By: John Riggins Jr MD, Taylor Douglas MD
Answer to Rhythm Nation June 2020…
You look at the ECG handed to you and interpret it.
ECG interpretation:
Rate: 144/min
Rhythm: sinus tachycardia; then regular, monomorphic wide-complex tachycardia
Axis: normal; then inferior
QTc: 582 ms
Now look at the transition from sinus tachycardia to wide-complex tachyarrhythmia:
Green bracket: QT interval
Red arrow: initiation of wide QRS tachyarrhythmia
Blue arrow: Ps suggesting AV dissociation (hallmark of monomorphic VT)
Left bundle branch pattern, precordial transition in V3
Back to our patient:
You place pads on the patient. He looks uncomfortable and complains of chest tightness. The monitor continues to show episodes of nonsustained VT.
His physical exam is as follows: HR 140/min BP 140/90 mm Hg RR 16/min T 98 SpO2 100% on RA FSG 92 mg/dl General: anxious, alert, following commands appropriately CVS: tachycardia, adequate pulses Lungs: tachypneic; clear and equal breath sounds; no wheezes, rales or rhonchi Abd: soft, non-distended, non-tender Extremities: warm, well-perfused, no pedal edema Skin: warm, well-perfused, no diaphoresis
Since his ECG shows a prolonged QTc, you give him 2 grams of magnesium sulfate and 2 grams of calcium gluconate. You give him 2 milligrams of midazolam for his anxiety. You also decide to load him with another 150 mg of amiodarone (for recurrent VT as per ACLS[1]).
(Note: Amiodarone is an antiarrhythmic agent that can further prolong the QTc in this case where the QTc is prolonged at baseline. Although rare, amiodarone can potentially promote further arrhythmias. [1])
Labs/imaging Potassium: 2.7 meq/L Troponin: <0.01ng/mL Ionized calcium: 4.33 mg/dL (low) Magnesium: 2.31 mg/dL
You replete his potassium with two doses of 20 meq K+ IV. After reviewing all the information so far, you realize that several factors might have triggered the episodes of VT.
The patient had hypokalemia perhaps due to taking a thiazide diuretic.[2] The patient had also been taking medications that could prolong the QT interval (i.e. hydroxyzine). Although his serum magnesium level was normal, there may have been intracellular hypomagnesemia.[3] The patient was very anxious and appeared tachycardic on the initial ECG which could have lead to a catecholaminergic-induced tachyarrhythmia.
You return to your medical school cardiac physiology days to review the cardiac action potential.
Quick Review of the Cardiac Action Potential
Figure 1: Cardiac Action Potential [4]
Phase 1- Transient opening K+ channels rapidly repolarize the cell
Phase 2- Calcium influx occurs through L type calcium channels, calcium-induced Ca2+ release occurs here and is vital for excitation-contraction coupling within the cell. As the efflux of potassium is balanced by the influx of calcium, a plateau phase is achieved here.
Phase 3- Calcium channels close; K+ channels open and allow for repolarization of the cell towards membrane potential; As membrane potential becomes more negative, Na+ channels begin to recover and prepare for next action potential
Phase 4- Baseline membrane resting potential is restored (this is dependent upon permeable open K+ channels; resting membrane potential = Ek)
You think about the possible mechanisms for VT: abnormal automaticity, re-entry, and triggered activity.[5,6]
You notice that the arrhythmia onset occurs during repolarization. This mechanism is known as triggered activity and also known as the “R on T” phenomenon.
Review of Triggered Activity
Triggered activity refers to an extrasystole that occurs as a result of a premature depolarization, leading to tachyarrhythmias. This usually occurs when the amplitude of an early or delayed afterdepolarization brings the cardiac membrane to its threshold potential and stimulates a spontaneous action potential at an inappropriate time in the cardiac cycle.
Early afterdepolarization (EAD) EAD is a premature secondary depolarization that disrupts the repolarization phases (phase 2 or 3) of the cardiac action potential. EADs usually occur in the Purkinje fibers and mid-myocardial M cells and usually result in the prolongation of the action potential duration.[7] Normally, the L-type calcium channels remain open during phase 2 in order to balance out the efflux of K. Recall that Phase 3 (repolarization) begins when these calcium channels close while potassium channels remain open. EADs occur when there is either an inward calcium current or interruption of outward potassium current in phase 3. EADs can also occur late in phase 3 by way of intracellular normal release of calcium from the sarcoplasmic reticulum; these have been independently identified as a mechanism of triggered activity.[8] Although the exact mechanism is poorly understood, bradycardia can lead to prolonged repolarization phase of the action potential and lengthen the QT interval. EAD amplitude is also rate-dependent and increases at a slow rate. Together, this is associated with an increased risk of tachyarrhythmias.[7] Factors that can influence the development of EADs include conditions that affect potassium, such as K+ channelopathies, K+ channel blockers, hypokalemic state, QT-prolonging medications, as well as ventricular hypertrophy and heart failure. EADs can lead to dysrhythmias including torsades de pointes and polymorphic ventricular tachycardia.
Delayed afterdepolarization (DAD) DAD is a premature secondary depolarization that occurs after full repolarization, during phase 4 of the action potential. DADs are usually a result of high levels of intracellular calcium that overwhelm the sarcoplasmic reticulum. The high levels of intracellular calcium can lead to spontaneous efflux of Ca2+ through the Na+/Ca2+ exchange channel causing a premature net depolarizing current due to the Na+ influx. Factors that can influence the development of DADs include catecholaminergic surge, cardiac glycoside toxicity (i.e. digoxin), ryanodine receptor mutations, and ischemic tissue that becomes partially depolarized due to excess presence of cations. DADs can lead to outflow tract (OT) tachyarrhythmias and catecholaminergic polymorphic VT.
Figure 2 : Diagram demonstrating triggered activity in the setting of EADs and DADs[9]
Underlying Etiologies of Triggered Activity and Specific Treatments
Long QTc states can be caused by genetic channelopathies or acquired states that involve electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) and QT-prolonging drugs. Many of the etiologies affecting cardiac calcium and potassium channels are important for repolarization. The prolongation of repolarization can lead to EADs through drug effects on hERG potassium channels in phase 3.
Acquired Long QTc states
Electrolyte abnormalities Treatment: IV magnesium and then potassium
Drugs (12) There are several classes of medications that can lead to an acquired long QT syndrome: Treatment: Discontinue culprit drug
Genetic Long QTc states
Long QTc syndrome There is a high risk for sudden cardiac death and TdP with this syndrome. The mutations leading to this syndrome result in a prolonged QTc interval on ECG. I.e. SCN5a gene mutation- results in defective sodium channel inactivation I.e. hERG gene mutation- defect in the delayed-rectifier potassium channel (results in decreased outward potassium current) Mutations in the cardiac sodium and potassium channels can lead to prolonged ventricular repolarization and can predispose the affected cardiac myocytes to EADs.[12] Treatment: Beta-blockers, AICD, Left cardiac sympathetic denervation, avoidance of QT-prolonging medications
1. Sodium channel mutations
2. Potassium channel mutations
Excess intracellular Ca2+
Excess intracellular Ca2+ DADs are triggered by various mechanisms that can increase the diastolic intracellular Ca2+ levels in the cardiac myocytes. Increased intracellular Ca2+ levels lead to increased Ca2+ mediated oscillations which can trigger new premature depolarizations. This mechanism can be seen in cardiac glycoside toxicity via inhibition of the Na/K pump which leads to the sarcoplasmic reticulum release of Ca2+.[7] Catecholamines can also cause increased levels of intracellular Ca2+ via an increase of the Na+/Ca2+ current and L-type calcium channels. Catecholamines stimulate beta-receptors that increase intracellular cAMP levels which are responsible for activating protein kinases. These activated protein kinases phosphorylate L-type calcium channel receptors which increase intracellular calcium levels. The opening of the L-type calcium channels allows calcium into the cell which stimulates calcium release from the sarcoplasmic reticulum. This phenomenon is called calcium-induced calcium release.[7,11] Treatment: Modified vagal maneuver, adenosine, beta-blockers, calcium channel blockers
So what factors could have triggered the patient’s arrhythmia?
1. Initiation of hydroxyzine (leading to a prolonged QTc interval which could have caused EADs, Phase 2 or 3 phenomena. Hydroxyzine could potentially inhibit the hERG potassium channels which would result in the prolongation of the QT (acquired prolonged QTc state). Several risk factors may increase the risk of arrhythmia including high plasma concentrations, high dosages (>100 mg/day), decreased renal clearance, and other concurrent, potentially QT-prolonging medications.[13]
2. Hypokalemia and hypomagnesemia related to thiazide diuretic use causing EADs, Phase 2 or 3 phenomenon, leading to TdP.[14,15]
3. Catecholaminergic surge due to anxiety-causing DADs, Phase 4 phenomenon, leading to an outflow tract VT.[16]
Case Discussion:
In the presented ECG, sinus tachycardia precedes the monomorphic, wide-complex tachyarrhythmia, suggesting that a catecholaminergic surge (possibly related to emotional stress) may have led to DAD that then “triggered” the VT. The case is consistent with a triggered, OT tachycardia, as the tachyarrhythmia starts with a PVC (DAD) that is similar to the ensuing complexes (as opposed to reentry where the initiating PVC is dissimilar) and there is an inferior axis and left bundle branch block pattern.[16] More detailed ECG analysis to predict the site (i.e. right versus left ventricle) from which an OT tachycardia originates is only important for the electrophysiologist to enable accurate mapping and ablation. Baseline echocardiography will also help to distinguish between etiologies of monomorphic VT, as OT tachycardia is the most common in patients without structural heart disease.[17] Although clinical recognition of monomorphic VT is typically not prioritized in the emergent setting, identifying OT tachycardia will assist in directing specific drug therapy. Outflow tract tachycardias are somewhat defined by their termination with adenosine, however, β-receptor blockers can also terminate OT tachycardias by antagonizing the arrhythmogenic effect of adrenergic stimulation.[18] In the case, intravenous amiodarone through its antiadrenergic effect may have been effective in suppressing the tachydysrhythmia. A cardioselective β-blocker that does not prolong repolarization would have been more appropriate given the concurrent, acquired prolonged QT syndrome.[19]
The identification of monomorphic VT is secondary to hemodynamic stabilization in the emergent setting, and typical guideline-directed management is likely to be effective for the majority of regular, wide-complex tachydysrhythmias. However, consideration of the underlying mechanism afterward may prompt the clinician to select the most appropriate treatment that may be required. As shown in the presented case, identifying an acquired long QT syndrome and suspecting triggered activity may alert the clinician to avoid the potentially deleterious effects of the generally recommended agents, procainamide and amiodarone, and instead administer suppressive magnesium and beta-receptor blocker infusions.
Case Conclusion:
The patient’s symptoms resolve and there are no further runs of VT or another malignant ventricular arrhythmia. You start the patient on an amiodarone drip and he is admitted to the intensive care unit. After the patient finishes his amiodarone drip, he is switched to PO amiodarone. An echo shows a normal EF (55-60%), normal RV systolic function, mild concentric LVH, and mildly increased left ventricular wall thickness. Upon EP study, VT is not inducible despite programmed ventricular stimulation and isoproterenol. This finding excludes re-entry as a mechanism for the tachydysrhythmia but triggered activity and abnormal automaticity remain possible mechanisms. [16] Given the morphology of the PVCs observed, the left ventricular outflow tract is mapped by the EP specialist. There is successful ablation of multiple PVC-initiating areas in the aorto-mitral continuity area, which is known to be an origin site of mitral annular VT. [18,20] The patient is started on apixaban for one month and switched to lisinopril and amlodipine for his hypertension. He is told to stop taking his thiazide diuretic and hydroxyzine. The ECG on the day of discharge shows QTc 464 ms. A zio-patch detects no VT episodes at subsequent follow-up eleven days later.
Take-Away Points:
- 1. Administer empiric magnesium in tachydysrhythmias associated with prolonged QTc intervals
- 2. Consider OT tachycardia due to triggered activity in patients presenting with wide-complex tachyarrhythmias in those patients who have no structural cardiac disease
- 3. Identification and classification of OT tachycardia can allow for selection of the most effective and appropriate treatment regimen – consider adenosine, cardioselective beta-blockers, or calcium channel blockers
Sources/Further Reading Edited by: Robby Allen PGY-3, Noah Berland PGY-4, Smruti Desai PGY-4
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