Impaired cardiopulmonary baroreflex function and altered cardiovascular responses to hypovolemia in patients with heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is associated with autonomic dysregulation, which may be related to baroreflex dysfunction. Thus, we tested the hypothesis that cardiac and peripheral vascular responses to baroreflex activation via lower-body negative pressure (LBNP; −10, −20, −30, −40 mmHg) would be diminished in patients with HFpEF (n = 10, 71 ± 7 yr) compared with healthy controls (CON, n = 9, 69 ± 5 yr). Changes in heart rate (HR), mean arterial pressure (MAP, Finapres), forearm blood flow (FBF, ultrasound Doppler), and thoracic impedance (Z) were determined. Mild levels of LBNP (−10 and −20 mmHg) were used to specifically assess the cardiopulmonary baroreflex, whereas responses across the greater levels of LBNP represented an integrated baroreflex response. LBNP significantly increased in HR in CON subjects at −30 and −40 mmHg (+3 ± 3 and +6 ± 5 beats/min, P < 0.01), but was unchanged in patients with HFpEF across all LBNP levels. LBNP provoked progressive peripheral vasoconstriction, as quantified by changes in forearm vascular conductance (FVC), in both groups. However, a marked (40%–60%) attenuation in FVC responses was observed in patients with HFpEF (−6 ± 8, −15 ± 6, −16 ± 5, and −19 ± 7 mL/min/mmHg at −10, −20, −30, and −40 mmHg, respectively) compared with controls (−15 ± 10, −22 ± 6, −25 ± 10, and −28 ± 10 mL/min/mmHg, P < 0.01). MAP was unchanged in both groups. Together, these data provide new evidence for impairments in cardiopulmonary baroreflex function and diminished cardiovascular responsiveness during hypovolemia in patients with HFpEF, which may be an important aspect of the disease-related changes in autonomic cardiovascular control in this patient group.

NEW & NOTEWORTHY Data from the current study demonstrate diminished cardiovascular responsiveness during hypovolemia induced by incremental lower-body negative pressure in patients with heart failure with preserved ejection fraction (HFpEF). These diminished responses imply impaired cardiopulmonary baroreflex function and altered autonomic cardiovascular regulation which may represent an important aspect of HFpEF pathophysiology.

INTRODUCTION

Heart failure with preserved ejection fraction (HFpEF) is a relatively understudied clinical population that involves multiorgan dysfunction resulting in the clinical manifestations of heart failure (HF) such as functional impairment, increased risk of hospitalization, and mortality (1). One of the primary pathophysiological aspects observed in the other prominent phenotype of HF, heart failure with reduced ejection fraction (HFrEF), is maladaptive changes in autonomic cardiovascular regulation (2, 3) although certain interventions have been developed that may improve autonomic function in these patients (4, 5). In contrast to HFrEF, there has been relatively less investigation into the various aspects of autonomic cardiovascular regulation in patients with HFpEF and it remains poorly understood (6). Given the potential for pharmacological interventions to favorably influence autonomic function in other patient populations (7), a better understanding of disease-related changes in autonomic cardiovascular control could be particularly relevant to the clinical care of patients with HFpEF.

Maladaptive alterations in autonomic cardiovascular control are known to occur across the spectrum of aging and age-related disease and may be accompanied by baroreflex dysregulation (8–10). The cardiopulmonary and arterial baroreflexes are known to play a crucial role in autonomic cardiovascular regulation, helping to regulate hemodynamic homeostasis. Each baroreflex represents a series of physiological events in which perturbations to hemodynamic homeostasis are sensed and relayed to the cardiovascular center of the medulla, where the balance of sympathetic (SNS) and parasympathetic (PNS) nervous system outflow are modulated to effect the appropriate response in target organs, such as the heart or peripheral vasculature.

Multiple experimental techniques have been developed to assess different aspects of baroreflex function. Of these techniques, lower-body negative pressure (LBNP) is one of the most robust and reproducible, in which various levels of hypovolemia may be titrated to provide a controlled orthostatic challenge to investigate multiple aspects of baroreflex function (8, 11, 12). In healthy adults, mild levels of LBNP (less than or equal to −20 mmHg) cause decreases in central venous pressure which is sensed by the cardiopulmonary baroreceptors, resulting in reflex peripheral vasoconstriction, whereas greater levels of LBNP (greater than −20 mmHg) may lead to reductions in arterial pulse pressure which may engage both the cardiopulmonary and arterial baroreceptors, resulting in peripheral vasoconstriction and increased heart rate (HR; 12, 13).

Altered baroreflex responsiveness has been documented with healthy aging (8), HFrEF (14, 15), and in several comorbid conditions common to HFpEF, including hypertension (HTN; 16), obesity (17), and type 2 diabetes (T2D; 18). Given the findings of impaired baroreflex across the spectrum of health, aging, and disease, it is reasonable to suspect that impairments may also exist in patients with HFpEF. Although initial evidence suggests that SNS responsiveness to spontaneous changes in diastolic blood pressure may be intact in patients with HFpEF (19), this only represents one aspect of the arterial baroreflex and does not indicate how the specific baroreflexes may sense and effect cardiovascular responses in these patients.

Therefore, the current study sought to investigate cardiovascular responsiveness during LBNP-induced hypovolemia in patients with HFpEF compared with healthy, age-matched control subjects to better define the pathophysiology related to autonomic cardiovascular regulation in this patient group. We hypothesized that both cardiac and peripheral vascular responsiveness during LBNP would be attenuated in patients with HFpEF compared with controls.

METHODS

Ethical Approval

The experimental protocol has been approved by the University of Utah and Salt Lake City Veteran’s Affairs Medical Center (VAMC) Institutional Review Board (IRB 40212) and is in compliance with clause 35 of the Declaration of Helsinki, except for registration in a database. Written informed consent was obtained from all participants before study participation.

Subjects

We recruited 10 patients with HFpEF (5 male and 5 female) and 10 similarly aged healthy controls (CON, 5 male, and 5 female) to participate in this study. Patients with HFpEF were recruited from the heart failure clinics at the University of Utah and the Salt Lake City Veterans Affairs Medical Center (VAMC), and healthy controls were recruited from the greater Salt Lake City community. Patients with HFpEF were screened in clinic and included upon criteria consistent with the TOPCAT trial (20), which is as follows; 1) heart failure defined by the presence of ≥1 symptom at the time of screening (paroxysmal nocturnal dyspnea, orthopnea, dyspnea on exertion) and 1 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, body mass index (BMI) >40 kg/m², prescription of β-blocking agents, or chronic use of nitrates beyond utilization for acute angina relief. For the control group, participants were free of overt cardiovascular disease and not taking any prescription medications, as indicated by a health history questionnaire. All participants were nonsmokers. Experiments were performed in a climate-controlled (21°C–22°C) dimly lit and quiet room in the Utah Vascular Research Laboratory located in the Salt Lake City Veterans Affairs Medical Center Geriatric Research, Education, and Clinical Center.

LBNP Protocol

At the time of testing, subjects had abstained from food for at least 4 h and caffeine for at least 12 h and refrained from vigorous exercise, consumption of vitamins and supplements, and alcohol for the previous 24 h. Upon arrival at the laboratory, body mass and height were recorded. Throughout the protocol, subjects rested in a supine position with the lower portion of their body sealed at the level of the iliac crests in a custom-built chamber designed for administering LBNP, as described previously (11). Following instrumentation, subjects rested quietly for 10 min, after which baseline measurements of central hemodynamics and peripheral (forearm) blood flow were performed. Then, LBNP was applied continuously in an incremental fashion (−10, −20, −30, and −40 mmHg, 5 min per stage), with measurements taken during the last minute of each stage, as described previously (8).

Measurements

Central blood volume.

To quantify LBNP-induced translocation of central blood volume, noninvasive impedance cardiography (NICO 100 C, Biopac, Goleta, CA) was used to determine thoracic impedance (Z), which is regarded as an accurate estimate of directional changes in central blood volume in comparison with central venous pressure (21, 22).

Central hemodynamics.

Heart rate (HR) was monitored continuously from a standard three-lead ECG (ECG100C, Biopac, Goleta, CA). Baseline brachial blood pressure was measured in triplicate on the upper arm (Omron, Kyoto, Japan) before LBNP, and the mean value was used. Continuous measures of HR and arterial blood pressures (systolic blood pressure, SBP; diastolic blood pressure, DBP; mean arterial pressure, MAP) were acquired during the protocol using finger photoplethysmography (Finometer, Finapres Medical Systems BV, Amsterdam, The Netherlands) at 200 Hz. Stroke volume (SV) was estimated using the Modelflow method (23), which, in combination with HR, was used to estimate cardiac output (CO). Total peripheral resistance (TPR) was calculated as the quotient of MAP/CO. The difference between SBP and DBP was used to determine pulse pressure (PP).

Peripheral hemodynamics.

Forearm blood flow (FBF) was calculated based on measurements of brachial arterial 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 the brachial artery. A linear array transducer operating at 14 MHz was utilized 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. Commercially available software (Logic 7) was used to assess vessel diameter as well as angle-corrected, time-averaged, mean blood velocity (V_mean). FBF data were analyzed in 12 s bins and averaged across the minute of data recording with BA diameter measured during diastole.

Data Acquisition and Analysis

Baseline MAP from the brachial artery was calculated as follows:

$$\text{MAP\hspace{0.17em}=\hspace{0.17em}1/3}\left(\text{PP}\right)\hspace{0.17em}+\hspace{0.17em}\left(\text{DBP}\right).$$

Central hemodynamics were averaged over a 1-min steady state for baseline measures and during the last minute of each consecutive stage of LBNP.

FBF was calculated as follows:

$$\text{FBF\hspace{0.17em}}\left(\text{mL/min}\right)\hspace{0.17em}=\hspace{0.17em}\left[{\text{Velocity}}_{\text{mean}}\left(\text{cm/s}\right)\text{×\hspace{0.17em}π\hspace{0.17em}}{\left(\text{vessel\hspace{0.17em}diameter\hspace{0.17em}}\left(\text{cm}\right)\text{/2}\right)}^2\text{×\hspace{0.17em}60\hspace{0.17em}}\left(\text{s}\right)\right].$$

Subsequently, FVC was calculated as follows:

$$\text{FVC\hspace{0.17em}}\left(\text{mL/min/mmHg}\right)\text{\hspace{0.17em}=\hspace{0.17em}FBF\hspace{0.17em}}\left(\text{mL/min}\right)\text{/MAP\hspace{0.17em}}\left(\text{mmHg}\right).$$

FBF and FVC were assessed in 12-s bins and averaged over the last minute of baseline measurement and each stage of LBNP.

Statistical Analysis

Statistical analyses and development of figures were performed using commercially available software (SigmaPlot 13, Systat Software Inc., Point Richmond, CA). Subject characteristics between groups and each dependent variable at baseline 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 × stage), repeated measures analysis of variance (ANOVA). LBNP-induced changes from baseline measures [%Δ = 100 × (Baseline value – value during LBNP)/Baseline value] in each dependent variable were compared across stages of LBNP using two-way (group × stage), repeated measures ANOVA. Tukey’s post hoc analyses were used when a significant main effect is detected. Statistical significance was set at P < 0.05. Box and whisker plots were utilized to identify any data that may be considered outliers. Values are presented as means ± SD.

RESULTS

Upon analysis, some data from one CON subject were identified as outliers for certain variables by box and whisker analysis. Statistical results were similar with and without these data and thus, data from this subject were removed from analysis. Therefore, the data reported here represent n = 9 CON and n = 10 HFpEF.

Subject Characteristics

Characteristics of CON and HFpEF subjects, as well as HFpEF-specific characteristics including comorbidities, echocardiographic data, and medications are displayed in Table 1. Age and height were not different between groups, although body mass and BMI were significantly higher in HFpEF compared with CON. SBP and DBP were lower in HFpEF compared with CON.

Table 1.

Subject Characteristics

	Control (n = 9; 4F/5M)	HFpEF (n = 10; 5F/5M)
Age, yr	70 ± 5	71 ± 7
Body Mass, kg	76 ± 13	88 ± 12*
Height, cm	173 ± 9	168 ± 7
Body mass index, kg/m2	25 ± 4	31 ± 5*
Systolic blood pressure, mmHg	131 ± 11	121 ± 9*
Diastolic blood pressure, mmHg	77 ± 7	71 ± 8*
NYHA Class		II/III (7/3)
Atrial fibrillation		4
Coronary artery disease		2
Hypertension		5
Pulmonary hypertension		6
Obstructive sleep apnea		4
Diabetes		1
B-type natriuretic peptide pg/mL		170 ± 110
Echocardiography
Ejection fraction, %		63 ± 5
LV IVSd, cm		0.9 ± 0.2
LV PWd, cm		0.9 ± 0.2
LV ID diastole, cm		4.8 ± 0.5
LV ID systole, cm		3.1 ± 0.5
LA ESV index, mL/m2		40 ± 14
Peak E Wave, cm/s		96 ± 30
Peak A wave, cm/s		77 ± 32
E/A ratio		1.3 ± 0.6
E' septal wall, cm/s		8 ± 1
E' lateral wall, cm/s		9 ± 2
E/E' septal ratio		11 ± 4
E/E' lateral ratio		14 ± 8
Mitral E-wave deceleration, ms		276 ± 100
Peak TR velocity, m/s		3.1 ± 0.7
RV SBP, mmHg		48 ± 19
Medications
SGLT2i		2
ACEi or ARB		5
Loop diuretic		6
Potassium sparing diuretic		5
Anticoagulant		4
Statin		5
Nitrate		2

Values are means ± SD. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; a wave, peak velocity of late transmitral flow; E′, peak velocity of early diastolic mitral annular motion; ESV, end systolic volume; E wave, peak velocity of early diastolic transmitral flow; ID, internal dimension; IVSd, interventricular septum thickness at end-diastole; LA, left atrium; LV, left ventricle; MAP; mean arterial pressure; NYHA, New York health association functional classification; PWd, posterior wall thickness; SGLT2i, sodium glucose cotransporter-2 inhibitor; TR, tricuspid regurgitation. Unpaired t test. *P < 0.05 vs. Control.

Impedance

LBNP provoked significant increases in thoracic impedance, indicating a reduction in central blood volume. %ΔZ was not different between groups at any point during LBNP (Table 2).

Table 2.

Central hemodynamic responses during incremental lower-body negative pressure

	BL	LBNP				P Values
	0 mmHg	−10 mmHg	−20 mmHg	−30 mmHg	−40 mmHg	Group	Condition	Interaction
HR, beats/min
Control	62 ± 8	61 ± 7	62 ± 7	65 ± 7#	68 ± 6#	0.99	<0.01	<0.01
HFpEF	63 ± 8	63 ± 8	64 ± 9	64 ± 8	64 ± 7
Stroke volume, mL/beat
Control	95 ± 12	94 ± 14	90 ± 15	88 ± 18	87 ± 21	0.40	0.30	0.11
HFpEF	96 ± 15	96 ± 17	97 ± 15	97 ± 17	97 ± 17
Cardiac output, L/min
Control	5.9 ± 1.0	5.7 ± 0.8	5.6 ± 0.9	5.6 ± 1.1	5.8 ± 1.3	0.42	0.56	0.65
HFpEF	6.1 ± 1.1	6.0 ± 1.1	6.1 ± 1.0	6.2 ± 1.3	6.2 ± 1.2
Systolic BP, mmHg
Control	131 ± 11	131 ± 12	129 ± 12	127 ± 11	127 ± 11#	0.07	0.02	0.11
HFpEF	121 ± 10*	119 ± 9*	121 ± 9	121 ± 10	118 ± 10
Diastolic BP, mmHg
Control	77 ± 7	77 ± 8	77 ± 7	79 ± 8	80 ± 9#	0.03	0.09	<0.01
HFpEF	71 ± 8	70 ± 9	69 ± 7	70 ± 9*	69 ± 9*
PP, mmHg
Control	53 ± 12	54 ± 12	53 ± 12	49 ± 12#	48 ± 13#	0.89	<0.01	<0.01
HFpEF	50 ± 9	50 ± 8	52 ± 9	52 ± 11	49 ± 10
MAP, mmHg
Control	94 ± 7	94 ± 8	93 ± 7	94 ± 7	95 ± 7	0.02	0.73	0.25
HFpEF	87 ± 8*	86 ± 8*	86 ± 6*	86 ± 7*	85 ± 8*
TPR, mmHg/L/min
Control	16.6 ± 3.4	16.8 ± 3.1	17.1 ± 3.0	17.3 ± 3.6	17.1 ± 4	0.11	0.92	0.50
HFpEF	14.7 ± 3.2	14.8 ± 3.3	14.4 ± 2.9	14.6 ± 3.5	14.2 ± 3.3
Impedance (ΔZ), %
Control		2.0 ± 0.9#	3.8 ± 1.4#	6.2 ± 1.3#	9.6 ± 2.3#	0.47	<0.01	0.47
HFpEF		2.2 ± 1.3#	3.7 ± 1.3#	5.3 ± 1.3#	8.7 ± 2.6#

Values are means ± SD. BP, blood pressure; HR, heart rate; MAP, mean arterial pressure; PP, pulse pressure; TPR, total peripheral resistance. Two-way repeated measures ANOVA (group × time). *P < 0.05 vs. Control; #P < 0.05 vs. BL (0 mmHg).

Central Hemodynamics

At baseline (BL), there were no group differences in HR, SV, CO, DBP, or PP, although BL values for SBP and MAP were significantly lower in patients with HFpEF (Table 2). In general, LBNP was well-tolerated by all subjects. Modest changes in SBP and DBP were observed at −30 and −40 mmHg in the CON group, whereas in patients with HFpEF, these variables were unchanged at any level of LBNP (Table 2). PP was not different between groups, but there were significant LBNP-induced changes in PP in CON (−30 mmHg: −6 ± 6 mmHg; −40 mmHg: +8 ± 5; P < 0.01 vs. BL), but not in patients with HFpEF (Table 2 and Fig. 1, top). Throughout progressive levels of LBNP, absolute HR values were not different between groups, but in CON, there were significant LBNP-induced changes in HR at the greater levels of LBNP (−30 mmHg: +3 ± 3 beats/min; −40 mmHg: +6 ± 5 beats/min; P < 0.01 vs. BL), whereas in patients with HFpEF, there were no significant LBNP-induced changes in HR (Table 2 and Fig. 1, bottom). SV, MAP, and TPR were invariant throughout the protocol in both groups (Table 2).

Figure 1.

Pulse pressure (PP) and heart rate (HR) responses during lower-body negative pressure (LBNP) in control (CON, n = 9, 5 male/4 female) and patients with HFpEF (n = 10, 5 male/5 female). Two-way, repeated measures ANOVA (group × time). *P < 0.05 vs. CON; #P < 0.05 vs. BL.

Peripheral Hemodynamics

At BL, there were no group differences in BA diameter, FBF, or FVC (Table 3). BA diameter was significantly decreased by LBNP in both groups at −20 mmHg and beyond (Table 3), with smaller changes in BA diameter in patients with HFpEF at −40 mmHg compared with CON (HFpEF: −3.3 ± 1.2% vs. CON: −5.1 ± 2.5%; P = 0.02; Fig. 2, top). LBNP caused reductions in FBF and FVC in both groups (P < 0.01; Table 3), although reductions in FBF and FVC were apparent in CON at the onset of LBNP (P < 0.01) whereas in HFpEF, FBF, and FVC were only reduced from BL after −20 mmHg (P < 0.01; Table 3). LBNP-induced changes in FBF (Fig. 2, middle) and FVC (Fig. 2, bottom) were lesser in patients with HFpEF at each stage of LBNP (P < 0.01).

Table 3.

Peripheral vascular responses during incremental lower-body negative pressure

	BL	LBNP				P Values
	0 mmHg	−10 mmHg	−20 mmHg	−30 mmHg	−40 mmHg	Group	Condition	Interaction
Brachial Artery Diameter, cm
Control	0.47 ± 0.09	0.46 ± 0.09	0.45 ± 0.08#	0.45 ± 0.09#	0.44 ± 0.09#	0.62	<0.01	0.14
HFpEF	0.44 ± 0.08	0.44 ± 0.08	0.43 ± 0.08#	0.43 ± 0.08#	0.43 ± 0.08#
Mean blood velocity, cm/s
Control	9.1 ± 3.0	7.9 ± 3.0	7.5 ± 2.8	7.4 ± 2.5	7.3 ± 2.4	0.30	<0.01	0.58
HFpEF	10.3 ± 4.0	9.8 ± 3.9	9.2 ± 3.5	9.1 ± 3.5	8.8 ± 3.5
Forearm blood flow, mL/min
Control	90 ± 28	76 ± 27#	70 ± 23#	68 ± 22#	65 ± 21#	0.52	<0.01	0.50
HFpEF	93 ± 34	87 ± 36	78 ± 26#	77 ± 27#	74 ± 26#
Forearm vascular conductance, mL/min/mmHg
Control	0.95 ± 0.29	0.81 ± 0.26#	0.74 ± 0.21#	0.72 ± 0.21#	0.68 ± 0.19#	0.21	<0.01	0.57
HFpEF	1.09 ± 0.44	1.03 ± 0.44	0.92 ± 0.34#	0.91 ± 0.35#	0.88 ± 0.34#

Values are means ± SD. BP, blood pressure; HR, heart rate; MAP, mean arterial pressure. Two-way repeated measures ANOVA (group × time). #P < 0.05 vs. BL (0 mmHg).

Figure 2.

Peripheral vascular responses during lower-body negative pressure (LBNP) in control (CON, n = 9, 5 male/4 female) and patients with HFpEF (n = 10, 5 male/5 female). LBNP-induced changes in brachial artery (BA) diameter (top), forearm blood flow (FBF; middle), and forearm vascular conductance (FVC; bottom) are illustrated. Two-way, repeated measures ANOVA (group × time). *P < 0.05 vs. CON; #P < 0.05 vs. BL.

DISCUSSION

This study evaluated cardiac and peripheral vascular responses to progressive hypovolemia to determine whether disease-related changes in baroreflex responsiveness are present in patients with HFpEF. Cardiac responses to LBNP differed between groups, with a significant HR response observed in the CON group at greater levels of LBNP (−30 and −40 mmHg), whereas HR was unchanged in patients with HFpEF across all LBNP levels, suggesting a disease-related alteration in cardiac responses to hypovolemia. In addition, smaller changes in FBF and FVC were observed in patients with HFpEF throughout all levels of LBNP suggesting diminished peripheral vascular responses to hypovolemia. In particular, blunted vasoconstrictor responses in patients with HFpEF during mild levels of LBNP (−10 and −20 mmHg) specifically implicate diminished cardiopulmonary baroreflex function in these patients. To the best of our knowledge, this is the first investigation of cardiovascular responses to progressive hypovolemia in patients with HFpEF, providing new evidence for alterations in cardiopulmonary baroreflex function and autonomic cardiovascular regulation in this patient group.

Cardiopulmonary and Integrative Baroreflex

Application of LBNP across multiple levels provokes progressive reductions in central blood volume that selectively unload discreet baroreceptor populations, providing the opportunity to investigate autonomic function in an integrative, noninvasive manner. Indeed, it is generally understood that in young healthy individuals, short exposures to mild levels of LBNP (less than or equal to −20 mmHg) primarily unload baroreceptors in the atria and pulmonary vasculature and elicit peripheral vasoconstriction, with no changes in HR. In contrast, during progressively greater levels of LBNP (−30 and −40 mmHg), arterial baroreceptors may sense decrements in arterial pulse pressure, provoking both cardiac responses to quickly adjust cardiac output and rectify these perturbations (12). It should be noted that evidence suggests that arterial baroreceptors play some role, albeit modest, in cardiovascular responses at mild levels of LBNP (24) and inherently, cardiopulmonary baroreceptors are involved in greater levels of LBNP. It has been shown that the arterial baroreflex has little influence on peripheral blood flow in the absence of cardiopulmonary baroreflex recruitment, but in combination, these reflexes may augment peripheral vascular responses (25). Thus, vascular responses to LBNP at or below −20 mmHg are primarily governed by the cardiopulmonary baroreflex, whereas cardiovascular responses beyond −20 mmHg are considered to be mediated by an integrative (cardiopulmonary + arterial) baroreflex. In the present study, the application of an incremental LBNP protocol (−10, −20, −30, and −40 mmHg) therefore afforded the opportunity to explore potential disease-related changes in cardiopulmonary and integrative baroreflex control in patients with HFpEF, which is an aspect of physiology that represents a significant knowledge gap in this patient group.

Interestingly, it appears that the effect of higher levels of LBNP (−30 and −40 mmHg) on PP is attenuated in older compared with young adults (8) and in patients with HFrEF compared with age-matched control subjects (14). In the current study, we report reductions in PP in our CON subjects at −40 mmHg (≈−7; Fig. 1, top) that are similar to those reported by Davy et al. (8) for the older subjects (approximately equal to −5) (8), but no significant effect of LBNP on PP in patients with HFpEF (Fig. 1, top). In both instances, the differential effects of LBNP on PP between different populations confounds assessment of the integrative baroreflex via this technique. Thus, although we may interpret cardiovascular responses to milder levels of LBNP (−10 and −20 mmHg) as indicative of cardiopulmonary baroreflex function, responses during greater levels of LBNP (−30 and −40 mmHg) may not explicitly represent integrative baroreflex function. Nonetheless, differences in LBNP-induced changes in PP allude to other alterations of the cardiovascular system that change the way in which the baroreflexes may sense or respond to hypovolemia.

Cardiac Responses during Incremental LBNP

In support of our hypothesis, the reflex increase in HR response to LBNP was markedly attenuated in patients with HFpEF compared with their healthy, older counterparts. Specifically, HR increased significantly in CON subjects at −30 mmHg (+3 ± 4 beats/min) and −40 mmHg (+7 ± 11 beats/min), whereas in HFpEF, HR was unchanged by any level of LBNP (Fig. 2). Previous studies (8, 26) have demonstrated HR responses during greater levels of LBNP (−30 and −40 mmHg) in older healthy adults similar to those observed here in the CON subjects, though the heart rate response is markedly attenuated (approximately equal to −50%) in older compared with young participants (8). Specific to HF, several studies to date have identified a marked impairment in the HR response to LBNP. Indeed, patients with HFrEF (EF < 50%) fail to mount any HR response across a similar range of LBNP (−10 to −40 mmHg; 14, 15). The lack of HR response is likely explained, in part, by the lack of LBNP-induced changes in PP, which may be a primary variable sensed by the arterial baroreflex (27). Although similar changes in impedance were observed in both groups (Table 2), which indicate a similar translocation of blood, cardiac, and arterial remodeling associated with HFpEF may influence the effect of LBNP on central hemodynamics and how they are sensed. Indeed, it is well-known that central and cardiac filling pressures are elevated in patients with HFpEF (28) with accompanying alterations in arterial structure and function (29, 30) although understanding the effect of these factors on baroreflex function requires further investigation. In addition, attenuated cardiac responses during LBNP observed here and with aging (8) and HFrEF (14, 15) may be influenced by reduced cardiac β-adrenergic responsiveness observed in aging (31), HFrEF (32), and HFpEF (33). Indeed, a curious observation in the context of aging is that cardiac responses to LBNP (−10 through −40 mmHg) were attenuated, whereas SNS responses were similar in older compared with young adults, suggesting a potential role for decreased cardiac β-adrenergic responsiveness in this observation. Importantly, in the current and previous studies in older adults and patients with HFrEF or HFpEF, β-blocking agents were either not prescribed or were withheld for experimental visits. Thus, the current finding of a negligible cardiac response to LBNP extends existing work in older individuals and patients with HFrEF, providing new evidence that cardiac regulation during incremental LBNP is attenuated by disease-related changes associated with HFpEF.

Peripheral Responses during Incremental LBNP

As outlined earlier, the application of mild LBNP selectively unloads the cardiopulmonary baroreceptors, provoking vasoconstriction in the peripheral circulation. During these mild levels of LBNP (−10 and −20 mmHg), CON participants demonstrated robust reductions (≈15%–25%) in both FBF and FVC. In contrast, patients with HFpEF demonstrated a clear diminution in peripheral vascular responsiveness in the forearm, with no significant changes in FBF and FVC at −10 mmHg, and more modest reductions (≈6%–15%) in these vascular parameters at −20 mmHg that were lesser compared with CON (P < 0.01; Fig. 2). These observations during the mild levels of LBNP (−10 and −20 mmHg) suggest that, in patients with HFpEF, the cardiopulmonary baroreflex is less capable of evoking peripheral vascular adjustments for a given hypovolemic stimulus and may thus indicate dysregulation of the cardiopulmonary baroreflex in these patients. To the best of our knowledge, this is the first study to evaluate disease-related impairment in cardiopulmonary baroreflex control of the peripheral vasculature, expanding our current understanding of this aspect of autonomic cardiovascular regulation in patients with HFpEF.

Across greater levels of LBNP, the pattern of differential peripheral responses persisted. Indeed, CON subjects demonstrated robust peripheral vasoconstriction in the forearm, where FBF and FVC were reduced by 25%–30% at LBNP −30 and −40 mmHg (Fig. 2, middle and bottom). Meanwhile, in patients with HFpEF, LBNP-induced changes in FBF and FVC were significantly lesser compared with CON at LBNP −30 and −40, where only a 15%–20% change was observed (Fig. 2, middle and bottom). In addition, although BA diameter was reduced by greater levels of LBNP (≥ 20 mmHg) in both groups (P < 0.05), the LBNP-induced change in BA diameter was lesser in patients with HFpEF at LBNP at −40 mmHg (Fig. 2, top). Importantly, LBNP-induced changes in thoracic impedance, which has been shown to accurately reflect changes in central blood volume (21, 22), were not different between groups (Table 2), suggesting that these divergent peripheral vascular responses were not due to differences in the hypovolemic stimulus. However, it is possible that during greater levels of LBNP, a lack of involvement of the integrative baroreflex in patients with HFpEF could contribute to the attenuated peripheral vascular responses observed at the greater levels of LBNP. Notwithstanding, the present data provide new evidence for an attenuated ability of the peripheral circulation to respond to LBNP including both the microvasculature and conduit arteries in patients with HFpEF.

The observed impairment in peripheral vascular responses to LBNP in patients with HFpEF adds to a small but long-standing body of literature focused on patients with HFrEF, while also reinforcing the unique nature of autonomic dysfunction between these two HF phenotypes. In a seminal study from Ferguson et al. (14), changes in forearm vascular resistance (FVR) in response to LBNP (−10 and −40 mmHg) were evaluated to determine the degree of baroreflex dysfunction in patients with left ventricular dysfunction (EF < 30%) compared with normal controls. In this study, an almost twofold increase in FVR was observed during progressive LBNP in the control group, whereas patients with left ventricular dysfunction failed to vasoconstrict during any level of LBNP, and in some patients, a paradoxical decrease in FVR was even observed. Although significant differences in methodology and experimental design preclude a direct comparison with the present study, these previous and present findings appear to suggest that the impairment in baroreflex control of the peripheral circulation may be more modest in HFpEF than in HFrEF, similar to the progressive pattern of SNS overactivity recently reported across the continuum of healthy older adults and patients with preserved, midrange, and reduced ejection fraction (19). However, further studies directly comparing HF subpopulations are needed to explore this interesting possibility.

Perspectives

In the current study, arterial blood pressure was maintained throughout LBNP in patients with HFpEF despite clear attenuation in both cardiac and peripheral vascular responsiveness, which may be related to disease-related changes in cardiovascular structure and function that impact both afferent and efferent aspects of baroreflex signaling. Indeed, considering that the cardiopulmonary baroreceptors are sensitive to both stretch and pressure (34, 35), in the face of cardiac stiffening (36) and elevated filling pressures commonly observed in patients with HFpEF (37), it is possible that these receptors may simply be less sensitive to the physical stimulus of hypovolemia during LBNP. Similarly, remodeling and stiffening in the large vessels such as the aorta and carotid arteries reported in patients with HFpEF (36) may impact arterial baroreceptor responsiveness, and thus impair the ability of arterial baroreceptors to sense perturbances caused to hypovolemia.

End-organ responses to sympathetic and vagal efferent activity provoked by baroreflex unloading may also be impaired in patients with HFpEF. For instance, preclinical (38) and clinical (33) studies suggest that cardiac β-adrenergic sensitivity is reduced in patients with HFpEF, and there is emerging evidence for disease-related changes in reflex vagal responsiveness, as demonstrated by a reduced change in HR during the Valsalva maneuver (39) and spontaneously occurring fluctuations in systolic blood pressure (40), in this patient group. Changes in β-adrenergic signaling could result in reduced cardiac responsiveness even if baroreceptors are adequately sensing hypovolemic stimuli. Similarly, in the peripheral circulation, changes in α-adrenergic signaling could impact peripheral vasoconstrictor responses to LBNP. The rationale for the expectation of disease-related changes in α-adrenergic signaling is based on initial evidence of elevated resting SNS activity in patients with HFpEF (19, 41), which may result in a decline in α-adrenergic responsiveness, as previously reported in healthy older adults (42, 43) and patients with HFrEF (44). Thus, although additional studies are needed to explore afferent and efferent aspects of baroreflex signaling, our data have demonstrated attenuated cardiovascular responses in patients with HFpEF to progressive hypovolemia during incremental LBNP and provide clear evidence of impaired cardiopulmonary baroreflex control in these patients.

Limitations

HFpEF is a heterogenous patient group, and as new data and diagnostic tools emerge, so too does the recognition of distinct HFpEF phenotypes (45, 46). To maximize the generalizability of findings, we did not exclude or separate patients with HFpEF beyond the current criteria outlined for inclusion and exclusion in the TOPCAT clinical trial (20) nor did these patients withhold any prescribed medications, which likely influenced lower blood pressure in the patients with HFpEF. So, although our techniques were able to detect significant differences in cardiovascular responsiveness to hypovolemia between the HFpEF and CON groups, it is possible that certain HFpEF phenotypes on different pharmacotherapies may exhibit differing cardiovascular responsiveness during LBNP than is reported here. For instance, the combination of obesity and HTN appears to exacerbate decrements in baroreflex function compared with HTN alone (47), although differences in BMI in this previous study were much more pronounced (HTN: 22 ± 1 vs. HTN + Obese: 37 ± 1 kg/m²) compared with the current study (CON: 25 ± 5 vs. HFpEF: 31 + 5 kg/m²). We also recognize that unique autonomic changes in postmenopausal women may be modulated by estrogen therapy (48, 49), and thus sex differences may influence cardiovascular responses during LBNP, especially in the context of geriatric populations such as the current HFpEF and CON groups. Although the determination of sex differences was not an a priori goal of the present study, an equal number of males and females were enrolled in both HFpEF and CON groups in an attempt to minimize the potential confounding influence of this factor. Finally, although the current data have provided new evidence of baroreflex dysregulation in patients with HFpEF, further investigation is required to understand different aspects of the baroreflex such as SNS and α-adrenergic signaling as well as alterations in regional (i.e., carotid, aortic, atrial, and pulmonary) baroreceptor subpopulations.

Conclusion

The current study has demonstrated diminished cardiovascular responsiveness in patients with HFpEF during incremental LBNP, providing new insight regarding baroreflex function and cardiovascular responsiveness to progressive hypovolemia in this patient group. First, blunted peripheral vasoconstrictor responses in patients with HFpEF during mild levels of LBNP (less than or equal to −20 mmHg) suggest impaired cardiopulmonary baroreflex function in these patients. Second, markedly attenuated HR and peripheral vascular responses in patients with HFpEF during greater levels of LBNP (up to −40 mmHg) suggest potential anatomical or physiological changes associated with HFpEF that lead to attenuated cardiovascular responsiveness to progressive hypovolemia.

DATA AVAILABILITY

Data will be made available upon reasonable request.

GRANTS

This work was funded in part by the NIH (HL162856, HL139451) and the U.S. Department of Veterans Affairs (CX002152, IK2RX003670).

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.I., 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.