Cardiovascular Implications of Immune Disorders in Women

Abstract

Immune responses differ between men and women, with women at higher risk of developing chronic autoimmune diseases and having more robust immune responses to many viruses, including HIV and hepatitis C virus. Although immune dysregulation plays a prominent role in chronic systemic inflammation, a key driver in the development of atherosclerotic cardiovascular disease (ASCVD), standard ASCVD risk prediction scores underestimate risk in populations with immune disorders, particularly women. This review focuses on the ASCVD implications of immune dysregulation due to disorders with varying global prevalence by sex: autoimmune disorders (female predominant), HIV (male-female equivalent), and hepatitis C virus (male predominant). Factors contributing to ASCVD in women with immune disorders, including traditional risk factors, dysregulated innate and adaptive immunity, sex hormones, and treatment modalities, are discussed. Finally, the need to develop new ASCVD risk stratification tools that incorporate variables specific to populations with chronic immune disorders, particularly in women, is emphasized.

Heart Failure in Chronic Infectious and Inflammatory Conditions: Mechanistic Insights from Clinical Heterogeneity

“…Several studies have described associations between chronic hepatitis C virus (HCV) infection and HF [127,128], yet limited pathophysiologic knowledge exists regarding this association. Perhaps the most likely mechanism by which HCV contributes to CVD and HF relates to chronic inflammation and immune dysregulation, similar to chronic HIV infection [129]. Patients with HCV have been observed to have higher levels of pro-inflammatory cytokines, including TNF-α and IL-6 [130][131][132][133].…”

“…HCV infection is also associated with intestinal bacterial overgrowth, which can lead to bacterial translocation into the bloodstream, increasing LPS levels, triggering toll-like receptor (TLR) activation, and resulting in systemic inflammation [134,135]. Importantly, effective treatment of HCV appears to decrease CVD risks [129,[136][137][138].…”

“…Although corticosteroids reduce systemic inflammation, they can induce dyslipidemia, insulin resistance, and obesity, known CVD risk factors, and increase risk of CVDs including HF [139]. Immunosuppressants, such as mycophenolate mofetil, cyclophosphamide, and azathioprine, have shown inconsistent associations with ASCVD risk, without as clearly defined effects on HF [129,[140][141][142][143]. Perhaps the clearest demonstration of the barriers between inflammatory disease-specific efficacy and broader application is with TNF-α antagonists: whereas observational studies of RA patients suggested a benefit of TNF-α antagonists in reducing rates of HF hospitalization [144], this HF-reducing benefit was not replicated when TNF-α antagonists were tested in the general HF population without RA [145,146].…”

A Scientific Imperative as Seen Through a Sharpened Lens: Sex, Gender, and the Cardiovascular Condition

“…11 While continuing to expand our recognition of dissimilarities, we need to press forward and more deliberately interrogate mechanisms as well as implications. [11][12][13][14][15][16] Why do we consistently observe these differences and what do they mean for the future of cardiovascular health in females and males, not only as the population ages but also as previously presumed static entities such as atherosclerosis evolve over time-and as new disease types emerge, especially in the setting of new forms of systemic perturbations and stressors. To understand these important differences, we need to include sex-specific studies across all of our work, rather than treating this approach as part of a niche area of expertise.…”

“…For instance, we are still at the beginning stages of appreciating how the diversity and range of proteins, metabolites, and immune-inflammatory markers vary by sex. [12][13][14] We are still at the start of understanding how and why cardiac and vascular diseases can present quite differently in females and males, particularly with aging. 11 While continuing to expand our recognition of dissimilarities, we need to press forward and more deliberately interrogate mechanisms as well as implications.…”