1. Aldosterone and Aldosterone Antagonism Bijan Roshan, MD, FASN Instructor in Medicine, Harvard Medical School

2. Aldosterone and Its Inhibitors Aldosterone Spironolactone and Eplerenone

3. MR (also affinity for 11-Beta- hydroxyglucosteroids)

4. Mineralocorticosteroid Receptor (MR) MR is comprised of 784 amino acids and is the longest member of the oxosteroid receptor subgroup of the nuclear receptor (NR) superfamily, which includes the androgen receptor (AR), glucocorticoid receptor (GR), and progesterone receptors (PR) The steroids aldosterone, cortisol, DOC, and 11-OH- progesterone are agonists of MR. Cortisone binds the MR with very low affinity. Progesterone binds MR with high affinity but is a poor activator of the receptor.

5. Cytosolic Receptor Signaling

6. Surface Receptor Signaling in Non-Epithelial Cells Function found in VSMC, skeletal muscle cells, cardiovascular cells, adipose tissue, liver, pancreas, brain, fibroblast, glomerular cells … Stimulation by either mineralocorticoid or by 11-Betahydroxysteroids Promotes inflammation, fibrosis, insulin resistance, beta-cell dysfunction, oxidative stress, endothelial dysfunction, … Activation of p38MAPK and NADPH oxidase via c-Src. Hypertension.2005;45:773-9.

7. Pathways and Effects of Aldosterone Signaling. Mol Cell Endocrinol. 2009;308(1-2):53-62

8. Randomized controlled double blind study 1663 Patients with CHF and EF<35% Blockade of aldosterone receptors by 25 mg daily spironolactone, in addition to standard therapy (including ACEI, loop diuretics,..) The primary end point was death from all causes Randomized Aldacton Evaluation Study (RALES) NEJM 1999; 341:709-7

9. RALES- Results 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heartfailure and sudden death from cardiac causes (p<0.001). 35 percent lowering risk of hospitalization in the spironolactone group (p<0.001). Spironolactone group had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001)

10. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) NEJM 2003; 348(14):1309-21 Hospitalized patients with CHF after acute MI complicated by LV systolic dysfunction, EF<40%) Randomized, double-blind, placebo-controlled trial. Patients who met the eligibility criteria were randomized 3 to 14 days after AMI to receive 25-50 mg daily eplerenone (n=3319) or placebo (n=3313) in addition to standard therapy The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.

11. EPHESUS- Results 1 Decreased all cause mortality (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was The secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03).

12. EPHESUS- Potassium Results Circulation. 2008 ;118(16):1643-50. 4.4% absolute increase in the incidence of K + >5.5 mEq/L, a 1.6% increase of K + 6.0 mEq/L. When all-cause mortality rates were evaluated by quartiles of K + changes, no indication was found that serum K + changes in the first 30 days had any significant effect on all-cause mortality Patients were excluded if baseline K + was >5.0 mEq/L or serum creatinine was >2.5 mg/dL

13. Aldoserone and HTN Retention of Salt and Water Reduced Endothelial Mediated Relaxation (Am.J Physiol. 1992; 263:974-9) Increasing Pro-Infalmatory Adipokines Potentiate the effect of Angiotensin II

14. Adippose Factors Involved in Obesity-related HTN ■ Aldosterone ■ Endothelin ■ Nonesterified fatty acids and other FFA ■ Interleukin 6 ■ Leptin ■ Renin ■ Tumor necrosis factor

15. Obesity/Metabolic stimulation of Aldosterone Secretion of Angiotensinogen and AT II by Visceral Adipose Tissue Increased Renin Activity Aldosterone secretion increased by Non-esterified FFAs Hyperinsulinemia Increased CNS sympathetic activity Production of a mineralocorticoid releasing factor by adipose tissue.Acad Sci USA, 2003;100:14211-16. Complement C1q TNF –related protein 1 (CTRP1)? FASEB J.2008;22:1502-11 Increased cortisol and bounding to 11 -Beta hydroxysteroid receptor in non-renal tubular cells

16. BMI Predicts Aldosterone Production in Normotensive Adults in High Salt Diet. J Clin Endocrinol Metab.2007; 92:4472-4475 Urinary aldosterone secretion and No change in basal serum aldosterone, serum K, supine PRA, or 24 hour urine cortisol AngII-stimuated serum aldosterone are increased in overweight (BMI >25, n=57), compared with lean (BMI<25, n=63) normotensive adults

17. BMI Predicts Plasma Aldosteron Concentrations in overweight-Obese primary HTN Patients. J.Clin Endocrinol Metab.2008;93:2566-71 PAPY study patient population used. BMI correlated with plasma aldosterone concentration independent of age, sex, sodium intake in primary HTN, but not in primary aldosteronism patients No significant impact of BMI on Aldo/PRA ratio in primary HTN patients

18. Aldosterone and Diabetes Mellitus Co-association with high BMI Increased adipokines causing reduced insulin receptor expression and glucose uptake (Endocr Res.2004:30:865-70) Reduced adiponectin Reduced insulin signaling via downregulation of insulin receptor substrate-1 (Hpertension.2007;50:750-5) Increased hepatic gluconeogenesis. Decreased secretion of Insulin (hypokalemia - dependent and independent) Beta-cell fibrosis Hyperinsulinemia increasing aldosterone secretion

19. Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply. Rossi, G. P. et al. J Am Coll Cardiol 2006;48:2293-2300 The protocol for the recruitment and investigation of the PAPY (PA Prevalence in Hypertensives) study population

20. PAPY (PA Prevalence in Hypertensives) study Newly diagnosed hypertensive patients referred to hypertension centers in Italy Overall prevalence of Primary Aldosteronism (PA) was 11.2% The prevalence of APA (adenoma causing PA) was 4.8%

21. Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply. Rossi, G. P. et al. J Am Coll Cardiol 2006;48:2293-2300 A substantial proportion of the patients with APA and IHA did have hypokalemia (red bars) at the time of presentation

22. Prevalence of Primary Aldosteronism (PA) in resistant HTN. Lancet.2008 13;371:1921-6 1616 patients with resistant HTN, retrospective observational single center study in Greece 338 patients (20.9%) had positive ARR 182 patients (11.3%) confirmed to have PA based on Saline Intravenous and fludrocortisone suppression test Conclusion: notion of an epidemic of primary aldosteronism is not supported

23. Copyright ©2006 American Society of Nephrology Epstein, M. et al. Clin J Am Soc Nephrol 2006;1:940-951 Selective Aldosterone Blockade with Eplerenone reduces albuminuria in patients with type 2 DM. Clin JASN. 2006 Sep;1(5):940-51

24. Percentage change in UACR over time

25. Addition of ARB or Mineralocorticoid Antagonism to Maximal ACE Inhibition in Diabetic Nephropathy. JASN 2009 Dec;20(12):2641-50 Double-blind, placebo-controlled trial in 81 patients with DM, HTN, and macroalbuminuria receiving lisinopril 80 mg once daily. Patients randomly assigned to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% in the group assigned to spironolactone and by 16.8% in the group assigned to losartan (both significant) Serum potassium level was significantly higher with the addition of either spironolactone or losartan

27. Fasting Plasma Glucose and Serum Lipids in patients with PA. Hypertension.2009;53:605-610 Controlled cross sectional study of 460 patients with PA (103 lateralized, 150 naturalized) and 1363 controls with essential HTN matched for age and sex No significant difference in prevalence of impaired fasting glucose or overt DM between groups. No significant difference in lipids (TG, total Cholesterol HDL, LDL)

28. Fasting Plasma Glucose and Serum Lipids in patients with PA. Hypertension.2009;53:605-610 61 patients with lateralized PA underwent adrenalectomy. Comparison of preoperative and postoperative results showed: No significant difference for values of FPG, total cholesterol, LDL, HDL. TG was higher postoperatively (P<0.040). Potassium increased postoperatively (p<0.001)

29. Young W F. Endocrinology 2003;144:2208-2213

30. Confirming PA after high PAC/PRA Not needed in patients with spontaneous hypokalemia, PAC >30 ng/dl AND undetectable PRA. Otherwise suppression tests: Saline Suppression Test Sodium loading and urine aldosterone measurements (>12 mcg/24 hr is positive) Captopril and Fludrocortisone suppression tests

31. Types of primary aldosteronism (PA) Aldosterone-producing adenoma (APA) Primary (unilateral) adrenal hyperplasia Aldosterone-producing adrenocortical carcinoma Bilateral idiopathic hyperplasia (IHA) Familial hyperaldosteronism (FH) Glucocorticoid-remediable aldosteronism (FH type I) FH type II (APA or IHA)

32. Subtype evaluation of primary aldosteronism. Young W F. Endocrinology 2003;144:2208-2213