“Exercise Prescription and Training in Health and disease”

1. Institute of Sports Science Exercise Physiology, Training & Training Therapy Research Group Annual conference of Doctoral School of Behavioural, Social and Health Sciences in ESTONIA; 01-03/11/2018 “Exercise Prescription and Training in Health and disease” Univ. Prof. Dr. Peter Hofmann, FACSM

2. Key Problems – CVD • Each year cardiovascular disease (CVD) causes 3.9 million deaths in Europe and over 1.8 million deaths in the European Union (EU). • CVD accounts for 45% of all deaths in Europe and 37% of all deaths in the EU. • In 2015, more than 85 million people in Europe were living with CVD and almost 49 million people were living with CVD in the EU. European Cardiovascular Disease Statistics 2017

3. Key Problems – Risk Factors • Dietary factors make the largest contribution to the risk of CVD mortality and CVD DALYs at the population level across Europe of all behavioral risk factors. High systolic blood pressure makes the largest contribution of all the medical risk factors. • The prevalence of smoking in the EU is lower than in Europe as a whole among men but higher than in Europe among women. • Few adults in European countries participate in recommended levels of physical activity, with inactivity more common among women than men. • Levels of obesity are high across Europe and in the EU in both adults and children, although rates vary substantially between countries. • The prevalence of diabetes in Europe is high and has increased rapidly over the last ten years, increasing by more than 50% in many countries. • Overall CVD is estimated to cost the EU economy €210 billion a year. European Cardiovascular Disease Statistics 2017

4. Key Problems – Life Style Related Diseases Warburton et al.: Healthbenefits of physicalactivity: theevidence. CMAJ 2006; 174 (6): 801-809. European Cardiovascular Disease Statistics 2017

5. Key problems - Physical InActivity • Lack of Physical Activityincreases the risk of heart disease and other chronic diseases. • The WHO showed an urgent needto increase physical activity worldwide in single individuals and on population wide basis. • Approx. 3% of health costs in developed countries are due to physical inactivity (= less than 2.5 hours of moderate or less than 1 hour of vigorous physical activity per week). 40% of all EU adults are physically inactive! European Cardio-Vascular Disease Statistics 2008

6. Key problems – Physical (In-)Activity Participation in regular physical activity and/or aerobic exercise training is associated with a reduction in cardiovascular disease prevalence and mortality, while a sedentary lifestyle increases the risk of CVD by increasing the risk of hypertension, high triglycerides, low HDL (‘good’) cholesterol, diabetes and obesity . The World Health Organization recommends that adults undertake at least 150 minutes of moderate intensity aerobic physical activity per week, at least 75 minutes of vigorous intensity aerobic activity, or a combination of moderate and vigorous activities. In older adults aged 65 years and above, the WHO additionally recommends participation in muscle strengthening activities on at least two days a week, while for children and adolescents, they recommend at least 60 minutes of moderate to vigorous intensity physical activity per day . European Cardiovascular Disease Statistics 2017

7. Physical Activity and Risik • A low fitness level increases the mortality risk substantially. • The increase in fitness reduces mortality risk by 44% in men. • A normal body weight (BMI below 25) and regular moderate to vigorous physical activity reduce mortality risk in middle aged and older men and women Scientific studies showed, that regular moderate physical activity significantly reduces the mortality risk and improves health and fitness. Type 2 diabetes may be prevented by a healthy life style in combination with early medical treatment! Ryan, A.S.: Exercise in aging: its important role in mortality, obesity and insulin resistance. Aging health. 2010 October ; 6(5): 551–563.

8. Key problems – Physical (In-)Activity European Cardiovascular Disease Statistics 2017

9. Key problems – Physical (In-)Activity European Cardiovascular Disease Statistics 2017

10. Key problems - Obesity • OverweightandObesityhave increased dramatically in the last decades and are still increasing. • The main causes are overfeedingandlack of Physical Activity! • Obesity and physical Inactivity increase the risk for cardiovascular diseases, type 2 – diabetes mellitus, hypertension, hyperlipidaemia and cancer. • Obesity and a low fitness levelare significantly related to an increased all cause and cardiovascular mortality risk. • Obesity , insulin resistance and Inactivity increases with age. Ryan, A.S.: Exercise in aging: its important role in mortality, obesity and insulin resistance. Aging health. 2010 October ; 6(5): 551–563.

11. Key Problems – Overweight / Obesity European Cardiovascular Disease Statistics 2017

12. US Obesity Trends 1990 – 2017 1990 2000 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory https://www.cdc.gov/obesity/data/prevalence-maps.html 2017 2010 No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30% 2017 ≥ 35%

13. Key problems – Obesity US European Cardiovascular Disease Statistics 2017

14. Key problems – Diabetes European Cardiovascular Disease Statistics 2017

15. Physical Inactivity in Adults ≥ 20 Jahre -2008 – (left) Diagnosed Diabetes rate in Adults ≥ 20 Jahre ≥ 20 years – (right) DIABETES ca. 600.000 in AUT INACTIVITY Obesity Percent Percent

16. Definitions Physical Activity, Exercise Training, Physical Fitness and Sport are terms prescribing different concepts. Physical Activity Physical Activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure (WHO). Exercise / Exercise Training Exercise Training is a sub-group of Physical Activity, which is planned, structured and regularly repeated exercises aiming to improve or stabilize exercise performance / fitness and its components. (Physical) Fitness Physical Fitness is a set of features related to health and/or performance. The degree of fitness is measured by specific fitness-/performance. Each kind of physical activity influences physical and mental fitness. Sport / Sports An activity involving physical exertion and skill in which an individual or team competes against another or others for entertainment.

17. Physical Activity & Mortality Associations between sedentary behaviors (daily sitting/TV-viewing time) and mortality from cardiovascular disease (CVD) and cancer dependent on levels of physical activity (PA). • A dose-response association between sitting time (9%-32% higher risk; p for trend <0.001) and TV time (3%-59% higher risk; p for trend <0.001) with CVD mortality was observed in the 'inactive', lowest quartile of PA. • Associations were less consistent in the second and third quartiles of PA, and there was no increased risk for CVD mortality with increasing sedentary behaviors in the most active quartile. • Associations between sedentary behaviors and cancer mortality were generally weaker; 6%-21% higher risk with longer sitting time observed only in the lowest quartile of PA. PA modifies the associations between sedentary behaviors and CVD and cancer mortality. These findings emphasize the importance of higher volumes of moderate and vigorous activity to reduce, or even eliminate these risks, especially for those who sit a lot in their daily lives. Ekelund U, et al: Do the associations of sedentary behaviour with cardiovascular disease mortality and cancer mortality differ by physical activity level? A systematic review and harmonised meta-analysis of data from 850 060 participants. Br J Sports Med. 2018 Jul 10. pii: bjsports-2017-098963. doi: 10.1136/bjsports-2017-098963.

18. Physical Activity & CVD / Diabetes The relationships between physical activity (PA) and both cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) have predominantly been estimated using categorical measures of PA, masking the shape of the dose-response relationship. In this systematic review and meta-analysis, for the very first time we are able to derive a single continuous PA metric to compare the association between PA and CVD/T2DM, both before and after adjustment for a measure of body weight. An increase from being inactive to achieving recommended PA levels(150 minutes of moderate-intensity aerobic activity per week)was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and T2DM incidence by 26% (relative risk [RR], 0.77 [0.71-0.84]), (RR, 0.83 [0.77-0.89]), and (RR, 0.74 [0.72-0.77]), respectively, after adjustment for body weight. The greatest gain in health is associated with moving from inactivity to small amounts of PA. Wahid A, et al.: Quantifying the Association Between Physical Activity and Cardiovascular Disease and Diabetes: A Systematic Review and Meta-Analysis. J Am Heart Assoc. 2016 Sep 14;5(9). pii: e002495. doi: 10.1161/JAHA.115.002495.

19. Physical Activity and Cancer Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers. Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma and prostate cancer. Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. Leisure-time physical activity was associated with lower risks (7%) of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings. Moore SC, et al.: Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern Med. 2016 Jun 1;176(6):816-25. doi: 10.1001/jamainternmed.2016.1548.

20. Physical Activity & Fitness Physical Inactivity – the biggest public health problem of the 21st century? The risk to die from cardio-vascular disease is significantly related to the level of fitness but independent from Body Mass Index (BMI). Physical inaktivity and a low fitness-level increase the risik. 2316 men with typ 2 diabetes at the start. 179 deaths during study. See also Poster by E. Mäestu et al.: Low fitness is associated with metabolic risk independently of central adiposity in a cohort of 18-year olds. Blair: Physical inactivity: the biggest public health problem of the 21st century. Brit. J. Sports Med. 2009; 43: 1-2.

21. Limitations and Needs Limitation is the measurement of Physical Activity • Heterogeneity of PA assessment across studies • Self-report methods mostly questionnaires • Validity of the method, especially for assessing PA in the past and low intensity PA Courneya, K.S., Friedenreich, Ch.M. (eds.): Physical Activity and Cancer. In: Schlag, P.M., Senn, J.-J. (Series eds.). Recent Results in Cancer Research. Springer Heidelberg 2011. Need for reproducible exercise prescription (intensity, duration, frequency, progression, volume and duration of the intervention)in RCT´s! Kristin L Campbell, K-L., Neil, S.E., Winters-Stone, K.M.: Review of exercise studies in breast cancer survivors: attention to principles of exercise training. BJSM Online First Hofmann P, Tschakert, G.:Special Needs to Prescribe Exercise Intensity for Scientific Studies. Cardiology Research and Practice. 2011, Article ID 209302, 10 pages, doi:10.4061/2011/209302. , published on June 10, 2011 as 10.1136/bjsm.2010.082719.

22. Evidence for Exercise as a Therapy Today there is clear evidence, that exercise training has positive effects on pathogenesis, aerobic exercise performance (fitness), Quality of Life (QoL) and symptoms in at least 26 different chronic diseases. Exercise training is therefore a powerful therapy option for most if not all chronic diseases. Kujala U.M.: Evidence on the effects of exercise therapy in the treatment of chronic disease. Br J Sports Med 2009, 43(8): 550-555. Pedersen B.K., Saltin B.: Evidence for prescribing exercise as therapy in chronic disease. Scandinavian Journal of Medicine and Science in Sports 2006, 16(1): 3-63). Pedersen BK, Saltin B.: Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sports. 2015 Dec;25 Suppl 3:1-72. Low exercise performance is a strong predictor of mortality. Warburton D.E.R., Nicol C.W., Bredin S.S.D.: Health benefits of physical activity: the evidence. CMAJ 2006, 174(6): 801-809.

23. Evidence

24. Evidence Pedersen B.K., Saltin B.: Evidence for prescribing exercise as therapy in chronic disease. Scandinavian Journal of Medicine and Science in Sports 2006, 16(1): 3-63). Pedersen BK, Saltin B.: Exercise asmedicine - evidence for prescribing exercise astherapy in 26 different chronicdiseases. Scand J MedSci Sports. 2015 Dec;25 Suppl 3:1-72.

25. Exercise Training Therapy • Short time ago patients suffering from chronic diseases were told not do any exercise, although some beneficial effects have been described in the literature. • Nowadaysexercise training is an integral part of the treatment of patients with chronic diseases. • Training intensity is increasing and today, highly intense interval training is applied. • However, we lack sufficient information regarding the mode and the intensity of safe exercise training in chronic disease.

26. Exercise and CV Mortality Although recommended in guidelines for the management of coronary heart disease (CHD), concerns have been raised about the applicability of evidence from existing meta-analyses of exercise-based cardiac rehabilitation (CR). Overall, CR led to a reduction in cardiovascular mortality (relative risk: 0.74; 95% confidence interval: 0.64 to 0.86) and the risk of hospital admissions (relative risk: 0.82; 95% confidence interval: 0.70 to 0.96). There was no significant effect on total mortality, myocardial infarction, or revascularization. The majority of studies (14 of 20) showed higher levels of health-related quality of life in 1 or more domains following exercise-based CR compared with control subjects. Exercise-based CR reduces cardiovascular mortality, hospital admissions and improvements in quality of life. These benefits appear to be consistent across patients and intervention types and were independent of study quality, setting, and publication date. These results support the Class I recommendation of current international clinical guidelines that CR should be offered to CHD patients Anderson L. et al.: Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. J Am Coll Cardiol. 2016 Jan 5;67(1):1-12. doi: 10.1016/j.jacc.2015.10.044.

27. Exercise Training Therapy & Guidelines

28. Exercise Training Therapy & Pharmacotherapy

29. Exercise and / or Drug Therapy? To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke. Diuretics were more effective than exercise in heart failure. Inconsistency between direct and indirect comparisons was not significant. Although limited in quantity, existing randomized trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes. Naci H, Ioannidis JP.: Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. Br J Sports Med. 2015 Nov;49(21):1414-22. doi: 10.1136/bjsports-2015-f5577rep.

30. Physical Activity & Fitness Changes of Fitness by Exercise Training. The higher the volume and intensity - the higher the effects!

31. Moderate vs. Strenous Intensity (O’Donavan et al. 2005) Effects of volume and / or intensity of exercise VO2max - maximal oxygenuptake TC – total cholesterol LDL-C – lowdensity („bad“ cholesterol Trig - triglicerids

32. Mechanisms Mechanims to explain health effects of Physical Activity and Exercise Training

33. Mechanisms Modulation of the immune system Positive influence on hormone systems (Estrogens und Steroids) Physical Activity reducedRisk ! Positive changes of insulin, blood glucose and adipocytokines Positive modulation of inflammatory processes McTiernan, A.: Mechanisms linking physical activity with cancer. Nature Reviews, Cancer, Volume 8, March 2008, 205-211.

34. Intensity of exercise Although there is still some lack about the specific physiological adaptations and the biological mechanisms induced by variable exercise training work loads, an increasing number of publications show that high-intensity training (constant or interval-type exercise) gained greater positive effects, than training at low or moderate intensity. Kemi O.J., Wisloff U.: High-intensity aerobic exercise training improves the heart in health and disease. J Cardiopulmon Rehab Prevent 2010, 30(1): 2-11 Tjonna A.E., Lee S.J., Rognomo O., Stolen T.O., Bye A., Haram P. M., Loennechen J.P., Al-Share Q.Y., Skogvoll E., Slordahl S.A., Kemi O.J., Najjar S.M., Wisloff U.: Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: A pilot study. Circulation 2008, 118: 346-354 or similar adaptations with a markedly lower training volume. Gibala M.J., McGee S.L.: Metabolic adaptations to short-term high-intensity interval training: A little pain for a lot of gain? Exerc Sport Sci Rev 2008, 36(2): 58-63

35. Standards Incremental Exercise

36. Lactate-Performance-Diagnostics • Three-zone model: • Zone 1 belowventilatory (VT)/lactate (LT) threshold 1; • Zone 2 above VT1/LT1 and below VT2/LT2; • Zone 3 above VT2 and below VO2peak. • (B) Five-zone model: • Zone 1: below VT1/LT1; • Zone 2 equalto VT1/LT1; • Zone 3 below VT2/LT2; • Zone 4 equalto VT2/LT2; • Zone 5 above VT2 and below VO2peak. • LT, lactate threshold; VT, ventilatory threshold. The past 2 decades have witnessed a growing body of work investigating the feasibility and efficacy of exercise therapy on a broad array of outcomes in many different oncology scenarios. Despite this heterogeneity, the exercise therapy prescription approach and the dose tested has been largely similar. Thus, current exercise therapy prescriptions in the oncology setting adopt a one-size-fits-all approach. In this article, then authors provide an overview of personalization of exercise therapy in cancer using the principles of training as an overarching framework. Specifically, we first review the fundamentals of exercise prescription in chronic disease before focusing attention on application of these principles to optimize the safety and efficacy of exercise therapyon (1) cancer treatment–induced cardiovascular toxicity and (2) tumor progression and metastasis. Jones LW, Eves ND, Scott JM.: Bench-to-Bedside Approaches for Personalized Exercise Therapy in Cancer. Am Soc Clin Oncol Educ Book. 2017;37:684-694.

37. Cell-to-Cell Lactate Shuttle Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilised continuously under fully aerobic conditions. ‘Cell-cell’ and ‘intracellular lactate shuttle’ concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges (i) between white-glycolytic and red-oxidative fibres within a working muscle bed (ii) between working skeletal muscle and heart; (iii) between tissues of net lactate release and gluconeogenesis. Lactate shuttles exist in diverse tissues including in the brain, where a shuttle between astrocytes and neurons is linked to glutamatergic signalling. Because lactate, the product of glycogenolysis and glycolysis, is disposed of by oxidative metabolism, lactate shuttling unites the two major processes of cellular energy transduction. Lactate disposal is mainly through oxidation, especially during exercise when oxidation accounts for 70–75% of removal and gluconeogenesis the remainder. Lactate flux occurs down proton and concentration gradients that are established by the mitochondrial lactate oxidation complex. Brooks, G.A., Fehey, Th.D., Baldwin, K.M.: Exercise Physiology. Human Bioenergetics and Ist Applications. (4th ed). McGraw Hill Boston, 2005: 84. Brooks, G.A.: Lactate. Link Between Glycolytic and Oxidative Metabolism. Sports Med 2007; 37 (4-5): 341-343

38. PHASE II PHASE I PHASE III LTP2 1st workload LTP1 rest 0 10 20 30 40 50 60 70 80 90 100 %Pmax PHASE II PHASE I PHASE III M S M S M S La>0 La=0 La>>0 E P P E E P P E P E EM > PM La rest ES = PM equilibrium ES < PM exp. increase

39. Lactate-concentration, lactate rate of appearance (Ra) und lactate rate of disappearance (Rd) Hofmann, P., Tschakert, G., Pokan, R., von Duvillard, S.P.: Three-Phase Time Course of Physiological Variables During Incremental Cycling in Young Male and Female Subjects. Med. Sci. Sports Exerc. 42, 2010, 5: S238. Brooks, G.A., Fehey, Th.D., Baldwin, K.M.: Exercise Physiology. Human Bioenergetics and Ist Applications. (4th ed). McGraw Hill Boston, 2005: 200.

40. Catecholamine Response Plasma-catecholamines present a similar pattern than the lactate performance curve. Above LTP2 / VT2 adrenalin, noradrenalin but also dopamin (not shown) increase substantially. Below LTP1 /VT1 there is no substantial increase in catecholamines but between LTP1 / VT1 and LTP2 / VT2 catecholmanines increase slightly. WONISCH, M., HOFMANN, P., SCHMID, P., POKAN, R.: Zusammenhang zwischen „anaerober Schwelle“, Katecholaminen und Arrhythmien bei Patienten mit Herzerkrankungen. Österr. J. Sportmed. 37, 2007, 2/3: 50-56.

41. VETP1 LTP1 Three –Phases Two Turn Points Hofmann, P. Tschakert, G.: Special Needs to Prescribe Exercise Intensity for Scientific Studies. Cardiology Research and Practice. Volume 2011, Article ID 209302, 10 pages doi:10.4061/2011/209302. Binder et al.; Methodological approach to the first and second lactate threshold in incremental cardiopulmonary exercise testing. European Journal of Cardiovascular Prevention and Rehabilitation 2008, 15:726–734. Hofmann, P., Pokan, R.: Value of the Application of the Heart Rate Performance Curve in Sports. Int. J. Sports Physiology and Performance 5, 2010, 4 (Dec): 437-447.

42. Lactate Performance Curve and Exercise Performance Time course of blood lactate concentration and first (LTP1) and second (LTP2) lactate turn points in an incremental cycle ergometer exercise test in differently trained male and female healthy sports students and two top level athletes. The determination of LTP´s was independent of the exercise performance. The main difference in performance can be seen by a later increase in blood lactate concentration at LTP1 in the trained subjects. This may indicate a lower lactate production or a higher intramuscular lactate clearance in these subjects. Hofmann, P., Dohr, K., Seibert, F.-J., Wonisch, M., Pokan, R., Smekal, G., Schwaberger, G.: Relationship between Lactate Turn Point and Maximal Performance in Young Healthy Male and Female Subjects of Different Exercise Performance Level. In: Cabri, J., Alves, F., Araujo, D., Barreiros, J., Diniz, J., Veloso, A. (eds.). Book of Abstracts of the 13th Congress of the European College of Sport Science, 9-12 July 2008 Estoril, Portugal, 2008: 470.

43. Exercise Training Therapy Pmax (168±4, 198±4, 213±5, 223±5 W) and P during phase I (64±2; 87±3; 101±3; 106± 3 W) increased significantly (p ≤ 0.001). %Pmax (38±1%, 44±1%, 47±1%, 48±1%) significantly increased from start to the end of the intervention. Pokan et al.: In CAD Patients, Performance Improvements are Achieved only During Phase I of Energy Supply While in Exercise Therapy. Med Sci Sports Exerc 2015.

44. Standards Constant Load Exercise

45. Critical Lactate Clearance & Maximal Lactate Steady State (MLSS) Beneke, R.: Methodological aspects of maximal lactate steady state–implications for performance testing. Eur J Appl Physiol (2003) 89: 95–99. Concept of a critical lactate clearance point. The relationship between lactate concentration and time is depicted (left) during four continuous exercises of graded intensities: A the easiest and D the hardest. Exercise intensity C is the maximum that can be tolerated without evoking a continuous rise in blood lactate. The capacity to clear lactate is sufficient to allow a maximal lactate concentration steady state. Though lactate clearance capacity may not be maximal at this point and clearance can increase if lactate rises (as in D) a critical clearance point has been achieved in C beyond which the dynamic steady state cannot be maintained. Brooks, G.A., Fehey, Th.D., Baldwin, K.M.: Exercise Physiology. Human Bioenergetics and Ist Applications. (4th ed). McGraw Hill Boston, 2005: 504.

46. PHASE II PHASE III PHASE I 1st workload LTP2 rest LTP1 0 10 20 30 40 50 60 70 80 90 100 %Pmax PHASE II PHASE I PHASE III M S M S M S La>0 La=0 La>>0 E P P E E P P E P E EM > PM La rest ES = PM equilibrium ES < PM exp. increase

47. Maximal Lactate Steady State Phase III Phase II Phase I Blood lactate concentration at four constant load exercise tests 5% below, at and 5% above LTP1 and LTP2 in trained and untrained male and female subjects of different age and fitness level. Tschakert, G., Müller, A., Gröschl, W., Burgsteiner, H., Wallner, D., Hofmann, P.: 2012, unpublished results)

48. Lactate & catecholamine response Moser, O.: Exercise in Type 1 Diabetes Mellitus: Effects of different standardized cycle ergometer exercise modalities on blood glucose concentration, metabolic, cardio-respiratory and hormonal response . Diss. Univ. Graz 2015-.

49. Standards Interval Exercise

50. Tschakert und Hofmann 2014 H I G H I N T E N S I T Y