Iron, inflammation and atherosclerosis risk in men vs. perimenopausal women

Highlights

• Iron balance may influence women's older age at first atherosclerotic event vs. men.

• A magnetic resonance arterial wall biomarker sensitive to endogenous iron was used.

• Arterial wall MRI-T2* parallelled hsCRP in early but not later menopause nor in men.

• Ferritin's link to MRI-T2* in women was lost after 2 years and was absent in men.

• Targeting iron homeostasis to lower incident atherosclerosis warrants further study.

Abstract

Objective

Age at first atherosclerotic event is typically older for women vs. men; monthly iron loss has been postulated to contribute to this advantage. We investigated the relationship between an MRI-based arterial wall biomarker and the serum inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) in perimenopausal women vs. men.

Methods and Results

Women without evident atherosclerotic disease were prospectively enrolled and observed over 24 months of menopause transition, indicated by hormone levels and reduction in median number of menstrual cycles from 4 [3–6] per year to 0 [0–1] per year (P < 0.01). Higher hsCRP predicted shorter carotid artery wall T2* in women entering the menopause transition (r = −0.3139, P = 0.0014); this relationship weakened after 24 months of perimenopause in women (r = −0.1718, P = 0.0859) and was not significant in a cohort of men matched for age and cardiovascular risk category (r = −0.0310, P = 0.8362). Serum ferritin increased from baseline to 24-month follow-up during women's menopause transition (37 [20–79] to 67 [36–97] ng/mL, P < 0.01), but still remained lower compared to men (111 [45–220] ng/mL, P < 0.01). Circulating ferritin levels correlated with arterial wall T2* values in women at baseline (r = −0.3163, P = 0.0013) but not in women after 24 months (r = −0.0730, P = 0.4684) of menopause transition nor in men (r = 0.0862, P = 0.5644).

Conclusions

An arterial wall iron-based imaging biomarker reflects degree of systemic inflammation in younger women, whereas this relationship is lost as women transition through menopause to become more similar to men. Iron homeostasis and inflammation in the arterial wall microenvironment warrants further investigation as a potential early target for interventions that mitigate atherosclerosis risk.

Introduction

Atherosclerosis causes the vast majority of acute coronary and cerebrovascular syndromes. While it affects both men and women, heart disease and stroke statistics have consistently shown a 10–20 year lag in first atherosclerotic event for women compared to men [1]. Furthermore, the incidence of heart attack and stroke increases after menopause beyond that predicted by chronologic age [2]. Both the Framingham Heart Study and the Multi-Ethnic Study of Atherosclerosis (MESA) indicate that early menopause increases atherosclerotic events [3], [4].

Women experience a rapid decline in sex steroid exposure with menopause. However, randomised trials have shown that hormone therapy provides inconsistent cardiovascular risk reduction [5], [6], [7] and even increased risk of stroke [8], [9], [10]. A less-explored alternate hypothesis to explain relative lag in events for women vs. men is that monthly iron loss prior to menopause is cardioprotective [11]. Iron excess accelerates, while iron restriction attenuates, atheroma formation in animals [12], [13] and humans [14]. Iron-generated free radicals oxidise LDL via Fenton chemistry [15], [16], In these reactions involving iron and oxygen, iron is essential to the production of reactive oxygen species that modify LDL [17], and LDL modification leads to foam cell production [18].

Just as carotid ultrasound-based intima medial thickness (cIMT) has been widely used in studies of atherosclerosis risk [19], non-contrast magnetic resonance imaging (MRI) of the carotid artery wall offers high reproducibility [20], agreement with cIMT [21], [22] and prognostic value [23] while offering unique tissue characterization approaches. For instance, the MRI relaxation parameter T2* can accurately estimate iron in liver and myocardium [24], [25], whereas serum measures such as ferritin do not reliably predict tissue iron content [26]. Our group has developed T2* mapping for the carotid artery wall and applied it to analyse both disease-free as well as atherosclerotic arteries, the latter providing histopathological evidence of T2* as a marker of arterial wall iron [27], [28], [29]. In this study, we incorporated this arterial wall imaging biomarker into a prospective study of perimenopausal women with atherosclerosis risk factors. We hypothesized that i) shorter carotid artery T2* correlates with higher levels of high-sensitivity C-reactive protein (hsCRP) in men and women at risk of atherosclerosis and ii) iron serologies do not consistently predict tissue-specific iron-based imaging measures.