1. ß-blocker therapy for heart failure at the turn of the millennium
Eric J Eichhorn, MD
University of Texas Southwestern and
Dallas VA Medical Centers
Dallas, Tx

2. Myocardial Dysfunction
Increased load
Reduced Systemic Perfusion
Activation of RAS, SNS, and cytokines
Altered gene expression
Growth and Remodeling
Ischemia and Energy Depletion
Direct Toxicity
Apoptosis
Necrosis
Cell Death
Eichhorn and Bristow. Circulation 1996;94:

3. Wall stress in CHF Stress µ Pr/h h h r r r r L L L L Normal Normal CHF
Spherical
Elliptical
Stress µ Pr/h

4. Effect of enalapril on remodeling in SOLVD
Variable n
Baseline
mean + SD
4 months
12 months
Response comparison over time*
EDV, ml
placebo
130
p=0.025
enalapril
128
LV mass, g
100
p<0.001
107
* p-value for repeated measures ANOVA response between groups
EDV end-diastolic volume
Greenberg et al. Circulation 1995; 91:

5. Effects of ACE inhibitors on survival in patients with CHF
Trial
ACEI
Controls
RR (95% CI)
Mortality
Chronic CHF
Consensus I
50 / (39%)
68 / (54%)
0.56 ( )
SOLVD
(Treatment)
452 / (35%)
510 / (40%)
0.82 ( )
SOLVD
(Prevention)
313 / (15%)
334 / (16%)
0.92 ( )
Post MI
SAVE
228 / (20%)
275 / (25%)
0.81 ( )
AIRE
170 / (17%)
222 / (23%)
0.73 ( )
TRACE
304 / (35%)
369 / (42%)
0.78 ( )
SMILE
38 / (5%)
51 / (6.5%)
0.75 ( )
Totals
1555 / 7290 (21%)
1829 / 7282 (25%)

6. V-HeFT II Change in norepinephrine (pg/ml) Enalapril months p=0.0001
180
120
Change in
norepinephrine
(pg/ml) 60
Enalapril
-60 12 24 36 48
months
Francis GS et al. Circulation 1993; 87:VI-40

7. US carvedilol trials MOCHA study Placebo Carvedilol 6.25 mg BID
Improvement in EF units at 6-months 2 5 6 8
6-month crude mortality rate
15.5%
6.0%
6.7%
1.1%
p<0.005
p<0.005
p<0.0001
p<0.05
p=0.07
p<0.001
Bristow et al. Circulation 1996; 94:

8. Changes in energetics after 3 months of therapy50
100
150
200
250
-50
-100 *
Myocardial
Efficiency
Stroke Work
Oxygen
Consumption * %
Change
p=0.07
p=0.04
p=0.05
= Placebo *
p < 0.05 vs pre therapy
= Metoprolol
Eichhorn et al. J Am Coll Cardiol 1994; 24:

9. Time course of ventricular function changes
0.20
0.25
0.30
0.35
0.40
Standard Therapy
Metoprolol
p<0.0001
p = for metoprolol vs standard therapy
p<0.05
EjectionFraction
BSLN
Day 1 1M 3M
BSLN
Day 1 1M 3M
Hall et al. J Am Coll Cardiol 1995; 25:

10. Effects of metoprolol on remodeling
LV Mass (g)
LV Sphericity
200
300
400
2.0
p = 0.029
p = 0.01
1.8
1.6
1.4
1.2
1.0
Baseline
3 Mo
18 Mo
Baseline
3 Mo
18 Mo
Hall et al. J Am Coll Cardiol 1995; 25:

11. ß-blocker effects on EF in CHF
Time (months)
ß-blocker initiated 1 3 6 8
ß-blocker Discontinued
Biological Effect
Pharmacological Effect

12. Hemodynamic response to ß-blockade in CHF
Negative Inotropic
Pharmacological Effect
Positive Inotropic Biological Effect
Reduced EF
Increased EF
No Cardiac Reserve
+ Cardiac Reserve

13. Change in fractional shortening vs risk of death in CIBIS trial
bisoprolol vs placebo, n=557
left ventricular fractional shortening (LVFS) increased in bisoprolol group vs placebo 5 months after inclusion
LVFS change over time correlated significantly with further survival
patients with improved LVFS over time were at lower risk
patients on bisoprolol with a reduction in shortening fraction had an increased mortality compared to placebo
Lechat P et al. Circulation 1997; 96:

14. CIBIS-II Bisoprolol p<0.0001 Placebo Survival
1.0
0.8
0.6
Bisoprolol
Survival
p<0.0001
Placebo
Annual Mortality
Bisoprolol = 9.0%
Placebo = 13.3%
Average follow-up 1.3 years
200
400
600
800
n = 2647
Time after inclusion (days)
CIBIS-II Investigators and Committees. Lancet 1999; 353: 9-13

15. MERIT-HF mortality Placebo Metoprolol CR/XL 20 15 10 5 Cumulative
p = (adjusted)
p = (nominal)
Placebo
Cumulative
Mortality (%)
Metoprolol CR/XL 3 6 9 12 15 18 21
Follow-up (months)
Lancet 1999; 353:

16. Conclusions
ß-blockade on top of ACE inhibitors results in a slowing or reversal of the pathological remodeling process
improvement in LVEF
improved remodeling, ventricular performance, energetics, and anti-arrhythmic effects of ß-blockers may translate into improved survival
effects of this therapy on more advanced heart failure populations and in certain subgroups are unclear