9. Heart failure - pathophysiology

Question 1

Which 4 main neurohormonal systems does decreased CO as a result of HF activate/inhibit?

Answer 1

activates:
1- sympathetic nervous system - NA release
2- Renin-Angiotensin-Aldosterone system
3- ADH

inhibits:
4- natriuretic hormones

Question 2

What causes activation of the SNS in HF?

Answer 2

low CO sensed by baroreceptors

Question 3

How does NA release in SNS activation initially improve CO?

Answer 3

1. increased HR and contractility
2. vasoconstriction
3. renin release and RAAS activation

Question 4

Why are the long term effects of SNS activation in HF deleterious?

Answer 4

Chronic high [NA] causes:

1. downregulation/uncoupling of beta-adrenergic receptors… decreased contractility and CO
2. direct cardiotoxicity: myocyte apoptosis and necrosis… decreased contractility and CO
3. long-term vasoconstriction and increased HR/inotropy cause increased wall stress… increased myocardial oxygen demand and LV hypertrophy… decreased contractility and CO
4. reduced heart rate variability (decreased paraSNS and increased SNS) - increased risk of arrhythmias

Question 5

What causes activation of the RAAS in HF?

Answer 5

i) decreased CO causes decreased kidney perfusion

ii) SNS induction of renin from macula densa/JGA

Question 6

Which 2 types of receptor does AngII act on?

Answer 6

AT1R - deleterious effects via vasoconstriction and sodium/water retention - key role in organ damage

AT2R - positive effects via stimulation of NO production and consequent vasodilation

Question 7

Why are the long term effects of RAAS activation in HF deleterious?

Answer 7

Leads to elevated levels of AngII:

1- potent vasoconstrictor… increased afterload… decreased CO

2- promotes LV hypertrophy and myocyte dysfunction

3- promotes aldosterone release… Na+/H2O retention

4- increases SNS activity

Question 8

How does AngII activation of AT1R affect the brain?

Answer 8

Causes atherosclerosis… stroke… death

Question 9

How does AngII activation of AT1R affect the kidney?

Answer 9

Causes decreased GFR, increased proteinuria, increased aldosterone release and glomerular sclerosis… renal failure… death.

Question 10

How does AngII activation of AT1R affect the heart?

Answer 10

Causes LV hypertrophy, fibrosis, remodelling and apoptosis… MI and HF… death.

Question 11

How does AngII activation of AT1R affect the blood vessels?

Answer 11

a) Causes vasoconstriction, vascular hypertrophy and endothelial dysfunction…
b) … hypertension…
c) … stroke, HF/MI and renal failure…
d) … death.

Question 12

What are the effects of ADH increase in HF?

Answer 12

1. increased H2O retention
2. tachycardia
3. increased systemic resistance

Long term lead to decreased CO.

Question 13

How does ADH mediate increased water retention in the kidney?

Answer 13

Acts on V2 receptors in the collecting duct, leading to increased expression of aquaporin-2 and increased water retention.

Question 14

What term decribes low Na+?How is this caused?

Answer 14

• hyponatraemia
• results from H2O in excess of Na+ retention, due to increased water intake or increased water reabsorption by action of ADH on V2 Rs

Question 15

What causes ANP and BNP release and what is the general effect of this?

Answer 15

• Released by atrial/ventricular myocyte stretch (i.e. high BP).
• Oppose the RAAS by promoting Na+/H2O loss and vasodilation.

Question 16

How do ANP/BNP act to oppose the RAAS?

Answer 16

1. Inhibit secretion of renin and aldosterone.
2. Constrict afferent and vasodilate efferent arterioles to kidneys.
3. Decrease Na+ reabsorption in collecting duct.
4. Systemic arterial and venous vasodilation?

Question 17

What is endothelin secreted by and what are its actions?

Answer 17

• Secreted by vascular endothelial cells.

- Potent system and renal vasoconstrictor acting via autocrine (local) activity… activated RAAS.

Question 18

Name 3 chemical mediators that might attenuate the effects of NA/RAAS.

Answer 18

1. Prostaglandins E2 (stimulated by NA and RAAS) - vasodilator of afferent renal arterioles
2. Nitric oxide - vasodilator produced by endothelial cells
3. Bradykinin - promotes naturesis and vasodilation via NA and stimulates prostaglandin production

Question 19

Which enzyme produces NO and how is the activity of this changed in HF?

Answer 19

• NO synthase

- may be blunted in HF

Question 20

Explain how increased Na+/H2O retention affects HF.

Answer 20

Increased retention… increased blood volume… increased preload… ventricular dilation and increased heart wall stress… decreased SV and CO… decreased renal perfusion… increased retention…

Question 21

Explain how increased vasoconstriction affects HF.

Answer 21

Vasoconstriction… increased systemic vascular resistance… increased outflow resistance…impaired LV function… decreased SV and CO.