Wednesday, June 2, 2010

VO2 Max: What do we know, and what do we still need to know

VO2 Max: What do we know, and what do we still need to know
By Benjamin D. Levine
Institute For Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, and the University of Texas Southwestern Medical Center at Dallas,TX, USA
From J Physiol 586.1 (2008) pp 25–34
Maximal oxygen uptake ( ˙VO2,max) is a physiological characteristic bounded by the parametric limits of the Fick equation: (left ventricular (LV) end-diastolic volume−LV end-systolic volume)×heart rate×arterio-venous oxygen difference. ‘Classical’ views of ˙VO2,max emphasize its critical dependence on convective oxygen transport to working skeletal muscle, and recent data are dispositive, proving convincingly that such limits must and do exist. ‘Contemporary’ investigations into the mechanisms underlying peripheral muscle fatigue due to energetic supply/demand mismatch are clarifying the local mediators of fatigue at the skeletalmuscle level, though the afferent signalling pathways that communicate these environmental conditions to the brain and the sites of central integration of cardiovascular and neuromotor control are still being worked out. Elite endurance athletes have a high ˙VO2,max due primarily to a high cardiac output from a large compliant cardiac chamber (including the myocardium and pericardium) which relaxes quickly and fills to a large end-diastolic volume. This large capacity for LV filling and ejection allows preservation of blood pressure during extraordinary rates of muscle blood flow and oxygen transport which support high rates of sustained oxidative metabolism. The magnitude and mechanisms of cardiac phenotype plasticity remain uncertain and probably involve underlying genetic factors, as well as the length, duration, type, intensity and age of initiation of the training stimulus

All that is gold does not glitter,
Not all those who wander are lost.
The old that is strong does not wither,
Deep roots are not reached by the frost.
(J. R. R. Tolkein, 1955)

Maximal oxygen uptake ( ˙VO2,max) is one of the most ubiquitous measurements in all of exercise science. The concept that there exists a finite rate of maximal oxygen transport from the environment to the mitochondria to support oxidative production of ATP to do physical work began with A.V. Hill (Hill & Lupton, 1923), and has been used diversely in clinical science as a measure of exercise performance (Mitchell et al. 1958; Levine & Stray-Gundersen, 1997; Hoppeler & Weibel, 2000; di Prampero, 2003), a marker of population-based fitness and cardiovascular disease (Blair et al. 1996; LaMonte et al. 2006), and even as a signal that patients with heart failure are on the verge of decompensation and should be referred for heart transplantation (Weber et al.

˙V O2,max; the classical view
The ‘classical’ view of maximal oxygen uptake is that maximal rates of oxygen utilization (and sustainable rates of oxidativeATP production) in skeletalmuscle are limited under most circumstances by the ability of the heart to deliver oxygen to and be accommodated by the working muscle (Saltin & Strange, 1992; Bassett & Howley, 1997). In some sense, this construct must be true as ˙VO2,max is easily altered by manipulations that increase ((Ekblom et al. 1972; Buick et al. 1980; Ekblom & Berglund, 1991) or decrease (Ekblom et al. 1972; Jilka et al. 1988; Pawelczyk et al. 1992; Levine et al. 1996) peripheral oxygen delivery without altering arterial PO2 ; and the maximal vasodilatory capacity of skeletalmuscle clearly exceeds the ability of the heart to deliver blood and still maintain adequate arterial perfusion pressure (Secher et al. 1977; Richardson et al. 1999).

Does a true ˙V O2,max exist and can we measure it?
Some investigators have contended recently though that the absence of a clear and consistent plateau in ˙VO2 with increasing running speed in the early Hill experiments argues that the concept of ˙VO2,max is not valid (Noakes, 1997). A number of scholarly reviews and rebuttals have been written about this issue (Saltin & Strange, 1992; Bassett & Howley, 1997, 2000; Bergh et al. 2000; Saltin & Calbet, 2006; Wagner, 2006) and these arguments will not be repeated here. To help answer this particular question and avoid the details of the ‘what limits ˙VO2,max‘ debate for the moment, let’s assume that there are ‘upstream’ and ‘downstream’ factors that provide oxygen to exercising skeletal muscle and then use it for physical work. The ‘upstream’ factors include all the physiological pathways that transferO2 from the environment to the blood, pump it to the periphery, and distribute it to and then inside the muscle cells. The ‘downstream’ factors include all the intracellular processes that occur once the O2 molecule is
transferred to the inside of the cell for oxidative production of ATP, and the neuromotor events that create calcium influx and muscle contraction.

A large part of the debate instigated by Noakes hinges on whether downstream factors, predominantly muscle motor recruitment, alone drive ˙VO2,max, orwhether ˙V O2,max has upstream limits independent of muscle motor recruitment. Indeed, Noakes has articulated what he considers a ‘new model’ of integrated performance physiology, which he has called The Central Governor Model (Noakes, 1997;Noakes et al. 2001, 2004a;Noakes&St Clair Gibson, 2004). In this formulation, a ‘central governor’ shuts down the body by putting a brake on muscle motor recruitment at very high work rates to avoid a ‘disturbance of homeostasis’. So, during an incremental exercise test, the highest ˙VO2 that is achieved doesn’t really reflect a true maximal ability to transport oxygen to the tissues and use it to make ATP to do physical work, because there remains lots of reserve that subjects don’t ‘choose’ to evoke.

For the purposes of framing the debate, Dr Noakes frequently likes to place investigators into two camps: those who believe the brain plays a role in exercise performance, and those who do not (Noakes et al. 2004b). However this straw man is specious. No one disputes that ‘the brain’ is required to recruit motor units – for example, spinal cord-injured patients can’t run. There is no doubt that motivation is necessary to achieve ˙VO2,max. A subject can elect to simply stop exercising on the treadmill while walking slowly because they don’t want to continue; no mystical ‘central governor’ is required to hypothesize or predict a ˙VO2 below maximal achievable oxygen transport in this case.

For more than a century, cardiovascular scientists have appreciated that that ‘central command’ initiates the cardiovascular response to exercise and plays a critical role in the exercise pressor reflex (Mitchell et al. 1983; Mitchell & Victor, 1996; Williamson et al. 2006). This is especially true for the regulation of heart rate; for example, when voluntary effort ceases at the end of exercise, heart rate rapidly returns to normal, even if metabolic signals are trapped within skeletal muscle by vascular occlusion (Alam & Smirk, 1937). When skeletal musclemotor units are inhibitedby curare, thus weakening themuscle contraction, the heart rate response to exercise is augmented (Leonard et al. 1985; Mitchell et al. 1989) as a function of increasing central command. Feedback to the brain from mechanically and metabolically sensitive skeletal muscle afferents also plays an essential role in increasing sympathetic nervous system outflow (Mitchell & Victor, 1996), as well as regulating the augmentation in cardiac output and the distribution of muscle blood flow – a response that is extremely tightly regulated with little effect of age, sex or fitness (McGuire et al. 2001; Fu & Levine, 2005). Indeed, when such signals are deranged, the cardiovascular response to exercise is dramatically altered, for example in patients with muscle metabolic disorders who may have 3–5 or, in extraordinary cases, more than 10 times the increase in cardiac output normally seen for a given increase in oxygen uptake (Lewis et al.1984; Haller et al. 1991; Taivassalo et al. 2003). There are hundreds if not thousands of papers on animals and humans on the topic of cardiovascular regulation in healthy and patient populations, demonstrating the intimate connection between skeletal muscle and the CNS. These were reviewed thoroughly in a recent ‘themed issue’ of Experimental Physiology (Raven, 2006).

So why the ‘controversy’?
One obvious reason is that a clear and unequivocal ‘plateau’ in oxygen uptake with increasing work may be difficult to demonstrate during incremental tests to exhaustion in different populations. The classic strategy to overcome this limitation is to continue to repeat tests using increasing work rates, even if this requires discontinuous exercise, until the rise in ˙VO2 is smaller by some fraction than that expected from the change in external work (Taylor et al. 1955). The most comprehensive study in this regard was that by Taylor et al. (1955). They studied over 100 healthy young subjects and repeated exercise tests near maximal work capacity daily, increasing the treadmill grade until the increase in ˙VO2 was less than half to one-third that which was observed at submaximal workrates. Only 7 of 115 subjects failed to achieve this criterion, thus firmly establishing the concept of ˙VO2,max as a measure of cardiorespiratory performance. However it must be acknowledged that this actual finite point can be challenging to demonstrate with small increments in external work. This is especially true in subjects with relatively small anaerobic capacities, who are unable to sustain the high work rates long enough for oxygen uptake to stabilize, and for whom the difference between expected and measured changes in ˙VO2 is within the experimental noise of the technique.

Fortunately this issue was put to rest recently by a study which provides unequivocal experimental evidence validating the concept of ˙VO2,max – that is, that there exists a finite rate of oxygen uptake of a given organism (at a particular fraction of inspired oxygen (FIO2 ) and fitness level), beyond which increasing the work rate does not lead to more oxygen uptake (Hawkins et al. 2007). In this study by Hawkins et al. (2007), a group of well-trained collegiate middle-distance runners performed an incremental exercise test, followed the next day by a ‘supramaximal’ test designed to determine anaerobic capacity from the accumulated oxygen deficit (Medbo et al. 1988). In this study, which included 156 pairs of incremental and supramaximal tests, the subjects were able to accomplish and sustain a very large amount of extra work – more than 30% greater than would be required to support such work rates oxidatively – using great motivation (and pain tolerance) and large amounts ofmuscle motor recruitment, and making energy for that work by high rates of glycolysis and substrate level phosphorylation; yet ˙VO2,max was rarely higher, and never substantively so, than on the incremental test. Most importantly, it never even came close to the oxidative requirements of the higher workload, despite the clear documentation of a levelling off of oxygen uptake in response to the acute initiation of the very intense work rate. The central figure from this study is reproduced as Fig. 1. Thus it cannot be argued that during the incremental test to ˙VO2,max, a ‘central governor’ stopped the test before an actual ˙VO2,max to avoid ischaemia or other disturbance, because the subjects were quite capable of exercising on a separate effort at a much higher external work rate yet no such ischaemia occurred. Others have reported similar data recently including reasonable estimates ofmyocardialwork (Brink-Elfegoun et al. 2007). Finally, it isworth emphasizing that patientswith coronary heart disease are regularly stressed beyond the point of myocardial ischaemia, which does not prevent them from continuing to exercise (Chaitman, 2005) – their ‘central governors’ must fail them all the time!

If ˙V O2,max exists, why is it so large in endurance athletes?
It should be emphasized that ˙VO2,max is not equivalent to sport performance, by which I mean the time it takes to cover a specific distance under competitive circumstances, or scoring more points then an opponent in a team or individual game sport. Rather it is a physiological characteristic bounded by the parametric limits of the Fick equation:
left ventricular (LV) end − diastolic volume − LV end− systolic volume) × heart rate × arteriovenous oxygen difference.

Some simple calculations help to highlight these boundaries. First, let’s assume a maximum haemoglobin concentration for competitive athletes of 17 g dl−1 for men, the upper limit established by the Federation Internationale de Ski (FIS) for allowing athletes to begin a race. If we assume 100% arterial oxygen saturation (i.e. no diffusion limitation or ventilation/perfusion ( ˙V _Q) mismatch, certainly an overestimation in competitive athletes), and the lowest mixed venous oxygen saturations measured–14%near the summit of Mount Everest (Sutton et al. 1988b), then the largest possible arteriovenous (a–v) O2 difference would be 200 ml l−1 (20 vol percentage). This value is within 10–20% or so of the values that have been reported in elite athletes (Ekblom & Hermansen, 1968). Notably, peak a–v O2 differences in non-athletes are not much below the values observed in elite athletes (Sutton et al. 1988a, 1992; Hagberg et al. 1985), arguing that the major factor underlying the large ˙VO2,max of endurance athletes is a large cardiac output. This contention is buttressed by the observations made by Mitchell et al. (1958), now half a century ago, that the levelling off of ˙VO2 with increasing workrate at ˙VO2,max was associated with a clear levelling off of cardiac output. Since maximum heart rate of athletes is, if anything, lower than that of non-athletes (Rowell, 1986), it follows that the primary distinguishing feature of athletes is their large stroke volume. Since end-systolic volume has never been reported to be smaller in athletes than non-athletes, the single most important factor allowing this large stroke volume is a large end-diastolic volume.

Work in our laboratory more than 15 years ago demonstrated the mechanism for this unique characteristic (Levine et al. 1991), using direct invasive techniques. Endurance athletes have a markedly greater ability to use the Starling mechanism to increase stroke volume. Contractility was not different between athletes and non-athletes, so virtually all the difference in stroke volume was due to a large end-diastolic volume. Athletes were able to achieve such a large end-diastolic volume by virtue of markedly enhanced cardiac chamber compliance (Fig. 2). Both static compliance determined from pressure (P)–volume (V) curves, and operational compliance determined from dV/dP of the P–V curve were substantially larger in the endurance athletes (Levine et al. 1991). In these studies, the largest hearts for male athletes showed an end-diastolic volume in the supine position during volume infusion of around 250 ml, which generated a stroke volume of around 130–150 ml; for peak heart rate of 200 beats min−1; this gives a peak cardiac output of about 30 l; Assuming maximal possible a–v O2 difference, these characteristics would give a ˙V O2,max of about 6–7 l min−1 as seen in large, elite skiers or rowers (Ekblom et al. 1968; Jensen et al. 2001). To the best of my knowledge, the largest published cardiac output during exercise along with the largest stroke volume may be those reported in a world-class orienteer of 42.3 l min−1 and world champion cyclist of 212 ml (Ekblom et al. 1968) respectively, though anecdotal unpublished comments have suggested the possibility of higher values ( The highest reported ˙VO2,max of which I am aware is 7.48 l min−1 in a large, elite skier (Saltin, 1996). Studies in dogs (Stray-Gundersen et al. 1986) and pigs (Hammond et al. 1992) provide evidence that the pericardium provides a critical restraint to maximal LV filling. When the pericardium was removed in these studies, maximal LV end-diastolic volume was significantly increased, leading to increased cardiac output and ˙VO2,max. Thus the key distinguishing characteristic of elite endurance athletes is a large end-diastolic volume due to compliant heart and a distensible pericardium.

Not only must the heart be compliant, but in order to fill to these large end-diastolic volumes during maximal exercise with very high heart rates, it must have very rapid diastolic relaxation with vigorous suction. Work by Ferguson et al. (2001) has shown that athletes do indeed have hearts that fill more rapidly at high levels of exercise intensity, which allows endurance athletes to continue to increase stroke volume at all levels of exercise (Gonzalez-Alonso et al. 2007). Diastolic suction develops because the remodelling of the athlete’s heart (Pelliccia et al. 1999) increases the equilibrium volume of the left ventricle, whichis the volume in the heart when transmural filling pressure is 0 mmHg (Nikolic et al. 1988; Yellin et al. 1990). When the heart contracts below the equilibrium volume in systole, it engages mechanical restorative forces which markedly augment the transmitral intraventricular pressure gradients that literally ‘suck’ blood from the left atrium across the mitral valve into the apex of the left ventricle (Yellin et al. 1990). This active process is particularly important during upright exercise when gravitational gradients must also be overcometo maximize venous return (Levine et al. 1997).

The point of going through these calculations is that there must be finite and fixed limitations to all the components of the Fick equation, thus providing absolute upper boundaries on maximum oxygen transport in humans (despite extraordinary rates of voluntary motor recruitment!). Assuming maximal possible a–v O2 difference, and the highest reported exercise cardiac output, this absolute upper limit for ˙VO2,max is about 8 l min−1 (and almost certainly lower due to the low likelihood of matching maximal possible a–vO2 difference with maximal cardiac output in the same athlete at the same time, due at least in part to ventilatory limitations which are prominent in endurance athletes (Dempsey & Wagner, 1999). Ultimately then, it is the broad concept of ˙V O2,max that is important for this discussion, not the fine distinction of the specific limitations which may change under different circumstances. Moreover, it doesn’t matter at all whether Hill did or did not actually ‘prove’ a plateau in ˙VO2,max in 1923 – it is the concept that these parametric limits exist that is important for understanding exercise performance. Of course the factors determining oxygen uptake are not independent, and where the ‘limits’ to ˙VO2,max lie depends on the nuance of howthe question is asked(Wagner, 2006). Thus, increasing cardiac output by itself may increase diffusion limitation at the lung or at the skeletalmuscle and therefore not buy more oxygen transport; this problem is especially true at high altitude where the gradients driving diffusion of oxygen from the alveoli into the pulmonary capillary are greatly reduced (Johnson, 1967; Wagner, 1993, 1996b). Indeed maximal rates of diffusion in the periphery are so limited at high altitude that even increasing oxygen content of the blood by transfusion (Young et al. 1996) or erythropoietin (Lundby & Damsgaard, 2006) do not increase ˙VO2,max, even though increasing O2 content by increasing FIO2 – emphasizing the importance of the pressure gradient from blood to muscle cell – obviously does (Savard et al. 1995; Boushel et al. 2001).Many detailed and scholarly discussions of the limitations to ˙VO2,max have been reported by others (Saltin & Strange, 1992;Wagner, 1996a, 2006; di Prampero, 2003; Saltin & Calbet, 2006) to name only a few.

So what? What is the relationship between ˙V O2,max and performance?
Although ˙VO2,max is not performance, it clearly is one of the major characteristics that determine performance in endurance sport (Peronnet et al. 1991; di Prampero, 2003). Sometimes this relationship may be obscure when only elite athletes with similar ˙VO2,max values are considered (Noakes, 1997, 1998; Bergh et al. 2000). However, an elite athlete with a ˙VO2,max of 80 ml kg−1 min−1 can surely run 5000m faster than a recreational athlete with a ˙V O2,max of 40 ml kg−1 min−1 can, so this characteristic is clearly closely tied to endurance performance (Bergh et al. 2000; di Prampero, 2003). Of course, it depends on the distance being covered, which determines the rate of optimal/possible energy utilization and the substrate used to produce ATP, how much ˙VO2,max contributes to performance (Peronnet et al. 1991; di Prampero, 2003; Joyner & Coyle, 2007).

Moreover, it has been widely recognized for decades that ˙VO2,max is not the only characteristic that determines how fast an athlete can travel, especially as the differences in outcome at a world-class level are measured in fractions of a second. Other traits such as sport-specific economy, anaerobic capacity and, for longer distances, fuel utilization and the speed or oxygen uptake at the maximal steady state will all contribute to the final count on the stop watch (Joyner, 1991; Peronnet et al. 1991; di Prampero, 2003; Joyner & Coyle, 2007). Since maximal oxygen delivery has little to do with most of these factors, it should not surprise anyone that athletes can perform at work rates higher than ˙VO2,max for brief periods of time, even if ˙VO2,max is indeed limited by cardiovascular performance. Every sprinter knows this fact – but no amount of voluntary motor recruitment can allow an athlete to run at a rate of 10ms−1 for the distance of a marathon. Why is this? Is it because humans do not have the motivation to sustain such high rates of muscle contraction for more than 10 s or so? Because a ‘central governor’ knows that it is dangerous to do so for more than 100 m? Or is it because human skeletalmuscle cannot produce enough ATP at a high enough rate for a sustained period of time (or regenerate it on a sustained basis via oxidative metabolism) to support this kind of external work? It seems clear that the muscle (not the brain) is fatiguing over these brief bursts of extremely high levels of motor recruitment, though of course such local signals are communicated to the brain and influence the athlete’s sense of how fast they can continue to run. Such sprint athletes are able to generate so much force from such intensemotor recruitment that they rip theirmuscles apart (Thelen et al. 2006), yet they don’t stop sprinting because of inadequate central drive or myocardial ischaemia. No one disputes the fact that motivation and voluntary motor recruitment influenced by sensations coming fromskeletal muscle (not the vague action of a ‘central governor’) play a role in exercise performance, and in noway does this reality violate any tenet of the concept of ˙VO2,max and cardiovascular performance.

It may be instructive to examine how ˙VO2,max changes with hypoxia at altitude, to demonstrate the tight relationship between ˙VO2,max and performance, even in athletes with relatively uniform ˙VO2,max. It has long been known that ˙VO2,max decreases with high-altitude exposure or hypoxia (for review, see Fulco et al. 1998), and that in athletes, this decrease is evident at altitudes as low as a few hundred metres (Terrados et al. 1985; Lawler et al. 1988; Gore et al. 1996; Wehrlin & Hallen, 2006). The mechanism for this reduction is related to diffusion limitation in the lung,which is exaggerated in athletes with high pulmonary blood flows (Johnson, 1967; Torre-Bueno et al. 1985; Levine & Stray-Gundersen, 1999) and who may develop exercise-induced hypoxaemia even at sea level (Dempsey &Wagner, 1999) (see Fig. 3). Not only does ˙VO2,max decrease, but exercise performance at altitude clearly deteriorates at all running distances greater than 800m (events lasting longer than 2 min (Peronnet et al. 1991). Noakes et al. (2001) have suggested that this decrease in ˙VO2,max and performance is a function of reduced motor recruitment, and argue that it provides evidence in support of the central governor model. However, this speculation has recently been proved convincingly to be incorrect.

Some insight can be obtained from an early studyby Medbo et al. (1988), who elaborated on the Krogh and Lindhard concept of the accumulated oxygen deficit as a measure of anaerobic capacity. In this study the investigators performed supramaximal exercise on a treadmill after careful assessment of individual running economy. During the uphill run, the total energy expended during the test was divided into aerobic and anaerobic components, and the anaerobic capacity was defined as the difference between the predicted cost of the total work if all energy had been derived from oxidative sources, and the directly measured accumulated oxygen uptake. Central to the proof that this measure is truly representative of anaerobic capacity is the demonstration that it is independent of oxygen uptake, and unaffected by hypoxia. Consistent with this hypothesis, the data showed that there was no difference in the anaerobic capacity measured under normoxic and hypoxic conditions, equivalent to an altitude of 3500 m; 100% of the reduction in performance (slower speed, lower grade) was due to a reduction in accumulated oxygen uptake. However, in order to keep the duration of the test constant in normoxia and hypoxia, the speed and grade of the treadmill had to be reduced.

More recently, Wehrlin & Hallen, (2006) extended this work by performing repeated supramaximal running tests in a group of trained athletes at multiple low to moderate altitudes from 300m to 2800 m. In order to ensure that motor recruitment and power output were the same in all tests, each supramaximal test was performed at exactly the same speed, at 107% normoxic velocity at ˙VO2,max. Despite keeping the speed absolutely constant at all altitudes, ˙V O2,max was reduced progressively and linearly by 0.6% per 100m altitude, in direct proportion to the reduction in oxygen saturation (SpO2 ) (Wehrlin & Hallen, 2006); performance was reduced by 1.4% per 100m altitude in direct proportion to the decrease in ˙VO2,max. This study provides strong evidence that: (a) ˙VO2,max is closely tied to oxygen transport, even when the differences are quite small, especially in well-trained endurance athletes; and (b) the reduction in ˙VO2,max at altitude is not likely to be due to decreased motor unit recruitment since running speed was constant at all altitudes studied.

What next?
So why do athletes stop exercising at ˙VO2,max? This is a complex question that is beyond the scope of this essay, and the answer unquestionably varies depending on the circumstances of the exercise effort. Certainly, oxygen-dependent pathways are involved in energetic failure (Kindig et al. 2005), though these may be more important in muscle fibres that are less rather than more oxidative (Howlett & Hogan, 2007). A very recent series of ‘mini-reviews’ summarizes the state of the art in this field (McKenna & Hargreaves, 2007) and emphasizes that there is a multiplicity of factors responsible for inducing local muscle fatigue, including failure of sarcoplasmic reticulum calcium release (Allen et al. 2007), impaired sodium/potassium pump activity (McKenna et al. 2007), and slowed cross-bridge cycling (Fitts, 2008) due to a variety of metabolic mediators including reactive oxygen species (Ferriera & Reid, 2008). It is also clear that these muscle factors stimulate a number of neural pathways (Todd et al. 2007) that ultimately lead to reduced central motor drive and neural activation (Amann & Calbet, 2007; Amann et al. 2006).Under certain conditions suchas severe acute hypoxia, central fatigue may be quite prominent and cause exercise effort to be compromised even before peripheral fatigue develops (Amann et al. 2007). It is highly likely that many of these factors are redundant, and may be more or less prominent in leading to cessation of effort under different circumstances. Defining the link between metabolic demand, cardiovascular control (including the regulation of cardiac output and local muscle blood flow), and fatiguing exercise including the afferent receptors, neural pathways and central integration will be an important direction for future research.

Lastly, it is intuitively obvious to anyone who has grown up on a playground that some individuals are more gifted athletically than others. Not only are there those that are bigger, stronger and faster, but also those with more endurance. Recent evidence suggests that at least some amount of ˙VO2,max is heritable (Bouchard et al. 1998; Hagberg et al. 2001), though identification of specific genes has been less convincing. For example, despite the early enthusiasm for genes that govern the angiotensin converting enzyme (Myerson et al. 1999; Gayagay et al. 1998), it is quite clear that large numbers of successful endurance athletes do not have the ‘endurance genotype’ (Gayagay et al. 1998;Woods et al. 2001; Tsianos et al. 2004; Lucia et al. 2005; Scott et al. 2005). How much does this have to do with differences in underlying genotype or, more importantly, gene–environment interactions? What are the limits of phenotypic plasticity in response to training? For example, training studies in our lab show the ability to achieve the same LV mass as elite endurance athletes with 1 year of training (Morrow et al. 1997, 1998; Levine et al. 1998). However, LV end-diastolic volume and compliance remain much lower than we have previously reported in cross-sectional studies of endurance athletes (Levine et al. 1991). Is this a function of pericardial constraint which needs more than 1 year to dilate? Do we just need many more years of training? Or rather is it more important that training occurs during growth and development to achieve optimal cardiac size and compliance (Saltin et al. 1995)?

In conclusion, the key take home messages from this essay are: (1) ˙VO2,max is an important determinant of endurance performance which represents a true parametric measure of cardiorespiratory capacity for an individual at a given degree of fitness and oxygen availability; (2) the primary distinguishing characteristic of elite endurance athletes that allows them to run fast over prolonged periods of time is a large, compliant heart with a compliant pericardium that can accommodate a lot of blood, very fast, to take maximal advantage of the Starling mechanism to generate a large stroke volume; (3) athletes stop exercising at ˙VO2,max because of severe functional alterations at the local muscle level due to what is ultimately a limitation in convective oxygen transport, which activates muscle afferents leading to cessation of central motor drive and voluntary effort.

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