The Asklepios study – a reference for arterial hemodynamics and stiffness in middle-aged individuals

The Asklepios Study is a longitudinal population study on healthy ageing with a main focus on the cardiovascular system and its interaction with other organ systems. took an onset in 2002 with a first screening round running over about 2 years. The study cohort includes 2524 participants (1301 women), aged 35-55-year-old and free from overt cardiovascular disease at study initiation with participants randomly sampled from the twinned Belgian communities of Erpe-Mere and Nieuwerkerken. The study was initiated by prof. Ernst Rietzschel in a close collaboration with the general practitioners of Erpe Mere and Nieuwerkerken.

Baseline examinations (all single-observer (prof. Rietzschel), single-device, single-site, single 2-year consecutive timeframe) include questionnaires, conventional risk factors and biochemistry, but above all a deep phenotyping of cardiovascular structure and function using ultrasound and applanation tonometry with a.o. measurement of carotid-femoral Pulse Wave Velocity, carotid and femoral stiffness (from local pressure and diameter distension waveforms), input and characteristic impedance, hemodynamic and wave reflection analysis, atherosclerosis (intima-media thickness, plaque), cardiac structure and function and heart-arterial interaction analysis. A novel aspect of the study is 'integrated' non-invasive biomechanical assessment of cardiac, arterial and ventriculo-vascular function through a combination of modelling, fundamental hemodynamic measurements and system identification techniques. Data were acquired using home-built hard- and software systems to ensure full access to raw data and an independency of any device manufacturer.

Figure. Effect of age on the modulus (A and C) and phase angle (B and D) of input impedance in men (left) and women (right). Increase in age leads to patterns indicative of increased windkessel-like behavior at higher age, whereas the arterial system seems to act more as a wave transmission system at lower age. Note the systematic increase with age in impedance modulus for the harmonics 1 through 4 in women. Values were adjusted for height and weight.

The Asklepios database has been the basis for numerous papers and several PhDs (see further), but a key study was published in 2007 in Hypertension. In that study, we analysed carotid pressure, central flow waveforms, and pulse wave velocity in 2026 participants with normal blood pressure and not taking any anti-hypertensive or lipid lowering medication, and having complete datasets. Input and characteristic impedance, reflection coefficient, the ratio of backward-to-forward pressure amplitude (reflection magnitude), and augmentation index were derived. Pulse wave velocity increased by 15% (from 6.1 to 7.0 m/s) both in men and women. In qualitative terms, input impedance evolved from a pattern indicative of wave transmission and reflection to a pattern more compatible with a windkessel-like system. In women, a decrease in total arterial compliance led to an increased input impedance in the low frequency range, whereas few changes were observed in men. Characteristic impedance did not change with age in women and even decreased in men (P<0.001) and could not be identified as the primary determinant of central pulse pressure. Augmentation index increased with age, as was expected, and was systematically higher in women (P<0.001). Reflection coefficient and reflection magnitude increased with age (P<0.001) without gender differences. We concluded that, in healthy middle-aged subjects, the age-related increase in arterial stiffness (pulse wave velocity) is not fully paralleled by an increase in arterial impedance, suggesting a role for age-dependent modulation of aortic cross-sectional area. Wave reflection increases with age and is not higher in women than in men.

The Asklepios dataset is also central to the database that was used to establish reference values for a.o. arterial stiffness in a pan-European study, published in the European Heart Journal (Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. The Reference Values for Arterial Stiffness' Collaboration)

The same individuals, now aged 45-65 years old, were invited from 2013 to 2017 for a follow-up exam (visit 2; same single operator). To this call, 2252 returning volunteers (89.2% of the invited subjects) had their second visit. A follow-up study on the 2007 impedance and wave reflection cross-sectional study, has been published in 2021 in Hypertension.

A major observation to notice from our longitudinal data is that for impedance and wave reflection parameters, longitudinal changes opposed to what was anticipated from the cross-sectional data over the studied age range. While the cross-sectional data showed a decrease with age in total arterial compliance and an increase in resistance, the longitudinal data demonstrated an increase in compliance and a decrease in resistance, mainly for men and at older ages. Pulse wave velocity accelerated with aging more in women than in men, and this was not paralleled by a decrease in arterial compliance, mainly in younger males. We hypothesize that aortic dilation and/or elongation play an important role determining the longitudinal age-related changes in impedance parameters for younger middle-aged subjects. Contrary to cross-sectional observations, wave reflection decreased with aging, supporting the hypothesis of impedance matching between the aorta and large peripheral arteries with aging, and suggesting limited effect of the backward pressure wave in the increase in pulse pressure at older age – at least in the age range studied. We concluded that the effective impact of aging on arterial system properties in our Asklepios population was not very well reflected by the round 1 cross-sectional data.