Myocardial excitability and conduction

Question 1

Describe the anatomy of the conduction system of the heart and the path taken by an electrical impulse generated in the SA node

Answer 1

• SA node → atrial muscle → AV node (slow conduction) → bundle of His (rapid conduction)→ branch bundles → Purkinje fibers → ventricular muscle
• Different cardiomyocytes differ in ion channel patterns → different AP morphologies in different parts of heart
• Allows depolarizing inward and repolarizing outward currents

Question 2

Explain what determines the resting membrane potential in a cardiomyocyte

Answer 2

• Electrochemical equilibrium for a single ion = Nernst equation
o Resting conditions: membrane has greatest permeability to K
o For K+: EK = (RT)/(zF) ln [K]o/[K]i
• R = gas constant
• T = absolute temperature
• Z = valence
• F = Faraday’s constant
o For EK = -90 mV (resting K+ equilibrium)

• Electrochemical gradient for combination of ions = Goldman equation
o Em = (PK/Ptot)EK + (PNa/Ptot)ENa + (PCl/Ptot)ECl
• Ohm’s Law: (V=IR) where g is conductance and equals 1/R
o IK = gK(Em – EK)
o Many channels have dynamic gating (g changes dramatically)
• Voltage-dependent changes
• Time-dependent changes
o Gating of ion channels is due to conformational changes

Question 3

Describe the Phase 0 of the cardiac action potential and the general ionic currents underlying the phase

Answer 3

Upstroke and AP overshoot
o In atrial, ventricular and Purkinje cells, due to rapid activation of voltage-gated Na channels
o Produces large inward (depolarizing) Na current (INa)
o Membrane potential moves toward Na+ equilibrium potential (+60 mV)
• Other ionic conductances present, AP overshoot reaches between +20 and +35
o Fast APs due to fast Na+ channel kinetics
• Depends on number of Na+ channels available
• More available for activation when resting Em <-100
• As Em increases: number of available channels decreases
• At -60 mV, all fast Na+ channels inactivated (fast upstroke AP can’t occur)
• Can still generate AP (via activating L-type Ca2+ channels), but slow APs
o In SA and AV nodal cells due to inward current through L-Type Ca2+ channels (ICa,L), some through T-type Ca2+ channels (ICa,T)
• Slower activation kinetics compared to Na+ channels
• Slow upstroke
• Slow APs
• Small overshoot since ICa,L peak is only slightly greater than outward currents

Question 4

Describe the Phase 1 of the cardiac action potential and the general ionic currents underlying the phase

Answer 4

spike of AP
o Inactivation of fast Na+ current
o Activation of outward K+ current (Ito)
o Absent in SA and AV nodal cells

Question 5

Describe the Phase 2 of the cardiac action potential and the general ionic currents underlying the phase

Answer 5

plateau of AP
o ICa,L continues for about 200 ms → carries inward depolarizing current
• Sustains plateu
o Increased membrane conductance to K+ from delayed rectifier K+ channels
• Slow, occurs only at end of plateau
• Result: little repolarizing influence
• Em dominated by ICa,L

Question 6

Describe the Phase 3 of the cardiac action potential and the general ionic currents underlying the phase

Answer 6

Repolarization
o Increase in K+ membrane permeability:
• All myocytes: activation of rapid and slow delayed rectifying K+ currents
• Atrial and nodal cells: also have IKur (ultra rapid delayed-rectifier K+ current)
o ICa,L inactivates
o Electrogenic effects of Na+/K+ pump → helps repolarize
o Inward rectifier K+ (IK1) channels

Question 7

Describe the Phase 4 of the cardiac action potential and the general ionic currents underlying the phase

Answer 7

resting potential or diastolic depolarization
o Non-automatic cells (atrial and ventricular muscle cells)
• Steady diastolic resting potential ~ -90 mV
• Results from high permeability of K+ (IK1)

o Automatic cells: diastolic depolarization to threshold
• Little or no IK1 in automatic cells → less outward current driving membrane potential toward EK
• Time- and voltage- dependent closure of delayed rectifier K+ channels during AP → progressive decline in K+ permeability
• Opening of special channel (pacemaker chanel) → allows Na+ to enter cell at negative values of Em
• Activated only at very negative Em
• Result: inward Na+ current (If) depolarizes membrane
• Inward Ca2+ current through L- and T-type Ca2+ channels
• Activate at maximum diastolic potential
• Inward current contributes to membrane depolarization
• Spontaneous release of small amounts of SR Ca2+ during diastole
• Activates 3Na in /1Ca out pump → inward current

Question 8

Summarize the basis of and difference between relative and absolute refractory periods.

Answer 8

• Absolute refractory period: regardless of stimuli strength, another AP cannot be generated
• Relative refractory period: stronger than normal stimulus can induce an AP

Question 9

Discuss how the autonomic nervous system regulates the automaticity of the sinus node

Answer 9

• Sympathetic stimulation
o Increases If
o Increases ICa,L
• Parasympathetic stimulation
o Increases IK,Ach
o Decreases If
o Decreases ICa,L

Question 10

Explain three conditions that could result in a shift in the site of fastest automaticity in the heart.

Answer 10

• Normally:
o SA node ~ 120 bpm (true pacemaker, rate decreases as age)
o AV node ~80-100 bpm
o His-Purkinje ~30-50 bpm
• Cause shift:
o Suppress the automaticity of SA node
• Next most automatic cells to become pacemaker
o Enhance automaticity of latent pacemaker cells
• Reach threshold before SA node and generate AP
o Block conduction between SA node and lower regions of heart
• SA node APs can’t reach ventricles
• Latent pacemakers below level of block are allowed to become pacemakers

Question 11

Explain the determinants of conduction velocity.

Answer 11

• Normal conduction:
o Atrial myocytes: ~0.3 m/sec
o AV node: 0.05 m/sec (slower)
o His-Purkinje system: 3-5 m/sec (very fast)
o Ventricular myocytes: ~0.3 m/sec in direction of long axis of myocytes

Determinants:
• Cell to cell coupling via gap junctions
• Intensity of depolarizing (inward) current
o Rate of depolarization
o Amplitude of overshoot (if any)
• Cell diameter (larger cells =less resistance = greater velocity)
• In heart: Anisotropic conduction
o Conduction varies depending on direction impulse travels through heart
o Most rapid in long axis of myocytes (and heart) with predominant end to end gap junctions more than side to side