Associations of baseline heart rate variability, cortisol, interleukin-6, and disease-free survival in bladder cancer: an exploratory cohort study

Chronic stress and inflammation are potential contributors to tumor progression, yet their interplay with autonomic regulation remains under-explored in bladder cancer (BC). This exploratory cohort study investigated associations between baseline heart rate variability (HRV), the inflammatory marker interleukin-6 (IL-6), the stress hormone salivary cortisol, psychological measures, and disease-free survival (DFS). In 73 patients, autonomic activity was assessed via 5-minute supine HRV recordings before surgery.

DFS was analysed using stratified Cox proportional hazards models. During follow-up, 26 recurrence events were observed and 47 patients were censored. Higher values of TINN (per 50 ms increase: HR = 1.450, 95% CI 1.090–1.929, p = 0.020) and the PNS index (per 1-unit increase: HR = 1.725, 95% CI 1.205–2.469, p = 0.006) were associated with a higher hazard of recurrence (shorter DFS).

Conversely, higher values of DFA-α2 (per 0.1-unit increase: HR = 0.653, 95% CI 0.476–0.897, p = 0.005) and the SNS index (per 1-unit increase: HR = 0.709, 95% CI 0.535–0.941, p = 0.012) were associated with a lower hazard of recurrence (longer DFS). A significant positive correlation was observed between cortisol and IL-6 (r = 0.24, p = 0.044). HRV moderated the association between cortisol and DFS: increasing cortisol levels were linked to a significantly higher recurrence hazard primarily in patients with high DFA-α2 (p = 0.022) or low TINN (p = 0.025).

Exploratory indirect association analyses suggested that psychological stress and health satisfaction are linked to DFS through these autonomic parameters. These findings identify preliminary associations that position HRV parameters as potential candidate biomarkers for recurrence hazard in BC, although their clinical utility remains to be established in larger, independent validation studies. The authors thank everyone who participated in this study.

We gratefully acknowledge Z. Tothova for their technical assistance, as well as Michaela Kopcova for her help in revising the ECG recordings. This work was supported by the Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences, grant number VEGA 1/0090/22, and the Slovak Research and Development Agency, grant number APVV-22-0231.

The funding sources were not involved in the conduct of the research or preparation of the article. Iveta Mikolaskova and Milan Zvarik contributed equally to this work. Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, Odborarske namestie 14, Bratislava, 811 08, Slovakia Iveta Mikolaskova, Vladimira Durmanova, Maria Bucova & Luba Hunakova Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Computer Science, Comenius University in Bratislava, Bratislava, Slovakia Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia Department of Urology, Saint Cyril and Methodius Hospital, and Bory Hospital, Bratislava, Slovakia The authors declare no competing interests.