Transcript Cindarella - Gastaldi Congressi

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
The Classic Genomic Action of
Aldosterone on Epithelial Tissue
Interstitium
Fluid
(Blood)
Lumen
11β-HSD2
Cortisone
Cortisol
Endoplasmic Reticulum
Aldosterone
Gene
MR
HRE
K+
K+
H20
H20
Nucleus
Sgk1
ATP
CHIF
Ki-Ras
ENaCNa+
Channel
Na+
Na+
ADP
Na+
Na+/K+
ATPase
K+
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*
(n =64)
Enalapril 40 mg*
(n =71)
Eplerenone 200 mg/
Enalapril 10 mg*
(n =67)
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
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
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
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.
Aldosterone Blockade and AT1 Receptor Blockade:
Trials in Post-MI LV Dysfunction and Heart Failure
RALES
EPHESUS
30% Risk reduction
RR 0.70 (0.60–0.82)
P < 0.001
1.00
0.90
15% Risk reduction
RR 0.85 (0.75–0.96)
P = 0.008
22
Placebo
18
Probability 0.75
of survival
0.60
Spironolactone
Cumulative 14
25 mg
incidence
10
(%)
6
Placebo
0.45
0.00
2
0
0
6
12
18
24
Months
30
36
Eplerenone
50 mg
0
6
12
18
24
30
36
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.
30-Month Mortality by treatment groups and PIIINP baseline levels
Data from RALES
Zannad, F. et al. Circulation 2000;102:2700-2706
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
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
Extraadrenal Production of Aldosterone by
Endothelial and Vascular Smooth Muscle Cells
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
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
Mechanisms of Aldosterone-Induced
Oxidative Stress and Endothelial Dysfunction
Aldosterone
O2
NADPH
NAD(P)H
Oxidases
G6PD
˙O2-
NADP+
ONOOL-Arginine
L-citrulline +
˙ NO
Nitric Oxide
Synthase
Ser1177 BH4
Aldosterone
PP2A
P
Marney AM and Brown NJ Clinical Science 2007; 113: 267-78
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
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
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
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
Crosstalk Between Insulin and RAAS:
Effects on Glucose Metabolism
↓ IRS protein content and phosphorilation
↓adipocyte differentiation
↑ TG secretion and accumulation
Activation
of the RAAS
↑ gluconeogenesis
↓glucose-mediated Insulin release
↓adiponectin production
Eplerenone
Src PPI inhibitor
Antioxidants
Metabolic Effects
of A II ↓IRS-1 content
and phosphorilation
↓ GLUT-4 translocation
Eplerenone
↑ MCP-1 expression in islets
↑ ROS Production
↓Glucose uptake
Hitomi H et al. 2007; 50:750-5
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
Aldosterone and
Progression of Renal Disease
REDUCTION OF PROTEINURIA
BY THERAPY
Ramipril
Ramipril+
Ibersartan
Ramipril+ Ramipril + Ibersartan +
Spironolactone Spironolactone
-1
-10
-15
-16
-20
DECLINE IN e-GFR BY THERAPY
-25
-30
-35
-40
-42
-45
-48
-50
128/75
132/76
135/73
130/76
Blood Pressure (mmHg)
Chrysostomu A et al. Clin J Am Soc Nephrol 2006; 1: 256-62
Bianch S et al. Kidney Int 2006; 2116-23
Percentage Declien in GFR (ml/min)
Reduction of Proteinuria
(%)
0
-5
0
-0.05
-0.1
-0.15
-0.2
-0.25
-0.3
-0.32
-0.35
-0.4
-0.45
-0.47
-0.5
Placebo
Spironolactone
Mechanisms of Aldosterone-Dependent Renal Injury
Kiyomoto H et al. J Pharmacol Sci 2008; 108: 399-405
Podocyte Abnormality
Renally-Produced Aldosterone
Increased MR in Mesangial Cells
MR in Mesangial cells
1% NaCl
Increased transcription of
Glomerular Sclerosis
MC-Responsive Genes
1% NaCl +
Aldosterone
ROS Production
Podocyte Injury
PROTEINURIA
Vehicle
+1% NaCl
1% NaCl + Aldosterone
1% NaCl
+ Aldosterone
+Eplerenone
1% NaCl
+Aldosterone
+ Tempol
Superoxide Dismutase Mimetic
Calcium Paradox of Aldosteronism and Its Consequences***
Vidal A et al. Am J Physiol Circ Physiol 2006; H286-H294
Increased Aldosterone and Na+
Spironolactone
Spironolactone
Hypercalciuria
(6 wks)
Hypermagnesuria
(6 wks)
Decreased Plasma
Ca2+ Concentration
Parathyroidectomy
Decreased Plasma
Mg2+ Concentration
Ca2+ Suppl.
or Vitamin D 3
 PTH & ET-1
CCM
Parathyroidectomy
C
E
L
L
Increased Cellular
Expression of Ca2+ Channels
PMBC
Skin
Skeletal
Muscle
Heart
Muscle
Cells
Vascular
Cells
Platelets
Sequestration of Cytosolic Ca2+ by Mitochondria
Parathyroidectomy
+Ca2+ Suppl.
*** ≈ Zinc
 H2O2-(1-2 wks)
↓α1AP–(1-6 wks)
 gp91- (4wk)
A
C
T
I
V
A
T
I
O
N
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)
Reduction of Fracture Risk by
Spironolactone in Men with CHF
Fracture
Site
Total
Cases Controls
Adjusted Odds
Ratio (95% CI)
p Value
167
668
0.575
(0.346-0.955)
0.0324
Hip
36
144
0.848
(0.255-2.825
0.7889
Wrist
10
40
-
-
Vertebral
69
276
0.581
(0.252-1.343)
0.2041
Other
52
208
0236
(0.077-0.726)
0.0118
Carbone LD et al. J Am Coll Cardiol 2008; 52: 135-8
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
Jorde, U. P. et al. Circulation 2002;106:1055-1057
Juurlink et al. NEJM 2004;351:543
after RALES: RX
after RALES:Death
Juurlink et al. NEJM 2004;351:543
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
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
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
Deleterious Actions of High Levels of Aldosterone
in the Cardiovascular System
Increased Aldosterone Level
Vasculature
Kidney
Heart
Na+ reabsorption and
water retention
K+ and Mg2+
excretion
Volume expansion
and edema
Electrolyte
imbalance
↓ NE uptake
↓ Myocardial
function
Ventricular
arrhythmias
Inflammation
And tissue injury
Myocardial
fibrosis
Endothelial
dysfunction
Perivascular
fibrosis
↓ Arterial
compliance
Baroreceptor
dysfunction
End-organ damage and cardiovascular disease
↓Vascular
reserve
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!