Abstract

Abstract Background Hypercholesterolemia is a recognized risk factor for cardiovascular disease; however, the ‘cholesterol paradox’, where lower cholesterol levels are associated with worse outcomes, challenges traditional understanding. The aetiology of this paradox remains unclear. Purpose To explore the cholesterol paradox, our study aims to determine if reverse causality and age-related factors contribute to this phenomenon. We hypothesise that in older adults, lower cholesterol levels may be indicative of poorer baseline health and nutritional status. Consequently, this could lead to higher mortality following percutaneous coronary intervention (PCI). Methods In a retrospective analysis of 1237 patients (median age 69; IQR [61 - 75]) undergoing PCI for stable angina from January 2015 to November 2019, we categorised patients based on presence or absence of hypercholesterolemia history. We employed cumulative hazard plots to compare all-cause mortality (ACM) and cardiovascular mortality (CVM) and conducted correlation tests between age and cholesterol levels. Results Consistent with the cholesterol paradox, a significant reduction in ACM was observed in patients with hypercholesterolemia history (HR 0.44, 95%CI(0.26 – 0.74), p = 0.0014). Intriguingly, CVM did not show any significant difference between groups (HR 0.63, 95%CI(0.30 – 1.33), p = 0.23) [Figure 1]. An inverse correlation between age and hypercholesterolemia history was noted (Pearson Coeff: -0.14, p<0.001). Conclusion The disparity in ACM, not paralleled by CVM, suggests non-cardiovascular factors may drive mortality in patients with lower cholesterol post-PCI. The inverse relationship between cholesterol levels and age supports the theory that cholesterol is influenced by the overall health status, and cholesterol acts as a surrogate biomarker for nutritional status and physiological reserve. These findings underscore the necessity for a multidisciplinary approach in managing patients with cardiovascular disease, where nutritional support and strategies to bolster physiological reserve, including physical activity, could play a critical role in improving outcomes. The elucidation of the underlying mechanisms of the cholesterol paradox warrants further investigation. Prospective studies are needed to explore the causal relationships and to confirm if interventions aimed at improving overall health and nutritional status can positively impact outcomes in this population. Our study sets the stage for such inquiries, highlighting the intricate interplay between lipid levels, age and mortality that extends beyond traditional cardiovascular risk factors.