Safety and feasibility of transcutaneous vagus nerve stimulation in mild cognitive impairment: VINCI-AD study protocol.

BACKGROUND: Over 55 million adults are living with dementia globally, which is projected to reach 157 million by 2050. Mild cognitive impairment (MCI), a syndrome of memory impairment with intact activities of daily living, may precede dementia by several years. Around 5-15% of individuals with MCI convert to dementia annually. Novel treatments which delay progression of MCI to dementia are urgently needed. Transcutaneous vagal nerve stimulation (tVNS) is a non-invasive neuromodulation technique that targets the vagus nerve. Importantly, tVNS has been shown to improve cognition in healthy volunteers, but has not been extensively examined as a potential therapeutic approach in MCI. VINCI-AD will examine the safety and feasibility of tVNS in older adults with MCI. DESIGN: VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 participants with amnestic MCI. All participants will attend for three consecutive study visits during which they will be randomised to receive no stimulation (baseline), active tVNS stimulation (stimulation at cymba conchae of left ear) or sham tVNS stimulation (at earlobe). Safety will be primarily assessed by ascertainment of adverse events. Further safety assessment will examine the impact of acute tVNS on subjective (orthostatic symptoms), peripheral (finometry-based blood pressure) and central (assessed via Near Infrared Spectroscopy [NIRS]) haemodynamic responses to active stand. Feasibility will be determined using a custom-designed occupational assessment of device usability. Exploratory secondary analysis in VINCI-AD will examine the potential impact of acute tVNS on associative memory, spatial memory and inhibitory control to inform sample size estimates for future trials of tVNS in older adults with MCI. DISCUSSION: VINCI-AD will report on the safety (adverse events/haemodynamic responses to active stand) and feasibility of tVNS as a potential therapeutic option in MCI. Detailed reporting of study eligibility and completion rates will be reported. Exploratory analysis will examine the potential cognitive benefits of acute tVNS on cognitive function in MCI to report potential effect sizes that may inform future clinical trials in this cohort. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT05514756 . Trial Registration Number NCT05514756 (24th August 2022 for this protocol, version 1.0.).

Asymptomatic orthostatic hypotension and risk of falls in community-dwelling older people.

INTRODUCTION: Many older people with orthostatic hypotension (OH) may not report typical symptoms of dizziness, light-headedness or unsteadiness. However, the relationships between OH and falls in the absence of typical symptoms are not yet established. METHODS: Continuous orthostatic blood pressure (BP) was measured during active stand using a Finometer at Wave 1 of The Irish Longitudinal Study on Ageing in participants aged ≥ 70 years.OH, with and without dizziness, was defined as a sustained drop in systolic BP ≥ 20 and/or diastolic BP ≥ 10 mm Hg at 30, 60 and 90 seconds post-standing.The association between symptoms of dizziness and orthostatic BP was assessed with multi-level mixed-effects linear regression; logistic regression models assessed the longitudinal relationship between OH and falls at 6-year follow-up (Waves 2-5). RESULTS: Almost 11% (n = 934, mean age 75 years, 51% female) had OH, two-thirds of whom were asymptomatic.Dizziness was not associated with systolic BP drop at 30 (ß = 1.54 (-1.27, 4.36); p = 0.256), 60 (ß = 2.64 (-0.19, 5.47); p = 0.476) or 90 seconds (ß = 2.02 (-0.91, 4.95); p = 0.176) after standing in adjusted models.Asymptomatic OH was independently associated with unexplained falls (odds ratio 2.01 [1.11, 3.65]; p = 0.022) but not explained falls (OR 0.93 [0.53, 1.62]; p = 0.797) during follow-up. CONCLUSIONS: Two-thirds of older people with OH did not report typical symptoms of light-headedness. Dizziness or unsteadiness after standing did not correlate with the degree of orthostatic BP drop or recovery. Participants with asymptomatic OH had a significantly higher risk of unexplained falls during follow-up, and this has important clinical implications for the assessment of older people with falls.

Design and Haemodynamic Analysis of a Novel Anchoring System for Central Venous Pressure Measurement.

BACKGROUND/OBJECTIVE: In recent years, treatment of heart failure patients has proved to benefit from implantation of pressure sensors in the pulmonary artery (PA). While longitudinal measurement of PA pressure profoundly improves a clinician's ability to manage HF, the full potential of central venous pressure as a clinical tool has yet to be unlocked. Central venous pressure serves as a surrogate for the right atrial pressure, and thus could potentially predict a wider range of heart failure conditions. However, it is unclear if current sensor anchoring methods, designed for the PA, are suitable to hold pressure sensors safely in the inferior vena cava. The purpose of this study was to design an anchoring system for accurate apposition in inferior vena cava and evaluate whether it is a potential site for central venous pressure measurement. MATERIALS AND METHODS: A location inferior to the renal veins was selected as an optimal site based on a CT scan analysis. Three anchor designs, a 10-strut anchor, and 5-struts with and without loops, were tested on a custom-made silicone bench model of Vena Cava targeting the infra-renal vena cava. The model was connected to a pulsatile pump system and a heated water bath that constituted an in-vitro simulation unit. Delivery of the inferior vena cava implant was accomplished using a preloaded introducer and a dilator as a push rod to deploy the device at the target area. The anchors were subjected to manual compression tests to evaluate their stability against dislodgement. Computational Fluid Dynamics (CFD) analysis was completed to characterize blood flow in the anchor's environment using pressure-based transient solver. Any potential recirculation zones or disturbances in the blood flow caused by the struts were identified. RESULTS: We demonstrated successful anchorage and deployment of the 10-strut anchor in the Vena Cava bench model. The 10-strut anchor remained stable during several compression attempts as compared with the other two 5-strut anchor designs. The 10-strut design provided the maximum number of contact points with the vessel in a circular layout and was less susceptible to movement or dislodgement during compression tests. Furthermore, the CFD simulation provided haemodynamic analysis of the optimum 10-strut anchor design. CONCLUSIONS: This study successfully demonstrated the design and deployment of an inferior vena cava anchoring system in a bench test model. The 10-strut anchor is an optimal design as compared with the two other 5-strut designs; however, substantial in-vivo experiments are required to validate the safety and accuracy of such implants. The CFD simulation enabled better understanding of the haemodynamic parameters and any disturbances in the blood flow due to the presence of the anchor. The ability to place a sensor technology in the vena cava could provide a simple and minimally invasive approach for heart failure patients.

A practical guide to active stand testing and analysis using continuous beat-to-beat non-invasive blood pressure monitoring.

PURPOSE: The average adult stands approximately 50-60 times per day. Cardiovascular responses evoked during the first 3 min of active standing provide a simple means to clinically assess short-term neural and cardiovascular function across the lifespan. Clinically, this response is used to identify the haemodynamic correlates of patient symptoms and attributable causes of (pre-)syncope, and to detect autonomic dysfunction, variants of orthostatic hypotension, postural orthostatic tachycardia syndrome and orthostatic hypertension. METHODS: This paper provides a set of experience/expertise-based recommendations detailing current state-of-the-art measurement and analysis approaches for the active stand test, focusing on beat-to-beat BP technologies. This information is targeted at those interested in performing and interpreting the active stand test to current international standards. RESULTS: This paper presents a practical step-by-step guide on (1) how to perform active stand measurements using beat-to-beat continuous blood pressure measurement technologies, (2) how to conduct an analysis of the active stand response and (3) how to identify the spectrum of abnormal blood pressure and heart rate responses which are of clinical interest. CONCLUSION: Impairments in neurocardiovascular control are an attributable cause of falls and syncope across the lifespan. The simple active stand test provides the clinician with a powerful tool for assessing individuals at risk of such common disorders. However, its simplicity belies the complexity of its interpretation. Care must therefore be taken in administering and interpreting the test in order to maximise its clinical benefit and minimise its misinterpretation.

Quantitative Ultrasound of the Mandible as a Novel Screening Approach for Osteoporosis.

This study used an axial transmission quantitative ultrasound (QUS) device to assess mandibular bone strength. The aim of the study was first to establish the precision and repeatability of the axial transmission QUS measurement for a range of mandibular anatomic sites, and second to investigate the ability of the modality to differentiate between osteoporotic subjects and a control group. Three groups of adult Caucasian women were recruited: (1) healthy premenopausal women (n = 26), (2) healthy postmenopausal women (n = 48), and (3) women with osteoporosis (n = 53). Subjects were excluded from groups 1 and 2 if they had any pre-existing bone conditions. Speed of sound (SOS) measurements were taken from the mandible using an OmniSense multisite QUS device. Group 3 had dual-energy X-ray absorptiometry scans of the lumbar spine and femur. The most suitable site on the mandible was determined by repeat SOS measurements in 10 healthy premenopausal subjects, at 5 different sites. The parasymphysis site had the lowest root mean squared coefficient of variation at 0.74%, and was chosen as the most suitable site for mandibular SOS measurements. Group 1 and group 2 had significantly higher mean SOS measurements than the osteoporotic subjects (group 3), with means of 3683 m/s (210), 3514 m/s (221), and 3312 m/s (264), respectively. A 1-way analysis of variance confirmed a statistically significant difference between mean SOS measurements from the 3 groups (p < 0.0001). Axial transmission QUS of the mandible can differentiate between subjects with osteoporosis and a healthy control group, and shows potential for use as a screening tool for osteoporosis.

The accuracy of anatomical landmarks for locating the carotid sinus.

BACKGROUND: carotid sinus massage (CSM) is a valuable clinical test for carotid sinus syndrome (CSS) and relies on accurately locating the carotid sinus (CS). OBJECTIVE: in this study, we sought to examine the accuracy of using anatomical landmarks for locating the CS. METHODS: consecutive patients (n = 20) were recruited prospectively. Two clinicians, trained in CSM, were asked to locate the CS using anatomical landmarks. A point on the skin overlying the CS was then marked by a vascular technician using ultrasound. Accuracy of techniques was compared using intra-class correlation coefficients and Bland-Altman statistics. RESULTS: anatomical landmarks underestimated the CS location by 1.5 ± 1.3 cm. Error extremes ranged from 4 cm below to 2 cm above CS using anatomical landmarks. A moderate correlation between ultrasound and anatomical landmarks was found, r = 0.371 (P = 0.031). CONCLUSION: this is the first study to characterise the accuracy of standard anatomical landmarks used in CSM. Results suggest that the point of maximal pulsation has the lowest associated error. Future work should examine CSM yield across this and a range of other methodological factors.

Age-related normative changes in phasic orthostatic blood pressure in a large population study: findings from The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: In this report, we provide the first normative reference data and prevalence estimates of impaired orthostatic blood pressure (BP) stabilization, initial orthostatic hypotension, and orthostatic hypotension based on beat-to-beat blood pressure methods in a population-representative sample. METHODS AND RESULTS: Participants were recruited from a nationally representative cohort study (≥50 years). Beat-to-beat systolic BP, diastolic BP, and heart rate records were analyzed among those who underwent an active stand test (n=4475). Normograms were estimated by use of generalized additive models for location, shape, and scale with Box-Cox power exponential distribution. Prevalence estimates of impaired BP stabilization, initial orthostatic hypotension, and orthostatic hypotension are reported. Orthostatic BP responses in adults aged 50 to 59 years stabilized within 30 seconds of standing, with older groups taking 30 seconds or longer. The total prevalence of impaired BP stabilization was 15.6% (95% confidence interval [CI], 14.1%-17.1%), increasing with age to 41.2% (95% CI, 30.0%-52.4%) in people ≥80 years old. Initial orthostatic hypotension occurred in 32.9% (95% CI, 31.2%-34.6%) of the population aged ≥50 years, with no age gradient evident. The prevalence of orthostatic hypotension was 6.9% (95% CI, 5.9%-7.8%) in the total population, increasing to 18.5% (95% CI, 9.0%-28.0%) in those aged ≥80 years old. CONCLUSIONS: Significant age-related differences exist in the time course of postural BP responses, with abnormal responses taking longer than 30 seconds to stabilize. Impaired BP stabilization is more common as we age, affecting more than two-fifths of the population aged ≥80 years, and may play a future role in the management of falls and syncope.

AF is associated with self-reported syncope and falls in a general population cohort.

BACKGROUND: syncope is an important, but underestimated clinical problem in older persons. It is often overlooked in clinical practice or mistaken for falls. Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little evidence exists regarding the association between AF, falls and syncope in the general population. METHODS: cross-sectional analyses within a population sample of people aged 50+, taken from The Irish Longitudinal Study on Ageing. Ten-minute electrocardiogram recordings (n = 4,885) were analysed to detect AF. Syncope (self-reported faints or blackouts) and falls in the past year, co-morbidities, health measures and medications were gathered through computer-aided personal interviews. Multivariable logistic regression was performed to study associations between AF, falls and syncope. RESULTS: mean age was 62 years (range: 50-91), 54% were female. Prevalence of AF was 3%, increasing to 8% in participants aged 75+. Of participants, 5% (n = 223) reported syncope and 20% (n = 972) reported falls. After adjustment for confounders, AF was significantly associated with faints and blackouts (odds ratio (OR) 2.0 [95% confidence interval (CI) 1.0-3.9]). After stratification by age category, we found that this association was strongest and only significant in participants aged 50-64 years (OR 4.4 [1.5-12.6]). Stratified for age group, AF was significantly associated with falls in participants aged 65-74 years (OR 2.0 [1.0-4.1]). CONCLUSIONS: adults aged 50+ with self-reported syncope and adults aged 65-74 years with falls are twice as likely to have AF at physical examination. These associations are independent of stroke, cardiovascular and psychotropic drugs and other confounders. Further longitudinal studies are needed to explore this association and potential causality further.

Higher orthostatic heart rate predicts mortality: The Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Orthostatic hemodynamic signals may predict adverse outcomes in elders. AIMS: To study the association between orthostatic hemodynamics and incident mortality in The Irish Longitudinal Study on Ageing (TILDA). METHODS: Wave 1 subjects underwent an active stand with non-invasive beat-to-beat blood pressure monitoring. We compared wave 1 active stands, dead vs alive in wave 2. RESULTS: Compared to the 4,415 participants who had not died, the 53 who had died had a higher baseline heart rate [HR mean of 69 vs 65 beats per minute (bpm)] and a higher mean orthostatic HR, especially between 30 and 60 s post-stand (mean of 79 vs 73 bpm). After adjusting for age, sex, baseline HR, mini-mental state examination score and cardiovascular comorbidities and medications, the mean HR between 30 and 60 s post-stand independently predicted mortality (baseline HR did not). DISCUSSION: Higher early orthostatic HR may be an independent risk marker. Further validation is required.

The Impact of Type 2 Diabetes on Peripheral and Cerebral Hemodynamic Responses to Active Stand.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is an established risk factor for cognitive impairment, the underlying mechanisms remain poorly explored. One potential mechanism may be through effects of T2DM on cerebral perfusion. The current study hypothesized that T2DM is associated with altered peripheral and central hemodynamic responses to orthostasis, which may in turn be associated with cognitive impairment in T2DM. METHODS: A novel use of function-on-scalar regression, which allows the entire hemodynamic response curve to be modeled, was employed to assess the association between T2DM and hemodynamic responses to orthostasis. Logistic regression was used to assess the relationship between tissue saturation index (TSI), T2DM, and cognitive impairment. All analyses used cross-sectional data from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA). RESULTS: Of 2 984 older adults (aged 64.3 ±â€…8.0; 55% female), 189 (6.3%) had T2DM. T2DM was associated with many features that are indicative of autonomic dysfunction including a blunted peak heart rate and lower diastolic blood pressure. T2DM was associated with reduced TSI and also with greater odds of impaired performance on the Montreal Cognitive Assessment (odds ratio [OR]: 1.62; confidence interval [CI: 1.07, 2.56]; p = .019). Greater TSI was associated with lower odds of impaired performance (OR: 0.90, CI [0.81-0.99]; p = .047). CONCLUSIONS: T2DM was associated with impaired peripheral and cerebral hemodynamic responses to active stand. Both T2DM and reduced cerebral perfusion were associated with impaired cognitive performance. Altered cerebral perfusion may represent an important mechanism linking T2DM and adverse brain health outcomes in older adults.

Cognitive function is associated with impaired heart rate variability in ageing adults: the Irish longitudinal study on ageing wave one results.

OBJECTIVE: To examine the independent association between heart rate variability (HRV) and cognitive performance, in a nationally representative population study of older adults. METHODS: Cross-sectional analysis of wave 1 data from the Irish longitudinal study on ageing (TILDA) was performed. A subset of 4,763 participants who underwent ECG recording during resting and paced breathing periods were used for the analysis. HRV indices were divided into quintiles for comparison of values and cognitive performance was defined using the Montreal cognitive assessment (MOCA) score. Multivariate linear regression was used to model the association between cognition and different quintiles of each HRV index, after adjustment for covariates. RESULTS: The mean age was 61.7 ± 8.3 years and 2,618 (55 %) were female. Lower quintiles of SDNN (P = 0.01-paced), LF (P = 0.001-paced), and LF:HF ratio (P = 0.049-paced) were significantly associated with lower MOCA scores (during both recording periods), independent of confounders. Sub-domains of MOCA responsible for the relationship were predominantly memory recall and language. INTERPRETATION: Reduced HRV is significantly associated with lower cognitive performance at a population level in people aged 50 and older. This further strengthens the relationship between autonomic dysfunction and cognitive disorders.

Insights into the clinical management of the syndrome of supine hypertension--orthostatic hypotension (SH-OH): the Irish Longitudinal Study on Ageing (TILDA).

BACKGROUND: Our previously proposed morphological classification of orthostatic hypotension (MOH) is an approach to the definition of three typical orthostatic hemodynamic patterns using non-invasive beat-to-beat monitoring. In particular, the MOH pattern of large drop/non-recovery (MOH-3) resembles the syndrome of supine hypertension-orthostatic hypotension (SH-OH), which is a treatment challenge for clinicians. The aim of this study was to characterise MOH-3 in the first wave of The Irish Longitudinal Study of Ageing (TILDA), with particular attention to concurrent symptoms of orthostatic intolerance (OI), prescribed medications and association with history of faints and blackouts. METHODS: The study included all TILDA wave 1 participants who had a Finometer® active stand. Automatic data signal checks were carried out to ensure that active stand data were of sufficient quality. Characterisation variables included demographics, cardiovascular and neurological medications (WHO-ATC), and self-reported information on comorbidities and disability. Multivariable statistics consisted of logistic regression models. RESULTS: Of the 4,467 cases, 1,456 (33%) were assigned to MOH-1 (small drop, overshoot), 2,230 (50%) to MOH-2 (medium drop, slower but full recovery), and 781 (18%) to MOH-3 (large drop, non-recovery). In the logistic regression model to predict MOH-3, statistically significant factors included being on antidepressants (OR = 1.99, 95% CI: 1.50 - 2.64, P < 0.001) and beta blockers (OR = 1.60, 95% CI: 1.26 - 2.04, P < 0.001). MOH-3 was an independent predictor of OI after full adjustment (OR = 1.47, 95% CI: 1.25 - 1.73, P < 0.001), together with being on hypnotics or sedatives (OR = 1.83, 95% CI: 1.31 - 2.54, P < 0.001). In addition, OI was an independent predictor of history of falls/blackouts after full adjustment (OR = 1.27, 95% CI: 1.09 - 1.48, P = 0.003). CONCLUSIONS: Antidepressants and beta blockers were independently associated with MOH-3, and should be used judiciously in older patients with SH-OH. Hypnotics and sedatives may add to the OI effect of MOH-3. Several trials have demonstrated the benefits of treating older hypertensive patients with cardiovascular medications that were not associated with adverse outcomes in our study. Therefore, the evidence of benefit does not necessarily have to conflict with the evidence of potential harm.

Cerebral Oxygenation Responses to Standing in Young Patients with Vasovagal Syncope.

Vasovagal syncope (VVS) is common in young adults and is attributed to cerebral hypoperfusion. However, during active stand (AS) testing, only peripheral and not cerebral hemodynamic responses are measured. We sought to determine whether cerebral oxygenation responses to an AS test were altered in young VVS patients when compared to the young healthy controls. A sample of young healthy adults and consecutive VVS patients attending a Falls and Syncope unit was recruited. Continuous beat-to-beat blood pressure (BP), heart rate, near-infrared spectroscopy (NIRS)-derived tissue saturation index (TSI), and changes in concentration of oxygenated/deoxygenated Δ[O2Hb]/Δ[HHb] hemoglobin were measured. BP and NIRS-derived features included nadir, peak, overshoot, trough, recovery rate, normalized recovery rate, and steady-state. Multivariate linear regression was used to adjust for confounders and BP. In total, 13 controls and 27 VVS patients were recruited. While no significant differences were observed in the TSI and Δ[O2Hb], there was a significantly smaller Δ[HHb] peak-to-trough and faster Δ[HHb] recovery rate in VVS patients, independent of BP. A higher BP steady-state was observed in patients but did not remain significant after multiple comparison correction. Young VVS patients demonstrated a similar cerebral circulatory response with signs of altered peripheral circulation with respect to the controls, potentially due to a hyper-reactive autonomic nervous system. This study sets the grounds for future investigations to understand the role of cerebral regulation during standing in VVS.

Increased multimorbidity is associated with impaired cerebral and peripheral hemodynamic stabilization during active standing.

BACKGROUND: Age-related morbidities and frailty are associated with impaired blood pressure (BP) and heart rate (HR) recovery after standing. Here we investigate how multimorbidity affects cerebral and peripheral hemodynamics during standing in a large sample of older patients. METHODS: Patients were recruited from a national Falls and Syncope Unit. They underwent an active stand test (5-10 min lying +3 min standing) with monitoring of continuous BP, HR, total peripheral resistance (TPR), stroke volume (SV), and a near-infrared spectroscopy (NIRS) derived cerebral tissue saturation index (TSI). A multimorbidity count was derived from a 26-item list of conditions. Features derived from the signals included: nadir, overshoot, value at 30 s, steady-state and recovery rate. Robust linear regression was used to assess the association between multimorbidity, TSI and peripheral hemodynamics while correcting for covariates. A p-value <0.05 was considered statistically significant. RESULTS: Multimorbidity was associated with poorer recovery of TSI at 30 s after standing (ß: -0.15, CI:[-0.25-0.06], p = 0.009) independent of all peripheral hemodynamics. Impaired diastolic BP (DBP) recovery at 30s (ß:-1.34, CI:[-2.29-0.40], p = 0.032), DBP steady-state (ß:-1.18, CI:[-2.04-0.32], p = 0.032), TPR overshoot-to-nadir difference (ß:-0.041, CI:[-0.070-0.013], p = 0.045), and SV at 30s (ß:1.30, CI:[0.45 2.15], p = 0.027) were also associated with increasing multimorbidity. After sex stratification, only females demonstrated impaired TSI with multimorbidity at overshoot (ß: -0.19, CI: [-0.32 -0.07], p = 0.009), 30 s (ß: -0.22 [-0.35-0.10], p = 0.005) and steady-state (ß: -0.20, CI:[-0.35-0.04], p = 0.023), independent of peripheral hemodynamics. CONCLUSIONS: Transient cerebral oxygenation and peripheral hemodynamic responses are impaired with multimorbidity (frailty) in older patients, particularly in females. This study demonstrates the feasibility of using NIRS in this clinical context and may inform the development of clinical management strategies targeting both cerebral oxygenation and blood pressure impairments in patients with faints and falls.

"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance.

The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability.

Impaired autonomic function after incomplete revascularisation.

INTRODUCTION: Incomplete cardiac revascularisation (ICR) assessed by residual SYNTAX score (rSs) is associated with increased 5-year mortality. Furthermore, in the general population, our group has demonstrated that impaired autonomic function determined by heart rate recovery time between 10 and 20 s (HRR10-20) following an active stand is associated with increased all-cause mortality. PURPOSE: We hypothesised that ICR would be associated with impaired autonomic function determined by HRR10-20. METHODS: After ethical approval and informed consent, consecutive patients attending cardiac rehabilitation in a tertiary referral centre were enrolled. All patients had percutaneous coronary revascularisation. During an active stand, real-time heart rate, blood pressure and ECG recordings were taken using non-invasive digital photoplethysmography and HRR10-20 determined. Assessment of autonomic function was performed by determining speed of HRR10-20 post-orthostatic challenge.Patients with an rSs >0 were considered incompletely revascularised and those with an rSs of 0 fully revascularised. Demographic data were recorded and statistical analysis performed. RESULTS: Patients (n=53) comprised those with complete revascularisation (CR) (n=37) and ICR (n=16). In the ICR group, mean rSs was 9.4.HRR10-20 was impaired in the ICR group (-3±0.60) compared with the CR cohort (-6.56±0.52) (p<0.0001). Completeness of revascularisation was strongly associated with HRR10-20 (Pearson's correlation coefficient 0.529; p<0.0001). Baseline demographics did not differ significantly. Use of rate-limiting medication was similar between cohorts (beta blockers, calcium channel blockers, ivabradine). CONCLUSIONS: Our data confirm significant correlation between ICR and impaired autonomic function determined by speed of heart rate recovery. Thus, determining autonomic dysfunction post-ICR may identify those at increased mortality risk.

Fatigue following COVID-19 infection is not associated with autonomic dysfunction.

BACKGROUND: The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients. METHODS: We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing's autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results. RESULTS: We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety. CONCLUSIONS: These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.

Systemic and cerebral circulatory adjustment within the first 60 s after active standing: An integrative physiological view.

Transient cardiovascular and cerebrovascular responses within the first minute of active standing provide the means to assess autonomic, cardiovascular and cerebrovascular regulation using a real-world everyday stimulus. Traditionally, these responses have been used to detect autonomic dysfunction, and to identify the hemodynamic correlates of patient symptoms and attributable causes of (pre)syncope and falls. This review addresses the physiology of systemic and cerebrovascular adjustment within the first 60 s after active standing. Mechanical factors induced by standing up cause a temporal mismatch between cardiac output and vascular conductance which leads to an initial blood pressure drops with a nadir around 10 s. The arterial baroreflex counteracts these initial blood pressure drops, but needs 2-3 s to be initiated with a maximal effect occurring at 10 s after standing while, in parallel, cerebral autoregulation buffers these changes within 10 s to maintain adequate cerebral perfusion. Interestingly, both the magnitude of the initial drop and these compensatory mechanisms are thought to be quite well-preserved in healthy aging. It is hoped that the present review serves as a reference for future pathophysiological investigations and epidemiological studies. Further experimental research is needed to unravel the causal mechanisms underlying the emergence of symptoms and relationship with aging and adverse outcomes in variants of orthostatic hypotension.

Mayer wave activity in vasodepressor carotid sinus hypersensitivity.

AIMS: Mayer waves are low frequency blood pressure waves, whose modulation involves central/peripheral baroreflex pathways. Although vasodepressor carotid sinus hypersensitivity (VDCSH) is a common hypotensive disorder in ageing, the mechanism of VDCSH is unknown. We hypothesize that VDCSH is due to impaired baroreflex function and that Mayer wave amplitude and oscillation frequency are therefore altered. METHODS AND RESULTS: Ten minutes ECG and continuous beat-to-beat blood pressure (TNO Finapres(c)) recordings were taken in supine position. Blood pressure variance, spectral power (0.04-0.15 Hz) and centre of frequency was examined across a number of frequency bands. Vasodepressor carotid sinus hypersensitivity was defined as 50 mmHg drop in systolic blood pressure (SBP) during carotid sinus massage. Syncope facility was used in this study. Twelve patients with VDCSH median age 72 range (50-92) were compared with 36 case-controls median age 78 range (48-88). Diastolic blood pressure variability (median SD) was significantly higher in the VDCSH 6.6 (1.9-12.9) mmHg compared with controls 4.0 (1.7-9.5) mmHg; P < 0.05. Mean arterial blood pressure (MAP) variability (median SD) was significantly higher in the VDCSH 6.6 (2.9-10.1) mmHg compared with controls 4.6 (2.5-9.1) mmHg; P < 0.05. Low frequency Mayer wave activity in MAP in VDCSH compared with controls was increased at 0.06 Hz [controls -21.7 mmHg(2)/Hz (IQR: 30.8); VDCSH -31.5 mmHg(2)/Hz (IQR: 72.0) P < 0.05] and at 0.1 Hz [controls -4.9 mmHg(2)/Hz (IQR: 9.4); VDCSH -11.5 mmHg(2)/Hz (IQR: 12.9) P < 0.1]. High frequency blood pressure fluctuations were significantly increased at 0.3 Hz in VDCSH group in SBP [controls -4.1 mmHg(2)/Hz (IQR: 10.4); VDCSH -17.4 mmHg(2)/Hz (IQR: 47.9) P < 0.05] and MAP records [controls -32.5 mmHg(2)/Hz (IQR: 76.9); VDCSH -64.6 mmHg(2)/Hz (IQR: 59.8) P < 0.01]. CONCLUSION: Blood pressure variability in particular activity at Mayer wave frequencies was higher in VDCSH. Future work will investigate this approach as a basis for diagnosis of VDCSH, with implications for syncope and falls management.

Orthostatic Hypotension, Cardiovascular Outcomes, and Adverse Events: Results From SPRINT.

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial of adults, age ≥50 years at high risk for cardiovascular disease with a seated systolic blood pressure (BP) of 130 to 180 mm Hg and a standing systolic BP ≥110 mm Hg. Participants were randomized to a systolic BP treatment goal of either <120 or <140 mm Hg. OH was defined as a drop in systolic BP ≥20 or diastolic BP ≥10 mm Hg 1 minute after standing from a seated position. We used Cox models to examine the association of OH with cardiovascular disease or adverse study events by randomized BP goal. During the follow-up period (median 3years), there were 1170 (5.7%) instances of OH among those assigned a standard BP goal and 1057 (5.0%) among those assigned the intensive BP goal. OH was not associated with higher risk of cardiovascular disease events (primary outcome: hazard ratio 1.06 [95% CI, 0.78-1.44]). Moreover, OH was not associated with syncope, electrolyte abnormalities, injurious falls, or acute renal failure. OH was associated with hypotension-related hospitalizations or emergency department visits (hazard ratio, 1.77 [95% CI, 1.11-2.82]) and bradycardia (hazard ratio, 1.94 [95% CI, 1.19-3.15]), but these associations did not differ by BP treatment goal. OH was not associated with a higher risk of cardiovascular disease events, and BP treatment goal had no effect on OH's association with hypotension and bradycardia. Symptomless OH during hypertension treatment should not be viewed as a reason to down-titrate therapy even in the setting of a lower BP goal. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.