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Rare Forms of Preexcitation

2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 4 Linguagem: Inglês

10.1161/circep.111.968917

1941-3149

Jayanthi N. Koneru, Mark A. Wood, Kenneth A. Ellenbogen,

Cardiac electrophysiology and arrhythmias

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 5, No. 4Rare Forms of Preexcitation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRare Forms of PreexcitationA Case Study and Brief Overview of Familial Forms of Preexcitation Jayanthi N. Koneru, MBBS, Mark A. Wood, MD and Kenneth A. Ellenbogen, MD Jayanthi N. KoneruJayanthi N. Koneru From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA. , Mark A. WoodMark A. Wood From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA. and Kenneth A. EllenbogenKenneth A. Ellenbogen From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA. Originally published1 Aug 2012https://doi.org/10.1161/CIRCEP.111.968917Circulation: Arrhythmia and Electrophysiology. 2012;5:e82–e87IntroductionA 16-year-old boy was brought to the hospital when he complained of chest pain while at a basketball game. In the emergency room, he was noted to have a wide complex tachycardia. The ECG at presentation is shown in Figure 1. He was cardioverted after administration of 150 mg of intravenous amiodarone. His ECG after cardioversion is shown in Figure 2. His physical examination and developmental evaluation were significant for obesity, synophrys, mild fifth digit clinodactyly, and subnormal intelligence. Cardiac magnetic resonance imaging with contrast showed massive left ventricular hypertrophy (LVH), with preserved ejection fraction, and several areas of delayed hyperenhancement in the subendocardium. Cardiac catheterization showed no obstructive coronary artery disease or anomalous coronary arteries. What are the diagnostic considerations for this constellation of findings of massive LVH, subendocardial necrosis, and abnormal ECGs?Download figureDownload PowerPointFigure 1. Wide complex tachycardia at presentation.Download figureDownload PowerPointFigure 2. Sinus rhythm ECG showing ventricular preexcitation and normal axis (see text for further details).DiscussionThe ECG in Figure 1 displays a wide complex tachycardia, with a right-bundle branch block morphology with a QRS complex duration >120 ms. A wide complex tachycardia with a right-bundle branch block morphology could be secondary to ventricular tachycardia originating from the left ventricle or a preexcited tachycardia in the presence of a left-sided bypass tract. However, the QS complex in lead V6 rules out a left-sided atrioventricular bypass tract, because such bypass tracts do not have the left ventricle apex as their ventricular insertion site, which is necessary to produce a QS complex in V6. A left-sided nodofascicular bypass tract with insertion in the distal His-Purkinje system can produce QS complexes in lead V6, but these are extraordinarily rare and occur more frequently on the right side. Initial R wave in lead aVR,1 a QS complex in lead V6, and northwest axis that is completely different from the preexcited QRS complex in sinus rhythm seen in Figure 2 argue for ventricular tachycardia being the mechanism of the tachycardia in Figure 1. Thus, the tachycardia depicted in Figure 1 is diagnosed as ventricular tachycardia. Figure 2 shows an ECG consistent with sinus rhythm, ventricular preexcitation, and a transition to R/S>1 in lead V2 with a relatively normal axis. Using the algorithm suggested by Arruda et al,2 the bypass tract causing preexcitation in this ECG will be localized to the anteroseptal region. However, fasciculoventricular bypass tracts (FVBT) share electrocardiographic features of both anteroseptal and midseptal pathways. Sternick et al3 systematically analyzed the value of (1) ECG frontal plane QRS and delta-wave axis; (2) QRS width; (3) R/S ratio in lead III; and (4) precordial lead transition to R/S>1 in distinguishing FVBT from anteroseptal and midseptal bypass tracts. They reported that transition to R/S>1 in the precordial leads occurred mainly in lead V2 in patients with manifest fasciculoventricular pathways, V3 in midseptal pathways, and V4 in anteroseptal bypass tracts. However, it should be noted that surface ECG cannot reliably differentiate FVBT from an anteroseptal or midseptal bypass tracts. Thus, a definitive distinction can only be made with an electrophysiological study.Wide complex tachycardia in our patient was secondary to ventricular tachycardia in the setting of structural heart disease. We performed an electrophysiological study to elucidate the cause of preexcitation, and the salient findings are, hereby, presented. Baseline intervals are as follows: PR interval, 157 ms; QRS duration, 140 ms; atrial-His interval (AH), 59 ms; and His-ventricular interval, 14 ms. The response to an atrial extrastimulus is shown in Figure 3. Ventricular preexcitation was absent once the atrioventricular nodal effective refractory period was reached. The response to His pacing is shown in Figure 4. Double ventricular extrastimuli at a drive cycle length of 600 ms and coupling intervals of 215 and 230 ms resulted in ventricular tachycardia with right-bundle branch block morphology and left-axis deviation, with a cycle length of 300 ms, and it terminated spontaneously. We were not able to induce the same wide complex tachycardia recorded in Figure 1. There was no ventriculoatrial conduction at baseline or during ventricular tachycardia.Download figureDownload PowerPointFigure 3. I, aVF, and V1 signify surface electrocardiographic recordings from respective leads. Pacing from the right atrial catheter is shown. The first 3 beats are part of an 8-beat drive train, and the 4th beat signifies an extrastimulus delivered after the drive train. The degree of ventricular preexcitation is fixed, regardless of the AH interval (see text for further details). HRA indicates high right atrium; Prox His, proximal His; and Rva, right ventricular apex.Download figureDownload PowerPointFigure 4. Schema similar to Figure 2. His pacing results in His and ventricular capture in the first 2 beats, whereas the third beat is most likely a capture of the right bundle and surrounding myocardium with no His capture. This is suggested by the antegrade depolarization of the His. The fixed preexcitation throughout the tracing, regardless of His capture, in conjunction with the findings in Figure 3 is suggestive of a fasciculoventricular bypass tract (see text for further details).Fixed preexcitation with variable AH intervals, dependence on atrioventricular nodal conduction, and preexcitation with junctional ectopy or His extrasystoles are pathognomonic features of FVBT.4,5 FVBT are interesting because their ECG appearance may simulate anteroseptal or midseptal accessory pathways, but they have never been proven to participate in tachycardia, except as bystanders. Wide complex tachycardia morphology that is different from preexcitation argues for ventricular tachycardia being the mechanism of the tachycardia in our patient and is probably caused by hypertrophic cardiomyopathy and diffuse scarring. As fasciculoventricular tracts are not true atrioventricular bypass tracts and do not participate in reciprocating tachycardia, ablation of these tracts is not recommended and, thus, not pursued in our patient. However, such variant forms of hypertrophy and scarring in association with preexcitation engendered suspicion for inherited forms of preexcitation. We, therefore, present a brief overview of genetic mutations that are known to result in Wolff–Parkinson–White syndrome in association with left ventricular hypertrophy.Danon DiseaseDanon disease is a malignant phenocopy of hypertrophic cardiomyopathy with multisystem involvement caused by lysosome-associated membrane protein 2 mutations.6–8 In addition to severe LVH, patients have skeletal myopathy, hepatic involvement, and mental retardation. ECGs in patients with Danon disease frequently demonstrate preexcitation. A representative ECG from a patient with Danon disease who underwent orthotopic heart transplantation at the age of 16 is shown in Figure 5.Download figureDownload PowerPointFigure 5. Pretransplant ECG from a 16-year-old patient with Danon disease. Note the presence of manifest preexcitation. (Courtesy: Ioana Dumitru, MD; University of Nebraska Medical Center.)Fabry DiseaseAnderson-Fabry disease is an X-linked recessive disorder because of α-galactosidase A deficiency. Severe LVH resulting in heart failure, atrial fibrillation, and conduction system diseases is known to be associated with Fabry disease.9 Fabry disease can be treated with biweekly infusions of the deficient enzyme. Recently the association among Fabry disease, atrioventricular, and atrio-Hisian bypass tracts has been reported.10PRKAG 2 MutationThe genetic mutation associated with familial Wolff–Parkinson–White syndrome was initially described in a large French-Canadian family in 1986. In this family, the members who were affected showed clinical findings that consisted of preexcitation, conduction abnormalities, and cardiac hypertrophy.11,12 The syndrome has an autosomal dominant mode of inheritance. Genetic linkage analysis identified the putative locus to be on chromosome 7 (7q3), and the gene was subsequently identified to be PKRAG2, which encodes the γ-2 subunit (noncatalytic subunit) of 5-AMP-activated protein kinase. Since this initial discovery, 5 more mutations in the same gene have been identified. All mutations have been missense mutations in PKRAG2. PRKAG2 mutation is associated with LVH and ventricular preexcitation, most notably with fasciculoventricular pathways.11,12 LVH in patients with PRKAG2 is caused by glycogen storage in the myofibrils, with a reported incidence of 26% to 74%.5 It is possible that the true incidence of these mutations is underestimated and that many cases are wrongly diagnosed as idiopathic hypertrophic cardiomyopathy. Some cases of patients with fasciculoventricular pathways and LVH without genetic assessment have also been reported.13PRKAG2 may play a role in the development of annulus fibrosus, and malfunction of the gene, by causing prominent structural disruptions with extensive arborization, may explain the remarkably high incidence of multiple atrioventricular accessory pathways seen in patients with the PRKAG2 mutation.14 In addition to the presence of bypass tracts, high incidence of conduction abnormalities and typical atrial flutter have also been reported in patients with PRKAG2 mutations.15 We have encountered a patient with PRKAG2 mutation, who has an anteroseptal pathway as the only route of antegrade conduction from the atrium to the ventricle. Interestingly, this patient also developed cavotricuspid isthmus-dependent flutter with rapid conduction via the accessory pathway. This flutter was successfully ablated.Mitochondrial Disorders That Are Maternally InheritedLeber hereditary optic neuropathy (LHON) is one of the most common mitochondrial genetic diseases, with an estimated prevalence of 1 in 25 000 in North East England.16 This is characterized by acute or subacute functional impairment in both eyes, mostly in men during early adulthood or midlife.17 The mitochondrial DNA mutations 11778G>A, 3460G>A, and 14484T>C are found in 95% of all LHON cases. Prolonged QT interval, cardiac conduction abnormalities, and preexcitation have been described in these patients.18–20 Structural abnormalities, including hypertrophic cardiomyopathy and abnormal left ventricular trabeculation, have also been described in patients with LHON.20,21 Electrocardiographic manifestation of preexcitation has been shown to be common not just in the Finnish population as initially thought, but also in other ethnic groups afflicted with LHON.22 Patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome caused by mitochondrial DNA 32343 A>G mutations have also been found to be afflicted with severe cardiac hypertrophy in association with preexcitation.23–25 There is no proven curative treatment for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, and the long-term life expectancy of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome is dependent on the organ systems involved.Tuberous SclerosisTuberous sclerosis is an autosomal dominant disease with frequent occurrence of cardiac rhabdomyomas. Clinical features include tumors in various organs that result in a variety of clinical manifestations that include intractable epilepsy and malignant arrhythmias. The putative genetic loci have been identified on chromosomes 9 and 16.26,27 Cardiac rhabdomyomas are thought to contribute to the occurrence of accessory pathways, but cases of tuberous sclerosis and Wolff–Parkinson–White syndrome without cardiac rhabdomyomas have also been reported.28Pompe DiseasePompe disease is an autosomal recessive disorder that results from the deficiency of acid α-glucosidase, a lysosomal hydrolase. Three major forms of the disorder are recognized: infantile, juvenile, and adult onset. The infantile form usually presents by the age of 6 months and is marked by a progressive and rapidly fatal course. Recombinant human α-glucosidase treatment has shown some promise in the treatment of this disease.29 The association of Pompe disease with preexcitation was reported as early as 1978.30 A synopsis of these genetic preexcitation syndromes is presented in the Table.Table. Genetic Disorders With PreexcitationDiseaseClinical FeaturesInheritanceGeneticsCommentsDanonLVH, CHFSkeletal myopathyHepatic involvementMental retardationX-linked dominantLAMP2 mutationsMen more frequently than womenFabryLVH, CHFAtrial fibrillationConduction system diseaseX-linked recessiveα-Galactosidase A deficiencyFabry disease can be treated with biweekly infusions of the deficient enzymeAtrio-Hisian and atriofascicular bypass tractsLHONAcute or subacute impairment in both eyesProlonged QT intervalCardiac conduction abnormalitiesHypertrophic cardiomyopathyAbnormal left ventricular trabeculationMatrilinealmtDNA mutations 11778G>A, 3460G>A, and 14484T>CMen are more often affectedMELASEncephalopathyUnexplained lactic acidosisStroke-like episodesDiabetes mellitusMatrilinealmtDNA 32343 A>GMen are more often affectedPompeInfantile form Cardiomegaly, cardiomyopathy arrhythmias, hypotonia, respiratory distress, skeletal myopathy, feeding difficulties, and failure to thrive Late-onset formImpairedcough, hypotonia, progressive myopathy, delayed motor milestones, difficulty with deglutition and mastication, and reduced vital capacityAutosomal recessiveDeficiency of acid α-glucosidase Mutation is localized to chromosome 17Recombinant human α-glucosidase treatment has shown some promise in the treatment of this disease29PRKAG2 mutationConduction abnormalities, severe LVH, subendocardial ischemia secondary to massive LVH, and atrial flutterAutosomal dominantChromosome 7 (7q3)Conduction abnormalities mandate careful evaluation of AV nodal and His-Purkinje function before ablation of SVTHigh prevalence of fasciculoventricular bypass tractsTuberous sclerosisCardiac rhabdomyomasAstrocytoma of the brainLymphangioleiomyomatosis of the lungPhakomaandcolobomas of the eyesAngiomyolipomas of the kidneysCafé aulait spots on the skinAutosomal dominantTSC 1: chromosome 9TSC 2: chromosome 16Surgical treatment might be necessary to cure intractable epilepsy and malignant arrhythmiasLVH, indicates left ventricular hypertrophy; CHF, congestive heart failure; LAMP2, lysosome-associated membrane protein; LHON, Leber hereditary optic neuropathy;mtDNA, mitochondrial DNA; MELAS, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; AV, atrioventricular; SVT supraventricular tachycardia; TSC, tuberous sclerosis complex.Careful electrophysiological analysis (when indicated) should be undertaken to demonstrate the presence of an accessory pathway in genetic preexcitation syndromes because preexcitation pattern in ECG in patients with storage disorders does not automatically imply the presence of an accessory pathway as demonstrated elegantly by Drs Bulkley and Hutchins in 1978,30 and more recently by Sternick et al15 in 2 families with PRKAG2 mutations—the so-called familial pseudopreexcitation syndrome. In these patients, enhanced atrioventricular nodal conduction with conduction disturbances in the His-Purkinje system resulted in short PR intervals in association with bundle branch block patterns on ECG.Danon disease was ruled out by molecular diagnostics, and further testing was advised to the patient. The patient and his family refused to undergo further testing; so the ultimate molecular diagnosis in this case remains elusive, although we believe it is most likely because of a PRKAG2 mutation.In contrast to the excellent long-term prognosis of patients with accessory pathways without structural heart disease and known genetic mutations, those with accessory pathways and genetic mutations that cause multisystem disease have a guarded prognosis. Patients in whom preexcitation is associated with unexplained cardiac hypertrophy should be evaluated for genetic mutations, and a multidisciplinary treatment plan should be instituted, should a mutation that affects multiple organ systems be discovered.DisclosuresNone.FootnotesCorrespondence to Jayanthi N. Koneru, MBBS, Cardiac Electrophysiology, Division of Cardiology, Virginia Commonwealth University, Gateway Building, 3rd Floor, PO Box 980053, Richmond, VA 23298–0053. E-mail [email protected]References1. Vereckei A, Duray G, Szénási G, Altemose GT, Miller JM. New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia.Heart Rhythm.2008; 5:89–98.CrossrefMedlineGoogle Scholar2. Arruda MS, McClelland JH, Wang X, Beckman KJ, Widman LE, Gonzalez MD, Nakagawa H, Lazzara R, Jackman WM. 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Occasionally pathway-related arrhythmia is the presenting feature of the underlying syndrome (Fabry disease and cytidine 51-monophosphate [CMP]-kinase defect).2,3 Accessory pathway ablation is generally a straightforward procedure; however, the electrophysiology trainee needs to be aware of and develop a systematic approach to dealing with the unusual, difficult accessory pathway.4Appearance of an Antegrade Conducting Accessory PathwayAtrioventricular (AV) bypass tracts connect the atrial and ventricular myocardium via a route other than through the AV node. Koneru et al1 describe a case where a pattern consistent with preexcitation is because of a fasciculoventricular tract. Here, the AV node is the only connection between the atrium and ventricle. However, a gap in the fibrous insulation separating the His bundle and proximal bundle branches, allows conduction to the myocardium. Thus, the HV interval is short, and there is slurring of the upstroke of the QRS.