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.

Integration of 3D nuclear imaging in 3D mapping system for ventricular tachycardia ablation in patients with implanted devices: Perfusion/voltage retrospective assessment of scar location.

Background: The identification of low-voltage proarrhythmic areas for catheter ablation of scar-mediated ventricular tachycardia (VT) remains challenging. Integration of myocardial perfusion imaging (single-photon emission computed tomography/computed tomography; SPECT/CT) and electroanatomical mapping (EAM) may improve delineation of the arrhythmogenic substrate. Objective: To assess the feasibility of SPECT/CT image integration with voltage maps using the EnSite Precision system (Abbott) in patients undergoing scar-mediated VT ablation. Methods: Patients underwent SPECT/CT imaging prior to left ventricular (LV) EAM with the EnSite Precision mapping system. The SPECT/CT, EAM data, and ablation lesions were retrospectively co-registered in the EnSite Precision system and exported for analysis. Segmental tissue viability scores were calculated based on SPECT/CT perfusion and electrogram bipolar voltage amplitude. Concordance, specificity, and sensitivity between the 2 modalities as well as the impact of SPECT/CT spatial resolution were evaluated. Results: Twenty subjects (95% male, 67 ± 7 years old, left ventricular ejection fraction 36% ± 11%) underwent EAM and SPECT/CT integration. A concordance of 70% was found between EAM and SPECT/CT for identification of cardiac segments as scar vs viable, with EAM showing a 68.5% sensitivity and 76.4% specificity when using SPECT/CT as a gold standard. Projection on low-resolution 3D geometries led to an average decrease of 38% ± 22% of the voltage points used. Conclusion: The study demonstrated the feasibility of integrating SPECT/CT with EAM performed retrospectively for characterization of anatomical substrates during VT ablation procedures.

Electroanatomical Navigation to Minimize Contrast Medium or X-Rays During Stenting: Insights From an Experimental Model.

Stents can be effectively implemented with no x-rays or contrast medium. Modified stents were successfully implanted in 9 of 11 attempted targets (82%) (7 carotid and 4 coronary arteries) using an impedance-sensitive navigation system and optical coherence tomography. Electroanatomical navigation systems can be used to assist interventionalists in performing arterial stenting while minimizing x-ray and contrast use, thereby potentially enhancing safety for both patients and catheterization laboratory staff members.

Peripheral Interventions Radiation Exposure Reduction Using a Sensor-Based Navigation System: A Proof-of-Concept Study.

BACKGROUND: Intravascular catheter positioning is done with radiography imaging. Increasing evidence indicates excessive ionizing radiation exposure for patients and physicians during catheterization procedures, making solutions to reduce radiation exposure a priority. This study evaluated the feasibility and impact of using sensor-based magnetic navigation on (i) fluoroscopy time and (ii) positioning accuracy and safety of a peripheral angioplasty balloon catheter. METHODS: All patients (n = 10) underwent a balloon-positioning protocol using 2 navigation methods sequentially: (i) magnetic navigation with minimal fluoroscopy; (ii) fluoroscopic navigation. The navigation method order was randomized, and 4 consecutive placements per method were performed. A target vascular bifurcation was used as a fiduciary landmark for both methods to determine accuracy. RESULTS: Balloon placements were successful with both navigation methods in all subjects, and no adverse events occurred. Magnetic guidance led to significant reductions in fluoroscopy time (0.37 ± 1.5 vs 15.0 ± 8.1 seconds, P < 0.001) and dose (0.3 ± 1.2 vs 24.1 ± 23.8 µGy.m2, P < 0.01). The time duration for balloon alignment was similar for the 2 navigation methods (4.8 ± 1.4 vs 4.8 ± 2.3 seconds, P = 0.89), and the accuracy was almost identical (0.51 ± 0.41 vs 0.51 ± 0.32 mm, P = 0.97). CONCLUSIONS: These results demonstrate the feasibility of using sensor-based magnetic guidance during simple peripheral interventional procedures; a significant reduction in ionizing radiation was achieved, with excellent positioning accuracy and safety. The clinical applications of magnetic guidance for device navigation during more complex percutaneous procedures should be evaluated.

CONTEXTE: Le positionnement d'un cathéter intravasculaire fait appel à l'imagerie radiographique. De plus en plus de données probantes indiquent que les patients et les médecins subissent une surexposition aux rayonnements ionisants pendant le cathétérisme, ce qui fait des solutions de réduction de l'irradiation une priorité. Cette étude a permis d'évaluer la faisabilité du guidage magnétique par capteur et son effet sur (i) la durée de la fluoroscopie et (ii) la précision et la sécurité du positionnement d'un cathéter d'angioplastie périphérique à ballonnet. MÉTHODOLOGIE: Chez tous les patients (n = 10), le positionnement du ballonnet a été effectué en fonction d'un protocole fondé sur deux méthodes de guidage mises en œuvre séquentiellement : (i) guidage magnétique avec fluoroscopie minimale; (ii) guidage fluoroscopique. L'ordre dans lequel les méthodes de guidage ont été mises en œuvre a été randomisé, et quatre positionnements consécutifs par méthode ont été effectués. Une bifurcation vasculaire cible a servi de repère de fond de chambre afin de déterminer la précision des deux méthodes. RÉSULTATS: Les deux méthodes de guidage ont permis un positionnement adéquat du ballonnet chez tous les patients, et aucun événement indésirable n'est survenu. Le guidage magnétique a entraîné des réductions significatives de la durée de la fluoroscopie (0,37 ± 1,5 vs 15,0 ± 8,1 secondes, p < 0,001) et de la dose de rayonnement (0,3 ± 1,2 vs 24,1 ± 23,8 µGy.m2, p < 0,01). La durée de l'alignement du ballonnet était similaire lors de la mise en œuvre des deux méthodes de guidage (4,8 ± 1,4 vs 4,8 ± 2,3 secondes, p = 0,89), et la précision était presque identique (0,51 ± 0,41 vs 0,51 ± 0,32 mm, p = 0,97). CONCLUSIONS: Ces résultats démontrent la faisabilité du guidage magnétique par capteur dans le cadre d'angioplasties périphériques simples. L'exposition aux rayonnements ionisants a été réduite de façon significative, et la précision ainsi que la sécurité du positionnement se sont avérées excellentes. Les applications cliniques du guidage magnétique dans le contexte d'interventions percutanées plus complexes représentent une avenue de recherche à explorer.

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

BACKGROUND: 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 < 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 < 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.

Electrical synchronization achieved by multipoint pacing combined with dynamic atrioventricular delay.

PURPOSE: Multipoint pacing (MPP) improves left ventricular (LV) electrical synchrony in cardiac resynchronization therapy (CRT). SyncAV automatically adjusts atrioventricular delay (AVD) according to intrinsic AV intervals and may further improve synchrony. Their combination has not been assessed. The objective was to evaluate the improvement in electrical synchrony achieved by SyncAV combined with MPP in an international, multicenter study. METHODS: Patients with LBBB undergoing CRT implant with a quadripolar lead (Abbott Quartet™) were prospectively enrolled. QRS duration (QRSd) was measured by blinded observers from 12-lead ECG during: intrinsic conduction, BiV pacing (conventional biventricular pacing, nominal static AVD), MPP (2 LV cathodes maximally spaced, nominal static AVD), BiV + SyncAV, and MPP + SyncAV. All SyncAV offsets were individualized for each patient to yield the narrowest QRSd during BiV pacing. QRSd changes were compared by ANOVA and post hoc Tukey-Kramer tests. RESULTS: One hundred and three patients were enrolled (65.7 ± 12.1 years, 67% male, 37% ischemic, EF 26.4 ± 6.5%, PR 190.3 ± 39.1 ms). Relative to intrinsic conduction (QRSd of 165 ± 16 ms), BiV reduced QRSd by 11.9% to 145 ± 18 ms (P < 0.001 vs intrinsic), and MPP reduced QRSd by 13.3% to 142 ± 19 ms (P < 0.001 vs intrinsic). However, enabling SyncAV with a patient-optimized offset nearly doubled this QRSd reduction. BiV + SyncAV reduced QRSd by 22.0% to 128 ± 13 ms (P < 0.001 vs BiV), while MPP + SyncAV reduced QRSd further by 25.6% to 122 ± 14 ms (P < 0.05 vs BiV + SyncAV). CONCLUSION: SyncAV can significantly improve acute electrical synchrony beyond conventional CRT, with further improvement achieved by superimposing MPP.

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™ on electrical synchrony as measured by vectorcardiography (VCG) derived QRS metrics during bi-ventricular (BiV) pacing. METHODS: Patients implanted with a cardiac resynchronization therapy (CRT) device and quadripolar left ventricular (LV) lead underwent 12­lead 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 ±â€¯9% ejection fraction) completed VCG assessment. QRSd during intrinsic conduction (166 ±â€¯25 ms) was narrowed successively by BiV Nominal (137 ±â€¯23 ms, p < .05 vs. intrinsic) and BiV + SyncAV Opt (122 ±â€¯22 ms, p < .05 vs. BiV Nominal). Likewise, 3D QRS area during intrinsic conduction (90 ±â€¯42 mV ∗ ms) was reduced by BiV Nominal (65 ±â€¯39 mV ∗ ms, p < .05 vs. intrinsic) and further by BiV + SyncAV Opt (53 ±â€¯30 mV ∗ ms, p = .06 vs. BiV Nominal). CONCLUSION: With VCG-based, patient-specific optimization of the programmable offset, SyncAV reduced electrical dyssynchrony beyond conventional CRT.

Generation of a cohort of whole-torso cardiac models for assessing the utility of a novel computed shock vector efficiency metric for ICD optimisation.

Implanted cardiac defibrillators (ICDs) seek to automatically detect and terminate potentially lethal ventricular arrhythmias by applying strong internal electric shocks across the heart. However, the optimisation of the specific electrode design and configurations represents an intensive area of research in the pursuit of reduced shock strengths and fewer device complications and risks. Computational whole-torso simulations play an important role in this endeavour, although knowing which specific metric should be used to assess configuration efficacy and assessing the impact of different patient anatomies and pathologies, and the corresponding effect this may have on different metrics has not been investigated. We constructed a cohort of CT-derived high-resolution whole torso-cardiac computational models, including variants of cardiomyopathies and patients with differing torso dimensions. Simulations of electric shock application between electrode configurations corresponding to transveneous (TV-ICD) and subcutaneous (S-ICD) ICDs were modelled and conventional metrics such as defibrillation threshold (DFT) and impedance computed. In addition, we computed a novel metric termed the shock vector efficiency (η), which quantifies the fraction of electrical energy dissipated in the heart relative to the rest of the torso. Across the cohort, S-ICD configurations showed higher DFTs and impedances than TV-ICDs, as expected, although little consistent difference was seen between healthy and cardiomyopathy variants. η was consistently <2% for S-ICD configurations, becoming as high as 13% for TV-ICD setups. Simulations also suggested that a total torso height of approximately 20 cm is required for convergence in η. Overall, η was seen to be approximately negatively correlated with both DFT and impedance. However, important scenarios were identified in which certain values of DFT (or impedance) were associated with a range of η values, and vice-versa, highlighting the heterogeneity introduced by the different torsos and pathologies modelled. In conclusion, the shock vector efficiency represents a useful additional metric to be considered alongside DFT and impedance in the optimisation of ICD electrode configurations, particularly in the context of differing torso anatomies and cardiac pathologies, which can induce significant heterogeneity in conventional metrics of ICD efficacy.

Dynamic programming of atrioventricular delay improves electrical synchrony in a multicenter cardiac resynchronization therapy study.

BACKGROUND: Patient-specific programming of cardiac resynchronization therapy (CRT) is often neglected, despite significant nonresponse rates. The device-based SyncAV CRT algorithm dynamically adjusts atrioventricular delays to the intrinsic AV interval, reduced by a programmable offset, to accommodate each patient's changing needs. OBJECTIVE: The purpose of this study was to evaluate the acute effect of biventricular (BiV) pacing enhanced by SyncAV on electrical synchrony in a broad patient population. METHODS: Patients with existing CRT implants were prospectively evaluated at 5 international centers. Blinded 12-lead electrocardiographic QRS duration (QRSd) measurements were used to compare intrinsic conduction with nominal BiV pacing, BiV + SyncAV (default 50 ms offset), and BiV + SyncAV (optimized, patient-specific offset). BiV configurations were tested twice using the latest activating and earliest activating left ventricular (LV) electrodes as cathodes. RESULTS: Ninety patients (mean age 67.1 ± 9.5 years; 67 (74%) men; 55 (63%) with left bundle branch block; 37 (43%) with ischemic cardiomyopathy; LV ejection fraction 32% ± 9%) with intact atrioventricular conduction (PR interval 195 ± 45 ms) were enrolled. With BiV pacing from the latest activating LV electrode, the intrinsic QRSd of 155 ± 29 ms was reduced by 9% ± 20% to 138 ± 27 ms using traditional BiV pacing and by 13% ± 14% to 133 ± 25 ms using BiV + SyncAV (50 ms offset). The maximal QRSd reduction by 20% ± 10% to 123 ± 22 ms was achieved by BiV + SyncAV with an optimized offset. Similar QRSd reductions were observed with BiV pacing from the earliest activating LV electrode across all settings. Of all baseline characteristics, intrinsic QRSd was the only significant predictor of QRSd reduction magnitude. CONCLUSION: SyncAV improved acute electrical synchrony beyond conventional CRT, particularly with patient-specific optimization. The degree of synchrony restored was contingent on intrinsic QRSd, but not limited by other baseline characteristics or by the LV pacing electrode used.

Multipoint left ventricular pacing improves response to cardiac resynchronization therapy with and without pressure-volume loop optimization: comparison of the long-term efficacy of two different programming strategies.

PURPOSE: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. METHODS: Patients undergoing CRT implant (Quadra Assura MP™ CRT-D and Quartet™ LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of ≥ 15% relative to baseline at 6 months as determined by a blinded observer. RESULTS: Patient characteristics at baseline (NYHA II-III, ejection fraction [EF] 27 ± 6%, QRS 151 ± 17 ms) were not significantly different between the PVL-OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p = 0.53). After 6 months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV - 20 ± 11 vs. - 22 ± 11%, p = 0.59; EF + 10 ± 4 vs. + 9 ± 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction ≥ 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). CONCLUSIONS: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization.

Predictive value of unipolar and bipolar electrograms in idiopathic outflow tract ventricular arrhythmia mapping and ablation.

INTRODUCTION: Radiofrequency catheter ablation is an effective therapy for focal idiopathic outflow tract ventricular arrhythmia (OTVA). However, visual inspection of the unipolar electrogram (EGM) QS morphology is subjective with a poor specificity for predicting successful ablation sites. This study aims to evaluate the predictive value of unipolar and bipolar EGMs in OTVA mapping and ablation. METHODS AND RESULTS: Twenty-two patients scheduled for idiopathic OTVA ablation were prospectively enrolled. During the procedure, unipolar and bipolar EGMs were recorded simultaneously and visually inspected by the operator to identify their values for predicting arrhythmogenic sites. Quantitative features of the unipolar EGM including the ratio of amplitude of the first positive peak versus the nadir (R-ratio), the maximum descending slope (MaxSlope), and the time interval between the initial deflection point to the MaxSlope (D-Max) were calculated for each target site in offline analysis. EGMs from 100 sites were collected in 20 patients and analyzed. The bipolar reverse polarity characteristic was not as practical for identifying successful ablation site as the unipolar QS characteristic. Successful ablation sites demonstrated smaller R-ratio and shorter D-Max than unsuccessful sites, but no significant difference in MaxSlope. A unipolar EGM-derived quantitative criterion provided significantly better specificity (0.70) than visual inspection (0.37) without compromising on the sensitivity (0.83 vs. 0.89). CONCLUSION: The bipolar reverse polarity characteristic was not a practical method for identifying target in idiopathic OTVA ablation. The unipolar EGM-derived quantitative criteria have better predictive performance than visual inspection of the QS characteristic and are likely to reduce unnecessary ablation sites.

Multipoint pacing improves peripheral hemodynamic response: Noninvasive assessment using radial artery tonometry.

BACKGROUND: Multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], Abbott, Sylmar, CA, USA) improves the response rate to cardiac resynchronization therapy (CRT). We evaluated the feasibility of noninvasive radial artery tonometry (RAT) to characterize arterial pressure morphology changes (pre-ejection period [PEP] and ejection duration [ED]) between conventional CRT and MPP pacing interventions. METHODS: Patients with a MPP-enabled CRT device (Quadra Assura MP™, Abbott) underwent noninvasive RAT assessment (SphygmoCor CVMS, AtCor Medical Inc., Itasca, IL, USA) at 3-6 months after implantation. A pacing protocol was performed in a randomized order including one optimized conventional biventricular CRT (CONV) configuration using the distal electrode and five MPP configurations. The PEP, ED, and PEP/ED ratio were determined for each intervention from the RAT pressure waveform and electrocardiogram. RESULTS: Pressure waveforms were successfully recorded in 19 patients (89% male, QRS 147 ± 16 ms, 63% ischemic). In 17/19 (89%) patients, at least one MPP intervention resulted in improved PEP, ED, and PEP/ED compared to CONV. The MPP intervention with greatest separation of LV cathodes and minimum intra-LV delay significantly improved PEP (mean PEP -15 ± 33% vs -8 ± 32% [CONV], P = 0.04) and ED (mean ED +8 ± 8% [MPP] vs +4 ± 7% [CONV], P = 0.02), and PEP/ED (-0.07 ± 0.14 [MPP] vs -0.04 ± 0.13 [CONV], P = 0.02) compared with CONV. CONCLUSIONS: Noninvasive RAT efficiently characterizes changes in PEP and ED between CONV and MPP interventions. MPP configurations using the widest separation among LV cathodes and minimum intra-LV delay may significantly improve RAT-derived parameters as compared to conventional CRT.

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

AIMS: 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 < 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 equivalents.

Improving cardiac resynchronization therapy response with multipoint left ventricular pacing: Twelve-month follow-up study.

BACKGROUND: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], St. Jude Medical) improves acute LV function and LV reverse remodeling at 3 months. OBJECTIVE: The purpose of this study was to test the hypothesis that MPP can also improve LV function at 12 months. METHODS: Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical) were randomized to receive pressure-volume (PV) loop optimized biventricular pacing with either conventional cardiac resynchronization therapy (CONV) or MPP. CRT response was defined by a reduction in end-systolic volume (ESV) ≥15% relative to BASELINE as determined by a blinded observer and alive status. RESULTS: Forty-four patients (New York Heart Association class III, ejection fraction [EF] 29% ± 6%, QRS 152 ± 17 ms) were enrolled and randomized to either CONV (N = 22) or MPP (N = 22). During the observation period, 2 patients died of noncardiac causes and 2 patients were lost to follow-up. After 12 months, 12 of 21 patients (57%) in the CONV group and 16 of 21 patients (76%) in the MPP group were classified as CRT responders (P = .33). ESV reduction and EF increase relative to BASELINE were significantly greater with MPP than with CONV (ESV: median -25%, interquartile range [IQR] [-39% to -20%] vs median -18%, IQR [-25% to -2%], P = .03; EF: median +15%, IQR [8% to 20%] vs median +5%, IQR [-1% to 8%], P <.001). CONCLUSION: Sustaining the trend observed 3 months postimplant, PV loop-guided multipoint LV pacing resulted in greater LV reverse remodeling and increased LV function at 12 months compared to PV loop-guided conventional CRT.

Multipoint left ventricular pacing in a single coronary sinus branch improves mid-term echocardiographic and clinical response to cardiac resynchronization therapy.

INTRODUCTION: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing in a single coronary sinus branch improves acute LV function. We hypothesized that multipoint pacing (MPP) can improve midterm echocardiographic and clinical response compared with conventional CRT. METHODS AND RESULTS: Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical, Sylmar, CA, USA) were randomized to receive biventricular (BiV) pacing with either conventional LV pacing (CONV group) or MPP (MPP group). For each patient, an optimal pacing configuration for the assigned pacing mode was programmed based on intraoperative pressure-volume (PV) loop measurements. A clinical evaluation and transthoracic echocardiogram were performed before implant (BASELINE) and at 3 months postimplant and analyzed by a blinded observer. A reduction in end-systolic volume (ESV) of ≥15% relative to BASELINE was prospectively defined as response to CRT. Forty-four patients (NYHA Class III, EF 29 ± 6%, QRS duration 152 ± 17 milliseconds) were enrolled and randomized. One patient in the MPP group was lost to follow-up and excluded from further analysis. After 3 months, 11 of 22 (50%) CONV patients and 16 of 21 (76%) MPP patients were classified as responders. ESV reduction, EF increase, and NYHA class reduction relative to BASELINE were significantly greater in the MPP group than in the CONV group (ESV: -21.0 ± 13.9 vs. -12.6 ± 11.1%, P = 0.03; EF: +9.8 ± 5.1 vs. +2.0 ± 7.8 percentage points, P < 0.001; ΔNYHA: -1.05 ± 0.22 vs. -0.72 ± 0.46 functional classes, P = 0.006). CONCLUSION: PV loop optimized BiV pacing with MPP resulted in an improved rate of response to CRT.

Multipoint left ventricular pacing improves acute hemodynamic response assessed with pressure-volume loops in cardiac resynchronization therapy patients.

BACKGROUND: Conventional cardiac resynchronization therapy (CRT) improves acute cardiac hemodynamics. OBJECTIVE: To investigate if CRT with multipoint left ventricular (LV) pacing in a single coronary sinus branch (MultiPoint Pacing [MPP], St Jude Medical, Sylmar, CA) can offer further hemodynamic benefits to patients. METHODS: Forty-four consecutive patients (80% men, New York Heart Association III, end-systolic volume 180 ± 77 mL, ejection fraction 27% ± 6%, and QRS duration 152 ± 17 ms) receiving a CRT device implant (Unify Quadra MP or Quadra Assura MP and Quartet LV lead, St Jude Medical) underwent intraoperative assessment of LV hemodynamics by using a pressure-volume loop system (Inca, CD Leycom). A pacing protocol was performed, including 9 biventricular pacing interventions with conventional CRT (CONV) using distal and proximal LV electrodes and various MPP configurations. Each pacing intervention was performed twice in randomized order with right ventricular pacing (BASELINE) repeated after every intervention. RESULTS: Evaluable recordings were obtained in 42 patients. Relative to BASELINE, the best MPP intervention significantly increased the rate of pressure change (dP/dtmax; 15.9% ± 10.0% vs 13.5% ± 8.8%; P < .001), stroke work (27.2% ± 42.5% vs 19.4% ± 32.2%; P = .018), stroke volume (10.4% ± 22.5% vs 4.1% ± 13.1%; P = .003), and ejection fraction (10.5% ± 20.9% vs 5.3% ± 13.2%; P = .003) as compared with the best CONV intervention. Moreover, the best MPP intervention improved acute diastolic function, significantly decreasing -dP/dtmin (-13.5% ± 10.2% vs -10.6% ± 6.8%; P = .011), relaxation time constant (-7.5% ± 9.0% vs -4.8% ± 7.2%; P = .012), and end-diastolic pressure (-18.2% ± 22.4% vs -8.7% ± 21.4%; P < .001) as compared with the best CONV intervention. CONCLUSIONS: CRT with MPP can significantly improve acute LV hemodynamic parameters assessed with pressure-volume loop measurements as compared with CONV.

Size and ionic currents of unexcitable cells coupled to cardiomyocytes distinctly modulate cardiac action potential shape and pacemaking activity in micropatterned cell pairs.

BACKGROUND: Cardiac cell therapies can yield electric coupling of unexcitable donor cells to host cardiomyocytes with functional consequences that remain unexplored. METHODS AND RESULTS: We micropatterned cell pairs consisting of a neonatal rat ventricular myocyte (NRVM) coupled to an engineered human embryonic kidney 293 (HEK293) cell expressing either connexin-43 (Cx43 HEK) or inward rectifier potassium channel 2.1 (Kir2.1) and Cx43 (Kir2.1+Cx43 HEK). The NRVM-HEK contact length was fixed yielding a coupling strength of 68.9±9.7 nS, whereas HEK size was systematically varied. With increase in Cx43 HEK size, NRVM maximal diastolic potential was reduced from -71.7±0.6 mV in single NRVMs to -35.1±1.3 mV in pairs with an HEK:NRVM cell surface area ratio of 1.7±0.1, whereas the action potential upstroke ([dV(m)/dt](max)) and duration decreased to 1.6±0.7% and increased to 177±32% in single NRVM values, respectively (n=21 cell pairs). Pacemaking occurred in all NRVM-Cx43 HEK pairs with cell surface area ratios of 1.1 to 1.9. In contrast, NRVMs, coupled with Kir2.1+Cx43 HEKs of increasing size, had similar maximal diastolic potentials, exhibited no spontaneous activity, and showed a gradual decrease in action potential duration (n=23). Furthermore, coupling single NRVMs to a dynamic clamp model of HEK cell ionic current reproduced the cardiac maximal diastolic potentials and pacemaking rates recorded in cell pairs, whereas reproducing changes in (dV(m)/dt)(max) and action potential duration required coupling to an HEK model that also included cell membrane capacitance. CONCLUSIONS: Size and ionic currents of unexcitable cells electrically coupled to cardiomyocytes distinctly affect cardiac action potential shape and initiation with important implications for the safety of cardiac cell and gene therapies.

Single-detector simultaneous optical mapping of V(m) and [Ca(2+)](i) in cardiac monolayers.

Simultaneous mapping of transmembrane voltage (V(m)) and intracellular Ca(2+) concentration (Ca(i)) has been used for studies of normal and abnormal impulse propagation in cardiac tissues. Existing dual mapping systems typically utilize one excitation and two emission bandwidths, requiring two photodetectors with precise pixel registration. In this study we describe a novel, single-detector mapping system that utilizes two excitation and one emission band for the simultaneous recording of action potentials and calcium transients in monolayers of neonatal rat cardiomyocytes. Cells stained with the Ca(2+)-sensitive dye X-Rhod-1 and the voltage-sensitive dye Di-4-ANEPPS were illuminated by a programmable, multicolor LED matrix. Blue and green LED pulses were flashed 180° out of phase at a rate of 488.3 Hz using a custom-built dual bandpass excitation filter that transmitted blue (482 ± 6 nm) and green (577 ± 31 nm) light. A long-pass emission filter (>605 nm) and a 504-channel photodiode array were used to record combined signals from cardiomyocytes. Green excitation yielded Ca(i) transients without significant crosstalk from V(m). Crosstalk present in V(m) signals obtained with blue excitation was removed by subtracting an appropriately scaled version of the Ca(i) transient. This method was applied to study delay between onsets of action potentials and Ca(i) transients in anisotropic cardiac monolayers.

Characterizing functional stem cell-cardiomyocyte interactions.

Despite the progress in traditional pharmacological and organ transplantation therapies, heart failure still afflicts 5.3 million Americans. Since June 2000, stem cell-based approaches for the prevention and treatment of heart failure have been pursued in clinics with great excitement; however, the exact mechanisms of how transplanted cells improve heart function remain elusive. One of the main difficulties in answering these questions is the limited ability to directly access and study interactions between implanted cells and host cardiomyocytes in situ. With the growing number of candidate cell types for potential clinical use, it is becoming increasingly more important to establish standardized, well-controlled in vitro and in situ assays to compare the efficacy and safety of different stem cells in cardiac repair. This article describes recent innovative methodologies to characterize direct functional interactions between stem cells and cardiomyocytes, aimed to facilitate the rational design of future cell-based therapies for heart disease.

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 alpha-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.