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  • Study antiarrhythmia drugs yourselves
  • If you stimulate cardiac cells enough, it hits a threshold that produces an all or nothing action potential response
  • ECG = integral of activity across billions of cells; but non invasive, non painful
    • Can't really get APs from single cells in non-invasive way
  • Numbers refer to the different phases of the action potential
    • 2 = long plateau, is the main difference between muscle and skeletal cells
    • if phase 1 is absent, you don't rename phase 2
  • 0-rapid depolarisation
  • 1-initial rapid repolarisation
  • 2-plateau phase
  • 3-repolarisation
  • 4-resting membrane
  • AP sits over the QRS and T of ECG
  • P wave = atrial depolarisation
  • QRS = 120ms, but a single cell it takes 1-2ms, because it takes a long time for the impulse to travel through all of the ventricular muscle (nb bundle of his, purkinje fibres etc)
  • ECG only represents when things are changing - e.g. ST segment should be flat
    • QRS is tallest because depolarisation is very rapid
  • atrial T wave is not visible
  • any initial downward inflection = Q
  • if the initial is upward = R; any subsequent is R' or R
  • all downward deflections are S (S1, S2 etc) except for the first one, which is Q
  • SAN/AVN = SA node and AV node
    • voltages are different - less negative
    • no resting potential - spontaneously depolarising to a smooth level that hits the next threshold. this is the pacemaker potential.
      • e.g. heart transplants - heart rate regulated completely without connection to brain except endocrine effects
    • phase 3 = rapid repolarisation back to maximum diastolic potential, which is affected by potassium efflux capacity

Actional potential - current flows

  • Phase 4: permeable to K+ but not Na+
  • Phase 0: Na gates open, Ca (slow) gates open
    • Na is much bigger faster upstroke
    • Ca comes in which triggers the contraction - without Ca there's no contraction
  • Phase 1: complex
  • Phase 2: plateau, so the heart is refractory to being restimulated, to prevent tetany (can't go above 200-300 bpm)
    • Sodium switches off, but Ca keeps coming in, and the Na-Ca exchange pump goes on (pump Ca out and let Na in; you need over time the same amount of Ca out as in; 3Na+ move for 1Ca2+ out; generates an inward current, tending to hold the cell depolarised. Permeability of the membrane for K+ (iK1) switches off on depolarisation and stays switches off).
  • Phase 3: iK (made of 2 channels: rapid and slow) switches on to allow repolarisation
    • some antiarrhythmic drugs block iKr; if you block too much, then the cell stops repolarising normally, generating unwanted arrhythmias

Pacemaker currents

  • Phase 1: Only inward current available is Ca (slow) - because the potential isn't low enough for Na+ channels to work
    • Speed that conduction between cells goes depends on the speed they depolarise
    • Hence AV and SA nodes have slower conduction
      • This is why AF doesn't cause ventricular tachycardia/VF, because AV node doesn't let that many beats go through
    • iK switches off, and then the Ca channels get into a range that they will open to let Ca come in --> drifting up Ca
      • fallback current = iF, the funny current; originally thought to be the main pacemaker, but it's actually a fallback mechanism. This current is probably the one which determines why we don't die of third degree heart block
  • Repolarisation same as the other

Mechanisms of tachycardia

  • Bradyarrhythmia = heart block, not treated with drugs
  • Tachyarrhythmias = treated with drugs, what this lecture is about
  • Normal heart rate = 60-100 consistently, for no good reason. E.g. sinus tachycardia is an early indicator of heart disease

Reentry circuits

  • Jellyfish blubber cut into donuts
    • Put a clamp on, start compression, remove clamp, then it can go around and around provided it doesn't catch up on its refractory tail.
  • Plug the hole with an electrical hole, stick it anywhere in the heart, it generates a re-entry circuit that, if it goes faster than the pacemaker, then it will take over making the pace of the heart
  • Reentry can occur on micro or macro scale
    • Around SA node, within atrium, within the his bundle, within the AVN
    • AVN reentry circuit is common cause of SVT
    • AAVC = accessory atrioventricular conduction, bridge of muscle that goes up past fibrous tissue - when some of the tissue from embryological development remains, electrically linking A and V. Need to get in and burn them off.

AV nodal reentrant tachycardia

  • 2 pathways between atrium and his bundles, with different (conduction velocity and refractory period duration) can cause problems
  • 1 if slow, the second pathway finds the his block refractory, stops
  • 2 alpha slower and beta has a longer refractory period. premature beat comes down, can't go down beta, goes down alpha. this produces a long PR interval. then if beta is out of refractory, then things go up beta, and go around, and produce the inverted wave in the ST-segment
  • 3 set up SVT - because it loops around and around, it goes faster than pacemaker

Reentry 1 of 3

  • clockwise direction advancing wavefront. black = refractory tail
  • 2 ways to kill it: make snake go faster (increase conduction velocity) or increase tail size (increase refractory period)
  • when the conduction time around circuit = refractory period means the black exactly fills the circle
    • there are an infinite number of refractory periods and conduction times where this is true
    • hyperbola xy=k
    • so xy ≤ k is the requirement for a reentry pathway
  • can escape by moving either right or up
  • but conduction velocity is max already; can't put more sodium channels into heart cell. The drugs we do have tend to decrease or have no effect on conduction velocity, and increase refractory period
    • result depends on where you start from
      • number 2 is the only situation where it's done what you wanted
      • number 3 has had a proarrhythmic effect - often life threatening
        • e.g. >1 reentry circuits in a diseased heart, can result in producing more arrhythmias that may be worse or better

Afterdepolarisations ("triggered activity")

  • Depolarisations after the main normal one
    • If it reaches threshold, it triggers more APs
      • Caused by overactivity of Na/Ca exchange pump (e.g. digoxin poisoning -- too much Ca in the cell)
  • Delayed afterdepolarisations are not very common

Early afterdepolarisations are more common

  • Slow down the repolarisation by stopping the K+ channel opening, eventually the Ca+ will have ended refractory, and then cause this small afterdpolarisation
  • Torsades de pointes - ventricular tachycardia - AP duration is prolonged (prolonged QT; congenital)

Antiarrhythmic drugs

Note that many of the drugs have multiple actions

  • Class 1 - sodium channel blockers (reduce conduction velocity)
    • Abnormal tissue is very sensitive to them - use in concentrations that abolished conduction completely in abnormal tissue.
    • Shouldn't have worked theoretically
  • Class 2 - antisympathetic action (= the beta blockers)
  • Class 3 - block outward potassium channel (HERG), blockers (prolong repolarisation). Most potent, used today. Overdose = torsade --> death
  • Class 4 - verapamil, diltiazem (note nifedipine only for vasodilation; not cardiac selective enough)
    • Very useful where part of the reentry circuit is the AV node as it only has Ca channel

Class 1

  • Block sodium channels in nerve (locally) and in heart (if done IV)
  • Know about: see list in the lecture
    • Digoxin only used in AF because vagotonic action, slow down AF rate (not really an arrhythmia)