Document

Abstracts
1. Perspectives on systolic hypertension. The
Framingham Study.

KANNEL WB, DAWBER TR, MCGEE DL
Abstract
Diastolic hypertension has been widely and justifiably accepted as a cause
of cardiovascular mortality. However, it has also been accepted that the
cardiovascular sequelae of hypertension derive chiefly from the diastolic
component. Because systolic and diastolic pressure are usually highly
correlated it is not easy to dissociate the effects of each. Statistical analysis
suggests that systolic pressure is actually the more potent contributor to
cardiovascular sequelae. Even isolated systolic pressure elevation is
associated witn an excess cardiovascular mortality. At low diastolic
pressures (i.e., less than 95 mm Hg), risk rises with the level of systolic
pressure. Also, isolated systolic hypertension is most ominous in the elderly,
in whom it is highly prevalent. Isolated systolic hypertension was related to
the occurrence of "direct" complications as well as to atherosclerotic
sequelae. It was also associated with excess mortality, taking into
account rigid vessels as judged from pulse-wave recordings. Trials to
determine whether the treatment of isolated systolic hypertension is
efficacious for avoiding its demonstrated excess cardiovascular morbidity
and mortality are urgently needed.
(Circulation 1980 Jun 61:1179-1182)
2. Assessment of vasoactive agents and vascular aging
by the second derivative of photoplethysmogram
waveform.

TAKAZAWA K, TANAKA N, FUJITA M, MATSUOKA O, SAIKI T,
AIKAWA M, TAMURA S, IBUKIYAMA C
Abstract
To evaluate the clinical application of the second derivative of the
fingertip photoplethysmogram waveform, we performed drug administration studies (study 1) and epidemiological studies (study 2). In study 1, ascending aortic pressure was recorded simultaneously with the fingertip photoplethysmogram and its second derivative in 39 patients with a mean+/-SD age of 54+/-11 years. The augmentation index was defined as the ratio of the height of the late systolic peak to that of the early systolic peak in the pulse. The second derivative consists of an a, b, c, and d wave in systole and an e wave in diastole. Ascending aortic pressure increased after injection of 2.5 microg angiotensin from 126/74 to 160/91 mm Hg and decreased after 0.3 mg sublingual nitroglycerin to 111/73 mm Hg. The d/a, the ratio of the height of the d wave to that of the a wave, decreased after angiotensin from -0.40+/-0.13 to -0.62+/-0.19 and increased after nitroglycerin to - 0.25+/-0.12 (P<0.001 and P<0.001, respectively). The negative d/a increased with increases in plethysmographic and ascending aortic augmentation indices (r=0.79, P<0.001, and r=0.80, P<0.001, respectively). The negative d/a reflects the late systolic pressure augmentation in the ascending aorta and may be useful for non-invasive evaluation of the effects of vasoactive agents. In study 2, the second derivative of the plethysmogram waveform was measured in a total of 600 subjects (50 men and 50 women in each decade from the 3rd to the 8th) in our health assessment centre. The b/a ratio increased with age, and c/a, d/a, and e/a ratios decreased with age. Thus, the second derivative aging index was defined as b-c-d-e/a. The second derivative wave aging index (y) increased with age (x) (r=0.80, P<0.001, y=0.023x-1.515). The second derivative aging index was higher in 126 subjects with any history of diabetes mellitus, hypertension, hypercholesterolemia, and ischemic heart disease than in age-matched subjects without such a history (-0.06+/-0.36 versus -0.22+/-0.41, P<0.01). Women had a higher aging index than men (P<0.01). The b-c- d-e/a ratio may be useful for evaluation of vascular aging and for screening of arteriosclerotic disease.

(Hypertension 1998 Aug 32:365-70).
3. Photoplethysmographic assessment of pulse wave
reflection. Blunted Response to Endothelium-
Dependent Beta2 - Adrenergic Vasodilation in Type
II Diabetes Mellitus

PHILIP J. CHOWIENCZYK, FRCP, RONAN P. KELLY, PHD, HELEN
MACCALLUM, BN, SANDRINE C. MILLASSEAU, MS, TOMAS L. G.
ANDERSSON, PHD, RAYMOND G. GOSLING, PHD, JAMES M.
RITTER, FRCP, ERIK E. ÄNGGÅRD, PHD
OBJECTIVES: We sought to determine whether a simple index of pressure
wave reflection may be derived from the digital volume pulse (DVP) and
used to examine endothelium-dependent vasodilation in patients with type II
diabetes mellitus.
BACKGROUND: The DVP exhibits a characteristic notch or inflection
point that can be expressed as percent maximal DVP amplitude (IPDVP).
Nitrates lower IPDVP, possibly by reducing pressure wave reflection.
Response of IPDVP to endothelium-dependent vasodilators may provide a
measure of endothelial function.
METHODS: The DVP was recorded by photoplethysmography. Albuterol
(salbutamol) and glyceryl trinitrate (GTN) were administered locally by
brachial artery infusion or systemically. Aortic pulse wave transit time from
the root of the subclavian artery to aortic bifurcation (TAo ) was measured by
simultaneous Doppler velocimetry.
RESULTS: Brachial artery infusion of drugs producing a greater than
threefold increase in forearm blood flow within the infused limb was
without effect on IPDVP , whereas systemic administration of albuterol and
GTN produced dose-dependent reductions in IPDVP. The time between the
first and second peak of the DVP correlated with TAo (r 5 0.75, n = 20, p <
0.0001). The effects of albuterol but not GTN on IPDVP were attenuated by
NG -monomethyl-L-arginine. The IPDVP response to albuterol (400 µg by
inhalation) was blunted in patients with type II diabetes mellitus as
compared with control subjects (fall 5.9 ± 1.8% vs. 11.8 ± 1.8%, n = 20, p <
0.02), but that to GTN (500 µg sublingually) was preserved (fall 18.3 ±
1.2% vs. 18.6 6± 1.9%, p = 0.88).
CONCLUSIONS: The IPDVP is influenced by pressure wave reflection. The
effects of albuterol on IPDVP are mediated in part through the nitric oxide
pathway and are impaired in patients with type II diabetes.
(J Am Coll Cardiol 1999;34:2007–14)
Correspondence to Dr P.J. Chowienczyk, Department of Clinical Pharmacology, St
Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail
[email protected]
4. The influence of the peripheral reflection wave on
left ventricular hypertrophy in patients with essential
hypertension.

IKETANI T, IKETANI Y, TAKAZAWA K, YAMASHINA A
Abstract
The objective of this study was to clarify the relationship between afterload,
which consists mainly of the vascular reflection wave, and left ventricular
hypertrophy in patients with untreated essential hypertension using the
fingertip photoplethysmogram (PTG) and second derivative wave
(SDPTG) methods, the simplest and most convenient tools for pulse wave
analysis. The augmentation index (AI) is defined as the ratio of the height of
the late systolic peak, augmented by the peripheral reflection wave, to that
of the early systolic peak caused mainly by left ventricular ejection in the
pulse. Increased AI of the PTG and negative d/a, obtained by multiplying
the ratio of the late re-decreasing wave (d wave) to the initial positive wave
(a wave) of the SDPTG by -1, have the same meaning as increased
ascending aortic AI. The left brachial artery blood pressure was measured in
60 patients. The PTG and SDPTG of the right second finger were recorded
by a digital photoplethysmograph. The left ventricular mass index (LVMI)
was investigated by ultrasonography. Subjects were assigned to one of two
groups: a low AI (AI of PTG<1.6; group 1) or a high AI (AI of PTG> or
=1.6; group 2) group. LVMI was significantly higher in group 2 than in
group 1. In the study group as a whole, the LVMI was positively correlated
with both the AI of PTG (r=0.60, p<0.0001) and negative d/a (r=0.63,
p<0.0001). An increase in the LVMI was seen in subjects with an
augmented late systolic component in the waveform. It was concluded that
an increase in the peripheral reflection wave on the left ventricle is one of
the important factors causing cardiac hypertrophy in patients with
hypertension.
(Hypertens Res 2000 Sep 23:451-8)
5. Arterial stiffness and pulse contour analysis: an age
old concept revisited
JOHN R COCKCROFT AND IAN B WILKINSON ‘In extreme old age, the arteries themselves, the grand instrument of the circulation, by the continual apposition of earth, become hard, and as it were bony, till, having lost the power of contracting themselves they can no longer propel the blood, even through the largest channels, in consequence of which death naturally ensues.’ ( John Wesley, 1703±1791) Hardening of the arteries, and its relation to aging, is far from a new phenomenon. Indeed, the fact that arteries stiffen with age, and that such changes are associated with an increased incidence of major cardiovascular events, is now established beyond doubt [1±4]. However, the influence of arterial stiffening on the interaction between the heart and large vessels, and on athersclerosis, is less well understood. Early researchers used pulse contour analysis of peripheral pressure waveforms to obtain information about arterial stiffness [5,6], but their results were mainly qualitative, and pulse contour analysis was largely abandoned by practicing clinicians in favour of conventional sphygmomanometry. With the increased longevity of modern societies and the recognition that arterial stiffness is an independent predictor of cardiovascular risk in selected populations, the factors underlying vascular stiffness have assumed major importance. In particular, there has been interest in the association between stiffness and cardiovascular risk factors, such as diabetes and hypertension in individuals without manifest atheroma [7]. It has become clear that arterial stiffness is not solely determined by structural elements within the vessel wall and distending pressure, but that there is also functional regulation by the sympathetic nervous system [8] and endothelial-derived NO[9]. This suggests that functional abnormalities, such as endothelial dysfunction, may underlie some of the large artery stiffening found in individuals with cardio- vascular disease and risk factors, and thus may potentially be reversible [10]. Moreover, assessment of arterial stiffness in such individuals may aid risk stratification. It is against this background that several groups have focused on the development of simple reproducible methods to assess arterial stiffness in clinical practice [11]. In this issue of Clinical Science, Millasseau et al. [12], in a series of elegant studies, describe the use of pulse contour analysis to derive quantitative data concerning large arterial stiffness in the hope of providing new insights into ventricular vascular interaction. Using the established technique of photoplethysmography [13,14], they have devised a reproducible parameter termed ‘stiffness index' by measuring the time delay between direct and reflected waves in the digital volume pulse [12]. Since this measure will be determined, to a large extent, by velocity of the arterial waveform in the aorta and large arteries, it is perhaps unsurprising that they were able to demonstrate a significant correlation between the stiffness index and carotid-femoral pulse wave velocity (PWV). In addition, both stiffness index and carotid-femoral PWV were, as expected, independently correlated with age and mean arterial pressure. Nevertheless, their results are important, as they suggest that stiffness index may be used as a valid surrogate for aortic PWV. Since digital pulse contour analysis is simple, operator-independent and relatively inexpensive, it may be, as the authors suggest [12], suitable for use in large clinical studies. However, several relatively simple commercial systems are available to measure PWV directly. Thus any perceived benefit of the stiffness index must be weighed against the fact that it is an indirect measure, as the authors [12] themselves note; indeed path length is not measured directly, instead height is used as a surrogate. Such limitations may not be important, but it is becoming increasingly clear that small changes in PWV may still be physiologically meaningful [9]. Indeed, in humans, femoral PWV changes by only 5% per decade [2]. Therefore, although Millasseau et al. [12] report only a ` modest' change in stiffness index and PWV following administration of glyceryl trinitrate, the potential importance of such a change should not be underestimated. As the authors discuss [12], in addition to the stiffness index, other parameters have been shown to correlate with PWV, including central augmentation index (AIx), derived by from the radial artery waveform using a validated transfer function [15,16]. The timing of the start of wave reflection (TR ) can also be derived from the ascending aortic waveform, and provides a surrogate of aortic PWV [17,18]. Interestingly, recent data [19], from the same cohort of patients with end-stage renal failure referred to by Millasseau et al. [12], demonstrates that central AIx and PWV are both independent predictors of mortality, despite the fact that the majority of subjects were receiving a wide variety of vaso active drugs [20]. Blood pressure varies throughout the arterial tree [21], and the normal ampli®cation of pulse pressure towards the periphery depends on a number of factors, including age and mean pressure [22]. Interestingly, central rather than peripheral pulse pressure seems to predict mortality in patients with end-stage renal failure [23], and carotid intima-media thickness in healthy men [24]. Therefore, it appears that in order to fully assess the impact of disease processes and drugs on large arteries, perhaps both aortic PWV and AIx should be assessed, together with central blood pressure. There is no doubt that the assessment of arterial stiffness will make a major contribution to the improved management of cardiovascular disease in the clinical arena and should be included in all future large in- tervention studies. However, the choice of technique will be in¯uenced by ease of use, cost and other less rationally chosen factors [25]. The race is on, and the technique of digital pulse contour analysis, as described by Millasseau et al. [12], is an important addition to the field. It is, however, robust outcome data that is likely to determine the eventual winner. (Clinical Science (2002) 103, 379–380)
JOHN R. COCKCROFT* and IAN B. WILKINSON** *Department of Cardiology, Wales Heart Research Institute, Cardiff CF14 4XN, Wales, U.K., and **Department of Clinical Pharmacology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, U.K. 6. Noninvasive Assessment of the Digital Volume
Pulse Comparison With the Peripheral Pressure
Pulse

SANDRINE C. MILLASSEAU, FRANCK G. GUIGUI, RONAN P.
KELLY, KRISHNA PRASAD, JOHN R. COCKCROFT, JAMES M.
RITTER, PHILIP J. CHOWIENCZYK
Abstract—The digital volume pulse can be recorded simply and
noninvasively by photoplethysmography. The objective of the present study
was to determine whether a generalized transfer function can be used to
relate the digital volume pulse to the peripheral pressure pulse and, hence, to
determine whether both volume and pressure pulse waveforms are
influenced by the same mechanism. The digital volume pulse was recorded
by photoplethysmography in 60 subjects (10 women, aged 24 to 80 years),
including 20 subjects with previously diagnosed hypertension. Simultaneous
recordings of the peripheral radial pulse and digital artery pulse were
obtained by applanation tonometry and a servocontrolled pressure cuff
(Finapres), respectively. In 20 normotensive subjects, measurements were
obtained after the administration of nitroglycerin (NTG, 500 mg
sublingually). Transfer functions obtained by Fourier analysis of the
waveforms were similar in normotensive and hypertensive subjects. In
normotensive subjects, transfer functions were similar before and after
NTG. By use of a single generalized transfer function for all subjects, the
radial and digital artery pressure waveforms could be predicted from the
volume pulse with an average root mean square error of 4.462.0 and 4.361.9
mm Hg (mean6SD) for radial and digital artery waveforms, respectively,
similar to the error between the 2 pressure waveforms (4.461.4 mm Hg).
The peripheral pressure pulse is related to the digital volume pulse by a
transfer function, which is not influenced by effects of hypertension or
NTG. Effects of NTG on the volume pulse and pressure pulse are likely to
be determined by a similar mechanism.
(Hypertension. 2000;36:952-956.)

From the Department of Clinical Pharmacology (S.C.M., F.G.G., R.P.K.,
J.M.R., P.J.C.), Centre for Cardiovascular Biology and Medicine, King’s
College, London, UK, and the Department of Cardiology (K.P., J.R.C.),
University of Wales College of Medicine, Cardiff, UK.
Correspondence to Dr P.J. Chowienczyk, Department of Clinical
Pharmacology, St Thomas’ Hospital, Lambeth Palace Road, London SE1
7EH, UK. E-mail [email protected]
7. Aortic Stiffness Is an Independent Predictor of
Primary Coronary Events in Hypertensive Patients.
A Longitudinal Study

PIERRE BOUTOUYRIE, ANNE ISABELLE TROPEANO, ROLAND
ASMAR, ISABELLE GAUTIER, ATHANASE BENETOS, PATRICK
LACOLLEY, STEPHANE LAURENT
Abstract-
Arterial stiffness may predict coronary heart beyond classic risk factors. In a
longitudinal study., we assessed the predictive value of arterial stiffness on
coronary heart disease in patients with essential hypertension and without
known clinical cardiovascular disease. Aortic stiffness was determined from
carotid-femoral pulse wave velocity at baseline in 1045 hypertensives. The
risk assessment of coronary heart disease was made by calculating the
Framingham risk score according to the categories of gender., age, blood
pressure, cholesterol, diabetes, and smoking. Mean age at entry was 51
years, and mean follow up was 5.7 years. Coronary events (fatal and
nonfatal myocardial infarction, coronary revascularization, and angina
pectoris) and all cardiovascular events served as outcome variables in Cox
proportional-hazard regression models. Fifty-three coronary events and 97
total cardiovascular events occurred. In univariate analysis, the relative risk
of follow-up coronary event or any cardiovascular event increased with
increasing level of pulse wave velocity; for 1 SD, ie, 3.5 m/s, relatives risks
were 1.42 (95% confidence interval [CI], 1.10 to 1.82; P<0.01) and 1.41
(95% C1, 1.17 to 1.70; P<O.001), respectively. Framingham score
significantly predicted the occurrence of coronary and all cardiovascular
events in this population (P<0.01 and P<:0.0001, respective]y). In
multivariate analysis, pulse wave velocity remained significantly associated
with the occurrence of coronary event after adjustment either of
Framingham score (for 3.5 m/s: relative risk, 1.34; 95% CI, 1.01 to 1.79;
P=0.039) or classic risk factors (for 3.5 m/s: relative risk, 1.39; 95% CI,
1.08 to 1.79; P=0.01). Parallel results were observed for all cardiovascular
events. This study provides the first direct evidence in a longitudinal study
that aortic stiffness is an independent predictor of primary coronary events
in patients with essential hypertension.
(Hypertension. 2002;39:10-15.)
Key Words: arterial stiffness, cardiovascular morbidity, cardiovascular
mortality, coronary heart disease
Correspondence to Professeur Stéphane Lament, Service de Pharmacologie,
Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de
Paris, 20 Rue Leblanc, 75908 Paris Cedex 15, France. Email
[email protected]
8. Impact of aortic stiffness attenuation on survival of
patients in end-stage renal failure.

GUERIN AP, BLACHER J, PANNIER B, MARCHAIS SJ, SAFAR ME,
LONDON GM.

BACKGROUND: Aortic pulse wave velocity (PWV) is a predictor of
mortality in patients with end-stage renal failure (ESRF). The PWV is partly
dependent on blood pressure (BP), and a decrease in BP can attenuate the
stiffness. Whether the changes in PWV in response to decreases in BP can
predict mortality in ESRF patients has never been investigated. METHODS
AND RESULTS: One hundred fifty ESRF patients (aged 52+/-16 years)
were monitored for 51+/-38 months. From entry until the end of follow-up,
the changes of PWV in response to decreased BP were measured
ultrasonographically. BP was controlled by adjustment of "dry weight" and,
when necessary, with ACE inhibitors, calcium antagonists, and/or beta-
blockers, in combination if necessary. Fifty-nine deaths occurred, including
40 cardiovascular and 19 noncardiovascular events. Cox analyses
demonstrated that independent of BP changes, the predictors of all-cause
and cardiovascular mortality were as follows: absence of PWV decrease in
response to BP decrease, increased left ventricular mass, age, and pre-
existing cardiovascular disease. Survival was positively associated with
ACE inhibitor use. After adjustment for all confounding factors, the risk
ratio for the absence of PWV decrease was 2.59 (95% CI 1.51 to 4.43) for
all-cause mortality and 2.35 (95% CI 1.23 to 4.41) for cardiovascular
mortality. The risk ratio for ACE inhibitor use was 0.19 (95% CI 0.14 to
0.43) for all-cause mortality and 0.18 (95% CI 0.06 to 0.55) for
cardiovascular mortality. CONCLUSIONS: These results indicate that in
ESRF patients, the insensitivity of PWV to decreased BP is an independent
predictor of mortality and that use of ACE inhibitors has a favourable effect
on survival that is independent of BP changes.
(Circulation, 103 (7) 987-92 2001)
9. Determination of age-related increases in large
artery stiffness by digital pulse contour analysis

MILLASSEAU SC, KELLY RP, RITTER JM AND CHOWIENCZYK PJ
Abstract
The stiffness of the aorta can be determined by measuring carotid-femoral
pulse wave velocity (PWVcf). 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 (SIDVP ) derived from
the digital volume pulse (DVP) measured by transmission of IR light (photo
- plethysmography) was examined. SIDVP 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. SIDVP was, therefore, expected to provide a measure of
stiffness similar to PWV. SIDVP was compared with PWVcf obtained by
applanation tonometry in 87 asymptomatic subjects (21±68 years; 29
women). The reproduciability of SIDVP and PWVcf and the response of SIDVP
to glyceryl trinitrate were assessed in sub- sets of subjects. The mean
within-subject coefficient of variation of SIDVP , for measurements at weekly
intervals, was 9.6 %. SIDVP was correlated with PWVcf (r =0.65, P <0.0001).
SI DVP and PWVcf were each independently correlated with age and mean
arterial blood pressure (MAP) with similar regression coefficients: SIDVP =
0.63+0.086xage+0.042xMAP (r =0.69, P<0.0001); PWVcf
=0.76+0.080xage+0.053xMAP (r =0.71, P <0.0001). Administration of
glyceryl trinitrate (3, 30 and 300 µg/min intravenous; each dose for 15 min)
in nine healthy men produced similar changes in SIDVP and PWVcf . Thus
contour analysis of the DVP provides a simple, reproducible, non-invasive
measure of large artery stiffness.
(Clinical Science (2002) 103, 371–377)
Correspondence: Dr P. J. Chowienczyk (e-mail
[email protected]).
10. Technical comparison of methods for measuring
arterial compliance (stiffness)

R.J. WOODMAN, G.F. WATTS, B.A. KINGWELL, L.J. BEILIN, S.E.
HAMILTON, A.M. DART
Background decreased arterial compliance is a significant predictor of cardiovascular disease. Systemic arterial compliance is principally determined by aortic compliance but its estimation using the 'area' method (Liu et al 1986) requires significant technical skill. Commercially available techniques that analyse the pulse pressure waveform are more practicable. Objectives To correlate arterial compliance measured by the 'area' and by commercial methods, and to assess the reproducibility of each technique. Methods Fifteen males with known coronary disease and 15 young healthy volunteers were recruited. Repeat measures were performed randomly and sequentially by the same operator: large and small artery compliance (C1 and C2) ('CR2000 TradeMark '), augmentation index (AI), central pulse wave velocity (PWV) and central pulse pressure (CPP) ('Sphygmacor TradeMark '), stiffness index (SI) ('Pulse Trace TM '), and the 'area' method. Reproducibility was assessed by coefficient of variation (CV), and correlations by linear regression. Results The CV's for C1, C2, AI, PWV, CPP, SI and the area method were 11.3%, 15.6%, 22.4%. 10.5%, 25.3%, 17.8% and 19.3% respectively. All techniques except SI correlated significantly with the 'area' method (r2=0.20 to 0.38, p<0.05). AI, SI, C2 and central PWV were all correlated with each other (r2=0.42 to 0.64, p<0.01). Conclusions All commercial methods showed good reproducibility but were weakly associated with an estimate of central aortic compliance. Other properties of the circulation, such as peripheral wave reflectance, may therefore also contribute to AI, C2, PWV and SI. The discriminatory value of these measures for the development of cardiovascular disease merits further examination. Correspondence to R J Woodman University Department of Medicine, University of Western Australia and West Australian Heart Research Institute, Perth, Australia [email protected] 11. First Experience With Salbutomol - Induced
Changes In The Photoplethysmogaphic Digital
Volume Pulse

ALEKSANDRAS LAUCEVICIUS, LIGITA RYLISKYTE, ZANETA
PETRUIONIENE, MILDA KOVAITE, NERIJUS MISONIS
Summary. Photoplethysmographic digital volume pulse analysis provides an
additional possibility to evaluate arterial stiffness and to analyse the
reflected pulse waves from the lower part of the body. Systemic effect of
beta2-adrenergic agonist salbutamol is partially mediated through the L-
arginine-NO pathway. Attenuation of photoplethysmographic digital
volume pulse parameters under salbutamol inhalation could be a means of
evaluating vasomotor endothelial dysfunction in cardiovascular patients.
The aim of the present study was to estimate the digital volume pulse
parameters after the inhalation of salbutamol in patients with arterial
hypertension, coronary heart disease and to compare them with the results
obtained in healthy adults. Normal response of digital volume pulse to
salbutamol in healthy subjects was a decreased height of the inflection point
(IP) and the prolongation of peak - to -peak time (PPT). In groups of
patients with arterial hypertension and
coronary heart disease the typical response was attenuation in the drop of
the height of the inflection point and the corresponding
minimal or absent prolongation of the PPT interval. The blunted response of
photoplethysmographic digital volume pulse
parameters to inhaled salbutamol in hypertensive and coronary patients
could suggest a disturbed endothelial vasomotor
function in these patients.

(Seminars in Cardiology. 2002; 8(1):87-93)
Correspondence to Prof Aleksandras Laucevicius, Department of
Cardiology, Vilnius University, Vilnius Lithuania email: [email protected]
12. Oxidative stress could precede endothelial
dysfunction and insulin resistance in Indian
Mauritians with impaired glucose metabolism

N.K. GOPAULL, M.D.MANRAJ, A. HÉBÉ, S.LEE KWAI YAN, A.
JOHNSTON, M.J.CARRIER, E. E. ÄNGGÅRD
Abstract
Aims/hypothesis. To measure oxidative stress, endothelial dysfunction and
insulin resistance in Indian Mauritians at different stages of development of
Type II (non-insulin-dependent) diabetes mellitus.
Methods. Plasma total 8-epi-PGF2a, an indicator of oxidative stress, was
determined in age-matched subjects with normal glucose metabolism (n=
39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8)
and established diabetes (n = 14). Plasma glucose and insulin were
measured at baseline and 2 h following an oral glucose tolerance test.
Endothelial function was assessed by non-invasive digital pulse wave
photoplethysmography.
Results. Plasma 8-epi- PGF2a increased in subjects with impaired glucose
tolerance (p < 0.05) compared with control subjects, and was even higher in
newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01)
diabetic patients. A tendency towards reduced endothelial function in
subjects with impaired glucose tolerance became significant in patients with
newly diagnosed and established diabetes (p < 0.01), and was correlated
with 8-epi- PGF2a (r = 0.36, p < 0.01). Insulin resistance (homeostasis
model assessment) did not change in subjects with impaired glucose
tolerance compared with control subjects, but increased in newly diagnosed
(p < 0.01) and established (p < 0.001) diabetic subjects: The 8-epi- PGF2a
was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r =
0.40,p < 0.001) and insulin resistance (r = 0.35, p < 0.001).
Conclusion/interpretation. Oxidant stress is an early event in the evolution
of Type II diabetes and could precede the development of endothelial
dysfunction and insulin resistance. (Diabetologia (2001) 44: 706-712)
Corresponding author; N.K. Gopaul, Department of Experimental
Therapeutics, William Harvey Research Institute, St. Bartholomew and
Royal London School of Medicine and Dentistry, Queen Mary,
Charterhouse Square, London EC1M 6BQ, UK
13. Beside digital plethysmography detects
endothelial dysfunction in recent onset angina.

I. BEETON, E LEATHAM, ROYAL SURREY COUNTY HOSPITAL,
CARDIAC DEPT., GUILDFORD, UNITED KINGDOM.
Background: Endothelial dysfunction (ED) may be an early marker of
ischaemic heart disease (IHD), but current assays are time-consuming and
laborious limiting them to chronic IHD. Consequently, the degree of ED in
very recent onset angina is not known. We assessed a 10-minute test in
patients attending a Rapid Access Chest Pain Clinic where patients are
assessed within 48 hours of new symptoms.
Method: Consecutive chest pain patients (54 noncardiac controls and 46
IHD had digital volume pulse plethysmograms before and after 400 ? g
inhaled salbutamol. The inflection point (IP) from the first derivative of the
waveform and its change from baseline (IP-response) were calculated. The
pulse wave response to salbutamol is dependent on nitric oxide synthase can
be inhibited with L-NMMA. Ischaemic heart disease diagnosis was based
on history and Bruce protocol exercise electrocadiography. Multiple
regression was used to control for age, mean blood pressure (BP) and
smoking status.
Findings: IP-response is lower in patients with new angina than those with
noncardiac chest pain. This is independent of age, smoking status and mean
BP (table).
IHD(n=46mean?SD) Noncardiac(n=54mean?SD) p-value Score
IP-response = percentage change in pulse wave inflection point from
baseline after salbutamol inhalation; Duke’s Score = ischaemia scoring
system based on Bruce exercise protocol; IHD = ischaemic heart disease.
Discussion: IP-response is a rapid bedside test that identifies endothelial
dysfunction early in the course of ischaemic heart disease. It may be useful
as a diagnostic marker of IHD and identifies the need for early initiation of
interventions aimed at improving endothelial dysfunction in this group of
patients.
14. Clinical Evaluation of a Noninvasive, Widely
Applicable Method for Assessing Endothelial
Function

IAN B. WILKINSON, IAN R. HALL, HELEN MACCALLUM, ISLA S.
MACKENZIE, CARMEL M. MCENIERY, BART J. VAN DER AREND,
YAE-EUN SHU, LAURA S. MACKAY, DAVID J. WEBB, JOHN R.
COCKCROFT

Abstract—Current methods for assessing vasomotor endothelial function
are impractical for use in large studies. We tested the hypothesis that pulse-
wave analysis (PWA) combined with provocative pharmacological testing
might provide an alternative method. Radial artery waveforms were
recorded and augmentation index (AIx) was calculated from derived aortic
waveforms. Thirteen subjects received sublingual nitroglycerin (NTG),
inhaled albuterol, or placebo. Twelve subjects received NTG, albuterol, and
placebo separately during an infusion of NG-monomethyl-L-arginine
(LNMMA) or norepinephrine. Twenty-seven hypercholesterolemic subjects
and 27 controls received NTG followed by albuterol. Endothelial function
was assessed by PWA and forearm blood flow in 27 subjects. Albuterol and
NTG both significantly and repeatably reduced AIx (P < 0.001). Only the
response to albuterol was inhibited by LNMMA (-9.8 ± 5.5% vs -4.7±2.7%;
P=0.02). Baseline AIx was higher in the hypercholesterolemic subjects, who
exhibited a reduced response to albuterol (P_=0.02) but not to NTG when
compared with matched controls. The responses to albuterol and
acetylcholine were correlated (r=0.5, P = 0.02). Consistent with an
endothelium-dependent effect, the response to albuterol was substantially
inhibited by LNMMA. Importantly, the response to albuterol was reduced in
subjects with hypercholesterolemia and was correlated to that of intra-
arterial acetylcholine. This methodology provides a simple, repeatable,
noninvasive means of assessing endothelial function in vivo.
(Arterioscler Thromb Vasc Biol. 2002;22:147-152.)
Correspondence to Dr I.B. Wilkinson, Clinical Pharmacology Unit,
University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ,
UK. E-mail [email protected]
15. Rapid non-invasive analysis of vascular function
in pre-eclampsia
LC MELSON1, SC MILLASSEAU2, PJ CHOWIENCZYK7, L POSTON6, A SHENNAN6 Background: Photoplethysmography, the measurement of infra-red light
transmission through the finger pulp provides a rapid method for deriving
the digital volume pulse (DVP). We have previously shown that indices
relating to pressure wave reflection (RI) and large artery stiffness (SI) can
be obtained from the DVP1. Both RI and SI are reduced in normal
pregnancy.
Objective: The aim of this study was to investigate whether RI and SI are
abnormal in pre-eclampsia.
Methodology: Women with pre-eclampsia, diagnosed according to the
ISSHP definition were studied shortly after admission and were not on anti-
hypertensive medication. Women with essential hypertension and diabetes
were excluded. Healthy normotensive pregnant women were studied in the
ante-natal clinic as controls (similar age, ethnicity and gestation)
Results: Subject characteristics (means ? SD) and mean (?SE) values of
heart rate (HR), blood pressure (BP), RI and SI are tabulated:
*P<0.01, **P<0.0001 (compared the healthy pregnant women).
Discussion and Conclusions: These results show that both RI and SI are
increased in pre-eclampsia with minimal overlap compared to normal
pregnant women. The increase in RI is likely to result from an increase in
tone of small arteries from which the majority of pressure wave reflection
occurs. The increase in SI may result from increased stiffness of the aorta
and large arteries. Both effects may contribute to adverse haemodynamic
consequences of pre-eclampsia. Prospective evaluation of these indices may
be helpful in identifying early circulatory changes caused by pre-eclampsia,
and women at increased risk who can be targeted for intervention.
References: 1. Chowienczyk PJ, Kelly R, MacCallum H, Millasseau SC,
Andersson T, Gosling RG, Ritter JM, Anggard EE. Photoplethysmographic
assessment of pulse wave reflection: Blunted response to endothelium-
dependent beta2-adrenergic vasodilation in type II diabetes mellitus. J Am
Coll Cardiol 1999; 34:2007-2014
(Hypertension in Pregnancy Jpurnal 2000 Vol 19 Sup 1).
1 Fetal Health Research Group, Department of Obstetrics and Gynaecology, St Thomas’ hospital 2 Department of Clinical Pharmacology, Centre for Cardiovascular Biology and Medicine, King’s college London 16. Comparison of central aortic augmentation index
obtained from radial and carotid tonometry
SC MILLASSEAU. PRESENTED AT THE BHS 2002 Aortic augmentation index (AIx), an indirect measure of arterial stiffness and pressure wave reflection is usually obtained by application of a transfer function to the pressure pulse recorded at the radial or carotid arteries by applanation tonometry. The accuracy of the transfer function approach for obtaining values of aortic systolic and diastolic blood pressures has been validated. AIx, however, depends upon higher frequency components of the pressure waveform and the accuracy of a transfer function to determine AIx has been questioned. We examined the agreement between AIx obtained from a transfer function applied to the radial artery (AIx-TFR) and AIx obtained from a transfer function applied to the carotid artery (AIx-TFC). We also examined the relation between augmentation indices derived from the radial and carotid arteries with no transfer function applied (AIx-R and AIx-C) and those derived from the transformed waveforms. Two groups of subjects were studied: young healthy normotensive subjects (23-45 years, n=10) and older subjects (47-69 years, n=8) with coronary artery disease (CAD). Subjects were studied in a temperature controlled laboratory after 10 min resting supine. Carotid and radial pressure waveforms were determined by arterial tonometry using a Millar tonometer and Sphygmocor PWA device (AtCor Medical, Australia). Six successive measurements were obtained from each artery at 3 min intervals by an observer with more than 1 year’s experience of arterial tonometry. Measurements for which automated quality control measures were not optimal were repeated. Augmentation indices were derived from radial and carotid waveforms using the software SCOR-2000 version 6.31 (AtCor Medical, Australia). Repeatability of AIx was similar to that obtained by other investigators with within subject standard deviations of 9.1 for AIx-R, 9.9 for AIx-C, 9.1 for AIx-TFR and 6.6% for AIx-TFC. All AIx were significantly greater in patients with CAD compared with young control men (32.5 ? 4% (range: 14% to 49%) vs. 2.0 ? 2% (range: –8% to 15%) for AIx-TFR in CAD and controls respectively (mean ?SE)). In men with CAD, AIx-TFR was closely correlated with AIx-TFC (R=0.91, P<0.005). The SD of the difference from the Bland-Altman summary statistic (AIx-TFR - AIx-TFC) was 7.3%. In control subjects, the correlation was weak (R=0.386, P=0.27, SD of the difference: 10.1%). In both groups AIx-R and AIx-C were closely correlated with AIx-TFR and AIx-TFC (R=0.88, P<0.0001 for AIx-R vs. AIx-TFR; R=0.98, P<0.0001 for AIx-C vs. AIx-TFC). The poor correlation between AIx-TFR and AIx-TFC in healthy subjects suggests that the transfer function for the radial or carotid waveforms or both is inaccurate in these subjects. The results do not question the use of a transfer function to obtain central aortic systolic and diastolic blood pressure. The close correlation between AIx-R and AIx-TFR raises the possibility that similar information to “central aortic augmentation index” may be obtained from the radial waveform without resort to a transfer function. 17. Comparison of central pulse pressure and
augmentation index derived from analyses of carotid
and radial artery waveforms

R.J. WOODMAN1, G.F. WATTS1, B.A. KINGWELL2, L.J. BEILIN1, S.E.
HAMILTON2, A.M. DART2
1University of Western Australia and West Australian Heart Research Institute, Perth, WA, 2Alfred Baker Medical Unit, Alfred Hospital and Baker Medical Research Institute, Melbourne, Victoria, Australia Background: Pulse pressure provides a surrogate marker of arterial stiffness and is an independent risk factor of cardiovascular disease. However peripheral pulse pressure does not reliably predict central pulse pressure. Analysis of peripheral artery waveforms using a generalised transfer function to evaluate central pulse pressure (CPP) and central augmentation index (CAI) is a simple technique but has recently been criticised. Objectives: To compare CPP and CAI assessed using carotid and radial artery pulse pressure waveforms. Methods: Fifteen males with known coronary disease and 15 young healthy volunteers were studied. Measures of CPP and CAI were performed using applanation tonometry of the right carotid artery (SPT-301, Millar instruments) and of the right radial artery using a generalised transfer function (SphygmaCor). Brachial blood pressure was recorded to permit calibration of the carotid arterial pressure contours using mean and diastolic blood pressure. Comparisons were made using linear regression and paired t-tests. Results: CPP and CAI were both significantly correlated using the two techniques (r=0.75, p<0.001 and r=0.84, p<0.001 respectively). However, radial CAI was significantly higher (14.8%, p<0.001 without heart rate correction, and 6.2%, p=0.003 with heart rate correction) than carotid CAI. Carotid CPP was higher (10.2mmHg, p<0.001) than radial CPP and exhibited proportional bias (p=0.02). Conclusions: Carotid and radial-derived measures of CPP and CAI were strongly associated. However, CPP is lower and CAI higher using analysis of radial artery waveforms with a generalised transfer function. Caution should be employed when comparing results obtained using methods based upon analysis of peripheral and central waveforms. Correspondence to R J Woodman University Department of Medicine, University of Western Australia and West Australian Heart Research Institute, Perth, Australia [email protected] 18. Pulse wave analysis

MICHAEL F. O'ROURKE, ALFREDO PAUCA & XIONG-JING JIANG
Introduction
Since the information which the pulse affords is of so great importance, and
so often consulted, surely it must be to our advantage to appreciate fully all
it tells us, and to draw from t every detail that it is capable of imparting' F.A.
Mahomed 872 [1].
It is now possible to generate the ascending aortic pressure wave from the
arterial pressure pulse, recorded non-invasively by applanation tonometry in
the radial or carotid artery. This represents a blend of nineteenth century
sphygmography with cuff sphygmomanometry, nd is made possible by
introduction of high fidelity tonometers, by characterization of arterial
hydraulic properties in the upper limb and neck, and through application of
mathematical engineering techniques in modern computer systems. This
review will consider historical development, theoretic background, present
status and future potential, as well as comparing this technique with radial
and carotid tonometry alone, and with analysis of low pulse and volume
pulse waveforms as determined by Doppler or photoplethysmographic
techniques.
Br J Clin Pharmacol, 51, 507±522

Correspondence: Professor M. F. O'Rourke, Medical Professorial Unit, St
Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia.
Tel.:61 29361 2350; Fax: 61 29361 2385; E-mail:
[email protected]
[1] Mahomed FA. The physiology and clinical use of the sphygmograph.
Med Times Gazette 1872; 1: 62.
19. Vascular Compliance and Cardiovascular Disease
A Risk Factor or a Marker?

STEPHEN P. GLASSER, DONNA K. ARNETT, GARY E. MCVEIGH,
STANLEY M. FINKELSTEIN, ALAN J. BANK,DENNIS J. MORGAN,
AND JAY N. COHN
Pathophysiologic changes in the blood vessels are associated with a wide
variety of cardiovascular events, but our ability to assess vascular structure
and function are limited. Although arteriography provides some information
regarding intimal pathology, it provides little information about the structure
of the arterial wall or its physiology. A reduction in arterial compliance has
long been regarded as a potentially useful indicator of the presence of
arterial disease.1 Changes in the arterial wall leading to reductions in
arterial compliance may precede the onset of clinically apparent disease, and
may identify individuals at risk before disease onset (symptoms due to
disease are, in general, late manifestations of alterations in organ function).
The ability to predict alterations in vascular structure and function before
the onset of clinical diseases such as atherosclerosis, hypertension, and
diabetes mellitus has potential advantages. Whether reduced vascular
compliance precedes the development of cardiovascular disease (i.e., is a
risk factor) or is the consequence of established cardiovascular disease (i.e.,
a marker) is a matter of debate. To qualify as a risk factor the presence of a
condition must increase the probability of disease compared to those
without the condition (implying stronger causality).Recent studies have
suggested that the ascending aorta of the aortic trunk in Chinese has a larger
diameter and thinner media than that in Australians and population
differences such as these may be genetically determined.2 Studies have
suggested that the angiotensin II type 1 receptor (AT1) gene is involved in
the development of aortic stiffness.3 A conceptual example where
abnormalities in vascular compliance might be both a risk factor and a
marker is hypertension. Hypertension may alter arterial wall tone and
structure increasing blood pressure, which results in a decrease in
compliance (i.e., the decrease in compliance is a marker for hypertension).
Alternatively, when sclerotic changes occur in vessels arising from diseases
that may or may not increase blood pressure, decreased compliance
becomes a risk factor for the development of hypertension. In the following
discussions, it should be kept in mind that there is both morphologic
(structural) and functional heterogeneity in the different vascular beds. Also,
there is no accepted ‘‘gold standard’’ methodology for estimating vascular
compliance, so comparison of results obtained with differing methodologies
is difficult if not impossible.

(AJH–October 1997–Vol. 10, No. 10, Part 1)
20. Characteristics of the dicrotic notch of the arterial
pulse wave in coronary heart disease

THOMAS R. DAWBER, M.D., M.P.H.,* H. EMERSON THOMAS, Jr.
M.D.,t PATRICIA M. McNAMARA:t:

Abstract - The number of non-invasive techniques available for the
assessment of the cardiovascular system is quite limited. A need exists for
simplified methods of determining or suggesting the presence of existing
disease and predicting its development in asymptomatic individuals. One
such technique which has been suggested to be of value for this purpose is
the pulse wave as determined by oscillometry. Oscillometric methods have
achieved a certain amount of popularity among European physicians.
However, in the United States these techniques have not been accepted as
useful tools in assessing the cardiovascular system. An example of the
general attitude toward oscillometry may be found in a standard textbook:
"To the experienced observer the oscillometer gives little information which
cannot be detected by simple palpation of the arteries and the observance of
postural color changes. The mechanism by which the normal pulse wave is
developed has been studied in moderate detail, but interest in this subject
has been primarily exhibited by physiologists rather than clinicians. Data
regarding the usefulness of the study of the peripheral pulse wave are
limited. In spite of the pessimism which had been previously expressed
recent studies of oscillography using the lower extremities have suggested
that this method of clinical investigation may have some usefulness in
determining which subjects have obstructive peripheral arterial disease.
Certain clinical studies have been carried out in the United States by Henry
Lax M.D., who continued his earlier investigations begun in Europe.
Together with his associates he succeeded in developing a reliable non-
invasive method of determining the pulse wave in the upper extremity}
Using a narrow cuff applied to a finger he was able to show that pulse wave
patterns provided by this method closely resembled those obtained directly
by an intra-arterial needle. The pulse wave pattern was also demonstrated to
be reproducible in the same subject. The instrument which he developed
was termed a Vasculograph and the recordings obtained, Vasculograms. Lax
and his associates studied the pulse wave patterns found in normal subjects.
They also compared the tracings observed in subjects with hypertension,
arteriosclerotic disease and diabetes mellitus. Although a number of
variables were measured, Lax et al concluded that the appearance of the
dicrotic notch was the single most important feature of the peripheral pulse
wave. Using as the criterion of abnormality the disappearance of an incisura
on the downward descent of the pulse tracing they were able to make certain
observations: e.g., out of 40 young adults 38 had "normal" tracings, i.e. a
definite incisura was observed. In 24 subjects, with "hypertensive vascular
disease" none had normal tracings. In a study of healthy ) young people
(ages 11-29) only eight per cent had abnormal tracings. However, 62 per
cent of 162 diabetic subjects of the same age distribution had abnormal
tracings. The smoking of cigarettes and cooling of the extremity prior to the
time of obtaining the vasculograms reduced the amplitude of the pulse wave
but did not change its configuration. The explanation for the appearance of
the dicrotic notch in the peripheral pulse wave has usually been attributed to closure of the aortic valve, with a rebound in the blood pressure due to the continued elastic recoil of the arterial tree. Peripheral factors including the tone of the smaller vessels in which the muscular layer plays a major role in blood vessel tone have been shown to exert an important role in the appearance of the dicrotic notch. Peripheral vasoconstriction induced by intravascular injection of adrenalin may cause the incisura to disappear. This observation is possibly inconsistent with the previously noted apparent negative effect of tobacco smoking on the pulse wave pattern. In the absence of aortic valvular disease or congestive heart failure with inadequate emptying of the left ventricle it appears reasonable to consider the configuration of the dicrotic notch as largely a function of arterial wall elasticity and muscular tension in the walls of the smaller arteries and arterioles in the periphery. In the absence of peripheral vasoconstriction the persistence of a normal incisura may thus be a good measure of maintenance of the normal elasticity observed in the young. The loss of elasticity of the arterial bed with age presumably reflects changes in the quality or quantity of elastin in the vascular wall. Conflicting reports regarding the changes in the elastin content of the aorta with age have been published. Some reports suggest that elastin does decrease with age, however, other reports suggest no essential change in elastin content according to age or sex. The loss of elasticity of the vascular bed with age may, however, be related to changes in the make-up of elastin since it is reported that the elastin of older persons contains more calcium (elastocalcinosis). The authors postulate that the increased binding of calcium to elastin is a prerequisite to the development of atherosclerosis. Calcium is deposited chiefly in the region of the elastic fibers. Medial calcification was found in only four per cent of subjects under the age of 20; in .58 per cent by the age of 40; and in 100 per cent of Subjects over the age of 50.10 The authors observed that the calcium concentration in dry elastin increased from 0.4 to 0.7 per cent before age 20 to 4.7 to 6.9 per cent over age 40. Lax's data suggest a relationship between disappearance of the dicrotic notch and the presence of existing vascular disease. However, he suggested the desirability that the method be tested again using a cross section of the general population. He believed that the method also had value for the prediction of the development of vascular disease in the apparently healthy population. Accordingly, he made available a vasculograph so that tracings could be made on members of the Framingham Study population. The Heart Disease Epidemiology Study ("Framingham Study") was established by the National Heart Institute in 1949 in Framingham, Massachusetts. It has investigated the natural history of coronary heart disease and other atherosclerotic diseases in 5,127 adults age 30-59 free of disease at entry into the study. These subjects have been examined periodically at two-year intervals. Observations regarding the life habits and personal characteristics as well as the development of disease have been made since the establishment of the study in 1949. Although the National Heart and Lung Institute is still making observations with respect to mortality and morbidity from death certificates and hospital records in the remaining subjects, the responsibility for the clinical evaluation of the subjects has now been undertaken by the Boston University Medical Center-Framingham Study. The present report represents our experience comparing the finger vasculography readings with disease diagnosed at the same examination. The ability of this test procedure to predict disease will be the subject of a
future report.

(Angiology 1973, Vol24, p244-255)
21. Vasoactive Drugs Influence Aortic Augmentation
Index Independently of Pulse-Wave Velocity in
Healthy Men

R.P. KELLY, S.C. MILLASSEAU, J.M. RITTER, P.J. CHOWIENCZYK

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 (R50.58, P,0.0001). Nitroglycerin (3
to 300 mg/min IV) reduced the aortic augmentation index from 4.862.3% to
211.965.3% (n510, P,0.002). Angiotensin II (75 to 300 ng/min IV)
increased the aortic
augmentation index from 9.362.4% to 18.362.9% (n512, P,0.001). These
drugs had small effects on aortic pulse-wave velocity, producing mean
changes from baseline of, 1 m/s (each P,0.05). In healthy men, vasoactive
drugs may change aortic augmentation index independently from aortic
pulse-wave velocity.
(Hypertension. 2001;37:1429-1433.)
22. Aortic Pulse-Wave Velocity and Its Relationship
to Mortality in Diabetes and Glucose Intolerance An
Integrated Index of Vascular Function?

KENNEDY CRUICKSHANK, MB, MD; LISA RISTE, PHD; SIMON G.
ANDERSON, PHD; JOHN S. WRIGHT, PHD; GRAHAM DUNN, PHD;
RAY G. GOSLING, PHD
Background—Arterial distensibility measures, generally from pulse-wave
velocity (PWV), are widely used with little knowledge of relationships to
patient outcome. We tested whether aortic PWV predicts cardiovascular and
all-cause mortality in type 2 diabetes and glucose-tolerance–tested (GTT)
multiethnic population samples.
Methods and Results—Participants were randomly sampled from (1) a
type 2 diabetes outpatient clinic and (2) primary care population registers,
from which nondiabetic control subjects were given a GTT. Brachial blood
pressures and Doppler-derived aortic PWV were measured. Mortality data
over 10 years’ follow-up were obtained. At any level of systolic blood
pressure (SBP), aortic PWV was greater in subjects with diabetes than in
controls. Mortality risk doubled in subjects with diabetes (hazard ratio 2.34,
95% CI 1.5 to 3.74) and in those with glucose intolerance (2.12, 95% CI
1.11 to 4.0) compared with controls. For all groups combined, age, sex, and
SBP predicted mortality; the addition of PWV independently predicted all-
cause and cardiovascular mortality (hazard ratio 1.08, 95% CI 1.03 to 1.14
for each 1 m/s increase) but displaced SBP. Glucose tolerance status and
smoking were other independent contributors, with African-Caribbeans
experiencing reduced mortality risk (hazard ratio 0.41, 95% CI 0.25 to
0.69).
Conclusions—Aortic PWV is a powerful independent predictor of mortality
in both diabetes and GTT population samples.
In displacing SBP as a prognostic factor, aortic PWV is probably further
along the causal pathway for arterial disease
and may represent a useful integrated index of vascular status and hence
cardiovascular risk.
(Circulation. 2002;106:2085-2090.)
23. Aortic Pulse Wave Velocity Predicts
Cardiovascular Mortality in Subjects >70 Years of
Age

S. MEAUME, A. BENETOS, O.F. HENRY, A. RUDNICHI, M.E. SAFAR
Abstract—Aortic pulse wave velocity (PWV) is a significant and
independent predictor of cardiovascular mortality in subjects with essential
hypertension and in patients with end-stage renal disease. Its contribution to
cardiovascular risk in subjects 70 to 100 years old has never been tested. A
cohort of 141 subjects (mean_SD age, 87.1_6.6 years) was studied in 3
geriatrics departments in a Paris suburb. Together with sphygmomanometric
blood pressure measurements, aortic PWV was measured with a validated
automatic device. During the 30-month follow-up, 56 patients died (27 from
cardiovascular events). Logistic regressions indicated that age (P_0.005)
and a loss of autonomy (P_0.01) were the best predictors of overall
mortality. For cardiovascular mortality, aortic PWV was the major risk
predictor (P_0.016). The odds ratio was 1.19 (95% confidence interval, 1.03
to 1.37). Antihypertensive drug treatment and blood pressure, including
systolic and pulse pressure, had no additive role. In subjects 70 to 100 years
old, aortic PWV is a strong, independent predictor of cardiovascular death,
whereas systolic or pulse pressure was not. This prospective result will need
to be confirmed in an intervention trial.
(Arterioscler Thromb Vasc Biol. 2001;21:2046-2050.)
24. Analysis of endothelium-dependent vasodilation
by use of the radial artery pulse wave obtained by
applanation tonometry.
OBJECTIVES: To evaluate applanation tonometry as a method to obtain arterial pulse waves suitable for pulse wave analysis of the height of the diastolic inflection point (IP), and to use this technique to study endothelium-mediated vasodilation by evaluation of the contribution of nitric oxide (NO) to the reduction in the height of the IP induced by beta2-adrenergic stimulation. METHODS: The radial artery pulse waveform was recorded by applanation tonometry in young healthy subjects before and after interventions both locally in the forearm and systemically by different vasodilators and vasoconstrictors, and vasodilatation was analysed as a change in the height of the IP. The mechanism behind the reduction in the height of the IP induced by terbutaline was investigated by systemic interventions with both N(G)-monomethyl-l-arginine (l-NMMA) and noradrenaline (NA). RESULTS: Applanation tonometry was a convenient method to obtain radial artery pulse waves of good quality. The reduction in IP was substantially more pronounced when vasodilators were given systemically than when given locally in the forearm, indicating that the effect was obtained through an effect on peripheral pulse wave reflection. Systemically given l-NMMA, but not NA, increased the IP (P<0.05). Systemically given l-NMMA also caused a more pronounced attenuation than NA of the reduction in IP following terbutaline injection (P<0.05). CONCLUSION: Changes in IP following beta2-adrenergic stimulation appears to be a measurement of pulse wave reflection mainly governed by NO. Applanation tonometry and pulse wave analysis is a minimally invasive method suitable to assess endothelium-dependent vasodilation in large-scale studies. (Clin Physiol & Func Im, 2003; 23:50-57)
25.Assessment of endothelial function using
peripheral waveform analysis: a clinical application.
HAYWARD CS, KRAIDLY M, WEBB CM, COLLINS P. OBJECTIVES: The study was done to determine whether radial artery applanation tonometry can be used as a noninvasive method of assessing global endothelial function. BACKGROUND; It is known that beta(2)-receptor stimulation results in endothelial release of nitric oxide. Furthermore, for over a century glyceryl trinitrate (GTN) has been known to markedly affect the arterial pressure waveform, even in the absence of significant blood pressure (BP) changes. Therefore, it was hypothesized that the change in the peripheral pressure waveform, as measured using tonometry and quantified using the augmentation index (AIx) and in response to Salbutamol (Salb), would allow assessment of global endothelial function. METHODS: The study contained three parts. In the first study, Salb (400 microg) was administered to 11 healthy subjects via inhalation after either intravenous N-omega-nitro-monomethyl-L-arginine (L-NMMA) (3 mg/kg over 5 min) or control solution (normal saline) in the supine, rested, fasted condition. The BP, heart rate and waveform responses were recorded each 5 min following Salb for 20 min. Next, GTN was given and responses recorded 5 min later. In the second study, both the reproducibility of Salb and the GTN responses were assessed in 9 subjects studied twice on separate days. In the third study, the Salb and GTN responses of 12 subjects with angiographic coronary artery disease (CAD) were compared with 10 age-matched control subjects with no atherosclerotic risk factors. RESULTS: After control infusion, AIx decreased following Salb, from 50.8 +/- 4.3% to 44.8 +/- 4.2%, a change of -11.8 +/- 3.7%, p < 0.01. After L-NMMA, AIx did not significantly change following Salb (54.2 +/- 5.1% vs. 52.9 +/- 5.3%, -2.0 +/- 3.1%). The GTN-induced decreases in AIx were similar after either infusion (35.1 +/- 3.3% vs. 36.5 +/- 3.3%). Reproducibility of Salb-induced changes in AIx between studies performed on separate days was good (r = 0.80, p < 0.01). Salb-induced changes in AIx in CAD patients were significantly less compared to control subjects (-2.4 +/- 1.9% vs. -13.2 +/- 2.4%, respectively, p < 0.002). The GTN-induced changes were not significantly different (-27.6 +/- 4.2 vs. -38.9 +/- 4.4%, p = 0.07). CONCLUSIONS: The peripheral arterial pressure waveform is sensitive to beta(2)-stimulation. Changes are related to nitric oxide release, are reproducible and can distinguish between clinical subject groups. Arterial waveform changes following Salb may thus provide a noninvasive method of measuring "global" arterial endothelial function. (J Am Coll Cardiol 2002; 40:521-528)
26. Aortic stiffness as a risk factor for recurrent acute
coronary events in patients with ischaemic heart
disease

C. STEFANADIS, J. DERNELLIS, E. TSIAMIS, C. STRATOS, L.
DIAMANTOPOULOS, A. MICHAELIDES AND P. TOUTOUZAS
Abstract

Aims Aortic elasticity is an important determinant of left ventricular
performance and coronary blood flow. Moreover, it has been shown that
aortic elastic properties deteriorate in patients with coronary artery disease.
However, the predictive role of aortic elasticity in the occurrence of
coronary events, has not been addressed so far. Therefore, we set out to test
prospectively the hypothesis that invasive as well as non-invasive measures
of aortic elastic properties, assessed at rest from pressure–diameter
relationships, could predict the development of recurrent coronary events.
Methods and Results Clinical variables and measures of aortic function
were assessed in 54 normotensive patients with coronary artery disease. The
aortic pressure–diameter relationship was derived invasively with a high-
fidelity Y shaped catheter (developed in our Institution) for aortic diameter
measurements, simultaneously with a Millar catheter for aortic pressure
measurements. Aortic root distensibility was assessed by non-invasive
techniques. During an average of 3 years follow-up, 12 of 54 patients either
developed unstable angina (n=8) or acute myocardial infarction (n=4). By
multivariate Cox model analysis, aortic stiffness was the strongest predictor
of progression to any end-point (relative risk: 3·24, CI: 1·79 to
5·83;P=0·000). When aortic stiffness was not considered, aortic
distensibility was the only independent predictor for acute coronary
syndromes (relative risk: 0·37 CI: 0·21 to 0·65;P=0·000).
Conclusion In patients with coronary artery disease, aortic elastic properties
are powerful and independent risk factors for recurrent acute coronary
events.
a Hippokration Hospital, Department of Cardiology, University of Athens,
Greece
Revised 15 June 1999; accepted 16 June 1999. Available online 25 March
2002.
27. Lack of effect of oral vitamin C on blood pressure,
oxidative stress and endothelial function in Type II
diabetes

D. DARKO*, A. DORNHORST*, F. J. KELLY†, J. M. RITTER‡ and
P. J. CHOWIENCZYK‡
ABSTRACT
Type II diabetes is characterized by increased oxidative stress, endothelial
dysfunction and hypertension. We investigated whether short-term
treatment with oral vitamin C reduces oxidative stress and improves
endothelial function and blood pressure in subjects with Type II diabetes.
Subjects (nØ35) received vitamin C (1.5 g daily in three doses) or matching
placebo for 3 weeks in a randomized, double-blind, parallel-group design.
Plasma concentrations of 8-epiprostaglandin F2a (8-epi-PGF2a), a non-
enzymically derived oxidation product of arachidonic acid, were used as a
marker of oxidative stress. Endothelial function was assessed by measuring
forearm blood Øow responses to brachial artery infusion of the
endothelium-dependent vasodilator acetylcholine (with nitroprusside as an
endothelium-independent control) and by the pulse wave responses to
systemic albuterol (endothelium-dependent vasodilator) and glyceryl
trinitrate (endothelium-independent vasodilator). Plasma concentrations of
vitamin C increased from 58³6 to 122³10 lmol/l after vitamin C, but 8-epi-
PGF2a levels (baseline, 95³4 pg/l ; after treatment, 99³5 pg/l), blood
pressure (baseline, 141³5/80³2 mmHg; after treatment, 141³5/81³3 mmHg)
and endothelial function, as assessed by the systemic vasodilator response to
albuterol and by the forearm blood flow response to acetylcholine, were not
significantly different from baseline or placebo. Thus treatment with
vitamin C (1.5 g daily) for 3 weeks does not significantly improve oxidative
stress, blood pressure or endothelial function in patients with Type II
diabetes.
(Clinical Science 2002 103, 339-344)
*Department of Metabolic Medicine, Imperial College School of Medicine,
Hammersmith Hospital, London, U.K.,
†The Rayne Institute, St. Thomas’ Hospital, London, U.K., and ‡Department of
Clinical Pharmacology,
St. Thomas’ Hospital, Centre for Cardiovascular Biology and Medicine, King’s
College, London, U.K.
28. Validity, reproducibility, and clinical significance
of noninvasive brachial-ankle pulse wave velocity
measurement.
YAMASHINA A, TOMIYAMA H, TAKEDA K, TSUDA H, ARAI T,
HIROSE K, KOJI Y, HORI S, YAMAMOTO Y.
The present study was conducted to evaluate the validity and reproducibility of noninvasive brachial-ankle pulse wave velocity (baPWV) measurements and to examine the alteration of baPWV in patients with coronary artery disease (CAD). Simultaneous recordings of baPWV by a simple, noninvasive method and aortic pulse wave velocity (PWV) using a catheter tip with pressure manometer were performed in 41 patients with CAD, vasospastic angina, or cardiomyopathy. In 32 subjects (15 controls and 17 patients with CAD), baPWV was recorded independently by two observers in a random manner. In 55 subjects (14 controls and 41 patients with CAD), baPWV was recorded twice by a single observer on different days. baPWV were compared among 172 patients with CAD (aged 62 +/- 8 years); 655 age-matched patients without CAD but with hypertension, diabetes mellitus, or dyslipidemia; and 595 age-matched healthy subjects without these risk factors. baPWV correlated well with aortic PWV (r=0.87, p<0.01). Pearson's correlation coefficients of interobserver and intraobserver reproducibility were r=0.98 and r=0.87, respectively. The corresponding coefficients of variation were 8.4% and 10.0%. baPWV were significantly higher in CAD patients than in non-CAD patients with risk factors, for both genders (p<0.01). In addition, baPWV were higher in non-CAD patients with risk factors than in healthy subjects without risk factors. Thus, the validity and reproducibility of baPWV measurements are considerably high, and this method seems to be an acceptable marker reflecting vascular damages. baPWV measured by this simple, noninvasive method is suitable for screening vascular damages in a large population. Second Department of Internal Medicine, Tokyo Medical University, Japan. [email protected]
(Hypertension Res.2002, Vol.25 No.3 359-364)
29. Increased arterial wall stiffness limits flow volume
in the lower extremities in type 2 diabetic patients.

SUZUKI E, KASHIWAGI A, NISHIO A ET AL
OBJECTIVE: To document an association between arterial wall stiffness
and reduced flow volume in the lower-extremity arteries of diabetic patients.
RESEARCH DESIGN AND METHODS: We recruited 60 consecutive type
2 diabetic patients who had no history or symptoms of peripheral arterial
disease (PAD) in the lower extremities and normal ankle/brachial systolic
blood pressure index at the time of the study (non-PAD group) and 20 age-
matched nondiabetic subjects (control group). We used an automatic device
to measure pulse wave velocity (PWV) in the lower extremities as an index
of arterial wall stiffness. At the popliteal artery, we evaluated flow volume
and the resistive index as an index of arterial resistance to blood flow using
gated two-dimensional cine-mode phase-contrast magnetic resonance
imaging. RESULTS: Consistent with previous reports, we confirmed that
the non-PAD group had an abnormally higher PWV compared with that of
the control group (P < 0.001). To further demonstrate decreased flow
volume and abnormal flow pattern at the popliteal artery in patients with a
higher degree of arterial wall stiffness, we assigned the 60 non-PAD
patients to tertiles based on their levels of PWV. In the highest group,
magnetic resonance angiograms of the calf and foot arteries showed
decreased intravascular signal intensity, indicating the decreased arterial
inflow in those arteries. The highest group was also characterized by the
lowest late diastolic and total flow volumes as well as the highest resistive
index among the groups. From stepwise multiple regression analysis, PWV
and autonomic function were identified as independent determinants for late
diastolic flow volume (r(2) = 0.300; P < 0.001). CONCLUSIONS: Arterial
wall stiffness was associated with reduced arterial flow volume in the lower
extremities of diabetic patients.

(Diabetic Care 2001, Vol 24, No. 12 2107-2114)
30. Aortic Stiffness Is an Independent Predictor of
All-Cause and Cardiovascular Mortality in
Hypertensive Patients

STÉPHANE LAURENT, PIERRE BOUTOUYRIE, ROLAND ASMAR,
ISABELLE GAUTIER, BRIGITTE LALOUX, LOUIS GUIZE, PIERRE
DUCIMETIERE, ATHANASE BENETOS
Abstract—Although various studies reported that pulse pressure, an
indirect index of arterial stiffening, was an independent risk factor for
mortality, a direct relationship between arterial stiffness and all-cause and
cardiovascular mortality remained to be established in patients with
essential hypertension. A cohort of 1980 essential hypertensive patients who
attended the outpatient hypertension clinic of Broussais Hospital between
1980 and 1996 and who had a measurement of arterial stiffness was studied.
At entry, aortic stiffness was assessed from the measurement of carotid-
femoral pulse-wave velocity (PWV). A logistic regression model was used
to estimate the relative risk of all-cause and cardiovascular deaths. Selection
of classic risk factors for adjustment of PWV was based on their influence
on mortality in this cohort in univariate analysis. Mean age at entry was
50613 years (mean6SD). During an average follow-up of 112653 months,
107 fatal events occurred. Among them, 46 were of cardiovascular origin.
PWV was significantly associated with all-cause and cardiovascular
mortality in a univariate model of logistic regression analysis (odds ratio for
5 m/s PWV was 2.14 [95% confidence interval, 1.71 to 2.67, P,0.0001] and
2.35 [95% confidence interval, 1.76 to 3.14, P,0.0001], respectively). In
multivariate models of logistic regression analysis, PWV was significantly
associated with all-cause and cardiovascular mortality, independent of
previous cardiovascular diseases, age, and diabetes. By contrast, pulse
pressure was not significantly and independently associated to mortality.
This study provides the first direct evidence that aortic stiffness is an
independent predictor of all-cause and cardiovascular mortality in patients
with essential hypertension.
(Hypertension. 2001;37:1236-1241.)
31.Effect of Antihypertensive Agents on Arterial
Stiffness as Evaluated by Pulse Wave Velocity.
ROLAND ASMAR
Structural and functional properties of the arterial wall have been reported to
be altered in hypertension, even at early stages of the disease. Morbidity
and mortality associated with hypertension are primarily related to arterial
damage that may affect one or several organs. Considering the potential
implications of arterial assessment in the prevention of cardiovascular
disease, evaluation of the arterial effects of anti-hypertensive agents is
recommended by numerous authorities. Among the non-invasive and
simple methods to evaluate large arteries, pulse wave velocity (PWV)
measurement is widely used as an index of regional arterial stiffness. This
method is related to the arterial geometry and wall function, simple and
reproducible, and thus, can easily be applied in clinical trials.
Several studies performed in various populations showed significant
powerful interactions between PWV and cardiovascular risk factors. In
addition, aortic PWV was shown to be forceful marker and predictor of
cardiovascular in normotensive individuals and patients with hypertension.
Furthermore, aortic PWV was shown to be an independent predictor of all
cause mortality in patients with essential hypertension.
In comparison with placebo, clinical studies have shown that in short and
long term trials, Antihypertensive agents improved arterial stiffness (as
evidenced by a reduction in PWV ) independently of blood pressure
reduction. The decrease of PWV was more pronounced with long term
treatment than with short term treatment. Whether Antihypertensive agents
differ in their arterial effects independently of blood pressure changes
remains unclear. Pharmacological studies, generally performed in small
numbers of patients, indicate that the long term effects of long term
treatment with ACE inhibitors, calcium channel antagonists and some ? -
blockers on arterial stiffness are generally similar. The effectiveness of an
Antihypertensive agent is reducing arterial stiffness may also be influenced
by the genetic background of the patient.
Recently, the Complior? Study has shown the feasibility to assess arterial
stiffness in clinical trials involving large populations using an automatic
device for measuring PWV. Long term treatment with an ACE inhibitor,
perindopril was associated with a decrease in blood pressure and aortic
PWV in patients with essential hypertension. In high risk patients with end
stage renal failure ACE inhibitors effectively decreased arterial stiffness and
had a favourable effect on survival which was independent of changes in
blood pressure. The correlation between reversion of arterial stiffness and
decrease in cardiovascular morbidity and mortality needs to be confirmed in
populations of patients with lower cardiovascular risk.
(Am J Cardiovasc Drugs 2001: 1 (5) 387-397)
32. Arterial Stiffness and cardiovascular risk factors
in a population based study,

AMAR J, RUIDAVETS JB, CHAMONTIN B ET AL.

OBJECTIVE: To determine the relationships between pulse wave velocity
(PWV), an estimate of arterial distensibility and cardiovascular risk factors.
DESIGN: This cross-sectional population-based study was carried out from
1995 to 1997 to investigate these relationships.
POPULATION AND METHODS: Some 993 subjects, aged 35-64 years
(52.7% men), living in the south-west of France, were randomly selected
from electoral rolls and participated in a cross-sectional study. Medical
examinations were performed by specially trained medical staff. Carotid-
femoral PWV was measured using a semiautomatic device (Complior,
Garges les Gonesse, France). The relationships between PWV and risk
factors were assessed, first in subjects not treated with hypolipidaemic,
antidiabetic and antihypertensive drugs and then in treated subjects. In
subjects not treated for cardiovascular risk factors, age, gender, systolic
blood pressure (SBP) and heart rate (P< 0.001) were the variables
significantly associated with PWV. In treated patients, age (P < 0.01), SBP
(P < 0.001), heart rate (P < 0.001), apolipoprotein B (P< 0.05) and the
number of treated cardiovascular risk factors (P< 0.05) were positively
correlated with PWV.
CONCLUSION: This study shows that, in a sample of subjects at high risk,
the cumulative influence of risk factors, even treated, is an independent
determinant of arterial stiffness. These results suggest that PWV may be
used as a relevant tool to assess the influence of cardiovascular risk factors
on aortic stiffness in high-risk patients.
(Journal of Hypertension 2001, Vol 19 No 3 381-387)

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