Physiological systemic and cerebrovascular determinants of the risk of stroke, chronic cerebral ischaemia and vascular cognitive impairment

Keywords: Hypertension
Pulsatility
Stroke
Physiology

Stroke and dementia are the commonest cause of neurological disability in the UK, but despite optimal secondary prevention there remains a >10% risk of recurrent, major cardiovascular events over 5 years. Furthermore, chronic damage to the small vessels in the brain, ‘Small Vessel Disease,’ is associated with up to 30% of strokes and 40% of dementia, yet the underlying mechanisms are unclear and there is no specific proven treatment.
Our previous work demonstrated that haemodynamic indices beyond mean blood pressure are associated with an increased risk of either stroke, small vessel disease and dementia, including blood pressure variability, arterial stiffness and cerebral arterial pulsatility. These indices are all associated with age and a history of hypertension, and represent intermediate cardiovascular phenotypes of vascular aging. However, their distribution in populations at risk, associated risk factors and relationship to cardiovascular events and small vessel disease remains poorly defined.
Within the OXVASC population-based cohort of all patients with cardiovascular events in a population of >92,000 in Oxfordshire, we have carried out physiological tests in consecutive, consenting patients presenting to the TIA and minor stroke clinic at the 1 month follow-up visit, since September 2010. This cohort undergo detailed clinical review and face-to-face follow-up to 10 years, and undergo measurement of arterial stiffness and aortic pressure by applanation tonometry (Sphygmocor), continuous non-invasive beat-to-beat blood pressure (Finometer) and cardiac monitoring for 5-10 minutes and transcranial ultrasound for assessment of cerebral blood flow velocity and cerebral arterial pulsatility (DWL DopplerBox).
In this population, I demonstrated that beat-to-beat blood pressure variability (BPV) is normally distributed at younger ages, but becomes progressively more positively skewed in older men and women, with an initial fall from younger patients to over 50, before a marked average rise, implying a transition from ‘healthy’ endogenous forms of increase BP variability in young patients to unhealthy, excessive BPV. Beat-to-beat BPV is particularly associated with increased arterial stiffness, a marker of vascular aging, but also shows a complex relationship with increase body mass index, which is linearly associated in men but increased both in underweight and overweight women. Beat-to-beat BP variability also progressed significantly over the age of 55 in 179 patients over five years. Finally it was associated with an increased risk of recurrent vascular events, independent of age and other risk factors.
In the second half of the thesis, I assessed the effect of arterial stiffness and its interaction with pulsatility of blood flow to the brain. In the UK Biobank study (chapter 7), increased arterial stiffness resulted in an earlier transition from mid-life hypertensive phenotypes with high diastolic and systolic blood pressures to a falling diastolic BP and a linearly rising systolic blood pressure (SBP) with age, at about age 55.
In OXVASC, aortic stiffness, aortic pulsatility and cerebral pulsatility increased with age, with a particularly strong association between aortic and cerebral pulsatility, partially mediated by aortic stiffness (chapter 8). All three progressed at older ages despite treatment, predominantly after 55 years for cerebral pulsatility (chapter 9).
Finally, cerebral arterial pulsatility was associated with cerebral small vessel disease and predicted the risk of recurrent cardiovascular events more strongly than other physiological indices, and independent of age and cardiovascular risk factors, although this relationship was not mediated by small vessel disease.
Overall, arterial stiffness, beat-to-beat BP variability and cerebral arterial pulsatility were all associated with vascular aging and a history of hypertension, they progressed after the age of 55 and were predictive of the risk of recurrent stroke. These reflect vascular aging and are key potential targets that may mediate the persistent cardiovascular risk in the elderly, despite optimal medical management.