1. Important pathophysiologic mechanisms in HF (1)

2. Important pathophysiologic mechanisms in HF (2)

3. Important pathophysiologic mechanisms in HF (3)

4. Neurohormonal model of HF

5. -Blockade normalizes Ang II-provoked release of norepinephrine in HF

6. Molecular model of HF

7. Regulation of key molecules in cardiac EC coupling by stress-activated pathways

8. Myocardial force generation increases in response to -blockade in HF after exposure to isoproterenol

9. The RAAS in HF AT2 receptor  Myocardial fibrosis  Adrenal catechols
Angiotensinogen
Kininogens
Angiotensin I
Bradykinin
ACE inhibitors
Bradykinin receptor
Norepinephrine
Vasodilation
Vessel permeability
tPA/prostaglandin release
Nonspecific chymases
ACE/kininase II
Inactive peptides
Angiotensin II
ARB
 Sympathetic activity
AT2 receptor
 Myocardial fibrosis
 Adrenal catechols
? Apoptosis
AT1 receptor
Myocardial fibrosis
Norepinephrine
Vasoconstriction
PAI/endothelin
 Nitric oxide
Aldosterone
Aldosterone antagonists
Increased afterload disease progression
Improved endothelial function
RAAS = renin-angiotensin-aldosterone system
Jamali AH et al. Arch Intern Med. 2001;161:

10. Escape of Ang II despite ACE inhibition

11. RESOLVD: Ang II concentrations similar at baseline and study end

12. AT1-receptor blockade improves vasorelaxation in HF by upregulation of eNOS via AT2 receptors

13. Primary targets of treatment in HF