S. Oparil

Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: A preliminary report

Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) ⩾140/90 mm Hg on ⩾3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea–hypopnoea index (AHI) ⩾15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25–50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m–2) were evaluated. After treatment with spironolactone, the AHI (39.8±19.5 vs 22.0±6.8 events/h; P<0.05) and hypoxic index (13.6±10.8 vs 6.7±6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.

Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy

We have previously shown rapid reversal of left ventricular hypertrophy (LVH) with 6 months of spironolactone therapy in patients with resistant hypertension (HTN), preserved left ventricular ejection fraction and no history of heart failure. In this substudy, we investigated the effect of mineralocorticoid receptor blockade with spironolactone on pre-clinical diastolic dysfunction. Thirty-four patients (19 with high and 15 with normal aldosterone levels) were treated with spironolactone and followed with cardiac magnetic resonance with tissue tagging at baseline, 3 and 6 months of treatment. Serum markers of collagen turnover (C-propeptide of type-I procollagen and carboxy-terminal telopeptide of type-I collagen) were measured at baseline and at 6 months. At baseline, patients demonstrated reduced E/A ratio (volumetric normalized peak early filling rate/late filling rate, normalized to left ventricular end-diastolic volume), lower peak early-diastolic mitral annular velocity and lower peak early-diastolic circumferential strain rates compared to the reference values obtained from 45 normal controls without HTN or cardiac disease (all comparisons, P<0.01). No significant change occurred in diastolic filling, relaxation parameters or collagen markers with spironolactone therapy at 6 months irrespective of aldosterone status despite significant reduction in left ventricular mass index in both high- and normal-aldosterone groups. In conclusion, resistant HTN patients with LVH demonstrate significant pre-clinical diastolic dysfunction. Short-term spironolactone therapy may not lead to improvement in diastolic function despite rapid reversal of LVH.

Renal Sympathetic Denervation for Treatment of Hypertension

Opinion statementSympathetic nervous system activation of the heart, kidney and peripheral vasculature increases cardiac output, fluid retention and vascular resistance and plays an important role in acute and chronic BP elevation. Renal sympathetic denervation via a percutaneous radiofrequency catheter based approach is a safe and effective procedure that lowers BP in patients with resistant hypertension. Exploratory studies in patients with resistant hypertension and a variety of comorbidities, including insulin resistance/metabolic syndrome, obstructive sleep apnea and the polycystic ovary syndrome, have shown benefit of renal denervation in attenuating the severity of the comorbid conditions, as well as reducing BP. However, more studies are needed to further address the long term effects of renal denervation and its safety and effectiveness in other disease states such as congestive heart failure.

High-salt diet and aldosterone induces vascular damage in patients with resistant hypertension

Purpose of the study was to test for racial differences in the prevalence of hyperaldosteronism in subjects with resistant hypertension. Consecutive subjects referred to the University of Alabama at Birmingham (UAB) hypertension clinic for resistant hypertension (uncontrolled blood pressure on 3 antihypertensive agents) were prospectively evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), a 24-hr urine collection for aldosterone, cortisol, sodium and potassium during a normal diet. All subjects were on a stable antihypertensive regimen without use of potassium sparing diuretics. For results see the table. The prevalence of hyperaldosteronism on the basis of ARR 20 (29.6% vs. 31.1%) or using PRA<1.0 and urinary aldosterone 12g/24- hr (23.7% Vs 22.6 %) was not different by race. These data demonstrate that there is no racial difference in the prevalence of hyperaldosteronism in subjects with resistant hypertension. These findings support equal vigor in screening African American and white patients with resistant hypertension for primary aldosteronism.Aldosterone increases sodium and fluid retention. However, the reported effects of aldosterone on the heart have been largely limited to left ventricular (LV) hypertrophy and fibrosis. Here we test the hypothesis that hyperaldosteronism (HA) results in volume overload of the heart.

Aldosterone induces intracardiac volume overload in patients with resistant hypertension - spironolactone but not thiazide diuretics overcomes it

Purpose of the study was to test for racial differences in the prevalence of hyperaldosteronism in subjects with resistant hypertension. Consecutive subjects referred to the University of Alabama at Birmingham (UAB) hypertension clinic for resistant hypertension (uncontrolled blood pressure on 3 antihypertensive agents) were prospectively evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), a 24-hr urine collection for aldosterone, cortisol, sodium and potassium during a normal diet. All subjects were on a stable antihypertensive regimen without use of potassium sparing diuretics. For results see the table. The prevalence of hyperaldosteronism on the basis of ARR 20 (29.6% vs. 31.1%) or using PRA<1.0 and urinary aldosterone 12g/24- hr (23.7% Vs 22.6 %) was not different by race. These data demonstrate that there is no racial difference in the prevalence of hyperaldosteronism in subjects with resistant hypertension. These findings support equal vigor in screening African American and white patients with resistant hypertension for primary aldosteronism.Aldosterone increases sodium and fluid retention. However, the reported effects of aldosterone on the heart have been largely limited to left ventricular (LV) hypertrophy and fibrosis. Here we test the hypothesis that hyperaldosteronism (HA) results in volume overload of the heart.

Hyperaldosteronism causes volume overload cardiac hypertrophy in patients with resistant hypertension

Objective: Primary aldosteronism is a common cause of resistant hypertension with a prevalence of approximately 20%. Racial differences in the prevalence of hyperaldosteronism in patients with resistant hypertension have not been previously described. Methods: Consecutive subjects referred to the University of Alabama at Birmingham hypertension clinic for resistant hypertension were prospectively evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), and a 24-hr urine collection for aldosterone, sodium, and potassium during the patient’s usual diet. All subjects were on a stable antihypertensive regimen without use of potassium sparing diuretics. Results: A total of 295 patients with resistant hypertension were evaluated, including 157 white and 138 black subjects. There were 86 black females and 64 white females. Clinic BP was higher in blacks compared to whites (148±20/89 ±16 vs. 143 ±20/83 ± 13, p 0.034) while receiving a similar number of prescribed medications. Diuretic use was the same, but whites were more likely on an ACE inhibitor and beta blocker than blacks. Whites had a higher plasma aldosterone (14.3 ± 9.5 vs. 11.0 ±8.0 ng/dl, p<0.001) and higher urinary potassium excretion (75.1± 34.4 vs. 52.2 ± 23.7 mEq/24-hr, p<0.001). Blacks had a lower PRA (1.9±3.3 vs. 2.8 ± 4.4 ng/ml/hr, p ns). Urinary aldosterone excretion tended to be higher in white compared to black subjects (13.7± 11.3 vs.11.9 ±7.6 mcg/24-hr, p=ns). In spite of higher aldosterone levels in white subjects, the prevalence of hyperaldosteronism based on a PRA<1.0 and urine aldo≥12 was not different in white (25.5%) vs. black subjects (26.1%). Hyperaldosteronism was more common in both black and white males compared to females (white males 38.7% vs. white females 6.3 %, p<0.001; black males 38.5% vs. black females 18.6%, p=0.018). Conclusion: These data demonstrate that hyperaldosteronism is equally common in African American and white patients with resistant hypertension. Males in both races have a higher prevalence of hyperaldosteronism than females. These findings support equal vigor in screening African American and white patients with resistant hypertension for primary aldosteronism.

Aldosterone and cortisol: Is there a common stimulus in subjects with resistant hypertension?

Background Resistant hypertension defined as blood pressure (BP) > 140/90 mm Hg on three antihypertensive agents is a common problem. It has been reported from centers worldwide that these patients have a near 20% prevalence of primary aldosteronism (PA). The etiology of the high prevalence of hyperaldosteronism in this high-risk group is unknown. The purpose of current study is to characterize resistant hypertensive patients and identify potential stimuli of aldosterone secretion in subjects with resistant hypertension. Methods Consecutive subjects referred for resistant hypertension and control subjects with normal or mildly elevated blood pressure were prospectively evaluated with plasma aldosterone concentration (PAC), plasma renin activity (PRA), brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and a 24-hour urine collection for aldosterone (Ualdo), creatinine, protein, cortisol (UCort), sodium (UNa), and potassium (UK) during a normal diet. All hypertensive subjects were on a stable antihypertensive regimen. Results 290 resistant hypertensive subjects and 53 controls were evaluated. Age (54.51 ± 10.83 vs 50.36 ± 10.15, p = .01), clinic BP (145 ± 21/85 ± 15 vs 125 ± 10/79 ± 7 mm Hg), PAC (13.07 ± 9.3 vs 8.44 ± 5.17 ng/dL, p = .0005), Ualdo (12.79 ± 9.98 vs 9.73 ± 6.58 μg/24 h, p = .033), BNP (41.49 ± 47.79 vs 22.48 ± 24.74 pg/mL, p = .0069), ANP (105.60 ± 76.51 vs 49.87 ± 16.65, p = .008) were higher in resistant hypertensive subjects compared with controls. BMI and waist and neck circumference were similar. A multivariate regression analysis with age, sex, race, BMI, Una, and UCort as covariates predicting aldosterone secretion shows that UCort is the strongest predictor of UAldo (p = .012). The R2 for this model is 17.4%. Subgroup analysis further showed that resistant hypertensive subjects with high UAldo (> 12 μg/24 h, n = 68), UCort (103.95 ± 40.51 vs 77.75 ± 42.94, p = .0004), UNa (200.34 ± 94.79 vs 172.96 ± 75.20 mEq/24 h, p = .0072), and UK (80.44 ± 33.79 vs 49.49 ± 20.62, p Conclusion Our findings indicate a state of hyperaldosteronism and in spite of diuretic use, persistent intravascular volume expansion evident from a high BNP and ANP values in subjects with resistant hypertension. These findings also suggest that in these subjects, there may be a common stimulus for cortisol and aldosterone such as ACTH, other stimuli being dietary sodium and/or dietary potassium.