The clinical complications of arterial aging, mainly heart failure and stroke, but also coronary and other arterial atherosclerotic disease, renal failure and dementia, are all major causes of loss of autonomy, morbidity, and mortality in older subjects. Arterial stiffness is a key arterial alteration during the aging process leading to cardiovascular morbidity and mortality. Assessment of arterial stiffness can identify the subjects who are at higher risk of developing cardiovascular complications and other age-related diseases. Several methods have been developed over the past few years in order to non-invasively measure arterial stiffness. The most common approach is the measurement of pulse wave velocity, which has shown promise over the last few years in detecting subjects at high risk of CV complications. However, PWV values depend on both the intrinsic elastic properties of the arterial wall and on distension pressure (blood pressure) levels. In this paper, we develop the topic of using methods that are much less dependent on BP levels, which especially in the very old, depend mainly on co-morbidities and frailty. In this respect, the use of the cardio-ankle vascular index (CAVI) in the assessment of age-related arterial stiffening is of major interest, since the dependency of CAVI on BP levels is much weaker. Therefore, CAVI can better assess the effects of ageing on intrinsic elastic properties.
Arterial aging: From concept to clinical practice
Aging is accompanied by significant structural changes reflecting a gradual remodelling of the arteries. Such changes are characterized by an increase in vessel diameter, wall hypertrophy, arterial calcifications, fragmentation and disruption of arterial elastic fibres, increased collagen content, and non-enzymatic glycation of collagen. These structural alterations associated also with endothelial dysfunction and modifications of the phenotypes of the vascular smooth muscle cells, lead to a decrease in the elastic properties of the arterial wall which is the main cause for the age-related increase in both systolic blood pressure (SBP and pulse pressure (PP).1
This age-related process defined as ‘arteriosclerosis’ or ‘arterial stiffness’ is responsible for several cardiovascular diseases in which prevalence dramatically increases with age: heart failure, ischaemic disease, and arrhythmias. The role of arterial stiffness as a major CV risk determinant has now been shown in several populations even in very old and frail subjects. Interestingly, over the past few years there is increasing evidence that arterial stiffness is not only a major determinant of cardiovascular morbidity and mortality, but also of several other age-related diseases, including frailty, cognitive decline, and loss of autonomy. Several clinical studies2,3 indicate that people with cardiovascular risk factors and vascular alterations are at increased risk for developing cognitive disorders including not only vascular dementia but also Alzheimer’s disease.4–11 Although the exact mechanisms for these observations remain unclear, several possible mechanisms have been suggested. It has actually been shown that arterial stiffness is responsible for lesions related to cognitive decline such as silent brain infarct12 and white matter hyperintensities (WMH).6,13,14 In addition, arterial stiffness leads to cerebral perfusion defects, which seem to promote neurodegenerative lesions and accumulation of amyloid plaques, i.e. the typical lesions of the Alzheimer disease.15,16 Moreover, a recent study showed that arterial stiffness was associated with increased pulsatile brain blood flow velocity and low cerebral blood flow.17 Although not found to be associated with impaired neuropsychological performance in this last study, findings of the Rotterdam Study suggested that cerebral hypoperfusion could precede and possibly contributes to the onset of clinical dementia.18
‘Reversibility’ of arterial stiffness and its complications
Although arterial stiffening is common, it is now confirmed that older subjects with increased arterial stiffness and systolic hypertension have higher cardiovascular morbidity and mortality. Moreover, we now have solid evidence for the beneficial effects of the treatment of systolic hypertension in aging people19 and more recently in relatively robust subjects over 80 years old.20 Therefore, there is no doubt that high BP and high risk of morbidity and mortality are strongly related and that at the population level, a decrease in BP is associated with improved CV health. However, presently two major questions remain unanswered:
Are there antihypertensive drugs with more pronounced effects on arterial stiffness?
Is the reduction of SBP always beneficial especially in the very old?
Concerning the first question a limited number of pharmacological clinical studies have suggested that ACEI and CCB had more pronounced effects on arterial function than beta-blockers, whereas the role of diuretics remains more controversial.21–23
However, presently we have very limited data from controlled clinical trials demonstrating the impact of such differences on morbidity and mortality.24 Some ongoing large clinical trials could provide an answer to this crucial question in the near future.
Concerning the second question, chronic BP reduction by drugs is beneficial in general even in very old subjects. However, although this is a very appealing message in terms of public health policy, it may be erroneous at the individual level. In fact, in most cases low BP levels reflect better arterial health and function. However, in some incidences this may not be the case. This could for example explain why in older people, low diastolic blood pressure (DBP), an indicator of exaggerated large artery stiffness, is associated with higher morbidity and mortality.25–28 Such an inverse relationship with risk has even been observed with SBP in very old subjects presenting several co-morbidities frailty and loss of autonomy.29–31 In other words, the risks related to high BP levels are not just the result of the mechanical ‘pressure’ stress that alters the cardiovascular system, but mainly the fact that high BP reflects an altered arterial system. Therefore, when the relationship between low BP and arterial health is disrupted, the predictive value of BP on CV events disappears or is even inverted. For DBP this ‘disruption’ occurs often after the age of 65 and is related to high arterial stiffness, which leads to low DBP whereas for SBP this ‘disruption’ often occurs in the very old due to co-morbidities, malnutrition, and frailty.
These considerations also raise the issue of methodological approaches in order to better assess the risk related to ‘arterial health’ especially in older subjects.
Methodological approaches for assessing arterial health and stiffness
Several approaches and devices have been developed over the past few years in order to assess arterial mechanical properties, wave reflections, and arterial stiffness.32 We present below three of these methods which are currently validated and widely used and in our opinion may have a particular scientific and clinical interest in the evaluation of older subjects: Pulse Wave Velocity (PWV); Peripheral/central pulse pressure amplification (PPA); andCardio-Ankle Vascular Index (CAVI).
Pulse wave velocity (PWV)
PWV is the speed with which the pulse wave spreads across an arterial segment.33–35 In order to measure this velocity, it is important to record the pressure waves (or blood velocity waves) on two arterial segments and know the distance that separates these two segments. This parameter is inversely proportional to the square root of distensibility of the arteries. The principle of PWV and its relationships with arterial elastic properties was initially described in the 19th century.34,36
Pulse wave velocity (PWV) is at the present moment the gold standard method for measuring arterial stiffness.37–40 PWV increases with age, being more pronounced after the age of 55–60 years.41 This age-related increase pertains essentially to aortic PWV, conventionally measured between the carotid and femoral arteries, and much less to PWV measured in peripheral arteries, particularly of the upper and lower limbs.23 Several clinical studies have established PWV as an independent factor of cardiovascular risk.23,42 The recommendations of the European Societies of Hypertension (ESH) and of Cardiology (ESC) in 200742 recognized for the first time the independent role of PWV in the risk of cardiovascular morbidity and mortality, and set the foundations for the clinical use of this parameter for predicting cardiovascular risk in hypertensive patients, and ultimately in other patients with risk factors. These guidelines have proposed that a PWV > 12 m/sec should be regarded as an abnormally high value and thus associated with increased cardiovascular risk. Nevertheless, PWV values are dependent on blood pressure levels during the measurement of this parameter, and are quite variable according to the method used. Therefore, despite its great interest, PWV has several limitations especially in the context of older individuals and requires further investigation to clarify normal threshold values.
Pulse pressure amplification (PPA)
In the arterial system, although Mean Arterial Pressure (MAP) is almost the same in all arteries, SBP and PP are higher in distal peripheral arteries than in the aorta and the other central arteries near the heart.33,43 This phenomenon called ‘BP amplification’ fits with the cardiovascular mechanical objective to achieve optimal peripheral perfusion with lowest cardiac effort. Actually, the higher the SBP amplification, the lower the central BP and the lower the after-load and hence heart work, and at the same time the higher the peripheral SBP and the higher the organ perfusion. This BP amplification is obtained thanks to the high elastic properties of the aorta and the other central arteries as compared to the stiffer peripheral arteries. During the aging process the central arteries stiffen more than the peripheral arteries and the reflection sites are closer to the heart having as a result an important increase in central SBP and PP. The assessment of PP amplification requires simultaneous recordings of peripheral and central BP. The PP amplification (PPA) may be expressed as a percentage increase: PPA (%) = [(peripheral PP/central PP)–1].31,43
Several studies have shown strong relationships between PPA and cardiovascular events in different populations.44–46 Recent studies from our research group have shown that low PPA in very old frail populations predicted cardiovascular events, overall mortality31 but also cognitive and functional decline.11 Interestingly, in this very old frail population, the predictive value of PPA was more pronounced as compared to the PWV. Actually, although PWV is mainly determined by arterial structure and function, it is also strongly influenced by BP levels and this is more pronounced in the very old subjects with comorbidities and frailty. Therefore, any co-morbidity that tends to decrease BP can also decrease PWV and therefore one can present relatively low PWV despite alterations in arterial mechanical properties. On the contrary, PPA, which is the ratio of peripheral to central pressure is therefore much less influenced by absolute BP values.31
However, PPA is determined not only by arterial stiffness but also the amplitude of the wave reflections and the positioning of the reflection sites and therefore cannot be considered a ‘pure’ and direct measurement of the arterial stiffness.
Cardio-ankle vascular index (CAVI)
The CAVI, represents another non-invasive approach for a direct measurement of the arterial stiffness. CAVI is actually a function of the stiffness index (β): CAVI = aβ + b. The stiffness index (β) relies relative changes in arterial diameter (ΔD/D) to the ratio of blood pressure over a cardiac cycle (SBP/DBP) according to the equation: ln(SBP/DBP) = β(ΔD/D)  and thus β = (ln(SBP/DBP))/(ΔD/D). The stiffness index β is actually the tangent line of the Pressure/Diameter relationship during the cardiac cycle and reflects the intrinsic elastic properties of the arterial wall.47 Since from the Bramwell-Hill equation PWV2: ΔP/2ρ X D/ΔD thus ΔD/D = PWV2 (2)/ΔP/2ρ by replacing the ΔR/R in formula  by , we can obtain β = (2ρ/ΔP) (ln(SBP/DBP)) PWV2.
Where, PWV: pulse wave velocity from valve orifice to ankle; ΔP: SBP–DBP; ρ: blood density.
Since CAVI is a measure of the increase in arterial stiffness between diastolic and systolic BP values, the stiffness index β incorporates information on intrinsic arterial properties during the entire cardiac cycle (diastolic-to-systolic ‘stiffening’).48 Thus, the stiffness index β corresponds to the slope of the relationship ratio [(Delta Diameter/Diameter)/Delta Pressure] and, as demonstrated by several authors, its dependency on BP values is weak.48,49 Actually, blood pressure influences measurements of arterial stiffness in two ways:
chronic elevation of blood pressure leads to structural and functional arterial changes leading to an increased stiffness of the arterial wall. This elevation in intrinsic arterial stiffness can be detected by both PWV and CAVI approaches.
Acute blood pressure elevation, increases the distension pressure of the arterial wall reducing arterial distensibility without any structural or functional alteration of the arterial wall. PWV is very dependent on these acute changes, whereas the stiffness index β is not significantly influenced by them.
We believe that the application of CAVI, which specifically detects the chronic effects of BP and of other risk factors on arterial function, provides additional value for the assessment of the impact of risk factors on arterial stiffening and atherosclerosis.50
CAVI can be easily measured with the currently available equipment VaSera (Fukuda Denshi Company, LTD, Tokyo, Japan). Several clinical studies have been conducted over the past few years in order to define reference values of CAVI and establish the interest of this parameter in the measurement of arterial stiffness, as well as CAVI as an additional marker of cardiovascular risk with valuable prognosis and therapeutic applications in Asian populations with various cardiovascular conditions.48,51–53 The coefficient of intra-observer variations has been shown to be 3.8%.52
Several clinical studies have shown that arterial stiffness measured with the CAVI approach was higher in men than in women and was strongly and linearly increasing with age.48 CAVI was also higher in the presence of metabolic risk factors54,55 whereas it showed lower arterial stiffness values after correction of metabolic disorders.56–58 In relatively small studies CAVI was also able to predict CV events59–61 and was associated with end organ damage.62,63 An important finding from several clinical studies was the relative independency of CAVI from the ‘acute’ blood pressure variations i.e. from the BP levels during the CAVI measurements.48,52 This is actually one of the major differences between the results obtained with CAVI vs. those obtained by measuring the PWV.48 Most of these clinical studies have been conducted in Asian countries where the CAVI approach is extensively used.
The International Society of Vascular Health and Aging (ISVH-Aging) initiated and coordinates a large European Study, the Advanced Approach to Arterial Stiffness, The Triple A European Multi-Center Study. The main objective of this longitudinal study is to assess the effects of metabolic syndrome (MetS) on the arterial mechanical properties evaluated with two different approaches: the CAVI of the Vasera system and the ‘classic’ carotid-femoral (cf) PWV. At baseline, 2348 subjects aged 40–85 years were enrolled after obtaining their informed written consent and had clinical, arterial, and metabolic evaluations for the purpose of that study. Subjects have been enrolled in 32 centres for cardiovascular preventive medicine coming from 18 European countries. As expected, both CAVI and cfPWV arterial parameters were correlated with age, but this relationship was much stronger with CAVI than with PWV (Benetos et al., unpublished data). Interestingly, the slope of the correlation between BP levels and PWV was approximately 2-fold higher than between BP and CAVI for both treated and untreated subjects (Figure 1) confirming previously reported data indicating the relative pressure-independency of CAVI. We also assessed the combined effects of age, BP, and sex on CAVI and c-fPWV by using multiple regression analysis. Table 1 shows these results indicating that age influences the variability of CAVI in a much stronger way than influences c-f PWV (beta2 35.2% vs. 9.9%, respectively); also CAVI but not c-f PWV was able to detect lower stiffness in women than in men. Another interesting result of this study is the fact that CAVI was able to show that the different elements of the metabolic syndrome have heterogeneous effects on arterial stiffness.
|Model||Standardized coefficient beta||t||P-value||beta2||Standardized coefficient beta||t||P-value||beta2|
|Model||Standardized coefficient beta||t||P-value||beta2||Standardized coefficient beta||t||P-value||beta2|
Legend: c-f PWV and CAVI show differences in the estimation of the impact of age, blood pressure, and sex on arterial stiffness.
CAVI strongly depends on age (35% of its variability) whereas the dependency from SBP levels is low (<1%). C-f PWV is also influenced by age (about 10%) but this influence is three times weaker than for CAVI; On the contrary the dependency from BP is >3% i.e. >3 times higher than for CAVI.
Also, CAVI detects lower arterial stiffness in women, which was not the case for c-f PWV probably due to a higher dispersion of the measured values with c-f PWV.
We therefore suggest that CAVI may have a major interest for the measurement of arterial stiffness especially in older individuals. This position is based on several arguments. First, CAVI values are very little influenced by BP levels at the moment of the measurement. In the previous paragraphs, we have extensively developed the interest of this aspect in the evaluation of the CV prognosis in very old subjects. Second, CAVI provides a measurement of the entire arterial system including proximal ascending aorta which is the arterial segment which experiences, more than any other artery, age-related stiffening and plays a major role in terms of LV post charge and risk for heart decompensation. Third, CAVI measured with the VaSera device is easy to use and provides automatic measurements without a significant subjective influence from the operator.
In conclusion, there is presently a high level of evidence for the interest of measuring arterial stiffness for the stratification of cardiovascular risk. Such evidence is weaker concerning the interest of these measurements for the evaluation of the benefits of treatment of CV risk factors and chronic CV diseases. The lack of such evidence is due to the fact that no large clinical trial has fixed the changes in arterial stiffness as the main end-point for the evaluation of different therapeutic strategies and also to the fact that arterial stiffness measured mainly with PWV is strongly dependent on blood pressure levels. CAVI measurements could be an accurate methodological approach to better assess the effects of stiffness and its changes with treatment since it is easily measured, highly reproducible, and much less dependent on acute BP variations.
Conflict of interest: A.B. has received honoraria from Fukuda Denshi Company, Tokyo.