Minute-Scale Sleep-Onset HRV as a Candidate Risk-Stratification Biomarker for Diabetic Retinopathy: An Exploratory Pilot Study

Background: Diabetic retinopathy (DR) is the most common microvascular complication of type 2 diabetes mellitus (T2DM), yet DR screening coverage remains inadequate worldwide. Diabetic autonomic neuropathy typically precedes DR, and heart rate variability (HRV) provides a non-invasive autonomic measure; however, whether HRV can screen for DR remains unexplored. Methods: This pilot study investigated whether sleep-onset minute-scale HRV indices—SDANN1 (standard deviation of 1-min segment means of normal-to-normal intervals) and SDANN2 (2-min segments)—serve as candidate screening biomarkers. Using a public 24-h Holter ECG dataset of T2DM inpatients (N = 39; 11 DR-positive, 28 DR-negative), sleep-onset time-points from cardiopulmonary coupling analysis were used to extract 30 min of post-onset ECG. Results: SDANN1 was significantly lower in the DR group (median 23.6 vs. 44.8 ms, p = 0.028, d = 0.74), with an area under the receiver operating characteristic curve of 0.731 (95% CI: 0.530–0.901). At the optimal threshold of ≤ 25 ms, the odds ratio was 8.1 (95% CI: 1.7–38.4), with DR prevalence of 58% in the high-risk versus 12.5% in the low-risk group. Among 12 candidates, only the SDANN family reached significance. Conclusions: sleep-onset minute-scale HRV shows promise as a candidate risk-stratification biomarker for DR; prospective longitudinal validation in larger, sex-balanced cohorts is required before any screening application.