Exercise limitations in heart failure with reduced and preserved ejection fraction

Abstract

The hallmark symptom of chronic heart failure (HF) is severe exercise intolerance. Impaired perfusive and diffusive O₂ transport are two of the major determinants of reduced physical capacity and lowered maximal O₂ uptake in patients with HF. It has now become evident that this syndrome manifests at least two different phenotypic variations: heart failure with preserved or reduced ejection fraction (HFpEF and HFrEF, respectively). Unlike HFrEF, however, there is currently limited understanding of HFpEF pathophysiology, leading to a lack of effective pharmacological treatments for this subpopulation. This brief review focuses on the disturbances within the O₂ transport pathway resulting in limited exercise capacity in both HFpEF and HFrEF. Evidence from human and animal research reveals HF-induced impairments in both perfusive and diffusive O₂ conductances identifying potential targets for clinical intervention. Specifically, utilization of different experimental approaches in humans (e.g., small vs. large muscle mass exercise) and animals (e.g., intravital microscopy and phosphorescence quenching) has provided important clues to elucidating these pathophysiological mechanisms. Adaptations within the skeletal muscle O₂ delivery-utilization system following established and emerging therapies (e.g., exercise training and inorganic nitrate supplementation, respectively) are discussed. Resolution of the underlying mechanisms of skeletal muscle dysfunction and exercise intolerance is essential for the development and refinement of the most effective treatments for patients with HF.

Keywords: HFpEF; HFrEF; diffusive O2 transport; exercise intolerance; exercise training; heart failure; perfusive O2 transport; skeletal muscle microcirculation.

Fig. 1.

Oxygen uptake (V̇o₂) plotted as a function of venous or microvascular Po₂ (Wagner diagram). Top: a schematic illustration of the perfusive [V̇o₂ =  Q̇O₂ (C_a − $\text{C}{\text{v}}_{{\text{O}}_2}$)] and diffusive (V̇o₂ = DO₂ × Po₂) components that interact to determine peak oxygen uptake (V̇o_2max). Note that the Fick principle line is not straight because it is directly reflective of the hemoglobin dissociation curve. Therefore, a left-shifted hemoglobin dissociation curve (greater hemoglobin O₂ affinity), resulting in a lower venous Po₂, will bisect the Fick law line earlier and will reduce V̇o_2max and vice versa. The slope of the straight line emanating from the origin is determined by the diffusing capacity (DO₂) of the muscle(s). What is often not appreciated within the Wagner diagram is that fractional O₂ extraction (C_a − $\text{C}{\text{v}}_{{\text{O}}_2}$) will be determined by the ratio of muscle diffusing capacity (DO₂) to blood flow (Q̇) according to C_a − $\text{C}{\text{v}}_{{\text{O}}_2}$ = V̇o₂/Q̇O₂ =  Q̇O₂ ($1-{\text{e}}^{-{\text{DO}}_2/\text{β}\dot{Q}}$), where β is the slope of the O₂ dissociation curve in the physiological range (105). That the ratio DO₂/Q̇ determines fractional O₂ extraction explains how a high C_a − $\text{C}{\text{v}}_{{\text{O}}_2}$ can be preserved by a very low Q̇ even in the face of a pathologically reduced DO₂ as in HFrEF. Bottom: V̇o_2max is plotted for individuals with chronic heart failure (HFrEF) and healthy control subjects. Note that the patients with HF (HFrEF) exhibit attenuated perfusional (Fick principle curve shifted downward) and diffusional (decreased slope of the Fick law line) conductances that contribute to the significant reductions in V̇o_2max.

Fig. 2.

A schematic representation of the relatively small ratio of cardiac capacity to skeletal muscle recruitment during standard cycle ergometry (top), the much greater ratio during single-leg knee extension (bottom), and the subsequently contrasting physiological responses to these exercise paradigms. Arrows designate relative change from resting.

Fig. 3.

Top: schematic illustration of Fick’s law applied to blood-myocyte O₂ transport within the skeletal muscle microcirculation. Po₂mv constitutes the main driving pressure for transmembrane O₂ flux given that intracellular Po₂ (Po₂intracel) approximates 0 during contractions [approximately 1–3 mmHg; particularly during maximal exercise (101)]. The direct consequence of reduced Po₂mv with HFrEF is thus impaired blood-myocyte O₂ transport. [Adapted from Hirai et al. (57).] DO₂m, muscle O₂ diffusing capacity; in, interstitium; p, plasma; RBC, red blood cell; V̇o₂; O₂ flux. See main text for further details. Bottom: spinotrapezius muscle microvascular Po₂ (Po₂mv) profiles during the rest-contraction transient in healthy and HF rats with reduced ejection fraction (HFrEF). Note that HFrEF speeds the kinetics of Po₂mv fall, thus lowering muscle microvascular oxygenation across the transient (blue area). Time 0 denotes the onset of contractions. Arrow designates the lowering of microvascular Po₂ by HFrEF during contractions. [Adapted from Poole et al. (95b).]

Fig. 4.

A schematic representation of the perfusive (Q̇O₂) and diffusive (DO₂) components that interact to determine V̇o_2peak in patients with HFrEF and healthy controls during both cycle (large muscle mass) and knee-extensor (KE; small muscle mass) exercise. Note, if reductions in V̇o_2peak in HFrEF were entirely due to reductions in Q̇O₂, then the response would follow from point A to B (without any change in the DO₂). However, the reductions in V̇o_2peak for both cycle and KE exercise in HFrEF were found to follow from point A to C. With this scenario, reductions in DO₂ also contributed to the reductions in V̇o_2peak in HFrEF as demonstrated by the changes in the slope of the line from B to C. These reductions in DO₂ occurred in HFrEF without any demonstrable change in muscle venous Po₂ (or muscle venous O₂ content) and thus without any changes in arterial-venous O₂ content difference.

Fig. 5.

Improvement in skeletal muscle diffusional conductance (DO₂) in relation to leg V̇o_2peak during maximal cycle and knee-extensor (KE) exercise afforded by 8 wk of KE training in patients with HFrEF compared with healthy sedentary controls. Note, the correlation coefficient only represents the relationship between the individual data.

Fig. 6.

A schematic illustration of the perfusive and diffusive components that interact to determine leg V̇o_2peak in both HF (HFrEF) and control subjects during cycle (large muscle mass) and knee-extensor exercise (KE; small muscle mass) and the subsequent changes as a consequence of KE training. Solid lines represent Fick’s law and principle lines for the healthy sedentary controls (intersecting at A; V̇o_2peak Healthy), whereas the dotted lines represent the patients with HFrEF. Following training, both groups share the solid Fick principle line. In both exercise modalities, before training, the patients with HFrEF exhibited attenuated perfusive and diffusive oxygen transport as evidenced by their V̇o_2peak being defined by the intercept of lower Fick’s law and principle lines (C) with B indicating the less severe reduction in V̇o_2peak had the patients only revealed a reduction in perfusive O₂ transport. KE training corrected both of these deficits, without increasing cardiac output, restoring both skeletal muscle perfusive and diffusive O₂ transport and therefore allowing V̇o_2peak to equal or exceed (KE) that of the healthy sedentary controls (E). D represents the consequence of exercise training if the increase in V̇o_2peak had only been driven by an increase in perfusive O₂ transport (C to D).

Fig. 7.

Top: spinotrapezius muscle microvascular Po₂ (Po₂mv) profiles during the rest-contractions transient in sedentary and endurance exercise-trained HF rats with reduced ejection fraction (HFrEF). Time 0 denotes the onset of contractions. SE bars are omitted for clarity. The inset displays the overall dynamics of Po₂mv fall during contractions (mean response time; MRT) in sedentary (S) and exercise-trained (T) HFrEF rats. Note that exercise training slows Po₂mv kinetics (↑MRT), thus increasing muscle microvascular oxygenation across the transient (red area). Gray arrow demonstrates training effect. Bottom: changes in muscle microvascular oxygenation (ΔPo₂area) with SNP and l-NAME in sedentary and exercise-trained HFrEF rats. ΔPo₂area is calculated as the difference in the area under the Po₂mv curve between control and SNP or l-NAME superfusion conditions. Note the lack of differences in ΔPo₂area between sedentary and exercise-trained HFrEF rats with l-NAME. This is consistent with the nonobligatory role of NO in microvascular oxygenation adaptations to exercise training in HFrEF skeletal muscle. [Adapted from Hirai et al. (57).] l-NAME, N^G-nitro-l-arginine methyl ester (nonspecific NO synthase blocker); SNP, sodium nitroprusside (NO donor). *P < 0.05 vs. sedentary HFrEF. See main text for further details.

Fig. 8.

Central tenets of impaired muscle Q̇O₂ as a primary cause of exercise intolerance in HFrEF and HFpEF. Notably, each cause of dysfunction in HFrEF is amenable to improvement with exercise training or nitrate/nitrite supplementation. In HFpEF, muscle structure and oxidative capacity may be better preserved, but reduced fractional O₂ extraction suggests Q̇O₂/V̇o₂ mismatching and low DO₂. Nitrate supplementation in HFpEF enhances vascular function and increases in Q̇O₂ raising exercise economy and capacity. As indicated, far less is known regarding muscle microvascular structure and function in HFpEF than HFrEF, making this a fertile area for investigation. Such information will be key to designing more effective therapeutic strategies, which are greatly needed in the burgeoning population of patients with HFpEF. No refers to either absence of these deficits or a lack of evidence, and ? is unknown. CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease.

Fig. 9.

A schematic illustration of the perfusive and diffusive components that interact to determine V̇o_2max in both HFrEF and HFpEF conditions. Solid lines represent Fick’s law and principle lines for the HFpEF condition and the V̇o_2max measured before and after exercise training. The dotted lines represent the untrained sedentary HFrEF condition. Note that, hypothetically, V̇o_2max before exercise training is similar between the HFrEF and HFpEF condition but that the HFrEF may have a greater arterial-venous O₂ content difference (greater reduction in venous or microvascular Po₂) compared with the HFpEF counterpart. This greater arterial-venous O₂ content difference would be associated with a larger reduction in perfusive O₂ transport (Fick principle) in the HFrEF condition. In contrast, HFpEF may have a larger reduction in diffusive O₂ transport (Fick’s law) when compared with the HFrEF condition. Potential effects of exercise training are depicted for the HFpEF condition demonstrating that significant changes in diffusive O₂ transport (associated with exercise training-induced changes at the microcirculatory level) may produce significant increases in V̇o_2max with potentially little or no changes in perfusive O₂ transport.