Gillian Manning

Clinical implications of white coat hypertension : an ambulatory blood pressure monitoring study

Within routine clinical practice, white coat hypertension (where blood pressure is persistently higher in the presence of the doctor or nurse but normal outside the medical setting) makes the diagnosis and management of hypertension difficult. There are conflicting data regarding the prevalence and significance of white coat hypertension. This study has used ambulatory blood pressure monitoring to detect the presence of white coat hypertension in 186 patients referred to an out-patient hypertension unit. The presence of white coat hypertension was defined as an average office blood pressure (measured on three occasions over a 2-month period) of >140/90 mm Hg and an ambulatory awake blood pressure ≤136/86 mm Hg. The prevalence of white coat hypertension in those patients with borderline hypertension (diastolic blood pressure 90–99 mm Hg) and those with mild-to-moderate hypertension (diastolic blood pressure ≥100 mm Hg) was determined. Echocardiography was used to assess left ventricular mass index in patients with and without white coat hypertension. The prevalence of white coat hypertension in the total group was 23%. However, the prevalence was higher (33%) in those patients with borderline hypertension compared to 9% of those patients with mild-to-moderate hypertension. There was a statistically significant increase in left ventricular mass index in patients with no evidence of white coat hypertension (125 gm/m2) compared to those with white coat hypertension (102 gm/m2). We conclude that, if office blood pressure is used to identify patients with hypertension who may require treatment, some patients will be incorrectly diagnosed and may be treated inappropriately. We recommend that ambulatory blood pressure monitoring is used in the routine assessment of all newly diagnosed hypertensive patients. Furthermore, we recommend echocardiography in patients with borderline hypertension as some will already have an increased left ventricular mass index.

Assessment of Lower Limb Microcirculation: Exploring the Reproducibility and Clinical Application of Laser Doppler Techniques

Purpose of Study: Non-invasive laser Doppler fluximetry (LDF) and laser Doppler imaging (LDI), combined with iontophoresis, have been used to study the microcirculation in a range of clinical conditions including lower limb venous disease. A prerequisite for an accurate measurement tool is that it is reproducible. However, there is currently no literature with respect to the reproducibility of LDF and LDI combined with iontophoresis in the lower limb (in general) and in the upright position (in specific). Furthermore, the two techniques have been used interchangeably by researchers and the association between these two different measurement methods has not been explored, nor have the factors that affect them been well described. Thus the aim of this study was to determine the reproducibility of LDF and LDI with iontophoresis in the lower limb and investigate factors that influence their clinical application. Procedures: Cutaneous microvascular responses in the lower limb were measured in the supine and standing positions using LDF and LDI combined with iontophoretic administration of endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside) vasodilators in 25 patients with uncomplicated isolated superficial venous incompetence (ISVI) and 26 healthy controls. Results: Maximum perfusion had the best reproducibility assessed by LDF (CV 20.5–24.3%) and LDI (15.8–17.6%). Both techniques were positively influenced by iontophoretic dose (e.g. p = 0.0001 for LDF) and the use of vasodilator agents (e.g. p = 0.0001 for LDF), but negatively influenced in the standing position and/or in the presence of ISVI (p = 0.0016 and 0.045, respectively, for LDF). There was a statistically significant positive relationship between the two techniques, for example ACh maximum perfusion versus LDF ACh maximum perfusion (r = 0.404, p = 0.016). Conclusions: Both techniques are reproducible, in line with similar studies undertaken in other areas of the human body, and provide useful information for the study of the lower-limb microcirculation. Direct comparison between techniques based on absolute numbers should be avoided and the technique choice should be based on individual study needs.

Comparative attainment of 5-year undergraduate and 4-year graduate entry medical students moving into foundation training.

BackgroundGraduate entry medicine is a recent innovation in UK medical training. Evidence is sparse at present as to progress and attainment on these programmes. Shared clinical rotations, between an established 5-year and a new graduate entry course, provide the opportunity to compare achievement on clinical assessments. To compare completion and attainment on clinical phase assessments between students on a 4-year graduate entry course and an established 5-year undergraduate medicine course.MethodsOverall completion rates for the 4 and 5 year courses, fails at first attempt, and scores on 14 clinical assessments, were compared between 171 graduate-entry and 450 undergraduate medical students at the University of Nottingham, comprising two graduating cohorts. Percentage assessment marks were converted to z-scores separately for each graduating year and the normalised marks then combined into a single dataset. Z-score transformed percentage marks were analysed by multivariate analysis of variance and univariate analyses of variance for each summative assessment. Numbers of fails at first attempt were analysed aggregated across all assessments initially, then separately for each assessment using χ2.ResultsCompletion rates were around 90% overall and significantly higher in the graduate entry course. Failures of assessments overall were similar, but a higher proportion of graduate entry students failed the final OSLER. Mean performance on clinical assessments showed a significant overall difference, made up of lower performance on 4 of 5 knowledge-based exams (as well as higher performance on the first exam) by the graduate entry group, but similar levels of performance on all the skills-based and attitudinal assessments.ConclusionsHigh completion rates are encouraging. The lower performance in some knowledge-based exams may reflect lower prior educational attainment, a substantially different demographic profile (age, gender), or an artefact of the first 2 years of a new graduate entry programme.

Review: Angiotensin-converting enzyme inhibitors and coronary heart disease prevention

A number of large randomised controlled trials have shown that angiotensin-converting enzyme (ACE) inhibitors, compared with placebo or other blood pressure-lowering drugs, improve coronary heart disease outcomes (fatal and non-fatal myocardial infarction, and coronary revascularisation) in diverse patient groups, e.g. in primary and secondary prevention, those with and without left ventricular dysfunction, and among hypertensive and non-hypertensive subjects. An updated meta-regression analysis which included five major trials in patients with established coronary artery disease (CAD) (EUROPA, INVEST, ACTION, PEACE and CAMELOT) concluded that ACE inhibitor (ACE-I) therapy has clear benefits in secondary prevention, but there are important and unexplained differences between trials in clinical outcome, baseline cardiovascular risk, blood pressure changes and trial design which deserve further discussion of the underlying mechanisms and clinical interpretation. For example, in placebo-controlled trials the biggest (20—22%) reductions in primary end points (including mortality) have been observed with perindopril and ramipril, whereas trials using trandolapril and quinapril had no effect on survival or recurrent CAD events. This review summarises and compares the major findings of these recent trials, and provides further analysis of the underlying mechanisms and clinical significance of secondary CAD prevention with ACE-I therapy.

Antiangiogenic effects and transcriptional regulation of pigment epithelium-derived factor in diabetic retinopathy

The effects of the antiangiogenic cytokine PEDF on key steps in retinal angiogenesis, specifically endothelial cell proliferation and vascular tubule formation, and the regulation of PEDF expression in retinal capillary endothelial cells were evaluated. HUVECs were co-cultured with fibroblasts to construct a model of angiogenesis using the Angiokit assay, and image analysis software was used to measure the effects of PEDF and VEGF on vascular tubule formation. Quantitative real-time PCR analysis was used to determine the expression of PEDF in microvascular endothelial cells exposed to glucose 20 mM, insulin 100 nM and VEGF 10 ng/ml. PEDF inhibited endothelial cell proliferation and significantly decreased the number of tubules (629+93 AU vs 311+31, p=0.001), number of branching points (145+19 AU vs 46+5, p=0.03) and total tubule length (4848+748 AU vs 11,172+2353, p=0.001). In bovine retinal capillary endothelial cells (BRCECs), PEDF mRNA and protein expression was suppressed by insulin (22%) in a rapamycin-sensitive manner; wortmannin had no effect. PEDF mRNA expression was also significantly reduced in the presence of high glucose (23%) and VEGF (25%). In conclusion, PEDF inhibits key steps in the angiogenic response of BRCECs, including endothelial cell proliferation and vascular tubule formation. Gene expression of PEDF is negatively regulated by glucose, insulin (via an mTOR-dependent pathway) and VEGF.

Twenty-four hour ambulatory blood pressure: a sample from a normal British population

The aims of this study were to determine 24 h blood pressure (BP) levels in a sample taken from a normal British population, and to investigate factors contributing to variation within the sample. Two hundred and eighty-two Caucasian subjects, with no known hypertension or cardiovascular disease were recruited from local light industry and a general practice population. Office and 24 h BPs were measured. The mean office BP was 120/75, ambulatory mean awake 115/72 and mean asleep 97/58 mm Hg. Males had a small but significantly higher mean office and awake BP but there were no differences in asleep BP. Multiple step-wise regression with age, gender, weight and height showed age to be the best predictor of variation in office BP and awake and asleep diastolic BP. However, age accounted for only a small amount of the variation and did not contribute towards the variation in systolic BP. The two standard deviation upper limits for this population for awake, asleep and overall BP were 136/86, 121/73 and 131/82 mm Hg, respectively. In conclusion, these data providing information on 24 h BP in a healthy British population may be of value in the clinical interpretation of 24 h ambulatory BP recordings in patients with suspected hypertension.

Effect of diabetes on the cutaneous microcirculation of the feet in patients with intermittent claudication

AIMS To evaluate endothelial-dependent and - independent cutaneous vasodilator responses in the feet of patients with peripheral arterial disease (PAD) with or without Type 2 diabetes. METHODS Cutaneous microvascular responses in the dorsum of both lower limbs were measured in the supine position using Laser Doppler Fluximetry combined with iontophoretic administration of endothelial-dependent (acetylcholine, Ach) and -independent (sodium nitroprusside, SNP) vasodilators in diabetic (n = 19) and non diabetic (n = 17) patients with PAD (presenting as unilateral calf intermittent claudication (IC). RESULTS In patients with diabetes and IC, endothelial-dependent vasodilation was significantly impaired in the symptomatic limb [74 (57,105) vs 68 (24,81) PU, Z =-2.79, p = 0.005] compared to the asymptomatic limb. Patients without diabetes showed no impairment of vasodilation. Resting ankle-brachial pressure index did not identify the presence of abnormalities in microvascular function. CONCLUSIONS The combination of diabetes and PAD is associated with a reduction in endothelial-dependent cutaneous vasodilation in the feet without an associated reduction in endothelial independent vasodilation.

Use of home blood-pressure monitoring in the detection, treatment and surveillance of hypertension.

Purpose of reviewUse of home blood-pressure monitoring is increasing but the technique and the equipment have limitations. We provide an overview of recent evidence in this rapidly evolving field. Recent findingsHome blood-pressure monitoring is an acceptable method for screening patients for hypertension. There is increasing evidence supporting the predictive power of home blood pressure for stroke risk even in the general population. The identification of white-coat and masked hypertension remains an important role for home blood-pressure monitoring. Unvalidated equipment and poor patient technique are major concerns. The purchase of devices needs to be linked to a simple patient-education programme, which is perhaps an opportunity for collaboration between healthcare providers and commercial companies. Devices that store the blood-pressure measurements in the memory are preferred to ensure accuracy of reporting. Data-transmission systems providing automatic storage, transmission and reporting of blood pressure, direct involvement of the patient and potentially a reduced number of hospital/general practitioner visits, offer significant advantages. To reduce patient anxiety, overuse of home blood-pressure monitoring should be avoided but there is the potential for self-modification of treatment, subject to certain safeguards. SummarySelf-monitoring of blood pressure is developing rapidly, linked to increasing awareness of the impact of reducing high blood pressure on public health and the marketing/advertising strategies used to sell automatic devices. Home blood-pressure monitoring has a role in the detection and management of blood pressure, but not at the expense of careful blood-pressure measurement in the office and adherence to national guidelines.

Characterising the time-course of microvascular vasodilator responses in humans using laser doppler fluximetry and iontophoresis

INTRODUCTION Laser Doppler Fluximetry (LDF) and iontophoresis of vasodilators have been combined to assess microvascular flow and vasodilator reactivity in humans for many years and their use established. However, traditional data analysis methods measure the magnitude of flux change but not its time-course, a factor that may be of importance in defining vascular health. The aim of this study was to develop and utilise a novel data analysis method using a standardised LDF and iontophoresis protocol, assessing time to peak vasodilation (Tmax). METHODS Endothelial-dependent and -independent vasodilator responses (using acetylcholine and sodium nitroprusside respectively) were measured in the perimalleolar region both supine and standing in patients with isolated superficial venous insufficiency (ISVI) (n=24) and controls (n=20), on two occasions. Tmax was measured at each post-iontophoretic period. RESULTS Tmax was slower while standing and in patients with ISVI. There was no statistical difference in Tmax between visits for both groups (p>0.05), with coefficients of variation being between 20.2%-25.4%. ISVI, position and vasodilatory agents were significant determinants of Tmax. DISCUSSION Tmax appears to be a reproducible method of assessing venous vasodilation, is not affected by the dose and is impaired in patients with of ISVI in both the supine and standing positions.

In vitro study of thrombin on tubule formation and regulators of angiogenesis.

Objective: Angiogenesis occurs within atherosclerotic plaques, and thrombin has been implicated in plaque progression by increasing smooth muscle cell proliferation and upregulating Vascular Endothelial Growth Factor (VEGF) receptor expression. This study investigated the effects of thrombin on key aspects of angiogenesis and expression of pro- and anti-angiogenic regulators: VEGF and Pigment Epithelial Derived Factor. Research Design and Methods: Human umbilical smooth muscle cells (HUASMC) were exposed to vehicle or thrombin at 10 U/ml. To quantify cell proliferation, methyl tetrazolium salt (MTS) solution was added after exposure to thrombin for 24, 48 and 72 hours and the absorbance at 490nm recorded using a plate reader. For Real-time RT-PCR cells were exposed to thrombin for 24hr before analysis of VEGF and PEDF mRNA. A commercial Angiokit was used to construct an in vitro angiogenesis model to measure tubule formation and branching. After 12 days treatment with thrombin 10 U/ml, cells were fixed and the AngioSys 1.0 software was used to analyse tubule morphology. Results: In comparison with controls, thrombin significantly increased HUASMC proliferation (p = 0.002, n = 11) and VEGF mRNA expression by 93% (n = 4, p = 0.024). However in the HUVEC/fibroblast co-cultures it decreased the number of junctions [132(9) vs 196(18), n = 6, p = 0.017] and tubules [537 (17) vs 589 (26), n = 6, p = 0.049], and tubule length [11393 (1601) vs 12195 (1014), n = 6, p = 0.044], indicating an anti-angiogenic effect. Conclusions: Thrombin stimulates vascular smooth muscle cell proliferation and VEGF expression, but attenuates endothelial cell-mediated growth of vascular tubules and branching of new vascular structures.