Yvette Schlussel

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

Echocardiographic Left Ventricular Mass and Electrolyte Intake Predict Arterial Hypertension

OBJECTIVE To identify predictors of arterial hypertension. PATIENTS One hundred thirty-two normotensive adults from a large employed population. METHODS Echocardiography, standard blood tests, and 24-hour urine collection, at baseline and after an interval of 3 to 6 years (mean, 4.7 +/- 0.8 years). RESULTS At follow-up, 15 subjects (11%; 7 men, 8 women) had a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg or both (mean, 143 +/- 7 and 87 +/- 6 mm Hg, respectively). At baseline, subjects who developed hypertension had a greater left ventricular mass index than those who did not (92 +/- 25 compared with 77 +/- 19 g/m2 body surface area; P less than 0.005) and higher 24-hour urinary sodium/potassium excretion ratio (3.6 +/- 1.7 compared with 2.6 +/- 1.4; P less than 0.04); there were no differences in race, initial age, systolic or diastolic blood pressure, coronary risk factors, or plasma renin activity. The likelihood of developing hypertension rose from 3% in the lowest quartile of sex-adjusted left ventricular mass index to 24% in the highest quartile (P less than 0.005); a parallel trend was less regular for quartiles of the sodium/potassium excretion ratio (P less than 0.04). In multivariate analyses, follow-up systolic pressures in all subjects and in the 117 who remained normotensive were predicted by initial age, systolic blood pressure, black race, and sex-adjusted left ventricular mass index; final diastolic blood pressure was predicted by its initial value, plasma triglyceride levels, urinary sodium/potassium ratio, low renin activity, black race, and plasma glucose level. CONCLUSIONS Echocardiographic left ventricular mass in normotensive adults is directly related to the risk for developing subsequent hypertension. Left ventricular mass improves prediction of future systolic pressure, whereas diastolic pressure is more related to initial metabolic status. Black race is also an independent determinant of higher subsequent blood pressure.

The effect of work environments on blood pressure : evidence from seven New York organizations

The prevalence of hypertension defined according to National Health and Nutrition Examination Survey II (NHANES II) criteria (140/90 mmHg and/or taking antihypertensive medication) was analyzed cross-sectionally at seven worksites in New York City (n = 4274; 2616 men and 1648 women), in order to assess whether exposure to different work environments and occupations contributes to blood pressure variation. The prevalence of hypertension across worksites was 26% among men and 12% among women. Blood pressure was significantly different across worksites even after controlling for known risk factors using analysis of covariance. Of the variation in systolic pressure, 34% was predicted significantly by eight variables; after adjusting for upper-arm circumference, age and body mass index, higher pressures were associated with worksite differences (9.0 mmHg), being male (7.2 mmHg), lacking a high-school education (4.3 mmHg), having a clerical occupation (2.9 mmHg) and being unmarried (1.8 mmHg). Similar results for diastolic pressure suggest that researchers should consider worksite and job characteristics as important predictors of blood pressure differences in working populations.

Assessing cardiovascular risk and stress-related blood pressure variability in young women employed in wage jobs

This overview discusses how aspects of behavior and stressors inherent in the lifestyles of contemporary women affect their cardiovascular health. Three main issues are addressed. The first is the applicability of cardiovascular risk data collected on prior generations of working women in predicting the health outcomes of the current generation of women. It is argued that the earlier data may not adequately describe the health risk of the current generation because of changes in the nature of womens paid employment in recent decades, and because the compartmentalization of economic, leisure, and domestic activities may have affected how stress associated with each influences cardiovascular measures such as blood pressure. Second, the influence of the environment on lifestyle is briefly discussed in the context that differences in the results of studies examining lifestyle stressors may occur as a consequence of local physical and cultural environmental differences which influence lifestyle. Third, the effects of daily microenvironmental changes on blood pressure are discussed and it is argued that perceived socioeconomic roles may influence the cardiovascular response to the stressors inherent in each microenvironment. Because the lifestyles of women change over the lifespan, it is concluded that the impact of lifestyle on cardiovascular risk must be studied at all stages of life.

Occupational Stress and Blood Pressure

The idea that stress may contribute to the development of high blood pressure and heart disease has been considered for many years, but convincing evidence for such an association has been difficult to find. One reason for this is that blood pressure is not a fixed entity but varies considerably from one moment to another. Furthermore, the conventional methods of measuring blood pressure, which typically involve a small number of readings taken in circumstances that are not representative of the normal daily environment, may result in distorted estimates of the true level.