As arterial stiffness is a characteristic of vascular ageing based on morphological changes in the arterial wall, there is also a need to better understand its haemodynamic consequence. A starting point is to try to list different characteristics of haemodynamic ageing and to try to understand the association with underlying morphological changes in the arteries (Table 14.1).

Well-known changes, as already alluded to, include an increase in brachial systolic blood pressure and a flattening off of the diastolic blood pressure to be followed by a decrease in diastolic blood pressure above the age of approximately 60–65 years. This will lead to increased risk of isolated systolic hypertension (ISH) and elevated pulse pressure, both conditions being associated with increased prospective risk of cardiovascular events [21]. The same holds true for corresponding changes in central systolic blood pressure and pulse pressure, because around the chronological age of 50 years, the blood pressure amplification between the central and peripheral circulation decreases, and thus central and brachial blood pressures tend to become more similar. These changes according to conventional blood pressure and central blood pressure recordings have previously been discussed in detail by Stanley Franklin et al. [21, 22]. For example, in participants from the Framingham Heart Study who were free of CVD events and antihypertensive therapy, in all 1,439, CVD events occurred between 1952 and 2001. In pooled logistic regression with the use of BP categories, combining SBP with DBP and PP with mean arterial pressure (MAP) improved model fit compared with individual BP components. Significant interactions were noted between SBP and DBP (p = 0.02) and between PP and MAP (p = 0.01) in multivariable models. The combination of PP + MAP (unlike SBP+DBP) had a continuous relation with cardiovascular risk and may provide greater insight into haemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events [21]. This analysis is based on conventional blood pressure variables, but reflecting the age-related changes that more modern and sophisticated technologies can reveal.

Some other features of haemodynamic ageing are less well characterised, but all linked to arterial stiffness as an underlying contributing factor, and thereby also explaining most of the risk associated with these different features. One of them is increased blood pressure variability (BPV), linked to increased cardiovascular risk, i.e. for stroke [23]. Increased BPV can be evaluated on a visit-to-visit basis with weeks or months between visits but also based on shorter time intervals (days, hours, even beat-to-beat timing), as recently reviewed by Gianfranco Parati et al. [24]. An underlying feature is arterial stiffness, and it is reasonable to believe that this factor might explain most of the increased risk associated with increased BPV, even if also some mechanical changes could play a role based on changes in blood flow, shear stress or transmission of increased pulse wave energy to small arteries and the peripheral circulation [24].

In a corresponding way, it has been reported that a decrease in heart rate variability (HRV) is a marker of ageing and increased cardiovascular risk but also associated with increased arterial stiffness, for example, in patients with type 1 diabetes [25]. The decrease in heart rate variability is supposed to be influenced by an imbalance between the sympathetic and parasympathetic parts of the autonomous nervous system.

Furthermore, it is well known that episodes of orthostatic hypotension are associated with increased cardiovascular risk during follow-up, based on data from several epidemiological studies. Also here we notice underlying arterial stiffness as a common denominator, as shown in the Rotterdam study of elderly subjects [26]. The link could be the impaired stretching (compliance) of the carotid arterial wall close to the baroreceptor due to arterial stiffness and superimposed atherosclerosis, leading to impaired baroreceptor function in response to change of body position. This could contribute to the understanding of arterial stiffness being the true risk marker behind orthostatic reactions, often seen in aged subjects with, for example, diabetes of long duration. These orthostatic reactions should be separated from benign vasovagal reactions with orthostatic reactions in younger subjects.

It is conceivable to think that more widespread changes in innervation and the autonomous nervous system could contribute to the ageing of the neural system and thus linked to vascular ageing and decreased baroreceptor function as well as imbalance between sympathetic and parasympathetic activity. In one recent study, the relationship was tested between direct measures of sympathetic traffic and PWV in healthy humans [27]. The authors examined MSNA (microneurography), PWV (Complior® device), heart rate and blood pressure in 25 healthy male participants (mean age 43 years). It was reported that PWV correlated significantly with age (r = 0.63), SBP (r = 0.43) and MSNA (r = 0.43) but not with BMI, waist circumference, waist-to-hip ratio, heart rate, pulse pressure or DBP. Multiple linear regression analysis revealed that only age and MSNA were linked independently to PWV (r ² = 0.62, p < 0.001), explaining 39 and 25 % of its variance, respectively. Individuals with excessive PWV had significantly greater MSNA than individuals with optimal PWV. Thus the relationship between MSNA and PWV is independent of age, BMI, waist circumference, waist-to-hip ratio, heart rate, pulse pressure or blood pressure [27]. This shows the contribution of neurophysiological ageing to vascular ageing.

In the arterial wall, there is a crosstalk between the sympathetic nervous system and the renin-angiotensin system that will further decrease elasticity and promote vascular ageing [28].

Finally, it is self-evident that haemodynamic changes associated with ageing are not possible to describe without taking cardiac changes into account. In fact, there is a so-called cardiac-arterial coupling process that can be illustrated by echocardiography examinations [29]. In the end there is thus a crosstalk between cardiac function, as well as morphological changes, and the general circulation in the arterial tree. With increasing stiffening of the proximal thoracic aorta, the reflex wave from the periphery back to the central circulation and the heart can no longer be accommodated, even if the aorta root widens. Instead this pulse wave energy will impact on the heart with increased pressure waves and augmentation during systole leading to increased strain on the left ventricle, causing left ventricular hypertrophy (LVH), and a decreased perfusion pressure during diastole, leading to impaired blood flow in the coronary circulation. These two trends combined will increase the risk of morphological changes (LVH) in combination with coronary ischaemia, thus increasing the risk of CHD events. This is therefore a haemodynamic mechanism explaining some of the risk potential of arterial stiffness, as measured by increased PWV, for the development of CHD. It contributes to what has been called the cardiovascular ageing continuum by O’Rourke et al. [30].

Even if it has been difficult to show a strong independent association between arterial stiffness and overt type 2 diabetes [31], there is evidence to show that hyperglycaemia as a continuous variable contributes to vascular ageing and arterial stiffness [32]. Diabetes mellitus was associated with c-f PWV in 52 % of studies in one meta-analysis, but the strength of the association was low [31]. Within the so-called metabolic syndrome (MetS), a number of risk factors tend to cluster, including hypertension, hyperglycaemia, dyslipidaemia (elevated triglyceride, decreased HDL cholesterol), increased waist circumference and underlying insulin resistance. Specific clusters of MetS components impact differentially on arterial stiffness (PWV). Recently, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium, the occurrence of specific clusters of MetS differed markedly across Europe and the USA. Based on data from 20,570 subjects included in nine cohorts representing eight different European countries and the USA in the MARE Consortium, MetS was defined in accordance with NCEP ATPIII criteria. PWV measured in each cohort was “normalised” to account for different acquisition methods. The results could show that MetS had an overall prevalence of 24.2 %. MetS accelerated the age-associated increase in PWV levels at any age and similarly in men and women. Therefore, different component clusters of MetS showed varying associations with arterial stiffness (PWV) across these nine cohorts [33].

Also in a local study from the Malmö Diet Cancer cohort, hyperglycaemia and dyslipidaemia showed independent associations with arterial stiffness in elderly subjects with mean age of 71 years [15].

It is well known that advanced chronic kidney disease is associated with vascular changes, as media sclerosis, and thus increasing arterial stiffness [34]. This is linked to oxidative stress and chronic inflammation [35, 36]. Uraemic toxins, particularly those associated with dysregulated mineral metabolism, can drive vascular smooth muscle cell damage and tissue changes that promote vascular calcification but may also promote DNA damage [36]. Epidemiological data suggest that some of these same risk factors in chronic kidney disease (CKD stages 1–5) associate with cardiovascular mortality in the aged general population. The advanced arterial changes in CKD thus resemble that of a fast progressing vascular ageing. This will further increase the overall cardiovascular risk that is very high in patients with CKD-5 and end-stage renal disease (ESRD).

The cardiovascular risk increases rapidly with advancing chronological age, based on arterial stiffness, advancing atherosclerosis and haemodynamic changes in the elderly [37, 38]. On the other hand, survival selection bias may influence the fact that some elderly subjects have survived in spite of advanced arterial stiffness. Epidemiological studies have thus shown that c-f PWV is a stronger risk marker in middle-aged as compared to elderly subjects [8]. No intervention studies exist so far to show the benefits of reducing arterial stiffness (PWV) in the elderly, as was already shown for control of hypertension in 80+-year-old subjects in the placebo-controlled HYVET trial [39].

Another aspect of great interest is the role of chronic inflammation and oxidative stress that are closely linked to the ageing process in general and therefore visible in elderly people [40]. If inflammation can be reduced, a reduction of arterial stiffness has been shown, for example, in patients with inflammatory bowel disease [41], a finding of great theoretical and practical importance. More studies should aim for control of inflammation to prevent cardiovascular disease, but still convincing human studies are lacking.

Arterial stiffness is also a reflection of biological and functional ageing in general. In the Whitehall II study in London, this has been investigated. Researchers aimed to analyse associations of arterial stiffness with age, subjective and objective measures of physical functioning and self-reported functional limitation [42]. Pulse wave velocity was measured by applanation tonometry among 5,392 men and women aged 55–78 years. Results showed that arterial stiffness was strongly associated with age (mean difference per decade: men, 1.37 m/s; women, 1.39 m/s). This association was robust to individual and combined adjustment for pulse pressure, mean arterial pressure, antihypertensive treatment and chronic disease. One SD higher stiffness was associated with lower walking speed and physical component summary score and poorer lung function adjusted for age, sex and ethnic group. Associations of stiffness with functional limitation were robust to multiple adjustments, including pulse pressure and chronic disease. The authors concluded that the concept of vascular ageing is reinforced by the observation that arterial stiffness is a robust correlate of physical functioning and functional limitation in early old age [42]. Why this is so merits further studies.

The development of the EVA concept [12–14] has also triggered research and interest in some other related biomarkers and in haemodynamic ageing [43]. Telomeres represent the end segment of the DNA helix with a shortening taking place with every cell division and therefore regarded as a marker of the biological clock of ageing [44, 45]. Even if discrepant results have sometimes been published, most studies support the notion that telomere length, or rather the telomere attrition rate over time, could represent an interesting aspect of vascular ageing [44, 45]. Previous studies have shown an association between telomere length and arterial stiffness, as measured by pulse pressure [46].