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Protein Drivers of Heart Attack Risk Disproportionately Affect Women

— Study suggests mechanistic underpinnings of known sex disparities in MI

MedpageToday
A computer rendering of a chain of amino acids.

Sex-specific molecules contributing to one's risk of myocardial infarction (MI) were identified by researchers using proteomic profiling.

Based on targeted cardio-metabolic proteomics on two large-scale biobanks, there were 45 proteins identified as being associated with MI risk. These proteins -- some not previously linked to the risk of MI -- implicate atherosclerosis, thrombosis, inflammation, immune system-related pathways, injury and tissue repair, coagulation, bone homeostasis, and iron metabolism as having a role in the pathogenesis of MI, according to a team led by Olga Titova, PhD, epidemiologist of Uppsala University in Sweden.

In a Mendelian randomization (MR) analysis, Titova's group established causal relationships between seven proteins and incident MI: greater risk with higher genetically predicted levels of renin, follistatin, and retinoic acid receptor responder protein 2; contrasting with lower risk with more tissue factor pathway inhibitor (TFPI), tumor necrosis factor receptor 1 (TNF-R1), tumor necrosis factor receptor 2 (TNF-R2), and placenta growth factor (PGF).

"Moreover, we have explored and identified several proteins linked to MI in a sex-specific manner, highlighting the importance of including both women and men in clinical and pre-clinical studies and further investigating sex differences in protein-disease relationships," Titova's group reported in the .

Protein-MI associations tended to be more pronounced in women than in men: study authors found 12 proteins correlating with greater MI risk in women but not men (e.g., C-X-C motif chemokine 16, urokinase plasminogen activator surface receptor, and fibroblast growth factor 23), while growth differentiation factor 15 had a stronger relationship with MI in women than in men.

"The proteins identified in this analysis shed light on the biological pathways that drive MI development in males and females, and may serve as potential targets for both preventive and therapeutic intervention," commented Martha Gulati, MD, of Smidt Heart Institute, Cedars-Sinai Medical Center in Los Angeles, and two colleagues.

Older evidence had already flagged female-specific risk factors such as premature age of menopause and adverse pregnancy outcomes as contributors to the development of cardiovascular disease (CVD) in women -- though a mechanistic understanding remains limited, they noted in an .

While women are thought to generally have greater protection than men against CVD due to estrogen, women have been shown to be at higher risk of 30-day mortality after ST-segment elevation MI (STEMI) despite contemporary therapy.

"In 1991, Bernadine Healy, the then Director of the National Institutes of Health, coined the term 'Yentl syndrome' to describe the striking gender disparities in outcomes for women with ischemic heart disease," Gulati's group recalled. "While we have since firmly established that sex differences in [CVD] are abundant, the mechanistic underpinnings remain elusive and gender disparities are as striking now as they were in 1991."

"Let us hope that with continued efforts to leverage molecular profiling to rigorously elucidate mechanisms driving CVD in females and further inclusion of females in clinical trials, we won't still be talking about Yentl syndrome three decades from now," the editorialists concluded.

For their study, Titova and colleagues had started with a discovery cohort of 11,751 older adults without prevalent MI in the Swedish SIMPLER biobank (mean age 71 years, 3.4% MI events over an average 8.3 years), which was linked to Swedish national records on MI and death.

The U.K. Biobank then served as a replication cohort (n=51,613; mean age 57 years, 2.6% MI events over 12.3 years of follow-up).

Finally, the investigators took genetic association summary statistics from the CARDIoGRAMplusC4D consortium and FinnGen studies for the MR analysis.

Notably, the associations between MI and TNF-R2, TNF-R1, PGF, and TFPI went in opposite directions in the observational and MR analyses.

Study authors acknowledged that their Swedish data lacked information distinguishing STEMI versus non-STEMI. Their findings may also have limited generalizability to people of non-European ancestry.

"Despite limitations related to external validity, these findings are an important addition to the currently limited body of evidence examining mechanisms of sex-based differences in CVD," Gulati's group commented.

"These findings highlight that sex differences in disease phenotype begin at the molecular level, underscoring the need to ensure that female sex is well represented across the spectrum of research from pre-clinical studies to large outcome clinical trials," the editorialists stressed.

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    Nicole Lou is a reporter for 51˶, where she covers cardiology news and other developments in medicine.

Disclosures

The study was funded by the EpiHealth consortium, the Åke Wiberg's foundation, Magnus Bergvalls Stiftelse, P. O. Zetterlings stiftelse, the Swedish Research Council and the Swedish Heart-Lung Foundation; with additional support from the foundation Olle Engkvist byggmästare and annual grants from Avtal om Läkarutbildning och Forskning.

Titova's group had no disclosures.

Gulati disclosed support from the National Heart, Lung, and Blood Institute; the National Center for Research Resources; the National Center for Advancing Translational Sciences; Department of Defense; the Gustavus and Louis Pfeiffer Research Foundation; The Women's Guild of Cedars-Sinai Medical Center; The Ladies Hospital Aid Society of Western Pennsylvania; QMED, Inc.; the Edythe L. Broad and the Constance Austin Women's Heart Research Fellowships; the Barbra Streisand Women's Cardiovascular Research and Education Program; The Society for Women's Health Research; the Linda Joy Pollin Women's Heart Health Program; the Erika Glazer Women's Heart Health Project; the Adelson Family Foundation; Robert A. Winn Diversity in Clinical Trials Career Development Award; and the Anita Dann Friedman Endowment in Women's Cardiovascular Medicine & Research.

A co-editorialist reported relationships with the National Institutes of Health, the American Heart Association, the Massachusetts Life Sciences Center, and Astellas Pharma.

Primary Source

European Heart Journal

Titova OE, et al "Plasma proteome and incident myocardial infarction: sex-specific differences" Eur Heart J 2024; DOI: 10.1093/eurheartj/ehae658.

Secondary Source

European Heart Journal

Barton AK, et al "Steps towards curing Yentl syndrome: appraising sex differences in circulating proteins and incident myocardial infarction" Eur Heart J 2024; DOI: 10.1093/eurheartj/ehae657.