Cellular Basis for Cardiac ArrhythmiasBy the end of the self study you should be able to:
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Clinical Problem: A fifty year-old professor presents to the emergency room with chest palpitations. He has had diabetes and hypertension for the past ten years and has smoked one pack of cigarettes per day for the past twenty years. His BP is unstable and varies between 150/85 mm Hg and 80/50 mm Hg. The patient is a well-developed man who weighs 90 kg. He is 5’6” tall. His ECG (lead I) reveals a sinus rhythm with an elevated ST segment and inverted T wave. Every few seconds there are rapid runs of abnormal beats that are not preceded by a definable P wave, have a wide QRS complex of large amplitude, and an inverted T wave. While being monitored, the patient suddenly develops a sustained ventricular tachycardia, and his blood pressure drops to 60/40 mm Hg.
I. Cardiac Arrhythmias are a Leading Cause of Morbidity & Mortality in the U.S.A cardiac arrhythmia is defined as a disturbance in the rate, rhythm, or pattern with which the heart contracts. Cardiac arrhythmias are potentially dangerous because they can produce vascular stasis (e.g. atrial fibrillation), or reduce cardiac output to the point that adequate blood flow cannot be maintained to vital organs. Cardiac arrhythmias related to myocardial infarction and other forms of heart disease have been a leading cause of death in the US for decades. Approximately 1.5 million Americans per year suffer from a myocardial infarction (MI). Of this 1.5 million, roughly 500,000 per year die from an MI, ~350,000 prior to reaching a hospital. Cardiac arrhythmias are seen in ~80% of patients suffering from an acute MI, and are the leading cause of death in these patients. Cardiac arrhythmias are also commonly observed in patients undergoing general anesthesia (50%), or treatment with digitalis glycosides (25%). II. There are Two Basic Cellular Mechanisms for the Genesis of Cardiac ArrhythmiasCardiac arrhythmias result from abnormalities in the electrophysiological properties of the heart. A variety of pathological conditions can produce electrophysiological disturbances that are proarrhythmic. These include: acute ischemia (related to coronary artery disease or thrombosis), structural and/or biochemical abnormalities resulting from chronic heart disease, electrolyte or hormonal imbalances, and various drugs that either directly alter ion fluxes and/or the effects of the autonomic nervous system on the heart (e.g. local anesthetic drugs, antiarrhythmics & digoxin). Research over the past few decades has provided strong evidence for 2 basic mechanisms that underlie cardiac arrhythmias. These are:
In some cases there may also be disturbances in both impulse formation and conduction (e.g. regions having slow diastolic depolarizations may exhibit slow conduction due to partial inactivation of sodium channels). III. Disturbances in ConductionA. Cellular MechanismsThe most common cause for a disturbance in myocardial conduction is depolarization of the resting potential to voltages that produce partial inactivation of the Na current. Depolarized (“low”) resting potentials are a common characteristic of cells exposed to ischemia (lack of blood flow due to coronary occlusion) or severe hypoxia. Acute myocardial ischemia results in a complex series of biochemical changes in heart muscle, including intracellular acidosis (followed by extracellular acidosis) and a rapid rise in the local extracellular K concentration (Fig 1). The rise in tissue extracellular K ion concentration typically reaches levels of 10-20 mM within several minutes after the occlusion of a coronary artery, and is associated with the onset of ventricular arrhythmias.
Figure 1. Simultaneous changes in extracellular K and pH associated with the onset of acute myocardial ischemia. Ion selective electrodes have been used in several studies to record the changes in extracellular K and pH in myocardium before and after ligation of the left anterior descending coronary artery in pig, rat, rabbit, and guinea pigs, with similar results. Note that extracellular [K] rises to a plateau level of ~12-14 mM within a few minutes. The late rise after ~30 minutes represents irreversible cell death. The changes observed during the first 20-60 minutes are reversible upon reperfusion. An early and late phase of ventricular arrhythmias (including ventricular fibrillation) is typically observed in ~50% of animals studied. The rise in extracellular K concentration can be significantly reduced by pretreatment with K-ATP channel blockers (e.g. glibenclamide)(Wilde et al, 1990). The rise in K concentration produces conduction disturbances due to membrane depolarization & associated inactivation of Na channels. The fall in pH will inhibit gap junctions between cardiac myocytes, and thereby further contribute to slowing of cell-to-cell conduction. The major mechanism for the rapid rise in local extracellular [K ]o appears to be a fall in intracellular ATP, which results in both the opening of a large number of ATP-modulated K channels that are “inhibited” by physiological levels of intracellular ATP, but become “uninhibited” (open) as a result of the fall in intracellular ATP that is associated with ongoing cellular metabolism in the absence of blood flow. The fall in intracellular ATP also inhibits the ATP-dependent Na/K pump, which would attempt to correct or reduce the rise in extracellular [K ]o. The uncorrected efflux of K results in a local rise in interstitial [K ]o to 10-15 mM (Fig 1). As predicted by the Nernst equation (Fig 2), a rise in extracellular [K ] from 4 to 15 mM results in a rapid depolarization of the resting potential to approximately -60 mV because the resting membrane is selectively permeable to potassium.
Figure 2. The relationship between extracellular potassium concentration ([K ]o) and resting potential in a ventricular muscle cell. The selective permeability of the membrane to K results in a resting potential that closely approximates the Nernst potential for K ions (EK). The local tissue hyperkalemia that occurs during acute myocardial ischemia results in depolarization of the resting potential. As illustrated in Figure 3, this level of depolarization will inactivate a majority of the normally functional Na channels. This in turn will result in disturbances in cardiac conduction because the amplitude of the sodium current, which mediates conduction in muscle cells (i.e. all cardiac cells outside of the SA and AV nodes), is mostly inactivated at such depolarized resting potentials. Other causes for depolarization of the resting potential include systemic hyperkalemia resulting from Addison’s disease or kidney failure, and myocardial stretch, which may occur during atrial or ventricular dilatation associated with congestive heart failure. Stretch is believed to result in membrane depolarization via the opening of stretch-activated channels that have a high conductance for Na , Ca2 or Cl-, all of which have reversal potentials more positive than the normal resting potential.
B. Arrhythmias Caused by Simple Conduction BlockThe simplest mechanism by which a disturbance in conduction can lead to a cardiac arrhythmia is by a simple complete block of the forward movement of the action potential along some point between the SA node and the ventricular myocardium. The type of arrhythmia and morbidity of the arrhythmia resulting from conduction block depends upon its location. For example, if an infarction results in complete conduction block in the bundle of His, the most likely result would be either asystole (no ventricular contraction), or a bradycardia, should an ectopic pacemaker develop at a site distal to the conduction block (e.g. within the Purkinje system). If conduction block were to occur below the bifurcation of the left and right bundle branches of the Purkinje system, the end result would likely be a normal heart rate, but with a reduced cardiac output due to the loss of synchronization required to produce an optimal squeezing contraction of both ventricles. This arrhythmia would be easily diagnosed as a right or left bundle branch block from measurements of the surface electrocardiogram. C. Reentry - a Mechanism Underlying a Majority of Clinically Significant ArrhythmiasReentrant excitation or “reentry” (Fig 4) is an event that can occur under conditions of slow conduction &/or in regions having a “dispersion of refractoriness” (an increased heterogeneity of refractory periods in tissue, where ERP values differ greatly in neighboring areas). Evidence indicates that reentry is responsible for the large majority of clinically significant cardiac arrhythmias (Podrid, 2016). There are three known criteria for reentry to occur:
Reentry can produce multiple types of arrhythmias including:
A sustained tachycardia can significantly reduce cardiac output for a prolonged period of time, and therefore be life-threatening. They may also degenerate into fibrillation, where hundreds to thousands of micro-reentrant circuits are present, resulting in a complete loss of synchronization of stimulation, and a no cardiac output. There are multiple mechanisms for reentry that have been identified from cardiac mapping studies. Two examples of how reentry can occur are shown in Figures 4 and 5.
Figure 4. A mechanism of unidirectional block and reentry in an ischemic venticle. A) Normal conduction pattern. An impulse is conducted down two branches of a Purkinje fiber twig into the ventricular wall. These impulses collide and extinguish each other after exciting the muscle cells to contract. B) The onset of endocardial ischemia following occlusion of a coronary artery by vasospasm or thromboembolism results in decrementally slower conduction along the damaged pathway until the strength of the impulse is too weak to excite the tissue ahead of it, resulting in conduction block in the normal direction (unidirectional block). C) Meanwhile, conduction down an undamaged pathway results in excitation of a large number of undamaged cells in the ventricular wall (constituting a large electrical stimulus) on the opposite side of the damaged region. This large electrical stimulus is strong enough to slowly conduct through the damaged region, summate, and elicit an action potential in the depressed region that conducts upward in a retrograde direction (which may occur primarily through the extracellular space, similar to saltatory conduction in nerve). This retrograde impulse excites tissue it had previously passed through resulting in a repetitive circular pattern of excitation. D) as long as the impulse does not run into cells within their effective refractory period, the reentrant circuit can function as an ectopic ventricular pacemaker. If rapid enough the circuit can produce a sustained ventricular tachycardia. In contrast, if a wavefront conducted from the SA node happens to invade a portion of the loop and makes it refractory, the reentrant circuit will be broken, and only a non-sustained ventricular tachycardia, or occasional premature ventricular complexes (PVCs) may occur. (Modified from BG Katzung's Basic and Clinical Pharmacology). Video on Reentry
ECG Interpretation of PVCs and Sustained Ventricular Tachycardia
Figure 5. Model for reentry in the AV Node (AVN). The AVN contains parallel pathways having different ERP's and conduction rates. The difference in pathway properties may become enhanced as a function of age or pathology. Panel A: During normal sinus rhythm the beat conducted down the fast pathway enters in the final common pathway in the bundle of His. Conduction through the slow pathway becomes blocked near the bundle of His when the impluse runs into the refractory period of the impulse previously conducted along the fast pathway. Panel B: A critically timed premature atrial beat finds the fast pathway still refractory from a previously conducted beat, but is able to conduct along the slow pathway that has a relatively short ERP. By the time the wavefront eventually reaches the distal end of the AV node, the fast pathway has recovered its excitability, and retrograde conduction occurs along the fast pathway back to the atrium. Panel C: A reentrant circuit is established, giving rise to a repetitive cycle of stimulation of both the atria and ventricles. Note that both the conduction time and ERP of the AV node are modulated by both branches of the autonomic nervous system. Panel D: AV node reentry produces a tachycardia with a narrow QRS because it utilizes the normal rapidly-conducting His-Purkinje fiber network to stimulate the ventricles. In some cases an inverted P wave may be observed following the QRS, but its presence is often hidden underneath the large QRS complex. As illustrated, a rapid rate may induce some ST segment depression if there is some degree of coronary occlusion, and oxygen demand exceeds oxygen delivery (angina pectoris). The ECG Lead II shows an example of SupraVentricular Tachycardia (179 beats/min) obtained from the wikipedia commons. This figure was adapted from Knight (2009). Dispersion of Refractoriness as a Cause of ReentryA mechanism contributing to the development of reentry in both the atrium & ventricle is a dispersion of refractoriness. This situation is known to occur under certain disease states such as dilated cardiomyopathy, myocardial infarction, acute atrial dilation associated with heart failure, or exposure to ion channel blockers that can produce unequal effects in different cells. Under such conditions, marked differences in cellular ERP’s in different regions, combined with multiple conduction pathways (along the direction of fiber bundles) can lead to the development of reentrant excitation, similar to what occurs for reentry in the AV node (Figure 5). This can result in the development of ectopic beats, a sustained tachycardia, or fibrillation. Drugs or conditions that increase the dispersion of refractoriness are “proarrhythmic”. D. Conduction Block in the AV NodeBlock of conduction through the atrioventricular node (AV block) can occur as the result of heart disease or abnormal high levels of vagal tone. Recall that vagal stimulation increases the strength of repolarizing (K) currents, and reduces the strength of the L-type Ca current in this region. The net effect of vagal stimulation will be to increase the PR interval, and increase the ERP in the AV node. AV block can present as either an abnormal slowing of conduction (abnormally long PR interval), or failure of impulse conduction (where every P wave is not followed by an associated QRS complex). AV block is classified as being of first, second or third degree: AV Conduction Block Subtypes:
IV. Disturbances in AutomaticityA. Enhanced Normal AutomaticityAn increase in the automaticity of any site outside of the SA node can result in the appearance of an ectopic pacemaker, and establish an abnormal heart rate (tachycardia) or rhythm (Figure 6). Such rhythms may occur under conditions that enhance the rate of phase 4 depolarization outside of the SAN. Three possible mechanisms for enhanced ectopic pacemaker automaticity include hypokalemia (which may reduce the background K conductance in Purkinje fibers more than in the SAN), a localized supersensitivity to catecholamines following an ischemic lesion, and myocardial stretch.
Figure 7. Development of an ectopic pacemaker due to enhanced normal automaticity. Following a myocardial infarction (inset), sympathetic innervation to the endocardial surface can be disrupted. This can result in a form of “denervation supersensitivity” resulting from increased expression of β1-receptors, and/or reduction of neuronal catecholamine uptake as a termination mechanism for circulating catecholamines. Purkinje fibers may also become stretched due to abnormal wall motion. Hypokalemia associated with diuretic therapy for CHF can also enhance automaticity of ectopic pacemakers. Whenever the cycle length of an ectopic pacemaker becomes shorter than the normal sinus cycle length, automaticity will become expressed. B. Two Causes of Abnormal Automaticity or Triggered Activity (EADs & DADs)The term “triggered activity” refers to a situation where heart tissue is stimulated once, but results in the production of more than one conducted beats. The two most common forms of triggered activity are Early After-depolarization's (EAD's) and Delayed Afterdepolarization's (DAD's). These are also sometimes called forms of “abnormal” automaticity because they reflect mechanisms for producing extra heart beats that are not present in a normal heart. EADs, Drugs, Dispersion of Repolarization & Torsade (TdP)EADs are one of two mechanisms known to produce a type of multifocal ventricular tachycardia called Torsade de Pointes (TdP) (French for “twisting of the points”). (Note: some scientists have spelled the arrhythmia as “Torsades de pointes”, but “Torsade” is the spelling now preferred amongst most American scientists). In this ventricular tachycardia the amplitude of the QRS changes continuously in a sinusoidal-like pattern, with the amplitude of the QRS appearing to “twist” around the isoelectric line (Fig 8).
Figure 8. Lead II ECG showing Torsade de pointes prior to the patient being shocked by an implantable cardioverter-defibrillator which converts the patient back to a normal cardiac rhythm. These arrhythmias are most likely to occur in the presence of a drug that slows the rate of repolarization combined with hypokalemia, hypomagnesemia & bradycardia (or a pause). Reproduced from wikipedia (http://en./wiki/Torsades_de_pointes). The development of Torsade is associated with conditions that produce a prolonged QT, and both can be produced by over a hundred drugs that block IKr (the rapid component of repolarization current in ventricular myocytes & Purkinje fibers)(Ayad et al, 2010; Credible Meds). This includes most drugs that fall within the following drug classes:
The classic observation of “quinidine syncope” (fainting during initiation of drug therapy) is known to be associated with this arrhythmia. For a more comprehensive and up-to-date list of drugs known to cause QT prolongation, visit the Credible Meds online database. TdP is potentially life-threatening and is treated as a medical emergency. For this reason patients who are initialized on most Class Ia or Class III drugs are typically hospitalized for the first day or two when initializing treatment (when this event is most likely to occur). EAD’s are secondary depolarizations that occur before phase 3 repolarization is complete (Fig 9). EAD's are increased in number and frequency by slowing of the heart rate (bradycardia), hypokalemia and hypomagnesemia. These are also the same conditions associated with a higher incidence of TdP in a clinical setting (Table 1).
Figure 9. Mechanism of EAD formation & initiation of Torsade de pointes. Drug-induced blockade of the HERG channel reduces IKr amplitude, which in turn reduces net outward current during the plateau, and prolongation of the ventricular APD and QT interval in the ECG (green). If net inward currents during phase 3 become larger than outward currents, this can form an EAD (blue). These changes are typically heterogeneous and can create a substrate for producing triggered beats in multiple locations, resulting in a multifocal ventricular tachycardia. (Adapted from Kannankeril et al, 2010). A Second Mechanism for TdP - Dispersion of RepolarizationHeterogeneity in action potential duration results in a myocardium that is more vulnerable to reentrant excitation, a second likely cause of TdP. As illustrated in Figure 10, ventricular cells in the middle of the ventricular wall (M cells) have an action potential duration that prolongs disproportionately compared to other cell types in response to a slowing of heart rate and/or the presence of drugs that prolong the APD (Anzelevitch & Burashnikov, 2011). M cells have also been found to be sensitized to the effects of APD-prolonging drugs (e.g. blockers of IKr) due to a larger expression of both an inward plateau Na current and a Na-Ca exchange current, as well as a smaller slow potassium current (IKs) compared to other ventricular myocytes (Anzelevitch & Burashnikov, 2011). Hypokalemia would also increase the effect of APD-prolonging drugs (see Fig 10 in Introduction to Antiarrhythmics).
Figure 10. A proposed mechanism for Torsade de pointes. Slowing of the heart rate in the presence of an APD-prolonging drug can enhance the normal transmural dispersion of repolarization that normally exists between mid-myocardial cells (M cells) and epicardial or endocardial cells (Antzelevitch & Fish, 2001). Cells from the mid-wall region have a longer APD compared to endocardial or epicardial cells, and greater sensitivity to the effects of APD-prolonging drugs. Under the combination of such drugs and slowing of the heart rate, the M cell APD widens disproportionately, resulting in an abnormally large dispersion of APD values between regions (as indicated by the width between the two vertical lines). A dispersion of repolarization can induce a spread of current from the depolarized M cell region to the epicardial region that has regained its excitability (Antzelevitch & Burashnikov, 2011). The source for depolarization can be either the L-type Ca current, Na-Ca exchange current (I-NCX), or a late plateau Na current (indicated by the red arrow). Heterogeneous changes in APD dispersion can produce multiple sites of re-excitation and induction of a multifocal ventricular tachycardia or TdP. (Figure modified after Roden, 2004). Risk Factors Associated with Torsade de pointesAs summarized in Table 1, there are a number of risk factors that increase the incidence of Torsade de pointes. The explanation for the increased risk associated with these conditions is summarized below.
* For a more extensive list of drugs causing TdP see the Torsade ECG wiki section DADs & Intracellular Calcium OverloadDAD's are secondary depolarizations that occur after repolarization is fully complete, during phase 4. DAD's are known to occur under conditions of intracellular calcium overload induced by chronic heart disease, exposure to excessive levels of digoxin or catecholamines, or by hypercalcemia, DAD's are also increased in amplitude by increases in heart rate (opposite to the behavior of EAD's).
Figure 12. The cellular mechanism underlying the formation of DADs. Excessive inhibition of the Na/K pump by digoxin, or high catecholamine levels can result in a situation of intracellular calcium overload. Under these conditions, most of the increase in intracellular calcium will be pumped into the sarcoplasmic reticulum. However, when calcium levels within the SR become too large, a spontaneous release of Ca from the SR occurs (perhaps as a self-protection mechanism). This results in activation of the Na/Ca exchange current. Efflux of one calcium ion in exchange for 3 sodium ions results in membrane depolarization during the diastolic interval. This is observed as a Delayed After Depolarization. DAD amplitude can reach threshold for producing an action potential if the depolarizing current is strong enough. High heart rates increase Ca uptake, resulting in a larger release of SR calcium, and an increased DAD amplitude. Hence the incidence and magnitude of DADs is enhanced at high heart rates (opposite to EADs, which are enhanced by slow heart rates). Interpreting Common Arrhythmias Using the ECGTo learn how to identify the following arrhythmias using the ECG, jump to the following bookmarks on the ECG companion wiki page: Ready to Take a Quiz?For more Information, continue to ECG Interpretation of Arrhythmias References:
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