THE ROLE OF ISOMETRIC EXERCISE TRAINING ON REDUCTIONS IN RESTING BLOOD PRESSURE: HUMAN TRIALS AND THE INFLUENCE OF PERIPHERAL VASOACTIVE AND INFLAMMATORY BIOMARKERS by Benjamin DH. Gordon A dissertation submitted to the faculty of The University of North Carolina at Charlotte in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biology Charlotte 2018 Approved by: ______________________________ Dr. Reuben Howden ______________________________ Dr. Larry Leamy ______________________________ Dr. Joseph Marino ______________________________ Dr. Adam Reitzel ______________________________ Dr. Jeanette Bennett ii ©2018 Benjamin DH. Gordon ALL RIGHTS RESERVED iii ABSTRACT BENJAMIN DH. GORDON. Role of Isometric Exercise Training On Reductions in Resting Blood Pressure: Human Trials and the Influence of Peripheral Vasoactive and Inflammatory Biomarkers (Under the direction of DR. REUBEN HOWDEN). Approximately 1 billion people worldwide and ~87 million adults in the United States alone are affected by hypertension [HTN: high blood pressure (HBP)]. Primary treatment avenues for HBP management include lifestyle modification (e.g. diet, exercise, weight loss, and smoking cessation) and pharmacological therapy. Research has indicated isometric exercise training (IET) is associated with lowering resting blood pressure (RBP). This activity is safe, relatively inexpensive, and easy to perform. While generally effective several factors may influence the degree of responsiveness to IET including age, chronic disease, current pharmacological management, time spent exercising, home-based training, effects of systemic biomarkers, and muscle mass. Therefore the aims of this dissertation were to determine the significance of several contributing factors including time, age, disease, the efficacy of home-based isometric exercise, biomarkers, and muscle mass on reductions in RBP following IET. This work identified the lasting effects of an extended isometric exercise training program (chapter 2), outlines the importance of disease and medications regimen in subject responsiveness to intervention (chapter 3), proposes the positive implications for home-based programming for training dissemination to the greater hypertensive population (chapter 4), and begins to elucidate upon unknown mechanisms contributing to lowered RBP following IET (chapter 5). In chapter 2, I assessed whether or not completing 12 weeks of IET programming can improve high blood pressure measures and sustain positive iv outcomes over extended periods of detraining in older recreationally active adults. In chapter 3, I assessed the efficacy of IET in cardiopulmonary rehabilitation patients. In Chapter 4, I evaluated efficacy of home-based training regimens compared to face-to-face lab-based protocols. In chapter 5, I assessed whether or not completing 6-weeks of IET in two different muscle groups influences both RBP and biomarkers of vasoactivity and inflammation acutely and with training. This dissertation will help to disseminate a critical next step, providing an opportunity for effective programming with hopes of characterizing a mechanism contributing to BP reductions induced by IET thus aiding in the fight against HBP both in the lab and in the community. v DEDICATION To my wife, Em and my parents vi ACKNOWLEDGEMENTS This work was made possible by the guidance and support of Dr. Reuben Howden throughout my graduate career. I sincerely thank you for including me as a member of the Laboratory of Systems Physiology (LSP) and for your mentorship and guidance these last 4 ½ years. I would like to thank all members of my committee Drs. Marino, Reitzel, Leamy, and Bennett for their continued feedback and support as I know for a fact, without their guidance this dissertation would not be possible. Thank you past and present members of the LSPs “Team IET”, Emily Zacherle, Brandon Shore, Sarah Whitmire, Adam Lavis, Erin Vinoski, Spencer Green, and Chris Stewart for their assistance in the lab throughout my graduate career. Thank you to Drs. Marino and Bennett for their patience and the unbelievable support and expertise they provided during my final project. I would like to thank the University of North Carolina at Charlotte Graduate School for their Graduate Assistant Support award for funding my graduate education. Additionally, I am grateful for grant support to finish my dissertation with the gracious contribution from Dr. Tom Reynolds, Dean of the Graduate School in the form of a research fellowship (Appendix 1.). I would like to especially thank Dr. Chris Blanchette for funding my last two years as a graduate research assistant, for this, I am forever grateful. Lastly, I would like to acknowledge my wife, parents, and friends for their patience and the unbelievable support I have been so fortunate to receive. Thank you. vii TABLE OF CONTENTS LIST OF TABLES xi LIST OF FIGURES xii LIST OF ABBREVIATIONS xv CHAPTER 1: BACKGROUND AND SIGNIFICANCE OF PROPOSED RESEARCH 1 Introduction 1 Background and Literature Review 5 Specific Aims 47 Experimental design and methods 51 Experimental Design 51 Participants 56 Participant Recruitment 60 Instrumentation and Procedures 63 Outcome measures 78 Testing Protocols 78 Statistical analyses 79 Power analysis 81 CHAPTER 2: RESTING BLOOD PRESSURE ADAPTATIONS 83 TO 12 WEEKS OF ISOMETRIC HANDGRIP TRAINING WITH 12 WEEKS DETRAINING IN AN ELDERLY POPULATION Abstract 83 Introduction 84 Methods 85 viii Statistical Analysis 87 Results 88 Discussion and Conclusions 89 Tables 95 Figures 97 References 102 CHAPTER 3: “GET A GRIP ON HYPERTENSION”: 106 EXPLORING THE USE OF ISOMETRIC HANDGRIP TRAINING IN CARDIOPULMONARY REHABILITATION PATIENTS Abstract 106 Introduction 107 Methods 107 Statistical analysis 109 Results 110 Discussion and Conclusions 111 Tables 114 Figures 116 References 120 CHAPTER 4: A COMPARISON OF BLOOD PRESSURE 122 REDUCTIONS FOLLOWING 12-WEEKS OF ISOMETRIC TRAINING IN THE LABORATORY OR AT HOME Abstract 122 Introduction 123 Methods 125 ix Statistical analysis 129 Results 130 Discussion and Conclusions 132 Tables 139 Figures 140 References 144 CHAPTER 5: THE EFFECTS OF VASOACTIVE BLOOD 149 MARKERS, INFLAMMATION, AND MUSCLES MASS IN ISOMETRICEXERCISE TRAINING INDUCED REDUCIONS IN RESTING BLOOD PRESSURE Abstract 149 Introduction 150 Methods 153 Statistical analysis 157 Results 157 Discussion and Conclusions 159 Tables 167 Figures 170 References 173 CHAPTER 6: DISSERTATION SUMMARY AND 180 GENERAL DISCUSSION Executive Summary and Primary Findings 180 State of IET research 182 Establishing a home-based IET program 187 for reducing RBP x Maintenance of Reductions in BP and Potential 190 Mechanisms Responsible Limitations 196 Future Directions 197 Conclusions 199 REFERENCES 201 APPENDIX 1: Thomas Reynolds Graduate Life Fellowship 223 (Awarded) APPENDIX 2: STUDY 2. RECRUITMENT FLYER 227 APPENDIX 3: STUDY 3. RECRUITMENT SCREENING 228 QUESTIONNAIRE APPENDIX 4: STUDY 3. RECRUITMENT FLYER 230 APPENDIX 5: STUDY 3. RECRUITMENT EMAIL FOR 231 PROSPECTIVE PARTICIPANTS APPENDIX 6: STUDY 3. HOME-BASED IET PARTICIPANT 233 PACKET APPENDIX 7: STUDY 4. RECRUITMENT EMAIL FOR 238 PROSPECTIVE PARTICIPANTS APPENDIX 8: STUDY 4. RECRUITMENT SCREENING 239 QUESTIONNAIRE xi LIST OF TABLES Table 1. Precision and sensitivity upper/ lower limits and % CV 70 for angiogenesis panel-1 (VEGF). Table 2. Precision and sensitivity upper/ lower limits and % CV 70 for inflammatory cytokines (IL-6). Table 3: Precision and sensitivity upper/ lower limits and % CV 71 for inflammatory cytokines (TNF-α). Table 4: Computed power calculations for determination of 82 sample size Table 5. Participant Demographics 95 Table 6. Antihypertensive medications by class taken 96 by participants, Table 7. Participant demographics 114 Table 8. Antihypertensive medications by class taken 115 by participants and disease comorbidities Table 9. Participant Demographics 139 Table 10. Participant resting blood pressure by week 139 Table 11. Participant Demographics 167 Table 12. Participant resting blood pressure by week 167 Table 13. Group vascular endothelial growth factor 168 (VEGF) response over time Table 14. Group interleukin-6 (IL-6) response over time 168 Table 15. Group tumor necrosis factor alpha (TNF-α) 169 response over time xii LIST OF FIGURES Figure 1: Schematic of Blood Pressure Regulation 7 Figure 2. Schematic of the studies contained within 53 this dissertation Figure 3. Double leg IET (ILE) participant set-up 72 Figure 4. Double arm curl (IBC) participant set-up 73 Figure 5a. Video still of home-based IHG instruction 76 Figure 5b. Video still of home-based IHG instruction 76 with onscreen timer. Figure 6. Home-based IHG participant tracking packet 77 Figure 7. IHG protocol representation for completion of 78 lab-based or home-based IET. Figure 8. Representation of double arm and double leg IET 79 Figure 9. Systolic blood pressure week 0 vs. 12 Control 97 and IHG Figure 10. Diastolic blood pressure week 0 vs. 12 Control 97 and IHG Figure 11. SBP following 12-weeks of IHG Participants 98 Figure 12. SBP following 12-weeks in Control Participants 98 Figure 13. Individual SBP responses following 12 weeks of IHG 99 Figure 14. Individual SBP responses following 12 weeks in 99 Control Figure 15. The effects of IET on SBP week 0 (baseline) – 100 week 24 detraining Figure 16. The effects of IET on pulse pressure in control 100 and IHG Figure 17a. Group regression analysis of SBP in IHG 101 xiii week 0 to 24 Figure 17b. Group regression analysis of SBP in Control 101 week