8. RAAS and SNS in HF Flashcards
___ (↑/↓) CO activates the RAAS.
Low ↓
The RAAS cooperates with the _____ to adapt the body to the failing cardiac performance.
SNS
The RAAS maintains _____ ______.
arterial pressure
Activation of the RAAS ______ Na and water.
retains
SNS stimulates ___ adrenergic receptors in the _________ region of the kidney
- β1
- juxtaglomerular
What receptor agonism causes the release of renin?
β1 agonism in the juxtaglomerular region of the kidney
Angiotensinogen is cleaved by _____ to form Ang I.
renin
Ang I is converted to Ang II by what enzyme?
ACE: angiotensin converting enzyme
Angiotensin II is a potent arterial vasodilator. (T/F)
False: vasoconstrictor
Ang II promotes Na and water ______.
retention
Ang II stimulates the release of what?
aldosterone
Where is aldosterone released from?
adrenal cortex
What RAAS hormone contributes to pathologic myocardial hypertrophy?
Ang II
In what tissue types is ACE expressed?
- cardiac myocytes
- fibroblasts
- vascular smooth muscle cells
- endothelial cells
Ang II may also be formed through non-ACE-dependent mechanisms. (T/F)
True
What is a tissue protease that converts Ang I into Ang II?
chymase
Both chymase and ACE expression are induced during HF. (T/F)
False: only ACE expression is induced in HF
In the heart, which enzyme is primarily responsible for generation of AngII?
ACE
What is the main mechanism by which ACE inhibitors improve HF?
reduce pathological remodeling of the heart
What is the standard treatment in all classes of HF?
ACE inhibitors
What are the therapeutic effects of ACE inhibitors in HF?
- inhibits formation of Ang II
- arterial and venous dilation: ↓ afterload and preload
- ↓ aldosterone release
- ↓ LV hypertrophy
What are the ACE inhibitors approved for use in HF? (7)
- Captopril
- Enalapril
- Ramipril
- Lisinopril
- Quinapril
- Fosinopril
- Trandolapril
ACE inhibitors have been proven to improve what aspects of HF?
- hemodynamics
- clinical status
- lessen symptoms
- reduce mortality
What are the ADRs of ACE inhibitors?
- hypotension (dizziness, syncope)
- increases renal insufficiency
- angioedema / cough
Why do ACE inhibitors increase renal insufficiency?
- Renal perfusion pressure is maintained by Ang II during ↓CO, constricting the efferent arteriole.
- When ACE-I prevents formation of Ang II, GFR ↓ significantly.
What is the predominant Ang II receptor in the vasculature?
Type 1 (AT1)
What Ang II receptors are expressed in human myocardium?
AT1 and AT2
The ADRs of ↑Ang II are mediated by the activation of what receptor?
AT1
What are the ADRs associate with ↑Ang II levels?
- vasoconstriction
- myocyte apoptosis
- cardiac myocyte growth
- norepinephrine release
- aldosterone release
What were the findings of the ELITE I trial?
Losartan is superior to an ACE inhibitor in elderly patients with HF.
What were the findings of the ELITE II trial?
ACE inhibitors were equal to or superior to Losartan in the larger heart failure population.
What were the findings of the VALIANT trial?
ACE inhibitors and ARBs show comparable efficacy after MI
What are the ARBs approved for HF when ACE inhibitors are poorly tolerated?
- Valsartan
- Candesartan
ACE inhibitors take weeks to months to decrease aldosterone levels. (T/F)
False: aldosterone levels decrease early in therapy
During chronic treatment of HF, aldosterone returns to normal or elevated levels. (T/F)
True
What are the physiological effects of aldosterone?
- Na retention
- ↑ preload
_______ causes myocardial fibrosis.
Aldosterone
How does aldosterone cause LV hypertrophy?
myocardial fibrosis by stimulating the production of collagen in the heart
Aldosterone inhibits the uptake of what NT?
norepinephrine
Aldosterone __ (↑/↓ ) extracellular concentrations of NE in the heart.
increases ↑
In what ways does spironolactone show benefit in Class IV HF?
- ↓ incidence of sudden death from arrhythmia
- improves NE uptake
In a normal heart there is what level of adrenergic stimulation in the LV during resting state?
none
What is the normal regulatory mechanism for increasing CO?
acute increases in SNS activity
What are the consequences of chronically elevated SNS activity?
- ↑ HR
- ↑ vasoconstriction
- ↑ retention of Na and water
Why do HF patients have chronically elevated SNS activity?
SNS activity is stimulated by reduced CO
What are the consequences of long term sympathetic stimulation?
- further depressed ventricular function
- ↑ heart’s demand for energy
In HF, why is there an increase in circulating NE?
reduced uptake
What are the consequences of increased circulating NE?
Excess NE is toxic to the heart due to excessive stimulation of β1 receptors
Which adrenergic receptor is expressed more densely in the heart?
β1 > α1
In the ventricles, which β subtype is more highly expressed?
β1 (80%) vs β2 (20%)
During HF, what adrenergic receptor is down regulated?
β1
What are the 3 classes of β-blocker?
1st gen: non selective
2nd gen: β1 selective
3rd gen: antagonize β and α receptors
What generation of β-blocker is used for HF?
2nd gen: β1 selective
What are the consequences of prolonged excessive β stimulation?
- β1 down-regulation
- ↓ adenylyl cyclase activity and cAMP levels
- down-regulation of CA uptake in SR
- hyper-phosphorylation of the CA release channel in SR
1st generation β-blockers are most effective in compensated HF. (T/F)
False: 1st gen are counterproductive
2nd and 3rd generation β-blockers are effective in most patients with mild to moderate HF. (T/F)
True
What are the therapeutic effects of β-blockers in HF?
- reverses down-regulation of β1 receptors
- produces more normal cardiac performance
- restores receptor coupling to adenylyl cyclase
- reduces remodeling and myocardial death
- reverses hyper-phosphorylation of the CA release channel in SR
What are the 2nd generation β-blocker agents that are used in HF?
- metoprolol succinate
- bisoprolol
What are the 3rd generation β-blocker agents that are used in HF?
carvedilol
What are the beneficial α1 effects of carvedilol?
- reduces afterload
- vasodilation counteracts the negative inotropic effects of β-blockade
What are the beneficial effects of antiadrenergics for treating HF?
- reduce the adverse effects of excessive NE
- stabilize cardiac rhythm
- reduce HR
In HF, decreased HR is associated with progressive reduction in cardiac function. (T/F)
False: increased HR
What are the potential ADRs of antiadrenergic therapy?
immediately after starting, may ↓ EF
