The Cardiovascular Response to Stress-Extra Reading

Question 1

Noble, 2005

Answer 1

• The Baroceptor Reflex is the primary mechanisms controlling BP-it keeps arterial pressures at a relatively constant level
• Heart failure affects 9% of 80 year olds and accounts for 5% of hospital admissions
• Systolic heart failure is most common
• Examples of systolic heart failure causes:
  1. Ischaemic heart disease (scarring/tissue damage)
  2. Aortic stenosis
  3. Dilated cardiomyopathy
• Examples of Diastolic heart failure causes:
  1. Hypertension
  2. Mitral/tricuspid stenosis
  3. Pericardial fibrosis
• Primary left heart failure is more common than right and left heart failure is the most common cause of right sided failure
• At rest, heart failure patients may be able to compensate. However, the increase in filling pressures needed to move up the frank starling curve is limited in heart failure which is why heart failure patients exhibit exercise intolerance
• Left ventricular systolic failure has an annual mortality rate of 15-30%

Question 2

Noble, 2005

Answer 2

-if only left side of heart is failing, the right continues to pump normal amounts of blood to the lungs where it eventually builds up
-the excess blood causes the lungs to become stiff and less compliant and so are resistant to inflation
-Pulmonary oedema can upset the distribution between lung ventilation and pulmonary blood flow so a Ventilation-Perfusion Mismatch occurs = ARTERIAL HYPOXAEMIA
-This arterial hypoxaemia further reduces oxygen delivery to tissues and worsens heart failure
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-The blood backed up in the lungs also increases the afterload from the right ventricle and eventually this causes right heart failure

If right heart failure occurs on its own due to a lung condition raising the pulmonary resistance it is known as COR PULMONALE

• In diastolic failure, ejection fraction is preserved because the amount of blood entering the heart is less and what is ejected is normal
• Systolic heart failure shows reduced ejection fraction
• Diastolic heart failure is exacerbated when heart rate increases because diastole is shortened

Question 3

Metabolic events in heart failure, Noble, 2005

Answer 3

• Impaired blood supply to the myocardium impairs ATP generation so muscle performance is impaired
• Cross-bridge formation to allow contraction needs the hydrolysis of ATP, so without ATP crossbridges for contraction are not formed
• ATP is also needed by SERCA to put Calcium back into the SR during diastole
• So ATP is needed for both contraction and relaxation meaning impaired blood supply to the myocardium affects both contraction and relaxation
• Experimental animal studies have shown that maintaining contractility can prevent the development of cardiac failure which demonstrates the importance of contractility

Question 4

Neurohormonal Aspects of Heart Failure, Noble 2005

Answer 4

• Activation of the sympathetic nervous system is a central component of the physiological response to heart failure:
  1. increased heart rate (not necessarily helpful)
  2. Vasoconstriction (to boost blood pressure and increase preload)
  3. Vasoconstriction in skin and skeletal muscle helps to maintain arterial pressure and direct blood to critical organs
  4. Increased contractility of myocytes mediated by b-adrenergic receptors
  5. Increased renin secretion from juxta-glomerular cells activating the RAAS system

Vascular endothelium secretes Endothelin-1 in heart failure to cause vasoconstriction in a bid to increase preload
-this is initially compensatory to boost inotropy and cardiac output, but over expression of ET-1 causes Myocardial Fibrosis, Myocyte Necrosis and Vasospasm (e.g coronary arteries) which all contribute to worsened cardiac performance

Question 5

Therapeutics for HF, NOble 2005

Answer 5

ACEi’s and ARBs:

• Inhibit compensation by the RAAS system
• too much compensation causes the heart to work harder to prevent congestion which ultimately does not happen because the heart is failing
• If RAAS fails to boost BP, it enlarges the extracellular fluid compartment which reduces CO even more and worsens cardiac performance
• Ang II is associated with fibrosis which damages heart muscle and reduces contraction so ACEi’s and ARBs stop this

-Endothelin-1 blockers are currently under clinical trial to prevent the effects that worsen cardiac output

SYMPATHOMIMMETIC INOTROPES:

• e.g Isoprotenerol (beta agonists)
• Provide short term increases in contractility
• good for use acutely
• but long term use is related to increased mortality
• Become less effective as HF progresses because B-adrenergic receptor sensitivity is decreased

PHOSPHODIESTERASE INHIBITORS

• inhibit breakdown of cAMP so promote the effects of sympathetic innervation
• means excessive levels of cAMP so are for short term use only to boost contractility

CARDIAC GLYCOSIDES e.g Digoxin

• Inhibits the Na/Ca ATPase in cardiac myocytes
• This increases intracellular Na so there is reduced Na/Ca exchange through the exchanger channel meaning calcium is not exchanged and so is RETAINED inside the cell
• the extra calcium causes an increase in cardiac contraction
• This is a mild inotrope but can be used for extended periods of time

DIURETICS:

• this group of drugs remains the primary therapeutic for heart failure
• used to return preload levels to optimum on the frank starling curve-stops the heart from being overloaded with fluid

ENTRESTO:
-a novel heart failure drug consisting of Sacubitril and Valsartan
-Valsartan is an ARB, Sacubitril inhibits Neprolysin
How does it work?
-Natiuretic Peptides are needed in heart failure to counteract the maladaptive effects of Neurohormonal systems, they lower blood pressure for example ANP detects increased preload and promotes the kidneys to increase diuresis
-Neprilysin is an enzyme that breaksdown Natriuretic Peptides which is BAD
-Sacubitril in Entresto INHIBITs this breakdown of Natriuretic peptides and promotes the countering of maladaptive mechanisms