Understanding Cardiovascular Risk: Insights from Obesity and Early Menopause

Abstract

Chapter 1: Introduction and Aims Global burden of CVD Cardiovascular disease (CVD) is a major public health issue that demands urgent attention. In the United States, CVD claims the life of one person approximately every 34 seconds, making it the leading cause of death and disability worldwide (1). This trend is expected to increase, driven in part by an ageing population and the growing obesity epidemic (2). The impact of CVD on healthcare systems and economies is substantial, with the cost of medical treatment and lost productivity reaching significant levels (3). The American Heart Association estimates that the total cost of CVD will double from $555 billion in 2015 to $1.1 trillion by 2035 in the United States alone (4). Despite effective therapies for CVD, residual risk remains high, underscoring the importance of continued efforts to better understand mechanisms linking metabolic risk factors and CVD to improve effective prevention and management strategies. The overarching objective of this thesis is to investigate two important aspects of cardiovascular risk: (1) obesity and adiposity as a major cardiovascular risk enhancer in light of rising rates of obesity, and (2) sex differences which lead to distinct disease presentations among men vs. women.

The role of obesity-associated pathways in cardiorespiratory fitness and HF Obesity affects over 40% of adults in the United States and directly contributes to development of cardiovascular disease across the spectrum of specific conditions including coronary artery disease and congestive heart failure (2). Obesity has various impacts on the cardiovascular system, including increased blood volume and cardiac output, reduced vascular resistance, and elevated blood pressure resulting from the activation of the renin-angiotensin-aldosterone and sympathetic nervous systems (5). Additionally, obesity leads to myocardial fat accumulation and fibrosis, which causes left ventricular diastolic dysfunction (6). Prior studies have demonstrated that obesity predisposes to future development of heart failure with preserved ejection fraction (HFpEF) more so than heart failure with reduced ejection fraction (HFrEF), the two major subtypes of heart failure (7). Although obesity and HFpEF have been tightly linked, the mechanisms by which obesity may affect exercise intolerance, the hallmark symptom of HFpEF, are not fully understood (8). Therefore, Chapter 2 of this Thesis explores such mechanisms by conducting a unique investigation of individuals who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring to diagnose HFpEF. By investigating obesity-related biomarkers representing inflammation, adipokine signaling, and insulin resistance, we aim to shed light on the association of potential obesity-related pathways that may lead to impairments in cardiorespiratory fitness that characterize HFpEF.

Sex differences in CVD: the role of early menopause Differences in cardiovascular risk factors and disease presentation in men and women are well-described but the mechanisms underlying these clinical sex differences remain incompletely understood. Traditional CVD risk factors such as diabetes, dyslipidemia, obesity, and autoimmune disease, portend a greater risk of subsequent CVD in women than in men (9). In addition to differential effects of traditional risk factors in men vs. women, female-specific factors may also play an important role. For example, there is a significant rise in CVD events in women after menopause (10). This association is even stronger in women with early menopause, defined as occurring before the age of 45 years (10). The risk of CVD progressively increases with earlier onset of menopause, independent of conventional CV risk factors (11–13). However, the mechanisms linking early menopause and increased cardiovascular risk beyond estrogen deficiency are not well understood. Separately, studies have shown that women have higher levels of CVD biomarkers related to inflammation and adiposity compared to men (14–16). In this context, we seek to understand the association of CVD biomarkers representing pathways of inflammation, adiposity, and others with early menopause in Chapter 3. Further, we examine whether early menopause may modify the effect of CVD biomarkers on incident CV outcomes.