The stiffness of the aorta can be determined by measuring carotid-femoral pulse wave velocity (PWV(cf)). PWV may also influence the contour of the peripheral pulse, suggesting that contour analysis might be used to assess large artery stiffness. An index of large artery stiffness (SI(DVP)) derived from the digital volume pulse (DVP) measured by transmission of IR light (photoplethysmography) was examined. SI(DVP) was obtained from subject height and from the time delay between direct and reflected waves in the DVP. The timing of these components of the DVP is determined by PWV in the aorta and large arteries. SI(DVP) was, therefore, expected to provide a measure of stiffness similar to PWV. SI(DVP) was compared with PWV(cf) obtained by applanation tonometry in 87 asymptomatic subjects (21-68 years; 29 women). The reproducibility of SI(DVP) and PWV(cf) and the response of SI(DVP) to glyceryl trinitrate were assessed in subsets of subjects. The mean within-subject coefficient of variation of SI(DVP), for measurements at weekly intervals, was 9.6%. SI(DVP) was correlated with PWV(cf) ( r =0.65, P <0.0001). SI(DVP) and PWV(cf) were each independently correlated with age and mean arterial blood pressure (MAP) with similar regression coefficients: SI(DVP)=0.63+0.086 x age+0.042 x MAP ( r =0.69, P <0.0001); PWV(cf)=0.76+0.080 x age+0.053 x MAP ( r =0.71, P <0.0001). Administration of glyceryl trinitrate (3, 30 and 300 microg/min intravenous; each dose for 15 min) in nine healthy men produced similar changes in SI(DVP) and PWV(cf). Thus contour analysis of the DVP provides a simple, reproducible, non-invasive measure of large artery stiffness.

Summary Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. Methods We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. Findings Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). Interpretation Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. Funding Alnylam Pharmaceuticals.

Stimulation of beta2-adrenergic receptors causes greater forearm vasodilation in premenopausal women, at midmenstrual cycle, than it does in men. This is sufficient to explain why vasoconstriction to brachial artery norepinephrine is attenuated in such women.

Abstract-Aortic augmentation index, a measure of central systolic blood pressure augmentation arising mainly from pressure-wave reflection, increases with vascular aging. The augmentation index is influenced by aortic pulse-wave velocity (related to aortic stiffness) and by the site and extent of wave reflection. To clarify the relative influence of pulse-wave velocity and wave reflection on the augmentation index, we studied the association between augmentation index, pulse-wave velocity, and age and examined the effects of vasoactive drugs to determine whether altering vascular tone has differential effects on pulse-wave velocity and the augmentation index. We made simultaneous measurements of the augmentation index and carotid-to-femoral pulse-wave velocity in 50 asymptomatic men aged 19 to 74 years at baseline and, in a subset, during the administration of nitroglycerin, angiotensin II, and saline vehicle. The aortic augmentation index was obtained by radial tonometry (Sphygmocor device, PWV Medical) with the use of an inbuilt radial to aortic transfer function. In multiple regression analysis, the aortic augmentation index was independently correlated only with age (Rϭ0.58, PϽ0.0001). Nitroglycerin (3 to 300 g/min IV) reduced the aortic augmentation index from 4.8Ϯ2.3% to Ϫ11.9Ϯ5.3% (nϭ10, PϽ0.002). Angiotensin II (75 to 300 ng/min IV) increased the aortic augmentation index from 9.3Ϯ2.4% to 18.3Ϯ2.9% (nϭ12, PϽ0.001). These drugs had small effects on aortic pulse-wave velocity, producing mean changes from baseline of Ͻ1 m/s (each PϽ0.05). In healthy men, vasoactive drugs may change aortic augmentation index independently from aortic pulse-wave velocity. Key Words: antihypertensive agents Ⅲ aorta Ⅲ arteries Ⅲ hemodynamics Ⅲ pulse S ystolic blood pressure is augmented by the reflection of pressure from the periphery of the circulation to the aortic root. 1 The aortic augmentation index (AIx) is defined as the increment in pressure from the first systolic shoulder (inflection point) to the peak pressure of the aortic pressure waveform expressed as a percentage of the peak pressure. 2 This index has been used to measure the additional load imposed on the left ventricle as a result of wave reflection and correlates with left ventricular mass. 3,4 AIx depends, at least in part, on aortic and large-artery pulse-wave velocity (PWV). A higher PWV results in earlier arrival of reflected waves and, hence, increased augmentation during early systole. 1,5 PWV is inversely related to arterial distensibility. 6 Therefore, AIx has been proposed as an index of "arterial stiffness" 7,8 and has been used as a measure of this. 9 -12 However, in addition to PWV, AIx may depend on the pattern of ventricular ejection and on arterial properties determining the amount and site of wave reflection. 1 These latter factors may be influenced by the vascular tone of the small muscular arteries/arterioles rather than by the elastic properties of the aorta. To clarify the relationship between AIx and PWV, we made simultaneous measurement...

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Analysis of the contour of the peripheral pulse to assess arterial properties was first described in the nineteenth century. With the recognition of the importance of arterial stiffness there has been a resurgence of interest in pulse wave analysis, particularly the analysis of the radial pressure pulse acquired using a tonometer. An alternative technique utilizes a volume pulse. This may conveniently be acquired optically from a finger (digital volume pulse). Although less widely used, this technique deserves further consideration because of its simplicity and ease of use. As with the pressure pulse, the contour of the digital volume pulse is sensitive to changes in arterial tone induced by vasoactive drugs and is influenced by ageing and large artery stiffness. Measurements taken directly from the digital volume pulse or from its second derivative can be used to assess these properties. This review describes the background to digital volume pulse contour analysis, how the technique relates to contour analysis of the pressure pulse, and current and future applications.

Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).

These results suggest that beta-adrenergic vasodilator responses in human forearm vasculature are mediated predominantly through beta 2-adrenergic receptors and are dependent on nitric oxide synthesis.