Why does blood pressure (BP) rise and fall in the Rothwell blood pressure variability study of older adults with a history of stroke or transient ischemic attack?

Blood Pressure Variability in the Rothwell Studies: Mechanisms of Rise and Fall

Primary Mechanisms Driving BP Fluctuations

Blood pressure rises and falls in the Rothwell studies primarily due to individual pharmacokinetic and pharmacodynamic properties of antihypertensive medications, combined with underlying arterial stiffness, autonomic dysfunction, and BP reactivity to stressors. 1, 2

The visit-to-visit BP variability that Rothwell identified—measured as changes in office BP between visits spaced 3 months apart—operates through fundamentally different mechanisms than short-term (beat-to-beat or 24-hour) BP fluctuations. 1

Physiological Correlates of BP Variability

Arterial Aging and Stiffness

• Aortic stiffness (measured by carotid-femoral pulse wave velocity) is strongly associated with both beat-to-beat and day-to-day BP variability (odds ratio per SD = 1.84 for beat-to-beat and 1.31 for home monitoring, both p<0.04). 2
• Aortic pulsatility shows even stronger associations with BP variability (OR 1.98 for beat-to-beat and 1.61 for home monitoring, both p<0.0001). 2
• These vessel wall characteristics drive the magnitude of BP fluctuations, particularly in elderly patients with prior stroke or TIA. 2

Autonomic Function

• Heart rate variability (coefficient of variation of normal-to-normal R-R intervals) correlates with both beat-to-beat and day-to-day systolic BP variability (OR 1.34 and 1.35 respectively, both p=0.03). 2
• Autonomic dysfunction contributes to impaired BP buffering capacity, allowing greater fluctuations in response to physiological stressors. 1, 2

BP Reactivity

• Response to mental arithmetic (a measure of BP reactivity to stress) is associated with increased beat-to-beat variability (OR 1.64, p<0.0001) and home BP monitoring variability (OR 1.41, p=0.025). 2
• This reactivity reflects the individual's tendency for exaggerated BP responses to daily stressors and activities. 2

Orthostatic Changes

• Orthostatic BP changes are uniquely associated with day-to-day home BP variability (OR 0.62, p=0.002) but not with beat-to-beat or ambulatory variability. 2
• This suggests that postural BP regulation contributes specifically to longer-term BP fluctuations. 2

Medication-Related Mechanisms

Drug Class Effects on Variability

• Beta-blockers and diuretics increase visit-to-visit BP variability most and reduce stroke risk least, despite comparable effects on mean BP. 1
• Calcium channel blockers increase variability least and reduce stroke risk most. 1
• ACE inhibitors and ARBs occupy intermediate positions for both variability and stroke protection. 1

Pharmacokinetic Factors

• Individual differences in drug absorption, metabolism, and elimination create fluctuating drug levels between doses and visits. 1
• Medication adherence patterns (missed doses, inconsistent timing) amplify visit-to-visit variability. 1
• The duration of drug action relative to dosing intervals determines how much BP "rebounds" between doses. 1

Clinical Significance in Stroke/TIA Populations

Prognostic Impact

• Visit-to-visit systolic BP variability (measured as standard deviation) is a strong independent predictor of subsequent stroke in TIA patients (top-decile hazard ratio: 6.22,95% CI 4.16-9.29, p<0.0001 over seven visits). 3
• Maximum systolic BP reached during follow-up is an even stronger predictor (top-decile HR: 15.01,95% CI 6.56-34.38, p<0.0001), independent of mean BP. 3
• The predictive power increases with more precise measurement—HR rises from 6.22 over seven visits to 12.08 over ten visits. 3

Age-Related Considerations

• BP variability measures are most predictive in younger patients and at lower (<median) values of mean systolic BP. 3
• Approximately three-fourths of individuals aged 70 years and older have hypertension, making variability management particularly relevant. 4
• After age 60, isolated systolic hypertension becomes predominant, with continued SBP rise while DBP gradually decreases. 5

Distinction from Short-Term Variability

Ambulatory BP Monitoring Variability

• Within-day variability on 24-hour ambulatory BP monitoring shows weak associations with the same physiological measures that strongly predict visit-to-visit variability. 2
• Only BP reactivity to mental arithmetic correlates with awake ambulatory variability (OR 1.40, p=0.01). 2
• Ambulatory variability is a weaker predictor of stroke and coronary events compared to visit-to-visit variability. 3

Time-Dependent Changes

• In elderly primary care patients, rate of BP change over time (not variability per se) shows a U-shaped relationship with mortality risk. 6
• Participants with little or no change in BP have the lowest mortality risk. 6
• When change over time is separated from visit-to-visit variability, variability alone is not an independent predictor of mortality. 6

Common Pitfalls to Avoid

• Ignoring medication selection: Choosing beta-blockers or diuretics as first-line agents in stroke/TIA patients may inadvertently increase BP variability and stroke risk despite adequate mean BP control. 1
• Focusing only on mean BP: Maximum BP reached and visit-to-visit variability provide independent prognostic information beyond mean BP levels. 3
• Insufficient measurement precision: Fewer BP measurements reduce the ability to detect clinically significant variability—at least 7-10 visits are needed for reliable assessment. 3
• Confusing variability types: Short-term (24-hour) variability and long-term (visit-to-visit) variability have different mechanisms and different prognostic implications. 1, 2

Therapeutic Implications

Medication Selection for Stroke/TIA Patients

• Calcium channel blockers should be strongly considered as they provide the most stable BP control over time in elderly patients with prior stroke/TIA. 1
• For patients with history of stroke or TIA, treating to SBP 130-140 mmHg reduces stroke recurrence (RR 0.76,95% CI 0.66-0.92) but not cardiac events or mortality. 7
• Current guidelines recommend BP target <130/80 mmHg for secondary stroke prevention. 8

Monitoring Strategy

• Measure BP at multiple consecutive visits (ideally 7-10) to adequately assess variability. 3
• Track both mean BP and maximum BP reached during follow-up. 3
• Consider home BP monitoring to capture day-to-day variability, which shares physiological mechanisms with visit-to-visit variability. 2