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Open Garvin- Dissertation - Final.Pdf The Pennsylvania State University The Graduate School The Intercollege Graduate Degree Program in Integrative Biomedical Physiology ASSOCIATION OF VARIABILITY IN CARDIOVASCULAR RESPONSIVENESS TO REFLEX ACTIVATION OF THE AUTONOMIC NERVOUS SYSTEM WITH GENETICS OF PERIPHERAL SENSORY RECEPTORS A Dissertation in Integrative and Biomedical Physiology by Nathan M. Garvin © 2017 Nathan M. Garvin Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2017 ii The dissertation of Nathan M. Garvin was reviewed and approved* by the following: James Anthony Pawelczyk Associate Professor of Integrative and Biomedical Physiology, and Kinesiology Dissertation Advisor Chair of Committee David Nathan Proctor Professor of Integrative and Biomedical Physiology, and Kinesiology Gail Doreen Thomas Professor of Integrative and Biomedical Physiology, and Medicine John E Hayes Associate Professor of Food Science Donna Hope Korzick Professor of Integrative and Biomedical Physiology, and Kinesiology Chair of the Intercollege Graduate Program in Integrative and Biomedical Physiology *Signatures are on file in the Graduate School. iii Abstract Cardiovascular disease accounts for approximately 1 in 3 deaths in the United States and high blood pressure (BP) is one of the risk factors implicated. Given its importance, extensive research has been done on the regulation of BP and BP responsiveness to stress. “Stress reactivity” has long been used as a metric to assess and predict morbidity and mortality of cardiovascular diseases. For example, exaggerated exercise and noxious cold water-induced BP changes may represent a risk factor for death from cardiovascular causes, act as a predictor for hypertension, and be related to heart disease and cardiovascular events. The source(s) of the variation in cardiovascular reactivity are probably multifaceted and poorly understood. This dissertation explores the thesis that genetic variation accounts for, at least in part, population differences in autonomic responses to stress. The general experimental design was two-fold: 1) the normal range of BP responses to post-exercise circulatory arrest (PECA) following static handgrip (SHG), a common laboratory exercise technique, was rigorously defined; and 2) these norms were used to selectively recruit groups with high and low responses to investigate the mechanisms accounting for the disparate BP responses between groups and to relate these differences to functional single-nucleotide polymorphisms (SNPs) in genes encoding sensory receptors. The first study (Chapter 3) aimed to define the normal range of BP responses to 2-min PECA following 3-min SHG at 30% of maximum voluntary contraction. Testing involved instrumentation for continuous measurement of BP (finger photoplethysmography) and heart rate (ECG) during PECA. Regression modeling of the BP change from control vs. the grip force was used to identify individuals with BP residuals at the highest and lowest response quartile. Average mean arterial pressure change from control was 29±12 mmHg during PECA after 3 min of SHG. iv Grip force during SHG accounted for ~37% of the variability in BP response. High and low response groups were defined as having a BP residual of +6 and –6 mmHg, respectively. The second study (Chapters 4-9) was designed to compare these explicitly defined cohorts with stressors that evoke autonomic responses and to test for associations of responsiveness to SNPs in the genes coding for several sensory afferent receptors. Thus, the aim of the study was to associate a BP phenotype with sensory afferent genotype. Volunteers recruited from each group performed up to 6 protocols in a single ~4 hour visit to the lab. Subjects were instrumented for the continuous measurement of BP (finger photoplethysmography), heart rate (ECG), blood flow (duplex Doppler ultrasound), and muscle sympathetic nerve activity (peroneal microneurography) and performed exercise (SHG and rhythmic handgrip (RHG); both followed by PECA), caloric stimulations of the hand (cold, hot, and thermoneutral water immersion), and hypercapnic, hyperoxic rebreathing. In general, there was an inter-stressor response specificity to stressors primarily sensed in the periphery (hand and forearm); that is, subjects with a high BP response during the initial PECA protocol, on average, had a high response to SHG, RHG, PECA, cold immersion, and hot immersion. Hypercapnic rebreathing, which is primarily transduced by central chemoreceptors, did not show any dichotomy between high and low response groups, suggesting that metabo/chemo-sensation during PECA after SHG is not related to chemosensation during hypercapnia. A chi-square test of independence was performed on the response group (high vs. low) and trait allele frequency (trait allele carriers vs. non-trait allele carriers). In addition, gene scores for multiple SNPs of interest were created by coding the trait allele in all individuals. Genetic results indicated that the frequency of trait allele carriers for the TRPV1 gene SNP rs8065080 may be present in different frequencies in the low and high response groups (P=0.055). The non- v carriers:carriers ratio of the trait allele was 13:12 and 9:24 for the low and high response groups, respectively. However, BP residuals, and BP and heart rate response during SHG and RHG with PECA, cold and hot immersion, and rebreathing could not be directly associated with any combination of SNPs via gene score analysis. The results of this dissertation can be summarized in three key findings: 1) the BP response to PECA following SHG is variable, normally distributed, and can be used to define groups with distinctly different BP responses; 2) subject BP responsiveness classification is maintained over several, but not all, types of stresses against homeostasis (SHG, RHG, PECA, and cold and hot water immersion, but not hypercapnia); and 3) the trait allele for the missense (isoleucine→valine) TRPV1 gene SNP rs8065080, that codes for an ion channel previously known to be expressed in afferent nerves, may appear with disproportionate frequency among high and low response groups and thus may partially explain the BP response variability between them. An exaggerated BP response to stress is of interest for cardiovascular health and disease. The genetics of peripheral sensory receptors may be one component of the variation of the normal human BP responsiveness to stress. vi TABLE OF CONTENTS LIST OF FIGURES ........................................................................................................................ x LIST OF TABLES ....................................................................................................................... xix LIST OF ABBREVIATIONS .................................................................................................... xxiii ACKNOWLEDGEMENTS ....................................................................................................... xxvi Dissertation Committee ................................................................................................. xxvi Special Thanks ............................................................................................................... xxvi Funding .......................................................................................................................... xxvi CHAPTER 1: INTRODUCTION ................................................................................................... 1 Background and Significance ............................................................................................. 1 Specific Aims ...................................................................................................................... 3 Delimitations and Assumptions .......................................................................................... 5 CHAPTER 2: REVIEW OF LITERATURE .................................................................................. 7 Cardiovascular and Autonomic Responsiveness ................................................................ 7 Static Exercise with a Focus on Handgrip .......................................................................... 9 Rhythmic Handgrip Exercise ............................................................................................ 13 The Exercise Pressor Reflex ............................................................................................. 16 Cold Pressor Test .............................................................................................................. 26 Hot Immersion Test .......................................................................................................... 29 Hyperoxic/Hypercapnic Rebreathing................................................................................ 31 Cell Membrane Ion Channels ........................................................................................... 34 Acid Sensing Ion Channels ................................................................................... 34 Purinergic Receptors ............................................................................................. 38 The Transient Receptor Potential Receptors ......................................................... 42 Selected Genes ...................................................................................................... 47 ASIC1- Acid Sensing Ion Channel Subunit 1....................................................... 49 ASIC2-
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