PARITY AND CARDIOVASCULAR DISEASE BY SHIVANI R AGGARWAL, M.B.B.S. A THESIS SUBMITTED TO THE GRADUATE FACULTY OF WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE Clinical and Population Translational Science May 2015 Winston-Salem, North Carolina Approved By: David M Herrington, M.D., M.H.S., Advisor Lynne Wagenknecht, Dr.P.H., Chair Joseph Yeboah, M.B.Ch.B., M.S. Daniel P Beavers, Ph.D. Acknowledgements I would like to thank my mentors, Dr. Herrington, Dr. Solimon and Dr. Rodriguez as well as my thesis committee including Dr. Yeboah and Dr. Beavers who have worked tirelessly to help me develop an understanding of how to perform good research. I would like to thank my CPTS directors and teachers who have helped me form a basic understanding of research methodologies and my co-authors who have guided me through this process. Last, but not least, I would like to thank my family, my husband, parents and siblings without whom I would not be here today. II TABLE OF CONTENTS List of Illustrations and Tables…………………………………………………………………...IV List of Abbreviations……………………………………………………………………………..VI Chapter 1: Physiologic Changes in Pregnancy and the Effects of Parity………………………….1 Chapter 2: Parity is associated with Aortic Stiffness, Remodeling and All-cause Mortality: The Multi-ethnic Study of Atherosclerosis (MESA)…………………………………………….……22 Chapter 3: Further Study Using the Echo SOL database…………………………………………47 Curriculum Vitae…………………………………………………………………………………61 Appendix: Licenses for Reproduction of Figures……………………………………...…………68 III LIST OF ILLUSTRATIONS AND TABLES Chapter 1 1. Figure 1. Morphometric Alterations in Response to Various Stimuli – Physiologic and Pathologic Hypertrophy 2. Figure 2. Haemodynamic Changes During Pregnancy 3. Figure 3. Hormonal Changes During Pregnancy by Gestational Age 4. Figure 4. Biology of Effects of Relaxin During Gestation 5. Figure 5: Signalling Pathways for the Physiologic Hypertrophy During Pregnancy 6. Figure 6: Conceptual Model Chapter 2 1. Table I: Baseline Characteristics 2. Table II: Association of central pressure indices with number of live births 3. Table III: Association of aortic dimensions with number of live births 4. Table IV: Association of Parity with Clinical Outcomes 5. Figure 1: Univariate association of Parity as a categorial variable with Central Pressure Indices and Aortic Dimensions 6. Figure 2: Frequency of Clinical Events by Parity over median 10 year follow-up period 7. Figure 3: Kaplan-Meier Curves for Clinical Outcomes by 3-level Parity 8. Figure 4: Kaplan-Meier Curves for Clinical Outcomes comparing women with 1-4 live births to grand-multiparous women 9. Figure 5: Conceptual Model Chapter 3 1. Table I: Baseline Characteristics IV 2. Table II: Multi-level multivariable adjusted linear regression models examining association of parity with cardiac volumes and mass 3. Figure 1. Grading of Diastolic Dysfunction in Echo-SOL 4. Figure 2. Prevalence of any-grade diastolic dysfunction by parity V LIST OF ABBREVIATIONS BP: Blood Pressure BSA: Body Surface Area CAD: Coronary Artery Disease CHF: Congestive Heart Failure cIMT: Carotid Intimal-Medial Thickness CKD: Chronic Kidney Disease CMR: Cardiac Magnetic Resonance Imaging CO: Cardiac Output CVA: Cerebrovascular Accident DBP: Diastolic Blood Pressure DM: Diabetes Mellitus ECM: Extracellular Matrix EDV: End Diastolic Volume EF: Ejection Fraction Hb: Hemoglobin HDL: High Density Lipoprotein HFpEF: Heart Failure with preserved Ejection Fraction VI HFrEF: Heart Failure with Reduced Ejection Fraction HR: Heart Rate HTN: Hypertension LA: Left Atrium LMP: Last Menstrual Period LS: Least squares LV: Left Ventricle LVMI: Left Ventricular Mass Index LVOT: Left Ventricular Outflow Tract MAP: Mean Arterial Pressure MESA: Multi-ethnic Study of Atherosclerosis MI: Myocardial Infarction MMP: Matrix Metalloproteinase MRI: Magnetic Resonance Imaging NHEFS: National Health and Nutrition Examination Survey National Epidemiologic Follow-up Study PAD: Peripheral Arterial Disease PV: Plasma volume VII SBP: Systolic Blood Pressure SV: Stroke Volume TGF: Transforming Growth Factor TIA: Transient Ischemic Attack TIMP: Tissue Inhibitor of Metalloproteinase TNF: Tumor Necrosis Factor TPVR: Total peripheral vascular resistance VEGF: Vascular Endothelial Growth Factor VIII Chapter 1: Physiologic Changes in Pregnancy and the Effects of Parity INTRODUCTION In order to support a fetus, the maternal cardiovascular system has to undergo immense adaptations which are generally believed to undergo complete involution (shrinkage/return of an organ to its normal size) after delivery. However, small lines of evidence (detailed later in this chapter) point to a potential pathologic process and differences in outcomes in women with multiple pregnancies which may contradict this common belief that these adaptations normalize post-partum. Studying this may help us understand a more novel risk factor for cardiovascular disease –the process of child-bearing and child-birth or more specifically, parity (technically defined as the number of fetuses a women carries till viability) which is taken as the number of live births. To understand this hypothesis we must first understand the changes which occur in the cardiovascular system during pregnancy and the underlying mechanisms for these changes. The physiologic adaptations of the cardiovascular system to pregnancy in many ways mimic the pathology of heart failure, while, there are subtle differences which render these changes both healthy and reversible. Here we will review these changes and the current knowledge of the underlying molecular mechanisms. Overall, in normal pregnancy left ventricular (LV) mass, cardiac output and arterial compliance increase and systemic vascular resistance decreases while the effects on diastolic and systolic function are less clear. One caveat is, in a majority of the studies that have determined the physiologic changes in pregnancy, investigators have considered the post-partum structure and function as the baseline for comparison (with the assumption that after involution the cardiac structure and function return to the pre-pregnant state). This, however, does not take into account that there may be incomplete involution of the changes and hence they may be under-estimating the actual change that occurs from a pre-pregnant state. Very few studies have actually enrolled patients prior to pregnancy to obtain baseline data. Furthermore as 1 many studies enrolled patients late in the 1st trimester much of the early adaptation may also have already occurred prior to enrollment. These are a few of the factors which have led to very variable results between studies, making an accurate analysis of the physiology difficult. PHYSIOLOGIC CHANGES IN PREGNANCY 1. Remodelling of the Heart 1.1 LV Mass and Wall thickness: During pregnancy the myocardium undergoes a reversible “physiologic” hypertrophy with increase in the LV mass by as much as 30-50%.1-4 Though there is increase in body mass and body surface area (BSA), the adjusted left ventricular mass index (LVMI) for BSA still increases by variable degrees in different studies from 5-25% revealing true cardiac hypertrophy in excess of increase in body size.5, 6 Hypertrophy can be seen as early as 12 weeks while the majority occurs in the third trimester.3 In the physiologic hypertrophy of pregnancy there is both thickening of myocardium and mild increase in chamber size. Most studies concur that there is none to mild increase in length of the myocyte compared to width (mild eccentric hypertrophy)7 while in pathologic hypertrophy, the length and breadth increase much more disproportionately: in volume overload models the length increases significantly more than the breadth (eccentric hypertrophy) and vice versa (concentric hypertrophy) in pressure overload models. Studies in pregnant rats have shown that in pregnancy the length to width ratio of myocytes is better preserved.8 In summary, in physiologic hypertrophy of pregnancy the ratio of LV chamber size to wall thickness (and myocyte length to width ratio) is maintained or mildly increased while in volume overload there is a more drastic increase in this ratio and in pressure overload a decrease in this ratio as shown in figure 1.9 1.2 LV Dimensions: The LV end diastolic dimension appears to increase progressively (by about 10%) till the later part of the second or early part of the third trimester in most studies.10-12 However some of these changes were seen only if the patient was examined in the left lateral 2