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

Jonica Campolo ¹ Paola Canale ² Gianluca Gazzaniga ³ Marina Parolini ¹ Emanuela Piccaluga ³ Irene Bossi ³ Jacopo Oreglia ³ Andrea Borghini ² Irene Marinaro ² Maria Grazia Andreassi ^2*

• ¹ CNR-Institute of Clinical Physiology, Milano, Italy
• ² CNR-Institute of Clinical Physiology, Pisa, Italy
• ³ Niguarda Ca' Granda Hospital, Milan, Lombardy, Italy

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 mtDNA 4977 deletion with the risk of EOCAD.The study included 118 patients (99 men, 51.0±5.6 years) with angiographically EOCAD (≤60years) and 150 healthy controls (94 men, 49.8±5.8years). Quantitative RT-PCR was used to quantify mtDNA-CN and mtDNA 4977 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 mtDNA 4977 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 mtDNA 4977 deletion were significantly higher in males (p=0.026) and hypercholesterolemic patients (p<0.001).The ROC curve of mtDNA-CN and mtDNA 4977 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 mtDNA 4977 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.