Cardiac Arrhythmias

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General Introduction

To facilitate diagnoses and treatment of cardiac arrhythmias a basic understanding of the physiological cardiac action potential and cardiac conduction system is required.

Cardiac Action Potential

The cardiac action potential is a result of ions flowing through different ion channels. Ion channels are passages for ions (mainly Na⁺, K⁺, Ca²⁺ and Cl^-) that facilitate movement through the cell membrane. Changes in structure of these channels can open, inactivate or close and control current inside and outside the myocytes. Due to different activity and expression of ion channels, the various parts of the cardiac conduction channel have slightly different action potential characteristics. Ion channels are mostly a passive passage, where movement of ions are caused by the electrochemical activity gradient. In addition to these passive ion channels a few ATP-dependent channels exist to fine-tune the action potential. These changes of membrane potential produce and action potential lasting a few hundreds of milliseconds. Disorders is single channels can lead to arrhythmias, as seen in the section Primary_Arrhythmias. The action potential is conducted throughout the heart by the depolarization of the immediate environment of the cells and through intracellular coupling with gap-junctions. The communication pores are located in cell to cell adhesion structures, the intercalated disks.

In summary during the depolarization, sodium ions stream into the cell followed by a influx of Ca²⁺ ions (both from the inside (sarcoplasmatic reticulum) and outside of the cell). These Ca²⁺ ions cause the actual muscular contraction. Shortly thereafter K+ ions stream out of the cell. During repolarization the ion concentration returns to its precontraction state. The action potential can be divided in five phases:

Phase 0: Rapid Depolarization

Rapid depolarization is started once the membrane potential reaches a certain threshold (about -70 to -60 mV), independent of the size of the depolarizing stimulus. This produces a rapid influx of Na⁺ and a rapid upstroke of the action potential. At higher potentials (-40 to -30) Ca²⁺ influx participates in the upstroke. In sinus node and AV node a slower upstroke can be observed (Figure 1). This caused because the upstroke in these cells are mainly mediated by the slower acting Ca²⁺ ion channels. The slow activation and inactivation produce a slower upstroke.

Phase 1: Early Rapid Repolarization

Immediately following rapid depolarization, the inactivation of I_Na and subsequent activation of the outward K⁺ current I_TO and the Na⁺/Ca²⁺ exchanger produce a early rapid repolarization. Due to the absence of I_Na in the upstroke of sinus node and AV node cells and the subsequent slower depolarization, this rapid repolarisation is not visible in their action potentials.

Phase 2: Plateau

The plateau phase represents an equal influx and efflux of ions producing a stable membrane potential. The influx is mediated by Ca²⁺ through the open L-type Ca²⁺ channels and the exchange of Na⁺ for internal Ca²⁺ by the Na⁺/Ca²⁺ exchanger. The efflux is the result of outward current carried by K⁺ and Cl^- ions.

Phase 3: Final Rapid Repolarization

Final repolarization is mainly caused by inactivation of Ca²⁺ channels, reducing the influx of positive ions. Furthermore repolarizing K⁺ currents (delayed rectifier current I_Ks and I_Kr and inwardly rectifying current I_K1 and I_K,Ach) are activated which increase efflux of positive ions. This result in an repolarization to the resting membrane potential.

Phase 4: Resting membrane potential

Depending on cell type the resting membrane potential is between -50 to -95 mV, sinus node and AV nodal cells have a predominately higher resting membrane potential (-50 to -60 mV and -60 to -70 respectively) in comparison with atrial and ventricular cardiomyocytes (-80 to -90 mV). This distribution is mainly caused by the Na+ outside the cell and the K⁺ inside the cell. Sinus node cells and AV nodal cells (and to a lesser degree Purkinje fibers cells) have a special voltage dependent channel I_f, the funny current. Furthermore they lack I_K1, a K⁺ current that maintains the resting membrane potential in atrial and ventricular tissue. This channel displays a slow depolarization in diastole, called the phase 4 diastolic depolarization, and results normal automaticity. Sinus node discharges are regulated by the autonomous nerve system and due to its high firing frequency dominates other potential pacemaker sites.

Cardiac conduction

The cardiac conduction system (figure 3) is the highway though which the electric activity of the heart spread from the atria to the ventricle. The characteristics of the different parts of the conduction system are a result of the different characteristics of the individual myocytes. On a larger level, function is controlled predominantly by the autonomic nerve system (both vagal and sympathetic nerve system). Especially the sinus node and atrioventricular node are responsive to the autonomic nerve system. The ganglionic plexi, a conglomeration of both vagal and sympathetic nerves, form the intrinsic cardiac nerve system and innervate through a network of nerve fibers the atria and ventricles. The vagal and sympathetic nerve system are both continually active in the heart, but vagal activity dominates the tonic background stimulation of the autonomic nerve system. Moreover the heart is more susceptible to vagal stimulation. Vagal stimulation provokes a rapid response and the effect dissipates swiftly in contrast to sympathetic stimulation which has a slow onset and offset. Vagal stimulation results in a reduction is in sinus node activation frequency and prolongs AV nodal conduction. These effects can occur simultaneously or independent of each other. Sympathetic stimulation exerts reverse effects, accelerating the sinus node firing frequency and improving AV nodal conduction. The autonomic nerve system has a small effect on cardiomyocytes. Vagal stimulation tends to prolong the refractory period and decreasing the myocardial contractility. Sympathetic stimulation has opposite effects on the cardiac tissue. Whereas the physiological modulation of cardiac conduction is vital to adaptation of the heart to rest and exercise it can attribute to the pathologic substrate in a diseased myocardium.

Sinus node

The sinus node is an densely innervated area located in the right atria which is supplied by the right (55%-60%) or circumflex (40%-45%) coronary artery. It is a small structure of 10-20mm long and 2-3mm wide and contains a diversity of cells. These include pacemaker cells which are discharged synchronously due to mutual entrainment. This results in an activation wave front activating the rest of the atria.

Atrium

The impulse formed in the sinus node is conducted through the atrium to the AV-node. Evidence indicates three preferential conduction pathways. The pathways show preferential conduction due to their anatomical structure and rather than specialized conduction properties. The three pathways are; the anterior internodal pathway, the middle internodal tract the posterior internodal pathway. The anterior internodal pathway connect to the anterior interatrial band, also known as the Bachmann bundle. This bundle of muscular tissue conducts the sinus wave front from the right to the left atrium.

AV node

The connection between atria and ventricles is facilitated through the AV node, lying in the right atrial myocardium and a penetrating part, the bundle of His. The AV node acts as a gatekeeper, regulating impulse conduction from the atrium to the ventricle. Additionally, due to the phase 4 diastolic depolarization it can exhibit impulse formation. The AV node is supplied in most cases (85%-90%) by the right coronary artery or in the remaining cases the circumflex artery.

Bundle of His

Connecting the distal AV node and the proximal bundle branches, the bundle of His is supplied by both the posterior and anterior descending coronary arteries. It is enclosed by the central fibrous body and membranous septum between the atria and the ventricles. The location and blood supply protect the bundle of His from external influences.

Bundle Branches

From the bundle of His the right bundle branch continues to the right ventricular apex. The left bundle branch splits of and divides in two or more fascicular branches. Commonly the left bundle branch consist of an anterior fascicle, that activates the anterosuperior portion of the left ventricle. The thicker and more protected posterior fascicle activates the inferoposterior part of the left ventricle.

Venticle

The ventricle is activated through the dense network of Purkinje fibers originating from the bundle branches. They penetrate the myocardium, but predominantly the endocardium, and are the starting point of the ventricular activation.

Mechanisms of Arrhythmia

Structural abnormalities or electric changes in the cardiomyocytes can impede impulse formation or change cardiac propagation facilitating arrhythmias. We briefly discuss the main causes of arrhythmia as these pathofysiological principles underlie to most common rhythm disorders and intervening in these mechanisms can terminate the arrhythmia.

Abnormal Impulse Formation

The mechanism of abnormal automaticity is similar to the normal automaticity of sinus node cells. Abnormal automaticity can be caused by changes in the cell ion channel characteristics due to drugs or changes in the electrotonic environment. Abnormal automaticity can result from an increase of normal automaticity in non-sinus node cells or a truly abnormal automaticity in cells that don't exhibit a phase 4 diastolic depolarization.

Abnormal Automaticity

The mechanism of abnormal automaticity is similar to the normal automaticity of sinus node cells. Abnormal automaticity can be caused by changes in the cell ion channel characteristics due to drugs or changes in the electrotonic environment. Abnormal automaticity can result from an increase of normal automaticity in non-sinus node cells or a truly abnormal automaticity in cells that don't exhibit a phase 4 diastolic depolarization.

Triggered Activity

Triggered activity is activity of a cell triggered by a preceding activation. Due to early or delayed afterdepolarizations the resting membrane depolarizes and, when reaching threshold potentials, activates the cell. These afterdepolarizations are depolarizations of the membrane potential initiated by the preceding action potential. Depending on the phase of the action potential in which they arise, they are defined as early or late afterdepolarizations.

• In early afterdepolarizations depolarization occurs during the action potential (phase 2 and 3) by a diversity of causes. Early afterdepolarizations can increase duration of the repolarization phase of the action potential. This increase can create heterogeneity in refractoriness and thereby creating the substrate for a re-entry circuit (see below).
• Delayed afterdepolarizations occur after the cell has recovered after completion of repolarization. In delayed afterdepolarization an abnormal Ca2+ handling of the cell is probably responsible for the afterdepolarizations due to release of Ca²⁺ from the storage of Ca2⁺ in the sarcoplasmatic reticulum. The accumulation of Ca²⁺ increases membrane potential and thus depolarizes the cell when it reaches a certain threshold.

Disorders of Impulse Conduction

Conduction block or conduction delay is a frequent cause of bradyarrhythmias, however tacharrhythmias can also result from conduction block and produce a reentrant circuit. Conduction block can develop in different conditions, for instance a deceleration block or a acceleration block. These conduction block develop due to deceleration or a slow heart rate or a acceleration or fast heart rate respectively. It is important to assess the cause of conduction block as explained in the section of bradycardia, for it is important in the treatment of the conduction delay or block.

Reentry

Reentry or circus movement can arise when an area is slowly conducting thereby remaining active while the rest of the heart depolarizes. When the rest of the heart has recovered from this refractory state, and can be reactivated, the impulse in the slow conducting zone can activate the heart. This process can repeat itself and thus form the basis of a reentry tachycardia. These areas of slow conduction can be anatomical or functional or a combination of both. Examples of reentry tachycardias are atrial flutter, atrial fibrillation and ventricular tachycardias originating from an infarct zone.

References

1. Braunwald's Heart Disease, 8th edition. Edited by Douglas P. Zipes. Philadelphia, Pa.: W.B. Saunders, 2008

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