Exercise cardiac power and the risk of heart failure in men : A population-based follow-up study

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY-NC-ND 4.0 https://creativecommons.org/licenses/by-nc-nd/4.0/ Exercise cardiac power and the risk of heart failure in men : A population-based followup study © 2020 Published by Elsevier B.V. on behalf of Shanghai University of Sport Accepted version (Final draft) Kurl, Sudhir; Jae, Sae Young; Mäkikallio, Timo H.; Voutilainen, Ari; Hagnäs, Magnus J.; Kauhanen, Jussi; Laukkanen, Jari A. Kurl, S., Jae, S. Y., Mäkikallio, T. H., Voutilainen, A., Hagnäs, M. J., Kauhanen, J., & Laukkanen, J. A. (2022). Exercise cardiac power and the risk of heart failure in men : A population-based follow-up study. Journal of Sport and Health Science, 11(2), 266-271. https://doi.org/10.1016/j.jshs.2020.02.008 2022 Journal Pre-proof Exercise cardiac power and the risk of heart failure in men: A population-based follow-up study Sudhir Kurl , Sae Young Jae , Timo H. M¨ akikallio , Ari Voutilainen , Magnus J. Hagn¨ as , Jussi Kauhanen , Jari A Laukkanen PII: S2095-2546(20)30021-1 DOI: https://doi.org/10.1016/j.jshs.2020.02.008 Reference: JSHS 595 To appear in: Journal of Sport and Health Science Received date: 6 April 2019 Revised date: 29 June 2019 Accepted date: 21 November 2019 Please cite this article as: Sudhir Kurl , Sae Young Jae , Timo H. M¨ akikallio , Ari Voutilainen , Magnus J. Hagn¨ as , Jussi Kauhanen , Jari A Laukkanen , Exercise cardiac power and the risk of heart failure in men: A population-based follow-up study, Journal of Sport and Health Science (2020), doi: https://doi.org/10.1016/j.jshs.2020.02.008 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ©2020 Published by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Highlights • Our study shows that ECP may provide prognostic information on heart failure risk prediction despite taking into account established risk factors such as smoking, lipids, hypertension, left ventricular hypertrophy, COPD, and diabetes. • This study shows that significant risk of HF was observed among men with the lowest level of ECP. A continuous increase in ECP (3.16 mL/mmHg) corresponds to 28% decrease in the risk for HF among these men. • Our study indicates that ECP may provide a valuable tool for the risk prediction for HF in the general population, although further studies are needed. Original article Exercise cardiac power and the risk of heart failure in men: A population-based follow-up study Sudhir Kurla,*, Sae Young Jaeb, Timo H. Mäkikallioc, Ari Voutilainena, Magnus J. Hagnäsd, Jussi Kauhanena, Jari A Laukkanena,e,f aInstitute of Public Health and Clinical Nutrition, Department of Medicine, University of Eastern Finland, Kuopio 70210, Finland bDepartment of Sports Informatics, College of Arts and Physical Education, University of Seoul, Seoul 130-743, Republic of Korea cDivision of Cardiology, Department of Internal Medicine, University Hospital of Oulu, Oulu 90220, Finland dDepartment of Internal Medicine, Lapland Central Hospital, Rovaniemi 96400, Finland eFaculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä 40014, Finland fCentral Finland Health Care District, Jyväskylä 40620, Finland *Correspondence author E-mail address: [email protected] (S. Kurl) Received 6 April 2019; revised 29 June 2019; accepted 21 November 2019 Running title: Exercise cardiac power and heart failure Abstract Background: Little is known about exercise cardiac power (ECP), defined as the ratio of directly measured maximal oxygen uptake with peak systolic blood pressure during exercise on heart failure (HF) risk. We examined the association of ECP and the risk of HF. Methods: This was a population-based cohort study of 2351 men from eastern Finland. The average time to follow-up was 25 years. Participants participated at baseline in an exercise stress test. A total of 313 cases of HF occurred. Results: Men with low ECP (<9.84 mL/mmHg, lowest quartile) had a 2.37-fold (95% confidence interval (CI): 1.68  3.35, p < 0.0001) hazards ratio of HF as compared with men with high ECP (>13.92 mL/mmHg, highest quartile), after adjusting for age. Low ECP was associated with a 1.96-fold risk (95%CI: 1.38  2.78, p < 0.001) of HF after additional adjustment for conventional risk factors. After further adjustment for left ventricular hypertrophy, the results hardly changed (hazards ratio = 1.87, 95%CI: 1.31  2.66, p < 0.001). One SD increase in ECP (3.16 mL/mmHg) was associated with a decreased risk of HF by 28% (95%CI: 17%  37%). Conclusion: ECP provides a non-invasive and easily available measure from cardiopulmonary exercise test in predicting HF. However, ECP did not provide additional value over maximal oxygen uptake. Keywords: Exercise cardiac power; Heart failure; Men 1. Introduction Aging of the population and decreased cardiac care are associated with an increasing incidence and prevalence of heart failure (HF). HF is associated with high morbidity and mortality and imposes a significant economic burden on health systems. It is therefore necessary to evaluate the putative risk factors that may have predictive or causal relevance to the risk for HF and, by evaluating them, help tailor preventive and therapeutic interventions. Cardiorespiratory fitness (CRF) is a relatively new measure of assessing cardiac and respiratory functioning. During recent years, the assessment of CRF has achieved significant clinical merit and is consid ered to be a vital part of patient risk assessment. Directly measured maximal oxygen uptake ( 2max), an objective and quantitative measure of CRF, is the gold standard for assessing the amount of oxygen consumption during exercise testing.1,2 In addition to systolic blood pressure (SBP) at rest, exercise-induced elevation of SBP has been found to be an independent predictor of hypertension,3,4 coronary heart disease,5-7 cardiovascular disease,8,9 and sudden cardiac death.10 Previous studies have shown that exercise cardiac power (ECP) predicts the risk of stroke, sudden cardiac death, and cardiovascular deaths.11-13 Although, CRF is a key marker of cardiovascular capacity, it does not take into account the detailed differences in cardiovascular resistance and cardiac afterload between the subjects, whereas ECP does take these factors into consideration. We therefore hypothesized that an index measure of ECP, defined as the ratio of directly measured 2max with peak SBP during exercise could give prognostic information on HF risk stratification. We investigated the association of ECP during exercise with the risk of HF in a population-based sample of men from eastern Finland. 2. Methods 2.1. Subjects Subjects were participants in the Kuopio Ischaemic Heart Disease Risk Factor Study, which was designed to investigate risk factors for cardiovascular diseases (CVD), carotid atherosclerosis, and related outcomes in a population-based, randomly selected sample of men from eastern Finland.12 Participants included 2682 men aged 42 years, 48 years, 54 years, or 60 years who resided in the city of Kuopio or its surrounding rural communities. Participants were examined at baseline between March 1984 and December 1989. A total of 198 participants were excluded because of death, serious disease, or migration away from the area. The Kuopio Ischaemic Heart Disease Risk Factor Study study was approved by the Research Ethics Committee of the University of Kuopio, and each participant gave written informed consent. Complete data on ECP was available on 2351 subjects with no history HF at baseline. 2.2. Assessment of ECP A maximal symptom-limited exercise tolerance test was performed between 8:00 a.m. and 10:00 a.m. using an electrically braked cycle ergometer.6 The standardized testing protocol involved an increase in workload of 20 W/min, with direct analyses of respiratory gases (Medical Graphics Corp., St. Paul, MN, USA O2max was defined as the highest value for, or the plateau of, oxygen uptake. Maximal exercise workload was defined as the highest workload achieved during the exercise test. Exercise workload was divided by body weight in kilograms. For safety reasons, all tests were supervised by an experienced physician with the assistance of an experienced nurse. An electrocardiogram, blood pressure, and heart rate were recorded during the exercise test.10,11 A week before the exercise test, between 8:00 a.m. and 10:00 a.m., the resting blood pressure of participants was measured after 5 min and 10 min of rest using a Hawksley random zero muddler sphygmomanometer ( Hawksley & Sons Ltd., Lancing, UK). An experienced nurse measured the blood pressure while participants were in a seated position in a quiet room. The mean value of the 2 blood pressure (after 5 min and 10 min of rest) was used as resting blood pressure. Resting hypertension was defined as hypertension confirmed by current use of antihypertensive medication and/or an SBP greater than 140mmHg and/or diastolic blood pressure (DBP) greater than 90mmHg. Immediately before the exercise phase (start), pre-exercise blood pressure was measured manually while the participant was sitting on the cycle ergometer (Tunturi EL 400; Tunturi New Fitness, Turku, Finland). Blood pressure was then measured every 2 min during and at 2 min after the exercise test. The maximal SBP was the highest value achieved during the test. ECP was defined as the ratio of directly measured 2max with peak SBP during exercise. The most common reasons for stopping the exercise test were leg fatigue (574), exhaustion (117), breathlessness (64), and pain in the leg muscles, joints, or back (56). The test was discontinued in 86 men because of cardiorespiratory symptoms or abnormalities such as dyspnea (48), chest pain (26), ischemic electrocardiographic change (4), arrhythmia (3), a marked change in SBP or DBP (2), and dizziness (3). 2.3. Assessment of other covariates Body mass index (BMI) was computed as the ratio of weight in kilograms to the square of height in meters. Information on use of medications and diagnosis of diseases was collected at the baseline examination by an internist.11 Alcohol consumption was assessed with the use of the Nordic Alcohol Consumption Inventory. Left ventricular hypertrophy (Sokolow-Lyon index) was recorded at rest. The collection of blood specimens and the measurement of serum lipids, serum lipoproteins, and insulin, as well as the definition of type 2 diabetes, have been described elsewhere.10,11 Serum C-reactive protein was measured with an immunometric assay (Immulite High Sensitivity C-reactive protein Assay; Diagnostic Products Corp., Los Angeles, CA, USA). 2.4. Ascertainment of incident HF events All incident HF cases that occurred from the time of study enrolment (from March 1984 to December 1989) through 2014 were included. There were no losses to follow-up.14,15 All study participants were under continuous surveillance for the development of new CVD events, including new incident HF cases. The sources of information on HF were based on hospital records and medico-legal reports. The diagnostic classification of HF cases was coded according to the International Classification of Disease, Tenth Revision (ICD-10), codes I00– I99, and I50.0–I50.9, I11.0, I42.0–I42.9. The diagnosis of HF was based on diagnostic guidelines of the European Society of Cardiology16 and included criteria such as symptoms, signs, and laboratory investigations including the determination of N-terminal pro-brain natriuretic peptide, chest radiography results, electrocardiographic findings, and echocardiography findings. The death certificates were assessed and classified by a team of independent experts. 2.5. Statistical analysis Descriptive data are presented as means and percentages. Risk factors for main outcomes were analyzed with a multivariate Cox model. ECP was entered into Cox proportional hazards models. Cox models were adjusted for age and other demographic and clinical factors previously reported to be predictive of HF by considering their clinical relevance. Hazards risks (HRs) with 95% confidence intervals (CIs), adjusted for clinical risk factors, were estimated as antilogarithms of the coefficients from multivariable models. The fit of the proportional hazards models was examined by plotting the hazard functions in different categories of risk factors over time. The proportional hazards assumption was verified for all variables by inspection of the plots of Schoenfeld residuals for covariates. The linearity assumption was satisfied for all continuous variables, and it was assessed with Martingale residuals for each continuous variable against survival time. p < 0.05 was considered statistically significant. This prospective population-based study provides the first evidence that ECP is associated with an increased risk of HF. Acknowledgments The authors would like to thank the staff of the Institute of Public Health and Clinical Nutrition at the University of Eastern Finland and the Kuopio Research Institute of Exercise Medicine for data collection. Authors’ contributions SK participated in the design of the study, data collection, analysis, and interpretation of results; SYJ, THM, and MJH participated in the design of the study; AV contributed to data analysis; JK participated in data collection; and JAL participated in data collection, study design, and interpretation of results. All authors contributed to the writing of the manuscript. All authors have read and approved the final version of the manuscript, and agree with the order of presentation of the authors. Competing interests The authors declare that they have no competing interests References 1. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. 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Overall Q1 Q2 Q3 Q4 p Age (year) 52.2 (5.2) 55.2 (3.9) 53.6 (4.6) 52.5 (4.8) 50.2 (5.3) <0.001 Cigarette smoking (pack-years)a 7.6 (15.4) 11.9 (19.7) 10.4 (17.4) 5.5 (13.1) 5.8 (13.0) <0.001 Serum total cholesterol (mmol/L) Serum LDL cholesterol (mmol/L) 5.90 (1.07) 4.04 (0.99) 6.05 (1.12) 4.14 (1.00) 6.00 (1.06) 4.15 (0.98) 5.86 (1.04) 4.00 (0.98) 5.70 (0.99) 3.84 (0.92) <0.001 <0.001 Serum triglycerides (mmol/ L) Systolic blood pressure (mmHg) 1.28 (0.81) 134.3 (16.8) 1.42 (0.86) 141.1 (19.6) 1.30 (0.86) 135.2 (15.6) 1.22 (0.80) 132.1 (15.3) 1.21 (0.72) 128.0 (13.3) 0.011 <0 .001 Diastolic blood pressure (mmHg) Type 2 diabetes (% of subjects) Body mass index (kg/m2) Leisure-time physical activity (kcal/day)b Serum C-reactive protein (mg/L) Alcohol consumption (g/week) 88.1 (10.4) 5.5 26.8 (3.5) 367.5 (333.9) 2.3 (3.4) 74.3 (121.4) 91.1 (11.2) 9.8 26.8 (3.6) 335.6 (325.1) 3.2 (4.5) 79.9 (157.8) 89.3 (10.2) 5.6 26.8 (3.4) 336.1 (295.9) 2.3 (2.9) 72.6 (104.8) 88.7 (10.3) 3.3 26.7 (3.3) 380.6 (373.0) 1.8 (2.9) 72.6 (111.4) 83.4 (9.3) 3.2 27.0 (3.4) 417.3(331.0) 1.8 (2.5) 72.1 (103.8) <0.001 0.001 0.317 <0.001 <0.001 0.640 Notes: Data are presented as mean (SD), expect Type 2 diabetes. Q1: ECP <9.84 mL/mmHg, Q2: ECP = 9.85 – 11.64 mL/mmHg, Q3: ECP = 11.65 – 13.92 mL/mmHg, Q4: ECP >13.92 mL/mmHg. a Pack-years denotes the lifelong exposure to smoking, which was estimated as a product of years smoked and the number of tobacco products smoked daily at the time of examination. b Leisure-time physical activity is defined as leisure time physical activity using the 12-month leisure-time physical activity questionnaire. Abbreviations: ECP = exercise cardiac power; LDL = low-density lipoprotein; Q = quartile. Table 2. Baseline exercise test characteristics and the percentage of subjects on medications according to the quarters of ECP. Overall Q1 Q2 Q3 Q4 p Peak 2max (ml/min)a 2400 (636) 1719 (393) 2224 (319) 2566 (341) 3095 (491) <0.001 Peak 2max (ml/ml/kg/min)a 30.2 (8.0) 22.4 (5.5) 28.1 (4.8) 32.4 (5.4) 37.7 (6.9) <0.001 Peak systolic blood pressure (mmHg)a Acetylsalicylic acid (%) 202.0 (28.0) 7.0 206.0 (32.0) 8.8 207.0 (27.6) 7.1 201.0 (25.3) 6.1 193.0 (24.0) 5.8 <0.001 Beta-blockers(%) Drugs for cholesterol (%) 17.6 0.6 29.2 1.5 18.8 0.5 12.5 0.2 9.7 0.2 Note: Q1: ECP = <9.84 mL/mmHg, Q2: ECP = 9.85 – 11.64 mL/mmHg, Q3: ECP = 11.65 – 13.92 mL/mmHg, Q4: ECP >13.92 mL/mmHg. a Data are presented as mean(SD). Abbreviations: ECP = exercise cardiac power; Q = quartile, 2max = maximal oxygen uptake. Table 3. The HR of heart failure (313 men) in the quartiles of ECP in 2351 men. ECP n HR (95%CI)b p HR (95%CI) c p Number of heart failures Number of heart failures /1000 personyears Q1 588 2.37 (1.68–3.35) <0.0001 1.96 (1.38–2.78) 0.001 107 9.9 Q2 587 1.57 (1.10–2.24) 0.012 1.39 (0.96–1.98) 0.076 84 6.8 Q3 588 1.22 (0.85–1.75) 0.282 1.21 (0.84–2.58) 0.300 71 5.2 Q4a 588 1.0 1.0 51 3.6 Note: Q1: ECP = < 9.84 mL/mmHg, Q2: ECP = 9.85 – 11.64 mL/mmHg, Q3: ECP = 11.65 – 13.92 mL/mmHg, Q4: ECP > 13.92 mL/mmHg. a Q4 is treated as reference. b Adjusted for age and examination year. c Adjusted for age, examination year, cigarette smoking, alcohol consumption, body mass index, type 2 diabetes, history of coronary heart disease, HDL cholesterol, and LDL cholesterol. Abbreviations: CI = confidence interval; ECP = exercise cardiac power; HR = hazards ratio; HDL = high-density lipoprotein; LDL = low-density lipoprotein; Q = quartile. Figure legends Fig. 1. The ageand examination-adjusted survival curves of heart failure in men according to quarters of ECP. ECP = exercise cardiac power. Graphic abstract