Ventricular pacing causes a threefold difference in myofiber work within the LV wall. This difference appears large enough to regard local myocardial function as an important determinant for abnormalities in perfusion, metabolism, structure and pump function during asynchronous electrical activation. Pacing at sites that cause more synchronous activation may limit the occurrence of such derangements.

Objective. The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported.Methods. In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebotreated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure.ClinicalTrials.gov identifier: NCT00847613.

While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult. Longitudinal databases of hundreds of subjects observed during several years with tens of validated biomarkers are becoming available, allowing the use of computational methods. We propose a widely applicable statistical methodology for creating a disease progression score (DPS), using multiple biomarkers, for subjects with a neurodegenerative disease. The proposed methodology was evaluated for Alzheimer’s disease (AD) using the publicly available AD Neuroimaging Initiative (ADNI) database, yielding an Alzheimer’s DPS or ADPS score for each subject and each time-point in the database. In addition, a common description of biomarker changes was produced allowing for an ordering of the biomarkers. The Rey Auditory Verbal Learning Test delayed recall was found to be the earliest biomarker to become abnormal. The group of biomarkers comprising the volume of the hippocampus and the protein concentration amyloid beta and Tau were next in the timeline, and these were followed by three cognitive biomarkers. The proposed methodology thus has potential to stage individuals according to their state of disease progression relative to a population and to deduce common behaviors of biomarkers in the disease itself.

Background-VDD pacing can enhance systolic function in patients with dilated cardiomyopathy and discoordinate contraction; however, identification of patients likely to benefit is unclear. We tested predictors of systolic responsiveness on the basis of global parameters as well as directly assessed mechanical dyssynchrony. Methods and Results-Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt max ) and ejection-phase (pulse pressure, PP) systolic function by 35Ϯ21% and 16.4Ϯ11%, respectively, and these changes correlated directly (rϭ0.7, Pϭ0.001). %⌬dP/dt max was weakly predicted by baseline QRS (rϭ0.6, PϽ0.02), more strongly by baseline dP/dt max (rϭ0.7, Pϭ0.001), and best by bidiscriminate analysis combining baseline dP/dt max Յ700 mm Hg/s and QRS Ն155 ms to predict %⌬dP/dt max Ն25% and %⌬PP Ն10% (PϽ0.0005, 2 ), with no false-positives. Benefit could not be predicted by %⌬QRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at Ϸ80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0Ϯ7.1% in normal subjects versus 201.4Ϯ84.3% in DCM patients (Pϭ0.001). Mechanical dyssynchrony also correlated directly with %⌬dP/dt max (rϭ0.85, Pϭ0.008). Conclusions-These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt max provides an excellent tool to identify maximal responders.

The temporal evolution of three-dimensional (3-D) strain maps derived from magnetic resonance imaging (MRI) tagging were used to noninvasively evaluate mechanical activation in the left ventricle (LV) while seven canine hearts were paced in situ from three different sites: the base of the LV free wall (LVb), the right ventricular apex (RVa), and the right atrium (RA). Strain maps plotted against time showed the evolution of shortening over the entire LV midwall and were used to generate mechanical activation maps showing the onset of circumferential shortening. RA pacing showed rapid synchronous shortening; LVb pacing showed a wave front of mechanical activation propagating slowly and steadily from the pacing site, whereas RVa pacing showed regions of rapid and slower propagation. The mechanical (M) activation times correlated linearly with the electrical (E) activation (M = 1.06E + 8.4 ms, R = 0.95). The time for 90% activation of the LV was 63.1 ± 24.3 ms for RA pacing, 130.2 ± 9.8 ms for LVb pacing, and 121.3 ± 17.9 ms for RVa pacing. The velocity of mechanical activation was calculated for LVb and RVa pacing and was similar to values reported for electrical conduction in myocardium. The propagation of mechanical activation for RVa pacing showed regional variations, whereas LVb pacing did not.