Download Aldosterone

The Role of Aldosterone and
Aldosterone Blockade in
Cardiovascular Disease
Gary E Sander, MD, PhD., FACC
Professor, Tulane - New Orleans
The Contemporary View
Myocardial
Fibrosis
Thrombotic
Phenomena
Vascular
Fibrosis
DELETERIOUS EFFECTS
OF ALDOSTERONE
Catecholamine
Potentiation
Sodium
Retention
Ventricular
Arrhythmias
Potassium
and
Magnesium
Loss
Central
Pressor Effects
Endothelial
Dysfunction
Cardiac and vascular damage*
Hypertension, Heart Failure, Ischemia, Ventricular Dysfunction,
Arrhythmia, Edema, Stroke, End-Stage Renal Disease
Delyani, Exp Opin Invest Drug 1998.
Zannad, Eur Heart J 1995.
Brown et al, Hypertension 1998.
* In the absence of aldosterone-receptor blockade,
aldosterone may cause cardiac and vascular
damage.
Aldosterone Stimulates Myocardial
Fibrosis in Animal Model
Plasma
Unilateral
renal artery
stenosis
Angiotensin II
Aldosterone
HB
P
Yes
LVH Fibrosis
Yes
Yes
Fibrosi
s
Aldosterone
infusion in
uninephric rat
Angiotensin II
Aldosterone
Yes
Yes
Yes
Fibrosi
s
Infrarenal
aortic
banding
Angiotensin II
Aldosterone
Yes
Yes
No
No fibrosis
HBP = high blood pressure, LVH = left ventricular hypertrophy
Brilla et al, Circ Res 1990.
Aldosterone Correlates With
Increased LV Mass
45
r=0.559
p<0.001
40
35
30
Aldosterone
(ng/dL)
25
20
15
10
5
0
0
50
100
150
Left ventricular mass index (g/m2)
Duprez et al, Am J Cardiol 1993.
200
250
Aldosterone Correlates With
Decreased Large-Artery Compliance
30
25
20
Plasma aldosterone
15
(ng/dL)
10
r=0.795
p<0.002
5
0
0
0.5
1.0
1.5
2.0
2.5
Proximal arterial compliance
(mL/mmHg)
Duprez et al, Eur Heart J 1998.
Enalapril/Epleronone Combination
SBP (mm Hg)
DBP (mm Hg)
LVM (gm)
epleronone
-24
-12
-15
enalapril
-25
-13
-20
combination
-29
-14
-27
The Role of Spironolactone in the
Treatment of Patients with Refractory
Hypertension
Inclusion:
•
•
•
•
essential HTN ≥ 6 months
Clinical and mean ABP > 140/90 on ≥ 2 drugs
No prior treatment with spironolactone
No renal insufficiency
Results
• after 1 month of therapy, 23/25 patients had clinical
BP < 140/90
• ABPM after 1 month: 152±2/86±2  128±2/76±2
Ouzan et al Am J Hypertens 2002:15:333-9
Aldosterone Synthesis Escape
• Aldosterone levels may fall initially in response to
ACE inhibition or angiotensin-II receptor
blockade, but return to normal or above baseline
levels (“escape”) by 12 weeks1
• Multiple homeostatic mechanisms exist to preserve
mineralocorticoid activity2,3
• Regulators of aldosterone secretion include
potassium, angiotensin II, ACTH, and other minor
stimulants3
1Staessen
et al, J Endocrinol 1981.
Am J Cardiol 1993.
3Zannad, Eur Heart J 1995.
2Weber,
Diuretic use, progressive heart failure, and death
in patients in the studies of left ventricular
dysfunction (SOLVD)
Event rate per 100 patient years
None
PSD only
Non-PSD
Only
Both
p
Hosp for HF
2.2 (237)
4.6(9)
8.0 (480)
5.0 (47)
0.0008
CV Death
4.7 (517)
7.1 (15)
12.1 (801)
7.9 (78)
0.0001
All-Cause
mortality
5.4 (594)
7.6 (16)
13.6 (900)
8.8 (87)
<10-5
Hosp for, or
death from,
HF
3.1 (341)
5.7 (12)
9.7 (640)
6.4 (63)
0.0004
Domanski et al JACC 2003;42:705-8.
Estimated Risks, With 95% Confidence Intervals, for Patients Taking Only
Non-PSDs and Those Taking PSDs Relative to the Risk of Patients Taking
No Diuretics at Baseline
None
PSD
p Value
Non-PSD Only
p Value
Hospitalization for HF
1.00
1.03 (0.75–1.41)
0.86
1.38 (1.11–1.71)
0.003
Death from CV disease
1.00
0.95 (0.75–1.20)
0.67
1.28 (1.09–1.50)
0.002
Death from all causes
1.00
0.93 (0.75–1.16)
0.52
1.28 (1.19–1.49)
0.0008
Hosp or death from HF
1.00
0.99 (0.76–1.30)
0.95
1.31 (1.09–1.57)
0.0004
Domanski et al JACC 2003;42:705-8.
Effect of spironolactone on cardiacsympathetic
nerve activity and left ventricular remodeling in
patients with dilated cardiomyopathy
Kasama et al JACC 2003;41:574-81
Correlation between the changes in the 123I-MIBG scintigraphic findings and changes in left
ventricular end-diastolic volume (LVEDV) after six months of spironolactone treatment in 15
patients with dilated cardiomyopathy. Delta LVEDV = LVEDV value after six months −
pretreatment value of LVEDV; delta TDS = total defect score (TDS) value after six months −
pretreatment value of TDS; delta H/M RATIO = H/M ratio after six months − pretreatment value
of H/M ratio; delta WR = washout rate (WR) value after six months − pretreatment value of WR.
Effect Of Spironolactone On Cardiac Sympathetic
Nerve Activity And Left Ventricular Remodeling In
Patients With Dilated Cardiomyopathy
Kasama et al JACC 2003;41:574-81
CONCLUSIONS
Spironolactone improves cardiac sympathetic nerve
activity and LV remodeling in patients with DCM
Dose-Dependent Effect of
Spironolactone in Heart Failure
Control Group (n=46)
Variable
Baseline
Follow-Up
Spironolactone (n=47)
Baseline
Follow-Up
LVEDV (ml)
257 ± 80
253 ± 89
275 ± 104
251 ± 105
LVESV (ml)
173 ± 71
168 ± 79
188 ± 94
171 ± 97
LVEF (%)
34 ± 7
34 ± 9
33 ± 7
36 ± 9
P < 0.05 for all
Cicoira et al JACC 2002;40:304-10.
Dose-Dependent Effect of
Spironolactone in Heart Failure
Cicoira et al JACC 2002;40:304-10.
Immediate Administration of Mineralocorticoid Receptor
Antagonist Spironolactone Prevents Post-Infarct Left
Ventricular Remodeling Associated With Suppression of a
Marker of Myocardial Collagen Synthesis in Patients With
First Anterior Acute Myocardial Infarction
Hayashi et al. Circulation 2003;107:2559-2565
• To evaluate the effect of mineralocorticoid receptor antagonist (MRA)
spironolactone on post-infarct LV remodeling, 134 patients with first
anterior acute myocardial infarction were randomly divided into the
MRA (n=65) or non-MRA (n=69) groups after revascularization.
• All patients were administered angiotensin-converting enzyme (ACE)
inhibitor and study drug just after revascularization.
• Left ventriculography with contrast medium was performed at the acute
stage and after 1 month to evaluate LV remodeling.
• ALD was measured at aortic root and coronary sinus. There was no
difference in the baseline characteristics including infarct size and LV
performance between the two groups.
Top, Changes in the LVEF, LVEDVI, LVESVI in the two randomized treatment groups from baseline to 1
month later. Bottom, Absolute change (value at 1 month-baseline) in LVEF, LVEDVI, and LVESVI. P<0.05;
P<0.01; P<0.0001: difference between baseline and 1-month values (within each group).
Beneficial Neurohormonal Profile Of Spironolactone In
Severe Congestive Heart Failure: Results From The
RALES Neurohumoral Substudy
Rousseau et al JACC 2002;40:1596-1601
CONCLUSIONS
• Andosterone antagonism appears to reduce
inflammation and to preserve endothelial
functional and tissue structural integrity in a
number of pathophysiological states
• Caution is required in the patient with diabetes,
particularly in the presence of reduced renal
function/Type IV RTA
• Avoid combinations with potassium, other Ksparing diruetics, and NSAIDS