20110113 Lecture 10 notes

From Iusmphysiology

  • started here on 01/13/2011 at 8AM (not 11AM like the schedule says)


Contents

[edit] The Cardiac AP

  • Michael Sturek, Ph.D., Professor and Chair 
Sturek has many office hours; visit.
  • Department of Cellular & Integrative Physiology, MS 385, 274-7772, Email msturek@iupui.edu
  • We'll be doing 3 lectures on cardiac AP and ECG.
  • Comment on overall approach:
    • Dr. Packer gives intro.
    • Look at notes before class.
    • Readiness questions are to understand what we already know.
    • Objectives are oriented toward step 1 boards and are similar to American Physiological Society's objectives.
    • The text is good; read it when you need some more information.
      • 50% of AP stuff is from the text.
      • 80% of ECG stuff is form the text.

[edit] References

  • Boron, W.F. and E.L. Boulpaep. (“B&B”) Medical Physiology. Philadelphia: Saunders, 2005.
  • Relevant reading –
    • B&B, Lederer, Chapter 20, Cardiac Electrophysiology and the Electrocardiogram
    • Berne RM and Levy MN. (“B&L”) Physiology. St. Louis, MO: CV Mosby, 1997 (or most recent edition)
    • Rhodes, R.A. and Bell, D.R. Medical Physiology: Principles for Clinical Medicine. Baltimore: Lippincott, 2009; Chapter 12.

[edit] Overall Learning Objective

  • Understand the electrical signaling system and underlying cellular ionic mechanisms in the heart, which are essential for the coordinated function of pumping blood.

[edit] Specific Learning Objectives

  • Know the electrical coupling between cardiac cells and its function.
  • Know how excitation spreads from the SA node to other regions of the heart.
  • Differentiate the shapes and the durations of action potentials in different regions of the heart.
  • Know the 3 physiological functions of cardiac action potentials.
  • Understand the ionic mechanisms underlying the different phases of an action potential in a myocardial and pacemaker cells.
  • Know the mechanisms of pacemaking by which the rhythm of the heart can be altered.
  • Understand the origin and significance of plateau phase of cardiac action potential relevant to the electrical refractoriness of cell.
  • Understand how ionic equilibrium potentials contribute to excitation of the heart.
  • Know the major ion channel types in myocardial cells.
  • Know how intracellular action potentials contribute to integrated extracellular electrical activity, which is the EKG.

[edit] Problem-Based Examples

  • Would Dr. Kevorkian use Na or K in his euthanasia cocktail and why?
    • K because high extracellular K reduces the potential across the membrane and decreases production of APs, thus stopping heart contraction.
  • Why does coronary artery disease, which results in increased extracellular K, slow electrical conduction?
    • Higher ECF K concentrations decrease the potential across the membrane, thus ....
  • What would be the composition of a cardioplegia solution that you would use to arrest the heart for open-heart surgery?
  • Long QT syndrome leading to sudden death – Na and K channel mutations
  • "Use-dependent" block of Na channels by anti-arrhythmic drugs (e.g. lidocaine)
  • Wolf-Parkinson-White syndrome – AMP kinase mutation leading to glycogen accumulation and accessory conduction pathway
  • Mishap in execution by lethal injection in Florida

[edit] Outline

  • Introduction and overview, resting, and action potentials
  • Ionic basis, ion channels
  • Pacemaker potentials
  • Cellular heterogeneity (specialization)
  • Cellular basis for electrocardiogram (ECG, EKG)


  • These notes contain all the information on cardiac electrophysiology and the ECG that is needed for this course.
    • Little red flags mean know it!

[edit] Ionic basis, ion channels

[edit] Pacemaker potentials

[edit] Cellular heterogeneity (specialization)

[edit] Cellular basis for electrocardiogram (ECG, EKG)

[edit] Introduction and overview, resting, and action potentials

  • Netter has a very nice drawing.
  • SA node is where pacemaking starts.
  • Automaticity, we'll talk more about it.
  • Spontaneous depolarization...more later.
  • Fibrous material provides a nice conduction delay to time the atria and ventricles.
  • Perkinje fibers:
    • Contractile and neuronal, a hybrid.
    • These require gap junctions, though, they do not have neuron axons or synapses.
  • Duration of ventricular APs can vary:
    • This will change the T wave.
    • Altered ST and T wave will be what we see in patients.
  • Time course ECG:
    • Broken down very nicely in the image.

[edit] Conduction of action potential via gap junctions

  • B&B, Fig. 9-1
  • Intercalated discs
  • Desomosomes provide stability
  • Gap junctions are permeable to ions.
    • This is how ions get from cell to cell to generate syncytium.
  • Actin and myosin for contractile apparatus.
  • How do you move the AP?
    • Via gap junctions
    • See animation
    • B&B makes this a bit confusing, he'll clarify.
      • He deleted the extracellular current flow; just consider depolarizing current through ion channels resulting in depolarization and the current flow through gap junctions.
    • There is a net increase in positive charge in the cell.
    • This makes the outside relatively negative.
    • Depolarization occurs.
    • Outside remains relatively negative.
    • Gap jxn allows propogation to the next cell and depolarization.
    • Not exactly like a nerve.

[edit] Functional syncytium of myocardium requires coupling of cells

[edit] Electrotonic spread of potentials (B&B, Fig. 20-2B)

  • There is an eletrotonic spread of the potential along a distance.
  • If it is above threshold, (less negative) when it hits the next cell, you will fire another AP and then at C and D etc.
  • If not, then that cell will not fire and the AP degrades.
  • Here the length constant is important.
  • You must have full blown AP to have calcium-induced calcium release and contraction.
  • What is threshold?
    • There isn't an absolute mV value.
    • Depends on the clel and such.
    • "When the net inward current is greater than the outward current."
    • "When the depolarizing current is greater than the repolarizing current."


  • Myelinated nerves have more passive conduction.
    • Heart doesn't have myelination, though.
    • "Myelinated nerves have more passive conduction; gap junctions and more regenerative action potentials needed in cardiac muscle."

[edit] Resting and action potentials

  • We'll look at the easiest cell model: ventricular cell.
  • Intracellular electrode is set in the cell and in the ECF to know the transmembrane potential.
    • Not performed clinically because we don't have a catheter that can do this and no pt gives cardiac biopsy.
  • This cell model gives the AP we've seen before.
  • We will see this again next year, too.
  • Along the time of an AP:
    • Na flows heavily inward.
    • Ca flows heavily inward.
    • K flows increasingly outward.
    • A little Na and Ca influx even at rest.
  • AP is 200 to 300 milliseconds.
    • 100 to 200 fold longer than the 2 millisecond AP of a nerve.
  • How can we have a longer duration of an AP in this cell?
    • Ca channels activate more slowly.
    • Ca channels stay open longer and offset the K that is effluxing.
    • K channels take a little longer to activate.
  • There is an electromechanical delay
    • Takes a bit of timem for ca-incudce ca-rlease and for the contract apparatus do do their thing.
    • Refractory period is important for proper contraction.
  • An AP is not necessarily indicative of contraction:
    • They can be disconnected.
    • Pts can have good ECG but bad contraction.
  • Resting membrane potential in neuron is -70 mV.
  • Resting membrane potential in cardiac is -93 mV, ish. But we don't need to know an exact value.
    • Different texts pick different numbers.
[edit] Nernst equation for ELECTROCHEMICAL equilibrium
  • Nernst will be on the boards.
  • This equiation combines the electrical and chemical forces over the membrane.
  • RT / zf simplifies to 61.54
    • What value you use depends on the temperature you put in there.
    • Whether you use 60 or 61.54 doesn't produce much difference.
  • For cardiac we say that at -91, the chemical and electrical forces balance one another.
  • Note that each ion, individually, gives a distinct positive, but they sum to a pretty negative potential.
  • Why is this important, clinically?
    • Cardiac glycosides: ouabain, digitalis, strophanthidin
      • Block Na pump to increase intracellular Na
      • Alters the Na equilibrium potential
    • Myocardial ischemia can cause increase in ECF potassium
      • Affects resting and equilibrium potential
      • Affects muscle excitability
  • What do tehse eequilibirum potentials give me?
    • Hard to understand them in a table.


  • In an ideal square cell:
    • High K inside low outside, etc. for all ions. 
Got a bit lost.  Read slides, understand.
    • This is resting vent cell. 
**Golden rule: resting membrane will go to ?
    • Overshoot will occur.
  • "Driving force . force driving Vm toward Eion"
    • "Basically, all ion concentrations tend toward equilibrium and the further from equilibrium the greater the force to achieve equilibrium."
    • "Vm will go toward Eion if membrane is permeable to the ion (conducts the ion)."

[edit] Ionic basis, ion channels

  • Here we see charge over time for ventricular cells
    • Na current if fast
    • K current is slower
      • Gives longer duration AP
  • ITO = transient outward current.
    • Gives transient bit of tendency to repolarize.
  • Ca currents are usally more delayed and long lasting (l type).
  • Ca-induced ca release (cicr)
  • Question 4: Increased voltage gated Na channels
    • Na current is high and gives overshoot.


[edit] Refractory period

  • Due to Na channel inactivation
  • Step through the animation
  • As cell repolarizes, more Na channels ahve gone out of the inactive state and can fire again.
  • The number of milliseconds can vary for refractory peiord--it is a fxn of inactivation time of na channels.
  • the longer you recover, the more na channels that are ready to activate to provide an enormous overshoot and a normal AP.

[edit] What if you have ECF increases in K?

  • In ischemia, Na channels are inactivated and are refractory.
  • Seen in hyperkelemia (high K) and bad ischemia which increases K. 
Why is K high?
Missed some stuff here.

[edit] Pacemakers

  • Emphasises phase 4 depolarization.
  • Recall that downward is outward flux as a convention in these diagrams.
  • See B&B.


  • stopped here on 01/12/11 at 9AM.
  • started here on 01/14/11 at 11AM.


[edit] Summary of major Currents

  • It is pretty well known that
  • There are > 20 K channels but we don't need to know them all.

[edit] Cellular heterogeneity

  • Syncronization of cells give the mechanical delay that is so important.
  • Table:
    • We have the different cells, and different currents.
    • Main point: if you have b-adrenergic signaling you'll have increased heart rate and increased strengths contractile.
      • Main point too: cholinergic is the opposite effect

[edit] Cellular basis for ECG

  • Need to understand the basis.
  • We will not measure the actual ap in cells in clinic but the ecg gives a good electrical profiling.
  • QS = depolarization
  • T wave is depolarization
  • We generally have 1 second R-R waave which gives 60 beats per minute.
  • Most paper is one block per 1 second / 0.2 seconds (by block size).
  • U wave is uncommon to see.

[edit] Translating single cell AP to the ECG

  • We are giong to think of cellular potentials still, but we will think about two different cells and subtract one from the other.
  • Endocardial cell potentials are higher than the epicardial cells.
    • Repolarization is from epicardium to endocardium (make sure that's right).


  • Quesiton 3: which AP is longer?
    • Endocardial AP is longer.


  • Endocardia AP is green, epicardial is blue.
  • We want to get the subtracted intracellular voltage to translate AP in cells to an ECG.
  • On the red line, 1, 2, 3, 4, 5 translates to the QRS and T.
  • Now for repolarization phase
    • If endo and epi repolar. were the same, you would have a negative T wave.
    • Because they are off-set, we see a positive spike (puke colored line in graphs).
      • This is the normal scenario.
  • Now remember that an ECG is an extracellular recording
    • This means we're getting electircal activity, not membrane potentials.
[edit] Extracellular action potentials
  • We start off measuring B and A with extracellular leads.
    • These are said to be on a lead axis of zero.
  • As we depolarize, the inside of A becomes positive and B becomes negative inside.
    • This causes the positive deflection on the readout.
    • The neg probe will have neg charge around it and positive will have positive.
  • With a lead axis of 180 degrees.
    • Then the positive node is in a negative field and vice versa.
    • This will cuase the exact opposite read out.
  • So, the point is that where you put the leads is important.
  • Note that all these exmaples will use depolarization from cell a to cell b.
  • Lead axis of 90s:
    • Here the nodes won't measure any change.
    • This is called an isoelectric lead.
    • Good for finding the isoelectric lead.

[edit] Problem-based examples

  • K for heart:
    • Will stop but only after ventricular fibrilation.
    • Why did it speed up first?
      • Concentration was such that SA node polarized more which increased SA node which increased pacemaking.
      • But then, with high concentrations....
    • You need to use a barbituate first. In Florida, they forgot the barbituate.
  • How do you change membrane potential?
    • Can be done by increasing K current to slow AP.
    • Could also increase sympathetic innervation (beta adrenergic receptor).
    • Could also decrease Ca current.
    • Epi and NE would increase IF and decrease K which would be the opposite of Ach.
    • Tomorrow will be ECG plus some wrap up from today.

[edit] Other currents

  • Yes, other currents matter.
  • Even Ca+ channels matter, too.


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