Testosterone-to-estradiol ratio and platelet thromboxane release in ischemic heart disease: the EVA project
Authors: Raparelli V. , Nocella C. , Proietti M. , Romiti G. F. , Corica B. , Bartimoccia S. , Stefanini L. , Lenzi A. , Viceconte N. , Tanzilli G. , Cammisotto V. , Pilote L. , Cangemi R. , Basili S. , Carnevale R. ,   The EVA Collaborators, Tiberti Claudio , Panimolle Federica , Isidori Andrea , Giannetta Elisa , Venneri Mary Anna , Napoleone Laura , Novo Marta , Quattrino Silvia , Ceccarelli Simona , Anastasiadou Eleni , Megiorni Francesca , Marchese Cinzia , Mangieri Enrico , Tanzilli Gaetano , Viceconte Nicola , Barillà Francesco , Gaudio Carlo , Paravati Vincenzo , Tellan Guglielmo , Ettorre Evaristo , Servello Adriana , Miraldi Fabio , Moretti Andrea , Tanzilli Alessandra , Mazzonna Piergiovanni , Al Kindy Suleyman , Iorio Riccardo , Di Iorio Martina , Petriello Gennaro , Gioffrè Laura , Indolfi Eleonora , Pero Gaetano , Cocco Nino , Iannetta Loredana , Giannuzzi Sara , Centaro Emilio , Sergi Sonia Cristina , Pignatelli Pasquale , Amoroso Daria , Bartimoccia Simona , Talerico Giovanni , Minisola Salvatore , Morelli Sergio , Fraioli Antonio , Nocchi Silvia , Fontana Mario , Toriello Filippo , Ruscio Eleonora , Todisco Tommaso , Sperduti Nicolò , Santangelo Giuseppe , Visioli Giacomo , Vano Marco , Borgi Marco , Antonini Ludovica Maria , Robuffo Silvia , Tucci Claudia , Rossoni Agostino , Spugnardi Valeria , Vernile Annarita , Santoliquido Mariateresa , Santori Verdiana , Tosti Giulia , Recchia Fabrizio , Morricone Francesco , Scacciavillani Roberto , Lipari Alice , Zito Andrea , Testa Floriana , Ricci Giulia , Vellucci Ilaria , Vincenti Marianna , Pietropaolo Silvia , Scala Camilla , Rubini Nicolò , Tomassi Marta , Rozzi Gloria , Santomenna Floriana , Cantelmi Claudio , Costanzo Giacomo , Rumbolà Lucas , Giarrizzo Salvatore , Sapia Carlotta , Scotti Biagio , Toni Danilo , Falcou Anne , Pilote Louise , Kaur Amanpreet , Azizi Zhara , Vestri Anna Rita , Ferroni Patrizia , Crescioli Clara , Antinozzi Cristina , Pignataro Francesca Serena , Bellini Tiziana , Zuliani Giovanni , Passaro Angelina , Gloria Brombo , Cutini Andrea , Capatti Eleonora , Dalla Nora Edoardo , Di Vece Francesca , D’Amuri Andrea , Romagnoli Tommaso , Luciani Francesco , Polastri Michele , Violi Alessandra , Fortunato Valeria , Bella Alessandro , Manfredini Roberto , De Giorgi Alfredo , Fabbian Fabio , Carnevale Roberto , Nocella Cristina , Catalano Carlo , Carbone Iacopo , Galea Nicola , Bertazzoni Giuliano , Suppa Marianna , Rosa Antonello , Galardo Gioacchino , Alessandroni Maria , Coppola Alessandro , Palladino Mariangela , Illuminati Giulio , Consorti Fabrizio , Mariani Paola , Neri Fabrizio , Salis Paolo , Segatori Antonio , Tellini Laurent , Costabile Gianluca 
Published: March 2022

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.