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P6-24
Poster 6 with implanted transmitters confirmed relative bradycardia in popdc1 (heart rate popdc1 531 ⫾ 10 bpm; WT 561 ⫾ 12 bpm). Isolated beating hearts showed prolonged atrial cycle lengths for popdc1 (popdc1 170 ⫾ 33 ms; WT 96 ⫾ 4 ms cycle length). The AV node appeared involved reflected by an increased Wenckebach point and a decreased response to -adrenergic stimulation (popdc1 112 ⫾ 15 ms; WT 85 ⫾ 8 ms; after -adrenergic stimulation by orciprenaline 1.6 ⫻ 10-6 M: Wenckebach popdc1 120 ⫾ 16 ms, WT 77 ⫾ 3 ms). Conclusions: popdc1 mice show sinus bradycardia and an increased Wenckebach point with -adrenergic stimulation. popdc1 is necessary for heart rate adaptation to stress.
P6-23 INSTABILITY OF REENTRY IN THICK MYOCARDIAL SLABS: NEGATIVE FILAMENT TENSION IN LUO-RUDY MODEL Alexander V. Panfilov, PhD and Segio Alonso, PhD. University of Utrecht, Utrecht, The Netherlands and Fritz Haber Institut, Berlin, Germany. The precise mechanisms responsible for the onset and maintenance of ventricular fibrillation (VF) are not yet understood. Several experimental studies showed that the onset of VF requires that the ventricular wall has a thickness above some critical value. Indeed, several ventricular thinning studies showed that there is a transition from VF to tachycardia, when the wall thickness was progressively decreased. Such observations stimulated interest in the mechanisms that may explain the specific role of the third dimension in the onset of VF. One of such mechanisms could be the ’negative tension’ hypothesis which explains the onset of VF by the inherent increasing of the length of the curved scroll wave filament, known as the negative filament tension phenomenon. Direct application of the negative filament tension phenomenon to electrophysiology, however, had the following problems: the negative tension was observed only in cardiac tissue with low excitability where, unlike real VF situation, the reentrant (scroll) waves have a large excitable gap; second, the negative tension was only reported in a simplified FitzHigh Nagumo (FHN) equations and not found in detailed ionic models for cardiac tissue. Here we report the first observation of the negative filament tension in an ionic model of cardiac tissue. We show that for some parameter region of the Luo-Rudy model of ventricular tissue, filaments of scroll waves with small curvature increase their length, thus show negative filament tension. We also find that unlike the predictions from the FHN models, the negative tension occurs in cardiac tissue with high excitability, where the scroll waves have a small excitable gap comparable to that during reentrant cardiac arrhythmias. We discuss the parameters, conditions and mechanisms of this effect and its potential application to the onset of VF in normal and ischemic tissue.
P6-24 VULNERABILITY TO REENTRY BY PREMATURE EXCITATIONS IN A HOMOGENEOUS CARDIAC TISSUE MODEL: ROLES OF ELECTRICAL RESTITUTIONS Jimmy Yang, BS, Diana Tran, BS, Alan Garfinkel, PhD, James N. Weiss, MD and Zhilin Qu, PhD. UCLA, Los Angeles, CA. Background: Electrical restitutions, including action potential duration (APD) restitution and conduction velocity (CV) restitution, are shown to be important controlling parameters for the genesis of cardiac alternans and the degeneration to fibrillation. However, their roles for the initiation of reentry by premature excitations have not been elucidated. Methods and Results: We simulated a two-dimensional (6 cm ⫻ 6 cm) homogeneous tissue model using the Luo and Rudy model. S1S2 and S1S2S3 protocols were used. S1 was applied in 2 mm ⫻ 2 mm area at the lower left corner of the tissue at 500 ms intervals. In the S1S2 protocol, S2
S309 was applied in a circular area in the center of the tissue. A critical electrode size (⬎2.5 cm2) is needed and the vulnerable window increases as the size of the stimulation area. The vulnerable window decreases as the APD restitution shape changes as indicated by the arrow in the Figure. In the S1S2S3 protocol, both S2 and S3 were applied in a fixed 2 mm ⫻ 2 mm area in the center of the tissue. In this case, both S2 and S3 electrodes are too small to induce reentry without the presence of dispersion of refractoriness. After S2, asymmetry in APD gradient was induced which created a substrate for unidirectional block of the S3 beat. A large dispersion of refractoriness was induced when APD restitution was steep and/or CV restitution was broad thus enlarging the vulnerable window for S3 induced reentry. When APD restitution was flat (two flat curves in the Figure), no reentry can be induced by S3. Conclusions: Electrical restitution is important for degeneration from ventricular tachycardia to ventricular fibrillation but it is also important for initiation. Prolonging APD and flattening APD restitution simultaneously are antiarrhythmic.
P6-25 HETEROGENEOUS ACTION POTENTIAL DURATION RESTITUTION CAN PRODUCE WAVEBREAK AND RE-ENTRY: A MODELLING STUDY Richard H. Clayton, PhD and Peter Taggart, MD. University of Sheffield, Sheffield, United Kingdom and University College London Hospitals, London, United Kingdom. Motivation: Recent studies have shown an association between heterogeneous action potential duration (APD) restitution and vulnerability to re-entry. We used a 3D computational model to examine how heterogeneous APD restitution can produce re-entry. Methods: We simulated action potential propagation in 50 ⫻ 50 ⫻ 12.5 mm tissue slabs, with and without rotational anisotropy. Membrane excitability was modeled by the 3-variable Fenton-Karma (3vFK) model. Two variants of the 3vFK model were used to describe excitation, v-1 had long APD at short diastolic interval (DI) and v-2 had short APD at short DI (see first graphic). Within the 3D slabs, we imposed a cylindrical region with v-1 restitution, and v-2 restitution elsewhere. Results: During pacing at long DI, APD was uniform. At shorter DI, regional differences in APD were exposed. A premature S2 stimulus produced a region of delayed recovery associated with v-1 restitution, and a premature S3 stimulus resulted in wavebreak (see second graphic, propagation from bottom right to top left). Re-entry was produced for a range of S1-S2 and S2-S3 intervals. With S1-S2 of 200ms and S2-S3 of 125ms, re-entry was non-sustained in the isotropic model, but sustained in the anisotropic model. Conclusions: Heterogeneous APD restitution can act as a substrate for wavebreak and re-entry following S1 S2 S3 stimulation. The potency of this substrate is increased by rotational anisotropy.
P6-23 INSTABILITY OF REENTRY IN THICK MYOCARDIAL SLABS: NEGATIVE FILAMENT TENSION IN LUO-RUDY MODEL Alexander V. Panfilov, PhD and Segio Alonso, PhD. University of Utrecht, Utrecht, The Netherlands and Fritz Haber Institut, Berlin, Germany. The precise mechanisms responsible for the onset and maintenance of ventricular fibrillation (VF) are not yet understood. Several experimental studies showed that the onset of VF requires that the ventricular wall has a thickness above some critical value. Indeed, several ventricular thinning studies showed that there is a transition from VF to tachycardia, when the wall thickness was progressively decreased. Such observations stimulated interest in the mechanisms that may explain the specific role of the third dimension in the onset of VF. One of such mechanisms could be the ’negative tension’ hypothesis which explains the onset of VF by the inherent increasing of the length of the curved scroll wave filament, known as the negative filament tension phenomenon. Direct application of the negative filament tension phenomenon to electrophysiology, however, had the following problems: the negative tension was observed only in cardiac tissue with low excitability where, unlike real VF situation, the reentrant (scroll) waves have a large excitable gap; second, the negative tension was only reported in a simplified FitzHigh Nagumo (FHN) equations and not found in detailed ionic models for cardiac tissue. Here we report the first observation of the negative filament tension in an ionic model of cardiac tissue. We show that for some parameter region of the Luo-Rudy model of ventricular tissue, filaments of scroll waves with small curvature increase their length, thus show negative filament tension. We also find that unlike the predictions from the FHN models, the negative tension occurs in cardiac tissue with high excitability, where the scroll waves have a small excitable gap comparable to that during reentrant cardiac arrhythmias. We discuss the parameters, conditions and mechanisms of this effect and its potential application to the onset of VF in normal and ischemic tissue.
P6-24 VULNERABILITY TO REENTRY BY PREMATURE EXCITATIONS IN A HOMOGENEOUS CARDIAC TISSUE MODEL: ROLES OF ELECTRICAL RESTITUTIONS Jimmy Yang, BS, Diana Tran, BS, Alan Garfinkel, PhD, James N. Weiss, MD and Zhilin Qu, PhD. UCLA, Los Angeles, CA. Background: Electrical restitutions, including action potential duration (APD) restitution and conduction velocity (CV) restitution, are shown to be important controlling parameters for the genesis of cardiac alternans and the degeneration to fibrillation. However, their roles for the initiation of reentry by premature excitations have not been elucidated. Methods and Results: We simulated a two-dimensional (6 cm ⫻ 6 cm) homogeneous tissue model using the Luo and Rudy model. S1S2 and S1S2S3 protocols were used. S1 was applied in 2 mm ⫻ 2 mm area at the lower left corner of the tissue at 500 ms intervals. In the S1S2 protocol, S2
S309 was applied in a circular area in the center of the tissue. A critical electrode size (⬎2.5 cm2) is needed and the vulnerable window increases as the size of the stimulation area. The vulnerable window decreases as the APD restitution shape changes as indicated by the arrow in the Figure. In the S1S2S3 protocol, both S2 and S3 were applied in a fixed 2 mm ⫻ 2 mm area in the center of the tissue. In this case, both S2 and S3 electrodes are too small to induce reentry without the presence of dispersion of refractoriness. After S2, asymmetry in APD gradient was induced which created a substrate for unidirectional block of the S3 beat. A large dispersion of refractoriness was induced when APD restitution was steep and/or CV restitution was broad thus enlarging the vulnerable window for S3 induced reentry. When APD restitution was flat (two flat curves in the Figure), no reentry can be induced by S3. Conclusions: Electrical restitution is important for degeneration from ventricular tachycardia to ventricular fibrillation but it is also important for initiation. Prolonging APD and flattening APD restitution simultaneously are antiarrhythmic.
P6-25 HETEROGENEOUS ACTION POTENTIAL DURATION RESTITUTION CAN PRODUCE WAVEBREAK AND RE-ENTRY: A MODELLING STUDY Richard H. Clayton, PhD and Peter Taggart, MD. University of Sheffield, Sheffield, United Kingdom and University College London Hospitals, London, United Kingdom. Motivation: Recent studies have shown an association between heterogeneous action potential duration (APD) restitution and vulnerability to re-entry. We used a 3D computational model to examine how heterogeneous APD restitution can produce re-entry. Methods: We simulated action potential propagation in 50 ⫻ 50 ⫻ 12.5 mm tissue slabs, with and without rotational anisotropy. Membrane excitability was modeled by the 3-variable Fenton-Karma (3vFK) model. Two variants of the 3vFK model were used to describe excitation, v-1 had long APD at short diastolic interval (DI) and v-2 had short APD at short DI (see first graphic). Within the 3D slabs, we imposed a cylindrical region with v-1 restitution, and v-2 restitution elsewhere. Results: During pacing at long DI, APD was uniform. At shorter DI, regional differences in APD were exposed. A premature S2 stimulus produced a region of delayed recovery associated with v-1 restitution, and a premature S3 stimulus resulted in wavebreak (see second graphic, propagation from bottom right to top left). Re-entry was produced for a range of S1-S2 and S2-S3 intervals. With S1-S2 of 200ms and S2-S3 of 125ms, re-entry was non-sustained in the isotropic model, but sustained in the anisotropic model. Conclusions: Heterogeneous APD restitution can act as a substrate for wavebreak and re-entry following S1 S2 S3 stimulation. The potency of this substrate is increased by rotational anisotropy.