The effects of exercise training on venous function in humans with hypertension
TABLE OF CONTENTS PAGES
Title Page iii
Copyright Page iv
Table of Contents vi
List of Illustrative Material vii-ix
Glossary of Key Terms & Abbreviations xii-xvi CHAPTER I Introduction 17-26 CHAPTER II Literature Review 27-98 CHAPTER III Effects of Sympathoexcitation on Calf Venous Compliance in Humans with High Blood Pressure 99-125 CHAPTER IV Effects of Aerobic Exercise Training on Venous Compliance Responses to Baroreflex Activation in Humans with High Blood Pressure 126-159 CHAPTER V Awareness of Heart Disease and Preventative Actions in Female Undergraduate Students 160-195 CHAPTER VI Conclusions, Strengths/Limitations, and Future Perspectives 196-201 CHAPTER VII Acknowledgments & Bibliography 202-220 CHAPTER VIII Appendix 221-242 CHAPTER X Curriculum Vitae 243-254
vii LIST OF ILLUSTRATIVE MATERIAL NOTE: Illustrative material is embedded within its respective chapter PAGE FIGURES CHAPTER II
1. Pressure – volume curve 38 2. Venoconstriction and venous volume 39 3. Unstressed volume and venous volume 40 4. Tracings of venous compliance measurements 92 CHAPTER III
5. Pressure-volume and pressure-compliance curves for baseline and lower body negative pressure 117 6. Slopes of pressure-compliance curves 118 7. Pressure-volume and pressure-compliance curves for baseline and post- handgrip exercise ischemia 119 CHAPTER IV
8. Calf and forearm pressure-volume curves pre- and post-training 150 9. Calf and forearm pressure-compliance curves pre- and post-training 151 10. Calf pressure-volume curves at baseline, lower body negative pressure, and lower body positive pressure pre-and post-training 152 11. Calf pressure-compliance curves at baseline, lower body negative pressure, and lower body positive pressure pre-and post-training 153
viii CHAPTER V
12. Responses for the questions “What is the leading cause of death for all women?” and “What is the greatest health problem facing women today?” 185 13. Preventative actions taken to improve health in the previous year 186 14. Rates of knowledge about services provided by the Health Center 187 15. Responses to the question “How often do you use each of the following recreational programs offered by the Department of Recreation Services?” 188
TABLES CHAPTER II
1. Hemodynamic profiles of each stage of hypertension 62 CHAPTER III
2. Anthropometric and hemodynamic characteristics 114 3. Pressure-volume regression parameters for baseline, lower body negative pressure and post-handgrip exercise ischemia 115 4. Changes in hemodynamics in response to lower body negative pressure and post-handgrip exercise ischemia 116 CHAPTER IV
5. Subject characteristics pre- and post-training 145 6. Maximal aerobic capacity, blood pressure, baroreflex sensitivity and pulse wave velocity pre- and post-training 146 7. Baseline calf and forearm pressure-volume regression parameters pre- and post-training in subjects with normal and high blood pressure 147
ix 8. Changes in hemodynamics in response to lower body negative pressure and positive pressure pre- and post-training 148 9. Calf pressure-volume regressions parameters for baseline, lower body negative pressure and positive pressure pre- and post-training 149 CHAPTER V
10. Demographic characteristics 175 11. Levels of awareness of heart disease in health-related majors vs. non-health related majors 176 12. Levels of awareness in students who had (informed) and had not (non- informed) heard, seen, or read any information about heart disease in the past 12 months 177 13. Percentage of female students correctly identified healthy CVD risk factor levels by area of study 178 14. Defined and perceived body composition status 179 15. Smoking and exercise experience 180 16. Define and perceived risk of heart disease 181 17. Relationship between awareness levels and preventative actions 182 18. Relationship between perceived risk of heart disease and preventative actions 183 19. Distribution of responses to how often the fitness facilities are used for aerobic and resistance exercise 184
x PREFACE This section provides clarifications about the objectives of this dissertation and its organization. In addition, acknowledgements to individuals who have significantly contributed to the completion of this work are included. This dissertation has two components. The primary component is focused on cardiovascular exercise physiology (Chapters II, III, IV), whereas the secondary component is devoted to public health education (Chapter V). The introduction (Chapter I) and conclusions (Chapter VI) include information regarding both parts of this dissertation. This organization reflects a bi-directional approach to my interest in cardiovascular health and disease and the effects of preventative actions (i.e. exercise training) on cardiovascular physiology. For clarity, a glossary of terms to define scientific concepts and words and a table with abbreviations and their definitions that often appear in the text are also included. This work would not have been possible without a number of individuals and organizations that granted me with unlimited support and encouragement. Specific acknowledgments must include my dissertation committee members, Dr. Kanaley, Dr. Carhart, Dr. DeRuisseau, and Dr. Tillotson for their guidance. In particular, I wish to thank my advisor, Dr. Kanaley, for encouraging me to experiment and helping me realize my research ideas. More so I would like to thank her for never curbing my passion and enthusiasm for experimentation in cardiovascular physiology. Working with Dr. Kanaley taught me how to be a professional, an educator and a scientist, and led me see the “big” picture in all topics we studied together. In addition to these individuals, I would like to give my warmest thanks to the other faculty members who have supported me and all
xi undergraduate and graduate students who assisted in this project. I am also grateful to all my friends and colleagues for their continuous support during my graduate years at Syracuse University. Additionally, I would like to thank all individuals who participated in this study; this project would not be possible without their effort and devotion. Several organizations should be acknowledged. I am thankful to the American Heart Association for funding me with a pre-doctoral fellowship. Other organizations include: Sigma Delta Epsilon—Graduate Women in Science, the Mid-Atlantic Regional Chapter of the American College of Sports Medicine, and the School of Education at Syracuse University. I would have not been able to complete this dissertation without my best friends and my family. I wish to thank my parents, my sister and my brother for supporting me in everything I do and for understanding that there was a good reason why I could not spend any holidays with them in the past 5 years. Lastly, I wish to thank my husband, Ted, for his complete support and encouragement. Thank you for listening to all my complaints and smiling every time I said that I would give up. And thank you for understanding how much I love what I am doing even when this takes too much time from us.
xii GLOSSARY OF KEY TERMS
Adrenergic receptors: receptors that are targets for norepinephrine and epinephrine Angiotensin: a protein that causes constriction of the blood vessels and increases in blood pressure Arteries: blood vessels that carry blood away from the heart Autonomic nervous system: part of the peripheral nervous system that acts as a control system at rest and during stress Baroreceptors: specialized stretch-sensitive neurons Baroreflex (or baroreceptor reflex): a negative feedback loop in which an increase in blood pressure reflexively causes a decrease in blood pressure and an increase in blood pressure reflexively causes a decrease in blood pressure. It involves the baroreceptors and the autonomic nervous system. The baroreceptors are activated by changes in blood pressure and this information is relayed to the brainstem so the autonomic nervous system can make appropriate adjustments to maintain blood pressure homeostasis. Bradycardia: reduced heart rate or heart rate that is below the normal range Cardiac output: the volume of blood being ejected by the heart per minute Cardiac preload: the initial stretching of cardiac myocytes prior to contraction Endothelial function: the ability of the inner layer of blood vessels to dilate when demand for blood flow increases Ganglionic blockade: a type of medication that inhibits post-ganglionic transmission blocking the actions of the autonomic nervous system
xiii Hysteresis: discordance between limb volumes measured during a rise in venous pressure vs. a fall in venous pressure. The relationship between pressure and volume is shifted to higher volumes after a period of venous distension Ischemia: restriction of blood supply Muscle metaboreflex: peripheral feedback loop initiated in the skeletal muscle via nerve endings that are sensitive to changes in the acidity of the muscle environment. For example, an acute bout of exercise increases the production of metabolic byproducts such and lactic acid and hydrogen ions which stimulate metabolically sensitive receptors. Activation of the muscle metaboreflex increases blood pressure. Nitroglycerin: medication to induce vasodilatation Norepinephrine: a catecholamine that acts as a hormone and as a neurotransmitter. Norepinephrine increases heart rate, vascular resistance and blood pressure. Phelynephrine: selective agonist of α-adrenergic receptors – causes vasoconstriction Phentolamine: antagonist of α-adrenergic receptors – causes vasodilatation Ploidy: the number of complete sets of chromosomes in a biological cell Sodium nitroprusside: medication that induces vasodilatation and reductions in blood pressure Stressed volume: the quantity of blood that can be moved from a vein before its transmural pressure falls to zero Stroke volume: the volume of blood being ejected by the heart per heart beat Sympathetic nervous system: a branch of the autonomic nervous system that it is active at a basal state (sympathetic tone). The actions of the sympathetic nervous system during stress involve the fight-or-flight response. Activation of the sympathetic nervous system
xiv increases heart rate, total vascular resistance, blood pressure and causes vascular constriction. Tachycardia: increased heart rate or heart rate that exceeds the normal range Transmural pressure: the pressure difference between the pressure inside and outside a blood vessel Total peripheral resistance: the sum of the resistance of all peripheral veins in the systemic circulation Unstressed volume: the quantity of blood remaining in the veins at zero transmural pressure Vascular Function: the integrated response of the multiple components of blood vessels to respond to the demand for blood flow. Veins: blood vessels that carry blood toward the heart Venoconstriction: a decrease in the cross-sectional area of the venous lumen when smooth muscle contracts Venous capacity: the total blood volume contained in the venous circulation at a specific pressure Venous compliance: the ratio of a change in volume to the concomitant change in transmural distending pressure. It is a quantitative measure of the elasticity of a vascular bed. Venous return: the flow of blood back to the heart Venous tone: the degree of constriction of a vein at a basal state
xv ABBREVIATIONS AHA: American Heart Association ACE: angiotensin converting enzyme AVP: arginine vasopressin BMI: body mass index BP: blood pressure C1: first cervical vertebrae CO: cardiac output CO 2 : carbox dioxide CV: coefficient of variation CVLM: caudal ventrolateral medulla CVD: cardiovascular disease DBP: diastolic blood pressure HBP: group with high blood pressure HGI: post-handgrip exercise ischemia HR: heart rate ICC: intraclass correlation coefficient L2: second lumbar vertebrae LBNP: lower body negative pressure LBPP: lower body positive pressure MAP: mean arterial pressure MCFP: mean circulatiry filling pressure MSNA: muscle sympathetic nervous activity
xvi NT: group with normal blood pressure NTS: nucleus tractus solitarius O 2 : oxygen PP: pulse pressure PWV: pulse wave velocity RVLM: rostral ventrolateral medulla SBP: systolic blood pressure SV: stroke volume T1-T5: first – fifth thoracic vertebra TPR: total peripheral resistance VO 2 peak: maximal oxygen consumption
17 CHAPTER I: INTRODUCTION
A. High Blood Pressure and Venous Compliance
Hypertension includes persons (a) with a systolic blood pressure (SBP) > 140 mm Hg or diastolic blood pressure (DBP) > 90 mm Hg; or (b) who are on anti-hypertensive medication, or (c) who have been told at least twice by their physician or other health care professional that they have hypertension (145). Using this definition national surveys have reported that an estimated 70 million Americans have hypertension (182). The most recent report of the National High Blood Pressure Education Program Coordinating Committee (a group of 41 organizations) introduced the term prehypertension to define the gray zone between normotension and hypertension and to highlight the blood pressure (BP) related risks among individuals with BP < 140/90 mm Hg (34). Current estimations from national data show that currently 72 million American adults have prehypertension (182). The probability of developing hypertension during one’s lifetime is greater than 90% for men and women who are not hypertensive at age 55-65 yr and survive up to 80-89 yr of age (266). Taken together, these alarming statistics indicate that more than half of the American adult population currently has hypertension (29%) or prehypertension (37%) and the majority of the Americans who live long enough will become hypertensive before death. Hypertension is an independent predisposing factor for development of coronary heart disease, strokes, peripheral artery disease, and heart failure (194). Data from clinical studies indicate that one third of stroke deaths occur before the establishment of
18 hypertension, suggesting that individuals with prehypertension (defined as SBP: 120-139 mm Hg or DBP: 80-89 mm Hg) also have high risk of cardiovascular disease and mortality (267). The high prevalence of prehypertension and hypertension and their association with cardiovascular disease signify the crucial role of research strategies that investigate contributing factors to the initiation of the disease and interventions that effectively control BP levels. The pathophysiology of hypertension has attracted attention by researchers from a wide variety of biomedical fields, who have tried to identify contributing factors to the distortion of BP regulation that occurs with hypertension. Among the various hypotheses developed throughout the years to elucidate the pathophysiology of hypertension is the “neurogenic nature of high BP” hypothesis suggestive of neural dysfunction as the primary factor leading to hypertension (86). Specifically, this hypothesis suggests that a dysfunction in sympathetic modulation of the cardiovascular system is responsible for the hypertensive process (86). A large number of animal and clinical studies have provided experimental support for the neurogenic hypothesis, demonstrating that hypertension is a hyperadrenergic state (84, 85, 121). Studies in adolescents with hypertension showed that juvenile hypertension is characterized by resting tachycardia, which is triggered by adrenergic overdrive (121). Elevated levels of norepinephrine (84) and direct recordings of sympathetic nerve traffic (85) have consistently shown elevated sympathetic outflow to different cardiovascular regions in individuals with hypertension. In an intact organism, the cardiovascular system is a closed fluid-containing system and therefore, its pressure is determined by the volume of the total contained fluid and by the dimensions of the system (i.e. fluid holding capacity). Given that
19 approximately 70% of the total blood volume is contained in the venous system (187), changes in the blood holding capacity of the veins should have a large impact on BP. Yet, under healthy conditions veins have large compliance (i.e. elasticity) that helps buffer changes in volume without large changes in BP (67). Reductions in venous compliance contribute to blood volume shifts to the central compartment of the circulation (i.e. heart) (63) or to small arteries (275), leading to increases in BP and contributing to the pathogenesis of hypertension. In fact, several lines of research show that animals and patients with hypertension have reduced venous compliance and reduced blood holding capacity (68, 183, 216, 252) and these reductions have been attributed to structural (i.e. alterations in the composition of the venous wall) (150) and functional changes (i.e. alterations in neural regulation of venous tone) (152). The neurogenic hypothesis of developing high BP is relevant to the proposed functional changes of the venous regulation (67). Specifically, alterations in sympathetic regulation of venous tone may lead to augmentation of venous tone (67). It has been hypothesized that chronic increases in sympathetic activity, such as those seen in hypertensive patients, lead to reduced venous compliance and augmented venous tone (152). Consequently, venous return and preload increase resulting in an increase in cardiac output (CO) (263). Concurrently, elevated sympathetic outflow has an impact on heart rate (HR) and vascular resistance (TPR) and collectively, these events lead to an increase in BP (4). The mechanisms responsible for the sympathetic overactivity seen in hypertension remain unclear. It has been suggested that derangement in the sympathetic modulation exerted by reflex mechanisms (i.e. baroreflex, metaboreflex) tonically alter
20 sympathetic outflow (86, 148, 201). Indeed, patients with hypertension present with reduced baroreflex sensitivity (137, 156) and augmented metaboreflex-mediated hemodynamic responses (220). It is unknown whether these alterations affect sympathetic regulation of venous tone in hypertension. Previous studies showed that application of ganglionic blockade reduced venous tone in hypertensive animals (152), suggesting that the augmented venous tone seen with hypertension is primarily due to sympathetic predominance. Delaney et al. (54) showed that venous compliance and capacitance did not respond to non-baroreflex mediated sympathoexcitation in hypertensive and normotensive humans; however, these investigators did not assess the effect of baroreflex-mediated mechanisms on venous tone. Previous studies demonstrated that venous compliance and capacitance responds to baroreflex-mediated but not to non-baroreflex mediated sympathoexcitation in normotensive subjects (166), indicating that the sympathetic modulation of the venous system is baroreflex specific. The most recent report of the National High Blood Pressure Education Program Coordinating Committee heavily stressed the importance of lifestyle modifications in the prevention and management of hypertension (34). Underscoring the complexity of the treatment of hypertension, pharmacological interventions suggest that reductions in BP per se are not sufficient to reduce risk for target organ damage unless vascular repair also occurs (61). Regular aerobic exercise training is often prescribed as an anti-hypertensive therapy at the early stages of hypertension due to its depressor effect and lack of side effects. Exercise training not only reduces BP (128) but also improves properties of the arterial side of the circulation, improving endothelial function (111) and decreasing arterial stiffness (40). While several lines of research implicate the venous system in the
21 pathogenesis of hypertension, the effects of aerobic exercise training on venous function have been significantly understudied. Research in older adults, who showed reduced venous compliance as a result of normal aging, found an increase in venous compliance by 20-30% following an endurance exercise training program (108). These findings demonstrate the restorative effects of exercise on venous compliance. Yet, it is unknown whether venous compliance of hypertensive subjects will have the same responses. Given this background, the overall aim of this study was to examine the responsiveness of venous compliance to aerobic exercise training and to sympathetic stimulation and autonomic peripheral reflexes in humans with high BP. Research suggests that the contribution of the venous system to hypertension may be important at the early stages of hypertension and not at the established stages of the disease (67). Therefore, only subjects with prehypertension and stage-1 were studied in this dissertation. The specific aims of the present study are as follows: 1. To compare the responses of limb venous compliance to activation of peripheral autonomic reflexes (i.e., metaboreflex, baroreflex) between individuals with high (i.e., prehypertension and stage-1 hypertension) and normal blood pressure. Hypothesis: Individuals with high BP will have reduced venous compliance and capacitance responses to baroreflex-mediated sympathoexcitation and augmented venous compliance and capacitance responses to metaboreflex activation compared to normotensive individuals. To test this hypothesis, venous compliance was measured in response to lower body negative pressure (LBNP, baroreflex-mediated
22 sympathoexcitatory task) and post-handgrip exercise ischemia (HGI, metaboreflex- mediated sympathoexcitatory task). 2. To determine if aerobic exercise training increases baseline limb venous compliance and whether venous compliance responses to aerobic exercise training are specific to the trained muscles or if they are a systemic adaptation in individuals with high BP. Hypothesis: Aerobic exercise training will increase limb venous compliance in individuals with high BP and this increase will be a local phenomenon. To test this hypothesis, cycle ergometer exercise was employed as the mode of exercise training and comparisons were made between baseline calf and forearm venous compliance. 3. To determine if aerobic exercise training affects baroreflex modulation of venous compliance in individuals with high BP. Hypothesis: Aerobic exercise training will increase venous compliance responses to baroreceptor stimulation. To test this hypothesis, baroreflex modulation of venous compliance was altered utilizing application of lower body negative pressure (LBNP, baroreceptor unloading) and lower body positive pressure (LBPP, baroreceptor loading).
Significance The present project is one of the first investigations to examine the plasticity of the venous system in humans with high BP. This study will provide insight about physiological mechanisms that regulate the elasticity of the venous system and will attempt to elucidate how these mechanisms are affected by high BP. In addition, the data from this investigation will further our understanding about the effects of aerobic exercise training – a lifestyle modification with well known depressor effects - on venous
23 function. A novel aspect of this study is that the plasticity of the venous system is studied in non-medicated individuals at the early stages of hypertension and without any cardiovascular complications. Identifying physiological alterations early on in the process of hypertension may help us understand the pathogenesis of the disease and target factors that may contribute to this process. This study may also provide an impetus for investigating the relationship of the duration and severity of hypertension, or the age of hypertensive individuals, with the degree of venous dysfunction, and the ability of the hypertensive veins to improve their compliance and responsiveness to physical stressors and anti-hypertensive therapies. This novel project will yield information that could be used in further attempts to develop pharmacological and non-pharmacological interventions to target hypertension and its physiological consequences in the early stages.
B. Cardiovascular Disease Awareness in Female Undergraduate Students
The term cardiovascular disease refers to all diseases of the circulatory system including hypertension, coronary heart disease, heart failure, stroke, and congenital cardiovascular defects. In this dissertation the term cardiovascular disease was used interchangeably with the term heart disease. Heart disease and stroke are the first and third primary causes of death among women in the United States (11). In 2005, 1 in 5 females died from cancer, while 1 in 3 females died from cardiovascular disease (CVD) (2). Despite the alarming statistics, CVD is preventable and CVD risk factors can be managed via lifestyle modifications (i.e.
24 weight loss, physical activity). Therefore, public educational interventions that target personal behaviors and promote lifestyle changes are of paramount importance. Despite the high prevalence of CVD among women, studies show that women have misconceptions about their risk for heart disease and they are not aware of healthy levels of CVD risk factors. Specifically, women believe CVD is a greater threat for men than for themselves (168) and do not know the normal range of healthy levels for BP and cholesterol (170). Educational strategies to increase heart disease awareness have been successful over the years increasing the overall awareness level of heart disease in women from 30% in 1997 to 55% in 2006 (170). A closer look at these statistics, however, reveals that educational interventions to increase heart disease awareness have not reached various age groups equally. The majority of these interventions targeted middle-aged and older women, because they are at higher risk of developing heart disease, yet the disease progression begins in our youth. To the best of our knowledge, research regarding young (< 25 yr) individuals and more specifically, young women’s awareness about CVD is sparse. Previous studies showed low levels of knowledge about heart disease among college males and females. Although studies in older adults (> 25 yr) have shown an association between preventative actions and heart disease awareness, studies in younger adults (< 25 yr) reported conflicting results. Vale et al. (265) demonstrated that although adolescent males and females knew about behavioral practices to prevent heart disease, they did not know how to implement them. Some investigators reported that college students show high awareness of CVD risk factors but low rates of involvement in preventative actions (75), whereas others suggested low awareness of heart disease
25 among college students and low rates of involvement in preventative actions. It is possible that students feel that the possibility of developing heart disease lies too far in the distant future to raise concerns (41). College students also believe that women have lower risk of developing heart disease compared to men and that breast cancer is a greater health concern for women (41). Collectively, these findings show low levels of awareness of heart disease among young individuals and misconceptions about the risk of heart disease among young women. Although heart disease is manifested at older ages, the pathogenesis starts at a young age. Therefore, educational strategies should target young age groups to increase heart disease awareness and promote lifestyle modifications. Tracking young women’s knowledge about heart disease and determining factors that influence their decisions to implement preventative actions can help develop successful educational interventions. Therefore, the overall aim of this study was to examine the level of knowledge about heart disease and preventative actions among female undergraduate students. The specific aims of this study were: 1. To determine the current level of awareness of CVD as the leading cause of death in female undergraduate students. Hypothesis: Female undergraduate students will have low levels of awareness of heart disease. 2. To evaluate the relationship between awareness status and preventative actions in female undergraduate students. Hypothesis: High levels of awareness will be associated with increased actions for improving health.
26 3. To evaluate the relationship between perceived risk of heart disease and actions to improve health. Hypothesis: Females who considered themselves to be in risk of developing heart disease will be more likely to engage in preventive actions. An exploratory aim of this study was to determine the current status of knowledge about heath-related services provided by the university to students, and the frequency of use of such services among female undergraduate students.
Significance The majority of the current research focuses on heart disease awareness in older women because CVD is manifested primarily in older age groups. However, certain lifestyle choices and actions (i.e., physical inactivity and unhealthy dietary habits) adopted early on in one’s life can predispose her/him for high risk of developing heart disease at an older age. Therefore, heart disease education should start at a young age and preventative strategies should also target young females and not only focus on older women. This study will give insight into the knowledge of cardiovascular risk factors and heart disease awareness in young females. The data from this study may help identify misconceptions about CVD and give insight into the preventative actions that young women take. This information can help us design educational interventions that reduce misconceptions about CVD, increase awareness about risk factors, and provide information and opportunities for risk management and prevention at a young age.