The study by Kornet et al.  in this issue of the journal makes an important contribution to the field of non-invasive investigations of baroreflex function. The article reports on the application of ultrasonic techniques of arterial diameter measurements to determine indices of baroreflex sensitivity. The accurate measurement of changes in vessel diameter throughout the cardiac cycle allows characterization of control mechanisms of blood pressure with wall stretch as the stimulus for the baroreceptors. This technique also allows the effect of wall stiffness to be taken into account and to effectively separate the mechanical and neural transduction components of the baroreflex arc. The study compares the consistency of results obtained from diameter and pressure measurements in young and elderly individuals to determine the mechanism of reduced baroreflex sensitivity with age. In comparing results from diameter and pressure measurements, the study also implicitly illustrates the inherent limitations of using peripheral pressure measurements in calculations of baroreflex sensitivity.
Autonomic cardiovascular control is characterized by baroreflex physiology, which traditionally has been assessed by measuring the heart rate response (or the R–R interval) to changes in arterial pressure . The importance of understanding mechanisms of blood pressure and heart rate variability cannot be overstated because they are crucial in maintaining homeostasis in cardiovascular health and disease. Dysfunction of autonomic control is associated with increased mortality [3–8]. Disorders in baroreflex activity are also responsible for falls and many presyncopal episodes in elderly individuals [9,10] as a result of variations in cerebral perfusion pressure. Because the efferent arc alters heart rate as well as vascular tone, variability in heart rate has been used to measure baroreceptor response.
Studies aimed at understanding the physiological mechanisms of open and closed loop components of baroreceptor function are necessarily invasive because they involve measurement of nerve firing frequency of the vagal and sympathetic nerves following changes in blood pressure . However, because of the limited applicability of these invasive techniques, other methods have been devised to obtain information on baroreptor function with non-invasive, or minimally invasive, procedures in humans under clinical conditions. Neck suction methods are used to study open loop gains of the carotid baroreceptors . Mechanical manoeuvres, such as the Valsalva manoeuvre, and pharmacological intervention by bolus injection of vasoactive agents are used for integrated baroreflex engagement [6,13,14], although there is some controversy regarding the use of specific agents such as nitrovasodilators for baroreflex sensitivity studies . The principal methods employed to assess baroreflex sensitivity in humans, and which are applied to investigations ranging from the laboratory to clinical studies and daily life activities, are covered in a recent comprehensive review by Parati et al. .
Baroreflex sensitivity is generally defined as the relation between variations in input (arterial pressure) and output (R–R interval) signals. The analysis lends itself to signal processing using classical spectral analysis techniques [17,18]. More recently, beat sequence techniques have been developed to study spontaneous baroreflex function in the time domain by detecting spontaneous beat-to-beat changes of blood pressure and pulse interval during long continuous periods of steady-state recordings [19,20]. Baroreflex sensitivity is then quantified by the slopes of the linear relationship of pulse interval and systolic pressure for contiguous pulse sequences where systolic pressure and pulse interval change in the same direction [9,19,20]. Although these techniques are used for non-invasive assessment of baroreflex sensitivity, they essentially characterize the cardiovagal reflexes and do not necessarily include the sympathetic arc. However, in conventional methods developed for non-invasive investigation of baroreflex function, there are two specific issues that deserve particular attention: (i) the stimulus to the baroreceptors is considered to be the arterial pressure; (ii) pressure is generally measured in a peripheral location.
Mechanical and neural transduction components and integrated baroreflex
The carotid baroreceptors are located in the walls on the bulb of the internal carotid arteries and the aortic baroreceptors in the wall of the aortic arch. In both cases, they are stretch-sensitive receptors, and there is a response of the afferent nerves when the receptors sense a change in length . Furthermore, the magnitude of the superimposed pulsatile component [22,23] and the direction of the pressure change  modulate the receptors’ response. The first assumption, that the stimulus to the stretch receptors can be considered as the arterial pressure, implies that intraluminal pressure is a surrogate of wall stretch, and is the stimulus that causes firing of the nerves. The second assumption implies that the peripheral pressure is a surrogate of the carotid and aortic pressure, and thus the stimulus signal for the baroreceptors.
Arterial pressure and diameter are related by the stiffness and viscoelastic properties of the arterial wall . For a compliant wall, a given change in pressure produces a certain change in diameter. For a stiff wall, the same change in pressure produces a smaller change in diameter. Hence, for a stiff wall, a similar pressure stimulus would produce a reduced baroreceptor response. Therefore, if a reduced baroreceptor sensitivity were determined in terms of the pressure/heart rate response, the reason for the reduction of the integrated baroreflex arc could not be explicitly determined. It could either be due to a reduction in the gain of the mechanical transduction component (arterial diameter/pressure) or a reduction in the gain of the neural transduction component (R–R interval/arterial diameter). The issue of the integrated baroreflex arc and the effect of vascular stiffness on baroreflex sensitivity was addressed in recent studies by Hunt et al. [26,27] who also described a methodology for quantifying the mechanical and neural transduction components by inclusion of arterial diameter measurement using ultrasound techniques.
Kornet et al.  propose the application of a new technique for the accurate investigation of baroreceptor sensitivity by means of continuous ultrasound recordings of carotid diameter. The details of the method and instrumentation were described in one of their previous publications . Similar to studies by Hunt et al. [26,27], the neural transduction arc was determined from diameter changes in the carotid artery and R–R interval. However, Kornet et al.  show that it is not simply the change in diameter, but the rate of change in diameter during early systole that is the parameter which is more closely associated with the baroreflex determination of heart rate. The study also compares a range of diameter parameters (i.e. systolic diameter, diastolic diameter, absolute distension, relative distension, absolute distension rate, relative distension rate) with arterial pressure parameters (systolic pressure, end-diastolic pressure, pulse pressure, relative pulse pressure, absolute systolic pressure rate, relative systolic pressure rate), respectively. The conclusion is that diameter parameters are superior to pressure parameters in predicting heart rate changes mediated by the baroreflex. By using diameter changes, Kornet et al.  effectively eliminate the mechanical transduction arc in quantifying baroreceptor function. Thus, when comparisons are made between young and older individuals, and a reduced baroreflex sensitivity is found in the older cohort, the conclusion is that such reduction is not due to the effects of arterial stiffness affecting the mechanical transduction component of the integrated baroreflex arc, but rather due to an intrinsic age-related deterioration of the neural transduction component. This is a major conclusion of their study.
However, the studies by Kornet et al.  and Hunt et al. [26,27], and many other investigations that characterize the integrated baroreflex arc in terms of arterial blood pressure and pulse interval, or the mechanical transduction component in terms of arterial pressure and diameter, all suffer from the same fundamental problem: baroreceptors are located in central arteries (carotid artery, aortic arch) but blood pressure is usually measured non-invasively in a peripheral location (e.g. finger artery) . Indeed, Kornet et al.  do emphasize that this presents a ‘limitation’ of their study. These issues are also relevant in studies examining the effect of arterial systemic compliance on baroreflex function [30–32]. Attempts have been made to study baroreflex sensitivity by obtaining continuous pressure and diameter signals at the carotid artery by direct applanation tonometry . However, these measurements need to be performed with extreme care as the pressure applied to the carotid artery during the applanation process to obtain a reliable and consistent pulse waveform may itself stimulate the baroreceptors and cause artefactual reflex changes in arterial pressure and heart rate. In addition, non-invasive carotid pressure presents a calibration problem. Van Bortel et al.  evaluated different methods where the central arterial pressure waveform is calibrated from a sphygmomanometric measurement of peripheral (brachial artery) pressure. They found that the least error with invasive measurements was obtained using the technique described by Kelly and Fitchett  where the average value and nadir of the central waveform are equated to the mean and diastolic pressure, respectively.
Amplification of the arterial pressure and effects of heart rate
The elastic and geometric non-uniformity of the arterial tree results in amplification of the arterial pulse as it travels from the heart to peripheral sites . Wave transmission characteristics present problems when using arterial pressure to detect the stimulus for the baroreceptors. If pressure could be measured at the carotid artery and aortic arch, and if arterial properties were to remain constant (with a passive consistent relationship between pressure change and diameter change), this would be quite appropriate. The problem with pressure measurement is that the peripheral pulse pressure amplitude is normally considerably greater (by some 40–60%) than in central arteries [36,37]. This amplification of the peripheral pulse usually decreases with age [38,39], but the effects of amplification can still be substantial with a change in posture from sitting or supine to standing, and with a change in heart rate or venous return [36,37]. Furthermore, wave transmission characteristics are frequency dependent such that the relationship (transfer function modulus) between aortic and peripheral (radial or finger artery) pressure is unity at low frequency, reaching a peak of approximately 3 at around 4 Hz and then returning to unity or below at higher frequencies [40,41]. This suggests that as the heart rate increases within the normal range, the peripheral pulse also increases for any given aortic pulse pressure. Indeed, a peripheral pressure pulse of some two to three times the aortic pulse can be measured during high levels of exercise .
The implication of the influence of wave transmission properties of arteries in studies of baroreceptor function is important. First, the use of peripheral pulse pressure with simultaneous measurements of carotid artery diameter to determine carotid artery distensibility parameters cannot be used in individuals of different ages because the amount of pulse amplification varies with age [38,39]. Second, in interventions where large changes in heart rate occur due to baroreflex effects, the heart-rate dependendent pulse amplification introduces non-linear effects where baroreflex sensitivity is quantified in terms of systolic pressure changes .
Recent advances in algorithms to derive central aortic pressure from the peripheral pulse provide solutions to some of these confounding problems [40,41,43,44]. Using mathematical models of the brachial artery system, it has been shown that reasonably accurate predictions of central aortic pressure can be made from the peripheral (finger or radial artery) pulse calibrated to the conventional brachial artery pressure measured by the sphygmomanometer [40,41,43,45]. The derived aortic pulse can also track changes in mean and pulse pressure during the Valsalva manoeuvre .
These methods were employed in our recent studies [43,46] investigating the different values of baroreflex sensitivity obtained with identical cardiac cycles using the beat sequence technique , and calculating them with peripheral systolic pressure and derived central aortic pressure. Substantial differences were seen, with baroreflex sensitivity values differing by more than 50%. Because of the non-linear effects, baroreflex–related beat sequences detected from the peripheral pulse were not identical to those detected from the central pulse . Similar discrepancies were also obtained in earlier studies by Hartikainan et al.  who compared simultaneous invasive and non-invasive evaluation of baroreflex sensitivity. The authors attributed the differences to possible errors in the measurement of finger (Finapres) arterial pressure [47,48], whereas the likely explanation may have been the physiological differences in central systolic pressure due to heart rate changes .
The present study by Kornet et al.  is important. It illustrates that baroreflex sensitivity, mediated by stretch-sensitive baroreceptors located in central arterial sites, can be quantified by non-invasive measurement of vessel wall parameters. In addition, Kornet et al. have extensive experience in ultrasonic techniques and the use of advanced instrumentation and signal processing in the development of methods and tools for non-invasive cardiovascular studies . They have also identified the problems with the use of peripheral pressure, and show that far more consistent results are obtained if baroreceptor stretch is measured directly from ultrasonic recordings of the change in carotid artery diameter. The authors confirm the change with age that occurs as a consequence of arterial stiffening, but show that even when this is considered, changes in baroreceptor function cannot be fully explained, and must involve degeneration of the whole arc and, presumably, of the autonomic nerves themselves. Recently, Dickinson  vigorously questioned the whole notion of baroreflex studies and their relevance to understanding disorders of complex biological systems, receiving an equally vigorous rebuttal by Sleight . It is clear that while many issues still remain to be resolved in the basic relationship of baroreflex research and cardiovascular disorders, such as hypertension, the technique proposed by Kornet et al.  promises to make a significant contribution to non-invasive studies of the baroreflex system, with improved ways of characterizing autonomic function and of identifying functional mechanisms of cardiovascular control in health and disease.
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