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.