Ignite Creation Date:
2024-05-06 @ 4:40 PM
Last Modification Date:
2024-10-26 @ 2:14 PM
Study NCT ID:
NCT05057884
Status:
SUSPENDED
Last Update Posted:
2024-05-09
First Post:
2021-09-16
Brief Title:
Breathing Exercise Against Dyspnoea in Heart Failure Patients to Improve Chemosensitivity
Sponsor:
Insel Gruppe AG University Hospital Bern
Organization:
Insel Gruppe AG University Hospital Bern
Study Overview
Official Title:
Breathing Exercise Against Dyspnoea in Heart Failure Patients to Improve Chemosensitivity and Ventilatory Efficiency - a Randomized Controlled Single-centre Trial
Status:
SUSPENDED
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
lack of finances
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Breathe-HF
Brief Summary:
An exaggerated ventilatory response minute ventilation VE to exercise relative to exhaled carbon dioxide VCO2 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 eg by apnoea Also nasal breathing has been found to reduce the VEVCO2 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 minday 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 VEVCO2 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
Detailed Description:
BACKGROUND
Ventilatory inefficiency most commonly quantified as an increased ventilation VE to carbon dioxide exhalation VCO2 slope during exercise is a landmark of heart failure patients both with reduced and preserved ejection fraction HFrEF HFpEF1 Numerous studies have found higher VEVCO2 slopes to be associated with poorer prognosis2-4 The components of the VEVCO2 slope are the arterial CO2 partial pressure PaCO2 that is affected by hyperventilation and the pulmonary dead spacetidal volume ratio VDVT that is affected by pulmonary perfusion abnormalities5 The exaggerated response in ventilation of HFrEF patients may be caused by hypersensitivity of chemoreceptors to CO26 andor a sympathetic nervous hyperactivity commonly found in HFrEF patients based on an increased activation of metaboreceptors in peripheral muscles response to increased anaerobic metabolism7 Chronic sympathetic nervous hyperactivity has been suggested to decrease aerobic capacity of skeletal muscles based on reduced capillarisation8 and reduced red blood cell flux9 leading to a shift in muscle fibre type towards a lower content on type I fibres10 The ensuing anaerobic muscle metabolism leads to increased muscle fatiguability11 and acidosis already at low levels of exercise which trigger exaggerated responses in ventilation12 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 continues13 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 HFrEF14 and HFpEF patients alike15 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 metabolism16 Despite the beneficial effects of exercise training in both centre-based and home-based settings17 18 adherence to physical activity has been found to be poor amongst HFrEF patients19 Surprisingly few studies have targeted ventilation directly with therapeutic approaches Only three studies have assessed the effects of slow-breathing training on cardiorespiratory function20 21 These studies found improved physical function reduced blood and pulmonary arterial pressure increased ejection fraction EF20 22 improved ventilatory efficiency20 and reduced sleep apnoea22 Further they found improved regulation of the autonomic nervous system by reducing sympathetic drive and increasing vagal activity23 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 exercise24 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 VEVCO2 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 minday 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 11 stratified for HFrEFHFpEF 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 ACSCCS 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 ACSCCS 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 LIFE 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 Association38 Ramp tests are performed as previously described31 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 VEVCO2 slope from rest to ventilatory threshold 2 VT2 peak VO2 and VO2 at VT1 are determined as previously described31
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 protocol39 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 response40 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 LIFE Milan Italy and analysed from a segment during a deep sleep phase as previously described by the investigators group42 Low-frequency power LF ms2 004-015 Hz high-frequency power HF ms2 015-04 Hz and the LFHF 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 ACSCCS old healthy young healthy
OUTCOMES
Primary outcome is VEVCO2 slope analysed by ANCOVA with repeated measures corrected for baseline values and EF and sex
Secondary outcomes are the nadir of the VEVCO2 ratio breathing pattern VDVT peak VO2 VO2 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 VEVCO2 ratio VE VO2 BF VT PetCO2 PetO2 O2HR and rapid shallow breathing index between nasal and oral breathing
REFERENCES
1 Agostoni P Guazzi M Exercise ventilatory inefficiency in heart failure some fresh news into the roadmap of heart failure with preserved ejection fraction phenotyping European journal of heart failure 2017 1912 1686-9
2 Ponikowski P Francis DP Piepoli MF et al Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis Circulation 2001 1037 967-72
3 Myers J Arena R Oliveira RB et al The lowest VEVCO2 ratio during exercise as a predictor of outcomes in patients with heart failure Journal of cardiac failure 2009 159 756-62
4 Nadruz W Jr West E Sengelov M et al Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced Midrange and Preserved Ejection Fraction Journal of the American Heart Association 2017 611
5 Johnson RL Jr Gas exchange efficiency in congestive heart failure Circulation 2000 10124 2774-6
6 Chua TP Clark AL Amadi AA et al Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure Journal of the American College of Cardiology 1996 273 650-7
7 Scott AC Davies LC Coats AJ et al Relationship of skeletal muscle metaboreceptors in the upper and lower limbs with the respiratory control in patients with heart failure Clinical science London England 1979 2002 1021 23-30
8 Duscha BD Kraus WE Keteyian SJ et al Capillary density of skeletal muscle a contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations Journal of the American College of Cardiology 1999 337 1956-63
9 Hirai DM Musch TI Poole DC Exercise training in chronic heart failure improving skeletal muscle O2 transport and utilization Am J Physiol Heart Circ Physiol 2015 3099 H1419-39
10 Sullivan MJ Duscha BD Klitgaard H et al Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure Med Sci Sports Exerc 1997 297 860-6
11 Schulze PC Linke A Schoene N et al Functional and morphological skeletal muscle abnormalities correlate with reduced electromyographic activity in chronic heart failure Eur J Cardiovasc Prev Rehabil 2004 112 155-61
12 Piepoli M Clark AL Volterrani M et al Contribution of muscle afferents to the hemodynamic autonomic and ventilatory responses to exercise in patients with chronic heart failure effects of physical training Circulation 1996 935 940-52
13 Coats AJ Clark AL Piepoli M et al Symptoms and quality of life in heart failure the muscle hypothesis Br Heart J 1994 722 Suppl S36-9
14 Tucker WJ Lijauco CC Hearon CM Jr et al Mechanisms of the Improvement in Peak VO2 With Exercise Training in Heart Failure With Reduced or Preserved Ejection Fraction Heart Lung Circ 2018 271 9-21
15 Fu TC Yang NI Wang CH et al Aerobic Interval Training Elicits Different Hemodynamic Adaptations Between Heart Failure Patients with Preserved and Reduced Ejection Fraction Am J Phys Med Rehabil 2016 951 15-27
16 Hambrecht R Niebauer J Fiehn E et al Physical training in patients with stable chronic heart failure effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles Journal of the American College of Cardiology 1995 256 1239-49
17 Ruku DM Tran Thi TH Chen HM Effect of center-based or home-based resistance training on muscle strength and VO2 peak in patients with HFrEF A systematic review and meta-analysis Enferm Clin Engl Ed 2021
18 Long L Mordi IR Bridges C et al Exercise-based cardiac rehabilitation for adults with heart failure Cochrane Database Syst Rev 2019 11 Cd003331
19 Cooper LB Mentz RJ Sun JL et al Psychosocial Factors Exercise Adherence and Outcomes in Heart Failure Patients Insights From Heart Failure A Controlled Trial Investigating Outcomes of Exercise Training HF-ACTION Circulation Heart failure 2015 86 1044-51
20 Parati G Malfatto G Boarin S et al Device-guided paced breathing in the home setting effects on exercise capacity pulmonary and ventricular function in patients with chronic heart failure a pilot study Circulation Heart failure 2008 13 178-83
21 Lachowska K Bellwon J Narkiewicz K et al Long-term effects of device-guided slow breathing in stable heart failure patients with reduced ejection fraction Clinical research in cardiology official journal of the German Cardiac Society 2019 1081 48-60
22 Kawecka-Jaszcz K Bilo G Drożdż T et al Effects of device-guided slow breathing training on exercise capacity cardiac function and respiratory patterns during sleep in male and female patients with chronic heart failure Pol Arch Intern Med 2017 1271 8-15
23 Lachowska K Bellwon J Moryś J et al Slow breathing improves cardiovascular reactivity to mental stress and health-related quality of life in heart failure patients with reduced ejection fraction Cardiology journal 2020 276 772-9
24 Roecker K Metzger J Scholz T et al Modified ventilatory response characteristics to exercise in breath-hold divers International journal of sports physiology and performance 2014 95 757-65
31 Marcin T Trachsel LD Dysli M et al Effect of self-tailored high-intensity interval training versus moderate-intensity continuous exercise on cardiorespiratory fitness after myocardial infarction A randomized controlled trial Ann Phys Rehabil Med 2021 101490
38 Fletcher GF Ades PA Kligfield P et al Exercise standards for testing and training a scientific statement from the American Heart Association Circulation 2013 1288 873-934
39 Duffin J Measuring the respiratory chemoreflexes in humans Respir Physiol Neurobiol 2011 1772 71-9
40 Duffin J Mohan RM Vasiliou P et al A model of the chemoreflex control of breathing in humans model parameters measurement Respir Physiol 2000 1201 13-26
41 Guyenet PG Regulation of breathing and autonomic outflows by chemoreceptors Compr Physiol 2014 44 1511-62
42 Herzig D Eser P Omlin X et al Reproducibility of Heart Rate Variability Is Parameter and Sleep Stage Dependent Frontiers in physiology 2017 8 1100
43 Heart rate variability Standards of measurement physiological interpretation and clinical use Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology European heart journal 1996 173 354-81
Ventilatory inefficiency most commonly quantified as an increased ventilation VE to carbon dioxide exhalation VCO2 slope during exercise is a landmark of heart failure patients both with reduced and preserved ejection fraction HFrEF HFpEF1 Numerous studies have found higher VEVCO2 slopes to be associated with poorer prognosis2-4 The components of the VEVCO2 slope are the arterial CO2 partial pressure PaCO2 that is affected by hyperventilation and the pulmonary dead spacetidal volume ratio VDVT that is affected by pulmonary perfusion abnormalities5 The exaggerated response in ventilation of HFrEF patients may be caused by hypersensitivity of chemoreceptors to CO26 andor a sympathetic nervous hyperactivity commonly found in HFrEF patients based on an increased activation of metaboreceptors in peripheral muscles response to increased anaerobic metabolism7 Chronic sympathetic nervous hyperactivity has been suggested to decrease aerobic capacity of skeletal muscles based on reduced capillarisation8 and reduced red blood cell flux9 leading to a shift in muscle fibre type towards a lower content on type I fibres10 The ensuing anaerobic muscle metabolism leads to increased muscle fatiguability11 and acidosis already at low levels of exercise which trigger exaggerated responses in ventilation12 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 continues13 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 HFrEF14 and HFpEF patients alike15 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 metabolism16 Despite the beneficial effects of exercise training in both centre-based and home-based settings17 18 adherence to physical activity has been found to be poor amongst HFrEF patients19 Surprisingly few studies have targeted ventilation directly with therapeutic approaches Only three studies have assessed the effects of slow-breathing training on cardiorespiratory function20 21 These studies found improved physical function reduced blood and pulmonary arterial pressure increased ejection fraction EF20 22 improved ventilatory efficiency20 and reduced sleep apnoea22 Further they found improved regulation of the autonomic nervous system by reducing sympathetic drive and increasing vagal activity23 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 exercise24 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 VEVCO2 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 minday 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 11 stratified for HFrEFHFpEF 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 ACSCCS 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 ACSCCS 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 LIFE 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 Association38 Ramp tests are performed as previously described31 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 VEVCO2 slope from rest to ventilatory threshold 2 VT2 peak VO2 and VO2 at VT1 are determined as previously described31
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 protocol39 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 response40 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 LIFE Milan Italy and analysed from a segment during a deep sleep phase as previously described by the investigators group42 Low-frequency power LF ms2 004-015 Hz high-frequency power HF ms2 015-04 Hz and the LFHF 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 ACSCCS old healthy young healthy
OUTCOMES
Primary outcome is VEVCO2 slope analysed by ANCOVA with repeated measures corrected for baseline values and EF and sex
Secondary outcomes are the nadir of the VEVCO2 ratio breathing pattern VDVT peak VO2 VO2 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 VEVCO2 ratio VE VO2 BF VT PetCO2 PetO2 O2HR and rapid shallow breathing index between nasal and oral breathing
REFERENCES
1 Agostoni P Guazzi M Exercise ventilatory inefficiency in heart failure some fresh news into the roadmap of heart failure with preserved ejection fraction phenotyping European journal of heart failure 2017 1912 1686-9
2 Ponikowski P Francis DP Piepoli MF et al Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis Circulation 2001 1037 967-72
3 Myers J Arena R Oliveira RB et al The lowest VEVCO2 ratio during exercise as a predictor of outcomes in patients with heart failure Journal of cardiac failure 2009 159 756-62
4 Nadruz W Jr West E Sengelov M et al Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced Midrange and Preserved Ejection Fraction Journal of the American Heart Association 2017 611
5 Johnson RL Jr Gas exchange efficiency in congestive heart failure Circulation 2000 10124 2774-6
6 Chua TP Clark AL Amadi AA et al Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure Journal of the American College of Cardiology 1996 273 650-7
7 Scott AC Davies LC Coats AJ et al Relationship of skeletal muscle metaboreceptors in the upper and lower limbs with the respiratory control in patients with heart failure Clinical science London England 1979 2002 1021 23-30
8 Duscha BD Kraus WE Keteyian SJ et al Capillary density of skeletal muscle a contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations Journal of the American College of Cardiology 1999 337 1956-63
9 Hirai DM Musch TI Poole DC Exercise training in chronic heart failure improving skeletal muscle O2 transport and utilization Am J Physiol Heart Circ Physiol 2015 3099 H1419-39
10 Sullivan MJ Duscha BD Klitgaard H et al Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure Med Sci Sports Exerc 1997 297 860-6
11 Schulze PC Linke A Schoene N et al Functional and morphological skeletal muscle abnormalities correlate with reduced electromyographic activity in chronic heart failure Eur J Cardiovasc Prev Rehabil 2004 112 155-61
12 Piepoli M Clark AL Volterrani M et al Contribution of muscle afferents to the hemodynamic autonomic and ventilatory responses to exercise in patients with chronic heart failure effects of physical training Circulation 1996 935 940-52
13 Coats AJ Clark AL Piepoli M et al Symptoms and quality of life in heart failure the muscle hypothesis Br Heart J 1994 722 Suppl S36-9
14 Tucker WJ Lijauco CC Hearon CM Jr et al Mechanisms of the Improvement in Peak VO2 With Exercise Training in Heart Failure With Reduced or Preserved Ejection Fraction Heart Lung Circ 2018 271 9-21
15 Fu TC Yang NI Wang CH et al Aerobic Interval Training Elicits Different Hemodynamic Adaptations Between Heart Failure Patients with Preserved and Reduced Ejection Fraction Am J Phys Med Rehabil 2016 951 15-27
16 Hambrecht R Niebauer J Fiehn E et al Physical training in patients with stable chronic heart failure effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles Journal of the American College of Cardiology 1995 256 1239-49
17 Ruku DM Tran Thi TH Chen HM Effect of center-based or home-based resistance training on muscle strength and VO2 peak in patients with HFrEF A systematic review and meta-analysis Enferm Clin Engl Ed 2021
18 Long L Mordi IR Bridges C et al Exercise-based cardiac rehabilitation for adults with heart failure Cochrane Database Syst Rev 2019 11 Cd003331
19 Cooper LB Mentz RJ Sun JL et al Psychosocial Factors Exercise Adherence and Outcomes in Heart Failure Patients Insights From Heart Failure A Controlled Trial Investigating Outcomes of Exercise Training HF-ACTION Circulation Heart failure 2015 86 1044-51
20 Parati G Malfatto G Boarin S et al Device-guided paced breathing in the home setting effects on exercise capacity pulmonary and ventricular function in patients with chronic heart failure a pilot study Circulation Heart failure 2008 13 178-83
21 Lachowska K Bellwon J Narkiewicz K et al Long-term effects of device-guided slow breathing in stable heart failure patients with reduced ejection fraction Clinical research in cardiology official journal of the German Cardiac Society 2019 1081 48-60
22 Kawecka-Jaszcz K Bilo G Drożdż T et al Effects of device-guided slow breathing training on exercise capacity cardiac function and respiratory patterns during sleep in male and female patients with chronic heart failure Pol Arch Intern Med 2017 1271 8-15
23 Lachowska K Bellwon J Moryś J et al Slow breathing improves cardiovascular reactivity to mental stress and health-related quality of life in heart failure patients with reduced ejection fraction Cardiology journal 2020 276 772-9
24 Roecker K Metzger J Scholz T et al Modified ventilatory response characteristics to exercise in breath-hold divers International journal of sports physiology and performance 2014 95 757-65
31 Marcin T Trachsel LD Dysli M et al Effect of self-tailored high-intensity interval training versus moderate-intensity continuous exercise on cardiorespiratory fitness after myocardial infarction A randomized controlled trial Ann Phys Rehabil Med 2021 101490
38 Fletcher GF Ades PA Kligfield P et al Exercise standards for testing and training a scientific statement from the American Heart Association Circulation 2013 1288 873-934
39 Duffin J Measuring the respiratory chemoreflexes in humans Respir Physiol Neurobiol 2011 1772 71-9
40 Duffin J Mohan RM Vasiliou P et al A model of the chemoreflex control of breathing in humans model parameters measurement Respir Physiol 2000 1201 13-26
41 Guyenet PG Regulation of breathing and autonomic outflows by chemoreceptors Compr Physiol 2014 44 1511-62
42 Herzig D Eser P Omlin X et al Reproducibility of Heart Rate Variability Is Parameter and Sleep Stage Dependent Frontiers in physiology 2017 8 1100
43 Heart rate variability Standards of measurement physiological interpretation and clinical use Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology European heart journal 1996 173 354-81
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None