ANTI-ALDOSTERONE DRUGS: ANTI-ALDOSTERONE DRUGS: WILL CINDERELLA BECOME A WILL CINDERELLA BECOME A

SUPERSTAR?SUPERSTAR?Maria Rosa Costanzo, M.D.Maria Rosa Costanzo, M.D.

Medical Director, Midwest Heart Specialists Heart Failure ProgramMedical Director, Midwest Heart Specialists Heart Failure ProgramMedical Director, Edward Hospital Center for Advanced Heart FailureMedical Director, Edward Hospital Center for Advanced Heart Failure

Naperville, Illinois U.S.ANaperville, Illinois U.S.A

The Renin Angiotensin Aldosterone SystemThe Renin Angiotensin Aldosterone System

The Classic Genomic Action of The Classic Genomic Action of Aldosterone on Epithelial TissueAldosterone on Epithelial Tissue

InterstitiumFluid

(Blood)

Cortisol

Aldosterone

HREGene

Nucleus

Sgk1CHIF

Ki-RasENaCNa+

ChannelNa+/K+

ATPase

Cortisone

MR

K+K+

H20H20

Na+ Na+

11β-HSD2Endoplasmic Reticulum

Na+

K+

ATP ADP

Lumen

Effects of Eplerenone, Enalapril and Eplerenone/Enalapril in Effects of Eplerenone, Enalapril and Eplerenone/Enalapril in Patients with Essential Hypertension and Left Ventricular Patients with Essential Hypertension and Left Ventricular Hypertrophy: Hypertrophy: The 4E-Left Ventricular Hypertrophy StudyThe 4E-Left Ventricular Hypertrophy Study

Hypertension with Echocardiographic Evidence of LVH

14-Day Placebo Run-IN

Eplerenone 200 mg*(n =64)

Enalapril 40 mg*(n =71)

Eplerenone 200 mg/Enalapril 10 mg*

(n =67)

Δ LV Mass by MRIΔ SBP/DBP

Δ UACRSafety

Pitt, B. et al. Circulation 2003;108:1831-1838

*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

The 4E-LVH StudyThe 4E-LVH Study

Pitt, B. et al. Circulation 2003;108:1831-1838

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

Greater Change in LV MassDespite Similar Reduction

In BP!

Proposed Mechanisms of Aldosterone Excess, Linking Proposed Mechanisms of Aldosterone Excess, Linking Polymorphism in CYP11B2 Gene to Hypertensive Phenotype Polymorphism in CYP11B2 Gene to Hypertensive Phenotype

with Increased Aldosterone to Renin Ratiowith Increased Aldosterone to Renin RatioCYP11B2 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 RatioMacKenzie SM and Connell JMC Current Hypertension Reports 2006; 8: 255-61

RALES and EPHESUS: Aldosterone RALES and EPHESUS: Aldosterone blockade in HF and post-MI LV dysfunctionblockade in HF and post-MI LV dysfunction

RALES (RALES (Randomized ALdactone Evaluation Study) • N = 1633 with NYHA class III/IV HF N = 1633 with NYHA class III/IV HF

• Randomized to placebo or spironolactone 25 mg Randomized to placebo or spironolactone 25 mg • Treatment in addition to ACE inhibitor and loop diuretic; Treatment in addition to ACE inhibitor and loop diuretic;

most patients also received digoxinmost patients also received digoxin

EPHESUSEPHESUS ((Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and SUrvival Study)

• N = 6632 with post-MI LV dysfunction and HF N = 6632 with post-MI LV dysfunction and HF

• Randomized to placebo or eplerenone 50 mg Randomized to placebo or eplerenone 50 mg

• Treatment in addition to ACEI or ARB, Treatment in addition to ACEI or ARB, -blockers, -blockers, diuretics, aspirin 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.

Aldosterone Blockade and ATAldosterone Blockade and AT11 Receptor Blockade: Receptor Blockade: Trials in Post-MI LV Dysfunction and Heart FailureTrials in Post-MI LV Dysfunction and Heart Failure

Pitt B et al. N Eng J Med. 1999;341:709-17.Pitt B et al. N Eng J Med. 2003;348:1309-21.

RALES

0.75

0.60

1.00

0

Placebo

Spironolactone25 mg

Months

Probability of survival

24 366

30% Risk reductionRR 0.70 (0.60–0.82)

P < 0.001

300.00

12 18

0.90

0.45

EPHESUS

22

10

2

6 24 300

Eplerenone50 mg

Months

18

14

6

3612

15% Risk reductionRR 0.85 (0.75–0.96)

P = 0.008

Cumulativeincidence

(%)

Placebo

018

Zannad, F. et al. Circulation 2000;102:2700-2706

30-Month Mortality by treatment groups and PIIINP baseline levels Data from RALES

Relationship Between Transcardiac Extraction of Aldosterone Relationship Between Transcardiac Extraction of Aldosterone and LV Remodeling in Patients with First AMIand LV Remodeling in Patients with First AMI

Hayashi, M. et al. J Am Coll Cardiol 2001;38:1375-1382

Antiarrhythmic Effects of Antiarrhythmic Effects of Aldosterone Blockade*Aldosterone Blockade*

Yee, K.-M. et al. J Am Coll Cardiol 2001;37:1800-1807

Heart Rate Variability QTC Dispersion ○ = placebo▲= spironolactone

*Direct modulation of of the activity of voltage-dependent K+ channelsDelpon E et al. Trends Pharmachol Sci 2005; 26:155-61

Extraadrenal Production of Aldosterone by Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth Muscle CellsEndothelial and Vascular Smooth Muscle Cells

Mechanisms of Aldosterone-Induced Vascular FibrosisMechanisms of Aldosterone-Induced Vascular Fibrosis

Extracellular Matrix

Fibroblast Transformation

monocyte

T-cell

Aldosterone Ang II

genomic

Brown, N. J. Hypertension 2008;51:161-7

Potential Mechanisms of Potential Mechanisms of Aldosterone-Induced Myocardial FibrosisAldosterone-Induced Myocardial Fibrosis

Renal DependentRenal Dependent– Increase in total body sodiumIncrease in total body sodium– HypertensionHypertension– Potassium DeficiencyPotassium Deficiency

Renal Independent (local vascular and cardiac effects)Renal Independent (local vascular and cardiac effects)– Direct Myocardial EffectsDirect Myocardial Effects

Increase in sodium influx into myocardial fibroblastsIncrease in sodium influx into myocardial fibroblastsActivation of transcription factors activator protein-1 and NFkBActivation of transcription factors activator protein-1 and NFkBIncrease in collagen synthesis (perivascular and interstitial)Increase in collagen synthesis (perivascular and interstitial)Increase in expression of procollagen mRNAIncrease in expression of procollagen mRNA

– VasculitisVasculitisEnhanced VasoconstrictionEnhanced Vasoconstriction

– Decrease in NO synthesisDecrease in NO synthesisCoronary endothelium-independent dysfunctionCoronary endothelium-independent dysfunction

Activation of proinflammatory moleculesActivation of proinflammatory molecules– Cyclooxygenase-2Cyclooxygenase-2– OsteopontinOsteopontin– Macrophage chemoattractant protein-1Macrophage chemoattractant protein-1– IL-1IL-1ββ, IL-6, IL-6– Reactive oxygen speciesReactive oxygen species

Formation of microthrombiFormation of microthrombi– Increase in PAI-1Increase in PAI-1

Mechanisms of Aldosterone-Induced Mechanisms of Aldosterone-Induced Oxidative Stress and Endothelial DysfunctionOxidative Stress and Endothelial Dysfunction

Marney AM and Brown NJ Clinical Science 2007; 113: 267-78

G6PD

NADPH

NAD(P)H Oxidases

NADP+ ˙O2-

Nitric Oxide Synthase

L-Arginine L-citrulline + ˙ NO

ONOO-

Aldosterone

Aldosterone PP2ASer1177

P

BH4

O2

Vidal, A. et al. Am J Physiol Heart Circ Physiol 2006;290: H286-H294

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

Martinez, D. V. et al. Hypertension 2002;39:614-618

Protection Against Myocardial Damage by Eplerenone or Low-Salt Diet in the L-NAME/Angiotensin II Model

*P<0.05 **P<0.001 *P<0.05

endothelium-dependent vasodilator

endothelium-independent vasodilator

competitive NOS inhibitor

vasoconstriction only through conversion to Ang II

Forearm Blood Flow ResponsesForearm Blood Flow Responses

Farquharson, C. A. J. et al. Circulation 2000;101:594-7

■ = placebo▲= spironolactone

*P<0.05

Sleep Apnea, Aldosterone, & Resistant Hypertension

Pratt-Ubunama M. N. et.al. Chest 2007;131:453-459Pimenta E et al. Progr Cardivasc Dis 2009; 51: 371-80

ρ = 0.44:p = 0.0002

Links between Aldosterone and OSA

Increased edema of nasopharingeal tissues

Oxidative Stress

Endothelial Dysfunction

Enhanced Endothelin-1 activity

Crosstalk Between Insulin and RAAS: Crosstalk Between Insulin and RAAS: Effects on Glucose MetabolismEffects on Glucose Metabolism

Activationof the RAAS

Metabolic Effects of A II

↓ IRS protein content and phosphorilation

↑ TG secretion and accumulation

↑ gluconeogenesis

↓glucose-mediated Insulin release

↑ MCP-1 expression in islets↑ ROS Production

↓adipocyte differentiation

↓adiponectin production

↓IRS-1 content and phosphorilation↓ GLUT-4 translocation

↓Glucose uptake

EplerenoneEplerenone

EplerenoneSrc PPI inhibitorAntioxidants

Eplerenone

Hitomi H et al. 2007; 50:750-5

Renal Actions Renal Actions of Aldosteroneof Aldosterone

Wenzel U Curr Opin Nephrol Hypertens 2008; 17: 44-50

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.

Aldosterone and Aldosterone and Progression of Renal DiseaseProgression of Renal Disease

-1

-16

-42-48

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Red

uctio

n of

Pro

tein

uria

(%

)

128/75 132/76 135/73 130/76

Blood Pressure (mmHg)

REDUCTION OF PROTEINURIA BY THERAPY

-0.47

-0.32

-0.5-0.45

-0.4-0.35

-0.3-0.25

-0.2-0.15

-0.1-0.05

0

Perc

enta

ge D

eclie

n in

GFR

(ml/m

in)

Placebo Spironolactone

DECLINE IN e-GFR BY THERAPY

Ramipril Ramipril+Ibersartan

Ramipril+Spironolactone

Ramipril + Ibersartan +Spironolactone

Chrysostomu A et al. Clin J Am Soc Nephrol 2006; 1: 256-62Bianch S et al. Kidney Int 2006; 2116-23

Mechanisms of Aldosterone-Dependent Renal InjuryMechanisms of Aldosterone-Dependent Renal InjuryKiyomoto H et al. J Pharmacol Sci 2008; 108: 399-405Kiyomoto H et al. J Pharmacol Sci 2008; 108: 399-405

1% NaCl 1% NaCl +Aldosterone

Vehicle +1% NaCl 1% NaCl + Aldosterone

1% NaCl+ Aldosterone+Eplerenone

1% NaCl+Aldosterone

+ Tempol

MR in Mesangial cells

Podocyte Abnormality

Glomerular Sclerosis

Superoxide Dismutase Mimetic

Renally-Produced AldosteroneRenally-Produced Aldosterone

Increased MR in Mesangial CellsIncreased MR in Mesangial Cells

Increased transcription of Increased transcription of MC-Responsive GenesMC-Responsive Genes

ROS ProductionROS Production

Podocyte InjuryPodocyte Injury

PROTEINURIAPROTEINURIA

Calcium Paradox of Aldosteronism and Its Consequences***Calcium Paradox of Aldosteronism and Its Consequences***Vidal A et al. Am J Physiol Circ Physiol 2006; H286-H294Vidal A et al. Am J Physiol Circ Physiol 2006; H286-H294

CELL

ACTIVATION

Sequestration of Cytosolic Ca2+ by Mitochondria

H2O2-(1-2 wks)↓α1AP–(1-6 wks)

gp91- (4wk)

Parathyroidectomy +Ca2+ Suppl.

Increased Aldosterone and Na+

Hypercalciuria(6 wks)

Hypermagnesuria(6 wks)

Loop DiureticsLoop Diuretics

Spironolactone Spironolactone

Decreased PlasmaCa2+ Concentration

Decreased PlasmaMg2+ Concentration

Ca2+ Suppl.or Vitamin D 3

*** ≈ Zinc

PTH & ET-1Parathyroidectomy

Increased Cellular Expression of Ca2+ Channels

PMBCPlateletsVascular

CellsHeart

MuscleCells

Skin

SkeletalMuscle

CCMParathyroidectomy

Human Counterparts of the Human Counterparts of the Calcium Paradox of ParathyroidismCalcium Paradox of Parathyroidism

↑↑ urinary Caurinary Ca2+ 2+ excretion, excretion, ↓↓plasma ionized Caplasma ionized Ca2+ 2+ , , ↑↑ plasma levels of PTH, plasma levels of PTH, and and ↑↑ cytosolic free [Ca cytosolic free [Ca2+2+]]i i found in pts. with low-renin HTNfound in pts. with low-renin HTN

(Brickman AS et al. Hypertension 1990; 16: 515)(Brickman AS et al. Hypertension 1990; 16: 515)

High dietary NaHigh dietary Na+,+, which suppresses renin and aldosterone, and elevated which suppresses renin and aldosterone, and elevated aldosterone, inappropriate for 1% dietary NaCl, are each accompanied by aldosterone, inappropriate for 1% dietary NaCl, are each accompanied by hypercalciuria. hypercalciuria.

(Ahokas RA et al. Circulation 2005; 111: 51-7(Ahokas RA et al. Circulation 2005; 111: 51-7

Immune cell activation accompanies secondary HPT of CRFImmune cell activation accompanies secondary HPT of CRF(Alexievic JM et al. Kidney Int. 1996; 50: 1249-54)(Alexievic JM et al. Kidney Int. 1996; 50: 1249-54)

Secondary HPT (elevated plasma PTH and ET-1 levels, osteopenia and Secondary HPT (elevated plasma PTH and ET-1 levels, osteopenia and osteoporosis) found in HF pts.osteoporosis) found in HF pts.

(Anker SD et al. Am J Cardiol 1999;83: 612-5)(Anker SD et al. Am J Cardiol 1999;83: 612-5)

Hypovitaminosis D common in HF pts. Hypovitaminosis D common in HF pts. (Shane E et al. Am J Med 1997; 103: 197-207(Shane E et al. Am J Med 1997; 103: 197-207

The cytokine profile of primary & secondary HPT resembles that of HFThe cytokine profile of primary & secondary HPT resembles that of HF (Mann DL et al. Chest 1994; 105:897-904)(Mann DL et al. Chest 1994; 105:897-904)

Loop diuretics exaggerate urinary CaLoop diuretics exaggerate urinary Ca2+2+ and Mg and Mg2+2+ excretion and promote excretion and promote further PTH release and greater bone lossfurther PTH release and greater bone loss

(Law PH at al. J Am Coll Cardiol 2005; 46: 142-6(Law PH at al. J Am Coll Cardiol 2005; 46: 142-6

The combination of thiazide diuretics and spironolactone reverses these The combination of thiazide diuretics and spironolactone reverses these losseslosses

(Runyan AL et al. Am J Med Sci 2005; 330: 1-7)(Runyan AL et al. Am J Med Sci 2005; 330: 1-7)

Reduction of Fracture Risk by Reduction of Fracture Risk by Spironolactone in Men with CHFSpironolactone in Men with CHF

Fracture Fracture SiteSite

CasesCases ControlsControls Adjusted Odds Adjusted Odds Ratio (95% CI)Ratio (95% CI)

p Valuep Value

TotalTotal 167167 668668 0.575 0.575 (0.346-0.955)(0.346-0.955)

0.03240.0324

HipHip 3636 144144 0.8480.848(0.255-2.825(0.255-2.825

0.78890.7889

WristWrist 1010 4040 -- --

VertebralVertebral 6969 276276 0.5810.581(0.252-1.343)(0.252-1.343)

0.20410.2041

OtherOther 5252 208208 02360236(0.077-0.726)(0.077-0.726)

0.01180.0118

Carbone LD et al. J Am Coll Cardiol 2008; 52: 135-8

Jorde, U. P. et al. Circulation 2002;106:1055-1057

Aldosterone Escape During Therapy with ACEIs

N = 11

Upper Limit of Normal Range for Plasma Aldosterone

7/ 11 (64%) had AII/AI ratio 0.05, indicating complete inhibition

of the vascular ACE

Juurlink et al. NEJM 2004;351:543

after RALES: RX

Juurlink et al. NEJM 2004;351:543

after RALES:Death

Guidelines for Minimizing the Risk of Hyperkalemia in Patients Treated With Aldosterone Antagonists

1. Impaired renal function is a risk factor for hyperkalemia during treatment with aldosterone antagonists. The risk of hyperkalemia increases progressively when sCr exceeds 1.6 mg/dL.*

In elderly patients or others with low muscle mass in whom sCr does not accurately reflect GFR, determination that GFR or Cr clearance exceeds 30 ml/min is recommended.

2. Aldosterone antagonists should not be administered to patients with baseline serum potassium > 5.0 mEq/L.

3. An initial dose of spironolactone of 12.5 mg or eplerenone 25 mg is recommended, following which the dose may be increased to spironolactone 25 mg or eplerenone 50 mg if appropriate.

4. The risk of hyperkalemia is increased with concomitant use of higher doses of ACEIs (captopril ≥ 75 mg daily; enalapril or lisinopril ≥ to 10 mg daily.

5. NSAIDs and COX-2 inhibitors should be avoided.

6. Potassium supplements should be discontinued or reduced.

7. Close monitoring of serum potassium is required; potassium levels and renal function should be checked in 3 days and at 1 week after initiating therapy and at least monthly for the first 3 months.

8. Diarrhea or other causes of dehydration should be addressed emergently.

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

Ezekowitz, J. A. et al. Eur Heart J 2009 30:469-77

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

01-Heart Failure

02-Myocardial Infarction

Effect of Aldosterone Blockers on LVEF in All Randomized Trials

Deleterious Actions of High Levels of AldosteroneDeleterious Actions of High Levels of Aldosterone in the Cardiovascular System in the Cardiovascular System

Increased Aldosterone Level

Kidney HeartVasculature

Na+ reabsorption and water retention

K+ and Mg2+

excretion

Volume expansionand edema

Electrolyte imbalance

↓ NE uptake Inflammation And tissue injury

↓ Myocardial function

Ventriculararrhythmias

Myocardialfibrosis

Perivascularfibrosis

↓ Arterialcompliance

Baroreceptordysfunction

Endothelial dysfunction

↓Vascularreserve

End-organ damage and cardiovascular disease

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