Implications of pulse pressure as a predictor of cardiac risk in patients with hypertension.

Previously we demonstrated that pulse pressure is a strong risk factor for coronary events in male hypertensive subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. In this study, we have assessed the implications of this finding in the treatment of mild essential hypertension. We examined the relationship between diastolic blood pressure and both coronary disease risk and stroke when these events were predicted by the above blood pressure measures using an empirical linear model and multivariate logistic regression models that contained data from the MRC trial. Under these circumstances, the predicted stroke risk increased progressively with increasing values of diastolic blood pressure, but in both empirical and formal statistical models, the predicted risk of a coronary event exhibited a J-shaped relationship with diastolic blood pressure. These results suggest that if coronary event risk in mild essential hypertension is predicted by pulse pressure then it may increase at low values of diastolic blood pressure, in contrast to stroke risk, which declines continuously as diastolic blood pressure falls within the physiological range. This raises the possibility that different sequelae of hypertension are best predicted by different measures of blood pressure and that the effect of treatment on stroke and coronary events in some circumstances may be discordant.

Glomerular hyperfiltration, high renin, and low- extracellular volume in high blood pressure.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial.

OBJECTIVES: The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension, and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients. METHODS: Logistic regression and Cox regression analyses were used to compare systolic and diastolic blood pressure, pulse pressure and mean blood pressure as predictors of coronary events and stroke in the MRC Mild Hypertension Trial. The effects of anti-hypertensive drug treatment with bendrofluazide and propranolol on pulse pressure were assessed using 1-year follow-up data. Event rates in the placebo-treated group and responses to anti-hypertensive treatment were measured in quartiles of age-adjusted entry pulse pressure. A 'four-corners' analysis was performed, with subjects divided into the upper and lower halves of the distributions of systolic and diastolic blood pressure at entry. RESULTS: Pulse pressure was a stronger predictor of coronary events than systolic, diastolic or mean blood pressure in males by logistic regression. Pulse pressure was similar to systolic pressure as a coronary event predictor on Cox regression. Stroke was predicted most strongly by mean blood pressure. Fatal and non-fatal coronary event rates increased progressively in ascending quartiles of age-adjusted pulse pressure, but there was also a strong correlation with systolic blood pressure. The values of partial logistic regression coefficients in models containing both systolic and diastolic blood pressure also supported a role for pulse pressure in predicting coronary events and for mean blood pressure in predicting stroke. Coronary risk, but not stroke, was inversely related to diastolic blood pressure in the four-corners analysis. In a Cox model, regressions of coronary event probability on systolic blood pressure at entry were significantly and inversely related to diastolic blood pressure categorized in quartiles. Bendrofluazide but not propranolol decreased pulse pressure significantly and was associated with a reduction in cardiovascular events overall, but no definite relationship between the effect of drugs on pulse pressure and specific responses to treatment was seen. CONCLUSION: Pulse pressure is a strong risk factor for coronary events in untreated hypertensive male subjects in the MRC Mild Hypertension Trial, whereas stroke is best predicted by mean blood pressure. Bendrofluazide and propranolol have different effects on pulse pressure which may be related to their relative efficacy in the treatment of hypertension, but this possibility requires further study in more suitable populations.

Mortality amongst patients of the Glasgow Blood Pressure Clinic was high in the 1970s and 80s but has fallen since, why?

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23-1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.

Is cancer related to hypertension or to its treatment?

Three questions related to cancer and blood pressure are discussed. (i) Is cancer related in some way to hypertension, or to blood pressure? Several studies show a relation of blood pressure and cancer in populations. However, our own experience, based on a cohort of 15,411 subjects with BP measured in the 1970s and with 1,392 fatal cancers since, shows no relation of cancer risk and diastolic pressure. Nor were cancer numbers (n=72) observed in the 1,078 untreated hypertensives of the Glasgow Blood Pressure Clinic different from those expected (n=71.2) in a control population matched for age, sex and smoking habit. (ii) Do antihypertensive drugs promote cancer? Atenolol and calcium channel blockers have been suspected of this, but evidence of larger studies, including two of our own, is negative: relative risk for cancer in our patients taking CCB was 1.02 (CI 0.82-1.27). (iii) Do antihypertensive drugs protect against cancer? A study of ours based on the Glasgow Clinic raises this possibility: relative risk for incident cancer amongst 1,559 patients taking ACE inhibitor was 0.72 (CI 0.55-0.92).

Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?

BACKGROUND: Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs. METHODS: Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry. FINDINGS: Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 (95% CI 0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, beta-blockers 2681), the corresponding relative risks were 110 (0.97-1.22) and 1.03 (0.87-1.20). The relative risk of cancer was lowest in women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer; 0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and beta-blockers had no apparent effect on risk of cancer. INTERPRETATION: Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

Cancer risk of hypertensive patients taking calcium antagonists.

OBJECTIVE: To measure rates of incident and fatal cancer in hypertensive patients taking calcium antagonists and to compare these with rates in three control groups. DESIGN: A retrospective analysis of cancer in patients of the Glasgow Blood Pressure Clinic prescribed either a calcium antagonist or other antihypertensive drugs (non-calcium antagonist group). Record linkage of the clinic with the West of Scotland Cancer Registry and with the Registrar General, Scotland provided information on incidence of cancer and on deaths and their causes. PATIENTS: 2297 patients were prescribed calcium antagonist and 2910 were prescribed antihypertensive drugs other than calcium antagonist. MAIN OUTCOME MEASURES: Relative risk of cancer, the ratio of observed to expected cancers in the calcium antagonist group, was estimated using expected values based on three control groups; namely the non-calcium antagonist group, a middle-aged population of Renfrew and Paisley and the West of Scotland population. RESULTS: There were 134 incident cancers in the calcium antagonist group, representing relative risks of 1.02 [95% confidence interval (CI) 0.82-1.271 compared with the non-calcium antagonist group, 1.01 (95% CI 0.84-1.18) compared with Renfrew-Paisley controls and 1.02 (95% CI 0.85-1.19) compared with West of Scotland controls. Findings for cancer mortality were similarly negative. Risks were no higher for older patients. CONCLUSIONS: Our study lends no support to the suggestion that calcium antagonists cause cancer.

Abnormal epinephrine release in young adults with high personal and high parental blood pressures.

BACKGROUND: Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. METHODS AND RESULTS: Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. CONCLUSIONS: Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

Serum potassium, cigarette smoking, and mortality in middle-aged men.

The relation between serum potassium level and all-cause mortality was examined in a prospective study of 7,636 middle-aged British men followed for 11.5 years (1978-1991). Men being treated for hypertension had a significantly lower mean (+/- standard error) potassium level than men not in treatment (4.24 +/- 0.03 mmol/liter vs. 4.32 +/- 0.01 mmol/liter; p < 0.01). During the follow-up period of 11.5 years, after exclusion of the 374 men under antihypertensive treatment, there were 771 deaths from all causes in the remaining 7,262 men. A low potassium level (< 3.7 mmol/liter) was not associated with increased mortality. Elevated potassium levels > or = 5.2 mmol/liter were associated with a significant increase in mortality, particularly noncardiovascular deaths, even after adjustment for potentially confounding factors. However, serum potassium was strongly related to smoking, and the increased risk of mortality associated with elevated potassium was seen only among current smokers. In current smokers with raised potassium levels (> or = 5.2 mmol/liter) compared with smokers with levels under 5.2 mmol/liter, the relative risks of mortality were 1.7 (95% confidence interval (CI) 1.2-2.5) for deaths from all causes, 1.8 (95% CI 1.0-3.2) for all cancer deaths, and 2.5 (95% CI 1.1-5.6) for lung cancer deaths. In the 374 men receiving regular antihypertensive treatment, a low potassium level was not associated with excess mortality; those with raised potassium levels had excess risks for both cardiovascular and noncardiovascular deaths. The findings suggest that either raised potassium levels in association with smoking have an influence on the risk of death from noncardiovascular disease, particularly lung cancer, or a raised serum potassium level is a marker for some other risk factor associated with smoking. The prognostic and therapeutic implications of these observations warrant further exploration.

Mechanisms by which the Hawksley random zero sphygmomanometer underestimates blood pressure and produces a non-random distribution of RZ values.

Four faults are reported in the Hawksley Random Zero Sphygmomanometer (RZS). Our study is of their mechanism. (i) Compared with a mercury sphygmomanometer the RZS underestimates blood pressure (BP). We confirm this: for 240 measurements by three experienced operators in 12 patients, systolic BP was 3.4 mm Hg lower in the RZS; diastolic pressure was not underestimated. A cause of under-estimation in 89% of measurements was that mercury stuck in the manometer giving a false high reading of random zero (RZ). Tilting the RZS before reading RZ reduced under-reading by 1.6 mm Hg. A rare cause is failure of the operator to completely close the reservoir tap. (ii) Values of RZ are not randomly distributed; non-randomness is most marked in measurements made by experienced operators whose speed of measurement provides insufficient time during cuff inflation for filling of the diaphragm chamber. Smaller contributions are made by the sticking of mercury in the manometer and by a leak of air through the air bleed screw. (iii) Consecutive RZ estimates often have similar value. This has two causes: short cuff inflation time and short interval between opening the reservoir tap and spinning the thumb-wheel. (iv) An inverse relation of RZ and BP suggested by earlier work and by our own data is probably an artifact: when BP is low, measurement is quick and RZ is falsely high; when BP is high, measurement takes longer and RZ is lower. These four faults could be partly or wholly avoided by a change in the operators' technique.

Low blood pressure in Down's syndrome, A link with Alzheimer's disease?

Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score -33 mm Hg, P < .0001) and DS outpatients (-25 mm Hg, P < .0001). It was normal in non-DS outpatients (-4.0 mm Hg, P = .3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of Ds patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.

Plasma concentrations of inactive renin in adult life are related to indicators of foetal growth.

OBJECTIVES: To determine whether plasma concentrations of inactive and active renin in adult life are related to foetal development. DESIGN: A follow-up study of a group of men and women whose weight and other measurements of body size had been recorded at birth. SETTING: Sheffield, England. SUBJECTS: In total 148 men and women born in the Jessop Hospital, Sheffield, during 1939-40 and now aged 50-53 years. MAIN OUTCOME MEASUREMENT: Plasma concentrations of inactive and active renin in adult life. RESULTS: Plasma concentrations of inactive and active renin in adult life tended to be higher in people who had been large at birth. The strongest relationship was between concentrations of inactive renin and abdominal circumference at birth; the median plasma concentration of inactive renin was 88.5 mu/ml in people whose abdominal circumference at birth had been 13 inches (33.02 cm) or more compared with 61 mu/ml in people whose abdomens had measured 11.5 inches (29.21 cm) or less. CONCLUSION: Impairment of foetal growth is associated with lower plasma concentrations of inactive renin in adult life. Alterations in the activity of the renin-angiotensin system may be a mechanism by which reduced foetal growth leads to raised adult blood pressure.

Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults.

BACKGROUND: We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures. METHODS AND RESULTS: LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01), and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size. CONCLUSIONS: These findings provide evidence in humans that angiotensin II exerts a direct on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.

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 beta-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 beta-blocker, and drugs of both types were well tolerated. There is a strong case for treating elderly hypertensives with a diuretic-based regimen.

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

Adjustment of the apparent benefits of treatment on stroke risk in the MRC mild hypertension trial using data from the placebo-treated group.

Clinical trials show that drug treatment significantly decreases stroke risk in hypertension. The benefit as measured in clinical trials may be affected by changes of blood pressure at entry and by departure from randomised treatment, but the magnitude of such effects is disputed. We have assessed benefit from reduction of stroke using data from the MRC Trial of mild to moderate hypertension, taking these factors into account, and have studied the likely effect of recent guidelines. The original analysis suggested that 850 patients needed treatment for 1 year to prevent one stroke. Under the more conservative of two assumptions made about the effect of treatment, this falls to 695 patients when allowance is made for reduction of stroke in placebo group patients withdrawn and actively treated, to 680 patients when allowance is made for the fall in blood pressure after entry, and to 556 patients with allowance for both. When benefit is assessed in patients whose entry diastolic blood pressure was > or = 100 mm Hg, 557 patients require treatment annually per stroke saved and this is decreased to 360 patients when allowance is made for withdrawal and active treatment of placebo group patients. These results suggest that benefit from reduction of stroke was underestimated in the MRC trial and that this is likely to be present in most trials. Changes to diagnostic criteria for hypertension in new management guidelines are likely to have significant effects on the number of patients treated per stroke prevented.

Blood pressure, 'white-coat' pressor responses and cardiovascular risk in placebo-group patients of the MRC Mild Hypertension trial.

OBJECTIVE AND PATIENTS: To study the relationship between blood pressure and cardiovascular risk in 8654 patients randomly assigned to receive placebo in the Medical Research Council Mild Hypertension trial; 339 patients had a cardiovascular event during 5 years of follow-up. RESULTS: Tracking of blood pressure and regression of blood pressure to and from the mean were demonstrated. Cardiovascular risk was related independently and positively to blood pressure, smoking and cholesterol, and inversely to low-normal plasma sodium. The relationship with blood pressure was stronger when measurements were made at entry to the trial by nurses and weaker when measurements were made by doctors. DISCUSSION: One reason for this finding was that blood pressure increased at entry and, because the rise was greater in females, in whom the risk was lower than in males, a low-risk group predominated in the upper part of the blood pressure distribution. Another reason was that the rise itself conferred little or no cardiovascular risk. This rise might be a 'white-coat' response, because the increase in blood pressure in individuals correlated with the subsequent decrease after entry. CONCLUSION: If the rise is a 'white-coat' effect and if, as the present study suggests, it is common and relatively free from risk, then changes are needed in the design of placebo-controlled trials and in the management of hypertension.