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Published on: December 14, 2011
Sex differences in proteomic correlates of coronary microvascular dysfunction among patients with heart failure and
Chanchal Chandramouli1,2, Tay W Ting1, Jasper Tromp1,3
1National Heart Centre Singapore, Singapore.
Insights
Sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF) reveal distinct proteomic profiles. While CMD prevalence is similar, inflammation drives it in men, whereas ventricular remodeling and fibrosis are key in women.
Area of Science:
- Cardiology
- Proteomics
- Sex Differences in Disease
Background:
- Coronary microvascular dysfunction (CMD) is a significant factor in heart failure with preserved ejection fraction (HFpEF).
- Limited data exists on sex-specific differences in CMD within the HFpEF population.
- Understanding these differences is crucial for targeted therapeutic strategies.
Purpose of the Study:
- To investigate sex-specific proteomic profiles associated with CMD in patients with HFpEF.
- To compare clinical and proteomic correlates of CMD between men and women with HFpEF.
Main Methods:
- Analysis of data from the multinational PROMIS-HFpEF study (n=182; 54.6% women).
- CMD defined as coronary flow reserve (CFR) < 2.5.
- Utilized lasso penalized regression on 242 biomarkers from proximity extension assays, adjusting for covariates.
Main Results:
- CMD prevalence was high and similar in men (77%) and women (70%) with HFpEF.
- Proteomic correlates of CFR differed significantly between sexes.
- Distinct sets of biomarkers were independently associated with CFR in men versus women, implicating different biological pathways.
Conclusions:
- While CMD prevalence is similar in men and women with HFpEF, the underlying mechanisms differ.
- Inflammation-driven pathways appear predominant in men, whereas ventricular remodeling and fibrosis may be more critical in women.
- These sex-specific drivers highlight the need for tailored approaches to managing CMD in HFpEF.
Aims:
Little information is available on sex differences in coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF). We investigated sex-specific proteomic profiles associated with CMD in patients with HFpEF.
Methods And Results:
Using the prospective multinational PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in HFpEF; n = 182; 54.6% women), we compared clinical and biomarker correlates of CMD (defined as coronary flow reserve [CFR] <2.5) between men and women with HFpEF. We used lasso penalized regression to analyse 242 biomarkers from high-throughput proximity extension assays, adjusting for age, body mass index, creatinine, smoking and study site. The prevalence of CMD was similarly high in men and women with HFpEF (77% vs. 70%; p = 0.27). Proteomic correlates of CFR differed by sex, with 10 versus 16 non-overlapping biomarkers independently associated with CFR in men versus women, respectively. In men, proteomic correlates of CFR included chemokine ligand 20, brain natriuretic peptide, proteinase 3, transglutaminase 2, pregnancy-associated plasma protein A and tumour necrosis factor receptor superfamily member 14. Among women, the strongest proteomic correlates with CFR were insulin-like growth factor-binding protein 1, phage shock protein D, CUB domain-containing protein 1, prostasin, decorin, FMS-like tyrosine kinase 3, ligand growth differentiation factor 15, spondin-1, delta/notch-like epidermal growth factor-related receptor and tumour necrosis factor receptor superfamily member 13B. Pathway analyses suggested that CMD was related to the inflammation-mediated chemokine and cytokine signalling pathway among men with HFpEF, and the P13-kinase and transforming growth factor-beta signalling pathway among women with HFpEF.
Conclusion:
While the prevalence of CMD among men and women with HFpEF is similar, the drivers of microvascular dysfunction may differ by sex. The current inflammatory paradigm of CMD in HFpEF potentially predominates in men, while derangement in ventricular remodelling and fibrosis may play a more important role in women.
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