John L. Reid

Calcium Antagonist Lacidipine Slows Down Progression of Asymptomatic Carotid Atherosclerosis Principal Results of the European Lacidipine Study on Atherosclerosis (ELSA), a Randomized, Double-Blind, Long-Term Trial

Background—Most cardiovascular events associated with hypertension are complications of atherosclerosis. Some antihypertensive agents influence experimental models of atherosclerosis through mechanisms independent of blood pressure lowering. Methods and Results—The European Lacidipine Study on Atherosclerosis (ELSA) was a randomized, double-blind trial in 2334 patients with hypertension that compared the effects of a 4-year treatment based on either lacidipine or atenolol on an index of carotid atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in far walls of common carotids and bifurcations (CBMmax). This index has been shown by epidemiological studies to be predictive of cardiovascular events. A significant (P <0.0001) effect of lacidipine was found compared with atenolol, with a treatment difference in 4-year CBMmax progression of −0.0227 mm (intention-to-treat population) and −0.0281 mm (completers). The yearly IMT progression rate was 0.0145 mm/y in atenolol-treated and 0.0087 mm/y in lacidipine-treated patients (completers, 40% reduction;P =0.0073). Patients with plaque progression were significantly less common, and patients with plaque regression were significantly more common in the lacidipine group. Clinic blood pressure reductions were identical with both treatments, but 24-hour ambulatory systolic/diastolic blood pressure changes were greater with atenolol (−10/−9 mm Hg) than with lacidipine (−7/−5 mm Hg). No significant difference between treatments was found in any cardiovascular events, although the relative risk for stroke, major cardiovascular events, and mortality showed a trend favoring lacidipine. Conclusion—The greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient, despite a smaller ambulatory blood pressure reduction, indicates an antiatherosclerotic action of lacidipine independent of its antihypertensive action.

Superoxide Anion Production Is Increased in a Model of Genetic Hypertension: Role of the Endothelium

The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.

Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial.

Summary Background Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. Methods In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7–10 days and, when practical, again at 25–30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533. Findings All patients were included in the analyses. The primary outcome occurred in 126 (10·0%) patients allocated to thigh-length GCS and in 133 (10·5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0·5% (95% CI −1·9% to 2·9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4·18, 95% CI 2·40–7·27). Interpretation These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results. Funding Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network.

Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society.

Several important new issues have arisen in the management of patients with hypertension. A working party of the British Hypertension Society has therefore reviewed available intervention studies on anti-hypertensive treatment and made recommendations on blood pressure thresholds for intervention, on non-pharmacological and pharmacological treatments, and on treatment goals. This report also provides guidelines on blood pressure measurement, essential investigations, referrals for specialist advice, follow up, and stopping treatment.

Clinical pharmacology and pharmacokinetics of clonidine

A 300‐µg oral dose of clonidine was administered to 5 normal volunteers and measurements of plasma concentration and effects upon blood pressure, heart rate, circulatory reflexes, sedation, and dry mouth were made for the following 8 hr. The plasma concentration rose to a peak of 1.02 ± 0.52 ng/ml (SD) at 90 min andfell with a mean half‐life of 12.7 hr. Blood pressure of the group fell from 111.0/77.0 to 87.2/60.4 after 3 hr and was 95.2/62.2 mm Hg at 8 hr. Heart rate in recumbency was slowed. Marked sedation and a fall in sativary flow followed the same time‐course as the plasma concentration. The cold pressor response was reduced but the Valsalva overshoot was tiftle affected.

Pharmacokinetics and concentration‐effect relationships of intravenous and oral clonidine

The kinetics of the disposition of intravenous and oral clonidine in five normotensive subjects have been determined. It is proposed that a two‐compartment model adequately describes the disposition of the drug. The drug is rapidly distributed (tllza = 10.8 ± 4.7 min) but slowly eliminated (t½β = 8.5 ± 0.9 hr). The bioavailability of oral clonidine in the tablets tested averaged 75.2% and 40 to 50% of the bioavailable dose is excreted unchanged in urine. Renal clearance of the drug showed considerable intersubject variation (1.82 ± 0.34 ml/min/kg) and exceed the calculated glomerular filtration rate in some subjects. Oral and intravenous clonidine induced significant falls in blood pressure (>20/15 mm Hg) in our normotensive subjects and consistently caused marked sedation and dryness of the mouth. Sedation and salivary flow correlated with plasma clonidine concentration over the range 0 to 4 ng/ml. Falls in blood pressure were related to plasma concentration to 1.5 to 2 nglml but at higher concentrations the hypotensive effect was attenuated.

Endothelin-1-Induced Reductions in Cerebral Blood Flow: Dose Dependency, Time Course, and Neuropathological Consequences

The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 μl of 10−7–10−4 M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10−5 M of 9 ± 11 ml 100 g−1 min−1 compared to 104 ± 22 ml 100 g−1 min−1 with vehicle, p < 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 ± 34 mm3 at 10−5 M compared to 0.22 ± 0.57 mm3 for vehicle, p < 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.

Central and peripheral adrenergic mechanisms in the development of deoxycorticosterone-saline hypertension in rats.

The role of the sympathetic nervous system in the development of deoxycorticosterone-sodium chloride (DOCA-saline) hypertension was investigated by measuring plasma levels of norepinephrine, total catecholamines, and dopamine-β-hydroxylase activity at intervals after the initiation of the DOCA-saline regimen. Plasma norepinephrine was significantly higher in DOCA-saline-treated rats at 4 and 7 weeks and in rats treated with saline alone at 4 weeks compared with that in untreated controls. Total plasma catechol-amine levels (epinephrine and norepinephrine) and dopamine-β-hydroxylase activity were similar in hypertensive rats, untreated controls, and rats that received either DOCA or saline alone. The increases in plasma norepinephrine levels may have resulted from centrally mediated increases in peripheral sympathetic neuronal activity, since the destruction of central catecholaminergic neurons with intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) prevented both the DOCA-saline-induced rise in blood pressure and the increases in plasma norepinephrine. Rats treated with 6-OHDA consistently drank less water or saline than did vehicle-treated controls. The actions of centrally administered 6-OHDA on blood pressure and plasma norepinephrine levels were not secondary to a reduction in salt intake, however, since intact rats given a similar reduced saline intake became hypertensive and demonstrated elevated plasma norepinephrine concentrations. Chronic salt loading may cause a centrally mediated increase in peripheral sympathetic neuronal activity with raised plasma concentrations of norepinephrine. The increased adrenergic activity in the presence of mineralocorticoid-induced sodium retention leads to the development of hypertension.

White-coat hypertension as a cause of cardiovascular dysfunction

BACKGROUND The increasing use of 24 h ambulatory blood pressure monitoring has allowed diagnosis of white-coat hypertension, in which blood pressures are higher on clinic measurements than on ambulatory monitoring. Treatment is not generally thought to be necessary for this disorder. However, there is evidence that patients with white-coat hypertension develop renal impairment and left ventricular hypertrophy. We undertook this study to assess whether white-coat hypertension, in the absence of cardiovascular structural abnormalities, is associated with cardiovascular functional abnormalities. METHODS Cardiovascular function was assessed by ultrasonography in three groups of patients classified as normotensive, persistently hypertensive, or white-coat hypertensive (23, 20, and 22 patients, respectively) on the basis of ambulatory blood pressure monitoring, carried out for 28 h with recordings taken every 15 min during the day and every 20 min during the night, and clinic measurements, made with a semi-automatic oscillometric device. RESULTS Similar abnormalities of diastolic left ventricular function were identified in the patients with persistent hypertension and those with white-coat hypertension; both groups differed in these indices from the normotensive group (E/A ratios 0.94 [SD 0.23], 1.06 [0.21], and 1.24 [0.31] respectively; ANOVA p < 0.005). In addition, the white-coat and persistently hypertensive groups, when compared with the normotensive group, showed similar abnormalities of elasticity, compliance, and stiffness (stiffness index 4.32 [1.90], 4.53 [1.38], and 3.27 [0.95] respectively; ANOVA p < 0.05) of the large arteries. INTERPRETATION Functional cardiovascular abnormalities were identified in white-coat hypertensive patients who had no identifiable structural abnormalities. Such functional abnormalities can be reversed by antihypertensive treatment. We propose that patients with white-coat hypertension might benefit from antihypertensive treatment as well as those with persistent hypertension. This hypothesis should be addressed in prospective clinical trials.

Effectiveness of geriatric rehabilitative care after fractures of the proximal femur in elderly women: a randomised clinical trial.

OBJECTIVE--To compare postoperative collaborative care between orthopaedic surgeons and physicians in geriatric medicine with routine orthopaedic care in elderly women with proximal femoral fracture. DESIGN--Exclusion of patients dying before fit enough to enter trial, those with pathological fractures, those likely to be discharged within seven days of entering the trial, and those remaining unfit for transfer to a peripheral hospital. Remainder allocated to two groups: treatment group and control group. SETTING--District hospital acute admission ward and rehabilitation ward. PATIENTS--144 sequentially admitted elderly women with proximal fracture of the femur; 36 excluded on above criteria and remainder entered into trial. INTERVENTION--Both treatment and control groups (n = 54 in each) received physiotherapy and other services. The treatment group also received thrice weekly supervision by a geriatrician. END POINTS--Physical independence, residence after discharge, and length of hospital stay. MEASUREMENTS AND MAIN RESULTS--At discharge significantly more patients in treatment group were independent in terms of activities of daily living than controls (41 v 25) and their median stay was 24 days (range 8-197) compared with 41 (9-365) (95% confidence intervals for difference 2 to 25). Significantly fewer treatment patients were discharged to institutional care (10% v 32%; 95% confidence interval for difference 6% to 37%) and more to their own homes (63% v 38%; 95% confidence interval for difference 6% to 44%). These beneficial effects were consistent across a range of ages and mental state. CONCLUSIONS--Both hospital and patient benefited when postoperative rehabilitation was provided in a setting specialising in such care for elderly patients with trauma.