abstain from caffeine, smoking, and alcohol for at least 12 hours before arterial stiffness measurements were performed. Physicians performing arterial stiffness measurements were unaware of patients' antihypertensive treatment (perspective, single-blind study).
Evaluation of Aortic Elastic Effects
The pulse travels at a higher velocity in a stiff aorta and vice versa. Pulse wave velocity (PWV) is a well-established index of arterial elastic effects and a prognosticator of cardiovascular risk.11 Carotid-femoral PWV (PWVc-f) and carotid-radial PWV (PWVc-r) were calculated from measurements of pulse transit time and the distance traveled between 2 recording sites (PWV = distance [m]/transit time [s]) using a validated noninvasive device (Complior; Dupont Medical, Pantin, France), which allows online pulse wave recording and automatic calculation of PWV. Two different pulse waves were simultaneously obtained at 3 sites (at the base of the neck for the common carotid and over the right femoral artery and the right radial artery) with 3 transducers. The distance was defined as: distance from the suprasternal notch to femoral artery - distance from carotid artery to the suprasternal notch and distance from the suprasternic notch to radial artery - distance from carotid artery to the suprasternal notch.
Measurements of Wave Reflections Indices
We used a validated, commercially available system (SphygmoCor; AtCor Medical, Sydney, Australia), which employs the principle of applanation tonometry and appropriate acquisition and analysis software for noninvasive recording and analysis of the arterial pulse. The technique has been described in detail previously.12,13 First, from the radial artery recordings, the ensemble-averaged radial pressure waveform is obtained. Then, this is calibrated according to sphygmomanometric systolic and diastolic pressure measured in the brachial artery, because there is practically negligible pressure pulse amplification between the brachial and the radial artery. Subsequently, the mean radial pressure is calculated by digital integration of the waveform. Thereafter, from the radial artery pressure waveform, the central (aortic) arterial pressure waveform is derived. This is done with the use of a generalized transfer function, which has been shown to give an accurate estimate of the central arterial pressure waveform and its characteristics and by assuming that the mean pressure in the aorta is the same as the mean pressure in the radial artery, because there is practically no change in mean pressure along the arterial tree.
Augmentation index (AIx) and augmented pressure of the central waveform were measured as indices of wave reflection. The pressure waveform recorded at any site of the arterial tree is the sum of the forward-traveling waveform generated by pump ejection and the backward traveling (the “echo” of the incident wave reflected at peripheral sites). The merging point of the incident and the reflected wave can be identified on the pressure waveform as an inflection point, which, in the majority of individuals, divides the systole into an early and late systolic phase. Augmented pressure, defined as: maximum systolic pressure - pressure at the inflection point, is the pressure added to the incident wave by the returning reflected wave and represents the pressure boost with which the left ventricle must cope and which is caused by wave reflection. AIx was defined as augmented pressure divided by pulse pressure and expressed as a percentage. AIx is a composite measure of the magnitude of wave reflection and arterial stiffness, which affects timing of wave reflection. Higher values of AIx indicate increased wave reflection from the periphery and/or earlier return of the reflected wave as a result of increased PWV (due to increased arterial stiffness), and vice versa.
Mean value and standard deviation of variables at baseline and after therapy were calculated and compared among groups of smokers and nonsmokers using analysis of variance followed by Bonferroni comparisons for individual significant differences. Arterial stiffness indices comparison between smokers and nonsmokers was performed after analysis of covariance. Proportions were compared by the chi-square test. Significance was assumed at a 2-tailed probability value of <.05. Statistical analysis was performed using SPSS package for Windows version 13.0 (SPSS Inc, Chicago, IL).
Aortic Elastic Effects and Wave Reflections
In the entire study population, irbesartan treatment reduced AIx in 64 patients (79%), PWVc-f in 59 patients (72.8%), and PWVc-r in 65 patients (80%). All mean values of elastic effects indices were decreased after irbesartan monotherapy (AIx, from 26.3% to 21.2% [P<.01], PWVc-f, from 7.7 m/s to 7.3 m/s [P<.05], and PWVc-r, from 8.9 m/s to 8.3 m/s [P<.001]) (Figure 1).
In our study, multivariate regression analysis revealed an independent association between AIx baseline values and age (standardized beta [SB], 0.196; P<.05), sex (SB, −0.735; P<.001), and body mass index (SB, −0.201; P<.05) and between PWVc-f and age (SB, 0.436; P<.001), baseline systolic BP values (SB, 0.434; P<.001), and baseline heart rate (SB, 0.215; P<.05). No significant difference was noted in the above-mentioned parameters between smoker and nonsmoker subgroups as shown in Table I and Table II. Moreover, in the entire study population, PWVc-r change was independently associated with baseline PWVc-r values (SB, −0.58; P<.001), and PWVc-f change was associated with systolic BP change (SB, 0.257; P<.05) and PWVc-f baseline values (SB, −0.296; P<.01), pointing to the regression to the mean phenomenon. No difference in systolic BP change (Table I) baseline PWVc-f values (7.73±1.29 vs 7.72±1.31 m/s; P=not significant) (Figure 2) was noted between smokers vs nonsmoker subgroups, but PWVc-r baseline values were found to be higher in the smoker compared with the nonsmoker subgroups (9.2±0.85 vs 8.8±0.92 cm/s; P<.05) (Figure 2).
Table II. Baseline Characteristics of the Study Population According to Smoking Status
High waist/hip ratio, %
Abbreviations: BMI, body mass index; IGT, impaired glucose tolerance; NS, not significant.
We noted no difference in AIx and PWVc-f change between smokers and nonsmokers (−6.47±7.4 vs −4.5±7.1%, and −0.63±1.15 vs −0.31±0.97 m/s, P=not significant (Figure 3), but PWVc-r change was greater in smokers compared with nonsmokers (−1.03±0.64 vs −0.49±1.13; P<.05).
Effect of Treatment With an ARB on Aortic Elastic Effects and Wave Reflection: Clinical Implications and Possible Mechanisms
This is a single-blind prospective study demonstrating that chronic antihypertensive treatment with irbesartan in a select group of hypertensive patients decreases aortic stiffness and wave reflection, along with the BP decrease. More precisely, this medication decreased arterial stiffness indices in >70% of the study population.
Previous studies have reported a beneficial effect of different AR B antihypertensive agents on wave reflection and aortic stiffness through various suggested mechanisms.14,15 It has been reported that losartan16 and valsartan17 decrease aortic stiffness and wave reflection, independent of systolic BP levels. Furthermore, it has been noted that there is a significant slowing of the progression of aortic atherosclerosis by long-acting ARB administration.18 In our study, AIx, PWVc-f, and PWVc-r mean values were significantly decreased after irbesartan administration.
The clinical implications of the effect of irbesartan on aortic stiffness and wave reflection are valid independent of the mechanism involved.
Although PWV reflects the functional and structural states of arterial wall elasticity, the results of our study suggest that the latter can be improved by intensive BP lowering to normal levels plus angiotensin II receptor blockade, sustained for at least 6 months. This is particularly important, since previous studies have shown that PWV predicts cardiovascular mortality and morbidity in hypertensive patients.19 Thus, PWV can be used as an indicator of the degree of vascular protection seen with chronic antihypertensive treatment.
The mechanisms underlying the effect of ARBs on arterial stiffness are not well-defined. Several in vitro studies have indicated that RAS acts directly on large arterial vessels.20 Common pathophysiologic processes, altered collagen turnover, and increased fibrosis may underlie both arterial stiffness and RAS-associated vascular damage. Given that RAS activation and aortic stiffness are significantly associated in hypertensive patients,21 the blockage of angiotensin type 1 receptors may improve aortic distensibility. Nevertheless, several other mechanisms may contribute to reduce stiffness. First, lowering BP per se lessens the stretch of the arterial wall, thereby favoring an increase in elasticity. Second, the direct or indirect effects of ARBs on arterial smooth muscle tone might favor smooth muscle relaxation, resulting in improvement of the mechanical arterial effects.22 Finally, arterial structural changes may be reversed by long-term ARB therapy.23
The Effect of Smoking
In the present study we further divided our patients into 2 groups according to their current smoking habits. In the smokers group, baseline PWVc-r levels were higher, while there was no significant difference in baseline PWVc-f, AIx levels, or systolic BP reduction. Irbesartan administration reduced PWVc-r levels, while no significant reduction was observed in PWVc-f and AIx. It has been reported in the past24 that ARB treatment has a beneficial effect on inflammatory indices in hypertensives who are current smokers, while it has also been mentioned that smoking affects the metabolism of irbesartan, causing a reduction in its metabolic rate.25 Levenson and colleagues26 showed that cigarette smoking and hypertension are independently associated with higher PWV and that this effect is cumulative, while Wollersheim and colleagues27 showed that long-term smokers exhibit an increase in stiffness in their peripheral muscular arteries but not in their central elastic arteries, as compared with nonsmokers. This finding is in line with our observation that smokers had higher baseline PWV-c levels. PWVc-r reflects the stiffness not only of the elastic arteries but also of the muscular arteries,28 thus cigarette smoking might have a relatively strong impact on PWVc-r, probably through increased sympathetic activation.29 Chronic ARB16,17 and ACEI30 treatment is reported to favorably affect central elastic artery stiffness as evaluated by PWVc-f, but little is known about its effect on PWVc-r. In the present study, irbesartan reduced PWVc-r to a greater extent in smokers compared with nonsmokers, independent of systolic BP reduction, which reflects that the favorable effect of irbesartan on arterial stiffness indices is better exerted in smokers through PWVc-r reduction, which implies a stronger impact on muscular arteries.
The present study has some limitations. First, the final cohort comprised a small number of select patients with high renin levels. A larger-scale study may add more valid information about the effect of irbesartan on arterial stiffness indices. Second, although the ARB markedly reduced BP levels, we hypothesize that vigorous BP lowering with these agents might overwhelm the compensatory mechanisms and cause a significant decrease in AIx and PWV. Third, our study did not include a comparative treatment group. Finally, the effect of irbesartan on arterial stiffness indices may only partly be attributed to its direct effect, because the BP lowering itself improves arterial stiffness. Thus, it is not safe to generalize these results; however, our findings are in line with several previous reports underlying the possible beneficial effect of ARBs on the arterial wall.
In conclusion, our study demonstrates that patients with elevated renin levels and responders to irbesartan monotherapy also note a beneficial effect on arterial stiffness indices. PWVc-r is the only index that was significantly reduced in smokers, and this reduction was independently associated with greater PWVc-r baseline values and systolic BP changes. Given the fact that arterial stiffness as well as smoking are independent predictors of cardiovascular risk, the role of ARBs beyond BP lowering is of great interest.