Arterial Stiffness in Predicting Preeclampsia ?

Abarham martadiansyaH

• There is emerging evidence that PE is associated with increased arterial stiffness (AS), which is itself an important predictor of outcome.

• A recent meta- analysis of 23 relevant studies showed a significant increase in all AS indices measured in pre-eclamptic compared with normotensive pregnant women.

• Aortic stiffness – reportedly varies throughout normal pregnancy, reaching its

nadir in the second trimester and rising again in the third– in pre-eclamptic women it continues to increase throughout

pregnancy.

ARTERIAL STIFFNESS

Definition

• Arterial Stiffness– The elasticity (or compliance) of the arteries.

• Arteriosclerosis – The hardening or stiffening of the arteries.

• The stiffness of arteries influences how hard the heart has to work to pump blood through the body.

Figure 1. Summary of the multiple causes and locations of arterial stiffness.

Susan J. Zieman et al. Arterioscler Thromb Vasc Biol. 2005;25:932-943

Copyright © American Heart Association, Inc. All rights reserved.

Arterial Stiffness and Its clinical Implications in woman

Peter M. Nilsson, Pierre Boutouyrie, Stéphane Laurent Hypertension. 2009;54:3-10

Arterial stiffness is a cumulative measure of the damaging effects of CV risk factors on the arterial wall with aging.

Arterial stiffness, which reflects the true arterial wall damage of CV risk factors, increases with aging, whereas blood pressure (MBP), glycemia, and lipids which are fluctuating along the follow-up of patients, may give a constant value when combined into a CV risk score if their fluctuations occur in opposite directions. Thus, measuring “circulating” biomarkers at a certain time may give only a “snapshot” and not the whole history of arterial wall damage.

Conclusion Women who had iatrogenic PTB, but not those who had spontaneous PTB, have increased SBPAo and arterial stiffness that is apparent from as early as the first trimester of pregnancy.

ConclusionWoman who develop GDM have increased SBP(Ao) and Arterial stiffness from the 1st TM of pregnancy before the clinical onset of GDM

• The aim of this study was to examine the potential value of assessment of SBPAo, PWV and AIx at 11–13weeks’ gestation in identifying women who subsequently develop pre-eclampsia.

• Results : – In the pre-eclampsia group vs unaffected controls, there was an increase in

Aix-75 (1.13 vs. 1.00 multiples of the median (MoM); P<0.0001), PWV (1.06 vs. 1.00 MoM; P<0.0001) and SBPAo (1.09 vs. 1.00 MoM; P<0.0001)

Conclusion :Compared with women who remain normotensive, women who develop pre-eclampsia have higher SBPAo and arterial stiffness, which is apparent from the first trimester of pregnancy

How can large artery stiffness be measured?

• Augmentation index (Aix) : – Using the shape of the pulse wave to provide measures of

endothelial function– Primarily reated to the endotheliaal function modulated

vascular tone of the arterioles and small arteries• Pulse Wave Velocity (PWF) :

– Measuring the time it take for a pressure pulse to travel between two points in the arterial system, usually the carotid artery (neck) and femoral artery (groin), and estimating the length of the artery between these two points.

– Related to the peripherial (brachial) Related to peripheral (brachial) BP and the Aix (wafe reflection)

• Central blood pressure : – The pressure that the heart acts against, tends

to increase with higher arterial stiffness.– Related to the peripheral (brachial) BP and the

Aix (wave reflection).• Carotid, intima-media thickness :

– using an ultrasound scan to gauge the thickness of the inner distance of the wall of the carotid artery.

• Carotid-femoral pulse wave velocity (cf-PWV), the most widely validated and universally accepted measure of AS, is considered the ‘gold-standard’ measurement of AS.

• PWV has not been adequately examined during pregnancy, and the potential utility of PWV as a predictor of PE has not yet been determined.

AORTIC PULSE WAVE VELOCITY

• A simple method to assess arterial stiffness and distensibility.

• A long-established and widely used technique.

• Non-invasive, accurate and reproducible.

Principles

L.V.Ejection generates a pulse wave which will propagate along the arterial walls at a certain speed.

Propagation along the arterial tree

Systole

L.V.

Blood = incompressible fluidArtery = elastic conduit }

The propagation velocity is determined by:• the elastic and geometric properties of

the arterial wall • the characteristics of the arterial wall

structure.

Higher velocity = higher stiffness = lower distensibility.

PULSE WAVE VELOCITY

Intermittent cardiac output

Systole Diastole

Large arteries store a part of the ejection volume during systole and restore it during diastole.

Arterial Buffering function

Continuous peripheral flow

•

Speed of the wave is related to the stiffness of the artery it is

traveling in

The stiffer the artery; the higher the wave speed

Wave speed is proportional to the square root of arterial stiffness

WHAT ARE THE TOOLS to measure PWV?• Doppler Ultrasound• Oscillometric

– Measure the fluctuations observed in an occluding cuff as the pressure is initially raised and then gradually dropped.

– Mathematically estimates the oscillation • Tonometric

– Using measurement at radial artery by applanation tonometry

• Piezo-electronic– Measuring changes in pressure, acceleration, or force by

converting to an electrical charge

Pros and CONS?

• Oscillometric– Easy to measure– Non invasive– Fast & Economic– Indirect calculation

• Tonometric and Piezoelectric– Real calculation of the formula– Non invasive– Training needed– Expensive

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 un-

derstanding its relationship to sex. The stability and compli- ance of the arterial wall is maintained by a well-regulated balance between its 2 main extracellular matrix proteins,

collagen and elastin. With aging, there is fatigue of the elastin fibres and dysregulation of this balance, with excessive degradation of its elastic component, elastin, and

replacement with tensile collagen fibres, 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 remodelling by increasing elastin production and decreasing collagen deposition in

human arteries.19

There is compelling evidence suggesting that sex differ- ences in vascular biology are related not only to the type and levels of sex hormones, but also to tissue and cellular

differ- ences responsible for sex-specific responses to various stimuli. For instance, the human aorta has estrogen20 and progester- one21 receptors, and women have more

arterial estrogen re- ceptors 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 re- ceptors in human blood vessels. In addition, it has been demonstrated that production of the potent vasodilator nitric oxide (NO) is greater in

premenopausal women than in men,24 and the endothelial-dependent, NO-mediated vaso- dilatory effects of estrogen differ between men and women, because intracoronary

injections of estradiol improve endo- thelial 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, because 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 might at least partially underlie the favourable 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 evaluated measures of arterial stiffness during

hormonal transition periods, such as before and after puberty, or throughout the menstrual cycle. Ahimastos and col- leagues27 studied 58 prepubertal and 52 postpubertal

healthy children and found that in the prepuberty period, girls had greater cfPWV (a measure of aortic stiffness) and PP (a global marker of arterial stiffness), than age-matched

boys. After puberty, girls’ cfPWV decreased, boys’ cfPWV increased, thereby dissipating the prepubertal differences; and PP was lower in postpubertal girls than in 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 because a

recent study has challenged this

Canadian Journal of Cardiology Volume 30 2014

concept.31 Use of oral contraceptives among women of reproductive age has been shown to be associated with greater PP and cfPWV,32 corroborating the notion that

suppression of female endogenous sex hormones might have an effect on arterial health and compliance.

In the postmenopausal 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 postmenopausal women,34-40 worsening again after HT withdrawal.41 The aforemen- tioned findings suggest that female sex

hormones (and/or the additional hormonal and metabolic milieu that accompany them) might 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 Heart and Estro- gen/Progestin Replacement Study (HERS),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 nonfatal 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 afore- mentioned 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 adminis- tration, 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.

Hypertensive Complications of PregnancyIt is estimated that approximately 10% of pregnant women experience hypertensive complications,80 including gestational hypertension, pre-eclampsia and eclampsia. Hypertensive complications can have devastating consequences to women and their families, including fetal loss and maternal death.81,82 Moreover, women who develop pre-eclampsia or eclampsia during gestation have a significantly greater risk of developing CVD later in life,83-85 with hazard ratios as high as 5.36 for women with severe pre-eclampsia/eclampsia.84

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 is well recognized that greater arterial stiffness is a common characteristic of women who develop hypertensive emergencies of pregnancy.86-90 In a meta-analysis of 9 studies, Hausvater and colleagues at McGill University found that cfPWV and AIx were significantly greater among women who had a history of pre-eclampsia than women with normotensive pregnancies.88 What remains unclear is whether arterial stiffness is implicated in the pathogenesis of hypertensive complications of pregnancy, or is simply a marker of increased risk. Endothelial dysfunction, inflammation, and changes in the renin-angiotensin-aldosterone system are abnormalities described in arterial stiffness and pre-eclampsia,88 and as such, increased arterial stiffness might be a simple marker of the physiologic and metabolic derangements that lead to hypertensive complications of pregnancy. By leading to the delivery of (deleterious) highly pulsatile energy to the end organs, it is also possible that arterial stiffness might 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 decreased by treatment with a-methyldopa.91 However, clinical trials are needed to determine whether therapeutically decreasing arterial stiffness will be efficacious in preventing hypertensive emergencies in pregnant women identified as having high risk of developing pre-eclampsia/eclampsia (Fig. 3).

• Augmentation Index • The augmentation index (A-Ix) is defined as the difference between the

second and first systolic peaks expressed as a percentage of the pulse pressure, is a measure of systemic arterial stiffness and wave reflection.

• Pulse wave velocity • The carotid-femoral PWV (cf-PWV) is calculated as the quotient of the

distance traveled by the pulse wave and the foot-to-foot time delay between the pulse waves.

• The carotid-radial PWV (cr-PWV), the method of calculation was the same; however the distal distance was measured from the sternal notch to the radial artery

Augmentation Index

Mills et al 2008

PULSE WAVE VELOCITY

Objective: • To assess arterial stiffness in pregnancies complicated by hypertensive

disorders: preeclampsia and chronic hypertension. Results: • Significantly higher PP and PWV and lower SI/PP were observed in

preeclamptic compared to uncomplicated pregnancies. Preeclamptic pregnancies also differed from chronic hypertensive pregnancies by higher PP and lower SI/PP. Women with chronic hypertension had significantly higher PWV than the control group, but PP and SI/PP were not different. In both hypertensive groups SVRI was exceptionally high.

Objective : • To evaluate the effect of the menstrual cycle, normal pregnancy, and preeclampsia

on central and systemic arterial stiffness. Result :• In normal pregnancy, pulse wave velocity and augmentation index increased from

24 weeks over the third trimester (P 0.01 for both). • All of the measures were increased in women with preeclampsia (P 0.01), with

augmentation index and carotid-femoral pulse wave velocity remaining elevated 7 weeks postpartum (P 0.02).

Objective :• To compare the maternal wave reflections and arterial stiffness in women with

established PE and those with normotensive pregnancies, after systematic adjustment for known confounders.

Result :• In the PE group, compared with controls, there was an increase in the median

pulse wave velocity of both the carotid to femoral [1.1, interquartile rage (IQR) 1.0–1.3 MoM vs. 0.9, IQR 0.9–1.0 MoM; P 0.0001] and carotid to radial (1.0, IQR 0.9 –1.1 MoM vs. 0.9, IQR 0.9 –1.0 MoM; P 0.01) parts of the arterial tree.

• In contrast, there were no significant differences between the two groups in the median augmentation index (0.9, IQR 0.7–1.1 MoM vs. 1.0, IQR 0.5–1.8 MoM; P 0.46).

Objective: • Investigate the association between PE and arterial stiffness. 23 relevant studies were

included. Results:• A significant increase in all arterial stiffness indices combined was observed in PE vs.

control [SD 1.62, 95% CI : 0.73–2.50]• cfPWV and AIx were also significantly increased (weighted mean difference, WMD

cfPWV 1.04, 95% CI 0.34–1.74; WMDAIx 15.10, 95% CI 5.08–25.11), whereas crPWV increase did not reach significance (WMD crPWV 0.99, 95% CI S0.07 to 2.05).

• Significant increases in arterial stiffness measurements were noted in women with preeclampsia compared with those with gestational hypertension. Arterial stiffness measurements may also be useful in predicting preeclampsia and may play a role in the increased risk of future cardiovascular complications seen in women with a history of PE

A systematic review and meta-analysis was conducted using MEDLINE, EMBASE, and the Cochrane Library

Objective:• To evaluated the diagnostic utility of pulse wave velocity (PWV) alone or in combination with other diagnostic

markers in predicting pre-eclampsia (PE) in high-risk women. Result:• Of 118 women recruited, 11 and 10 women developed early-onset PE (<34 weeks) and late-onset PE (>34 weeks),

respectively.• Of the five diagnostic markers tested, PWV showed the highest detection rate for all cases (21) of PE (81%) and for

early-onset PE (82%) at a fixed 10% false-positive rate (FPR), and when combined with sFlt-1, these figures increased to 90% and 92%, respectively.

• Despite the reduced ability of PWV to predict late-onset PE (detection rate 20%), the combination of PWV with sFlt-1 achieved a detection rate of 50% at a fixed 10% FPR.

• A suggested cutoff value of 9 m/s for PWV resulted in optimal sensitivity (91%) and specificity (86%) for predicting early-onset PE.

• This study is the first to show that PWV may be a potentially promising predictor of early-onset PE in women at high risk for PE. The combination of PWV with sFlt-1 may further improve the screening efficacy for predicting PE.

Figure 2. PWV (m s 1) and sFlt-1 (pg ml 1) the non-PE and PE groups. at 22–26 weeks of gestation in

DISCUSSION• These findings suggest that pre-existing maternal

subclinical endothelial dysfunction and atherosclerosis may render pregnant women more sensitive to maladaptive hemodynamic responses including increased AS, and thus placing them at high risk for developing PE.

• PWV was significantly higher in the early-onset PE group compared with the late-onset, and that are compatible with the concept that early- and late-onset PE may be two different disorders where early-onset PE is related to reduced placental perfusion and late-onset PE is associated with maternal factors.

• Screening for PE is believed to be most relevant during the first trimester because preventive interventions are more likely to be effective if initiated early in pregnancy when pathogenic mechanisms may be modified.

• PWV, a simple, low-cost noninvasive method for assessing AS, measured during the second trimester, may prove useful in predicting PE, particularly early-onset PE, in high-risk women.

• The predictive characteristics of PWV were further improved when it was used in concert with sFlt-1. T

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