European Heart Journal Advance Access originally published online on November 2, 2005
European Heart Journal 2006 27(3):302-309; doi:10.1093/eurheartj/ehi619
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Flow-mediated changes in pulse wave velocity: a new clinical measure of endothelial function
1Michaelidion Cardiac Center, University of Ioannina, Ioannina GR45 110, Greece
2Department of Cardiology, Hull Royal Infirmary, Hull HU3 2JZ, UK
3Department of Cardiology, Queen Elizabeth University Hospital, Edgbaston, Birmingham B15 2TH, UK
4Department of Cardiology, Princess of Wales Hospital, Bridgend CF31 1RQ, UK
5Cardiovascular Sciences Research Group, Wales Heart Research Institute, Cardiff CF4 4XN, UK
Received 1 March 2005; revised 2 October 2005; accepted 6 October 2005; online publish-ahead-of-print 2 November 2005.
* Corresponding author. Tel: +30 26510 97710; fax: +30 26510 97865. E-mail address: anaka{at}cc.uoi.gr
See page 255 for the editorial comment on this article (doi:10.1093/eurheartj/ehi652)
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Abstract |
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Aims To test whether measuring hyperaemic changes in pulse wave velocity (PWV) could be used as a new method of assessing endothelial function for use in clinical practice.
Methods and results Flow-mediated changes in vascular tone may be used to assess endothelial function and may be induced by distal hyperaemia, while endothelium-mediated changes in vascular tone can influence PWV. These three known principles were combined to provide and test a novel method of measuring endothelial function by the acute effects of distal hyperaemia on upper and lower limb PWV (measured by a recently developed method). Flow-mediated changes in upper and lower limb PWV were compared in 17 healthy subjects and seven patients with stable chronic heart failure (CHF), as a condition where endothelial function is impaired but endothelium-independent dilator responses are retained. Corroborative measurements of PWV and brachial artery diameter responses to endothelium-dependent and -independent pharmacological stimuli were performed in a further eight healthy subjects. Flow-mediated reduction of PWV (by 14% with no change in blood pressure) was found in normal subjects but was almost abolished in patients with CHF. PWV responses appear to be inversely related to and relatively greater than brachial artery diameter responses.
Conclusion The method may offer potential advantages of practical use and sensitivity over conduit artery diameter responses to measure endothelial dysfunction.
Key Words: Endothelial function • Pulse wave velocity • Flow-mediated dilatation • Distensibility • Atherogenesis
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Introduction |
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Endothelial function is altered by many pathophysiological insults. Such endothelial activation (‘dysfunction’) is recognized to play a seminal role in atherogenesis1,2 and in reducing circulatory efficiency.3,4 It is characterized by impairment of flow-mediated arterial dilatation, which thereby provides a non-invasive measure of potentially cumulative but therapeutically amenable, composite atherogenic risk.4 Flow-mediated changes in brachial artery diameter have been widely used for this purpose, but are recognized to be critically dependent on operator skills, limiting the clinical usefulness of this approach. A robust method of measuring impairment of normal endothelial function in clinical practice could have wide application.
Pulse wave velocity (PWV), which is inversely related to distensibility, has attracted much interest in recent years as a measure of conduit artery stiffness. Distensibility, however, is influenced by dynamic changes in vascular tone as well as by chronic structural changes in the artery wall and may thus be used to measure acute changes in vascular tone. PWV has indeed been shown to be acutely influenced by constitutively released NO.5,6 We here describe the use of acute flow-related reduction of PWV to provide, without pharmacological provocation,7 a new method of measuring endothelial function that appears to be relatively robust and operator-independent.
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Methods |
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Subjects
Twenty healthy men from the departmental staff were invited and agreed to participate in the non-invasive study, of whom three were unable to attend for practical reasons unrelated to the study so that 17 normal subjects [aged 32.5 (11.0) years] were studied in this group. Eight additional healthy men [aged 34.0 (3.3) years] from the same source agreed to participate in the invasive study involving arterial puncture. Initial assessment showed that there were no differences in demographic characteristics between these two separate groups of normal subjects and that none of the 25 normal participants was hypertensive, dyslipidaemic, or diabetic, none smoked, and none was taking medication (Table 1). Seven older male patients [aged 60.2 (6.5) years], with stable uncomplicated chronic heart failure (CHF) secondary to ischaemic heart disease, were also studied to provide a group of patients with impaired endothelial function (Table 1).5,8,9 Eight were originally selected arbitrarily from well-documented such patients attending the Unit, but one was not studied further because his brachial artery could not be visualized adequately for diameter measurements. The CHF patients were in New York Heart Association Class II/III with left ventricular ejection fraction <40% by radionuclide ventriculography. All were in sinus rhythm and none had valvular disease. Maintenance therapy comprised optimal doses of diuretics, angiotensin-converting enzyme inhibitors, and beta-blockers which were continued throughout the study. The study complied with the Helsinki Declaration and was approved by the Local Research Ethics Committee. All healthy volunteers and patients gave informed consent for participation in the study.
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Pulse wave velocity
PWV was measured by oscillometry (QVLTM SciMed, Bristol, UK; time resolution, 2 ms) in upper and lower limbs simultaneously, using a method developed to identify waveforms by their early phase in order to improve wave recognition and timing, as previously reported and shown to give reproducible results.10 Pressure waveforms were simultaneously obtained from pressure transducers attached to four non-occlusive cuffs, placed over the brachial and radial arteries (just above the wrist) and at the mid-thigh and ankle, and inflated to 65–70 mmHg. Waveforms were characterized by a computer program with respect to time at 30, 40, and 50% of peak pressure along their ascending phase, which is relatively immune to reflected waves that may alter overall waveforms. The program was designed to discard ectopic beats and abnormally shaped waveforms. Quality control was further enhanced by visual inspection to exclude any aberrant waveforms not screened out by the program. Pressure wave transit times were measured from brachial-to-radial, brachial-to-thigh, and brachial-to-ankle cuffs, enabling derivation of thigh-to-ankle transit times, with the brachial artery as the common reference point. Transit distances were measured between each pair of cuffs. Each measurement of PWV took ca. 15 s. Blood pressure in the study arm was monitored continuously using digital plethysmography (Finapres, Ohmeda, UK).
Brachial artery diameter
This was measured as previously described5,11 using an ultrasonic wall-tracking system, comprising a specially adapted duplex colour flow ultrasound machine (Hitachi EUB 525 Ultrasound) with a 7.5 MHz linear phased-array transducer (giving high axial resolution), a personal computer, and a 4 MB high-speed memory—adapted from the method introduced by Celermajer et al.12 A stand-off device containing ultrasound coupling gel prevented compression of the anterior wall of the artery. The brachial artery was imaged above the antecubital crease. When a clear B-mode image of the artery anterior and posterior walls was obtained, the transducer was held in a stereotactic clamp and the position held constant for the duration of the study. The radio-frequency (RF) signals (sampling frequency 1 kHz) from the M-mode image were relayed to the wall-tracking system (Vadirek TM, Oosterbeck, The Netherlands). On completion of 10 s data acquisition, the RF signal was displayed as a waveform allowing manual placement of cursors on the anterior and posterior brachial artery walls. Vessel wall movements were tracked automatically using the acquired data. The stored RF signals were used to produce a displacement waveform of the anterior and posterior vessel walls. The resultant distension waveform enabled measurement of intravascular ‘end-diastolic’ diameter for each beat (theoretical resolution 3 µm).
Study protocol
All studies were done in the morning, with the subjects fasting, relaxing supine, and silent in a quiet darkened room temperature-controlled at 21–23°C for 30 min, as previously described.5,10,11 Caffeine was avoided for 12 h.
Study 1
Upper and lower limb PWV responses to increased flow were studied in 17 normal subjects and in the seven CHF patients, with monitoring of heart rate and blood pressure. Increased flow through the artery segment under study was provided by local hyperaemic responses following the abrupt release of distally sited wrist and ankle cuffs inflated for 5 min to supra-systolic pressure (250 mmHg). PWV responses to 400 µg sublingual glyceryl trinitrate (GTN)-metered spray were similarly measured to assess endothelium-independent dilator responses (after the flow studies because of its relatively prolonged response) in the 17 normal subjects and seven CHF patients. This supra-maximal dose of GTN was used to ensure full dilator response for the purpose of the study. In the seven CHF patients, brachial artery diameter responses to flow and GTN were also measured to confirm the loss of endothelium-dependent responses in the patients studied here.
Study 2
Brachial artery diameter, upper and lower limb PWV responses to intra-arterial acetylcholine (ACh), and N-monomethyl-L-arginine (L-NMMA) were measured in the eight additional normal subjects who agreed to intra-arterial infusion. A 27-gauge cannula was inserted into the brachial artery of the non-dominant arm, 3–5 cm distal to the proximal upper limb cuff and 5–10 cm above the imaging site, for infusion of drugs to act on the arterial segment between the two upper limb cuffs: (i) normal saline (0.5 mL/min) to provide baseline data, (ii) ACh (7.5 µg/min, 0.5 mL/min) to stimulate nitric oxide (NO) production, (iii) L-NMMA (Clinalfa) (3 mg/min, 0.5 mL/min12) to inhibit NO production—the last of multiple interventions because of its long action. Return to stable baseline levels was confirmed between interventions.
PWV measurements
PWV was measured as the mean of 10 consecutive pulses at each time point. Baseline PWV is recorded as the mean of a series of 10 consecutive measurements made at 1 min intervals. In the hyperaemic studies, PWV was measured at 1 min intervals for 10 min following cuff deflation. The reduction in PWV relative to baseline (‘the response’) is recorded (i) as the maximum (‘peak’) response (which occurs ‘immediately’, i.e. at 1 min after cuff deflation) and (ii) as the overall 10 min response measured as the mean of the 10 one-min data points (to include information also about the duration of the response). Following GTN, PWV was measured at 1 min intervals for 10 min after GTN administration and the reduction in PWV relative to baseline (‘the response’) is recorded as the steady-state (which equates to the maximum) response, measured as the mean of the 6–10 min (inclusive) data points, representing the duration of the steady-state maximum response to this drug. Following intra-arterial pharmacological intervention, PWV was measured every minute (starting after 2–5 min and continuing for 10 min) and is recorded as the maximum steady-state response level.
Brachial artery diameter measurements
Baseline brachial artery end-diastolic diameter is recorded as the mean of a series of measurements taken over 10 min after stabilization. In the hyperaemic studies in the CHF patients, brachial diameter is recorded as the maximum response (which occurs at 1 or 2 min after cuff deflation). Following GTN and the intra-arterial pharmacological intervention, brachial diameter is recorded as the maximum steady-state level (which is reached within 10 min of starting the intervention).
Statistics
Data are given as mean (standard deviation) in absolute units in the figures, and in the text both as absolute units and, to normalize for differing baseline levels, as % responses. The unpaired Student's t-test was used to compare baseline characteristics between the groups and relative responses between normal subjects and CHF patients, whereas the paired t-test was used to compare responses (post-intervention cf. baseline) within each group. All tests were two-tailed and a P-value of <0.05 was considered statistically significant. All analyses were performed using the SPSS 12.0 for Windows.
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Pulse wave velocity
Increased flow
In the healthy normal subjects (n=17), deflation of the occluding distal cuffs reduced peak PWV relative to baseline levels in both the upper and lower limbs (in all 17 subjects individually and significantly in the group as a whole)—by 14.2 (5.2)%, from 7.1 (0.7) m/s at baseline to 6.2 (0.7) m/s (P<0.0001) 1 min after cuff deflation in the upper limb and by 13.9 (6.1)%, from 8.4 (0.9) m/s at baseline to 7.3 (0.8) m/s (P<0.0001) 1 min after cuff deflation in the lower limb (Figure 1A). PWV levels returned to the baseline level by 10 min. The mean reduction in PWV over the 10 min after cuff deflation relative to baseline was by 10.1 (4.5)%, from 7.1 (0.7) to 6.4 (0.8) m/s (P<0.0001) in the upper limb and by 8.3 (5.5)%, from 8.4 (0.9) to 7.7 (0.9) m/s (P<0.0001) in the lower limb. There were no associated changes in blood pressure or heart rate (Figure 2).
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P<0.05 at this time point cf. baseline, *P<0.05 cf. baseline for PVW averaged over min. 1–10 during hyperaemia and 6–10 after GTN).
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In the heart failure (CHF) patients (n=7), the normal reduction in PWV was almost absent during distal hyperaemia (Figure 1B). At the first reading (1 min after cuff deflation), PWV was only slightly and not significantly reduced—by 5.1 (8.0)%, from 6.7 (0.8) to 6.4 (0.5) m/s (P=0.13 cf. baseline) in the upper limb, and by 8.8 (12.0)%, from 9.2 (1.8) to 8.2 (0.8) m/s (P=0.08 cf. baseline) in the lower limb, returning rapidly to baseline levels after 1 min. Measured as the mean reduction over 10 min, it was completely abolished in the upper limb, where PWV increased by 3.0 (12.0)%, from 6.7 (0.8) to 6.9 (0.7) m/s (P=0.6, cf. baseline), and was insignificantly reduced by 2.8 (5.8)%, from 9.2 (1.8) to 8.8 (1.2) m/s (P=0.2 cf. baseline) in the lower limb. Comparing the hyperaemic PWV responses in CHF patients with those in normal subjects, the early peak reduction in the upper limb was only 5.1% in CHF compared with 14.2% in normals (P=0.004), and in the lower limb was 8.8% compared with 13.9% (P=0.19), whereas the 10 min average reduction in PWV in the upper limb was abolished (to a paradoxical increase of 3.0%) in CHF patients compared with 10.1% reduction in normal subjects (P=0.0006), and in the lower limb was only 2.8% compared with 8.3% in normals (P=0.04). Heart rate and blood pressure remained unchanged.
GTN
In the normal subjects (n=17), sublingual GTN significantly reduced PWV in both upper and lower limbs—by 8.8 (7.9)%, from 6.9 (0.9) m/s at baseline to 6.3 (1.0) m/s (P=0.0002) in the upper limb and by 7.7 (6.6)%, from 8.3 (0.8) m/s at baseline to 7.7 (0.8) m/s (P=0.0002), in the lower limb (Figure 1A). This was associated with small increases in systolic blood pressure by 8.0 (6.1)% (P<0.0001 cf. baseline), diastolic blood pressure by 6.1 (9.9)% (P=0.02 cf. baseline), and heart rate by 5.4 (5.4)% (P=0.001 cf. baseline) (Figure 2).
The PWV response to GTN in the CHF patients (n=7) was similar to that in the normal subjects (Figure 1B). PWV was reduced in both upper and lower limbs—by 9.0 (8.1)%, from 7.0 (0.8) m/s at baseline to 6.3 (0.6) m/s (P=0.03 cf. baseline) (P=0.95 cf. normals) in the upper limb and by 13.0 (9.4)%, from 9.2 (1.6) m/s at baseline to 7.9 (0.8) m/s (P=0.02 cf. baseline) (P=0.13 cf. normals) in the lower limb, with no change in heart rate or blood pressure.
Intra-arterial ACh and L-NMMA
In the eight additional normal subjects, intra-arterial ACh reduced and L-NMMA increased PWV in the arm into which they were infused—PWV was reduced by 9.4 (5.7)%, from 9.4 (1.7) m/s at baseline to 8.5 (1.5) m/s with ACh (P=0.008) and increased by 18.2 (16.8)%, to 10.9 (1.4) m/s with L-NMMA (P=0.009), with no effect on PWV in the ‘control’ lower limb (Figure 3), and no change in heart rate or blood pressure. Intra-arterial interventions were not performed in the CHF patients for ethical reasons.
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Brachial artery diameter
Increased flow and GTN
In the CHF patients (n=7), hand hyperaemia increased end-diastolic diameter only by 0.7 (0.5)% [from 4.10 (0.56) mm at baseline to 4.13 (0.56) mm, P=0.01]. In contrast, GTN increased diameter in these CHF patients by 7.4 (3.8)% [from 4.07 (0.61) mm to 4.36 (0.60) mm, P=0.002]. These responses in normal subjects are known and were not here repeated.
Intra-arterial ACh and L-NMMA
In normal subjects (n=8), ACh increased brachial artery diameter by 6.2 (3.0)%, from 4.2 (0.5) to 4.5 (0.6) mm (P=0.0004) and L-NMMA decreased it by 2.3 (1.0)%, from 4.2 (0.5) to 4.1 (0.5) mm (P=0.0007).
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Discussion |
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Distensibility of muscular conduit arteries is determined by structural components of the artery wall, transmural pressure, and smooth muscle tone. PWV is inversely related to the square root of distensibility. Previous clinical studies have shown that PWV can be acutely altered by endothelium-related changes in vascular tone5 and constitutively released NO.6 This study addressed the potential use of PWV measurements to assess acute flow-mediated relaxation of conduit artery vascular tone as a new method with which to measure impairment of endothelial function—coupling PWV measurement as previously described,10 with distal hyperaemia as extensively used to induce acute flow-mediated, endothelium-dependent changes in upstream artery diameter.11,12 In using the acute response to increased flow, each patient may be said to act as his own control, in contrast to the use of resting PWV as a measure of arterial stiffness with its multiple contributing influences (which may include endothelial dysfunction) and consequent biological variation.
In normal healthy subjects, distal hyperaemia induced flow-mediated reduction of PWV (by 14% at maximal ‘immediate’ response and by 8–10% in mean 10 min response) in both upper and lower limbs, associated with its well-documented vasodilator response of increase in brachial artery diameter (by 7–9%).5,11,13,14 In patients with heart failure, where endothelial function and flow-mediated vasodilatation are known to be impaired,5,8,9 the reduction of PWV induced by distal hyperaemia was almost abolished, particularly in the upper limb and when measured as the 10 min averaged response (when it was completely abolished), as was the increase in brachial artery diameter. Endothelium-independent dilatation, in contrast, was preserved in CHF, as previously reported.5 GTN reduced PWV by 8–9% in both limbs in normal subjects and similarly by 9–13% in the CHF patients, associated with retained dilator response as evidenced by increased brachial artery diameter of 7%. Previously reported ‘wall-tracking’ studies of similar normal subjects in our laboratories have shown that the flow-mediated increase in brachial artery diameter is abolished by L-NMMA11 indicating its dependence on NO, as was the case in a similar study of radial artery diameter where peak flow was reported to remain three-fold greater than at baseline.15 L-NMMA has been shown similarly to inhibit hyperaemic PWV responses (unpublished observations).
Intra-brachial ACh and L-NMMA reduced and increased upper limb PWV by 9 and 18% respectively, with no effect on the ‘control’ lower limb PWV and, in agreement with previous reports,5,11,13 increased and decreased brachial artery diameter by 6 and 2% respectively. The hyperaemic and pharmacological responses in normal subjects thus accord with the expected inverse relationship between PWV and brachial artery diameter responses. The % difference in PWV change tends, however, to exceed that in artery diameter change. Hyperaemia in normal subjects reduced PWV by 14%, compared with its known increase in brachial diameter by 7–9%.5,11,13,14 L-NMMA in normal subjects (the only intervention acting to decrease distensibility) increased PWV by 18% but reduced diameter by only 2%. These observations suggest that acute flow-induced changes in PWV may provide a more sensitive measure of endothelial dysfunction than similarly induced changes in artery diameter.
The flow-related reduction in PWV may be expressed also as the overall (mean) 10 min response, which includes the later phase of the response to which there is evidence that NO contributes,15 thus potentially increasing its sensitivity as an index of reduced NO activity. In normal subjects, the mean reduction of PWV over the 10 min was ca. 10%, whereas in CHF patients it was abolished. This is illustrated in Figure 1 where the time course of the nearly absent response in CHF suggests that it is abbreviated. The data suggest that discrimination between normal and abnormal responses is better in the upper than the lower limb and when measured as the 10 min average than as the early peak response.
Hyperaemic peak systolic brachial artery blood flow velocity, measured by angled continuous wave Doppler imaging and corrected for angle and cross-sectional area, provides an acceptable surrogate for acute changes in relative shear stress on the endothelium. Importantly, the flow signal does not appear to differ between conditions of normal and impaired endothelial function where the occluding cuff is placed at the wrist,11 contrary to findings where the cuff is placed more proximally.16 Others and we have shown that peak flow signal during hand hyperaemia is not influenced by L-NMMA in normal subjects,11,16 and we have shown that it increased similarly six-fold both in normal subjects and in CHF patients.5 This is consistent with evidence that metabolic signals involved in hyperaemic flow can compensate17 within the limits of dilator capacity for any impairment of endothelium-dependent dilatation downstream from the artery in which PWV and brachial artery diameter are being measured. The observed changes in brachial artery diameter and in PWV thus appear predominantly to reflect changes in the response of the artery under investigation, rather than any change in the relevant early peak hyperaemic flow signal as influenced by downstream events.15
PWV can be increased by a rise in mean arterial blood pressure (reflecting transmural distending pressure)18 and by a reduction in distensibility resulting from an increase in arterial tone.5 The flow-mediated responses observed in this study, however, were not associated with any measured change in blood pressure. With GTN, blood pressure and heart rate were slightly increased (possibly as a sympathetic response to venodilatation, reduced cardiac filling, and reduced cardiac output), but this would have tended to increase PWV and thus to attenuate rather than invalidate interpretation of the observed decrease in PWV as attributable to a GTN-induced reduction of arterial tone.
Impairment of ACh-induced coronary responses has been shown to be associated with impairment of hyperaemic brachial responses,19 supporting the view that endothelial dysfunction is generalized when it is the consequence of systemic, as distinct from local adverse conditions. Its demonstration in large limb arteries appears therefore to serve as a marker of generalized endothelial activation.
Measurements of endothelial function and of arterial stiffness provide different information. Increased arterial stiffness (although susceptible to the additional influence of acute changes in blood pressure and vasomotor tone) is usually considered as chronic resting stiffness related predominantly to structural changes in the arterial wall, as influenced by ageing,20 hypertension,21 and genetic pre-disposition,22–25 to which chronic endothelial dysfunction may contribute.26–29 It carries an adverse cardiovascular prognosis,30–32 attributable to accelerated pressure wave reflection which increases cardiac loading and prejudices diastolic coronary perfusion, and is a prognostic marker.33 Measurement of endothelial dysfunction (activation), in contrast, enables monitoring of ongoing atherogenic risk (as well as of its potential contribution to arterial stiffness), which is dynamically variable and therapeutically amenable. It may also give potentially important information about the efficiency of microvascular perfusion, control of whose homogeneity has been shown experimentally to be endothelium-dependent.3 This study suggests that the acute PWV response to increased blood flow provides a practical method of achieving this, which could also prove more sensitive than measurements of arterial diameter.
The study has some limitations. Its purpose is to describe a new approach to measuring endothelial function that has practical advantages over ‘wall-tracking’ of conduit artery diameter, but the numbers studied are relatively small and only one clinical condition to exemplify loss of endothelial function was studied. Formal studies comparing different methods of characterizing wave onset were not undertaken, but the method of measuring PWV and its reproducibility, as previously reported,10 was developed specifically to overcome known criticisms of methods which depend on waveform characteristics later during their course when they are susceptible to modification by reflected waves. PWV was, moreover, measured over relatively short distances, so further limiting the potential influence of wave reflections. Although wave reflections can also be influenced by vascular changes downstream of the distal occluding cuff, the method here used to time the wave early in its upstroke should exclude any such influence on PWV. Theoretical reservations relating to differing harmonic PWVs cannot be entirely excluded, but the validity of the method is empirically supported by the findings. Operator independence was not formally confirmed in blind studies, but informal directly compared measurements by different operators were found to be identical.
In summary, it would be useful to be able to measure endothelial function in clinical practice and thereby monitor and better manage composite, changeable atherogenic risk (comparable otherwise in this respect to measuring the single risk factor of blood pressure), as distinct from accumulated chronic consequences of endothelial dysfunction. The findings support the potential use of measuring the acute PWV response to hyperaemic increase in flow as a new, relatively operator-independent method with which to achieve the goal of assessing endothelial function—a method which promises to improve on measurement of conduit artery diameter responses, both in practical use and in sensitivity. Larger studies are merited to test its robustness in clinical practice and its application across a wider range of clinical conditions.
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Acknowledgements |
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We are grateful to Prof. A.M. Dart for helpful critical comments, Prof. R.R. West for statistical advice, and Dr D. Parthimos and Ms M. Ashton for valuable technical assistance.
Conflict of interest: none declared.
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