Pulse Pressure Amplification, Arterial Stiffness, and Peripheral Wave Reflection Determine Pulsatile Flow Waveform of the Femoral Artery
Aortic stiffness, peripheral wave reflection, and aorta-to-peripheral pulse pressure amplification all predict cardiovascular risk. However, the pathophysiological mechanism behind it is unknown. Tonometric pressure waveforms were recorded on the radial, carotid, and femoral arteries in 138 hypertensive patients (age: 56±13 years) to estimate aorta-to-peripheral amplifications, aortic augmentation index, and aortic (carotid-femoral) pulse wave velocity. The femoral Doppler velocity waveform was recorded to calculate the reverse/forward flow index and diastolic/systolic forward flow ratio. The aorta-to-femoral and aorta-to-radial amplifications correlated inversely with the aortic augmentation index and pulse wave velocity. The femoral flow waveform was triphasic, composed of systolic forward, subsequent reverse, and diastolic forward phases in 129 patients, whereas it was biphasic and lacked a diastolic forward flow in 9 patients. Both the femoral reverse index (30±10%) and diastolic forward ratio (12±4%) correlated positively with the aorta-to-femoral amplification and inversely with the aortic augmentation index and pulse wave velocity; these correlations were independent of age, sex, diastolic pressure, and femoral artery diameter. Patients with biphasic (versus triphasic) flow were older, shorter, included more diabetics, had smaller femoral diameters, and showed greater aortic pulse wave velocity even when adjusted for all of these covariates. In conclusion, because of the inverse (peripheral-to-aortic) pressure gradient, pulse pressure amplification normally produces a substantial reversal of the femoral flow, the degree of which is determined by the aortic distensibility and peripheral wave reflection. Arteriosclerosis (increased stiffness, increased augmentation, and reduced amplification) decreases both the reverse and diastolic forward flows, potentially causing circulatory disturbance of truncal organs and lower extremities.
The arterial pulse provides important information on the cardiovascular prognosis. There is substantial evidence that the aortic pulse wave velocity (PWV) and augmentation index (AIx) predict cardiovascular morbidity and mortality in a variety of populations, as confirmed by recent meta-analysis studies.1,2 Similar prognostic significance has been also demonstrated for pulse pressure amplification from the central aorta to peripheral medium-sized muscular arteries.3–5 These pulse indices (PWV, AIx, and pulse amplification) depend on the structural and functional properties of the central elastic and peripheral muscular arteries, which interact closely through pressure wave transmission and reflection.6–9 Potential mechanisms mediating these pulse abnormalities and cardiovascular disease progression include elevated central pressure leading to an increase in cardiac afterload10,11 and widened pulsatile pressure causing circumferential tensile stress that damages the vulnerable microvasculature in brain and kidney.12–14
It is not only blood pressure but also blood flow that is involved in target organ damage. Pulsatile flow produces tangential (frictional) shear stress on the arterial endothelium, whereas the mean flow contributes to tissue perfusion. Pulsatile flow stress may exert deleterious effects on the microvasculature synergistically with pulsatile pressure stress.12 The flow pulse waveforms of carotid15 and ophthalmic16 arteries have been shown to change with aging, indicating their association with arteriosclerosis.
The femoral arteries, located between the body trunk and lower extremities, serve to supply blood flow inherently downstream. However, quite differently from the carotid and ophthalmic waveforms, the femoral flow waveform normally exhibits a triphasic pattern, including reverse (upstream) flow toward the central aorta.17–19 Previous investigations studied the reversal of femoral flow in association with cardiovascular risk factors and pharmacological intervention20–22 and even postulated a potential connection with renal blood flow.23 Nevertheless, little attention has so far been paid to the fundamental, mechanical etiology of the generation of the flow reversal.
The pressure wave reflection responsible for aortic augmentation arises mainly from the lower body, particularly from the lower extremities.6 Central-to-peripheral (including aorta-to-leg) pulse amplification has been attributed to such peripheral wave reflection and gradual stiffening of arteries toward the periphery.9,24 However, another and possibly more important aspect of pulse amplification may be that it creates an inverse pressure gradient, namely from the periphery to the central aorta. We hypothesized in this study that pulse amplification would generate femoral reverse flow on account of the lower limb-to-aortic pressure gradient. To test this hypothesis, we examined hypertensive patients to evaluate the relationship between pressure pulse indices and the femoral flow waveform and its potential alteration with arteriosclerosis.
An expanded Methods section is provided in the online Data Supplement (please see http://hyper.ahajournals.org).
We studied 138 consecutive patients with hypertension, who were seen at the Division of Nephrology, Hypertension, and Endocrinology at Tohoku University Hospital. We excluded from the analysis patients with heart failure, peripheral artery disease, aortitis syndrome or aortic coarctation, thoracic or abdominal aortic aneurysm, sustained atrial fibrillation, and patients who had a history of acute coronary or stroke events within 6 months of the study. The study protocol had official approval from the institutional ethics committee of Tohoku University, and all of the subjects gave written informed consent.
Body height and weight were recorded for each subject to determine the body mass index. Details on laboratory measurements are provided in the online Data Supplement.
Blood Pressure Measurements
A series of vascular measurements were made in a quiet and temperature-controlled environment in accordance with consensus documentations.7 Patients rested in the supine position for 20 minutes, after which time blood pressure was measured twice over the brachial artery using a validated, automated cuff-oscillometric device (HEM-907, Omron Healthcare).
Pressure Pulse Wave Analysis
The radial artery pressure wave was recorded from the wrist with the applanation tonometry technique using a high-fidelity micromanometer (SPT-301, Millar Instruments). Details on pulse wave analysis are provided in the online Data Supplement. Briefly, the beat-to-beat pulse waveforms were ensemble averaged and calibrated using brachial systolic and diastolic pressures.5,9 The averaged radial waveform was then converted with a validated generalized transfer function (SphygmoCor version 8.2, AtCor Medical) to a corresponding central aortic waveform.6,25 Hence, aorta-to-radial pulse pressure amplification (AMPA-R) was determined as the percentage ratio of the radial pulse pressure (PPR) to the aortic pulse pressure (PPA)9,26:
The aortic augmented pressure and aortic AIx (standardized for a heart rate of 75 bpm) were also measured, as described previously.25,27 The round-trip travel time of the pressure wave from the heart to the major reflecting sites and back was estimated as the time from the beginning upstroke of the aortic pressure wave to the systolic upstroke of the reflected wave (inflection point).27
Subsequently, the tonometric waveform was recorded in a similar manner on the common femoral artery. Additional recording was also made on the dorsalis pedis artery in a subset of subjects (n=101). Similar to the radial waveform, the femoral and dorsalis pedis waveforms were calibrated using brachial pressures, that is, by equating the mean and diastolic pressure levels of both aortic and peripheral signals.5,9 Thus, the pulse amplification ratios of the aorta-to-femoral and aorta-to-dorsalis pedis regions (AMPA-F and AMPA-DP) were obtained according to the following equations:
where PPF and PPDP represent the femoral pulse pressure and dorsalis pedis pulse pressure, respectively. The femoral AIx (adjusted for heart rate of 75 bpm) was determined in the same manner as the aortic AIx.
Based on the sequential pressure wave recordings, the PWV was measured, as described previously.28 Specifically, the measurements were made centrally from the carotid to femoral artery for all of the subjects and, in addition, distally from the femoral to dorsalis pedis artery for a subset of subjects (n=101). The carotid-femoral PWV measures elastic artery stiffness, whereas the femoral-dorsal pedis PWV measures muscular artery stiffness.6 Detailed methods for the PWV measurements are provided in the online Data Supplement.
Doppler Flow Measurements
The femoral blood flow velocity measurement was made using duplex ultrasonography equipped with a 7.5-MHz linear transducer (Vivid i, GE Healthcare). Detailed methods for the Doppler flow recording are provided in the online Data Supplement. The diameter of the femoral artery was determined by B-mode imaging.
Flow Pulse Wave Analysis
The beat-to-beat femoral pulse flow waveforms were ensemble averaged for 10 consecutive pulses using the foot points of the systolic upstrokes for synchronization (please see the online Data Supplement for details). From the averaged waveform, we determined the following parameters in terms of flow velocity and relevant time (Figure 1): systolic forward (maximum) peak velocity (VF); reverse (minimum) peak velocity (VR); end-diastolic velocity (VD); time-averaged mean velocity (VM); acceleration time (TACL); and deceleration time (TDCL). In most cases, the diastolic forward flow followed the reverse flow, so its peak velocity (VF2) was also measured whenever available. Then, we calculated the following parameters as relative ratios: (1) reverse-to-forward flow ratio = |VR|÷|VF|×100 (%); (2) reverse-to-forward flow index=|VR− VD|÷|VF−VD|×100 (%); and (3) diastolic-to-systolic forward flow ratio=|VF2|÷|VF|×100 (%).
Femoral flow volume (in milliliters per minute) was also calculated from the time-averaged mean flow velocity and the femoral artery diameter. Femoral vascular resistance (in millimeters of mercury per milliliter per minute) was obtained by dividing the mean arterial pressure by the flow volume.
Data analyses were performed with SPSS software (version 13.0). Univariate comparisons were made using Student t test, ANOVA with a post hoc Bonferroni test, paired t test, or χ2 test, as appropriate (please see the online Data Supplement for more details). Univariate correlations were evaluated as Pearson correlation coefficients (r). Multivariate linear regression analysis was performed to investigate independent correlates of the femoral reverse-flow index and diastolic forward-flow ratio. Multivariate comparisons of pulse wave parameters between patients with triphasic and biphasic flow were made using ANCOVA.
Data are provided as mean±SD or percentages. All of the reported P values are 2 sided, and a P value of <0.05 was considered statistically significant.
Baseline characteristics of the study subjects are presented in Table 1. The subjects included 52 men and 86 women, with a mean age of 56±13 years (range: 20 to 88 years). Mean brachial systolic/diastolic pressure was 125/69 mm Hg, and most of the subjects had their blood pressure controlled well with antihypertensive treatment. Some subjects had hypercholesterolemia (31.9%) and diabetes mellitus (29.7%).
Pressure Pulse Parameters
Pulse pressure amplifications of aorta-to-femoral, aorta-to-dorsalis pedis, and aorta-to-radial regions were all >100% for every subject (Table 1). The amplification was greatest for the aorta-to-dorsalis pedis region, followed by the aorta-to-radial and, then, aorta-to-femoral regions (P≤0.001). The 3 amplifications had moderate-to-close inverse correlations with the aortic AIx standardized for the heart rate (aorta-to-femoral: r=−0.37; aorta-to-dorsalis pedis: r=−0.52; aorta-to-radial: r=−0.83; P<0.001 for all) and relatively mild inverse correlations with the aortic (ie, carotid-femoral) PWV (aorta-to-femoral: r=−0.25, P=0.004; aorta-to-dorsalis pedis: r=−0.31, P=0.002; aorta-to-radial: r=−0.22; P=0.01). The peripheral (ie, femoral-dorsalis pedis) PWV had no significant correlations with the pulse amplifications.
Femoral Flow Waveform
Of the 138 subjects, 129 (93.5%) had a triphasic femoral flow velocity waveform, which was composed of the initial forward (positive) phase that flows in systole toward the peripheral leg arteries, the secondary reverse (negative) phase that flows backward to the central aorta, and the tertiary forward phase that flows in diastole toward the periphery (Figure 1 and Figure S1A, available in the online Data Supplement). The remaining 9 subjects (6.5%) had a biphasic velocity waveform lacking a definite diastolic forward flow (Figure S1B). There were no patients showing a monophasic flow pattern suggestive of stenotic or occlusive arterial lesions.
The femoral flow velocity increased rapidly in early systole to reach the systolic peak (VF), with a mean acceleration time of 106 ms (Table 1 and Figure 1). Subsequently, it gradually decreased to reach the minimum reverse peak (VR) with a deceleration time of 200 ms; the deceleration time was longer than the acceleration time (P<0.001). The amplitude of the reverse flow velocity (|VR|) was always smaller than that of the systolic forward velocity (|VF|; P<0.001) and greater than that of the diastolic forward velocity (|VF2|; P<0.001). The end-diastolic flow velocity (VD) ranged across 0 between positive (9.5 m/s) and negative (−7.9 m/s) values among the subjects, whereas the time-averaged mean velocity (VM) was invariably positive (range: 3.2 to 24.3 m/s). The mean reverse-to-forward flow ratio (|VR|/|VF|), reverse-to-forward flow index (|VR−VD|/|VF−VD|), and diastolic-to-systolic forward flow ratio (|VF2|/|VF|) were 28.1%, 29.5%, and 12.0%, respectively (Table 1).
Determinants of Femoral Reverse Flow
Figure 2 shows the relationships between the femoral reverse-to-forward flow index and various pressure pulse parameters. The reverse flow index was significantly and positively correlated with each of the 3 pulse pressure amplifications; the correlation was stronger with the aorta-to-femoral and aorta-to-dorsalis pedis amplifications than with the aorta-to-radial amplification. Significant inverse correlations were also found with aortic PWV and AIx, despite the lack of a correlation with the peripheral PWV (Figure 2). The femoral reverse-flow index was correlated also with femoral AIx (r=−0.30; P<0.001). There was only a marginal correlation between the femoral reverse flow index and the femoral vascular resistance (r=0.16; P=0.06).
Subject characteristics were evaluated separately for the tertile groups divided according to femoral reverse flow index (Table S1). When compared with the lowest tertile, the highest tertile of the reverse flow index included more men who were taller of stature and had higher diastolic blood pressure and greater femoral artery diameters. Also, the pulse amplifications were significantly greater and the aortic AIx and PWV were lower in the highest reverse-flow tertile. There were no differences in age, body mass index, biochemical parameters, prevalence of hypercholesterolemia or diabetes mellitus, brachial or aortic systolic pressure, or heart rate among the 3 tertiles of the reverse-flow index.
Multivariate regression analysis revealed that the significant independent predictors of the femoral reverse-flow index were the aorta-to-femoral pulse amplification, carotid-femoral PWV, and diastolic blood pressure (Table 2). Age, sex, height, and femoral artery diameter were not significantly associated. When substituted for the aorta-to-femoral amplification in this model, the aortic or femoral AIx was able to independently predict reverse flow index (aortic AIx: β=−0.26, P=0.02; femoral AIx: β=−0.31, P=0.002), but aorta-to-radial amplification was only marginally able to do so (β=−0.17; P=0.06). Replacement of the diastolic blood pressure by the femoral vascular resistance or the mean arterial pressure did not meaningfully alter any of the results (Table S2). Similar but weaker associations were observed when the reverse-flow ratio instead of the index was used as a dependent variable (data not shown).
Determinants of Femoral Diastolic Forward Flow
Figure 3 shows comparisons of the femoral diastolic-to-systolic forward-flow ratio among the quartile groups divided according to each of 6 pressure pulse parameters. The diastolic forward-flow ratio increased in a dose-dependent manner with increasing quartiles of the aorta-to-femoral, as well as aorta-to-dorsalis pedis and aorta-to-radial, pulse amplifications. There was a significant decrease in the diastolic forward-flow ratio with increasing aortic PWV and AIx quartiles, although there was no difference among the peripheral PWV quartiles. A similar decrease was seen with increasing femoral AIx quartiles (P<0.001). A close correlation was observed between the diastolic forward-flow ratio and reverse-flow index (r=0.52; P<0.001).
As shown in Table S3, division of the subjects into tertiles according to diastolic forward-flow ratio suggested that higher diastolic forward flow was associated with younger age, male sex, taller stature, lower prevalence of diabetes mellitus and hypercholesterolemia, lower blood pressure, and larger femoral artery diameter. There was no association between the diastolic forward-flow ratio and femoral vascular resistance.
In a multivariate model considering these relevant factors, diastolic forward-flow ratio was predicted significantly and independently by carotid-femoral PWV, as well as by age, diastolic blood pressure, diabetes mellitus and aorta-to-femoral amplification (Table 2). On replacement of the aorta-to-femoral amplification, the aortic AIx was also capable of independently predicting the diastolic forward-flow ratio (β=−0.20; P=0.02). Femoral vascular resistance was not an independent predictor of the diastolic forward-flow ratio (Table S2).
Determinants of Flow Acceleration Time
The acceleration time of the systolic forward flow correlated inversely with age (r=−0.17; P=0.04), systolic pressure (r=−0.26; P=0.002), mean arterial pressure (r=−0.19; P=0.02), aortic PWV (r=−0.17; P=−0.04), and peripheral PWV (r=−0.33; P=0.001) and correlated positively with the round-trip travel time of the pressure wave (r=0.34; P<0.001). Even after adjustment for age and systolic pressure, peripheral PWV and round-trip travel time were significantly related to the flow acceleration time (β=−0.24, P=0.02 and β=0.29, P=0.004), whereas the aortic PWV was not.
Subject Characteristics of Biphasic Versus Triphasic Femoral Flow
When compared with subjects with a typical triphasic flow waveform, those with a biphasic waveform lacking diastolic forward flow were significantly older of age, shorter of stature, and more frequently female and diabetic and had lower diastolic blood pressure and smaller femoral artery diameter (Table S4). They also showed smaller pulse amplifications, greater aortic AIx, and higher carotid-femoral but similar femoral-dorsalis pedis PWVs. The patients with a biphasic flow pattern had a reverse stiffness gradient, that is, the aortic PWV tended to be greater than the peripheral PWV. After adjusting for age, sex, height, diabetes mellitus, diastolic blood pressure, and femoral artery diameter by ANCOVA, the significance of differences in pulse amplifications and aortic AIx disappeared, but the difference in carotid-femoral PWV persisted with high significance (P=0.005) between the subjects with triphasic flow (adjusted mean PWV: 7.8 m/s [95% CI: 7.5 to 8.0 m/s]) and those with biphasic flow (adjusted mean PWV: 9.5 m/s [95% CI: 8.3 to 10.6 m/s]).
The existence of significant reverse flow in the femoral arteries has long been recognized, although questions remain concerning the source of the flow reversal. The present study investigated the femoral velocimetric flow with respect to the pulsatile pressure differences between various arterial sites using time-domain analysis and, to our knowledge, for the first time found that the central-to-peripheral pulse pressure amplification determines the degree of flow reversal. Because pulse amplification means, by definition, higher systolic and pulse pressures in peripheral (eg, femoral and dorsalis pedis) arteries than in the central aorta,9 it naturally generates an inverse (peripheral-to-central) pressure gradient during late systole and early diastole, which follows a forward (central-to-peripheral) pressure gradient because of cardiac ejection in early systole. Our results indicate that this inverse pressure gradient is responsible for the femoral reverse flow. This interpretation agrees with the physiological principle that the pressure gradient along the artery, rather than the pressure itself, determines pulsatile flow.6 Such a view is also supported by the present finding that the lower-body (ie, aorta-to-femoral and aorta-to-dorsalis pedis) amplifications were more closely correlated with the femoral reverse flow than the upper-body (aorta-to-radial) amplification (Figure 2), suggesting an important role of the local pressure gradient at the femoral site in determining the reverse flow.
Our results indicating the contribution of the pulse amplification to the femoral reverse flow accord well with the observations of previous relevant studies. For instance, both pulse amplification29 and femoral reverse flow18,20,22 have been shown to increase in response to treatment with nitrate vasodilators. Both are decreased by cigarette smoking21,30 and with aging.17,31 All of these parallel changes are probably explicable by direct causality between them.
The present study showed that the aortic AIx and carotid-femoral PWV were correlated inversely with the femoral reverse-flow index (Figure 2). It is well recognized that peripheral wave reflection–induced aortic pressure augmentation reduces the pulse amplification.24,32,33 Considering this together with the close inverse relationship between the aortic AIx and pulse amplification observed in the present study, the influence of the pressure wave reflection on the femoral reverse flow may be largely through pulse amplification. It is important to note that a lower rather than higher AIx was associated with greater femoral reverse flow (Figure 2 and Table S1), because this finding indicates that it is not the magnitude of the reflected pressure wave itself but rather the pressure gradient generated by the summation of the incident and reflected waves that causes the flow reversal. In contrast, the influence of aortic stiffness on the femoral reverse flow appears to be, at least in part, independent of the pulse amplification (Table 2), although it is attributable in part to the “nonaugmented” incident wave amplification.24,33 This indicates that the amount of the femoral reverse flow is determined not only by the pressure gradient but also by the distensibility of upstream arteries that can passively receive the reversed flow. The important relevance of arterial distensibility to pulsatile flow is consistent with Bramwell and Hill’s equation34 showing that the blood volume change depends on the PWV, as well as on the blood pressure change.
The femoral diastolic forward flow had essentially the same determinants as the reverse flow, including pulse amplification, aortic stiffness, and peripheral wave reflection (Figure 3 and Table 2). Also, a close correlation was observed between the two. These results may suggest that the femoral diastolic forward flow originates at least in part from the reverse flow; in other words, blood first accumulates in the distensible aorta during late systole and early diastole on account of the reverse (upstream) flow, and then the blood flows out of the aorta during middiastole on account of the aortic elasticity (Windkessel function). Such a transition from reverse to forward flow could also result from secondary reflection (rereflection) of the reflected pressure waves.6 Because the femoral reverse flow is usually greater than the diastolic forward flow (Table 1), it seems reasonable to assume that some reverse flow becomes antegrade flow into internal organs of the body trunk,23 the rest going into the lower extremities.
Interestingly, the acceleration time of the femoral flow was found to depend on the peripheral (rather than central) PWV and on the round-trip travel time of the pressure wave. One may speculate from this finding that the transition from flow acceleration to deceleration relates to the time of the pressure wave to travel from the femoral artery to distal (downstream) reflecting sites and back.35
In the present study, a small but significant number of subjects (6.5%) had a biphasic femoral flow waveform (Figure S1B). Although this flow pattern clearly differs from the monophasic pattern suggestive of stenotic or occlusive arterial lesions, it appears not to be an independent entity distinct from the typical triphasic pattern but rather to represent its extreme of reduced diastolic forward flow. The biphasic flow pattern related to an increased aortic PWV even after adjustment of various relevant factors (Table S4), indicating that aortic stiffening (arteriosclerosis) can markedly reduce diastolic flow into lower extremities owing solely to an impaired Windkessel function, even without accompanying peripheral artery stenosis.36
This study has several strengths in terms of methodology. The pulsatile flow was recorded as the instantaneous, spatially averaged mean velocity at a constant interval of 100 Hz continuously over 16 seconds, and steady-state flow waveforms of as many as 10 pulse beats were ensemble averaged using a dedicated program. Such automatic recording of the pulse waveform and quantitative evaluation of the flow parameters enabled us to minimize potential observer and data selection biases. Estimation of the pulse amplification was made from the pulse waveforms alone and, therefore, was free from any influence of the cuff pressure measurement that might be more prone to error.2,25,26 Calculation of the reverse flow index (rather than the ratio) enabled us to eliminate any potential interference on the pulsatile flow of the steady flow (ie, end-diastolic flow) that could be modulated by peripheral vascular resistance.18,37 In fact, the present data confirmed that the relevance of pulse pressure amplification and arterial stiffness to the femoral reverse flow is independent of the femoral vascular resistance (Table S2).
This study has some limitations. Blood flow was quantified as velocity rather than volume, because it is quite difficult with commonly available ultrasonographs to measure minute instantaneous changes of the arterial diameter simultaneously with the flow velocity. However, it should be noted that this study focused not on the absolute values of, but on the relative ratio between, the pulsatile flow components, on which the influence of arterial diameter seems to be negligibly small. Another limitation is the cross-sectional, observational nature of this study. The suggested causal relationship between pressure and flow needs be confirmed further by prospective interventional studies.
Our data demonstrated substantial reverse flow from lower extremities toward the abdominal aorta in hypertensive subjects and its reduction attributed to aortic stiffening. Of interest, previous data by Bogren and Buonocore23 suggest that reverse flow in the lower body supplies diastolic flow to internal abdominal organs, such as the kidneys, and it importantly contributes to visceral perfusion. Taken together, it seems likely that the reduction in femoral reverse flow resulting from aortic stiffening causes visceral diastolic hypoperfusion leading to target organ failure (Figure 2). On the other hand, aortic stiffening could predispose to peripheral artery disease in consequence of reduced diastolic flow into lower extremities (Figure 3).36 Our study suggests that normalization of the pulse amplification and/or aortic stiffness by pharmacological treatment could help to restore blood flow into internal organs, as well as lower extremities. Verification of this possibility requires future studies.
We are grateful to Dr Berend E. Westerhof, BMEYE (Amsterdam, the Netherlands) for programming software dedicated to flow waveform analysis.
Sources of Funding
This work was supported by a grant from Tohoku University Hospital.
- Received July 14, 2010.
- Revision received July 31, 2010.
- Accepted August 30, 2010.
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