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Basic Research in Cardiology
https://doi.org/10.1007/s00395-025-01110-3
ORIGINAL CONTRIBUTION
Reinstating respiratory heart rate variability improves hemodynamic
responses duringexercise inheart failure withreduced ejection
fraction
JuliaShanks1· MridulaPachen1· NigelA.Lever2· JulianF.R.Paton1· RohitRamchandra1
Received: 23 February 2025 / Revised: 8 April 2025 / Accepted: 11 April 2025
© The Author(s) 2025
Abstract
Individuals with heart failure have significantly reduced exercise capacity, a critical life-limiting symptom for those liv-
ing with the disease. Heart failure is negatively correlated with decreased heart rate variability, including the loss of heart
rate variability in tune with breathing—termed respiratory heart rate variability (RespHRV). We tested the hypothesis that
restoration of RespHRV would improve exercise tolerance. Heart failure was induced in adult female sheep using a micro-
embolization technique, and the sheep were divided into two groups: RespHRV paced and monotonically paced. Follow-
ing a 1-week baseline recording, the sheep underwent 2weeks of pacing. Direct recordings of hemodynamic parameters,
including arterial pressure, cardiac output, coronary artery blood flow, and heart rate, were taken at rest and during treadmill
exercise. Reinstating RespHRV significantly increased resting cardiac output, a change not observed in monotonically paced
sheep. Neither group showed a change in resting coronary artery blood flow. During exercise, RespHRV-paced sheep showed
increased cardiac output, coronary artery blood flow, cardiac power output, and faster heart rate recovery post-exercise. In
contrast, monotonically paced sheep showed no changes in exercise-induced cardiac function. A separate group of heart
failure animals were studied to determine if these benefits would persist alongside heart failure medications. RespHRV pacing
continued to improve resting cardiac output with concurrent heart failure medications. Our results indicate that reinstating
RespHRV may be a novel approach for improving outcomes in heart failure, including exercise capacity.
Keywords Heart failure· Respiratory heart rate variability (RespHRV)· Cardiac output· Coronary artery blood flow· Pre-
clinical· Exercise· Sheep
Abbreviations
DEMG Diaphragmatic electromyograph
Mono Monotonic
RespHRV Respiratory heart rate variability
Introduction
Heart failure is a pressing global concern, affecting an esti-
mated 64 million individuals worldwide [49]. The preva-
lence of heart failure continues to rise [12], imposing sub-
stantial economic burdens on both individuals and society
due to direct costs of hospital care and medication, as well as
indirect costs such as decreased productivity [24]. Chronic
heart failure with reduced ejection fraction (HFrEF) is char-
acterized by diminished left ventricular pump function, lead-
ing to decreased exercise tolerance [57], autonomic imbal-
ance [17, 20], and a significant decline in the quality of life
[25]. In healthy individuals, the heartbeat naturally varies
with every breath (called respiratory heart rate variability,
abbreviated as RespHRV). However, in patients with HFrEF,
RespHRV is lost [23], which is a negative prognostic indica-
tor of cardiovascular diseases[ 56]. Over the last 2 decades,
pacemakers which are used to restore heart rhythm have
evolved to more closely mimic cardiac physiology[ 1, 2, 55].
Julia Shanks and Mridula Pachen: Joint first authors.
* Rohit Ramchandra
R.Ramchandra@auckland.ac.nz
1 Department ofPhysiology, Faculty ofMedical andHealth
Sciences, Manaaki Manawa – The Centre forHeart
Research, University ofAuckland, 85 Park Road, Grafton,
1023Auckland, NewZealand
2 Department ofCardiology, Auckland City Hospital,
Auckland District Health Board, Park Road, Grafton,
Auckland, NewZealand
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Basic Research in Cardiology
While this has improved outcomes in patients, these devices
still have limitations[ 15] and no commercially available
pacemaker can currently reinstate physiological RespHRV.
The overarching aim of this study was to examine how rein-
statement of RespHRV would alter heart function in HFrEF.
During acute demands on the heart, such as exercise, cor-
onary artery blood flow increases to respond to the increased
oxygen demand of the working myocardium [35]. An early
symptom of HFrEF is reduced cardiac capacity during exer-
cise, including impaired coronary artery blood flow, which
is directly linked to myocardial dysfunction [26]; all this
contributes significantly to reduced quality of life in patients
with HFrEF [45]. Patients also experience cardiac vagal
autonomic dysfunction, which is observed in delayed post-
exercise heart rate recovery [3, 5, 29, 37]. While RespHRV
pacing improves cardiac output at rest [51], its ability to
adapt cardiac function to meet the increased energy demands
during exercise is unknown and was the primary aim of the
present study. We also assessed whether heart rate recovery
post-exercise, a hallmark indicator of cardiovascular fitness,
would be improved with RespHRV pacing.
Before clinical translation, it is crucial to demonstrate the
efficacy of any treatment against a backdrop of current medi-
cations. To determine if the beneficial effects of RespHRV
would persist with medications, we also examined the
response to reinstatement of RespHRV against a background
of β-blocker and angiotensin AT1R blocker therapy in a sep-
arate group of animals. Our study was specifically designed
to investigate the clinical impact of reinstating RespHRV
in chronic heart failure, where the loss of RespHRV is cor-
related to increased adverse outcomes.
Methods
Sheep
All animal studies and surgical procedures followed rel-
evant guidelines and were approved by the Animal Ethics
Committee of the University of Auckland (#2082). Adult
(3–6year old) female Romney sheep (n = 32 total) were
sourced from Ngāpouri Liggins research farm and housed
in individual crates at the University of Auckland, large ani-
mal unit. All sheep used were novel for this study and not
included in our previous publication. Sheep were acclima-
tized to laboratory conditions (18°C, 50% relative humidity,
12-h light–dark cycle) and human contact for 1week before
any experiments. Sheep were fed 2–2.5kg/day (Country
harvest pellets) and had access to water adlibitum. Male
sheep (rams) are often unpredictable and aggressive, mak-
ing measuring echocardiography and stable hemodynamics
difficult in conscious animals. Although we anticipate that
the results obtained from this study will apply to both males
and females, we acknowledge that the absence of males is a
limitation of this study.
Two protocols were used: The first 16-week protocol
is described below; a summary is schematized in Fig.1A
(Protocol A). The second 18-week protocol, which included
heart failure medication (Protocol B), is described later in
the Methods section. This study focused on observing the
benefits of reinstating RespHRV compared to non-respira-
tory modulated (monotonic) pacing in heart failure; studying
RespHRV pacing in healthy animals was irrelevant to this
study.
Data availability
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
Induction ofheart failure: embolization surgical
procedure
To determine the effects of RespHRV pacing on measures of
exercise capacity (Protocol A), two groups of heart failure
sheep were studied: respiratory HRV (RespHRV: n = 9) and
monotonically (mono: n = 10) paced. To determine if the
effects of RespHRV pacing persisted with medications (Pro-
tocol B), a separate group of RespHRV animals (n = 8) were
studied. In both protocols, a microembolization technique
was used to induce reduced ejection fraction heart failure as
previously described [3, 51]. In brief, sheep were anaesthe-
tized with an induction by 2% Diprivan (Propofol) (5mg/kg
i.v. AstraZeneca, AUS), maintained with a 2% isoflurane-air-
O2mixture and were intubated for mechanical ventilation.
Anesthesia depth was monitored throughout the surgery by
an absence of the corneal reflex and an absence of a with-
drawal response to a noxious pinch. One femoral artery was
accessed percutaneously using an 8F (CORDIS®, USA)
sheath and under fluoroscopic guidance, the catheter was
progressed into the left main coronary. Prior to the injection
of microspheres, β-blocker (metoprolol up to 20mg/kg, IV)
and lignocaine (2mg/kg, IV) were injected intravenously
to prevent ventricular arrhythmias. Polystyrene latex micro-
spheres (45μm diameter; 1.4mL, Polysciences, Warrington,
PA, USA) were injected into the coronary artery to induce
ischemic heart failure. Following recovery for a week, up to
two more embolizations were conducted until the ejection
fraction dropped to our target value (~ 45%).
Conscious sheep underwent echocardiography (GE S70);
ejection fraction dropped from 60–70% (pre-embolization)
to ~ 45% (3days post-embolization). Echocardiograms were
repeated 3months post-embolization to confirm sheep were
in heart failure. In the short-axis M-mode, diastole, systole,
and ejection fraction were obtained and calculated for the
left ventricle.
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Basic Research in Cardiology
A total of n = 32 sheep underwent microembolization sur-
gery, n = 3 sheep did not reach the ejection fraction cut-off
criteria for heart failure and were excluded from the study.
For the first protocol, the remaining sheep were randomly
assigned to the RespHRV or the monotonic groups. One
sheep in each of the monotonic- and RespHRV-paced groups
did not maintain stable pacing with high enough efficacy
[51] across the 2-week pacing period due to lack of contact
of the pacing lead and were excluded from the analysis. This
resulted in data being collected and analyzed in RespHRV-
paced (n = 9) and monotonically paced (n = 10) sheep. For
the second protocol (Protocol B), two sheep lost cardiac
output or respiratory signals during the protocol so were
excluded and this resulted in n = 6 animals in this group. No
sheep died during either of the pacing protocols.
Instrumentation surgery
Following induction (Propofol, 2% Diprivan. 5mg/kg i.v.,
AstraZeneca, AUS) and maintenance (2–3% isoflurane-
air-O2mixture) of anesthesia, sheep were placed on their
right side, and instrumentation was carried out in sterile
conditions. A 10cm incision was made on the left side of
the neck. A single-tip pressure probe (Millar Inc., Texas,
USA. Model # 320–6590) was inserted into the left com-
mon carotid artery to get an index of blood pressure, and
a cannula was inserted into the left jugular vein for drug
infusion. The pressure probe and catheter were secured with
a purse string suture (Filasilk, 3.0 non-absorbable braided
silk suture) to maintain blood flow through the vessel.
An intercostal nerve block was performed by injecting
bupivacaine (0.25%. Aspen, New Zealand) into the second,
third, fourth, fifth, and sixth intercostal spaces (7.5µg per
injection, ~ 0.625µg/kg total). Anesthesia depth was rou-
tinely monitored throughout the surgery by checking the
response to pinching the hoof and the response to eye-lid
contact. If necessary, the level of isoflurane was altered
(within the 2–3% range). A dorsal to ventral incision was
made on the left side of the chest, and the fourth rib was
removed to access the heart. A Doppler flow probe (Size
28, Transonic, AU) was placed around the ascending aorta
to measure directly beat-to-beat cardiac output. A Doppler
flow probe (Size 6, Transonic, AU) was placed around the
left main coronary artery to measure coronary artery blood
flow. For cardiac pacing, two pacing leads (Biotonik, Berlin,
Germany, Solia S 53; in case of failure in one) were secured
externally to the left atrium with 3.0 Filasilk suture and
insulated in silicone gel. To gain a measure of respiration,
electrodes were implanted into the diaphragm to measure
diaphragmatic EMG ('DEMG') as an index of inspiration as
previously described (Fig.1B) [51].
Flow probes were tunneled subcutaneously and exited
percutaneously on the dorsum of the sheep to connect to
chronic, continuous recording devices after recovery. Sheep
Fig. 1 Experimental set-up. A, Timeline of experimental protocol. B,
Schematic of the experimental set-up and representative simultane-
ous recordings in awake sheep during RespHRV pacing. Blue ovals
on the heart schematic indicate the placement positions of implanted
flow probes. BP; blood pressure, CO; cardiac output, CoBF; coronary
artery blood flow, dEMG; diaphragmatic electromyography (edited to
remove ECG contamination for visual presentation), HR; heart rate
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Basic Research in Cardiology
were given antibiotic injections (20mg /kg intra-muscular;
oxytetracycline, Phoenix, NZ) and analgesia (ketoprofen
10%, 2mg/kg intra-muscular; Merial, Boehringer Ingelheim,
NZ) at the start of surgery, and for the first 3days postop-
eratively. Animals were allowed to recover for 7days post-
surgery before beginning the exercise acclimatization proto-
col. All parameters were recorded from conscious sheep on
a desktop computer with a CED Micro-1401 interface and a
data acquisition program (Spike2 v8, Cambridge Electronic
Design, UK).
Hemodynamic measurements andanalysis
A baseline recording period was acquired when heart rate
and cardiac output had stabilized postoperatively (between
5 and 7days. Table1). Continuous arterial blood pressure,
cardiac output, and coronary artery flow were recorded 24/7
for around 6weeks, all sampled at 1000Hz. Heart rate was
calculated from the inter-pulse interval of the blood flow in
the ascending aorta. DEMG signal was amplified (X10, 000)
and filtered (band pass 0.3–3.0kHz).
Pacing Protocol A
The cardiac pacing was set at 10–15 beats per minute
above the resting heart rate of each sheep, with stimula-
tion parameters of 1.5–2.5V 2ms pulse width (Fig.2C).
Pacing voltage was increased if pacing became intermittent
during the protocol. For the monotonically (Mono) paced
group (n = 10), pacing leads were connected to a stimula-
tor (Grass Instruments). For the RespHRV group (n = 9),
RespHRV pacing was achieved using a biofeedback device
described previously [40–42], with an RespHRV magnitude
(peak-to-trough) of 12 beats per minute; this was optimized
previously [7, 51]. RespHRV pacing was visually checked
at least once daily against the DEMG channel to ensure the
rising phase of heart rate correlated with inspiration and the
falling phase with expiration (Fig.1B).
Pacing Protocol B
The cardiac pacing in this group was also set at 10–15 beats
per minute above the resting heart rate of each sheep, with
stimulation parameters of 1.5–2.5V 2 ms pulse width.
Pacing voltage was increased if pacing became intermit-
tent during the protocol. RespHRV pacing was achieved
using the same biofeedback device as Protocol A with an
RespHRV magnitude (peak-to-trough) of 12 beats per min-
ute. RespHRV pacing was visually checked at least once
daily against the DEMG channel to ensure the rising phase
of heart rate correlated with inspiration and the falling phase
with expiration.
Pacing efficacy
Pacing efficacy was calculated to determine the percentage
of the day (24h) the animals were being paced. For mono-
tonically paced sheep, the number of total heartbeats versus
those at an R-R interval outside the target paced range was
calculated as a percentage for 24h. For RespHRV-paced
animals, a threshold horizontal cursor was placed on the
heart rate channel below the pre-set peak heart rate change
during inspiration. For a 24-h period, the number of heart-
beats that were modulated by the pacemaker was divided
by the number of breaths calculated from the dEMG signal
and converted to a percentage to give RespHRV pacing effi-
cacy [51]. ‘Loss’ of RespHRV pacing usually occurred over
extended periods (mins) when intrinsic heart rate rose above
the RespHRV threshold. To be included in the RespHRV-
paced group, pacing efficacy needed to be ≥ 35% of all
Table 1 Raw values for resting hemodynamic parameters in conscious free-standing sheep that underwent the exercise protocol (Protocol A):
24-h averages
Baseline (not paced) 1-week pacing 2-week pacing
RespHRV
(pre-pace)
Mono
(pre-pace)
RespHRV
(paced)
Mono (paced) RespHRV
(paced)
Mono (paced)
Heart rate (bpm)
RespHRV, n = 6
Mono, n = 8
97 ± 5.5 98 ± 5.5 112 ± 6.7 112 ± 5.1 113 ± 5.4 114 ± 4.6
Cardiac output (L/min)
RespHRV, n = 6
Mono, n = 8
8.0 ± 0.9 7.5 ± 0.5 9.2 ± 0.9 7.4 ± 0.5 9.7 ± 0.9 7.4 ± 0.6
Coronary artery blood flow (ml/min)
RespHRV, n = 5
Mono, n = 5
95 ± 16 77 ± 12 97 ± 13 77 ± 16 101 ± 17 73 ± 15
Mean arterial pressure (mmHg)
RespHRV, n = 5
Mono, n = 6
83 ± 3.3 84 ± 2.1 90 ± 7.9 83 ± 3.6 81 ± 3.6 80 ± 4.0
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Basic Research in Cardiology
breaths for the average 24-h period, as previously reported
[51], and mimicked in clinical conditions where RespHRV
is most prominent during non-REM sleep and lost during
activity [4, 39]. When not respiratory modulated pacing, the
RespHRV-paced group was paced at a fixed rate equivalent
to the monotonic-paced group.
Exercise test inProtocol A
Seven days after instrument implantation surgery, sheep
were acclimatized to the treadmill exercise protocol for
3days before the experimental exercise test, as previously
described [52]. A previously optimized exercise protocol
of an incrementing intensity to a maximum of 2.5km/h
with a 15% incline over 18min was used for sheep either
monotonically or RespHRV paced; in both cases, pacing
was switched off during the exercise trials (Fig.3B). The
sheep walked freely with no negative reinforcement. At the
end of the exercise session, the treadmill was switched off,
and the animals were allowed to rest on the treadmill for
15min for post-exercise recovery measurements. Exercise
recovery measures were taken at 10-, 20-, 30-, 60, and 120-s
post-exercise.
Measurements of blood pressure, cardiac output, and
coronary artery blood flow were recorded throughout the
exercise protocol and presented as averages of 30s at the
end of each level of exercise (Figs.3, 4), or exported as
individual beats (using custom written scripts, Spike2),
normalized to heart period, and averaged over 50 beats at
baseline and maximum exercise (Fig.5). For the individual
beats, cardiac output and coronary artery blood flow were
exposed as max flow per heartbeat, and area under the curve
to measure stroke volume and coronary flow per beat. Due
to experimental constraints and access to the treadmill,
(RespHRV, n = 6) and (Mono, n = 8) underwent exercise test-
ing. Although all sheep were implanted with all recording
probes, not all sheep maintained signal in all probes over the
entire experimental period (Table1). All exercise data are
paired pre-to post-pacing per sheep; data are only included
when the signal is maintained throughout both exercise chal-
lenges (before and 2weeks after pacing) (Table1).
Drug administration inProtocol B
In this protocol, following a baseline period of 5days, the
pharmacological agents were administered over the next
4weeks continuously. A β-adrenergic receptor blocker
(0.075mg/kg/hr propranolol hydrochloride, AK Scientific,
Inc. USA, Catalog No. J95387) and an AT1 receptor (AT1R)
antagonist (0.08mg/kg/hr losartan potassium, AK Scien-
tific, Inc. USA, Catalog No.1934) were administered intra-
venously at a constant infusion rate of 1ml/hr, 24h a day for
4weeks. Following 2weeks of the drug protocol, RespHRV
pacing was initiated and continued for 14days while the
drug infusion continued over the next 2weeks(Table2).
The nonselective β-blocking agent, propranolol, was cho-
sen given the negative chronotropic effects of propranolol
which can be beneficial [27] while also reducing myocardial
oxygen expenditure in heart failure [59].
Statistical analysis
All data are expressed as mean ± SEM, except where
indicated. All time course data (cardiac output, coronary
artery blood flow, heart rate, mean arterial pressure) were
analyzed between groups using a repeated measures 2-way
ANOVA, or mixed-effects model if any missed data points
were 'missing at random'. The effect of time (or exercise)
within group monotonic or RespHRV paced was ana-
lyzed using a one-way ANOVA. Total peripheral resist-
ance (SVR mmHg/L/min) was calculated by mean arterial
pressure/cardiac output, and coronary vascular resistance
(CoVR mmHg/ml/min) was calculated by mean arterial
pressure/coronary artery blood flow. Cardiac power out-
put, used as a measure of energy output or work done by
the heart, was calculated using the equation mean arterial
Table 2 Raw values for resting
hemodynamic parameters
in conscious free-standing
sheep that underwent the
drugs + RespHRV protocol
(Protocol B): 24-h averages
Baseline
(not paced)
2weeks of drug infu-
sion
(not paced)
4weeks of drug
infusion and
2weeks of
RespHRV
pacing
(paced)
Heart rate (bpm)
RespHRV, n = 6
100 ± 7.5 93 ± 7.3 118 ± 2.7
Cardiac output (L/min)
RespHRV, n = 6
8.4 ± 0.9 8.9 ± 0.8 10.1 ± 0.7
Coronary artery blood flow (ml/min)
RespHRV, n = 6
80 ± 15 67 ± 16 77 ± 16
Mean arterial pressure (mmHg)
RespHRV, n = 6
86 ± 2.9 78 ± 6.5 70 ± 6.4
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Basic Research in Cardiology
pressure x cardiac output/451 as previously described [18,
33]. Heart rate recovery post-exercise was fitted with a
first-order exponential decay with statistics presented as
the time constant Tau using a paired t test [44] in Micro-
soft Excel. All other statistical analyses were performed in
SPSS (v8.1). Data were considered significant ifP < 0.05.
Results
Reinstating RespHRV inheart failure (Protocol A)
There were no differences in baseline ejection fraction
before the induction of heart failure (microemboliza-
tion) (RespHRV: 63.9 ± 3.4%. Mono: 66.7 ± 3.6%) or
8–10weeks later, after the establishment of chronic heart
failure and before the start of the experiments (RespHRV:
45.8 ± 3.4%. Mono: 43.0 ± 3.7%) between groups (experi-
mental timeline Fig.1).
Hemodynamic measures, including arterial pressure,
cardiac output, coronary artery blood flow, and heart rate,
were recorded for 24h a day for 4weeks in conscious
sheep (Fig.1). Reinstatement of RespHRV for 2weeks
in fully instrumented conscious sheep with chronic heart
failure increased cardiac output (Δ 1.65 ± 0.2 L/min,
n = 6, mean ± SEM) from baseline; in contrast, there was
no change in cardiac output in sheep paced monotoni-
cally (-0.18 ± 0.5 L/min, n = 8, mean ± SEM) (Fig.2A).
Both groups were paced to the same mean heart rate
(Fig.2B), showing that the increase in cardiac output in
the RespHRV-paced group was not dependent on a dif-
ference in the number of heartbeats between groups. In
RespHRV-paced sheep, the cardiac output increased after,
on average (median), days 2.5 of pacing, and this climbed
steadily over the first 5–7days (Fig.2A and supplemental
Fig S1A). Interestingly, the increase in cardiac output was
not associated with a change in coronary artery blood flow
or coronary vascular resistance throughout the RespHRV
pacing. RespHRV pacing did not affect breathing rate as
previously reported [51]. Circadian modulation of cardiac
output was maintained in both RespHRV and monotoni-
cally paced groups (Supplemental Fig.S1). There were
no significant changes in any of the other variables in the
monotonic pacing group. There was no statistical differ-
ence between mean arterial pressure, systemic vascular
resistance, coronary artery blood flow, or coronary vascu-
lar resistance between groups over time (Fig.2C–F). Pac-
ing efficacy (percentage of the day sheep were paced) was
35 ± 6.7% at 1week, 40 ± 8.2% at 2weeks in RespHRV
paced and 87 ± 5.1% at 1week, and 91 ± 2.8% at 2weeks
in monotonically paced sheep.
Cardiovascular responses toexercise inheart failure
beforeandafterRespHRV pacing
Hemodynamic parameters from conscious sheep were
recorded during a graded exercise protocol (Fig.3A + B).
There were no differences in any of the hemodynamic
changes during exercise between the RespHRV-paced and
monotonic-paced groups at the pre-pacing (baseline) time
point. After 2weeks of RespHRV pacing, sheep exhibited
comparable heart rate changes during exercise compared
to before pacing (Fig.3C). However, after 2weeks of
RespHRV pacing, sheep exhibited greater increases in car-
diac output, coronary artery blood flow and cardiac power
output during exercise, compared to pre-pacing (difference
baseline + post-pacing: P < 0.001. Figure3D–F), indicating
increased cardiac function and efficiency during moderate
exercise. There was a comparable increase in mean arterial
pressure (Fig.3G), and systemic vascular resistance (Sup-
plemental Fig S2) before and after pacing. Interestingly,
RespHRV pacing increased post-exercise heart rate recov-
ery compared to the pre-pacing baseline value (P < 0.05,
Fig.3F). One sheep in the RespHRV-paced group did not
complete the full exercise protocol at baseline (completed up
to and including level 5 of 6); however, this sheep went on
to complete the whole protocol after 2weeks of RespHRV
pacing.
Cardiovascular responses toexercise inheart failure
beforeandaftermonotonic pacing
At baseline (after instrumentation surgery and before cardiac
pacing) and 2weeks after monotonic pacing, there was no
difference in any parameters measured during exercise in
the monotonically paced group (Fig.4A–E), and no change
in the rate of heart rate recovery post-exercise (Fig.4F).
In the monotonically paced group, one sheep did not com-
plete the full exercise protocol at baseline (completed up to
and including level 4 of 6). This animal and one additional
animal did not complete the full exercise protocol after
2weeks of monotonic pacing (both sheep completed up to
and including level 5 of 6).
Single beat dynamics duringexercise
Given the beat-to-beat measures of variables, we compared
the change in single-beat aortic flow dynamics (normal-
ized to heart period) during baseline (Pre-pace) exercise
(Fig.4A) to change in single-beat aortic flow dynam-
ics during exercise after RespHRV pacing (post-pace)
(Fig.4B). RespHRV pacing resulted in a greater increase
in stroke volume per beat during exercise (Fig.5B) but
no difference in the peak aortic flow per beat (Fig.5C).
Both total coronary flow and max coronary flow increased
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Basic Research in Cardiology
by a greater amount during exercise after RespHRV pac-
ing (Fig.5F + G). There was no difference in the change
in single-beat cardiac output or coronary flow dynamics
during exercise after cardiac pacing in the mono-paced
group (Fig.5D + E, H + I). Mean arterial pressure and
Fig. 2 Conscious 24-h data for 3-week protocol. A, Two weeks of
RespHRV pacing (blue: n = 6) significantly increased cardiac out-
put compared to monotonic pacing (red: n = 8) (A, RespHRV: *
P = 4.82 × 10–6. One-way ANOVA, effect of time. # P = 0.0065. Two-
way ANOVA, interaction effect). B, Both RespHRV and mono groups
were paced to an equivalent heart rate (RespHRV: * P = 0.027, n = 6,
Mono: * P = 2.68 × 10–6, n = 8 One-way ANOVA, effect of time). No
change in C, mean arterial pressure (RespHRV: n = 5, Mono: n = 6),
D, systemic vascular resistance (RespHRV: n = 5, Mono: n = 6), E,
coronary artery blood flow (both groups, n = 5), or F. coronary artery
vascular resistance (RespHRV: n = 5, Mono: n = 4) between 2 weeks
RespHRV or monotonic pacing. A–F, Each data point is a 24-h aver-
age
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Basic Research in Cardiology
heart rate changes during exercise were not different in
either paced group (Fig.5J-M).
Reinstatement ofRespHRV inheart failure
withcurrent medications (Protocol B)
After baseline recordings, constant intravenous infusions of
a combined β-blocker (Propranolol) and an AT1R blocker
(Losartan) for 14days before RespHRV pacing resulted in a
significant decrease in heart rate and a significant increase in
cardiac output (Fig.6B + D). The increase in cardiac output
was not associated with a change in coronary artery blood
flow or coronary vascular resistance over the 14days of the
medications (Fig.6F + G). To confirm that the AT1R blocker
was given at an effective dose to block the AT1 receptor, the
pressor response to intravenous angiotensin II was tested
as previously described [54]. AT1R blockade was tested
at baseline before the administration of the AT1R blocker,
after the administration of the AT1R blocker, and at the end
of the study. The angiotensin II-mediated pressor response
was significantly reduced after administration of an AT1R
blocker compared to baseline (Supplemental Fig S3). The
decreased resting heart rate indicated an effective blockade
of the β-adrenergic receptors. Previously published heart
failure ‘time-control’ experiments using the same chronic
recordings show no reduction in heart rate over time [51].
Reinstatement of RespHRV, against this background of med-
ications, further increased cardiac output (Δ 1.33 ± 0.2 L/
min from the start of RespHRV pacing, n = 6, mean ± SEM)
in heart failure. However, the time course of onset was
Fig. 3 Hemodynamic responses to exercise in RespHRV-paced
heart failure sheep. A Raw data trace of the hemodynamic exercise
responses. B, A timeline of the graded exercise protocol. Change
compared to baseline C, heart rate (baseline: *P = 4.1 × 10–4; post
2-week RespHRV -pacing: **P = 1.7 × 10–3. One-way ANOVA,
effect of exercise, n = 6). D, cardiac output (baseline: *P = 2.6 × 10–5;
post 2-week RespHRV pacing: **P = 1.6 × 10–3. One-way ANOVA,
effect of exercise. # P = 3.7 × 10–4. Two-way ANOVA, Group effect,
n = 6). E, cardiac power (baseline: *P = 2.4 × 10–4; Post 2-weeks
RespHRV pacing: *P = 0.022. One-way ANOVA, effect of exercise.
# P = 1.6 × 10–4. Two-way ANOVA, group effect, n = 5). F, coronary
artery blood flow (baseline: *P = 4.1 × 10–3; post 2-weeks RespHRV
pacing: * P = 6.6 × 10–5. One-way ANOVA, effect of exercise. #
P = 1.7 × 10–3. Two-way ANOVA, group effect. † P = 0.078. Mixed-
effects analysis, interaction effect, n = 5). G, Mean arterial pressure,
(baseline only: *P = 0.019. One-way ANOVA, effect of exercise,
n = 5) during exercise before (light blue) or after (dark blue) 2weeks
of RespHRV pacing. H, Heart rate recovery post-exercise (n = 6.
# P = 0.046, paired t test). BP; blood pressure, CO; cardiac output,
CoBF; coronary artery blood flow, HR; heart rate
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Basic Research in Cardiology
slower compared to when no drugs were on board (day 2.5
of pacing in RespHRV-paced sheep without medication ver-
sus day 6 on RespHRV-paced sheep with medications on
board) (Supplemental Fig S2). Systemic vascular resistance
showed a significant decrease (P < 0.001, Fig.6.E). No sta-
tistically significant changes were observed in mean arterial
pressure, coronary artery blood flow, or coronary vascular
resistance in RespHRV-paced sheep with medications over
time (Fig.6B, F, G).
Discussion
Our study presents four major novel findings on the clini-
cal benefits of reinstating physiological RespHRV in heart
failure. First, RespHRV pacing causes no change in coronary
artery blood flow at rest, while cardiac output increased in a
completely novel set of animals to those reported previously
[51]. Second, during exercise, RespHRV pacing improved
cardiac output, coronary artery blood flow, and cardiac
power output, independent of changes in heart rate com-
pared to pre-pacing. Third, post-exercise heart rate recov-
ery is improved after RespHRV pacing. Fourth, against a
background of a β-blocker and an AT1R blocker, RespHRV
pacing further increased cardiac output with no change in
coronary artery blood flow at rest. Taken together, our find-
ings suggest new generation pacemakers should incorporate
RespHRV.
Effect ofRespHRV pacing oncoronary artery blood
flow atrest
The relationship between cardiac output and coronary artery
blood flow is complex, influenced by metabolic factors,
autoregulation, and endothelial function [28]. In chronic
ischemic heart disease, this relationship is impaired [26],
contributing to both the cause and progression of cardiac
dysfunction [26]. We anticipated that the increase in car-
diac output with RespHRV pacing would be accompanied
by increased coronary artery blood flow. However, after
2weeks of RespHRV pacing, there was no change in coro-
nary flow or vascular resistance at rest suggesting improved
cardiac efficiency rather than enhanced oxygen delivery.
Our previous mathematical modeling data, which proposed
that the functional role of RespHRV is to improve cardiac
efficiency, aligns with these findings [8]. The mechanism
behind RespHRV-induced efficiency gains remains unclear
but may involve mitochondrial function, cell-to-cell commu-
nication [16, 36], or myocyte structure restoration [14, 51].
Fig. 4 Hemodynamic responses to exercise in monotonically paced
heart failure sheep. In stark contrast to RespHRV-paced sheep (see
Fig. 3) A–F, no difference in any hemodynamic parameters during
exercise before (red) or after 2weeks of monotonic pacing (dark red)
were observed. A, Heart rate (baseline: *P = 6.3 × 10–7; post 2-week
mono-pacing: *P = 1.5 × 10–9. One-way ANOVA, effect of exercise,
n = 8). B, Cardiac output (baseline: *P = 1.8 × 10–5; post 2-week
Mono-pacing: *P = 7.4 × 10–8. One-way ANOVA, effect of exercise,
n = 8). C, Cardiac power (baseline: *P = 7.9 × 10–4; post 2-week
mono-pacing: *P = 1.0 × 10–6. One-way ANOVA, effect of exercise,
n = 6). D, Coronary artery blood flow (baseline: *P = 0.014; post
2-week mono-pacing: **P = 3.5 × 10–2. One-way ANOVA, effect of
exercise, n = 5). E, Mean arterial pressure (baseline: *P = 0.020; post
2-week mono-pacing: *P = 0.030. One-way ANOVA, effect of exer-
cise, n = 6). F, Heart rate recovery, presented fitted with first-order
exponential decay (n = 8)
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Basic Research in Cardiology
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Basic Research in Cardiology
Effect ofRespHRV pacing onexercise capacity
inheart failure
The most life-limiting symptom of living with heart failure
is reduced exercise tolerance. During exercise in healthy
individuals, cardiac output increases to meet the increased
metabolic demands of the body, including the myocardium
[35] and this cardiac output increase is one of the primary
determinants of exercise capacity [9]. While exercise intoler-
ance is multifactorial in patients with heart failure, the ina-
bility to sufficiently increase cardiac output during exercise
directly correlates to reduced exercise capacity and worsen-
ing quality of life [9, 46]. Following 2weeks of RespHRV
pacing, cardiac output was not only increased at rest but was
further elevated during moderate exercise. The increase in
cardiac output during exercise was due to an increase in
stroke volume, independent of heart rate changes. Moreover,
beat-to-beat stroke volume increased during exercise after
RespHRV pacing, but the maximum aortic flow per beat did
not. These results suggest that an increase in the peak force
of contraction is not driving the increase in cardiac output
during exercise, but rather increased diastolic function and
ventricular filling. The total increase in cardiac output dur-
ing exercise was ~ 35% greater after RespHRV pacing; this
compares to ~ 20% increase in cardiac output with current
best use pacemakers [50].
Although no change in resting coronary flow was
observed after RespHRV pacing at rest, 2 weeks of
RespHRV pacing resulted in a significant increase in coro-
nary blood flow during exercise. This increase in coronary
blood flow during exercise after RespHRV pacing was
observed as an increase in maximum and total flow per
beat (normalized to heart period). The enhanced ability to
increase total beat-to-beat coronary blood flow from rest
suggests increased coronary flow reserve after RespHRV
pacing [53]. As maximum coronary flow occurs during
diastole, the increased maximum coronary flow per beat
further indicates improved diastolic function during exercise
after RespHRV pacing. This is similar to changes observed
with CRT pacing, where total coronary flow at rest is not
altered but there is an increase in coronary flow reserve to a
hyperaemic challenge [19, 31, 34].
In addition to the changes in flow dynamics, 2weeks of
RespHRV pacing resulted in an increase in cardiac power
output during exercise. Maximum cardiac power output has
been shown to strongly correlate with exercise capacity [13],
and VO2max [6]. In patients with chronic heart failure, the
ability to increase cardiac power output during exercise is
a strong predictor of adverse cardiac outcomes [11, 58, 60]
and mortality [58]. Our data indicate that RespHRV pacing
can augment increases in cardiac power output and may,
therefore, prolong life in heart failure.
All the beneficial effects of 2weeks of RespHRV pacing
on cardiac function during exercise were observed while the
pacemaker was turned off (the pacemaker was always off
when the sheep was on the treadmill). We have previously
reported myocyte remodeling after RespHRV pacing and
that the resting cardiac output takes up to 7days to return
to baseline after the pacemaker is turned off [51], indicating
that RespHRV pacing induces benefits that exist beyond the
pacemaker being switched off. Current pacing strategies to
increase heart rate during activity, rate-adaptive pacing, have
not shown any benefits in increasing exercise capacity [10],
suggesting a novel improvement in exercise capacity with
restoration of ResHRV pacing.
Effect ofRespHRV pacing onheart rate recovery
RespHRV pacing improved post-exercise heart rate recovery,
indicating better autonomic balance. Reduced parasympa-
thetic nerve activity in heart failure is linked to slower heart
rate recovery after exercise [21, 43], predicting poor cardio-
vascular outcomes [29], hospitalizations [5], and death [38].
Two weeks of RespHRV pacing led to faster heart rate recov-
ery post-exercise, suggesting increased parasympathetic
nervous system responsiveness. Studies in control rats [32]
and sheep [52] have recently shown that increased parasym-
pathetic activity during exercise benefits cardiac function
and increases coronary blood flow. It is tempting to specu-
late that the improved cardiac function may be mediated, in
part, by restoration of parasympathetic activity, though this
requires further evaluation.
Effect ofβ‑blocker and AT1R blocker together
withRespHRV pacing onheart function
In Protocol A, sheep with heart failure were not on any com-
mon heart failure medications, unlike the expected clinical
population. To further establish the benefits of RespHRV
Fig. 5 Single beat hemodynamics, normalized to heart period, during
exercise. A Representative schematics of single-beat hemodynamics.
Yellow highlighted area indicates area under the curve: cardiac output
(CO) = stroke volume, coronary artery blood flow (CoBF) = total cor-
onary blood flow per beat. Red asterisk indicates peak flow per beat.
All data are normalized to heart period. B – M, Data points represent
the change in a given parameter from baseline (stood on treadmill)
to max exercise. Lighter circles represent the pre-pacing exercise test,
with connecting lines to darker circles showing post-pace exercise
test. B Change in stroke volume, normalized to heart period increases
after RespHRV pacing (P = 0.025, paired t test), with no change in
peak aortic flow C. D + E, No change in stroke volume of peak aortic
flow after monotonic pacing. F + G, Total coronary artery blood flow,
and peak coronary artery blood flow per beat increase more during
exercise after RespHRV pacing (F: P = 0.017, G: P = 0.014, paired t
test). H + I, With no change in coronary hemodynamics during exer-
cise after monotonic pacing. J–M, Neither RespHRV nor monotonic
pacing resulted in a change in the increase in mean arterial pressure
or heart rate (HR) during exercise
◂
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Basic Research in Cardiology
pacing alongside these medications, we conducted a separate
protocol with HF sheep on a combined β-blocker and AT1R
blocker therapy (Protocol B). While 2weeks of administra-
tion of these drugs alone improved cardiac output, it was
to a lesser extent than RespHRV pacing alone (in Protocol
A). Importantly, reinstatement of RespHRV pacing, while
sheep were still receiving the β-blocker and AT1R blocker,
resulted in a further increase in cardiac output. These results
indicate that the improvement in cardiac output was in addi-
tion to the benefit of the medications. There was no change
in resting coronary artery blood flow with either medications
alone or medications with RespHRV pacing. An important
point that warrants further consideration is that the increase
in cardiac output appeared to be delayed compared to when
no medications were on board (day 6 versus day 2.5). The
reasons for the delay are unclear, but important to be aware
of before initiating large-scale clinical trials.
Study limitations
Only female sheep are used in this study. Therefore, sex as
a biological variable cannot be assessed. Coronary artery
blood flow was measured using a Doppler flow probe chroni-
cally implanted around the left coronary artery. Therefore,
we cannot draw any conclusions about changes in epicar-
dial to endocardial blood flow, which may be important in
cardiac function in heart failure. The microembolization
Fig. 6 Experimental set-up and 5-week drugs with RespHRV pro-
tocol. A, A modified timeline from Fig.1A showing experimental
protocol in drug animals. B, Two weeks of RespHRV pacing on the
background of drugs (n = 6) significantly increased cardiac output
(*P = 7.5 × 10–14, one-way ANOVA, effect of time), D, heart rate over
time (*P = 3.9 × 10–28, one-way ANOVA, effect of time, drugs for
4weeks, drugs + paced for 2 weeks), E, systemic vascular resistance
(*P = 3.7 × 10–9, one-way ANOVA, effect of time). No change in C,
mean arterial pressure (n = 6), F, coronary artery blood flow (n = 6),
or G. coronary artery vascular resistance (n = 6). B-G, Each data
point is a 24-h average
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Basic Research in Cardiology
model of HFrEF was chosen based on our previous experi-
ence with developing a consistent model of heart failure [3]
while adhering to animal welfare principles. We acknowl-
edge that microembolization does not fully replicate acute
heart failure resulting from acute myocardial infarction. This
model has been used by multiple groups to produce heart
failure whereby the microvascular obstruction and dysfunc-
tion result in patchy microinfarcts contributing to progres-
sive myocardial contractile dysfunction [22, 30, 48]. This
model simulates key features of HFrEF, including impaired
heart rate variability and autonomic imbalance making it an
ideal platform to study the effects of modulating RespHRV.
Our study used the nonselective β-blocking agent, proprano-
lol. We acknowledge that the effects of more recent cardio-
selective beta-blockers together with RespHRV pacing needs
to be investigated.
Clinical implications
Cardiac device development is a rapidly advancing field,
shifting beyond the traditional view of the heart as a simple
pump towards integrating physiological mechanisms that
regulate cardiac function. Pacemakers developed in the last
2 decades include chamber synchronization [19, 50, 55],
cardiac contractility modulation [2], and rate-adaptive pac-
ing [10] to reflect this. To date, none of the commercial
pacemakers incorporate RespHRV and our study highlights
the enormous potential of reinstating RespHRV alongside
standard heart failure medications. While our preclinical
study used diaphragmatic electrodes as a stable respiratory
sensor in conscious sheep, we anticipate clinical RespHRV
devices to be integrated with nasal thermocouples or chest
wall impedance sensors.
Conclusion
Cardiovascular fitness is a key predictor of overall morbidity
and mortality [47], with exercise intolerance being a pri-
mary symptom of patients with heart failure. Novel treat-
ments are needed urgently. Here, we show that reinstating
RespHRV in heart failure increases cardiac output without
changing coronary artery blood flow at rest and improves
exercise tolerance. These findings indicate that restoring
RespHRV may improve cardiac efficiency and as well as
exercise capacity in heart failure. Importantly, these benefi-
cial effects of RespHRV pacing persist with medications on
board. Our study emphasizes the importance of implement-
ing RespHRV restoration in clinical trials for individuals
living with heart failure.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00395- 025- 01110-3.
Acknowledgements We acknowledge the technical expertise of Linley
Nisbet and Bindu George. We would also like to acknowledge Maree
Schollum, Renee Singh, Melanie Hyslop, and Kayla Briden for their
excellent technical assistance. We would also like to acknowledge Gra-
ham Fisher for his contribution to developing electronics to support the
experiments. The pacemaker is a proprietary device, and we kindly
thank Ceryx Medical Ltd for loaning it to us.
Funding Open Access funding enabled and organized by CAUL and its
Member Institutions. This work was supported by the Health Research
Council of New Zealand (RR, JS, NL, JP, # 20/158; JS Fellowship
#23/119), Ceryx Medical Limited (RR & JFRP), the University of
Auckland Faculty Research Development Fund and the National Heart
Foundation of New Zealand (JS, RR, # 1925), supported in part by
The Ernest Hyam Davis and Ted and Mollie Carr Legacies, and TM
Hosking Charitable Trust.
Declarations
Conflict of interest Professor Julian Paton is a co-founder of Ceryx
Medical Limited. Dr. Rohit Ramchandra and his lab has received fund-
ing from Ceryx Medical Ltd.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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