The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial.

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union's Horizon 2020 programme. Trial registration: NCT03082014.

White matter damage due to pulsatile versus steady blood pressure differs by vascular territory: A cross-sectional analysis of the UK Biobank cohort study.

Small vessel disease is associated with age, mean blood pressure (MAP) and blood pressure pulsatility (PP). We used data from the UK Biobank cohort study to determine the relative importance of MAP versus PP driving white matter injury within individual white matter tracts, particularly in the anterior and posterior vascular territory. The associations between blood pressure and diffusion indices in 27 major tracts were analysed using unadjusted and fully-adjusted general linear models and mixed-effect linear models. Blood pressure and neuroimaging data were available for 37,041 participants (mean age 64+/-7.5 years, 53% female). In unadjusted analyses, MAP and PP were similarly associated with diffusion indices in the anterior circulation. In the posterior circulation, the associations were weaker, particularly for MAP. In fully-adjusted analyses, MAP remained associated with all diffusion indices in the anterior circulation, independently of age. In the posterior circulation, the effect of MAP became protective. PP remained associated with greater mean diffusivity and extracellular free water diffusion in the anterior circulation and all diffusion indices in the posterior circulation. There was a significant interaction between PP and age. This implies discordant mechanisms for chronic white matter injury in different brain regions and potentially in the associated stroke risks.

Age and sex distribution of beat-to-beat blood pressure variability after transient ischemic attack and minor stroke: A population-based study.

BACKGROUND: Beat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear. AIMS: To determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke. METHODS: In consecutive patients within six weeks of transient ischemic stroke or non-disabling stroke (Oxford Vascular Study), non-invasive blood pressure was measured beat-to-beat over five minutes (Finometer). The age-sex distribution of blood pressure variability (residual coefficient of variation) was determined for systolic blood pressure and diastolic blood pressure. The risk of top-decile blood pressure variability was estimated (logistic regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 908 of 1013 patients, excluding 54 in atrial fibrillation and 51 with low quality recordings, residual coefficient of variation was positively skewed with a median systolic residual coefficient of variation of 4.2% (IQR 3.2-5.5) and diastolic residual coefficient of variation of 3.9% (3.0-5.5), with 90th centile thresholds of 7.2 and 7.3%. Median systolic residual coefficient of variation was higher in patients under 50 years (4.5 and 3.0-5.3) compared to 60-70 years (4.1 and 3.2-5.2), but rose to 4.5% (3.5-6.9) above 80 years, with an increasingly positive skew. The proportion of patients with markedly elevated blood pressure variability in the top-decile increased significantly per decade (OR 1.72, p < 0.001), after adjustment for sex and risk factors. CONCLUSIONS: Median beat-to-beat blood pressure variability fell in midlife, reflecting loss of physiological, organized blood pressure variability. However, rates of markedly elevated blood pressure variability significantly increased with greater age, suggesting that blood pressure variability may be particularly important in older patients.

Physiological determinants of residual cerebral arterial pulsatility on best medical treatment after TIA or minor stroke.

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4-6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling's pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.