The Neuro-Inflammatory-Vascular Circuit: Evidence for a Sex-Dependent Interrelation?

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide with mortality rates in women currently exceeding those in men. To date, evidence is widely lacking for unique female determinants of CVD. However, strong associations with psychological stress, obesity or elevated inflammatory biomarkers with adverse cardiovascular outcomes in women have been identified in various studies. Interestingly, amygdalar metabolic activity, a central neural structure involved in emotional stress processing, has proven to be an independent predictor of major adverse cardiovascular events (MACE). Moreover, upregulated amygdalar metabolism was directly linked to myocardial injury in women, but not in men. This newly suggested sex-dependent brain-heart interrelation was further supported by the discovery that bone marrow activity, a surrogate parameter of inflammation, represents a potential bridging link between amygdalar activity and cardiovascular pathology by fueling inflammatory processes that promote atherosclerotic disease. Such malignant cascade of events might account, at least in part, for the excess female mortality seen in women with coronary artery disease and calls for sex-specific research toward pharmacologic or behavioral modulators to improve cardiovascular outcomes, particularly in women. This mini review summarizes recent advances in cardiovascular sex-specific medicine, thereby focusing on the interplay between the limbic system, autonomic regulation and inflammatory biomarkers, which may help to tailor CVD management toward the female cardiovascular phenotype.

Keywords: autonomous nervous system; cardiovascular; inflammation; limbic system; sex.

FIGURE 1

Potential involvement of the heart-brain axis in sex-dependent risk factors and presentations of cardiovascular disease (CVD). BMI, body mass index; CAD, coronary artery disease; CMVD, coronary microvascular dysfunction; CRP, C-reactive protein; MACE, major adverse cardiac events; ACS, acute coronary syndromes; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

FIGURE 2

Hypothetic mechanisms of the neuro-inflammatory-vascular circuit. (1) Activity in the brain’s salient network is induced by acute stress (orange arrow) and chronic stress (red arrow), thereby triggering the activation of the amygdala. (2) Efferent projections to the brainstem upregulate sympathetic activity as well as the hypothalamic-pituitary-adrenal axis leading to an increase in circulating norepinephrine and cortisol. In an acute setting this results in an increased heart rate and blood pressure, which can be pharmacologically targeted by sympatholytic agents. In a chronic state, the tonic firing of the amygdala leads to modulation of central brain structures, such as the locus coeruleus, and to a chronic inflammatory state. (3) This is reflected by enhanced bone marrow activity and release of progenitor inflammatory cells. (4) Inflammatory cytokines (interleukin-6 and interleukin-18) promote endothelial dysfunction and progression of atherosclerosis. (5) The latter increases the risk of adverse cardiac events. Targeted anti-inflammatory treatment or behavioral strategies (e.g., stress reduction concepts) have the potential to diminish detrimental effects on the cardiovascular system.