SEX HORMONES IN LONG QT SYNDROME AND TORSADES DE POINTES (TDP)

BACKGROUND: Systemic inflammation and male hypogonadism are two increasingly recognized “nonconventional" risk factors for long-QT syndrome (LQTS) 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. Furthermore, female sex is a well-recognized risk factor for LQTS and TdP, likely reflecting the influence of sex hormones on ventricular repolarisation. Overall, estradiol prolongs, while progesterone and testosterone shorten heart rate-corrected QT-interval. However, no studies have comprehensively evaluated sex hormone levels in male and female LQTS patients developing TdP, nor their implications in terms of clinical outcomes and electrophysiological changes. AIM OF THE STUDY. Aim of the study was to analyse the acute impact of systemic inflammation on circulating levels of testosterone and other sex hormones in men, also defining whether these alterations play a role in increasing the risk of LQTS/TdP. To address this objective, we investigated the levels of sex hormones and their relationship with inflammatory markers and QTc duration in male patients with different types of acute inflammatory diseases, during the active phase and recovery, and the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected from the general population over 10 years. Furthermore, the study was aimed at determining the sex hormones profiles in males and females TdP patients and define their role in this clinical setting. In other words, our principal goals were: 1. To investigate the levels of sex hormones and their relationship with inflammatory markers in patients with systemic inflammation 2. To investigate the correlation between the levels of sex hormones and QTc duration in male patients with different types of acute inflammatory diseases, during the active phase and recovery. 3. To investigate the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP. 4. To determine the sex hormones profiles in males and females in TdP patients, also defining their possible role in this clinical setting PATIENTS AND METHODS. First, 22 men were enrolled with elevated C‐reactive protein (CRP) levels in several different inflammatory diseases, including acute infections, chronic immune‐mediated diseases during flares, or acute microcrystalline arthritis (inflammatory cohort). These subjects underwent blood sample withdrawal and ECG recording during the active phase (PRE), and after different pharmacological treatments resulting in a CRP decrease >75% when compared with baseline conditions (POST). None of the patients in this cohort was under treatment with drugs potentially influencing circulating levels of sex hormones, specifically androgen‐deprivation therapy. Moreover, subjects presenting with or developing electrolyte abnormalities or atrial fibrillation/flutter were excluded from the study. A second cohort of 10 men, comparable in terms of age and comorbidities (comorbidity controls), but without signs of systemic inflammation, was enrolled as a confirmatory group to further compare laboratory and ECG findings of the inflammatory cohort, in both PRE and POST conditions. Furthermore, subjects belonging to a cohort of 75 consecutive TdP patients were collected in our department in the last years (2008-2020). Of a total of 30 men with TdP who came to our observation, 19 were included in the study (TdP cohort). Notably, inflammatory cohort patients and comorbidity controls were selected to be comparable in terms of age with these 19 patients with TdP. All subjects under study underwent a blood withdrawal in the morning (before 11:00 am) to measure circulating levels of inflammatory markers and sex hormones. Moreover, the blood sample in patients with TdP was obtained within 24 hours of arrhythmia occurrence. In the other subjects, blood withdrawals and ECG recordings were simultaneous. Testosterone (total, free, and bioavailable), sex hormone–binding globulin (SHBG), 17β‐oestradiol, progesterone, follicle‐stimulating hormone (FSH), and LH were also assessed. Measurements of heart rate, RR interval, QT interval, and QTc (Bazett’s formula) in patients with inflammatory diseases and controls was automated and obtained from 3 ECG strips consecutively recorded. A single investigator (cardiologist) blinded to the clinical and laboratory findings of the patients reviewed all ECGs to validate the measured intervals. QTc was additionally evaluated using alternative correction formulas, i.e. Fridericia [QT/RR interval1/3], and Hodges [QT+1.75 (heart rate−60)], the latter being recognized as the correction formula showing the least heart rate dependence. Since all the subjects in the study were men, QTc was considered prolonged if >470 ms, in accordance with the American Heart Association/American College of Cardiology recommendations [43]. Diagnosis of TdP was based on the presence of at least 1 episode of polymorphic ventricular arrhythmia with a rate ranging from 160 to 240 beats/min, associated with QTc prolongation. As regards the fourth aim of our study, data from our TdP cohort, including women, were used. We performed the same measurements with the same methodology described above; besides, we investigated the relationship between sex hormones and arrhythmia outcome in TdP males and females. RESULTS. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interIeukin-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 CRP, testosterone, and 17-β-estradiol levels; in these patients, increased CRP and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Over 13 years, 68 TdP patients (42 females) were consecutively enrolled. Compared to controls, a differential sex hormone profile was observed in TdP men and women, primarily reduced testosterone in males, and increased 17-β-estradiol in females. Within the TdP cohort, lower testosterone in men and higher 17-β-estradiol in women were associated with a worse short-term arrhythmia outcome. CONCLUSIONS. During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in male, 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. Different sex hormone profiles, primarily low testosterone in males and high 17-β-estradiol in females, are associated with TdP occurrence and outcome in men and women. These endocrine milieus act, at least in part, via direct and reversible effects on cardiac electrophysiology, thereby supporting the antiarrhythmic potential of sex-specific hormonal-modulating therapies