Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease

Bay B, Fuh MM, Rohde J, Worthmann A, Goβling A, Arnold N, Koester L, Lorenz T, Blaum C, Kirchhof P, Blankenberg S, Seiffert M, Brunner FJ, Waldeyer C, and Heeren J. (2024) Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease. Lipids in Health and Disease

In Europe, coronary artery disease (CAD) caused by atherosclerotic cardiovascular disease (ASCVD) established in the coronary wall is a main cause of death. Many factors that are associated with the development, manifestation, and outcome of CAD have been well established, such as low-density lipoprotein cholesterol (LDL-c) and other lipoproteins as well as changes to the lipidome. In addition, when in combination with atherogenic lipoproteins, bile acids (BAs) have recently been suggested to influence ASCVD. Many cardiovascular risk factors are known to be similar for males and females, but sex-associated differences have been poorly understood. Bay et al were interested in determining if there are any sex-related differences in the lipidome and BA profile that are associated with risk for CAD.

To investigate whether there are differences in the lipidome and BA profile of people with CAD based on sex, a subgroup of the INTERCATH cohort, which consists of 3012 patients who received coronary angiography at the University Heart and Vascular Center in Hamberg-Eppendorf, Germany, were chosen using a propensity score matching algorithm. Exclusion criteria including if they had myocardial infarction, previous coronary artery bypass graft surgery, history of malignancy, use of lipid-lowering mediation other than stanins, cardiac transplantation, or diabetes mellitus type 1 was applied, leaving 192 patients. Finally, 15 more were removed due to missing blood samples, prevalent manifest hepatic disease or misclassification of CAD, leaving 177 patients selected for this analysis. This cohort was then separated into subgroups based on CAD vs no CAD, 1st vs 3rd tertile of LDL-c, and male vs female.

Liquid chromatography with tandem mass spectrometry was used to analyze lipids in blood and bile acid so a comparison could be made between females and males and those with and without CAD. Thirteen lipid classes were analysed when determining baseline characteristics and a similar pattern was found in lipid class concentrations between the male and female subgroups. As expected, the 3rd LDL-c group demonstrated significantly higher cholesteryl esters and sphingomyelins in both males and females. Interestingly, significantly more cholesterol ester species were found in females compared to males in the 1st LDL-c tertile compared to the 3rd LDL-c tertile.

When each sex was observed for the lipid level differences in the plasma and bile acid, in females phosphatidylcholine (PC) 18:0/20:1 and diacylglycerol (DAG) 18:1/22:4 were reduced in those with CAD compared to those without CAD. As well, phosphatidylethanolamine (PE; also called ethanolamine plasmalogens) (P-16:0/20:4) was greater in females with CAD, however no differences were found in bile acid between females with and without CAD. There were also no differences in the high LDL-c subgroup in females. For the males, DAG 18:0/22:6, 16:0/16:0, 14:0/16:0, 16:0/18:0, and 16:1/18:0 were lower in those with CAD compared to those without CAD while cholesteryl esters 24:0, 20:0, and DAG 20:0/20:0 were all increased in males with CAD. Different from what was seen in females, there were differences in the lipidome of bile acids in the males and this was associated with the presence or absence of CAD. In those with CAD, the concentrations of PE (P-18:0/20:4), PE (O-18:0/20:4), and PE (P-18:1/20:4) were greater than those without CAD. As well, many plasmalogens species were greater in the males in the low LDL-c subgroup compared to the high LDL-c subgroup.

Bay et al were interested in determining whether the lipidome differences seen in CAD are sex-specific. A subgroup from the INTERCATH cohort that consisted of people who had received coronary angiography was chosen using a propensity score matching algorithm. Comparisons were made between subgroups with and without CAD, those that fell in the 1st or 3rd tertile of LDL-c, and males vs females. Lipids in blood and bile acid were determined and the authors demonstrated that there were some lipid differences when either sex was compared between those with and without CAD. Interestingly, females with CAD had reduced PC (18:0/20:1) levels, while males showed now difference in this. The group with the greatest plasmalogen levels were male patients with CAD and low LDL-c levels, which was surprising since inflammatory diseases are normally associated with lower plasmalogens levels. However, plasmalogens can be involved in both proinflammatory responses and anti-inflammatory responses, so further work could determine the mechanism allowing plasmalogen levels to increase in this subgroup. Females also had no differences in the lipidome of bile acid when comparing those with and without CAD, but in males there were differences between these two groups. The knowledge that there are these sex-specific differences in CAD are important when determining drivers of CAD development. These differences are important to know especially when determining risk level of patients with cardiovascular disease and future work should aim to elucidate the mechanisms causing these lipidome changes.