Introduction

The heart carries out the vital function of pumping oxygenated blood around the body, and it must contract and relax in a coordinated fashion. This contraction process is preceded by electrical excitation, which under normal conditions is initiated by the sinoatrial node as an action potential.[1] An action potential is the rapid sequence of changes in the membrane potential that results in an electrical impulse. This electrical impulse then travels down through the heart's electrical conduction system to cause myocardial contraction, followed by relaxation in an orderly fashion.[2] There are 2 main cell types in the heart to consider: cardiomyocytes and pacemaker cells. Each of these cell types has a distinct pattern of action potentials, divided into several phases.[3] A shared characteristic common to both cell types is the third phase, designated as repolarization. Repolarization refers to the resetting of the cell's electrochemical gradients to prepare for a new action potential. The action potential (AP) of the working myocardium lasts for several hundred milliseconds, with the delayed repolarization securing a refractory state for new excitations throughout the entire contraction phase. Delayed repolarization in the human myocardium relies mainly on the vast diversity of cardiac potassium channels, but also on a particular redundancy in the heart known as the "repolarization reserve," in which 1 current takes over if another fails.[1] The time required for repolarization can vary among cardiac myocytes. This heterogeneity, termed dispersion, can be a sign of pathology, especially when cardiac output is impaired.[4]

Cellular Level

The adult mammalian heart comprises many cell types. These include cardiomyocytes, fibroblasts, endothelial cells, and perivascular cells. Of these, the cardiomyocytes occupy a significant volume of the heart.[5] Functionally, these cardiomyocytes can, in turn, be differentiated into general cardiomyocytes and Pacemaker cells. Also, to understand transmural dispersion of repolarization, cardiomyocytes are classified as epicardial (near the surface), M cells, and endocardial (near the ventricular cavity).

Pacemaker cells are highly specialized myocardial cells with an intrinsic ability to depolarize rhythmically and to initiate action potentials.[6] The pacemaker cells are located primarily in the sinoatrial and atrioventricular nodes, with some cells also in the bundle of His and Purkinje fibers. Pacemaker cells possess a characteristic known as automaticity, which enables them to initiate action potentials on their own.[7] This action potential is conducted down the cardiac conduction system as an electrical impulse and also between 1 cardiomyocyte and another through gap junctions. This conduction helps the heart to contract in a synchronized fashion

Conduction system: The sinoatrial node is located superiorly in the right atrium near the opening of the superior vena cava. From the sinoatrial node, the depolarization current spreads through the right atrium via gap junctions and also passes to the left atrium via Bachmann's bundle. From the sinoatrial node, the impulse passes to the atrioventricular node through the internodal fibers. The atrioventricular node's location is also in the right atrium, but inferiorly at the interatrial septum. The atria and the ventricles are isolated electrically, and the electrical impulses can only pass from the atria to the ventricles via the atrioventricular node. Atrioventricular node conduction is characterized by a conduction delay, which ensures that ventricular contraction occurs after the atria empty their blood into the ventricles. From the atrioventricular node, a depolarization wave passes through the bundle of His, located in the interventricular septum. From here, the action potential passes via the 2 bundle branches and the Purkinje fibers to the ventricular cardiomyocytes.[2][6]

Organ Systems Involved

In contrast to the cardiac system, action potentials of the nervous system propagate through similar mechanisms and can elicit contractions of skeletal muscles. However, cardiac action potentials, particularly those of pacemaker cells, exhibit automaticity.

Function

Cardiac action potentials and their associated repolarizations are vital for stimulating and maintaining the heart's regular contractions, which are essential for perfusion of the body's vital organs.

Mechanism

Cardiac cells can propagate action potentials only because of an electrochemical potential gradient across cellular membranes. Ions, mainly sodium (Na⁺), potassium (K⁺), and calcium (Ca²⁺), are present in different concentrations inside the cells vs their surrounding environments. Sodium and calcium concentrations are more extracellular, while potassium is present at a higher concentration inside the cell.[8] Voltage-sensitive ion channels are available on cellular membranes to facilitate the movement of these ions. The tendency of ions to move down their chemical gradient and the tendency for charges to balance out across membranes contribute to a net electrochemical potential that varies with the status of ion channels. The term used for these variations in status is "phase". Cycles of these phases initiate when the cell membranes reach a threshold potential. This threshold potential differs between cardiomyocytes and pacemaker cells. Cells can reach threshold potential in response to stimuli from adjacent cells or, if they are pacemaker cells, possess automaticity.

Pacemaker Cells

Characteristically, a pacemaker action potential has only 3 phases, designated phases 0, 3, and 4.

• Phase 0 is the depolarization phase. This phase starts when the membrane potential reaches -40 mV, the threshold potential for pacemaker cells. Voltage-gated Ca²⁺ channels open upon reaching threshold, causing Ca²⁺ influx. This influx of cations results in an upstroke in the membrane potential from -40 mV to +10 mV. Because calcium channels are slow channels (compared to sodium channels), the upstroke is not as steep as that of cardiomyocytes.
• Phases 1 and 2 are not present in pacemaker cells. As a result, phase zero is followed by phase 3.
• Phase 3 is repolarization, involving the closing of Ca²⁺ channels, blocking the flow of Ca²⁺ ions. Voltage-gated K⁺ channels open, allowing for efflux of K+ ions. This efflux of cations contributes to a rapid decrease in membrane potential from +10 mV to -60 mV.
• Phase 4, a phase of gradual depolarization, is unique to the pacemaker cells. This gradual depolarization mainly occurs via a depolarization current or pacemaker current (If). Pacemaker current arises from the slow influx of Na⁺ ions through the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel).[9] This pacemaker current causes the membrane potential to change from -60 mV to reach the threshold potential of -40 mV. The slope of phase 4 determines heart rate and differs among pacemaker cells in different regions. Sinoatrial node pacemaker cells depolarize at a rate of 60 to 100 per minute, while the atrioventricular node at 40 to 60 per minute. The pacemaker with the fastest depolarization rate takes over as the primary pacemaker. In healthy individuals, this is the sinoatrial node. 

Cardiomyocyte

The myocardiocyte action potential differs from that of pacemaker cells and has 5 phases: 0 through 4. Phase 0 is the phase of depolarization; Phases 1 through 3 are the phases during which repolarization occurs; Phase 4 is the resting phase with no spontaneous depolarization.

• During phase zero, the phase of rapid depolarization, voltage-gated Na⁺ channels open, resulting in a rapid influx of Na⁺ ions. Because of the influx of the cation, the membrane potential changes from -70 mV to +50 mV. Voltage-gated sodium channels are faster than calcium channels; hence, we get a steep upstroke of the action potential.
• In phase 1, there is inactivation of the previously opened voltage-gated Na⁺ channels along with the activation of the transient outward potassium current (Ito). A slight drop in the membrane electrochemical potential initiates phase 2.
• During phase 2, or the plateau phase, Ca²⁺ influx occurs through an opening of voltage-gated L-type Ca²⁺ channels. This calcium influx balances the K⁺ efflux, creating a plateau at an electrochemical potential of approximately +50 mV. This plateau is a component of the Effective refractory period, during which the influx of Ca²⁺ also stimulates the calcium release from the sarcoplasmic reticulum, initiating muscle contraction. No initiation of new action potentials can occur during this period (Absolute Refractory Period)
• Repolarization follows in phase 3, involving K⁺ efflux through the opening of rapid delayed rectifier K⁺ channels and closing of the voltage-gated Ca²⁺ channels.[10][1]

Dispersion of Repolarization

• In the heart, the wave of depolarization current originates in the sinoatrial node under normal conditions and reaches the ventricular myocardium via the conduction system. Anatomically, the ventricular depolarization travels from apex to base and from endocardium to epicardium. The wave of repolarization moves in the opposite direction from the epicardium to the endocardium. Thus, the action potential duration is not the same across the thickness of the ventricular wall, with cardiomyocytes near the epicardium depolarizing last and repolarizing first. Time taken by M cells for repolarization is the longest, while that of endocardial cells is intermediate between epicardial and M cells. This difference is due to intrinsic differences in the activity of the various ion channels among the 3 cell types. Hence, there is transmural dispersion during repolarization. Thus, dispersion of repolarization is defined as a difference in repolarization time (activation time plus action potential duration).[11]
• Transmural dispersion of repolarization is clinically significant because it can lead to arrhythmias by forming re-entry circuits. These re-entry circuits are an essential factor in maintaining Torsades de pointes.

Repolarization Reserve

Roden coined the concept of repolarization reserve to address the difficulty of predicting the development of Torsades de pointes with drugs that prolong repolarization in different individuals. Repolarization reserve means that under normal physiologic conditions, there is a significant reserve in outward repolarization current. Thus, repolarization is not controlled by a single ion channel, and there is considerable overlap and redundancy in the opening and closing of different ion channels. Thus, a drug that blocks 1 channel, for example, IKs, does not cause failure of depolarization or marked QT prolongation unless there is concurrent blockade of another channel; this shows that when 1 channel fails, other channels take over.

Some of the crucial currents that affect repolarization reserve are: 

1. Persistent inward sodium current (INa): Normally, after phase 0, the current through the sodium channel decreases and does not contribute significantly to cardiac action potential duration. However, it does not entirely cease; a small inward current persists during the plateau phase. There is an increase in this inward current in certain conditions like heart failure and long QT syndrome Type 3 (LQTS 3). As a result, more potassium should move out of the cell to balance this and promote repolarization, thereby decreasing the outward repolarizing current reserve. INa is inherently more prominent in the M cells than in the epicardial and endocardial cells
2. Rapid delayed rectifier outward potassium current (IKr): This channel activates rapidly on depolarization, but its inactivation precedes depolarization-mediated activation. Then, around the end of phase 2, it opens rapidly as the membrane potential becomes more negative, then inactivates slowly. This current is the primary repolarizing current, which contributes to phase 3 of the action potential. A drug that only blocks this channel, when given in higher concentrations, can cause QT prolongation by itself (Class 3 anti-arrhythmic). It shows that this is the primary current responsible for maintaining the repolarization reserve. This channel's activity is affected under many conditions, including long QT syndrome type 2. Serum potassium levels also affect this current. When serum potassium levels decrease, more of these channels are internalized, thereby decreasing the strength of the current. Thus, hypokalemia causes QT interval prolongation, whereas hyperkalemia shortens it. Also, due to the specific kinetics of this channel, when any cause prolongs the action potential duration, the activity of IKr decreases, thereby forming a positive loop and hence causing more QT prolongation
3. Slow delayed rectifier outward potassium current (IKs): This channel activates slowly during phase 2 and deactivates rapidly. Under normal physiologic conditions, IKs do not significantly contribute to Phase 3 of repolarization. However, under conditions such as increased sympathetic stimulation or IKr blockade, the current passing through this channel increases. Thus, IKs provide a repolarization reserve or a physiologic check to prevent excess action potential duration lengthening and QT prolongation. This current is defective in long QT syndrome type 1. This current is more active in the epicardial and endocardial cells and intrinsically weak in the M cells. Thus, any physiologic or pathologic conditions that increase or decrease this current affect cells in these regions differently, thereby increasing the transmural dispersion of repolarization.
4. Inward rectifier potassium current (IK1): This channel is open during diastole. Its primary function as repolarization reserve is to prevent spontaneous delayed afterdepolarization during Phase 4 of the action potential.[12]

Other channels, such as the Sodium Potassium ATPase and L-type Ca channel, also affect the repolarization reserve. Thus, the degree of QT prolongation when we block a particular potassium channel with either a cardiac or a non-cardiac drug depends on which channel we block and on the functioning of other channels that affect the repolarization reserve.

Related Testing

Electrocardiograms are the most readily available method for analyzing the heart's overall electrical activity. P wave corresponds to atrial depolarization, and the QRS complex corresponds to ventricular depolarization (Phase 0). The QRS complex masks atrial repolarization, but the T wave allows visualization of ventricular repolarization. The peak of the T wave corresponds to the repolarization of the shortest epicardial action potential, while the end of the T wave corresponds to the repolarization of the M cell with the most prolonged action potential duration.[11]

The QT interval is the time from the start of the QRS wave to the end of the T wave. It represents 1 cycle of ventricular electrical activity from the start of ventricular depolarization to the end of ventricular repolarization. Changes in this interval can signify pathologies, such as long QT and short QT syndromes. Further testing modalities include electrophysiology tests, which involve trained personnel inserting electrodes into a patient's body through a catheter, manipulating the electrodes with magnets, and measuring the heart's electrical activity. Other methods of testing to consider would include Holter monitors, event monitors, and implantable loop recorders. These are all different means of monitoring heart rhythm over extended periods in the ambulatory setting.

Pathophysiology

Repolarization abnormalities can occur due to a variety of reasons. One of the most common abnormalities is long QT syndrome. Long QT syndrome is often due to congenital defects in cardiac ion channels that affect their opening and closing durations.

• Long QT syndrome type 1: Here, there is a defect in the slow delayed rectifier potassium current (IKs). On ECG, this presents as a prolonged QT interval with a broad-based T wave. As discussed earlier, because IKs activity differs across cells, this syndrome also increases transmural repolarization dispersion. Beta-adrenergic stimulation, which increases IKs and thus results in a greater decrease in action potential duration in epicardial and endocardial cells than in M cells, mimics LQTS 1.[11]
• Long QT syndrome type 2: Here, there is a defect in the rapid delayed rectifier potassium channel, which causes significant slowing of repolarization in all 3 cell types. On ECG, there is a prolonged QT interval and low-amplitude T waves with a bifurcated appearance. Class 3 antiarrhythmic, such as sotalol, which blocks IKr, mimics LQTS2. There is a more significant prolongation of the action potential duration of the M cells than the epicardial and endocardial cells. Thus, here as well, there is increased transmural dispersion of repolarization.[11]
• Long QT syndrome type 3 – here, there is an increase in the current passing through late sodium current (INa). ECG shows QT interval prolongation and widened T waves. Here, as this current is more active in M cells than in epicardial and endocardial cells, it can increase transmural dispersion of repolarization. Thus, the proarrhythmic effects of long QT syndromes are due to a decrease in repolarization reserve and an increase in the transmural dispersion of repolarization.[11]

Outside factors are the more common effectors of repolarization abnormalities. Many medications can cause QT prolongation, including anti-arrhythmics such as amiodarone, specific antibiotics such as fluoroquinolones, and antipsychotics.[13] Many of these medications act by blocking the IKr current.[14] Differences in refractory periods among cardiac cells then lead to dysrhythmias and possible cardiac demise.

Clinical Significance

Cardiac arrhythmias result from functional and structural defects at the molecular, cellular, tissue, and organism levels.[15] These defects cause membrane potential instability, which in turn leads to abnormal excitations (eg, extrasystoles) and abnormal impulse conduction. Delayed afterdepolarizations (DAD) are abnormal excitations occurring during the phase 4 resting potential or the plateau phase, while those occurring during the early part of Phase 3 repolarization are referred to as early afterdepolarizations (EAD).

EAD occurs due to critical prolongation of action potential duration (APD). This prolonged APD may cause the inactivated Na/Ca channel to reopen, providing extra current for depolarization. Thus, EAD may trigger torsades de pointes (TdP), a polymorphic ventricular tachycardia that can, in turn, progress to ventricular fibrillation.[1] DAD is due to abnormal calcium handling. Here, increased intracellular calcium, as occurs after myocardial infarction, increases the activity of Na/Ca exchanger. The net effect of this channel is 1 inward depolarizing current, which may initiate an extrasystole on reaching threshold potential.

While earlier noted, even though the initiation of torsades de pointes (TdP) is due to EAD, subsequent TdP occurs due to re-entry phenomenon. Usually, an impulse spreads in all directions, and tissue behind the depolarization front is refractory. However, when the action potential has to pass around an obstacle, either anatomical (eg, scar tissue) or functional (a cardiomyocyte in its absolute refractory period), it can cause re-entry and re-excitation of origin tissue. Thus, tissue heterogeneity in refractoriness is a potent enhancer of re-entry arrhythmia. Hence, large transmural dispersion of repolarization, which increases this heterogeneity, increases the risk of re-entry arrhythmia.[1][11] Thus, evaluating repolarization through analysis of electrical activity is a useful clinical tool for assessing cardiac function, as variations in repolarization can contribute to the development of potentially lethal cardiac rhythms.[16]

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Disclosure: Xingyu Wei declares no relevant financial relationships with ineligible companies.

Disclosure: Sandesh Yohannan declares no relevant financial relationships with ineligible companies.

Disclosure: John Richards declares no relevant financial relationships with ineligible companies.