The concept that blood pressure variability measurements add information about stroke risk has been available since at least the early 1990s based on observations by the Swedish Trial in Old Patients (STOP) investigators that blood pressure lowering therapy decreased stroke risk more than expected compared to mean blood pressure lowering alone [29]. Interest in the topic was substantially rekindled and studied by Rothwell and colleagues in a series of publications in 2010 [30–33]. The Rothwell and colleagues’ studies and review may be summarized as follows: (1) visit-to-visit SBP variability, beyond mean blood pressure, independently predicts stroke; (2) independent of mean SBP, calcium-channel blockers and diuretics, drugs that reduce visit-to-visit blood pressure variability provide the best stroke prevention, whereas non-selective beta blockers are least effective; and (3) visit-to-visit blood pressure variability accounts for the difference in treatment effect for stroke prevention in select clinical trials [29].

Therefore, in relation to stroke prevention , Rothwell and colleagues make a substantial argument that drugs that reduce blood pressure variability may be more beneficial than those that do not [30–33]. Instability or variation of blood pressure is not well-tolerated by the brain [34]. Consequences oflong-term blood pressure variability may include brain atrophy, subcortical ischemic lesions, and cognitive impairment. Rothwell and colleagues replicated key prior findings in an observational study of home blood pressure monitoring, which showed that after transient ischemic attack or minor stroke, calcium channel blockers and diuretics decreased blood pressure variability and maximum home SBP [35]. The results were largely driven by improvement of morning blood pressure readings. Limitations of the Rothwell and colleagues conclusions are discussed elsewhere by Carlberg and Lindholm [29].

Table 10.3 summarizes additional select studies relating to blood pressure variability and non-ABPM measures [36–42].

Interest in circadian patterns of blood pressure variation has led to the study of daytime and night time variations in blood pressure. For example, at most individuals experience a dip in blood pressure by about 10–20 % which may be followed by a morning surge of blood pressure between the hours of 6 AM and 12 noon [43]. The morning surge has been associated with an increased risk of cardiovascular events such as stroke. A number of factors may contribute to the morning surge of blood pressure and include sympathetic nervous system and renin–angiotensin system activity, increases in platelet aggregation, plasminogen activator inhibition, mechanical flow abnormalities, ubiquitin–proteasome system, oxidative stress, plasma cortisol, older age, African-American race/ethnicity, and other factors [43]. In addition, external stimuli may underlie blood pressure surges. Previously, we reported cold weather-induced brain hemorrhage and hypothesized that a sudden surge in blood pressure induced by extreme cold weather could trigger intraparenchymal brain hemorrhage [44].

In relation to blood pressure regulation, it has been observed that night time may be a high risk period for ischemic brain injury , but an opportunity for interventional blood pressure management [45]. Night time is a period when normal blood pressure dipping, non-dipping, or extreme (exaggerated) blood pressure dipping may occur. Non-dipping and extreme dipping of blood pressure have been linked to ischemic brain injury. It has been shown, for example, that the frequency of white matter lesions on MRI head study may be more common in persons who have elevated nocturnal blood pressure on ABPM [46]. By targeting the underlying mechanism (e.g., sympathetic nervous system, renin–angiotensin system) with properly timed (evening) and appropriate type of antihypertensive, one may be able to avert such brain injury [47, 48].

When considering nighttime blood pressure, one must take into account sleep disturbances such as sleep-disordered breathing . For example, in one study short sleep duration was associated with incident stroke in hypertensive persons with silent cerebral infarcts [49]. Treatment of an emerging risk for stroke obstructive sleep apnea (OSA), with continuous positive airway pressure (CPAP) , may lead to better blood pressure control, especially when there is resistant hypertension [50].

One should keep in mind that certain groups of patients may be at a higher risk of blood pressure variability. Long-term blood pressure variability may be exaggerated in Blacks, diabetics, and those with cardiovascular disease [51].

A number of ABPM studies that relate specifically to stroke or stroke surrogate markers will now be discussed. Substantial interest in blood pressure and stroke in Asia has led to a number of ABPM studies originating from these regions. Kario and colleagues have been leaders in the field. We now review key select studies or reviews on ABPM and stroke from this investigative group who studied elderly Japanese persons with hypertension, some of whom were enrolled in the Jichi Medical School ABPM Study.

Key findings from the Kario and colleagues’ studies of ABPM are summarized [52–61]: (1) Japanese patients with hypertension who are extreme dippers at nighttime may be at higher risk of silent cerebral infarcts and clinical strokes during sleep due to either hypotension during night time hours or an exaggerated morning blood pressure surge, whereas reverse dipping may heighten risk of intracranial hemorrhage ; (2) among hypertensive patients, hyperinsulinemia is associated with lacunar-type silent cerebral infarcts in the subcortical white matter, and hemostatic abnormalities are associated with multiple silent cerebral infarcts, especially those observed in the basal ganglia; (3) a higher morning blood pressure surge is associated with stroke risk independent of ambulatory and nocturnal falls in blood pressure, and the morning surge of blood pressure is associated with alpha-adrenergic activity and advanced silent hypertensive brain disease ; (4) sleep pulse pressure and awake mean blood pressure are predictors of stroke after adjusting for stroke events; (5) hypertension in the morning is the strongest predictor of future stroke events; (6) in the International Collaborative Study of Prognostic Utility of ABPM, the amount of blood pressure dipping was a significant inverse predictor of stroke but not of cardiac events; (7) high-sensitivity C-reactive protein is associated with clinical stroke in addition to silent cerebral infarcts in elderly persons with hypertension; (8) the degree of morning blood pressure surge is associated with an increase of morning platelet aggregation activity; and (9) After adjustment for 24-h SBP, prothrombin fragments 1 + 2 are positively associated with white matter hyperintensities.

We now review findings from additional ABPM studies of stroke. Nakamura, Oita, and Yamaguchi utilized a portable blood pressure monitor in 81 patients with chronic ischemic cerebrovascular disease and classified the subjects into two groups according to levels of diurnal and nocturnal blood pressure [62]. The main finding was that nocturnal blood pressure dipping in patients treated with blood pressure lowering medication might accelerate the risk of ischemic brain disease. Tomii and colleagues analyzed 24-h ABPM in 104 acute ischemic stroke patients on the second and eighth hospital days to assess global outcome according to the modified Rankin Scale score at 3 months [63]. Overall, mean values of systolic and diastolic blood pressure , pulse pressure, and heart rate based on the first ABPM determination and heart rate based on the second ABPM determination were inversely associated with functional independence and mean values of systolic and diastolic blood pressure on the first determination of ABPM and mean heart rate on the second ABPM determination were positively associated with poor global outcome.

In a case–control study, Zhang and colleagues enrolled 76 patients with transient ischemic attack or minor stroke and 82 controls from a normal population to determine whether circadian blood pressure differed when using 24-h ABPM and short-term measurement of heart rate variability [64]. As might be expected, a history of hypertension was more common among cases than controls (72.4 % vs. 48.8 %); however, circadian blood pressure patterns and heart rate variability were similarly distributed among patients and controls. Thus, the main findings of no differences between cases and controls for circadian blood pressure patterns were contrary to other studies of acute or subacute stroke patients .

Klarenbeek and colleagues carried out 24-h ABPM in 122 first-ever lacunar stroke patients to determine possible associations between ABPM and total burden of cerebral small vessel disease on brain magnetic resonance imaging (MRI) [65]. Markers of cerebral small vessel disease on MRI included asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces. The authors reported that after adjustment for age and sex, higher 24-h systolic and diastolic ABPM measures at night or daytime were significantly associated with an increasing burden of cerebral small vessel disease.

Finally, based on 24-h ABPM results, Aznaouridis and colleagues explored the predictive value of an Ambulatory Systolic-Diastolic Pressure Regression Index (ASDPRI) from meta-analyses of seven longitudinal studies [66]. The predictive value of the ASDPRI was determined for future outcome events including cardiovascular ones, stroke, and all-cause mortality. An increase of 1 standard deviation of the ASDPRI was associated with an adjusted increase of risk of total cardiovascular events and stroke by 15 % and 30 %, respectively. Furthermore, the ASDPRI was a better predictor of stroke than total cardiovascular events, and furthermore, it predicted stroke better in non-hypertensives than hypertensives.

Table 10.4 summarizes key findings from additional select studies on stroke and ABPM [67–73].

There is a growing literature in relation to cognition, white matter lesions and other subcortical small vessel cerebrovascular disease, and ABPM, which is beyond the scope of this chapter. For further information on this topic, the reader is referred to several authoritative references [74, 75].

In the 2014 AHA/ASA guidance statement on primary stroke prevention, the following pertinent acknowledgements about blood pressure are discussed: (1) intra-individual variability of blood pressure may confer risk of stroke beyond mean blood pressure determination alone; (2) calcium channel blockers may be beneficial to reduce blood pressure variability, but such is not observed with beta blockers; and (3) measurement of nocturnal blood pressure (e.g., reverse or extreme dipping) and the ratio of nighttime to daytime blood pressure may provide useful information beyond mean 24-h blood pressure determination [28]. Furthermore, additional study is called for about possible stroke risk reduction by reduction of intra-individual blood pressure variability and nocturnal blood pressure [28].

Table 10.5 lists key 2014 AHA/ASA guideline recommendations for management of blood pressure to prevent a first stroke [28].