JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2002; 39:1005-1011
© 2002 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilkinson, I. B.
Right arrow Articles by Cockcroft, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilkinson, I. B.
Right arrow Articles by Cockcroft, J. R.

CLINICAL STUDY: CORONARY ARTERY DISEASE

Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia

Ian B. Wilkinson, MA, BM*, Krishna Prasad, MB{dagger}, Ian R. Hall, BSc, MB{dagger}, Anne Thomas, BN{dagger}, Helen MacCallum, BN*, David J. Webb, MD{dagger}, Michael P. Frenneaux, MD{dagger} and John R. Cockcroft, BSc, MB{dagger},*

* Clinical Pharmacology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
{dagger} Department of Cardiology, University of Wales College of Medicine, University Hospital, Cardiff, United Kingdom

Manuscript received January 13, 2000; revised manuscript received December 7, 2001, accepted December 21, 2001.

* Reprint requests and correspondence: Dr. John R. Cockcroft, Department of Cardiology, University of Wales College of Medicine, University Hospital, Cardiff CF4 4XN, United Kingdom.
cockcroftjr{at}cf.ac.uk


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
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.

Abbreviations and Acronyms
  PMAP
  AIx
  augmentation index
  DPTI
  diastolic pressure time integral
  FH
  familial hypercholesterolemia
  HDL
  high-density lipoprotein
  LDL
  low-density lipoprotein
  PMAP
  peripheral mean arterial pressure
  PWA
  pulse wave analysis
  TTI
  tension time index

Arterial stiffening is an inevitable part of the aging process in nearly all societies (1,2), and it is associated with a rise in pulse pressure (3). The importance of pulse pressure as a predictor of cardiovascular mortality has been demonstrated by several recent population-based and interventional studies (4–7) and has focused attention on arterial stiffness as a key determinant of cardiovascular risk. "Premature arterial stiffening" occurs in association with several important cardiovascular risk factors including hypertension, diabetes mellitus and cigarette smoking (8), which are also associated with endothelial dysfunction (9). Whether arterial stiffening represents a marker of occult atheroma, or endothelial dysfunction, or is more directly involved in the process of atherosclerosis remains unclear (10).

Hypercholesterolemia is a major risk factor for cardiovascular disease, and it is also associated with endothelial dysfunction (11). However, there are conflicting data concerning the relationship between hypercholesterolemia and local arterial stiffness (12). Moreover, the effect of hypercholesterolemia on systemic arterial stiffness has only been investigated in one previous study (13), and central blood pressures were not assessed. We hypothesized that hypercholesterolemia would be associated with increased systemic arterial stiffness and central pulse pressure, and the aim of this study was to test this hypothesis in a group of otherwise healthy individuals with hypercholesterolemia and matched controls using the technique of pulse wave analysis (PWA). We have previously demonstrated that PWA is a reproducible, noninvasive method for assessing central blood pressure and augmentation index (AIx) (14)—a measure of the contribution that wave reflection makes to the arterial pressure waveform. The amplitude and timing of the reflected wave ultimately depend on the stiffness of the small (preresistance) vessels and large arteries and thus, AIx provides a measure of systemic arterial stiffness.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Sixty-eight patients with hypercholesterolemia, defined as a total serum cholesterol ≥6.5 mmol/l, were recruited from the cardiovascular risk clinics at the Western General Hospital in Edinburgh and the University Hospital of Wales in Cardiff and from general practices local to both hospitals. Concurrently, normocholesterolemic controls (total serum cholesterol < 6.5 mmol/l) were recruited from the same sources and community databases of volunteers held at both hospitals and selected such that, as a group, their distribution of age, gender and weight closely matched the patient group. Approval for the study was obtained from the respective Local Research Ethics Committees, and informed consent was obtained from each participant. Patients with elevated blood pressure (brachial artery blood pressure >160/100 mm Hg), treated hypertension, diabetes mellitus (British Diabetic Association criteria) or a clinical history of cardiovascular disease were excluded, as were subjects receiving any medication. Cigarette smokers were allowed to participate, having abstained for at least 4 h.

Blood pressure measurement.   Systolic and diastolic blood pressure were recorded in duplicate in the dominant arm using a validated oscillometric technique (HEM-705CP, Omron Corporation, Tokyo, Japan) (15). Peripheral mean arterial pressure (PMAP) was calculated by integration of the pressure waveform using the sphygmoCor version 6.1 software (AtCor Medical, Sydney, Australia).

Measurement of arterial stiffness and central blood pressure.   Pulse wave analysis was used to determine systemic arterial stiffness (sphygmoCor version 6.1 software) as previously described (14). A high-fidelity micromanometer (SPC-301, Millar Instruments, Houston, Texas) was used to obtain accurate recordings of the peripheral pressure waveforms by flattening, but not occluding, the radial artery of the dominant arm using gentle pressure (16). Data were collected directly into a microcomputer and, after 20 sequential waveforms had been acquired, an averaged peripheral waveform was generated. A corresponding averaged central pressure waveform was then generated using a validated transfer function (17–20), and, from this, augmentation, AIx, ascending aortic pressure and heart rate were then determined using the integral software.

Augmentation represents the difference between the second and first systolic peaks of the central pressure waveform, and AIx is defined as augmentation expressed as a percentage of the pulse pressure (Fig. 1) and is a measure of systemic arterial stiffness. The tension time index (TTI), the area under the systolic portion of the pressure waveform per minute (the systolic pressure-time integral), an index of systolic stress and the diastolic pressure-time integral (DPTI) were also determined (21,22). The aortic pulse wave velocity was estimated by calculating the time between the foot of the pressure wave and the inflection point, which provides a measure of the timing of the reflected wave, as described previously (23,24).



View larger version (9K):
[in this window]
[in a new window]
  		Figure 1 Representative ascending aortic waveforms from a young and older subject (Murgo type "C" and "A" waves, respectively); note the prominence of the second systolic peak (*) in the older individual. Augmentation index is defined as the difference between the second and first systolic peaks ({Delta}P) expressed as a percentage of the pulse pressure (PP).

 
Study protocol.   After 5 min seated rest in a quiet room, blood pressure was measured. Augmentation, AIx and central arterial pressure were then determined using PWA. All measurements were made in duplicate and mean values used for analysis. Venous blood was then drawn from the antecubital fossa for measurement of plasma glucose, total serum cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides. Finally, height and weight were recorded and body mass index calculated.

Data analysis.   Data were analyzed using unpaired, two-tailed Student t tests and multiple regression analysis (SPSS software package, version 10, SPSS Inc., Chicago, Illinois). Unless stated otherwise, all results are presented as means ± SD. Significance was defined as p < 0.05.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Sixty-eight subjects with hypercholesterolemia, aged 51 ± 10 years (range: men 29 to 77 years, women 39 to 73 years), and 68 control subjects, aged 51 ± 10 years (range: men 25 to 75 years, women 32 to 74 years), were entered into the study. There was no significant difference in age, gender, height, weight or the number of smokers between the two groups, but serum LDL cholesterol and triglycerides were significantly higher in the hypercholesterolemic group (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1 Subject Characteristics

 
A summary of the peripheral and central hemodynamics is presented in Table 2 and Figure 2. Peripheral blood pressure did not differ between the groups, although the control group had a higher resting heart rate. Augmentation, AIx and central pulse pressure were significantly higher in the subjects with hypercholesterolemia compared with controls, and there was a trend towards a higher central systolic pressure in the hypercholesterolemic group. The difference in AIx between the two groups persisted after correction for height and heart rate (18.4 ± 7.6 vs. 23.1 ± 6.1, p = 0.004). The TTI (2,296 ± 380 vs. 2,320 ± 438, p = 0.7) and DPTI (3,743 ± 559 vs. 3,613 ± 455, p = 0.2) were similar in both groups. There were fewer Murgo type "A" waves (23) in the control subjects compared with the subjects with hypercholesterolemia (40 vs. 57) and more type "B" (20 vs. 10) and "C" (8 vs. 1) waves (p = 0.003 for trend; chi-square).


View this table:
[in this window]
[in a new window]
  		Table 2 Hemodynamics

 


View larger version (9K):
[in this window]
[in a new window]
  		Figure 2 Box and whisker plots for augmentation index (AIx), augmentation and estimated aortic pulse wave velocity (TR) for the hypercholesterolemia (HC) and control subjects. Solid horizontal lines = median values; error bars = 95% confidence intervals; shaded area = interquartile range. n = 163; *p = 0.01; **p < 0.001.

 
Data from all 136 subjects were used to construct two multiple regression models with AIx and estimated aortic pulse wave velocity as the dependent variables. Age, gender, height, heart rate, PMAP, smoking history, LDL cholesterol, HDL cholesterol and triglycerides were entered into the models as known or likely determinants of arterial stiffness. Age, short stature, PMAP, smoking and LDL cholesterol, but not HDL cholesterol or triglycerides, correlated positively with AIx, and there was an inverse correlation with heart rate and male gender (Table 3). The model explained ~62% of the variability in AIx observed in the study (p < 0.001). Substituting augmentation for the dependent variable did not make a significant difference to the correlations in the regression model, neither did the addition of plasma glucose or changing the method of analysis to stepwise regression. Estimated aortic pulse wave velocity correlated positively with LDL cholesterol and smoking and inversely with male gender and height (Table 4).


View this table:
[in this window]
[in a new window]
  		Table 3 Results of the Multiple Regression Analysis With Augmentation Index as the Dependent Variable

 

View this table:
[in this window]
[in a new window]
  		Table 4 Results of the Multiple Regression Analysis With Estimated Aortic Pulse Wave Velocity (TR) as the Dependent Variable

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
A number of studies have investigated the relationship between hypercholesterolemia and arterial stiffness. In animals, hypercholesterolemia, induced by a cholesterol-rich diet, results in an initial reduction in arterial stiffness, followed by a progressive increase over time (25,26), which can be reversed by lowering serum cholesterol (26,27). In humans, a variety of techniques have been used to assess vascular stiffness in vivo, with conflicting results. Lehmann et al. (28) demonstrated increased distensibility, as determined by aortic pulse wave velocity, in a group of young patients with heterozygous familial hypercholesterolemia (FH) but, in contrast, reported reduced aortic distensibility in adults with FH (12). Others have also observed reduced radial artery compliance in adults with FH compared with controls (29). However, Toikka et al. (30) reported no difference in aortic or carotid compliance between asymptomatic adults with FH and controls.

In subjects without FH, most (30–33), but not all (13), studies have reported an inverse relationship between either LDL cholesterol or total cholesterol and aortic compliance. Differences in the vessels studied, patient selection and small sample sizes are likely to account for these discrepant findings. Indeed, Kool et al. (34) reported reduced arterial distensibility in some, but not all, arteries in individuals with hypercholesterolemia. However, all of these studies, with one exception (13), have focused on the stiffness of easily accessible arterial beds or even one small segment of an artery, and not on systemic arterial stiffness, which has a major influence on the interaction between the arterial tree and the left ventricle (35). Indeed, the shape of the central pressure waveform partly determines left ventricular workload (35). Therefore, assessing systemic stiffness may be of more clinical importance than measuring compliance within an isolated vascular bed. Moreover, the effect of hypercholesterolemia on central blood pressure has not been previously investigated.

In this study we recorded peripheral pressure waveforms using applanation tonometry and generated corresponding central arterial pressure waveforms using PWA. The main novel findings were an increased AIx and central pulse pressure in individuals with hypercholesterolemia compared with matched normocholesterolemic controls (Fig. 2). The AIx is a measure of the contribution made by the reflected pressure wave to the ascending aortic pressure waveform (36) and, thus, provides a measure of systemic arterial stiffness (37). Therefore, the present data demonstrate that hypercholesterolemia is associated with increased systemic arterial stiffness; this conclusion is supported by the higher frequency of Murgo type "A" waves among the subjects with hypercholesterolemia. Importantly, aortic pulse wave velocity, estimated from the timing of the reflected wave, was also increased in the subjects with hypercholesterolemia, indicating increased aortic stiffness and that the observed changes in AIx were not solely due to differences in wave reflection.

A number of factors, including gender, heart rate and height are known to influence AIx, independently of changes in stiffness (22,38). However, none of these variables, other than heart rate, differed significantly between the two groups. Moreover, after correction for heart rate and height, AIx remained significantly higher in the hypercholesterolemic group. Furthermore, in the multiple regression model, which included known confounding variables, LDL, but not HDL, cholesterol was a significant independent determinant of AIx (Table 3). The model accounted for ~65% of the observed variability of AIx, which compares favorably with other published multiple regression models (22,32). In addition, we also confirmed the positive relation of age, female gender, short stature, PMAP and low heart rate with AIx (22) and here, for the first time, demonstrated that chronic smoking is associated with an increased AIx (Table 3). We and others have previously demonstrated that individuals with diabetes mellitus (39) and insulin resistance (40) have a higher AIx than matched controls and that insulin per se can influence arterial stiffness (41). However, there was no relation between AIx and serum glucose in this present study. The most likely explanation for this is that we actively excluded patients with diabetes mellitus and, therefore, only studied individuals within a rather narrow range of serum glucose concentrations.

The multiple regression model investigating the determinants of estimated aortic pulse wave velocity confirmed that LDL cholesterol was independently associated with aortic stiffening. Height was inversely related to estimated pulse wave velocity, which is to be expected, as we did not correct for path length but simply used the arrival of the reflected wave as a measure of aortic pulse wave velocity. Therefore, for a given pulse wave velocity, taller subjects with a longer aortae will have a prolonged transit time.

Peripheral pulse pressure, a surrogate measure of arterial stiffness and important predictor of cardiovascular mortality (4,5,42), did not differ significantly between the two groups. However, we have demonstrated, for the first time, increased central pulse pressure in subjects with hypercholesterolemia compared with controls and a reduction in the degree of pressure amplification. Systolic pressure varies throughout the arterial tree due to wave reflection and differences in vessel stiffness. Normally, there is an amplification of pulse pressure from the central to peripheral arteries, but the degree of amplification depends on a number of factors including heart rate (38) and posture (43). Therefore, peripheral pulse pressure does not always predict central pulse pressure, which is important because central, not brachial artery, pressure best defines left ventricular workload and, thus, left ventricular mass—an important and independent predictor of cardiovascular mortality (44). Moreover, carotid pulse pressure correlates more closely with carotid intima-media thickness than brachial pulse pressure (45) and predicts restenosis after angioplasty (46). However, whether measurement of central pulse pressure will improve risk stratification remains to be proven. Nevertheless, we have demonstrated that simply assessing brachial artery pressure does not reliably predict central hemodynamics, which may explain the lack of correlation between peripheral blood pressure and serum cholesterol in a recent study (47).

Whether structural changes in the arterial wall alone are responsible for the increase in arterial stiffness reported in this and other studies is unclear. Although we did not include subjects with a history of vascular disease or manifest evidence of atheroma, we cannot exclude the possibility of occult atheroma in the hypercholesterolemic group being responsible for the observed arterial stiffening. However, mounting evidence suggests that there is a degree of functional regulation of stiffness by the vascular endothelium (48,49). Hypercholesterolemia is strongly associated with endothelial dysfunction and reduced nitric oxide bioavailability (11,49), which may lead to a degree of functional and, therefore, potentially reversible arterial stiffening. Indeed, in animal models of hypercholesterolemia, cholesterol lowering appears to reduce arterial stiffness (26,27). In humans, HMG-CoA reductase (statin) therapy has also been associated with a reduction in aortic pulse wave velocity within six months (50), but not any improvement in femoral, carotid or brachial artery distensibility within eight weeks (34). Finally, although we assessed arterial stiffness and central pressures noninvasively using PWA rather than directly, the transfer function involved has been validated. However, aortic pulse wave velocity was estimated from the timing of the reflected pressure wave rather than measured using a foot-to-foot methodology.

In summary, we have shown increased systemic arterial and aortic stiffness and, for the first time, central pulse pressure in asymptomatic patients with hypercholesterolemia. Stiffness was independently correlated with LDL but not HDL cholesterol. Large-scale studies are now required to investigate further the influence of hypercholesterolemia on central arterial pressure and left ventricular load. Multicenter studies investigating the effect of various therapeutic interventions on arterial stiffness, including cholesterol-lowering and folate supplementation in hypercholesterolemic subjects (Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine [SEARCH]), are currently ongoing (51), and these will serve not only to provide data concerning the importance of systemic arterial stiffness as a predictor of outcome but will also determine the effects of therapeutic intervention. Mechanistic studies are also required to investigate the relationship between cholesterol, arterial stiffness and endothelial function and may serve to elucidate the role of the endothelium in regulation of arterial stiffness.


   Acknowledgments
 
We thank Mr. B. van der Arend and Mr. M. van der Steen for their technical assistance.


   Footnotes
 
Supported, in part, by the High Blood Pressure Foundation, by a local Research and Development Grant (Lothian Universities NHS Hospital Trust) and by an unrestricted educational grant from Bayer Pharmaceuticals, PLC. Dr. I. B. Wilkinson, Dr. J. R. Cockcroft and Prof. Dr. J. Webb are supported by a Biomedical Research Collaboration Grant from the Wellcome Trust (056223). Prof. D. J. Webb is currently in receipt of a Research Leave Fellowship from the Wellcome Trust (052633). Dr. Wilkinson is now at the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Avolio AP, Fa-Quan D, Wei-Qiang L, et al. Effects of ageing on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation. 1985;71:202–210[Abstract/Free Full Text]
  2. Kelly RP, Hayward C, Avolio AP, O’Rourke MF. Noninvasive determination of age-related changes in the human arterial pulse. Circulation. 1989;80:1652–1659[Abstract/Free Full Text]
  3. Franklin SS, Gustin IVW, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation. 1997;96:308–315[Abstract/Free Full Text]
  4. Benetos A, Safar M, Rudnichi A, et al. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension. 1997;30:1410–1415[Abstract/Free Full Text]
  5. Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998;32:560–564[Abstract/Free Full Text]
  6. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation. 1999;100:354–360[Abstract/Free Full Text]
  7. Miller JA, Lever AF, Burke V. Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension Trial. J Hypertens. 1999;17:1065–1072[CrossRef][Medline]
  8. Glasser SP, Arnett DK, McVeigh GE, et al. Vascular compliance and cardiovascular disease: a risk factor or a marker? Am J Hypertens. 1997;10:1175–1189[CrossRef][Medline]
  9. Celermajer DS. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol. 1997;30:325–333[Abstract]
  10. Hodes RJ, Lakatta EG, McNeil CT. Another modifiable risk factor for cardiovascular disease? Some evidence points to arterial stiffness. J Am Geriatr Soc. 1995;43:581–582[Medline]
  11. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilatation of forearm resistance vessels in hypercholesterolemia. Lancet. 1992;340:1430–1432[CrossRef][Medline]
  12. Lehmann ED, Hopkins KD, Gosling RG. Aortic compliance measurements using Doppler ultrasound: in vivo biochemical correlates. Ultrasound Med Biol. 1993;19:683–710[CrossRef][Medline]
  13. Cameron JD, Jennings GL, Dart AM. The relationship between arterial compliance, age, blood pressure and serum lipid levels. J Hypertens. 1995;13:1718–1723[Medline]
  14. Wilkinson IB, Fuchs SA, Jansen IM, et al. The reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens. 1998;16:2079–2084[CrossRef][Medline]
  15. O’Brien E, Mee F, Atkins N, Thomas M. Evaluation of three devices for self measurement of blood pressure according to the revised British Hypertension Society Protocol: the Omron HEM-705CP, Philips HP5332, and Nissei DS-175. Blood Press Monit. 1996;1:55–61[Medline]
  16. Kelly RP, Hayward CS, Ganis J, Daley JM, Avolio AP, O’Rourke MF. Noninvasive registration of the arterial pulse waveform using high fidelity applanation tonometry. J Vasc Med Biol. 1989;1:142–149
  17. Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J. 1993;14:160–167[Abstract/Free Full Text]
  18. Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension. 2001;38:932–937[Abstract/Free Full Text]
  19. Takazawa K, O’Rourke M, Fujita M. Estimation of ascending aortic pressure from radial arterial pressure using a generalized transfer function. Z Kardiol. 1996;85:137–139
  20. Segers P, Qasem A, DeBacker T, Carlier S, Verdonck P, Avolio A. Peripheral "oscillatory" compliance is associated with aortic augmentation index. Hypertension. 2001;37:1434–1439[Abstract/Free Full Text]
  21. Buckberg GD, Fixler DE, Archie JP, Hoffman JIE. Experimental subendocardial ischaemia in dogs with normal coronary arteries. Circ Res. 1972;30:67–81[Abstract/Free Full Text]
  22. Hayward CS, Kelly RP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol. 1997;30:1863–1871[Abstract]
  23. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure waveforms. Circulation. 1980;62:105–116[Free Full Text]
  24. Marchais SJ, Guerin AP, Pannier BM, Levy BI, Safar M, London GM. Wave reflections and cardiac hypertrophy in chronic uremia. Hypertension. 1993;22:876–883[Abstract/Free Full Text]
  25. Pynadath TI, Mukherjee DP. Dynamic mechanical properties of atherosclerotic aorta: a correlation between the cholesterol ester content and the viscoelastic properties of atherosclerotic aorta. Atherosclerosis. 1977;26:311–318[CrossRef][Medline]
  26. Farrar DJ, Bond MG, Riley WA, Sawyer JK. Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation. 1991;83:1754–1763[Abstract/Free Full Text]
  27. Farrar DJ, Green HD, Wagner WD, Bond G. Reduction in pulse wave velocity and improvement of aortic distensibility accompanying regression of atherosclerosis in the rhesus monkey. Circ Res. 1980;47:425–432[Free Full Text]
  28. Lehmann ED, Watts GF, Fatemi-Langroudi B, Gosling RG. Aortic compliance in young patients with heterozygous familial hypercholesterolaemia. Clin Sci. 1992;83:717–721[Medline]
  29. Giannattasio C, Mangoni AA, Failla M, et al. Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia. Atherosclerosis. 1996;124:249–260[CrossRef][Medline]
  30. Toikka JO, Niemi P, Ahotupa M, et al. Large-artery elastic properties in young men: relationships to serum lipoproteins and oxidized low-density lipoproteins. Arterioscler Thromb Vasc Biol. 1999;19:436–441[Abstract/Free Full Text]
  31. Dart AM, Lancombe F, Yeoh JK, et al. Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplantation. Lancet. 1991;338:270–273[CrossRef][Medline]
  32. Hopkins KD, Lehmann ED, Gosling RG, Parker JR, Sonksen P. Biochemical correlates of aortic distensibility in vivo in normal subjects. Clin Sci. 1993;84:593–597[Medline]
  33. Giannattasio C, Mangoni AA, Failla M, et al. Combined effects of hypertension and hypercholesterolemia on radial artery function. Hypertension. 1997;29:583–586[Abstract/Free Full Text]
  34. Kool M, Lustermans F, Kragten H, et al. Does lowering of cholesterol levels influence functional properties of large arteries? Eur J Clin Pharmacol. 1995;48:217–223[Medline]
  35. Nichols WW, O’Rourke MF. McDonald’s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 4th Ed. London: Arnold; 1998.
  36. O’Rourke MF, Kelly RP. Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens. 1993;11:327–337[Medline]
  37. Safar ME, London GM. Therapeutic studies and arterial stiffness in hypertension: recommendations of the European Society of Hypertension. The Clinical Committee of Arterial Structure and Function. Working Group on Vascular Structure and Function of the European Society of Hypertension. J Hypertens. 2000;18:1527–1535[CrossRef][Medline]
  38. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol. 2000;525:263–270[Abstract/Free Full Text]
  39. Wilkinson IB, MacCallum H, Rooijmans DF, et al. Increased augmentation index and systolic stress in type 1 diabetes mellitus. Q J Med. 2000;93:441–448
  40. Westerbacka J, Vehkavaar S, Bergholm R, Wilkinson I, Cockcroft J, YkiJarvinen H. Marked resistance of the ability of insulin to decrease wave reflection in the aorta characterizes human obesity. Diabetes. 1999;48:821–827[Abstract]
  41. Westerbacka J, Wilkinson I, Utriainen T, Vehkavaar S, Cockcroft J, YkiJarvinen H. Diminished wave reflection in the aorta: a novel physiological action of insulin. Hypertension. 1999;33:1118–1122[Abstract/Free Full Text]
  42. Blacher J, Staessen J, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000;160:1085–1089[Abstract/Free Full Text]
  43. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and peripheral arterial pressure pulses during rest, exercise and tilted position in man. Circ Res. 1955;3:623–632[Abstract/Free Full Text]
  44. Levy D, Garrison R, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med. 1990;332:1561–1566
  45. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation. 1999;100:1387–1393[Abstract/Free Full Text]
  46. Nakayama Y, Tsumura K, Yamashita N, Yoshimaru K, Hayashi T. Pulsatility of ascending aortic pressure waveform is a powerful predictor of restenosis after percutaneous transluminal coronary angioplasty. Circulation. 2000;101:470–472[Abstract/Free Full Text]
  47. Glorioso N, Troffa C, Filigheddu F, et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension. 2000;34:1281–1286
  48. Wilkinson IB, Quasem A, McEinery CM, Webb DJ, Avolio A, Cockcroft JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002;105:213–217[Abstract/Free Full Text]
  49. Wilkinson IB, Cockcroft JR. Cholesterol, endothelial function and arterial stiffness. Curr Opin Lipidol. 1998;9:237–442[CrossRef][Medline]
  50. Muramatsu J, Kobayashi A, Hasegawa N, Yokouchi S. Hemodynamic changes associated with reduction in total cholesterol treatment with the HMG-CoA reductase inhibitor pravastatin. Atherosclerosis. 1997;130:179–182[CrossRef][Medline]
  51. Wilkinson IB, Cockcroft JR, Webb DJ. Pulse wave analysis and arterial stiffness. J Cardiovasc Pharmacol. 1998;32(Suppl 3):33–37



This article has been cited by other articles:


Home page
 HypertensionHome page
J.-F. Argacha, D. Adamopoulos, M. Gujic, D. Fontaine, N. Amyai, G. Berkenboom, and P. van de Borne
Acute Effects of Passive Smoking on Peripheral Vascular Function
Hypertension, June 1, 2008; 51(6): 1506 - 1511.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
C. M. McEniery, Yasmin, B. McDonnell, M. Munnery, S. M. Wallace, C. V. Rowe, J. R. Cockcroft, I. B. Wilkinson, and on Behalf of the Anglo-Cardiff Collaborative Trial
Central Pressure: Variability and Impact of Cardiovascular Risk Factors: The Anglo-Cardiff Collaborative Trial II
Hypertension, June 1, 2008; 51(6): 1476 - 1482.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
J. E. Sharman, C. M. McEniery, R. Campbell, P. Pusalkar, I. B. Wilkinson, J. S. Coombes, and J. R. Cockcroft
Nitric Oxide Does Not Significantly Contribute to Changes in Pulse Pressure Amplification During Light Aerobic Exercise
Hypertension, April 1, 2008; 51(4): 856 - 861.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
M. L. Macedo, D. Luminoso, M. D. Savvidou, C. M. McEniery, and K. H. Nicolaides
Maternal Wave Reflections and Arterial Stiffness in Normal Pregnancy as Assessed by Applanation Tonometry
Hypertension, April 1, 2008; 51(4): 1047 - 1051.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
L. Ghiadoni, G. Penno, C. Giannarelli, Y. Plantinga, M. Bernardini, L. Pucci, R. Miccoli, S. Taddei, A. Salvetti, and S. Del Prato
Metabolic Syndrome and Vascular Alterations in Normotensive Subjects at Risk of Diabetes Mellitus
Hypertension, February 1, 2008; 51(2): 440 - 445.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. J. Sommerfield, I. B. Wilkinson, D. J. Webb, and B. M. Frier
Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia
Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1274 - E1279.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
K. G. Moulakakis, D. P. Sokolis, D. N. Perrea, T. Dosios, I. Dontas, M. V. Poulakou, C. A. Dimitriou, G. Sandris, and P. E. Karayannacos
The Mechanical Performance and Histomorphological Structure of the Descending Aorta in Hyperthyroidism
Angiology, June 1, 2007; 58(3): 343 - 352.
[Abstract] [PDF]

Home page
 J Am Coll CardiolHome page
I. J. Kullo and A. R. Malik
Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification
J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1413 - 1426.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
S. Laurent, J. Cockcroft, L. Van Bortel, P. Boutouyrie, C. Giannattasio, D. Hayoz, B. Pannier, C. Vlachopoulos, I. Wilkinson, H. Struijker-Boudier, et al.
Expert consensus document on arterial stiffness: methodological issues and clinical applications
Eur. Heart J., November 1, 2006; 27(21): 2588 - 2605.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. Pirro, G. Schillaci, R. Paltriccia, F. Bagaglia, C. Menecali, M. R. Mannarino, M. Capanni, A. Velardi, and E. Mannarino
Increased Ratio of CD31+/CD42- Microparticles to Endothelial Progenitors as a Novel Marker of Atherosclerosis in Hypercholesterolemia
Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2530 - 2535.
[Abstract] [Full Text] [PDF]

Home page
 ANGIOLOGYHome page
S. Oren, I. Isakov, B. Golzman, J. Kogan, S. Turkot, R. Peled, and C. Yosefy
The Influence of Smoking Cessation on Hemodynamics and Arterial Compliance
Angiology, October 1, 2006; 57(5): 564 - 568.
[Abstract] [PDF]

Home page
 HypertensionHome page
C. M. McEniery, S. Wallace, I. S. Mackenzie, B. McDonnell, Yasmin, D. E. Newby, J. R. Cockcroft, and I. B. Wilkinson
Endothelial Function Is Associated With Pulse Pressure, Pulse Wave Velocity, and Augmentation Index in Healthy Humans
Hypertension, October 1, 2006; 48(4): 602 - 608.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
P. J. D. Owen, C. Rajiv, D. Vinereanu, T. Mathew, A. G. Fraser, and J. H. Lazarus
Subclinical Hypothyroidism, Arterial Stiffness, and Myocardial Reserve
J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2126 - 2132.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
S. Van Doornum, G. McColl, and I. P. Wicks
Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis
Rheumatology, November 1, 2005; 44(11): 1428 - 1432.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
M. J. Roman, R. B. Devereux, J. E. Schwartz, M. D. Lockshin, S. A. Paget, A. Davis, M. K. Crow, L. Sammaritano, D. M. Levine, B.-A. Shankar, et al.
Arterial Stiffness in Chronic Inflammatory Diseases
Hypertension, July 1, 2005; 46(1): 194 - 199.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
F. Verbeke, P. Segers, S. Heireman, R. Vanholder, P. Verdonck, and L. M. Van Bortel
Noninvasive Assessment of Local Pulse Pressure: Importance of Brachial-to-Radial Pressure Amplification
Hypertension, July 1, 2005; 46(1): 244 - 248.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. R. Rubin, M. S. Maurer, D. J. McMahon, J. P. Bilezikian, and S. J. Silverberg
Arterial Stiffness in Mild Primary Hyperparathyroidism
J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3326 - 3330.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
J. E. Sharman, Z. Y. Fang, B. Haluska, M. Stowasser, J. B. Prins, and T. H. Marwick
Left Ventricular Mass in Patients With Type 2 Diabetes Is Independently Associated With Central but not Peripheral Pulse Pressure
Diabetes Care, April 1, 2005; 28(4): 937 - 939.
[Full Text] [PDF]

Home page
 HypertensionHome page
G. de Simone, M. J. Roman, M. H. Alderman, M. Galderisi, O. de Divitiis, and R. B. Devereux
Is High Pulse Pressure a Marker of Preclinical Cardiovascular Disease?
Hypertension, April 1, 2005; 45(4): 575 - 579.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
Yasmin, S. Wallace, C. M. McEniery, Z. Dakham, P. Pusalkar, K. Maki-Petaja, M. J. Ashby, J. R. Cockcroft, and I. B. Wilkinson
Matrix Metalloproteinase-9 (MMP-9), MMP-2, and Serum Elastase Activity Are Associated With Systolic Hypertension and Arterial Stiffness
Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 372 - 378.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
S Van Doornum, G McColl, and I P Wicks
Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis
Ann Rheum Dis, December 1, 2004; 63(12): 1571 - 1575.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
D. Lemogoum, L. Van Bortel, B. Najem, A. Dzudie, C. Teutcha, E. Madu, M. Leeman, J.-P. Degaute, and P. van de Borne
Arterial Stiffness and Wave Reflections in Patients With Sickle Cell Disease
Hypertension, December 1, 2004; 44(6): 924 - 929.
[Abstract] [Full Text] [PDF]

Home page
 Diabetes CareHome page
S. A. Hope, D. B. Tay, I. T. Meredith, and J. D. Cameron
Use of Arterial Transfer Functions for the Derivation of Central Aortic Waveform Characteristics in Subjects With Type 2 Diabetes and Cardiovascular Disease: Response to Wilkinson and McEniery and Avolio, Cockcroft, and O'Rourke
Diabetes Care, October 1, 2004; 27(10): 2565 - 2567.
[Full Text] [PDF]

Home page
 HypertensionHome page
I. B. Wilkinson, S. S. Franklin, and J. R. Cockcroft
Nitric Oxide and the Regulation of Large Artery Stiffness: From Physiology to Pharmacology
Hypertension, August 1, 2004; 44(2): 112 - 116.
[Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
Yasmin, C. M. McEniery, S. Wallace, I. S. Mackenzie, J. R. Cockcroft, and I. B. Wilkinson
C-Reactive Protein Is Associated With Arterial Stiffness in Apparently Healthy Individuals
Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 969 - 974.
[Abstract] [Full Text]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. M. Dart, C. D. Gatzka, J. D. Cameron, B. A. Kingwell, Y.-L. Liang, K. L. Berry, C. M. Reid, and G. L. Jennings
Large Artery Stiffness Is Not Related to Plasma Cholesterol in Older Subjects with Hypertension
Arterioscler. Thromb. Vasc. Biol., May 1, 2004; 24(5): 962 - 968.
[Abstract] [Full Text]