Aortic pulse wave velocity (PWV) which relates to vascular stiffness, independently predicts cardiovascular risk including stroke (Hametner et al., 2013; Vishram-Nielsen et al., 2020). PWV values above 10 m/s have been suggested as threshold indicating increased risk (Van Bortel et al., 2012) and are included in current hypertension guidelines for assessing hypertension-mediated organ damage and guiding secondary prophylaxis (Williams et al., 2018). Local PWV measurements are also feasible using two points close or more distant to each other as well as measurements of pressure-velocity loops at one single spot. However, the guidelines do not specify certain methods to measure PWV. Measurements at different sites including the thigh were used in large scale studies. However, this PWV assessment is difficult to implement in busy clinics or during daily routine. Oscillometric blood pressure monitors estimating PWV based on age and blood pressure could simplify vascular assessment (Hametner et al., 2013; Hametner et al., 2021). Indeed, estimated PWV correlates with age (Schwartz et al., 2019) and invasively measured PWV (Hametner et al., 2013). These monitors operate observer-independent, are easy to use, and are, therefore, applied in clinical practice and in clinical studies alike (Paiva et al., 2020). However, in a study investigating beneficial effects of competitive lifelong physical exercise in elite Masters Athletes, we obtained estimated PWV results suggesting that the approach adds little information to classical cardiovascular risk assessment. We decided comparing the methodology with aortic PWV measurements in an independent set of healthy persons participating in a head-down-tilt bedrest study.

During the 23rd Masters Athletics Championships 2018 in Málaga, Spain, we approached 163 master athletes. We excluded athletes with atrial fibrillation or significant cardiovascular disease assessed by echocardiography. In the remaining 129 athletes (88 men/41 women, 56 ± 11 [range 35–86] years, 24.0 ± 3.5 kg/m²), we acquired blood pressure, heart rate, and estimated PWV thrice on the same arm after 10 min supine rest (Arc-Solver-Algorithm, CardioCube, AIT, Vienna, Austria).

In 24 healthy participants (16 men/8 women, 33 ± 9 years, 24.3 ± 2.1 kg/m²) of the AGBRESA (artificial gravity bedrest) study, which was conducted in collaboration with NASA and ESA in Cologne, Germany (Hoffmann et al., 2021), we assessed estimated PWV before head-down-tilt bedrest as described above. As the estimated PWV has been validated against invasive catheter measurements derived from the ascending aorta to the aortic bifurcation (Hametner et al., 2013), we mimicked this approach non-invasively by measuring pulse wave arrival time from the electrocardiographic R-peak to the arrival of the pulse wave at an oscillometric thigh cuff. We corrected pulse wave arrival time for isovolumetric contraction time, the time from the R-peak in the ECG to aortic valve opening assessed by 2D-pulsed-wave-doppler echocardiography. Corrected pulse wave arrival time represents pulse wave travel time from the aortic valve opening to the arrival at the thigh. Moreover, in contrast to the carotid-femoral PWV, this approach includes the ascending aorta and the aortic arc, which are commonly affected by aging-associated vascular disease. Dividing jugulum-thigh cuff distance by corrected pulse wave arrival time resulted in measured PWV.

All subjects provided informed consent and consent to publish before enrollment. The bedrest study as well as the study in master athletes was approved by the Northrine-Medical-Association (Ärztekammer Nordrhein, 2018143 and 2018171) ethics committee and registered at the German Clinical Trial Register (DRKS00015677 and DRKS00015172).

According to Kolmogorov-Smirnov test, all data were normally distributed, and results are reported as mean values ± standard deviation. Based on other cardiovascular risk estimate models, we used a quadratic regression model.

Resting heart rate was 61 ± 11 bpm, and blood pressure was 128 ± 15/78 ± 8 mmHg in master athletes. Estimated PWV ranged from 5.5 to 14.5 with a mean of 8.3 ± 1.8 m/s. In a quadratic regression model, age and mean arterial pressure predicted estimated PWV (beta value 0.93 and 0.14, p<0.001), whereas, sex and BMI had no influence. The model explained 95% (R² = 0.95) of estimated PWV’s variance. Age alone explained 90% (R² = 0.90).

Resting heart rate was 62 ± 9 bpm, and blood pressure was 125 ± 11/70 ± 7 mmHg in the AGBRESA bedrest study. Estimated PWV was 5.8 ± 1.1 m/s, and measured PWV was 4.8 ± 0.6. Age and estimated PWV were highly correlated (R² 0.88, p<0.001, Figure 1A). The correlation between measured PWV and age was weaker (R² 0.55, p<0.001). In a quadratic regression model, age (beta value 0.99, p<0.001) but not BMI, sex, or mean arterial pressure predicted estimated PWV. The model explained 98% of estimated PWV’s variance. R² between estimated and measured PWV was 0.40 (p<0.05). We observed an increasing bias between estimated and measured PWV with advancing age with an average 0.96 ± 0.83 m/s difference between methods (Figure 1B). When adjusting the correlation of measured and estimated PWV for age we could no longer observe a significant relationship (p=0.267).

Figure 1

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To assess influences of entered rather than chronological age on estimated PWV, we repeated measurements in one male person, who is in his 50s and has normal BMI, and randomly changed the entered age in decades from 30 to 80 years. We obtained measurements in each entered age decade thrice. Again, estimated PWV related to entered age (R² 0.996, p<0.001, Figure 1C) akin to the relationship between estimated PWV and chronological age in athletes and in bedrest study participants.

The idea of obtaining vascular measurements, such as PWV, is gaining insight in individual vascular risk above and beyond traditional risk factors. The clinical goal is to target preventive measures to patients most likely to benefit. Similarly to other studies (Schwartz et al., 2019), we observed an almost perfect correlation between estimated PWV and age in two independent cohorts. Strikingly, estimated PWV in elite Master Athletes, which would be expected to benefit from lifelong exercise, and in healthy bedrest study participants of average physical fitness were located on the same regression line. Suffice it to say that many athletes were frustrated when we reported their findings.

Theoretically, our findings could result from methodological limitations of PWV estimates or a rather limited effect of lifelong exercise on aortic stiffness. A previous study showed significantly lower measured PWV in endurance trained compared with sedentary older men (Vaitkevicius et al., 1993) making a methodological limitation more likely. Indeed, in our study, estimated PWV substantially overestimated PWV, particularly in older persons. Moreover, the modest correlation between estimated and measured PWV was attenuated after adjusting for age in our relatively small bedrest cohort. Finally, in a previous study, estimated PWV highly correlated with PWV calculated solely from age and blood pressure (Hametner et al., 2021). Thus, the algorithm providing PWV estimates appears to weigh age so strongly that subtle influences on vascular wall properties caused by hemodynamic changes and physical training cannot be discerned. Even more so, estimated PWV mainly reflects data entered prior to measuring blood pressure rather than true vascular properties. The clinical implication is that estimated PWV is no substitute for measured PWV, which likely limits the utility of the methodology in individualizing risk assessment. In fact, simply asking the patient in front of us for his or her age and measuring blood pressure provides almost as much information as estimating PWV. Instead, vascular aging assessment using established methodologies rather than estimates should be considered (Jordan et al., 2015).

As we obtained personal health data from human subjects, we cannot make their raw data publicly available. However, an interested researcher is able to access the original data by sending a project proposal to the corresponding author. This project proposal will be reviewed by the medical board of the DLR Institute of Aerospace Medicine. If the project is scientifically valuable, the committee decides to what extent the original data can be made available. Commercial research is excluded from this option. The syntax used for statistical analysis and the numerical data used to generate the figures are stored in Dryad: https://doi.org/10.5061/dryad.8931zcrsb.

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Decision letter after peer review:

Thank you for submitting your article "Utility of estimated pulse wave velocity for assessing vascular stiffness: comparison of methods" for consideration by eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and a Senior Editor. The following individual involved in the review of your submission has agreed to reveal their identity: Jonathan P Mynard (Reviewer #2).

The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this letter to help you prepare a revised submission.

Essential revisions:

1) Please address the following point by revising the text of your manuscript:

line 66: not all PWV measurements require a measurement on the thigh. Also, local measurements are feasible (2 points close to each other), as well as single-point measurements using two different biosignals (e.g. PU-loop method).

2) Please address the following point, both in your responses to both Reviewers and in revised text of your manuscript:

Why have you used PAT (corrected by isovolumic contraction time) from the heart to the thigh cuff to estimate PWV? When this reviewer understands the measurement setup correctly, another cuff was placed at the upper arm, which would allow PWV estimation using PTT.

Reviewer #1 (Recommendations for the authors):

line 66: not all PWV measurements require a measurement on the thigh. Also local measurements are feasible (2 points close to each other), as well as single-point measurements using two different biosignals (e.g. PU-loop method).

Why have you used PAT (corrected by isovolumic contraction time) from heart to the thigh cuff to estimate PWV? When this reviewer understands the measurement setup correctly, another cuff was placed at the upper arm, which would allow PWV estimation using PTT.

Reviewer #2 (Recommendations for the authors):

The authors used an unconventional (but acceptable) approach to measure aortic PWV, by using the ECG R-wave as the first timing marker, corrected for isovolumic contraction time. I suggest this approach could be made clearer, e.g. by stating that the time of aortic valve opening was used as the first timing marker, and this, in turn, was obtained from the ECG R-wave and echo-derived isovolumic contraction time.

Essential revisions:

1) Please address the following point by revising the text of your manuscript:

line 66: not all PWV measurements require a measurement on the thigh. Also, local measurements are feasible (2 points close to each other), as well as single-point measurements using two different biosignals (e.g. PU-loop method).

We addressed this point in the manuscript (line 64-66). Please also see our comments to the reviewers for more details.

2) Please address the following point, both in your responses to both Reviewers and in revised text of your manuscript:

Why have you used PAT (corrected by isovolumic contraction time) from the heart to the thigh cuff to estimate PWV? When this reviewer understands the measurement setup correctly, another cuff was placed at the upper arm, which would allow PWV estimation using PTT.

We addressed this point in the manuscript (line 106-111). Please also see our comments to the reviewers for more details.

Reviewer #1 (Recommendations for the authors):

line 66: not all PWV measurements require a measurement on the thigh. Also local measurements are feasible (2 points close to each other), as well as single-point measurements using two different biosignals (e.g. PU-loop method).

We responded to the comment and added a sentence regarding different approaches to measure PWV including single point measurements. However, large clinical trials showing the prognostic relevance of aortic or carotid femoral pulse wave velocity employed two point measurements at the carotid artery and femoral artery. Classical tonometric measurements were replaced later on by thigh cuff measurements mainly for practical reasons. We also appreciate the public review of reviewer 1, which comes to the conclusion that the role of different methodologies in estimating PWV remains to be shown. The major aim of our paper was to demonstrate that PWV estimates based on the ArcSolver algorithm exhibit major limitations in detecting changes induced by aging, bedrest, or lifelong physical activity. While some of these limitations have been previously recognized, blood pressure measurement devices incorporating such algorithms appear to promise more than they can keep. The recent literature suggests that clinicians and scientists who are no experts in PWV methodologies may not be aware of this limitation.

Why have you used PAT (corrected by isovolumic contraction time) from heart to the thigh cuff to estimate PWV? When this reviewer understands the measurement setup correctly, another cuff was placed at the upper arm, which would allow PWV estimation using PTT.

The reviewers are correct and we now explain more clearly (see also the comment to reviewer 2) our somewhat unconventional approach to use the R-peak of the ECG as first time marker corrected by the time interval until aortic valve opening (isovolumetric contraction time). Measuring the difference between the two arrival times of the pulse wave at the upper arm and at the thigh excludes the ascending and aortic arch part of the thoracic aorta, which may be relevant. Hence, we aimed with our approach to get a more complete picture comparable to the invasive catheter method or to the newly developed 4D-flow MRI measurements.

Reviewer #2 (Recommendations for the authors):

The authors used an unconventional (but acceptable) approach to measure aortic PWV, by using the ECG R-wave as the first timing marker, corrected for isovolumic contraction time. I suggest this approach could be made clearer, e.g. by stating that the time of aortic valve opening was used as the first timing marker, and this, in turn, was obtained from the ECG R-wave and echo-derived isovolumic contraction time.

Please see the response to reviewer 1. We revised the description of our corrected PAT approach and stated the advantage of using the R-peak of the ECG corrected by the time to aortic valve opening (isovolumetric contraction time) to measure aortic pulse wave travel time including the ascending aorta and the aortic arch.

Author details

1. Stefan Möstl

   Department of Cardiovascular Aerospace Medicine, Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - original draft

   Contributed equally with

   Fabian Hoffmann

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4983-4754

2. Fabian Hoffmann

   1. Department of Cardiovascular Aerospace Medicine, Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany
   2. Department of Cardiology, University Hospital Cologne, Cologne, Germany

   Contribution

   Data curation, Formal analysis, Visualization, Writing - original draft

   Contributed equally with

   Stefan Möstl

   Competing interests

   No competing interests declared

3. Jan-Niklas Hönemann

   1. Department of Cardiovascular Aerospace Medicine, Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany
   2. Department of Cardiology, University Hospital Cologne, Cologne, Germany

   Contribution

   Visualization, Writing - original draft

   Competing interests

   No competing interests declared

4. Jose Ramon Alvero-Cruz

   Department of Human Physiology and Physical Sports Education, Faculty of Medicine, University of Málaga, Málaga, Spain

   Contribution

   Conceptualization, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

5. Jörn Rittweger

   Department of Muscle and Bone Metabolism, Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany

   Contribution

   Conceptualization, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

6. Jens Tank

   Department of Cardiovascular Aerospace Medicine, Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany

   Contribution

   Conceptualization, Project administration, Resources, Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

7. Jens Jordan

   1. Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany
   2. Chair of Aerospace Medicine, University of Cologne, Cologne, Germany

   Contribution

   Resources, Supervision, Writing - original draft

   For correspondence

   Jens.Jordan@dlr.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4518-0706

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