title: Novel Interventions to Improve Cerebral and Peripheral Vascular Function
Creators: name: Maxwell, J
Publisher: name: Liverpool John Moores University
Year: 2021

description: Cardiovascular diseases (CVD) are major causes of morbidity and mortality worldwide. Complications associated with CVD encompass the entire vascular system, including blood vessels that supply brain. Impairments to cerebral blood flow (CBF) and cerebrovascular function result in increased risk of cognitive impairment, vascular dementia and stroke. Identifying interventions that can attenuate the age-related decline in CBF and enhance cerebrovascular function are essential, especially in individuals at high risk of CVD. Remote ischaemic preconditioning (rIPC), which involves cyclical periods of ischaemia-reperfusion applied noninvasively to a limb, has been shown to improve measures of peripheral vascular function and cardiovascular endpoints when applied acutely (one episode) or repeatedly (e.g. daily, 3 times per week). There is also emerging evidence that repeated rIPC elicits beneficial effects within the cerebral circulation in stroke patients. However, the mechanisms of how rIPC can improve cerebrovascular function are unknown. The overreaching aim of this thesis was to investigate whether acute and repeated rIPC could enhance cerebral and peripheral vascular function in cohorts with increased risk of CVD. In a crossover study design, Study 1 aimed to assess the impact of a single acute bout of rIPC on cerebrovascular function. Eleven young healthy (28±4 years) and nine individuals at risk of CVD (53±7 years) underwent assessment of cerebrovascular function. Using Transcranial Doppler (TCD), markers of cerebrovascular function were assessed following either bilateral arm rIPC or sham condition. There was no change in middle cerebral artery velocity (MCAv) or blood pressure (BP) during rIPC. Application of rIPC did not alter cerebrovascular reactivity (CVR) compared to sham (0.002 MCACVC/mmHg, 95%CI= -0.001, 0.005, P=0.24), nor did it affect any parameter of dynamic cerebral autoregulation (dCA) (0.028 normalised gain%/mmHg-1, 95%CI= -0.080, 0.137, P=0.59). This study suggested that an acute bout of rIPC does not influence cerebrovascular function in healthy young individuals and older subjects with increased risk for CVD. In a randomised control-pilot design, Study 2 aimed to obtain estimates for the change in peripheral conduit and cerebrovascular function following a 7-day rIPC intervention. Twenty-one type 2 diabetes mellitus (T2DM) patients performed either 7-day daily rIPC or control (no rIPC). Peripheral conduit artery function was assessed using flow mediated dilation (FMD) before and after an endothelial ischemia-reperfusion (IR) injury. Cerebrovascular function was assessed using TCD to examine dCA (0.10Hz squat stand manoeuvres). All measurements were performed at three time points; pre, immediately post intervention, and 8 days post intervention. Using pre-intervention data as a covariate, the change from pre-post in FMD was 1.3% (95%CI= 0.69, 3.80; P=0.09) and 0.23 %/mmHg-1 (95%CI -0.12, 0.59; P=0.18) in dCA normalised gain with rIPC versus control. The directional changes outline FMD can be enhanced by daily rIPC in patients with T2DM, whilst cerebrovascular function is unaltered. In Study 3, in a randomised design, nineteen participants at risk of CVD were allocated into either 8 weeks of aerobic exercise training and rIPC (rIPC + Ex) or 8 weeks of rIPC only performed 3 times per week. Assessment of cerebrovascular function was performed using TCD and FMD was used to examine peripheral vascular function before and after an IR injury. Measurements were performed before (week 0) and immediately after (week 8) each intervention. Neither intervention changed resting CBFv, dCA (spontaneous or forced BP oscillations) or CVR. FMD increased by 1.6% (95% CI= 0.4, 2.8) in the rIPC + Ex intervention and by 0.3% (95% CI= -1.1, 1.5) in the rIPC only intervention, whilst no statistical difference was found between interventions (P=0.65). Data from this study suggests that combining exercise with rIPC does not result in greater changes in cerebral or peripheral vascular function. In Study 4, dCA and baroreflex sensitivity (BRS) data collected during 0.10Hz squat stands manoeuvres was obtained from 206 individuals and analysed using transfer function analysis. Cross-sectional associations between ages were examined using linear regression adjusting for sex. Multivariable linear regression was used to adjust for sex, health status and VO2max. Age, sex, CVD risk and VO2max do not impact on dCA parameters normalised gain, phase or coherence (P&gt;0.05). dCA (absolute) gain reduced with age when adjusting for sex, and CVD risk. The data from this study suggest that dCA parameters, when adjusted for BP, does not decline with age in either sex. Collectively, the data contained within this thesis suggests rIPC interventions appear to be effective in improving peripheral endothelial function, but have little effect on cerebrovascular function. Additionally dCA, a frequently measured marker of cerebrovascular function seems to be unaffected by aging, CVD risk factors or cardio-respiratory fitness.