A new sympathetic understanding of exercise blood flow regulation in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common clinical syndrome, with over 50% of all heart failure diagnoses in the USA being HFpEF. Adults with HFpEF present with dyspnoea upon exertion and severe exercise intolerance, leading to reduced ability to perform activities of daily living. Despite increasing efforts to understand HFpEF pathophysiology, the mechanisms of disease development are unclear. One probable barrier to progress is the heterogeneity of the disease. Although the mechanisms underpinning low exercise capacity were initially attributed to central limitations, such as elevated ventricular filling pressure and chronotropic incompetence, a growing body of research suggests vascular, skeletal muscle and pulmonary impairments are important determinants of low exercise capacity in HFpEF (Bunsawat et al., 2024). Dynamic exercise elicits an integrated sympathetic, mechanical and vascular response aiming to increase leg blood flow (LBF; exercise hyperaemia) and oxygen delivery to working skeletal muscle, which challenges the maintenance of arterial pressure in face of profound local vasodilatation. The tightly co-ordinated response is achieved through a balance between metabolic vasodilatation and sympathetically-mediated vasoconstriction. However, the ability of contracting skeletal muscles to blunt sympathetically-mediated vasoconstriction, termed functional sympatholysis, is known to be impaired by ageing and in several disease states. Determining whether central or peripheral limitations play a major role in limiting exercise capacity is often difficult because these two components are interdependent. Small muscle mass exercise is a common approach to investigate peripheral limitations to exercise because this paradigm minimizes central (cardiac and pulmonary) limitations. In this vein, using both whole body dynamic cycling exercise and single leg knee extensor exercise, recent findings have demonstrated significant contributions of peripheral abnormalities, such as poor skeletal muscle oxygen utilization and diffusive capacity, to exercise intolerance in HFpEF (Skow et al., 2024). Whether altered sympathetic regulation of skeletal muscle blood flow underlies these peripheral abnormalities in HFpEF remained to be investigated until the recent publication in The Journal of Physiology by Alpenglow et al. (2024). In a relatively small sample of seven adults with HFpEF (three females; age, 70 ± 6 years; body mass index, 32 ± 5 kg m−2) and seven healthy age-matched controls (three females; body mass index, 25 ± 3 kg m−2), Alpenglow et al. (2024) assessed adrenergic regulation of skeletal muscle LBF at rest and during progressive isolated single knee extensor exercise (0, 5 and 10 W). Participants were instrumented with femoral arterial and venous catheters to measure local oxygen uptake ( V ̇ O 2 V̇_O₂ ) and to perform intra-arterial infusions of three different pharmacological agents to investigate sympathetic vascular control: (1) propranolol (β-adrenergic antagonist to block β-mediated vasodilatation), (2) phenylephrine (α1-adrenergic agonist to stimulate α1-mediated vasoconstriction) and (3) phentolamine (non-selective α-adrenergic antagonist to block α-mediated vasoconstriction). LBF was calculated from measured common femoral artery diameter and velocity via Doppler ultrasound; arterial and venous blood pressure were directly measured by pressure transducers. Leg vascular conductance (LVC), leg oxygen delivery and leg V ̇ O 2 V̇_O₂ were also calculated from LBF, mean arterial pressure (MAP) and the arterial-venous oxygen difference (∆a- V ̇ O 2 V̇_O₂ ). At rest, LBF and LVC were higher but MAP was lower in adults with HFpEF compared to healthy controls. Infusion of the β-adrenergic antagonist decreased LVC in HFpEF only; there were no group differences in the response to infusion of the α-adrenergic antagonist. The relative changes in LBF and LVC in response to infusion of the α1-adrenergic agonist were lower in HFpEF compared to control; the absolute changes were not different between groups. Peak work rate during single knee extensor exercise was lower in HFpEF (23 W) compared to controls (36 W). Under control conditions (no drug infusion) at 10 W, MAP, LBF, LVC, leg oxygen delivery and V ̇ O 2 V̇_O₂ were lower in HFpEF; ∆a- V ̇ O 2 V̇_O₂ was not different between groups. Infusion of a non-selective α-adrenergic antagonist increased LBF and oxygen delivery by a greater magnitude in HFpEF compared to healthy controls, increasing V ̇ O 2 V̇_O₂ in HFpEF only. Infusion of the α-adrenergic agonist decreased LVC at rest in both groups, with a greater reduction in controls. Also, the vasoconstrictor response was attenuated in an intensity-dependent manner in healthy individuals, but not in adults with HFpEF. Exercise intolerance is a defining feature of HFpEF and peripheral mechanisms of oxygen transport and utilization are important determinants of low exercise capacity in this population (Bunsawat et al., 2024). The work of Alpenglow et al. (2024) furthers our understanding of the potential peripheral mechanisms of exercise intolerance in HFpEF. Despite previous reports of higher resting muscle sympathetic nerve activity (MSNA), adults with HFpEF showed similar α-adrenergic restraint of vascular tone at rest, which may suggest lower α-receptor responsiveness, as confirmed by the blunted LVC response to phenylephrine in HFpEF. However, during exercise + phentolamine adults with HFpEF presented with greater α-adrenergic restraint, as demonstrated by greater increases in LVC. The changes in LBF were similar between-groups during low intensity exercise (0 and 5 W) despite the greater relative work rate at which adults with HFpEF exercised during the 5 and 10 W bouts (∼22% and ∼43% vs. ∼14 and ∼28% peak work rate). At 10 W, adults with HFpEF showed greater adrenergic restraint compared to controls. Because there was no difference in baseline tonic α-adrenergic restraint between groups, the increased restraint at higher work loads may be related to greater MSNA recruitment in HFpEF as a result of higher relative work rate. The potentially greater MSNA during exercise would restrain blood flow to working skeletal muscles, limiting V ̇ O 2 V̇_O₂ and possibly contributing to exercise intolerance. The findings from Alpenglow et al. (2024) have clear relevance for the field as this study demonstrated that α-adrenergic restraint is a potential mechanism limiting V ̇ O 2 V̇_O₂ , a key functional outcome in adults with HFpEF. Participants exercised at a low fixed work rate during infusion of the α1-agonist to ensure the adults with HFpEF could sustain an exercise load for a given duration and reach metabolic steady-state. Although practically feasible and a valid approach, the use of a fixed work rate elicited a lower V ̇ O 2 V̇_O₂ in HFpEF. It is fundamental to consider differences in V ̇ O 2 V̇_O₂ when interpreting these results as the metabolic stimulus is an important, but not the only factor contributing to the magnitude of functional sympatholysis in working skeletal muscles (Horiuchi et al., 2014; Wray et al., 2009). The leg V ̇ O 2 V̇_O₂ during 10 W knee extension in adults with HFpEF was similar to that observed during 0 W exercise in healthy controls. As such, the between-group differences in functional sympatholysis may be influenced by the lower V ̇ O 2 V̇_O₂ in HFpEF, which is a key stimulus for sympatholysis. Additionally, the higher relative intensity of exercise in adults with HFpEF could induce greater changes in MSNA activity resulting in a greater total vasoconstrictor stimulus (phenylephrine + endogenous MSNA) to be overcome. Future studies should include assessments at the same absolute and relative V ̇ O 2 V̇_O₂ when comparing groups with differences in functional capacity. Because patients with HFpEF had higher resting LBF and lower thigh lean mass, the effective dose of phenylephrine during the dose response may have been lower and contributed to the smaller relative change in LBF and LVC. The potentially different dose could influence the conclusions drawn regarding the lower α-adrenergic sensitivity in HFpEF, particularly during lower doses. However, the finding that there was no greater constriction with doubling of the 0.12 μg min−1 dL−1 thigh volume dose in either group supports the conclusion that the HFpEF blunted maximal α-adrenergic responsiveness. Nevertheless, the higher LBF in HFpEF does mean that, per unit time, the dose of phenylephrine was lower in HFpEF. Flow-adjustment of the phenylephrine infusion would provide the most rigorous paradigm to interrogate between-group differences in α-adrenergic sensitivity across the dose–response curve. When comparing the magnitude of sympathetic vasoconstriction between groups, it is recommended to use the relative change in vascular conductance, especially when they present with different baseline blood flow and pressure; for an expanded discussion of this nuance, see Buckwalter & Clifford (2001). Alpenglow et al. (2024) reported that the relative change in LVC was lower in HFpEF (group effect; figure 3). However, the absolute LBF and LVC responses (group × dose interactions) to phenylephrine were not significantly different between groups (table 5). Thus, it appears that the absolute and relative changes are discordant which may cause confusion. Notably, upon further inspection of the data, we calculated the absolute change in LVC from rest to the highest dose of phenylephrine and found it be lower in HFpEF (−0.66) compared to controls (−0.78; table 5), which is congruent with the primary findings of lower α-adrenergic sensitivity in HFpEF based on the relative changes in LVC. These data emphasize the importance of conducting comprehensive statistical analysis of data expressed in both absolute and relative forms when interrogating sympathetic vascular control. Small muscle mass exercise is a very strong experimental paradigm to interrogate adrenergic control and functional sympatholysis. However, there is mismatch between the background physiology between this paradigm and whole-body exercise. Unlike whole-body exercise, during low-intensity small muscle mass exercise MSNA, arterial pressure and cardiac output are unchanged, all of which are important determinants of LBF. Adults with HFpEF often present with a hyperdynamic circulation (higher Q ̇ C Q̇C - V ̇ O 2 V̇_O₂ slope) during whole-body exercise (Bhella et al., 2011). However, the hyperdynamic circulation during whole-body exercise in HFpEF contrasts with the present findings of lower LBF during small muscle mass exercise in HFpEF. As such, the role and potential differences in functional sympatholysis during whole-body exercise, where blood flow (re)distribution is in an important determinant of exercise capacity and functionally dependent on α-adrenergic responsiveness, remains to be elucidated in healthy adults and those with HFpEF. The findings reported by Alpenglow et al. (2024) highlight new potential mechanisms leading to exercise intolerance in adults with HFpEF. The significant increase in V ̇ O 2 V̇_O₂ following infusion of an α-adrenergic antagonist may represent a target for future interventional studies aiming to understand and improve functional capacity in HFpEF. Together, these data advance our understanding of HFpEF pathophysiology and identify important differences in α-adrenergic regulation of blood flow and muscle V ̇ O 2 V̇_O₂ . Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. G.M. and D.J.W. were responsible for the conception or design of the work, as well as drafting the work or revising it critically for important intellectual content. All authors have read and approved the final version of the manuscript submitted for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. Denis J. Wakeham is supported by an American Heart Association postdoctoral fellowship, which is co-funded by the Harry S. Moss Heart Trust. We thank Dr Christopher M. Hearon Jr, PhD, for his critical review of the manuscript.