Clinical Trial Details
— Status: Suspended
Administrative data
NCT number |
NCT05057884 |
Other study ID # |
Breathe-HF |
Secondary ID |
|
Status |
Suspended |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
March 1, 2022 |
Est. completion date |
September 1, 2025 |
Study information
Verified date |
May 2024 |
Source |
Insel Gruppe AG, University Hospital Bern |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
An exaggerated ventilatory response (minute ventilation, V̇E) to exercise relative to exhaled
carbon dioxide (V̇CO2) is common in heart failure (HF) patients with reduced as well as
preserved left ventricular ejection fraction (HFrEF, HFpEF). Severity of this exaggerated
response is associated with poor prognosis. This response may be triggered by pulmonary
congestion and peripheral muscle myopathy. A vicious circle is fuelled by hypersensitivity of
chemoreceptors to hypercapnia and sympathetic nervous hyperactivity, resulting in
hyperventilation (low PaCO2). Low PaCO2 is predictive of mortality in these patients. PaCO2
can be increased acutely, e.g. by apnoea. Also, nasal breathing has been found to reduce the
V̇E/V̇CO2 slope during exercise compared to oral breathing. Three previous slow breathing
studies in HFrEF patients have had encouraging results with regard to reducing sympathetic
activity, reflected in lowered arterial (pulmonary) blood pressure and increased EF. The
investigators hypothesise that a 12-week training with nasal slow breathing followed by
end-expiratory apnoea based on education, centre-based introduction and home-based 15 min/day
breathing training will be effective at reducing the exaggerated ventilatory response to
exercise. A total of 68 patients with stable HF seen at the HF clinics of the Inselspital (34
HFrEF, 34 HFpEF) will be randomised to the breathing intervention or usual care. Primary
outcome will be V̇E/V̇CO2 slope at 12 weeks. If breathing training successfully ameliorates
the exaggerated ventilatory response and perception of dyspnea during exercise, it offers an
attractive tele-health based add-on therapy that may add to or even amplify the beneficial
effects of exercise training.
Description:
BACKGROUND
Ventilatory inefficiency, most commonly quantified as an increased ventilation (V̇E) to
carbon dioxide exhalation (V̇CO2) slope during exercise, is a landmark of heart failure
patients both with reduced and preserved ejection fraction (HFrEF, HFpEF).[1] Numerous
studies have found higher V̇E/V̇CO2 slopes to be associated with poorer prognosis.[2-4] The
components of the V̇E/V̇CO2 slope are the arterial CO2 partial pressure (PaCO2), that is
affected by hyperventilation, and the pulmonary dead space/tidal volume ratio (VD/VT) that is
affected by pulmonary perfusion abnormalities.[5] The exaggerated response in ventilation of
HFrEF patients may be caused by hypersensitivity of chemoreceptors to CO2,[6] and/or a
sympathetic nervous hyperactivity commonly found in HFrEF patients, based on an increased
activation of metaboreceptors in peripheral muscles response to increased anaerobic
metabolism.[7] Chronic sympathetic nervous hyperactivity has been suggested to decrease
aerobic capacity of skeletal muscles based on reduced capillarisation[8] and reduced red
blood cell flux[9] leading to a shift in muscle fibre type towards a lower content on type I
fibres.[10] The ensuing anaerobic muscle metabolism leads to increased muscle
fatiguability[11] and acidosis already at low levels of exercise, which trigger exaggerated
responses in ventilation.[12] Hyperventilation, on the other hand, is well known to stimulate
sympathetic nervous activity, and so the vicious circle of sympathetic nervous activity
driving hyperventilation and hyperventilation activating sympathetic nervous activity
continues.[13] This suggests that hyperventilation may not only be a consequence of poor left
ventricular (LV) function, but also a driver.
Besides pharmaceutical therapies and electrophysiological interventions, exercise therapy has
been found to have beneficial effects on hemodynamic and ventilatory parameters in HFrEF[14]
and HFpEF patients alike.[15] The main mechanisms of exercise are thought to be reduced
peripheral resistance and hence cardiac afterload by improvement of endothelial function,
increased capillarisation leading to improved oxygenation of skeletal muscles and improved
aerobic metabolism.[16] Despite the beneficial effects of exercise training in both,
centre-based and home-based settings,[17, 18] adherence to physical activity has been found
to be poor amongst HFrEF patients.[19] Surprisingly, few studies have targeted ventilation
directly with therapeutic approaches. Only three studies have assessed the effects of
slow-breathing training on cardiorespiratory function.[20, 21] These studies found improved
physical function, reduced blood and pulmonary arterial pressure, increased ejection fraction
(EF),[20, 22] improved ventilatory efficiency[20] and reduced sleep apnoea.[22] Further, they
found improved regulation of the autonomic nervous system by reducing sympathetic drive and
increasing vagal activity.[23] It is unknown whether slow breathing may increase PaCO2
sufficiently to change the sensitivity or set point of chemoreceptors. On the other hand,
apnoea training has been found to lead to large changes in PaCO2 levels tolerated by
chemoreceptors at rest and during exercise.[24, 25] However, to date there are no published
studies that have implemented apnoea into a breathing training in HF patients. Further,
previous studies have not investigated whether the effect of slow breathing on improving the
V̇E/V̇CO2 slope was due to a chronic increase in PaCO2 or a decrease in ventilatory dead
space.
HYPOTHESIS
The investigators hypothesise that a 12-week training with nasal slow breathing followed by
end-expiratory apnoea based on education, centre-based introduction and home-based 15 min/day
breathing training will be effective at reducing the exaggerated ventilatory response to
exercise.
METHODS
Study design
Prospective randomised controlled study. Eligible patients are identified during their yearly
check-up at the Heart Failure Clinic and Preventive Cardiology of the Inselspital in Bern.
Patients will be randomised 1:1 (stratified for HFrEF/HFpEF and sex) to an intervention and
control group. Patients in the intervention group perform the breathing training additionally
to standard care and those in the control group receive standard care and are offered the
breathing training after the end of the study. The study design and breathing intervention
have been developed with direct input by a patient group (from pilot study).
In an additional cross-sectional substudy, the same measurements of the RCT are performed in
a group of 15 patients after acute or chronic coronary syndrome (ACS/CCS) with inefficient
ventilation, 15 healthy age-matched and 15 healthy young controls. Further, the
cross-sectional substudy compares pulmonary gas exchange and breathing patterns during 5 min
of oral versus 5 min of nasal breathing during submaximal continuous exercise in the HF,
ACS/CCS, old healthy, and young healthy groups.
Breathing intervention
The respiratory pattern modulation training is performed at home for 12 weeks twice daily for
15 min per session and consists of three components: 1) education on abnormal ventilation in
heart failure, the effect of ventilation on PaCO2 and the autonomous nervous system, and
chemoreceptor sensitivity; 2) 1-3 sessions of guided and monitored face-to-face training with
slow nasal abdominal breathing and intermittent apnoea supported by the Healer vest
(L.I.F.E., Milan, Italy) measuring electrocardiogram (ECG), and chest excursions at the level
of the xiphoid, thoracic manubrium, and abdomen; 3) independent home-based apnoea training
supported by hand-outs, videos and weekly phone calls to monitor progress and adherence,
answer questions and encourage further progression with duration of breath-hold.
Measurements
Measurements are performed during visit 1 before and visit 2 at the end of the intervention
period.
Cardiopulmonary exercise testing (CPET)
CPETs are performed on a cycle ergometer according to the recommendations of the American
Heart Association.[38] Ramp tests are performed as previously described.[31] O2 consumption
and CO2 production will be measured continuously in an open spirometric system (Quark,
Cosmed, Rome, Italy) and registered as average values over 8 breaths. Every 2 min, patients
are asked about their perception of dyspnoea on the modified Borg scale. V̇E/V̇CO2 slope from
rest to ventilatory threshold 2 (VT2), peak V̇O2 and V̇O2 at VT1 are determined as previously
described.[31]
Blood analyses
Blood samples are obtained from the antecubital vein for analysis of haemoglobin and
NT-proBNP. Arterialized blood are extracted from the ear lobe at rest and peak exercise for
analysis of PaCO2, oxygen (PaO2), bicarbonate and pH.
Sensitivity of chemoreceptors
The sensitivity of chemoreceptors is measured by a rebreathing protocol.[39] The subjects are
resting supine and breathe through a mouthpiece of an open spirometric system (Innocor,
Cosmed, Rome, Italy). With the 3-way-valve open to room air, the test begins with 2-5 min of
hyperventilation, allowing end-tidal partial CO2 pressure (PETCO2) to drop. Following
hyperventilation, the subject breathes comfortably, while the 3-way-valve is switched to the
rebreathing bag. Equilibration of PCO2 in bag, lungs, and arterial blood to mixed venous
blood is achieved by taking three deep breaths. During the following minutes, PETCO2 is
allowed to rise, while PETO2 is clamped at 150 mmHg during hyperoxic testing, and at 50 mmHg
during a second, hypoxic test run by feeding 100% O2 into the circuit by a port at the
rebreathing bag. Central and peripheral chemoreflex responses to CO2 are estimated by the
difference between hyperoxic and hypoxic ventilatory response.[40, 41]
Patient reported outcomes
The Kansas City Cardiomyopathy Questionnaire (KCCQ) are filled in during visit 1 and visit 2
to assess quality of life and dyspnoea. During visit 2, a structured interview is performed
with the patient to assess feasibility and barriers with the breathing training. Adherence to
training is monitored based on verbal information by the patients during the weekly phone
calls.
Heart rate variability (HRV) and breathing frequency (BF)
HRV is measured from 24-hour ECG recorded with the Healer vest (L.I.F.E., Milan, Italy) and
analysed from a segment during a deep sleep phase as previously described by the
investigators' group.[42] Low-frequency power (LF, ms2, 0.04-0.15 Hz), high-frequency power
(HF, ms2, 0.15-0.4 Hz), and the LF/HF are analysed [43]. BF is measured by strain gauges from
Healer vest.
Submaximal tests of cross-sectional substudy
After a 15 min break following the CPET ramp test, patients cycle 5 min at 50% of peak power
output as assessed during the ramp test with exclusively nasal, and 5 min with exclusively
oral breathing in randomised order, with a 15 min break between the two tests. Pulmonary gas
exchange parameters and breathing pattern are measured and compared between the two breathing
modes and between the four groups (HF, ACS/CCS, old healthy, young healthy).
OUTCOMES
Primary outcome is V̇E/V̇CO2 slope analysed by ANCOVA with repeated measures corrected for
baseline values and EF and sex.
Secondary outcomes are the nadir of the V̇E/V̇CO2 ratio, breathing pattern, VD/VT, peak V̇O2,
V̇O2 at VT1, resting PETCO2, peripheral and central chemoreceptor sensitivity, arterial blood
gases, NT-proBNP, heart rate, HRV, ventricular premature beats from 24-hour ECG, KCCQ,
feasibility and adherence.
Outcomes of cross-sectional study are VE/VCO2 ratio, VE, VO2, BF, VT, PetCO2, PetO2, O2/HR
and rapid shallow breathing index between nasal and oral breathing.
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