Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

INFOMATAS multi-center systematic review and meta-analysis individual patient data of dynamic cerebral autoregulation in ischemic stroke.

RATIONALE: Disturbances in dynamic cerebral autoregulation after ischemic stroke may have important implications for prognosis. Recent meta-analyses have been hampered by heterogeneity and small samples. AIM AND/OR HYPOTHESIS: The aim of study is to undertake an individual patient data meta-analysis (IPD-MA) of dynamic cerebral autoregulation changes post-ischemic stroke and to determine a predictive model for outcome in ischemic stroke using information combined from dynamic cerebral autoregulation, clinical history, and neuroimaging. SAMPLE SIZE ESTIMATES: To detect a change of 2% between categories in modified Rankin scale requires a sample size of ∼1500 patients with moderate to severe stroke, and a change of 1 in autoregulation index requires a sample size of 45 healthy individuals (powered at 80%, α = 0.05). Pooled estimates of mean and standard deviation derived from this study will be used to inform sample size calculations for adequately powered future dynamic cerebral autoregulation studies in ischemic stroke. METHODS AND DESIGN: This is an IPD-MA as part of an international, multi-center collaboration (INFOMATAS) with three phases. Firstly, univariate analyses will be constructed for primary (modified Rankin scale) and secondary outcomes, with key co-variates and dynamic cerebral autoregulation parameters. Participants clustering from within studies will be accounted for with random effects. Secondly, dynamic cerebral autoregulation variables will be validated for diagnostic and prognostic accuracy in ischemic stroke using summary receiver operating characteristic curve analysis. Finally, the prognostic accuracy will be determined for four different models combining clinical history, neuroimaging, and dynamic cerebral autoregulation parameters. STUDY OUTCOME(S): The outcomes for this study are to determine the relationship between clinical outcome, dynamic cerebral autoregulation changes, and baseline patient demographics, to determine the diagnostic and prognostic accuracy of dynamic cerebral autoregulation parameters, and to develop a prognostic model using dynamic cerebral autoregulation in ischemic stroke. DISCUSSION: This is the first international collaboration to use IPD-MA to determine prognostic models of dynamic cerebral autoregulation for patients with ischemic stroke.

Inter-subject analysis of transfer function coherence in studies of dynamic cerebral autoregulation.

OBJECTIVE: The gain and phase of the arterial blood pressure (BP)-cerebral blood flow velocity (CBFV) relationship, assessed by transfer function analysis (TFA), are widely used dynamic cerebral autoregulation (CA) metrics, but their reliability depend on the statistical significance of the magnitude squared coherence (MSC) function. We tested a new approach, based on inter-subject data, to estimate the confidence limits of MSC. APPROACH: Five minute beat-to-beat time series of mean arterial BP (MAP, Finometer) and CBFV (transcranial Doppler) were used for intra-subject (MAP and CBFV from same subject) and inter-subject (BP and CBFV swapped between subjects) estimates of MSC. The 95% confidence limit of MSC was obtained by non-parametric methods for the cases of single frequency harmonics in the range (0.02-0.50 Hz), and also from the mean value of all possible frequency intervals in this range. MAIN RESULTS: Intra-subject estimates of MSC were obtained from 100 healthy subjects (48 female, age range: 21-82 years old) allowing calculation of 9900 inter-subject estimates, with 95% confidence limits in excellent agreement with classical values derived from surrogate random data. Confidence limits of MSC, derived from mean values, decreased asymptotically to around 0.16 with the increasing number of harmonics averaged. SIGNIFICANCE: Replacing estimates of MSC at a single frequency harmonic by the mean calculated over the range (0.02-0.30 Hz) could lead to more robust studies of dynamic CA with greater acceptance of recordings, an important consideration in clinical studies where measurements tend to be more susceptible to noise and artefacts.

Sex differences in cerebral haemodynamics across the physiological range of PaCO2.

OBJECTIVE: Cerebral blood flow (CBF) is influenced by changes in arterial CO2 (PaCO2). Recently, cerebral haemodynamic parameters were demonstrated to follow a four parameter logistic curve offering simultaneous assessment of dCA and CO2 vasoreactivity. However, the effects of sex on cerebral haemodynamics have yet to be described over a wide range of PaCO2. APPROACH: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in healthy volunteers at baseline, and in response to hypo- (-5 mmHg and -10 mmHg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. MAIN RESULTS: Forty-five subjects (19 male, 26 female, mean age 37.5 years) showed significant differences between males and females in CBFV (50.9 ± 10.4 versus 61.5 ± 12.3 cm · s-1, p = 0.004), EtCO2 (39.2 ± 2.8 versus 36.9 ± 3.0 mmHg, p = 0.005), RAP (1.16 ± 0.23 versus 0.94 ± 0.40 mmHg cm · s-1, p = 0.005) and systolic BP (125.2 ± 8.0 versus 114.6 ± 12.4 mmHg, p = 0.0372), respectively. Significant differences between sexes were observed in the four logistic parameters: y min, y max, k (exponential coefficient) and x (EtCO2 level) across the haemodynamic variables. Significant differences included the CBFV-EtCO2 and ARI-EtCO2 relationship; ARImin (p = 0.036) and CBFVmax (p = 0.001), respectively. Furthermore, significant differences were observed for both CrCPmin (p = 0.045) and CrCPmax (p = 0.005) and RAPmin (p < 0.001) and RAPmax (p < 0.001). SIGNIFICANCE: This is the first study to examine sex individually within the context of a multi-level CO2 protocol. The demonstration that the logistic curve parameters are influenced by sex, highlights the need to take into account sex differences between participants in both physiological and clinical studies.

How many squat-stand manoeuvres to assess dynamic cerebral autoregulation?

PURPOSE: Squat-stand manoeuvres (SSMs) have been used to induce blood pressure (BP) changes for the reliable assessment of dynamic cerebral autoregulation. However, they are physically demanding and thus multiple manoeuvres can be challenging for older subjects. This study aimed to determine the minimum number of SSMs required to obtain satisfactory coherence, thus minimising the subjects' workload. METHOD: 20 subjects performed SSMs at a frequency of 0.05 Hz. End-tidal CO2, cerebral blood flow velocity, heart rate, continuous BP and the depth of the squat were measured. 11 subjects returned for a repeat visit. The time points at which subjects had performed 3, 6, 9, 12 and 15 SSMs were determined. Transfer function analysis was performed on files altered to the required length to obtain estimates of coherence and the autoregulation index (ARI). RESULTS: After three SSMs, coherence (0.05 Hz) was 0.93 ± 0.05, and peaked at 0.95 ± 0.02 after 12 manoeuvres. ARI decreased consecutively with more manoeuvres. ARI was comparable across the two visits (p = 0.92), but coherence was significantly enhanced during the second visit (p < 0.01). The intra-subject coefficients of variation (CoV) for ARI remained comparable as the number of manoeuvres varied. CONCLUSIONS: This analysis can aid those designing SSM protocols, especially where participants are unable to tolerate a standard 5-min protocol or when a shorter protocol is needed to accommodate additional tests. We emphasise that fewer manoeuvres should only be used in exceptional circumstances, and where possible a full set of manoeuvres should be performed. Furthermore, these results need replicating at 0.10 Hz to ensure their applicability to different protocols.

Modelling the cerebral haemodynamic response in the physiological range of PaCO2.

OBJECTIVE: Arterial CO2 (PaCO2) has a strong effect on cerebral blood flow (CBF), but its influence on CBF regulatory mechanisms and circulatory systemic variables has not been fully described over the entire physiological range of PaCO2. APPROACH: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in 45 healthy volunteers (19 male, mean age 37.5 years, range 21-71) at baseline, and in response to hypo- (-5 mm Hg and -10 mm Hg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. MAIN RESULTS: CBFV, cerebral dynamic autoregulation index (ARI), heart rate (HR), arterial blood pressure (ABP), critical closing pressure (CrCP) and resistance-area product (RAP) changed significantly (all p < 0.0001) for hypo- and hyper-capnia. These parameters were shown to follow a logistic curve relationship representing a 'dose-response' curve for the effects of PaCO2 on the cerebral and systemic circulations. The four logistic model parameters describing each 'dose-response' curve were specific to each of the modelled variables (ANOVA p < 0.0001). SIGNIFICANCE: The ability to model the CBFV, ARI, HR, ABP, CrCP and RAP dependency of PaCO2 over its entire physiological range is a powerful tool for physiological and clinical studies, including the need to perform adjustments in disease populations with differing values of baseline PaCO2.

Dynamic cerebral autoregulation is impaired during submaximal isometric handgrip in patients with heart failure.

The incidence of neurological complications, including stroke and cognitive dysfunction, is elevated in patients with heart failure (HF) with reduced ejection fraction. We hypothesized that the cerebrovascular response to isometric handgrip (iHG) is altered in patients with HF. Adults with HF and healthy volunteers were included. Cerebral blood velocity (CBV; transcranial Doppler, middle cerebral artery) and arterial blood pressure (BP; Finometer) were continuously recorded supine for 6 min, corresponding to 1 min of baseline and 3 min of iHG exercise, at 30% maximum voluntary contraction, followed by 2 min of recovery. The resistance-area product was calculated from the instantaneous BP-CBV relationship. Dynamic cerebral autoregulation (dCA) was assessed with the time-varying autoregulation index estimated from the CBV step response derived by an autoregressive moving-average time-domain model. Forty patients with HF and 23 BP-matched healthy volunteers were studied. Median left ventricular ejection fraction was 38.5% (interquartile range: 0.075%) in the HF group. Compared with control subjects, patients with HF exhibited lower time-varying autoregulation index during iHG, indicating impaired dCA ( P < 0.025). During iHG, there were steep rises in CBV, BP, and heart rate in control subjects but with different temporal patterns in HF, which, together with the temporal evolution of resistance-area product, confirmed the disturbance in dCA in HF. Patients with HF were more likely to have impaired dCA during iHG compared with age-matched control subjects. Our results also suggest an impairment of myogenic, neurogenic, and metabolic control mechanisms in HF. The relationship between impaired dCA and neurological complications in patients with HF during exercise deserves further investigation. NEW & NOTEWORTHY Our findings provide the first direct evidence that cerebral blood flow regulatory mechanisms can be affected in patients with heart failure during isometric handgrip exercise. As a consequence, eventual blood pressure modulations are buffered less efficiently and metabolic demands may not be met during common daily activities. These deficits in cerebral autoregulation are compounded by limitations of the systemic response to isometric exercise, suggesting that patients with heart failure may be at greater risk for cerebral events during exercise.

Reproducibility of task activation using the Addenbrooke's cognitive examination in healthy controls: A functional Transcranial Doppler ultrasonography study.

INTRODUCTION: Cerebral blood flow velocity (CBFv) changes occurring with cognitive stimulation can be measured by Transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the reproducibility of CBFv changes to the Addenbrooke's cognitive examination (ACE-III). NEW METHOD: 13 volunteers underwent bilateral TCD (middle cerebral artery), continuous heart rate (HR, 3-lead ECG, Finometer), beat-to-beat mean arterial pressure (MAP, Finometer), and end-tidal CO2 (ETCO2, capnography). After 5min baseline, all ACE-III tasks were performed in 3 domains (A/B/C). Data presented are population CBFv peak normalised changes and area under the curve (AUC). Statistical analysis was by 2-way repeated measures (ANOVA), intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). RESULTS: 12 bilateral data sets were obtained (10 right hand dominant, 6 female). Baseline parameters (MAP, HR, ETCO2) did not differ between visits. All tasks increased CBFv. Only domain A on AUC analysis differed significantly on ANOVA, and one task on post hoc testing (p <0.05). ICC values were poor (<0.4) for most tasks, but 3 tasks produced more consistent results on AUC and peak CBFv analysis (range ICC: 0.15-0.73, peak CV: 16.2-56.1(%), AUC CV: 23.2-60.2(%), peak SEM: 2.5-6.0 (%), AUC SEM: 21.8-135.8 (%*s). COMPARISON WITH EXISTING METHODS: This is the first study to examine reproducibility of CBFv changes to a complete cognitive assessment tool. CONCLUSIONS: Reproducibility of CBFv measurements to the ACE-III was variable. AUC may provide more reliable estimates than peak CBFv responses. These data need validating in patient populations.

Transcranial Doppler ultrasonography in the assessment of neurovascular coupling responses to cognitive examination in healthy controls: A feasibility study.

BACKGROUND: We tested the hypothesis that paradigms from the Addenbrooke's Cognitive Examination (ACE-III), including those that had not been studied using TCD previously (novel) versus those which had been (established), would elicit changes in CBF velocity (CBFv). NEW METHOD: Healthy subjects were studied with bilateral transcranial Doppler (TCD), beat-to-beat blood pressure (Finapres), continuous electrocardiogram (ECG), and end-tidal CO2 (nasal capnography). After a 5-min baseline recording, cognitive tests of the ACE-III were presented to subjects, covering attention (SUB7, subtracting 7 from 100 sequentially), language (REP, repeating words and phrases), fluency (N-P, naming words), visuospatial (DRAW, clock-drawing), and memory (MEM, recalling name and address). An event marker noted question timing. RESULTS: Forty bilateral data sets were obtained (13 males, 37 right-hand dominant) with a median age of 31 years (IQR 22-52). Population normalized mean peak CBFv% in the dominant and non-dominant hemispheres, respectively, were: SUB7 (11.3±9.6%, 11.2±10.5%), N-P (12.7±11.7%, 11.5±12.0%), REP (12.9±11.7%, 11.6±11.6%), DRAW (13.3±11.7%, 13.2±15.4%) and MEM (13.2±10.3%, 12.0±10.1%). There was a significant difference between the dominant and non-dominant CBFv responses (p<0.008), but no difference between the amplitude of responses. COMPARISON WITH EXISTING METHODS: For established paradigms, our results are in excellent agreement to what has been found previously in the middle cerebral artery. CONCLUSIONS: Cognitive paradigms derived from the ACE-III led to significant lateralised changes in CBFv that were not distinct for novel paradigms. Further work is needed to assess the potential of paradigms to improve the interpretation of cognitive assessments in patients at risk of mild cognitive impairment.

Post-Carotid Endarterectomy Hypertension. Part 1: Association with Pre-operative Clinical, Imaging, and Physiological Parameters.

OBJECTIVE/BACKGROUND: Post-endarterectomy hypertension (PEH) is a well recognised, but poorly understood, phenomenon after carotid endarterectomy (CEA) that is associated with post-operative intracranial haemorrhage, hyperperfusion syndrome, and cardiac complications. The aim of the current study was to identify pre-operative clinical, imaging, and physiological parameters associated with PEH. METHODS: In total, 106 CEA patients undergoing CEA under general anaesthesia underwent pre-operative evaluation of 24 hour ambulatory arterial blood pressure (BP), baroreceptor sensitivity, cerebral autoregulation, and transcranial Doppler measurement of cerebral blood flow velocity (CBFv) and pulsatility index. Patients who met pre-existing criteria for treating PEH after CEA (systolic BP [SBP] > 170 mmHg without symptoms or SBP > 160 mmHg with headache/seizure/neurological deficit) were treated according to a previously established protocol. RESULTS: In total, 40/106 patients (38%) required treatment for PEH at some stage following CEA (26 in theatre recovery [25%], 27 while on the vascular surgical ward [25%]), while seven (7%) had SBP surges > 200 mmHg back on the ward. Patients requiring treatment for PEH had a significantly higher pre-operative SBP (144 ± 11 mmHg vs. 135 ± 13 mmHg; p < .001) and evidence of pre-existing impairment of baroreceptor sensitivity (3.4 ± 1.7 ms/mmHg vs. 5.3 ± 2.8 ms/mmHg; p = .02). However, PEH was not associated with any other pre-operative clinical features, CBFv, or impaired cerebral haemodynamics. Paradoxically, autoregulation was better preserved in patients with PEH. All four cases of hyperperfusion associated symptoms were preceded by PEH. Length of hospital stay was significantly increased in patients with PEH (p < .001). CONCLUSION: In this study, where all patients underwent CEA under general anaesthesia, PEH was associated with poorly controlled pre-operative BP and impaired baroreceptor sensitivity, but not with other peripheral or central haemodynamic parameters, including impaired cerebral autoregulation.

Cerebral hemodynamics with intra-aortic balloon pump: business as usual?

OBJECTIVE: Intra-aortic balloon pump (IABP) is commonly used as mechanical support after cardiac surgery or cardiac shock. Although its benefits for cardiac function have been well documented, its effects on cerebral circulation are still controversial. We hypothesized that transfer function analysis (TFA) and continuous estimates of dynamic cerebral autoregulation (CA) provide consistent results in the assessment of cerebral autoregulation in patients with IABP. APPROACH: Continuous recordings of blood pressure (BP, intra-arterial line), end-tidal CO2, heart rate and cerebral blood flow velocity (CBFV, transcranial Doppler) were obtained (i) 5 min with IABP ratio 1:3, (ii) 5 min, starting 1 min with the IABP-ON, and continuing for another 4 min without pump assistance (IABP-OFF). Autoregulation index (ARI) was estimated from the CBFV response to a step change in BP derived by TFA and as a function of time using an autoregressive moving-average model during removal of the device (ARI t ). Critical closing pressure and resistance area-product were also obtained. MAIN RESULTS: ARI with IABP-ON (4.3 ± 1.2) were not different from corresponding values at IABP-OFF (4.7 ± 1.4, p = 0.42). Removal of the balloon had no effect on ARI t , CBFV, BP, cerebral critical closing pressure or resistance area-product. SIGNIFICANCE: IABP does not disturb cerebral hemodynamics. TFA and continuous estimates of dynamic CA can be used to assess cerebral hemodynamics in patients with IABP. These findings have important implications for the design of studies of critically ill patients requiring the use of different invasive support devices.

Cerebral Hemodynamic Effects of Cheyne-Stokes Respiration in a Patient with Stroke.

INTRODUCTION: Cheyne-Stokes respiration (CSR) and central sleep apnea (CSA) are common in patients with heart failure and/or stroke. We aim to describe the cerebrovascular effects of CSR during the acute phase of stroke in a heart failure patient. CASE REPORT: A 74-year-old male with previous dilated cardiomyopathy had sudden onset of right hemiparesis and aphasia. A transcranial Doppler was performed with continuous measurement of blood pressure (BP) (Finometer) and end-tidal CO2 (nasal capnography). Offline analysis of hemodynamic data disclosed relatively large periodic oscillations of both cerebral blood flow velocity and BP related to the CSR breathing pattern. Derivate variables from the cerebrovascular resistance were calculated (critical closing pressure and resistance-area product), demonstrating that there may be a myogenic impairment of cerebral blood flow (CBF) control in the affected hemisphere of this subgroup of patient. CONCLUSION: There is an impairment of CBF regulation in the affected hemisphere of the patient with ischemic stroke and CSR, highlighting the role of cerebral hemodynamic monitoring in this scenario.

What influences healthcare professionals' treatment preferences for older women with operable breast cancer? An application of the discrete choice experiment.

INTRODUCTION: Primary endocrine therapy (PET) is used variably in the UK as an alternative to surgery for older women with operable breast cancer. Guidelines state that only patients with "significant comorbidity" or "reduced life expectancy" should be treated this way and age should not be a factor. METHODS: A Discrete Choice Experiment (DCE) was used to determine the impact of key variables (patient age, comorbidity, cognition, functional status, cancer stage, cancer biology) on healthcare professionals' (HCP) treatment preferences for operable breast cancer among older women. Multinomial logistic regression was used to identify associations. RESULTS: 40% (258/641) of questionnaires were returned. Five variables (age, co-morbidity, cognition, functional status and cancer size) independently demonstrated a significant association with treatment preference (p < 0.05). Functional status was omitted from the multivariable model due to collinearity, with all other variables correlating with a preference for operative treatment over no preference (p < 0.05). Only co-morbidity, cognition and cancer size correlated with a preference for PET over no preference (p < 0.05). CONCLUSION: The majority of respondents selected treatment in accordance with current guidelines, however in some scenarios, opinion was divided, and age did appear to be an independent factor that HCPs considered when making a treatment decision in this population.

Latest developments in clinical stroke care.

Stroke medicine has seen rapid developments in diagnosis and management, and consequently improved prognosis. Management of ischaemic stroke, in particular, has benefited from these advances. The approach to management has evolved from one of historical passivity to active intervention with time of the essence following stroke onset. The last decade has seen the comparative effectiveness of several pharmacological agents being tested, creating significant randomised controlled trial evidence to support the management of common clinical problems following acute stroke. While several of these interventions are widely available, some remain less accessible. This review will discuss the latest developments in clinical stroke medicine, based on a symposium presentation at the Royal College of Physicians of Edinburgh, and reference key randomised controlled trial evidence in an effort to provide a balanced perspective on our current understanding of acute ischaemic and haemorrhagic stroke.

Cerebral blood flow autoregulation in ischemic heart failure.

Patients with ischemic heart failure (iHF) have a high risk of neurological complications such as cognitive impairment and stroke. We hypothesized that iHF patients have a higher incidence of impaired dynamic cerebral autoregulation (dCA). Adult patients with iHF and healthy volunteers were included. Cerebral blood flow velocity (CBFV, transcranial Doppler, middle cerebral artery), end-tidal CO2 (capnography), and arterial blood pressure (Finometer) were continuously recorded supine for 5 min at rest. Autoregulation index (ARI) was estimated from the CBFV step response derived by transfer function analysis using standard template curves. Fifty-two iHF patients and 54 age-, gender-, and BP-matched healthy volunteers were studied. Echocardiogram ejection fraction was 40 (20-45) % in iHF group. iHF patients compared with control subjects had reduced end-tidal CO2 (34.1 ± 3.7 vs. 38.3 ± 4.0 mmHg, P < 0.001) and lower ARI values (5.1 ± 1.6 vs. 5.9 ± 1.0, P = 0.012). ARI <4, suggestive of impaired CA, was more common in iHF patients (28.8 vs. 7.4%, P = 0.004). These results confirm that iHF patients are more likely to have impaired dCA compared with age-matched controls. The relationship between impaired dCA and neurological complications in iHF patients deserves further investigation.

Gene and Protein Expression of Chemokine (C-C-Motif) Ligand 19 is Upregulated in Unstable Carotid Atherosclerotic Plaques.

OBJECTIVE/BACKGROUND: The aim was to investigate the expression of genes associated with carotid plaque instability and their protein products at a local and systemic level. METHODS: Carotid plaques from 24 patients undergoing carotid endarterectomy (CEA) were classified as stable or unstable using clinical, histological, ultrasound, and transcranial Doppler criteria, and compared using whole genome microarray chips. Initial results of differentially expressed genes were validated by quantitative reverse transcriptase polymerase chain reaction in an independent group of 96 patients undergoing CEA. The protein product of genes significantly differentially expressed between patients with stable and unstable plaques were analysed by plaque immunohistochemistry and serum protein quantification by enzyme-linked immunosorbent assay on a further independent cohort. RESULTS: Expression of chemokine (c-c-motif) ligand 19 (CCL19) was significantly upregulated in plaques from patients with clinically unstable disease (p < .001). Cathepsin G expression was upregulated in histologically unstable plaques (p = .04). Serum concentration of CCL19 was significantly higher in patients with clinically unstable plaques (p = .02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (p = .03). CCL19 also co-localised with CD3+ T-cell lymphocytes in the core region, around where CCL19 was expressed. CONCLUSIONS: CCL19 is significantly overexpressed in patients with unstable carotid atherosclerotic plaques and may be a possible novel biomarker for identifying high-risk patients in whom more urgent intervention may be indicated.

The carotid artery as an alternative site for dynamic autoregulation measurement: an inter-observer reproducibility study.

The internal carotid artery (ICA) has been proposed as an alternative site to the middle cerebral artery (MCA) to measure dynamic cerebral autoregulation (dCA) using transcranial Doppler ultrasound (TCD). Our aim was to test the inter-operator reproducibility of dCA assessment in the ICA and the effect of interaction amongst different variables (artery source × operator × intra-subject variability). Two operators measured blood flow velocity using TCD at the ICA and MCA simultaneously on each side in 12 healthy volunteers. The autoregulation index (ARI) was estimated by transfer function analysis. A two-way repeated measurements ANOVA with post-hoc Tukey tested the difference between ARI by different operators and interaction effects were analysed based on the generalized linear model. In this healthy population, no significant differences between operator and no interaction effects were identified amongst the different variables. This study reinforced the validity of using the ICA as an alternative site for the assessment of dCA. Further work is needed to confirm and extend our findings, particularly to disease populations.

Statistical criteria for estimation of the cerebral autoregulation index (ARI) at rest.

The autoregulation index (ARI) can reflect the effectiveness of cerebral blood flow (CBF) control in response to dynamic changes in arterial blood pressure (BP), but objective criteria for its validation have not been proposed. Monte Carlo simulations were performed by generating 5 min long random input/output signals that mimic the properties of mean beat-to-beat BP and CBF velocity (CBFV) as usually obtained by non-invasive measurements in the finger (Finometer) and middle cerebral artery (transcranial Doppler ultrasound), respectively. Transfer function analysis (TFA) was used to estimate values of ARI by optimal fitting of template curves to the output (or CBFV) response to a step change in input (or BP). Two-step criteria were adopted to accept estimates of ARI as valid. The 95% confidence limit of the mean coherence function (0.15-0.25 Hz) ([Formula: see text]) was estimated from 15 000 runs, resulting in [Formula: see text] = 0.190 when using five segments of data, each with 102.4 s (512 samples) duration (Welch's method). This threshold for acceptance was dependent on the TFA settings and increased when using segments with shorter duration (51.2 s). For signals with mean coherence above the critical value, the 5% confidence limit of the normalised mean square error (NMSEcrit) for fitting the step response to Tieck's model, was found to be approximately 0.30 and independent of the TFA settings. Application of these criteria to physiological and clinical sets of data showed their ability to identify conditions where ARI estimates should be rejected, for example due to CBFV step responses lacking physiological plausibility. A larger number of recordings were rejected from acute ischaemic stroke patients than for healthy volunteers. More work is needed to validate this procedure with different physiological conditions and/or patient groups. The influence of non-stationarity in BP and CBFV signals should also be investigated.