Regional patterns of dyssynchrony: lateral wall delay is desirable but not essential for left ventricular remodeling in biventricular pacing.

BACKGROUND: Tissue synchronization imaging (TSI), a parametric imaging technique based on tissue velocity imaging, often demonstrates patterns other than lateral delay in patients evaluated for cardiac resynchronization therapy (CRT). The prevalence of these patterns and their response to CRT has not been well described. We hypothesized that regional patterns of dyssynchrony might correlate with the extent of reverse remodeling. METHODS: A consecutive series of 32 patients underwent echocardiographic study prior to CRT implant and 3 months postimplant. TSI was used to color-code the time-to-peak positive systolic velocity at six basal and six mid-LV segments. Each patient was assigned to one of four groups based on the predominant location of greatest delay (≥ 2 segments): (1) posterolateral delay, (2) septal delay, (3) no dyssynchrony, or (4) other. RESULTS: Patients were classified as follows: posterolateral delay in 44% of patients (n = 14), septal delay in 28% (n = 9), no dyssynchrony in 16% (n = 5), and other pattern in 13% (n = 4). At 3-month follow-up, the group with the lateral delay pattern was associated with the greatest decrease in left ventricular end-systolic volume (LVESV) and the largest improvement in left ventricular ejection fraction (LVEF) (-45 mL and +9.3%, respectively, P < 0.05). The LVESV in the other three groups changed as follows: -24 mL (septal), -28 mL (no dyssynchrony), and -15 mL (other). Similar trends were observed for LVEF and left ventricular end-diastolic volume. CONCLUSIONS: Despite the presence of wide QRS and a left bundle branch block, the most delayed segment is not always the posterolateral wall. Posterolateral delay is associated with the best response to CRT, while other patterns respond at a lower magnitude.

Effects of age on circadian rhythms are similar in wild-type and heterozygous Clock mutant mice.

The amplitudes of many circadian rhythms, at the behavioral, physiological, cellular, and biochemical levels, decrease with advanced age. Previous studies suggest that the amplitude of the central circadian pacemaker is decreased in old animals. Recently, it has been reported that expression of several circadian clock genes, including Clock, is lower in the master circadian pacemaker of old rodents. To test the hypothesis that decreased activity of a circadian clock gene renders animals more susceptible to the effects of aging, we analyzed the circadian rhythm of locomotor activity in young and old wild-type and heterozygous Clock mutant mice. We found that the effects of age and the Clock mutation were additive. These results indicate that age-related changes in circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants, suggesting that the Clock mutation does not render mice more susceptible to the effects of age on the circadian pacemaker.

The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude.

The mouse Clock gene encodes a basic helix-loop-helix-PAS transcription factor, CLOCK, that acts in concert with BMAL1 to form the positive elements of the circadian clock mechanism in mammals. The original Clock mutant allele is a dominant negative (antimorphic) mutation that deletes exon 19 and causes an internal deletion of 51 aa in the C-terminal activation domain of the CLOCK protein. Here we report that heterozygous Clock/+ mice exhibit high-amplitude phase-resetting responses to 6-h light pulses (Type 0 resetting) as compared with wild-type mice that have low amplitude (Type 1) phase resetting. The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation. However, the amplitude of the circadian rhythms of Per gene expression are significantly reduced in Clock homozygous and heterozygous mutants. Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in Clock heterozygotes. The phase-response curves to changes in culture medium are Type 0 in Clock heterozygotes, but Type 1 in wild types, similar to that seen for light in vivo. The increased efficacy of resetting stimuli and decreased PER expression amplitude can be explained in a unified manner by a model in which the Clock mutation reduces circadian pacemaker amplitude in the suprachiasmatic nuclei.