Abstract
Aortic augmentation index (AIx) is a marker of central aortic pressure burden and is modulated by antihypertensive drugs. In patients with peripheral arterial disease (PAD) undergoing antihypertensive treatment, aortic pressures parameters, heart rate–adjusted augmentation index (AIx75), and unadjusted AIx were determined. The (aortic) systolic and diastolic blood pressure did not differ between PAD patients who were taking β‐blockers (n=61) and those who were not taking β‐blockers (n=80). In patients taking β‐blockers, augmentation pressure and pulse pressure were higher than in patients who did not take β‐blockers (augmentation pressure, P=.02; pulse pressure, P=.005). AIx75 was lower in PAD patients taking β‐blockers than in patients not taking β‐blockers (P=.04), while the AIx did not differ between PAD patients taking and not taking β‐blockers. The present study demonstrates that β‐blockers potentially affect markers of vascular hemodynamics in patients with PAD. Because these markers are surrogates of cardiovascular risk, further studies are warranted to clarify the impact of selective β‐blocker treatment on clinical outcome in patients with PAD.
Peripheral arterial disease (PAD) is a common manifestation of advanced atherosclerosis. In industrialized countries, PAD affects almost one fourth of the population older than 50 years.1 PAD is associated with a substantial increase in cardiovascular morbidity and mortality compared with healthy patients.2 Therefore, cardiovascular risk reduction is the primary goal in the therapeutic management of patients with PAD.
In patients with clinically manifested atherosclerosis, the central augmentation index (AIx) has emerged as an independent predictor for the future occurrence of cardiovascular events.3 The AIx constitutes the proportion between the second and first peak of the arterial pulse wave. It can be measured noninvasively by radial applantation tonometry. The AIx mainly depends on pressure wave reflections from peripheral arteries and peripheral arterial stiffness.
Peripheral arterial tone as well as wave reflections may potentially be influenced by antihypertensive medication. Previous data have shown that antihypertensive drugs can differently influence the arterial pulse wave morphology and the AIx.4 Within the spectrum of antihypertensive drugs, β‐blockers are related to a higher AIx as a result of their negative chronotropic effects.4 In patients with PAD, angiotensin‐converting enzyme (ACE) inhibitors have been proposed to lower AIx.5 While ACE inhibitors have been well established as antihypertensive treatment in patients with PAD, the use of β‐blockers has been controversially debated over the past years.6, 7, 8
Up to now, there is no evidence that β‐blockers adversely affect peripheral arterial perfusion and PAD‐associated symptoms.9 In particular, the impact of β‐blockers on vascular hemodynamics in patients with PAD is still a matter of discussion.
Hence, the aim of the present study was to assess differences in vascular hemodynamics between PAD patients with and without β‐blocking treatment in the setting of a cross‐sectional study.
Methods
Patients
Consecutive patients with stable PAD (Rutherford categories 0–3) who were referred to the Clinic of Angiology at the University Hospital Zurich were eligible for the study. Exclusion criteria comprised critical limb ischemia (Rutherford categories 4–6), presence of an inflammatory vascular disease, and cardiac arrhythmias.
The study was performed according to the recommendations of the Declaration of Helsinki and the Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice guidelines, and the protocol was approved by the institutional ethical committee. Written informed consent was obtained before inclusion from all patients.
Clinical Data
All patients underwent a complete clinical examination. Demographic data including patients’ age, sex, body mass index, smoking habits, and medication were systematically recorded. The diagnosis of PAD was established according to current guidelines.10 Patients with PAD were clinically classified according to Rutherford's categories for PAD.11
The presence of arterial hypertension and dyslipidemia were diagnosed referring to the respective guidelines.12, 13 Diabetes mellitus was diagnosed in patients taking continuous antidiabetic medication or in accordance with current recommendations for the diagnosis of diabetes.14 The presence of coronary artery disease or cerebrovascular disease was declared in the patients’ medical history. In addition to arterial hypertension, a history of coronary artery disease was an indication for the use of β‐blockers and/or ACE inhibitors/angiotensin receptor blockers (ARBs).
Generation/Class of β‐Blockers
For further differentiation, β‐blockers were stratified by generation15: first‐generation/nonselective β‐blockers: propranolol; second‐generation/selective β1‐blockers: atenolol, metoprolol, bisoprolol; and third‐generation/β‐blockers with assumed vasodilating activity: carvedilol, nebivolol.
Hemodynamic Measurements
Blood pressure (BP) and pulse wave analyses were performed in a quiet room with a constant room temperature after a resting period of 15 minutes. All measurements were obtained with the patient in a supine position.
As previously published, BP measurements of the lower limbs were obtained using a hand‐held 6‐MHz Doppler probe (Kranzbühler, Logidop 2, Pilger Medical Electronics, Switzerland) and appropriate sphygmomanometer cuffs.16 Thereby, the systolic BPs of the anterior and posterior tibial arteries were measured at the ankle of each patient's limb. Further, bilateral brachial BP measurements were obtained in all patients. The ankle brachial index (ABI) for each leg was calculated as the ratio of the highest systolic ankle BP of the respective side and the highest systolic brachial BP of both sides. For further analyses, the ABI of the most affected limb was used. Radial artery pressure waveforms were recorded by applanation tonometry using a high‐fidelity micromanometer (Millar Instruments, Houston, TX).17 The aortic pressure waveforms were derived from the radial pressure waveforms using SphygmoCor software (AtCor Medical, Sydney, Australia) and a generalized transfer function.18 The (aortic) systolic BP and the (aortic) diastolic BP were determined from the aortic pressure waveforms. The (aortic) pulse pressure was calculated as the difference between systolic BP and diastolic BP. The (aortic) augmentation pressure constitutes the differences between the second and first peaks of the central (aortic) pressure waveform. The AIx (%) was calculated as the ratio between the augmentation pressure and the pulse pressure. As the main outcome parameter, the AIx was adjusted to a heart rate of 75 beats per minute (AIx75). Unadjusted AIx was also analyzed.
Statistical Analysis
Continuous data are presented as mean±standard deviation. Discrete data are given as counts and percentages. The primary endpoint was the difference in hemodynamic variables (AIx75, AIx, PP, augmentation pressure, aSBP, aDBP) between users and nonusers of the respective antihypertensive drugs (ACE inhibitors, β‐blockers, CCBs, and diuretics). For study analyses, ACE inhibitors and ARBs were grouped as one class of antihypertensive drug. For group comparisons, an independent‐samples t test was used. Correlations were examined by calculating Pearson or Spearman‐Rho correlations coefficients as appropriate. Multivariate linear regression analysis was used to further assess the independent association between β‐blocker intake and AIx75. A two‐sided P value <.05 was considered statistically significant. Calculations were performed using SPSS for Mac (version 20.0, IBM Corp, Armonk, NY).
Results
A total of 141 patients with a mean age of 68.9±10.5 years (90 men, 63.8%) who were admitted to the Clinic of Angiology at the University Hospital Zurich were included into this cross‐sectional study. Of these 141 patients, 45 patients (31.9%) were classified as having Rutherford category 0, 33 (23.4%) were classified as having Rutherford category 1 or 2, and 63 (44.7%) were classified as having Rutherford category 3 PAD.
Included patients had a mean body mass index of 25.5±4 kg/m2, and 91 (64.5%) patients were diagnosed with dyslipidemia and 37 (26.2%) with type 2 diabetes mellitus. A history of arterial hypertension was present in 116 patients (82.3%) and coronary artery disease in 41 patients (29.1%). Demographic and clinical data of included patients are given in Table 1.
Table 1.
Clinical Characteristics Study Patients With Peripheral Arterial Disease
| Characteristic | N=141 |
|---|---|
| Male | 51 (36.2) |
| Age, y | 68.9±10.5 |
| Height, cm | 169±8.1 |
| Weight, kg | 72.6±13.4 |
| BMI, kg/m² | 25.5±4 |
| ABIa | 0.77±0.19 |
| Rutherford categorya | |
| Category 0 | 45 |
| Category 1 or 2 | 33 |
| Category 3 | 63 |
| Coronary artery disease | 41 (29.1) |
| Cerebrovascular disease | 38 (27) |
| Diabetes mellitus | 37 (26.2) |
| Dyslipidemia | 91 (64.5) |
| Ever smokers | 109 (77.3) |
| Aspirin | 127 (90.1) |
| Clopidogrel | 53 (37.6) |
| Vitamin K antagonist | 14 (9.9) |
| Statins | 121 (85.8) |
| β‐Blockers | 61 (43.3) |
| ACE inhibitors/ARBs | 141 (63.1) |
| CCBs | 42 (29.8) |
| Diuretics | 60 (42.6) |
Abbreviations: ABI, ankle brachial index; BMI, body mass index; ACE, angiotensin‐converting enzyme; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers.
Mainly affected limb. Data are given as absolute counts (percentage) or mean±standard deviation.
Of the included 141 patients, 61 patients (43.3%) were taking β‐blockers (first‐generation: two patients, second‐generation: 49 patients, third‐generation: 10 patients). Demographic and clinical data of patients according to their β‐blocker treatment status are given in Table 2.
Table 2.
Clinical Characteristics of 141 Patients With Peripheral Arterial Disease According to β‐Blocker Treatment Status
| β‐Blockers | No β‐Blockers | P Value | |
|---|---|---|---|
| No. | 61 | 80 | |
| Male | 17 (27.9) | 34 (42.5) | .07 |
| Age, y | 70.3±9.9 | 67.8±10.8 | .15 |
| Height, cm | 169±6.8 | 168±9 | .43 |
| Weight, kg | 75.5±13.3 | 70.3±13.2 | .02 |
| BMI, kg/m² | 26.4±4.2 | 24.8±3.7 | .02 |
| ABIa | 0.75±0.19 | 0.78±0.19 | .49 |
| Rutherford categorya | |||
| Category 0 | 22 | 23 | .36 |
| Category 1 or 2 | 16 | 17 | .49 |
| Category 3 | 23 | 40 | .15 |
| Coronary artery disease | 29 (47.5) | 12 (15) | <.0001 |
| Cerebrovascular disease | 18 (29.5) | 20 (25) | .55 |
| Diabetes mellitus | 20 (32.8) | 17 (21.3) | .12 |
| Dyslipidemia | 42 (68.9) | 49 (61.3) | .35 |
| Ever smokers | 45 (73.8) | 64 (80) | .38 |
| Aspirin | 53 (86.9) | 74 (92.5) | .27 |
| Clopidogrel | 18 (29.5) | 35 (43.8) | .08 |
| Vitamin K antagonists | 9 (14.8) | 5 (6.3) | .09 |
| Statins | 54 (90.2) | 67 (83.8) | .42 |
| ACE inhibitors/ARBs | 44 (72.1) | 45 (56.3) | .13 |
| CCBs | 25 (41) | 17 (21.3) | .01 |
| Diuretics | 35 (57.4) | 25 (31.3) | .002 |
Abbreviations: ABI, ankle brachial index; BMI, body mass index; ACE, angiotensin‐converting enzyme; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers.
Mainly affected limb. Data are given as absolute counts (percentage) or mean±standard deviation.
Antihypertensive Drugs and Vascular Hemodynamics
AIx75 was lower in patients taking β‐blockers than in patients not taking β‐blockers (P=.04, Figure 1A), while (heart rate–unadjusted) AIx did not differ between patients taking and not taking β‐blockers (Figure 1B). Heart rate (69±10 beats per min [bpm]) was inversely related to (heart rate–unadjusted) AIx (P=−0.42, r<0.0001). In PAD patients, AIx75 was lower than AIx (AIx75: 30.9±7.8% vs AIx: 33.7±8.4%, P<.0001). The difference between AIx75 and AIx was more pronounced in patients taking β‐blocker than in patients not taking β‐blocker treatment (Figure 2).
Figure 1.
Bar charts (means) and respective error bars (±2 standard error) illustrating the (A) heart rate–adjusted (75 beats per min) aortic augmentation index (AIx75) and (B) the unadjusted aortic augmentation index (AIx) in patients with peripheral arterial disease receiving/not receiving angiotensin‐converting enzyme inhibitors (ACE‐Is)/angiotensin receptor blockers (ARBs), β‐blockers, calcium channel blockers (CCBs), and/or diuretics.
Figure 2.
Bar charts (means) and respective error bars (±2 standard error) illustrating the unadjusted augmentation index (AIx) vs the heart rate–adjusted augmentation index (AIx75) in patients with peripheral arterial disease receiving/not receiving β‐blockers.
The generation of β‐blockers was neither associated with the AIx75 (P=.47, Spearman correlation coefficient r=0.1), nor with the (heart rate–unadjusted) AIx (P=.94, Spearman correlation coefficient r=0.01). Further, the ABI (of the mainly affected limb) was neither related to the AIx75 (P=.11, Pearson correlation coefficient r=−0.14), nor to the (unadjusted) AIx (P=.23, Pearson correlation coefficient r=−0.16). The pulse pressure and the augmentation pressure were higher in patients taking β‐blockers than in patients not taking β‐blockers (Table 3).
Table 3.
Hemodynamic Data of 141 Patients With Peripheral Arterial Disease
| β‐Blockers | No β‐Blockers | P Value | |
|---|---|---|---|
| No. | 61 | 80 | |
| Heart rate, beats per min | 67±9 | 71±10 | .005 |
| Brachial systolic blood pressure, mm Hg | 152±22 | 147±21 | .12 |
| Brachial diastolic blood pressure, mm Hg | 77±12 | 80±11 | .15 |
| Aortic systolic blood pressure, mm Hg | 141±22 | 136±20 | .2 |
| Aortic diastolic blood pressure, mm Hg | 80±17 | 82±11 | .55 |
| Pulse pressure, mm Hg | 75±18 | 67±17 | .005 |
| Augmentation pressure, mm Hg | 21±10 | 19±9 | .02 |
No significant difference in AIx75 and unadjusted AIx was found between patients who were taking ACE inhibitors/ARBs, CCBs, and diuretics compared with patients not taking the respective antihypertensive drugs (Figure 1A and 1B). Patients who were taking ACE inhibitors/ARBs had higher systolic BP values than patients who were not taking ACE inhibitors/ARBs (Figure 3A). No differences in diastolic BP values were observed between users and nonusers of ACE inhibitors/ARBs, β‐blockers, CCBs, and diuretics (Figure 3B).
Figure 3.
Bar charts (means) and respective error bars (±2 standard error) illustrating the (A) aortic systolic blood pressure and (B) aortic diastolic blood pressure in patients with peripheral arterial disease receiving/not receiving angiotensin‐converting enzyme inhibitors (ACE‐Is)/angiotensin receptor blockers (ARBs), β‐blockers, calcium channel blockers (CCBs), and/or diuretics.
Multivariate Model
To account for potential confounders we included patients’ age, sex, height, smoking status, pulse pressure, and use of other antihypertensive drugs (eg, ACE inhibitors/ARBs, CCBs, diuretics) in a multivariate model. In this model, β‐blocker treatment was still associated with a significantly lower AIx75 (mean adjusted difference: −4.1; 95% CI −7.9 to −0.3; P=.04). In contrast, ACE inhibitors/ARBs, CCBs, and diuretics were not related to AIx75 in this model (ACE inhibitors/ARBs: mean adjusted difference, 0.1; 95% CI, −3.6 to 3.9 [P=.94]; CCB: mean adjusted difference, −3.3; 95% CI, −7.4 to 0.8 [P=.11], diuretics: mean adjusted difference, 0.3; 95% CI, −3.3 to 4 [P=.85]).
Discussion
The main finding of the present study is that patients with PAD who took β‐blockers had a lower AIx75 compared with patients who did not take β‐blockers. Comparable differences were not found for the other main classes of antihypertensive drugs (ACE inhibitors/ARBs, CCBs, and diuretics).
In the therapeutic management of PAD, adequate BP control is an important aim. According to the Reduction of Cardiovascular Events in the Heart Outcomes Prevention Evaluation (HOPE) study,6 ACE inhibitors have been established as the preferred antihypertensive drug in patients with PAD. In the past, (early‐generation) β‐blockers were avoided in patients with PAD based on a purportedly unfavorable effect on peripheral perfusion.8 However, concerns on the use of β‐blockers in PAD were refuted by a meta‐analysis of 11 randomized controlled studies which showed that β‐blockers did not adversely affect symptoms in patients with mild to moderate peripheral perfusion deficits.19 Another more recent meta‐analysis demonstrated an association between β‐blockers and an increase in AIx in hypertensive patients.20 It should be noted, however, that neither of these studies allowed conclusions to be drawn with respect to the relationship between β‐blockers and AIx in PAD patients.
The present study focused on PAD patients and revealed a lower AIx75 in those taking β‐blockers than in those not taking β‐blockers. In line with previous data, AIx was inversely related to heart rate in the present study.21 Although heart rate was lower in patients taking β‐blockers than in patients not taking β‐blockers, the unadjusted AIx did not differ between both groups. It should be noted, however, that adjustment for heart rate led to a decrease in AIx in patients taking and not taking β‐blockers. This may be conjointly attributed to the average heart rate, which was below 75 bpm in the majority of included patients, as well as to the inverse correlation between heart rate and AIx. The decline from AIx to AIx75 was more pronounced in patients taking β‐blockers (with a larger heart rate difference between baseline and adjusted heart rate of 75 bpm) than in patients not taking β‐blockers.
Interestingly, neither the ABI nor the generation of β‐blocker was associated with AIx75 in PAD patients. The comparably lower AIx75 in PAD patients taking β‐blockers stands in contrast to previous findings of AIx in hypertensive patients.20 Apart from the above‐mentioned impact of heart rate on the difference in AIx between patients taking and not taking β‐blockers, two mechanisms could additionally contribute to β‐blocker–associated differences in AIx75: (1) β‐blockers affect the cardiac inotropy, which might consequently have an impact on the AIx75, and (2) β‐blockers might target the magnitude of peripheral pulse wave reflections. Notably, the AIx75 is not a measure but constitutes a ratio between augmentation pressure and pulse pressure. In the present study, both components, augmentation pressure and pulse pressure, were higher in PAD patients taking β‐blockers than in patients not taking β‐blockers.
The pulse pressure itself constitutes the difference between systolic and diastolic BP. In the present study, systolic BP tended to be higher and diastolic BP tended to be lower in patients taking β‐blockers than in patients not taking β‐blockers. Taken separately, the between‐group differences in systolic and diastolic BP were statistically not significant. However, these differences seem to sum up in pulse pressure, which subsequently explains the higher pulse pressure in PAD patients taking β‐blockers than in patients not taking β‐blockers.
Regarding other antihypertensive drugs, systolic BP was higher in PAD patients taking ACE inhibitors than in PAD patients not taking ACE inhibitors. Nevertheless, we found no significant difference in AIx between patients taking and not taking ACE inhibitor treatment. In purely arithmetical terms, this is a consequence of not only higher systolic BP, but also higher diastolic BP in patients taking ACE inhibitors in the present study.
The second component of the AIx75, augmentation pressure, is a surrogate of wave reflection.22 In the present study, the augmentation pressure was higher in PAD patients taking β‐blockers than in those not taking β‐blockers. However, the difference in augmentation pressure between patients taking and not taking β‐blockers was much less pronounced than the difference in pulse pressure. Accordingly, the ratio of both components—with pulse pressure as the denominator—led to the lower AIx75 in PAD patients taking β‐blockers.
Study Limitations and Strengths
The findings of the present study should be viewed in light of its limitations. First, the modest sample size of the present study has to be acknowledged. Although we detected significant differences in AIx75 between patients taking and not taking β‐blockers, we cannot exclude that a larger number of patients would have revealed further differences in other BP‐lowering drugs. Second, this was a cross‐sectional study without follow‐up measurements of AIx75. Therefore, the proposed findings have to be interpreted with caution regarding a potential causal connection between the intake of β‐blockers and AIx75.
Nonetheless, the major strength of this investigation warrants mention. Up to now, data on the impact of β‐blockers on vascular hemodynamics in patients with PAD are scarce. To our knowledge, this is the first investigation to show a potential impact of β‐blockers on vascular hemodynamics in patients with PAD. Nevertheless, further studies are required to clarify whether the lower AIx75 and higher pulse and augmentation pressures in PAD patients taking selective β‐blockers has an impact on clinical outcome.
Conclusions
Vascular hemodynamics may be affected by β‐blocker treatment in patients with PAD. Additional studies are needed to clarify whether the association between β‐blockers and vascular hemodynamics contributes to clinical outcome in PAD.
Acknowledgments
The study has been supported by grants from the Swiss Heart Foundation and Matching Funds of the University Hospital of Zurich (both to Dr Husmann).
Conflicts of Interest
The authors have no conflicts of interest to disclose.
J Clin Hypertens (Greenwich). 2016;18:1244–1249. DOI: 10.1111/jch.12854. © 2016 Wiley Periodicals, Inc.
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