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
HRE
Gene
Nucleus
Sgk1CHIF
Ki-RasENaCNa+
ChannelNa+/K+
ATPase
Cortisone
MR
K+K+
H20H20
Na+ Na+
11β-HSD2
Endoplasmic Reticulum
Na+
K+
ATPADP
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 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
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
30
0.00
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
AldosteroneAng 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
Re
du
cti
on
of
Pro
tein
uri
a
(%)
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
Per
cen
tag
e D
ecli
en i
n G
FR
(m
l/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 Diuretics
Loop Diuretics
SpironolactoneSpironolactone
Decreased PlasmaCa2+ Concentration
Decreased PlasmaMg2+ Concentration
Ca2+ Suppl.or Vitamin D 3
*** ≈ Zinc
PTH & ET-1Parathyroidectomy
Increased Cellular Expression of Ca2+ Channels
PMBC
PlateletsVascularCells
HeartMuscleCells
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!