Evidence of impaired functional sympatholysis in patients with heart failure with preserved ejection fraction

Abstract

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., “functional sympatholysis”). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, −20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the “magnitude of sympatholysis” was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: −9.5 ± 5.5 vs. Con: −21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: −5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: −9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: −15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group.

NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

INTRODUCTION

Heart failure with preserved ejection fraction (HFpEF) is a relatively understudied clinical syndrome, hallmarked by severe exercise intolerance underpinned by a disease-related reduction in peak aerobic capacity (V̇o_2peak; 1, 2). Although initial evidence emphasized deficits in central (cardiac) function limiting V̇o_2peak in HFpEF (3), the contribution of noncardiac factors has been increasingly recognized (2), highlighting the importance of disease-related changes in peripheral vascular regulation to exercise intolerance (2, 4). Indeed, our laboratory (5–7) and others (8) have identified reductions in exercising muscle blood flow in HFpEF during small muscle mass exercise, although the exact mechanisms responsible for these deficits remain unknown. Although it is recognized that multiple regulatory pathways may contribute to impaired blood flow in this patient group, disease-related changes in sympathetic nervous system (SNS) signaling are likely to play a primary role. Indeed, there is emerging evidence for SNS overactivity in HFpEF during exercise (9, 10), potentially resulting in excessive SNS-mediated vasoconstriction, contributing to the observed reduction in blood flow to exercising muscle.

Although the exercise-induced elevation in SNS activity is a global reflex response, sympathetic vasoconstriction is “fine tuned” in the peripheral vasculature to optimize perfusion of the exercising muscle. Regional attenuation of SNS-mediated vasoconstriction is a phenomenon called “functional sympatholysis” (11) and has been recognized as an important mechanism for matching blood flow to metabolic demands of exercising muscle. Interestingly, in certain populations that demonstrate elevated SNS activity, such as aging (12) or HFrEF (13), end-organ (α-adrenergic) responsiveness is diminished at rest, yet is sustained in the exercising limb, thereby demonstrating impaired functional sympatholysis. However, to our knowledge, vascular responsiveness during a sympathetic stimulus has not been determined at rest or during exercise in patients with HFpEF, and whether functional sympatholysis is intact in these patients is thus unknown.

Therefore, we determined forearm vascular conductance at rest and during small muscle mass, submaximal handgrip exercise (HG) before and during physiological reflex SNS activation via lower body negative pressure (LBNP) in patients with HFpEF compared with similarly aged, healthy controls. We hypothesized that 1) at rest, vasoconstrictor responses during LBNP would be lesser in HFpEF compared with control subjects; and 2) during HG, vasoconstrictor responses during LBNP would be maintained to a greater degree, relative to the response at rest, in HFpEF compared with controls, indicative of impaired functional sympatholysis in this patient group.

METHODS

Ethical Approval

The experimental protocol was approved by the University of Utah and Salt Lake City (SLC) Veterans Affairs Medical Center (VAMC) Institutional Review Board (IRB 40212) in compliance with clause 35 of the Declaration of Helsinki, except for registration in a database. All subjects provided written informed consent before participation in any experimental procedure.

Subjects

Patients with HFpEF were screened in a clinic and were included upon criteria consistent with the TOPCAT trial (14), which is as follows: 1) heart failure (HF) defined by the presence of ≥1 symptom at the time of screening (paroxysmal nocturnal dyspnea, orthopnea, dyspnea on exertion) and one sign (edema, elevation in jugular venous distention) in the previous 12 mo, 2) LVEF ≥ 45%, 3) controlled systolic blood pressure, and 4) either ≥1 hospitalization in the previous 12 mo for which HF was a major component of hospitalization or B-type natriuretic peptide (BNP) in the previous 60 days ≥ 100 pg/mL. Exclusion criteria for the HFpEF group included significant valvular heart disease, acute atrial fibrillation, and body mass index (BMI) > 40. For the control group, participants were free of overt cardiovascular disease and not taking any prescription medications, as indicated by a health history. All participants were nonsmokers. Subjects reported to the Utah Vascular Research Laboratory and experiments were performed in a climate controlled (21°C–22°C), dimly lit room.

Protocol

The experimental time line is depicted in Fig. 1. At the time of testing, subjects had abstained from food for 4 h and caffeine for 12 h, and refrained from vigorous exercise, consumption of supplements, and alcohol for 24 h. Subjects were laid in a supine position with their lower body sealed in a chamber designed for administering LBNP −20 mmHg, as described previously (15, 16). Following instrumentation, subjects rested for 10 min, after which resting responses were recorded (i.e., rest and rest + LBNP), separated by 3 min of recovery. Subjects then performed four bouts of rhythmic handgrip exercise (HG) at 30% maximum voluntary contraction (MVC) in a randomized manner (i.e., HG or HG + LBNP). Heart rate (HR), mean arterial pressure (MAP), and thoracic impedance (Z) were recorded continuously, with forearm blood flow (FBF) determined during the last minute of each condition.

Figure 1.

Experimental time line. HG, handgrip exercise; LBNP, lower-body negative pressure; MVC, maximum voluntary contraction.

Lower Body Negative Pressure

Lower body negative pressure (LBNP) was used as a sympathoexcitatory maneuver at a level (−20 mmHg) that has been shown to reliably elicit reflex increases in SNS activity and SNS-mediated vasoconstriction (17). Importantly, LBNP-induced increases in SNS activity have also been shown to be similar at both rest and during exercise (17). Briefly, subjects lie in a supine position with the lower portion of their body sealed at the level of the iliac crests in a custom-made chamber designed for administering LBNP (15). Negative pressure was generated within the chamber by a commercial vacuum motor (Lamb, Ametek, Kent, OH) controlled by a variable power transformer (Staco Variac, ISE, inc., Cleveland, OH). Pressure inside the chamber was monitored via a pressure transducer (P55, Validyne, Northridge, CA) and transmitted to the data acquisition system (AcqKnowledge, Biopac Systems, Goleta, CA).

Handgrip Exercise

Isometric rhythmic HG exercise, an upper limb small muscle mass paradigm, was implemented in this study and has been described previously (6). Briefly, subjects lie supine with their right arm abducted to ∼90° and elbow fully extended. Then, maximal voluntary contraction (MVC) for each subject was established by taking the highest value of three maximal contractions using a handgrip dynamometer (TSD121C, Biopac Systems, Goleta, CA). HG exercise was then performed at 30% MVC at a rate of 1 Hz for 3 min/bout. Thirty percent MVC HG exercise has previously been shown to be effective in counteracting LBNP-induced vasoconstriction and demonstrating functional sympatholysis in older healthy adults (16, 18). Four randomized bouts of HG exercise of 3 min each were performed: two with and two without LBNP. Measurements were taken during the last minute of each bout of HG exercise. Participants were allowed at least 3 min of recovery between each bout. Return to baseline values of physiological variables was confirmed before the start of each new bout of either LBNP or HG.

Measurements

Central hemodynamics.

Heart rate (HR) was monitored continuously from a standard three-lead ECG (ECG100C, Biopac, Goleta, CA), and arterial blood pressure was recorded continuously using finger photoplethysmography (Finometer, Finapres Medical Systems BV, Amsterdam, The Netherlands) at 200 Hz.

Peripheral hemodynamics.

Forearm blood flow (FBF) and forearm vascular conductance (FVC) were calculated based on measurements of the common brachial artery blood velocity and vessel diameter assessed using a Logiq 7 ultrasound Doppler system (GE Medical Systems, Milwaukee, WI). Insonation of the vessel occurred at least 2 cm proximal to the bifurcation of common brachial artery. A linear array transducer operating at 14 MHz was used for vessel wall imaging and was collected, simultaneously, with the same transducer at a Doppler frequency of 5 MHz in high-pulsed repetition frequency mode (2–25 kHz). Sample volume was optimized in relation to vessel diameter and centered within the vessel. An angle of insonation of ≤ 60° was used for all measurements of blood velocity. Measurements of the brachial artery diameter were made on a beat-to-beat basis during diastole in accordance with current guidelines (19). Commercially available software (Logic 7) was used to assess vessel diameter as well as angle-corrected, time-averaged, mean blood velocity (V_mean).

Central blood volume.

To quantify LBNP-induced translocation of blood volume, noninvasive impedance cardiography (NICO 100 C, Biopac, Goleta, CA) was used to record changes in thoracic impedance (Z), which is regarded as an accurate estimate of directional changes in central blood volume in comparison with central venous pressure (20).

Data Acquisition and Analysis

Baseline MAP was calculated as follows: MAP = 1/3[pulse pressure (PP)] + diastolic blood pressure (DBP). Continuous MAP and HR were acquired from the Finometer at 200 Hz via data acquisition system (AcqKnowledge, Biopac Systems, Goleta, CA). Central hemodynamics were averaged during the last minute of each bout with or without LBNP at rest and during HG exercise. FBF was calculated as follows: FBF (mL/min) = V_mean × π(vessel diameter/2)² × 60. Subsequently, FVC was calculated as follows: FVC (mL/min/mmHg) = FBF (mL/min)/MAP (mmHg). FBF and FVC were assessed in 12-s bins and averaged over the last minute of each bout of PRE or LBNP at rest and during HG exercise. Changes in all outcome measures in response to individual trials were performed in duplicate (Rest + LBNP, HG, and HG + LBNP) and averaged for each subject and then combined to provide a group mean, in line with previous work assessing functional sympatholysis via LBNP and HG (21).

Statistical Analysis

Statistical analyses were performed using commercially available software (SigmaPlot 13). Power analyses were performed to make an a priori sample size calculation based on previous work investigating functional sympatholysis using a similar paradigm with LBNP and HG exercise. In the study by Vongpatanasin et al. (22), the magnitude of sympatholysis was lesser in hypertensive (−6 ± 3%) compared with normotensive (−19 ± 4%) subjects. Calculations based on these data indicated that the proposed study would be well powered (>99%) with n = 10 in each group and anticipated difference in means of 13 (SD = 3, α = 0.05) and would remain well powered (96%) even with a lesser effect size (difference in mean = 8, SD = 3). Subject characteristics were compared using Student’s unpaired t tests. Absolute values for each dependent variable, before and after LBNP within each stage, were compared using two-way (group × condition), repeated-measures analysis of variance (ANOVA). LBNP-induced changes (%Δ) in dependent variables were compared across stages using two-way (group × time), repeated-measures ANOVA. SNS-mediated vasoconstrictor responses were assessed by comparing LBNP-induced changes (%Δ) in forearm vascular conductance (FVC). The magnitude of sympatholysis was calculated as the difference between %ΔFVC at rest and during HG. Holm–Sidak post hoc analyses were used when a significant main effect was detected. Linear regression analysis was performed to examine the relationship between functional sympatholysis and FBF during HG. Statistical significance was set at P < 0.05. Values are presented as means ± SD.

RESULTS

Subject Characteristics

Subject characteristics are displayed in Table 1. Age and height were not different between groups, although mass and body mass index (BMI) were significantly higher in HFpEF (P < 0.01). Systolic and diastolic blood pressures were lower in HFpEF (P < 0.01). MVC was similar between groups (P = 0.47).

Table 1.

Subject characteristics

	Control	HFpEF
n (females/males)	11 (6/5)	12 (7/5)
Age, yr	69 ± 4	69 ± 7
Body mass index, kg/m2	25 ± 4	33 ± 6*
Systolic blood pressure, mmHg	134 ± 10	118 ± 11*
Diastolic blood pressure, mmHg	81 ± 8	72 ± 7*
Maximal voluntary contraction, kg	23 ± 7	21 ± 8
NYHA class, I–IV (females/males)		II/III (5/7)
Atrial fibrillation, n		5
Coronary artery disease, n		1
Hypertension, n		7
Pulmonary hypertension, n		7
Chronic obstructive pulmonary disease, n		6
Obstructive sleep apnea, n		6
Diabetes, n		3
B-type natriuretic peptide, pg/mL		119 ± 30
Echocardiography
Ejection fraction, %		63 ± 4
LV IVSd, cm		0.9 ± 0.1
LV PWd, cm		0.9 ± 0.2
LV ID diastole, cm		4.7 ± 0.9
LV ID systole, cm		3.0 ± 0.6
LA ESV index, mL/m2		39 ± 11
Peak E wave, cm/s		97 ± 8
Peak A wave, cm/s		86 ± 27
E/A ratio		1.1 ± 0.4
E′ septal wall, cm/s		7 ± 1
E′ lateral wall, cm/s		9 ± 2
E/E′ septal ratio		12 ± 4
E/E′ lateral ratio		14 ± 7
Mitral E-wave deceleration, ms		266 ± 82
Peak TR velocity, m/s		2.9 ± 0.6
TR gradient, mmHg		31 ± 3
Medications, n
SGLT2i		3
ACEi or ARB		5
Diuretic		10
Anticoagulant		6
Statin		6

Values are means ± SD; n = number of subjects. NYHA, New York Health Association; LV, left ventricle; IVSd, interventricular septum diameter at diastole; PWd, posterior wall diameter at diastole; ID, internal diameter; ESV, end-systolic volume; TR, tricuspid regurgitation; SGLT2i, sodium/glucose cotransporter-2 inhibitors; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. *P < 0.05 vs. control.

LBNP Responses during Rest

There were no group differences in resting FBF (P = 0.72) or FVC (P = 0.80; Table 2). LBNP caused reductions in FVC in both groups (P < 0.01; Table 2), although LBNP-induced %ΔFVC at rest were lesser in HFpEF (−9.5 ± 5.5 vs. −21.0 ± 8.0%; P < 0.01; Fig. 2A). There were no group differences in HR (P = 0.98), while MAP was lower in HFpEF (P < 0.01; Table 2). LBNP caused an increase in HR in Con only (P < 0.01) but did not affect MAP in either group (P = 0.25; Table 2). LBNP evoked positive changes in Z, indicating reductions in central blood volume that were similar between groups (P = 0.75; Table 2).

Table 2.

Central and peripheral hemodynamics

	Rest		P Values
	Rest	Rest + LBNP	Group	Condition	Interaction
ΔZ, %
Control		5.4 ± 1.5	0.75
HFpEF		5.7 ± 1.7
HR, beats/min
Control	59 ± 7	63 ± 7#	0.98	<0.01	<0.01
HFpEF	61 ± 7	61 ± 7
MAP, mmHg
Control	98 ± 6	98 ± 6	<0.01	0.25	0.60
HFpEF	87 ± 5*	86 ± 5*
FBF, mL/min
Control	109 ± 66	83 ± 42#	0.72	<0.01	0.09
HFpEF	94 ± 52	82 ± 44#
FVC, mL/min/mmHg
Control	1.11 ± 0.64	0.86 ± 0.41#	0.80	<0.01	0.12
HFpEF	1.11 ± 0.67	0.98 ± 0.57#

	HG exercise (30% MVC)
	HG	HG + LBNP
ΔZ, %
Control		5.0 ± 2.67	0.85	–	–
HFpEF		5.0 ± 1.45
HR, beats/min
Control	67 ± 6	68 ± 6	0.721	0.03	0.78
HFpEF	68 ± 7	70 ± 11
MAP, mmHg
Control	107 ± 12	107 ± 12	0.04	0.39	0.53
HFpEF	96 ± 10*	97 ± 12
FBF, mL/min
Control	374 ± 105	355 ± 107#	0.04	<0.01	0.26
HFpEF	285 ± 91*	260 ± 84*#
FVC, mL/min/mmHg
Control	3.56 ± 1.12	3.39 ± 1.21#	0.22	<0.01	0.12
HFpEF	3.03 ± 1.11	2.74 ± 1.07#

Values are means ± SD. LBNP, lower-body negative pressure; ΔZ, change in thoracic impedance; HFpEF, heart failure with a preserved ejection fraction; HR, heart rate; MAP, mean arterial pressure; FBF, forearm blood flow; FVC, forearm vascular conductance. Two-way repeated-measures ANOVA was performed. *P < 0.05 vs. control; #P < 0.05 vs. before LBNP.

Figure 2.

Lower-body negative pressure (LBNP)-induced changes in vascular conductance at rest and during 30% maximum voluntary contraction (MVC) handgrip exercise (HG; A); magnitude of sympatholysis, calculated as the difference between changes in forearm vascular conductance (FVC) at rest and during exercise (B); and relationship between functional sympatholysis and forearm blood flow during exercise (C) in control [Con, n = 11, 5 male (M)/6 female (F)] and heart failure with a preserved ejection fraction [(HFpEF); n = 12, 5 M/7 F]. Two-way, repeated-measures ANOVA (group × time) (A), unpaired t test (B), and linear regression analysis (C) were performed. *P < 0.05 vs. Con; †P < 0.05 vs. rest.

LBNP Responses during HG Exercise

Exercising FBF was lower in HFpEF compared with Con (P = 0.04; Table 2). During HG + LBNP, there were reductions in FVC in both groups (P < 0.01) although %ΔFVC tended to be greater in HFpEF (−9.9 ± 2.5 vs. −5.8 ± 6%; P = 0.09; Fig. 2A). However, compared with the responses during rest, LBNP-induced %ΔFVC was attenuated in Con (P < 0.01), whereas in HFpEF, LBNP-induced %ΔFVC was not different between rest and HG exercise (P = 0.88; Fig. 2A). The magnitude of sympatholysis was lesser in HFpEF (−0.4 ± 4.7 vs. −15.2 ± 11.8%; P < 0.01; Fig. 2B). A significant relationship existed between the magnitude of functional sympatholysis and FBF during HG (P = 0.01) such that a lesser magnitude of sympatholysis was related to lower FBF (Fig. 2C). During HG, LBNP did not affect HR or MAP in either group but did evoke positive changes in Z that were similar between groups (P = 0.85; Table 2).

DISCUSSION

The present study sought to investigate the efficacy of functional sympatholysis in patients with HFpEF. In control subjects, LBNP-induced vasoconstriction provoked a robust %ΔFVC at rest that was nearly abolished during HG. In contrast, LBNP provoked a lesser %ΔFVC at rest that persisted during HG in HFpEF, demonstrating impaired functional sympatholysis. Furthermore, functional sympatholysis was significantly related to FBF during HG. The present observations also align with previous reports demonstrating reduced blood flow to exercising muscle in HFpEF (5–8). To the best of our knowledge, this is the first study to identify an impairment in functional sympatholysis in HFpEF compared with similarly aged, healthy counterparts. These new observations extend current understanding of HFpEF pathophysiology, implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

Hemodynamic Responses to LBNP-Induced Sympathoexcitation at Rest

In Con, a robust (≈20%) %ΔFVC was observed in response to LBNP, whereas a lesser vasoconstrictor response was observed in HFpEF (Fig. 2A). One possible explanation for these findings is that chronically elevated SNS activity reported in HFpEF (9, 23) may result in disease-related changes in end-organ (α-adrenergic) responsiveness. Indeed, it appears that vascular responsiveness to direct α-adrenergic stimulation is diminished with aging (12) and HFrEF (13), both populations displaying elevated SNS activity (23, 24). Similarly, diminished vascular responsiveness during LBNP at −20 mmHg has been reported in older adults (24) and patients with HFrEF (25) despite SNS responses that were not different from their respective control subjects. Given that HFpEF appears to lay between healthy aging and HFrEF on the spectrum of SNS activity (23), it may be speculated that the current observation of diminished vascular responses in HFpEF to LBNP at −20 mmHg is likely mediated by diminished end-organ responsiveness, rather than a lesser SNS response. However, it is beyond the scope of this study to determine these specific mechanisms.

Functional Sympatholysis in Patients with HFpEF

The inability to appropriately modulate SNS-mediated vasoconstriction during exercise may be an important factor underlying diminished blood flow to exercising skeletal muscle observed in these patients (5–8). In Con subjects, LBNP-induced vasoconstriction was significantly attenuated in the exercising forearm during HG versus rest (Fig. 2A), resulting in ≈15% magnitude of sympatholysis (Fig. 2B). In contrast, LBNP-induced %ΔFVC was almost identical between rest and HG in HFpEF, and the magnitude of sympatholysis was all but absent (Fig. 2B). Furthermore, a moderate and significant negative relationship existed between the magnitude of sympatholysis and FBF during HG, such that a lesser magnitude of sympatholysis was related to lower FBF during HG (Fig. 2C). These data suggest that functional sympatholysis plays an important role in the hyperemic response during HG and that the lack of sympatholysis in HFpEF may contribute to lower FBF during exercise in these patients.

To the best of our knowledge, this is the first study to examine functional sympatholysis in patients with HFpEF and to identify an impairment in this aspect of vascular regulation. The diminished ability to oppose SNS-mediated vasoconstriction is particularly relevant given recent evidence suggesting elevated SNS activity in HFpEF during exercise (9, 10). Although it is possible that vascular (α-adrenergic) responsiveness to SNS activation may be lesser in HFpEF, as discussed earlier, substantially elevated SNS activity during exercise and impaired ability to counteract it could potentially overwhelm local vasodilating signals, resulting in exaggerated vasoconstriction in the exercising limb. Therefore, the observed reduction of FBF in HFpEF may likely be explained, in part, by exaggerated SNS activity and impaired functional sympatholysis.

Implications of Impaired Functional Sympatholysis on Exercise Intolerance in HFpEF

Exercise intolerance in HFpEF is underpinned by low V̇o_2peak (1, 2), and multiple studies have shown that the improvement in V̇o_2peak in HFpEF after exercise training occurs independent of improvements in central hemodynamic factors (2, 8). Therefore, improvement in V̇o_2peak must occur via restoration of peripheral deficits. Indeed, Hearon et al. (8) recently demonstrated that exercise training improved V̇o_2peak independent of changes in central factors, but with improvement in leg vascular conductance, highlighting the plasticity of vascular regulation to exercising muscle and the potential role it may play not only in contributing to low V̇o_2peak in HFpEF, but as a target for improvement. Although, theoretically, impaired perfusion of the exercising muscle could be compensated for by increased oxygen extraction at the exercising muscle, evidence suggests that this does not occur in HFpEF (2, 8, 26). Altogether, these previous and current observations imply that impairments in vascular control, such as functional sympatholysis, play an important role in the dysregulation of blood flow to exercising muscle, and may contribute exercise intolerance in HFpEF.

Potential Mechanisms

Although functional sympatholysis is an integrative response that has not been reduced to any single mechanism (27), deficiencies related to endothelial dysfunction (28, 29) and skeletal muscle disuse (30) have been shown to diminish functional sympatholysis, and may help to explain the current observations. Indeed, in healthy older adults, a population that also displays impaired functional sympatholysis (31, 32), augmentation of endothelial-dependent vasodilatory signaling improved functional sympatholysis (29). This observation highlights the pivotal role the endothelium plays in functional sympatholysis in aging. Given the evidence of endothelial dysfunction in HFpEF (33, 34), this may also be an important factor contributing to impaired functional sympatholysis in these patients.

Impaired functional sympatholysis in HFpEF may also be related to abnormalities in skeletal muscle documented in this patient group (35). In healthy adults, functional sympatholysis becomes impaired after only 2 wk of muscle immobilization (30) but can be improved with exercise training in not only healthy adults (36) but also in patients with HFrEF(37). These observations fall in line with the “muscle hypothesis” of HF implicating deficits in peripheral vascular function related to a detrained skeletal muscle phenotype (38) and indicate potential for functional sympatholysis as a modifiable target for improvement in HFpEF.

Experimental Considerations

Considering phenotypic differences within the general HFpEF patient population has been increasingly recognized (2). Although our enrollment criteria served to maximize generalizability of findings, we cannot exclude the possibility that the presence of comorbidities such as obesity, hypertension (HTN), or type 2 diabetes (T2D) could affect our results. However, this concern is somewhat mitigated by prior work that failed to identify a significant effect of adiposity on functional sympatholysis in healthy adults (39). In addition, in T2D, functional sympatholysis appears to depend upon the status of endothelial function (28), indicating that functional sympatholysis may be related to accumulated damage to the endothelium rather than T2D per se. Furthermore, while functional sympatholysis may be impaired in untreated HTN, patients with treated HTN may display intact functional sympatholysis (40). Given that the current patient cohort had pharmacologically managed blood pressure but still displayed impaired functional sympatholysis, indicate that this finding may be mediated by factors beyond HTN. In addition, without a direct assessment of SNS responses, discretion may be warranted when interpreting these results. Although there is precedent for the expectation of similar SNS responses in patients with HFpEF and controls based on previous findings in young and older adults (24), as well as patients with HFrEF (25), we cannot exclude the possibility that LBNP −20 mmHg provoked a differential sympathetic stimulus between groups. Thus, future studies should consider including direct nerve recordings during LBNP or other sympathoexcitatory maneuvers to further explore SNS function in these patients.

Perspectives and Significance

The current study has demonstrated that in patients with HFpEF, SNS-mediated vasoconstriction is diminished at rest but is sustained during HG, indicating that functional sympatholysis is impaired in these patients. Functional sympatholysis was also related to FBF during HG, supporting the important role this mechanism plays in the regulation of blood flow to exercising muscle. These observations provide new mechanistic insight concerning the regulation of muscle blood flow in this patient group, suggesting that inadequate functional sympatholysis may be an important aspect of peripheral HFpEF pathophysiology that contributes to reduced exercising muscle blood flow in this patient group.

DATA AVAILABILITY

Data will be made available upon reasonable request.

GRANTS

This work was funded in part by National Heart, Lung, and Blood Institute Grants HL162856 (to D.W.W.) and HL139451 (to J.C.C.) and U.S. Department of Veterans Affairs Grants CX002152 (to D.W.W.) and IK2RX003670 (to K.B.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

J.K.A. and D.W.W. conceived and designed research; J.K.A., K.B., M.A.F., J.C.C., and J.J.I. performed experiments; J.K.A. analyzed data; J.K.A., K.B., J.C.C., J.J.R., and D.W.W. interpreted results of experiments; J.K.A. prepared figures; J.K.A. drafted manuscript; J.K.A., K.B., M.A.F., J.C.C., J.J.I., J.J.R., and D.W.W. edited and revised manuscript; J.K.A., K.B., M.A.F., J.C.C., J.J.I., J.J.R., and D.W.W. approved final version of manuscript.