Mechanical and neural components of the cardiac baroreflex: new insights into complex physiology

The arterial baroreflex: a fundamental homeostatic mechanism with complex physiology The arterial baroreflex is known to represent a mechanism of fundamental importance for short-term blood pressure homeostasis in daily life. It is also deeply involved in the pathophysiology of several cardiovascular diseases [1–5], where its impairment may contribute to the appearance of clinical complications [6–14]. This has stimulated a progressive increase in the interest towards the evaluation of baroreflex function in man and, in particular, towards the assessment of cardiac baroreflex modulation. The latter can now be explored either through conventional laboratory methods, or by means of more modern approaches, aimed at quantifying the sensitivity of cardiac baroreflex regulation through computer analysis of spontaneously occurring fluctuations in blood pressure, coupled with linearly related changes in heart rate, with no need of any direct or indirect interference with spontaneous baroreflex function [13,15–20] (Table 1).Table 1: Methods to assess baroreflex cardiovascular modulation in humansHowever, at variance from the relatively simple, although mostly indirect, nature of the methods available to explore baroreflex function in humans, the arterial baroreflex remains a highly complex cardiovascular control mechanism, in which cardiac, vascular respiratory and cerebral components involved in short-term blood pressure regulation are deeply interconnected [1] (Fig. 1). Evidence on the clinical implications of alterations occurring at different levels in the baroreflex arch has been provided by several studies. These include observations on alterations at the carotid artery level, based on baroreflex measurements obtained before and after carotid surgery demonstrating a change in baroreflex function after carotid thromboendoarterectomy [21]. They also include observations on alterations of baroreceptor signal processing in the central nervous system, exemplified by data on baroreflex impairment after acute stroke [22], an impairment that was also shown to predict mortality after stroke [23]. Finally, they include observations on alterations at the effector organs level, exemplified by the demonstration that cardiac hypertrophy is associated with a perturbation of arterial baroreflex function [14].Fig. 1Ageing and arterial baroreflex function Among the various determinants of arterial baroreflex sensitivity and, more specifically, of the sensitivity of the cardiac baroreflex, a major role is played by ageing itself, which has been shown to be associated with an impairment of the cardiac baroreflex and, to a lesser extent, of the baroreflex modulation of vascular tone [24–26]. This age-related baroreflex impairment may be of considerable clinical importance in terms of postural adaptation, particularly in those subjects receiving vasodilatory drugs. The effects of ageing on arterial baroreflex sensitivity appear to become manifest mainly in middle-aged subjects, as any further worsening of baroreflex sensitivity with advancing age appears to be only marginal in size [27]. The mechanisms explaining the age-related alteration in baroreflex function are not fully understood. Even if they theoretically involve all components of the reflex arch, including the vascular (receptors in the arterial wall), neural (afferent and efferent fibres and central neural integration) and cardiac (cardiac receptors, sinus node) components, it has been suggested that, in most cases, the responsible alteration may be located in the sensing vascular portion of the baroreflex loop. In fact, ageing does lead to vascular stiffening, and this is particularly evident at the level of the carotid arteries or the aorta [28–30]. This stiffening has been related to an impaired baroreflex function. For example, Bonyhay et al. [31] reported that carotid distensibility is strongly and positively correlated with baroreflex sensibility in healthy humans. Even though the precise mechanism underlying this correlation remains an unanswered question, it is likely that the elastic properties of the carotid artery may influence the patterns of baroreceptor response to arterial stretch. However, this issue is still a matter of debate, and data are also available supporting an alternative hypothesis, i.e. that baroreflex dysfunction in the elderly is mainly due to an alteration in the neural components of the reflex arch [1]. An additional important confounder, when investigating the mechanisms involved in the genesis of a baroreflex dysfunction in subjects with advancing age, is represented by the associated changes in blood pressure levels, which are also important determinants of baroreflex function. Indeed, differentiating the specific effects of ageing and hypertension on baroreflex function is by no means an easy task. This is because, on the one hand, increasing age is usually associated with increasing blood pressure (mainly systolic) levels and, on the other hand, ageing and hypertension share a number of similar effects on arterial structural changes, particularly with respect to vascular remodelling, with arterial hypertension often being referred to as a factor leading to ‘arterial ageing’. These difficulties in fully characterizing the mechanisms involved in age-related arterial dysfunction emphasize the importance of methods that might allow a better discrimination between alterations occurring at different sites of the arterial baroreflex loop. A method for differentiating between vascular and neural mechanisms involved in age-related baroreflex dysfunction In this issue of the journal, Kornet et al. [32] provide some interesting data concerning the possibility of more deeply assessing the respective effects of ageing and high blood pressure on the mechanisms responsible for baroreflex impairment, which is highly relevant to the above considerations. By means of an elegant approach, the authors have tried to bypass the possible influence of between-subject differences in carotid artery wall stiffness on cardiac baroreflex sensitivity. This was achieved by the quantification of the sensitivity of baroreflex control of heart rate by considering the carotid diameter/R-R interval relationship (‘stretch-derived’ baroreflex indices) instead of the conventionally employed relationship between changes in systolic blood pressure and changes in R-R interval (‘blood pressure-derived’ baroreflex indices). Changes in carotid diameter and carotid distensibility were assessed through careful continuous monitoring of the carotid end-diastolic arterial diameter and the arterial distension waveform by means of carotid ultrasonography. By quantifying the actual degree of carotid artery distensibility in response to blood pressure changes, and by separately measuring the reflex heart rate effects of blood pressure-related changes in carotid diameter (‘stretch-derived’ baroreflex indices), this approach therefore enabled identification of the effect of ageing on other portions of the baroreflex loop (sensing ability, neural components, effector organ response), beyond the first step represented by the distention of carotid walls in response to blood pressure variations. An additional advantage of this study was the inclusion of both hypertensive and normotensive subjects. This further allowed assessment of the specific contribution of ageing to baroreflex impairment as a function of blood pressure levels. The conclusions drawn by Kornet et al. [32] are that the baroreflex alterations observed in elderly subjects are attributable at least in part to a dysfunction of the portion of the baroreflex loop beyond the initial coupling between changes in blood pressure and changes in arterial distensibility. In fact, there was a sustained effect of age not only on the blood pressure–heart rate reflex link, but also on this ‘stretch-derived baroreflex’, and this was the case both in hypertensive and normotensive subjects. The specific effect of hypertension on this new ‘stretch-derived’ index of baroreflex function appears to remain poorly defined at present. A hypertension-related alteration in ‘stretch-derived’ indices of baroreflex function, independent from an age-related alteration, was only distinguishable when focusing on carotid diameter changes and on subjects who were aged below 50 years. Conversely, beyond this age, an independent contribution of these two components was no longer identifiable and no effects of hypertension were observed at any age when focusing on other parameters of the ‘stretch-derived baroreflex’ besides carotid diameter (i.e. when considering carotid distension and distension rate). Whatever the modality of stretch-derived baroreflex assessment, values of baroreflex sensitivity were fairly low above the age of 50 years and normotensive subjects were not easily distinguished from hypertensive subjects, with any blood pressure effect apparently being masked by age. Although interesting, these findings are partly in disagreement with what is known from studies using the conventional ‘blood pressure-derived’ baroreflex indices. Indeed, the effect of age on the ‘blood pressure-derived’ baroreflex sensitivity is mainly observed in middle-aged patients, but remains relatively stable at older ages [27]. On the other hand, an effect of different blood pressure levels on the ‘blood pressure-derived baroreflex’ appears to exist in elderly subjects [33], which is at variance from what reported for ‘stretch-derived’ baroreflex indices in the study by Kornet et al. [32]. It is unfortunate that no assessment of the ‘blood pressure-derived’ baroreflex sensitivity was performed in the study by Kornet et al. [32] because this would have allowed a comparison of possible differences in the changes of ‘blood-pressure’ derived and ‘stretch-derived’ baroreflex indices with age and blood pressure levels in the same subjects and in the same study conditions. Without this information, the different patterns that apparently characterize younger and older subjects, as well as normotensive and hypertensive individuals, when considering ‘blood pressure-derived’ baroreflex function rather than the newer ‘stretch-derived’ baroreflex indices [32] remain an issue that still needs to be addressed in future studies before any final conclusion can be drawn. Conclusions Even with the above-mentioned limitations, the study by Kornet et al. [32] opens the way for interesting new approaches to the assessment of baroreflex function in humans. These approaches might complement the traditional assessment of ‘blood pressure-derived’ baroreflex indices and offer a deeper insight into the complex interaction between the different determinants of baroreflex dysfunction in several pathological conditions. Another merit of the study by Kornet et al. [32] is the demonstration that modern methods of assessing ‘spontaneous’ baroreflex function [13] do indeed reflect baroreflex physiology. Some doubts in this regard were recently raised by Lipman et al. [34] who were unable to observe any association between spontaneous baroreflex sensitivity indices and spontaneous arterial distensibility. The study by Kornet et al. [32] disproves the conclusions reached by Lipman et al. [34] and adds further support to the evidence gathered by a number of experimental and clinical studies on the pathophysiological and clinical usefulness of methods aimed at quantifying ‘spontaneous’ baroreflex sensitivity by focusing on spontaneous blood pressure and carotid diameter fluctuations, either in the time or in the frequency domain [13,32,35].