R-R' interval in the left bundle branch block predicts long-term outcomes after cardiac resynchronization therapy by estimating greater mechanical dyssynchrony and viable myocardium.

BACKGROUND: Typical left bundle branch block (LBBB) shows 2 peaks of the R wave, which reflect activation reaching the interventricular septum (R) and posterolateral wall (R') sequentially. OBJECTIVE: The purpose of this study was to investigate the relationship among R-R' interval (RR'), mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes in cardiac resynchronization therapy (CRT) candidates. METHODS: The study enrolled 49 patients (34 men; mean age: 69 ± 11 years) with LBBB who received CRT. The LBBB definition used requires the presence of mid-QRS notching in leads V1, V2, V5, V6, I, and aVL. Baseline evaluations were QRS duration (QRSd) and RR' measured from the 12-lead electrocardiogram; eyeball dyssynchrony (apical rocking and septal flash) and opposing-wall delay by speckle tracking from echocardiography, and extent of viable myocardium assessed by thallium-201 single-photon emission computed tomography. Primary outcomes included the combination of all-cause death and heart failure-related hospitalization. RESULTS: RR' predicted volumetric response better than QRSd (area under the curve 0.73 vs 0.67, respectively). The long RR' group (≥48 ms) revealed more frequent eyeball dyssynchrony and significantly greater radial (SL) and circumferential dyssynchrony (AP and SL) and %viable segment than the short RR' group. In multivariate regression analysis, only RR' ≥48 ms was independently associated with higher event-free survival rates following CRT (hazard ratio 0.21; P = .014). CONCLUSION: These findings suggest that RR' in complete LBBB was associated with mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes following CRT.

Analysis of Pattern Formation by Colored Petri Nets With Quantitative Regulation of Gene Expression Level.

Modeling and simulation are becoming indispensable tools for studying multicellular events such as pattern formation during embryonic development. In this paper, we propose a new approach for analyzing multicellular biological phenomena by combining colored hybrid Petri nets (ColHPNs) with newly devised biological experiments that can control level of a gene quantitatively. With this approach, we analyzed patterning of the boundary cells in the Drosophila large intestine, where one-cell-wide domain of boundary cells differentiate through Delta-Notch signaling. Biological experiments regulating the level of Delta resulted in six distinct patterns of boundary cells correlating with the level of Delta. All these patterns were successfully reproduced by simulation based on ColHPN modeling only by changing the parameter related to the level of Delta. By monitoring the concentration of the active form of Notch in each cell during simulation, it was revealed that these distinct modes of patterning correlate with the fluctuation range of active Notch. Combination of simulation and quantitative manipulation of a gene activity described here is a reliable and powerful approach for analyzing and understanding the patterning process regulated by Notch signaling. This approach can be easily adapted to address other similar pattern formation issues in the systems biology area.

Comparisons of Edoxaban Versus Warfarin on Levels of Plasma Prothrombin Fragment in Patients With Nonvalvular Atrial Fibrillation.

The effect of edoxaban on plasma prothrombin fragment 1+2 (PTF1+2), a sensitive maker of in vivo thrombin generation, has not been fully investigated in nonvalvular atrial fibrillation (NVAF). We compared plasma PTF1+2 levels between 25 NVAF patients receiving warfarin and 100 NVAF patients receiving edoxaban and additionally analyzed the association between plasma PTF1+2 levels and the dose of edoxaban. Plasma PTF1+2 levels were significantly higher in patients receiving edoxaban than in those receiving warfarin (141.5 ± 50.0 pmol/l vs 93.1 ± 55.7 pmol/l, p < 0.001). The prevalence of plasma PF1+2 levels above the upper limit (229 pmol/l) of the normal range did not differ between the 2 groups (4% vs 4%), whereas the prevalence of plasma PTF1+2 levels below the lower limit (69 pmol/l) of the normal range was significantly lower in patients receiving edoxaban than in those receiving warfarin (1% vs 48%, p < 0.001). Multiple linear regression analysis identified age and warfarin treatment as independent variables associated with the plasma PTF1+2 level. In a subgroup analysis, plasma PTF1+2 levels were significantly higher in 58 receiving edoxaban of 30 mg/day than in 42 receiving edoxaban of 60 mg/day (157.6 ± 50.8 pmol/l vs 121.6 ± 39.8 pmol/l, p = 0.01); however, after adjusting for confounding factors, the dose of edoxaban was not independently associated with the plasma PTF1+2 level. In conclusion, edoxaban sufficiently inhibits thrombin generation unrelated to its dose in NVAF, although its inhibitory effect is weaker compared with warfarin.