Transient Hypogonadism Is Associated With Heart Rate–Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men

Author:

Lazzerini Pietro Enea1ORCID,Cantara Silvia1ORCID,Bertolozzi Iacopo2,Accioli Riccardo1,Salvini Viola1,Cartocci Alessandra3ORCID,D’Errico Antonio1,Sestini Fausta1,Bisogno Stefania1,Cevenini Gabriele3ORCID,Capecchi Matteo1,Laghi‐Pasini Franco1ORCID,Castagna Maria Grazia1,Acampa Maurizio4ORCID,Boutjdir Mohamed56ORCID,Capecchi Pier Leopoldo1ORCID

Affiliation:

1. Department of Medical Sciences, Surgery and Neurosciences University of Siena Italy

2. Cardiology Intensive Therapy Unit Department of Internal Medicine Nuovo Ospedale San Giovanni di Dio Florence Italy

3. Department of Medical Biotechnologies University of Siena Italy

4. Stroke Unit University Hospital of Siena Italy

5. VA New York Harbor Healthcare SystemSUNY Downstate Health Sciences University New York NY

6. NYU School of Medicine New York NY

Abstract

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized “nonconventional” risk factors for long‐QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate–corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C‐reactive protein and interleukin‐6 levels. Reduction of testosterone levels, which also inversely correlated with 17‐β estradiol over time, significantly contributed to inflammation‐induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C‐reactive protein, testosterone, and 17‐β estradiol levels; in these patients, increased C‐reactive protein and reduced testosterone were associated with a worse short‐term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin‐6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen‐to‐estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long‐QT syndrome/TdP risk in men.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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