Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion.

BACKGROUND: Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. METHODS: We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using

Relation of dietary salt and aldosterone to urinary protein excretion in subjects with resistant hypertension.

Experimental data indicate that the cardiorenal effects of aldosterone excess are dependent on concomitant high dietary salt intake. Such an interaction of endogenous aldosterone and dietary salt has not been observed previously in humans. We assessed the hypothesis that excess aldosterone and high dietary sodium intake combine to worsen proteinuria in patients with resistant hypertension. Consecutive subjects with resistant hypertension (n=84) were prospectively evaluated by measurement of 24-hour urinary aldosterone (Ualdo), sodium, and protein (Uprot) excretion. Subjects were analyzed according to aldosterone status (high: Ualdo >or=12 microg/24 hours; or normal: <12 microg/24 hours) and dietary salt intake based on tertiles of urinary sodium. The mean clinic blood pressure for all of the subjects was 161.4+/-22.4/89.8+/-13.5 mm Hg on an average of 4.3 medications. There was no blood pressure difference between study groups. Uprot was significantly higher in the 38 subjects with high Ualdo compared with the 46 subjects with normal Ualdo (143.0+/-83.8 versus 95.9+/-81.7 mg/24 hours; P=0.01). Among subjects with high Ualdo, Uprot increased progressively across urinary sodium groups (P<0.05). In contrast, there was no difference in Uprot across sodium tertiles among subjects with normal Ualdo. A positive correlation between Uprot and urinary sodium (r=0.47; P=0.003) was observed in subjects with high Ualdo but not in subjects with normal Ualdo (r=0.18; P value not significant). These results suggest that aldosterone excess and high dietary salt combine to increase urinary protein excretion.

Aldosterone excess and resistance to 24-h blood pressure control.

BACKGROUND: Aldosterone excess has been reported to be a common cause of resistant hypertension. To what degree this represents true treatment resistance is unknown. OBJECTIVE: The present study aimed to compare the 24-h ambulatory blood pressure monitoring (ABPM) levels in resistant hypertensive patients with or without hyperaldosteronism. METHODS: Two hundred and fifty-one patients with resistant hypertension were prospectively evaluated with an early-morning plasma renin activity (PRA), 24-h urinary aldosterone and sodium, and 24-h ABPM. Daytime, night-time, and 24-h blood pressure (BP) and nocturnal BP decline were determined. Hyperaldosteronism (H-Aldo) was defined as suppressed PRA (<1.0 ng/ml per h or <1.0 mug/l per h) and elevated 24-h urinary aldosterone excretion (>/= 12 mug/24-h or >/= 33.2 nmol/day) during ingestion of the patient's routine diet. RESULTS: In all patients, the mean office BP was 160.0 +/- 25.2/89.4 +/- 15.3 mmHg on an average of 4.2 medications. There was no difference in mean office BP between H-Aldo and normal aldosterone status (N-Aldo) patients. Daytime, night-time, and 24-h systolic and diastolic BP were significantly higher in H-Aldo compared to N-Aldo males. Daytime, night-time, and 24-h systolic BP were significantly higher in H-Aldo compared to N-Aldo females. Multivariate analysis indicated a significant interaction between age and aldosterone status such that the effects of aldosterone on ambulatory BP levels were more pronounced with increasing age. CONCLUSIONS: In spite of similar office BP, ABPM levels were higher in resistant hypertensive patients with H-Aldo. These results suggest that high aldosterone levels impart increased cardiovascular risk not reflected by office BP measurements.

Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension.

OBJECTIVE: Obstructive sleep apnea (OSA) and primary aldosteronism are common in subjects with resistant hypertension; it is unknown, however, if the two disorders are causally related. This study relates plasma aldosterone and renin levels to OSA severity in subjects with resistant hypertension, and in those with equally severe OSA but without resistant hypertension serving as control subjects. METHODS: Seventy-one consecutive subjects referred to the University of Alabama at Birmingham (UAB) for resistant hypertension (BP uncontrolled on three medications) and 29 control subjects referred to UAB Sleep Disorders Center for suspected OSA were prospectively evaluated by an early morning plasma aldosterone concentration (PAC) and renin level, and by overnight, attended polysomnography. RESULTS: OSA (apnea-hypopnea index [AHI] > or = 5/h) was present in 85% of subjects with resistant hypertension. In these subjects, PAC correlated with AHI (rho = 0.44, p = 0.0002) but not renin concentration. Median PAC was significantly lower in control subjects compared to subjects with resistant hypertension (5.5 ng/dL vs 11.0 ng/dL, p < 0.05) and not related to AHI. In male subjects compared to female subjects with resistant hypertension, OSA was more common (90% vs 77%) and more severe (median AHI, 20.8/h vs 10.8/h; p = 0.01), and median PAC was significantly higher (12.0 ng/dL vs 8.8 ng/dL, p = 0.006). CONCLUSION: OSA is extremely common in subjects with resistant hypertension. A significant correlation between PAC and OSA severity is observed in subjects with resistant hypertension but not in control subjects. While cause and effect cannot be inferred, the data suggest that aldosterone excess may contribute to OSA severity.

Aldosterone antagonists: effective add-on therapy for the treatment of resistant hypertension.

Resistant hypertension is defined as blood pressure that remains above target levels despite treatment with three different antihypertensive agents. Cross-sectional analyses and hypertension outcome studies indicate that it is a common clinical problem, which will undoubtedly become increasingly prevalent with an aging and increasingly overweight population. Secondary causes of hypertension are common in patients with resistant hypertension, particularly hyperaldosteronism, with a prevalence of approximately 15-20%. This, however, is likely to be an underestimation of the role excess aldosterone plays in causing resistance to treatment. In subjects with resistant hypertension, suppressed renin levels are common, exceeding 60% in studies conducted by the authors and from centers elsewhere in the world, suggesting occurrence of excess aldosterone beyond cases of true primary aldosteronism. Recent clinical studies indicate that aldosterone antagonists provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension independent of aldosterone levels. These agents are generally well tolerated. Hyperkalemia is an uncommon complication of aldosterone antagonists, but it can occur. Therefore, biochemical monitoring is necessary, particularly in high-risk patients.

Aldosterone antagonism: an emerging strategy for effective blood pressure lowering.

Aldosterone antagonists have been available for many decades for the treatment of hypertension, but their use has been mostly limited to patients with classic primary aldosteronism or to combination products with hydrochlorothiazide to minimize risk for hypokalemia. Recently, indications for aldosterone antagonists have been expanded to include congestive heart failure and first-line treatment of mild-to-moderate hypertension. In addition, we have reported that spironolactone has significant antihypertensive benefit when added to existing regimens in patients with resistant hypertension. This benefit was present in patients with and without hyperaldosteronism and was additive to chronic renin-angiotensin blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Eplerenone, a selective aldosterone antagonist, avoids the androgen and progesterone receptor-related adverse events that sometimes occur with spironolactone, such as breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. In clinical trials, eplerenone has been shown to have antihypertensive benefit in treating mild-to-moderate hypertension similar to other widely used classes of agents. With recent demonstrations of benefit in multiple segments of the hypertensive population, aldosterone antagonists represent emerging opportunity for controlling high blood pressure.