1. MODULATABLE (STIMULATION) FUNCTION SECONDARY DAMAGE SUPPORT ACTIVATION OF COMPENSATORY MECHANISMS* ● Adrenergic ● RAAS ● Other INTRINSIC (RESTING) FUNCTION CARDIAC INSULT (e.g., myocardial infarct, chronic hypertension) PRIMARY DAMAGE ATTENUATION 1.  heart rate 2.  contractility 3. Frank-Starling mechanism 4. Hypertrophy *

2.  1 -adrenergic signaling Myopathic pathways, PKA independent Fetal gene Program induction Apoptosis Other (  P-PLN, altered metabolism,  P-RyR 2, etc)  Cardiac function, PKA dependent  Systolic function  Diastolic function  Heart rate + – Yang Yin Ideal anti-adrenergic Rx Progressive Desensitization: Arrhythmias

3. altered  receptor signal transduction decreased myocardial reserve, decreased max exercise progressive myocardial dysfunction adverse biologic effects on cardiac myocytes HEART FAILURE  modulatable function  intrinsic function  chamber mass, volumes INCREASED CARDIAC NE support of myocardial function short-term long-term  Exercise Tolerance  EF  -blockade

4. % of Total [22] [23] LV AS [24] Conc Hty Ecc Hty Conc Remod

5. mean  SEM *p<0.05 vs. respective chamber in nonfailing heart ‡ p<0.05 vs. respective chamber in biventricular failure § p<0.05 vs. LV Nonfailing (n=12) Biventricular failure (n=54) PPH, isolated RV failure (n=12) 0 20 40 60 80 100 LVRVLVRV fmol/mg § § * ** ‡ ‡ 11 22

6. Nonfailing (n=9) Biventricular failure (n=39) PPH, isolated RV failure (n=5) mean  SEM *p<0.05 vs. respective chamber in nonfailing heart ‡ p<0.05 vs. respective chamber in biventricular failure § p<0.05 vs. LV 0 200 400 600 800 1000 1200 1400 1600 1800 LVRVLV RV Norepinephrine NPY ng/g (NE) or pg/mg (NPY) * * * ‡ ‡ § § * * * § ‡ M10043

7. Molecules x 10 5 /µg total RNA  1 AR  2 AR  1 AR  2 AR Molecules x 10 5 /µg total RNA Receptor density (fmol/mg)  -MHC  -MHC ANPSRCA

8. C U V I Carvedilol LV [37] (n=21) Carvedilol RV (n=11) p <0.05 vs. placebo * % change from baseline EFDVISVIEFDVI 50 40 30 20 10 0 –10 –20 –30 Placebo LV (n=15) Placebo RV (n=11) SVI †p <0.05 vs. BsL † † † † CarvedilolPlacebo * * * * * [38] [37] [38]

9. 0 0.1 1.0 10 100 -0.1 -10 -100  1 AR  2 AR ANP SRCA  MHC  MHC Responders (n=26): LVEF 20  2  39  2; RVEF 32  2  43  2 Nonresponders (n=6): LVEF 20  2  18  3; RVEF 40  3  38  6 * p<.05 vs. not improved # p<.05 vs. BSL † p <.10 vs. BSL Change in Gene Expression Molecules mRNA 105/  g Total RNA # # *, #, *, # * † 0 ¶ p <.05 vs. Placebo, test for interaction ¶