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.

An atrial fibrillation rotor, mapped conventionally.

This case illustrates that the condition of atrial fibrillation (AF) may harbor site(s) of regular rotational activity, reentry may be an underlying mechanism, high periodicity and wavebreak through areas of the scar may generate fibrillatory conduction, and disintegration of the "rotor" may not abolish AF.

Left ventricular paced activation in cardiac resynchronization therapy patients with left bundle branch block and relationship to its electrical substrate.

BACKGROUND: Cardiac resynchronization therapy (CRT) uses left ventricular (LV) pacing to restore rapid synchronized LV activation when it is delayed in patients with myocardial disease. OBJECTIVE: Although intrinsic LV activation delays are understood, little is known about reactions to LV stimulation and whether they are affected by QRS duration (QRSd), morphology, LV substrate, or choice of electrode pair. The purpose of this study was to test these interactions. METHODS: In 120 heart failure patients with left bundle branch block (LBBB) and QRS >120 ms receiving CRT with quadripolar LV leads, device-based measurements of intrinsic activation delay (qLV) and paced inter- (and intra-) LV conduction times were evaluated at the proximal and distal LV bipoles. RESULTS: During intrinsic conduction, qLV varied little between the proximal and distal pairs in patients with LBBB (n = 120; age 68 ± 11 years; 63% male; ejection fraction 25% ± 7%; 33% ischemic cardiomyopathy; QRSd 162 ± 19 ms). A minority (30%) had conduction barriers (ie, gradients) (ΔqLV 29 ± 8 ms vs 9 ± 5 ms in patients without gradients; P <.01), which occurred equally in ischemic and nonischemic patients. A majority were functional (and not scar-mediated), as they resolved with pacing in most patients (75%). Importantly, LV-paced conduction times were unrelated to baseline QRS morphology (LBBB 166 ± 30 ms vs RBBB control 172 ± 30 ms; P = NS), longer than intrinsic conduction (166 ± 30 ms vs 129 ± 28 ms; P <.01), and varied significantly by electrode pair (ie, small distances) and etiology. Correlation between intrinsic activation delay (qLV) and LV-paced conduction time was poor (R2 = 0.278; P <.05). CONCLUSION: LV-paced effect, which is core to CRT, is unpredictable based on conventionally used measures and should be considered during CRT optimization.

Programming Cardiac Resynchronization Therapy for Electrical Synchrony: Reaching Beyond Left Bundle Branch Block and Left Ventricular Activation Delay.

BACKGROUND: QRS narrowing following cardiac resynchronization therapy with biventricular (BiV) or left ventricular (LV) pacing is likely affected by patient-specific conduction characteristics (PR, qLV, LV-paced propagation interval), making a universal programming strategy likely ineffective. We tested these factors using a novel, device-based algorithm (SyncAV) that automatically adjusts paced atrioventricular delay (default or programmable offset) according to intrinsic atrioventricular conduction. METHODS AND RESULTS: Seventy-five patients undergoing cardiac resynchronization therapy (age 66±11 years; 65% male; 32% with ischemic cardiomyopathy; LV ejection fraction 28±8%; QRS duration 162±16 ms) with intact atrioventricular conduction (PR interval 194±34, range 128-300 ms), left bundle branch block, and optimized LV lead position were studied at implant. QRS duration (QRSd) reduction was compared for the following pacing configurations: nominal simultaneous BiV (Mode I: paced/sensed atrioventricular delay=140/110 ms), BiV+SyncAV with 50 ms offset (Mode II), BiV+SyncAV with offset that minimized QRSd (Mode III), or LV-only pacing+SyncAV with 50 ms offset (Mode IV). The intrinsic QRSd (162±16 ms) was reduced to 142±17 ms (-11.8%) by Mode I, 136±14 ms (-15.6%) by Mode IV, and 132±13 ms (-17.8%) by Mode II. Mode III yielded the shortest overall QRSd (123±12 ms, -23.9% [P<0.001 versus all modes]) and was the only configuration without QRSd prolongation in any patient. QRS narrowing occurred regardless of QRSd, PR, or LV-paced intervals, or underlying ischemic disease. CONCLUSIONS: Post-implant electrical optimization in already well-selected patients with left bundle branch block and optimized LV lead position is facilitated by patient-tailored BiV pacing adjusted to intrinsic atrioventricular timing using an automatic device-based algorithm.

Real-time guidewire localization using impedance-based electroanatomic mapping: experimental results and clinical validation during cryoballoon ablation of atrial fibrillation.

AIMS: Cryoballoon ablation is an emerging therapy for atrial fibrillation (AF). However, the Arctic Front cryoballoon (Medtronic) cannot be localized on current electroanatomic mapping (EAM) systems. We describe a technique to visualize guidewires in an impedance-based EAM system. METHODS AND RESULTS: A novel technique for real-time guidewire localization in an EAM (Ensite Velocity, St Jude Medical) was prospectively evaluated among patients referred for cryoballoon AF ablation. The guidewire was visualized as an 'orb' on the EAM and localization in each of the pulmonary veins (PVs) compared with orthogonal fluoroscopy, contrast venography, and intra-cardiac echocardiography. Application of the technique in 21 consecutive patients [median age 58 (interquartile range 21); 71.4% male; 85.7% paroxysmal AF] demonstrated agreement with respect to guidewire localization in 82 of 82 (100%) PVs. Discrimination of guidewire position in the left atrial appendage from the left PVs was also demonstrated. When compared with 21 consecutive cryoballoon procedures over the same time period in which the technique was not used, fluoroscopy time was reduced [median 53.2 (25.9) vs. 72.3 (47.6) min, P = 0.008], and a trend towards reduced radiation exposure [median 372 (656.0) vs. 581 (849.9) mGy, P = 0.08] was noted, without effect on acute procedural or mid-term endpoints. Ex vivo assessment of the technique in a saline bath left atrial model demonstrated that the 'orb' localizes to the centroid of the exposed portion of the guidewire. CONCLUSION: This simple, novel technique provides real-time, accurate guidewire localization to enable guidewire and catheter navigation during cryoballoon AF ablation.

Relationship between catheter forces, lesion characteristics, "popping," and char formation: experience with robotic navigation system.

INTRODUCTION: Popping, char and perforation are complications that can occur following catheter ablation. We measured the amount of grams (g) applied to the endocardium during ablation using a sensor incorporated in the long sheath of a robotic system. We evaluated the relationship between lesion formation, pressure, and the development of complications. METHODS: Using a robotic navigation system, lesions were placed in the left atrium (LA) at six settings, using a constant duration (40 seconds) and flow rate of either 17 cc/min or 30 cc/min with an open irrigated catheter (OIC). Evidence of complications was noted and lesion location recorded for later analysis at necropsy. RESULTS: Lesions using 30 Watts (W) were more likely to be transmural at higher (>40 g) than lower (<30 g) pressures (75% vs 25%, P < 0.001). Significantly higher number of lesions using >40 g of pressure demonstrated "popping" and crater formation as compared with lesions with 20-30 g of pressure (41% vs 15%, P = 0.008). A majority of lesions placed using higher power (45 W) with higher pressures (>40 g) were associated with char and crater formation (66.7%). No lesions using 10 g of pressure were transmural, regardless of the power. Lesions placed with a power setting less than 35 W were more likely to result in "relative" sparing of the endocardial surface than lesions at a power setting higher than 35 W (62% vs 33.3%, P = 0.02) regardless of the pressure. CONCLUSIONS: When using an OIC, lower power settings (

Distribution of TRPC channels in a visceral sensory pathway.

Until recently most of the published studies addressing the mechanisms of activation of TRPC channels have been carried out in heterologous expression systems. Lack of specific antagonists for the TRPC channels has hampered functional studies of endogenous channels. We approached the role of TRPC channels in native tissue with a study of the distribution of the channel proteins in the carotid chemosensory pathway in the rat. In a previous report we showed that TRPC3/4/5/6 and TRPC7 were present in neurons throughout the petrosal ganglion while TRPC1 was expressed in only a subpopulation of petrosal neurons, at least half of which projected to the carotid body. The TRPC proteins were differentially distributed to the branches of the axons that project centrally to the nucleus of the solitary tract and peripherally to the carotid body. The smallest unmyelinated sensory fibres projecting to the carotid body contained TRPC1/3/4/5 or TRPC6 but not TRPC7. TRPC1 and TRPC3 were concentrated in the larger diameter fibres. Interestingly, only TRPC1 and TRPC4 could be demonstrated in the final terminal endings within glomus cell clusters of the carotid body. In the central axon of the sensory neurons, both TRPC4 and TRPC5 were demonstrated in fibres exiting the solitary tract and projecting to the secondary relay neurons the nucleus of the solitary tract.

Maitotoxin-induced cell death cascade in bovine aortic endothelial cells: divalent cation specificity and selectivity.

The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial cells (BAECs), a model for Ca(2+) overload-induced toxicity, reflects three sequential changes in plasmalemmal permeability. MTX initially activates Ca(2+)-permeable, nonselective cation channels (CaNSC) and causes a massive increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)). This is followed by the opening of large endogenous cytolytic/oncotic pores (COP) that allow molecules <800 Da to enter the cell. The cells then lyse not by rupture of the plasmalemma but through the activation of a "death" channel that lets large proteins (e.g., 140-160 kDa) leave the cell. These changes in permeability are accompanied by the formation of membrane blebs. In this study, we took advantage of the well-known differences in affinity of various Ca(2+)-binding proteins for Ca(2+) and Sr(2+) vs. Ba(2+) to probe their involvement in each phase of the cell death cascade. Using fluorescence techniques at the cell population level (cuvette-based) and at the single-cell level (time-lapse videomicroscopy), we found that the replacement of Ca(2+) with either Sr(2+) or Ba(2+) delayed both MTX-induced activation of COP, as indicated by the uptake of ethidium bromide, and subsequent cell lysis, as indicated by the uptake of propidium iodide or the release of cell-associated green fluorescent protein. MTX-induced responses were mimicked by ionomycin and were significantly delayed in BAPTA-loaded cells. Experiments at the single-cell level revealed that Ba(2+) not only delayed the time to cell lysis but also caused desynchronization of the lytic phase. Last, membrane blebs, which were numerous and spherical in Ca(2+)-containing solutions, were poorly defined and greatly reduced in number in the presence of Ba(2+). Taken together, these results suggest that intracellular high-affinity Ca(2+)-binding proteins are involved in the MTX-induced changes in plasmalemmal permeability that are responsible for cell demise.

Activation of vanilloid receptor type I in the endoplasmic reticulum fails to activate store-operated Ca2+ entry.

To evaluate interaction of vanilloid receptor type 1 (TRPV1) with endogenous Ca(2+) signalling mechanisms, TRPV1 was expressed in Spodoptera frugiperda (Sf 9) insect cells using recombinant baculovirus. Stimulation of TRPV1-expressing cells, but not control Sf 9 cells, with resiniferatoxin (RTX), capsaicin or anandamide, produced an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), with EC(50) values of 166 pM, 24.5 nM and 3.89 microM respectively. In the absence of extracellular Ca(2+), both capsaicin and RTX caused an increase in [Ca(2+)](i) with EC(50) values of approx. 10 microM and 10 nM respectively. This TRPV1-induced release of Ca(2+) from intracellular stores was not blocked by U73122, suggesting that phospholipase C was not involved. Substantial overlap was found between the thapsigargin- and RTX-sensitive internal Ca(2+) pools, and confocal imaging showed that intracellular TRPV1 immunofluorescence co-localized with the endoplasmic reticulum targeting motif KDEL. To determine if TRPV1-induced mobilization of intracellular Ca(2+) activates endogenous store-operated Ca(2+) entry, the effect of 2-aminoethoxydiphenyl borate (2-APB) on Ba(2+) influx was examined. 2-APB blocked thapsigargin-induced Ba(2+) influx, but not RTX-induced Ba(2+) entry. In the combined presence of thapsigargin and a store-releasing concentration of RTX, the 2-APB-sensitive component was essentially identical with the thapsigargin-induced component. Similar results were obtained in HEK-293 cells stably expressing TRPV1. These results suggest that TRPV1 forms agonist-sensitive channels in the endoplasmic reticulum, which when activated, release Ca(2+) from internal stores, but fail to activate endogenous store-operated Ca(2+) entry. Selective activation of intracellular TRPV1, without concomitant involvement of plasmalemmal Ca(2+) influx mechanisms, could play an important role in Ca(2+) signalling within specific subcellular microdomains.