Systolic Blood Pressure Response to Exercise in Relation to Oxygen Uptake in Endurance Athletes

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Linköping University | Faculty of Medicine and Health Sciences Scientific Project, 30 credits| The Medical Programme Spring 2021

Systolic Blood Pressure

Response to Exercise in

Relation to Oxygen Uptake

in Endurance Athletes

Gustaf Eklund

Main Supervisor: Kristofer Hedman

Co Supervisors: Anna Carlén, Magnus Ekström

Project performed at Department of Clinical Physiology in Linköping, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden

Linköping University SE-581 83 Linköping, Sweden +46 13 28 10 00, www.liu.se

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Abstract

Background: During incremental exercise, systolic blood pressure (SBP) increases due to increasing cardiac output. However, the impact of workload on SBP has often been

overlooked. Indexing the increase in SBP to the increase in workload could provide a way of accounting for this. Athletes often reach higher maximal SBP (SBPmax) than untrained

subjects, which has been attributed to their superior cardiac capacity. How this affects the relation between SBP and workload is not established.

Aim: We sought to characterise the novel metrics SBP/VO2-slope and SBP/Watt-slope in

endurance athletes and to analyse possible correlations between these metrics and maximal oxygen uptake (VO2max) in a population of endurance athletes and healthy, non-athletic

subjects. We also sought to compare the SBP response of athletes to values predicted by newly published reference equations accounting for workload.

Methods: In 24 endurance athletes and 5 healthy non-athletes we assessed the workload-indexed blood pressure response during a graded bicycle ergometer test. SBPmax was defined

as the last SBP during exercise, VO2max as the mean of the two highest consecutive VO2

measurements at end of exercise.

Results: The mean SBP/VO2-slope was 31.1 ± 9.7 mmHg/l/min and the mean

SBP/Watt-slope was 0.28 ± 0.08 mmHg/Watt. We found no significant correlation between VO2max and

the SBP/VO2-slope or the SBP/Watt-slope, nor with SBP at 50 W or at 200 W. In males there

was a significant correlation between VO2max and SBPmax. The endurance athletes had less

steep SBP/Watt-slopes and higher SBPmax than predicted by reference equations.

Conclusion: The SBP/VO2-slope offers a precise way of indexing blood pressure to workload

and could provide a valuable tool in future studies investigating the SBP response to exercise. Our results suggest that different reference equations than in the general population might be needed when evaluating the SBP response in athletes.

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Populärvetenskaplig sammanfattning

Vid fysiskt arbete med ökande intensitet stiger blodtrycket till följd av att hjärtat arbetar hårdare och pumpar större volym blod per minut. I tidigare studier har man funnit samband mellan ett förhöjt blodtryck vid arbete och en förhöjd risk att senare utveckla högt blodtryck i vila, något som vi vet ökar risken för hjärt-kärlsjukdom. Hittills har man dock inte i någon större utsträckning tagit hänsyn till belastningen när man bedömer vad som ska räknas som ett förhöjt blodtryck under arbete.

Nya rön har visat att det är viktigt att relatera blodtrycksökningen vid arbete till vilken belastning personen i fråga klarar av för att kunna bedöma personens prognos. Ett enkelt sätt att göra detta är genom att dividera ökningen i blodtryck under arbete med ökningen av arbetets belastning. Arbetets belastning kan mätas antingen i antal Watt som personen klarar av att trampa på en testcykel eller i hur stort personens syreupptag är. Nyligen presenterades referensekvationer baserade på ett stort antal friska försökspersoner som kan förutsäga hur snabbt blodtrycket kan förväntas öka i förhållande till belastningsökningen.

Vi ville testa detta nya sätt att mäta blodtryck under arbete och lät därför en grupp vältränade konditionsidrottare och en mindre grupp relativt otränade, friska personer utföra maximala arbetsprov på testcykel samtidigt som vi mätte deras blodtryck och syreupptag.

Våra resultat visar att hos studiedeltagarna ökade blodtrycket med i genomsnitt 31 mmHg för varje liter per minut som syrgasupptaget ökade med. Resultaten visar också att

konditionsidrottarna nådde ett högre maximalt blodtryck men hade en lägre ökningstakt än vad referensekvationerna förutspådde.

Vi tror att våra resultat tillsammans med framtida forskning kan hjälpa oss att bättre förstå hur blodtrycket regleras under arbete. Vi tror också, utifrån våra resultat, att andra

referensekvationer än de som används för allmänheten kan behövas för att bedöma idrottares blodtryck under arbete.

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Abbreviations

Abbreviation Meaning

AHA American Heart Association CPET cardiopulmonary exercise test

EBPR exaggerated blood pressure response ESC European Society of Cardiology

IPAQ International Physical Activity Questionnaire IQR interquartile range

MAP mean arterial pressure MET metabolic equivalent of task SBP systolic blood pressure

SBPmax maximal systolic blood pressure

SD standard deviation

VCO2 carbon dioxide elimination

VO2 oxygen uptake

VO2max maximal oxygen uptake

Wmax maximal workload, in Watts

Wmaxcorr maximal workload, in Watts. Standardized to an increment rate of 15 or

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Introduction

One of the most impressive features of the human body is its capability to constantly adapt to new challenges such as exercise. During maximal exercise tremendous stress is put on the body’s systems, most notably its cardiovascular system, triggering several physiological changes. A clear example of this is the elite athlete, who during strenuous exercise can increase cardiac output as much as seven times compared to in the resting state (1).

Cardiopulmonary exercise testing (CPET) is commonly used in clinical practice to assess patients presenting with dyspnea of unknown cause and to evaluate cardiorespiratory fitness. In Europe, CPET is most often performed on a bicycle ergometer. During maximal ramp testing, the braking force of the ergometer is gradually increased until the test subject is unable to continue pedaling. As the external work increases, concomitant changes in several physiological parameters can be monitored. One of these is the arterial blood pressure.

The mean arterial pressure (MAP) is the product of the cardiac output and the total peripheral vascular resistance. Cardiac output and the oxygen uptake both increase linearly in proportion to the work performed (2). Simultaneously, blood flow to the working muscle increases because of vascular dilatation which causes a decrease in total peripheral vascular resistance (3). However, the increase in cardiac output is greater than the decrease in total peripheral vascular resistance and, consequently, the MAP rises during dynamic exercise of increasing intensity (2). The increase in MAP is driven by an increase in systolic blood pressure (SBP) while diastolic blood pressure remains relatively constant (4).

An exaggerated blood pressure response (EBPR) has been defined as a SBP during exercise above 210 or 190 mmHg, for men and women, respectively, according to the current scientific statement by the American Heart Association (AHA) (5). There have been studies indicating that an EBPR could imply an increased risk for future hypertension, an important risk factor for cardiovascular disease (6). Others, however, suggest that an EBPR could be associated with a decreased risk for all-cause mortality (7). Current guidelines from the European Society of Cardiology (ESC) state that there is currently no consensus regarding the normal blood pressure response to exercise (8). However, in both clinical practice and research, the impact of workload on the SBP has often been overlooked when interpreting the blood pressure response to exercise (9). Until very recently, workload-indexed reference values for the blood pressure response to exercise have been lacking (10).

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This has been problematic particularly in athletes, who often reach workloads far exceeding those of the general population. Endurance-training enables people to reach a higher SBP during exercise than they were able to in the untrained state (11), often above the thresholds defining EBPR. The higher SBP during exercise in athletes has been explained by greater maximal cardiac output and thus seen as a sign of high fitness (12).

One way of accounting for workload when interpreting the blood pressure response to exercise is by relating the increase in SBP to the increase in workload, expressed either in Watt or as oxygen consumption. The metabolic equivalent of task (MET) is an estimation of a person’s oxygen consumption during exercise relative to at rest. One MET approximates the oxygen consumption of a person sitting quietly at rest, 3.5 ml/min/kg body weight (13). According to the AHA, the SBP is expected to rise by approximately 10 mmHg/MET during incremental exercise (5). This value has recently been questioned by several research groups, including by Hedman et al. (2020) who found a markedly lower median increase in a large American sample of males (9, 14). In the same study, the SBP/MET-slope was a stronger predictor of all-cause mortality than the peak value for SBP. Recently, reference equations for workload-indexed SBP during bicycle ergometry based on a Swedish sample of apparently healthy subjects were published, including the SBP/Watt-slope (10).

The workload-indexed systolic blood pressure response to exercise has been scarcely studied in athletes. Recently, Bauer et al. (2020) found that the SBP/MET-slope in a population of male professional German indoor athletes was lower (5.4 mmHg/MET) than the 10

mmHg/MET proposed by the AHA, and that the SBP/MET-slope correlated negatively to estimated maximal oxygen uptake (VO2max) (15). The same group of researchers also found

that the SBP/Watt-slope in a group of young male and female professional handball and football players was markedly steeper in women than in men (16). This corresponds well to previous findings in healthy, untrained subjects (10). In contrast, the SBP/MET-slope in athletes was similar regardless of sex (16).

To date, all studies have estimated MET values from the cycle ergometer workload using equations instead of using actual, measured oxygen uptake (VO2), the latter a more exact way

of measuring METs (14-16). The SBP/VO2-slope has, to the best of our knowledge, never

been studied in athletes, and would give a more accurate and precise measure of the SBP increase relative to workload.

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It remains to be elucidated if the negative correlation between the SBP/MET-slope and VO2max found by Bauer et al. (2020) is persistent in athletes from sports with a more

pronounced endurance component or outside the athletic population (15).

Aim of the study

The aim of this study was to characterize the SBP response to exercise, including the SBP/VO2-slope and the SBP/Watt-slope, in healthy, fit subjects. In addition, it sought to

investigate possible correlations between measurements of the SBP response to exercise and VO2max, not only in athletes but in a larger population including also less athletic subjects.

A secondary aim of this study was to compare the SBP/Watt-slope and the maximal SBP during exercise in an athletic population to recently published reference values for the general population.

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Material and methods

Study design and sample

This was a cross-sectional study of healthy volunteers. Subjects of varying fitness were included from an ongoing study on cardiac adaptations to exercise, recruiting endurance athletes and non-athletic control subjects. Data were collected at the Department of Clinical physiology at Linköping University Hospital, Linköping, Sweden, between January 2020 and February 2021.

Recruitment of endurance athletes was conducted through text posts in social media aimed at a local sports club (Appendix 1 and Appendix 2) and echocardiography was performed on athletes interested in study participation. Athletes with a body size-indexed left-ventricular end-diastolic diameter above the upper limit of normal, with normal systolic and diastolic function and no structural heart disease, were included. Non-athletes were recruited among employees at the Department of Clinical physiology at Linköping University Hospital voluntarily enrolling for the study.

We included all subjects recruited to date. After being recruited, one of the subjects was found to have an abnormal echocardiography reading and was thus excluded. A flowchart describing the inclusion of study participants is presented in figure 1.

For the purpose of this study, subjects who did not have a SBP measurement during the last two minutes of exercise were excluded in analyses for maximal SBP (SBPmax). For analyses

comparing the SBP/Watt-slope and SBPmax in athletes to reference values only subjects

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Figure 1. Flowchart describing the inclusion of study participants.

SBP: Systolic Blood Pressure; SBPmax: Maximal Systolic Blood Pressure.

Upon inclusion, all participants answered questionnaires on tobacco use, asthma, prior heart disease, prior chemotherapy treatment for malignant disease, and current medications. All participants also filled out a short form International Physical Activity Questionnaire (IPAQ), assessing level of physical activity (17).

Subjects recruited for ongoing study

(n=30)

Included in this study (n=29) Abnormal echocardiography (n=1) Endurance athletes (n=24) Non-athletic control subjects (n=5) Included in correlation analyses and descriptive statistics using SBPmax (n=22) Included in comparison of SBPmax (n=17) Included in correlation analyses and descriptive statistics

not using SBPmax

(n=29) No SBP measurement last 2 min (n=7) No SBP measurement last 2 min (n=7) Included in comparison of the SBP/Watt-slope (n=24)

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Cardiopulmonary exercise test

Participants’ heights and weights were measured before starting the exercise test. Participants performed a maximal CPET on a cycle ergometer (eBike Comfort, Ergoline GmbH, Bitz, Germany) using an individualized ramp protocol. The protocol started with five minutes of warm-up at 50 W. A continuous ramp protocol with an increment of 20 W/min hereafter commenced at either 50 W, 100 W or 150 W, depending on the subject’s predicted maximal work capacity aiming for a total ramp exercise time of 8-12 minutes. Ventilatory and

respiratory parameters including VO2, carbon dioxide elimination (VCO2), breathing

frequency, ventilation and end-tidal concentrations of respiratory gases were measured continuously throughout the test using Vyntus CPX equipment (Carefusion GmbH,

Hoechberg, Germany). Continuous ECG-recordings were made from a few minutes before the start of the test and followed throughout the test until the last blood pressure measurement after the test, during which heart rate was registered automatically in a digital exercise protocol (CardioSoft version 6.73, GE Medical Systems, Milwaukee,WI, USA). During the test participants were asked to rate their level of perceived exertion and dyspnea every second minute and the ratings were added manually to the digital exercise protocol. All tests were driven as near maximal exertion as possible. The tests were supervised by only a small number of physicians and all measurements were made by a small number of experienced biomedical scientists.

Blood pressure measurements

Blood pressure was measured both in the supine and sitting position before the start of the test, at the end of the 5-minute warm-up at 50 W and after that once every second minute. Systolic blood pressure was also measured at 200 W and as close as possible to the

termination of the test for all participants. For each measurement during exercise the subject was asked to relax and extend their right arm. The SBP was then measured using a manual sphygmomanometer and a doppler probe placed over the subject’s radial artery. SBP was recorded at the appearance of the first Korotkoff sound, and each SBP measurement was recorded in the digital exercise test protocol, with the corresponding test time, heart rate and workload added automatically.

Ethical considerations

The study was approved by the Swedish Ethical Review Authority (dnr: 2017-67-31) and all subjects gave written informed consent prior to participation in the study.

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Calculations

Predicted values for maximal workload (Wmax) were calculated for all subjects using Swedish

reference equations (18). To allow calculations of percent of predicted exercise capacity, our subjects’ measured Wmax was re-calculated to a standard protocol with an increment of 15

W/min (men) and 10 W/min (women) by the following formulas: Wmaxcorr(men) =

Wmax*(20/15)1/6; Wmaxcorr (women) = Wmax*(20/10)1/6 (19).

Predicted values for VO2max were calculated for all subjects using the reference equations

provided by Gläser et al. (2010) (20).

The SBP/Watt-slope was calculated as the ratio of the difference in SBP from the first to the last SBP measurement during exercise over the increment in Watt between these two

measures, as proposed by Hedman et al. (2020) (10). Using the same rationale, the SBP/VO2

-slope was calculated as the ratio of the difference in SBP from the first to the last SBP measurement during exercise over the difference in VO2 between these two measures (figure

2). Predicted values for SBPmax and SBP/Watt-slope were calculated for all participants using

the formulas provided by Hedman et al. (2020) (10).

Figure 2. Rationale for calculating the SBP/VO2-slope. The SBP/VO2-slope was calculated as the ratio

of the difference in SBP (ΔSBP) from the first to the last SBP measurement during exercise over the difference in VO2 (ΔVO2) between these two measures.

SBP: systolic blood pressure; VO2: oxygen uptake

Data on the amount of physical activity from the IPAQ-questionnaires was converted to the continuous score “MET-minutes/week” following the guidelines provided online by the IPAQ-group (21). 100 120 140 160 180 200 220 240 0 1000 2000 3000 4000 5000 S y s tol ic bl oo d pres s ure (m m Hg) Oxygen uptake (ml/min)

SBP/VO

₂

-slope

Δ SBP ΔVO2

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Statistical analyses

No prospective sample size analysis was performed for this study. However, retrospective power analyses for the analyses comparing the endurance athletes’ values to the values predicted by reference equations were performed and are described in the results.

Exercise test data was extracted from CardioSoft and SentrySuite and incorporated into an Excel (Microsoft Excel for Office 365)spreadsheet to which background data and data from IPAQ-questionnaires was added manually. Statistical analyses were performed using SPSS statistics software version 27.0 (IBM corp., Armonk, NY, USA). Two-sided statistical significance was set at p < 0.05 in all analyses.

Descriptive analyses were carried out on all study variables for the total sample and separated by athletes and non-athletic control subjects. Since some variables, including SBPmax and

VO2max, are known to be influenced by sex, further descriptive analyses were performed

stratified by sex. All data are presented as mean ± standard deviation (SD) or as median and interquartile range (IQR) based on its distribution. The Shapiro–Wilk test and manual inspection of histograms were used to determine normal distribution.

To investigate the relation between either of VO2max and VO2max/kg with SBPmax, with SBP at

standardized workloads (50 W and 200 W) as well as with the SBP/VO2-slope and the

SBP/Watt-slope, we performed Pearson correlation analyses. For these analyses, both subjects recruited as endurance athletes and subjects recruited as non-athletic controls were included. Since VO2max and VO2max/kg generally is higher in men than in women, correlation analyses

were performed for each sex separately.

To compare the athletic subjects’ SBPmax and SBP/Watt-slope to the values predicted by

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Results

Cohort characteristics

A total of 29 subjects were included in the study, 24 endurance athletes (15 men, 9 women) and 5 non-athletic control subjects (4 men, 1 woman).

Seven of the subjects (endurance athletes) had no SBP measurement recorded during the last two minutes of exercise and were thus excluded from descriptive statistics and analyses using SBPmax.

Anthropometric data, CPET characteristics and data on the amount of physical activity per week for the subjects are presented in table 1.

Five participants had missing measurements for single data points other than SBPmax. Details

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Table 1. Subject and CPET characteristics for all subjects separated by endurance athletes and non-athletic control subjects, and for the endurance athletes separated by males and females.

Non-athletic control subjects

Endurance athletes

All Males Females

n 5 24 15 9 % men 80 63 Age (yrs) 32 ± 6 41 ± 10 45 ± 10 33 ± 7 Height (cm) 176 ± 5 176 ± 8 179 ± 7 170 ± 6 Weight (kg) 82.3 ± 6.7 69.7 ± 8.4 73.7 ± 6.4 62.9 ± 6.9 BMI (kg/m2₎ _{26.7 ± 2.4} _{22.5 ± 1.6} _{22.9 ± 1.4} _{21.8 ± 1.8} Physical activity (MET-minutes/week) 2079 (2467) 3213 (3136) 2980 (1573) 4452 (6292)

Before test, at rest

SBPlying (mmHg) 124 ± 7 125 ± 11 129 ± 10 118 ± 11

DBPlying (mmHg) 77 ± 10 75 ± 8 75 ± 8 76 ± 8

SBPsitting (mmHg) 127 ± 4 126 ± 13 130 ± 12 120 ± 14

During exercise test

RPEmax (Borg RPE) 19 (0) 18 (2) 19 (2) 17 (1)

Dyspneamax (CR10) 9 (2) 8 (2) 8.5 (1) 7 (1.5) Wattmax 266 ± 51 316 ± 53 344 ± 39 269 ± 39 Wattmaxcorr 282 ± 50 339 ± 50 361 ± 41 302 ± 44 % of predicted Wattmaxcorr 115 ± 22 154 ± 19 146 ± 17 168 ± 14 HRmax (beats/min) 188 ± 13 175 ± 11 174 ± 12 176 ± 9 % of age-predicted HRmax 100 ± 9 98 ± 6 100 ± 6 94 ± 3

VO2max (ml/min) 3069 ± 494 3455 ± 518 3727 ± 353 3002 ± 430 VO2max/kg (ml/min/kg) 37.5 ± 6.4 49.6 ± 4.8 50.7 ± 4.9 47.7 ± 4.4 % of predicted VO2max 115 ± 7 153 ± 17 145 ± 13 167 ± 15 Data presented as mean ± SD or as median (IQR) depending on its distribution. Exercise test data was obtained during a progressive, maximal CPET.

CPET: cardiopulmonary exercise test; BMI: body mass index; MET: metabolic equivalent of task; SBP: systolic blood pressure; DBP: diastolic blood pressure; VO2: oxygen uptake; RPE: rating of perceived

exertion; CR10: category ratio; HR: heart rate; lying: measure at supine rest before exercise; sitting: sitting

on bicycle before exercise; max: highest value during the test; maxcorr: Watt standardized to an increment

rate of 15 or 10 Watt/min in males and females, respectively.

Blood pressure response to exercise and correlations with maximal oxygen uptake Data concerning the blood pressure response to exercise are presented in table 2.

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Table 2. Blood pressure response to exercise for all subjects separated by endurance athletes and non-athletic control subjects, and for the endurance athletes separated by males and females.

Non-athletic control subjects

Endurance athletes

All Males Females

SBPmax (mmHg) 201 ± 5 211 ± 26 * 224 ± 24 ** 196 ± 21 *** SBP/Watt-slope (mmHg/Watt) 0.27 ± 0.06 0.28 ± 0.09 0.28 ± 0.06 0.28 ± 0.12 SBP/VO2-slope (mmHg/l/min) 32.8 ± 5.8 30.7 ± 10.4 30.1 ± 6.2 31.9 ± 15.6 SBP50W (mmHg) 146 ± 8 145 ± 16 148 ± 15 140 ± 17 SBP200W (mmHg) 190 ± 11 188 ± 19 191 ± 17 184 ± 22

Data presented as mean ± SD or as median (IQR) depending on its distribution. Data was obtained during a progressive, maximal CPET.

* n = 17, ** n = 9, *** n = 8

SBP: systolic blood pressure; VO2: oxygen uptake; max: highest value during the test; 50W: measured at

50 W; 200W: Measured at 200 W.

Values for all study subjects’ SBP/VO2-slopes are visualized in figure 3.

Figure 3. SBP/VO2-slope for 19 men and 10 women, separated by endurance athletes and

non-athletic control subjects. Data obtained during a progressive, maximal CPET. The SBP/VO2-slope was

calculated as the ratio of the difference in SBP from the first to the last SBP measurement during exercise over the difference in VO2 between these two measures.

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One female athlete was an outlier in regards of the SBP/VO2-slope and the SBP/Watt-slope

(figures 3-5). This female outlier also reported one of the highest amounts of physical activity per week. After re-examining her echocardiography recording, no abnormality was found. By excluding this female outlier, the means for the SBP/VO2-slope changed from 30.7 to 29.1

mmHg/l/min and from 31.9 to 27.4 mmHg/l/min, for all endurance athletes and for the female endurance athletes, respectively. The means for the SBP/Watt slope changed from 0.28 to 0.27 mmHg/Watt and from 0.28 to 0.25 mmHg/Watt, for all endurance athletes and for the female endurance athletes, respectively.

Scatterplots showing the relation between variables of the systolic blood pressure response to exercise and VO2max are presented in figures 4 and 5.

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Figure 4. Relation between blood pressure response to exercise and maximal oxygen uptake, measured in 19 men and 10 females during a progressive, maximal CPET. Correlations were analyzed with Pearson correlation analyses for each sex separately.

(a): Relation between the SBP/VO2-slope and VO2max/kg. The SBP/VO2-slope was calculated as the

ratio of the difference in SBP from the first to the last SBP measurement during exercise over the difference in VO2 between these two measures.

(b): Relation between the SBP/Watt-slope and VO2max/kg. The SBP/Watt-slope was calculated as the

ratio of the difference in SBP from the first to the last SBP measurement during exercise over the difference in Watts between these two measures.

(c): Relation between SBP measured at 50 W and VO2max/kg.

(d): Relation between SBP measured at 200 W and VO2max/kg.

SBP: systolic blood pressure; VO2: oxygen uptake; max: highest value during the test; CPET:

cardiopulmonary exercise test

There were no significant correlations between the SBP/VO2-slope, the SBP/Watt-slope, SBP

at 50 W or at 200 W and either of VO2max or VO2max/kg for any of the sexes. For the males,

there were significant correlations between SBPmax and both VO2max (r = 0.580, p = 0.038, n =

13) and VO2max/kg (r = 0.705, p = 0.007, n = 13). For the Females, there were no significant

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Figure 5. Relation between maximal systolic blood pressure and maximal oxygen uptake, measured in 13 men and 9 females during a progressive, maximal CPET. Subjects lacking a SBP measurement during the last 2 minutes of exercise are not included. Correlations were analyzed with Pearson correlation analyses for each sex separately.

(a): Relation between SBPmax and VO2max/kg.

(b): Relation between SBPmax and VO2max.

Scatterplots showing the relation between variables of the systolic blood pressure response to exercise and age are presented in figure 6.

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Figure 6. Relation between blood pressure response to exercise and age, and between maximal oxygen uptake and age measured in 19 men and 10 females during a progressive, maximal CPET. (a): Relation between the SBP/VO2-slope and age. The SBP/VO2-slope was calculated as the ratio of

the difference in SBP from the first to the last SBP measurement during exercise over the difference in VO2 between these two measures.

(b): Relation between the SBP/Watt-slope and age. The SBP/Watt-slope was calculated as the ratio of the difference in SBP from the first to the last SBP measurement during exercise over the difference in Watts between these two measures.

(c): Relation between SBPmax and age.

(d): Relation between VO2max/kg and age.

Comparison between athletes and their predicted values

Paired samples T-tests showed that the athletes’ SBP/Watt-slope was lower than their predicted values (mean difference 0.11 mmHg/Watt (= 28 %), SD = 0.09, 95% confidence interval: 0.07-0.15). In contrast, the SBPmax was higher than the values predicted by the

reference equations (mean difference 13.2 mmHg (= 7 %), SD = 18.8, 95% confidence interval: 3.5-22.8).

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Retrospective power analysis revealed a power of 80 % to detect a mean difference of 0.06 mmHg/Watt in the SBP/Watt-slope between observed and predicted values (alfa = 0.05, SD = 0.09, sample size n = 24). For SBPmax the power was 80 % to detect a mean difference of 14.5

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Discussion

This study is, to the best of our knowledge, the first to investigate the SBP/VO2-slope in

healthy subjects and endurance athletes. The main finding is that in our sample the mean SBP/VO2-slope was ~31 mmHg/l/min and contrary to what we hypothesized, we found no

correlation between maximal oxygen uptake and the SBP/VO2-slope, the SBP/Watt-slope,

SBP at 50 W or at 200 W. Additionally, in our sample the endurance athletes had less steep SBP/Watt-slopes and higher SBPmax than predicted by newly published reference equations

accounting for maximum workload (10).

The SBP/VO2-slope provides a novel, precise way of indexing the SBP response to workload

and could provide a valuable tool in further studies investigating the SBP response to exercise. Ultimately, it could guide physiologists in distinguishing a pathological blood pressure response, possibly implying an increased risk of hypertension (6), from a

physiologically high exercise SBP. This could be particularly relevant in an athlete population as athletes often reach high SBP values during exercise, owing to a high maximal workload and high fitness. Further, our findings suggest that different reference equations than in the general population might be needed when evaluating the SBP response in well-trained endurance athletes.

There are few studies investigating the workload-indexed blood pressure response in athletes, and no studies measuring the SBP/VO2-slope. The use of different exercise test protocols,

some with stepwise load increments and some with continuous increments, limits comparison across studies. Our test protocol included a rapid increase from the warmup at 50 W to either 100 W or 150 W just before starting the continuous workload increment for most participants. This may have influenced the measurements for some subjects, especially those with a

relatively low maximal work output. Further, cycling ergometry has been shown to elicit higher SBP recordings compared to treadmill testing (22), which limits comparisons across studies employing different testing modalities. However, a few meaningful comparisons can be made.

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Bauer et al. have studied the SBP/Watt-slope in athletes in two recent studies. In one of them, a sample of 95 professional male German handball players and 30 healthy age-matched controls were studied (23). The handball players are in some ways comparable to our sample reaching similar maximal work outputs, (339 vs. 344 W) maximal heart rates (179 vs. 174 bpm) and ratings of perceived exertion at peak workload (18.5 vs. 19 Borg RPE) as the male endurance athletes included in our study. However, the handball players studied by Bauer et al. were younger (26 vs. 45 years old) and heavier (92 vs. 74 kgs) than the male endurance athletes in our sample. The mean SBP/Watt-slope for the handball players was 0.35

mmHg/Watt and the mean SBPmax was 200 mmHg, compared to 0.28 mmHg/Watt and 224

mmHg for the male athletes in our sample. The lower SBP/Watt-slope found in our sample was rather unexpected whereas the higher SBPmax among our endurance athletes was more

anticipated, considering the findings by Hedman et al. suggesting that both the SBP/Watt-slope and the SBPmax increases with increasing age in the general population (10).

Of note, in the same study Bauer et al. registered the SBP at 200 W for the participants, which was also done in our study. The handball players’ mean SBP200W was markedly lower than

that of the male endurance athletes included in our study (169 vs. 191 mmHg).

The higher SBP200W and lower SBP/Watt-slope in our male endurance athletes may partly be

explained by higher pre-exercise SBP (130 vs. 123 mmHg), which is consistent with the dominant view that resting SBP increases with increasing age. However, it is probable that also other factors influence the different SBP/Watt-slopes. One possibility is that the different exercise protocols used may have influenced the results. Bauer et al. employed stepwise workload increments of 50 W every second minute, whereas our protocol used a continuous increment with an increment rate of 20 W/minute. Another possibility is that the different training methods used in more pronounced endurance sports compared to handball may affect the blood pressure response to exercise significantly. Future studies may reveal if and how the workload-indexed SBP response to exercise differ between different sports disciplines.

In the other study, Bauer et al. (2021) found no significant difference in the SBP/MET-slope between professional male handball players and professional female football players (5.7 mmHg/MET vs. 5.1 mmHg/MET, p = 0.158) (16). Due to the small sample size in our study, we chose not to analyze differences between the male and female endurance athletes

statistically. However, our findings of numerically similar values for the SBP/VO2-slope in male and female athletes can still be considered consistent with those of Bauer et al.

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Concerning the SBP/Watt-slope however, our results are different from those of Bauer et al., which indicated a major difference between men and women (16). In our sample the mean SBP/Watt-slope was numerically very similar in male and female endurance athletes (0.28 vs. 0.28 mmHg/Watt), whereas Bauer et al. found a large difference between the male handball players and the female football players (0.34 vs. 0.53 mmHg/Watt). On a population level, the data presented by Hedman et al. suggests that the SBP/Watt-slope is indeed steeper in women than in in men (10), why our findings of similar values in males and females were rather surprising. Although not tested statistically, the suspected difference in age and in % of

predicted VO2max between the male and female endurance athletes included in our study limits

the interpretation of the results. However, it is possible that the comparison of athletes from different sporting discipline might have exaggerated the difference between the sexes found by Bauer et al. (16).

In this study, we found no significant correlations between VO2max and the SBP/VO2-slope.

Neither did we find any significant correlations between VO2max and the SBP/Watt-slope.

This was in contrast to our hypothesis and is inconsistent with previous findings in

professional male handball and ice-hockey players (15). One possible reason might be that we only studied relatively fit subjects, since all except one of the subjects in our sample had a VO2max exceeding 120% of their predicted values. It is possible that with a greater span of

fitness level, correlations may be detected. However, similar findings were presented by Bauer et al. who studied only elite athletes, which imply other underlying mechanisms.

In studies investigating the general population, age has been found to be a major determinant of both workload-indexed blood pressure response to exercise and maximal oxygen uptake, with older subjects typically presenting with a higher SBP/Watt-slope, a higher SBPmax and a

lower VO2max (10, 24). When examining the data obtained from our sample, no such

relationship could be observed.

There are many possible reasons for this. Firstly, the absence of an influence of age on the above-mentioned variables could be due to the small sample size and the relatively small variation of age of the sample. Only 29 subjects were included, and all subjects were between 23 and 58 years old, why possible underlying trends might not be obvious in our sample. Secondly, the absence of an influence of age in our sample could be due to selection bias among the more elderly athletes. Possibly, endurance athletes who had more success in their younger years, implying a higher VO2max at that time, continue training intensively up into

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their fifties. In this case, a decline in maximal oxygen uptake with age might be true also in our sample, although hidden by the supposed previously higher VO2max in the older athletes

earlier in their careers. Our inclusion criteria demanding a left-ventricular end-diastolic diameter above the upper limit of normal also may have caused selection among the older athletes, with athletes experiencing a decline in VO2max also experiencing a decreasing

left-ventricular diameter. A third possibility might be that endurance training slows the age-related decline in VO2max significantly. Even though athletes on a group level experience declines in

VO2max at the same or higher rates than sedentary individuals (25, 26), selection may have

caused only individuals who through extensive exercise regimes manage to maintain their high VO2max through aging to be included in this study.

One female athlete was an outlier in regards of the SBP/VO2-slope and the SBP/Watt-slope.

Whereas all other subjects displayed slopes below 40 mmHg/l/min and 0.4 mmHg/Watt, the corresponding values for the outlier were 68 mmHg/l/min and 0.53 mmHg/Watt, respectively. The same female athlete also displayed a relatively low VO2max, despite being one of the

participants reporting the highest amounts of physical activity per week. After re-examining her echocardiography recording, no abnormality was found. Thus, the outlier subject was included in all analyses, and had an impact on the group mean values.

We found a significant correlation between VO2max and SBPmax, which support that a high

SBPmax during exercise in athletes can be seen as a sign of high fitness (12). However, high

SBPmax has been associated with increased risk of developing hypertension in young athletes

(27). It is plausible that the blood pressure-slope values, taking into account workload and fitness, may be a better predictor of future risk of hypertension in this group, although this remains to be evaluated.

Limitations and strengths

First, our study sample was relatively small and only one non-athletic subject had a VO2max <

115 % of their predicted value. This precludes interpolation of our results to subjects with lower fitness. Also, all athletes included were endurance athletes, which precludes

interpolation of the results to different sports disciplines. Second, due to the small sample size, possible differences between the male and female endurance athletes were not analyzed statistically. This limits the value of comparisons between the sexes. Last, our CPET protocol included an instant workload increase at the start of the ramp protocol aimed to reduce the total work time for athletes with a high exercise capacity. This rapid increase in workload

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might have influenced the results for some of the participants, especially for those reaching a relatively low maximal workload.

A strength of this study is that we used actual VO2 measurements to index the blood pressure

response. This is a more precise way of measuring work performed than estimating the oxygen consumption through equations, as have been done in previous studies. Further, all CPETs were supervised by only a small number of physicians and all measurements were made by a small number of experienced biomedical scientists. Through this, good consistency through all CPETs was upheld.

Ethical considerations

CPET is used regularly in clinical practice and is considered a very safe examination method, and even more so in a young, apparently healthy study population. Exercising to maximal exertion may be considered unpleasant by some. However, it is something that the endurance athletes included in the study voluntarily expose themselves to regularly. When weighed against the benefits of this study, including an increased understanding of human physiology and a method which in the future possibly may allow identification of more individuals at risk, the exposure of untrained individuals to something possibly unpleasant can be considered a very minor harm.

Conclusion

This study is the first to investigate the workload-indexed blood pressure response to exercise by using VO2-measurments, the most precise way of measuring aerobic work performed. In

our cohort the mean SBP/VO2-slope was ~31 mmHg/l/min and we found no correlation

between VO2max and measurements of the workload-indexed blood pressure response to

exercise. This indicates the metric’s usefulness as a measure independent of fitness that could be of value in future studies in this group. Our results indicate that different reference

equations than in the general population might be needed for the SBP response in athletes.

Acknowledgements

First, I would like to thank my supervisors Kristofer Hedman, Anna Carlén and Magnus Ekström for their support and feed-back throughout the whole of this process. Second, I wish to thank all volunteers for participating in the study.

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Appendix

Appendix 1

Text post used in recruitment of endurance athletes, in Swedish.

Försökspersoner sökes! Vi söker nu fler deltagare till den hälsovetenskapliga studien Hjärtfunktion och fysisk aktivitet som handlar om hjärtats anpassning till träning. Studien består av tre delar: • cykelarbetsprov med mätning av maximal syreupptagningsförmåga • ultraljudsundersökning av hjärtat i vila och under cykelarbete • magnetkameraundersökning av hjärtat. Vi söker dig som konditionstränar minst 5–6 timmar per vecka. Alla

intresseanmälningar är välkomna, och konditionsidrottande kvinnor är av extra intresse denna gång. För att se om du är lämplig för att vara med i studien gör vi först en kort

ultraljudsundersökning av ditt hjärta. Om måtten på hjärtat passar studiens kriterier får du därefter mer information för att ta ställning till om du vill vara med. Anmäl ditt intresse till denna mailadress, och ange ungefärlig träningsmängd. PS. Vi söker även personer med begränsad konditionsträning (max ca 1-2 h/vecka) till en jämförande grupp. Kanske har du en vän/anhörig som du tror skulle vara intresserad? Tipsa gärna!

Appendix 2

Text post used in recruitment of endurance athletes, translated into English.

Test subjects wanted! We are in search of more participants to a study in the field of health science called “Heart function and physical activity” concerning the heart’s adaptation to exercise. The study consists of three parts. • Exercise testing on bicycle with measurement of maximal oxygen uptake • Ultrasound examination of the heart, at rest and during exercise • Magnetic resonance imaging (MRI) of the heart We search for individuals who partake in endurance exercise at least 5-6 hours per week. Every notice of interest is welcome, and endurance trained women are of extra interest this time. To see if you are eligible for

participation, we will conduct an ultrasound examination of your heart. If the measurements are in line with the study criteria you will get more information about the study to determine if you want to partake. Send your notice of interest and an estimation of how much you exercise to this e-mail address. P.S. We are also searching for individuals with limited amounts of endurance exercise per week (maximum 1-2 hour per week) for a comparing group in the study. Maybe you have a friend or relative who might be interested? Feel free to tell them about the study!

Appendix 3

Details on missing data.

Other than the missing data for SBPmax described under “results”, these data were missing

from the data set.

Four endurance athletes (3 males, 1 female) were missing data on the amount of physical activity per week.

One female endurance athlete was missing data on blood pressure measured in the supine position before exercise (SBPlying and DBPlying).

Systolic Blood Pressure Response to Exercise in Relation to Oxygen Uptake in Endurance Athletes