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Opinion ARTICLE

Front. Cardiovasc. Med., 12 June 2019 | https://doi.org/10.3389/fcvm.2019.00078

Skeletal Muscle O2 Diffusion and the Limitation of Aerobic Capacity in Heart Failure: A Clarification

David Montero* and Candela Diaz-Canestro
  • Faculty of Kinesiology, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada

Introduction

The capacity to convey oxygen (O2) from the atmosphere in to mitochondria essentially determines maximal aerobic metabolism in humans (16). The inherent constitution of the O2 transport and utilization chain is asymmetrical, not all steps have the same importance (7, 8). Intracellular biochemical mechanisms that could in theory limit O2 utilization are overbuilt in relation to the potential delivery of O2 through the circulatory system (2, 3, 9). Peak oxygen consumption (VO2peak), a hallmark of aerobic capacity elicited by incremental exercise involving more than half of total muscle mass, is mainly determined by the circulatory capacity to deliver O2 to working muscle even in the presence of compromised muscle oxidative capacity (5, 7, 8). Glaring evidence of the impact of the circulatory system on VO2peak includes conditions such as heart failure (HF), intrinsically linked with impaired cardiac output and thus limited convective O2 delivery (2, 6). VO2peak is a strong and independent predictor of survival in HF patients used to determine eligibility for cardiac transplantation (6, 10, 11). After diagnosis of HF, survival estimates do not exceed 50% at 5 years (12, 13).

Understanding the physiology of O2 delivery and thereby VO2peak in HF may facilitate the identification of target mechanisms and the advent of effective treatments. While classic empirical studies in HF patients support the primary role of impaired cardiac pumping capacity in the limitation of VO2peak (14, 15), a recent paradigm based on theoretical assumptions attribute the main importance to skeletal muscle abnormalities in O2 diffusion from capillaries in to mitochondria (16). Given the radical change of rehabilitation programs implicit in the “skeletal muscle” paradigm, herein we sought to shed light on the foundation of this relatively new tenet in the HF field. In particular, a fundamental aspect will be clarified: the measurement and calculation of O2 diffusion in skeletal muscle.

O2 Transport Assessment: de facto Measurement of O2 Diffusion in Skeletal Muscle

The transport of O2 in living organisms follows well-known physical phenomena. O2 molecules move via (i) convection, due to the bulk motion of fluids, and (ii) diffusion, spontaneously spreading out from a region of high concentration to a region of low concentration. Along the O2 cascade, convection is the mode of O2 transport between the atmosphere and the lungs, and between pulmonary capillary blood and tissue microvascular beds, respectively determined by the bulk motion of air and circulating blood. Diffusion of O2 mainly occurs from alveoli in to pulmonary capillaries, and from tissue microvascular beds in to mitochondria. With respect to the measurement of O2 transport, both convection steps (air-to-lung, blood circulation) can be measured with relatively high accuracy in humans by means of spirometers, air/blood gas analyzers, arterial/venous blood samples and indicator-dilution/ultrasound techniques (17, 18). These well-established research methods may also be used to assess lung O2 diffusion. The final O2 diffusion step in the skeletal muscle microcirculation, however, cannot yet be directly measured. The level of resolution required to capture O2 extraction in microvessels supplying active muscle fibers is beyond reach owing to technical limitations including temporal and spatial constraints (8, 19).

The possibility seemingly exists, nonetheless, to make use of partial measurements and multiple assumptions to deliver a quantitative value for skeletal muscle O2 diffusion capacity (DMO2) (2022). Notably, in the field of HF (16), some clinical researchers are currently applying a method for estimating DMO2 conceived almost 3 decades ago (2022). Herein, DMO2 is portrayed as the ratio of skeletal muscle O2 consumption (VO2) and O2 pressure gradient between microvessels and mitochondria (21, 23, 24).

DMO2 = skeletal muscle VO2O2 pressure gradient

At first sight the notion of DMO2 appears consistent, albeit a close scrutiny of the actual measurements reveals salient incongruences. Skeletal muscle O2 consumption—calculated by the product of leg blood flow (LBF) and the difference between femoral arterial and venous O2 content (16, 21)—is primarily determined by convective O2 delivery, since LBF is substantially impaired (up to −40%) in HF conforming to the reduced pumping capacity of the failing heart (6, 25). Moreover, femoral vein O2 content is close to zero in HF patients at VO2peak (2). Therefore, the first component (numerator) of the DMO2 equation, i.e., skeletal muscle VO2, is essentially a function of convective O2 delivery (LBF × arterial O2 content) a fundamental mathematical flaw for a variable claimed to represent diffusive O2 transport (Figure 1).

FIGURE 1
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Figure 1. Common schematic illustration of convective and diffusive components of oxygen consumption (VO2) by proponents of abnormalities in skeletal muscle O2 diffusion. Leg O2 consumption is represented as a function of leg microvascular partial pressure of oxygen (PO2). Black lines depict Fick and “Diffusion” lines for healthy control individuals; red lines refer to heart failure (HF) patients. The intersection of these lines reflects the VO2 achieved (blue circles). Curved lines are derived from the established Fick Principle. Straight “Diffusion” lines are calculated by the product of skeletal muscle O2 diffusion capacity (DMO2) and O2 pressure gradient. Given that DMO2 cannot be directly measured, the “Diffusion” lines are intrinsically dependent on VO2, which is at least in part determined by cardiac output (Q), i.e., convective O2 delivery, according to the Fick Principle. Hence, “Diffusion” lines are compounded representations of convective and diffusive components of VO2.

The O2 pressure gradient between skeletal muscle microvessels and mitochondria is also estimated from femoral arterial and venous O2 content measurements, both pertaining to the macro- instead of microcirculation (16, 21). A myriad of assumptions are thus necessary to infer the postulated denominator of the DMO2 equation (20). For instance, the inherent heterogeneity of leg microvascular blood flow (26, 27), which even at VO2peak perfuses tissues (e.g., adipose tissue, bone, inactive muscle) not demanding a high VO2, is neglected (20, 21). Similarly, altered capillarization as well as anatomical and/or functional shunting within the lower limb, which may have a substantial influence in HF patients at VO2peak (28, 29), is ignored (16, 21). Taken together, the estimation of the O2 pressure gradient entails as a necessary premise that all blood flow downstream of the femoral artery perfuses active muscle fibers, in a perfect match between O2 delivery and metabolic demand, an untenable shortcoming (2628).

Considering the actual measurements underpinning the concept of DMO2, its mathematical equation would be more accurately expressed as:

DMO2 = LBF × arteriovenous O2 difference Blood flow distribution × O2 pressure gradient

Hence, the numerator and denominator of DMO2 comprise variables reflecting convective O2 delivery, LBF and blood flow distribution, respectively. The observation of reduced DMO2 in HF patients is therefore not surprising (16, 23, 24). To conclude from these studies that mechanisms underlying skeletal muscle O2 diffusion should be primarily targeted for therapy is questionable (30). Caution should be taken in the interpretation of lower DMO2 in HF patients, which can be largely attributed to abnormalities in convective O2 delivery, let alone presenting DMO2 results as the main buttress of a new paradigm (31, 32). Further research taking advantage of technological developments in measurement accuracy and resolution of O2 dynamics in skeletal muscle will have to elucidate its role in the limitation of VO2peak in HF populations.

Author Contributions

DM and CD-C contributed to study design, interpretation, and manuscript writing.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: exercise intolerance, oxygen delivery, muscle diffusion, blood flow distribution, heart failure

Citation: Montero D and Diaz-Canestro C (2019) Skeletal Muscle O2 Diffusion and the Limitation of Aerobic Capacity in Heart Failure: A Clarification. Front. Cardiovasc. Med. 6:78. doi: 10.3389/fcvm.2019.00078

Received: 09 April 2019; Accepted: 29 May 2019;
Published: 12 June 2019.

Edited by:

Chris J. Pemberton, University of Otago, New Zealand

Reviewed by:

Daryl Owen Schwenke, University of Otago, New Zealand
Risto Kerkela, University of Oulu, Finland

Copyright © 2019 Montero and Diaz-Canestro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: David Montero, david.monterobarril@ucalgary.ca