Sex differences in the genetic and molecular mechanisms of coronary artery disease

Sakkers, Tim R.; Mokry, Michal; Civelek, Mete; Erdmann, Jeanette; Pasterkamp, Gerard; Diez Benavente, Ernest; den Ruijter, Hester M.

doi:10.1016/j.atherosclerosis.2023.117279

Cited by 24 publications

(5 citation statements)

References 169 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 Regarding the latter, differences are observed in plaque composition, vulnerability, and burden between men and women, pointing toward a respectively more atheromatous versus fibrous phenotype. [13][14][15] The plasma proteome reflects the dynamic biological state, which, prior to disease, may provide insight into the mechanisms of (sex-specific) CAD onset. The UK Biobank is a largescale biomedical healthcare database comprising population-scale data of 2,922 unique plasma proteins in 54,219 individuals.…”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] A limited number of genomic studies has identified multiple sex-specific candidate genes as risk factors for CAD, within risk loci that encode for proteins that were primarily engaged in processes involved in lipid metabolism and vascular remodelling. [20][21][22] Focusing on lesion development, human regulatory network analyses using patient material have indicated the existence of sex-specific plaque subphenotypes 13,23 and cell signatures. 24,25 Translating experimental findings into the identification of druggable targets is vital to enable clinical application.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sex-Specific Associations of the Plasma-Proteome with incident Coronary Artery Disease

Sier,

Willems van Dijk,

van Heemst

et al. 2024

Preprint

View full text Add to dashboard Cite

Background and Aims The aetiology of coronary artery disease (CAD) is different for men and women, yet insights into underlying sex-specific biological and pathophysiological mechanisms are limited. We investigated the sex-specific associations of the plasma-proteome with incident CAD. Methods In 40,829 participants from UK Biobank free-of-CAD from baseline to 365 days thereafter (55% women, mean 56.9, standard deviation 8.1 years), we analysed associations between 2,922 plasma-proteins and CAD incidence. Baseline plasma samples (2006-2010), were analysed in relation to incident CAD over a median follow-up of 13.7 (IQR: 13.1,14.4) years. Combined and sex-specific analyses were performed using Cox-proportional hazard models, adjusting for considered confounders, and causal inference using Mendelian Randomisation (MR). Results Multivariable-adjusted Cox-proportional hazard models identified 1,138 proteins associated with incident CAD (false-discovery-rate-corrected p-value<0.05), of which 219 showed evidence for potential causality using MR. Overrepresentation analyses identified involvement of cytokine-cytokine receptor interactions (p<0.0001), matrix remodelling (p<0.0001), regulation of innate and adaptive immune cells (p<0.0001), and angiogenesis (p<0.0001) pathways associated with incident CAD. Sex-specific analyses revealed additional 412 female-exclusive and 37 male-exclusive proteins and distinct CAD-risk pathways were identified for women (e.g., innate immune response) and men (e.g., tube morphogenesis (angiogenesis)). Translation toward druggability on targets with causal evidence revealed sex-specific clinical drug candidates such as C1S (men) and FOXO1 (women). Conclusions Although the majority of proteins showed consistent associations with incident CAD in both sexes, multiple proteins and biological pathways were either more strongly associated with incident CAD in men or in women, potentially indicating sex-specific pathogenesis and opening new alleys for prevention and clinical strategies.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sex-Specific Associations of the Plasma-Proteome with incident Coronary Artery Disease

Sier,

Willems van Dijk,

van Heemst

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Although CAD affects both sexes, some specific differences are connected with symptoms and the characteristics of risk factors and outcomes between men and women. According to some authors, the reasons for the differences may be different sex chromosomes, gene expression, and hormone levels [32][33][34]. Addressing these risk factors is fundamental for both the prevention and management of CAD.…”

Section: Introductionmentioning

confidence: 99%

Sex-Related Differences in the Prevalence of Classical, Non-Classical Risk Factors and Management of the Chronic Coronary Syndrome

Muszyński,

Pawluczuk,

Pasławska

et al. 2023

JCM

View full text Add to dashboard Cite

(1) Background: Coronary artery disease (CAD) remains the leading cause of death in both sexes. The male sex is considered a classical atherosclerosis risk factor, whereas females should be protected by hormonal effects until menopause. Although there are known differences in the development, type, and prognosis of chronic coronary syndrome (CCS) between both sexes, there are no differences in approach in the guidelines. (2) Methods: The sex-related differences in CAD risk factors, treatment, echocardiographic, and angiographic results were assessed among 3291 patients with CCS. (3) Results: Women were older and had a higher prevalence of hypertension, dyslipidaemia, and diabetes mellitus than men. Women were more often treated conservatively than men. There was no difference in the use of beta-blockers and statins among the sexes. The LDL cholesterol goal was less frequently reached by women. Women were treated less often with aspirin than men, but they were treated more often with angiotensin receptor blockers than men. The left ventricle ejection fraction was higher among females. The number of obstructed vessels was higher in men. (4) Conclusions: Women may be more exposed to the risk factors of CAD than men. Men are diagnosed with CAD earlier, and their prevention and therapy are more efficient.

show abstract

“…ROS and lipids induce cell death, thereby destabilizing atherosclerotic plaques. High oxidative stress also increases Th1/Th17 and decreases Th2/Treg cell immune response, further enhancing inflammation and cell death [14,15].…”

Section: Introductionmentioning

confidence: 99%

Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases

Holvoet

2023

Cells

View full text Add to dashboard Cite

We performed a systematic search of the PubMed database for English-language articles related to the function of adipose-derived stem cells in the pathogenesis of cardiovascular diseases. In preclinical models, adipose-derived stem cells protected arteries and the heart from oxidative stress and inflammation and preserved angiogenesis. However, clinical trials did not reiterate successful treatments with these cells in preclinical models. The low success in patients may be due to aging and metabolic reprogramming associated with the loss of proliferation capacity and increased senescence of stem cells, loss of mitochondrial function, increased oxidative stress and inflammation, and adipogenesis with increased lipid deposition associated with the low potential to induce endothelial cell function and angiogenesis, cardiomyocyte survival, and restore heart function. Then, we identify noncoding RNAs that may be mechanistically related to these dysfunctions of human adipose-derived stem cells. In particular, a decrease in let-7, miR-17-92, miR-21, miR-145, and miR-221 led to the loss of their function with obesity, type 2 diabetes, oxidative stress, and inflammation. An increase in miR-34a, miR-486-5p, and mir-24-3p contributed to the loss of function, with a noteworthy increase in miR-34a with age. In contrast, miR-146a and miR-210 may protect stem cells. However, a systematic analysis of other noncoding RNAs in human adipose-derived stem cells is warranted. Overall, this review gives insight into modes to improve the functionality of human adipose-derived stem cells.

show abstract

Sex differences in the genetic and molecular mechanisms of coronary artery disease

Cited by 24 publications

References 169 publications

Sex-Specific Associations of the Plasma-Proteome with incident Coronary Artery Disease

Sex-Specific Associations of the Plasma-Proteome with incident Coronary Artery Disease

Sex-Related Differences in the Prevalence of Classical, Non-Classical Risk Factors and Management of the Chronic Coronary Syndrome

Aging and Metabolic Reprogramming of Adipose-Derived Stem Cells Affect Molecular Mechanisms Related to Cardiovascular Diseases

Contact Info

Product

Resources

About