A new sympathetic understanding of exercise blood flow regulation in HFpEF

Introduction

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common cardiovascular disease, with over 50% of all heart failure diagnoses in the United States 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 likely barrier to progress is the heterogeneity of the disease. Whilst 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 hyperemia) and oxygen delivery to working skeletal muscle, which challenges the maintenance of arterial pressure in face of profound local vasodilation. The tightly coordinated response is achieved through a balance between metabolic vasodilation 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 aging and in several disease states. To determine whether central or peripheral limitations play a major role in limiting exercise capacity is often difficult as these two components are interdependent. Small muscle mass exercise is a common approach to investigate peripheral limitations to exercise as 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 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 by Alpenglow et al. (2024) in The Journal of Physiology.

Methods

In a relatively small sample of seven adults with HFpEF (3 females; age, 70 ± 6 years; BMI, 32 ± 5 kg/m²) and seven healthy age-matched controls (3 females; BMI, 25 ± 3 kg/m²), 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 Watts). Participants were instrumented with femoral arterial and venous catheters to measure local oxygen uptake ($\stackrel{.}{\mathrm{V}}$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 vasodilation), 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 $\stackrel{.}{\mathrm{V}}$O₂ were also calculated from LBF, mean arterial pressure (MAP) and the arterial-venous oxygen difference (Δa-vO₂).

Primary Study Findings

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 Watts) compared to controls (36 Watts). Under control conditions (no drug infusion) at 10 Watts, MAP, LBF, LVC, leg oxygen delivery and $\stackrel{.}{\mathrm{V}}$O₂ were lower in HFpEF; Δa-vO₂ 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 $\stackrel{.}{\mathrm{V}}$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.

Discussion

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 and colleagues (2024) furthers our understanding of the potential peripheral mechanisms of exercise intolerance in HFpEF.

α-adrenergic restraint

Despite previous reports of higher resting 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 Watts) despite the greater relative work rate at which adults with HFpEF exercised during the 5 and 10 Watts bouts (~22% and ~43% vs. ~14 and ~28% peak work rate). At 10 Watts 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 due to higher relative work rate. The potentially greater MSNA during exercise would restrain blood flow to working skeletal muscles, limiting $\stackrel{.}{\mathrm{V}}$O₂ and possibly contributing to exercise intolerance. The findings from Alpenglow and colleagues (2024) have clear relevance for the field as this study demonstrated that α-adrenergic restraint is a potential mechanism limiting $\stackrel{.}{\mathrm{V}}$O₂, a key functional outcome in adults with HFpEF.

Functional sympatholysis

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. While practically feasible and a valid approach, the use of a fixed work rate elicited a lower $\stackrel{.}{\mathrm{V}}$O₂ in HFpEF. It is fundamental to consider differences in $\stackrel{.}{\mathrm{V}}$O₂ when interpreting these results as the ability of contracting skeletal muscles to blunt sympathetically-mediated vasoconstriction is influenced by the absolute metabolic stimulus (Wray et al., 2009; Horiuchi et al., 2014). The leg $\stackrel{.}{\mathrm{V}}$O₂ during 10W knee extension in adults with HFpEF was similar to that observed during 0W exercise in healthy controls. As such, the between-group differences in functional sympatholysis may be influenced by the lower $\stackrel{.}{\mathrm{V}}$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 VO₂ when comparing groups with differences in functional capacity.

Considerations

As resting LBF and LVC and thigh lean mass were higher, the HFpEF group could have received a lower effective dose of phenylephrine which may contribute to the smaller relative change in LBF and LVC. The potentially different dose would influence the conclusions drawn regarding the lower α-adrenergic responsiveness in HFpEF. Due to these baseline differences in LBF and LVC we believe it is important to consider the absolute vascular responses to phenylephrine and not just the relative change in LVC which was lower in HFpEF (group effect; Figure 3). The absolute LBF and LVC responses (group*dose interactions) to phenylephrine were not significantly different between groups (Table 5); however, the absolute change in LVC we calculated from rest to the highest dose of phenylephrine was lower in HFpEF compared to controls (HFpEF: −0.66 vs Control: −0.78; Table 5). Together, it is important to consider the effective drug dose and baseline blood flow when studying adrenergic responsiveness.

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 $\stackrel{.}{\mathrm{Q}}$c-$\stackrel{.}{\mathrm{V}}$O₂ slope) during whole-body exercise (Bhella et al., 2011). However, the hyperdynamic circulation during whole-body exercise in HFpEF contrasts 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.

Significance and perspectives.

The present findings from Alpenglow and colleagues highlight new potential mechanisms leading to exercise intolerance in adults with HFpEF. The significant increase in $\stackrel{.}{\mathrm{V}}$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 $\stackrel{.}{\mathrm{V}}$O₂.