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Impact of Atrial Fibrillation on Ventricular Ion Channel and Gap Junction Expression
S82
Abstracts CSANZ Abstracts 2011
ABSTRACTS
Results: Following a MI, atrial electrical remodelling was observed as an increased refractory period (87.0 ± 3.1 ms) compared to controls (57.8 ± 2.2 ms) averaged across all time-points (P < 0.001). Changes in conduction parameters were also observed as a decreased conduction velocity (P < 0.001), increased conduction heterogeneity and increased total activation time (P < 0.005). The occurrence of arrhythmic events were more frequent post-MI (6.2 ± 0.7%) than in control animals (3.9 ± 0.5%) (P < 0.05). Conclusion: Electrical remodeling of the left atrial appendage was observed as alterations in conduction parameters as early as 3 hours post-MI, resulting in the increased frequency of arrhythmic events. doi:10.1016/j.hlc.2011.05.202 200 High Density Epicardial Mapping of the Pulmonary Vein–LA Junction in Humans: Insights into Mechanisms of Pulmonary Vein Arrhythmogenesis G. Lee ∗ , S. Spence, R. Brown, V. Atkinson, M. Larombina, J. Goldblatt, J. Kalman The Royal Melbourne Hospital, Australia Introduction: The electrophysiological characteristics of the PV–LA junction was assessed using high-density epicardial mapping. Methods: Seventeen patients undergoing cardiac surgery were studied. A 128-point epicardial plaque was positioned at the RSPV covering three regions: LA, PV–LA Junction (Jn) and RSPV. Isochronal maps were created during: 1. SR, 2. Atrial pacing (AP), 3. Programmed-stimulation (PES) 10 ms above ERP. Conduction slowing/block (CS/CB) was defined by a CV of 10–20 cm s−1 and <10 cm s−1 . Results: A region of isochronal crowding representing CS/CB developed in the centre of the plaque at the PV–LA Jn in 84% of maps. Three patterns of activation were seen. Pattern 1 (five patients) Uniform SR activation without CS/CB. AP and PES caused one to two lines of isochronal crowding (CS/CB) at the PV–LA Jn. Pattern 2 (three patients) CS/CB occurred at the PV–LA Jn in SR. Atrial pacing and PES caused an increase in CS/CB at the PV/LA Jn with widely split double potentials (DP) and fractionated signals (FS). Pattern 3 (nine patients) a single incomplete line of CS at the PV–LA Jn in SR. With AP and PES multiple lines (≥3) of CS/CB developed at the PV–LA Jn with evidence of circuitous activation and a marked increase in DP and FS. FS/DP were present at the PV–LA Jn in 10 ± 11% SR, 21 ± 11% AP and 31 ± 16% PES (p < 0.001). Conclusion: In patients undergoing cardiac surgery, functional conduction delay occurs at the PV–LA junction rather than within the PV muscle sleeve. Atrial pacing and premature stimulation results in decremental conduction and circuitous activation patterns at the PV–LA junction, creating the substrate for re-entry. doi:10.1016/j.hlc.2011.05.203
Heart, Lung and Circulation 2011;20S:S1–S155
201 High-Density Epicardial Mapping of Human Atrial Fibrillation: Spatial relationship between Complex Electrograms and Regions of High Dominant Frequency G. Lee 1,∗ , K. Roberts-Thomson 2 , S. Spence 1 , A. Teh 1 , J. Kalman 1 1 The 2 The
Royal Melbourne Hospital, Australia Royal Adelaide Hospital, Australia
Introduction: Complex fractionated atrial electrograms (CFAE) and regions of High Dominant Frequency may both identify sites critical to the maintenance of human AF. The anatomic and spatial relationship between these regions is unclear. Methods: Ten patients with long-lasting PerAF underwent high-density epicardial mapping of the posterior LA. Using a 128-point electrode mapping plaque, 10 second segments of simultaneous data were analysed. Simultaneous point-by-point analysis was performed to determine the spatial relationship between CFAE (multi-component and/or continuous signals) and High DF sites (local DF 20% greater than the DF of adjacent sites). Results: Complex fractionated atrial electrograms were present at 25 ± 8% of sites. 17 ± 5 HDF sites were identified per patient with a median DF of 8.7 Hz (IQR 7.6–10.4 Hz). HDF sites were distributed equally throughout the posterior LA. There was poor point-by-point correlation between CFAE and HDF (r = 0.107). Only 35% of points representing HDF also showed CFAE. Despite this poor point by point correlation, spatial analysis revealed 84% of CFAE were found adjacent (<2.5 mm) to and partially surrounding a HDF site, 12% were 2.5–5 mm and 4% 5–10 mm away from a HDF site. No CFAE were found >10 mm away from a HDF site. There was a poor correlation between HDF sites and regions of AFCL < 120 ms, r = 0.188. Conclusions: Sites of visual CFAE and regions of high dominant frequency infrequently show anatomic overlap. However, high density spatial analysis reveals that CFAE are usually observed adjacent to and surrounding sites of HDF. This is consistent with CFAE representing wavebreak around a high frequency focus as previously described in animal studies. doi:10.1016/j.hlc.2011.05.204 202 Impact of Atrial Fibrillation on Ventricular Ion Channel and Gap Junction Expression L. Ling 1,∗ , F. Amirahmadi 1 , O. Khammy 1 , A. Foster 2 , L. Zhang 2 , C. dos Remedios 3 , C. Chen 2 , D. Kaye 1 1 Baker
IDI Heart and Diabetes Institute, Melbourne, Australia
2 School of Biomedical Sciences; University of Queensland, Bris-
bane, Australia Research Group, University of Sydney, Australia
3 Muscle
Introduction: Among ICD recipients, AF predicts appropriate device therapy, but mechanisms underlying ventricular proarrhythmic are unclear. We hypothesised
that irregular ventricular activation alters ion channel expression and cellular electrophysiology. Methods: mRNA expression of ion channels and accessory subunits was examined in neonatal rat ventricular myocytes (NVCMs) paced either regularly or irregularly for 24 hours to simulate ventricular activation in sinus rhythm (SR) and AF respectively. Relevant transmembrane currents were measured after 96 hours of regular vs irregular pacing using whole cell patch clamp approach. LV myocardium from end-stage heart failure (ESHF) patients in SR and chronic AF undergoing cardiac transplantation also underwent mRNA expression studies as guided by results from the NVCM model. Results: Irregular pacing induced a 48% increase in NVCM mRNA expression of KCNA4. However, there was no difference in Ito current density across pacing strategies. Irregular pacing induced trivial changes in NVCM mRNA expression for the Na channel SCN5A (11% reduction), and the Ca channels CACNA1C (19% increase), and CACNA1H (8% decrease). No differences were observed for ion channels CACNA1G, KCNQ1, KCNH2, KCND3, KCNJ2, and KCNJ11; accessory subunits KCNE1, KCNE2, KCNIP2, and ABCC9; and gap junction subunits GJA1 and GJA5. There were no differences in mRNA expression of SCN5A, CACNA1C, CACNA1H, or KCNA4 in LV myocardium from ESHF patients in AF vs SR. Conclusion: In an acute model, irregular ventricular activation associated with AF induces modest changes in mRNA expression of some ion channels, but fails to account for differences in electrophysiologic phenotype among patients with HF. doi:10.1016/j.hlc.2011.05.205 203 Increased Susceptibility to Electrical Instability in Isolated Obese Rat Atria M. Neo ∗ , D. Morris, P. Kuklik, P. Sanders, D. Saint University of Adelaide, Australia Introduction: Obesity is modifiable risk factor for atrial fibrillation (AF). The associations between electrical activity of the atria, obesity and risk of new-onset AF are unknown. Methods: Atria were isolated from age-matched Zucker obese (Ob; n = 4) and lean (Ln; n = 5) rats (3½–4½ months old) and positioned with the epicardial surface in contact with the multi-electrode array (MEA). Intracellular recordings from identical regions were obtained from the endocardial surface during atrial pacing using a microelectrode. The atrial orientation and pacing sites were consistent for each experiment. Results: Compared to Ln rats, Ob rats were heavier (468 ± 26 vs 328 ± 7 g; p = 0.03) with no differences in systolic blood pressure. There were no significant differences in effective refractory period during pacing at 400 (53 ± 3 vs 43 ± 5 ms, p = 0.1) and 100 ms (70 ± 10 vs 40 ± 7 ms, p = 0.1); conduction velocity during pacing at 400 (0.2 ± 0.2 vs 0.2 ± 0.3 m/s, p = 0.7) and 100 ms (0.1 ± 0.008
Abstracts CSANZ Abstracts 2011
S83
vs 0.2 ± 0.02 m/s, p = 0.5); conduction heterogeneity index during pacing at 400 (3.3 ± 0.6 vs 3.4 ± 0.7, p = 0.8) and 100 ms (3.7 ± 0.7 vs 3.0 ± 0.4, p = 0.2). However, action potential duration at 80% of repolarisation (APD80 ) was significantly shorter in Ob at all cycle lengths tested (18 ± 3 vs 28 ± 5 ms at 400 ms; 15 ± 4 vs 24 ± 6 ms at 300 ms; 15 ± 5 vs 24 ± 5 ms at 200 ms; 20 ± 5 vs 22 ± 5 ms at 100 ms). Conclusion: A significant difference between obese and lean Zucker rats was found in action potential restitution. This suggests that repolarisation heterogeneity may play an important role as a potential arrhythmogenic substrate in obese individuals. doi:10.1016/j.hlc.2011.05.206 204 Is Rapid Atrial Pacing Associated with Thrombogenesis in Normal Hearts? C. Schultz 1,∗ , S. Willoughby 1 , H. Lim 1 , B. John 2 , S. Chandy 2 , D. Lau 1 , K. Roberts-Thomson 1 , G. Young 1 , P. Sanders 1 1 Centre for Heart Rhythm Disorders, University of Adelaide, Royal Adelaide Hospital, Australia 2 Department of Cardiology, Christian Medical College, Vellore, India
Introduction: Atrial arrhythmias are associated with an increased thrombotic risk. This study investigated the effect of increased atrial rates on platelet reactivity and cellular adhesion, as markers of thrombogenesis. Methods: Six patients (aged: 36 ± 11 years) with left sided accessory pathway, with structurally normal hearts, undergoing ablation were studied. Immediately following transseptal puncture, simultaneous blood samples were taken from the femoral vein (peripheral), right atria (RA) and left atria (LA). Patients were then atrially paced at 150 beats/min for 10 minutes. Blood samples were collected subsequently from each site at 5 and 10 minutes of pacing. Platelet activation was measured by percentage expression of platelet P-selectin (CD62P) using flow cytometry; plasma levels of vascular cell adhesion molecule (VCAM-1) were determined by ELISA. Results: Prior to pacing there was no difference in Pselectin expression or VCAM-1 levels between sampling sites (p = 0.97, p = 0.73 respectively). Similarly following 5 and 10 minutes of rapid atrial pacing there was no difference in platelet activation or cellular adhesion at any of the sample sites (5 min: p = 0.98 and p = 0.87; 10 min: p = 0.96 and p = 0.86 respectively). Conclusion: This study demonstrates that rapid atrial pacing in normal hearts is not associated with increased prothrombotic tendencies. Sample site
Peripheral Right atria Left atria
P-selectin (CD62P, %)
VCAM-1 (ng/mL)
Baseline
5 min
10 min
Baseline
5 min
21.7 ± 9 23.1 ± 10 23.9 ± 13
28.7 ± 14 26.7 ± 11 27.4 ± 11
22.5 ± 14 24.2 ± 12 27.1 ± 13
385.4 ± 160 408.7 ± 104 451.6 ± 76
495.0 ± 50 467.4 ± 107 450.4 ± 171
doi:10.1016/j.hlc.2011.05.207
10 min 394.5 ± 154 464.0 ± 223 419.8 ± 165
ABSTRACTS
Heart, Lung and Circulation 2011;20S:S1–S155
Abstracts CSANZ Abstracts 2011
ABSTRACTS
Results: Following a MI, atrial electrical remodelling was observed as an increased refractory period (87.0 ± 3.1 ms) compared to controls (57.8 ± 2.2 ms) averaged across all time-points (P < 0.001). Changes in conduction parameters were also observed as a decreased conduction velocity (P < 0.001), increased conduction heterogeneity and increased total activation time (P < 0.005). The occurrence of arrhythmic events were more frequent post-MI (6.2 ± 0.7%) than in control animals (3.9 ± 0.5%) (P < 0.05). Conclusion: Electrical remodeling of the left atrial appendage was observed as alterations in conduction parameters as early as 3 hours post-MI, resulting in the increased frequency of arrhythmic events. doi:10.1016/j.hlc.2011.05.202 200 High Density Epicardial Mapping of the Pulmonary Vein–LA Junction in Humans: Insights into Mechanisms of Pulmonary Vein Arrhythmogenesis G. Lee ∗ , S. Spence, R. Brown, V. Atkinson, M. Larombina, J. Goldblatt, J. Kalman The Royal Melbourne Hospital, Australia Introduction: The electrophysiological characteristics of the PV–LA junction was assessed using high-density epicardial mapping. Methods: Seventeen patients undergoing cardiac surgery were studied. A 128-point epicardial plaque was positioned at the RSPV covering three regions: LA, PV–LA Junction (Jn) and RSPV. Isochronal maps were created during: 1. SR, 2. Atrial pacing (AP), 3. Programmed-stimulation (PES) 10 ms above ERP. Conduction slowing/block (CS/CB) was defined by a CV of 10–20 cm s−1 and <10 cm s−1 . Results: A region of isochronal crowding representing CS/CB developed in the centre of the plaque at the PV–LA Jn in 84% of maps. Three patterns of activation were seen. Pattern 1 (five patients) Uniform SR activation without CS/CB. AP and PES caused one to two lines of isochronal crowding (CS/CB) at the PV–LA Jn. Pattern 2 (three patients) CS/CB occurred at the PV–LA Jn in SR. Atrial pacing and PES caused an increase in CS/CB at the PV/LA Jn with widely split double potentials (DP) and fractionated signals (FS). Pattern 3 (nine patients) a single incomplete line of CS at the PV–LA Jn in SR. With AP and PES multiple lines (≥3) of CS/CB developed at the PV–LA Jn with evidence of circuitous activation and a marked increase in DP and FS. FS/DP were present at the PV–LA Jn in 10 ± 11% SR, 21 ± 11% AP and 31 ± 16% PES (p < 0.001). Conclusion: In patients undergoing cardiac surgery, functional conduction delay occurs at the PV–LA junction rather than within the PV muscle sleeve. Atrial pacing and premature stimulation results in decremental conduction and circuitous activation patterns at the PV–LA junction, creating the substrate for re-entry. doi:10.1016/j.hlc.2011.05.203
Heart, Lung and Circulation 2011;20S:S1–S155
201 High-Density Epicardial Mapping of Human Atrial Fibrillation: Spatial relationship between Complex Electrograms and Regions of High Dominant Frequency G. Lee 1,∗ , K. Roberts-Thomson 2 , S. Spence 1 , A. Teh 1 , J. Kalman 1 1 The 2 The
Royal Melbourne Hospital, Australia Royal Adelaide Hospital, Australia
Introduction: Complex fractionated atrial electrograms (CFAE) and regions of High Dominant Frequency may both identify sites critical to the maintenance of human AF. The anatomic and spatial relationship between these regions is unclear. Methods: Ten patients with long-lasting PerAF underwent high-density epicardial mapping of the posterior LA. Using a 128-point electrode mapping plaque, 10 second segments of simultaneous data were analysed. Simultaneous point-by-point analysis was performed to determine the spatial relationship between CFAE (multi-component and/or continuous signals) and High DF sites (local DF 20% greater than the DF of adjacent sites). Results: Complex fractionated atrial electrograms were present at 25 ± 8% of sites. 17 ± 5 HDF sites were identified per patient with a median DF of 8.7 Hz (IQR 7.6–10.4 Hz). HDF sites were distributed equally throughout the posterior LA. There was poor point-by-point correlation between CFAE and HDF (r = 0.107). Only 35% of points representing HDF also showed CFAE. Despite this poor point by point correlation, spatial analysis revealed 84% of CFAE were found adjacent (<2.5 mm) to and partially surrounding a HDF site, 12% were 2.5–5 mm and 4% 5–10 mm away from a HDF site. No CFAE were found >10 mm away from a HDF site. There was a poor correlation between HDF sites and regions of AFCL < 120 ms, r = 0.188. Conclusions: Sites of visual CFAE and regions of high dominant frequency infrequently show anatomic overlap. However, high density spatial analysis reveals that CFAE are usually observed adjacent to and surrounding sites of HDF. This is consistent with CFAE representing wavebreak around a high frequency focus as previously described in animal studies. doi:10.1016/j.hlc.2011.05.204 202 Impact of Atrial Fibrillation on Ventricular Ion Channel and Gap Junction Expression L. Ling 1,∗ , F. Amirahmadi 1 , O. Khammy 1 , A. Foster 2 , L. Zhang 2 , C. dos Remedios 3 , C. Chen 2 , D. Kaye 1 1 Baker
IDI Heart and Diabetes Institute, Melbourne, Australia
2 School of Biomedical Sciences; University of Queensland, Bris-
bane, Australia Research Group, University of Sydney, Australia
3 Muscle
Introduction: Among ICD recipients, AF predicts appropriate device therapy, but mechanisms underlying ventricular proarrhythmic are unclear. We hypothesised
that irregular ventricular activation alters ion channel expression and cellular electrophysiology. Methods: mRNA expression of ion channels and accessory subunits was examined in neonatal rat ventricular myocytes (NVCMs) paced either regularly or irregularly for 24 hours to simulate ventricular activation in sinus rhythm (SR) and AF respectively. Relevant transmembrane currents were measured after 96 hours of regular vs irregular pacing using whole cell patch clamp approach. LV myocardium from end-stage heart failure (ESHF) patients in SR and chronic AF undergoing cardiac transplantation also underwent mRNA expression studies as guided by results from the NVCM model. Results: Irregular pacing induced a 48% increase in NVCM mRNA expression of KCNA4. However, there was no difference in Ito current density across pacing strategies. Irregular pacing induced trivial changes in NVCM mRNA expression for the Na channel SCN5A (11% reduction), and the Ca channels CACNA1C (19% increase), and CACNA1H (8% decrease). No differences were observed for ion channels CACNA1G, KCNQ1, KCNH2, KCND3, KCNJ2, and KCNJ11; accessory subunits KCNE1, KCNE2, KCNIP2, and ABCC9; and gap junction subunits GJA1 and GJA5. There were no differences in mRNA expression of SCN5A, CACNA1C, CACNA1H, or KCNA4 in LV myocardium from ESHF patients in AF vs SR. Conclusion: In an acute model, irregular ventricular activation associated with AF induces modest changes in mRNA expression of some ion channels, but fails to account for differences in electrophysiologic phenotype among patients with HF. doi:10.1016/j.hlc.2011.05.205 203 Increased Susceptibility to Electrical Instability in Isolated Obese Rat Atria M. Neo ∗ , D. Morris, P. Kuklik, P. Sanders, D. Saint University of Adelaide, Australia Introduction: Obesity is modifiable risk factor for atrial fibrillation (AF). The associations between electrical activity of the atria, obesity and risk of new-onset AF are unknown. Methods: Atria were isolated from age-matched Zucker obese (Ob; n = 4) and lean (Ln; n = 5) rats (3½–4½ months old) and positioned with the epicardial surface in contact with the multi-electrode array (MEA). Intracellular recordings from identical regions were obtained from the endocardial surface during atrial pacing using a microelectrode. The atrial orientation and pacing sites were consistent for each experiment. Results: Compared to Ln rats, Ob rats were heavier (468 ± 26 vs 328 ± 7 g; p = 0.03) with no differences in systolic blood pressure. There were no significant differences in effective refractory period during pacing at 400 (53 ± 3 vs 43 ± 5 ms, p = 0.1) and 100 ms (70 ± 10 vs 40 ± 7 ms, p = 0.1); conduction velocity during pacing at 400 (0.2 ± 0.2 vs 0.2 ± 0.3 m/s, p = 0.7) and 100 ms (0.1 ± 0.008
Abstracts CSANZ Abstracts 2011
S83
vs 0.2 ± 0.02 m/s, p = 0.5); conduction heterogeneity index during pacing at 400 (3.3 ± 0.6 vs 3.4 ± 0.7, p = 0.8) and 100 ms (3.7 ± 0.7 vs 3.0 ± 0.4, p = 0.2). However, action potential duration at 80% of repolarisation (APD80 ) was significantly shorter in Ob at all cycle lengths tested (18 ± 3 vs 28 ± 5 ms at 400 ms; 15 ± 4 vs 24 ± 6 ms at 300 ms; 15 ± 5 vs 24 ± 5 ms at 200 ms; 20 ± 5 vs 22 ± 5 ms at 100 ms). Conclusion: A significant difference between obese and lean Zucker rats was found in action potential restitution. This suggests that repolarisation heterogeneity may play an important role as a potential arrhythmogenic substrate in obese individuals. doi:10.1016/j.hlc.2011.05.206 204 Is Rapid Atrial Pacing Associated with Thrombogenesis in Normal Hearts? C. Schultz 1,∗ , S. Willoughby 1 , H. Lim 1 , B. John 2 , S. Chandy 2 , D. Lau 1 , K. Roberts-Thomson 1 , G. Young 1 , P. Sanders 1 1 Centre for Heart Rhythm Disorders, University of Adelaide, Royal Adelaide Hospital, Australia 2 Department of Cardiology, Christian Medical College, Vellore, India
Introduction: Atrial arrhythmias are associated with an increased thrombotic risk. This study investigated the effect of increased atrial rates on platelet reactivity and cellular adhesion, as markers of thrombogenesis. Methods: Six patients (aged: 36 ± 11 years) with left sided accessory pathway, with structurally normal hearts, undergoing ablation were studied. Immediately following transseptal puncture, simultaneous blood samples were taken from the femoral vein (peripheral), right atria (RA) and left atria (LA). Patients were then atrially paced at 150 beats/min for 10 minutes. Blood samples were collected subsequently from each site at 5 and 10 minutes of pacing. Platelet activation was measured by percentage expression of platelet P-selectin (CD62P) using flow cytometry; plasma levels of vascular cell adhesion molecule (VCAM-1) were determined by ELISA. Results: Prior to pacing there was no difference in Pselectin expression or VCAM-1 levels between sampling sites (p = 0.97, p = 0.73 respectively). Similarly following 5 and 10 minutes of rapid atrial pacing there was no difference in platelet activation or cellular adhesion at any of the sample sites (5 min: p = 0.98 and p = 0.87; 10 min: p = 0.96 and p = 0.86 respectively). Conclusion: This study demonstrates that rapid atrial pacing in normal hearts is not associated with increased prothrombotic tendencies. Sample site
Peripheral Right atria Left atria
P-selectin (CD62P, %)
VCAM-1 (ng/mL)
Baseline
5 min
10 min
Baseline
5 min
21.7 ± 9 23.1 ± 10 23.9 ± 13
28.7 ± 14 26.7 ± 11 27.4 ± 11
22.5 ± 14 24.2 ± 12 27.1 ± 13
385.4 ± 160 408.7 ± 104 451.6 ± 76
495.0 ± 50 467.4 ± 107 450.4 ± 171
doi:10.1016/j.hlc.2011.05.207
10 min 394.5 ± 154 464.0 ± 223 419.8 ± 165
ABSTRACTS
Heart, Lung and Circulation 2011;20S:S1–S155