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Int J Angiol
DOI: 10.1055/a-2740-8916
Original Article

Sex Moderates the Fibrinogen-mediated Pathways between Cardiometabolic Factors and Lower Ankle Brachial Index: A Moderated-mediation Analysis

Authors

  • Laith Ashour 

    1   Jordan University Hospital, The University of Jordan, Amman, Jordan

  • Malak Ababneh 

    2   Ministry of Health, Amman, Jordan

  • Ibrahim Alfadel 

    3   Hamad Medical Corporation, Doha, Qatar

  • Lina E. Alowisat

    4   Faculty of Medicine, The Hashemite University, Zarqa, Jordan

  • Afaf El Sharabi 

    5   Faculty of Medicine, The University of Jordan, Amman, Jordan

  • Rima Heramas 

    6   King Hussein Medical City, Royal Medical Services, Amman, Jordan

  • Motasem Al-Hawwari 

    7   Ministry of Health, Al-Basheer Hospitals, Amman, Jordan

  • Jawad Alburqan 

    8   Faculty of Medicine, Volgograd State Medical University, Volgograd, Russia

  • Ahmad Mohammad Hammad 

    7   Ministry of Health, Al-Basheer Hospitals, Amman, Jordan

  • Dalia Mustafa 

    9   Arab Medical Center, Amman, Jordan

  • Neda'a Ayed Almuala 

    6   King Hussein Medical City, Royal Medical Services, Amman, Jordan

  • Noura F. Al-Nawaiseh 

    10   Department of Medicine, Faculty of Medicine, Al-Balqa Applied University, As-Salt, Jordan
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Abstract

This study aimed to evaluate whether fibrinogen (FGN) and intercellular adhesion molecule-1 (ICAM-1) mediate the associations between multiple risk factors and the ankle–brachial index (ABI), and to determine whether these associations and mediations differ by sex. We analyzed biomarker data from the Midlife in the United States (MIDUS 3, 2017–2022) study using bias-corrected bootstrapped moderated-mediation models. The analysis assessed the mediating roles of FGN and ICAM-1 in the relationship between seven predictors—body mass index (BMI), low-density lipoprotein (LDL), systolic blood pressure (SBP), age, HbA1c, smoking, and statin use—and ABI. Sex was specified as a moderator, and all continuous covariates were mean-centered. After excluding inapplicable cases, 708 participants were included, with a slight predominance of women (56.6%) and a mean age of 66.2 years (SD = 9.7). In men, FGN fully mediated the association between HbA1c and ABI (coefficient per +5% HbA1c = −0.02; 95% CI: −0.045 to −0.005), partially mediated the negative association between age and ABI (coefficient per +10 years = −0.004; 95% CI: −0.01 to −0.0001), and partially mediated the inverse association between BMI and ABI (coefficient per +10 kg/m2 = −0.01; 95% CI: −0.02 to −0.001), despite a positive total effect of BMI on ABI (coefficient per +10 kg/m2 = 0.05; 95% CI: 0.01 to 0.08). Additionally, FGN mediated (indirect-only mediation) the associations of LDL and smoking history with ABI (coefficient per +30 mg/dL LDL = −0.006; 95% CI: −0.011 to −0.001; coefficient for smoking history = 0.01; 95% CI: 0.001 to 0.02). Among women, only SBP predicted a lower ABI without evidence of mediation (coefficient per +10 mm Hg = −0.01; 95% CI: −0.02 to −0.002). Unexpectedly, higher LDL levels were associated with higher ABI (coefficient per +30 mg/dL = 0.03; 95% CI: 0.01 to 0.04). ICAM-1 showed no significant mediation in either sex. Statin use was not associated with ABI, FGN, or ICAM-1 levels. These findings underscore the importance of investigating sex-specific differences in the pathophysiology and management of peripheral arterial disease (PAD).

Keywords

ankle–brachial index - fibrinogen - ICAM-1 - peripheral arterial disease

Declaration of GenAI Use

Authors used AI tool (ChatGPT) solely to enhance the readability and language of the manuscript. After utilizing the tool, the authors thoroughly reviewed and edited the content as needed and have full responsibility for the final published article.


Contributors' Statement

L.A. contributed to conceptualization, data acquisition, formal analysis, project administration and supervision. R.H., I.A., A.E., L.E.A. reviewed relevant literature, identified gaps in current knowledge, provided critical input in formulating the research objectives and overall study concept, and drafted sections of the original manuscript linking the literature to the study rationale. D.M., N.A.A., A.M.H., M.A., MA, NFA, and JA interpreted the study results, emphasized the significance of the findings within the context of existing literature, and drafted the sections addressing study implications and related content. All authors validated the results, reviewed and approved the final version of the manuscript, and are accountable for all aspects of the work. The sequence of author's names was based on their scientific contributions and was approved by all authors.


Ethical Approval

This study represents a secondary analysis of publicly available MIDUS data. All MIDUS study protocols were approved by the Institutional Review Board of the University of Wisconsin–Madison.




Publication History

Received: 26 September 2025

Accepted: 06 November 2025

Article published online:
26 November 2025

© 2025. International College of Angiology. This article is published by Thieme.

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