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Aims: The prerequisite and the rationale for the benefit of cardiac resynchronization therapy (CRT) is that it is able to resynchronize left ventricular (LV) walls that have a delayed activation., Methods and Results: In 69 consecutive patients who underwent biventricular (BIV) pacemaker implantation, we assessed the magnitude of intraventricular resynchronization achieved by means of simultaneous (BIV 0) and sequential BIV pacing (with an individually optimized VV interval value among +80 ms and -80 ms) using pulsed-wave tissue Doppler imaging techniques and in particular the measurement of the intra-LV electromechanical delay. The intra-LV delay was defined as the difference between the longest and the shortest activation time in the six basal segments of the LV. An abnormal intra-LV delay was defined as a value >41 ms. The intra-LV delay was 63 +/- 28 ms baseline, decreased to 44 +/- 26 ms with BIV 0 and to 26 +/- 15 ms with optimized BIV (P = 0.001). BIV 0 determined the shortest delay in 28 (41%) patients (23 +/- 12 ms). In 41 (59%) patients, a better resynchronization was achieved with optimized VV intervals (LV first in 32 and RV first in 5) or single-chamber pacing (LV in 3 and RV in 1). With BIV 0, the intra-LV delay remained abnormal in 41% and was longer than baseline in 30% of patients compared with 9 and 12% with optimized BIV, respectively (P = 0.001)., Conclusion: A sub-optimal resynchronization is achieved with simultaneous BIV pacing in most patients. A tailored programming of the relative contribution of RV and LV pacing forms the prerequisite for improving CRT results.

To acquire information on the relationships between structural maturation of proteins in the endoplasmic reticulum (ER) and their transport along the secretory pathway, we have analyzed the destiny of an assembly-defective form of the trimeric vacuolar storage glycoprotein phaseolin. In leaves of transgenic tobacco, where assembly-competent phaseolin is correctly targeted to the vacuole, defective phaseolin remains located in the ER or a closely related compartment where it represents a major ligand of the chaperone BiP. Defective phaseolin maintained susceptibility to endoglycosidase H and was slowly degraded by a process that is not inhibited by heat shock or brefeldin A, indicating that degradation does not involve transport along the secretory pathway. These results provide evidence for the presence of a quality control mechanism in the ER of plant cells that avoids intracellular trafficking of severely defective proteins and eventually leads to their degradation.

Many of the proteins that are translocated into the endoplasmic reticulum are glycosylated with the addition of a 14-saccharide core unit (Glc3Man9GlcNAc2) to specific asparagine residues of the nascent polypeptide. Glucose residues are then removed by endoplasmic reticulum-located glucosidases, with diglucosylated and monoglucosylated intermediates being formed. In this study, we used a cell-free system constituted of wheat germ extract and bean microsomes to examine the role of glucose trimming in the structural maturation of phaseolin, a trimeric glycoprotein that accumulates in the protein storage vacuoles of bean seeds. Removal of glucose residues from the N-linked chains of phaseolin was blocked by the glucosidase inhibitors castanospermine and N-methyldeoxynojirimycin. If glucose trimming was not allowed to occur, the assembly of phaseolin was accelerated. Conversely, polypeptides bearing partially trimmed glycans were unable to form trimers. The effect of castanospermine on the rate of assembly was much more pronounced for phaseolin polypeptides that have two glycans but was also evident when a single glycan chain was present, indicating that glycan clustering can modulate the effect of glucose trimming on the rate of trimer formation. Therefore, the position of glycan chains and their accessibility to the action of glucosidases can be fundamental elements in the control of the structural maturation of plant glycoproteins.