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Cardiometabolic biomarkers in men and women exhibit different patterns of expression. One of the most comprehensive analyses of sex-based biomarker profiles found that cardiovascular disease (CVD) develops along different pathways in men and women, setting the stage for future investigations that will incorporate sex-based differences into prevention efforts.

Men and women share one thing in common: Heart disease is the number 1 cause of death regardless of sex. However, as the study’s authors explain in their published findings, which appear in the journal Circulation, CVD manifests itself differently among the sexes. While the incidence of disease isn’t as high in women as in men, men tend to present at an earlier stage of acute coronary syndrome than women, whereas heart failure manifests at a later age in women. 

Atrial fibrillation incidence is also less prevalent in women than men, although women with this condition have higher rates of stroke risk and death than men of the same age. Women who smoke, or have dyslipidemia or diabetes seem to be at greater risk of developing CVD than their male counterparts. Sex hormones may also play a role in explaining these variations in pathogenesis of CVD. 

Very little research has compared CVD biomarkers between the sexes in the general population. “Circulating biomarkers may provide additional insight into the mechanisms underlying sex-based differences in CVD,” the authors observed. 

Using data from the landmark Dallas Heart Study, investigators sought to analyze the differences among men and women for 30 different biomarkers representing six pathophysiological pathways. Four multivariable linear regression models assessed sex-based differences for disease risk factors, body composition, and cardiac morphology. 

The investigators compared results from these models against an “unadjusted model,” which assessed biomarker levels between men and women in absence of other factors that differ between the sexes, and a “fully adjusted” model, which included all of the adjustment variables, James de Lemos, MD, the study’s senior author and professor of medicine at UT Southwestern Medical Center, told CLN Stat

After weeding out participants with CVD, the study ended up including more than 3,400 individuals, 56% of whom were women. The average age of participants was 43. 

It was surprising just how many markers were different based on sex, which suggests multiple potential pathways contributing to sex-based differences in CVD, de Lemos observed. The researchers observed differences among inflammatory biomarkers, lipids, kidney function, myocyte injury and stress, endothelial dysfunction, and adipokines. 

Compared with men, women had higher levels of high-density lipoprotein cholesterol and high-density lipoprotein particle concentration, but lower levels of low-density lipoprotein cholesterol. Women also had higher levels of leptin and d-dimer. They had lower levels than men for a number of endothelial biomarkers, including soluble endothelial cell-selective adhesion molecule and symmetrical dimethylarginine. 

The importance of body composition, and in particular, fat distribution as a contributor to the sex-based differences was an interesting finding, de Lemos noted. 

Women had lower homoarginine levels than men in unadjusted models, but once body composition was accounted for, this biomarker demonstrated higher levels in women. Monocyte chemoattractant protein-1 levels were lower in women after adjusting for body composition, whereas in unadjusted models no differences were seen among men and women for this inflammatory biomarker. 

“Certain biomarkers revealed strong associations with sex independent of confounding factors, highlighting potential intrinsic differences in circulating biomarkers between women and men,” the researchers stressed. As an example, d-dimer was the only inflammatory biomarker that strongly associated with the female sex. Even after factoring in fat mass and distribution differences among men and women, leptin levels were still higher in women. 

In a finding that supports prior research, the authors reported lower levels of cardiac troponin and higher levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) in women. “It is important to note that we found that NT-proBNP levels remained higher in women even after accounting for differences between sexes in body composition and LV [left ventricular] mass,” the investigators noted. 

For both unadjusted and fully adjusted models, women had lower levels of kidney biomarker cystatin C than men. Although it has been linked to increased LV mass and other issues such as heart failure and higher death rates, “the exact role that cystatin C plays in the development of CVD remains unclear and warrants further investigation,” the authors suggested. Under fully adjusted models, women also had lower levels of adiponectin, lipoprotein-associated phospholipase A2 mass and activity, and asymmetrical dimethylarginine. 

“Differences in biomarker profiles between men and women highlight potentially important sex-based differences in the pathophysiological mechanisms contributing to cardiovascular disease,” the authors concluded. 

De Lemos offered that more work needs to be done before introducing different treatment plans for men and women in the clinic setting. 

Even for something as straightforward as myocardial infarction (MI) diagnosis, “it is not clear that sex-based troponin thresholds improve MI diagnosis, even though we know that levels are so different between men and women,” he said. The study served as a broad, descriptive overview of the differences in blood among the sexes. “Future research will have to dig deeper into the individual biological pathways to tease out what the underlying mechanisms are,” he suggested.