The notion that having a high blood pressure is not healthy is far from being surprising to doctors and most patients. It is supported by robust scientific evidence showing that blood pressure is in a linear, direct relationship with adverse cardiac (coronary heart disease, heart failure) and cerebral (ischaemic and haemorrhagic stroke, transient ischaemia) consequences. Initially, blood pressure was only estimated based on office measurements but, over time, technological progress has led to the development of techniques that allow discontinuous automated ambulatory blood pressure monitoring (ABPM) over extended periods of time (typically 24 h). The information on average blood pressure obtained by ABPM demonstrated a closer correlation with cardiovascular outcome compared to traditional office measurements [1,2]. An additional advantage of ABPM compared to isolated office readings is its ability not only to provide information on average blood pressure levels, but also to quantify blood pressure changes over time. A number of studies have shown that at least three main patterns of blood pressure variability are prognostically relevant: (i) nocturnal blood pressure fall ; (ii) morning blood pressure surge [3,4]; and (iii) overall blood pressure variability (quantified by its standard deviation) [5,6]. Although this evidence has raised interest towards blood pressure variability phoenomena, the precise mechanisms responsible for their prognostic consequences remain a matter of debate. In particular, it is still unclear whether the amplitudes and temporal patterns of changes in blood pressure themselves contribute to cardiovascular damage, or whether the latter depends more on concomitant differences in the average blood pressure levels.
In this issue of the journal, Metoki et al.  demonstrate the occurrence of a relationship between blood pressure measured at different times of day and night, and cardiovascular mortality of different causes. The data were obtained in individuals participating in the Ohasama cohort study in Japan. The authors calculated moving 2-h averages of systolic blood pressure centred at each hour of 24-h ABPM and, for each of them, evaluated the strength of their relationship with the risk of cardiovascular death over 10.6 years of follow-up. Importantly, to take into account the fact that different individuals have different temporal behaviour patterns, the time span from awakening, rather than the absolute time of blood pressure measurement, was used to identify different periods over 24 h. Such an approach has been suggested to provide better results than using clock times because changes in the cardiovascular system in the morning are mainly due to changes in individuals' activity rather than to ‘intrinsic’ circadian factors. The main finding of this study was that deaths caused by haemorrhagic stroke were mostly related to morning and daytime blood pressure levels, whereas those caused by ischaemic stroke and by cardiac problems were mainly related to night-time blood pressure.
The key message to take home when considering the above results is that the association of different types of cardiovascular events with alterations in blood pressure may depend on different mechanisms, including the impact of chronic blood pressure elevation and the dynamic stress on heart and vessel walls exerted by short-term blood pressure fluctuations. On one hand, the most common cause of cardiac deaths and deaths related to ischaemic stroke is atherosclerosis, which can take decades to develop and is accelerated by a chronic exposure to high blood pressure levels, such as in persistent nocturnal hypertension. In the study by Metoki et al. , ischaemic cardiac and cerebral deaths were mainly associated with nocturnal hypertension, suggesting that chronic exposure to elevated blood pressure at night (and possibly also to conditions associated with autonomic dysfunction such as diabetes) accelerates structural atherosclerotic changes, which increases the risk of thrombotic events.
On the other hand, daytime and even more so morning blood pressure are much more dependent on the individuals' activity. Blood pressure over these periods typically varies much more rapidly and reaches higher maximum values compared to night-time. This is most evident in the hours around the awakening time when a rapid increase in blood pressure, known as the morning blood pressure surge, occurs. Such rapid changes in blood pressure represent an important stress to the arteries and, if combined with structural abnormalities (congenital aneurysms, atherosclerotic lesions) and/or impaired coagulation, may lead to haemorrhagic complications and, most importantly, to haemorrhagic stroke. This hypothesis is supported by data obtained through computer analysis of 24-h ambulatory continuous intra-arterial blood pressure recordings. The speed of blood pressure changes was higher in hypertensive than in normotensive individuals throughout 24 h, resulting in steeper blood pressure fluctuations in the former group both during night sleep and during daytime activities, which might contribute to vascular damage . An excessive blood pressure response to activity might indeed have been responsible for the stronger association of morning and daytime blood pressure with haemorrhagic events observed in the study by Metoki et al. .
Although the results of their analysis are undoubtedly interesting, it should be noted that they may only refer to the Japanese population, which differs from other populations in many respects. For example, the Japanese population is characterized by a much higher incidence of stroke compared to European or US populations, and this may affect its relationship with ABPM parameters.
The conclusions drawn by Metoki et al.  on 24-h distribution of the risk of blood pressure-related cardiovascular events, should be considered on the background of the information on the prognostic relevance of ABPM parameters provided by other studies. In the Syst-Eur study, night-time blood pressure was prognostically superior to daytime blood pressure in relation to cardiovascular endpoints, and a close relationship with stroke was found not only for nocturnal mean blood pressure levels, but also for night-time blood pressure variability, in the placebo group . On the other hand, in the OvA study, daytime blood pressure displayed a tendency to be more closely related to cardiovascular events than night-time blood pressure . However, these two studies are difficult to compare with the Ohasama data because: (i) they included only hypertensive individuals (in Syst-Eur only those with isolated systolic hypertension) and (ii) all patients in the OvA study, and half of the patients included in the Syst-Eur study, were receiving active antihypertensive treatment. This may have influenced the results because antihypertensive drugs, especially those that do not cover the whole 24-h period evenly (such as nitrendipine and enalapril, which were used in Syst-Eur), may exert an inhomogeneous influence on blood pressure over different periods of day and night, and may thus adversely affect the degree of blood pressure variability.
Moreover, none of the above studies analysed the risk of haemorrhagic stroke separately. Because both studies were performed in European populations, it is likely that in these patients fewer haemorrhagic strokes occurred. Thus, the results should probably better be compared with the non-haemorrhagic portion of the Ohasama stroke data. Unfortunately, to date, limited evidence is available in Western populations  on the prognostic relevance of morning blood pressure (or morning blood pressure surge) in terms of cardiovascular events.
In conclusion, the results of the study by Metoki et al. , together with the data provided by previous investigations, strongly suggest that, when dealing with the prognostic consequences of elevated blood pressure levels over 24 h, different blood pressure variability patterns over the day and night may be responsible for different types of organ damage and cardiovascular events. An obvious implication of these findings is that individuals characterized by different alterations in blood pressure variability patterns are likely to benefit from therapeutic interventions specifically aimed at their correction. However, until now, a direct demonstration that controlling an elevated nocturnal blood pressure, or a steeper morning blood pressure rise, provides specific benefits independent from the treatment-induced reduction in average 24 h blood pressure levels is still missing. Based on the data provided by Metoki et al. , we may expect a clear-cut reduction of risk of haemorrhagic stroke if excessive blood pressure changes in the morning and during daytime are prevented, whereas controlling nocturnal hypertension may be beneficial in a long-term perspective by counteracting atherosclerotic changes. Hopefully, additional evidence on this interesting but still controversial issue may be provided by large clinical outcome trials using ABPM and including a sufficiently large number of individuals.
Until then, and on the background of the available data, a wise approach to protect all hypertensive patients from an enhanced risk of cardiovascular events appears to require a smooth blood pressure reduction by treatment over the entire 24 h period [10,11].
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