Cardiac Rhythm (LeGrice)

Question 1

Describe the spread of electrical activation in the normal heart

Answer 1

The initiation and spread of electrical activation in the normal heart is represented in figure above.

• Activation begins with spontaneous depolarization of cells in sino-atrial (SA) node
• It then spreads across the atrial chambers and enters the atrioventricular (AV) node, where the progression of activation from atria to ventricles is slowed.
• Activation then propagates rapidly through i_nterventricular septum_ and across endocardial surfaces of both ventricles via His-Purkinje system.
• As a result, a coordinated wavefront of depolarization spreads through ventricular walls from endocardial to epicardial surface and from apex to base.

This sequence of cardiac activation facilitates efficient contraction by heart and is defined as sinus rhythm. Note that the spatio-temporal summation of action potentials across the heart gives rise to ECG measured on the body surface.

Question 2

Define Sinus Rhythm

Answer 2

A sinus rhythm is any cardiac rhythm where depolarization of the cardiac muscle begins at the sinusnode

Question 3

How is the Sinus Rhythm Maintained?

Answer 3

Sinus rhythm is maintained by following features:

• Entrainment and suppression of lower pacemakers.
  
  • Working cells of atrial and ventricular myocardium do not normally display spontaneous electrical activity in mammalian heart. However, cells in AV node and in other regions of conduction system have an unstable membrane potential during diastole, and therefore have capacity to act as pacemakers.
    
    • SA node normally drives lower pacemakers because it has fastest spontaneous rate. This entrainment tends to suppress inherent automaticity of lower pacemakers.
    • Due to overdrive suppression, slower AV node pacemaker may not take over immediately when activation by SA node is blocked suddenly (as can occur in sick sinus syndrome).
• _Programmed coordinated excitatio_n via specialised conduction system.
• Existence of a prolonged refractory period in myocardium.

Question 4

Describe the Action Potential of Cardiac Myocytes

Answer 4

Duration and characteristics of refractory period for typical myocardial cell include:

• Absolute or effective refractory period (ARP or ERP) is when propagated action potential cannot be elicited regardless of stimulus strength.
• This is followed by relative refractory period (RRP), during which greater stimuli than normal (reach normal threshold) can generate a propagated action potential. Action potentials generated in RRP and SNP propagate slowly.
• This is followed by supernormal period (SNP), during which smaller stimuli than normal can generate a propagated activation. Action potentials generated in RRP and SNP propagate slowly.

Question 5

What are the 2 broad categories of causes of Arrhythmias?

Answer 5

Arrhythmia

Basic Arrhythmic Mechanisms

Heart rhythm disturbance is the most prevalent cause of death and is implicated in most types of sudden death. Any deviation from sinus rhythm is defined as an arrhythmia. Arrhythmias may be due to:

• 1) Disorders of impulse formation
  
  • Early discharge of a pacemaker (abnormal automaticity) or activity triggered by an unstable resting membrane potential in working myocardial cells (DAD, EAD). These give rise to extrasystoles.
• 2) Disorders of impulse conduction
  
  • Conduction abnormalities such as partial or complete AV block, l_eft or right bundle branch block,_ and reentry.
  • The first gives rise to slowed heart rate or bradycardia, while the others alter the time-course of the ventricular activation sequence. Conduction abnormalities may arise because of spatial or temporal dispersion of repolarization
    
    • ​Important: different rates of repolarization in different areas of the heart or different times- cells are in different states of excitatbility

Question 6

Define Arrhythmias

Answer 6

Heart arrhythmia, also known as irregular heartbeat or cardiac dysrhythmia, is a group of conditions where the heartbeat is irregular, t_oo slow_, or too fast.

Arrhythmias are broken down into: Slow heartbeat: bradycardia. Fast heartbeat: tachycardia. Irregular heartbeat: flutter or fibrillation.

Heart rhythm disturbance is the most prevalent cause of death and is implicated in most types of sudden death. Any deviation from sinus rhythm is defined as an arrhythmia.

Question 7

When are ectopic electrical stimulations dangerous?

Answer 7

Arrhythmia is relatively common, but most arrhythmias are benign.

However, it is possible to cause potentially life-threatening arrhythmias in normal heart by ectopic electrical stimulation during T wave of ECG.

This is a time when much of ventricular myocardium is in its relative refractory period, and excitation elicits slowly propagating action potentials. It is viewed as “vulnerable window” within activation sequence.

• Under certain conditions, this can initiate reentrant arrhythmia, which is repeated circulation of a wave of activation within a region of ventricular wall, which gives rise to ventricular tachycardia (VT).
• It may progress to ventricular fibrillation (VF), which is chaotic reentrant activity at multiple sites throughout the ventricles. In VF, heart loses its capacity to pump and death follows quickly if condition is not reversed.

Question 8

Name the types of reentrant arrhythmias

Answer 8

1) Atrial Flutter
2) Atrial Fibrillation
3) Ventricular Tachycardia
4) Ventricular Fibrillation

Question 9

Define Reentrant Arrhythmia

Answer 9

Reentry, which occurs when a propagating impulse fails to die out after normal activation of the heart and persists to re-excite the heart after the refractory period has ended, is the electrophysiologic mechanism responsible for the majority of clinically important arrhythmias.

Question 10

Describe Atrial Reentrant Arrhythmias

Answer 10

Atrial Reentrant Arrhythmia

Atrial flutter and fibrillation (relatively common in elderly) can occur as a result of heart valve lesions or congestive heart failure.

• While atrial rhythm disturbances can be distressing and impair exercise performance, they are not directly life threatening.
• However, there is a significant risk of clot formation, and subsequent pulmonary embolism and stroke in patients with atrial flutter and atrial fibrillation.

Atrial Flutter

Atrial flutter is associated with fast regular atrial rate (250-350 beats/min).

• It is caused by a single atrial reentrant circuit.
• At high atrial rates, partial atrioventricular block is likely to occur.

Atrial Fibrillation (AF)

Atrial fibrillation is associated by rapid disorganised atrial activation (350-600 ‘beats’/min).

• Not all impulses are conducted to ventricles via AV node.
• Atrial fibrillation can lead to a rapid disordered ventricular rhythm.
• Risk of embolization.

Question 11

Describe this type of arrhythmia

Answer 11

Atrial flutter is associated with fast regular atrial rate (250-350 beats/min).

• It is caused by a single atrial reentrant circuit.

At high atrial rates, partial atrioventricular block is likely to occur.

Question 12

Describe this type of Arrhythmia

Answer 12

Atrial fibrillation is associated by rapid disorganised atrial activation (350-600 ‘beats’/min).

• Not all impulses are conducted to ventricles via AV node.

Atrial fibrillation can lead to a rapid disordered ventricular rhythm. Risk of embolization

Question 13

What illness/disorders can increase the risk of Ventricular Reentrant Arrhythmia ?

Answer 13

Ventricular Reentrant Arrhythmia

Ventricular tachycardia and fibrillation can occur:

1. In acute myocardial ischaemia;
2. As a result of structural remodelling associated with healed myocardial infarction;
3. In heart failure;
4. As a result of herditary ion channel mutations;
5. In other situations.

Question 14

Describe the types of Ventricular Reentrant Arrhythmia

Answer 14

Ventricular Tachycardia (VT)

Ventricular tachycardia is associated with rapid ventricular activation (110-250 beats/min).

• There is impaired mechanical function, and risk of ventricular fibrillation.

Ventricular Fibrillation (VF)

Ventricular fibrillation is associated with chaotic ventricular activity leads to circulatory arrest and death.

Question 15

Describe this type of arrythmia

Answer 15

Ventricular fibrillation is associated with chaotic ventricular activity leads to circulatory arrest and death

tion.

Question 16

Describe this type of arrhythmia

Answer 16

Ventricular tachycardia is associated with rapid ventricular activation (110-250 beats/min).

There is impaired mechanical function, and risk of ventricular fibrillation

Question 17

Describe the basic mechanism of ion currents

Answer 17

Mechanisms of Ionic Currents

Actual ionic currents that cross cardiac cell membrane during action potential are determined by status of membrane channels that carry specific ions and also influenced by membrane potential.

• Inward currents (below baseline, negative) depolarize the cell.
• Outward currents (above baseline, positive) repolarize or hyperpolarize the cell.

Cardiac action potential is generated by movement of (mainly) cations (sodium, calcium and potassium) across cell membrane. Direction of this charge movement is determined in part by transmembrane concentration gradient of these ions.

• _Na⁺ and Ca²⁺ _are both present at higher concentrations in the extracellular compartment than inside the cell, whereas opposite is true for K⁺.
• Therefore, there is a tendency for Na⁺ and Ca²⁺ to enter cell, and for K+ to leave cell.

There is one exception to this. Current I_Na/Ca is carried by sodium calcium exchanger rather than a membrane ion channel. Current movement is due to stoichiometry of exchanger, which exchanges 3 Na⁺ for 1 Ca²⁺. Therefore:

• Extrusion of Na+ early after activation transfers net positive charge out of cell (outward current, repolarisation),
• Extrusion of Ca²⁺ later in action potential transfers net positive charge into cell (inward current, depolarisation).

Question 18

Describe the movement of ions in a cardiac AP

Answer 18

Cardiac Action Potential

Depolarization occurs in phase 0, followed by early repolarization in phase 1, plateau in phase 2, r_epolarization in phase 3_, lastly resting state in phase 4.

• When membrane potential is brought to threshold, rapid (though short-lived) opening of sodium channels which carry fast sodium current I_Na causes depolarization.
  
  • Depolarization reduces permeability of potassium channels which carry I_K1 (maintains membrane potential at rest)
  • Depolarization also causes slow calcium channels which carry I_Ca,L to open.
• Early repolarization is due to t_ransient outward potassium current I_to._ Thereafter, inward and outward currents remain in rough balance throughout plateau phase.
• Action potential duration is determined by time of repolarization, which is due to progressive increase in potassium ion current carried by fast and slow delayed rectifier channels (I_Kr and I_Ks respectively).
• As the cell membrane repolarizes, I_K1 increases and membrane potential returns to resting levels.

Question 19

Describe the activaction and inactivation of the sodium channel in the cardiac muscles

Answer 19

Fast sodium channel provides an important example of this. Different kinetics of these processes ensures that there is a b_rief delay between activation and inactivation_, and channel is open during this time period.

• Activation gates are shut at r_esting potential,_ but open rapidly with depolarization.
• Inactivation gates are open at rest, but after depolarization. They progressively begin to reset (open) during repolarization.

Membrane potential dependence of Na⁺ channel inactivation is responsible for prolonged refractory period of cardiac action potential.

Cardiac cells c_annot be re-activated_ during effective refractory period because (1) membrane potential is above threshold (>–50mV) and (2) inactivation gates are closed.

Question 20

Why can’t cardiac cells be re-activated in the Absolute Refractory Period?

Answer 20

Cardiac cells cannot be re-activated during effective refractory period because

(1) membrane potential is above threshold (>–50mV)
(2) inactivation gates are closed.

Question 21

Describe the Mechanisms Underlyingd Reentrant Arrhythmia

Answer 21

Principal components of reentrant circuit model (arrhythmia) are outlined in above figure, which represents propagation of electrical activity around a region in which activation is blocked (due to refractory or completely inexcitable).

• In figure 6A, activation arrives at the top of the region of block and propagates with equal velocity around both sides. The two waves collide at the bottom and stop. Therefore, it doesn’t give rise to reentrant arrhythmia.
• In figure 6B, activation arriving at the top is able to propagate around left-hand side of region of block, but not around right-hand side (path is blocked).
  
  • Subsequently, though, it is able to pass retrograde up left-hand side of the region of block to top (block was unidirectional), where it reactivates tissue to generate sustained activation around reentrant circuit.
  • This can occur if t_ime taken to propagate around circuit_ is same as effective refractory period (ERP) of tissue.
    
    • In normal human heart, ERP is 250-300ms and activation spreads through ventricular myocardium at ~1m/s.
    • Under these circumstances, wavelength necessary to support re-entrant arrhythmia is ~250-300mm (very long path distance compared to dimensions of human heart).
    • Because l = ERP CV, vulnerability increases with (1) decreased CVelocity; (2) decreased refractory period

Reentrant circuit model indicates that sustained reentrant activation can be set up around a region of block provided that:

• A circuit; and
• A trigger; and
• Unidirectional block; and
• Slow conduction and/or short ERP.

Re-entrant circuits can be anatomic or functional.

In ventricular myocardium, slow conduction and unidirectional block can occur when repolarization is not spatially homogeneous.

Question 22

Reentrant circuit model indicates that sustained reentrant activation can be set up around a region of block provided that….

Answer 22

Reentrant circuit model indicates that sustained reentrant activation can be set up around a region of block provided that:

• A circuit; and
• A trigger; and
• Unidirectional block; and
• Slow conduction and/or short ERP.

Re-entrant circuits can be anatomic or functional.

In ventricular myocardium, slow conduction and unidirectional block can occur when repolarization is not spatially homogeneous.

Question 23

Describe an example of a MACRO re-entrant arrhythmia

Answer 23

Reentrant circuit model was used to explain Wolff Parkinson White (WPW) syndrome. In WPW syndrome, bundle of Kent provides an accessory pathway (in addition to AV node) for electrical activity to pass between atria and ventricles.

Normally, early activation of ventricles occurs via this accessory pathway and collides with activation that has propagated more slowly via AV node.

• This gives rise to characteristic ECG signs, including wide QRS complex with a slurred beginning (delta wave) and associated short PR interval.
• This normally has little effect on function.

However, given anatomical substrate, it is possible for a macro re-entry to occur.

• For example, if an _ectopic activatio_n occurs in atria or ventricles (while cardiac tissue in one of pathways is in its refractory period), a run of rapid tachycardia may result. This can cause faintness and seldom leads to ventricular fibrillation and death.
• For instance, ectopic atrial activation is _blocked in accessory pathwa_y, but propagates to ventricles via AV node.
  
  • Conduction delays through AV system are sufficiently long to enable this activation to re-excite atria via accessory pathway.
  • This set up a s_table reentrant circuit_ with a repetition rate that is significantly faster than SA node.
  • In this case, ventricular activation is via fast conduction system, thus it is a “narrow-complex” tachycardia.
• If reentrant circuit is in o_pposite direction_ (less common), going through AV node in retrograde direction, then a “wide-complex” tachycardia is generated.

There are also other arrhythmia mechanisms in WPW patients, e.g. when there is atrial fibrillation or atrial flutter.

Question 24

Describe what the Rate of Propagation of Electric Activation are determined by

Answer 24

Rate of propagation of electrical activation in cardiac myocardium is determined by:

• Electrical properties of myocytes
  
  • Increased electrical coupling between myocytes (gap junction density) increases propagation rate
  • Larger diameter cells increase propagation rate
• Inward current during excitation (most important)
  
  • Density and status of sodium channels (greater current, faster propagation cf. refractoriness)

Question 25

Explain why ectopic excitation in vulnerable period (T wave) has a high probability of inducing reentrant arrhythmia.

Answer 25

Rate Of Propagation Of Ectopic Beat (Potential For Reentry)

It also explains why ectopic excitation in vulnerable period (T wave) has a high probability of inducing reentrant arrhythmia.

• Sodium channels is not fully reset so reduced sodium current, hence slower propagation
  
  • During vulnerable period, ventricular myocardium has a membrane potential around -50mV. As a result, relatively few of closed inactivation gates (shortly after depolarization) will have reset.
  • Numbers of sodium channels that can be opened during the relative refractory period is small and hence propagation of electrical activity is slow.
• Repolarization is non-uniform, hence greater probability of local conduction block

Because wavelength for sustained re-entrant activation is product of conduction velocity and effective refractory period (l = CV ERP), vulnerability of reentrant arrhythmia increases with (1) decreased CV; (2) decreased ERP

Question 26

Myocardial ischaemia can result in …..(4) which can increase the risk of reentrant arrhythmia

Answer 26

During acute ischaemia (due to MI), cellular homeostasis is perturbed in affected region of heart. Myocardial ischaemia results in:

1. Slow conduction (reduced wavelength__)
2. Reduced action potential duration (APD) (reduced wavelength__)
3. Non-uniform repolarization (increased probability of local conduction block).
4. After-depolarizations which generate ectopic activation (DADs) (trigger)

This markedly i_ncrease probability of reentrant arrhythmia._

Question 27

How can Slow Conduction occur due to Myocardial Ischaemia?

Answer 27

1) In myocardial iscaemia, [ATP]_i decreases, thus sodium/potassium ATPase is inhibited/reduced.

• This leads to reduced transmembrane Na+ and K+ gradients.
• Increased [K⁺]_o reduces resting membrane potential (partial membrane depolarization), thus inactivates Na⁺ channels (reduced I_Na)
• This gives rise to slowed conduction velocity.

2) Ischaemia also leads to regional metabolic acidosis.

• Low pH leads to decoupling of gap junction hemi-channels, which i_ncreases electrical resistanc_e between adjacent cells.
• This further reduces conduction velocity in ischaemic myocardium.

Question 28

How can Changes in Action Potential occur due to Myocardial Ischaemia?

Answer 28

Reduced Action Potential Duration And Non-Uniform Repolarization

Since sodium/potassium ATPase is reduced (due to decreased [ATP]_i), ­[K⁺]_o and ­[Na⁺]_i.

• This leads to reduced transmembrane Na+ and K+ gradients.
• Increased [K⁺]_o increases I_Kr, which shortens AP duration (I_Kr is [K⁺]_o-dependent)
• Increased activation of I_K,ATP (ATP-dependent potassium current) reduced [ATP]i, which also shortens AP duration.

In the ischaemic regions, there is also inhomogeneous repolarization (electrical properties).

Question 29

How can Delayed After-Depolarizations occur after Myocardial Ischaemia?

Answer 29

Delayed afterdepolarizations (DADs) begin during phase 4, after repolarization is completed but before another action potential would normally occur via the normal conduction systems of the heart

Delayed After-Depolarizations (DADs)

In myocardial ischaemia, d_ecreased [ATP]_i_ reduces Ca²⁺-ATPase (impaired Ca²⁺ homeostasis/ not enough Ca2+ is pumped out), thus increased [Ca²⁺]_{intracellular} in diastole.

• This leads to spontaneous release of Ca²⁺ from overloaded sarcoplasmic reticulum generates calcium transients that increase extrusion of Ca²⁺ via Na/Ca exchanger. (calcium-induced calcium release)
• Due to the electrogenic properties (stoichiometry) of exchanger, a large inward current is generated that depolarizes membrane and may generate delayed after-depolarization (DADs) (typically do not occur immediately after repolarization).
• This may trigger activation.

Question 30

How can V.Tachycardia turn into V.Fib in Acute MI?

Answer 30

Summary: Cardiac Rhythm with Acute MI (Potential For Arrhythmia)

Onset of ventricular tachycardia (VT) may lead to a positive feedback situation in which rhythm becomes totally irregular and ventricular fibrillation (VF) occurs.

If VT develops, there is increased heart rate and poor contraction, which leads to:

• Increases O2 demand and reduces diastolic perfusion, when O2 supply is reduced over a significant region of myocardium.
• It may also further impair ventricular performance when this is already reduced, leading to decreased cardiac output and arterial pressure, over and above those that may have occurred as a result of initial ischaemia. These and other associated changes potentially increase extent of ischaemic region.

This means ventricular tachycardia is more likely to become ventricular fibrillation.

Question 31

Describe the effect on cardiac rhythm with healed MI

Answer 31

While reentrant arrhythmia is most common in acute phase of MI, it can occur in infarct border zone complex (border zone adjacent to a healed infarct).

This electrical dysfunction is generally attributed to:

• Tissue heterogeneity,
• Disordered structure,
• Altered electrical coupling between cells.

These are viewed as providing a substrate for abnormal electrical activity and reentry.

It often results in monomorphic VT, which is stabilized by structure.

• Monomorphic= VT that occurs each time is the same shape.

Question 32

Describe the Cardiac Rhythm in Heart Failure (not ischaemic heart disease)

Answer 32

In congestive heart failure, there is increased risk of AF due to:

1. There is structural and cellular changes in ventricles and atria. This provides a substrate for ectopic electrical activity and re-entrant activation.
2. Atria become dilated and atrial pressure is increased, which promotes AF by increasing potential re-entrant pathlength and by stimulating stretch-activated ion channels.
3. It causes extensive atrial fibrosis, which is associated with marked region-dependent slowing of conduction.
4. There is changed expression and function of sodium-calcium exchanger (NCX), which cause delayed after-polarisations (DADs) triggering re-entrant arrhythmia.
5. There is also heterogeneous remodel of ANS inputs to atria, which will also influence electrical properties.
6. Finally, AF causes changes in cellular electrical properties which sustain it (AF begets AF).

In congestive heart failure, there is also increased risk of VT and VF due to ventricular remodelling, fibrosis, scarring and altered cellular electrical properties.

Question 33

Describe how EADS can be produced in Long QT syndrome

Answer 33

Long QT Syndrome (LQTS) And Early After-Depolarizations (EADs)

Mechanisms

LQTS can cause ventricular arrhythmias, leading to fainting and sudden death. It is thought to be cause of much unexplained sudden death in young persons.

In LQTS, there is after-depolarizations late in plateau phase or early in repolarization. This is called early after-depolarizations (EADs), which are caused by prolonged AP.

• Prolonged AP provides sufficient time for L-type calcium channels I_<u>Ca(</u>L) to recover and reactivate.
• There is increased sensitivity of these channels to adrenergic stimulation. This means risk of sudden death with LQTS is increased during exercise or emotional stimulation.
• Activation during vulnerable window carries significant risk of _reentrant arrhythmi_a, even in the normal heart. Increased non-uniformity of repolarization in LQTS may amplify this risk.

Question 34

What might cause Long QT Syndrome?

Answer 34

• _Drugs and die_t, e.g. hypokalaemia and the anti-arrhythmic drug amiodarone increase QT interval
• Reduced extracellular potassium concentration (hypokalaemia) (decreased [K⁺]_o ® decreases I_Kr)
• Potassium ion channel mutations which lead to reduced effectiveness of delayed rectifier I_K (LQT1 [I_Ks] and LQT2 [I_Kr]), thus increased probability of EAD formation.
• Sodium ion channel mutations that affect inactivation of I_Na (LQT3), thus increased probability of EAD formation.

Question 35

What does a VT caused by Long QT syndrome look like on an ECG?

Answer 35

In LQTS, typical ECG appearance of VT resulting from EADs is a continuously varying polymorphic VT,

named Torsade de Pointes (twisting of the points).

This may resolve spontaneously or progress to VF.