Longitudinal changes in retinal fractal dimension before and after CVD events and associations with mortality

Background The retinal fractal dimension (FD) reflects microvascular network complexity and has been associated with cardiovascular disease (CVD) risk. However, longitudinal changes in FD around cardiovascular events and their prognostic relevance remain unclear. Purpose To examine longitudinal changes in retinal arteriolar (FDa) and venular (FDv) fractal dimension before and after cardiovascular events, compare trajectories with non-CVD participants, and assess associations with cardiovascular mortality. Methods This study used data from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort of individuals with type 2 diabetes. FDa and FDv were quantified from fundus photographs using VAMPIRE software. Mixed-effects models evaluated changes in FD before and after incident acute myocardial infarction (AMI) or stroke. Among 5,990 participants (327 with CVD), 37,418 FD measurements were analysed. Cox models assessed associations with cardiovascular mortality with multivariable adjustment. Results Participants who developed CVD were older (72.9 ± 9.5 vs 67.4 ± 11.3 years; p < 0.001) and had longer diabetes duration (15.4 ± 11.6 vs 10.8 ± 10.0 years; p < 0.001). Smoking, statin use, and antihypertensive therapy were also more common in the CVD group (all p ≤ 0.046). Within the CVD group, both FDa and FDv were significantly lower after the cardiovascular event compared with the pre-event period (FDa: 1.474 ± 0.029 vs 1.458 ± 0.037; FDv: 1.457 ± 0.029 vs 1.450 ± 0.035; both p < 0.001). In mixed-effects models adjusted for demographic and cardiovascular risk factors, pre-event arteriolar FD declined more steeply in the CVD group compared with non-CVD participants (β = −0.0010; p = 0.03). Post-event arteriolar FD declined significantly within the CVD group (β = −0.0078/year; p < 0.01). Venular FD demonstrated a significant immediate reduction at the time of the event (intercept shift β = −0.0018; p = 0.02), with a significant between-group difference in intercept shift (β = −0.0031; p = 0.02). Lower baseline FD was associated with increased cardiovascular mortality after age- and sex-adjustment (FDa: HR 0.89; p = 0.00; FDv: HR 0.92; p = 0.02), with similar associations observed for lower post-event FD (FDa: HR 0.90; FDv: HR 0.88; both p < 0.01). Greater decline in FD across the cardiovascular event was associated with increased mortality in univariate analyses (FDa slope: HR 0.85, p = 0.01; FDv slope: HR 0.80, p = 0.00), this association was attenuated after multivariable adjustment. Conclusion These findings suggest that reduction in retinal vascular branching may reflect systemic microvascular remodelling associated with cardiovascular disease, including acute myocardial infarction and stroke. Changes in retinal fractal dimension over time may reflect vascular changes that occur around cardiovascular events and could act as a non-invasive marker of cardiovascular risk.