Title : Reduced blood flow through intrapulmonary arteriovenous anastomoses at rest and during exercise in lowlanders during acclimatization to high altitude

Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) is elevated during exercise at sea level (SL) and at rest in acute normobaric hypoxia. Following high altitude (HA) acclimatization, resting Q̇IPAVA is similar to SL, but it is unknown if this is true during exercise at HA. We hypothesized that exercise at HA (5,050 m) would exacerbate Q̇IPAVA due to heightened pulmonary arterial pressure. Using a supine cycle ergometer, seven healthy adults free from intracardiac shunts underwent an incremental exercise test at SL (25, 50, 75% of SL V̇O2peak) and at HA (25, 50% of SL V̇O2peak). Echocardiography was used to determine cardiac output (Q̇) and pulmonary artery systolic pressure (PASP) and agitated saline contrast was used to determine Q̇IPAVA (bubble score; 0-5). The principle findings were: (1) Q̇ was similar at SL-rest (3.9 {plus minus} 0.47 l min-1) compared to HADisclaimer: This is a confidential document. rest (4.5 {plus minus} 0.49 l min-1; P=0.382), but increased from rest during both SL and HA exercise (P<0.001); (2) PASP increased from SL-rest (19.2 {plus minus} 0.7 mmHg) to HA-rest (33.7 {plus minus} 2.8 mmHg; P=0.001) and, compared to SL, PASP was elevated during HA exercise (P=0.003); (3) Q̇IPAVA was increased from SL-rest (0) to HA-rest (median=1; P=0.04) and increased from resting values during SL exercise (P<0.05), but were unchanged during HA exercise (P=0.91), despite significant increases in Q̇ and PASP. Theoretical modeling of microbubble dissolution suggests that the lack of Q̇IPAVA in response to exercise at HA is unlikely caused by saline contrast instability. New Findings: What is the central question of this study? To determine whether exercise following 4-7 days at 5,050 m would augment blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) compared to sea level exercise using the technique of agitated saline contrast echocardiography. What is the main finding and its importance? Despite a significant increase in both cardiac output and pulmonary pressure during exercise at high altitude, there is very little Q̇IPAVA at rest or during exercise following 4-7 days of acclimatization. Mathematical modeling suggests bubble instability at high altitude is an unlikely explanation for the reduced Q̇IPAVA. Dual Publication: No Funding: Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada): Glen E Foster, 2014-05643 Disclaimer: This is a confidential document. Title: Reduced blood flow through intrapulmonary arteriovenous anastomoses at rest and during exercise in lowlanders during acclimatization to high altitude. Authors: Lindsey M. Boulet Andrew T. Lovering Michael M. Tymko Trevor A. Day Mike Stembridge Trang Anh Nguyen Philip N. Ainslie Glen E. Foster Affiliations: Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Science, University of British Columbia, Kelowna, Canada. Department of Human Physiology, University of Oregon, Eugene, USA. Department of Biology, Faculty of Science and Technology, Mount Royal University, Calgary, Alberta, Canada. Cardiff School of Sport, Cardiff Metropolitan University, Cardiff, UK. Department of Biomedical Engineering, International University, Vietnam National University, Ho Chi Minh City, Vietnam Correspondence: Glen E. Foster, PhD. School of Health and Exercise Science Faculty of Health and Social Development University of British Columbia 1147 Research Rd. Kelowna, BC, V1V 1V7 Telephone: 250-807-8224 Fax: 250-807-9665 Email: glen.foster@ubc.ca Running head: Exercise-induced intrapulmonary shunt at altitude Intrapulmonary Shunt at Altitude 2 NEW FINDINGS • What is the central question of this study? To determine whether exercise following 4-7 days at 5,050 m would augment blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) compared to sea level exercise using the technique of agitated saline contrast echocardiography. • What is the main finding and its importance? Despite a significant increase in both cardiac output and pulmonary pressure during exercise at high altitude, there is very little Q̇IPAVA at rest or during exercise following 4-7 days of acclimatization. Mathematical modeling suggests bubble instability at high altitude is an unlikely explanation for the reduced Q̇IPAVA. Intrapulmonary Shunt at Altitude 3 ABSTRACT Blood flow through intrapulmonary arteriovenous anastomoses (Q̇IPAVA) is elevated during exercise at sea level (SL) and at rest in acute normobaric hypoxia. Following high altitude (HA) acclimatization, resting Q̇IPAVA is similar to SL, but it is unknown if this is true during exercise at HA. We hypothesized that exercise at HA (5,050 m) would exacerbate Q̇IPAVA due to heightened pulmonary arterial pressure. Using a supine cycle ergometer, seven healthy adults free from intracardiac shunts underwent an incremental exercise test at SL (25, 50, 75% of SL V̇O2peak) and at HA (25, 50% of SL V̇O2peak). Echocardiography was used to determine cardiac output (Q̇) and pulmonary artery systolic pressure (PASP) and agitated saline contrast was used to determine Q̇IPAVA (bubble score; 0-5). The principle findings were: (1) Q̇ was similar at SL-rest (3.9 ± 0.47 l min) compared to HA-rest (4.5 ± 0.49 l min; P=0.382), but increased from rest during both SL and HA exercise (P<0.001); (2) PASP increased from SL-rest (19.2 ± 0.7 mmHg) to HA-rest (33.7 ± 2.8 mmHg; P=0.001) and, compared to SL, PASP was elevated during HA exercise (P=0.003); (3) Q̇IPAVA was increased from SL-rest (0) to HA-rest (median=1; P=0.04) and increased from resting values during SL exercise (P<0.05), but were unchanged during HA exercise (P=0.91), despite significant increases in Q̇ and PASP. Theoretical modeling of microbubble dissolution suggests that the lack of Q̇IPAVA in response to exercise at HA is unlikely caused by saline contrast instability.