Ian B. Wilkinson

Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis

Objective The aim of this study was to determine the reproducibility of pulse wave velocity (PWV) and augmentation index (AIx) measured using pulse wave analysis (PWA), prior to its use in large-scale clinical trials. Methods Arterial pressure waveforms were recorded and analysed using an established technique (Sphygmocor). Subjects with and without a range of recognized cardiovascular risk factors were studied to provide a wide range of values. Measurements were made after a brief introduction to the technique in a clinical setting. Two observers recorded aortic and brachial PWV in 24 subjects, each on two occasions, in a random order. In a separate study, two different observers used PWA to determine AIx in 33 subjects, each on two occasions, in a random order. Data were analysed using Bland-Altman plots and presented as mean ± SD. Results Brachial PWV was 8.65 ± 1.58 m/s (range 6.16–10.95 m/s) and aortic PWV was 8.15 ± 3.01 m/s (5.01–17.97 m/s). Within-observer variability was 0.14 ± 0.82 m/s for brachial PWV and 0.07 ± 1.17 m/s for aortic PWV. Corresponding between-observer values were −0.44 ± 1.09 m/s and −0.30 ± 1.25 m/s. AIx ranged from −15.0 to + 45.0%, with a group mean of + 19.6 ± 12.0%. The within-observer difference was 0.49 ± 5.37% and between-observer difference 0.23 ± 3.80%. Conclusion PWA is a simple and reproducible technique with which to measure PWV and AIx. Reproducibility accords with that reported by other workers using different methodologies. PWA may, therefore, be suitable for large-scale population and intervention studies investigating the clinical relevance of vascular stiffness.

Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'Establishing normal and reference values'

Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

The influence of heart rate on augmentation index and central arterial pressure in humans

1 Arterial stiffness is an important determinant of cardiovascular risk. Augmentation index (AIx) is a measure of systemic arterial stiffness derived from the ascending aortic pressure waveform. The aim of the present study was to assess the effect of heart rate on AIx. We elected to use cardiac pacing rather than chronotropic drugs to minimize confounding effects on the systemic circulation and myocardial contractility. 2 Twenty‐two subjects (13 male) with a mean age of 63 years and permanent cardiac pacemakers in situ were studied. Pulse wave analysis was used to determine central arterial pressure waveforms, non‐invasively, during incremental pacing (from 60 to 110 beats min−1), from which AIx and central blood pressure were calculated. Peripheral blood pressure was recorded non‐invasively from the brachial artery. 3 There was a significant, inverse, linear relationship between AIx and heart rate (r=−0.76; P < 0.001). For a 10 beats min−1 increment, AIx fell by around 4 %. Ejection duration and heart rate were also inversely related (r=−0.51; P < 0.001). 4 Peripheral systolic, diastolic and mean arterial pressure increased significantly during incremental pacing. Although central diastolic pressure increased significantly with pacing, central systolic pressure did not. There was a significant increase in the ratio of peripheral to central pulse pressure (P < 0.001), which was accounted for by the observed change in central pressure augmentation. 5 These results demonstrate an inverse, linear relationship between AIx and heart rate. This is likely to be due to alterations in the timing of the reflected pressure wave, produced by changes in the absolute duration of systole. Consideration of wave reflection and aortic pressure augmentation may explain the lack of rise in central systolic pressure during incremental pacing despite an increase in peripheral pressure.

Central Blood Pressure Measurements and Antihypertensive Therapy. A Consensus Document

The 2003 European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension1 included 2 important novel recommendations: assessment of the total cardiovascular risk should be taken into account in the management of the hypertensive patient, and quantification of risk should include subclinical target organ damage. These guidelines acknowledged that central (aortic) blood pressure (BP), which is the pressure exerted on the heart and brain, may be different from the pressure that is measured at the arm. They also recognized that central pressure may be predictive of outcome in specific populations2 and differently affected by antihypertensive drugs. However, although these guidelines accepted that central augmentation index and pulse wave velocity may be important as measures of subclinical organ damage, they also stressed the need for prospective trials to establish their predictive values given that such studies were lacking at that time (2003). After publication of these guidelines, additional data have strengthened the pathophysiological importance of central BP. Clinical studies have indicated that central BP may have predictive value independent of the corresponding peripheral (brachial) BP. More importantly, recent large-scale trials have shown that central hemodynamics may provide a worthwhile treatment target. In addition, central hemodynamics can now be reliably assessed noninvasively with a number of devices. Accordingly, because arterial stiffening and central hemodynamics are markers and manifestations of organ damage, the pertinent key question is whether the balance of evidence on their importance and issues related to clinical practice allows for implementation in patient management. Central (aortic and carotid) pressures are pathophysiologically more relevant than peripheral pressures for the pathogenesis of cardiovascular disease.3,4 It is aortic systolic pressure that the left ventricle encounters during systole (afterload), and the aortic pressure during diastole is a determinant of coronary perfusion. Furthermore, the distending pressure in the …

C-Reactive Protein Is Associated With Arterial Stiffness in Apparently Healthy Individuals

Objective—C-reactive protein (CRP) levels predict outcome in healthy individuals and patients with atherosclerosis. Arterial stiffness also independently predicts all-cause and cardiovascular mortality and may be involved in the process of atherosclerosis. The aim of this study was to investigate the relationship between stiffness and inflammation in a cohort of healthy individuals. Methods and Results—Pulse wave velocity (PWV) and blood pressure were assessed in 427 individuals. Subjects with cardiovascular disease, diabetes, hypercholesterolemia and those using medication were excluded. CRP correlated with age, mean arterial pressure (MAP), brachial and aortic PWV, and pulse pressures. In multiple regression models, aortic PWV correlated independently with age, CRP, male gender, and MAP (R2= 0.593; P <0.001). CRP was also independently associated with brachial PWV. Aortic augmentation index correlated with age, gender, MAP, and inversely with heart rate and height, but not with CRP (R2=0.794; P<0.001). Aortic, carotid, and brachial pulse pressures were also independently associated with CRP levels. Conclusion—Aortic and brachial PWV, and pulse pressure, relate to levels of inflammation in healthy individuals, suggesting that inflammation may be involved in arterial stiffening. Anti-inflammatory strategies may, therefore, be of benefit in reducing arterial stiffness and thus cardiovascular risk, especially in patients with premature arterial stiffening.

Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti–Tumor Necrosis Factor-α Therapy

Background— Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti–tumor necrosis factor-&agr; (TNF-&agr;) therapy. Methods and Results— Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-&agr; therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P=0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2=0.701; P<0.0001). Aortic PWV was reduced significantly by anti-TNF-&agr; therapy (8.82±2.04 versus 7.94±1.86 versus 7.68±1.56 m/s at weeks 0, 4, and 12, respectively; P<0.001); concomitantly, endothelial function improved. Conclusions— RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-&agr; therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.

Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia

OBJECTIVES The goal of this study was to investigate the relation between serum cholesterol, arterial stiffness and central blood pressure. BACKGROUND Arterial stiffness and pulse pressure are important determinants of cardiovascular risk. However, the effect of hypercholesterolemia on arterial stiffness is controversial, and central pulse pressure has not been previously investigated. METHODS Pressure waveforms were recorded from the radial artery in 68 subjects with hypercholesterolemia and 68 controls, and corresponding central waveforms were generated using pulse wave analysis. Central pressure, augmentation index (AIx) (a measure of systemic stiffness) and aortic pulse wave velocity were determined. RESULTS There was no significant difference in peripheral blood pressure between the two groups, but central pulse pressure was significantly higher in the group with hypercholesterolemia (37 +/- 11 mm Hg vs. 33 +/- 10 mm Hg [means +/- SD]; p = 0.028). Augmentation index was also significantly higher in the patients with hypercholesterolemia group (24.8 +/- 11.3% vs. 15.6 +/- 12.1%; p < 0.001), as was the estimated aortic pulse wave velocity. In a multiple regression model, age, short stature, peripheral mean arterial pressure, smoking and low-density lipoprotein cholesterol correlated positively with AIx, and there was an inverse correlation with heart rate and male gender. CONCLUSIONS Patients with hypercholesterolemia have a higher central pulse pressure and stiffer blood vessels than matched controls, despite similar peripheral blood pressures. These hemodynamic changes may contribute to the increased risk of cardiovascular disease associated with hypercholesterolemia, and assessment may improve risk stratification.

Matrix Metalloproteinase-9 (MMP-9), MMP-2, and Serum Elastase Activity Are Associated With Systolic Hypertension and Arterial Stiffness

Background— Arterial stiffness is an independent determinant of cardiovascular risk, and arterial stiffening is the predominant abnormality in systolic hypertension. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes, including matrix metalloproteinase-9 (MMP-9) and MMP-2. We hypothesized that elastase activity would be related to arterial stiffness and tested this using isolated systolic hypertension (ISH) as a model of stiffening and separately in a large cohort of healthy individuals. Methods and Results— A total of 116 subjects with ISH and 114 matched controls, as well as 447 individuals free from cardiovascular disease were studied. Aortic and brachial pulse wave velocity (PWV) and augmentation index were determined. Blood pressure, lipids, C-reactive protein, MMP-9, MMP-2, serum elastase activity (SEA), and tissue-specific inhibitor 2 of metalloproteinases were measured. Aortic and brachial PWV, MMP-9, MMP-2, and SEA levels were increased in ISH subjects compared with controls (P=0.001). MMP-9 levels correlated linearly and significantly with aortic (r=0.45; P=0.001) and brachial PWV (r=0.22; P=0.002), even after adjustments for confounding variables. In the younger, healthy subjects, MMP-9 and SEA were also independently associated with aortic PWV. Conclusions— Aortic stiffness is related to MMP-9 levels and SEA, not only in ISH, but also in younger, apparently healthy individuals. This suggests that elastases including MMP-9 may be involved in the process of arterial stiffening and development of ISH.

Central Pressure: Variability and Impact of Cardiovascular Risk Factors: The Anglo-Cardiff Collaborative Trial II

Pulse pressure varies throughout the arterial tree, resulting in a gradient between central and peripheral pressure. Factors such as age, heart rate, and height influence this gradient. However, the relative impact of cardiovascular risk factors and atheromatous disease on central pressure and the normal variation in central pressure in healthy individuals are unclear. Seated peripheral (brachial) and central (aortic) blood pressures were assessed, and the ratio between aortic and brachial pulse pressure (pulse pressure ratio, ie, 1/amplification) was calculated in healthy individuals, diabetic subjects, patients with cardiovascular disease, and in individuals with only 1 of the following: hypertension, hypercholesterolemia, or smoking. The age range was 18 to 101 years, and data from 10 613 individuals were analyzed. Compared with healthy individuals, pulse pressure ratio was significantly increased (ie, central systolic pressure was relatively higher) in individuals with risk factors or disease (P<0.01 for all of the comparisons). Although aging was associated with an increased pulse pressure ratio, there was still an average±SD difference between brachial and aortic systolic pressure of 11±4 and 8±3 mm Hg for men and women aged >80 years, respectively. Finally, stratifying individuals by brachial pressure revealed considerable overlap in aortic pressure, such that >70% of individuals with high-normal brachial pressure had similar aortic pressures as those with stage 1 hypertension. These data demonstrate that cardiovascular risk factors affect the pulse pressure ratio, and that central pressure cannot be reliably inferred from peripheral pressure. However, assessment of central pressure may improve the identification and management of patients with elevated cardiovascular risk.

Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans

Arterial stiffness is an independent predictor of mortality and is regulated by a number of factors, including vascular smooth muscle tone. However, the relationship between endothelial function and definitive measures of arterial stiffness and wave reflections has not been described in healthy individuals. Therefore, we tested the hypothesis that endothelial function is inversely correlated with aortic pulse wave velocity (PWV), central pulse pressure, and augmentation index in healthy individuals. Peripheral and central pulse pressure and augmentation index were determined at rest, and global endothelial function was measured using pulse wave analysis and administration of sublingual nitroglycerin and inhaled albuterol. Aortic PWV was also determined at baseline in a subset of 89 subjects. In a separate group of subjects (n=89), aortic PWV was measured and brachial artery flow-mediated dilatation assessed as a measure of conduit artery endothelial function. Global endothelial function was significantly and inversely correlated with aortic PWV (r=−0.69; P<0.001), augmentation index (r=−0.59; P<0.001), and central (r=−0.34; P<0.001) and peripheral pulse pressure (r=−0.15; P=0.03). Moreover, there was a stronger correlation between central rather than peripheral pulse pressure. After adjusting for potential confounders, global endothelial function remained independently and inversely associated with aortic PWV and augmentation index. There was also a significant, inverse relationship between conduit artery endothelial function and aortic PWV (r=0.39, P<0.001), which remained independent after adjusting for confounding factors. In healthy individuals, a decline in endothelial function is associated with increased large artery stiffness, wave reflections, and central pulse pressure.