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 ResultsSeventy‐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.ConclusionsPost‐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.
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.
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