Peak oxygen pulse responses during maximal cardiopulmonary exercise testing: Reference standards from FRIEND (Fitness Registry and the Importance of Exercise: an International Database)

Journal Pre-proof Peak oxygen pulse responses during maximal cardiopulmonary exercise testing: Reference standards from FRIEND (Fitness Registry and the Importance of Exercise: an International Database)

Ross Arena, Jonathan Myers, Mathew Harber, Ulrik Wisloff, Dorthe Stensvold, Leonard A. Kaminsky PII:

S0167-5273(19)31338-5

DOI:

https://doi.org/10.1016/j.ijcard.2019.11.106

Reference:

IJCA 28139

To appear in:

International Journal of Cardiology

Received date:

11 March 2019

Revised date:

19 September 2019

Accepted date:

13 November 2019

Please cite this article as: R. Arena, J. Myers, M. Harber, et al., Peak oxygen pulse responses during maximal cardiopulmonary exercise testing: Reference standards from FRIEND (Fitness Registry and the Importance of Exercise: an International Database), International Journal of Cardiology(2019), https://doi.org/10.1016/j.ijcard.2019.11.106

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© 2019 Published by Elsevier.

Journal Pre-proof Peak Oxygen Pulse Responses During Maximal Cardiopulmonary Exercise Testing: Reference Standards from FRIEND (Fitness Registry and the Importance of Exercise: An International Database). Ross Arena, PhD, PT1 Jonathan Myers, PhD2 Mathew Harber, PhD3

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Ulrik Wisloff, PhD4

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Dorthe Stensvold, PhD4

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Leonard A. Kaminsky, PhD5 1

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Department of Physical Therapy, College of Applied Science, University of Illinois, Chicago, IL VA Palo Alto Health Care System and Stanford University

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Clinical Exercise Physiology Laboratory, Ball State University, Muncie, IN

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Fisher Institute of Health and Well-Being, Ball State University, Muncie, IN

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The Cardiac Exercise Research Group, Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway

Address for correspondence:

Ross Arena, PhD, PT, FAHA Professor Department of Physical Therapy College of Applied Health Sciences University of Illinois Chicago 1919 W. Taylor Street (MC 898) Chicago, IL 60612 Office: (312) 355-3338 [email protected] Word Count: Abstract: 200, Text: 1,500 1

Journal Pre-proof Abstract Introduction: Cardiopulmonary exercise testing (CPX) is the gold-standard approach to assessing cardiorespiratory fitness (CRF). The current study puts forth reference standards for peak oxygen (O2) pulse from the “Fitness Registry and the Importance of Exercise: A National Data Base” (FRIEND) Registry. Methods: The current analysis included 13,318 tests from CPX laboratories in the United States, Canada and Europe. Inclusion criteria included CPX data on

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apparently healthy men and women: 1) aged > 20 years; 2) with exercise tests performed on a

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treadmill; and 3) achieving a peak respiratory exchange ratio ≥1.00. Results: Peak O2 pulse 50th

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percentile values decreased from 20.8 ml/beat in the 2nd decade to 11.2 ml/beat in the 8th decade

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in men and from 13.6 ml/beat in the 2nd decade to 7.9 ml/beat in the 8th decade in women. Linear regression analysis results produced the following statistically significant (p<0.001) equation:

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peak O2 pulse (ml/beat) = 23.2 - 0.09(age) - 6.6(sex); female = 1 and male = 0. Discussion: The

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assessment of CRF through CPX is an important health metric. Reference standards, such as those put forth in the current study, allow for the comparison of key measures of CRF to

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expected normal responses across the adult lifespan.

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Key words: Exercise testing; Cardiorespiratory fitness; Stroke volume; Percent-predicted

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Journal Pre-proof Introduction Cardiopulmonary exercise testing (CPX) is the gold-standard approach to assess the cardiorespiratory fitness (CRF) vital sign. 1 While peak oxygen consumption (VO2) is a primary CPX measure, a number of other measures provide clinically valuable information and, as such, collective assessment of a panel of core CPX measures allows for a more comprehensive CRF evaluation.2, 3 Oxygen (O2) pulse is determined by dividing VO2 (ml/min) by heart rate

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(beats/min). The peak O2 pulse reflects left ventricular stroke volume2, 4, disease severity in

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patient populations5, and significantly predicts adverse event risk2, 5-7. The American Heart

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Association Scientifice Statement on the Clinician’s Guide to Cardiopulmonary Exercise Testing

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in Adults includes peak O2 pulse as an important measure obrained from CPX. 2 In addition to assessing actual CPX measures, there is additional importance to simultaneously compare

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measured values to normative responses derived from apparently healthy cohorts. Such

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normative values are readily available for peak VO28 as well as other CPX measures9, 10. However, few data are available regarding normal standards for peak O 2 pulse. The primary aim

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of the current study is to determine reference standards for peak O2 pulse in a large international

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cohort from the “Fitness Registry and the Importance of Exercise: A National Data Base” (FRIEND) Registry. Methods The FRIEND Registry The FRIEND Registry was established with the primary charge of establishing normative CRF values across the adult lifespan.8, 11 The CPX laboratories currently contributing data to the FRIEND Registry function consistent with recommendations provided in recently published guidelines including the use of valid and reliable calibration and testing procedures as well as

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Journal Pre-proof employing experienced personnel qualified to conduct exercise tests.12, 13 Institutional review board approval for participating CPX laboratories and the core CPX laboratory were obtained. Cohort Characteristics, Inclusion/Exclusion Criteria and Study Data Points The current analysis included 13,318 tests from the following participating CPX laboratories: 1) Ball State University; 2) John Hopkins University; 3) Southern Connecticut State University; 4) Brigham and Women’s Hospital; 5) Brooke Army Medical Center; 6) Johns

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Hopkins University; 7) Kansas University Medical Center; 8) Norwegian University of Science

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and Technology; 9) Norwegian University of Science and Technology – HUNT Research

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Center; 10) Queens University; 11) Taylor University; 12) Toronto Rehab/University Health

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Network; 13) University of Tennessee, Knoxville. Inclusion criteria for the current analysis included CPX data on men and women: 1) aged > 20 years; 2) with maximal exercise tests

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performed on a treadmill; and 3) achieving a peak respiratory exchange ratio (RER) value ≥1.00,

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which is an accepted threshold for sufficient exercise effort2, 3. Any subject identified as having a pre-existing medical condition was excluded. Thus, the cohort included apparently healthy

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subjects (i.e., subjects without a pre-existing medical condition) who achieved maximal exertion

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by established peak RER criteria.2 Peak oxygen consumption (VO2), peak RER, and maximal HR were the CPX variables reported in the current study. Peak VO2, peak RER, and maximal HR, were the CPX variables reported in the current study. Peak O2 pulse was calculated as dividing peak VO2 (ml/min) by maximal HR (beats/min). Statistical Analysis Continuous data are reported as mean and standard deviation while categorical data are reported as percentages. Tenth to 90th percentiles for peak O2 pulse from the 2nd to 8th decade of life was determined in both men and women. A linear regression equation was initially used to

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Journal Pre-proof derive a peak O2 pulse prediction equation in the entire cohort. Using all 13,318 subjects, bootstrapping was used for validation, with 1000 bootstrap samples drawn. Next, random sampling was used to create a validation (70% of the cohort, n= 9,364) or cross-validation (30% of the cohort, n=3954) cohort. The independent sample t-test and chi-square tests were used to compare differences in key continuous and categorical variables, respectively, in the validation and cross-validation cohorts. Stepwise linear regression analysis (entry and removal stepping

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method criteria 0.05 and 0.10, respectively) was used to derive a peak O2 pulse prediction

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equation using age and sex in the validation cohort. The same stepwise linear regression analysis

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approach was then run in the cross-validation cohort. The SPSS 24.0 (IBM, Armonk, New

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York) statistical software package was used for all analyses. All tests with a p-value <0.05 were considered statistically significant.

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Results

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Peak O2 pulse percentile tables are presented in Tables 1a (men) and 1b (women). Values were higher in men compared to women in each decade. Fiftieth percentile values

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decreased from 20.8 ml/beat in the 2nd decade to 11.2 ml/beat in the 8th decade in men and from

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13.6 ml/beat in the 2nd decade to 7.9 ml/beat in the 8th decade in women. Linear regression analysis results using the entire cohort produced the following statistically significant (p<0.001) equation: peak O2 pulse (ml/beat) = 23.2 - 0.09(age) - 6.6(sex); female = 1 and male = 0. The bootstrap analysis for this regression produced a small standard error (SE) and narrow 95% confidence intervals (CI) for all coefficients; 1) Constant: SE = 0.11 and 95% CI =22.9 to 23.4; 2) Age: SE = 0.002 and 95% CI =-0.089 to -0.081; 3) Sex: SE = 0.06 and 95% CI =-6.72 to 6.50.

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Journal Pre-proof Key comparisons between the validation and cross-validation cohorts are listed in Table 2 withno significant differences. Mean peak VO2 values indicate a well-preserved aerobic capacity in the 40th decade of life. The mean maximal heart rate response was what may be expected in the 40th decade of life using available prediction equations.14 Lastly, effort was excellent as indicated by a mean peak RER >1.10 in both groups. Stepwise linear regression analysis for the validation and cross validation cohorts

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produced the following equations: 1) Validation cohort – Peak O2 pulse (ml/beat) = 23.1 -

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6.6(sex) - 0.09(age); female = 1 and male = 0, r-value =0.71, standard error of estimate = 3.5

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ml/beat, 95% CI = Constant: 22.9 to 23.4, Sex: -6.8 to -6.5, Age: -0.09 to -0.08, p-value <0.001

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for constant and both predictor variables; and 2) Cross validation cohort – Peak O2 pulse (ml/beat) = 23.2 - 6.6(sex) -0.09(age); female = 1 and male = 0, r-value =0.70, standard error of

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estimate = 3.7 ml/beat, 95% CI = Constant: 22.8 to 23.6, Sex: -6.8 to -6.4, Age: -0.09 to -0.08, p-

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value <0.001 for constant and both predictor variables. Moreover, the r-values, standard errors

identical.

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Discussion

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of the estimate and the beta-coefficients between the two regression equations were nearly

The current analysis puts forth reference standards for peak O 2 pulse derived from maximal treadmill CPX in a large cohort of apparently healthy (i.e., subjects without a preexisting medical condition) males and females. Few studies have attempted to propose normative peak O2 pulse exercise responses.15-17 The analysis by Hansen et al.15 was a United States-based study that included <100 male subjects tested on a cycle ergometer. Herdy et al. 16 included 3,992 apparently healthy men and women from Brazil tested on a treadmill, reporting mean peak O2 pulse responses across 6 age subgroups; 15-24, 25-34, 35-44, 45-54, 55-64, and

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Journal Pre-proof 65-74 years old. This study reported mean peak O2 pulse values as opposed to percentiles reported in the current study. Moreover, the age groups in the study by Herdy et al. 16 differed from the current study. Loe et al.17 reported peak O2 pulse from treadmill CPX in 3,816 apparently healthy men and women between 20 and 90 years of age. Mean peak O2 pulse was reported for each decade (i.e., 2nd to the ≥7th decade) that, when compared to the 50th percentile peak O2 pulse in the current study, was comparable. The current study builds upon previous

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work in several ways: 1) The current cohort, to our knowledge, is the largest dataset used to

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develop peak O2 pulse reference standards, allowing for substantial samples in the majority of

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decade subgroups used to derive 10th to 90th percentile values; 2) The cohort was derived from an international sample, including established CPX laboratories from the United States, Canada and

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Europe; 3) Reference standards are reported from 10th to 90th percentiles across adulthood in

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both men and women; and 4) A prediction equation is proposed and validated using a validation

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and cross-validation cohort, both with large samples. Collectively, the aforementioned strengths of the current study speak to the ability of the reference standards proposed herein to accurately

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reflect normative responses in apparently healthy men and women.

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A limitation of the current analysis is the relatively small subgroups in the 8 th decade for both men and women. In addition, all tests were conducted on a treadmill, not allowing for application of our findings to exercise tests conducted on a lower extremity ergometer. As mentioned previously, peak O2 pulse provides insight into left ventricular function4 and prognosis.6, 7 Future research is needed to determine if the reference standards proposed in the current study, allowing for peak O2 pulse to be expressed as a percent-predicted or percentile value, further refines it’s diagnostic and prognostic significance.

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Journal Pre-proof In conclusion, the assessment of CRF through CPX is recognized as an important health metric. Reference standards allow for the comparison of key measures of CRF to expected normative responses across the lifespan.

Acknowledgments FRIEND Consortium Contributors are as follows: Ball State University (Leonard Kaminsky),

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Brigham and Women’s Hospital (Amil Shah), Brooke Army Medical Center (Kenneth Leclerc),

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Johns Hopkins University (Kerry Stewart), Kansas University Medical Center (Sandra Bullock),

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The Nord-Trøndelag Health Study (HUNT) which is a collaboration between the HUNT

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Research Centre (Faculty of Medicine and Health Sciences at the Norwegian University of Science and Technology), the Nord-Trøndelag County Council, Central Norway Health

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Authority and the Norwegian Institute of Public Health (Ulrik Wisløff), Norwegian University of

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Science and Technology (Dorthe Stensvold, Ulrik Wisløff), Queens University (Robert Ross), Southern Connecticut State University (Robert Axtell), Taylor University (Erik Hayes), Toronto

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Bassett)

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Rehab/University Health Network (Susan Marzolini), University of Tennessee, Knoxville (David

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Reference List

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1. Ross R, Blair SN, Arena R, Church TS, Despres JP, Franklin BA, Haskell WL, Kaminsky LA, Levine BD, Lavie CJ, Myers J, Niebauer J, Sallis R, Sawada SS, Sui X and Wisloff U. Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign: A Scientific Statement From the American Heart Association. Circulation. 2016;134:e653-e699.

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2. Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV, Cardiac AHAE, Prevention CE, Dis CPV and Quality IC. Clinician's Guide to Cardiopulmonary Exercise Testing in Adults A Scientific Statement From the American Heart Association. Circulation. 2010;122:191-225. 3. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, Arena R, Fletcher GF, Forman DE, Kitzman DW, Lavie CJ, Myers J, European Association for Cardiovascular P, Rehabilitation and American Heart A. EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation. 2012;126:2261-74. 4. Bhambhani Y, Norris S and Bell G. Prediction of stroke volume from oxygen pulse measurements in untrained and trained men. Canadian journal of applied physiology = Revue canadienne de physiologie appliquee. 1994;19:49-59. 9

Journal Pre-proof 5. Yuan P, Ni HJ, Chen TX, Pudasaini B, Jiang R, Liu H, Zhao QH, Wang L, Gong SG and Liu JM. Sex-specific cardiopulmonary exercise testing parameters as predictors in patients with idiopathic pulmonary arterial hypertension. Hypertens Res. 2017;40:868-875. 6. Lavie CJ, Milani RV and Mehra MR. Peak exercise oxygen pulse and prognosis in chronic heart failure. Am J Cardiol. 2004;93:588-93.

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7. Oliveira RB, Myers J, Araujo CG, Arena R, Mandic S, Bensimhon D, Abella J, Chase P, Guazzi M, Brubaker P, Moore B, Kitzman D and Peberdy MA. Does peak oxygen pulse complement peak oxygen uptake in risk stratifying patients with heart failure? Am J Cardiol. 2009;104:554-8.

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8. Kaminsky LA, Arena R and Myers J. Reference Standards for Cardiorespiratory Fitness Measured With Cardiopulmonary Exercise Testing: Data From the Fitness Registry and the Importance of Exercise National Database. Mayo Clin Proc. 2015;90:1515-23.

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9. Sabbahi A, Arena R, Kaminsky LA, Myers J and Phillips SA. Peak Blood Pressure Responses During Maximum Cardiopulmonary Exercise Testing: Reference Standards From FRIEND (Fitness Registry and the Importance of Exercise: A National Database). Hypertension (Dallas, Tex : 1979). 2018;71:229-236.

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10. Kaminsky LA, Harber MP, Imboden MT, Arena R and Myers J. Peak Ventilation Reference Standards from Exercise Testing: From the FRIEND Registry. Med Sci Sports Exerc. 2018;50:2603-2608.

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11. Kaminsky LA, Arena R, Beckie TM, Brubaker PH, Church TS, Forman DE, Franklin BA, Gulati M, Lavie CJ, Myers J, Patel MJ, Pina IL, Weintraub WS, Williams MA, American Heart Association Advocacy Coordinating Committee CoCC, Council on Nutrition PA and Metabolism. The importance of cardiorespiratory fitness in the United States: the need for a national registry: a policy statement from the American Heart Association. Circulation. 2013;127:652-62. 12. Myers J, Arena R, Franklin B, Pina I, Kraus WE, McInnis K, Balady GJ, Cardiology CC and Nursing CC. Recommendations for Clinical Exercise Laboratories A Scientific Statement From the American Heart Association. Circulation. 2009;119:3144-3161. 13. Myers J, Forman DE, Balady GJ, Franklin BA, Nelson-Worel J, Martin BJ, Herbert WG, Guazzi M, Arena R, Cardiology CC, Hlth CLC, Prevention CE and Nursing CCS. Supervision of Exercise Testing by Nonphysicians A Scientific Statement From the American Heart Association. Circulation. 2014;130:1014-1027. 10

Journal Pre-proof 14. Arena R, Myers J and Kaminsky LA. Revisiting age-predicted maximal heart rate: Can it be used as a valid measure of effort? Am Heart J. 2016;173:49-56. 15. Hansen JE, Sue DY and Wasserman K. Predicted values for clinical exercise testing. Am Rev Respir Dis. 1984;129:S49-55. 16. Herdy AH and Uhlendorf D. Reference values for cardiopulmonary exercise testing for sedentary and active men and women. Arq Bras Cardiol. 2011;96:54-9.

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17. Loe H, Rognmo O, Saltin B and Wisloff U. Aerobic capacity reference data in 3816 healthy men and women 20-90 years. Plos One. 2013;8:e64319.

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Table 1a: Maximal Oxygen Pulse According to Percentiles and Decade in Males Percentiles 20-29 30-39 40-49 50-59 60-69 70-79 80-89 years years years years years years years (n=744) (n=1386) (n=1914) (n=1550) (n=962) (n=790) (n=67) 10th 15.8 15.2 14.6 13.8 12.9 12.4 8.4 th 20 17.4 16.7 16.2 15.4 14.5 13.4 9.1 30th 18.7 18.2 17.4 16.5 15.6 14.4 9.8 th 40 19.7 19.2 18.5 17.5 16.5 15.2 10.3 th 50 20.8 20.3 19.6 18.6 17.4 15.9 11.2 60th 21.9 21.2 20.7 19.6 18.4 16.7 11.9 th 70 23.0 22.5 21.9 20.7 19.3 17.7 14.0 80th 24.3 23.6 23.3 21.9 20.4 18.7 16.3 th 90 26.4 25.6 25.3 23.8 22.3 20.2 17.6

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Table 1b: Maximal Oxygen Pulse According to Percentiles and Decade in Females Percentiles 20-29 30-39 40-49 50-59 60-69 70-79 80-89 years years years years years years years (n=663) (n=1016) (n=1353) (n=1221) (n=762) (n=840) (n=50) 10th 10.3 9.4 9.3 9.0 8.4 8.2 5.6 th 20 11.2 10.4 10.3 10.0 9.4 8.9 6.5 30th 12.1 11.2 11.1 10.8 10.1 9.6 6.9 th 40 12.8 11.9 11.8 11.4 10.8 10.2 7.6 50th 13.6 12.8 12.6 12.1 11.4 10.8 7.9 th 60 14.4 13.5 13.4 12.8 12.2 11.3 8.1 70th 15.1 14.4 14.3 13.5 12.8 11.8 8.9 th 80 16.0 15.4 15.3 14.4 13.7 12.7 9.9 th 90 17.6 16.9 16.6 15.7 14.9 13.8 10.4 Legend: Values in ml/beat

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Table 2: Comparison of the Validation and Cross Validation Group Validation Cohort Cross-Validation Cohort (n=9,364) (3,954) 48 ±15 49 ±15 Age (years) 56/44 55/45 Sex (percent male/female) 2 26.5 ±5.0 26.4 ±5.0 BMI (kg/m ) 173 ±18.0 173 ±18.0 Peak HR (beats/minute) 16.1 ±5.0 16.0 ±5.1 Peak O2 pulse (ml/beat) -1 -1 35.9 ±11.0 35.6 ±10.7 Peak VO2 (mlkg min ) 1.15 ±0.09 1.15 ±0.09 Peak RER Legend: BMI, body mass index; HR, heart rate; O2, oxygen; VO2, oxygen consumption; RER, respiratory exchange ratio

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Journal Pre-proof Highlights 

Cardiorespiratory fitness, determined by exercise testing, is considered a vital sign

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Comparing actual exercise testing responses to reference standards for key measures is needed for a comprehensive assessment

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The peak oxygen pulse is determined by dividing peak oxygen consumption by peak heart rate Peak oxygen pulse provides insight into cardiac function during exercise

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The current analysis provides reference standards for peak oxygen pulse across the adult

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lifespan in men and women

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