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
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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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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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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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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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