Sex differences in circulating proteins in heart failure with preserved ejection fraction

Abstract

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. Methods: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. Results: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18. Conclusion: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.

Plasma ACE2 species are differentially altered in COVID‐19 patients

“…Studies of the human secretome have shown that the average concentration of ACE2 protein in the plasma of males is higher than that in females 66 . These differences have been confirmed in different human cohorts 67‐71 . However, similarly to our study, others have failed to demonstrate clear differences in ACE2 expression between males and females or between younger and older persons in any tissue 72 or plasma 73 .…”

“…Forty-six plasma samples were collected during the following 1-3 days after hospitalization ("COVID-19 acute phase group"). Twenty-nine plasma samples were collected after recovery from COVID-19 with an interval of 63 ± 1 (58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70) days from the onset of symptoms. In the "recovered" group, six patients had been treated with glucocorticoids, five patients had received the IL-6-receptor inhibitor tocilizumab, and six patients had been treated with both therapies.…”

Gender-Specific Long-Term Prognostic Values of QRS Duration, QT Interval, and QTc from Automated ECG Analysis for Mortality and Adverse Outcomes in Patients Hospitalized for Heart Failure

“…We showed important differences in clinical outcomes between sexes. Previous studies have demonstrated sex differences in clinical outcomes (21), and the reasons underlying such differences are multi-faceted, including genetic and aetiological differences, as well as different responses to pharmacotherapy (22)(23)(24). Importantly, analyses have demonstrated significant underrepresentation of women in clinical trials, which likely impacts the efficacy of guideline-driven medical therapy in female patients with heart failure (25).…”

Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies

“…Recent serum studies indicate strong evidence of increased circulating ACE2 levels in healthy males and males with comorbidities ( 132 , 164 , 217 , 280 , 282 , 283 , 301 ). Studies are revealing comorbidities, e.g., endocrine manifestations, hypertension, heart failure, end-stage renal disease, exacerbating increased serum ACE2 in men ( 164 , 217 , 282 , 301 ). Sama et al ( 164 ) observed male sex as the strongest predictor of elevated concentrations of ACE2 in control and heart failure cohorts (coefficient = 0.19 and 0.26, respectively; P < 0.001), and Stienen et al ( 301 ) detected lower ACE2 levels in females with preserved ejection fraction heart failure.…”

“…Studies are revealing comorbidities, e.g., endocrine manifestations, hypertension, heart failure, end-stage renal disease, exacerbating increased serum ACE2 in men ( 164 , 217 , 282 , 301 ). Sama et al ( 164 ) observed male sex as the strongest predictor of elevated concentrations of ACE2 in control and heart failure cohorts (coefficient = 0.19 and 0.26, respectively; P < 0.001), and Stienen et al ( 301 ) detected lower ACE2 levels in females with preserved ejection fraction heart failure. These effects suggest that gender-specific factors and behaviors may potentiate ACE2 receptors and thus demand investigation.…”