CEREBRAL BLOOD FLOW IN HEART TRANSPLANT RECIPIENTS AT REST AND DURING INCREMENTAL EXERCISE by JONATHAN DAVID SMIRL B.Sc., The University of Victoria, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in College of Graduate Studies (Interdisciplinary Studies) [Health and Exercise Sciences] THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) September 2011 © Jonathan David Smirl, 2011 i Abstract Pathological impairments to cardiac output may impact cerebral blood flow (CBF). Prior studies on heart transplant recipients (HTR) have reported increases of 25-53% in CBF, 1-6 months following transplant. It is currently unknown if CBF is chronically altered in the years following transplant or during progressive exercise stress, when compared with aged- matched controls (AM). Donor population controls (DC) were included to determine if the responses observed in HTR are related to the age of the donor rather than the individual. The aim of this thesis was to examine the influence of long-term heart transplantation on the regulation of CBF velocity (CBFv) at rest and during incremental exercise. Two hypotheses were tested: 1) CBFv would be similar in HTR when compared to AM, but lower than DC; 2) that during incremental exercise, the HTR would have reduced elevations in CBFv compared with AM and DC. To address these hypotheses, HTR were tested who have a reported inability to acutely increase cardiac output during exercise. Seven male clinically stable HTR (62 ± 9 yrs of age, 9 ± 7 yrs post-transplant), seven male AM (62 ± 7 yrs), and seven male DC (22 ± 3 yrs) were recruited for this study. Bilateral middle cerebral arteries were insonated using transcranial Doppler ultrasound to obtain an index of CBFv. Data were obtained while seated and during an incremental cycling test to volitional exhaustion. A repeated measures ANOVA was applied to identify differences across exercise intensity. Comparisons between groups were performed with Fisher‟s LSD post hoc test. The main findings were: 1) Rest: CBFv was comparable between HTR and AM (40 vs. 41 cm/s), as expected, CBFv was 68% higher in the DC compared with the HTR and AM ii groups (P<0.05). 2) Incremental exercise: mean CBFv was not significantly different between the HTR and AM groups across any of the exercise intensities. In conclusion, the CBFv of long-term HTR are comparable to AM both at rest and during incremental exercise that despite a suppressed VO2 Peak (and likely Q) CBFv is well maintained during incremental exercise in long – term HTR. iii Preface This study was approved by the University of British Columbia Clinical Research Ethics Board (H11-02576 – CBF in HTR) and the University of Alberta Clinical Research Ethics Board. (Pro00011560). Chapters three, four and five are based on data collected in the Mazankowski Alberta Heart Institute at the University of Alberta by Dr. Philip Ainslie, Dr. Mark Haykowsky, Dr. Luis Altamirino-Diaz, Dr. Helen Jones, Kit Marsden, Mike Nelson and Jonathan Smirl. The data were analyzed in the cardiovascular physiology laboratory at the University of British Columbia by Jonathan Smirl. Dr. Ainslie and Dr. Haykowsky were responsible for the overall design and concept of the study, technical assistance, data collection, equipment acquisition, subject recruitment, and funding for the study. Dr. Altamirino-Diaz was responsible for the collection and analysis of the echocardiograph images. Dr. Jones, Kit Marsden and Mike Nelson assisted in the collection of the data. Jonathan Smirl was responsible for assisting in the overall study design and study concept. Jonathan coordinated the data collection involved in this study, and analyzed all of the data, including statistical analyses and writing. There has been a version of chapters three, four and five accepted for an oral presentation at Physiological 2011 (annual scientific meeting of the Physiological Society). Jonathan D. Smirl, Mark J. Haykowsky, Katelyn R. Marsden, Helen Jones, Michael D. Nelson, Luis A. Altamirano-Diaz, and Philip N. Ainslie. (2011) Cerebral blood flow in heart transplant recipients: rest and during exercise. Jonathan Smirl was responsible for the data collection, data analysis, writing, and formatting of the abstract. iv Table of Contents Abstract…….. ........................................................................................................................... ii Preface…………… .................................................................................................................. iv Table of Contents ..................................................................................................................... v List of Tables .......................................................................................................................... vii List of Figures ........................................................................................................................ viii List of Abbreviations ............................................................................................................... ix Acknowledgements .................................................................................................................. xi Dedication ............................................................................................................................... xii Chapter One: Introduction and Review of the Literature ...................................................... 1 1.1. Brief Background on Heart Transplantation .........................................................1 1.2. Regulation of CBF ...............................................................................................3 1.2.1. Neurogenic Control of CBF............................................................................4 1.2.2. Influences of Cardiac Function on CBF ..........................................................6 1.2.3. Autoregulatory Control of CBF ......................................................................9 1.2.4. Regulation of CBF by PaCO2 ....................................................................... 10 1.2.5. Effects of Cerebral Metabolism on CBF at Rest and During Exercise ........... 11 1.3. Cognitive Impairment in CHF ............................................................................ 12 1.4. Influences of Cardiac Disease on CBF ............................................................... 13 1.4.1. Congestive Heart Failure .............................................................................. 13 1.4.2. Ischemic Heart Disease ................................................................................ 14 1.5. Changes in CBF in HTR .................................................................................... 15 Chapter Two: Purpose, Aims and Hypotheses .......................................................................22 2.1. Purpose of Thesis ............................................................................................... 22 2.2. Aims .................................................................................................................. 22 2.3. Hypotheses ........................................................................................................ 23 Chapter Three: Methods .........................................................................................................24 3.1. Participants ........................................................................................................ 24 3.2. Instrumentation .................................................................................................. 27 3.3. Transcranial Doppler Ultrasound........................................................................ 29 3.3.1. Validity of TCD ........................................................................................... 31 3.3.2. Principle of TCD .......................................................................................... 31 3.3.3. Technique of TCD........................................................................................ 32 3.4. Incremental Cycling Exercise Protocol ............................................................... 33 3.5. Statistical Data Analysis..................................................................................... 34 v Chapter Four: Results .............................................................................................................35 4.1. Participant Characteristics .................................................................................. 35 4.2. Incremental Exercise Test .................................................................................. 35 4.3. Rest.................................................................................................................... 38 4.4. VO2peak ............................................................................................................... 40 4.5. HRreserve Relationships ........................................................................................ 43 4.6. Mild, Moderate and Intense Exercise ................................................................. 45 Chapter Five: Discussion and Conclusion ..............................................................................49 5.1. Principle Findings .............................................................................................. 49 5.2. Influence of HT on CBF at Rest - Comparison with Previous Studies................