L7.2 Cardiac ischemia

Question 1

Why does the heart need sufficient O2?

Answer 1

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

Question 2

Definition of ischemia

Answer 2

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

Question 3

What are the determinants of O2 demands?

Answer 3

Increase in O2 demand leads to compensatory increase in heart mass

• 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

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 → Increase NO production
  • Increase vasoconstriction & Decrease O2 supply
  • Vessel obstruction
• O2 carrying capacity
  
  • Hb levels & O2 saturation
  • Usually max O2 extraction in heart

Question 5

Determinants of coronary vascular tone

Answer 5

• Metabolic
• Endothelial
• Neural/hormonal

Question 6

How is atherosclerosis formed

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

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 10

Classification of MI

Answer 10

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

Question 11

Features of MI

Answer 11

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

Question 12

Indication of MI

Answer 12

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

Question 13

Mechanism of MI

Answer 13

• 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 14

What does the lack of SERCA and build of up H lead to?

Answer 14

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

Question 15

Features of reperfusion of after MI

Answer 15

• 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 16

What role does CAMKII play in ischemia

Answer 16

• 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