Physiology, Cardiac Repolarization Dispersion and Reserve

Article Author:
Xingyu Wei
Article Editor:
John Richards
Updated:
1/1/2019 7:56:56 PM
PubMed Link:
Physiology, Cardiac Repolarization Dispersion and Reserve

Introduction

Action potentials determine the regular rhythm of heartbeats. These action potentials propagate from the sino-atrial (SA) node of the heart and travel downward through the heart. There are two main classifications of cells in the heart to be considered: cardiomyocytes and pacemaker cells. Each of these individual cell types has its own pattern of action potentials that divide into several distinct phases. A shared, characteristic common to both cell type's patterns is the third phase, designated as repolarization. Repolarization defines the resetting of the electrochemical gradients of the cell to prepare for a new action potential. The time required for repolarization to occur can vary. Abnormal changes in the duration of repolarization, termed dispersion, can be a sign of pathology, especially when the heart isn’t able to perfuse the body due to disturbances in cardiac output.

Cellular

Two major categories of cells to consider include cardiomyocytes and pacemaker cells. The pacemaker cells are primarily located in the SA and atrioventricular (AV) nodes, with some cells in the Bundle of His of the heart as well. Pacemaker cells possess a characteristic known as automaticity and initiate action potentials on their own. In the normal physiologic state, the pacemaker cells of the SA node determine the heart rate.[1] The cardiomyocytes then conduct the currents initiated by the pacemaker cells.

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, specifically those of the pacemaker cells, possess automaticity.

Function

Cardiac action potentials and their associated repolarizations are vital in stimulating and maintaining the regular contractions of the heart, which is essential in maintaining perfusion to the vital organs of the body.

Mechanism

The cardiac cells can only propagate action potentials because of an electrochemical potential across cellular membranes. Ions, mainly sodium (Na+), potassium (K+), and calcium (Ca2+), are present in different concentrations in cells vs. their surrounding environments.[2] Voltage-sensitive ion channels are available on cellular membranes to facilitate movement of these ions. The tendency of ions to move down their chemical gradient and the tendency for charges to balance out across membranes contributes to a net electrochemical potential that varies with the status of ion channels. The term used for these variations in status is a phase. Cycles of these phases initiate when cells membranes reach a threshold potential. Cells can reach threshold potential through stimulus by adjacent cells, or, if they are pacemaker cells, possess automaticity.

Characteristically, a pacemaker action potential has only three phases designated phases zero, three, and four. Phase zero is where there is an influx of Ca2+ ions through the opening of voltage-gated Ca2+ channels. This influx results in a small upstroke in membrane potential. Phases one and two are not present in pacemaker cells. As a result, phase zero is followed by phase three in pacemaker cells. Phase three is repolarization, involving the closing of Ca2+ channels, blocking the flow of Ca2+ ions. Voltage-gated K+ channels then open allowing for efflux of K+ ions. This efflux contributes to a rapid decrease to baseline membrane potential. Phase four is characterized by a gradual depolarization to threshold again via activation of Na+/K+ channels. Upon reaching the threshold, the stimulation for the Ca2+ channels responsible for phase zero occurs again. The slope of phase four determines heart rate. This phase accounts for the automaticity of pacemaker cells.

In contrast to pacemaker cells, the myocardiocyte action potential is characterized by five phases, zero through four. During phase zero, voltage-gated Na+ channels open due to local extracellular changes, resulting in a rapid influx of Na+ ions. Afterward, phase one characteristically is where inactivation of the previous voltage-gated Na+ channels takes place along with the opening of voltage-gated K+ channels. A slight drop in the membrane electrochemical potential results in the initiation of phase two. During phase two, Ca2+ influx occurs through an opening of voltage-gated Ca2+ channels. This calcium influx balances the K+ efflux of the previous phase creating a plateau in electrochemical potential. 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. Repolarization follows in phase three, involving K+ influx through the opening of voltage-gated slow K+ channels and closing of the voltage-gated Ca2+ channels. Finally, phase four involves a return to the baseline electrochemical gradient until the next stimulus.[3]

Related Testing

Electrocardiograms are the most readily accessible method of analyzing the overall electrical activity of the heart. The QRS complex masks the atrial repolarization, but the T wave allows visualization of ventricular repolarization. The T wave is a component of the QT interval. Changes in this interval can signify pathology, such 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 electric activity of the heart. 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 of time 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 the ion channels of the heart that affect the duration of opening and closing. However, outside factors are the more common effectors of repolarization abnormalities. Many medications can stimulate long QT syndrome (also termed QT prolongation), including antiarrhythmics such as amiodarone, specific antibiotics such as fluoroquinolones, and antipsychotics.[4] Many of these medications act by blocking the opening of K+ channels through phases one and two of the cardiomyocyte action potentials.[5] Differences in refractory periods among cardiac cells then lead to dysrhythmias and possible cardiac demise.

Clinical Significance

Evaluation of repolarization through analysis of electrical activity is a useful clinical tool to assess cardiac function. Variations in repolarization can be deadly and are known to contribute to the development of potentially lethal cardiac rhythms.[6]


References

[1] Ambesh P,Kapoor A, Biological pacemakers: Concepts and techniques. The National medical journal of India. 2017 Nov-Dec     [PubMed PMID: 30117443]
[2] Nerbonne JM,Kass RS, Molecular physiology of cardiac repolarization. Physiological reviews. 2005 Oct     [PubMed PMID: 16183911]
[3] Amanfu RK,Saucerman JJ, Cardiac models in drug discovery and development: a review. Critical reviews in biomedical engineering. 2011     [PubMed PMID: 22196160]
[4] Al-Akchar M,Siddique MS, Rhythm, QT Prolongation null. 2018 Jan     [PubMed PMID: 28722890]
[5] Chen L,Sampson KJ,Kass RS, Cardiac Delayed Rectifier Potassium Channels in Health and Disease. Cardiac electrophysiology clinics. 2016 Jun     [PubMed PMID: 27261823]
[6] Antzelevitch C, Cardiac repolarization. The long and short of it. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2005 Sep     [PubMed PMID: 16102498]