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 *

 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

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

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

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) LVRVLVRV fmol/mg § § * ** ‡ ‡ 11 22

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 LVRVLV RV Norepinephrine NPY ng/g (NE) or pg/mg (NPY) * * * ‡ ‡ § § * * * § ‡ M10043

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

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

 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 ¶