L7.2 Cardiac ischemia

Question 1

Why is it essential for the heart to have sufficient O2?

Answer 1

It is essential for the heart to have sufficient O2 to prod ATP to keep pumping

Question 2

What is ischemia?

Answer 2

Ischemia = Coronary flow is inadequate to maintain steady-state metabolism

Question 3

What are the determinants of O2 demands?

Answer 3

• Ventricular wall stress
  
  • Stretch increase O2 consumption
  • Increased wall thickness decreases consumption/g tissues (compensatory by decreases load of each cell) BUT → there is an increase in muscle mass → increased total O2 demand
  • Increase SBP (afterlaod) → pump harder → Increased O2 consumption
• HR
• Contractility

Question 4

What are the determinants of O2 supply?

Answer 4

• DBP
  
  • Coronary flow is max during DBP
  • Aortic DBP determines coronary flow
• Coronary resistance
  
  • Increased by vessel compression (maximal compression in systole)
  • Autoregulation of vascular tone
    
    • Endothelial cells dysfunction → Decreased NO production
      
      • Increase vasoconstriction & Decrease O2 supply
  • Vessel obstruction
    
    • Loss of NO-mediated supression of platelet aggregation
• O2 carrying capacity
  
  • Hb levels & O2 saturation
  • Usually max O2 extraction in heart

Question 5

Coronary vascular constrictors/dilators

Answer 5

Question 6

Characteristics of atherosclerosis

Answer 6

• Macrophage ingest lipids
• Streaks formed by migration of SM cells

Question 7

Stable and vulnerable plaque?

Answer 7

• Stable plaque → lipid core expands + SM cells prolif → bulges with fibrous cap
• Vulnerable plaque → Plaque cap ruptures → collagen, platelets exposed → inflammation → clot → occludes flow downstream

Question 8

Classification of obstruction

Answer 8

• 70% → minimal effect on flow (compensatory dilation)
• 70-90% → episodic ischemia
• >90% → basal ischemia
• 100% → Thrombosis (Total occlusion → maintained ischemia → myocardial infarction)

Question 9

Classification of MI

Answer 9

• Hibernation: Chronic metabolic suppression (reversible)
• Stunning: Heart muscles not killed → prolonged contractile depression (reversible)
• Necrosis: Permanent cell death (Irreversible)

Question 10

How are MI formed?

Answer 10

• 90% from ruptured plaque → thrombosis
• Pain similar to angina (25% don’t have pain)

Question 11

How is MI detected?

Answer 11

• Serum analysis: detec intracellular macromolecules (CK, TnT, TnI)
  
  • Onset: 4-8h
  • Peak: 24h
  • Baseline: 48-72h

Question 12

Mechanism of MI

Answer 12

• Ischemia → Decreased O2 → Decreased ATP → ATP dependent pumps fail
  
  • X SERCA → X reuptake → Ca build up inside cell
  • X Na/K ATPase → altered RMP & ion balance inside cell → arrhythmia
• Build up of H inside cell form anaerobic process (due to ischemia) → leaves cell via Na/H ex → H reaches equilibrium inside & Outside cell → Na build up from Na/H ex → Turns Na/Ca ex in reverse mode → Ca goes in cell

Question 13

What does the build up of Ca inside the cell lead to?

Answer 13

Lack of SERCA & build up of H leads to Ca build up inside cell → protease/lipase activation → cell death

Question 14

Features of reperfusion

Answer 14

• Restores BF to heart and restores O2, BUT further increase cardiac dysfunction and death
• ATP pumps work again (suboptimally) BUT:
  
  • Built up H conc outside swept away by blood → disequilibrium of H → Increase H out and Na in via ex → Na overload (slightly dulled by ‘restored’ Na/K ATPase) → Ca overload
  • Furhter arrhythmia, cell death, and contractile dysfunction

Question 15

What is the role of CAMKII and what is the relationship of it with ischemia?

Answer 15

• Activated by increase in Ca which upregulates Ca & Na handling proteins → Good under normal physiological conditions BUT NOT during ischemia
• Inhibition of CAMKII (by KN93):
  
  • Sig decrease in arrhythmia and myocyte death
  • Sig reduction in reperfusion pathologies