Blood pressure variability, target organ damage and cardiovascular events

The physiology of blood pressure is characterized by continuous fluctuations, both in response to daily life stimuli and as a result of the complex interplay between cardiovascular control mechanisms [1]. The first clear description of the occurrence of blood pressure variations over time was provided in 1733 by Stephen Hales, in his pioneering studies performed by inserting a glass pipe into the crural artery of a mare, with the declared aim of ‘seeing the arterial pulse'. Hales was so impressed by the continuous changes of blood levels within the pipe, as to conclude that blood pressure was likely ‘never to be exactly the same, any two minutes, throughout the whole life of an animal’ [2]. During the XVIII and XIX Centuries, a number of scientists, including von Haller, Marey, Herisson, Dudgeon, Ludwig and Mayer, to mention just the most famous ones, further clarified the features of blood pressure oscillations in the experimental animal, and provided experimental evidence that blood pressure is also highly variable in humans. In humans, however, only anecdotal observations could be obtained, using instruments that were devised to reproduce the arterial pulse non-invasively, but which were unable to provide quantitative information on blood pressure variability (BPV). Among the first non-invasive, but at the same time quantitative descriptions of BPV in humans obtained in a clinical setting, we should acknowledge the contribution provided at the end of the XIX century by the Italian scientist Scipione Riva-Rocci, who described the occurence of blood pressure changes associated with different behavioural conditions in a paper where he reported the results of his first experiences with the sphygmomanometer [3]. However, a major step-forward in the assessment of BPV in humans over 24 h was only possible in the 1960s, thanks to the technique for ambulatory intra-arterial blood pressure monitoring known as the ‘Oxford System’ [4,5]. Additional, although less precise, information on 24-h BPV has subsequently been obtained through use of the techniques for non-invasive discontinuous ambulatory blood pressure monitoring, now commonly employed in clinical practice [6]. The results obtained by applying these techniques over the last 30 years have stimulated studies aimed at obtaining a deeper insight into the physiology and the pathophysiology of BPV and, in particular, at investigating the possible role of an enhanced BPV in producing cardiovascular complications. These studies have focussed on the following research issues: (i) the possible consequences of an increased BPV on cardiovascular structural changes; (ii) the relationship between BPV and cardiovascular risk; (iii) the mechanisms involved in determining an increase in BPV (including the possible role of arterial baroreflex dysfunction); and (iv) the mechanisms underlying the cardiovascular alterations associated with an enhanced BPV. An important finding of these studies was that BPV has a very close relationship with blood pressure levels, with a higher mean blood pressure being associated with a more pronounced degree of blood pressure variation [1,5]. For studies assessing the possible prognostic value of BPV, this has meant that the effects of mean blood pressure levels must be split from those of blood pressure fluctuations. In this context, animal models characterized only by an increase in BPV and not in blood pressure levels have been proposed as a unique tool to investigate the consequences of BPV on target organs. These models are often based on the surgical opening of the baroreflex loop, through interruption of carotid and aortic baroreceptor afferents (sino-aortic denervation, SAD). In chronic conditions, SAD animals are characterized by an increased BPV with a normal average blood pressure level [7–9], and previous studies making use of this approach have offered evidence that an increased BPV, in the presence of normal average blood pressure values, is indeed associated with vascular and cardiac damage [10–13]. BPV and cardiovascular structural changes: new evidence In this issue of the Journal, Miao and Su provide additional experimental data, based on the same animal model, on the association of cardiovascular structural alterations with an increased BPV [14]. This was carried out in rats by assessing the impact of a SAD-induced increase in BPV on the development of hypertrophy in the aorta and in the left ventricle. The study included both animals undergoing a sham procedure and animals undergoing SAD. The surgical procedure was characterized by a high mortality rate, leading to a variably reduced number of animals available for the assessment of the relation between BPV and aortic and left ventricular hypertrophy at 2, 10 and 16 weeks after surgery. Chronic SAD was associated with a marked increase in BPV with no changes in the average level of blood pressure compared to sham control rats. The increase in BPV was more pronounced at 2 weeks than at 16 weeks after SAD. Aortic hypertrophy was already evident after 2 weeks and persisted after 10 and 16 weeks, while left ventricular hypertrophy was only found in SAD rats at 10 and 16 weeks. Both aortic and left ventricular hypertrophy were significantly and positively correlated with blood pressure variability, but not with mean blood pressure levels. The major strength of this study is to provide, for the first time, information on the time course of the vascular and cardiac consequences of an increase in BPV, and to show that they do not occur at the same time. The data by Miao and Su strongly suggest that vascular hypertrophy is the first damage to appear as a consequence of an increased BPV, being observed as early as 2 weeks after SAD. Moreover, the continuous relationship found between BPV and the aortic weight during the follow-up strongly supports a causal role of BPV on vascular hypertrophy. The earlier appearance of aortic compared to cardiac hypertrophy could partly be expected as the vascular hypertrophy induced by an increased BPV may lead to an impaired arterial distensibility [11,12], increasing left ventricular load and, in turn, favouring left ventricular hypertrophy. Factors affecting blood pressure variability The study by Miao and Su is also relevant in relation to the mechanisms involved in determining the degree of BPV, which is an issue that is still a matter of debate [1]. There is no question that behavioural factors play a important role [1,5,15] because of their ability to cause increases (emotions, exercises, sexual intercourse, etc.) or reductions (sleep, posture, etc.) in blood pressure characterized by different slopes and duration. This suggests that neural factors, mediating the effects of behavioural changes, play a role of paramount importance in the determination of the size of daily life blood pressure variations in any given individual [16–18]. However, their effects should be considered in combination with those of non-neural mechanisms, which can also modify blood pressure values, either from moment-to-moment or in a more sustained fashion [1]. For example, the direct vasomotor effect of temperature may be responsible for the seasonal blood pressure changes [19]. Endothelial factors may also directly affect vasomotor tone in a fashion that modifies short-term blood pressure variability [20]. This may also be the case for angiotensin II produced at renal or extra-renal levels, which has been shown to correlate with blood pressure variability [21]. Among the neural cardiovascular control mechanisms, the arterial baroreflex appears to exert an effective anti-oscillatory action, at least when considering overall blood pressure variance [1,16–18,22,23]. Evidence is available that baroreflex sensitivity shows an inverse relationship with BPV, indicating that whenever the baroreflex is more effective, blood pressure variability tends to be less and vice-versa [16,22]. Interestingly, baroreflex sensitivity shows a positive relationship with heart rate variability, suggesting that the baroreflex favours heart rate oscillations presumably as a means to buffer blood pressure changes through changes in cardiac output. It is believed that an impairment of the baroreflex may be one of the factors responsible for the increased blood pressure and reduced heart rate variability which is typical of ageing [16,17,22]. It is also believed that the same mechanism may contribute to the increased blood pressure variability typical of hypertension, in which heart rate variability may also be somewhat reduced [17,23,24]. Other factors, such as a faster and/or a greater blood pressure response to stressful stimuli reflecting the enhanced sympathetic activity typical of this condition [25], may play a role in the greater blood pressure variability seen in hypertension. The demonstration, provided by Miao and Su [14], and by others [7–9], that BPV undergoes a remarkable increase when the influence of the arterial baroreflex on cardiovascular regulation is removed, further supports the relevance of this reflex mechanism in the modulation of the amplitude and frequency of blood pressure fluctuations [7]. Clinical importance of blood pressure variability An additional merit of the study by Miao and Su [14] is that they offer further experimental support for the suggestion, made on the basis of a number of previous studies, that BPV may have a prognostic value. In fact, for the same 24 h average blood pressure, a patient's clinical status and outcome may depend on the magnitude of spontaneous 24-h blood pressure variations [26]. This was shown when focusing on target organ damage or vascular dementia both in cross-sectional [27–31] and in longitudinal studies [32,33]. More recently, this was also shown to be the case in longitudinal studies focussing on the risk of cardiovascular events and cardiovascular mortality [33,34]. Thus, the adverse consequences of hypertension on the cardiovascular system may depend not only on 24-h average blood pressure, but also on the magnitude of spontaneous blood pressure variability, presumably because these variations add to cardiac workload and increase the adverse effect of intravascular pressure on the vessel wall. Problems with the study by Miao and Su Notwithstanding its merits, the study by Miao and Su [14] has a number of limitations. Among them is the lack of new insights into the mechanisms underlying the reported cardiovascular alterations of SAD rats. Mechanical determinants are likely to play an important role in this regard. Lacolley et al. [11] have shown that, in SAD rats, an increased BPV is associated with structural changes of the arterial wall, which is characterized by an increased collagen content. In another model of arterial pressure lability obtained by chronic sympathectomy, the same group showed that an enhanced BPV was again associated with vascular changes, this time represented by a decreased elastin content [12]. It is noteworthy that the haemodynamic pattern is partly different between the two models, being represented both by hypertensive and hypotensive episodes in the SAD model and mainly by depressor episodes in the sympathectomized animals. Neuro-humoral factors may also play a role in explaining the clinical consequences of BPV. This would be of critical importance because, if humoral factors are involved in the deleterious role played by an increased BPV, the selection of drugs able to target these humoral systems might be more effective in counteracting the adverse effects of an enhanced BPV. In their study, Miao and Su note the possible role of the renin–angiotensin system (RAS) in this regard [14] as they observed, in preliminary experiments, an increase of angiotensin II content in the arterial wall of SAD rats. Given the accumulating evidence that the RAS plays a major role in terms of cardiovascular consequences [35–39], and because RAS is expressed either at the vascular and at the cardiac level, it may indeed represent a very plausible candidate in this context. Such a role is also supported by the growing body of evidence concerning the efficacy of RAS blockers on cardiovascular remodelling [39,40]. At present, however, this represents only a stimulating hypothesis and deserves to be further investigated by studies aimed at assessing the efficacy of drugs counteracting the RAS in reducing BPV and in preventing the adverse cardiovascular consequences of its increase. As mentioned above, there may be other mechanisms involved in determining both the increase in blood pressure variability observed in hypertension and its adverse effects on the cardiovascular system. These include an increased sympathetic neural activity or a dysfunction of the nitric oxide system. Preliminary evidence is available indicating that changes in blood pressure variability are associated with changes in sympathetic activity and that central sympatholytic agents may buffer the degree of blood pressure fluctuations, mainly in the very low frequency region [26]. It has also been reported that experimentally induced endothelial dysfunction in animals is accompanied by changes in BPV [20], and both these mechanisms may also contribute to the associated cardiovascular alterations. Additional studies are needed to better clarify the importance of these findings in humans. Finally, two additional limitations of the study by Miao and Su should be considered. First, due to the increased mortality rate after surgery, a reduced number of animals was available to assess the effects of SAD at different times after the procedure. Second, the SAD model would also have been perfectly suited to assess the prognostic implications of blood pressure variability by simply monitoring the mortality rate of these animals compared to sham-operated ones; however, no information is provided on this issue in their study. Perspectives for the future A survey of the studies available on this issue clearly shows that, in humans, the relationship between BPV and target organ damage is difficult to assess. This may be related to the reported collinearity between the increase in mean blood pressure levels and the increase in BPV. Other difficulties arise from the observation that while an increase in BPV may lead to organ damage, the presence of organ damage may in turn enhance blood pressure fluctuations in response to a given simulation, and this makes it impossible to establish a causal link between BPV and cardiovascular complications based on cross-sectional studies only. Moreover, in humans, changes in BPV due to an alteration in reflex control of circulation are commonly associated with other cardiovascular risk factors, such as age, serum cholesterol and heart rate [41] (i.e. with factors that are also able to influence target organ damage directly). Thus, the adverse effects of an isolated increase of BPV need to be assessed with caution in humans because the degree of BPV may not only represent a risk factor per se, but also be a marker of a more generalized increase in the risk of cardiovascular problems. Whether an increased BPV does indeed represent a marker of risk that is independent of other classical risk factors requires further investigation through longitudinal controlled studies. It has to be emphasized that, in this context, proper assessment of BPV would require continuous blood pressure recordings to be implemented [42], as discontinuous blood pressure monitoring may offer only an approximate estimate of slower blood pressure changes and does not allow any assessment of fast, beat-by-beat, blood pressure fluctuations [43]. Until recently, accurate beat by beat monitoring of BPV was only possible using intra-arterial recordings [4,5]. The present availability of non-invasive devices which are able to reliably track blood pressure changes over time on a beat-by-beat basis [44–48] should make studies on BPV easier to perform, and might offer the possibility for assessing the clinical relevance of BPV in larger groups of subjects. In conclusion, while the study of Miao and Su offers additional experimental evidence for the relevance of BPV as a determinant of structural changes in the heart and the arterial vessels, the definitive demonstration in humans that an increased BPV carries an increased cardiovascular risk still needs to be confirmed by additional data. In particular, what is still missing are data from intervention studies that should be aimed at investigating whether drugs able to reduce BPV are also able to reduce the degree of target organ damage and, more importantly, the rate of cardiovascular events. Addressing this issue, it remains a major challenge for future. These studies however, might now be easier to perform thanks to the availability of better tools for reliable non-invasive continuous blood pressure monitoring.

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