No abstract

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.

The carotid bifurcation is a common site for clinically significant atherosclerosis, and the development of this disease may be influenced by the local hemodynamic environment. It has been shown that vessel geometry and pulsatile flow conditions are the predominant factors that determine the detailed blood flow patterns at the carotid bifurcation. This study was initiated to quantify the velocity profiles and wall shear stress (WSS) distributions in an anatomically true model of the human carotid bifurcation using data acquired from magnetic resonance (MR) imaging scans of an individual subject. A numerical simulation approach combining the image processing and computational fluid dynamics (CFD) techniques was developed. Individual vascular anatomy and pulsatile flow conditions were all incorporated into the computer model. It was found that the geometry of the carotid bifurcation was highly complex, involving helical curvature and out-ofplane branching. These geometrical features resulted in patterns of flow and wall shear stress significantly different from those found in simplified planar carotid bifurcation models. Comparisons between the predicted flow patterns and MR measurement demonstrated good quantitative agreement.

Abstract. We present a method for retinal blood vessel segmentation based upon the scale-space analysis of the first and second derivative of the intensity image which gives information about its topology and overcomes the problem of variations in contrast inherent in these images. We use the local maxima over scales of the magnitude of the gradient and the maximum principal curvature as the two features used in a region growing procedure. In the first stage, the growth is constrained to regions of low gradient magnitude. In the final stage this constraint is relaxed to allow borders between regions to be defined. The algorithm is tested in both red-free and fluorescein retinal images.

Since renin catalyses the first and rate-limiting step of the renin-angiotensin system (RAS) cascade, interruption of the generation of angiotensin II (Ang II) by renin inhibitors at this highly specific initial step of the cascade has long been a therapeutic goal. The early development of renin inhibitors was hampered by problems with bioavailability and high costs of synthesis. However, more recently a potent non-peptidic inhibitor of renin, aliskiren, with acceptable oral bioavailability, has been synthesised. Aliskiren effectively reduces Ang II levels in normal volunteers and has been shown to lower blood pressure (BP) in patients with mild-to-moderate hypertension.Renin inhibitors would be expected to have similar, but not identical effects to those of the established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of Ang II production may be more effective with renin inhibition than with angiotensin-converting enzyme (ACE) inhibition.Furthermore, because renin has high specificity for only one substrate, angiotensinogen, side-effects would be expected to be less frequent. It is currently unclear whether blockade of Ang II type 1 (AT 1 ) receptors, leaving other Ang II receptors (AT 2 , AT 3 and AT 4 ) unblocked, is preferable to the reduction in plasma and tissue Ang II levels achieved with either ACE or renin inhibition.Pharmacological suppression of the RAS, through ACE inhibition, or blockade of AT 1 , β-adrenoceptor or mineralocorticoid receptors, has been proven to reduce morbidity and mortality in patients with hypertension, diabetes mellitus, atherosclerosis, heart failure and nephropathy. While, to date, aliskiren has only been shown to reduce BP, it appears likely that orally-active renin inhibitors could prove useful in the management of a wide range of cardiovascular pathologies. BackgroundThe importance of the renin-angiotensin system (RAS) in the regulation of blood pressure (BP) and electrolytes 1 and on atherogenesis and vascular damage 2 has long been recognised. Renin was discovered in 1898 by Robert Tigerstedt; he showed that when saline extracts of rabbit kidneys were injected into anaesthetised rabbits, constriction of resistance vessels and marked increases in BP resulted.3 It was nearly half a century later, that Braun-Menedez and colleagues 4 and Page and Helmer 5 independently