Published online before print August 11, 2003, doi: 10.1161/01.HYP.0000085199.33254.15
(Hypertension. 2003;42:253.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Effects of Heart Rate Changes on Arterial Distensibility in Humans
From Clinica Medica (C.C., M.F., A. Capra, G.G., G.M.) and the Divisione di Cardiologia (A.V., A. Cirò, S.D.C., R.B.), Milano-Bicocca University and San Gerardo Hospital, Monza; Centro Interuniversitario di Fisiologia Clinica e Ipertensione (C.G., G.M.), Università di Milano, Milano Bicocca e Pavia; and IRCCS Istituto Auxologico Italiano (C.G., G.M.), Milano, Italy.
Correspondence to Prof G. Mancia, Clinica Medica, Ospedale S Gerardo, Via Donizetti 106, 20052 Monza (MI), Italy. E-mail giuseppe.mancia{at}unimib.it
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Abstract |
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In rats, an increase in heart rate by pacing is accompanied by progressive large-artery stiffening. Whether this is also the case in humans is unknown. We enrolled 20 patients who were chronically implanted with a pacemaker because of atrioventricular block or sick sinus syndrome. Arterial distensibility was measured by an echo-tracking device. In 10 patients, the evaluation was performed on the radial artery by using continuous finger blood pressure measurements, whereas in the remaining 10 patients, the common carotid artery was studied with a semiautomatic measure of brachial artery blood pressure. Diastolic diameter, systodiastolic diameter change, and distensibility were obtained at baseline (heart rate 63±2 beats/min) and after atrial and ventricular sequential pacing at a heart rate of 90 and 110 beats/min. At baseline, the diameter was 7.8±0.3 mm in the carotid artery and 2.4±0.1 mm in the radial artery; the respective systodiastolic diameter change values were 375.4±31.0 and 55.9±9.0 (µm) and the distensibility values were 1.4±0.1 and 0.7±0.1 (1/mm Hg 10-3). Blood pressure and diameter were not significantly modified by increasing heart rate, which markedly modified systodiastolic diameter change and distensibility. In the radial artery, distensibility was reduced by 47% (P<0.05) at a heart rate of 90 beats/min with no further reduction at 110 beats/min. In the carotid artery, distensibility was reduced by 20% at a heart rate of 90 beats/min (P<0.05) with a further reduction at 110 beats/min (45%, P<0.05). These data provide the first evidence in humans that acute increases in heart rate markedly affect arterial distensibility and that this occurs in both large- and middle-size muscle arteries within the range of "normal" heart rate values.
Key Words: arterial stiffness • heart rate • risk factors • human
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Introduction |
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Studies performed in rats have shown that when heart rate (HR) is increased by pacing, carotid and femoral artery distensibilities (Dist) are reduced.1 This suggests that HR might be one of the factors that modulates arterial mechanical properties and thus, potentially participates in their abnormality in several conditions and diseases.
Little evidence exists, however, as to whether HR plays a similar role in humans. This is because although a weak, positive correlation has been reported to exist between HR and pulse wave velocity in a cross-sectional survey of normotensive and hypertensive individuals,2 studies measuring arterial stiffness during HR changes have given conflicting results.3–6
The purpose of the present study was to fill this gap by measuring arterial Dist in response to pacing-induced increases in HR. Dist was measured both in a carotid (CA) and a radial (RA) artery because previous studies had shown that large elastic and middle-size arteries behave differently in a number of circumstances,7–10 including those elicited in animals by HR changes.1,11 Care was taken to exclude subjects with uncontrolled blood pressure (BP) values, hypercholesterolemia, diabetes, and large-artery atherosclerosis to avoid testing the effect of HR on (1) the stiffer portion of the BP-Dist curve12 and (2) arteries made already stiffer by metabolic abnormalities13–15 or by the far-distant stiffening influence of atherosclerotic plaques.16
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Methods |
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Subjects
We investigated 20 outpatients (14 men; mean±SE age, 61.5±2.9 years) chronically implanted with a dual-chamber pacemaker (Medtronic K DR and Thera DR) because of sick sinus syndrome or an atrioventricular block of grade II to III. The subjects were either normotensive (n=15) or had their BP controlled by a diuretic (hydrochlorothiazide or furosemide) and/or a calcium antagonist (amiloride or lercanidipine), 2 in the RA group and 3 in the CA group (see below) based on 3 sphygmomanometric values <140 mm Hg systolic and 90 mm Hg diastolic. In no patients were other drugs used, and no subject had history, physical, or laboratory evidence of cardiac diseases (except the rhythm disturbance); hypercholesterolemia (serum cholesterol >200 mg/dL) and other metabolic diseases; renal damage; or noncardiovascular diseases. There were no atherosclerotic plaques in the CA and femoral arteries at echo color Doppler examination. Six subjects were moderate smokers (<10 cigarettes per day). All individuals agreed to participate in the study after explanation of its nature and purpose. The study protocol was approved by the Ethics Committee of our institution.
RA and CA Distensibility
RA diameter was measured in the nondominant arm by a B/M-mode echo-tracking device based on the Doppler shift (Wall Track System, PIE Medical) and on a transducer operating at a frequency of 7.5 MHz.17 The transducer was stereotaxically positioned over the RA 2 to 4 cm above the wrist with a gel as the medium. With the subject supine and the arm immobile at the heart level, the transducer was oriented perpendicular to the longitudinal axis of the RA, based on the M-mode image and the acoustic Doppler signal, so that its focal zone was located in the center of the artery and the backscattered echoes from both anterior and posterior walls could be visualized and acquired at 50 Hz. The device resolution of the probe is 308 µm17. BP was recorded noninvasively and continuously from a finger ipsilateral to the RA by using a device (Finapres, Ohmeda), which has been shown to have an accuracy similar to intra-arterial RA BP measurements and a resolution of 2 mm Hg.18 RA Dist was derived according to the following formula: Dist=[(2
DxD)+D2]/PPxD2,19 where D is the systodiastolic diameter change, D the arterial diameter, and PP the corresponding pulse pressure (systolic BP minus diastolic BP; average of 3 measurements of 10 seconds each).17
CA diameter and Dist were obtained from the right side, 2 cm below the bifurcation with the neck in partial extension and left rotation. The device and the calculation procedures were the same as for the RA, except that (1) based on the M-mode image and the acoustic Doppler signal, the transducer was manually oriented and kept perpendicular to the longitudinal axis of the vessel and (2) BP was measured semiautomatically from the brachial artery as the average of 3 measurements (Dinamap 1846 SX/SXPI, Critikon).
Protocol and Data Analysis
The study was performed in the afternoon in a room kept at constant temperature (21°C) and after a 24-hour abstinence from alcohol, smoking, and caffeine plus a light morning meal.19 The protocol for the RA study was as follows: (1) Each subject was placed in the supine position and fitted with standard ECG leads, the pacemaker programmer, the BP measuring device, and the echo-tracking device. (2) After a 10-minute interval, the echo-tracking signal was continuously recorded for 10 minutes together with the Finapres signal and the ECG (which was displayed on the pacemaker-controller screen), thereby obtaining baseline arterial diameter, BP, and HR values. The baseline measurements were performed during ventricular atrium-triggered pacing or during sequential pacing at 60 beats/min. (3) The pacing rate was set first at 90 and then at 110 beats/min in the atrioventricular sequential-pacing mode, the aforementioned measurements being repeated for each step during a 5-minute interval. (4) The original pacemaker setting was restored. The same protocol was followed for the CA study. Data were not obtained at a pacing rate >110 beats/min because (1) excessive HR increases for the relatively prolonged period necessary for data acquisition were regarded as potentially unsafe and (2) an HR range up to 110 beats/min encompasses most of the values occurring throughout the day. Atrioventricular delay was set at 120 ms. In each subject, arterial diameter at diastole, systodiastolic diameter changes, and arterial Dist were obtained by averaging five 6-second beat-to-beat measurements (1) during the 10-minute baseline period and (2) between the fourth and fifth minute of each increase in HR. All measurements were made by a single investigator. In our laboratory, the intraobserver coefficient of variation of RA diameter and Dist values (calculated for 2 sets of values obtained in standardized conditions) are, respectively, 2.5% and 5.0%. The corresponding figures for CA are 2.2% and 4.5%. The statistical significance of the differences in mean values was assessed by ANOVA for repeated measures. The 2-tailed t test for paired observations (with the Bonferroni correction for multiple comparisons) was used to locate differences between baseline values and values during each step increase in HR. A value of P<0.05 was taken as the level of statistical significance. Throughout the text, " ±" symbol refers to the SEM.
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Results |
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As shown in the Table and the Figure, compared with the values obtained at baseline (HR=63±2 beats/min), increasing HR by pacing caused small and nonsignificant changes in brachial or finger BP, together with small and nonsignificant changes in CA or RA diameter. On the contrary, in both arteries, the systodiastolic diameter change was significantly and markedly reduced by the pacing-induced increase in HR. Compared with the baseline HR, for example, at a rate of 110 beats/min, the reduction in systodiastolic diameter excursion was 45% in the CA and 41% in the RA. This meant a concomitant significant reduction in the calculated arterial Dist. In the RA, the reduction was marked at the pacing rate of 90 beats/min with no further effect at 110 beats/min. In the CA, the reduction was more progressive, with a maximum at the pacing rate of 110 beats/min. In the 5 hypertensive patients taking antihypertensive drugs, baseline CA and RA data were similar to those of the remaining 15 patients and so were the reductions in Dist: at 110 beats/min, -38% in RA Dist and -46% in CA Dist.
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Discussion |
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In our patients, increasing HR by pacing did not cause any consistent change in BP, which showed a small and nonsignificant increase when measured at the finger level and a small and nonsignificant reduction when measured more proximally at the brachial artery level. It caused, however, a marked reduction in the Dist of both the CA and the RA. It can thus be concluded that in humans, HR changes negatively affect the mechanical properties of both large elastic and middle-size muscular arteries. This is not indirectly due to HR-dependent changes in BP that might passively affect this arterial function.11 It is due to HR per se, which has then to be included among the factors that modulate the tendency of arterial vessels to distend in response to their intravascular pressure.
Several other results of our study deserve to be mentioned. First, in our patients, arterial Dist underwent a marked reduction in response to increases in HR that were within the normal range. This suggests that HR is an important modulator of human arterial Dist and that its influence is likely to be exerted on the largest temporal portion of the daytime. Second, although qualitatively similar, the effect of increasing HR on vascular Dist was somewhat different for the CA and the RA. This is because although CA Dist showed a progressive reduction when HR progressively increased, RA Dist showed a maximal reduction at the HR of 90 beats/min, with no further change at 110 beats/min. This adds to previous observations that changes in arterial Dist in response to stimuli or as a consequence of disease might be quantitatively and sometimes even qualitatively different in elastic and muscular arteries.7–10 Finding a change in one artery does not therefore guarantee that a similar change occurs in all other arteries, making assessment of distensibility at multiple vessel sites desirable. It would be desirable, in particular, to also directly assess distensibility in the aorta and the femoral artery to have a comprehensive assessment of the effect of HR on mechanical properties throughout a considerable portion of the large-arterial tree. Third, the mechanisms through which HR modulates arterial Dist are not addressed by our study. We can speculate that an increase in HR might cause a reduction in stroke and cardiac volume, leading to an unloading of baroreceptors and cardiac receptors that reflexly increase sympathetic tone.20 This would have a pronounced stiffening effect, because sympathetic tone restrains arterial Dist, presumably by augmenting the contracted state of smooth muscle in the arterial wall.21,22 However, in the rat, HR increases cause arterial stiffening, even after "nonsympathetic" mechanisms. For example, an increase in HR might, through a modification of flow-related shear stress, reduce endothelial secretion of nitric oxide, resulting in a reduction of smooth muscle tone in the muscular wall. Also, HR might operate through the viscoelastic component of the vessel wall that makes its distensibility time dependant.23–26 Namely, that makes the vessel behave more a like rigid structure if the time allowed for it to distend is reduced.
Our study has 3 limitations and several pathophysiologic and methodological implications. The first limitation is that the data were obtained in a short-term setting, which means that whether HR changes similarly modify arterial distensibility in chronic conditions remains to be determined. The second limitation is that to measure CA distensibility, systodiastolic changes in the CA diameter were related to pulse pressure values obtained from the brachial artery, a procedure that might be somewhat inaccurate because the pulse-wave reflection phenomenon makes peripheral and central pulse pressure different.27 However, this could hardly affect the conclusion of the study: that an increase in HR is accompanied by arterial stiffening, because when HR was increased to 110 beats/min, the systodiastolic excursion in carotid diameter was so marked as to make a similar reduction in carotid pulse pressure virtually responsible. This applies even more to the RA data, because for that artery, (1) the reduction in diameter excursion when HR was increased was similarly marked, (2) BP was measured in the finger, ie, at a site close to the arterial diameter measurement, and (3) previous data28 have shown good agreement between radial diameter–pressure curves when BP is measured at the finger level or invasively from the RA itself. The third limitation is that, although the results were similar in normotensive and treated hypertensive subjects, these 2 subgroups were too small to conclude that the stiffening effect of tachycardia on the large-artery wall is similar at normal and high BP. This would thus need additional information.
Our data offer an explanation to the observations that HR is a cardiovascular risk factor, and its increase also has an atherogenic influence when changes are confined to the normal range of HR values.29–32 This might be due, at least in part, to the HR-induced large-artery wall stiffening that increases the trauma exerted by intravascular pressure, facilitating the cascade of events that leads to the appearance, progression, and rupture of an atherosclerotic plaque. Second, they suggest that the adverse cardiovascular consequences of sympathetic hyperactivity33 might also be mediated by arterial stiffening caused directly through contraction of vascular smooth muscle (which is also present in elastic arteries) and indirectly through the stiffening effect of an increase in HR per se. Third, our data emphasize that studies comparing arterial distensibility in different conditions and diseases should consider the confounding effect of different HR values and try to correct for it. Correction factors will require, however, additional investigations, because our findings on normotensive normocholesterolemic individuals with an age >60 years do not necessary apply to the effect of HR on arterial distensibility in subjects with a different age or with metabolic abnormalities.
Perspectives
Our data partially explain the evidence that HR is a cardiovascular risk factor: it can be a consequence of HR-induced large-artery stiffening. On the other hand, these data suggest that arterial distensibility evaluation must be done after taking in consideration HR differences as a possible confounding factor.
Received January 21, 2003; first decision February 17, 2003; accepted June 26, 2003.
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