Electrocardiographic imaging demonstrates electrical synchrony improvement by dynamic atrioventricular delays in patients with left bundle branch block and preserved atrioventricular conduction

Aims: Cardiac resynchronization therapy programmed to dynamically fuse pacing with intrinsic conduction using atrioventricular (AV) timing algorithms (e.g. SyncAV) has shown promise; however, mechanistic data are lacking. This study assessed the impact of SyncAV on electrical dyssynchrony across various pacing modalities using non-invasive epicardial electrocardiographic imaging (ECGi). Methods and results: Twenty-five patients with left bundle-branch block (median QRS duration (QRSd) 162.7 ms) and intact AV conduction (PR interval 174.0 ms) were prospectively enrolled. ECGi was performed acutely during biventricular pacing with fixed nominal AV delays (BiV) and using SyncAV (optimized for the narrowest QRSd) during: BiV + SyncAV, LV-only single-site (LVSS + SyncAV), MultiPoint pacing (MPP + SyncAV), and LV-only MPP (LVMPP + SyncAV). Dyssynchrony was quantified via ECGi (LV activation time, LVAT; RV activation time, RVAT; LV electrical dispersion index, LVEDi; ventricular electrical uncoupling index, VEU; and biventricular total activation time, VVtat). Intrinsic conduction LVAT (124 ms) was significantly reduced by BiV pacing (109 ms) (P = 0.001) and further reduced by LVSS + SyncAV (103 ms), BiV + SyncAV (103 ms), LVMPP + SyncAV (95 ms), and MPP + SyncAV (90 ms). Intrinsic RVAT (93 ms), VVtat (130 ms), LVEDi (36 ms), VEU (50 ms), and QRSd (163 ms) were reduced by SyncAV across all pacing modes. More patients exhibited minimal LVAT, VVtat, LVEDi, and QRSd with MPP + SyncAV than any other modality. Conclusion: Dynamic AV delay programming targeting fusion with intrinsic conduction significantly reduced dyssynchrony, as quantified by ECGi and QRSd for all evaluated pacing modes. MPP + SyncAV achieved the greatest synchrony overall but not for all patients, highlighting the value of pacing mode individualization during fusion optimization

Electrotonic loading of anisotropic cardiac monolayers by unexcitable cells depends on connexin type and expression level

Understanding how electrotonic loading of cardiomyocytes by unexcitable cells alters cardiac impulse conduction may be highly relevant to fibrotic heart disease. In this study, we optically mapped electrical propagation in confluent, aligned neonatal rat cardiac monolayers electrotonically loaded with cardiac fibroblasts, control human embryonic kidney (HEK-293) cells, or HEK-293 cells genetically engineered to overexpress the gap junction proteins connexin-43 or connexin-45. Gap junction expression and function were assessed by immunostaining, immunoblotting, and fluorescence recovery after photobleaching and were correlated with the optically mapped propagation of action potentials. We found that neonatal rat ventricular fibroblasts negative for the myofibroblast marker smooth muscle α-actin expressed connexin-45 rather than connexin-43 or connexin-40, weakly coupled to cardiomyocytes, and, without significant depolarization of cardiac resting potential, slowed cardiac conduction to 75% of control only at high (>60%) coverage densities, similar to loading effects found from HEK-293 cells expressing similar levels of connexin-45. In contrast, HEK-293 cells with connexin-43 expression similar to that of cardiomyocytes significantly decreased cardiac conduction velocity and maximum capture rate to as low as 22% and 25% of control values, respectively, while increasing cardiac action potential duration to 212% of control and cardiac resting potential from −71.6 ± 4.9 mV in controls to −65.0 ± 3.8 mV. For all unexcitable cell types and coverage densities, velocity anisotropy ratio remained unchanged. Despite the induced conduction slowing, none of the loading cell types increased the proportion of spontaneously active monolayers. These results signify connexin isoform and expression level as important contributors to potential electrical interactions between unexcitable cells and myocytes in cardiac tissue

Dynamic atrioventricular delay programming improves ventricular electrical synchronization as evaluated by 3D vectorcardiography

Background: Optimal timing of the atrioventricular delay in cardiac resynchronization therapy (CRT) can improve synchrony in patients suffering from heart failure. The purpose of this study was to evaluate the impact of SyncAV (TM) on electrical synchrony as measured by vectorcardiography (VCG) derived QRS metrics during biventricular (BiV) pacing. Methods: Patients implanted with a cardiac resynchronization therapy (CRT) device and quadripolar left ventricular (LV) lead underwent 12-lead ECG recordings. VCG metrics, including QRS duration (QRSd) and area, were derived from the ECG by a blinded observer during: intrinsic conduction, BiV with nominal atrioventricular delays (BiV Nominal), and BiV with SyncAV programmed to the optimal offset achieving maximal synchronization (BiV + SyncAV Opt). Results: One hundred patients (71% male, 40% ischemic, 65% LBBB, 32 +/- 9% ejection fraction) completed VCG assessment. QRSd during intrinsic conduction (166 +/- 25 ms) was narrowed successively by BiV Nominal (137 +/- 23 ms, p <.05 vs. intrinsic) and BiV + SyncAV Opt (122 +/- 22 ms, p Conclusion: With VCG-based, patient-specific optimization of the programmable offset, SyncAV reduced electrical dyssynchrony beyond conventional CRT. Crown Copyright (C) 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

A modified choline-deficient, ethionine-supplemented diet reduces morbidity and retains a liver progenitor cell response in mice

The choline-deficient, ethionine-supplemented (CDE) dietary model induces chronic liver damage, and stimulates liver progenitor cell (LPC)-mediated repair. Long-term CDE administration leads to hepatocellular carcinoma in rodents and lineage-tracing studies show that LPCs differentiate into functional hepatocytes in this model. The CDE diet was first modified for mice by our laboratory by separately administering choline-deficient chow and ethionine in the drinking water (CD+E diet). Although this CD+E diet is widely used, concerns with variability in weight loss, morbidity, mortality and LPC response have been raised by researchers who have adopted this model. We propose that these inconsistencies are due to differential consumption of chow and ethionine in the drinking water, and that incorporating ethionine in the choline-deficient chow, and altering the strength, will achieve better outcomes. Therefore, C57Bl/6 mice, 5 and 6 weeks of age, were fed an all-inclusive CDE diet of various strengths (67% to 100%) for 3 weeks. The LPC response was quantitated and cell lines were derived. We found that animal survival, LPC response and liver damage are correlated with CDE diet strength. The 67% and 75% CDE diet administered to mice older than 5 weeks and greater than 18 g provides a consistent and acceptable level of animal welfare and induces a substantial LPC response, permitting their isolation and establishment of cell lines. This study shows that an all-inclusive CDE diet for mice reproducibly induces an LPC response conducive to in vivo studies and isolation, whilst minimizing morbidity and mortality

Additional electrodes on the Quartet™ LV lead provide more programmable pacing options than bipolar and tripolar equivalents

International audienceAIMS: The aim of this study was to evaluate any benefits to the number of viable pacing vectors and maximal spatial coverage with quadripolar left ventricular (LV) leads when compared with tripolar and bipolar equivalents in patients receiving cardiac resynchronization therapy (CRT). METHODS AND RESULTS: A meta-analysis of five previously published clinical trials involving the Quartet™ LV lead (St Jude Medical, St Paul, MN, USA) was performed to evaluate the number of viable pacing vectors defined as capture thresholds ≤2.5 V and no phrenic nerve stimulation and maximal spatial coverage of viable vectors in CRT patients at pre-discharge (n = 370) and first follow-up (n = 355). Bipolar and tripolar lead configurations were modelled by systematic elimination of two and one electrode(s), respectively, from the Quartet lead. The Quartet lead with its four pacing electrodes exhibited the greatest number of pacing vectors per patient when compared with the best bipolar and the best tripolar modelled equivalents. Similarly, the Quartet lead provided the highest spatial coverage in terms of the distance between two furthest viable pacing cathodes when compared with the best bipolar and the best tripolar configurations (P \textless 0.05). Among the three modelled bipolar configurations, the lead configuration with the two most distal electrodes resulted in the highest number of viable pacing vectors. Among the four modelled tripolar configurations, elimination of the second proximal electrode (M3) resulted in the highest number of viable pacing options per patient. There were no significant differences observed between pre-discharge and first follow-up analyses. CONCLUSION: The Quartet lead with its four electrodes and the capability to pace from four anatomical locations provided the highest number of viable pacing vectors at pre-discharge and first follow-up visits, providing more flexibility in device programming and enabling continuation of CRT in more patients when compared with bipolar and tripolar equivalent

PO05-46: Novel insights into activation pattern along a quadripolar left ventricular lead in cardiac resynchronization therapy patients: Effect of right ventricular pacing vs. normal sinus rhythm

Introduction: The nature and significance of electrical delay between right (RV) and left ventricular (LV) pacing leads are poorly understood. We evaluated differences in RV-LV electrical delay and LV activation pattern along a quadripolar LV lead during RV pacing (RVP) and normal sinus rhythm (NSR). Methods: Electrical delays between the RV and all 4 poles of the LV lead (D1, M2, M3, and P4, distal to proximal) were measured during RVP and NSR in 164 pts receiving a CRT implant with a quadripolar lead. The activation pattern was defined by the order of earliest to latest LV electrode activation, either sequential distal-to-proximal, or sequential proximal-to distal, or non-sequential. Results: The average RV-LV electrical display was significantly longer during RVP than NSR (each p≤0.001, Fig A). The latest activating electrode was frequently D1 of P4 during both RVP (D1: 32%, P4: 42%) and NSR (D1: 34%, P4: 37%) (Fig B), while the earliest activating electrode was most frequently D1 for both RVP (55%) and NSR (54%) (Fig C). A non-sequential activation pattern was observed in 81/164 (49%) patients during RVP and 77/164 (47%) during NSR (Fig D). A difference in activation pattern between RVP and NSR was observed in 130/164 (79%) patients. RVP produced greater electrical delay between the latest and earliest activating LV electrodes than NSR (24±18 vs. 20±11 ms, p = 0.015). Conclusions: Activation pattern along a quadripolar LV lead was frequently different between RV pacing and normal sinus rhythm, with RV pacing producing greater delay between early and late sites. These results may have important implications for using conduction delays to optimize CRT programming with a quadripolar LV lead

Ventricular activation patterns during intrinsic conduction and right ventricular pacing in cardiac resynchronization therapy patients

International audienceBackground Cardiac resynchronization therapy (CRT) involves stimulation of both right ventricle (RV) and left ventricle (LV). LV pacing from the sites of delayed electrical activation improves CRT response. The RV-LV conduction is typically measured in intrinsic rhythm. The differences in RV-LV conduction patterns and timing between intrinsic rhythm and during paced RV activation, these differences are not fully understood. Methods Enrolled patients were implanted with a de novo CRT device and quadripolar LV lead, with lead implant locations at the implanting physician's discretion. QRS duration and conduction delay between the RV lead and each of the four LV electrodes (D1, M2, M3, and P4) were measured during intrinsic conduction and RV pacing. Results Conduction measurements were collected from 275 patients across 14 international centers (68 +/- 13 years of age, 73% male, 45% ischemic, 158 +/- 22 ms QRS duration). Mean RV-LV conduction time was shorter during intrinsic conduction versus RV pacing by 59.6 ms (106.5 +/- 36.5 versus 166.1 +/- 32.1 ms, p &lt; 0.001). The intra-LV activation delay between the latest and earliest activating LV electrode was also shorter during intrinsic conduction versus RV pacing by 6.6 ms (20.6 +/- 13.1 vs. 27.2 +/- 21.2 ms, p &lt; 0.001). Intrinsic conduction and RV pacing resulted in a different activation order in 72.7% of patients, and the same LV activation order in 27.3%. Conclusions Differences in RV-LV conduction time, intra-LV conduction time, and activation pattern were observed between intrinsic conduction and RV pacing. These findings highlight the importance of evaluating intrinsic versus paced ventricular activation to guide LV pacing site selection in CRT patients