Hammer, Shane M.

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance, with respiratory muscle dysfunction as a contributing factor. Patients with HFpEF have exaggerated cardiovascular responses to respiratory muscle metaboreflex activation. In this study, we determined the impact of inspiratory muscle training (IMT) on the respiratory muscle metaboreflex in HFpEF. We found that 8 wk of IMT improved inspiratory muscle strength and attenuated the respiratory muscle metaboreflex-mediated cardiovascular responses in patients with HFpEF.

Introduction: Obesity and hypertension (HTN) are highly prevalent comorbid risk factors for heart failure with preserved ejection fraction (HFpEF). Obesity and HTN independently increase sympathetic nervous activity and impair muscle blood flow during exercise. Previous work has reported attenuated limb blood flow in patients with HFpEF; however, these findings were compared to controls with dissimilar comorbidities and during small muscle mass exercise. It is unclear if HFpEF alters muscle blood flow responses independent of the obesity- and HTN-mediated alterations. Hypothesis: We hypothesized the muscle blood flow response during cycling would be lower in HFpEF patients than age, sex, BMI, and HTN matched controls (CTL). Methods: HFpEF patients (n=14, 9M/5W, 71±7yrs, 32±4 kg/m 2 ) and CTL (n=12, 8M/4W, 69±7yrs, 31±4 kg/m 2 ) performed an incremental cycling test. Blood pressure was measured by manual sphygmomanometry, cardiac output (Q) by open-circuit acetylene wash-in technique, and systemic vascular resistance (SVR) was calculated. Vastus lateralis blood flow index (BFI) was measured by near-infrared spectroscopy and indocyanine green dye injections and venous norepinephrine concentration was measured. Changes from rest to 40 W of the incremental test are reported. Results: Resting Q, mean arterial pressure, SVR, and venous norepinephrine concentration were not statistically different between groups (p>0.18). From rest to 40 W, the increases in Q (CTL: 3.9±0.8 vs. HFpEF: 3.6±0.7 L/min), mean arterial pressure (CTL: 5.7±2.7 vs. HFpEF: 6.6±6.1 mmHg), and SVR (CTL: -7.3±2.1 vs. HFpEF: -6.0±2.0 mmHg/L/min) were not statistically different between groups (all, p>0.13). The HFpEF group had smaller increases in vastus lateralis BFI at 40 W compared to CTL (CTL: 7.2±3.6 vs. HFpEF: 4.2±2.6 fold-increase from rest) (p=0.02). The HFpEF group had greater increases in venous norepinephrine concentration from rest to 40 W than CTL (CTL: 164±216 vs. HFpEF: 377±247 pg/mL) (p=0.05). Conclusions: Our findings suggest that, compared to age, sex, BMI, and HTN matched controls, patients with HFpEF have an impaired locomotor muscle blood flow response during submaximal cycling exercise likely due to higher locomotor muscle vascular resistance.

ABSTRACTExtreme‐intensity exercise is described by W′ext (analogous to J′ for isometric exercise) that is smaller than W′ of severe‐intensity exercise (W′sev) in males. Sex differences in exercise tolerance appear to diminish at near‐maximal exercise, however, there is evidence of greater contributions of peripheral fatigue (i.e. potentiated twitch force; Qpot) in males during extreme‐intensity exercise. Therefore, the current study tested the hypotheses that J′ext would not be different between males and females, however, males would exhibit a greater reduction in neuromuscular function (i.e. maximal voluntary contraction, MVC; Qpot) following extreme‐intensity exercise. Seven males and 7 females completed three severe‐ (Tlim: 2–4 min, S3; 5–8 min, S2; 9–15 min, S1) and three extreme‐intensity (70, 80, 90%MVC) knee‐extension bouts. MVC and Qpot relative to baseline were compared at task failure and at 150 s of recovery. J′ext was significantly less than J′sev in males (2.4 ± 1.2kJ vs 3.9 ± 1.3kJ; p = 0.03) and females (1.6 ± 0.8kJ vs 2.9 ± 1.7kJ; p = 0.05); however, there were no sex differences in J′ext or J′sev. MVC (%Baseline) was greater at task failure following extreme‐intensity exercise (76.5 ± 20.0% vs 51.5 ± 11.5% in males, 75.7 ± 19.4% vs 66.7 ± 17.4% in females), but was not different at 150 s of recovery (95.7 ± 11.8% in males, 91.1 ± 14.2% in females). Reduction in Qpot, however, was greater in males (51.9 ± 16.3% vs 60.6 ± 15.5%) and was significantly correlated with J′ext (r2 = 0.90, p < 0.001). Although there were no differences in the magnitude of J′ext, differences in MVC and Qpot are evidence of sex‐specific responses and highlight the importance of appropriately characterizing exercise intensity regarding exercise domains when comparing physiological responses in males and females.Highlights We have previously shown evidence that extreme‐intensity dynamic exercise is described by W′ext in males and smaller than W′sev. We currently tested for potential sex differences in J′ext (isometric analogue to W′) and neuromuscular responses (i.e. maximal voluntary contraction, MVC; potentiated twitch force, Qpot) during extreme‐intensity exercise. J′ext and extreme‐intensity exercise tolerance was not different between males and females. The reduction in MVC was not different across extreme‐intensity exercise across males and females, whereas the reduction in Qpot was greater in males following all extreme‐intensity exercises, although not after exercise at 90%MVC. Together, although extreme‐intensity exercise tolerance is not different, these data highlight differences in the contributing mechanisms of fatigue during severe‐ and extreme‐intensity exercise between males and females.

Respiratory muscle dysfunction is thought to contribute to exercise intolerance in heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are unknown. In the present study, patients with HFpEF had greater increases in leg muscle vascular resistance index and greater decreases in leg muscle blood flow index compared with controls during inspiratory resistive breathing (to activate the metaboreflex). Furthermore, respiratory muscle blood flow index responses normalized to pressure generation during inspiratory resistive breathing were exaggerated in HFpEF compared with controls.

New Findings What is the central question of this study? Do humans with high‐affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near‐infrared spectroscopy‐derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. AbstractRecently, researchers in our laboratory have shown that humans with genetic mutations resulting in high‐affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal‐affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near‐infrared spectroscopy‐derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal‐affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

We have previously shown that, similar to the severe‐intensity power duration relationship (i.e., W’ sev ), there exists a separate, smaller power‐duration relationship for the extreme‐intensity domain (W’­ ext ) in men. We have also shown that there may be differences in contributions of central and peripheral fatigue between men and women during and immediately following extreme‐intensity exercise. The current study tested the hypotheses that 1) the W’ ext would be significantly less than W’ sev in both sexes, but not different between men and women, 2) absolute Maximum Voluntary Contractions (MVC) would be reduced to greater extent at end‐exercise following severe‐ and extreme‐intensity exercise in men compared to women but not when scaled relative to baseline, and 3) peripheral fatigue would be greater at task failure (T lim ) in men compared to women following severe‐intensity exercise, with no sex difference following extreme‐intensity exercise. Following familiarization, 7 men and 7 women completed three severe‐ (T lim : 2‐4 min, S3; 5‐7 min, S2; 8‐12 min, S1) and three extreme‐intensity (70, 80, 90% MVC) isometric knee‐extension bouts to task failure. MVC and potentiated twitch force (Q pot ) were measured and compared at baseline, task failure, and 150 s of recovery. W’ ext was significantly smaller compared to W’ sev in men (2.4 ± 1.2 kJ vs 3.9 ± 1.3 kJ; p = 0.03) and in women (1.6 ± 0.8 kJ vs 2.9 ± 1.7 kJ; p = 0.05), however there were no sex differences in either W’ ext or W’­ sev . There were no sex differences in MVC at task failure following severe‐intensity exercise. However, MVC was lower in women following extreme‐intensity exercise compared to men, although there were no sex differences in MVC relative to baseline. Further, there were no differences in MVC by the end of recovery compared to baseline in men or women following extreme‐intensity exercise. Q pot was not different at task failure following severe‐ and extreme‐intensity exercise between men and women. However, men showed lower Q pot relative to baseline, suggesting greater peripheral fatigue development, with the exception of exercise at 90% MVC. These data provide evidence that important sex differences exist in the contributions of peripheral fatigue to task failure and in recovery from exercise which depend on exercise intensity. Therefore, practitioners need to consider exercise intensity and the time course of recovery when prescribing exercise to men and women.