arythmia

• • Impulse Propagation: sinoatrial node to the atrioventricular (AV node) to the His-Purkinje followed by distribution throughout the ventricle

  • Normal AV nodal delay (0.15 seconds) -- sufficient to allow atrial ejection of blood into the ventricles

  • Definition: arrhythmia -- cardiac depolarization different from above sequence --

    • Abnormal origination (not SA nodal)

    • Abnormal rate/regularity

    • Abnormal conduction characteristics

• Transmembrane potential -- determined primarily by three ionic gradients

  • Na⁺, K⁺, Ca ²⁺

    • Water-soluble, i.e. not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins)

  • Movement through channels depend on controlling "molecular gates"

    • Gate-status controlled by:

      • Ionic conditions

      • Metabolic conditions

      • Transmembrane voltage

  • Maintenance of ionic gradients:

    • Na⁺/K⁺ ATPase pump

    • termed "electrogenic" when net current flows as a result of transport (e.g., three Na⁺ exchange for two K⁺ ions)

  • Initial permeability state -- resting membrane potential

    • sodium: relatively impermeable

    • potassium: relatively permeable

  • Cardiac cell permeability and conductance:

    • Conductance: determined by characteristics of ion channel protein

    • Current flow = voltage X conductance

    • Voltage = (actual membrane potential - membrane potential at which no current would flow, even with channels open)

  • Sodium

    • Concentration gradient: 140 mmol/L Na⁺ outside: 10 mmol/L Na⁺ inside;

    • Electrical gradient: 0 mV outside; -90 mV inside

    • Driving force, both electrical and concentration, tend to move Na⁺ into the cell.

    • In the resting state: sodium ion channels are closed therefore no Na⁺ flow through the membrane

In the active state: channels open causing a large influx of sodium which accounts for phase 0 depolarization

• Note the rapid "upstroke" characteristic of Phase 0 depolarization.

• This abrupt change in membrane potential is caused by rapid, synchronous opening of Na⁺ channels.

• Note the relationships between the the ECG tracing and phase 0

• Potassium:

  • Concentration gradient (140 mmol/L K⁺ inside; 4 mmol/L K⁺outside)

  • Concentration gradient tends to drive potassium out

  • Electrical gradient tends to hold K⁺ in.

  • Some K⁺ channels ("inward rectifier") are open in the resting state -- however, little K⁺ current flows because of the balance between the K⁺ concentration and membrane electrical gradients

  • Cardiac resting membrane potential: mainly determined

    • By the extracellular potassium concentration and

    • Inward rectifier channel state

• Spontaneous Depolarization (pacemaker cells)-- phase 4 depolarization

  • Spontaneous Depolarization occurs because:

    • Gradual increase in depolarizing currents (increasing membrane permeability to sodium or calcium)

    • Decrease in repolarizing potassium currents (decreasing membrane potassium permeability)

    • Both factors are important.

• • Ectopic pacemaker: (not normal SA nodal pacemakers) --

    • Facilitated by hypokalemic states

    • Increasing potassium: tends to slow or stop ectopic pacemaker activity

• Channel Activation Sequence:

  • Depolarization to threshold voltage--Na⁺

    • m gate activation (activation gate); assuming inactivation (h) gates are not closed then

    • Sodium permeability dramatically increased; intense sodium current

    • Depolarization

    • h gate closure; Na⁺ current inactivation.

Influence of Membrane Resting Potential on Action Potential Properties

• The extent and synchrony of sodium channel activation is dependent on the resting membrane potential.

  • Inactivation gates of sodium channels close in the membrane potential range of -75 to -55 mV (less channels available for sodium ion inward current)

  • For example, less intense sodium current if the resting potential is - 60 mV compared to -80 mV

  • Consequences of reduced sodium activation due to reduced membrane potential (less negative)

    • Reduced of velocity upstroke (V_max) [phase 0] (maximum rate of membrane potential change)

    • Reduced excitability

    • Reduced conduction velocity-- a significant cause of arrhythmias

    • Prolongation of recovery:-- an increase in effective refractory period

• Plateau Phase:

  • Plateau phase -- Na channels mostly inactivated

  • Repolarization (h gates reopen)

  • "Refractory period": time between phase 0 and phase 3 -- during this time the stimulus does not result in a propagated response

  • Altered refractoriness may cause or suppress arrhythmias

• Factors that reduce the membrane resting potential & reduce conduction velocity

  • Hyperkalemia

  • Sodium pump block

  • Ischemic cell damage

• Conduction in severely depolarized cells

  • With decreased membrane potentials (e.g., -55 mV), sodium channels are inactivated

  • Under some circumstances, increased calcium permeability or decreased potassium permeability allow for slowly conducted action potentials with slow upstroke velocity

  • Ca²⁺-inward current-mediated action potentials are normal for the specialized conducting SA nodal and AV nodal tissues, which have resting membrane potentials in the -50 to-70 mV range.

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241.

• Factors that may precipitate or exacerbate arrhythmias

  • Ischemia

  • Hypoxia

  • Acidosis

  • Alkalosis

  • Abnormal electrolytes

  • Excessive catecholamine levels

  • Autonomic nervous system effects (e.g., excess vagal tone)

  • Excessive catecholamine levels

  • Autonomic nervous system effects (e.g., excess vagal tone)

  • Drug effects: e.g., antiarrhythmic drugs may cause arrhythmias)

  • Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure)

  • Presence of scarred/diseased tissue which have altered electrical conduction properties

Hondeghem, L.M. and Roden, D.M., "Agents Used in Cardiac Arrhythmias", in Basic and Clinical Pharmacology, Katzung, B.G., editor, Appleton & Lange, 1998, pp 216-241

Pathophysiology

• • Antiarrhythmic drugs may work by:

    • (a) Suppressing initiation site (automaticity/after-depolarizations) and/or

    • (b) Preventing early or delayed afterdepolarizations and/or

    • (c) By disrupting a re-entrant pathway.

• (a) Automaticity: Automaticity may be diminished by:

  • (1) Increasing the maximum diastolic membrane potential

  • (2) Decreasing the slope of phase 4 depolarization

  • (3) Increasing action potential duration

  • (4) Raising the threshold potential

    • All of these factors make it take longer or make it more difficult for the membrane potential to reach threshold.

      • (1) The diastolic membrane potential may be increased by adenosine and acetylcholine.

      • (2) The slope of phase 4 depolarization may be decreased by beta receptor blockers

      • (3) The duration of the action potential may be prolonged by drugs that block cardiac K⁺ channels

      • (4) The membrane threshold potential may be altered by drugs that block Na⁺ or Ca²⁺ channels

• (b) Delayed or Early Afterdepolarizations:

  • Delayed or early afterdepolarizations may be blocked by factors that

    • (1) prevent the conditions that lead to afterdepolarizations.

    • (2) directly interfere with the inward currents (Na⁺, Ca²⁺) that cause afterdepolarizations.

    • (c) Reentry

      • For anatomically-determined re-entry such as Wolf-Parkinson-White syndrome (WPW) drugs the arrhythmia can be resolved by blocking action potential (AP) propagation. (In WPW syndrome, an accessory conduction pathway, linking atria and ventricles and bypassing the atrioventricular node, is the structure responsible for the arrhythmia)

• Prolongation of tissue refractoriness can be accomplished by those antiarrhythmic drugs that block Na⁺ channels.

  • Sodium channel blockers reduces the percentage of recovered channels (following inactivation by depolarization) at any given membrane potential.

  • Examples of antiarrhythmic drugs classified as sodium channel blockers include lidocaine, quinidine, and tocainide.

  • "Although any type of arrhythmia can occur in a patient with WPW, the two most common are CMTs (circus
    movement tachycardias) and atrial fibrillation (AFib).

    • CMT is the more common arrhythmia of the two

    • Treatment of CMTs associated with WPW is similar to treating PSVT

    • In a stable patient, adenosine (rapid IV push; if unsuccessful, repeat after dosage adjustment rapid IV push) should be the first-line treatment in any regular tachycardia, regardless of whether the complex is wide or narrow

  • Treatment of AFib associated with WPW is necessarily different than for a patient with a normal heart. AFib is an irregular rhythm as opposed to the regular rhythm seen in CMTs.

    • The basic treatment principle in WPW AFib is to prolong the anterograde refractory period of the accessory pathway relative to the AV node. This slows the rate of impulse transmission through the accessory pathway and, thus, the ventricular rate.

    • If AFib were treated in the conventional manner by drugs that prolong the refractory period of the AV node (eg, calcium channel blockers, beta-blockers, digoxin), the rate of transmission through the accessory pathway likely would increase, with a corresponding increase in ventricular rate. This could have disastrous consequences, possibly causing the arrhythmia to deteriorate into V fib.

    • Procainamide (17 mg/kg IV infusion, not to exceed 50 mg/min; hold for hypotension or 50% QRS widening) blocks the accessory pathway, but it has the added effect of increasing transmission through the AV node.

      • Thus, although procainamide may control the AFib rate through the accessory pathway, it may create a potentially dangerous conventional AFib that may require treatment with other medications.

        1. Prompt cardioversion of patients with WPW and AFib is recommended.

      • Medical management may be a viable option in some patients, but it may have unpredictable results.

        1. Note that cardioversion is always the treatment of choice in unstable patients."

        2. From emedicine cited material originally authored by Mel Herbert, MD, MBBS, Assistant Professor of Medicine and Nursing, Department of Emergency Medicine, Olive View-University of California at Los Angeles Medical Center. This material has been subsequently updated; the new material is authored by Christopher Ellis, MD

• Accordingly, drugs which may reduce ventricular rate by reducing AV nodal conduction include:

  • Calcium channel blockers (verapamil (Isoptin, Calan), diltiazem (Cardiazem))

  • β-adrenergic receptor blockers (propranolol (Inderal)), and

  • Dgitalis glycosides.

• Treatment of atrial fibrillation: Verapamil (Isoptin, Calan) and Diltiazem (Cardiazem)

  • Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

    • Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.

  • Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.

• Treatment of atrial fibrillation: Propranolol (Inderal)

  • Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade.

    • Normally, sympathetic drive results in increased in Ca²⁺ ,K⁺ ,and Cl^- currents.

  • Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias.

    • These effects are blocked by β-adrenergic receptor blockers.

  • β-adrenergic receptor blockers increase AV conduction time (takes longer) and increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

  • β-adrenergic receptor blockade can also help reduce ventricular following rates in atrial flutter and fibrillation, again by acting at the AV node.

  • Adverse effects of beta blocker therapy can lead to fatigue, bronchospasm, depression, impotence, and attenuation of hypoglycemic symptoms in diabetic patients and worsening of congestive heart failure.

• Research Channel: Stanford University Medical Center

• Reference: https://www.youtube.com/watch?v=8su2I1JOtWg

• "An irregular heartbeat might be linked with a more serious medical condition such as Atrial Fibrillation (AF), the most common type of heart arrhythmia in the United States. Professors and physicians at Stanford University Medical Center stress the importance of early diagnosis and appropriate treatment for a number of cardiac arrhythmias that affect more than 2 million Americans. What is the difference between a benign palpitation and a life-threatening affliction?'

• Drugs assist in restoring and maintaining normal sinus rhythm include quinidine and procainamide.

  • Quinidine; Quinidine gluconate (Quinaglute, Quinalan)
    Although classified as a sodium channel blocker, quinidine also blocks K+ channels.

    • Most antiarrhythmic agents have such multiple actions.

    • Sodium channel blockade results in

      • An increased threshold

      • Decreased automaticity.

    • Potassium channel blockade results in action potential (AP) prolongation (width increases).

    • Quinidine gluconate-Clinical Use:

      • Maintains normal sinus rhythm in patients who have experienced atrial flutter or fibrillation.

      • Prevents ventricular tachycardia or fibrillation.

    • Quinidine gluconate (Quinaglute, Quinalan) administration results in vagal inhibition (anti-muscarinic) and alpha-adrenergic receptor blockade.

    • Adverse effects include cinchonism (headaches and tinnitus), diarrhea.

    • Quinidine is also associated with torsades de pointes, a ventricular arrhythmias associated with marked QT prolongation.

      • This potentially serious arrhythmia occurs in 2% - 8% if patients, even if they have a therapeutic or subtherapeutic quinidine blood level.

  • Procainamide (Procan SR, Pronestyl-SR)

    • Quinidine and Procainamide exhibit similar electrophysiological properties.

    • By contrast to quinidine, procainamide does not exhibit either vagolytic or alpha-adrenergic blocking activity.

    • Useful in acute management of supraventricular and ventricular arrhythmias.

• • • Long term use is associated with side effects, including a drug-induced lupus syndrome which occurs at a frequency of 25% to 50%.

      • In slow acetylators, the procainamide-induced lupus syndrome occurs more frequently and earlier in therapy than in rapid acetylators.

The red dot highlights the AV node

• • Valsalva maneuver

  • α-adrenergic receptor agonist administration

  • Digoxin administration

  • by administration of drugs that reduce AV transmission:

    • Adenosine (Adenocard), verapamil (Isoptin, Calan), diltiazem (Cardiazem), esmolol (Brevibloc) or DC cardioversion.

      • Adenosine (Adenocard)

        • Effects mediated through G protein-coupled adenosine receptor.

        • Activates acetylcholine-sensitive K+ current in the atrium and sinus and A-V node.

        • Decreases action potential duration, reduces automaticity

        • Increases A-V nodal refractoriness

        • Rapidly terminates re-entrant supraventricular arrhythmias (I.V)

      • Verapamil (Isoptin, Calan) and Diltiazem (Cardiazem)

        • Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

        • Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.

        • Major adverse effect (i.v. administration) is hypotension. Heart block or sinus bradycardia can also occur.

      • Esmolol (Brevibloc)

        • Esmolol is a very short acting, cardioselective beta-adrenergic receptor antagonist.

        • I.V. administration is used for rapid beta-receptor blockade in treatment of atrial fibrillation with high ventricular following rates.

        • Antiarrhythmic effects are due mainly to beta-adrenergic receptor blockade. Normally, sympathetic drive results in increased in Ca²⁺ ,K⁺and Cl^- currents.

        • Increased sympathetic tone also increases phase 4 depolarization (heart rate goes up), and increases DAD (delayed afterdepolarizations) and EAD (early afterdepolarization) mediated arrhythmias.

          • These effects are blocked by β-adrenergic receptor blockers.

        • β-adrenergic receptor blockers

          • Increase AV conduction time

          • Increase AV nodal refractoriness, thereby helping to terminate nodal reentrant arrhythmias.

• Three mechanisms have been associated with many tachyarrhythmias.

  • Enhanced Automaticity

    • Enhance automaticity is associatied with an increase in the slope of phase 4 depolarization results in

      • As a result of the increase in phase 4 slope the cell reaches threshold more often per minute resulting in higher heart rate.

      • Factors that increase automaticity include

        • Mechanical stretch

        • β-adrenergic stimulation

        • Hypokalemia

        • Ischemia can induce abnormal automaticity, i.e. automaticity that occurs in cells not typically exhibiting pacemaker activity.

  • Triggered Automaticity

    • Triggered automaticity occurs when a second depolarization occurs prematurely.

      • One type of triggered automaticity is a delayed afterdepolarization (DAD).

        • If this late depolarization reaches threshold (a) second beat(s) may occur.

      • Factors that predispose to delayed afterdepolarizations include:

        • Excessive adrenergic activity

        • Digitalis toxicity

        • High intracellular Ca²⁺

    • A second type of triggered automaticity is Early Afterdepolarization (EAD) which is associated with significant prolongation of the action potential duration.

      • In this case, during a prolonged phase 3 repolarization, the repolarization is interrupted by a second depolarization.

      • Factors that predispose to Early Afterdepolarizations include

        • Bradycardia

        • Low extracellular K⁺

        • Certain drugs, including some antiarrhythmics

    • Torsades de pointes, a polymorphic ventricular arrhythmia- associated with

      • Prolongation of cardiac repolarization (prolonged Q-T interval)

      • Possibly induced by early afterdepolarizations.

    • The antiarrhythmic drug quinidine gluconate (Quinaglute, Quinalan) can cause this arrhythmia. Many other drugs can also cause this effect.

    • Reentry is the most common cardiac conduction abnormality leading to arrhythmias.

• • PF: Branched Purkinje Fiber terminating on ventricular muscle (VM).

• Shaded Area: Depolarized region with unidirectional (one-way) block (Decremental conduction, impulse slowly dies out)

  • slowed conduction may be due to depression of Na ⁺ or Ca²⁺ currents (e.g. AV node)

• Retrograde impulses (wavy line) propagate slow enough such that cells in branch 1 are no longer refractory and can be activated by the re-entry potential.

• Drugs that terminate reentry may further depress conduction, converting the "unidirectional" block to a "bidirectional" block

• A reentrant circuit involves a pathway that bifurcates into two branches.

  • One pathway is blocked to anterograde conduction, but can be excited in a retrograde manner by the impulse that traversed the unblocked path.

  • Retrograde conduction occurs until excitation of now non-refractory tissue re-initiates the process.