Anthony F. Lever

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.

Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure.

AIM To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people. SUBJECTS Eight hundred and sixty-four people aged 16-24 years and their parents. SETTING Ladywell Medical Centre, Edinburgh, Scotland, UK. METHOD Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine samples were taken for biochemical and genetic analyses. RESULTS Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure). CONCLUSION The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new sampling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.

Mortality in patients of the Glasgow blood pressure clinic

The mortality of 3783 non-malignant hypertensive patients attending the Glasgow Blood Pressure Clinic between 1968 and 1983 and followed for an average of 6.5 years was compared with that in three control groups: the general population of Strathclyde a group of 15 422 subjects aged 45-64 years and screened in Renfrew and Paisley between 1972 and 1976, and a group of hypertensives seen in a blood pressure clinic based on general practice in Renfrew. Average blood pressure for men at entry to the Glasgow Clinic was 181/111 mmHg falling to 158/96 mmHg during treatment. Corresponding values for women were 185/109 mmHg and 161/96 mmHg. Seven hundred and fifty clinic patients (451 males) died during follow-up, the commonest causes of death in both sexes being myocardial infarction and stroke. All-cause age-adjusted mortality (deaths per 1000 patient-years) was 41.4 for men and 22.1 for women. At all ages in both sexes and for all levels of initial blood pressure mortality was less in patients whose blood pressure was reduced most. Without a randomized control group it is not certain that lower mortality in those with well controlled blood pressure was due to treatment, although this is the most likely explanation. Cigarette smoking, a history of myocardial infarction, angina or stroke, retinal arterio-venous nipping, raised blood urea, an abnormal electrocardiogram (ECG) and secondary hypertension were associated with increased risk, but heavy alcohol intake, obesity, haematocrit greater than 45%, hypokalaemia and social class were not. Life table analysis showed that, despite some reduction of mortality by treatment, the relative risk to men and women in the clinic remained two- to five-times that of the general population. The benefits of treatment were not such as to restore normal expectation of life even when blood pressure was well controlled. Excess mortality in the clinic could not be explained by difference of smoking habit or social class. This suggests that there is in the hypertensive patients of the Glasgow Clinic an element of irreducible risk, that treatment may be beneficial in some respects but harmful in others, or that patients at particularly high risk are selectively referred to the clinic.

Essential hypertension: a disorder of growth with origins in childhood?

PURPOSE To review evidence that essential hypertension is a growth-related disorder with origins in childhood and manifestations in adult life. PRINCIPAL EVIDENCE Blood pressure rises with age in children and adults. In children, the rise closely relates to growth and to skeletal and sexual maturation. Adolescents with highest pressure are heavier and had as children grown fastest; as adults, they show the greatest increase of pressure with age and are more likely to develop hypertension and coronary heart disease. In adults, the rate of increase of pressure relates to earlier pressure. One interpretation of this is that a self-perpetuating mechanism is at work. Genetic and environmental factors influence these events. HYPOTHETICAL MECHANISMS Most forms of secondary hypertension have two pressor mechanisms; a primary cause, e.g. renal clip, and a second process, which is slow to develop, capable of maintaining hypertension after removal of the primary cause, and probably self-perpetuating in nature. We suggest that essential hypertension also has two mechanisms, both based upon cardiovascular hypertrophy: (1) a growth-promoting process in children (equivalent to the primary cause in secondary hypertension); and (2) a self-perpetuating mechanism in adults.

Treatment of hypertension in the elderly

Purpose: The outcome of treatment in elderly hypertensives is examined in six major randomized controlled trials. Thiazide diuretics were first- or second-line drugs in each, and P-blockers were first- or second-line drugs in four. Data identification: All compared immediate active treatment, with drugs added stepwise until blood pressure was controlled, versus withholding antihypertensive treatment unless blood pressure exceeded predetermined safety levels. Results of data analysis: Because placebo-treated patients required active treatment and actively treated patients required more than one drug, benefits were underestimated and the comparisons were not of single drugs with each other or with placebo. The incidence of fatal stroke was reduced by 33%, of fatal coronary events by 26% and cardiovascular mortality by 22%. Because cardiovascular risk varied among the trial populations, the absolute benefit from treatment varied markedly. Conclusions: In trials representative of unselected patients, treatment of diastolic hypertension might prevent cardiovascular complications in 1.4-2.2% of patients each year and fatal cardiovascular complications in 0.5-1.3% each year. In isolated systolic hypertension, treatment might prevent cardiovascular complications in 1.1% of patients each year. Generally, diuretic treatment proved superior to treatment with P-blocker, and drugs of both types were well tolerated. There is a strong case for treating elderly hypertensives with a diuretic-based regimen.

Hypertension in chronic renal failure: An abnormal relation between sodium and the renin-angiotensin system

Abstract Hypertensive patients with chronic renal failure show evidence of an abnormal relationship between sodium and the reninangiotensin system in that circulating levels of renin and angiotensin II are abnormally high in relation to exchangeable sodium. The abnormality may well contribute to the hypertension in this syndrome. In a minority of cases blood pressure cannot be controlled by dialysis. In these, renin levels are particularly high and rise even further in response to therapeutic sodium depletion. It is suggested that this may perpetuate the hypertension. In most patients, however, blood pressure can be controlled by dialysis and, in these, renin and angiotensin II levels are lower, but, again, their relation to exchangeable sodium is abnormal. It is suggested that the rise in arterial pressure in this group results from a failure of renin to suppress normally with sodium retention. This would also explain the fall in blood pressure with sodium depletion at hemodialysis. The inflexibility of the renin-angiotensin system in its relation to sodium may be the cause of hypertension as well as the basis for its cure.

Effects of ACTH and Cortisol Administration on Blood Pressure, Electrolyte Metabolism, Atrial Natriuretic Peptide and Renal Function in Normal Man

Both Adrenocorticotrophin (ACTH) and glucocorticoids raise blood pressure in man and animals, but the relationship of this and altered renal function to other cardiovascular variables, and the differences and similarities of the effects of the two agonists have not been fully explained. The present study compares the effects of ACTH (0.5 mg i.m; every 12 h) and cortisol (50 mg orally, every 6 h) in six normal men over a period of 5 days, preceded and followed by control periods of 3 and 2 days, respectively. Plasma cortisol levels were higher during ACTH treatment than during cortisol treatment. Both treatments raised blood pressure significantly and caused a marked antinatriuresis and expansion of extracellular fluid and plasma volume. ACTH also enhanced potassium excretion but this was less obvious for cortisol. Plasma concentrations of atrial natriuretic peptide rose to more than twice the basal level with both treatments. Both treatments markedly altered renal function. They raised glomerular filtration rate (GFR), i.e. inulin clearance (141% with ACTH; 113% with cortisol) although creatinine clearance was not changed, showing this to be an unreliable index during steroid administration. Filtration fraction (FF) also increased during both treatments, and renal blood flow (RBF) fell, although this achieved statistical significance only during cortisol treatment. Effective renal plasma flow [para-amino hippurate (PAH) clearance] remained unchanged while calculated renal vascular resistance increased. Fractional sodium reabsorption also rose but achieved statistical significance only during ACTH treatment. The similarity of response to treatment suggests that cortisol is largely responsible for the effects of ACTH. The respective roles of the marked increases in sodium retention, changes in fluid volume and vascular reactivity in the increases in blood pressure remain to be defined.

Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin.

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery. Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment. In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied. Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped. In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.

Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey.

The relation between plasma cholesterol concentration and mortality from coronary heart disease, incidence of and mortality from cancer, and all cause mortality was studied in a general population aged 45-64 living in the west of Scotland. Seven thousand men (yielding 653 deaths from coronary heart disease, 630 new cases of cancer, and 463 deaths from cancer) and 8262 women (322 deaths from coronary heart disease, 554 new cases of cancer, and 395 deaths from cancer) were examined initially in 1972-6 and followed up for an average of 12 years. All cause mortality was not related to plasma cholesterol concentration. This was largely a consequence of a positive relation between cholesterol values and mortality from coronary heart disease being balanced by inverse relations between cholesterol and cancer and between cholesterol and other causes of death. These changes were highly significant for coronary heart disease and cancer in men and significant for coronary heart disease and other causes of death in women. The inverse association between cholesterol concentration and cancer in men was strongest for lung cancer, was not merely a function of the age at which a subject died, was present for the incidence of cancer as well as mortality from cancer, and persisted when new cases or deaths occurring within the first four years of follow up were excluded from the analysis.

PLASMA RENIN, RENIN SUBSTRATE, ANGIOTENSIN II, AND ALDOSTERONE IN HYPERTENSIVE DISEASE OF PREGNANCY

Abstract Plasma concentrations of renin, renin substrate, angiotensin II, and aldosterone were measured in the peripheral venous blood of women with hypertension and proteinuria in late pregnancy and in a control group of normal pregnant women matched for age, parity, time of gestation, and posture. All four substances were found to be significantly lower in the hypertensive group as compared with normal pregnancy. Therefore, raised circulating levels of renin, renin substrate, angiotensin II, and aldosterone cannot be invoked in the pathogenesis of pregnancy hypertension. This suppression of the renin-angiotensin-aldosterone system in hypertensive disease of pregnancy could represent an adjustment to an increase in the circulating level of some unidentified pressor agent or mineralocorticoid.