Cardiac Electrical Properties Flashcards
similarities from cardiac action potentials to action potentials
na creates depolarization, K responsible for repolarization
differences between cardiac fast-response APs and other APs
long plateau phase, lower resting potential, much longer time
key players in the fast-response AP
Na- initial spike (minor impact: slower Ca influx and K efflux)
K- dip after the spike
Ca- heading back up and hanging out in the plateau (balancing out the potassium efflux)
K efflux- eventually brings us back to rest.
K- sets resting potential
Phases of fast-response AP
Phase 0: depolarization Phase 1: early repolarization Phase 2: plateau phase Phase 3: repolarization Phase 4: resting membrane potential
Fast-Response AP Phase 0
Depolarization;
Upstroke
Begins when depolarization opens voltage-gated Na+ channels
Primarily due to rapid Na+ influx
Minor: Slower Ca2+ influx and K+ efflux
Na+ activation gates open quickly (~ 0.1 ms)
Na+ inactivation gates close (several milliseconds)
Fast-Response AP Phase 1
Early Repolarization
Primarily due to K+ efflux via K+ channels (ito) “transient outward current”
Notch is less prominent with K+ channel blocker, demonstrating role of K+
Na+ influx slows as majority of Na+ channels inactivate
Delayed Ca2+ influx (T-type, L-type)
Fast-Response AP Phase 2
Plateau Phase
Primarily due to slow Ca2+ influx (L-type)
Very minor Na+ influx may continue
K+ efflux continues and counters (iK, iK1, ito)
Contributes to longer duration of cardiac AP
Fast-Response AP Phase 3
Repolarization
K+ efflux (iK, iK1, ito) unopposed
Majority of Na+ & Ca2+ channels are closed
Gradually recovering from effective refractoriness (many inactivation gates reset by ~ -50 mV)
Repolarization completed at the end of phase 3
Block K+ channels: AP duration increases
Fast-respons AP Phase 4
Resting Membrane Potential
Fully polarized state of resting cardiac cell
Membrane will remain polarized until reactivated by next depolarizing stimulus (i.e., next ‘heartbeat’ and signal propagation via Purkinje fibers or ventricular myocytes cell-to-cell)
Atrial Muscle AP
3 time- and voltage-dependent currents: INa, IK, ICa
AP duration shorter in atrial vs. ventricular: due to greater efflux of K+ during plateau phase
APs spread directly from cell-to-cell among cardiac myocytes within each atrium
No pacemaker activity in normal atrial m.
Ventricular Muscle AP
3 time- and voltage-gated currents: INa, ICa, IK
No pacemaker activity in normal ventricular m.
Rapid upstroke from threshold:
Depolarizing stimulus could be impulse conducted by a Purkinje fiber or by adjacent ventricular m. cell
Plateau phase (phase 2): prolonged
Ca2+ current activates SR Ca2+ release for contraction
AP duration varies among ventricular cells
Differences in the delayed rectifier (iK) K+ currents
Purkinje Fiber AP
4 time- and voltage-dependent currents: INa, ICa, IK, and If
Typically exhibit fast-response APs
Normally bundle branch currents activate Purkinje fibers
Rapid upstroke (phase 0) mediated by INa and ICa
Rapid AP conduction velocity due to large cell diameter & INa
Long refractory periods: limit conduction of PACs to ventricles
Slowest intrinsic pacemaker rate (tertiary pacemakers)
Become functional pacemakers only if SA & AV nodes fail
Spontaneous purkinje fiber activity may activate ventricles, but only very slowly (unreliable pacemaker activity)
Slow Response Cardiac Action Potentials
No true RMP
Slow depolarization (pacemaker potential)
Threshold: ~ - 40 mV
Less steep AP upstroke (phase 0)
Minimal INa contribution
No early repolarization (phase 1)
Absent or less distinct plateau (phase 2)
Gradual repolarization (phase 3)
Less negative Vm during “rest” (~ − 60/65 mV) (phase 4)
Less IK, less negative Vm (retain intracellular +); If, mainly Na+ influx
What ion is responsible for initial depolarization in slow response cardiac action potentials?
Calcium
Phase 4 in Slow-Response APs
Slow, steady diastolic depolarization toward threshold
Firing frequency of pacemaker
cells can be altered by:
- Depolarization rate (altering ion currents)
- Vm during phase 4
- Threshold
Major currents in phase 4 of slow-response APs
Slow diastolic depolarization (phase 4) is mediated by 3 major currents:
- If: inward current (mainly Na+) activated during hyperpolarization
- ICa: Ca2+ influx
- IK: K+ efflux
I(f): Funny Current on slow-response APs
If : slow activation near end of repolarization (phase 3)
Activated by membrane hyperpolarization
Activation increases with increasingly negative Vm
Mainly Na+ influx via non-specific cation channels
I(Ca) in slow-response APs
ICa: contributes to slow diastolic depolarization (phase 4)
Activated near end of phase 4 at ~ -55 mV
Ca2+ influx increases rate of depolarization to threshold
ICa: influx is major contributor to AP upstroke (phase 0) via L-type channels
I(K) in slow-response APs
K+ efflux: major current contributing to repolarization (phase 3)
IK opposes If and ICa during phase 4 (efflux via delayed rectifier K+channels)
K+ efflux continues beyond maximal repolarization, but gradually decreases during phase 4
Opposition to depolarizing ICa and If begins to decrease and threshold is reached
SA and AV Nodes
3 time-dependent & voltage-gated currents: IK, ICa, If
Intrinsic pacemaker rate of SA node is > AV node
If SA node fails, AV node (secondary pacemaker) can take over pacemaker role to drive HR
Purkinje Fiber AP
4 time- and voltage-dependent currents: INa, ICa, IK, and If
Typically exhibit fast-response APs
Normally bundle branch currents activate Purkinje fibers
Rapid upstroke (phase 0) mediated by INa and ICa
Rapid AP conduction velocity due to large cell diameter & INa
Long refractory periods: limit conduction of PACs to ventricles
Slowest intrinsic pacemaker rate (tertiary pacemakers)
Become functional pacemakers only if SA & AV nodes fail
Spontaneous purkinje fiber activity may activate ventricles, but only very slowly (unreliable pacemaker activity)
What does conduction velocity depend on?
Amplitude of action potential
Greater AP amplitude can more effectively depolarize adjacent membrane
[Na+]o and [Ca2+]o impact amplitude
RMP or maximal diastolic potential (baseline) impacts amplitude
- Rate of change of potential during phase 0 (Slope of depolarization)
Gradual depolarization may not produce a large enough current to depolarize adjacent membrane (for example, during post-repolarization refractoriness)
Extracellular fluid ion concentrations– how do they affect APs?
Na+ impacts Fast-response AP amplitde
ECF Ca2+ impacts slow-response AP amplitude (higher concentration increases amplitude)
How Does Vm Impact Conduction Velocity?
Effect of RMP on Na+ & Ca2+ channel inactivation:
Depolarization → greater number of inactivated channels
Normally depolarization proceeds rapidly, majority of channels do not inactivate until end of phase 0
If a partial depolarization of RMP occurs gradually, channels have time to inactivate (~ -50mV)
If many channels are already inactivated, only a fraction are open for Na+ or Ca2+ influx during phase 0
Results in:
↓ amplitude & slope of depolarization ↓ conduction velocity
How Does Hyperkalemia Impact Conduction Velocity?
↑ [K+]o depolarizes RMP channel inactivation
↓ Amplitude & duration of APs
↓ Slope of upstroke
↓ Conduction velocity
At high enough [K+]o levels, Vm is sufficiently depolarized to inactivate majority of fast Na+ channels Fast-response APs begin to look like Slow-response APs as Ca2+ current remains slow-depolarizing current
Hyperkalemia resulting from CAD and MI: membrane depolarization
Blood flow reduction and ischemia
↓ ATP to power Na+/K+-ATPase: ↑ ECF [K+] and loss of hyperpolarizing current Membrane depolarization
ATP-dependent K+ channels open when ATP is decreased: ↑ ECF [K+] as K+ leaves the cell Initial membrane hyperpolarization, but ultimately depolarization as hyperkalemia develops
M.I.
Infarcted cells release intracellular K+ stores ↑ ECF [K+] as K+ leaves the cell
Elevated [K+]o and resulting membrane depolarization can result in ↓ conduction velocity and rhythm disruption
Some other variable which can alter conduction velocity
Anatomic
Congenital accessory pathways
Degeneration of conduction system
Premature Excitation
If membrane is not fully repolarized following previous AP
Ischemia/hypoxia
CAD
Autonomic
Sympathetic activation (b1 receptors)
Parasympathetic (vagal) activation (via M2 receptors)
Chemical
Circulating hormones (ex: catecholamines)
Autonomic drugs (ex: β-blockers)
Antiarrhythmic drugs (ex: Na+ or Ca2+ channel blockers)
Changes in Ion Distribution
Types of refractory periods
Effective and relative
Effective refractory period (ERP)
Effective refractory period (ERP) = Absolute Refractory Period
After AP initiation, the depolarized cell is not excitable until partial repolarization
Subsequent electrical stimulus (of any size) has no effect
Due to the fact INa and ICa are largely inactivated by depolarization
Phase 0 ~ mid phase 3: Repolarization and recovery from inactivation (~ -50 mV)
Relative refractory period (RRP)
Cell is not fully excitable until complete repolarization
Before repolarization is complete, another AP may be initiated if stimulus is strong enough
ICa, INa possible as channels re-set with repolarization
Phase 3: repolarization with increased IK (efflux)
Initiation of AP during relative refractory period
AP characteristics vary based on Vm at time of stimulation
More channels recovered from inactivation as repolarization proceeds during phase 3
Later in the relative refractory period → greater amplitude and slope of upstroke
↑ amplitude and slope of upstroke → ↑ conduction velocity
Post-repolarization refractoriness
APs evoked early in the RRP have small amplitudes & shallow upstrokes
Results in slower conduction velocity, can lead to conduction blocks
Recovery of full excitability is slower in slow- vs. fast-response APs
APs evoked later in the RRP have progressively increasing amplitudes and upstroke slopes
How do refractory periods promote effective myocardial contractions?
- Prevent Sustained Tetanic Contraction
Relaxation of cardiac muscle: mainly during AP phase 4
Tetanus would result in sustained contraction & interfere with normal intermittent contractions that promote effective filling and ejection
- Safety measure:
Limits extraneous pacemakers from triggering ectopic beats (would also reduce pump efficiency)
Abnormal Conduction Caused by Ectopic Foci
Ectopic foci: Generation of an AP from a source other than the SA node
Cause of most premature contractions
Generally do not follow normal conduction pathways
Myocytes take longer to depolarize cell-to-cell via gap junctions
Ventricular ectopic foci: wide QRS (PVCs, Ventricular Tachycardia)
Possible causes of ectopic foci
Local areas of ischemia
Mildly toxic conditions can irritate fibers of the A-V node, Purkinje system, or myocardium (ex: various drugs, nicotine, or caffeine, alcohol)
Calcified plaques irritating adjacent cardiac fibers
Cardiac catheterization: mechanical initiation of premature contractions
Afterdepolarizations
Triggered activity resulting from abnormal electrical impulses during the repolarization phase
May increase pacemaker activity of existing pacemakers, induce pacemaker activity in Purkinje fibers, or in ventricular myocytes
Can result in abnormal atrial or ventricular beats: single, pairs, “runs” (3+), or a sustained ectopic rhythm (ex: ventricular tachycardia)
Factors that may promote afterdepolarizations and/or prolong AP duration
Mutant channels Ion channel blockers Ion gradients Drugs altering ion transporters and internal Ca2+ stores Anti-arrhythmic drugs Long QT Syndrome
Early AFterdepolarizations (EAD)
More likely to occur when AP duration is increased
Abnormal depolarizing currents or repolarizing currents late phase 2 or phase 3. For example:
Augmented Ca2+ channel opening (phase 2)
Na+ channel inactivation gates re-open or delay inactivation (phase 3)
K+ channel blockers; K+ channel mutations
Timing of afterdepolarization determines clinical significance
EADs: Early in Relative Refractory Period (RRP) Slowed conduction of the early, triggered impulse due to decreased slope and amplitude
Reentry is more likely to occur
Fibrillation may develop
Long QT Syndrome
EADs more likely to occur when AP duration is prolonged
Long QT Syndrome
Genetic disorder: different channel mutations possible
K+ channel mutations: ↓ repolarizing current necessary to terminate AP prolonged AP duration
Na+ channel mutations: failure to remain inactivated late depolarizing current prolonged AP duration
Ca2+ channel mutations: lack of proper voltage-dependent inactivation prolonged Ca2+ influx and depolarizing current
Associated with development of Torsades de Pointes (specific form of polymorphic ventricular tachycardia)
Delayed afterpolarizations (DAD)
AP generation during phase 4 repolarization before another AP would normally occur
Associated with ↑ [Ca2+]i (ex: digitalis toxicity, excessive catecholamine stimulation)
Proposed role of 3 Na+/Ca2+ exchanger current resulting in a transient, net depolarizing current (not completely understood)
Timing of afterdepolarization determines clinical significance
DADs: Late in RRP or after full repolarization: Premature depolarization is likely less significant
Reentry
Abnormal impulse conduction: impulse re-excites myocardial regions which it has already excited
May result in “circus” movements
“Bad” timing is KEY
Responsible for many arrhythmias (may eventually result in fibrillation)
Reentry types (2)
Global Reentry (Macroreentry)
Between atria & ventricles
Can cause supraventricular tachycardia (SVT)
Ex: Wolff-Parkinson-White syndrome
Local Reentry (Microreentry)
Within atria or ventricles
Causes atrial or ventricular tachycardia
Wolf-Parkinson-White (WPW) Syndrome: Common accessory pathway
Alternate path around AV node (Bundle of Kent)
AP conducted directly from atrium to ventricle
Conduction is faster than via normal AV nodal pathway
Then ventricular depolarization generally occurs more slowly than normal
Accessory depolarization path (does not follow normal path of Purkinje fibers)
May result in reentry and can cause a supraventricular tachyarrhythmia
requirements for reentry (things that can go wrong and lead to reentry)
- Potential circuit or circular pathway for conduction
- Unidirectional ‘block’ within part of circuit
(Resulting in only partial depolarization of conduction circuit) - Bad Timing
Timing such that region of the circuit that was initially ‘blocked’ is able to be stimulated by initial impulse after it travels around circuit
Delayed conduction velocity of impulse
Decreased Effective Refractory Period (ERP)
Bad Timing –> reentry
When re-entrant current arrives at previously blocked region after the Effective Refractory Period (ERP)
Duration of ERP of re-entered region must be shorter than propagation time around loop
OR
Propagation time around loop must be longer than ERP of re-entered region
** Key : what factors can impact timing?
Factors promoting reentry in pathologic cardiac conditions
SUPER IMPORTANT
- Lengthened conduction pathway
Commonly occurs in dilated heart chambers
Ex: atrial fibrillation due to atrial enlargement associated with valve lesions or ventricular failure - Decreased conduction velocity
Ex: Purkinje system block, ischemia, hyperkalemia, vagal inputs - Reduced refractory period
Can occur in response to various drugs
Ex: epinephrine
