- Email: [email protected]
P4-24
S226 to shocks of various strengths delivered through ICD lead and active can positioned to accurately represent an ICD configuration. The ventricles were paced apically, and biphasic shocks were applied over a range of coupling intervals and a vulnerability area (VA) constructed from which the ULV was determined. ICD lead was then placed in several positions closer to the LV apex and the corresponding VAs and ULVs were determined. For each electrode configuration, the distribution of postshock excitable areas within the 3D ventricular volume was examined the related to the postshock activation site of origin. Results: 3D simulations revealed that in all cases examined, the main postshock excitable area was located within the LV anterior wall; for failed shocks, all postshock activations arose at this location. Positioning the shock electrode towards the apex diminished the spatial extent of the excitable area. Lowering the ICD lead by 7.6 mm towards the apex produced 5.74% smaller excitable gap and 17% decrease in ULV. Conclusion: These results have possible implications for decreasing the defibrillation threshold by careful electrode positioning. P4-23 LOCAL REGULATION OF SR CA2ⴙ RELEASE VIA NAⴙ/CA2ⴙ EXCHANGER Anna Sher, MS, Robert Hinch, PhD, Penny Noble, MS, David Gavaghan, PhD and Denis Noble, PhD. Oxford University, Oxford, United Kingdom. It is established that SR Ca2⫹ release within microdomains (diadic spaces) is triggered by elevated [Ca2⫹] entry via L-Type Ca2⫹ Channels (LCCs). However, there is debate on the role of Na⫹/Ca2⫹ exchanger (NCX) in the local control of Ca2⫹-induced Ca2⫹ release (CICR). NCX is electrogenic and depends on Na⫹ and Ca2⫹ gradients, making it difficult to predict its effect on Ca2⫹ dynamics. We introduce local NCX current in the diadic space to study the effect of local NCX on regulation of SR release under physiological and pathological conditions, such as ischemia and heart failure. We developed a local control model of CICR incorporating NCX in the diadic space and studied the effect of local NCX on the excitationcontraction coupling gain, Cai2⫹ transient and SR content. We investigated responses to voltage-clamp stimuli under various conditions such as Na⫹ overload, Ca2⫹ overload, overexpression of and downregulation in SERCA ATPase, LCC and NCX activity. Our simulations are in accord with experimental data by Litwin et al. 1998, Reuter et al. 2003, Seth et al. 2004 and Zhang et al. 2001. We observed that Na⫹ overload (elevated Nai⫹ from 10mM to 20-30 mM) broadens Ca2⫹ transient voltage dependence at high potentials due to activation of SR release by reverse mode of NCX. We demonstrated that under ischemic conditions (elevated Nai⫹ and reduced Nae⫹ from 140 to 100 mM) NCX may act as a trigger of SR release. NCX overexpression (increase in NCX activity by 350%) substantially reduced gain of excitation-contraction coupling especially at lower potentials and reduced Ca2⫹ transient and SR content. Our simulations suggested that NCX up-regulation, observed in models of congestive heart failure, may be a compensatory mechanism in response to contractile dysfunction such as, for example, SERCA ATPase downregulation. Also, at high potentials NCX overexpression by 300% could compensate for 50% reduction in activity of LCCs. Finally, we observed that the effect of NCX overexpression on SR Ca2⫹ content depends on extracellular [Ca2⫹]. Our model supports the claim that NCX regulates the local control of Ca2⫹ in the diadic space and provides a tool for investigating the control of SR Ca2⫹ release under pathological conditions. P4-24 VULNERABILITY TO ELECTRIC SHOCKS IN REGIONAL ISCHEMIA Blanca Rodriguez, PhD, Brock Tice, BS, Robert C. Blake III, BS, James Eason, PhD, David Gavaghan, PhD and Natalia A. Trayanova, PhD. Oxford University Computing Laboratory, Oxford, United Kingdom, Tulane University, New Orleans, LA and Washington and Lee University, Lexington, VA.
Heart Rhythm, Vol 3, No 5, May Supplement 2006 Defibrillation is the only effective therapy against sudden cardiac death. However, defibrillation research has focused mostly on normal hearts, while the majority of patients who undergo the procedure exhibit cardiac pathophysiology secondary to coronary artery disease. Little is known about defibrillation in the setting of ischemic disease. The goal of this study is to aid understanding of defibrillation failure in ischemic hearts by studying changes in cardiac vulnerability to electric shocks during the first 10min following LAD occlusion. Methods: A 3D anatomically accurate bidomain model of the regionally ischemic ventricles following LAD occlusion was developed based on experimental data. The model includes realistic ischemic zone (IZ), lateral and endocardial border zones, and IZ transmural gradients. Ischemic substrate was represented by progressive changes in membrane dynamics due to hyperkalemia, acidosis, and hypoxia. After 7 paced beats, 8ms truncated exponential monophasic shocks of varying strengths and coupling intervals (CIs) were applied via large external electrodes. The upper limit of vulnerability (ULV) and the vulnerable window (VW) at various stages post-occlusion were determined and compared to that of normoxia. Results: Results show that, despite the profound electrophysiological changes in the IZ, ULV remains at its normal value, 26.7V/cm, during the first 10min post-occlusion. This is due to the fact that, for high shock strengths, epicardial and transmural virtual electrode polarization (VEP) and wavefront characteristics immediately after shock-end are not affected by ischemia. However, the VW progressively widens over the course of ischemia, from spanning 60ms (CI from 110 to 170ms) in normoxia to 90ms (CI from 90 to 180ms) 10min post-occlusion. The main cause of VW enlargement in ischemia is slow conduction in the IZ, which increases the likelihood of the establishment of a reentrant circuit following 11-17V/cm strength shocks. Conclusion: Electrophysiological changes occurring in the first 10min following LAD occlusion do not alter the ULV but result in a progressive increase in the VW, caused by slow conduction in the IZ, rather than by changes in shock-induced VEP. P4-25 CARDIAC RESPONSE TO LARGE ELECTRIC FIELDS: THE IMPACT OF A DISCONTINUOUS MYOCARDIUM Mark L. Trew, PhD, Darren A. Hooks, MD, PhD, Gregory B. Sands, PhD, Ian J. Legrice, MD, PhD, Andrew J. Pullan, PhD and Bruce H. Smaill, PhD. Bioengineering Institute, Auckland, New Zealand. The objective of this study is to gain insight into the impact of mesoscale discontinuous structures in normal myocardium on tissue response to large electric fields, by using detailed computer models based on specific samples of rat LV cardiac tissue. Cardiac ventricular myocytes are arranged in discrete bundles separated by cleavage planes or collagenous septae. There is strong evidence that this heterogeneity of myocyte organization has a significant effect on cardiac electrical activity. It is acknowledged that defibrillating shocks would not produce cardioversion if the myocardium behaved as a continuum and structural discontinuity has been proposed to explain response to high voltage shocks. Specific tissue samples were processed, automatically milled and imaged using a confocal microscope rig. Cleavage planes and other myocardial discontinuities were segmented from the images. The image segmentations were mapped onto computational modeling meshes. Detailed bidomain models accounting for the tissue structure were solved on these meshes. Electrical shocks of varying shape, strength and duration were applied in both diastole and systole. Cleavage planes enforce disparate distributions of myocardial and extracellular current densities, causing depolarization on the anodal side, and hyperpolarisation on the cathodal side of the plane. In diastole, large extracellular electric fields in conjunction with significant cleavage planes create distributed activation sources, resulting in rapid transmural depolarisation. Shocks applied in systole introduce positive and negative fluctuations in the plateau transmembrane potential which results in transmural heterogeneity of the APD. The model results are consistent with recent experimental findings. On the basis of these model results, it is postulated that myocardial discontinuities at the level of cleavage planes act to: (i)
Heart Rhythm, Vol 3, No 5, May Supplement 2006 Defibrillation is the only effective therapy against sudden cardiac death. However, defibrillation research has focused mostly on normal hearts, while the majority of patients who undergo the procedure exhibit cardiac pathophysiology secondary to coronary artery disease. Little is known about defibrillation in the setting of ischemic disease. The goal of this study is to aid understanding of defibrillation failure in ischemic hearts by studying changes in cardiac vulnerability to electric shocks during the first 10min following LAD occlusion. Methods: A 3D anatomically accurate bidomain model of the regionally ischemic ventricles following LAD occlusion was developed based on experimental data. The model includes realistic ischemic zone (IZ), lateral and endocardial border zones, and IZ transmural gradients. Ischemic substrate was represented by progressive changes in membrane dynamics due to hyperkalemia, acidosis, and hypoxia. After 7 paced beats, 8ms truncated exponential monophasic shocks of varying strengths and coupling intervals (CIs) were applied via large external electrodes. The upper limit of vulnerability (ULV) and the vulnerable window (VW) at various stages post-occlusion were determined and compared to that of normoxia. Results: Results show that, despite the profound electrophysiological changes in the IZ, ULV remains at its normal value, 26.7V/cm, during the first 10min post-occlusion. This is due to the fact that, for high shock strengths, epicardial and transmural virtual electrode polarization (VEP) and wavefront characteristics immediately after shock-end are not affected by ischemia. However, the VW progressively widens over the course of ischemia, from spanning 60ms (CI from 110 to 170ms) in normoxia to 90ms (CI from 90 to 180ms) 10min post-occlusion. The main cause of VW enlargement in ischemia is slow conduction in the IZ, which increases the likelihood of the establishment of a reentrant circuit following 11-17V/cm strength shocks. Conclusion: Electrophysiological changes occurring in the first 10min following LAD occlusion do not alter the ULV but result in a progressive increase in the VW, caused by slow conduction in the IZ, rather than by changes in shock-induced VEP. P4-25 CARDIAC RESPONSE TO LARGE ELECTRIC FIELDS: THE IMPACT OF A DISCONTINUOUS MYOCARDIUM Mark L. Trew, PhD, Darren A. Hooks, MD, PhD, Gregory B. Sands, PhD, Ian J. Legrice, MD, PhD, Andrew J. Pullan, PhD and Bruce H. Smaill, PhD. Bioengineering Institute, Auckland, New Zealand. The objective of this study is to gain insight into the impact of mesoscale discontinuous structures in normal myocardium on tissue response to large electric fields, by using detailed computer models based on specific samples of rat LV cardiac tissue. Cardiac ventricular myocytes are arranged in discrete bundles separated by cleavage planes or collagenous septae. There is strong evidence that this heterogeneity of myocyte organization has a significant effect on cardiac electrical activity. It is acknowledged that defibrillating shocks would not produce cardioversion if the myocardium behaved as a continuum and structural discontinuity has been proposed to explain response to high voltage shocks. Specific tissue samples were processed, automatically milled and imaged using a confocal microscope rig. Cleavage planes and other myocardial discontinuities were segmented from the images. The image segmentations were mapped onto computational modeling meshes. Detailed bidomain models accounting for the tissue structure were solved on these meshes. Electrical shocks of varying shape, strength and duration were applied in both diastole and systole. Cleavage planes enforce disparate distributions of myocardial and extracellular current densities, causing depolarization on the anodal side, and hyperpolarisation on the cathodal side of the plane. In diastole, large extracellular electric fields in conjunction with significant cleavage planes create distributed activation sources, resulting in rapid transmural depolarisation. Shocks applied in systole introduce positive and negative fluctuations in the plateau transmembrane potential which results in transmural heterogeneity of the APD. The model results are consistent with recent experimental findings. On the basis of these model results, it is postulated that myocardial discontinuities at the level of cleavage planes act to: (i)