Breathing Exercise Against Dyspnoea in Heart Failure Patients to Improve Chemosensitivity

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. 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; 19(12): 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; 103(7): 967-72. 3. Myers J, Arena R, Oliveira RB, et al. The lowest VE/VCO2 ratio during exercise as a predictor of outcomes in patients with heart failure. Journal of cardiac failure 2009; 15(9): 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; 6(11). 5. Johnson RL, Jr. Gas exchange efficiency in congestive heart failure. Circulation 2000; 101(24): 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; 27(3): 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; 102(1): 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; 33(7): 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; 309(9): 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; 29(7): 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; 11(2): 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; 93(5): 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; 72(2 Suppl): S36-9. 14. Tucker WJ, Lijauco CC, Hearon CM, Jr., et al. Mechanisms of the Improvement in Peak VO(2) With Exercise Training in Heart Failure With Reduced or Preserved Ejection Fraction. Heart Lung Circ 2018; 27(1): 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; 95(1): 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; 25(6): 1239-49. 17. Ruku DM, Tran Thi TH, Chen HM. Effect of center-based or home-based resistance training on muscle strength and VO(2) 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; 1(1): 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; 8(6): 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; 1(3): 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; 108(1): 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; 127(1): 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; 27(6): 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; 9(5): 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; 128(8): 873-934. 39\. Duffin J. Measuring the respiratory chemoreflexes in humans. Respir Physiol Neurobiol 2011; 177(2): 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; 120(1): 13-26. 41\. Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 2014; 4(4): 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; 17(3): 354-81.