Within the realms of physiology and medicine, it is axiomatic that cardiac output is distributed among and within tissues according to their specific needs (14,33,40). Those needs vary widely from substrate delivery and utilization (O2, glucose, free fatty acids, La−), metabolite (CO2, H+, La−) and heat removal, fluid homeostasis, hormonal function, and absorption to the sensory functions of, for example, the carotid bodies. Consequently, it is not surprising that the venous effluent from different organs, even at rest, contains a range of O2 contents reflecting disparate fractional O2 extractions. Specifically, the left ventricle of the heart extracts more than 60% of its inflowing arterial O2, whereas that for the carotid body is a vanishingly small 1% to 2%. This broad range is ignored tacitly when the whole-body average of approximately 25% at rest is reported. Even within skeletal muscle in the resting individual, there exists a substantial range of blood flows (Q˙m) (30). This range becomes far wider during exercise depending, in part, on the exercise intensity (moderate, heavy, severe) and mode (small muscle mass such as knee extensor exercise or large muscle mass such as cycling or running) and how these dictate recruitment patterns across muscles and muscle groups. Thus, during severe-intensity exercise when cardiac output may increase more than fivefold above resting (Fig. 1), 80% to 90% of that blood flow is directed to skeletal muscle and whole-body fractional O2 extraction approaches 90% (30).
At these severe intensities of exercise, there may be a 10-fold range in Q˙m between and within individual muscles and muscle portions (32,42). Because muscle fractional O2 extraction can increase only approximately 3.5-fold above rest (25% to 90%) and yet muscle V˙O2 can rise 100-fold, it is evident that directing Q˙m according to local V˙O2 requirements is essential to support sustained contractile performance. This brief review focuses on the nature of the Q˙m/V˙O2 or, more correctly, Q˙O2/V˙O2 matching during rest and especially exercise in health and the causes and consequences of its derangement in aging and disease (heart failure, diabetes) among/within muscles.
During the past three decades, our view of Q˙m (and Q˙O2) heterogeneity has undergone radical revision from purely pejorative to the formulation of the novel hypothesis that exquisite temporal and spatial Q˙O2/V˙O2 matching is fundamental for effective muscle and exercise performance in health and disease.
However, key questions remain:
- What is the optimal Q˙O2/V˙O2 ratio (or distribution/heterogeneity thereof) where blood-myocyte O2 flux and intramyocyte PO2 are high enough to sustain optimal oxidative function, which also minimizes changes in high-energy phosphates required for a given V˙O2 (i.e., ensure no O2 supply dependency of mitochondrial V˙O2 kinetics, limit glycolytic activation)?
- How does the Q˙O2/V˙O2 ratio differ among muscles composed of different fiber types and could this help explain or influence their metabolic behavior?
- How does prior exercise and exercise training impact the Q˙O2/V˙O2 ratio and when are such changes intrinsic to faster V˙O2 kinetics and improved exercise performance?
- Aging and disease states, such as diabetes and chronic heart failure (CHF), each compromise the Q˙O2/V˙O2 ratio such that, across the rest-exercise transition, microvascular PO2 falls below that seen in healthy young individuals and V˙O2 kinetics are slowed. What are the mechanistic bases for this effect and can they be reversed?
- The heart is a highly oxidative muscle and sustains very high (and variable) V˙O2 at rest and especially during exercise. Can this muscle help us better understand skeletal muscle Q˙O2/V˙O2 relationships during exercise and after exercise training?
This article will present what is known at present, in these regards, and identify fruitful directions for further investigation.
What Is the Optimal Q˙O2/V˙O2 Ratio or Blood Flow Distribution/Heterogeneity?
The regional Q˙O2/V˙O2 ratio is extremely important because it determines the upstream driving pressure (i.e., microvascular PO2) crucial for achieving a given blood-myocyte O2 flux and also is an important determinant of intramyocyte PO2 and, therefore, metabolic regulation (4,6,35). On the other hand, heterogeneity in the present context can be defined as uneven distribution of blood or substrate delivery within or among/between muscles. It can be temporal or spatial in nature — the latter being the principal focus herein. Blood flow heterogeneity determines the efficacy of oxygen (and nutrient) delivery and, ultimately, tissue oxygenation levels. Although less heterogeneous blood flow has been regarded as the superior condition for good tissue oxygenation, this judgment cannot be made without considering the local muscle V˙O2 demands and the efficacy of microvascular hemodynamics, muscle O2-diffusing capacity, and mitochondrial energetics across all muscles and muscle regions recruited. Whereas it is true that a wide range of Q˙O2/V˙O2 ratios can, in theory, lead to regions where blood-muscle O2 flux is compromised, heterogeneity is not ipso facto counterproductive. Rather, this situation also may be beneficial, reflecting system flexibility and the capacity to sustain the V˙O2 kinetics response across a range of Q˙O2/V˙O2 ratios (Table). Thus, the presence of microvessel blood flow heterogeneity is not necessarily a sign of poor vascular function, and findings need to be contextualized using multiple techniques/models where possible to develop a greater understanding of the relationship(s) between Q˙O2/V˙O2 heterogeneities and function/dysfunction. In this regard, it is pertinent that both near-infrared spectroscopy (NIRS) and phosphorescence quenching have high temporal fidelity and can follow the dynamics of muscle microvascular oxy/deoxygenation across rest-exercise transitions, whereas positron emission tomography and proton magnetic resonance spectroscopy (H+MRS) are principally used for steady-state responses.
How Does the Q˙O2/V˙O2 Ratio Differ Among Muscles Composed of Different Fiber Types?
In animals and humans, Q˙m at rest and during exercise is usually the highest in muscle parts that consist mostly of slow-twitch highly oxidative muscle (30). Across the spectrum of exercise intensities, there is a biphasic profile of Q˙m heterogeneity: Greater recruitment of these highly oxidative fibers increases their Q˙m at low-to-moderate exercise intensities, but this response is absent in their lower oxidative counterparts, increasing Q˙m heterogeneity (18,32). This Q˙m heterogeneity is subsequently reduced during severe-intensity exercise as the entire spectrum of fibers is recruited (18,32). It is important to note, however, that even at supra-V˙O2max running speed, there may be an order of magnitude higher Q˙m in high versus low oxidative muscles or muscle parts (42). There also is the imperative to note here that recruitment of muscle fibers and increased Q˙m do not necessarily imply that more microvascular units or capillaries are recruited but rather that blood flow (i.e., red blood cell and plasma flux) increases within already flowing capillaries (39). In muscles composed of highly oxidative fibers, vasoactive mechanisms including endothelium-mediated vasodilation (e.g., (34)) are upregulated and α-adrenergic–mediated vasoconstriction is reduced (3) compared with their low oxidative counterparts. Thus, even when the muscles are recruited and increase their oxygen demand, microvascular PO2 falls faster and to a far lower absolute level in fast-twitch than slow-twitch muscles or muscle parts (7,35).
With respect to the increase of muscle glucose uptake during exercise, both intermuscular and intramuscular heterogeneities decrease from rest to exercise (17). Interestingly, at least during moderate-intensity exercise, muscle regional free fatty acid uptake is correlated with Qm (31), but this is not true for glucose uptake in humans (31). Whether this is the case for higher exercise intensities where there is a more uniform muscle fiber recruitment and glucose is the primary energy substrate remains to be determined.
When addressing the participation of different vasoactive mechanisms on the Q˙m response to exercise and Q˙O2-to-V˙O2 matching, it must be recognized that animal and human studies have not always been in agreement. In the case of nitric oxide (NO), it may not be possible ethically to get full NO synthase (NOS) blockade in humans (20), whereas acetylcholine challenge affirms that this is achievable in animals (i.e., rats) (9–11,23). Accordingly, both eNOS- and nNOS-derived NO contribute significantly to the Q˙m responses to moderate/heavy- and severe-intensity exercise in the rat (9–11,24). Reducing Q˙m via L-NAME reduces the contracting muscle Q˙O2/V˙O2 ratio and decreases microvascular PO2 (12,13). Interestingly, nNOS contributes proportionally more of the Q˙m response to fast-twitch muscles when these are recruited at the faster (severe) running intensities (11). Downregulation of NO bioavailability, therefore, may constitute an important mechanism for impairment of Q˙O2-to-V˙O2 matching evident in aged individuals (especially nNOS (5,23)) and in diseases such as CHF and diabetes (12,24,37).
Investigations in humans suggest that neither inhibition of NO formation (20), α-adrenergic stimulation or blockade (21), nor combined exercise and systemic hypoxia (22) significantly affects resting or exercising Q˙m heterogeneity. This is true despite the fact that resting mean Q˙m usually is altered drastically. Interestingly, however, NOS inhibition with L-NMMA does influence utilization of circulating energy substrates (19). Moreover, α-adrenergic inhibition alters limb Q˙m distribution markedly, and adenosine may play a role in distributing Q˙ to adipose tissue (15) as well as influencing Q˙m heterogeneity (18). Thus, our knowledge of the mechanistic bases for Q˙m (and Q˙O2/V˙O2) heterogeneity particularly in animals is well advanced and is helping to facilitate design and testing of provocative hypotheses in humans. It is anticipated that so doing will elucidate key elements responsible for exercise intolerance especially in aged and patient populations.
How Do Prior Exercise (Acute Response) and Exercise Training (Chronic Adaptations) Impact the Q˙O2/V˙O2 Ratio?
Whereas V˙O2max is inarguably O2 delivery limited, the presiding view is that, for most young healthy individuals performing moderate-intensity exercise, this is not the case for V˙O2 kinetics. Specifically, these individuals lie to the right of the O2 delivery limitation “tipping point” hypothesized by Poole and Jones (41). Specifically, unlike aged or patient (heart failure, diabetes) populations (41), the kinetics of Q˙O2 appear sufficiently fast to support unimpeded mitochondrial V˙O2 kinetics (see Murias et al. (36) for a provocative counterposition). One intriguing consequence of the fiber-type differences in microvascular PO2 response described above is that, when a greater fast-twitch fiber population is recruited, these fibers will necessarily be closer to the O2 delivery tipping point than their slow-twitch counterparts. It also is pertinent that, even though there may be no O2 delivery dependence of either V˙O2 or V˙O2 kinetics, this does not mean that raising (↓Δ[PCr], [ADPfree], [Pi], [NADH]) or lowering (↑Δ[PCr], [ADPfree], [Pi], [NADH]) the intracellular PO2 will not have metabolic consequences (for review, see (41)).
The NIRS-derived muscle deoxygenation (i.e., the increase in deoxygenated hemoglobin and myoglobin [HHb + Mb]) reflects O2 extraction (i.e., Q˙O2/V˙O2). The primary component kinetics of muscle [HHb + Mb] after the onset of exercise is spatially heterogeneous (30). However, in keeping with the concept that the speed of the V˙O2 kinetics is not O2 delivery limited, the degree of dynamic heterogeneity in [HHb + Mb] is not associated with any systematic variation of the pulmonary phase II V˙O2 (thus, muscle V˙O2) profile after the onset of cycling exercise.
Prior exercise (acute response)
The compelling weight of evidence supports that heavy-intensity priming exercise does not speed V˙O2 kinetics during moderate-intensity exercise (41). In marked contrast, Murias et al. (36) did observe priming-induced faster kinetics in a cohort of subjects whose initial (nonprimed) kinetics were considered to be relatively slow (i.e., time constant >20 s). Furthermore, because their [HHb + Mb]-to-V˙O2 ratio during the rest-exercise transition decreased in proportion to the speeded V˙O2 kinetics, this was considered to be evidence of O2 supply limitation in the nonprimed condition. A plausible alternative is simply that priming induced relatively greater speeding of vascular (Q˙O2) versus mitochondrial (V˙O2) dynamics.
The mechanistic bases for the changes in pulmonary V˙O2 kinetics induced by prior heavy exercise on subsequent heavy exercise (i.e., increased primary component amplitude, decreased slow component) are more robust across subject populations than those for moderate-intensity exercise above. These presumably involve enhanced mitochondrial function and/or increased O2 delivery mediated by an accentuated vasodilatation and/or a right shift in the oxyhemoglobin dissociation curve. Importantly, prior heavy exercise reduces the spatial heterogeneity of muscle oxygenation kinetics (30); the slowing of deoxygenation kinetics supports the presence of a greater Q˙O2/V˙O2 ratio at multiple intramuscular sites. However, this reduced spatial heterogeneity of muscle [HHb + Mb] kinetics did not translate into faster primary component pulmonary V˙O2 kinetics, suggesting that the heterogeneity of microvascular O2 delivery (in relation to pulmonary/muscle V˙O2) was not associated with any discernible O2 delivery limitation of the primary phase of muscle V˙O2 kinetics in healthy young subjects (30). However, intersubject variations in heterogeneity and V˙O2 kinetics may have been too small to test rigorously whether these variables were indeed correlated.
Exercise training (chronic adaptations)
Exercise training increases the speed of pulmonary (48) and muscle (30) V˙O2 kinetics. It is well documented that speeding occurs concomitant with enhanced vasodilatory capacity within skeletal muscle and that there also is a redistribution of Q˙m away from low oxidative muscles or muscle parts toward their more oxidative counterparts (33). Recently, it has been determined that training slows the fall of muscle microvascular PO2 during the rest-contractions transition indicating that, despite a training-induced increase in muscle oxidative capacity and thus faster V˙O2 kinetics, the speeding of the vascular response (and Q˙O2) must have occurred to a greater extent (23). Intriguingly, when the progressive adaptations to training were documented, the dynamics of bulk muscle(s) Q˙m was speeded (45), as was V˙O2 (38), and this occurred before a detectable elevation of muscle oxidative enzyme activity. Whether this finding represents evidence for faster Q˙O2 dynamics facilitating those of V˙O2 or rather a limitation of the muscle biopsy technique remains uncertain. Irrespective of this possibility and, whether or not Q˙O2 were limiting in the untrained condition (6), it was even less likely to be so after training. These findings are consistent with the training-induced reduction of the [HHb + Mb]-to-V˙O2 ratio after the onset of exercise found by Murias et al. (36) in humans. Thus, even if Q˙O2 is not limiting for V˙O2 kinetics, the elevation of microvascular and consequently intramyocyte PO2 after training may enhance metabolic control and muscle contractile function.
Regarding NIRS, to date this technique has investigated only relatively superficial muscles/muscle parts in humans. However, current technical advances using high-power time-resolved spectroscopy will allow studies of deeper muscles such as m. vastus intermedius. Furthermore, in combination with indocyanine green dye to measure Q˙m (and Q˙O2), the standard oxygenation/deoxygenation measurements could feasibly monitor regional matching of Q˙m and V˙O2 with high temporal/spatial fidelity throughout the entire recruited muscle mass. This technology, thus, has substantial potential to answer pressing questions regarding heterogeneity and its relationship with metabolic control in health and disease.
Regarding investigations with other techniques, Richardson et al. (43) used MRS at the individual voxel level (1 cm3) to determine that, in healthy young subjects, the spatial matching of Q˙O2 and V˙O2 (assessed via phosphocreatine depletion) was far from perfect (Fig. 2). This perspective, however, was changed when the sampled volume was increased to encompass the four individual parts of m. quadriceps femoris (26). In endurance-trained subjects, Q˙O2 and V˙O2 are better matched than in their untrained counterparts (26) (Fig. 3) possibly as a consequence of less hyperperfused and heterogeneous Q˙m-to-V˙O2 distributions. Although capillary red blood cell transit times generally are not considered to limit fractional O2 extraction, the improvements in muscle O2-diffusing capacity (DO2) resulting from a greater capillary and red blood cell volume adjacent to the contracting myocytes may serve to reduce Q˙O2 spatial heterogeneity and enhance Q˙O2 and/or metabolic control (27).
What Are the Mechanistic Bases for Compromised Q˙O2/V˙O2 Ratio and Slowed V˙O2 Kinetics in Aging, Diabetes, and CHF and Can They Be Reversed?
Compromised muscle O2 delivery (either as decreased Q˙O2 or arterial/microvascular PO2) slows V˙O2 kinetics, necessitating greater intracellular perturbations (i.e., Δ[PCr], [ADPfree], [Pi], [H+]) accelerated glycogen utilization and ultimately impaired exercise tolerance (8,41). Aging, diabetes, and CHF all reduce exercise capacity through a complex array of physiological/pathophysiological changes. Common features among conditions include a reduced maximal cardiac output, V˙O2max, and slowed V˙O2 kinetics. With respect to the question at hand, each condition also is characterized by various degrees of vascular and microvascular dysfunction that alters bulk muscle Q˙O2, lowering the overall Q˙O2/V˙O2 ratio (Table). More distally, there is profound arteriolar dysfunction and red blood cell flux may cease in as much as 50% of the capillary bed (diabetes, CHF), creating a condition where the capacity to spatially distribute Q˙O2 relative to V˙O2 within and between muscles is degraded (40). Not surprisingly, the microvascular Q˙O2/V˙O2ratio, measured via phosphorescence quenching (i.e., microvascular PO2, animals) or NIRS ([HHb + Mb], humans/animals), is reduced either during the dynamic transition (aging, moderate CHF) and/or in the subsequent steady state (severe CHF, diabetes) (5,40,41).
When vascular/microvascular PO2 (the product of a low Q˙O2/V˙O2 ratio) is reduced, exercising skeletal muscle(s) experiences a decreased capacity to spatially distribute microvascular O2 delivery to meet local energetic requirements (i.e., V˙O2, (8)). Although aging and CHF and, to a degree, diabetes are all associated with a reduced structural capacity for muscle Q˙O2 (e.g., decreased vascularity), there is an often profound downregulation of NO bioavailability. Accordingly, acute NO increases achieved by means of NO/nitrite/nitrate supplementation or sildenafil treatment improve the overall Q˙O2/V˙O2 ratio (12,46) and enhance exercise tolerance — at least in CHF (46). Moreover, increased NO and endothelium-mediated function may constitute an important (although certainly not sole) contributor to the improved Q˙O2/V˙O2 ratios found after exercise training in young rats (23) and its counterpart ([HHb + Mb]-to-V˙O2) in young and older humans (36). In this latter instance, the training-induced ΔV˙O2 kinetics correlated with the reduced [HHb + Mb]-to-V˙O2 ratio that may, or may not, be indicative of an O2 delivery limitation to V˙O2 kinetics in the untrained state. Furthermore, for the support of physical activity and exercise training in healthy aging, there is evidence that aerobic exercise training can correct the cardiac output distribution impairments (2) and facilitate a more effective exercise hyperemic response to muscle contractions despite smaller muscles in elderly people (44).
Can the Heart Help Us to Better Understand Muscular Q˙O2/V˙O2 Matching During Exercise and Especially After Exercise Training?
Exercise training increases fractional O2 extraction by elevating muscle(s) O2-diffusing capacity (DO2) to a greater extent than maximal Q˙m (i.e., higher DO2/Qm ratio) (30). In contrast, CHF increases fractional O2 extraction, at a given V˙O2, by reducing Q˙m more than DO2m (40). Interpretation of fractional O2 extraction is therefore context dependent (Table) and must be viewed relative to the extant muscle V˙O2. Whereas we have seen that the normal response after the onset of exercise is for microvascular PO2 to fall, reflecting an increased fractional O2 extraction (a consequence of the decreasing Q˙O2/V˙O2 ratio), a lower microvascular PO2 than normal, as is manifested in aged and diseased muscle(s), is a consequence of pathology and may lead to slowed V˙O2 kinetics and exercise intolerance.
The heart, like the brain, is critically dependent on adequate Q˙O2 and, given its extremely high V˙O2 and rapid response (i.e., increased heart rate <1 s) after the onset of exercise must effectively match Q˙O2-to-V˙O2 on a second-by-second basis. The relevant question here is whether the heart can support these fast kinetics in the presence of a low Q˙O2/V˙O2 ratio (and, therefore, low microvascular PO2)? Both dogs (47) and humans (25) at the onset of moderate-to-severe exercise evince a biphasic coronary venous O2 saturation profile. Specifically, while myocardial O2 demands are increasing most rapidly, coronary venous O2 saturation falls precipitously (indicative of increased fractional O2 extraction and lowered microvascular PO2) before a brief recovery and subsequent reduction to its lower exercising value (47). Compared with skeletal muscle in these species, the heart has an impressively high capillarity and mitochondrial volume density (i.e., ∼23% vs <10%). These attributes may be crucial for supporting very fast myocardial V˙O2 kinetics even in the face of low coronary venous O2 saturation and, thus, microvascular PO2. This suggests that peripheral skeletal muscle adaptations, for example, in response to exercise training might facilitate faster V˙O2 kinetics and associated improvements in exercise tolerance even in disease conditions where compromised cardiac output places a low limiting ceiling on muscle Q˙O2 and, therefore, microvascular PO2.
In contrast to skeletal muscles, the work rate of the heart in vivo cannot be set with precision and consequently certain facets of the training response may be determined by extraneous adaptations. These adaptations include a reduced peripheral resistance and increased blood volume, which will modify the cardiac workload at a given pulmonary V˙O2. Notwithstanding this situation, there is recent evidence that endurance exercise training reduces myocardial Q˙ (and Q˙O2) and enhances fractional O2 extraction both at rest and during submaximal exercise in humans (16). These adaptations are attributed, in part, to enhanced myocardial vascular resistance and longer mean red blood cell transit times in the myocardial capillaries, respectively. These findings contrast with the unchanged bulk hindlimb blood flows seen in trained rats (1), faster Q˙m kinetics in humans (45), and higher transient microvascular PO2 in the contracting rat spinotrapezius (unchanged steady state) (23). Laughlin and colleagues (1,32) also reported that, although bulk hindlimb Q˙ was unchanged after training in rats, there was an enhanced redistribution away from the low oxidative toward the highly oxidative fibers. It is unknown whether the trained human myocardium and/or skeletal muscles are able to better distribute Q˙m to improve Q˙O2-to-V˙O2 matching. Alternatively, it is possible that posttraining either prolonged capillary red blood cell transit times (because of lower Q˙m and possibly capillary neogenesis) and/or enhanced DO2m enables adequate blood-myocyte O2 flux at a reduced microvascular PO2. Interestingly, this latter response occurs in mouse gastrocnemius muscle after PGC-1α–induced upregulation of capillarity and oxidative capacity (28).
One crucial consideration here is where the muscle, be it skeletal or myocardial, sits on the Q˙O2 continuum (41). If there is an O2 dependency of mitochondrial function (left of tipping point), blood-myocyte O2 flux will be compromised by any reduction in microvascular PO2. This condition is more likely to be present in muscles of aged individuals as well as diabetic and CHF patients and especially when the exercise necessitates recruitment of fast-twitch fibers (see the section How Does the Q˙O2/V˙O2 Ratio Differ Among Muscles Composed of Different Fiber Types?). Alternatively, by occupying any position to the right of that tipping point, there is a tolerance for lowering microvascular PO2 that may be enhanced by adaptations such as exercise training or upregulation of PGC-1α (28).
CONCLUSIONS AND FUTURE PERSPECTIVES
The temporal and spatial distribution of Q˙m and, therefore, Q˙O2 between and within muscles in proportion to their energetics requirements is crucial to sustain mitochondrial and, thus, contractile function. To accomplish this Q˙O2-to-V˙O2 balance, increases in cardiac output and sympathetic tone must work in concert with local vasoactive control within the active muscle(s). That local control is mediated by a complex interaction of fiber recruitment patterns and multiple vasoactive pathways (including NO, cyclooxygenase, purinergic, adrenergic, hydrogen peroxide, vasoactive metabolites) that operate in a fiber type–specific manner to control the local Q˙O2/V˙O2 ratio and, thus, microvascular PO2.
It is intuitive that “good” matching of Q˙O2 and V˙O2 is better than “bad” matching, but what constitutes each is not readily apparent and may differ under certain circumstances in health and disease (Table). Specifically, does a lower Q˙O2/V˙O2 ratio (and therefore lower microvascular PO2 and higher fractional extraction) mean better matching or, alternatively, lower microvascular PO2 such that blood-myocyte O2 flux and metabolic control are suboptimal? Within a given region, a high Q˙O2/V˙O2 ratio raises microvascular (and intracellular) PO2, better facilitating blood-myocyte O2 flux and metabolic control. However, unless there is no limit imposed on bulk blood flow by a cardiac output ceiling, for example, small muscle mass exercise (2- to 3-kg active muscle) versus conventional cycling (∼15-kg active muscle), this high Q˙O2/V˙O2 ratio in one region will come at the expense of a lower ratio (and microvascular PO2) in another region and ultimately may compromise function (Table). Rather than relegating these decisions (akin to “robbing Peter to pay Paul”) to the periphery, an overall greater increase in cardiac output may be desirable if such can be achieved without negative cardiac consequences. CHF and diabetes lower bulk muscle Q˙O2, resulting in an overall lower Q˙O2/V˙O2 ratio and, because in part of widespread capillary hemodynamic dysfunction/stasis, an inability to distribute O2 according to V˙O2 requirements at the microvascular level. These conditions reduce muscle O2-diffusing capacity and result in very low microvascular PO2, crippling blood-myocyte O2 flux and impairing metabolic and contractile function. Whereas this situation inarguably presents a problem, what constitutes an ideal Q˙O2-to-V˙O2 distribution is far from certain and is likely context dependent. For example, for exercise at submaximal levels, endurance-type training redistributes Q˙ (and Q˙O2) away from low oxidative fibers toward their more oxidative counterparts — an example of better Q˙O2-to-V˙O2 matching. Aging does the opposite in the presence of lowered or unchanged overall muscle Q˙. How much of the increased (training) or decreased (aging) function can be attributed to this phenomenon remains unknown. It is recognized that the heart achieves effective blood-cardiomyocyte O2 flux and rapid V˙O2 kinetics despite low microvascular PO2. Understanding the structural and functional bases for this capability will help inform and direct therapeutic approaches to improving oxidative function in compromised muscle(s).
In CHF, evidence is emerging that therapeutic treatments that raise the Q˙O2-to-V˙O2 ratio, via strategies that augment NO bioavailability by either nitrate/nitrite supplementation or phosphodiesterase inhibition (sildenafil), speed V˙O2 kinetics and improve exercise performance. Further investigations using established and novel technological approaches (e.g., deep muscle and time-resolved NIRS) may help define the key control features of truly effective Q˙O2-to-V˙O2 matching and the responsible mechanisms. Undoubtedly, the role of chronic exercise and other NO- or perhaps non–NO-based therapeutic strategies to correct dysfunction will feature strongly in this endeavor. These further studies also might usefully define the extent to which increased or decreased Q˙O2-to-V˙O2 heterogeneity is beneficial/detrimental under physiological and/or pathophysiological conditions.
The research of the authors I.H. and K.K. has been supported by The Academy of Finland, The Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, and Ministry of Education and Culture, State of Finland. S.K. was supported by grants from Japan Society for the Promotion of Science (KAKENHI-18207019, 20650103, 21370111, 22370091, 22650151, 24650401, 24247046, 26560362). D.C.P. and T.I.M. were funded by grants from the National Institutes of Health (HL-50306 and HL-108328) and the American Heart Association, Heartland Affiliate.
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