Cardiac and vascular complications in lupus: Is there a role for sex?

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disorder and is characterized by autoantibody formation and subsequent immune complex deposition into target organs. SLE affects nearly nine women to every one man worldwide. Patients with SLE are at an enhanced risk for cardiovascular disease (CVD) morbidity and mortality. CVD is the leading cause of death worldwide and includes heart and blood vessel disorders, cerebrovascular disease, and rheumatic heart disease. Specific mechanisms by which cardiac and vascular pathophysiology develops in patients with SLE are still not fully known. Not only do we not understand this correlation between SLE and CVD, but there is also a critical gap in scientific knowledge on the contribution of sex. In this review, we will discuss the cardiac and vascular pathological disease states that are present in some patients with SLE. More importantly, we will discuss the potential mechanisms for the role of sex and sex hormones in the development of CVD with SLE.

Keywords: cardiac; cardiovascular complications; lupus; sex differences; vascular.

Figure 1

Sex differences in systemic lupus erythematosus (SLE). Numerous mechanisms have been demonstrated to contribute to the sex-dependent development of SLE in both patients and animal models. Sex hormones and receptors, sex chromosomes, and Toll-like receptors all have been implicated as key mechanisms in SLE. In female patients and mice (left), elevated estrogen and estrogen receptor signaling, along with the X chromosome-linked proinflammatory genes (Cxcr3, Cd40, Tlr7), contribute to the frequency and/or severity of SLE. In male patients and mice (right), an imbalance of estrogen and testosterone, elevated estrogen receptor signaling, increased copies of the X chromosome (Klinefelter’s syndrome), and TLR7 signaling contribute to the severity and development of SLE.

Figure 2

Common and disparate mechanisms of SLE and cardiovascular disease (CVD). In the development of SLE or CVD, there are both disparate and common mechanisms. In SLE (red oval), elevated levels of estrogen and estrogen receptor signaling promote the severity and frequency of the disease. In CVD (black oval), estrogen and receptor signaling are cardioprotective until menopause. Differences in immune cell populations including B cells and monocytes may contribute to CVD. However, numerous mechanisms are shared between SLE and CVD (middle oval) including dysregulation of the immune system, increases in oxidative stress, and development of atherosclerosis through dyslipidemia. These common pathways may contribute to CVD complications that are frequently seen in patients with SLE.