Muscle Sympathetic Excitatory Response to Dynamic 1-Leg Cycling in Heart Failure With Preserved Ejection Fraction

Abstract

We provide the first description in a patient with heart failure with preserved ejection fraction of the “paradoxical,” exaggerated reflex increase in muscle sympathetic nerve activity in the opposite, stationary limb during dynamic 1-leg cycling exercise that was documented previously in patients with reduced ejection fraction. (Level of Difficulty: Advanced.)

Central Illustration

Sympathetic activation and exercise intolerance are present in most patients with heart failure, regardless of left ventricular ejection fraction (LVEF).^1,2 We recently identified, in the contralateral limb during 1-leg dynamic cycling exercise, a “paradoxical” reflex increase in muscle sympathetic nerve activity (MSNA) in patients with heart failure with reduced ejection fraction (HFrEF) that related inversely to peak oxygen uptake (VO₂peak).³ Whether patients with heart failure with preserved ejection fraction (HFpEF) exhibit similar “paradoxical” sympathoexcitation during dynamic exercise is unknown.

Replicating our published protocol,³ we recorded heart rate, blood pressure (BP), and fibular MSNA (microneurography) in the seated position, in 2 74-year old Caucasian women in sinus rhythm, during 2 minutes of baseline, 4 minutes of 1-leg cycling (2 minutes each at mild and moderate intensity), and 2 minutes of recovery. One patient had a clinical diagnosis of HFpEF (body mass index [BMI], 24.3 kg/m²; LVEF, 63%; brain natriuretic peptide, 355 pg/mL; estimated glomerular filtration rate, 86 mL/min/1.73 m²), paroxysmal atrial fibrillation, and coronary artery disease, was receiving aspirin (81 mg), apixaban (5 mg twice daily), diltiazem (60 mg twice daily), and atorvastatin (80 mg), and had a resting BP of 93/56 mm Hg and a resting heart rate of 54 beats/min. The second, who volunteered as a non–heart failure control subject (resting BP, 98/53 mm Hg; resting heart rate, 66 beats/min), was obese (BMI, 31.3 kg/m²) but otherwise healthy and unmedicated. These protocols were approved by the University Health Network Research Ethics Board; both patients provided informed, written consent.

Figure 1 illustrates the concordant increases in BP during exercise and the contrasting sympathetic neural response. Heart rate increased similarly in both. At rest, MSNA burst frequency (a proxy for neural norepinephrine release and neurogenic vasoconstriction) was elevated in the HFpEF patient vs control (36 vs 31 bursts/min). The healthy participant’s burst frequency decreased during mild (−6 bursts/min) and moderate (−7 bursts/min) cycling exercise. Conversely, the HFpEF patient’s burst frequency increased during both mild (+13 bursts/min) and moderate (+16 bursts/min) cycling exercise.

Figure 1.

Blood Pressure and MSNA Burst Frequency Responses During Baseline, Mild, and Moderate 1-Leg Cycling and Recovery

BSL = baseline; HFpEF = heart failure with preserved ejection fraction; MOD = moderate; MSNA = muscle sympathetic nerve activity; REC = recovery.

Most patients with HFpEF experience exercise intolerance, the magnitude of which predicts both quality of life and survival.^1,2 Responsible mechanisms evidently are multifactorial,¹ but essentially absent from the HFpEF literature is the concept that exaggerated MSNA may act to constrain VO₂peak by impairing the normal vasodilator response to exercise. In our previous experiments, with the identical moderate-intensity 1-leg cycling protocol, the MSNA of healthy volunteers decreased (−6 ± 2 bursts/min), yet it increased in patients with HFrEF (+7 ± 2 bursts/min).³ We subsequently documented, in the HFrEF cohort but not in control subjects, an inverse relationship between the exercise-elicited change in MSNA from baseline and patients’ predicted VO₂peak, with the former contributing to ∼18% of the variance in the latter. Herein, burst frequency decreased during 1-leg cycling in the non–heart failure control subject, whereas in the HFpEF patient, it increased during mild and moderate cycling by 36% and 44%, respectively. To our knowledge, this represents the first report of “paradoxical” reflex sympathoexcitation during dynamic exercise in HFpEF.

The likely functional consequence of such sympathoexcitation, during this simulated walking protocol, is augmented neurogenic vasoconstriction, thus constraining exercise capacity by reducing skeletal muscle blood flow. We posit that augmented sympathoexcitatory responses to exercise represent a pathologic mechanism encompassing all patients with heart failure, regardless of HFpEF or HFrEF phenotype.

Few effective, evidence-based therapies currently exist for patients with HFpEF.² Although the present observation requires confirmation, in an appropriately sized HFpEF cohort, complemented by control groups carrying similar comorbidities, our documentation, in this patient with HFpEF, of an exaggerated increase in muscle sympathetic discharge during dynamic cycling exercise may offer novel mechanistic insight into one of its most symptom-inducing consequences (ie, exercise intolerance) and encourages investigation of exercise rehabilitation as a sympathoinhibitory strategy for such patients.

Funding Support and Author Disclosures

This work was supported by a Canadian Institutes of Health Research (CIHR) project grant (no. PJT178242). Dr Badrov has received support from a CIHR Postdoctoral Fellowship Award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.