Prognostic value of mitochondrial DNA4977 deletion and mitochondrial DNA copy number in patients with stable coronary artery disease. (September 2018) - Vecoli, Cecilia
Abstract: Background and aims: Mitochondrial DNA copy number (mtDNA-CN) depletion has been recently associated with an increased cardiovascular risk. However, the integrity of mtDNA is another key aspect of the energy metabolism and mitochondrial function. We investigated the prognostic role of peripheral blood common mitochondrial deletion (mtDNA 4977 ) and mtDNA-CN on long-term major adverse cardiac events (MACEs) and all-cause mortality in a cohort of patients with coronary artery disease (CAD). Methods: Within the Italian GENOCOR (Genetic Mapping for Assessment of Cardiovascular Risk) cohort, we studied 515 patients (450 males, 65 ± 8 years) with known or suspected stable CAD. mtDNA 4977 deletion and mtDNA-CN were assessed in peripheral blood using qRT-PCR. Results: During a mean follow-up of 4.5 ± 1.1 years, 78 (15%) patients had MACEs (15 cardiac deaths, 17 nonfatal myocardial infarction and 46 coronary revascularizations) and 28 patients died for non-cardiac causes. Patients with high levels of mtDNA 4977 deletion (>75th) had increased risk of MACEs (log rank = 7.2, p =0.007) and all-cause mortality (log rank = 5.7, p =0.01) compared with patients with low mtDNA 4977 deletion (≤75th). Multivariate Cox regression analysis showed that log mtDNA 4977 was a significant predictor of MACEs (HR = 2.17; 95% CI, 1.31–3.59; p =0.003) and all-cause mortality (HR = 2.03; 95% CI: 1.13–3.65, p =0.02). Log mtDNA-CN was not significantly associated with MACEs or all-cause mortality. However, patients with high mtDNA 4977 deletion (>75th) and low mtDNA-CN (<25th) had significantly increased risk for MACEs (HR: 3.73; 95% CI: 1.79–7.79; p =0.0005). Conclusions: Mitochondria DNA damage was associated with an increased risk of MACEs and all-cause mortality in patients with stable CAD, confirming the critical role of mitochondrial dysfunction in atherosclerosis. Highlights: High levels of mtDNA 4977 deletion were associated with MACEs and all-cause mortality in the CAD population. The presence of high mtDNA 4977 deletion/ low mtDNA-CN levels was associated with an increased risk of MACEs and all-cause death. Mitochondrial DNA damage may be an important pathogenetic factor and a potential target of therapeutic intervention.