Variations in Levels of Blood Pressure: Of Prognostic Value or Not?

Diurnal Rhythm in Blood Pressure 

In healthy individuals, blood pressure dips in the initial hours of sleep and peaks in the early waking hours (morning surge). The difference between the 2 extremes is about 10% to 20%. A number of studies have shown that subjects with a less than 10% decrease in nocturnal blood pressure levels (nondippers) have an enhanced risk of cardiac, cerebral, kidney, and vascular damage.11 Generally, individuals with hypertension or kidney disease or of African American descent show attenuated dipping and are observed to be at high risk. Restoration of a nocturnal dip in blood pressure has been associated with improvement in left ventricular ejection fraction.12 It is speculated that enhanced risk of cardiovascular disease in patients with chronic kidney disease may be mediated in part by abnormal diurnal rhythm.

Daytime Versus Nighttime Mean Blood Pressure Levels 

Epidemiological studies indicate that in the healthy population, daytime blood pressure levels are greater than nighttime levels. A reversal of this pattern with increased nighttime levels has been associated with adverse outcomes, including mortality.13 Interestingly, unlike daytime measurements, nighttime blood pressure levels do not correlate with office readings. Evidence suggests a greater benefit of a decrease in nighttime blood pressure on cardiovascular outcomes.14 Thus, tracking nighttime blood pressure levels in response to antihypertensive agents may be particularly valuable for optimal benefit from therapy.15

In patients with chronic kidney disease, increased nighttime systolic blood pressure has more strongly correlated with proteinuria than corresponding daytime values or office readings.16 However, the direction of causality of this association and potential extension to faster progression to kidney failure remains to be established.

Blood Pressure Variability 

Blood pressure variability is the beat-to-beat alteration in actual blood pressure around the predicted mean level. These continuous fluctuations in blood pressure levels are a result of complex interplay between external environmental stimuli and biological autonomic circulatory regulation. In clinical studies, blood pressure variability is generally measured by using an ambulatory device and calculated by means of the SD of the 24-hour average blood pressure value. These parameters have provided incremental prognostic information over conventional office blood pressure measurements.17

Individuals with hypertension compared with those without hypertension have enhanced variability during both daytime and nighttime. It is speculated that wide swings in blood pressure have a mechanical impact on the vasculature. Evidence of the prognostic significance of blood pressure variability is accumulating, and results have been conflicting. Most studies have shown that 24-hour variability in systolic blood pressure is associated with cardiovascular complications in patients with treated hypertension, after accounting for risk attributable to increased levels of blood pressure. Excessive variability in daytime or awake systolic blood pressure has correlated with arthrosclerosis and end-organ damage (carotid intima-media thickness and left ventricular hypertrophy) in individuals in the general population and those with treated and untreated hypertension.17, 18 In the latter, this association was incremental to that caused by mean systolic blood pressure. However, similar relationships were not observed with nighttime variability, which probably reflects the concomitant beneficial impact of nocturnal dipping of blood pressure levels on cardiovascular outcomes. Consistent with this notion, revised computation of 24-hour variability after excluding a nocturnal decrease in blood pressure has been recommended by some.19 At the same time, a number of studies, primarily of patients with treated hypertension, have failed to show a relationship between blood pressure variability and increased left ventricular mass.20 It is possible that treatment with antihypertensive agents may have attenuated this risk, or there is no such association. This needs to be studied formally. Moreover, the reported associations are based on cross-sectional studies; therefore, causal relationships cannot be established.

Dialysis Patients and Variations in Blood Pressure Levels 

There has been considerable inconsistency in methods used to study variations in blood pressure, including blood pressure variability in patients on dialysis therapy.21 Some have used ambulatory devices assessing a large number of values obtained every 15 to 30 minutes, whereas others have relied on single measurements obtained on predialysis days (generally thrice weekly) over months to years. The metrics used for defining blood pressure variability have also varied. Overall, these studies suggest that most patients on dialysis therapy are nondippers and are subject to marked blood pressure swings. Both increased interdialytic fluid gain and insufficient amount of dialysis enhance these fluctuations.22 Additional factors affecting variations in blood pressure in these patients are seasonal changes and arterial stiffness, which are captured better in long-term (weeks to months) studies.23 The blunted decrease in nocturnal blood pressure in patients on dialysis therapy has been independently associated with increased left ventricular mass even after adjustment for mean blood pressure.24 Evidence also suggests that long-term blood pressure variability measured by means of either coefficient of variation or difference between maximum and minimum levels of predialysis systolic blood pressure are associated with mortality.25

The findings of Brunelli et al4 are based on a large retrospective observational study of 6,961 incident hemodialysis patients. Predialysis blood pressure readings from days 91 to 180 were used. Raw blood pressure levels were transformed into various metrics. The average residual was computed as the difference between the observed and predicted blood pressure, with the latter based on a linear mixed-effects regression model of observed blood pressure over time. The model accounted for initial systolic blood pressure for the cohort, mean blood pressure slope for the cohort, and terms to account for differences between an individual's initial blood pressure and slope. The intercept represented initial blood pressure for each participant. The metric of residual to intercept ratio was used to account for greater fluctuations with higher mean blood pressure. Both systolic and diastolic blood pressure variability were associated with all-cause mortality during the subsequent 6 months of follow-up. Other expressions for variability, including coefficient of variation, did not have a stronger relationship. In addition, a U-shaped association was also observed between mean blood pressure and mortality.2 Unfortunately, information for interdialytic weight gain and adherence to antihypertensive medications was not obtained. It therefore is not possible to determine whether these modifiable behaviors contributed to the observed relationship of blood pressure variability with mortality. The reproducibility of blood pressure measurements and mathematical constructs of the models also need validation. Moreover, because 24-hour measurements of blood pressure were not obtained, comparative predictability with the office-based parameter of variability could not be assessed. Nevertheless, the advantage offered by ease of measurement in the routine dialysis setting is not trivial.

If the findings of Brunelli et al4 are confirmed in other well-designed prospective studies, the robust association between long-term blood pressure variability based on office measurement of predialytic reading with mortality may be of high practical prognostic significance. Finally, as with all prognostic factors, randomized trials will be necessary to determine whether blood pressure variability based on predialysis readings is a therapeutic target.