BACKGROUND It has been well established that arterial stiffness, manifest as an increase in arterial pulse wave velocity or late systolic amplification of the carotid artery pressure pulse, increases with age. However, the populations studied in prior investigations were not rigorously screened to exclude clinical hypertension, occult coronary disease, or diabetes. Furthermore, it is unknown whether exercise capacity or chronic physical endurance training affects the age-associated increase in arterial stiffness. METHODS AND RESULTS Carotid arterial pressure pulse augmentation index (AGI), using applanation tonometry, and aortic pulse wave velocity (APWV) were measured in 146 male and female volunteers 21 to 96 years old from the Baltimore Longitudinal Study of Aging, who were rigorously screened to exclude clinical and occult cardiovascular disease. Aerobic capacity was determined in all individuals by measurement of maximal oxygen consumption (VO2max) during treadmill exercise. In this healthy, largely sedentary cohort, the arterial stiffness indexes AGI and APWV increased approximately fivefold and twofold, respectively, across the age span in both men and women, despite only a 14% increase in systolic blood pressure (SBP). These age-associated increases in AGI and APWV were of a similar magnitude to those in prior studies of less rigorously screened populations. Both AGI and APWV varied inversely with VO2max, and this relationship, at least for AGI, was independent of age. In endurance trained male athletes, 54 to 75 years old (VO2max = 44 +/- 3 mL.kg-1.min-1), the arterial stiffness indexes were significantly reduced relative to their sedentary age peers (AGI, 36% lower; APWV, 26% lower) despite similar blood pressures. CONCLUSIONS Even in normotensive, rigorously screened volunteers in whom SBP increased an average of only 14% between ages 20 and 90 years, major age-associated increases of arterial stiffness occur. Higher physical conditioning status, indexed by VO2max, was associated with reduced arterial stiffness, both within this predominantly sedentary population and in endurance trained older men relative to their less active age peers. These findings suggest that interventions to improve aerobic capacity may mitigate the stiffening of the arterial tree that accompanies normative aging.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

8. Wirtz H, Hasenclever D, Schwabe K, et al. ACE inhibitor for lung protection during mechanical ventilation for acute lung injury-results of the double-blind, placebo controlled, randomised ACEmeVENT pilot study.

Background The current paradigm of Sinoatrial Node (SAN) impulse generation: (i) is that full-scale action potentials (APs) of a common frequency are initiated at one site and are conducted within the SAN along smooth isochrones; and (ii) does not feature fine details of Ca 2+ signalling present in isolated SAN cells, in which small subcellular, subthreshold local Ca 2+ releases (LCRs) self-organize to generate cell-wide APs.Objectives To study subcellular Ca 2+ signals within and among cells comprising the SAN tissue. MethodsWe combined immunolabeling with a novel technique to detect the occurrence of LCRs and AP-induced Ca 2+ transients (APCTs) in individual pixels (chonopix) across the entire mouse SAN images. ResultsAt high magnification, Ca 2+ signals appeared markedly heterogeneous in space, amplitude, frequency, and phase among cells comprising an HCN4 + /CX43cell meshwork.The signalling exhibited several distinguishable patterns of LCR/APCT interactions within and among cells. Apparently conducting rhythmic APCTs of the meshwork were transferred to a truly conducting HCN4 -/CX43 + network of straited cells via narrow functional interfaces where different cell types intertwine, i.e. the SAN anatomical/functional unit. At low magnification, the earliest APCT of each cycle occurred within a small area of the HCN4 meshwork and subsequent APCT appearance throughout SAN pixels was discontinuous. ConclusionsWe have discovered a novel, microscopic Ca 2+ signalling paradigm of SAN operation that has escaped detection using low-resolution, macroscopic tissue isochrones employed in prior studies: APs emerge from heterogeneous subcellular subthreshold Ca 2+ 105 and is also made available for use under a CC0 license.

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Failing human ventricular cardiomyocytes contain functional beta 2-adrenergic receptors. Canine myocytes also contain functional beta 2-adrenergic receptors. The canine ventricular response to beta 2-agonists is increased in tachypacing failure. Positive inotropic responses to beta 2-stimulation are not mediated by increases in cAMP or cAMP-dependent phosphorylation of phospholamban.