3 - Mechanisms of Dysrhythmias Flashcards
Intro question: the refractory period of an action potential is related to which ion channel?
Sodium channels
Describe the absolute refractory period
- On the graph, it is the plateau phase (phase 2)
- The cell is NOT ready to accept an impulse
Describe the relative refractory period
- On the graph, it is the phase where the plateau is steadily decreasing (phase 3)
- You won’t normally get an action potential during this time, but if there is a strong enough impulse, there is a possibility the cell will respond
What are the two types of gates in a sodium channel?
- Intracellular plug (intracellular inactivation gate)
- Actual gate (pore region activation gate)
Which gate is open and which gate is closed in a resting cell’s sodium channel
- Intracellular plug (intracellular inactivation gate) is open at rest
- Actual gate (pore region activation gate) is closed at rest
Describe what occurs once an impulse is generated
Once an impulse is generated along the membrane, the pore region opens allowing a rapid influx of sodium and depolarization of the intracellular environment.
After some time, the inactivation gate closes the pore; no more sodium can flow into the cell.
After additional time and change in voltage, the channel recovers to the initial configuration
What does gate closure depend on?
TIME-dependent phenomenon
What does recovery of the sodium channel correspond to?
The absolute refractory period
Describe the absolute refractory period in terms of sodium ion gates
Absolute
- The inactivation gate “plugs” the channel
- This occurs after an action potential
- As time passes, the inactivation gate slowly begins to be removed
Describe the relative refractory period in terms of sodium ion gates
Relative
- When the inactivation gate from the absolute refractory period is slowly being removed, a very strong impulse could alter the inner pore region and an action potential could be generated
- The impulse during this time would have to be very large to get the cell to response
How can channelopathies (genetic channel mutations) and some pharmacological agents affect action potentials?
When mutations or pharm agents affect sodium channels, they can change the kinetics of the channel, which manifests in differences in the refractory period
In addition, this can lead to changes in the flux of other ions and can contribute to arrhythmogenesis
What is excitation-contraction coupling?
The excitation (action potential in the heart cell) leads to the mechanical event (contraction of the heart muscle)
Describe the delay between electrical event and mechanical event in a cardiac muscle cell compared to a skeletal muscle cell
Cardiac = 150 msec. Skeletal = 2-10 msec.
What accounts for this difference?
In cardiac muscle cells, the extended absolute refractory period does not allow another incoming impulse to generate an action potential
Also, cardiac muscle cells (unlike skeletal) cannot be “recruited” when additional force is needed… The electrical events of the heart occur in an “all or non” fashion
What requirement exists for cardiac muscle cell contraction in relation to calcium?
Calcium INFLUX
This is NOT the case for skeletal muscle
Describe the influx of calcium in cardiac muscle cells
In cardiac muscle cells, muscle contraction is dependent upon calcium-induced calcium release
Calcium influx is an absolute requirement for the activation of the calcium-release channels on the SR
Describe the role of calcium in skeletal muscle cells
Calcium influx is not required
- Once stimulated, an end-plate potential can initial skeletal muscle contraction
- Calcium that is released from the sarcoplasmic reticulum in skeletal muscle causes a conformational change in calcium channels, which is the only calcium-related requirement
Describe the “trigger calcium” or “calcium spark” of cardiac muscle cells
The initial calcium influx, which is a required critical step in muscle contraction
Describe how the “trigger calcium” or “calcium spark” is implicated in disease processes
Aging, hypertension, heart failure, diabetes can all lead to…
- Diminished calcium spark
- Reduced contractile potential of the heart muscle
Describe the steps in cardiac muscle cell contraction
1 - Calcium release channels (ryanodine receptors) are activated
2 - Calcium is released into the cytoplasm
3 - Shortening of the muscle occurs as actin filaments interact with the myosin head of thick filaments
4 - Calcium released from intracellular stores bind to troponin protein causing a conformational change
5 - The conformational change uncovers the myosin-binding site on the thin actin filament
6 - Contractile shortening of the sarcomere results
Describe the steps in cardiac muscle cell relaxation
1 - Calcium dissociates from the troponin
2 - Calcium is taken back up into storage via sarcoplasmic reticulum calcium pump (SERCA)
3 - Calcium is bound to proteins within the sarcoplasmic reticulum (SR) in a process involving calsequestrin
4 - Calcium is pumped out of the cell at the cell membrane via the sodium/calcium exchanger (NCX) and the plasma membrane Ca++ pump (plasma Ca-ATPase)
5 - Some believe the mitochondria have a role in calcium cycling
Two types of arrhythmias
1 - Active
2 - Passive
Active arrhythmias
Arrhythmias related to abnormal or enhanced automaticity, triggered activity and reentrant circuits
Automaticity
Automaticity is an intrinsic property of (some) cells of the heart. The sinoatrial (SA) node displays automaticity, as well as cells of the atrioventricular (AV) node, and Purkinje fibers.
SA node
Sinus node is the automatic pace maker of the heart (fastest)
What accounts for the normal physiological automaticity?
This normal, physiological automaticity is due to the phase 4 diastolic depolarization of the action potential in these cells due to the ion flux through the hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel
Which automaticity has the highest slope?
Under normal conditions, the SA node has the fastest rate of diastolic depolarization (highest slope of the phase 4 depolarization) and generates the rhythm that sets the rate for the entire myocardial mass.
What would increasing the slope of phase 4 depolarization result in?
An increased heart rate because if you reach threshold sooner, more action potentials will be possible and the heart rate will therefore be increased
Sinus bradycardia
Sinus bradycardia describes a slower than normal (
Sinus tachycardia
Sinus tachycardia describes a rate faster than normal (>100 bpm)
How can automaticity be enhanced when needed?
By the action of previously latent (non-active) pacemakers within the heart
What are the latent pacemakers of the heart?
Cells of the…
- Atria
- AV junction (node)
- Ventricle
When would these latent pacemakers be called into action?
If the discharge from the SA node is diminished or abolished (e.g. due to ischemia, fibrosis)
What is the HCN channel?
Hyperpolarization-activated cyclic nucleotide-gated cation channel
What is the importance of the HCN channel?
The normal automaticity that is due to phase 4 diastolic depolarization occurs because of the ion flux through the HCN channels in SA node cells
What changes in terms of HCN channels when latent pace makers take over?
The concentration and activity of the HCN underlies the ability of latent pacemakers to transform into the primary pacemaker
This means that if the SA node is damaged, there will be an increase in number and activity of HCN channels in the AV node
How does the sympathetic nervous system modulate automaticity?
Sympathetics increase heart rate by activating HCN and calcium flux, therefore inducing a sinus tachycardia
This is a state of “enhanced automaticity”
How does the parasympathetic nervous system modulate automaticity?
Parasympathetics release ACh to increase potassium current, reduce the slope of the diastolic depolarization and therefore reduce the heart rate to generate a sinus bradycardia
Calcium-ATPase
Diastolic depolarization underlies a major difference in channel expression between nodal and non-nodal cells. What ion channels are not present in non-nodal tissue?
A - Calcium-ATPase B - Sodium-potassium ATPase C - Sodium-calcium exchanger D - Hyperpolarization-activated cyclic nucleotide-gated channels E - β-adrenergic receptors
Answer: D
Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channel)
How does acetylcholine affect phase 4 diastolic depolarization of nodal cells?
- Increases potassium current
- Reduces slope of phase 4
- Decreases heart rate
- Bradycardia
How does norepinephrine affect phase 4 diastolic depolarization of nodal cells?
- Increases calcium and funny current
- Increases slope of phase 4
- Increases heart rate
- Tachycardia
How does hypokalemia and ischemia affect phase 4 diastolic depolarization of nodal cells?
- Decreases potassium current
- Decreases time between action potentials
- Increases slope of phase 4
- Increases heart rate
- Tachycardia
How does mild hyperkalemia affect phase 4 diastolic depolarization of nodal cells?
- Increases maximum diastolic potential
- Increases slope of phase 4
- Increases heart rate
- Tachycardia
How does severe hyperkalemia affect phase 4 diastolic depolarization of nodal cells?
- Significantly depolarizes membrane potential
- Cells become inexcitable
- NO action potentials will occur (heart will stop beating)
Why do we consider latent pacemakers to be abnormal in their automaticity?
Latent pacemakers generate impulses which are especially sensitive to phase 4 modulation
The concentration of what other ion can alter automaticity?
Calcium
What is a “delayed afterpolarization”?
AKA DAD
- A triggered activity where the arrhythmia is generated at a time when the cell is fully repolarized (during phase 4)
- Occurs when there is a cytosolic and/or sarcoplasmic reticulum (SR) calcium overload
What is an “early afterpolarization”?
AKA EAD
- A triggered activity in which the arrhythmia is generated during phase 2 or 3, depending on the underlying channelopathy
- Occurs when there is an altered ion flux during the plateau phase
What does a characteristic EAD action potential look like?
EADs display characteristically extended action potential durations
What accounts for the characteristic prolonged action potential duration of EAD (early afterdepolarizations)?
- Reduced potassium current (takes longer to get to phase 3)
- Increased calcium (extends plateau)
- Increased sodium-calcium exchanger activity (more Na+ coming in, more depolarization of the cell)
- Increased late sodium current (stay depolarized longer)
What accounts for the presence of DADs (delayed afterdepolarizations)?
- Intracellular calcium excess
- Mutations in calcium channels or calcium-binding proteins
Why can DADs (delayed afterdepolarizations) be exacerbated by high heart rates?
At high heart rates, you need to increase speed of calcium cycling proteins, so if you don’t, you’re going to have a higher chance of a DAD – arrhythmia
What are reentrant circuits in terms of arrhythmogenesis?
ACTIVE arrhythogenesis
Impulses that travel more than one pathway in the heart
Examples
- Wolff-Parkinson-Whie syndrome
- AVNRT
- Atrial flutter
- PSVT
What is a reentrant circuit in terms of functionality?
The absence of a defined anatomical pathway
- A piece of the heart is not working how it should be
- There is an area of inexcitable tissue at core
- The circuit is not static in space
Two types of spiral waves
- Monomorphic VT: stable spiral wave
- Polymorphic VT/ VF: meandering, drifting spiral waves
What two principles do reentrant circuits rely on?
- Electrical anisotropy
- Spatial (tissue) inhomogeneities
Describe electrical anisotropy
Anisotropy = differences in the electrical properties of cells throughout the heart
- We want all the action potentials in the heart to look similar and overlap
- In the case of anisotropy, this is not achieved
Describe spatial (tissue) inhomogeneities
Inhomogeneities = there are differences in the tissue properties or the cellular properties of different cells in the cardiac tissue
- Maybe some of the cells get bigger and some are smaller so electrical signals travel differently through the cell and create problems
How do these relate to reentrant circuits causing arrhythmias?
Simply put, there must be a spatial and/or electrical difference between cells to generate differences in signal conduction (differences = arrhythmias)
They allow wavefronts to “reenter” sooner than they should
How does the actual arrhythmia occur from these differences?
A propogating action potential in a reentrant circuit meets a patch of cells that are in the relative refractory period and they are able to generate an action potential as well - this changes the refractory period, which is pro-arrhythmic
What else can induce a reentrant circuit?
- Changes in conduction velocity because if the action potential travels faster, it can get back to the origin sooner and therefore change the refractory period
- Spatial changes that induce ventricular tachycardia or fibrillation
What is Wolff-Parkinson-White syndrome?
Wolff–Parkinson–White syndrome (WPW) is one of several disorders of the electrical system of the heart that are commonly referred to as pre-excitation syndromes.
WPW is caused by the presence of an abnormal accessory electrical conduction pathway between the atria and the ventricles. Electrical signals traveling down this abnormal pathway (known as the bundle of Kent) may stimulate the ventricles to contract prematurely, resulting in a unique type of supraventricular tachycardia referred to as an atrioventricular reciprocating tachycardia.
How is WPW syndrome related to the AV node?
Accessory pathway links atrial tissue to ventricular tissue, bypassing AV node.
AV node functions to slow conduction, therefore the accessory pathway is abnormally fast
How does WPW syndrome appear on an ECG?
Seen as shortened PR interval on ECG
What is a PASSIVE arrhythmia?
Passive arrhythmias denote a conduction abnormality as a result of tissue structure. Cardiac remodeling can contribute to arrhythmogenesis in disease states
What pathologies can contribute to a passive arrhythmia?
Contributing factors
- Alterations in the expression of gap junctions
- Alterations in the distribution of gap junctions
- Fibrosis
- Fat deposition
- Innervation (nerve endings)
- Cell size (hypertrophy)
How do changes in gap junctions contribute to arrhythmias?
Gap junctions provide low(er) resistance connections between cells of the heart and are configured that one cell is half of a gap junction and another cell is the other half (“hemichannels”), so cahnges in the resistivity of gap junctions alter the conduction velocity of propogating signals
So pretty much, they change the conduction velocity
What is the “source-sink” relationship?
Source = where the action potential is coming from and the strength of the impulse
Sink = where the action potential is going and the amount of tissue the source must excite on its way
How does the “source-sink” relationship relate to arrhythmogenesis?
When the impulse passes a patch of “non-excitable” tissue, the source-sink relationship is changed and there will be changes in how the action potential spreads
What will specifically change in the action potential?
The duration of the AP
- In front of the non-excitable area, current sink decreases leading to longer action potential duration
- In contrast, behind this area current sink is increased, which shortens the action potential
So, LONGER APs before the block and SHORTER APs after the block
What is the role of nerves in the formation of passive arrhythmias?
Three scenarios
- Developmental disorder where structure impedes the growth of nerves and some areas are excitable and others are not
- Remodeling occurs with the formation of a scar after injury (MI) and you can either get an increase (hypersensitivity) or decrease in nerve sprouting near the injury
- Diabetes results in differences in nerve growth patterns and electrical properties of the heart
How else can you classify passive arrhythmias?
By their anatomical point of origination
What is a supraventricular arrhythmia?
arrhythmias arising upstream of the ventricular conduction system or ventricular muscle cells
What is a ventricular arrhythmia?
a bundle branch block or ventricular dysrhythmia
