The mitochondrial dysfunction, alongside the modifiable burden of traditional risk factors, drives the development of early-onset coronary artery disease

Objective: Mitochondrial dysfunction is associated with increased risk of atherosclerosis by disrupting key cellular processes that contribute to premature vascular ageing. However, the specific role of mitochondrial dysfunction in early-onset coronary artery disease (EOCAD), which is increasing at a particularly alarming rate, remains largely unexplored. This study investigated the association of leukocyte mtDNA-CN and mtDNA4977 deletion with the risk of EOCAD. Methods: The study included 118 patients (99 men, 51.0 ± 5.6 years) with angiographically EOCAD (≤60 years) and 150 healthy controls (94 men, 49.8 ± 5.8 years). Quantitative RT-PCR was used to quantify mtDNA-CN and mtDNA4977 deletion rate. Results: The EOCAD group had a higher prevalence of male gender (p < 0.001), smoking (p = 0.001), hypertension (p < 0.001), diabetes mellitus (p = 0.04) and obesity (p < 0.001) than controls. EOCAD patients had lower mtDNA-CN (p < 0.001) and higher mtDNA4977 deletion (p = 0.026). Low mtDNA-CN levels were significantly associated with male gender (p < 0.001), smoking (p = 0.004), hypertension (p = 0.039), hypercholesterolemia (p < 0.001), and obesity (p < 0.001). Increased levels of the mtDNA4977 deletion were significantly higher in males (p = 0.026) and hypercholesterolemic patients (p < 0.001). The ROC curve of mtDNA-CN and mtDNA4977 deletion in predicting EOCAD showed an AUC of 0.902 (95% CI 0.867–0.937, p < 0.001) and 0.762 (95% CI 0.691–0.834, p < 0.001), respectively. Logistic regression analysis adjusted for confounders showed that both mtDNA-CN and mtDNA4977 deletion were independent significant predictors of EOCAD (p < 0.001 and p = 0.001, respectively). Conclusions: EOCAD is characterized by a high prevalence of modifiable risk factors and mitochondrial damage, underscoring the need for more efforts to reduce the burden of traditional risk factors and highlighting the potential for innovative mitochondrial-targeted therapies.