Authored by Evan Peikon*,
Abstract
It is widely believed that peak cardiac output and total body hemoglobin content are the dominant and deterministic pathways that account for the vast majority of interindividual variability in VO2max. This article presents a case that VO2max represents the maximum integrated capacity of the cardiovascular, pulmonary, and muscular system, and that ‘limiting’ factors for VO2max can vary between individuals.
Introduction
It is popularly believed that the dominant and deterministic pathways that account for the vast majority of interindividual variability in VO2max are well known and center on total body hemoglobin content and peak cardiac stroke volume, and as a result, cardiac output [1]. Some go as far as to assert that VO2 max improvements are determined by an increase in stroke volume and relatively preserved oxygen-carrying capacity of the blood [2,3]. This paradigm emerged as a result of Archibald Hill’s work in the early 1900’s. Undoubtedly, Archild Hill’s work contained many partial truths, but its partial validity should not mask its shortcomings. There are certain instances where other factors can become the “weak link” in the transport and utilization of oxygen. One example is in elite athletes with high maximal cardiac outputs. The decreased transit time of red blood cells in the pulmonary capillary can also lead to a pulmonary diffusion limitation [4,5].
According to the late philosopher Karl Popper, a theory or conjecture can only belong to the empirical sciences if it is falsifiable. According to this criterion, a theory is falsifiable if it is refutable. Naturally, it follows that a theory is refutable if there exists at least one potential falsifier [6]. Although many logical refutations have been made to the idea that cardiac output is the dominant factor contributing to interindividual variations in VO2max, it is still the dominant paradigm in exercise physiology. According to Tim Noakes, this belief has straight-jacketed exercise physiology for the past sixty-two years [7]. If scientific observations don’t agree with the dominant theory, the theory is meant to be abandoned. At least, that is how it is supposed to happen. In practice, people are very reluctant to give up a theory in which they have invested a lot of time, and effort into or dominant paradigms remain due to path dependency, as has often been the case in exercise science [8,9]. According to the late physicist Stephen Hawking, “[scientists] usually start by questioning the accuracy of the observations. If that fails, they try to modify the theory in an ad hoc manner. Eventually, the theory becomes a creaking and ugly edifice. Then someone suggests a new theory in which all the awkward observations are explained in an elegant and natural manner” [10].
This paper reviews the evidence that the central cardiovascular systems’ ability to transport oxygen to the tissues is not the principal determinant of VO2max, but one of a handful of potential physiological rate-limiting factors that can limit VO2max in an individual. Additionally, this paper asserts that in addition to the central cardiovascular system, other deterministic pathways accounting for interindividual variations in VO2max are the pulmonary diffusion capacity for oxygen and carbon dioxide, which is largely impact by the fatigue resistance of the diaphragm muscle, as well as the metabolic capacity of skeletal muscle, among other secondary factors which will be discussed further in this paper. These assertions should not be interpreted as attacks on tradition. In order to see further than scientists of the past we must stand on their shoulders, pay them respect, and learn from them. We do not honor the past, however, when we cling to its conventions in the face of disconfirming evidence.
Classical Views of VO2max
What is VO2max and how is it measured?
VO2max refers to the maximum rate of oxygen consumption measured during intense exercise. VO2max can be measured in absolute liters of oxygen consumed per minute (L/min) or relative to weight in milliliters of oxygen consumer per kilogram of body mass per minute (mL/Kg/min). The concept that there exists a finite rate of oxygen transport from the environment to the mitochondria of exercising muscles began with Archibald Hill and Hartley Lupton [11]. Since then, VO2max has become one of the most ubiquitous measurements in all of exercise science. VO2max is a physiological characteristic bounded by the parametric limits of the Fick Equation, which states the following: VO2max = Q*[CavO2], where Q stands for cardiac output, which can be calculated as stroke volume multiplied by heart rate and Ca-vO2 represents the arterio-venous oxygen difference [12].
The best-accepted method for measuring VO2max is the cycle ergometer ramp test completed to exhaustion, though other modalities can be used effectively. This test involves exercising at an intensity that increases every few minutes until the participant reaches volitional failure at a maximal exertion point. During this test, a participant will wear a face mask to measure the volume of gas concentrations of inspired and expired air. It’s important to note that an individual’s maximum attainable rate of oxygen consumption will vary slightly based on the specific protocol they are tested with and the modality they are tested on. As a result, it’s important to conceptualize VO2max as a range of values rather than a single discrete number for each individual.
Classical views of VO2max emphasize its critical dependence on convective oxygen transport to the working muscles. Yet, there is little discussion of how the pulmonary or local muscle oxidative capacity may impact VO2max. This belief that central factors, such as stroke volume and cardiac output, are the primary limiters of VO2max has become so entrenched within exercise physiology that these underlying assumptions are rarely questioned. This isn’t to say that central factors are not of high importance in predicting an individual’s VO2 max. That would be disingenuous based on the large body of literature suggesting otherwise, which I will analyze in the next subsection section of the paper. However, I believe there is good reason to believe that other factors can, and do, limit VO2 max and performance in both novice and elite athletes, which will be discussed later on.
Classic views regarding limitations to VO2max
As previously discussed, VO2max is calculated by the Fick Equation, which states the VO2max = Q*[Ca-vO2] where Q stands for cardiac output, which is calculated as stroke volume multiplied by heart rate and Ca-vO2 represents the arterio-venous oxygen difference [12]. Although oxygen transport to the skeletal muscle is a product of both blood flow and arterial oxygen saturation, the latter has been dismissed as a potential limiting factor in healthy athletes. Instead, the dominant paradigm is that central factors primarily constrain VO2max and that cardiac output, and more specifically stroke volume, is the most critical physiological or structural component of VO2max in humans [1].
Despite the fact that heart rate is also a prime contributor to cardiac output, the fact that heart rate is similar among young humans has been used to assert that stroke volume is the most important factor contributing to inter-individual differences in VO2max [1]. This makes sense given that the enlargement in cardiac dimension, improved contractility of the heart, and an increase in blood volume are all common cardiovascular adaptations to exercise training, all of which allow for a greater filling of the ventricles and consequently, increased stroke volume [13]. Additionally, the thoracic pump can also function to increase stroke volume, thereby linking changes in breathing to increases in cardiac output as well. When one takes a deep breath in, there is an immediate decrease in intrathoracic pressure, which decreases central venous pressure. When central venous pressure drops, it creates an increased driving pressure, which promotes greater venous return. Because the cardiovascular system is a closed-circuit, any increase in venous return will ultimately increase cardiac output. In the case of the thoracic pump, an increase in venous return causes an increase in end-diastolic volume, stroke volume, and, subsequently, cardiac output.
There is also evidence that changes in blood hemoglobin concentrations and hemoglobin mass will impact the central factors that constrain VO2max. For example, Per-Olof Åstrand showed a close relationship between total Hb mass and VO2 max such that the differences between adults and children and between men and women were primarily due to differences in total hemoglobin [14]. Additionally, it has been shown that an acute reduction in Hb concentration, even when blood volume is maintained, results in lower endurance performance due to a decreased oxygencarrying capacity of the blood [15]. Conversely, an increase in Hb concentration is associated with enhanced endurance capacity and is also proportional to the increase in the blood’s oxygen-carrying capacity [15]. Because increases in blood volume will also thereby lead to an increase in end-diastolic volume, ejection fraction, and stroke volume, there is a clear association between increases in Hb concentration and blood volume and an increase in VO2max (Figure 1).
Counterevidence to central factors as the dominant & deterministic limiters to VO2max
There is substantial evidence that central factors, namely maximal cardiac output, is a limiting factor for VO2max [16]. However, the presence of one limitation does not mean that VO2max cannot be limited by other factors like the pulmonary system or oxygen utilization within the working skeletal muscle or that there aren’t cases where improving maximal cardiac output does not improve VO2max. Simply put, the existence of one phenomenon does not disprove the presence of another. Similarly, the efficacy of one training method that has shown to be efficacious for improving VO2max, like high-intensity interval training, does not mean that different exercise prescriptions will not also show an improvement in the same variable [17]. George Brooks eloquently presented this idea when he said, “It is wise to note that we are all individuals and that whereas physiological responses to particular stimuli are largely predictable, the precise responses and adaptations to those stimuli will vary among individuals. Therefore, the same training regimen may not equally benefit all those who follow it” [18]. There is evidence that the inter-individual variability in response to a specific training method may have to do with what physiological systems are best developed at the time of the workout in an individual and what their limiting factor for VO2max is.
As early as the early 1900s, it was speculated that other factors limit oxygen delivery to the working muscle than the circulatory system. According to Hill, Long, and Lupton, “In running the oxygen requirement increases continuously as the speed increases, attaining enormous values at the highest speeds; the actual oxygen intake, however, reaches a maximum beyond which no effort can drive it. The oxygen intake may attain its maximum and remain constant merely because it cannot go any higher owing to the limitations of the circulatory and respiratory system” [19]. Since then, there has been additional evidence supporting the belief that the pulmonary system can be a limiting factor in maximal effort exercise. For example, in elite athletes with very high maximal cardiac outputs, the decreased transit time of red blood cells in the pulmonary capillaries can lead to a pulmonary diffusion limitation. This was demonstrated in 1965 when the former mile world record holder Peter Snell performed a maximal treadmill step test, where he finished with a SpO2 level of 80% [20]. Additionally, this finding was later confirmed by Dempsey et al. and Powers et al. when they showed that arterial oxygen desaturation occurs in some highly trained endurance athletes and they when these subject’s breath hyperoxic gas mixtures, their hemoglobin saturation and VO2max increase [21,22]. It has also been shown that arterial desaturation occurs in intermediate to advanced Crossfit competitors when performing maximal step tests and sport-specific competitions [23]. This data suggests that pulmonary gas exchange may contribute significantly to the limitation of VO2max in highly trained athletes who exhibit exercise-induced reductions in SpO2 at sea level, as well as the fact that a healthy pulmonary system may become a socalled ‘limiting’ factor to oxygen transport and utilization as well as CO2 transport and elimination during maximum short-term exercise in the highly trained.
According to the Fick equation, every change in VO2max is matched by a concomitant change in maximal cardiac output or arteriovenous difference [24]. One mechanism by which impaired pulmonary diffusion would limit VO2max would be by lessening the arteriovenous difference. If that reason holds, then a widening of the arteriovenous difference, in individuals with a pulmonary limitation, should be accompanied by an increased VO2max, which has been shown to occur [22]. Additionally, an oxygen extraction limitation may be present, which would also truncate the arteriovenous oxygen difference. As a result, an improvement in oxygen extraction would be accompanied by an increase in VO2max in individuals with impaired oxygen extraction due to an increase in the arteriovenous difference [25].
It’s important to consider that improvements in VO2max from increased maximal cardiac output and a widened arteriovenous difference are not independent phenomena. As alluded to previously, it is not a question of ‘either, or’, but a question of which variable is the primary ‘limiting’ factor in oxygen transport and utilization in an individual. This has been demonstrated by Skovereng, et al., where it was shown that VO2max was increased through both an improvement in peak cardiac output as well as a widened a-v¯O2 diff, which were attributed to cardiac remodeling and mitochondrial biogenesis respectively [26].
When we analyze the VO2max literature through the privileged lens of twenty-first-century scientific insight, the traditional view that maximal cardiac output is the dominant and deterministic limiter to VO2max longer fit. The collapse of the traditional paradigms conceptual foundations leaves a void, yet simultaneously creates opportunities to re-evaluate conventional doctrines and evolve more nuanced perspectives. As a result, I propose we make an affordance of David Poole’s definition of VO2max and redefine the term as the maximum integrated capacity of the pulmonary, cardiovascular, and muscular systems to uptake, transport, and utilize oxygen, respectively [27
Re-Envisioning Traditional Paradigms of Exercise Limitations
VO2max as a measure of integrated capacity
In this last section, I suggested that we re-define the term VO2max to mean the maximum integrated capacity of the pulmonary, cardiovascular, and muscular system to uptake, transport, and utilize oxygen [27]. This is in opposition to the traditional definition of VO2max, which is the maximum rate of oxygen consumption measured during intense exercise. The latter is a reductionist take on a complex variable, whereas the former is more holistic. In spite of the fact that there is mounting evidence that VO2max can be limited by multiple different physiological variables including pulmonary diffusion capacity for oxygen, maximal cardiac output, peripheral circulation, and metabolic capacity of skeletal muscle, most coaches and physiologists still do not hold this view [28]. Instead, most coaches and physiologists believe that the central cardiovascular system’s capacity to transport oxygen to the working muscles is the principal determinant of VO2max.
This paradigm emerged as a result of Archibald Hill’s work in the early 1900’s. Archild Hill’s work undoubtedly contained many partial truths, but its partial validity should not mask its shortcomings. It is crucially important to remember that Archibald Hill formulated his hypothesis based on a small number of measurements, specifically of expired respiratory gases [11]. He included no measurements of cardiovascular function or detailed respiratory function, nor did he take any measurements of skeletal muscle, metabolic, or contractile function. An unfortunate consequence of this is that generations of exercise scientists have been taught that you can simply use respiratory gas analysis to give you answers on the factors that limit human performance, but I believe this inherited wisdom is incorrect. For example, in Hill’s quantitative estimates, he calculated that arterial blood would be 90% saturated during allout exercise, and mixed venous blood would be 10-30% saturated, and these values would be generalizable to all exercising athletes [16]. This assumption leads one to assume that the arteriovenous difference would be nearly fixed, which would lead to the natural conclusion that cardiac output would be the primary determinant of VO2max, as Hill asserted. As citizens of the 21st century, we have the privilege of information and past technological innovations that Hill would not have access to, like the ability to measure both arterial oxygen saturation (SpO2) and muscle oxygen saturation (SmO2). As a result, we know that there is quite a bit of variability in athletes’ arterial oxygen saturation levels during maximal effort exercise as well as the ability to utilize oxygen in the working muscles, which means that there is a range of arteriovenous oxygen differences that can occur [29,23,30]. This opens the door for us to explore other limiting factors for VO2max other than maximal cardiac output like pulmonary diffusion limitations or skeletal muscle oxidative capacity limitations [31,24]. These variations in individual rate-limiting factors for VO2max can explain why different athletes’ responses to standardized training programs can be remarkably diverse [32]. Many of these inter-individual variations can be observed with technologies like near-infrared spectroscopy.
The Future is NIRS
NIRS stands for near-infrared spectroscopy. NIRS is a technology that allows one to measure in vivo oxidative metabolism in human skeletal muscle. A NIRS device consists of a light source emitting two or more wavelengths in the near-infrared range of 650-1000nm and a detector placed at a known distance from the light source. Since near-infrared light is able to penetrate biological tissues with less scattering and absorption than visible light, it offers many advantages for imaging and quantitative measurements. These quantitative measurements depend on the physics principle of reflectance, which is outlined in the Beer- Lambert law. This law states that certain materials attenuate the transmission of light at specific wavelengths, and when this equation is adapted to match the properties of human muscle, it allows one to measure changes in oxygenated and deoxygenated hemoglobin concentrations within a given muscle. This is made possible because the chromophores hemoglobin and myoglobin are oxygen carriers in the blood and skeletal myocytes, respectively, and their absorbance of near-infrared light depends on whether they are in an oxygenated or deoxygenated state [33]. As a result, NIRS measurements can be used to reflect the balance of oxygen delivery to the working muscles and oxygen consumption in the capillary beds [34]. This makes NIRS a very useful tool for assessing two of the major determinants of exercise capacity, which are oxygen delivery and oxygen utilization, respectively [33].
According to Tim Noakes, the belief that oxygen delivery alone limits maximal exercise performance has straight-jacketed physiology. Thus, performance during both maximal and submaximal exercise has been explained exclusively in terms of oxygen transport, and local muscle intrinsic factors have largely been ignored [7]. At the time when VO2max testing procedures were conceived, the ability to measure local muscle intrinsic factors was limited, but with the increased accessibility of NIRS devices, we can now measure in vivo oxidative metabolism, which has massive implications for exercise testing. For example, it was previously believed that the arteriovenous difference was nearly fixed, which leads one to make the natural assumption that maximal cardiac output accounts for the vast majority of inter-individual differences in VO2max [11,16,19]. At the time when this assertion was first made, it was not possible to measure the oxygen concentration of mixed venous blood. However, NIRS technology makes that possible. In figure II, we see two NIRS trends from two competitive Crossfit athletes performing a 30-second maximal sprint on an exercise bike. We see that the athlete on the left is only capable of desaturating local muscle oxygen saturation down to 37%, while the athlete on the right is capable of desaturating the working muscles down to 3% muscle oxygen saturation [23]. This suggests that the former athlete has an oxygen extraction limitation, which truncates their arteriovenous oxygen difference. As a result, improved oxygen extraction in this individual would likely result in an increase in VO2max due to an expanded arteriovenous oxygen difference. However, the later athlete is incapable of expanding their arteriovenous oxygen difference, and as a result, the vast majority of improvements in VO2max would come through increased maximal cardiac output for this individual [23] (Figure 2).
Conclusion
These findings and many others, strongly suggest that there are many instances where factors other than maximal cardiac output can become the ‘weak link’ in the transport and utilization of oxygen, and subsequently, VO2max. I suspect that innovative coaching practices, both in the past and present, have already incorporated dimensions of what I’ve noted here into elite training ethos and systems. Importantly, however, such practices have been driven primarily by coaching intuition and experience. Such coaching innovations and systems sit outside conventional training theory and remain ignored in the endurance training literature. As a result, it is often said that science follows the best coaches by decades. This paper is my best attempt to pick up the breadcrumbs left by innovative coaches and present a theory that can be further tested and expanded upon in the future.
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