Sex-specific heart attack risk factors linked to circulating proteins

Uppsala University and Karolinska Institutet researchers have identified 45 proteins in the blood that are associated with the risk of myocardial infarction (MI), commonly known as a heart attack.

Of the 45 protein associations, 13 were specific to women, and one was specific to men. The identification of sex-specific protein associations might explain the observed disparities in MI risk between men and women and could lead to more targeted prevention and treatment strategies.

Cardiovascular diseases remain the leading cause of premature death worldwide, with atherosclerosis being the primary cause of MI. Traditional risk factors such as diabetes, hypertension, and smoking are well-known, but the molecular pathways influencing MI risk are not fully understood. Differences in MI risk between men and women have also been observed, but the underlying reasons remain unclear.

In a paper titled “Plasma proteome and incident myocardial infarction: sex-specific differences,” published in the European Heart Journal, the research team explored circulating proteins associated with MI using data from two large cohorts.

The discovery cohort included 11,751 Swedish adults aged between 55 and 93 years. Replication analyses were performed on 51,613 participants from the UK Biobank.

Blood samples were analyzed for 259 proteins related to cardiometabolic health using Olink proximity extension assays. Participants were monitored for incident MI and death over eight years through linkage to Swedish national registers.

After multiple testing and adjusting for confounders, 45 proteins were significantly associated with the risk of MI. Among these, 13 protein associations were specific to women, highlighting potential sex-specific biological mechanisms in MI risk.

In the analyses, higher levels of renin, follistatin, and retinoic acid receptor responder protein 2 were linked to increased risk of MI.

Higher levels of tissue factor pathway inhibitor, tumor necrosis factor receptors 1 and 2, and placenta growth factor were associated with a reduced risk.

These findings suggest that atherosclerosis, thrombosis, inflammation, and immune system-related pathways play significant roles in the development of MI.

In an editorial comment titled “Steps towards curing Yentl syndrome: appraising sex differences in circulating proteins and incident myocardial infarction,” published with the study paper, A. K. Barton and colleagues provide historical context that underscores the significance of the current study.

They point out that back in 1991, Bernadine Healy, Director of the National Institutes of Health, coined the term “Yentl syndrome” to describe the striking disparities in outcomes for women with ischemic heart disease.

“Being different from men has meant being second-class and less than equal,” Healy wrote at the time. Thirty-three years later, the disparities remain.

This study is among the first to explore circulating proteins and their sex-specific associations with MI in large, population-based cohorts. The researchers emphasize the importance of including both women and men in clinical studies to better understand and address sex differences in cardiovascular health.

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