CARDIAC ELECTROPHYSIOLOGY
Mark Tuttle, 2011 Nernst Potentials: The voltage which is necessary to oppose the electrochemical force for a given ion
E (K + ) =
● ● ●
−61 Z
+
[K ]in log [K =− 96 mV + ]out +
E (N a+ ) =
−61 Z
[N a ]in log [N =+ 52 mV + a ]out
E (Ca+ ) =
−61 Z
[Ca ]in log [Ca =+ 154 mV + ]out
+
● Z is the valence of the ion. (Calcium is +2) -61 is the ideal gas constant (joules per kelvin per mole) times the temperature in Kelvin Resting myocyte membrane potential is -90 mV so there is a net outward driving force for K+ ions (+6). For sodium and calcium, there is a net inward driving force at the resting potential of -90 mV.
Membrane potential: depends on the nernst potential and the membrane conductance of each ion ● ●
E M = g ′K E K + g ′N a E N a + g ′Ca E Ca + (g ′Cl E Cl ) +
where g = relative conductance
K conductance is the greatest, so it’s nernst potential contributes most to the resting membrane potential
Myocyte action potential (200-400 ms)
Nerve cell action potential (1 ms)
Resting potential: -90 mV, threshold: -70 mV Phase 0: Fast Na+ channels open, K+ channels close (1ms) Phase 1: Kto channels transiently open Phase 2: Slow L-type (long) Ca2+ channels open Phase 3: Ca2+ channels close, K+ channels open, Ca2+/Na+ exchangers open, SERCA Ca2+ ATPase pumps open Resting potential: -70 mV, threshold: -55 mV Effective (absolute) refractory period: during phases 0, 1, 2, and part of 3 another AP cannot be initiated ● Due to inactivated Na+ channels not yet being reset. They are reset at -50 mV. ○ Once -50 mV is reached and the Na+ channels are reset, another AP can be initiated ● Responsible for maximum heart rate ● Drugs which extend this (ex. amiodarone lengthening phase 3) can help abolish reentry current Conduction velocity through the heart ● AV node: 0.05 m/s ● Myocardium (atrial and ventricular): 0.5 m/s ● Bundle of His and right and left bundle branches: 2 m/s ● Purkinje fibers: 4 m/s
CARDIAC ELECTROPHYSIOLOGY Pacemaker action potential
Mark Tuttle, 2011
“Resting” potential: -60 mV, threshold: ~ -35 mV ● Pacemaker cells lack fast Na+ channels, slope of phase 0 is much less steep as a result. ● There is no phase 1 or 2 Phase 4: Slow Na+ channels open (“funny” current If), and T-type Ca2+ channels open. Slow decline of repolarizing outward K+ current as these channels continue to close. Phase 0: Slow L-type (long) Ca2+ channels open, funny current declines as does T-type Ca2+ current Phase 3: Ca2+ channels close, K+ channels open, Ca2+/Na+ exchangers open, SERCA Ca2+ ATPase pumps open
How the tracing is recorded ● The first EKG tracings were made with analog oscilloscopes using a cathode ray system as shown below. The beam of electrons were generated with a heated coil and accelerated. The course of their trajectory was altered by applying a voltage across the magnetic plates which were attached to EKG leads. When they impacted the phosphorus screen, they lit up in a pattern approximating the EKG tracing.
Regulation of pacemaker activity ● SA node has an intrinsic rate of 100 bpm, but is under constant vagal tone, resulting in HR of 70-80 ○ Mostly influenced by right vagus nerve but some left vagus activity has been noted ● Autonomic activity ○ Parasympathetic tone (ACh effect): flattening of slope of phase 4 (especially SA and AV nodal cells) ■ M2 muscarinic receptors (Gi type): ↓ intracellular cAMP, generally inhibitory type effects. ● Adenosine purinergic receptors are coupled with the same G-protein- K+ channel ■ Ion conductances: pacemaker current (If) is suppressed (flatter phase 4) ● ↑ K+ conductance, via M2 coupled K+ channels which open when stimulated by ACh ● ↓ slow inward conductance of Ca2+ and Na+ ○ Sympathetic activity (NE effect): steeper phase 0 and 3 (faster depolarization and repolarization) ■ β adrenergic receptors (Gs type): ↑ intracellular cAMP, stimulatory-type effects. ● PKA activated by cAMP, phosphorylates: ○ L-Type calcium channel on cell membrane, ↑ Ca2+ conductance ○ Ryanodine calcium channel on sarcolemmal membrane, ↑ Ca2+ conductance ○ Phospholamban on sarcolemmal membrane, inhibiting it. It normally inhibits the ryanodine receptor, so the net effect is ↑ Ca2+ conductance ■ In addition to chronotropic (heart rate) effects, it has inotropic effects (contractility) ■ ↑ automaticity of AV node and ventricular myocardium ■ Suppresses vagal activity via neuropeptide Y
CARDIAC ELECTROPHYSIOLOGY ●
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●
Mark Tuttle, 2011
Ion concentrations ○ Hypokalemia ■ Pacemaker cells: ↑ the slope of phase 4 depolarization and causes tachycardia ● ↓ K+ conductance during phase 4. ■ Less extracellular K+ increases the transcellular gradient, hyperpolarizing the cell. However, this paradoxically causes cardiac tissue to be hyperexcitable. ● More Na+ channels are available to fire at AP since less were open at resting potential ● IKr channels are stimulated by extracellular K+ leading to decreased repolarization since K+ levels are low. ○ QT prolongation ○ Hyperkalemia ■ ↑ extracellular K+ ↓’s K+ gradient and the membrane potential becomes less negative. ■ The slope of phase 0 (Vmax) is proportional to the resting membrane potential at AP onset ● Vmax is lower at less negative resting potentials because the not fully polarized membrane potential activates some of the voltage-gated Na+ channels at rest (a small percentage) and thus not all of them are available when a “real” AP comes around. ● Na+ channels don’t begin to be activated until around -70 mV ■ Decreased Vmax causes PR, P, and QRS prolongation ■ IKr channels are stimulated by extracellular K+ leading to enhanced repolarization ● ST-T segment depression,peaked T waves, and QT interval shortening Hypoxia (usually from ischemia): Na+/K+ ATPase activity is decreased with less available ATP ○ Membrane is not as easily repolarized, so it is easier to reach threshold ○ Ischemia can transform a normal myocyte AP into a pacemaker AP ■ Normal depolarization occurs, but the cell cannot fully repolarize since the Na+/K+ ATPase is not functioning. Fast sodium channels remain inactivated since the membrane potential never repolarizes enough to re-enable them. ■ At this partially-repolarized state, action potentials can still be elicited, but fast Na+ channels do not participate since they remained inactivated, so the AP is primarily the result of slow Ca2+ currents, producing an AP that resembles a true pacemaker Drugs ○ Calcium-channel blockers: ↓ heart rate (bradycardia) ■ ↓ slow inward Ca2+ currents in phase 4 (flatter slope) and 0 ○ β-blockers: ↓ heart rate (bradycardia) ○ Digitalis: ↓ HR by ↑ vagal tone (but ↑ automaticity at toxic concentrations)
Sources ● http://www.cvphysiology.com ● Barrett KE, Barman SM, Boitano S, Brooks H, "Chapter 33. Cardiovascular Regulatory Mechanisms" (Chapter). Barrett KE, Barman SM, Boitano S, Brooks H: Ganong's Review of Medical Physiology, 23e ● Walter A. Parham, Ali A. Mehdirad, Kurt M. Biermann,, Carey S. Fredman. Hyperkalemia Revisited. Tex Heart Inst J 2006;33:40-7