Testosterone-to-estradiol ratio and platelet thromboxane release in ischemic heart disease: the EVA project

Abstract

Background: Data on the interplay between sexual hormones balance, platelet function and clinical outcomes of adults with ischemic heart disease (IHD) are still lacking.

Objective: To assess the association between the Testosterone (T)-to-Estradiol (E2) Ratio (T/E2) and platelet activation biomarkers in IHD and its predictive value on adverse outcomes.

Methods: The EVA study is a prospective observational study of consecutive hospitalized adults with IHD undergoing coronary angiography and/or percutaneous coronary interventions. Serum T/E2 ratios E2, levels of thromboxane B₂ (TxB₂) and nitrates (NO), were measured at admission and major adverse events, including all-cause mortality, were collected during a long-term follow-up.

Results: Among 509 adults with IHD (mean age 67 ± 11 years, 30% females), males were older with a more adverse cluster of cardiovascular risk factors than females. Acute coronary syndrome and non-obstructive coronary artery disease were more prevalent in females versus males. The lower sex-specific T/E2 ratios identified adults with the highest level of serum TxB₂ and the lowest NO levels. During a median follow-up of 23.7 months, the lower sex-specific T/E2 was associated with higher all-cause mortality (HR 3.49; 95% CI 1.24-9.80; p = 0.018). In in vitro, platelets incubated with T/E2 ratios comparable to those measured in vivo in the lowest quartile showed increased platelet activation as indicated by higher levels of aggregation and TxB₂ production.

Conclusion: Among adults with IHD, higher T/E2 ratio was associated with a lower long-term risk of fatal events. The effect of sex hormones on the platelet thromboxane release may partially explain such finding.

Keywords: Estradiol; Ischemic heart disease; Mortality; Testosterone; Thromboxane.

Fig. 1

Study population

Fig. 2

Levels of Vasoactive Molecules by Sex-specific Quartiles of T/E2 Ratio. Serum thromboxane B₂ (TxB₂) across quartiles of T/E2 (A) and comparing the highest versus the other quartiles of T/E2 ratio (I–II–III vs IV) (B); Serum nitric oxide (NO) across quartiles of T/E2 (C) comparing the highest versus the other quartiles of T/E2 ratio (I–II–III vs IV) (D). TxB₂ and NO levels were compared with Mann–Whitney U (for the comparisons between two groups, I–II–III vs IV) and Kruskal–Wallis H (for the comparisons between three or more group)

Fig. 3

Cumulative Incidence of All-cause Death by Sex-specific T/E2 Quartiles. Log-Rank test was used to compare the two groups

Fig. 4

Sex-specific Quartiles of T/E2 Ratio and Platelet Activation. Platelet aggregation (A) and TxB2 biosynthesis (B) were evaluated in platelets from healthy subjects incubated with different T/E2 ratio, 11.63 or 22.19 corresponding to the lowest and highest quartiles of the T/E2 ratio for male and 0.897 or 2.71 corresponding to the lowest and highest quartiles of the T/E2 ratio for female, before stimulation with a subthreshold concentration of collagen (STC, 0.25 μg/ml). Data shown are means ± SD and were compared with Mann–Whitney U (for the comparisons between two groups) and Kruskal–Wallis H (for the comparisons between three or more group). *p < 0.05; **p < 0.01; ***p < 0.001