J. D. Swales

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty.

Early restenosis in over 30% of cases limits the benefits of percutaneous transluminal coronary angioplasty (PTCA). The mechanisms that underlie restenosis are uncertain, although experimental evidence suggests that the renin-angiotensin system is involved in the vascular response to angioplasty. An insertion(I)/deletion(D) polymorphism in the angiotensin-converting enzyme (ACE) gene, which influences plasma ACE level, has been associated with an increased risk of myocardial infarction in those with the DD genotype. To investigate whether this polymorphism influences the risk of restenosis after PTCA, 233 patients who underwent single-vessel angioplasty in the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) study were genotyped for the I/D polymorphism and pre-PTCA, post-PTCA, and 4-month clinical and quantitative angiographic data were compared in the three genotype groups. The groups, (II 53, ID 117, and DD 63) were well matched for baseline clinical and both pre- and post-PTCA angiographic features. At 4-month follow-up there was no significant difference between the genotype groups with respect to any of the quantitative angiographic criteria of restenosis: minimal luminal diameter at the site of the angioplasty (DD 1.35 [SE 0.10] mm, ID/II 1.43 [0.05] mm, difference -0.08 [95% CI -0.30 to 0.14]), numbers of subjects with more than 50% diameter stenosis (DD 49%, ID/II 46%, relative risk 1.06 [0.79 to 1.43]), or the number of subjects with more than 50% loss of the acute diameter gain after PTCA (DD 54%, ID/II 43%, 1.26 [0.94 to 1.67]). Likewise, there was no difference in the number of subjects with angina or a positive exercise stress test. We conclude that, in patients undergoing elective PTCA, the I/D polymorphism in the ACE gene does not influence the extent of restenosis, and typing for the polymorphism will not be a useful predictor of risk before the procedure.

Leucocyte membrane sodium transport in normotensive populations: dissociation of abnormalities of sodium efflux from raised blood-pressure.

Sodium efflux rates were measured in leucocytes from eighteen normotensive subjects who had one or more first-degree relatives with essential hypertension and from twenty-four matched controls with no such family history. The total efflux rate constant was significantly lower in those with a family history of hypertension, owing to reduced ouabain-sensitive sodium pump activity. The presence of a membrane electrolyte handling abnormality characteristic of essential hypertension in normotensive individuals genetically predisposed to hypertension points to an underlying genetic factor. At the same time, the fact that blood-pressure was normal in these subjects indicates that the abnormality does not participate directly in blood-pressure elevation. Rather, the abnormality, like other red-cell changes in electrolyte handling, seems to be a marker for a genetically determined alteration in membrane structure, and thus only indirectly related to hypertension.

Current clinical practice in hypertension: The EISBERG (Evaluation and Interventions for Systolic Blood Pressure Elevation—Regional and Global) project ☆ ☆☆ ★

Hypertension is one of the major treatable factors contributing to the burden of disease worldwide. However, despite national programs to encourage detection and treatment, there are still shortcomings in hypertension management. A large proportion of these can be attributed to socioeconomic factors, professional shortcomings, and patient noncompliance with management regimens. The Evaluation and Interventions for Systolic Blood pressure Elevation-Regional and Global (EISBERG) project was conceived to examine the reasons for suboptimal management of hypertension in more detail. Emphasis was placed on control of elevated systolic blood pressure because this is often neglected despite evidence that it is more important than diastolic pressure in predicting cardiovascular risk. The goals of the project include analysis of the relative importance of systolic and diastolic blood pressure as cardiovascular risk factors, identification of any necessary changes in practice, and the development and implementation of programs to promote appropriate changes in practice or attitudes. The three components of the initiative are a formal collection of epidemiologic evidence to examine the relation between systolic blood pressure and outcome; a cross-sectional, quantitative database (CardioMonitor) providing information on the treatment of patients with cardiovascular diseases including hypertension in seven countries, and qualitative research into hypertension management to assess attitudes, awareness, and knowledge among primary care physicians, patients and their carers. The study showed more effort was directed toward control of diastolic than systolic blood pressure. Adequate control of systolic blood pressure was seldom achieved. Blood pressure targets tended to be raised in elderly patients in conflict with recommendations and evidence that there is greater benefit in treating hypertension more aggressively in this population. Despite awareness of guidelines for treating hypertension, doctors were unsuccessful in practice.

REVERSIBLE HYPERTENSION AND HYPOTHYROIDISM

Six patients with hypothyroidism and hypertension whose blood pressure fell to normal when treated with thyroxine (172.7.2/112.2.1 to 140.3.2/84.1.6 mmHg, P<0.001) are described. Plasma renin activity (1.76±0.63 ng angiotensin I.ml−1.h−1) was low before treatment. Hypertension with low plasma renin is consistent with sodium retention. Hypertension in the hypothyroid patient only requires further evaluation if it persists after adequate treatment with thyroxine.

LOW-RENIN HYPERTENSION : NEPHROSCLEROSIS ?

A substantial group of patients with essential hypertension have abnormally low renin levels which respond poorly to stimulation. Important differences in response to therapy and in prognosis have been described between these and other hypertensive patients. It is suggested that the vascular changes of nephrosclerosis, which may be seen in both hypertensive and normal subjects, result in a reduction of afferent arteriolar distensibility, with impairment of basal renin secretion and responsiveness. This hypothesis accords with both of the known clinical characteristics of low-renin hypertension and with the known effect of arterial changes upon the activity of other baroreceptors.

Comparison of Angiotensin II Antagonist and Antiserum Infusion with Nephrectomy in the Rat with Two-Kidney Goldblatt Hypertension

Factors responsible for maintaining blood pressure were studied in rats with one renal artery constricted and the contralateral kidney intact. Rats with short-term ( < 3 weeks) and chronic (> 4 months) hypertension were infused with angiotensin II antiserum until the pressor effect of exogenous angiotensin II was blocked. The blood pressure response to an infusion of an angiotensin antagonist (1-Sar-8-Ala-angiotensin II) was then recorded. Blood pressure was also measured following subsequent unilateral nephrectomy (ischemic kidney). Antiserum produced a small, sustained, nonsignificant fall in mean blood pressure, whereas the antagonist produced a major reduction. In rats with short-term hypertension, the antagonist reduced blood pressure to normal or near-normal levels. In rats with chronic hypertension, mean blood pressure fell but still remained above the upper limit of the normal range. Removal of the ischemic kidney produced a fall in blood pressure to a mean level close to that obtained after antagonist infusion. Mean cumulative sodium balance in the rats with short-term hypertension was slightly negative. On the basis of this and previously reported work, it is suggested that angiotensin II is generated at a vascular site which is inaccessible to antibody but readily accessible to antagonist. Moreover, since the effects of angiotensin II antagonist and nephrectomy do not differ significantly, it seems that the ischemic kidney sustains hypertension in this two-kidney model through activity of the renin-angiotensin system, although extrarenal factors assume greater importance when blood pressure remains elevated for longer periods.

Population advice on salt restriction: the social issues

The scientific evidence that underlies public health advice depends upon critical integration of information from several sources. The most informative evidence relating to the effects of population reduction in salt intake comes from systematic reviews of clinical trials. Recent rigorous reviews of salt restriction trials in normal subjects show extremely small effects ranging from 1 to 2 mm Hg for systolic blood pressure and 0.1 to 1.0 mm Hg for diastolic pressure. These are the result of much greater reductions in sodium intake than can be achieved by population advice, and may be further amplified by publication bias and effects of changes in other dietary components. There is little trial evidence to enable possible benefits and adverse effects to be balanced. Reviews biased by the inclusion of nonrandomized studies exaggerate the apparent blood pressure fall 5- to 50-fold and create spurious apparent progressive falls in blood pressure. Nevertheless, citation analysis shows that they are quoted much more frequently than rigorous reviews reaching more negative conclusions. This appears to be the result of an attempt to create an impression of scientific consensus. The salt debate has important implications for social policy.

Vascular angiotensin II receptors and sodium balance in rats. Role of kidneys and vascular renin activity.

The relationship between the vascular response to angiotensin II and sodium balance was studied by measuring the volume of specific antiserum needed to block the pressor response to a standard dose of angiotensin II in rats. In normal rats, sodium depletion reduced the volume of antiserum required to prevent a pressor response to 50 ng of angiotensin II from 0.32 to 0.22 ml; sodium loading increased the volume required to 0.65 ml. After bilateral nephrectomy, there was a progressive increase in the antibody requirement to a maximum of 0.63 ml at 6 hours. At this stage, there was no change in the blocking requirement with sodium depletion by either pretreatment with a low-salt diet (0.60 ml) or peritoneal dialysis (0.62 ml). The pressor response to a 50-ng bolus of angiotensin II was closely correlated with the antibody requirement in all experiments (r = + 0.93). These observations indicate that sodium-induced changes in the vascular response to angiotensin II require the presence of kidney tissue. We suggest that such changes in response are mediated by alterations in vascular renin which generates angiotensin II at an arteriolar site that is not accessible to antibody molecules. This locally formed angiotensin II reduces the number of receptors free to respond to circulating angiotensin II and raises the threshold of the pressor response.

Vascular renin-angiotensin system: the unanswered questions.

Study of the vascular renin-angiotensin system can be approached in a number of ways. The capacity of the blood vessel to generate angiotensin II, when exposed to angiotensinogen, immunocytochemical demonstration of renin, the presence of renin mRNA and functional changes attributable to local generation of angiotensin have all been used. Although each of these techniques requires careful and critical examination from the standpoint of specificity and sensitivity, there is now strong evidence for a functionally important system in the arterial wall. The relative importance of uptake and local synthesis and the physiological role of this system, as distinct from the renal renin system, still remains to be elucidated.

The hunt for renal hypertension.

The proportion of cases of hypertension with a renal cause which can be corrected by surgery is very small. Radiological diagnosis of such a cause is expensive and time-consuming; hence the rewards of intensive investigation are small compared with the cost. Measurement of plasma-renin offers a good method of selecting those patients who require further investigation, if the cut-off point is carefully considered in the light of the acceptable incidence of false-positive and false-negative results.