Mari K. Nishizaka

Hyperaldosteronism Among Black and White Subjects With Resistant Hypertension

Abstract—Recent reports suggesting that the prevalence of primary hyperaldosteronism may be higher than historically thought have relied on an elevated plasma aldosterone concentration/plasma renin activity ratio to either diagnose or identify subjects at high risk of having primary hyperaldosteronism and have not included suppression testing of all evaluated subjects. In this prospective study of 88 consecutive patients referred to a university clinic for resistant hypertension, we determined the 24-hour urinary aldosterone excretion during high dietary salt ingestion, baseline plasma renin activity, and plasma aldosterone in all subjects. Primary hyperaldosteronism was confirmed if plasma renin activity was <1.0 ng/mL per hour and urinary aldosterone was >12 &mgr;g/24-hour during high urinary sodium excretion (>200 mEq/24-hour). Eighteen subjects (20%) were confirmed to have primary hyperaldosteronism. The prevalence of hyperaldosteronism was similar in black and white subjects. Of the 14 subjects with confirmed hyperaldosteronism who have been treated with spironolactone, all have manifested a significant reduction in blood pressure. In this population, an elevated plasma aldosterone/plasma renin activity ratio (>20) had a sensitivity of 89% and a specificity of 71% with a corresponding positive predictive value of 44% and a negative predictive value of 96%. These data provide strong evidence that hyperaldosteronism is a common cause of resistant hypertension in black and white subjects. The accuracy of these results is strengthened by having done suppression testing of all evaluated subjects.

Efficacy of low-dose spironolactone in subjects with resistant hypertension

BACKGROUND Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and, to a lesser degree, subjects with resistant hypertension. METHODS In current analysis, we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in subjects with resistant hypertension with and without primary aldosteronism. Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity, 24-h urinary aldosterone and sodium during a high dietary salt ingestion. The diagnosis of primary aldosteronism was confirmed with a renin activity <1.0 ng/mL/h, urinary aldosterone >12 mug/24 h and urinary sodium >200 mEq/24 h. After biochemical evaluation, spironolactone (12.5 to 25 mg/d) was added to each subjects antihypertensive regimen. If blood pressure (BP) remained uncontrolled, the dose of spironolactone was titrated up to 50 mg/d. Follow-up BP was determined at 6 weeks, 3 months, and 6 months. RESULTS A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 +/- 21/10 +/- 14 mm Hg at 6 weeks and 25 +/- 20/12 +/- 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics. CONCLUSIONS We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism.

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 <or=2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. RESULTS Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. CONCLUSIONS Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.

Impaired Endothelium-Dependent Flow-Mediated Vasodilation in Hypertensive Subjects With Hyperaldosteronism

Background—Recent studies suggest that aldosterone may impair endothelium-dependent vascular function through suppression of nitric oxide formation. Assessments of forearm blood flow or arterial compliance suggest a similar effect in humans. The present study was designed to determine whether chronic aldosterone excess in subjects with resistant hypertension impairs endothelium-dependent vascular reactivity as indexed by direct assessment of brachial artery flow-mediated dilation (FMD). Methods and Results—Consecutive subjects (n=80) with resistant hypertension were prospectively evaluated with an early-morning ratio of plasma aldosterone to plasma renin activity and 24-hour urinary aldosterone and sodium. Changes in brachial artery diameter during reactive hyperemia were measured by high-resolution ultrasound. Hyperaldosteronism was diagnosed on the basis of a renin activity <1.0 ng · mL−1 · h−1, urinary aldosterone >12 μg/24 h, and urinary sodium >200 mEq/24 h. FMD was significantly lower in 36 subjects with hyperaldosteronism (1.8±1.3% versus 3.9±1.9% from baseline; P <0.0001) compared with the 44 subjects without hyperaldosteronism. FMD was negatively and significantly correlated with plasma aldosterone (r =−0.38, P =0.0006), 24-hour urinary aldosterone (r =−0.49, P <0.0001), and ratio of plasma aldosterone to plasma renin activity (r =−0.43, P <0.0001) but was independent of blood pressure, age, and body mass index. In 30 subjects, 3 months of treatment with spironolactone significantly increased FMD (2.5±1.7 versus 6.0±2.0%; P <0.0001) independently of blood pressure change. Conclusions—These data demonstrate a strong association between aldosterone excess and impaired endothelial function in human subjects as indexed by flow-mediated arterial vasodilation. These results suggest that chronic aldosteronism may have a blood pressure–independent effect on cardiovascular disease progression in subjects with resistant hypertension.

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 ≥12 &mgr;g/24 hours; or normal: <12 &mgr;g/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 μg/l per h) and elevated 24-h urinary aldosterone excretion (≥ 12 μg/24-h or ≥ 33.2 nmol/day) during ingestion of the patients 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.

Use of aldosterone antagonists in resistant hypertension.

Resistant hypertension is defined as an elevated blood pressure in spite of treatment with 3 different antihypertensive agents. The prevalence of resistant hypertension is unknown, but recent cross-sectional analyses and hypertension outcome studies suggest it is a common clinical problem and will become even more so with an aging and increasingly heavy population. Secondary causes of hypertension are common in patients with resistant hypertension, in particular, obstructive sleep apnea and hyperaldosteronism. Treatment of resistant hypertension is predicated upon identification and reversal of secondary causes of hypertension, as possible, and effective use of multidrug regimens. Recent clinical studies indicate that aldosterone antagonists, spironolactone and amiloride, provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension. Both 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.

Cumulative Hypoxemia During Sleep Predicts Vascular Endothelial Dysfunction in Patients With Sleep-Disordered Breathing

BACKGROUND Sleep-disordered breathing (SDB) is associated with repeated intermittent hypoxemia, and it is known as one of the risk factors for cardiovascular diseases. Previous studies assessing the effects of frequency and depth of hypoxemia on cardiovascular diseases have shown conflicting results. The aim of the current study was to clarify what SDB-related parameters most predict endothelial dysfunction to better understand the pathogenesis of endothelial dysfunction in patients with SDB. METHODS We conducted polysomnography (PSG) and measured flow-mediated vasodilation response (%FMD) in 50 outpatients suspected of SDB. Evaluated indices included: apnea-hypopnea index (AHI), 3% oxygen desaturation index (3%ODI), averaged arterial oxygen saturation (averaged SpO2), lowest arterial oxygen saturation (lowest SpO2), ratio of arterial oxygen saturation <90% (<SpO2 90%), and averaged time desaturation summation index (TDS: [100%-averaged SpO2] × total sleep time). RESULTS Significant differences were observed only in the TDS between the first and third (P = 0.03) and between the first and forth (P = 0.04) quartile groups, stratified by %FMD. The %FMD showed a significant relationship with TDS (β = -0.47, P = 0.001), even after adjusting for confounding factors (β = -0.33, P = 0.02). In contrast, AHI, 3%ODI, averaged SpO2, lowest SpO2, and <SpO2 90% showed no significant relationships. CONCLUSIONS This study shows the validity of TDS in predicting endothelial damage in patients with SDB. Cumulative hypoxemia, rather than the frequency of hypoxemic events presented as AHI, may be a greater contributing factor in causing endothelial dysfunction. A simple index like TDS may be a useful and novel indicator of the influence of SDB on the vasculature.

Prevalence of Sleep Disordered Breathing among Patients with Nocturia at a Urology Clinic

OBJECTIVE We assessed the prevalence of sleep disordered breathing (SDB) and characteristics among patients who visited a urology clinic complaining of nocturia (URO group) and those who visited a sleep apnea (SA) clinic complaining of excessive daytime sleepiness (EDS) (SA group). Additionally, we evaluated the effects of continuous positive airway pressure (CPAP) therapy in the URO group patients with nocturia and SDB resistant to conventional therapy for nocturia. METHODS Questionnaires were used to assess EDS, nocturia and lower urinary tract symptoms in 34 URO group patients and 49 age-matched SA group patients. We also compared these factors in the male patients in both groups and the male and female patients in the SA group. Significant SDB was diagnosed as a 3% oxygen desaturation index (3%ODI) on pulse oximeter of >5/h. The treatment response was analyzed in six URO group patients treated with CPAP after not responding to the conventional medical treatment. RESULTS SDB was found in 91.8% of the SA group patients and 70.6% of the URO group patients. The level of EDS and lower urinary tract symptoms were similar in both groups. The SA group showed higher 3%ODI values, while the frequency of urination during bedtime was higher in the URO group. The frequency of nocturnal urination was reduced after CPAP in the subjects resistant to conventional therapy. CONCLUSION SDB is as prevalent in patients who visit a urology clinic complaining of nocturia as in those who visit a sleep apnea clinic. Patients who complains of nocturia must be assessed for SDB before starting therapy for nocturia.

Obstructive sleep apnea-related symptoms in Japanese people with Down syndrome

This study evaluated the prevalence of obstructive sleep apnea-related symptoms and assessed the relationship with obesity or unusual sleep postures in Down syndrome patients in Japan. We obtained the demographic characteristics, sleep postures, and obstructive sleep apnea-related symptoms experienced by 90 people as reported by their caregivers. Although 71% reported snoring and 59% arousals, obstructive sleep apnea-related symptoms were not significantly different between obese and non-obese participants. The youngest age group had the fewest obstructive sleep apnea-related symptoms, especially symptoms of snoring. The odds for arousal, nocturia, and apnea tended to be higher in the unusual sleep-postures group. Unusual sleep postures were most frequent in the group 6-15 years of age. People with Down syndrome might sleep in unusual postures to avoid upper airway obstruction caused by other anatomical factors. For nurses and other health professionals working in mainstream service, it is important to screen all persons with Down syndrome for symptoms suggestive of obstructive sleep apnea, particularly those six years of age and older, and to refer them for further evaluation for sleep disorders.