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Early Vascular Ageing Syndrome - could it be defined? Peter M Nilsson
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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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