Early Vascular Ageing Syndrome - could it be defined?

Peter M Nilsson

For more than 20 years the so called Metabolic syndrome has been in focus as a

model to better understand the etiology of cardiovascular disease in relation to

metabolic abnormalities. However, during the last few years an increasing wave of

criticism has made the metabolic syndrome disputed and now some people think that

it should better be abandoned [1]. Therefore there is a need to find new models for

both theoretical understanding and intervention on increased cardiovascular risk in

order to prevent cardiovascular disease manifestations. In this perspective it is

therefore of interest to discuss the most important cardiovascular risk factor of all –

the ageing process and more specifically vascular ageing.

Cardiovascular risk is determined not only by conventional risk factors of importance

in adult life, but also on early life programming based on intrauterine fetal growth

retardation, often to be followed by rapid catch-up growth patterns [2]. This is called

the early life developmental origins of cardiovascular disease [3], or sometimes even

the “Mis-match” hypothesis [4], thereby depicting that there is a mis-match between

the conditions that the fetus is programmed for in utero, and the environment that the

new-born child meets in early postnatal life. There are several important

consequences of this programming effect, as shown to influence glucose metabolism

based both on changes in insulin sensitivity and beta-cell function [5,6], as well as

haemodynamic control [7], neuroendocrine regulation [8,9] and also kidney function

[10]. In addition, several reports have now documented that also vascular structure

and function is more or less programmed in early life. This includes several

mechanisms that can eventually lead to morphological and functional changes of

importance for the development of adult cardiovascular risk. For example, it has been

shown that an impaired fetal growth is associated with capillary rarefaction [11],

endothelial dysfunction [12] and less arterial diameter [13], as compared to what has

been recorded in children with normal fetal growth.

One consequence of this development is an increased risk of elevated blood

pressure and later on overt hypertension, as now documented in numerous studies.

This is accompanied by a tendency for early arterial changes included in the new

concept of an early vascular ageing [14,15], that can also be called the EVA

syndrome [16]. One typical clinical example of this is the early arterial ageing

observed in young patients with essential hypertension. An increased “intrinsic”

stiffness of the arterial wall material (Young’s elastic modulus) was found in younger

hypertensive patients but not in middle-aged and older hypertensive patients

compared with age- and gender-matched normotensive individuals. Several

arguments favour an interaction between hypertension and diabetes to accelerate

vascular aging and increase the cardiovascular risk [18].

Vascular ageing and arterial stiffening In normal ageing there is a well-known age-related arterial stiffening process

(arteriosclerosis) due to quantitatively less elastin and more collagen, but also

qualitative changes, in the content of the arterial vessel wall, in association with

impaired endothelial-mediated vasodilation [15]. In patient with hyperglycaemia and

overt type-2 diabetes, an additional component of glycaemic changes in vessel wall

proteins (glycosylation) will add to the process of arterial stiffening, a process that is

reflected not only by HbA1c levels, but also by the Advanced Glycation End (AGE)

products [19]. AGE has recently been shown to predict cardiovascular events in

Finnish women with type 2 diabetes, even if no correlation with plasma glucose levels

or HbA1c was found [20].

Aging is the major determinant of all measurements and indirect evaluations of

arterial stiffness and wave reflection. One measure of arterial stiffening is the

increased pulse wave velocity (PWV), also known to predict cardiovascular events,

based on data from more than 13,000 subjects in 12 studies [21,22]. The risk

increases linearly with PWV but is especially increased above 12 m/sec that is now

recommended to be a threshold for increased risk according to the 2007 Guidelines

for the management of arterial hypertension. The measurement of pulse wave

velocity (PWV) is generally accepted as the most simple, non-invasive, robust, and

reproducible method with which to determine arterial stiffness. Carotid-femoral PWV

is a direct measurement, and it corresponds to the widely accepted propagative

model of the arterial system. Measured along the aortic and aorto-iliac pathway, it is

the most clinically relevant, since the aorta and its first branches are what the left

ventricle “sees”, and are thus responsible for most of the pathophysiological effects of

arterial stiffness. PWV is usually measured using the foot-to-foot velocity method

from various waveforms: PWV is thus calculated as the ratio between the distance

covered by the wave (i.e. the surface distance between the two recording sites) and

the transit time (i.e. the time delay measured between the feet of the two waveforms).

Ageing is the major determinant of PWV, explaining up to 33% of PWV variance in

multivariate analysis.

New ways are currently investigated to increase our knowledge on arterial stiffness

and wave reflection in human hypertension, as summarised in a European expert

consensus document [22] and further detailed in a recent review [23]. First, local

arterial stiffness of superficial arteries can be determined using ultrasound devices.

Carotid stiffness may be of particular interest, since in that artery atherosclerosis is

frequent. All types of classical, bi-dimensional vascular ultrasound systems can be

used to determining diameter at diastole and stroke changes in diameter, but most of

them are limited in the precision of measurements because they generally use a

video-image analysis. At present some researchers also measure local arterial

stiffness of deep arteries like the aorta using magnetic resonance imaging (MRI).

However, most of pathophysiological and pharmacological studies have used echo-

tracking techniques. A major advantage is that local arterial stiffness is directly

determined, from the change in pressure driving the change in volume, i.e. without

using any model of the circulation. However, because it requires a high degree of

technical expertise, and takes longer than measuring PWV, local measurement of

arterial stiffness is only really indicated for mechanistic analyses in pathophysiology,

pharmacology and therapeutics, rather than for epidemiological studies. In

multivariate analysis, aging is the major determinant of carotid stiffness, and explains

a larger part of the variance of carotid than aortic stiffness, up to 64% in

normotensives.

Central aortic pressure.

Central pulse wave analysis has recently gained a large amount of popularity, after

the publication of the CAFÉ study, showing that a combination of a calcium channel

blocker and an ACE inhibitor could be more effective for lowering aortic systolic blood

pressure than a combination of a diuretic and a beta-receptor blocker, despite similar

effect of brachial blood pressure. Central augmentation index and central pulse

pressure have shown independent predictive values for all-cause mortality in patients

with end-stage renal disease, and CV events in patients undergoing percutaneous

coronary intervention and in the hypertensive patients of the CAFÉ study [24].

Central systolic and pulse pressures are influenced by aortic stiffness and the

geometry and vasomotor tone of small arteries. In the case of stiff arteries, like in the

elderly, PWV rises and the reflected wave arrives back at the central arteries earlier,

adding to the forward wave, and augmenting the systolic pressure. Indeed, the

arterial pressure waveform is a composite of the forward pressure wave created by

ventricular contraction and a reflected wave. Waves are reflected from the periphery,

mainly at branch points or sites of impedance mismatch. Wave reflection can be

quantified through the augmentation index (AIx) - defined as the difference between

the second and first systolic peaks of the pressure wave, expressed as a percentage

of the pulse pressure. Apart from a high PWV, also changes in reflection sites can

influence the augmentation index. In clinical investigation, age is a major determinant

of AIx and central PP, in addition to aortic PWV, DBP and height.

Arterial pressure waveform should be analysed at the central level, i.e. the ascending

aorta, since it represents the true load imposed to the left ventricle and central large

artery walls [22]. Aortic pressure waveform can be estimated either from the radial

artery waveform, using a transfer function, or from the common carotid waveform. On

both arteries, the pressure waveform can be recorded non-invasively with a pencil-

type probe incorporating a high-fidelity Millar strain gauge transducer. The most

widely used approach is to perform radial artery tonometry and then apply a transfer

function to calculate the aortic pressure waveform from the radial waveform.

In summary, various methodologies are available for determining arterial aging in

individuals, under non-invasive conditions of clinical investigation, and for comparing

observed data with reference values of a normal “aging” population.

The addition of atherosclerosis and inflammation Superimposed on the normal arterial ageing is pathological arterial ageing induced

by chronic inflammation, lipid deposit and start of the atherosclerotic process. This is

even more evident in patients with uncontrolled hypertension for whom the normal

increase in pulse pressure above 60 years of age is more pronounced and can serve

as an easy accessible measure of the combined effect of both processes:

arteriosclerosis and superimposed atherosclerosis.

Using the methodologies described above, it has been shown that markers of

inflammation, e.g. hs-CRP and the primary pro-inflammatory cytokines TNF-α and IL-

6 are associated with morphological changes of both atherosclerosis and increased

arterial stiffening. In addition, chronic inflammation, such as during rheumatoid

arthritis or systemic lupus erythematosus, has been reported to stiffen the large

arteries. This may occur through various mechanisms including endothelial

dysfunction, cell release of a number of inducible matrix metalloproteinases

(including MMP-9), medial calcifications, changes in proteoglycan composition and

state of hydration, and cellular infiltration around the vasa vasorum leading to vessel

ischaemia.

How to define EVA?

Some controversy exists on how the EVA syndrome should best be defined. One

might argue that there is no need of a definition as this concept is more like a

biological model of understanding, and not a fixed model. On the other hand it should

be possible to analyze the distribution of pulse wave velocity, as a marker of arterial

stiffness and EVA, in various age-groups, stratified for gender. EVA could then be

defined as the outliers more than highest +2SD of the distribution for a specific

population and in relation to age-group and gender. This is something that will soon

be accomplished based on European collaboration within an extensive data-base on

PWV measurements (Laurent S, personal communication). Another way to define

EVA would be to analyze the remaining part of PWV that is not explained by

conventional cardiovascular risk factors in a multiple regression analysis, when

adjustment is made for age, gender, blood pressure, hyperlipideamia, smoking,

hyperglycaemia and drug treatment. This is still something that is not fully explored

and work in progress. An important aspect is how PWV or arterial stiffness is

measured as different methods exist (Complior, Sphygmocor, Arterigraph, ultrasound

devices) and should be validated against each other.

In summary, the EVA syndrome is a useful concept to increase awareness of the

pathophysiological consequences of a heavy cardiovascular risk factor burden for

CVD [24,25]. It is measurable and can be followed over time, for example for

changes in pulse wave velocity. The broad evaluation and treatment of risk factors is

necessary to achieve long-terms benefits, as most visibly shown in the Steno-2 study

for patients with type 2 diabetes. The goal for systolic blood pressure in diabetes is

still, however, not well defined.

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