Accepted Manuscript

Arterial Stiffness and its Clinical Implications in Women

Thais Coutinho, MD

PII: S0828-282X(14)00166-4

DOI: 10.1016/j.cjca.2014.03.020

Reference: CJCA 1152

To appear in: Canadian Journal of Cardiology

Received Date: 4 November 2013

Revised Date: 17 March 2014

Accepted Date: 18 March 2014

Please cite this article as: Coutinho T, Arterial Stiffness and its Clinical Implications in Women, CanadianJournal of Cardiology (2014), doi: 10.1016/j.cjca.2014.03.020.

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Arterial Stiffness and its Clinical Implications in Women

Thais Coutinho, MD

Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada

Running Title: Arterial Stiffness and Cardiovascular Diseases in Women

Correspondence: Thais Coutinho, MD

Address: University of Ottawa Heart Institute

40 Ruskin St.

Ottawa, ON - K1Y 4W7

Phone : 613-761-5046

Fax : 613-761-5039

E-mail : tcoutinho@ottawaheart.ca

Text Word count: 3437

Abstract: 230

Number of References: 95

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Brief Summary:

Arterial stiffness is a marker of cardiovascular health and aging. Older women have been

shown to have greater aortic stiffness than men, leading to poor hypertension control, worse

diastolic function, impaired ventricular-arterial coupling and left ventricular concentric

remodeling, all of which are associated with cardiovascular diseases and adverse outcomes. The

present review aims at highlighting current evidence supporting sex differences in arterial

stiffness, its potential underlying mechanisms, and its role on cardiovascular diseases in women.

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Abstract:

The burden of cardiovascular diseases (CVD) in women is increasing, and CVD

presently kills more North-American women than men, highlighting the need for sex-specific

research aimed at disentangling the complex interactions between sex, aging and cardiovascular

health. In the last decade, arterial stiffness has emerged as an independent predictor of adverse

cardiovascular events and mortality, and its non-invasive, safe evaluation makes it an attractive

tool for a snapshot assessment of cardiovascular health. Increasing reports have documented

greater aortic stiffness in older women than men, which appears to have close relationships with

blood pressure control, diastolic dysfunction, impaired ventricular coupling and left ventricular

remodeling in women. Thus, arterial stiffness is thought to play a role in the female-

predominance of several diseases such as isolated systolic hypertension, refractory hypertension,

heart failure with preserved ejection fraction, and paradoxical low flow, low gradient, normal

ejection fraction severe aortic stenosis. Furthermore, greater arterial stiffness is a common

characteristic of women who develop hypertensive complications of pregnancy. Thus, better

understanding sex differences in arterial stiffness and aging may provide valuable insights into

CVD in women, and help identify novel risk stratification tools and therapeutic targets. To this

end, the present review aims at describing sex differences in arterial stiffness, exploring the

potential role of sex hormones and menopause on arterial aging, and highlighting the role of

arterial stiffness in specific cardiovascular diseases that preferentially affect women.

Keywords: arterial stiffness, aorta, sex, women, cardiovascular diseases

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Introduction

At present, cardiovascular diseases (CVD) kill more North American women than men.

Similar statistics are reported in Europe, where 52% of mortality among women is attributed to

CVD (versus 42% in men).1 Moreover, the incidence of CVD increases disproportionately in

women after menopause, 2-4 and while the mechanisms underlying the loss of cardiovascular

protection with menopause are unclear, it is thought that arterial aging/ stiffness leading to

greater elevations of systolic and pulse pressure (PP) in women may play a role. 5-9 Thus, it is

increasingly evident there are significant sex differences in the timing, etiology, pathology,

clinical manifestations and prognosis of CVD, highlighting the need for sex-based research

aimed at disentangling the complex interactions of sex with cardiovascular health and aging.

Arterial aging is a natural phenomenon, but its acceleration and exacerbation by cardiovascular

risk factors 10 make its noninvasive assessment an attractive option for a snapshot evaluation of

cardiovascular health. Thus, over the past decade, arterial stiffness has emerged as an important

tissue biomarker given its associations with future cardiovascular events, 11-14 target-organ

damage 15 and increased mortality risk; 13, 14 and evaluating potential sex differences in arterial

stiffness may aid in the understanding of the sexual dimorphism of CVD and its outcomes.

Arterial Stiffness Assessment

Before embarking in a discussion about the sex differences and biological determinants

of arterial stiffness, a brief description of the methodology used to assess arterial compliance is

warranted. Although initially described with invasive methods, there are several accepted ways

to non-invasively assess arterial stiffness: arterial tonometry, aortic ultrasound (by

transesophageal echocardiography), carotid ultrasound or magnetic resonance imaging.16 Arterial

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tonometry is the most widely used technique, given its ease of use, portability, validation, and

robust associations with adverse outcomes.14, 17 With arterial tonometry, we can calculate the

carotid-femoral pulse wave velocity (cfPWV- Figure 1), considered the gold standard measure of

aortic stiffness, as well as measures of wave reflection (augmentation index – AIx) and central

hemodynamics (such as central blood pressure) (Figures 1 and 2), among others. Such

assessment provides incremental information to brachial blood pressure, which not only allows

better understanding of the hemodynamic pathophysiology underlying several diseases, but also

aids in prognostic assessment 14, 17 and represents a fertile field for research in cardiovascular

health.

Sex Hormones and Arterial Biology

Although the complex pathophysiology underlying the arterial stiffening process is

beyond the scope of this review, knowledge of its basic mechanisms is relevant for better

understanding its relationship to sex. The stability and compliance of the arterial wall is

maintained by a well-regulated balance between its two main extracellular matrix proteins,

collagen and elastin. With aging, there is fatigue of the elastin fibers and dysregulation of this

balance, with excessive degradation of its elastic component, elastin, and replacement with

tensile collagen fibers, leading to stiffening of the arterial wall. In the presence of cardiovascular

risk factors, an adverse inflammatory and hormonal milieu further exacerbates this process. 18

Estrogen has been shown to directly affect arterial wall remodeling by increasing elastin

production and decreasing collagen deposition in human arteries. 19

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There is compelling evidence suggesting that sex differences in vascular biology are

related not only to the type and levels of sex hormones, but also by tissue and cellular differences

responsible for sex-specific responses to various stimuli. For instance, the human aorta has both

estrogen 20 and progesterone 21 receptors, and women have more arterial estrogen receptors than

men. 22 Although androgen receptors have been identified in primate vascular tissues, 23 there

have been no reports of the localization or distribution of androgen receptors in human blood

vessels. In addition, it has been demonstrated that production of the potent vasodilator nitric

oxide (NO) is greater in pre-menopausal women than men, 24 and the endothelial-dependent,

NO-mediated vasodilatory effects of estrogen differ between men and women, as intracoronary

injections of estradiol improve endothelial function and coronary flow in women with coronary

artery disease, but not in men. 25 Such vasodilatory effects of estrogen in women appear to be

time-dependent, as they vary inversely with the length of estrogen deprivation. 26 Thus, sex

differences in arterial estrogen receptors coupled with a direct effect of endogenous estrogens on

endothelial function and arterial stiffness via NO may at least partially underlie the favorable

hemodynamic and risk profile attributed to women of reproductive age; and help explain the

adverse hemodynamic and cardiovascular transitions that often follow menopause.

A potential role for sex hormones in the regulation of arterial function, tone and elasticity

is further suggested by studies that evaluate measures of arterial stiffness during hormonal

transition periods, such as pre- and post- puberty, or throughout the menstrual cycle. Ahimastos

and colleagues 27 studied 58 pre-pubertal and 52 post-pubertal healthy children and found that in

pre-puberty period, girls had higher carotid-femoral pulse wave velocity (cfPWV, a measure of

aortic stiffness) and pulse pressure (PP, a global marker of arterial stiffness), than age-matched

boys. Post-puberty, while girls’ cfPWV decreased, boys’ cfPWV increased, dissipating the pre-

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pubertal differences; and PP was lower in post-pubertal girls than boys. In addition, stiffness has

been shown to vary during the menstrual cycle in young, healthy women of reproductive age, 28-

30 although this matter remains debatable as a recent study has challenged this concept.31 On the

other hand, use of oral contraceptives among women of reproductive age has been shown to be

associated with higher pulse pressure and cfPWV,32 corroborating the notion that suppression of

female endogenous sex hormones may have an effect on arterial health and compliance.

In the post-menopausal period, age-related increases in arterial stiffness are observed, 33

however several studies have shown that arterial stiffness is ameliorated by administration of

hormonal therapy (HT) in post-menopausal women, 34-40 worsening again after HT withdrawal.

41 The aforementioned findings suggest that female sex hormones (and/or the additional

hormonal and metabolic milieu that accompany them) may have a role in the regulation of large-

artery compliance. However, the results of the HT studies deserve special interpretation in the

context of the HERS study,42 which showed no difference in the incidence of cardiovascular

events in women taking HT vs. placebo, and the Women’s Health Initiative,43 which showed

greater risk of non-fatal myocardial infarction and stroke among women taking HT (although

absolute rates of events were low). Interestingly, despite the lack of protection against

cardiovascular events, both studies showed a beneficial effect of HT on cardiovascular risk

factors such as blood pressure and lipids, which mirrors the aforementioned results of HT in

arterial stiffness. Whether these divergent effects of HT on arterial stiffness/ risk factors and

cardiovascular events are related to timing of HT administration, lack of enough follow-up time

for improvement in hard outcomes, or additional thrombogenic mechanisms that are independent

of arterial compliance and risk factors is not the focus of the present review, but remain

amenable to further testing and discussion.

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Sex Differences in Arterial Stiffness and Pulsatility: Role of Arterial Aging in Men and

Women

Increased pulse pressure is not only a marker of greater arterial stiffness, but also an

established cardiovascular risk marker. Several studies suggest that women (mostly post-

menopausal) have greater arterial pulsatility than men. We have shown that in a community-

based cohort enriched for hypertension, women had higher central PP, aortic characteristic

impedance (Zc, a measure of proximal aortic stiffness and a major determinant of PP), and

augmentation index (AIx, a measure of arterial wave reflections and also a determinant of PP)

than men, independently of body size and aortic size. 44 Greater Zc in women was also

demonstrated in a cohort of hypertensives, 45 and the finding of higher PP and AIx in women has

also been replicated in numerous studies of older women. 5, 46-50

There are several potential explanations for the observed sex differences in measures of

arterial stiffness and pulsatility. For instance, since women have shorter aortic length, wave

travel time is faster, thus the reflected pressure wave arrives earlier in the cardiac cycle,

increasing AIx and central PP. The value of AIx as a measure of arterial stiffness and as a

determinant of PP diminishes with age, however, since the progressive stiffening of the aorta

leads to a decrease in impedance mismatch and an increase in the effective distance to the

reflection sites. 51 With advancing age and in the presence of hypertension, increased Zc has a

greater contribution to pulse pressure, especially in women. 45 In addition, the increase in Zc with

advancing age has been shown to be much steeper in women than men. 52 Since Zc is strongly

(inversely) associated with aortic size, it has been hypothesized that higher Zc in women is due to

women’s smaller aortas and impaired matching between aortic diameter and flow.53 However,

we 44 and others 54 have shown that sex differences in Zc and PP persist despite adjustment for

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aortic size, suggesting intrinsic differences in proximal aortic properties between men and

women.

Although sex differences in arterial aging exist, 52, 55 simply attributing it to sex hormones

may be an oversimplification of a very complex process. Although the aforementioned studies of

arterial stiffness during puberty and menopause, and the effects of HT administration and

withdrawal provide compelling indirect evidence of an influence of sex hormones on arterial

elastic properties, this concept is challenged by other studies that failed to demonstrate an effect

of menopause on blood pressure 56 and arterial stiffness 57 independently of age. The hormonal

and metabolic alterations that occur with aging and menopause are multiple and intricate, 58 thus

the direct effects of sex hormones (and lack thereof) on arterial stiffness needs to be further

assessed in larger mechanistic studies.

The Role of Arterial Stiffness in Cardiovascular Diseases that are More Prevalent in

Women (Figure 3)

Ventricular-Arterial Coupling and Heart Failure with Preserved Ejection Fraction: Differences

Between Men and Women

The heart is often implied as the sole contributor to cardiovascular function and

dysfunction. However, it is now well established that cardiovascular performance depends not

only on cardiac work, but also on the pressure-buffering properties of the elastic arteries. In

young, healthy individuals, a compliant aorta serves to buffer pressure pulsatility generated by

the heart with each beat, which could otherwise increase cardiac workload and be deleterious to

end-organs. Thus, a compliant arterial system is essential for optimization of cardiovascular

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performance, allowing greater transfer of blood from the heart to the periphery while limiting

swings in pressure.

With the progressive aortic stiffening that accompanies aging and CV risk factors,

cardiac workload and wall stress increase, and a series of adaptive mechanisms take place to

maintain optimal stroke volume in the presence of greater afterload, such as increases in left

ventricular systolic stiffness and wall thickness. Although this ventricular-arterial coupling

occurs to maintain cardiovascular efficiency, it can come at the cost of adverse effects.

Ventricular- arterial stiffening results in greater volume sensitivity, therefore relatively small

changes in volume produce greater increases in systolic and pulse pressure. 59 In addition, arterial

stiffening also impairs left ventricular relaxation; 60 and the chronic increases in arterial load

promote left ventricular wall thickening to normalize wall stress, resulting in concentric

remodeling and hypertrophy, which are known to be associated with adverse cardiovascular

events. 61 62-64 All of these mechanisms, centering upon ventricular-arterial stiffening, are thought

to contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF).65

HFpEF affects twice as many women than men, 66 thus understanding sex differences in

ventricular-arterial interactions may provide insights into the mechanisms underlying the

predilection for older women to develop HFpEF.

Age-related ventricular-arterial stiffening has been shown to be exacerbated in women

compared to men. 67, 68 In addition, sex differences in the associations of arterial stiffness with

left ventricular structure and function have been reported. Increased arterial stiffness has been

shown to be associated with left ventricular diastolic dysfunction 44, 46, 47 and impaired

ventricular-arterial coupling 44 in women but not men; and women are more likely to develop

concentric left ventricular remodeling in response to high afterload. 62, 69 Thus, greater arterial

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stiffness in older women, leading to increased hemodynamic load and greater opposition to flow

from the left ventricle may promote adverse alterations in left ventricular structure and function

that ultimately render women’s cardiovascular systems more labile and more susceptible to

changes in loading conditions, despite a normal left ventricular ejection fraction. As such,

increased arterial and ventricular stiffness may represent a link between female sex and HFpEF,

and future research efforts should focus on the development and evaluation of arterial de-

stiffening therapies as means of preventing and/or ameliorating the symptoms of HFpEF in

women.

Isolated Systolic Hypertension and Uncontrolled Refractory Hypertension

Hypertension is now recognized as the principal cause of death and disability

worldwide.70 The most common hypertension subtype among middle-aged and elderly

individuals is isolated systolic hypertension (ISH), 71, 72 characterized by elevated systolic blood

pressure with normal or low diastolic blood pressure, thus elevated PP. ISH is also the most

common blood pressure pattern among patients with poorly controlled or uncontrolled/

refractory hypertension.73

Blood pressure can be divided into 2 components, a steady component (mean arterial

pressure), which is determined by peripheral vascular resistance, and a pulsatile component

(pulse pressure), which mainly determined by large-artery compliance). Thus, aortic stiffening is

thought to be the main pathophysiologic derangement underlying ISH. 60, 74-76 As such, large

populational studies have shown that increases in mean arterial pressure are minimal beyond age

55-60 years, while pulse pressure increases steadily with age, mirroring the increases in aortic

stiffness.52 Analogously, most of the ant-hypertensive medications currently available for clinical

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use have been designed to affect peripheral vascular resistance, thus lowering mean arterial

pressure, but have little effect on arterial compliance and pulse pressure. As a result, ISH is

difficult to treat, and often leads to refractory hypertension.73

Sex differences have also been reported in the epidemiology of ISH, which is more

common in older women than men,8, 77 and greater aortic stiffness is thought to contribute to the

higher prevalence of ISH in women. 5 Further, in the ambulatory care setting, hypertensive

women are less likely than men to achieve optimal control of blood pressure independently of

age or other potential confounders. 78, 79 These data give rise to the hypothesis that greater arterial

stiffness in older women may represent a common link between the higher prevalence of ISH

and poorer hypertension control in older women, and increasing efforts to better understand and

treat aortic stiffness and ISH may have a significant health impact going forward.

Paradoxical Low Flow, Low Gradient, Normal Ejection Fraction Severe Aortic Stenosis

In 2007, Hachicha and colleagues at Laval University first described a group of patients

with severe aortic stenosis by aortic valve area, but who unexpectedly had low transvalvular flow

and low aortic gradients despite a normal ejection fraction, coining the term “paradoxical low

flow, low gradient, normal ejection fraction severe aortic stenosis” (LFLGAS).80 The authors

found that patients with LFLGAS had significantly lower survival than their normal flow, high

gradient counterparts.

Mirroring the clinical characteristics of HFpEF, patients with LFLGAS are more likely to

be older, hypertensive women with high pulse pressure, more pronounced left ventricular

concentric remodeling and worse diastolic function. 81 In addition, one of the hallmark

characteristics of this group of patients, when compared to aortic stenosis patients with normal

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flow and high gradients, is greater arterial load, marked by higher systemic vascular resistance

and lower systemic arterial compliance. 80, 81 Thus, a systemic arterial compliance < 0.6 mL/mm

Hg/m2 has been proposed as one of the diagnostic criteria for this new entity. 81 Although

LFLGAS has been recently described and is still not fully characterized, the aforementioned data

highlight a role for aortic stiffness in its pathophysiology and in its predilection for women; and

present an interesting avenue for future investigations aimed at further understanding this

disease.

Hypertensive Complications of Pregnancy

It is estimated that approximately 10% of pregnant women experience hypertensive

complications, 82 including gestational hypertension, pre-eclampsia and eclampsia. Hypertensive

complications can have devastating consequences to women and their families, including fetal

loss and maternal death. 83, 84 Moreover, women who develop pre-eclampsia or eclampsia during

gestation have a significantly higher risk of developing CVD later in life, 85, 86 87 with hazard

ratios as high as 5.36 for women with severe pre-eclampsia/ eclampsia. 86

Because of the significant health burden associated with hypertensive complications of

pregnancy, increasing efforts have been devoted to understanding its pathophysiology and

identifying markers for risk stratification. It has now well recognized that greater arterial

stiffness is a common characteristic of women who develop hypertensive emergencies of

pregnancy. 88-92 In a meta-analysis of 9 studies, Hausvater and colleagues at McGill University

found that cfPWV and AIx were significantly higher among women who had a history of pre-

eclampsia than women with normotensive pregnancies.90 What remains unclear is whether

arterial stiffness is implicated in the pathogenesis of hypertensive complications or pregnancy, or

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is simply a marker of increased risk. Endothelial dysfunction, inflammation and changes in the

renin-angiotensin-aldosterone system are abnormalities described in both arterial stiffness and

pre-eclampsia,90 and as such increased arterial stiffness may be a simple marker of the

physiologic and metabolic derangements that lead to hypertensive complications of pregnancy.

On the other hand, by leading to the delivery of (deleterious) highly-pulsatile energy to the end-

organs, it is also possible that arterial stiffness may promote endothelial dysfunction and vascular

damage, which in turn trigger the cascade that culminates in pre-eclampsia or eclampsia. Further

basic science and prospective studies are needed to disentangle the complex associations of

arterial stiffness and hypertensive complications of pregnancy.

Although measures of arterial stiffness appear to have a role in predicting future

development of pre-eclampsia/ eclampsia, its role as a therapeutic or preventative target remains

unknown. Khalil et al demonstrated that, among women with pre-eclampsia, arterial stiffness

was significantly lowered by treatment with alpha methyldopa. 93 However, clinical trials are

needed in order to determine whether therapeutically lowering arterial stiffness will be

efficacious in preventing hypertensive emergencies in pregnant women identified as having high

risk of developing pre-eclampsia/eclampsia.

All-Cause and Cardiovascular Mortality

Although the independent association of arterial stiffness with mortality is now well

established, 13, 13 sex-specific data are scant. Regnault et al 94 studied a large community-based

cohort (>125,000 patients) for a mean of 12 years, and found that the disappearance of the PP

amplification between carotid and brachial arteries was a stronger predictor of all-cause and

cardiovascular mortality in women than men (hazard ratio [95% confidence interval] for overall

mortality: 1.51[1.47–1.56] in men and 2.46 [2.27–2.67] in women; for cardiovascular mortality:

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1.81 [1.70–1.93] in men, 4.46 [3.66–5.45] in women, P<0.01 for the interactions with sex); and

these differences were even more prominent in post-menopausal women. Authors concluded that

greater aortic stiffness in older women may play a role in the greater incidence of hypertension

and cardiovascular complications in post-menopausal women. Given the robust body of evidence

demonstrating sex differences in arterial stiffness and pulsatility, future prospective studies

assessing the effects of arterial stiffness on survival should report sex-specific results in order to

further elucidate the prognostic role of arterial stiffness in women.

Conclusions and Future Directions

Arterial stiffness is an independent risk factor for cardiovascular events and mortality. It

has been increasingly recognized that older women have greater aortic stiffness and arterial

pulsatility than men, which appears to play a role in the female predominance of isolated systolic

hypertension, uncontrolled hypertension, heart failure with preserved ejection fraction and low

flow, low gradient, normal ejection fraction severe aortic stenosis. The menopausal transition has

been shown to affect arterial stiffness in women, but the direct contribution of sex hormone

withdrawal versus other metabolic and hormonal alterations that accompany menopause still

needs further clarification. Lastly, measures of arterial stiffness have also emerged as

independent predictors of hypertensive emergencies in pregnant women, highlighting its

potential role for clinical use.

Measuring arterial stiffness is safe, non-invasive, reproducible and relatively inexpensive,

making it an ideal research and clinical tool. From a clinical perspective, although there are no

specific guidelines and recommendations for arterial stiffness assessment in women at present,

the European Societies of Cardiology and Hypertension currently recommend assessing arterial

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stiffness in all hypertensives (men and women), where the technique is available.95 Based on the

data reviewed here, assessment of aortic stiffness and wave reflections in women may be prove

clinically useful in the realms of hypertension, heart failure, pregnancy, menopause and aortic

valve disease. From a research perspective, further studies of sex differences in arterial stiffness

may provide important insights into the pathophysiology of cardiovascular diseases that

predominantly affect women, while identifying clinically applicable tools for risk stratification

and therapeutic interventions aimed at decreasing women’s cardiovascular health burden.

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Acknowledgements:

None.

Funding Sources:

TC receives internal research operating funds from the University of Ottawa Heart Institute and

is part of the CIHR Vascular Network initiative.

Disclosures:

None.

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References

1. Nichols M, Townsend N, Scarborough P, Rayner M. European cardiovascular disease

statistics 4th edition 2012: Euroheart ii. Eur Heart J. 2013;34:3007

2. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. J Am Med

Associat. 1991;265:1861-1867

3. Ellekjaer H, Holmen J, Indredavik B, Terent A. Epidemiology of stroke in innherred,

norway, 1994 to 1996. Incidence and 30-day case-fatality rate. Stroke. 1997;28:2180-

2184

4. Thrift AG, Dewey HM, Macdonell RA, McNeil JJ, Donnan GA. Stroke incidence on the

east coast of australia: The north east melbourne stroke incidence study (nemesis). Stroke.

2000;31:2087-2092

5. Berry KL, Cameron JD, Dart AM, Dewar EM, Gatzka CD, Jennings GL, Liang YL, Reid

CM, Kingwell BA. Large-artery stiffness contributes to the greater prevalence of systolic

hypertension in elderly women. J Am Geriat Soc. 2004;52:368-373

6. Franklin SS, Gustin Wt, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D.

Hemodynamic patterns of age-related changes in blood pressure. The framingham heart

study. Circulation. 1997;96:308-315

7. Staessen JA, Ginocchio G, Thijs L, Fagard R. Conventional and ambulatory blood

pressure and menopause in a prospective population study. J Hum Hypertens.

1997;11:507-514

8. Martins D, Nelson K, Pan D, Tareen N, Norris K. The effect of gender on age-related

blood pressure changes and the prevalence of isolated systolic hypertension among older

adults: Data from nhanes iii. J Gend Spec Med. 2001;4:10-13, 20

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

18

9. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM,

Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA,

Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth

LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS,

Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani

SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics C, Stroke

Statistics S. Heart disease and stroke statistics--2013 update: A report from the american

heart association. Circulation. 2013;127:e6-e245

10. Mitchell GF, Guo CY, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D.

Cross-sectional correlates of increased aortic stiffness in the community: The

framingham heart study. Circulation. 2007;115:2628-2636

11. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA,

Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: The framingham heart

study. Circulation. 2010;121:505-511

12. Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML,

Schalekamp MA, Asmar R, Reneman RS, Hoeks AP, Breteler MM, Witteman JC.

Arterial stiffness and risk of coronary heart disease and stroke: The Rotterdam study.

Circulation. 2006;113:657-663

13. Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C.

Prediction of cardiovascular events and all-cause mortality with central haemodynamics:

A systematic review and meta-analysis. Eur Heart J.31:1865-1871

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

19

14. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and

all-cause mortality with arterial stiffness: A systematic review and meta-analysis. J Am

Coll Cardiol.55:1318-1327

15. Coutinho T, Turner ST, Kullo IJ. Aortic pulse wave velocity is associated with measures

of subclinical target organ damage. JACC Cardiovasc Imag. 2011;4:754-761

16. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B,

Vlachopoulos C, Wilkinson I, Struijker-Boudier H. Expert consensus document on

arterial stiffness: Methodological issues and clinical applications. Eur Heart J.

2006;27:2588-2605

17. Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C.

Prediction of cardiovascular events and all-cause mortality with central haemodynamics:

A systematic review and meta-analysis. Eur Heart J. 2010;31:1865-1871

18. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of

arterial stiffness. Arteriosc Thromb Vasc Biol. 2005;25:932-943

19. Natoli AK, Medley TL, Ahimastos AA, Drew BG, Thearle DJ, Dilley RJ, Kingwell BA.

Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and

matrix metalloproteinase expression. Hypertension. 2005;46:1129-1134

20. Campisi D, Cutolo M, Carruba G, Lo Casto M, Comito L, Granata OM, Valentino B,

King RJ, Castagnetta L. Evidence for soluble and nuclear site i binding of estrogens in

human aorta. Atherosclerosis. 1993;103:267-277

21. Ingegno MD, Money SR, Thelmo W, Greene GL, Davidian M, Jaffe BM, Pertschuk LP.

Progesterone receptors in the human heart and great vessels. Lab Investig. 1988;59:353-

356

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

20

22. Nakamura Y, Suzuki T, Sasano H. Estrogen actions and in situ synthesis in human

vascular smooth muscle cells and their correlation with atherosclerosis. J Steroid

Biochem Mol Biol. 2005;93:263-268

23. Lin AL, McGill HC, Jr., Shain SA. Hormone receptors of the baboon cardiovascular

system. Biochemical characterization of aortic cytoplasmic androgen receptors.

Arteriosclerosis. 1981;1:257-264

24. Forte P, Kneale BJ, Milne E, Chowienczyk PJ, Johnston A, Benjamin N, Ritter JM.

Evidence for a difference in nitric oxide biosynthesis between healthy women and men.

Hypertension. 1998;32:730-734

25. Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG,

Poole-Wilson PA. 17 beta-estradiol attenuates acetylcholine-induced coronary arterial

constriction in women but not men with coronary heart disease. Circulation. 1995;92:24-

30

26. Vitale C, Mercuro G, Cerquetani E, Marazzi G, Patrizi R, Pelliccia F, Volterrani M, Fini

M, Collins P, Rosano GM. Time since menopause influences the acute and chronic effect

of estrogens on endothelial function. Arteriosc Thromb Vasc Biol. 2008;28:348-352

27. Ahimastos AA, Formosa M, Dart AM, Kingwell BA. Gender differences in large artery

stiffness pre- and post puberty. J Clin Endocrin Metabol. 2003;88:5375-5380

28. Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K,

Komesaroff PA. Variations in endothelial function and arterial compliance during the

menstrual cycle. J Clin Endocrin Metabol. 2001;86:5389-5395

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

21

29. Robb AO, Mills NL, Din JN, Smith IB, Paterson F, Newby DE, Denison FC. Influence of

the menstrual cycle, pregnancy, and preeclampsia on arterial stiffness. Hypertension.

2009;53:952-958

30. Stamatelopoulos KS, Georgiopoulos G, Papaioannou T, Lambrinoudaki I, Kouzoupis A,

Vlachopoulos C, Georgiou SP, Manios E, Alevizaki M, Papamichael CM, Sfikakis PP.

Can premenstrual syndrome affect arterial stiffness or blood pressure? Atherosclerosis.

2012;224:170-176

31. Yu A, Giannone T, Scheffler P, Doonan RJ, Egiziano G, Gomez YH, Papaioannou TG,

Daskalopoulou SS. The effect of oral contraceptive pills and the natural menstrual cycle

on arterial stiffness and hemodynamics (cyclic). J Hypertens. 2014;32:100-107

32. Hickson SS, Miles KL, McDonnell BJ, Yasmin, Cockcroft JR, Wilkinson IB, McEniery

CM, Investigators ES. Use of the oral contraceptive pill is associated with increased large

artery stiffness in young women: The enigma study. J Hypertens. 2011;29:1155-1159

33. Staessen JA, van der Heijden-Spek JJ, Safar ME, Den Hond E, Gasowski J, Fagard RH,

Wang JG, Boudier HA, Van Bortel LM. Menopause and the characteristics of the large

arteries in a population study. J Hum Hypertens. 2001;15:511-518

34. Rajkumar C, Kingwell BA, Cameron JD, Waddell T, Mehra R, Christophidis N,

Komesaroff PA, McGrath B, Jennings GL, Sudhir K, Dart AM. Hormonal therapy

increases arterial compliance in postmenopausal women. J Am Coll Cardiol.

1997;30:350-356

35. Gompel A, Boutouyrie P, Joannides R, Christin-Maitre S, Kearny-Schwartz A, Kunz K,

Laurent S, Boivin JM, Pannier B, Pornel B, Struijker-Boudier HA, Thuillez C, Van

Bortel L, Zannad F, Pithois-Merli I, Jaillon P, Simon T. Association of menopause and

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

22

hormone replacement therapy with large artery remodeling. Fertil Steril. 2011;96:1445-

1450

36. da Costa LS, de Oliveira MA, Rubim VS, Wajngarten M, Aldrighi JM, Rosano GM, Neto

CD, Gebara OC. Effects of hormone replacement therapy or raloxifene on ambulatory

blood pressure and arterial stiffness in treated hypertensive postmenopausal women. Am J

Cardiol. 2004;94:1453-1456

37. Miura S, Tanaka E, Mori A, Toya M, Takahashi K, Nakahara K, Ohmichi M, Kurachi H.

Hormone replacement therapy improves arterial stiffness in normotensive

postmenopausal women. Maturitas. 2003;45:293-298

38. Kawecka-Jaszcz K, Czarnecka D, Olszanecka A, Rajzer M, Jankowski P. The effect of

hormone replacement therapy on arterial blood pressure and vascular compliance in

postmenopausal women with arterial hypertension. J Hum Hypertens. 2002;16:509-516

39. Scuteri A, Lakatta EG, Bos AJ, Fleg JL. Effect of estrogen and progestin replacement on

arterial stiffness indices in postmenopausal women. Aging. 2001;13:122-130

40. Nagai Y, Earley CJ, Kemper MK, Bacal CS, Metter EJ. Influence of age and

postmenopausal estrogen replacement therapy on carotid arterial stiffness in women.

Cardiovasc Res. 1999;41:307-311

41. Waddell TK, Rajkumar C, Cameron JD, Jennings GL, Dart AM, Kingwell BA.

Withdrawal of hormonal therapy for 4 weeks decreases arterial compliance in

postmenopausal women. J Hypertens. 1999;17:413-418

42. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E.

Randomized trial of estrogen plus progestin for secondary prevention of coronary heart

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

23

disease in postmenopausal women. Heart and estrogen/progestin replacement study (hers)

research group. J Am Med Associat. 1998;280:605-613

43. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML,

Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing

Group for the Women's Health Initiative I. Risks and benefits of estrogen plus progestin

in healthy postmenopausal women: Principal results from the women's health initiative

randomized controlled trial. J Am Med Associat. 2002;288:321-333

44. Coutinho T, Borlaug BA, Pellikka PA, Turner ST, Kullo IJ. Sex differences in arterial

stiffness and ventricular-arterial interactions. J Am Coll Cardiol. 2013;61:96-103

45. Mitchell GF, Lacourciere Y, Ouellet JP, Izzo JL, Jr., Neutel J, Kerwin LJ, Block AJ,

Pfeffer MA. Determinants of elevated pulse pressure in middle-aged and older subjects

with uncomplicated systolic hypertension: The role of proximal aortic diameter and the

aortic pressure-flow relationship. Circulation. 2003;108:1592-1598

46. Shim CY, Park S, Choi D, Yang WI, Cho IJ, Choi EY, Chung N, Ha JW. Sex differences

in central hemodynamics and their relationship to left ventricular diastolic function. J Am

Coll Cardiol.57:1226-1233

47. Goto T, Ohte N, Fukuta H, Wakami K, Tani T, Kimura G. Relationship between effective

arterial elastance, total vascular resistance, and augmentation index at the ascending aorta

and left ventricular diastolic function in older women. Circulation J. 2013;77:123-129

48. Noon JP, Trischuk TC, Gaucher SA, Galante S, Scott RL. The effect of age and gender

on arterial stiffness in healthy caucasian canadians. J Clin Nurs. 2008;17:2311-2317

49. Gatzka CD, Kingwell BA, Cameron JD, Berry KL, Liang YL, Dewar EM, Reid CM,

Jennings GL, Dart AM, Inhibitor AiACOToA-CE, Diuretic-Based Treatment of

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

24

Hypertension in the E. Gender differences in the timing of arterial wave reflection

beyond differences in body height. J Hypertens. 2001;19:2197-2203

50. Mitchell GF, Gudnason V, Launer LJ, Aspelund T, Harris TB. Hemodynamics of

increased pulse pressure in older women in the community-based age, gene/environment

susceptibility-reykjavik study. Hypertension. 2008;51:1123-1128

51. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS, Levy D.

Changes in arterial stiffness and wave reflection with advancing age in healthy men and

women: The framingham heart study. Hypertension. 2004;43:1239-1245

52. Mitchell GF, Wang N, Palmisano JN, Larson MG, Hamburg NM, Vita JA, Levy D,

Benjamin EJ, Vasan RS. Hemodynamic correlates of blood pressure across the adult age

spectrum: Noninvasive evaluation in the framingham heart study. Circulation.

2010;122:1379-1386

53. Mitchell GF, Conlin PR, Dunlap ME, Lacourciere Y, Arnold JM, Ogilvie RI, Neutel J,

Izzo JL, Jr., Pfeffer MA. Aortic diameter, wall stiffness, and wave reflection in systolic

hypertension. Hypertension. 2008;51:105-111

54. Dart AM, Kingwell BA, Gatzka CD, Willson K, Liang YL, Berry KL, Wing LM, Reid

CM, Ryan P, Beilin LJ, Jennings GL, Johnston CI, McNeil JJ, MacDonald GJ, Morgan

TO, West MJ, Cameron JD. Smaller aortic dimensions do not fully account for the

greater pulse pressure in elderly female hypertensives. Hypertension. 2008;51:1129-1134

55. Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME. Comparative effects of

aging in men and women on the properties of the arterial tree. J Am Coll Cardiol.

2001;37:1374-1380

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

25

56. Casiglia E, d'Este D, Ginocchio G, Colangeli G, Onesto C, Tramontin P, Ambrosio GB,

Pessina AC. Lack of influence of menopause on blood pressure and cardiovascular risk

profile: A 16-year longitudinal study concerning a cohort of 568 women. J Hypertens.

1996;14:729-736

57. O'Neill SM, Liu J, O'Rourke MF, Khoo SK. The menopausal transition does not appear

to accelerate age-related increases in arterial stiffness. Climacteric. 2013;16:62-69

58. Chahal HS, Drake WM. The endocrine system and ageing. J Pathol. 2007;211:173-180

59. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-

ventricular and vascular stiffening with age: Implications for pressure regulation and

cardiac reserve in the elderly. J Am Coll Cardiol. 1998;32:1221-1227

60. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial

stiffening in patients with heart failure and preserved ejection fraction: Implications for

systolic and diastolic reserve limitations. Circulation. 2003;107:714-720

61. Gaasch WH, Zile MR. Left ventricular structural remodeling in health and disease: With

special emphasis on volume, mass, and geometry. J Am Coll Cardiol. 2011;58:1733-1740

62. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated

systolic hypertension. Am J Cardiol. 1993;72:310-313

63. Gerdts E, Cramariuc D, de Simone G, Wachtell K, Dahlof B, Devereux RB. Impact of

left ventricular geometry on prognosis in hypertensive patients with left ventricular

hypertrophy (the life study). Eur J Echocard. 2008;9:809-815

64. Pierdomenico SD, Di Nicola M, Pierdomenico AM, Lapenna D, Cuccurullo F.

Cardiovascular risk in subjects with left ventricular concentric remodeling at baseline

examination: A meta-analysis. J Hum Hypertens. 2011;25:585-591

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

26

65. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: Pathophysiology,

diagnosis, and treatment. Eur Heart J. 2011;32:670-679

66. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes

within the heart failure spectrum. Circulation. 2011;123:2006-2013; discussion 2014

67. Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-

related ventricular-vascular stiffening: A community-based study. Circulation.

2005;112:2254-2262

68. Borlaug BA, Redfield MM, Melenovsky V, Kane GC, Karon BL, Jacobsen SJ,

Rodeheffer RJ. Longitudinal changes in left ventricular stiffness: A community-based

study. Circ Heart Fail. 2013;6:944-952

69. Kostkiewicz M, Tracz W, Olszowska M, Podolec P, Drop D. Left ventricular geometry

and function in patients with aortic stenosis: Gender differences. Intern J Cardiol.

1999;71:57-61

70. Lim SS, Vos T, Flaxman AD, Danaei G, et al. A comparative risk assessment of burden

of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions,

1990-2010: A systematic analysis for the global burden of disease study 2010. Lancet.

2012;380:2224-2260

71. Franklin SS, Jacobs MJ, Wong ND, L'Italien GJ, Lapuerta P. Predominance of isolated

systolic hypertension among middle-aged and elderly us hypertensives: Analysis based

on national health and nutrition examination survey (nhanes) iii. Hypertension.

2001;37:869-874

72. Kannel WB. Elevated systolic blood pressure as a cardiovascular risk factor. Am J

Cardiol. 2000;85:251-255

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

27

73. Alam MG, Barri YM. Systolic blood pressure is the main etiology for poorly controlled

hypertension. American J Hypertens 2003;16:140-143

74. Martins LC, Figueiredo VN, Quinaglia T, Boer-Martins L, Yugar-Toledo JC, Martin JF,

Demacq C, Pimenta E, Calhoun DA, Moreno H, Jr. Characteristics of resistant

hypertension: Ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and

vascular stiffness. J Hum Hypertens. 2011;25:532-538

75. Acelajado MC, Oparil S. Hypertension in the elderly. Clin Geriat Med. 2009;25:391-412

76. Chen CH, Fetics B, Nevo E, Rochitte CE, Chiou KR, Ding PA, Kawaguchi M, Kass DA.

Noninvasive single-beat determination of left ventricular end-systolic elastance in

humans. J Am Coll Cardiol. 2001;38:2028-2034

77. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the

distribution of body mass index among us adults, 1999-2010. J Am Med

Associat.307:491-497

78. Keyhani S, Scobie JV, Hebert PL, McLaughlin MA. Gender disparities in blood pressure

control and cardiovascular care in a national sample of ambulatory care visits.

Hypertension. 2008;51:1149-1155

79. Wilkins K, Gee M, Campbell N. The difference in hypertension control between older

men and women. Health reports / Statistics Canada, Canadian Centre for Health

Information = Rapports sur la sante / Statistique Canada, Centre canadien d'information

sur la sante. 2012;23:33-40

80. Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low-gradient

severe aortic stenosis despite preserved ejection fraction is associated with higher

afterload and reduced survival. Circulation. 2007;115:2856-2864

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

28

81. Pibarot P, Dumesnil JG. Low-flow, low-gradient, normal ejection fraction aortic stenosis.

Curr Cardiol Rep. 2010;12:108-115

82. Wagner SJ, Barac S, Garovic VD. Hypertensive pregnancy disorders: Current concepts. J

Clin Hypertens. 2007;9:560-566

83. Berg CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancy-related mortality in the

united states, 1991-1997. Obstet Gynecol. 2003;101:289-296

84. Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal

mortality. Curr Op Obstet Gynecol. 2013;25:124-132

85. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of

cardiovascular disease and cancer in later life: Systematic review and meta-analysis. Brit

Med J. 2007;335:974

86. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae

of preeclampsia/eclampsia: A systematic review and meta-analyses. Am Heart J.

2008;156:918-930

87. Weissgerber TL, Turner ST, Bailey KR, Mosley TH, Jr., Kardia SL, Wiste HJ, Miller

VM, Kullo IJ, Garovic VD. Hypertension in pregnancy is a risk factor for peripheral

arterial disease decades after pregnancy. Atherosclerosis. 2013;229:212-216

88. Estensen ME, Remme EW, Grindheim G, Smiseth OA, Segers P, Henriksen T, Aakhus S.

Increased arterial stiffness in pre-eclamptic pregnancy at term and early and late

postpartum: A combined echocardiographic and tonometric study. Am J Hypertens.

2013;26:549-556

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

29

89. Khalil A, Akolekar R, Syngelaki A, Elkhouli M, Nicolaides KH. Maternal

hemodynamics at 11-13 weeks' gestation and risk of pre-eclampsia. Ultras Obstet

Gynecol. 2012;40:28-34

90. Hausvater A, Giannone T, Sandoval YH, Doonan RJ, Antonopoulos CN, Matsoukis IL,

Petridou ET, Daskalopoulou SS. The association between preeclampsia and arterial

stiffness. J Hypertens. 2012;30:17-33

91. Savvidou MD, Kaihura C, Anderson JM, Nicolaides KH. Maternal arterial stiffness in

women who subsequently develop pre-eclampsia. PLoS One. 2011;6:e18703

92. Thadhani R, Ecker JL, Kettyle E, Sandler L, Frigoletto FD. Pulse pressure and risk of

preeclampsia: A prospective study. Obstet Gynecol. 2001;97:515-520

93. Khalil A, Jauniaux E, Harrington K. Antihypertensive therapy and central hemodynamics

in women with hypertensive disorders in pregnancy. Obstet Gynecol. 2009;113:646-654

94. Regnault V, Thomas F, Safar ME, Osborne-Pellegrin M, Khalil RA, Pannier B, Lacolley

P. Sex difference in cardiovascular risk: Role of pulse pressure amplification. J Am Coll

Cardiol. 2012;59:1771-1777

95. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESC/ESC guidelines for the management

of arterial hypertension: The task force for the management of arterial hypertension of the

european society of hypertension (esh) and of the european society of cardiology (esc). J

Hypertens. 2013;31:1281-1357

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Figure Legends.

Figure 1.

Title: Carotid-femoral pulse wave velocity (cfPWV) and central arterial waveform assessment

by arterial applanation tonometry.

Caption: Adapted from: Coutinho T, Kullo IJ. Cardiovascular Risk Assessment in the Vascular

Laboratory. In: Strandness’ Duplex Scanning in Vascular Disorders, 5th Edition.

LEFT: Estimation of cfPWV, which is the gold-standard non-invasive measure of aortic

stiffness: With ECG gating, waveforms are sequentially obtained from the right carotid and

femoral arteries using arterial applanation tonometry. cfPWV is estimated as the distance

between the carotid and femoral sampling sites, D, divided by the time delay between the 2

waveforms, t. cfPWV=D/t, in m/s.

RIGHT: To obtain a central aortic pressure waveform with arterial applanation tonometry, there

are 2 possibilities: (1) to use a carotid artery waveform as a surrogate of central pressure given its

proximity to the aorta, or (2) to apply a mathematical transfer function to the radial artery

waveform (shown on the right side of the figure), which derives an aortic waveform from the

radial waveform.

Figure 2.

Title: Central arterial pressure waveform– systolic pulse contour analysis

Caption: Adapted from: Coutinho T, Kullo IJ. Cardiovascular Risk Assessment in the Vascular

Laboratory. In: Strandness’ Duplex Scanning in Vascular Disorders, 5th Edition.

From the central (aortic) pressure waveform, central pulse pressure (CPP) is calculated as central

systolic – diastolic blood pressure. The difference between the 1st (P1) and 2nd (P2) systolic

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pressure peaks is the augmented pressure (AP). Augmentation index (AIx), which represents the

contribution of arterial wave reflections to the CPP, is calculated as: AIx = AP/CPP. Tr

represents the time delay between onset of systole and arrival of the reflected pressure wave.

Figure 3.

Title: Potential mechanisms linking arterial stiffness with cardiovascular diseases that are more

prevalent in women, and with increased risk of mortality in women

Caption: cfPWV: carotid-femoral pulse wave velocity. CV: cardiovascular. HFpEF: heart failure

with preserved ejection fraction. HTN: hypertension. LFLGAS: paradoxical low-flow, low-

gradient, normal ejection

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