Building on pre-existing lines of investigation (Dr. O’Donnell’s RIU) on mild COPD, several collaborative publications explored the mechanisms underlying exercise intolerance in the early stages of the disease. Specific emphasis was given to exercise ventilatory inefficiency, which we showed to constitute a relevant physiological biomarker across the whole spectrum of disease severity. The modulating effects of obesity on breathlessness were also explored. Several studies were published on the negative consequences of impaired muscle and cerebral O2 delivery and the effects of non-pharmacological interventions on these outcomes. Our results hold clinical implications for early treatment, dyspnea management, assessment of disease severity and progression and the effects of interventions on physical capacity in patients with COPD. 1. Rodrigues MK, Oliveira MF, Soares A, Treptow E, Neder JA. Additive effects of non-invasive ventilation to hyperoxia on cerebral oxygenation in COPD patients with exercise-related O2 desaturation. Clin Physiol Funct Imaging. 2013 Jul; 33(4):274-81. 2. Ciavaglia CE, Guenette JA, Ora J, Webb KA, Neder JA, O'Donnell DE. Does exercise test modality influence dyspnoea perception in obese patients with COPD? Eur Respir J. 2014 Jun;43(6):1621-30 3. Elbehairy AF, Webb KA, Neder JA, O'Donnell DE. Should Mild COPD Be Treated? Evidence for Early Pharmacological Intervention. Drugs. 2014 Jan;74(1):155. Drugs. 2013 Dec;73(18):1991-2001. 4. Ramos RP, Ota-Arakaki JS, Alencar MC, Ferreira EV, Nery LE, Neder JA. Ciavaglia CE, Guenette JA, Ora J, Webb KA, Neder JA, O'Donnell DE. Does exercise test modality influence dyspnoea perception in obese patients with COPD? Eur Respir J. 2014 Jun;43(6):1621-30. 5. O'Donnell DE, Laveneziana P, Webb K, Neder JA. Chronic obstructive pulmonary disease: clinical integrative physiology. Clin Chest Med. 2014 Mar;35(1):51-69. 6. O'Donnell DE, Ciavaglia CE, Neder JA. When obesity and chronic obstructive pulmonary disease collide. Physiological and clinical consequences. Ann Am Thorac Soc. 2014 May;11(4):635-44. 7. Laveneziana P, Webb KA, Wadell K, Neder JA, O'Donnell DE. Does expiratory muscle activity influence dynamic hyperinflation and exertional dyspnea in COPD? Respir Physiol Neurobiol. 2014 Aug 1;199:24-33. 8. Scuarcialupi ME, Berton DC, Cordoni PK, Squassoni SD, Fiss E, Neder JA. Can bronchodilators improve exercise tolerance in COPD patients without dynamic hyperinflation? J Bras Pneumol. 2014 Mar-Apr;40(2):111-8. 9. Guenette JA, Chin RC, Cheng S, Dominelli PB, Raghavan N, Webb KA, Neder JA, O'Donnell DE. Mechanisms of exercise intolerance in global initiative for chronic obstructive lung disease grade 1 COPD. Eur Respir J. 2014 Nov;44(5):1177-87. 10. Langer D, Ciavaglia CE, Neder JA, Webb KA, O'Donnell DE. Lung hyperinflation in chronic obstructive pulmonary disease: mechanisms, clinical implications and treatment. Expert Rev Respir Med. 2014 Dec;8(6):731-49. 11. Neder JA, O'Donnell CD, Cory J, Langer D, Ciavaglia CE, Ling Y, Webb KA, O'Donnell DE. Ventilation Distribution Heterogeneity at Rest as a Marker of Exercise Impairment in Mild-to-Advanced COPD. COPD. 2015 Jun;12(3):249-56. 12. Neder JA, Arbex FF, Alencar MC, O'Donnell CD, Cory J, Webb KA, O'Donnell DE. Exercise ventilatory inefficiency in mild to end-stage COPD. Eur Respir J. 2015 Feb;45(2):377-87. 13. Elbehairy AF, Raghavan N, Cheng S, Yang L, Webb KA, Neder JA, Guenette JA, Mahmoud MI, O'Donnell DE. Physiologic characterization of the chronic bronchitis phenotype in GOLD grade IB COPD. Chest. 2015 May;147(5):1235-45. 14. Medeiros WM, Fernandes MC, Azevedo DP, de Freitas FF, Amorim BC, Chiavegato LD, Hirai DM, O'Donnell DE, Neder JA. Oxygen delivery-utilization mismatch in contracting locomotor muscle in COPD: peripheral factors. Am J Physiol Regul Integr Comp Physiol. 2015 Jan 15; 308(2):R105-11. 15. Elbehairy AF, Ciavaglia CE, Webb KA, Guenette JA, Jensen D, Mourad SM, Neder JA, O'Donnell DE; Canadian Respiratory Research Network. Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance. Am J Respir Crit Care Med. 2015 Jun15;191(12):1384-94. 16. Faisal A, Zoumot Z, Shah PL, Neder JA, Polkey MI, Hopkinson NS. Effective Bronchoscopic Lung Volume Reduction Accelerates Exercise Oxygen Uptake Kinetics in Emphysema. Chest. 2015 Jun 25. 17. Mazzuco A, Medeiros WM, Sperling MP, de Souza AS, Alencar MC, Arbex FF, Neder JA, Arena R, Borghi-Silva A. Relationship between linear and nonlinear dynamics of heart rate and impairment of lung function in COPD patients. Int J Chron Obstruct Pulmon Dis. 2015 Aug 17;10:1651-61. 18. O'Donnell DE, Neder JA, Elbehairy AF. Physiological impairment in mild COPD. Respirology. 2015 Sep 2. [Epub ahead of print].19. Faisal A, Alghamdi BJ, Ciavaglia CE, Elbehairy AF, Webb KA, Ora J, Neder JA, O'Donnell DE. Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders. Am J Respir Crit Care Med. 2015 Sep 25. [Epub ahead of print]

COPD-Heart Failure Overlap
These studies explored the complex pathophysiological inter-relationships between COPD and systolic heart failure using the stress of exercise to unravel abnormalities in ventilation, lung mechanics and O2 transport and utilization. Our results hold clinical implications for pulmonary function and cardiopulmonary exercise testing interpretation, prognosis stratification, disease management and assessment of interventions in patients with COPD-CHF. 1. Oliveira MF, Arbex F, Alencar MC, Soares A, Borghi-Silva A, Almeida D, Neder JA. Heart failure impairs cerebral oxygenation during exercise in patients with COPD. Eur Respir J. 2013 Nov;42(5):1423-6. 2. Chiappa GR, Vieira PJ, Umpierre D, Corrêa AP, Berton DC, Ribeiro JP, Neder JA. Inspiratory resistance decreases limb blood flow in COPD patients with heart failure. Eur Respir J. 2014 May;43(5):1507-10. 3. Apostolo A, Laveneziana P,….. Neder JA, Agostoni P. Impact of chronic obstructive pulmonary disease on exercise ventilatory efficiency in heart failure. Int J Cardiol. 2015; 189:134-40. 4. Oliveira MF, Zelt JT, Jones JH, Hirai DM, O'Donnell DE, Verges S, Neder JA. Does impaired O2 delivery during exercise accentuate central and peripheral fatigue in patients with coexistent COPD-CHF? Front Physiol. 2015 Jan 7; 5:514. 5. Oliveira MF, Alencar MC, ….. Neder JA. Effects of Heart Failure on Cerebral Blood Flow in COPD: Rest and Exercise. Respir Physiol Neurobiol 2016;221:41-8. 6. Oliveira MF, Arbex F, …..Neder JA. Heart Failure Impairs Muscle Blood Flow and Endurance Exercise Tolerance in COPD. COPD (in press). 7. Alencar MC, Arbex F…..Neder JA. Does Exercise Ventilatory Inefficiency Predict Poor Outcome in Heart Failure Patients with COPD? J Cardiopul Rehab Prev (in press). 8. Arbex FF, Alencar MC, …..Neder JA. Exercise Ventilation-CO2 Output Relationship in COPD: Influence of Heart Failure. COPD (submitted). 9. Souza AS, Sperandio PA, …..Neder JA. Influence of Heart Failure on Resting Lung Volumes in Patients with COPD. J Bras Pneumol (submitted).

Pulmonary Vascular Diseases
Mechanisms of exercise intolerance and the usefulness of non-invasive cardiopulmonary exercise testing (CPET) parameters for prognosis stratification have been investigated in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. Our results hold clinical implications for cardiopulmonary exercise testing interpretation, prognosis stratification and functional assessment of interventions in patients with pulmonary hypertension.1.Valois FM, Nery LE, Ramos RP, Ferreira EV, Silva CC, Neder JA, Ota-Arakaki JS. Contrasting cardiopulmonary responses to incremental exercise in patients with schistosomiasis-associated and idiopathic pulmonary arterial hypertension with similar resting hemodynamic impairment. PLoS One. 2014 Feb 3; 9(2):e87699. 2. Ferreira EV, Ota-Arakaki JS, Ramos RP, Barbosa PB, Almeida M, Treptow EC,Valois FM, Nery LE, Neder JA. Optimizing the evaluation of excess exercise ventilation for prognosis assessment in pulmonary arterial hypertension Eur J Prev Cardiol. 2014 Nov; 21(11):1409-19. 3. Ramos RP, Ota-Arakaki JS, Alencar MC, Ferreira EV, Nery LE, Neder JA. Exercise oxygen uptake efficiency slope independently predicts poor outcome in PAH. Eur Respir J. 2014 May;43(5):1510-2 4. Neder JA, Ramos RP, Ota-Arakaki JS, Hirai DM, D'Arsigny CL, O'Donnell D. Exercise intolerance in pulmonary arterial hypertension. The role of cardiopulmonary exercise testing. Ann Am Thorac Soc. 2015 Apr; 12(4):604-12. 5. Neder JA, Jones JH, Zelt JT, Ramos RP, Ota-Arakaki JS, Hirai DM, Sperandio PA, Alencar MC, Arbex FF, O'Donnell DE. Pulmonary artery wedge pressure and exercise oscillatory ventilation in pre-capillary pulmonary hypertension. Int J Cardiol. 2015 Nov 10. [Epub ahead of print], 6. Neder JA. Ramos R, ….O'Donnel DE. Insights Into Ventilation-Gas Exchange Coupling in Chronic Thromboembolic Pulmonary Hypertension. Eur Respir J (in press)

Healthy Subjects/Aging
These investigations focused on the predations brought by senescence on cardio-pulmonary interactions and exercise ventilatory efficiency. Our results hold clinical implications for exercise testing interpretation in elderly patients with coexistent cardiopulmonary diseases. 1. Chiappa GR, Roseguini BT, Neder JA, Ribeiro JP. Inspiratory loading and lactate clearance after exercise. Med Sci Sports Exerc. 2013 Jan; 45(1):212-3. 2. Reis MS, Berton DC, Arena R, Catai AM, Neder JA, Borghi-Silva A. Determination of anaerobic threshold through heart rate and near infrared spectroscopy in elderly healthy men. Braz J Phys Ther. 2013 Oct; 17(5):506-15. 3. Faisal A, Webb KA, Guenette JA, Jensen D, Neder JA, O'Donnell DE; Canadian Respiratory Research Network. Effect of age-related ventilatory inefficiency on respiratory sensation during exercise. Respir Physiol Neurobiol. 2015 Jan1; 205:129-39.

Other Clinical Populations
These studies used clinical physiology concepts to explore the effects of pharmacological and non-pharmacological interventions on different clinical populations, including chronic kidney disease, peripheral vascular disease, coronary artery disease and mitochondrial myopathy. An additional paper has being published on a previous productive line of research that is also relevant to Canada: asbestos related lung disease. 1. Reinecke NL, Cunha TM, Heilberg IP, Higa EM, Nishiura JL, Neder JA, Almeida WS, Schor N. Exercise capacity in polycystic kidney disease. Am J Kidney Dis. 2014 Aug;64(2):239-46. 2. Roseguini BT, Hirai DM, Alencar MC, Ramos RP, Silva BM, Wolosker N, Neder JA, Nery LE. Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication. Am J Physiol Regul Integr Comp Physiol. 2014 Aug 15;307(4):R396-404. 3. Reboredo MM, Neder JA, Pinheiro BV, Henrique DM, Lovisi JC, Paula RB. Intra-dialytic training accelerates oxygen uptake kinetics in hemodialysis patients. Eur J Prev Cardiol. 2015 Jul;22(7):912-9. 4. Cipriano G Jr, Neder JA, Umpierre D, Arena R, Vieira PJ, Chiappa AM, Ribeiro JP, Chiappa GR. Sympathetic ganglion transcutaneous electrical nerve stimulation after coronary artery bypass graft surgery improves femoral blood flow and exercise tolerance. J Appl Physiol (1985). 2014 Sep 15;117(6):633-8. 5. Gimenes AC, Bravo DM, Nápolis LM, Mello MT, Oliveira AS, Neder JA, Nery LE. Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy. Braz J Med Biol Res. 2015 Apr;48(4):354-62. 6. Terra-Filho M, Bagatin E, Nery LE, Nápolis LM, Neder JA, de Souza Portes Meirelles G, Silva CI, Muller NL. Screening of miners and millers at decreasing levels of asbestos exposure: comparison of chest radiography and thin-section computed tomography. PLoS One. 2015 Mar 19; 10(3):e0118585.

Cardiopulmonary Exercise Testing (CPET)
These investigations advanced technical and interpretative aspects of CPET as applied to patients with chronic cardiopulmonary diseases. The awardee has a co-leading role on an official statement of the European Respiratory Society on constant work rate CPET to assess the effects of clinical interventions. 1. Ramos RP, Alencar MC, Treptow E, Arbex F, Ferreira EM, Neder JA. Clinical usefulness of response profiles to rapidly incremental cardiopulmonary exercise testing. Pulm Med. 2013; 2013:359021. 2. Marciniuk DD, Johnson BD, Neder JA, O'Donnell DE. Cardiopulmonary exercise testing. Pulm Med. 2013; 2013:686104. 3. Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, O’Donnell DE, Onorati P, Porszasz J, Rabinovich R, Rossiter HB, Singh S, Troosters T, Ward S. Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur Respir J 2015

Research Collaborations
- The awardee was able to maintain strong collaborative links with his previous laboratory (SEFICE) which included two 14-day visits to the Federal University of Sao Paulo, Brazil for research seminars, experiments and graduate student supervision. He has also established a national research network involving laboratories led by his previous MD/PhD students and post-doctoral fellows. He had the initiative to pursue a Queen’s-Sao Paulo Research Funding Agency cooperative agreement which will be effective in 2016.
- His laboratory received research visits from Prof. Samuel Verges (Grenoble University, France) leading to an ongoing study on central fatigue and Prof. Daniel Langer (University of Leuven, Belgium) leading to a multi-national trial on inspiratory muscle training in COPD-heart failure (led by Queen’s). He maintained a collaborative study with Prof. Susan Ward (Crickwell, UK) on interval exercise in COPD.
- Key collaborations at Queen’s include: Division of Respirology: Dr. Denis O’Donnell (COPD, lung mechanics, dyspnea) and the Canadian Respiratory Research Network, Dr. Christine D’Arsigny (pulmonary vascular diseases (PVD)) and Dr. Onofre Moran (interstitial lung disease); Division of Cardiology: Drs. Stephen Archer and Amer Johri (PVD and right ventricular failure) from Queen’s Cardiopulmonary Unit; Division of Rheumatology: Dr. Mala Joneja (PVD and connective tissue disease); School of Kinesiology: Profs. Michael Tschakovsky, Brendon Gurd and Kira Pyke (endothelial and peripheral vascular function); Department of Biomedical and Molecular Sciences: Dr. John Fisher (respiratory physiology).