Heart rate fragmentation as a marker of autonomic function in healthy young individuals: insights from graded head-up tilt test and controlled breathing.

Introduction: Heart rate fragmentation (HRF) quantifies rapid beat-to-beat irregularity in cardiac intervals and has emerged as a predictor of adverse cardiovascular outcomes. While standard heart rate variability (HRV) indices primarily reflect autonomic modulation, HRF has been proposed to capture intrinsic sinoatrial node dynamics largely independent of autonomic influences. However, the extent to which HRF is shaped by cardiac autonomic balance in healthy individuals remains unclear. We examined whether HRF responds to controlled physiological shifts in autonomic modulation and investigated its relationship with established HRV indices. Methods: Twenty healthy adults (29 ± 4 years) underwent two complementary autonomic challenges: a graded head-up tilt test to progressively increase sympathetic drive and attenuate vagal cardiac modulation, and controlled breathing at 0.1 Hz to selectively enhance cardiac parasympathetic activity in a slow frequency band. HRF indices were quantified along with standard time- and frequency-domain HRV parameters and symbolic dynamic analysis. Associations between HRF and HRV indices were assessed using Spearman's rank correlation coefficients. Results: Graded tilt produced a progressive reduction in HRF indices that closely paralleled decreases in vagally mediated HRV parameters. HRF indices, particularly the percentage of inflection points (PIP), showed strong correlations with the 2UV symbolic pattern (r = 0.74). Controlled breathing enhanced parasympathetic modulation and elicited a shift of respiratory oscillations from high- to low-frequency spectral bands. All variations corresponding to high frequencies (HF, 2UV%, PIP, and other indices related to more fragmented rhythms) decreased in favor of an increase in low-frequency variations (LF/HF, 0V%, 2LV%). Discussion: Rather than providing information purely about cardiovascular autonomic control, these findings indicate that, in healthy subjects, both HRV and HRF indices are strongly influenced by cardiorespiratory coupling. Collectively, these results provide the first evidence that HRF in healthy individuals is significantly influenced by autonomic activity, especially parasympathetic modulation. These findings challenge the prevailing view of HRF as a purely intrinsic, autonomic-independent marker, indicating that it is also influenced by the respiratory frequency range. Taken together, these observations indicate that HRF reflects autonomic mechanisms under physiological conditions. Whether this relationship is preserved or altered under pathological conditions remains to be established and warrants investigation in future studies.