Augmentation pressure has emerged as a surrogate marker for cardiovascular disease, and endothelial dysfunction has been proposed as related factor. However, the relationship between augmentation pressure and digital endothelial function has not yet been well defined. We investigated the relationship between augmentation pressure and digital reactive hyperemia (RH) in patients with hypertension using peripheral arterial tonometry (PAT), which is regarded as being representative of endothelial function.
One hundred hypertensive patients (64 males; mean age, 49 ± 12 years) without a history of taking antihypertensive medication were enrolled in this study.
The mean augmentation pressure and augmentation index (AIx) normalized for a heart rate of 75 beats/min (AIx75) were 15 ± 8 mm Hg and 26 ± 11%, respectively. The mean RH-PAT index and log transformed PAT ratio were 2.24 ± 0.55 and 0.62 ± 0.30. There was an inverse relationship between the RH-PAT index and age, male sex, and body mass index. The log transformed PAT ratio also showed inverse relationship with age and male sex. The RH-PAT index and the log transformed PAT ratio showed no relationship with augmentation pressure or AIx75. In a multiple linear regression analysis, age, height, and central systolic BP demonstrated an independent association with augmentation pressure and AIx75.
In patients with hypertension, the RH-PAT index determined using PAT was not associated with augmentation pressure or AIx75. Digital vascular function may be a less important factor for pressure augmentation in patients with hypertension.
American Journal of Hypertension, advance online publication 8 September 2011; doi:10.1038/ajh.2011.132
Although elevated brachial blood pressure (BP) is the standard for diagnosis and treatment of hypertension, recent studies have found that central BP, rather than brachial BP, may have a stronger predictive value for future cardiovascular events.1 Central aortic pressure more closely reflects the hemodynamic load imposed on the left ventricle and the cerebral circulation than does the brachial BP.2 Recent studies have reported central BP as an independent predictive factor for cardiovascular outcomes above and beyond that of brachial BP.3,–5 Recent guidelines have reflected the important role of central BP and pulse wave analysis.6
The arterial pulse wave is generated by the sum of the forward pressure wave, timing of the reflected wave, and the magnitude of the reflected wave along the arterial trees.2,7 Arterial wave reflection occurs in peripheral arteries due to changes in arterial properties or in the architecture of the arterial tree.7 Reflected waves can be measured as augmentation pressure or augmentation index (AIx), which has emerged as a surrogate marker for cardiovascular disease.8,9
Several mechanisms for increased wave reflection have been proposed, such as arterial wall properties, vascular smooth muscle tone, and endothelial dysfunction.10,11 Theoretically, impairment in flow-mediated peripheral reactivity will increase peripheral vascular resistance and the magnitude of the reflected wave. Previous studies have demonstrated that AIx is correlated with the global endothelial function or the endothelial function of the conduit artery.12,–14 However, an association between endothelial dysfunction of resistant vessels and small arteries, such as the digital arteries, and pressure augmentation has not yet been demonstrated. Hypertension is associated with vascular inflammation and increased oxidative stress in the vascular beds, which subsequently results in endothelial dysfunction.15 Because resistance vessels are the major determinants of peripheral vascular resistance, we hypothesized that digital reactive hyperemia (RH), a measure of peripheral endothelial function, is associated with the AIx and augmented pressure in untreated hypertensive patients.
Study subjects. One hundred hypertensive patients without a history of taking antihypertensive medication were enrolled in this study. We recruited hypertensive subjects who had a systolic BP >140 mm Hg and/or a diastolic BP >90 mm Hg after being at rest (in a sitting position) for at least 5 min, as measured during at least two independent visits. Exclusion criteria included valvular heart disease, peripheral vascular disease, significant systemic disease, history of inflammatory disease and/or treatment with anti-inflammatory medications, clinically significant atrioventricular conduction disturbances, history of atrial fibrillation or other serious arrhythmias, severe hypertension (>210/130 mm Hg), or serum creatinine levels >1.4 mg/dl. The presence of valvular heart disease was ruled out by echocardiography. Peripheral vascular disease was diagnosed on the basis of overt symptoms, such as claudication.
This study was approved by our institutional ethics committee and complies with the Declaration of Helsinki. All patients provided informed consent.
BP measurements. After 5 min of rest, brachial BP was measured in a sitting position three times at 2-min intervals in the dominant arm with an OMRON HEM 7080IT device, which has previously been validated by the British Hypertension Society.16 The average of the last two measurements was used in the statistical analyses.
Pulse wave analysis. Central hemodynamics were evaluated in the sitting position after 10 min of rest using a commercially available radial artery tonometry device (SphygmoCor; AtCor Medical, Sydney, Australia). Using a high-fidelity micromanometer (Millar Instruments, Houston, TX), peripheral pressure waveforms were recorded from the radial artery at the wrist, as previously reported.8,17 Central systolic BP, diastolic BP, pulse pressure, augmentation pressure, forward wave amplitude, and AIx were acquired from the pulse waveform analysis. Pulse pressure was calculated as the difference between systolic and diastolic pressure. Augmentation pressure is the difference between the second and first systolic peak pressures, and the AIx is defined as the ratio of augmentation pressure to aortic pulse pressure. The AIx, normalized for a heart rate of 75 beats/min (AIx75), was calculated, as this measurement is influenced by heart rate.
Digital measures of vascular function. Pulse amplitude at rest was measured in the fingertips by positioning a peripheral arterial tonometry (PAT) device (Endo-PAT2000; Itamar Medical, Caesarea, Israel). Two flexible probes were placed on the index fingers of the right (ischemic) and left (control) hands. RH was provoked by a 5-min forearm cuff occlusion. The recorded pulse amplitude was analyzed by a computerized, semiautomated algorithm (Itamar Medical). Endothelial dysfunction was assessed using the RH-PAT index and the log transformed PAT ratio as described previously.18,19 The RH-PAT index was calculated as the ratio of the average PAT amplitude over 60 s following 90 s of cuff deflation to the average PAT amplitude over 2.5 min before cuff inflation in the occluded hand divided by the same values in the control hand and then multiplied by a baseline correction factor. The log transformed PAT ratio was calculated as the natural logarithm transformed ratio of the post-deflation pulse amplitude to the baseline pulse amplitude in the 90–120-s post-deflation time period divided by the corresponding ratio from the contralateral hand.
Statistical analysis. Continuous variables are presented as the mean ± s.d.; categorical variables are reported as the number of subjects (%). The normality assumption was tested using the Kolmogrov–Smirnov test. Independent predictors of aortic augmented pressure and AIx75 were determined via multiple linear regression analysis, using a standard, simultaneous regression method. Briefly, variables that were significant at the P < 0.10 level based on a simple linear regression analysis, and/or those known to be significantly associated with augmentation pressure and AIx75, were entered into the multiple linear regression analysis. Because augmented aortic pressure was not normally distributed, it was log transformed for linear regression analysis. Independent determinants for the low RH-PAT index and log transformed PAT ratio were also determined via a multiple linear regression analysis in the same manner. P values < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS V.18.0 software (SPSS, Chicago, IL).
Patient baseline characteristics are presented in Table 1. The average age was 49 ± 12 years and 64 subjects were male. The average brachial systolic and diastolic BP were 151 ± 14 mm Hg and 96 ± 10 mm Hg, respectively. Table 2 presents the indices of the central hemodynamics and digital vascular measures determined using EndoPAT. The mean augmentation pressure and AIx75 were 15 ± 8 mm Hg and 26 ± 11%, respectively, and the RH-PAT index and log transformed PAT ratio by EndoPAT were 2.24 ± 0.55 and 0.62 ± 0.30.
Relationships between augmentation pressure and digital endothelial dysfunction
Comparisons of the AIx75 were done according to tertiles of the RH-PAT index and the log transformed PAT ratio in both sexes. The result demonstrated that there were no increases in the AIx75 with decreasing the RH-PAT index and the log transformed PAT ratio in either sex (see Supplementary Figure S1 online). In a multiple linear regression analysis, older age, male sex, and an increased body mass index were independently associated with a low RH-PAT index after adjusting for BP and cholesterol (Table 3). Older age and male sex were also independently related with a low log transformed PAT ratio (Table 3).
The RH-PAT index and the log transformed PAT ratio showed no relationship with pulse pressure, pulse pressure amplification or pulse wave velocity. The RH-PAT index and the log transformed PAT ratio demonstrated no significant association with either augmentation pressure or AIx75 as well. In univariate linear regression analyses, female sex, age, central systolic BP, and height were correlated with augmentation pressure and AIx75. In a multiple linear regression analysis, age, height, and central systolic BP demonstrated independent relationships with augmentation pressure and AIx75 (Table 4).
In the present study, we investigated the relationships between pressure augmentation and peripheral endothelial dysfunction, as assessed by digital RH response with PAT. We found that endothelial dysfunction, as assessed by digital RH, was not significantly associated with an increase in pressure augmentation. As described in previous studies,20,21,22 pressure augmentation demonstrated a significant relationship with age, height, heart rate, and systolic BP, but not with RH-PAT index or log transformed PAT ratio. To our knowledge, the present study is the first to evaluate the association of pressure augmentation with digital endothelial function, as assessed by digital RH response with PAT.
Assessment of endothelial dysfunction by RH response with PAT
Previous studies have demonstrated that pressure augmentation correlates with endothelial function assessed by pulse wave changes after β-2-stimulation or flow-mediated vasodilatation (FMD) of the brachial artery.12,–14 However, global endothelial function assessment based on pulse wave changes after β-2-stimulation is not the gold standard for assessment of conduit endothelial function. The measurement of brachial FMD could be representative of conduit endothelial function, but measurements of FMD have technical problems in terms of defining the standard reference.23 Also, as brachial artery reactivity represents the local endothelial function of a local conduit artery, it may not reflect the reactivity of the peripheral vasculature and resistance arteries, which are the major determinants of peripheral vascular resistance. Recently, it has been demonstrated that the digital pulse wave amplitude measured using PAT is related to endothelial function.18 The measurement of RH with PAT is a noninvasive and automatic test used to assess digital hyperemic response and endothelial dysfunction. The degree of digital RH response has proven to be related with cardiovascular risk factors and ischemic heart disease.19,24,25 A recent study demonstrated that low RH measured with PAT is associated with adverse cardiovascular events.26 These results support the utility of digital endothelial dysfunction assessment using PAT.
The relationship between digital RH response measured with PAT and pressure augmentation pressure
Recently, Hamburg et al. determined that brachial measures of vascular function by FMD and digital measures by PAT were not related to each other and had differing associations with cardiovascular risk factors.24 They suggested that endothelial function may vary significantly according to vessel size and location. Although endothelial dysfunction is thought to be associated with pressure augmentation, whether or not endothelial dysfunction of resistant vessels, such as digital arteries, is also associated with pressure augmentation has yet to be determined. Therefore, we sought to evaluate whether digital endothelial function is also associated with augmentation pressure. The results of this study demonstrate that digital endothelial dysfunction is not related to AIx or pressure augmentation. This finding is contrary to the results of previous studies that assessed endothelial function using a pulse wave change following β-2 stimulation or with FMD of a brachial conduit artery.12,13,14
There are several possible mechanisms that could explain the results observed in this study. Different vascular function according to size and location may contribute to this observation, as proposed by Hamburg et al.24 The degree of endothelial dysfunction may differ by vessel, and the main pulse wave reflection might be present in conduit arteries but not in digital resistant arteries. The major determinants of reflection wave magnitude are the vascular characteristics of the arterial branching regions and impedance mismatch between the proximal and distal arteries, rather than the degree of peripheral vascular reactivity.
Also, we cannot rule out the possibility that the characteristics of the study subjects may have influenced the results of study. We only enrolled patients with a new diagnosis of hypertension. The patients in this study demonstrated relatively preserved endothelial function. Previous studies of spontaneously hypertensive rats have shown that young hypertensive rats with newly developed hypertension have normal vascular function, unlike older hypertensive rats.27 Although, there are numerous data demonstrating the existence of endothelial dysfunction in hypertension, endothelial dysfunction may be a consequence, rather than a cause, of hypertension.28,29,30 Therefore, in patients with newly developed hypertension, the elevation of BP or augmentation pressure may not be associated with the degree of endothelial dysfunction.
This study had several limitations. First, due to the relatively small sample size, there is a possibility that a significant correlation between RH-PAT index and AIx may be demonstrated with larger number of patients. However, the sample size of 100 patients is enough to determine a statistically significant correlation when the correlation coefficient is >0.27 with α = 0.05 and 1–β = 0.08. Since a sample size of 100 patients is enough to detect a weak correlation, we believe that the negative correlation between RH-PAT index and AIx that was demonstrated in this study is valid. Also, notwithstanding the relative small sample size, the value of this study resides in the fact that this study evaluated the relationship between digital arterial function assessed by PAT and augmentation pressure for the first time. Second, selection bias was possible as a result of the fact that we enrolled only subjects with newly diagnosed and untreated hypertension. Third, measurement of the brachial FMD may have clarified the interpretation of the results as only the digital endothelial function was evaluated.
In patients with hypertension, the RH-PAT index, as measured by EndoPAT, is not associated with either augmentation pressure or AIx75. Digital vascular function may be a less important factor for determining pressure augmentation in patients with hypertension.
Supplementary material is linked to the online version of the paper at http://www.nature.com/ajh
Supplementary Figure S1
The authors declared no conflict of interest.
This work was supported by a grant of the faculty research grant of Yonsei University College of Medicine for 2010 (6-2010-0079) and the Happy tech program through the National Research Foundation of Korea (NRF) funded by the ministry of Education, Science, and Technology (2010-0020766). We thank J.H. Kim and S.O. Jung for expert technical assistance.