EXPERIMENTAL STUDY
Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiachypertrophy and Wolff-Parkinson-White syndrome
Vickas V. Patel, MD, PhD*,
Michael Arad, MD ,
Ivan P. G. Moskowitz, MD, PhD ,
Colin T. Maguire, BS ,
Dorothy Branco, BS,
J. G. Seidman, PhD,
Christine E. Seidman, MD, FACC|| and
Charles I. Berul, MD, FACC,*
* Molecular Cardiology Research Center and Section of Cardiac Electrophysiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA
Department of Pathology and Cardiac Registry, Children's Hospital, Boston, Massachusetts, USA
Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
|| Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
Manuscript received December 26, 2002;
revised manuscript received May 8, 2003,
accepted May 21, 2003.
* Reprint requests and correspondence: Dr. Charles I. Berul, Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
charles.berul{at}cardio.chboston.org
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Abstract
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OBJECTIVES: We sought to characterize an animal model of the Wolff-Parkinson-White (WPW) syndrome to help elucidate the mechanisms of accessory pathway formation.
BACKGROUND: Patients with mutations in PRKAG2 manifest cardiac hypertrophy and ventricular pre-excitation; however, the mechanisms underlying the development and conduction of accessory pathways remain unknown.
METHODS: We created transgenic mice overexpressing either the Asn488Ile mutant (TGN488I) or wild-type (TGWT) human PRKAG2 complementary deoxyribonucleic acid under a cardiac-specific promoter. Both groups of transgenic mice underwent intracardiac electrophysiologic, electrocardiographic (ECG), and histologic analyses.
RESULTS: On the ECG,  50% of TGN488I mice displayed sinus bradycardia and features suggestive of pre-excitation, not seen in TGWT mice. The electrophysiologic studies revealed a distinct atrioventricular (AV) connection apart from the AV node, using programmed stimulation. In TGN488I mice with pre-excitation, procainamide blocked bypass tract conduction, whereas adenosine infusion caused AV block in TGWT mice but not TGN488I mice with pre-excitation. Serial ECGs in 16 mice pups revealed no differences at birth. After one week, two of eight TGN488I pups had ECG features of pre-excitation, increasing to seven of eight pups by week 4. By nine weeks, one TGN488I mouse with WPW syndrome lost this phenotype, whereas TGWT pups never developed pre-excitation. Histologic investigation revealed postnatal development of myocardial connections through the annulus fibrosum of the AV valves in young TGN488I but not TGWT mice.
CONCLUSIONS: Transgenic mice overexpressing the Asn488Ile PRKAG2 mutation recapitulate an electrophysiologic phenotype similar to humans with this mutation. This includes procainamide-sensitive, adenosine-resistant accessory pathways induced in postnatal life that may rarely disappear later in life.
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Abbreviations and Acronyms
| | AMP | = adenosine monophosphate | | AV | = atrioventricular | | CCh | = carbamyl choline | | EPS | = electrophysiologic study | | ERP | = effective refractory period | | HBE | = His-bundle electrogram | | MHC | = myosin heavy chain | | SVT | = supraventricular tachycardia | | VA | = ventriculo-atrial | | WPW | = Wolff-Parkinson-White |
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Wolff-Parkinson-White (WPW) syndrome or other supraventricular tachycardias (SVTs) typically occur without obvious monogenic inheritance patterns. However, genetic mutations play a role in the development of some cases of WPW syndrome. Families with WPW syndrome and/or SVT, with or without hypertrophic cardiomyopathy, are described (1). The frequency of SVT in certain congenital heart defects and mitochondrial disorders implicates mutations that disrupt both cardiac structural and electrical system development (2,3). Although most patients with WPW syndrome have structurally normal hearts, a subset exists with ventricular pre-excitation, intraventricular conduction delay, and cardiac hypertrophy with familial occurrence. Recently, Gollob et al. (4) and Arad et al. (5) described families with profound conduction disorders and WPW syndrome with (4,5) and without (6) ventricular hypertrophy. Several missense mutations in PRKAG2, the gene for the gamma-2 regulatory subunit of adenosine monophosphate (AMP)-activated protein kinase, were identified. To better understand the molecular and physiologic mechanisms underlying this inherited form of ventricular pre-excitation, transgenic mice were created by overexpressing the wild-type or mutant human PRKAG2 complementary deoxyribonucleic acid (Asn488Ile) under the cardiac-specific alpha-myosin heavy chain (MHC) promoter (7).
We describe here the natural history, developmental maturation, electrophysiology, and pharmacology of accessory atrioventricular (AV) connections in a murine model that recapitulates the clinical profile from which the mutation was derived. Our data provide evidence that an adenosine-resistant, procainamide-sensitive AV connection, apart from the normal AV node-His pathway, is present in mice carrying the mutant transgene, and these accessory AV connections manifest in postnatal life.
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Methods
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Animals.
Creation of transgenic mice was recently described (7). Surface electrocardiograms (ECGs) were obtained for 28 transgenic mutant PRKAG2 (TGN488I) mice (4 to 16 weeks old), 13 age-matched transgenic wild-type PRKAG2 (TGWT) mice, and 13 control nontransgenic mice. A subset (n = 26) underwent in vivo electrophysiologic studies (EPS) with pharmacologic testing. A group of 10 older TGN488I mice (9 to 15 months old) and 10 littermate controls also underwent ECG and EPS. Finally, serial ECGs were obtained weekly from birth to 12 weeks in a cohort of 16 mice from two litters. Mice were inbred in an FVB background and are genetically equivalent. All protocols conformed to the Association for the Assessment and Accreditation of Laboratory Animal Care and the Children's Hospital Animal Care and Use Committee.
Preprocedural preparation.
Protocols for the in vivo mouse EPS have been described in detail (8,9). Mice were anesthetized with pentobarbital (0.033 mg/kg intraperitoneally), and multilead ECGs were obtained using subcutaneous electrodes. A jugular vein cutdown was performed, and an octapolar 2F electrode catheter (CIBer mouse-EP; NuMED, Inc., Hopkinton, New York) was placed in the right atrium and ventricle under electrographic guidance to confirm the catheter position.
EPS.
In vivo EPS were performed in 26 mice (17 TGN488I and 9 TGWT mice). Standard pacing protocols were used to assess atrial and ventricular conduction, refractoriness, and arrhythmia inducibility (8,9). The ECG channels were filtered between 0.5 and 250 Hz, and intracardiac electrograms were filtered between 5 and 400 Hz. The analog signal was digitized with 12-bit precision at a sampling rate of 2 kHz. Recording of a triphasic His-bundle electrogram (HBE), a fixed distance from the ventricular electrogram at baseline, was accomplished using simultaneous multielectrodes and persistent catheter manipulation (9). The ECG intervals were measured in six limb leads and precordial V leads by two observers who were blinded to the genotype. To assess the presence of an accessory AV connection, adenosine (0.5 µg/g intravenously [IV]) was administered during steady-rate atrial pacing, followed by ventricular pacing. Isoproterenol was administered (1 ng/g IV) and the EPS repeated after a 25% heart rate increase. Procainamide was administered (30 µg/g IV) to assess the effects of increased refractoriness and slowed conduction upon the accessory AV connection and arrhythmia inducibility. In the older group of mice, after baseline electrophysiologic parameters were recorded, carbamyl choline (CCh) was administered (50 ng/g IP). The atrial pacing protocol was repeated 5 min after CCh to assess muscarinic modulation and attempt atrial fibrillation induction to measure accessory pathway conduction characteristics (10).
ECG vector analysis.
Electrocardiographic "delta" wave vector analysis was performed according to a method modified from Arruda et al. (11). Onset of ventricular activation in each ECG lead, determined by two observers, was measured from the onset of the earliest delta wave. The polarity of the delta wave was measured within the first 5 ms of the onset of pre-excitation.
Histology and morphology.
Hearts were excised from TGN488I, TGWT, and wild-type mice, washed in Dulbecco's phosphate-buffered saline, arrested in 50 mmol/l KCl, and formalin-fixed (12). Intact hearts were serially sectioned (5 µM) in the sagittal plane and stained with Masson trichrome to allow visualization of the annulus fibrosum of the AV valves. Sections were analyzed on a compound microscope and digitally photographed. Hearts were analyzed by an experienced cardiac pathologist who was blinded to the genotype and ECG.
Statistical analysis.
Continuous variables, such as ECG intervals and conduction parameters, were measured by two observers and summarized as the mean value ± SD. Mean values for TGN488I mice with and without pre-excitation were compared with control values, using one-way analysis of variance followed by the Scheffé method of multiple comparisons. The Fisher exact test was used for categorical variables (13). A p value <0.05 was considered significant.
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Results
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EPS and ECG findings.
The findings of a short PR interval with a wide, slurred QRS complex on the ECG were consistent with manifest ventricular pre-excitation, present in 8 of 17 TGN488I mice. Based on these initial ECG features, TGN488I mice were classified into two groups: those with apparent pre-excitation (TGN488I+BPT) and without pre-excitation (TGN488I–BPT). The ECG intervals (Table 1) revealed a slower resting heart rate with a shorter PR interval and wider QRS complex in TGN488I+BPT compared with TGN488I–BPT mice. Heart rates and ECG intervals were similar among TGN488I–BPT and TGWT mice. The ECG and EPS data in TGWT mice are similar to control FVB nontransgenic mice (data not shown).
To demonstrate the presence of an additional AV connection and elucidate the electrophysiologic effects of the N488I mutation, intracardiac EPS were performed. Atrial pacing and programmed stimulation could induce accessory pathway block, resulting in conduction down the AV node, identified by HBE potentials during accessory pathway refractoriness (Fig. 1). The EPS also established that AV intervals were shorter in TGN488I+BPT mice than in TGN488I-BPT and TGWT mice (Table 2). The AV node effective refractory period (ERP) was longer in TGN488I–BPT mice and the ventricular ERP was longer in both TGN488I+BPT and TGN488I–BPT mice than in TGWT mice. Retrograde conduction up the accessory connection was robust at baseline, with 1:1 ventriculo-atrial (VA) conduction at cycle lengths of <50 ms in all TGN488I+BPT mice. However, procainamide induced retrograde accessory pathway block with ventricular pacing at >100 ms, shifting retrograde conduction up the AV node (Fig. 2). Pacing and programmed stimulation, with or without isoproterenol, did not induce SVT, although re-entrant echo beats could be provoked.
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Figure 1 Two distinct AV pathways are present in mutant transgenic mice. (A) Electrocardiographic leads I, II (LI and LII), and aVF are shown, as well as the His-bundle electrogram (HBE). Atrial pacing at 110 ms with conduction down the bypass tract for the first five beats and fusion of atrial (A) and ventricular (V) intracardiac electrograms on the HBE. The sixth beat (arrow) and subsequent beats conduct with a longer PR interval and narrower QRS complex, suggesting block in the bypass tract and conduction down the AV node. Note separation of the atrial and ventricular electrograms on the HBE and the presence of a His potential (HIS). (B) The left panel displays ECG leads I, II, and aVF, as well as the HBE, and shows a premature atrial extrastimuli (S2) delivered at a coupling interval of 105 ms and a drive train (S1) at 150 ms. All three beats conduct with a short PR interval and wide QRS complex, suggestive of manifest pre-excitation down an accessory AV pathway. The middle panel displays the same electrograms, with the premature atrial extrastimulus coupled at 100 ms. The first two beats conduct with a short PR interval and wide QRS complex, but the atrial extrastimulus conducts with a longer PR interval and narrow QRS complex, and the A and V electrograms are separated by a clear HIS. This indicates that the accessory pathway is refractory and conduction is via the AV node. The right panel displays the same electrograms in another mouse, with the atrial extrastimuli coupled at 75 ms to the drive train at 150 ms. The first two beats and atrial extrastimuli conduct with a short PR interval and wide QRS complex; on the HBE, there is fusion between the A and V electrograms, suggesting conduction down the accessory AV connection. The last beat is followed by retrograde atrial depolarization (Echo), with a long VA time, suggesting retrograde conduction up the AV node.
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Figure 2 Retrograde conduction in mutant transgenic mice. Electrocardiographic leads I and II (LI and LII) are shown with right ventricular (RV EG) and right atrial electrograms (RA EG). Ventricular pacing at 115 ms in the presence of procainamide, with retrograde conduction up the bypass tract for the first eight beats and fusion of atrial (A) and ventricular (V) electrograms on both the RV EG and RA EG. The ninth beat (arrow) and subsequent beats conduct with a longer RP interval, revealing retrograde block in the bypass tract and conduction up the AV node. Note there is now separation of the A and V electrograms on both intracardiac electrograms.
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Pharmacologic findings.
To further confirm the presence of a separate AV connection in TGN488I mice, we observed the effect of procainamide and adenosine on the ECG intervals and AV conduction. Intravenous procainamide prolonged the PR interval and narrowed the QRS complex in six of eight TGN488I+BPT mice (Fig. 3A). Procainamide lengthened the AV Wenckebach cycle length in these six TGN488I+BPT mice (85 ± 8 ms vs. 142 ± 13 ms, p < 0.001). Intravenous adenosine during atrial pacing resulted in AV block in six of six TGWT mice but zero of six TGN488I+BPT mice (Fig. 3B).
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Figure 3 Pharmacologic effects on pre-excitation in mutant transgenic mice. (A) The left panel shows a six-lead electrocardiogram (ECG) at baseline, with a short PR interval and wide, initially slurred QRS complex. The right panel shows the same six-lead ECG 2 min after procainamide infusion, which lengthens the PR interval and narrows the QRS complex. The initial positive deflection of the QRS complex in leads I, II, III (LI, LII, and LIII), and aVF in the left panel suggests an anteroseptal accessory AV pathway. (B) In the left panel, surface ECG leads I, II, and aVF, as well as the HBE, from a wild-type mouse are displayed. Atrial pacing at 130 ms initially conducts 1:1 to the ventricles; however, adenosine infusion (arrow) produces AV block with 2:1 conduction to the ventricles. In the right panel, the same ECG leads, along with the HBE, are displayed from a TGN488I mouse. Atrial pacing at 100 ms conducts 1:1 to the ventricles, despite the presence of adenosine. A = atrial electrogram; AVB = atrioventricular block; His = His potential; V = ventricular electrogram.
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Neonatal development of pre-excitation.
To investigate the natural history of pre-excitation induced by the PRKAG2 mutation, we performed serial ECG analysis in a cohort of 16 neonatal mice. Immediately after birth, no pups showed evidence of pre-excitation, but by the first postnatal week, two of eight TGN488I pups displayed pre-excitation. This increased to seven (88%) of eight TGN488I pups by postnatal week 4 (Fig. 4). None of the eight wild-type pups showed pre-excitation through 12 weeks. By week 9, one TGN488I+BPT mouse lost pre-excitation on the ECG, confirmed by EPS (Fig. 5).
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Figure 4 Time course of developing pre-excitation in mutant transgenic mice. (A) The PR intervals from a cohort of 16 mice pups are plotted over 12 weeks. At birth (week 0), all pups have normal PR intervals without pre-excitation. By week 1, two of eight transgene positive mice (solid circles) develop short PR intervals and pre-excitation, increasing to seven mice by week 4. No transgene-negative mice (open circles) had short PR intervals or pre-excitation. (B) The top portion shows electrocardiogram (ECG) leads I, II (LI and LII), and aVF from a TGWT mouse. The PR interval remains distinct and unchanged from birth through four weeks. The bottom portion displays the same ECG leads from a TGN488I mouse. At week 0, the PR interval is similar to that of the TGWT mouse. By week 1, a short PR and wide QRS complex develop, suggestive of ventricular pre-excitation. At week 4, the PR interval remains short, with a wide QRS complex, sinus bradycardia, and sinus arrhythmia.
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Figure 5 Loss of ventricular pre-excitation in a mutant mouse. (Top panel) Electrocardiographic leads I, II (LI and LII), and aVF displayed from a TGN488I mouse. An electrocardiogram (ECG) pattern of pre-excitation is evident at postnatal week 2. At week 4, the phenotype was lost, but intermittent pre-excitation returned in week 5. By week 7, the phenotype was completely lost, with a normal ECG. (Bottom panel) Electrocardiographic leads are displayed, along with the HBE (EG). At week 10, adenosine infusion (arrow) during atrial burst pacing at 150 ms results in AV block with a slow ventricular response. A = atrial electrogram; V = ventricular electrogram.
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By employing ECG algorithms for localizing human accessory pathways (11), 10 of 12 TGN488I+BPT mice appeared to develop anteroseptal accessory AV connections; one was posteroseptal and one was anterolateral by delta wave vector analysis (Fig. 6A). We attempted to directly identify the anatomic location of the bypass tracts by comparing histologic findings on hearts from 1- and 2.5-week-old TGN488I, TGWT, and wild-type mice. Two animals from each cohort underwent ECG recording; then, the hearts were removed and serially sectioned. Histologic assessment revealed myocardial connections through the annulus fibrosis of the AV valves of both 2.5-week-old TGN488I mice, but not in the other mice analyzed. Atrioventricular connections were present in the right anteroseptal region of hearts from both TGN488I mice with WPW syndrome at 2.5 weeks of age, concordant with the ECG vector analysis (Fig. 6B). Histologically, these connections resembled ventricular muscle and appeared similar to those described in humans (14). No discernable AV connections were identified in the hearts of one-week-old TGN488I or TGWT mice and wild-type animals at either age.
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Figure 6 Accessory connection localization in mutant transgenic mice. (A) Vector analysis of surface six-limb lead ECG recordings from three TGN488I mice. In each panel, the solid line is placed at the onset of pre-excitation, and the dotted line is placed 5 ms later, intersecting the preexcited waveform. The left panel shows a pattern consistent with an anteroseptal AV connection (leads I and aVL and leads II, III, and aVF are positive). The middle panel shows a pattern consistent with a left lateral AV connection (leads I and aVL are negative and leads II, III, and aVF are positive), and the right panel shows a pattern of a posteroseptal AV connection (lead I is isoelectric, lead aVL is positive, and leads II, III, and aVF are negative). (B) Masson trichrome-stained sections (x5) from one-week-old TGN488I (left panels) and 2.5-week-old TGN488I (right panels) hearts through the right paraseptal area anterior to the aortic outflow tract. The fibrous separation between the atrial and ventricular myocardium is intact in the mutant heart from the one-week-old animal, whereas there is physical contact between the atrial and vacuolated ventricular myocytes from the 2.5-week-old animal in the right anteroseptal region. Bottom inserts magnified x20.
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Electrophysiologic assessment in older TGN488I mice.
A separate group of 10 older TGN488I and wild-type mice underwent EPS. Of these, 7 of 10 TGN488I mice manifested pre-excitation, and all 10 had intact AV conduction. However, the sinus cycle length was slower in preexcited TGN488I mice (338 ± 52 ms, p < 0.001) compared with non–pre-excited older mice (226 ± 48 ms) or younger preexcited TGN488I mice (251 ± 50 ms). Spontaneous, nonsustained SVT, atrial bigeminy, marked sinus bradycardia, and pauses up to 1.6 s were seen in older TGN488I mice. Atrioventricular node and accessory pathway conduction characteristics were similar between 9- to 14-month-old and 4- to 16-week-old TGN488I mice.
Carbamyl choline was administered and the atrial pacing protocol repeated in an attempt to induce atrial fibrillation and assess accessory pathway conduction (10). The CCh dose utilized, determined by a dose-response curve (data not shown), led to a 20% heart rate decrease and shortening of atrial refractoriness (atrial ERP150 = 55 ± 9 ms before CCh vs. 43 ± 8 ms after CCh, p < 0.05). A stable heart rate was observed within 5 min of intraperitoneal CCh and maintained for 30 min, considered effective cholinergic stimulation. However, atrial pacing did not provoke atrial fibrillation in any TGN488I mice; thus, anterograde accessory pathway conduction during atrial fibrillation could not be assessed.
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Discussion
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A missense mutation in PRKAG2 induced accessory AV connections in the murine heart. Several lines of evidence support the formation of accessory AV connections in this transgenic model. Programmed electrical stimulation in TGN488I mice switched the ECG pattern to produce a longer PR interval and narrow QRS complex, with a distinct His potential on the HBE recording, from one with a short PR interval and a wide QRS complex with AV fusion on the HBE. This suggests that the extrastimuli are blocked in the accessory connection and conduct through the AV node. Procainamide produced similar ECG and intracardiac effects, with block induced in the accessory AV connection and conduction transferred to the AV node. Further evidence for an accessory AV connection is demonstrated by continued AV conduction with adenosine in pre-excited TGN488I mice, but adenosine-sensitive AV block in TGWT mice.
This transgenic mouse model recapitulates many phenotypic characteristics of human familial WPW syndrome. Pre-excitation was present in 23% of patients in a family from which the N488I mutation was derived (5). The EPS performed in four individuals from another PRKAG2 family showed seven accessory pathways at various locations (15). Similarly, 14 of 28 TGN488I mice had accessory AV connections with variable anatomic location. In TGN488I mice, AV connections were localized using vector analysis of the initial QRS complex deflection, extrapolating ECG algorithms derived from humans (11). Although these algorithms were not designed for analysis of mouse ECGs, they appear to localize the AV connections. In several TGN488I mouse hearts, accessory AV connections anatomically correlated with the surface ECG "delta" wave vector axis (Fig. 6). Other electrophysiologic characteristics that this mouse model recapitulates include sinus bradycardia and AV conduction disorders. Clinically, 31% of patients with the N488I mutation developed sinus bradycardia; the sinus cycle length of TGN488I+BPT mice was longer than that of TGWT mice. Also, 8% of these patients developed AV block and 15% required pacemakers (5). Although complete AV block was not observed, AV node refractoriness was significantly longer in TGN488I versus TGWT mice.
Despite firm evidence for the presence of an accessory AV connection and observation of spontaneous, nonsustained SVT in older TGN488I mice, orthodromic AV reciprocating tachycardia could not be induced, even with isoproterenol or procainamide. There are two potential reasons why SVT could not be induced: 1) retrograde conduction up the accessory AV connection is brisk (1:1 VA conduction >1,200 beats/min in all TGN488I+BPT mice); and 2) most had anteroseptal AV connections in close proximity to the His-Purkinje system, which may be particularly germane in the small murine heart. Together, these factors produce a small re-entrant circuit with a rapid transit time, so the His bundle cannot recover from refractoriness and maintain tachycardia, even when bypass tract conduction is slowed. Perhaps with a combination of advancing age, growth of the heart, and slower VA conduction, these factors may be more conducive for initiation and maintenance of SVT. In the present series, mice were studied up to 15 months, whereas the incidence of arrhythmia may increase with age, as in humans with this mutation (5). In fact, we have observed SVT, sinus bradycardia, and pauses in older mice (>50 weeks) by single-lead telemetric ECG, including several episodes correlated with sudden bradycardic death (7). However, on EPS, these mice did not have inducible AV re-entrant tachycardia or atrial fibrillation.
Interestingly, during serial ECG recordings in newborns, no TGN488I pups had pre-excitation immediately after birth. After the first postnatal week, 25% of TGN488I mice showed pre-excitation, increasing to 88% by week 4. Because the transgene is under control of the murine alpha-MHC promoter, we did not expect the phenotype to express until postnatal life, as cardiac alpha-MHC expression increases 16-fold during the first postnatal week (16). This provides evidence that the mutant PRKAG2 gene is responsible for expression of the phenotype, but more intriguingly, the accessory AV connections are induced in postnatal life after completion of cardiac organogenesis. This suggests that constitutively activating AMP kinase mutations induce formation of accessory AV connections, independent of septation and organogenesis. Although AMP kinase is known to regulate ribonucleic acid transcription (17), the mechanism by which these tracts form postnatally remains unknown. However, the anatomic basis for pre-excitation in PRKAG2 mutants does not appear to be failed resorption of embryonic AV tracts.
In this regard, we saw one PRKAG2 mutant mouse that developed pre-excitation but lost the phenotype after several weeks. The EPS with adenosine revealed no evidence of accessory pathways, with a relatively short AV node ERP (70 ms) and good anterograde AV node conduction (AV Wenckebach node = 85 ms). These data suggest that ion channel remodeling may have induced concealment of the AV connection in the anterograde direction (by enhancing AV node conduction and slowing accessory tract conduction), rather than physical loss of the AV connection. Another possibility is that late remodeling and fibrosis anatomically altered the accessory connection and affected its conductive properties. The AMP kinase modulates adenosine triphosphate-dependent ionic conductance (18), so accessory pathway conductance may increase by direct effects of AMP kinase on ion channels. These cardiomyocytes accumulate large amounts of cytoplasmic glycogen (4–7), which can absorb water and alter the ionic environment and conductive properties. The accumulation of cardiac glycogen may promote accelerated conduction, as seen in Pompe’s disease, or contribute to disruption of the annulus fibrosis, causing a novel acquired form of WPW syndrome. The creation of this animal model allows for molecular and basic electrophysiologic analyses to provide further insight into the mechanisms governing the development and maintenance of accessory AV pathways.
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Acknowledgments
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We are grateful to Kimberlee Gauvreau, ScD, for assistance with statistical analysis. We also thank John Triedman, MD, and Edward Walsh, MD, for critical review of the EPS data.
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Footnotes
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Drs. J. Seidman, C. Seidman, and I. Moskowitz were supported by the Howard Hughes Medical Institute. Dr. Berul was supported by the Children's Hospital Research Foundation. Drs. Patel and Arad contributed equally to this work.
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M. Arad, C. E. Seidman, and J.G. Seidman
AMP-Activated Protein Kinase in the Heart: Role During Health and Disease
Circ. Res.,
March 2, 2007;
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474 - 488.
[Abstract]
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J. R. B. Dyck and G. D. Lopaschuk
AMPK alterations in cardiac physiology and pathology: enemy or ally?
J. Physiol.,
July 1, 2006;
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[Abstract]
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F. Ahmad, M. Arad, N. Musi, H. He, C. Wolf, D. Branco, A. R. Perez-Atayde, D. Stapleton, D. Bali, Y. Xing, et al.
Increased {alpha}2 Subunit-Associated AMPK Activity and PRKAG2 Cardiomyopathy
Circulation,
November 15, 2005;
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[Abstract]
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J. Li, V. V. Patel, I. Kostetskii, Y. Xiong, A. F. Chu, J. T. Jacobson, C. Yu, G. E. Morley, J. D. Molkentin, and G. L. Radice
Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis
Circ. Res.,
September 2, 2005;
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[Abstract]
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D. J. Milan and C. A. MacRae
Animal models for arrhythmias
Cardiovasc Res,
August 15, 2005;
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[Abstract]
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F. A. Ismat, M. Zhang, H. Kook, B. Huang, R. Zhou, V. A. Ferrari, J. A. Epstein, and V. V. Patel
Homeobox Protein Hop Functions in the Adult Cardiac Conduction System
Circ. Res.,
April 29, 2005;
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[Abstract]
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M.R.M. Jongbloed, M.C.E.F. Wijffels, M.J. Schalij, N.A. Blom, R.E. Poelmann, A. van der Laarse, M.M.T. Mentink, Z. Wang, G.I. Fishman, and A.C. Gittenberger-de Groot
Development of the Right Ventricular Inflow Tract and Moderator Band: A Possible Morphological and Functional Explanation for Mahaim Tachycardia
Circ. Res.,
April 15, 2005;
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[Abstract]
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M. Arad, B. J. Maron, J. M. Gorham, W. H. Johnson Jr., J. P. Saul, A. R. Perez-Atayde, P. Spirito, G. B. Wright, R. J. Kanter, C. E. Seidman, et al.
Glycogen Storage Diseases Presenting as Hypertrophic Cardiomyopathy
N. Engl. J. Med.,
January 27, 2005;
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[Abstract]
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F. Rothenberg, V. P. Nikolski, M. Watanabe, and I. R. Efimov
Electrophysiology and anatomy of embryonic rabbit hearts before and after septation
Am J Physiol Heart Circ Physiol,
January 1, 2005;
288(1):
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[Abstract]
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D. P. Zipes
The year in electrophysiology
J. Am. Coll. Cardiol.,
April 7, 2004;
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A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y. W. Lew, and S. Tsimikas
Highlights of the year in JACC 2003
J. Am. Coll. Cardiol.,
December 17, 2003;
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