Low‐dose Lithium is Associated with Left Ventricular Ejection Fraction in Healthy Young Men but not Women

Abstract

The impact of lithium (Li) exposure on the cardiovascular system is perplexing, as beneficial, negative, and null effects have been identified. Li is an inhibitor of glycogen‐synthase kinase 3β (GSK3‐β) which has been identified as a possible therapeutic target for cardiovascular disease (CVD) and mental health disorders. While earlier ecological studies suggest that trace amounts of Li may protect against CVD, no study to date has investigated the effects of low‐dose Li exposure on cardiac structure and function in healthy young adults without CVD and whether these associations are sex dependent. The purpose of the present investigation was to examine the association between Li exposure and left ventricular mass (LVM) and function in healthy young adults. This investigation represents a cross‐sectional analysis of the Niagara Longitudinal Heart Study (NLHS) at the midpoint of data collection for 156 participants aged 19 – 25 years. A final sample size of 117 had both valid Li and left ventricular data upon analyses. LVM was indexed to height2.7 (LVMi), ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) were assessed following echocardiography in the parasternal long‐axis view of the left ventricle. Serum Li levels were measured using inductively‐coupled plasma mass spectrometry. Li concentration was significantly associated with EF (r = −0.183, p = 0.05) and ESV (r = 0.197, p = 0.03) among the total sample. Li concentration did not differ when examined by sex (p > 0.05), however LVMi, ESV, EDV, SV, and EF were all significantly higher in males than females (p < 0.05). Li was only significantly correlated with EF in men (r = −0.320, p = 0.02) however no correlation was observed among women (p > 0.05). The novel result of our investigation was naturally occurring concentration of Li is associated with decreased EF in men, but not women, although, there was no significant difference in SV. Further, there was no effect of low‐dose Li on LVMi. This is in contrast to some animal studies which demonstrate long‐term exposure to Li has potent hypertrophic effect on the left ventricle, although, Li concentrations in our sample were considerably lower and fall within a normal physiological range. These findings may result from differential sensitivities of the GSK‐3β receptor to Li in the left ventricle in men and women, although further investigation is required.Support or Funding InformationThis research project is funded by the Canadian Institutes of Health Research (CIHR #s 363774, 399332). KSD is funded by a CIHR Doctoral Research Award – Frederick Banting and Charles Best Canada Graduate Scholarship (RFN#167014). VAF is supported by a Brock Explore Grant and an NSERC Discovery Grant (2019‐05833).