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ANTI-ALDOSTERONE DRUGS: WILL CINDERELLA BECOME A SUPERSTAR?

ANTI-ALDOSTERONE DRUGS: WILL CINDERELLA BECOME A SUPERSTAR?. Maria Rosa Costanzo, M.D. Medical Director, Midwest Heart Specialists Heart Failure Program Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois U.S.A. The Renin Angiotensin Aldosterone System.

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ANTI-ALDOSTERONE DRUGS: WILL CINDERELLA BECOME A SUPERSTAR?

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  1. ANTI-ALDOSTERONE DRUGS: WILL CINDERELLA BECOME A SUPERSTAR? Maria Rosa Costanzo, M.D. Medical Director, Midwest Heart Specialists Heart Failure Program Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois U.S.A

  2. The Renin Angiotensin Aldosterone System

  3. The Classic Genomic Action of Aldosterone on Epithelial Tissue Interstitium Fluid (Blood) Lumen 11β-HSD2 Cortisol Cortisone Endoplasmic Reticulum Aldosterone Gene MR HRE Nucleus K+ K+ Sgk1 CHIF Ki-Ras H20 H20 ADP ATP Na+ ENaCNa+ Channel Na+/K+ ATPase K+ Na+ Na+

  4. Effects of Eplerenone, Enalapril and Eplerenone/Enalapril in Patients with Essential Hypertension and Left Ventricular Hypertrophy: The 4E-Left Ventricular Hypertrophy Study Hypertension with Echocardiographic Evidence of LVH 14-Day Placebo Run-IN Eplerenone 200 mg/ Enalapril 10 mg* (n =67) Eplerenone 200 mg* (n =64) Enalapril 40 mg* (n =71) Δ LV Mass by MRI Δ SBP/DBP Δ UACR Safety *Add-on therapy at week 8 with hydrochlorothiazide 12.5 or 25 mg and/or amlodipine 10 mg in patients with DBP 90 mm Hg or SBP >180 mm Hg Pitt, B. et al. Circulation 2003;108:1831-1838

  5. The 4E-LVH Study Greater Change in LV Mass Despite Similar Reduction In BP! P<0.001 for Δ bsl for each group; *P=0.007 for epl/enal vs epl; † P=0.107 for epl/enal vs enala; ‡P=0.258 for epl vs enal Pitt, B. et al. Circulation 2003;108:1831-1838

  6. Proposed Mechanisms of Aldosterone Excess, Linking Polymorphism in CYP11B2 Gene to Hypertensive Phenotype with Increased Aldosterone to Renin Ratio CYP11B2 Polymorphism in Lactic Dehydrogenase with Variants in CYP11B1 Reduced 11β-Hydroxylase activity Reduced Cortisol Production Chronic Compensatory Increase in ACTH Drive Adrenocortical Hyperplasia Increased Aldosterone Synthetic Capacity Hypertension with Increased Aldosterone to Renin Ratio MacKenzie SM and Connell JMC Current Hypertension Reports 2006; 8: 255-61

  7. RALES and EPHESUS: Aldosterone blockade in HF and post-MI LV dysfunction • RALES (Randomized ALdactone Evaluation Study) • N = 1633 with NYHA class III/IV HF • Randomized to placebo or spironolactone 25 mg • Treatment in addition to ACE inhibitor and loop diuretic; most patients also received digoxin • EPHESUS(Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and SUrvival Study) • N = 6632 with post-MI LV dysfunction and HF • Randomized to placebo or eplerenone 50 mg • Treatment in addition to ACEI or ARB, -blockers, diuretics, aspirin Pitt B et al. N Engl J Med. 1999;341:709-17. Pitt B et al. N Engl J Med. 2003;348:1309-21.

  8. Aldosterone Blockade and AT1 Receptor Blockade: Trials in Post-MI LV Dysfunction and Heart Failure RALES EPHESUS 15% Risk reduction RR 0.85 (0.75–0.96) P = 0.008 30% Risk reduction RR 0.70 (0.60–0.82) P < 0.001 1.00 22 Placebo 0.90 18 Spironolactone 25 mg 0.75 Cumulative incidence (%) Eplerenone 50 mg 14 Probability of survival 10 0.60 6 Placebo 0.45 2 0.00 0 6 18 0 12 24 30 36 18 0 6 12 30 36 24 Months Months Pitt B et al. N Eng J Med. 1999;341:709-17. Pitt B et al. N Eng J Med. 2003;348:1309-21.

  9. 30-Month Mortality by treatment groups and PIIINP baseline levels Data from RALES Zannad, F. et al. Circulation 2000;102:2700-2706

  10. Relationship Between Transcardiac Extraction of Aldosterone and LV Remodeling in Patients with First AMI Hayashi, M. et al. J Am Coll Cardiol 2001;38:1375-1382

  11. Antiarrhythmic Effects of Aldosterone Blockade* Heart Rate Variability QTC Dispersion ○ = placebo ▲= spironolactone Yee, K.-M. et al. J Am Coll Cardiol 2001;37:1800-1807 *Direct modulation of of the activity of voltage-dependent K+ channels Delpon E et al. Trends Pharmachol Sci 2005; 26:155-61

  12. Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth Muscle Cells

  13. Mechanisms of Aldosterone-Induced Vascular Fibrosis Aldosterone Ang II T-cell genomic monocyte Fibroblast Transformation Extracellular Matrix Brown, N. J. Hypertension 2008;51:161-7

  14. Potential Mechanisms of Aldosterone-Induced Myocardial Fibrosis • Renal Dependent • Increase in total body sodium • Hypertension • Potassium Deficiency • Renal Independent (local vascular and cardiac effects) • Direct Myocardial Effects • Increase in sodium influx into myocardial fibroblasts • Activation of transcription factors activator protein-1 and NFkB • Increase in collagen synthesis (perivascular and interstitial) • Increase in expression of procollagen mRNA • Vasculitis • Enhanced Vasoconstriction • Decrease in NO synthesis • Coronary endothelium-independent dysfunction • Activation of proinflammatory molecules • Cyclooxygenase-2 • Osteopontin • Macrophage chemoattractant protein-1 • IL-1β, IL-6 • Reactive oxygen species • Formation of microthrombi • Increase in PAI-1

  15. Mechanisms of Aldosterone-Induced Oxidative Stress and Endothelial Dysfunction Aldosterone O2 NADPH NAD(P)H Oxidases G6PD ˙O2- NADP+ ONOO- L-Arginine ˙ NO L-citrulline + Nitric Oxide Synthase BH4 Ser1177 Aldosterone PP2A P Marney AM and Brown NJ Clinical Science 2007; 113: 267-78

  16. Aldosterone-Induced Oxidative Stress as Demonstrated by Immunohistochemical Study of Activation of gp91phox in Coronal Cryostat Sections of Ventricle Control gp91phox , A Subunit of NADPH Oxidase Activity During Aldosterone Administration Aldosterone-Induced gp91phox Activity Attenuated, but Not Prevented by Parathyroidectomy Vidal, A. et al. Am J Physiol Heart Circ Physiol 2006; 290: H286-H294

  17. Protection Against Myocardial Damage by Eplerenone or Low-Salt Diet in the L-NAME/Angiotensin II Model Martinez, D. V. et al. Hypertension 2002;39:614-618

  18. Forearm Blood Flow Responses *P<0.05 **P<0.001 *P<0.05 endothelium-dependent vasodilator ■ = placebo ▲= spironolactone vasoconstriction only through conversion to Ang II endothelium-independent vasodilator *P<0.05 competitive NOS inhibitor Farquharson, C. A. J. et al. Circulation 2000;101:594-7

  19. Sleep Apnea, Aldosterone, & Resistant Hypertension ρ = 0.44: p = 0.0002 • Links between Aldosterone and OSA • Increased edema of • nasopharingeal tissues • Oxidative Stress • Endothelial Dysfunction • Enhanced Endothelin-1 activity Pratt-Ubunama M. N. et.al. Chest 2007;131:453-459 Pimenta E et al. Progr Cardivasc Dis 2009; 51: 371-80

  20. Eplerenone Src PPI inhibitor Antioxidants Eplerenone Crosstalk Between Insulin and RAAS: Effects on Glucose Metabolism ↓ IRS protein content and phosphorilation ↑ TG secretion and accumulation ↓adipocyte differentiation Activation of the RAAS ↓adiponectin production ↑ gluconeogenesis ↓glucose-mediated Insulin release Metabolic Effects of A II ↓IRS-1 content and phosphorilation ↓ GLUT-4 translocation Eplerenone Eplerenone ↓Glucose uptake ↑ MCP-1 expression in islets ↑ ROS Production Hitomi H et al. 2007; 50:750-5

  21. Renal Actions of Aldosterone Reabsorbed Na is pumped out of the cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane. Spironolactone and eplerenone act by competing with aldosterone. Triamterene and amiloride function as indirect aldosterone antagonists by closing the epithelial sodium channels. Wenzel U Curr Opin Nephrol Hypertens 2008; 17: 44-50

  22. Aldosterone and Progression of Renal Disease Ramipril+ Ibersartan Ramipril Ramipril+ Spironolactone Ramipril + Ibersartan + Spironolactone Chrysostomu A et al. Clin J Am Soc Nephrol 2006; 1: 256-62 Bianch S et al. Kidney Int 2006; 2116-23

  23. Renally-Produced Aldosterone Increased MR in Mesangial Cells Increased transcription of MC-Responsive Genes ROS Production Podocyte Injury PROTEINURIA Mechanisms of Aldosterone-Dependent Renal InjuryKiyomoto H et al. J Pharmacol Sci 2008; 108: 399-405 Podocyte Abnormality 1% NaCl 1% NaCl + Aldosterone MR in Mesangial cells Glomerular Sclerosis 1% NaCl + Aldosterone 1% NaCl + Aldosterone +Eplerenone 1% NaCl +Aldosterone + Tempol Vehicle +1% NaCl Superoxide Dismutase Mimetic

  24. Increased Aldosterone and Na+ Spironolactone Spironolactone Hypercalciuria (6 wks) Hypermagnesuria (6 wks) Loop Diuretics Loop Diuretics Decreased Plasma Ca2+ Concentration Decreased Plasma Mg2+ Concentration Ca2+ Suppl. or Vitamin D 3 Parathyroidectomy  PTH & ET-1 C E L L A C T I V A T I O N Increased Cellular Expression of Ca2+ Channels CCM Parathyroidectomy PMBC Skin Heart Muscle Cells Skeletal Muscle Vascular Cells Platelets Sequestration of Cytosolic Ca2+ by Mitochondria Parathyroidectomy +Ca2+ Suppl.  H2O2-(1-2 wks) ↓α1AP–(1-6 wks)  gp91- (4wk) Calcium Paradox of Aldosteronism and Its Consequences***Vidal A et al. Am J Physiol Circ Physiol 2006; H286-H294 *** ≈ Zinc

  25. Human Counterparts of the Calcium Paradox of Parathyroidism • ↑ urinary Ca2+ excretion, ↓plasma ionized Ca2+ , ↑ plasma levels of PTH, and ↑ cytosolic free [Ca2+]i found in pts. with low-renin HTN (Brickman AS et al. Hypertension 1990; 16: 515) • High dietary Na+, which suppresses renin and aldosterone, and elevated aldosterone, inappropriate for 1% dietary NaCl, are each accompanied by hypercalciuria. (Ahokas RA et al. Circulation 2005; 111: 51-7 • Immune cell activation accompanies secondary HPT of CRF (Alexievic JM et al. Kidney Int. 1996; 50: 1249-54) • Secondary HPT (elevated plasma PTH and ET-1 levels, osteopenia and osteoporosis) found in HF pts. (Anker SD et al. Am J Cardiol 1999;83: 612-5) • Hypovitaminosis D common in HF pts. (Shane E et al. Am J Med 1997; 103: 197-207 • The cytokine profile of primary & secondary HPT resembles that of HF (Mann DL et al. Chest 1994; 105:897-904) • Loop diuretics exaggerate urinary Ca2+ and Mg2+ excretion and promote further PTH release and greater bone loss (Law PH at al. J Am Coll Cardiol 2005; 46: 142-6 • The combination of thiazide diuretics and spironolactone reverses these losses (Runyan AL et al. Am J Med Sci 2005; 330: 1-7)

  26. Reduction of Fracture Risk by Spironolactone in Men with CHF Carbone LD et al. J Am Coll Cardiol 2008; 52: 135-8

  27. Aldosterone Escape During Therapy with ACEIs N = 11 7/ 11 (64%) had AII/AI ratio 0.05, indicating complete inhibition of the vascular ACE Upper Limit of Normal Range for Plasma Aldosterone Jorde, U. P. et al. Circulation 2002;106:1055-1057

  28. Juurlink et al. NEJM 2004;351:543 after RALES: RX

  29. after RALES:Death Juurlink et al. NEJM 2004;351:543

  30. Hunt SA et al.2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults J Am Coll Cardiol, 2009; 53:1-90

  31. Effects of Aldosterone Blockers on All-Cause Mortality in All Randomized Trials 01-Heart Failure 02-Myocardial Infarction Ezekowitz, J. A. et al. Eur Heart J 2009 30:469-77

  32. Effect of Aldosterone Blockers on LVEF in All Randomized Trials 01-Heart Failure 02-Myocardial Infarction Ezekowitz, J. A. et al. Eur Heart J 2009 30:469-77

  33. Deleterious Actions of High Levels of Aldosterone in the Cardiovascular System Increased Aldosterone Level Vasculature Kidney Heart Na+ reabsorption and water retention Inflammation And tissue injury Endothelial dysfunction K+ and Mg2+ excretion ↓ NE uptake Volume expansion and edema ↓Vascular reserve Electrolyte imbalance ↓ Myocardial function Myocardial fibrosis Perivascular fibrosis ↓ Arterial compliance Baroreceptor dysfunction Ventricular arrhythmias End-organ damage and cardiovascular disease

  34. Conclusions • Aldosterone has been shown to have deleterious cardiovascular and renal effects due to his genomic and non-genomic actions • Aldosterone escape occurs in humans treated with ACEIs and ARBs; the addition of aldosterone antagonists can reduce BP and proteinuria, and importantly, reduce morbidity and mortality in HF pts. • The risks of hyperkalemia in pts. treated with RAAS inhibitors and aldosterone antagonists are not insignificant, mandating close F/U, especially in pts. with underlying kidney disease • Given the effects of aldosterone on fibrosis, inflammation, oxidative stress and endothelial dysfunction, aldosterone antagonists are headed for “Super Star” status!

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