Cardiac Arrhythmias

Cardiac dysrhythmia (also known as arrhythmia) is a term for any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.

Normal Heart Rhythm

Normal heart rhythm is generated and driven by the spontaneous firing of pacemakers cells of the sinoatrial (SA) node located in the posterior wall of the right atrium. These cells have an intrinsic firing rate of 100-110 depolarizations per second. However, this intrinsic rate is under the control of autonomic nerves, which may either increase or decrease this rate. At rest, the sinoatrial rate, and therefore heart rate when the heart is in sinus rhythm (i.e., controlled by SA node), may be in the range of 60-80 beats/minutes (bpm), which is well below the intrinsic firing rate. This reduced resting rhythm is due to vagal tone. Efferent vagus nerve fibers innervating the SA node normally have a high level of activity under resting conditions. These nerves release acetylcholine, which binds to muscarinic (M₂) receptors on the SA nodal cells to cause the decrease in firing rate. The SA node is also innervated by sympathetic fibers. These autonomic nerves release norepinephrine, which binds principally to beta₁-adrenoceptors located on SA nodal cells. When the activity of sympathetic efferent nerves is increased, the SA node firing rate increases. Normally, there is a reciprocal relationship between the parasympathetic (vagal) and sympathethic influences acting on the SA node so that a reduction in heart rate is brought about by increased vagal activity and decreased sympathetic activity. The opposite changes produces an increase in heart rate.
In normal sinus rhythm, the impulses generated by the SA node travel through the atria and converge at the atrioventricular (AV) node where the speed of conduction is reduced to give the atria sufficient time to contract and empty their contents into the ventricles prior to ventricular contraction. Impulses from the AV node travel into the ventricles via the Bundle of His, and then branch into the left and right bundle branches, the terminal Purkinje fibers, and finally are conducted to the ventricular myocytes. Because of this spread of electrical activity from the atria to the ventricles, every atrial depolarization and contraction is normally followed by ventricular depolarization and contraction. In other words, there is normally a one-to-one correspondence between atrial and ventricular depolarization and contraction.

Types of Arrhythmias

Arrhythmias can be divided into three categories: altered rate, premature beats and altered conduction.

Altered Rate

Normal resting heart rates are between 60 and 100 bpm. A rate lower than 60 bpm is called bradycardia and a rate greater than 100 bpm is called tachycardia. There are subcategories of altered rate such as sinus tachycardia or bradycardia (rate is determined by SA node), atrial tachycardia or bradycardia (rate governed by atrial pacemaker site), supraventricular tachycardia, and ventricular tachycardia (rhythm originating from within ventricles). Atrial tachycardias having a rate of 250-350 bpm (>200 bpm in ventricles) are call flutter, and can be either atrial or ventricular in origin. Fibrillation occurs (either atrial or ventricular) when the frequency is so high and irregular that the rate cannot be determined.

Premature Beats

Sometimes a cell within the atria or ventricles that is not normally a pacemaker cell (called an ectopic foci) spontaneously fires off an action potential. When this occurs, it can cause what is called a premature beat. If this occurs in the atria the impulse will generally be conducted to the ventricles and produce an early depolarization and contraction of the atria and ventricles. If the premature beat originates from a ventricular ectopic foci, this will lead to an early depolarization and contraction in the ventricles without affecting the atrial rhythm.

Altered Conduction

Delays in the conduction of electrical impulses within the heart produce abnormal electrical activation of the heart that are termed conduction defects. These most commonly occur at the AV node. Less severe conduction delays at the AV node will only delay the time it takes for the impulse to reach the ventricles (called a first degree AV block). However, if AV nodal conduction is depressed sufficiently, only some of the impulses may be able to travel into the ventricles leading to a loss of the one-to-one correspondence between the atria and ventricles (called a second degree AV block). If the AV node (or Bundle of His) become completely blocked, the atrial will depolarize normally, but ventricular depolarization will no longer be triggered by atrial impulses. When this occurs, pacemaker sites within the ventricle will drive ventricular rate, although at a much lower rate (30-40 bpm) than normal sinus rate (>60 bpm). This is called a third degree AV block. Conduction blocks can also occur in the ventricular bundle branches. These blocks do not normally alter the ventricular rhythm, although they will alter ventricular activation and ventricular mechanical function. Special types of partial conduction blocks, sometimes in conjunction with abnormal conduction pathways (e.g., Wolff-Parkinson-White syndrome), can lead to reentry pathways that produce tachycardia.

Specific Arrhythmias - definitions:

• Sinus bradycardia - low sinus rate <60 beats/min.
• Sinus tachycardia - high sinus rate of 100-180 beats/min as occurs during exercise or other conditions that lead to increased SA nodal firing rate.
• Sick sinus syndrome - a disturbance of SA nodal function that results in a markedly variable rhythm (cycles of bradycardia and tachycardia).
• Atrial tachycardia - a series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min; usually due to abnormal focus within the atria and paroxysmal in nature.  This type of rhythm includes paroxysmal atrial tachycardia (PAT).
• Atrial flutter - sinus rate of 250-350 beats/min.
• Atrial fibrillation - uncoordinated atrial depolarizations.
• Junctional escape rhythm - SA node suppression can result in AV node-generated rhythm of 40-60 beats/min (not preceded by P wave).
• AV blocks - a conduction block within the AV node (or occasionally in the bundle of His) that impairs impulse conduction from the atria to the ventricles.

First-degree AV nodal block - the conduction velocity is slowed so that the P-R interval is increased to greater than 0.2 seconds.  Can be caused by enhanced vagal tone, digitalis, beta-blockers, calcium channel blockers, or ischemic damage.
Second-degree AV nodal block - the conduction velocity is slowed to the point where some impulses from the atria cannot pass through the AV node.  This can result in P waves that are not followed by QRS complexes.  For example, 1 or 2  P waves may occur alone before one is followed by a QRS.  When the QRS follows the P wave, the P-R interval is increased.  In this type of block, the ventricular rhythm will be less than the sinus rhythm.
Third-degree AV nodal block - conduction through the AV node is completely blocked so that no impulses are able to be transmitted from the atria to the ventricles.  QRS complexes will still occur (escape rhythm), but they will originate from within the AV node, bundle of His, or other ventricular regions.  Therefore, QRS complexes will not be preceded by P waves.  Furthermore, there will be complete asynchrony between the P wave and QRS complexes.  Atrial rhythm may be completely normal, but ventricular rhythm will be greatly reduced depending upon the location of the site generating the ventricular impulse.  Ventricular rate typically range from 30 to 40 beats/min.

• Supraventricular tachycardia (SVT) - usually caused by reentry currents within the atria or between ventricles and atria producing high heart rates of 140-250.
• Ventricular premature beats (VPBs) - caused by ectopic ventricular foci; characterized by widened QRS.
• Ventricular tachycardia (VT) - high ventricular rate caused by aberrant ventricular automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.
• Ventricular flutter - ventricular depolarizations >200/min.
• Ventricular fibrillation - uncoordinated ventricular depolarizations. 

Causes of Arrhythmias

Bradycardia

Sinus bradycardia results from reduced SA nodal firing rate. This can occur because of excessive vagal stimulation (e.g., during fainting) or because of damage to the SA node (e.g., damage caused by ischemia or disease). Ventricular bradycardia usually occurs as a result of AV block, which leads to the expression of a pacemaker site within the ventricles that fires at a slow rate (30-40 beats/min).

 

Tachycardia

 

Sinus tachycardia most commonly results from excessive sympathetic nerve stimulation of the SA node or high circulating levels of catecholamines (e.g., pheochromocytoma). Sinus tachycardia that occurs during exercise, for example, is physiologic and normal. However, sinus tachycardia at rest is not normal. Atrial (non-sinus) tachycardia can occur due to either an ectopic foci firing at a high frequency or to reentry mechanisms within the atria. Both of these mechanisms may be stimulated by ischemia or increased sympathetic activity. Supraventricular tachycardia caused by global reentry involves an abnormal conduction pathway. For example, accessory pathways between the right atrium and right ventricle (Bundle of Kent) can cause Wolff-Parkinson-White syndrome. Reentry within the AV node can also precipitate a supraventricular tachycardia. These reentry mediated tachycardias can be triggered by elevated sympathetic activity, which alters conduction velocity within the cardiac tissue and the effective refractory period of action potentials. In some forms of heart disease, ventricular and or atrial dilation occurs, which can lead to tachyarrhythmias or premature beats. Fibrillation is usually caused by diseased ischemic myocardium.

Premature Beats

Atrial and ventricular premature beats are seen as premature atrial complexes (PAC) or premature ventricular complexes (PVC) on the electrocardiogram. These premature beats can be caused by disturbances that increase the excitability of cardiac cells. Stretching of the tissue and ischemia are common causes. Increased sympathetic activity and circulating catecholamines can also precipitate premature beats.

Conduction Blocks

AV conduction blocks can occur during excessive vagal stimulation or removal of normal sympathetic influences on the AV node, which tips the autonomic balance toward a more dominant vagal influence. This can occur, for example, as a consequence of beta₁-adrenoceptor blockade. The most common cause of AV conduction blocks is changes in the electrophysiological properties of the specialized cells within the AV node and Bundle of His. Ischemia, damage caused by trauma, infection or inflammation, or degenerative changes caused by age or disease can lead to AV conduction blocks. These same mechanisms (except for vagal) can cause conduction blocks in other regions of the conduction system, such as the bundle branches.

Antiarrhythmic Drugs

Therapeutic Use and Rationale

The ultimate goal of antiarrhythmic drug therapy is to restore normal rhythm and conduction. When it is not possible to revert to normal sinus rhythm, drugs may be used to prevent more serious and possibly lethal arrhythmias from occurring. Antiarrhythmic drugs are used to:

• decrease or increase conduction velocity
• alter the excitability of cardiac cells by changing the duration of the effective refractory period
• suppress abnormal automaticity

All antiarrhythmic drugs directly or indirectly alter membrane ion conductances, which in turn alters the physical characteristics of cardiac action potentials. For example, some drugs are used to block fast sodium channels. These channels determine how fast the membrane depolarizes (phase 0) during an action potential. Since conduction velocity is related to how fast the membrane depolarizes, sodium channel blockers reduce conduction velocity. Decreasing conduction velocity can help to abolish tachyarrhythmias caused by reentry circuits. Other types of antiarrhythmic drugs affect the duration of action potentials, and especially the effective refractory period. By prolonging the effective refractory period, reentry tachycardias can often be abolished. These drugs typically affect potassium channels and delay repolarization of action potentials (phase 3). Drugs that block slow inward calcium channels are used to reduce pacemaker firing rate by slowing the rate of rise of depolarizing pacemaker potentials (phase 4 depolarization). These drugs also reduce conduction velocity at the AV node, because those cells, like SA nodal cells, depend on the inward movement of calcium ions to depolarize.
Because sympathetic activity can precipitate arrhythmias, drugs that block beta₁-adrenoceptors are used to inhibit sympathetic effects on the heart. Because beta-adrenoceptors are coupled to ion channels through defined signal transduction pathways, beta-blockers indirectly alter membrane ion conductance, particularly calcium and potassium conductance.
In the case of AV block, drugs that block vagal influences (e.g., atropine, a muscarinic receptor antagonist) are sometimes used. AV block can occur during beta-blocker treatment and therefore simply removing a beta-blocker in patients being treated with such drugs may normalize AV conduction.
Sometimes ventricular rate is excessively high because it is being driven by atrial flutter or fibrillation. Because it is very important to reverse ventricular tachycardia, drugs are often used to slow AV nodal conduction. Calcium channel blockers and beta-blockers are useful for this indication. Digitalis, because of its ability to activate the vagus nerve (parasympathomimetic effect), can also be used to reduce AV conduction velocity in an attempt to normalize ventricular rate during atrial flutter or fibrillation.



Classes of Drugs Used to Treat Arrhythmias

Classes of drugs used in the treatment of arrhythmias are given below

Antiarrhythmic drug classes:

• Class I - Sodium-channel blockers
• Class II - Beta-blockers
• Class III - Potassium-channel blockers
• Class IV - Calcium-channel blockers
• Miscellaneous - adenosine
  - electrolyte supplement (magnesium and potassium salts)
  - digitalis compounds (cardiac glycosides)
  - atropine (muscarinic receptor antagonist)

 Drug Classes Used in the Treatment of Arrhythmias

The following table summarizes which antiarrhythmic drugs may be used to treat different types of arrhythmias. It is important to note that for a given condition a particular drug may not be efficacious, and in fact, it may precipitate other arrhythmias or adverse cardiovascular effects (e.g., cardiac depression, hypotension). Therefore, drug efficacy and safety must be carefully evaluated and individualized to the patient when treating arrhythmias. 

Condition	Drug	Comments
Sinus tachycardia	Class II, IV	Other underlying causes may need treatment
Atrial fibrillation/flutter	Class IA, IC, II, III, IV digitalis adenosine	Ventricular rate control is important goal; anticoagulation required
Paroxysmal supraventricular tachycardia	Class IA, IC, II, III, IV adenosine
AV block	atropine	Acute reversal
Ventricular tachycardia	Class I, II, III
Premature ventricular complexes	Class II, IV Mg++ salts	PVCs are often benign and not treated
Digitalis toxicity	Class IB Mg++ salts; KCl