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We examined the influence of the systolic left ventricular pressure (LVP) waveform on the rate of isovolumetric LVP fall, as assessed by the time constant tau. Seven open-chest dogs were instrumented with a micromanometer in the left ventricle, with segment length gauges in the anterior and posterior midwall of the left ventricle, and with a balloon-tipped catheter in the proximal aorta. The intra-aortic balloon was inflated before the onset of ejection (early) or during midejection (late) to produce timed and graded increases in peak LVP of 2-20 mmHg. The rate of LVP fall slowed significantly more with late than with early increases in LVP (tau increased 1.5 +/- 0.5 vs. 0.5 +/- 0.3%/mmHg increase in peak LVP, respectively, P less than 0.001). For a similar increase in peak LVP, there was a progressively greater increase in tau when the timing of balloon inflation was progressively delayed from early to late ejection (in 10-ms increments). The differential effect of early vs. late pressure increases on tau was not related to regional differences in segment length behavior nor to an increase in regional nonuniformity between anterior and posterior sites. We conclude that under the experimental conditions of an intact, ejecting left ventricle, the systolic pressure profile is an important determinant of the rate of pressure fall. The rate of LVP fall slows in direct proportion to the magnitude of increase in systolic pressure. The sensitivity to systolic load increases progressively throughout the ejection period, so that the rate of LVP fall slows significantly more with late than with early pressure increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. Methods and Results We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20,634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5,306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, beta=−0.075±0.012 SD/allele, P = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). Combined results for rs7152623 from 11 cohorts gave beta=−0.076±0.010 SD/allele, P=3.1x10−15. The association persisted when adjusted for mean arterial pressure (beta=−0.060±0.009 SD/allele, P = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) and older (9 cohorts, N=12,026, beta=−0.061±0.014 SD/allele, P=9.4x10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004). Conclusions Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.

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