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0Journal of Arrhythmia I (I
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Journal of Arrhythmia
journal homepage: www.elsevier.com/locate/joa
Review
Management of electrical storm: The mechanism matters
Mitsunori Maruyama, MD, PhD*
Cardiovascular Center, Chiba-Hokusoh Hospital, Nippon Medical School, 1715 Kamakari, Inzai-shi, Chiba 270-1694, Japan ARTICLE INFO ABSTRACT
Article history: An electrical storm is a life-threatening syndrome that is characterized by clustering of recurrent episodes of
Received 31 Januaiy 2014 ventricular tachycardia (VT) or ventricular fibrillation (VF) within a relatively short period of time. Electrical
Revived in re^ed form storms occur in a wide variety of conditions, and successful treatment depends on a correct understanding of
A6 March 20:14 ^ 2014 the mechanism underlying the recurrent arrhythmias. Management of electrical storms is challenging, but
p classifying patients according to the type of recurrent arrhythmia (monomorphic VT or polymorphic VT/VF)
and the presence or absence of structural heart disease would aid differential diagnosis and allow for more
Keywords: specific therapies.
Hertriral storm & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V.
Ventricular tachycardia
Ventricular fibrillation
Mechanism
Management
Contents
1. Introduction..........................................................................................................1
2. Principles of management...............................................................................................2
3. Monomorphic VT storms in structurally normal hearts........................................................................2
4. Monomorphic VT storms in structural heart disease..........................................................................4
5. Polymorphic VT/VF storms in structurally normal hearts......................................................................4
6. Polymorphic VT/VF storms in structural heart disease........................................................................6
7. Conclusions..........................................................................................................6
Conflict of interest.........................................................................................................6
Acknowledgments.........................................................................................................7
References...............................................................................................................7
1. Introduction
The term "electrical storm" describes a state of electrical instability of the heart characterized by clustering of recurrent episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) in a short period of time. In recent years, implantable cardioverter defibrillators (ICDs) have significantly improved the survival of patients with VT/VF. However, electrical storms remain associated with high mortality and morbidity, and have a negative impact on long-term outcomes [1]. Although there is no consensus regarding the definition of an electrical storm, the generally
* Tel.: + 81 476 99 1111; fax: + 81 476 99 1908. E-mail address: maru@nms.ac.jp
http://dx.doi.org/10.1016/jjoa.2014.03.012
1880-4276/© 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V.
accepted definition in clinical practice and recent literature is the occurrence of > 2 separate VT/VF episodes or > 3 appropriate ICD therapies for VT/VF in a 24-h period [2]. In more than half of the patients with an electrical storm, the intervals between the VT/VF episodes are < 1 h, with the shortest interval of < 1 min [3]. A sustained VT/VF that resumes immediately after ( > 1 sinus cycle) successful defibrillation/cardioversion is regarded as a severe form of electrical storm. This may masquerade as shock-refractory VT/ VF, since a brief sinus period followed by immediate VT/VF recurrence can be concealed by post-shock electrocardiographic (ECG) saturation [4]. Therefore, a severe form of electrical storm might also be responsible for the events that occur in some patients with shock-refractory VT/VF, which are commonly seen during cardiopulmonary resuscitation. It is imperative to improve the treatment strategy for electrical storms, because the incidence
Table 1
Causes of electrical storms.
Structural heart diseases Ischemic heart diseases Acute or recent myocardial infarction Prior myocardial infarction
Non-ischemic cardiomyopathy Dilated cardiomyopathy Hypertrophic cardiomyopathy
Arrhythmogenic right ventricular dysplasia/cardiomyopathy
Valvular heart diseases Corrected congenital heart diseases Myocarditis Cardiac sarcoidosis Chagas disease Metastatic cardiac tumor
Abnormal electrical substrate (structurally normal hearts) Primary causes Idiopathic Brugada syndrome Early repolarization syndrome Long QT syndrome Short QT syndrome
Catecholaminergic polymorphic ventricular tachycardia
Secondary causes Electrolyte abnormalities Toxic/drug related Endocrinologic Perioperative
Iatrogenic (T wave pacing)
of electrical storms is not low (10-28% in patients with an ICD implanted for secondary prevention and 4% for primary prevention) [1].
This review discusses the practical and efficacious management of electrical storms. Here, I emphasize that the treatment outcome greatly depends on the understanding of the pathophysiology of electrical storms. An approach tailored to the underlying mechanism seems essential for successful management.
2. Principles of management
Patients who present with an electrical storm often have structural heart disease; however, functional electrical abnormalities also provoke electrical storms in patients with structurally normal hearts. The underlying conditions that cause electrical storms are listed in Table 1.
Since an electrical storm is a medical emergency, it is generally managed in line with a treatment algorithm, typically the Advanced Cardiovascular Life Support (ACLS) protocol [5], regardless of the etiology of the electrical storm. Such a pre-specified algorithmic approach is highly effective in critical patient care, which requires a prompt response to life-threatening conditions. Nevertheless, I propose that treatment should be as specific to the underlying mechanism as possible, because electrical storms of some etiologies actually require a completely opposite treatment. Specifically, sympathetic blockade is effective in controlling electrical storms in patients with the majority of structural heart diseases [6-8], congenital long QT syndrome (LQTS) [9], and catecholaminergic polymorphic VT (CPVT) [10], whereas sympathetic stimulation with isoproterenol is useful for inhibiting electrical storms caused by Brugada syndrome [11], early repolarization syndrome [12], and short QT syndrome (SQTS) [13]. Alternatively, antiarrhythmic drugs commonly used for the treatment of electrical storms [5] can aggravate the situation in LQTS by further lengthening the QT interval [14]. Therefore, an empirical approach to treat recurrent VT/VF is potentially harmful in certain
cases, and a mechanism-directed therapy would be preferable. Although it is difficult to perform a complete diagnostic evaluation during an electrical storm, standard workups such as transthoracic echocardiography and 12-lead ECG can help one understand whether patients have structural heart disease, and/or some specific ECG findings including ischemic ST-T changes, abnormal QT interval, Brugada-type ECG, and others. Myocardial ischemia, worsening heart failure, and electrolyte disturbances are a common trigger of electrical storms [15]. If such an inciting factor is found, emergent revascularization, correcting the electrolyte abnormality or treatment for heart failure must be performed.
The type of ventricular arrhythmia (monomorphic VT or polymorphic VT/VF) responsible for the electrical storm provides an important diagnostic clue to its pathophysiology (Fig. 1). In this review, we address the diagnosis and specific treatments according to the type of ventricular arrhythmia and the presence or absence of structural heart disease.
3. Monomorphic VT storms in structurally normal hearts
The majority of patients with monomorphic VT storm have structural heart disease, but monomorphic VT storms can occur in structurally normal hearts on rare occasions [16,17] (Fig. 2).
Monomorphic VT occurring in structurally normal hearts is referred to as idiopathic VT. The characteristics of idiopathic VT depend on the origin of the VT. VT arising from the outflow tract is the most common form of idiopathic VT (OT-VT), which is characterized by VT with left bundle branch block (LBBB) and inferior axis QRS morphology. The typical mechanism of OT-VT involves triggered activity due to cyclic adenosine monophosphate (AMP)-mediated delayed afterdepolarizations (DADs) [18]. Beta-adrenergic stimulation increases the intracellular cyclic AMP and intracellular Ca2+ levels, resulting in spontaneous Ca2 + release from the sarcoplasmic reticulum (SR), DADs, and triggered activity. Therefore, OT-VT can be suppressed typically by beta-blockers that lower the stimulated levels of cyclic AMP (and thus decrease intracellular Ca2+) or non-dihydropyridine Ca2+ channel blockers (verapamil or diltiazem) that directly reduce intracellular Ca2 + by inhibiting the inward L-type Ca2+ current. As a second-line therapy, class IC or III antiarrhythmic agents are also effective for suppressing OT-VT [19]. Radiofrequency catheter ablation (RFCA) is a safe and reliable technique for the treatment of OT-VT, unless it has an epicardial origin that may require less safe approaches through the coronary venous system, a subxyphoid approach for RFCA, or surgical ablation (an epicardial origin is suggested by delayed initial precordial QRS activation as quantified by a maximum deflection index > 0.55 [20], Q wave amplitude in aVL to aVR > 1.4, or S wave amplitude in V1 > 1.2 mV [21]). If available, RFCA can be the first choice of treatment for OT-VT not only when OT-VT is refractory to medical therapy, because RFCA can be a curative treatment for OT-VT. Activation mapping is useful when seeking the VT origin during an electrical storm. The earliest activation at successful ablation sites typically precedes the surface QRS onset by 20-40 ms, with unipolar electrograms exhibiting a QS pattern with a rapid initial downstroke [22].
Fascicular VT, also known as idiopathic left VT, is the second leading cause of idiopathic VT. The mechanism of fascicular VT is supposed to be macro-reentry involving the Purkinje fiber network, which connects to the left fascicle [23,24]. Fascicular VT is sub-classified based on the ECG morphology (a right bundle branch block [RBBB] pattern and superior or inferior QRS axis) and corresponding fascicle coupled to the reentrant circuit: left posterior fascicular VT, left anterior fascicular VT, and left upper septal VT [23]. Left posterior fascicle VT is the most common manifestation. Fascicular VT has a characteristic ECG with a relatively narrow QRS width that reflects the rapid spread of
M. Maruyama | Journal of Arrhythmia l (l
Electrical or pharmacologic cardioversion/defibrillation Sedation, respiratory, and circulatory assistance if necessary
Medical and drug history 12-lead ECG, transthoracic echocardiography Routine labs (electrolytes, thyroid function, etc.)
Structurally normal heart
Structural heart disease
Monomorphic VT
OT-VT PM-VT Annular VT Focal Purkinje VT
Beta-blockers Ca2+ antagonists Class IC or III AADs Ablation
Fascicular VT
Verapamil Ablation
Polymorphic VT/VF
Congenital LQTS
Beta-blockers Magnesium Verapamil CSD
Late Na+ blockade (LQT3)
Acquired LQTS
Discontinue offending drugs Magnesium Pacing
Class IA or III AADs Isoproterenol
Brugada syndrome, ERS
Isoproterenol Quinidine Cilostazol, bepridil Ablation (Brugada)
CPVT (Normal baseline ECG)
Beta-blockers Verapamil CSD
IVF (Normal baseline ECG)
Verapamil Ablation
Monomorphic VT
Beta-blockers Procainamide (unless heart failure) Class III AADs ICD reprogramming Ablation CSD
Polymorphic VT/VF
Ischemic heart
Beta-blockers Amiodarone Revascularization Ablation CSD
With QT prolongation
Discontinue offending drugs Magnesium Pacing
Heart failure
Amiodarone Beta-blockers Heart failure treatment Ablation
Fig. 1. Management of electrical storms. AAD=antiarrhythmic drugs; CPVT=catecholaminergic polymorphic ventricular tachycardia; CSD=cardiac sympathetic denervation; ERS=early repolarization syndrome; ICD=implantable cardioverter defibrillator; LQTS=long QT syndrome; OT-VT=outflow ventricular tachycardia; PM-VT=papillary muscle ventricular tachycardia; SQTS = short QT syndrome; VF=ventricular fibrillation; VT=ventricular tachycardia.
Fig. 2. Monomorphic ventricular tachycardia storm in a patient with a structurally normal heart. Continuous electrocardiographic strips in a patient with recurrent syncopal episodes are shown.
activation using the specialized conduction system. The prognosis of fascicular VT is usually excellent, but a fascicular VT case with tachycardia-induced cardiomyopathy leading to a life-threatening electrical storm has been described [17]. The distinctive feature of fascicular VT is its sensitivity to verapamil. The efficacy of class I
antiarrhythmic drugs or beta-blockers is variable (can be harmful [25]), and intravenous verapamil is the first-line therapy for sustained fascicular VT. As with OT-VT, RFCA is highly effective as a long-term cure. Early activation of the His bundle potential usually preceding the local ventricular septal electrogram confirms
the close coupling of the VT circuit with the fascicle. The earliest pre-systolic fascicular potential with or without a late diastolic Purkinje potential is an optimal ablation target for fascicular VT [23].
The other uncommon types of idiopathic VT such as non-reentrant focal Purkinje VT, papillary muscle VT, and mitral/ tricuspid annular VT may also present as incessant or repetitive forms of monomorphic VT. Importantly, an incessant nature of the VTs can secondarily decrease the global (not segmental) left ventricular (LV) function, despite the normal heart structure [16,17,26]. The prognosis of such patients is excellent if the VT is controlled by RFCA or medical therapy with complete recovery of the LV function.
4. Monomorphic VT storms in structural heart disease
Monomorphic VT storms associated with structural heart disease are the most common type of electrical storm. Reentry is responsible for most monomorphic VTs. Conduction and repolar-ization abnormalities lie within heterogeneous areas of scarred myocardium caused by fibrosis and collagen deposition of various etiologies (Table 1). Bundles of surviving myofibrils around the border of the scar provide an anatomic substrate for conduction pathways, allowing electrically stable reentry. Focal mechanisms usually play an important role in initiating reentry, but may also contribute to maintenance of the VT, especially in patients with non-ischemic cardiomyopathy [27]. An experimental study has shown that beta-adrenergic stimulation due to sympathetic activation, which generally follows hemodyamically-unstable VT, contributes greatly to focal ventricular ectopy and VT recurrence through the DAD mechanism [28]. Beta-adrenergic stimulation enhances intracellular Ca2 + overload secondary to rapid activation during VT, and Ca2+/calmodulin-dependent protein kinase II activation may promote Ca2 + handling abnormality and DADs [29]. The genesis of a DAD requires high membrane responsiveness to changes in intracellular Ca2 + (i.e., high intracellular Ca2+-membrane voltage coupling gain) [28], and it is known that Ca2+-voltage coupling gain increases in heart failure via down-regulation of the inward rectifier K+ current and upregulation of the Na+ -Ca2 + exchange current [30]. Purkinje cells display a greater propensity to develop a Ca2 + handling abnormality than ventricular myocytes [31], and DADs seem to arise predominantly from Purkinje fibers [28]. Furthermore, the Purkinje fiber network itself can serve as a substrate for the VT reentrant circuit by a similar mechanism to idiopathic fascicular VT in patients with prior myocardial infarction [32] and non-ischemic cardiomyopathy [33], leading to a monomorphic VT storm.
Intravenous administration of class I antiarrhythmic drugs can be used for the treatment of monomorphic VT storms. Procaina-mide is reported to be superior to lidocaine for termination of monomorphic VT [34]. However, electrical storms tend to occur in patients with structural heart disease and severely reduced LV function, where class I antiarrhythmic drugs can be harmful. In such cases, class III antiarrhythmic drugs, such as intravenous amiodarone [5] and nifekalant [35], are useful unless the patient has a prolonged QT interval.
In light of the role of DADs in triggering monomorphic VT storm, sympathetic blockade is a key treatment to control the VT storm. Beta-blockers that suppress DADs by alleviating intracel-lular Ca2 + overload rank foremost for this purpose. It should be noted that not all beta-blockers offer the same level of antiar-rhythmic effects [36], which might depend on beta-1 selectivity, a lipophilic nature, or other pleiotropic effects. Recent experimental studies have shown that carvedilol inhibits DADs by a direct action on ryanodine receptor type 2 (RyR2) independent of its
beta-blocking effect [37]. Future clinical studies are needed to determine which beta-blocker has the most favorable effects. Sedation with short-acting anesthetics such as propofol, benzo-diazepines, and some general anesthesia agents is also helpful in suppressing VT storms [38], since physical and emotional stresses in association with electrical storms contribute to the enhancement of sympathetic activity. Sedation may also help prevent any post-treatment psychological distress [39]. Hence, all patients who have electrical storms should be sedated appropriately. If a pharmacologic sympathetic blockade is not sufficient to control the VT storm, neural modulation with a left or bilateral stellate ganglion blockade [8] or thoracic epidural anesthesia [40] may be a potential treatment of choice for VT storms. Owing to limited data, neural modulation should be reserved for patients who are resistant to drugs and RFCA.
Currently, RFCA is indicated if pharmacologic therapies are unsuccessful [41]. Myocardial substrates for reentrant VT and/or the origin of focal VT are the ablation target for monomorphic VT storms. Although ablating multiple and unstable VTs is challenging, modern computerized mapping and catheter navigation technologies enable them to be treated with a substantial success rate [42]. When the hemodynamics during the VT are sufficiently stable for VT mapping, an ablation target can be localized using the conventional criteria of activation and entrainment mapping
[43]. It is important to be aware that some types of monomorphic VT involve the bundle branch (bundle branch reentry) or Purkinje fibers (similar to fascicular VT) in the VT circuit, as the ablation target is very different from that of myocardial VT (i.e., the bundle branch or Purkinje potentials) [32,33]. When the targeted VTs are unmappable owing to hemodynamic instability, difficulty with induction, or unstable morphology in response to attempted entrainment pacing, substrate mapping during sinus rhythm is useful with the assistance of an electroanatomic mapping system
[44]. Substrate modification using several RFCA strategies can render the unmappable VTs non-inducible and suppress mono-morphic VT storms [45].
If patients with an ICD receive frequent shocks for mono-morphic VT, the ICD treatment protocol should be reviewed to determine if device reprogramming is desirable. Programming an ICD to deliver antitachycardia pacing for a fast VT can reduce the need for shocks. In the Pain-Free Rx II trial [46], antitachycardia pacing effectively treated fast VTs (188-250 bpm). The Primary Prevention Parameters Evaluation (PREPARE) investigators [47] evaluated the effect of extending the VT duration needed to trigger ICD shocks to prevent repeated shocks for non-sustained VT. The PREPARE study patients were less likely to receive a shock in the first year compared with the control patients (9% vs. 17%), without any increase in arrhythmic syncope. The Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) trial [48] showed that programming ICD therapies for VT to z 200 bpm for z 2.5 s or with a prolonged delay in therapy (60 s for VT between 170 and 199 bpm and 12 s for VT between 200 and 249 bpm) was associated with a reduction in all-cause mortality.
5. Polymorphic VT/VF storms in structurally normal hearts
Polymorphic VT/VF storms are relatively rare in structurally normal hearts but occur in patients with electrical disorders of primary (genetic) or secondary causes or an unknown etiology, termed idiopathic VF (Table 1). In this category, differential diagnosis is of particular importance because the treatment strategies differ greatly among the causes of polymorphic VT/VF storms. The baseline ECG characteristics have a high diagnostic yield for the primary causes, while gathering the patient's information (medical
history, drugs, etc.) and identifying extra-cardiac pathologies are the keys to a correct diagnosis of secondary causes.
If the QT interval is markedly prolonged, the polymorphic VT is most likely Torsades de points (TdP, a specific form of polymorphic VT in which the QRS complexes seem to twist around the iso-electric line), which is attributable to congenital or acquired LQTS. Congenital LQTS is an ion channel disorder with at least 15 different related genes. Mutations in the KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) genes represent the most common causes of LQTS and account for an estimated 60-75% of the genotype-positive LQTS cases [49]. On the other hand, acquired LQTS is caused by QT-prolonging drugs (e.g., antiarrhythmic drugs, several antibiotics such as macrolides and fluoroquinolones, antipsychotics, etc.) and an electrolyte imbalance (hypokalemia, hypocalcemia, or hypomagnesemia) with or without genetic susceptibility [50]. In LQTS, triggered activity due to early after-depolarization (EAD) leads to TdP. Recent studies showed that not only reactivation of the L-type Ca2 + current (/Ca,L) but also spontaneous SR Ca2 + release also play a role in the genesis of phase 2 EADs [51]. Furthermore, heterogeneous prolongation of the action potential duration (APD) sets the stage for reentry and phase 3 EADs caused by electrotonic reexcitation at the sites with a steep repolarization gradient [51]. The initial treatment for polymorphic VT storms in LQTS is the discontinuation of possible QT-prolonging medications and rapid correction of an electrolyte imbalance, if present. Beta-blockers are the first-line therapy for congenital LQTS (particularly in LQT1 and LQT2), which is associated with defective ion channels needed to adequately adapt to beta-adrenergic stimulation [49]. Left cardiac sympathetic dener-vation may be useful for LQTS patients who cannot tolerate or are resistant to beta-blocker therapy [52]. In contrast to congenital LQTS, beta-blockers may worsen the situation in acquired LQTS because bradycardia, which is promoted by beta-blockers, further prolongs the QT interval and heterogeneous repolarization [51]. Thus, temporary pacing is the treatment of choice for patients with bradycardia-dependent polymorphic VT in LQTS. Isoproter-enol can be used in the interim while awaiting pacing treatment, but it might aggravate the polymorphic VT if it does not increase the heart rate enough to shorten the QT interval, since phase 2 EADs are enhanced by the isoproterenol-induced increase in Ca2 + influx. Intravenous verapamil blocks /Ca,L and effectively suppresses polymorphic VT refractory to beta-blockers in congenital LQTS [53]. Magnesium modulates Ca2 + ions and has been called "nature's physiologic Ca2 + blocker." Intravenous magnesium sulfate can facilitate termination of polymorphic VT associated with LQTS [54]. Magnesium sulfate has few hemody-namic effects and seems safer for hemodynamically unstable patients. If the LQTS genotype is known to be LQT3, which is attributed to a gain-of-function mutation in the SCN5A gene, drugs with late Na+ current blocking effects such as mexiletine, ranola-zine, and propranolol are useful [49].
SQTS is relatively rare, but should be considered if the QT interval is markedly abbreviated and the ST segment is nearly absent with peaked and symmetrical T waves. Thus far, mutations in 5 different genes have been found, but genetic testing remains investigational because these genes account for only a small proportion of patients with SQTS. Heterogeneous abbreviation of the action potential in SQTS increases transmural dispersion of repolarization and promotes the reentry responsible for polymorphic VT [55]. Class IA and III antiarrhythmic drugs, including quinidine, disopyramide, nifekalant, and amiodarone, are effective in prolonging the QT interval [55,56]. Bun et al. [13] reported that isoproterenol rapidly suppressed polymorphic VT/VF storms in a patient with SQTS. Isoproterenol reduced the transmural voltage gradients, likely because of an increased heart rate (blunting the transient outward current [/to] current) and increase in JCaL.
Brugada syndrome is characterized by a distinct ECG morphology, the absence of structural heart disease, and a high risk of polymorphic VT/VF and sudden cardiac death. To date, 12 mutations in different genes encoding the proteins of Na+, Ca2+, and K+ channels have been found [57]. Brugada syndrome can present as an electrical storm [58]. Hypokalemia, high vagal tone, brady-cardia, and fever are predisposing factors for an electrical storm. The Brugada-pattern ECG is divided into 3 types. The type 1 ECG has prominent coved ST segment elevation with a J-point amplitude of > 2 mm, followed by a negative T wave in > 1 lead among the right precordial leads (V1 and V2) in the second, third, or fourth intercostal space [59]. A type 1 ECG is a specific finding for the diagnosis of Brugada syndrome. A transmural voltage gradient is physiologically present, which is attributable to an /to-mediated spike-and-dome morphology or notch in the ventricular epicar-dium, but not the endocardium. A net outward shift in the membrane currents during phases 1 and 2 of the right ventricular epicardial action potential results in depression or loss of the action potential dome and ST-segment elevation, leading to enhancement of the transmural voltage gradient, phase 2 reentry, and polymorphic VT/VF [57]. Isoproterenol has been proven to normalize ST segment elevation and suppress electrical storms in Brugada syndrome, likely because isoproterenol increases the JCaL and aids recovery of the action potential dome [11]. Class I antiarrhythmic agents are Na+ channel blockers that shift the net currents during the early phase of the action potential outwardly and aggravate the Brugada-pattern ECG changes, therefore, most are contraindicated because they heighten the risk of VT/VF. However, quinidine prevents polymorphic VT/VF by blocking the Jto. Other drugs that can be useful in Brugada syndrome include denopamine and cilostazol (increasing /Ca,L), as well as bepridil (blocking /to) [11]. Epicardial right ventricular outflow tract RFCA of a fractionated electrogram may be an option for severely affected patients with polymorphic VT/VF storms [57].
If the 12-lead ECG shows a J-point elevation of > 1 mm, QRS slurring or notching in > 2 contiguous inferior and/or lateral leads in a patent with polymorphic VT/VF storm, early repolarization syndrome is diagnosed [59]. Underlying genetic abnormalities in early repolarization syndrome have not yet been demonstrated, except for a reported case with an ATP-sensitive K+ channel (/^<ATP) gene mutation [60]. Early repolarization syndrome and Brugada syndrome are considered to share common pathophysiologic mechanisms despite their differing responses to Na+ channel blockade [61]. As in Brugada syndrome, isoproterenol acutely suppresses polymorphic VT/VF storms, and quinidine chronically prevents electrical storms in early repolarization syndrome [12]. One matter of concern is that the early repolarization ECG pattern may be merely an innocent bystander, as the incidence of the early repolarization ECG pattern is high in the general population (5%) [62]. Therefore, if beta-blockers are used in storm patients with early repolarization of unknown significance, it is prudent to use an ultra-short-acting beta-blocker such as esmolol and landiolol [7], in case of subsequent isoproterenol infusion.
If a structurally normal patient with polymorphic VT/VF storm has a completely normal baseline ECG, the possible diagnosis includes CPVT and idiopathic VF. CPVT is an inherited disorder of intracellular Ca2 + handling, which can cause polymorphic VT/VF storms [10]. Abnormal SR Ca2 + release from defective ryanodine receptors produces DADs, triggering activity in the Purkinje system, which is the proposed mechanism of polymorphic VT in CPVT patients. Mutations in the gene encoding RyR2 lead to Ca2+ leak from the SR in an autosomal dominant form (CPVT1), while mutations in the gene encoding cardiac calsequestrin (CASQ2), an SR-buffering protein, lead to the less common autosomal-recessive form (CPVT2). CPVT1 and CPVT2 account for approximately 60% of CPVT patients. A history of stress or exertion-induced syncope in a
young patient is suggestive of CPVT, which is usually tachycardia dependent. The hallmark of CPVT is bidirectional VT that exhibits alternating LBBB and RBBB QRS patterns. Beta-blockers are the mainstay treatment of CPVT, since beta-adrenergic stimulation increases intracellular Ca2+, which triggers DADs and polymorphic VT. An experimental study suggests that carvedilol is the most effective beta-blocker because it can directly block RyR2 with a CPVT mutation [37]. Verapamil has an additional effect on CPVT in cases of electrical storms that are resistant to beta-blockers [10]. A recent study has shown that flecainide suppresses DADs and CPVT by inhibiting spontaneous SR Ca2 + release as well as the Na+ channel [63]; however, its usefulness in electrical storms remains to be confirmed. If pharmacologic treatment fails to control the CPVT, left cardiac sympathetic denervation should be considered [52]. One recent case report has shown that RFCA targeting premature ventricular VF-triggering contractions was successful for controlling recurrent CPVTs refractory to beta-blocker therapy [64].
Idiopathic VF is a clinical entity in which no cardiac anatomic or functional abnormality can be identified despite extensive clinical evaluation for the cause of VF. Therefore, the pathophysiology of idiopathic VF must include multifactorial disorders of unknown origin. However, the similar clinical presentation of this entity indicates that these disorders share some common mechanisms. Leenhardt et al. [65] first described a group of patients consistent with the clinical picture of idiopathic VF, but they termed it "short-coupled variant of TdP." The interesting characteristic observed in these patients is the unusually short coupling interval of the precipitating VF (245 + 28 ms). Verapamil was the only effective drug, supporting the theory that the verapamil-sensitive ventricular myocardium might be involved in permitting triggered activity and VF. Antiarrhythmic drugs and beta-blockers are ineffective; in fact, class I antiarrhythmic drugs can be harmful [66]. It is notable that RFCA of triggered premature ventricular contractions that emanate from either Purkinje fibers or the ventricular myocardium, particularly in the right ventricular outflow tract, can be successful in suppressing and preventing electrical storms due to idiopathic VF [66,67]. These observations also indicate the important role of the Purkinje system in the genesis of idiopathic VF.
6. Polymorphic VT/VF storms in structural heart disease
In the absence of a prolonged QT interval, the most common cause of polymorphic VT is myocardial ischemia. Indeed, the specific arrhythmia that arises from acute myocardial ischemia is almost always polymorphic VT/VF. Hence, polymorphic VT/VF storms in patients with coronary disease are strongly suggestive of acute myocardial ischemia. Myocardial ischemia leads to repetitive inductions of VT through various mechanisms, including abnormal automaticity with altered membrane potential, triggered activity, and phase 2 reentry. Revascularization procedures may be urgently needed for polymorphic VT/VF storms associated with myocardial ischemia. Sympathetic blockade with beta-blockers or left cardiac sympathetic denervation has been shown to result in a better outcome than class I antiarrhythmic drugs in patients with polymorphic VT/VF storms associated with recent myocardial infarction [6]. Nevertheless, antiarrhythmic drugs remain a useful adjunctive therapy for controlling polymorphic VT/VF storms in the presence of ischemia. In ischemic conditions, lidocaine is believed to be effective by its preferential binding to fast Na+ channels in ischemic myocytes, but intravenous amiodarone appears to be more effective than lidocaine and other antiarrhythmic drugs [68]. In some patients, polymorphic VT/VF still occurs despite revascularization and medical therapy. Purkinje
fibers are relatively resistant to ischemia, as they are supplied by cavity blood and have higher glycogen levels and fewer myofibrils. Following myocardial infarction, surviving Purkinje fibers in ischemic lesions have increased SR Ca2 + leak and triggered activity [69]. RFCA aimed at the Purkinje potentials preceding the QRS onset of ventricular premature contractions that initiate polymorphic VT/VF can terminate and prevent electrical storms in patients with acute myocardial infarction [70] and ischemic cardiomyopathy [71]. During the acute phase of myocardial infarction, bradycardia-dependent polymorphic VT/VF can occur with marked QT prolongation [72]. In these cases, pharmacologic therapies and pacing are useful in the same manner as those used for acquired LQTS.
Polymorphic VT/VF storms can occur in patients with severe heart failure, independent of their underlying causes. Recent experimental studies using a pacing-induced heart failure model showed that heart failure facilitates acute shortening of the APD immediately after VF termination [73]. Persistent elevation of intracellular Ca2 + due to Ca2 + overload following VF activates inward Ca2+-sensitive currents during the late phase 3 of the action potential, which induces triggered activity and spontaneous VF (i.e., late phase 3 EAD). This arrhythmogenic post-shock APD shortening after VF defibrillation occurs in heart failure via upregulation of the apamin-sensitive small-conductance K+ current (IIIAS) in failing hearts [74]. In this heart failure model, blocking /KAS prevents recurrent VF, resulting in the termination of VF storms. In fact, IIKAS upregulation also occurs in human hearts with severe heart failure [75]. Notably, amiodarone blocks IIKAS [76]. In addition, sympathetic stimulation accelerates post-shock APD shortening, late phase 3 EADs, and VF recurrence by nonischemic activation of II<ATP [4]. Myocardial ischemia during VF further enhances IKATP activation. It has been reported that amiodarone also inhibits sarcolemmal I^<ATP [77]. Taken together, the combined use of intravenous amiodarone and beta-blockers is a reasonable treatment for polymorphic VT/VF storms in patients with heart failure.
Amiodarone has been shown to increase the short-term survival of patients with shock-refractory VT/VF when compared with lidocaine [78]. This beneficial effect of amiodarone may be partially attributable to the prevention of immediate VT/VF recurrence (i.e., severe form of electrical storms) mimicking shock-refractory VT/VF.
RFCA is also useful in treating polymorphic VT/VF storms resistant to medical therapies in patients with non-ischemic cardiomyopathy. Purkinje-like potentials recorded along the scar border zone can be ablation targets [79].
7. Conclusions
Electrical storms are a life-threatening syndrome and the appropriateness of acute management determines the patient's survival. Despite the difficulties associated with a comprehensive evaluation of this critical condition, a diagnostic approach based on the type of ventricular arrhythmia (monomorphic or polymorphic) and the presence or absence of structural heart disease facilitates the mechanism-directed therapy of electrical storms. Recent advances in non-pharmacologic treatment, particularly RFCA, have greatly improved the clinical outcomes. Nonetheless, optimal pharmacologic treatment remains essential for successful management of electrical storms.
Conflict of interest
The author has no conflict of interest to disclose.
M. Maruyama / Journal of Arrhythmia l (l
Acknowledgments
The authors thank Mr. John Martin for his linguistic assistance for this manuscript.
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