Jean E. Sealey

Association of the Renin-Sodium Profile with the Risk of Myocardial Infarction in Patients with Hypertension

BACKGROUND To test the prognostic value of plasma renin activity prospectively, we determined the pretreatment renin-sodium profile of 1717 subjects with mild-to-moderate hypertension (mean age, 53 years; 36 percent white; 67 percent men) in a systematic work-site treatment program. METHODS Renin profiles, obtained by plotting plasma renin activity against the urinary excretion of sodium, were classified as high (12 percent of the subjects), normal (56 percent), and low (32 percent), and there were expected variations according to age, sex, and race. Modified stepped-care treatment for hypertension, prescribed without reference to the renin profile, was similar in the three renin groups. RESULTS Mean (+/- SD) blood pressure at entry was 151 +/- 19/100 +/- 10 mm Hg in the subjects with a high renin profile, 151 +/- 19/97 +/- 10 mm Hg in those with a normal profile, and 151 +/- 20/96 +/- 11 mm Hg in those with a low profile. During 8.3 years of follow-up, there were 27 myocardial infarctions. As adjusted for age, sex, and race, the incidence of myocardial infarction per 1000 person-years was 14.7 among the subjects with a high renin profile, 5.6 among those with a normal profile, and 2.8 among those with a low profile (rate ratio for high vs. low, 5.3; 95 percent confidence interval, 3.4 to 8.3). The rate of mortality from all causes was 9.3 in the high-profile group, 5.3 in the normal-profile group, and 3.9 in the low-profile group. The independent association of a high renin profile with myocardial infarction (but not with stroke or noncardiovascular events) was affirmed by Cox analyses (rate ratio for high vs. normal plus low, 3.2; 95 percent confidence interval, 1.2 to 8.4) after adjustment for race, sex, age at entry, serum cholesterol level, smoking status, electrocardiographic evidence of left ventricular hypertrophy, blood glucose level, body-mass index, history of cardiovascular disease or treatment, blood pressure, and use of beta-blockers. CONCLUSIONS In the study population, whose blood pressure before and during treatment was in a narrow range, and after other cardiovascular risk factors had been considered, the renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction.

Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients

Although the role of the renin-angiotensin system in the pathogenesis of hypertension remains a subject of active investigation and debate, there is increasing recognition that pharmacological inhibition of the system can be a potent mechanism by which blood pressure can be lowered. Buhler and coworkers,1 in examining the renin-lowering effect of β-adrenergic blockade in patients with essential and malignant hypertension, found that propranolol in low to moderate doses lowers blood pressure in high an normal renin forms of hypertension but does not significantly lower blood pressure in low renin hypertensive pateints. These findings have been confirmed by many investigators using propranolol and a variety of other β-blocking agents.2–4 It is also now apparent that propranolol can actually raise blood pressure in some patients with low levels of renin activity.5

Divalent cations in essential hypertension. Relations between serum ionized calcium, magnesium, and plasma renin activity

We studied the relation of plasma renin activity to serum levels of ionized calcium and magnesium in 102 normotensive patients and in 98 patients with essential hypertension who were divided into low-renin, normal-renin, and high-renin groups. Serum magnesium levels were higher in patients with low-renin hypertension and lower in patients with high-renin hypertension than in those with normal-renin hypertension (P less than 0.025 for both comparisons) or in normotensive controls (P less than 0.005, P less than 0.05, respectively). In contrast, serum levels of ionized calcium were lower in patients with low-renin hypertension and higher in patients with high-renin hypertension than in those with normal-renin hypertension (P less than 0.001, P less than 0.05, respectively) or in normotensive controls (P less than 0.001, P less than 0.05, respectively). Altogether, the range of plasma renin activity in essential hypertension shows a continuous negative correlation with the serum magnesium level (r = -0.60, P less than 0.001) and a positive correlation with the serum ionized calcium level (r = 0.44, P less than 0.001). Accordingly, plasma renin activity in hypertension may reflect or contribute to changes in calcium and magnesium fluxes across cell membranes.

An Angiotensin Converting-Enzyme Inhibitor to Identify and Treat Vasoconstrictor and Volume Factors in Hypertensive Patients

Abstract The antihypertensive action of nonapeptide competitive inhibitor of angiotensin-1-converting enzyme was evaluated in 13 hypertensive patients. In 12 a single injection (1 to 4 mg per kilog...

Renovascular hypertension: renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability.

Abstract Twenty-nine hypertensive patients with renal arterial stenosis were evaluated preoperatively with determinations of peripheral renin activity and differential renal vein renin levels. Three indicators were defined and evaluated to identify renovascular hypertension and to predict its curability: (1) an abnormally high peripheral plasma renin activity in relation to sodium excretion indicating increased renin secretion, (2) complete suppression of renin secretion (V−A ~ O) from the contralateral uninvolved kidney, and (3) an abnormally increased renal vein renin content relative to arterial renin from the suspect kidney [(V−A)/A > 0.48] which reflects and can be used to estimate the degree of renal ischemia, provided there is complete suppression of renin secretion from the contralateral uninvolved kidney. Each of the three indices, taken separately, are subject to sufficient technical variability to make them somewhat unreliable. Accordingly, a scoring system has been devised which weighs information contributed by each of the three indicators that appears to provide a high order of predictability of cure of renovascular hypertension. In 19 adult patients, in whom all three indices were measured, this scoring system predicted surgical cure in 13 of 13 (100 per cent), as well as lack of cure in 5 of 5 (100 per cent) and identified a technical error in 1. Altogether this analysis of the data supports the view that abnormal renin secretion is intimately involved in the pathogenesis of curable renovascular hypertension in man.

Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy

Abstract Sixty-nine pregnant women were studied sequentially throughout pregnancy and again four to six weeks postpartum. Average blood pressures were lower during pregnancy than postpartum, with diastolic pressures reduced more than systolic pressures. The lowest pressures occurred close to the 28th week of gestation and then tended to return towards nonpregnant levels. Increases in blood pressure that occurred during a change in position from the left lateral recumbent to the supine position did not predict subsequent hypertension in pregnancy; in 51 patients in whom diastolic blood pressure increased by 20 mm Hg or more with this maneuver, hypertension did not develop. Monthly plasma sampling in 19 patients revealed marked stimulation of the renin-aldosterone system, which became maximal in the third trimester. Plasma renin activity (PRA) increased sevenfold over nonpregnant levels. About 50 per cent of this increase could be attributed to an increase in plasma renin substrate. Mean plasma renin substrate increased by fourfold, plasma aldosterone by eightfold, whereas urinary aldosterone excretion increased even more. Both urine and plasma aldosterone correlated with increasing PRA. Plasma progesterone, estradiol and estriol also progressively increased throughout pregnancy and were correlated closely with each other. Altogether, these studies describe an early and sustained stimulation of the renin-aldosterone system in normal pregnancy that is independent of changes in sodium or potassium excretion. The increases observed in PRA are of lesser magnitude and are more consistent throughout pregnancy in individual subjects than previously reported, perhaps because inadvertent cryoactivation of inactive renin was avoided prior to renin measurement. Increases in the renin system activity in pregnancy very likely involve increased stimulation of renal renin secretion consequent to hemodynamic and fluid volume changes which tend to compromise effective arterial blood volume and pressure. These data provide base line patterns for study of the pathogenesis of hypertensions and toxemias of pregnancy.

Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects: Role of fibrinogen and concentration

Blood pressure and components of blood viscosity were measured in 49 normal subjects and in 49 untreated patients with essential hypertension. Blood viscosity values measured at six different shear rates were significantly correlated with blood pressure (r = 0.432 to 0.505, p less than 0.001). Blood viscosity was higher in hypertensive patients. This was due to both higher plasma viscosity (1.29 +/- 0.08 standard deviation versus 1.24 +/- 0.05 centipoise (cPs), p less than 0.001) and increased hematocrit values (44.4 +/- 4 percent versus 41.5 +/- 3 percent, p less than 0.005). When blood viscosity was evaluated in subgroups of normal and hypertensive subjects with matched hematocrit values, it remained higher in the hypertensive patients, and the relationship between blood pressure and viscosity was still significant. Regardless of the hematocrit value, fibrinogen levels were elevated in hypertensive patients (p less than 0.006) and, in association with the increased globulin concentration, fibrinogen was largely responsible for the increased plasma viscosity in hypertensive patients. Since the viscosity of defibrinated blood was similar in normal and hypertensive subjects with matched hematocrit values, the elevated fibrinogen level also affected whole blood viscosity. Defibrinated blood viscosity and arterial pressures were not correlated. These studies demonstrate a direct correlation between blood pressure and blood viscosity among normotensive and hypertensive subjects. This relationship is, in part, due to the rheologic effects of an elevated fibrinogen level and to an increased hematocrit value. The basis for hyperfibrinogenemia in hypertensive patients is unclear.

Diagnosis and Treatment of Primary Hyperaldosteronism

Primary aldosteronism is characterized by hypertension, hypokalemia, and low plasma renin activity and is most commonly caused by an adrenal adenoma that produces aldosterone. The plasma aldosterone level of affected patients usually fails to increase when renin activity increases during either upright posture or infusion of angiotensin II; thus, aldosterone will be secreted independently from the renin-angiotensin system [1]. A less common cause of this syndrome is idiopathic hyperaldosteronism, characterized by nonadenomatous hyperplasia and low plasma renin activity, in which the adrenal gland usually responds to angiotensin II. However, this syndrome has considerable phenotypic heterogeneity, with diagnostic variants differing from the more typical forms by their responsiveness to angiotensin. For example, a subset of adrenal hyperplasia mimics an aldosteronoma because it is associated with angiotensin-independent aldosterone overproduction and can be cured by unilateral adrenalectomy [2]. Conversely, some adenomas respond to angiotensin; Tunny and colleagues [3] have correlated the magnitude of this aldosterone response with the proportion of glomerulosa cells present in the tumor. This biochemical diversity is also manifested by characteristic patterns of steroid metabolism. In adenomas, levels of C-18 methyl oxidation metabolites of cortisol (18-oxocortisol and 18-hydroxycortisol) exceed those in idiopathic hyperaldosteronism and were elevated in patients with hyperplasia who were cured by adrenalectomy [4, 5]. The presence of an adrenal adenoma that produces aldosterone is considered the major clinical characteristic distinguishing primary aldosteronism that is curable by surgery. Refinements of imaging techniques have facilitated the detection of subtle adrenal abnormalities early in the clinical course. Coordinated use of these diagnostic approaches should improve the ability to determine which patients are likely to be cured by adrenalectomy. However, several studies have shown that the chances for curing hypertension are less predictable than those for the related biochemical abnormalities. Accordingly, these studies showed that only 50% of patients with adenomas were normotensive 5 years after adrenalectomy and that older patients were more likely to require postoperative antihypertensive medications [6, 7]. The clinical and biochemical diversity of this syndrome has important implications regarding its pathophysiology and responsiveness to therapy. We sought to characterize patients with primary aldosteronism who are followed at The Cardiovascular Center at The New York Hospital-Cornell Medical Center to identify features that would predict favorable responses to treatment and to attempt to understand why adrenalectomy often fails to produce a sustained reduction in blood pressure. Methods Patients A retrospective analysis of the medical records at The Cardiovascular Center of The New York Hospital-Cornell Medical Center indicated that 82 patients with primary aldosteronism were evaluated from 1976 to 1991. This diagnosis was established by the following criteria: 1) hypertension; 2) elevated rates of urinary aldosterone excretion as determined by an established nomogram that relates 24-hour urinary sodium excretion with urinary aldosterone and plasma renin activity [8]; 3) low renin activity [in most patients]; and 4) hypokalemia that was either spontaneous or diuretic-induced and associated with inappropriate renal potassium loss (>40 mmol/d). Diagnoses Adenomas (n = 52) were diagnosed when an adrenal tumor was observed by contrast-enhanced computed tomographic (CT) scan. When possible, this was corroborated by lateralization of adrenal aldosterone secretion by adrenal vein sampling or evidence of functional autonomy, defined by a failure of the plasma aldosterone level to increase when the patient was in upright posture. An adenoma was confirmed surgically in 47 patients. Five patients had radiographic and biochemical features that indicated adenoma, but they refused surgery and were treated medically. Idiopathic hyperaldosteronism was diagnosed in 22 patients whose CT scans showed unilateral or bilateral adrenal hyperplasia without an adenoma. These patients were treated with antihypertensive medication. Eight additional patients with nonadenomatous hyperplasia had adrenalectomy because their preoperative evaluation suggested an adrenal adenoma; 3 of these 8 patients had adrenal sampling and lateralized aldosterone secretion. Biochemical Studies In 56 patients (34 with adenomas and 22 with hyperplasia), medications were withdrawn approximately 2 weeks (for spironolactone, at least 1 month) before hemodynamic, biochemical, and hormonal evaluation. Dietary intake of sodium and potassium was not controlled in most patients during their evaluation. Hormonal profiling was usually done when patients were hypokalemic, although some received potassium supplements. Demographic, blood pressure, and biochemical data from 26 patients (18 with adenomas and 8 with idiopathic aldosteronism) who did not discontinue drug therapy before treatment were excluded from the statistical analysis of pretreatment diagnostic features. Assays for plasma renin activity [9], urinary and plasma aldosterone [10, 11], cortisol (Coat-A-Count Cortisol, Diagnostic Products Corporation, Los Angeles, California; 12), and atrial natriuretic peptide levels [13] have been described previously. In our laboratory, a plasma renin activity of 0.15 ng/mL per hour is at the lower limit of detection. We recently reported urinary excretion rates of 18-hydroxycortisol and 18-oxocortisol from 42 patients with primary aldosteronism [5]. We evaluated the clinical characteristics of a subset of these patients (15 with adenomas and 9 with hyperplasia) and include here the levels of these cortisol metabolites. A positive postural stimulation test result was defined by an ambulatory plasma aldosterone level that was either lower than the supine baseline level or that was increased less than 30% above that value [14]. For this test, plasma samples for aldosterone, renin, and cortisol were obtained from supine patients at 0800 h before they arose from their overnight recumbency, and again after 2 hours of ambulation. We excluded data from analysis if plasma cortisol and aldosterone levels simultaneously increased (for cortisol levels, an increase >30% greater than supine levels) because an increase in cortisol levels after 0800 h indicates a stress adrenocorticotropin hormone response that can also increase aldosterone secretion. We obtained adrenal vein aldosterone samples using percutaneous catheterization. Adrenal vein catheterization was considered successful when the plasma cortisol level from the adrenal vein was two times higher than the level from the inferior vena cava [15]. The mean plasma cortisol level for the adrenal vein was more than 10 times higher than that from the inferior vena cava (256 g/dL compared with 16 g/dL [difference, 240g/dL; CI of the difference, 320g/dL to 160g/dL; P < 0.001]). We defined lateralization of adrenal aldosterone secretion as a ratio of adrenal vein (aldosterone/cortisol levels)/inferior vena cava (aldosterone/cortisol levels) greater than 1.0 from the ipsilateral adrenal vein and 1.0 or less from the contralateral adrenal vein [16, 17]. Clinical Outcomes We considered hypertension to be cured when blood pressure decreased to 140/90 mm Hg or less after adrenalectomy and if postoperative antihypertensive medication was not required, to be improved when systolic pressure decreased by at least 10 mm Hg and diastolic pressure decreased by more than 5 mm Hg after adrenalectomy or medication, or to be not improved when the preceding criteria were not met after treatment. Statistical Analysis We used unpaired t-tests to compare baseline blood pressure and hormonal values between groups and used paired t-tests to compare treatment-related changes in these variables within groups. We calculated 95% confidence intervals for the differences in sample means. Chi-square analysis was used to evaluate differences in the numbers of patients in the diagnostic groups for demographic, blood pressure, and laboratory characteristics. Results Patient Characteristics Demographics Of the 82 patients with primary aldosteronism, 52 had adenomas and 30 had hyperplasia. Patients with adenomas were younger (46 years compared with 54 years [difference, 8 years; CI, 6 years to 10 years]). The sex and race distributions were similar in both groups. The 56 patients (34 with adenomas and 22 with nonadenomatous hyperplasia) who were studied after therapy with antihypertensive medication was discontinued were representative of all 82 patients with primary aldosteronism. Blood Pressure Patients with adenomas had higher mean systolic and diastolic blood pressures Table 1, although moderate to severe hypertension was common in both groups. After medical therapy was discontinued, systolic blood pressure was 175 mm Hg or greater in 66% of patients with adenomas but only in 15% of patients with hyperplasia (P < 0.001). Diastolic pressure was 114 mm Hg or greater in 50% of patients with adenomas and in 19% of those with hyperplasia (P = 0.09). Table 1. Blood Pressure and Laboratory Values before Treatment Renal Disease Baseline creatinine clearance was similar in both groups (1.88 mL/s for the adenoma group and 1.65 mL/s for the hyperplasia group; P = 0.18). Only one patient had an elevated serum creatinine level (>141.4 mol/L [1.6 mg/dL]). However, pathologic levels of proteinuria or microalbuminuria, defined as a daily protein excretion of greater than 0.2 g or an albumin excretion of greater than 0.03 g, were observed in more than 40% of patients in both groups. The most abundant proteinuria (1.5 g every 24 hours) occurred in the patient with adenoma who had the highest plasma renin activity (2.1 ng/mL per hour), although mean plasma renin activ

Possible Role of Renin in Hypertension as Suggested by Renin-Sodium Profiling and Inhibition of Converting Enzyme

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.

The captopril test for identifying renovascular disease in hypertensive patients

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.