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​: K​to​ channels transiently open Phase 2​: Slow L-type (long) Ca​2+​ channels open Phase 3​: Ca​2+​ channels close, K​+​ channels open, Ca​2+​/Na​+ exchangers open, SERCA Ca​2+​ 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 I​f​), and T-type Ca​2+​ channels open. Slow decline of repolarizing outward K+ current as these channels continue to close. Phase 0​: Slow L-type (long) Ca​2+​ channels open, funny current declines as does T-type Ca​2+​ current Phase 3​: Ca​2+​ channels close, K​+​ channels open, Ca​2+​/Na​+​ exchangers open, SERCA Ca​2+​ 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) ■ M​2​ muscarinic receptors (G​i​ type): ↓ intracellular cAMP, generally inhibitory type effects. ● Adenosine purinergic receptors are coupled with the same G-protein- K​+​ channel ■ Ion conductances: pacemaker current (I​f​) is suppressed (flatter phase 4) ● ↑ K+ conductance, via M​2​ coupled K​+​ channels which open when stimulated by ACh ● ↓ slow inward conductance of Ca​2+​ and Na​+ ○ Sympathetic activity (NE effect): steeper phase 0 and 3 (faster depolarization and repolarization) ■ β adrenergic receptors (G​s​ type): ↑ intracellular cAMP, stimulatory-type effects. ● PKA activated by cAMP, phosphorylates: ○ L-Type calcium channel on cell membrane, ↑ Ca​2+​ conductance ○ Ryanodine calcium channel on sarcolemmal membrane, ↑ Ca​2+​ conductance ○ Phospholamban on sarcolemmal membrane, inhibiting it. It normally inhibits the ryanodine receptor, so the net effect is ↑ Ca​2+​ 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 ●

●

●

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 ● I​Kr​ 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 (V​max​) is proportional to the resting membrane potential at AP onset ● V​max​ 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 V​max​ causes PR, P, and QRS prolongation ■ I​Kr​ 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 Ca​2+ currents, producing an AP that resembles a true pacemaker Drugs ○ Calcium-channel blockers: ↓ heart rate (bradycardia) ■ ↓ slow inward Ca​2+​ 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