The Impact of Hypoxia on Aerobic Exercise Capacity _____________________________________________________________________________________________________ Dissertation zur Erlangung der naturwissenschafltichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Christoph Andreas Siebenmann aus Aarau AG Promotionskomitee Prof. Dr. Carsten Lundby (Vorsitz) Prof. Dr. Max Gassmann Dr. Paul Robach Zürich, 2012 Contents Summary ..………………………………………………………………………………... III Zusammenfassung ……………………………………………………………................ V Acknowledgments ….…………………………………………………………………….. VII 1. Introduction …….………………………………………………………………….. 1 1.1. Background …………………………………………………………………… 1 1.2. Acute Hypoxia and aerobic exercise …………………………………………… 2 Direct implication of a reduced PO for aerobic exercise ……………………... 2 2 Aim 1: Limitations induced by the pulmonary circulation …..………………… 5 Aim 2: Limitations induced by the cerebral circulation ……………………… 7 1.3. Chronic Hypoxia and aerobic exercise ..………………………………………. 10 Aim 3: The effect of Live High – Train Low on elite athletes ……….…………. 11 2. Manuscripts …… …………………………………………………………………… 13 2.1. Dexamethasone Improves Maximal Exercise Capacity of Individuals Susceptible to High Altitude Pulmonary Edema at 4559m …………………... 14 2.2. Maximal exercise capacity in individuals susceptible to high altitude pulmonary edema at 4559 m …………………………………………………. 23 2.3. Hypocapnia during hypoxic exercise and its impact on cerebral oxygenation, ventilation and maximal whole body O uptake ………………………………. 35 2 2.4. “Live high–train low” using normobaric hypoxia: a double-blinded, placebo- controlled study ……………………………………………………………….. 53 2.5. The role of haemoglobin mass on VO max following normobaric „live high- 2 train low‟ in endurance-trained athletes ………………………………………. 65 3. Discussion and outlook …………………………………………………………….. 72 3.1. Limitations to exercise in acute hypoxia induced by the pulmonary circulation 72 3.2. Limitations to exercise in acute hypoxia induced by the cerebral circulation 73 3.3. The effect of Live High – Train Low on exercise capacity of elite athletes 73 4. Bibliography ............................................................................................................... 75 5. Curriculum Vitae ..…………………………………………………………………. 84 Summary Acute hypoxia impairs aerobic exercise by reducing the capacity for maximal O uptake 2 (VO max). This is mainly the consequence of a lower arterial O content (c O ) and, in severe 2 2 a 2 hypoxia, cardiac output during maximal exercise as the combination of these two factors attenuates convective O supply to the exercising muscle cells. Nevertheless, the 2 incapacitating effect of hypoxia is partially restored during prolonged exposure as an increased renal erythropoietin release induces polycythemia that normalizes c O . Since this a 2 mechanism may benefit performance not only in hypoxia but also in normoxia different forms of altitude training were developed all aiming to enhance athletic performance at sea level. The purpose of the present project was to enhance our understanding regarding the interaction between both, acute and chronic hypoxia and aerobic exercise. In acute hypoxia the contribution of the intrinsic responses of the pulmonary and the cerebral circulation to the reduction in VO max was investigated. Specifically, we hypothesized that the hypoxia- 2 induced rise in pulmonary artery pressure induces exercise limitations by increasing right ventricular afterload and/ or promoting pulmonary ventilation-perfusion mismatch. Furthermore, we suggested that the cerebral hypoxia that develops during exercise at altitude would limit VO max by accelerating the development of supraspinal fatigue. Regarding 2 chronic hypoxia we tested the efficacy and underlying mechanisms of the contemporary altitude training strategy, i.e. the Live High – Train Low approach, on elite endurance athletes in a double-blinded and placebo-controlled study design. The results collected in three independent studies revealed the following: 1) At 4,559 m altitude pulmonary vasodilation induced by the glucocorticoid Dexamethasone elevates VO max of individuals present with an excessive 2 vasoconstrictive response to hypoxia without affecting arterial O saturation (S O ). A 2 a 2 direct comparison to normal individuals further suggested a larger hypoxia-induced exercise impairment in these individuals but also no differences in S O during maximal a 2 exercise. We thus conclude that hypoxic pulmonary vasoconstriction may contribute to the reduced VO max in acute hypoxia potentially by increasing right ventricular afterload 2 and thereby attenuating cardiac output. 2) Although administration of CO during exercise at 3,454 m altitude elevated cerebral 2 blood flow and, as a consequence, cerebral oxygenation, VO max remained unaffected. 2 This indicates that the contribution of the reduced cerebral oxygenation on the limitation III of VO max in hypoxia is neglectable. Nevertheless, as a VO max test induces 2 2 progressive demand for muscular O supply, the capacity of the O transport system 2 2 might have been exhausted before supraspinal fatigue occurred, and thus we cannot exclude that the decline in cerebral oxygenation may play a role during submaximal exercise in hypoxia. 3) Four weeks of discontinuous (16 hours per day) exposure to normobaric hypoxia corresponding to 3,000 m combined with daily training in normoxia failed to benefit the performance of elite endurance athletes. This was explained by the absence of an effect of hypoxia on total red cell volume. These findings suggest a potential role of a placebo- effect in earlier studies and indicate that four weeks of discontinuous hypoxic exposure may be insufficient to induce physiological adaptations. Athletes should take this into consideration before shouldering the inconveniences associated with Live High – Train Low altitude training. In brief, the present results support a limiting role of pulmonary vasoconstriction but not of attenuated cerebral oxygenation on VO max in hypoxia. They further indicate that altitude 2 training following the Live High – Train Low strategy may not be superior to conventional endurance training. IV Zusammenfassung Akute Hypoxie führt zu einer Reduktion der maximalen O Aufnahmekapazität (VO max) 2 2 und beeinträchtigt dadurch die aerobe Leistungsfähigkeit. Die Hauptursache für die Abnahme von VO max ist ein verringerter O Transport zu der arbeitenden Muskulatur, der durch einen 2 2 tieferen arteriellen O -Gehalt (c O ) und in schwerer Hypoxie zusätzlich durch ein 2 a 2 vermindertes maximales Herz-Minuten-Volumen zustande kommt. Bei chronischer Hypoxie-Exposition führt jedoch eine verstärkte renale Erythropoietin- Ausschüttung zu einer Erhöhung der Hämoglobinkonzentraion im Blut. Dadurch normalisiert sich c O allmählich, wodurch sich auch die aerobe Leistungsfähigkeit teilweise erholt. Da a 2 eine solche Anpassung des Blutes allerdings nicht nur die Leistungsfähigkeit in Hypoxie, sondern auch die in Normoxie verbessern könnte, erhoffen sich viele Athleten einen Wettkampfvorteil aus dem Akklimatisationsprozess. Dazu wurden verschiedene Formen von Höhentraining entwickelt, die alle eine Verbesserung der Leistungsfähigkeit in Normoxie anstreben. Das Ziel dieses Projekts war es, die Auswirkungen von akuter und chronischer Hypoxie auf die aerobe Leistungsfähigkeit zu untersuchen. In akuter Hypoxie wurde getestet, ob die spezifischen Reaktionen von Lungen- und Hirnkreislauf zu der Verminderung von VO max 2 beitragen. Wir vermuteten, dass die pulmonale Vasokonstriktion in Hypoxie VO max 2 beinträchtigt, indem sie die rechtsventrikuläre Nachlast erhöht und ein optimiertes Ventilations/ Perfusions-Verhältnis verhindert. Weiterhin spekulierten wir, dass die verminderte O Versorgung des Gehirns die Entstehung von supraspinaler Ermüdung 2 beschleunigt und dadurch eine raschere Erschöpfung erzwingt. Hinsichtlich chronischer Hypoxie untersuchten wir die Wirkung der vielverspechendsten Höhentrainingsstrategie (Hoch leben – Tief trainieren) auf die Leistungsfähigkeit von hochtrainierten Ausdauerathleten, sowie die Mechanismen, die einer eventuellen Verbesserung unterliegen. Die folgenen Ergebnisse stammen aus drei unabhängigen Studien: 1) Bei Probanden, die in akuter Hypoxie zu exzessiver pulmonaler Vasokonstriktion neigen, verbesserte eine durch das Glukokortikoid Dexamethason bewirkte pulmonale Vasodilatation VO max auf einer Höhe von 4„559 m.ü.M. Dies geschah ohne eine 2 Erhöhung der arteriellen O -Sättigung (SaO ) bei maximaler Belastung. Weiterhin 2 2 tendierten diese Probanden im direkten Vergleich zu einer Kontrollgruppe zu einer V stärkeren Verringerung von VO max in Hypoxie, wobei auch hier keine Unterschiede in 2 SaO bei maximaler Belastung vorlagen. Aus diesen Ergebnissen schliessen wir, dass die 2 pulmonale Vasokonstriktion in akuter Hypoxie zur Verringerung von VO max beiträgt. 2 Die Ursache könnte eine gesteigerte rechtsventrikuläre Nachlast sein, die das Herz- Minuten-Volumen reduziert. 2) Auf 3„454 m.ü.M. erhöhte eine inspiratorische Administration von CO die arterielle 2 Blutversorgung und damit die Oxygenierung des Gerhirns. Entgegen unserer Hypothese hatte diese jedoch keinen Effekt auf VO max. Dies zeigt, dass die Abnahme der 2 cerebralen Oxygenierung bei der Verringerung von VO max in Hypoxie keine 2 entscheidende Rolle spielt. Allerdings könnte die zunehmende Belastung während der VO max Tests und der damit verbundene ansteigende O Bedarf in den Skelettmuskeln 2 2 die Kapazität des O Transportsystems überfordert haben, bevor bevor die cerebrale 2 Hypoxie zu supraspinaler Ermüdung führte. Daher kann nicht ausgeschlossen werden, dass die verminderte cerebrale Oxygenierung in Hypoxie die Leistungsfähigkeit in submaximalen Tests beeinflussen könnte. 3) Vier Wochen diskontinuierliche normobare Hypoxie-Exposition (16 Stunden/ Tag, entsprechend 3„000 m.ü.M.) bewirkten keine Erhöhung des Gesamtvolumens der Erythrozyten von hochtrainierten Ausdauerathleten und führte daher zu keiner Leistungsverbesserung. Dies lässt vermuten, dass Athleten in früheren Studien von einem Placebo-Effekt profitiert hatten. Weiterhin zeigt es, dass vier Wochen diskontinuierliche Hypoxie möglicherweise nicht genügen um eine physiologische Adaptation zu erwirken. Athleten sollten sich dessen bewusst sein, bevor sie sich entscheiden die Unannehmlichkeiten eines Höhentrainings auf sich zu nehmen. Insgesamt zeigen die vorliegenden Resultate, dass die pulmonale Vasokonstriktion, nicht aber die verminderte cerebrale Oxygenierung VO max in Hypoxie beeinträchtigen. Weiterhin 2 deuten sie darauf hin, dass Höhentraining nach der „Hoch leben – Tief trainieren“ Strategie keine grössere Leistungssteigerung zur Folge hat als konventionelles Ausdauertraining. VI Acknowledgments I would like to thank the following persons: Prof. Dr. Carsten Lundby for supervising my PhD-project and for sharing his exceptional knowledge in this field. Prof. Dr. Max Gassmann for attendance in my PhD-committee and for all his help and advice. Dr. Paul Robach for attendance in my PhD-committee and for his practical support particularly during the Live High – Train Low study. Dr. Peter Rasmussen for many suggestions that helped to improve my work and for statistical advice. Robert Jacobs for his friendship and humour that lightened many long days in the office. Maja Schlittler for her love and her never-ending support, patience and understanding. My family for all the encouragement and support that helped me to get to this point. Finally, all the persons that volunteered as subjects in the studies of my PhD-project. VII 1. Introduction 1.1 Background The reduced O availability in hypoxia has a variety of effects on the human organism 2 whereof one of the most noticeable is an impairment of aerobic exercise capacity. While the extent of this is largest in the initial phase of the hypoxic exposure, it attenuates with time as different physiological adaptive mechanisms partially restore uptake and transport of O to the 2 skeletal muscles. The factors underlying the impeding impact of hypoxia have traditionally been of great interest in medicine and physiology as these do not only affect healthy individuals at altitude, but also a large number of patients suffering from conditions that abate internal O availability 2 (55). However, despite a long history of research (25, 27, 134) our knowledge in this field remains far from complete. The purpose of the present PhD-project was to gain new insights into the interaction between hypoxia and aerobic exercise. To better understand the limitations induced by acute hypoxia, the contributions of two mechanisms other than those conventionally assumed responsible were investigated. Regarding the effect chronic hypoxia, the process of acclimatization and the resulting implications for subsequent sea level performance were studied in endurance athletes conducting the contemporary form of altitude training. After a brief review of the present state of knowledge in each respective field, the results are presented and discussed in five manuscripts (102, 114-117), four of which are to date in press or published in peer-reviewed journals. 1 1.2 Acute hypoxia and aerobic exercise The incapacitating effect of hypoxia has been recognized ever since humans started to ascend to altitude, but for a long time the underlying mechanisms were not understood. In the beginning of the 20th century systematic investigations identified the reduced partial pressure of O (PO ) rather than the barometric pressure per se as the perpetrator (35, 143), and 2 2 subsequently a long list of studies have revealed how this may impair aerobic exercise capacity. Direct implication of a reduced PO for aerobic exercise 2 Performance in tasks that rely on aerobic metabolism is related to three components: i) maximal oxygen uptake (VO max), which sets the notional upper limit for aerobic 2 performance, ii) the fraction of VO max that is sustainable for the required time and yields the 2 “performance VO ” and iii) exercise efficiency, which determines the work rate that is 2 generated at the O cost corresponding to the performance VO (figure 1) (17, 65). While the 2 2 latter two components are not affected by acute hypoxia (42, 140) VO max decreases with the 2 inspired PO in a curvi-linear relationship (figure 2) (30, 34, 44, 92). To understand how acute 2 hypoxia impairs aerobic exercise it is thus necessary to distinguish the factors determining VO max and how they are affected by the reduction in PO . 2 2 During incremental whole body exercise pulmonary VO rises linearly due to an accelerating 2 aerobic metabolism in the active skeletal muscles (59). However, as VO max is reached near 2 maximal effort, the VO curve plateaus and becomes irresponsive to further elevations in 2 workload (13, 59). This indicates failure to either increase muscular O supply or O 2 2 consumption by the mitochondria. If an exercise task involves a large muscle mass, as it is required for the achievement of whole body VO max, mitochondrial capacity clearly exceeds 2 the highest rate of O delivery (20) and thus VO max is limited by O transport rather than 2 2 2 utilization. 2 To reach the muscle‟s mitochondria O is carried along a cascade of four consecutive 2 processes, i.e. pulmonary ventilation, alveolar-capillary diffusion, convective transport by the circulation and capillary-mitochondrial diffusion (27, 133). While pulmonary ventilation and convective O transport are active processes that are stimulated as the demand for O 2 2 increases, diffusive transport at the pulmonary and the muscular sites is passively driven by the PO gradient over the according membranes. These steps are challenged during exercise 2 as the increasing cardiac output shortens capillary transit time, i.e. the time available for O 2 diffusion (131, 132). During normoxic exercise the hyperpnoea-related increase in alveolar PO generally accelerates trans-alveolar diffusion sufficiently to prevent a significant drop in 2 arterial O saturation (SaO ) (17, 91). In contrast, capillary-mitochondrial diffusion is more 2 2 sensitive to shortened transit times and may limit O transport (106, 131), but probably only 2 to a small extent (33, 109). Accordingly, the bottleneck is the convective process that connects the two sites of diffusive transport and as such, an individual‟s VO max is mainly 2 determined by the capacity to increase cardiac output (17, 68, 109, 110). However, this order shifts in acute hypoxia where, despite an immediate reflex stimulation of pulmonary ventilation (139), alveolar PO decreases (74, 93). Due to the passive nature of diffusive 2 transport into the pulmonary capillaries arterial PO diminishes in a direct response hereof. 2 Furthermore, the narrower alveolar-capillary PO gradient induces a growing pulmonary 2 3