Blood pressure variability, target organ damage and antihypertensive treatment

The occurrence of continuous blood pressure fluctuations, either generated by the complex interplay between several cardiovascular control mechanisms, or elicited by shifting between different daily life behaviours and triggered by environmental stimulations, is an intrinsic feature of the cardiovascular system. Typical examples of these changes are the blood pressure rise in response to physical activity or psychological stress and the blood pressure fall during relaxation and sleep. The extent of these fluctuations is different in different populations, and is greater in patients with impaired cardiovascular control mechanisms [1]. In particular, an increase in blood pressure variability has been demonstrated with advancing age and in subjects with elevated blood pressure levels [1–3]. These observations, made possible on a large scale by the availability of ambulatory blood pressure monitoring techniques, have stimulated a number of studies on the mechanisms responsible for the modified blood pressure variability patterns typical of specific clinical conditions, and have also led to the hypothesis that an increased amplitude of blood pressure fluctuations, as typically found in hypertensive patients, might contribute to the adverse cardiovascular consequences of this condition [1,4]. Indeed, over the last 15 years, evidence has been provided that both the target organ damage and the rate of cardiovascular events of hypertensive patients are significantly and independently related to the degree of blood pressure variability, an association that in most cases was found to persist after accounting for the effects of elevated blood pressure levels. This is the case when blood pressure variability was quantified as the standard deviation of 24-h, daytime and night-time average blood pressure [5–9]. This is also the case when the focus was on specific components of blood pressure variability, such as an excessive blood pressure fall at night or a steeper morning blood pressure rise [10–15], or when behaviourally-induced blood pressure changes were quantified after removing the contribution to blood pressure variability of the cyclic, circadian component of 24-h blood pressure [16,17]. However, data on this issue from large groups of patients is still lacking and, despite the consistent evidence provided from population studies [9,16] on the prognostic values of blood pressure variability, there is still the need for additional evidence to definitely include blood pressure variability among the established cardiovascular risk factors. This is mainly due to a number of methodological difficulties in assessing the link between blood pressure variability and cardiovascular complications. These problems are discussed in turn below. First, proper assessment of blood pressure variability would require beat-by-beat blood pressure tracings to be available. Until a few years ago, in humans, this was possible only though invasive procedures, by use of intra-arterial catheters [2,18], an approach clearly unsuitable for routine clinical use. More recently, progress in technology has offered the possibility to obtain 24-h beat-by-beat blood pressure recordings non-invasively, through implementation of the so-called vascular clamp technique for continuous finger blood pressure monitoring (Portapres device, Finapres Medical Systems, Arnhem, The Netherlands) [19,20]. However, this approach is also not easily applicable due to the high cost of the device, which at present still remains largely a research tool. Thus, a number of the available studies on blood pressure variability have made use of discontinuous blood pressure monitoring techniques, which can provide some insight into these phenomena, at least when focusing on slow blood pressure fluctuations and on circadian blood pressure changes. However, they cannot provide any insight into fast- and short-lasting blood pressure variations [1,21,22]. Second, proper assessment of a causal link between enhanced blood pressure variability and the adverse consequences of hypertension requires data to be obtained from longitudinal studies, which are undoubtedly more difficult to perform than cross-sectional observations because of the confounding interference of antihypertensive treatment. Third, given that blood pressure variability shows a tendency to increase with increased blood pressure mean levels, the real prognostic relevance of blood pressure variability has to be assessed after accounting for differences in mean blood pressure levels. This can be carried out either by patients stratification in percentiles of mean blood pressure levels [5,7,23], or by quantifying blood pressure variability in normalized units (coefficient of variation = SD × 100/mean blood pressure level), or finally through multiple regression analysis, by setting both blood pressure mean levels and blood pressure variability as independent variables and the cardiovascular complications as the dependent variable. Fourth, due to the opposite prognostic value reported for nocturnal blood pressure fall (favourable effect) and for overall 24-h blood pressure variability (unfavourable effect), became the latter parameter includes also the nocturnal blood pressure fall, there is still uncertainty as to whether blood pressure variability should be assessed separately over the daytime and the night-time, or whether, as recently suggested, it might be more appropriate to quantify 24-h blood pressure variability after removing the contribution of day–night blood pressure changes [16,17]. Finally, to definitively prove the prognostic role of blood pressure variability, evidence is also needed from therapeutic intervention studies that a reduction in blood pressure variability, through a suitable treatment, is associated with a reduction in organ damage and/or in the rate of cardiovascular events. Such a demonstration might also provide clinicians with important practical indications on the choice of the most appropriate antihypertensive drug or drug combination in case of enhanced blood pressure fluctuations. It may also clarify whether the selection of drugs that guarantee a smooth blood pressure reduction and buffer the increased blood pressure variability of hypertensive patients might provide additional benefit in terms of cardiovascular protection [24–26]. In the present issue of the journal, Liu et al. [27] offer an additional interesting contribution to the discussion on this still debated issue. In particular, their study addresses the last of the above-mentioned topics, namely whether, by reducing blood pressure variability, any improvement of the cardiovascular negative effects of hypertension can be achieved. Liu et al. [27] report on data obtained in spontaneously hypertensive rats by investigating the effects of long-term treatment with nitrendipine and hydralazine on both blood pressure variability and end-organ damage. After 4 months of treatment, nitrendipine significantly decreased blood pressure mean levels and long-term blood pressure variability. This was associated with a reduction in the end-organ damage score, carefully quantified on the basis of macroscopic and microscopic examination of the heart, kidneys, brain and spleen, inspected after the animals were sacrificed. Conversely, hydralazine significantly reduced blood pressure, but did not lower blood pressure variability. Moreover, no effect on end-organ damage score could be observed in hydralazine-treated rats. In the untreated animals of a control group, the end-organ damage score showed a weak relationship with systolic blood pressure levels and short-term blood pressure variability, and a closer association with long-term blood pressure variability. The above findings were also confirmed when blood pressure levels and blood pressure variability were separately computed over the night-time and the daytime subperiods, rather than over the entire 24 h, thus addressing another of the critical issues related to the assessment of blood pressure variability, namely the relevance of blood pressure fluctuations when the contribution of the day–night blood pressure changes is removed. Finally, stepwise multiple regression analysis confirmed that on treatment long-term systolic blood pressure variability was the most important determinant of end-organ damage score, after accounting for on treatment blood pressure values. Long-term systolic blood pressure variability was particularly important in relation to cardiac damage score and renal damage score, when separately considered. Conversely, short-term blood pressure variability was a determinant of total end-organ damage score when separately computed over the daytime only [27]. By specifically addressing some of the crucial issues related to the assessment of the actual clinical value of differences in blood pressure variability, the authors offer an important contribution to the ongoing research in this difficult field. For the first time, the study by Liu et al. [27] yields clear evidence that a drug such as nitrendipine, which is able to reduce not only mean blood pressure levels, but also blood pressure variability, is able to reduce organ damage, whereas this is not the case for a drug such as hydralazine, which is able to provide the same reduction in mean blood pressure levels but not modify blood pressure variability. The finding that a dihydropyridine calcium antagonist is able to reduce blood pressure variability, an effect which, among other possible mechanisms, may depend on an improvement in cardiovascular control mechanisms and, in particular, in baroreflex sensitivity, is in line with previous evidence that administration of a lipophylic calcium antagonist such as lacidipine was associated with a reduction in systolic blood pressure variability and by a parallel increase in spontaneous baroreflex sensitivity over 24 h in hypertensive patients with diabetes mellitus [28]. In the study by Liu et al. [27], the association between reduction in organ damage and reduction in systolic blood pressure variability remains evident when separately considering daytime and night-time values (thus removing the influence of day–night blood pressure changes), and when accounting for the parallel reduction in mean blood pressure levels through stepwise multiple regression analysis. Finally, an important merit of their study is the possibility, offered by an experimental and longitudinal study in animals, to directly observe and thus precisely quantify target organ damage. However, despite these interesting results and methodological merits, the study by Liu et al. [27] is not immune to limitations when referred to current research in humans. First, the data were obtained in rats, and their direct extrapolation to humans should be made with great caution, due to the well-known important between-species differences in cardiovascular function and cardiovascular control mechanisms. Second, the effects of drug treatment on blood pressure variability and on the related changes in organ damage were apparent only when considering long-term, between half hour, blood pressure variability. Once more, it remains to be assessed whether this is a specific finding in rats, and possibly also dependent on the research protocol, or whether this also holds true in humans, in whom previous studies showed that both short-term and long-term blood pressure fluctuations have clinical relevance. Third, given the different dietary habits of different animals, and due to the fact that five animals were housed together in each cage, the daily drug intake in individual animals might not have been homogeneous, and this may have introduced some noise in the data collection. However, even with these limitations, the information provided by Liu et al. [27] appears to represent an important step forward, through an interventional approach, towards a more precise definition of the clinical role of blood pressure variability. Obviously, further interventional studies are now required to provide a comparable demonstration in humans, aimed at comparing the effects on blood pressure variability and on the cardiovascular adverse consequences of hypertension exerted by different treatment strategies. The achievement of this demonstration is needed to definitively shift the assessment of blood pressure variability from present status of research issue [29] to being acknowledged as a cardiovascular risk factor in the prognostic stratification of hypertensive patients, as well as of patients with impaired cardiovascular control mechanisms.