Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis

Abstract

BackgroundMitochondria are energy-producing structure of the cell and help to maintain redox environment. In cardiovascular disease, the number of mitochondrial DNA (mtDNA) will changes accordingly compare to normal condition. Some investigators ask whether it has a clear association between mtDNA and cardiovascular disease with its adverse events. Thus, we conduct the meta-analysis to assess the role of circulating mtDNA in evaluating cardiovascular disease.MethodsThe meta-analysis was conducted in accordance with a predetermined protocol following the recommendations of Cochrane Handbook of Systematic Reviews. We searched the Pubmed, Embase, the Cochrane Central Register of Controlled Trials and World Health Organization clinical trials registry center to identify relevant studies up to the end of October 2017. Data were analyzed using STATA. Besides, publication bias and meta-regression analysis were also conducted.ResultsWe collected results from 5 articles for further analyses with 8,252 cases and 20,904 control. The normalized mtDNA copy number level is lower in cardiovascular disease (CVD) than the control groups with a pooled standard mean difference (SMD) of -0.36(95%CI,-0.65 to -0.08); The pooled odds ratio (OR) for CVD proportion associated with a 1-SD (standard deviation) decrease in mtDNA copy number level is 1.23 (95% CI,1.06–1.42); The OR for CVD patients with mtDNA copy number lower than median level is 1.88(95% CI,1.65–2.13); The OR for CVD patients with mtDNA copy number located in the lowest quartile part is 2.15(95% CI, 1.46–3.18); the OR between mtDNA copy number and the risk of sudden cardiac death (SCD) is 1.83(95% CI, 1.22–2.74).ConclusionAlthough inter-study variability, the overall performance test of mtDNA for evaluating CVD and SCD revealed that the mtDNA copy number presented the potential to be a biomarker for CVD and SCD prediction. Given that, the fewer copies of mtDNA, the higher the risk of CVD.

Mitochondrial DNA copy number and incident heart failure: The Atherosclerosis Risk in Communities (ARIC) study

“…Decreased mtDNA-CN is associated with CVD events, including sudden cardiac death, all-cause mortality, hypertension, diabetes, and chronic kidney disease. [12][13][14][15][16][17][18] However, the association between mtDNA-CN and incident HF is largely unknown. In animal studies, mtDNA damage and depletion were associated with the development of dilated cardiomyopathy and impaired left ventricular remodeling after ischemic injury.…”

“…10,11 Reduced mtDNA-CN measured in peripheral blood is associated with cardiovascular disease (CVD), all-cause mortality, hypertension, diabetes, chronic kidney disease, and sudden cardiac death. [12][13][14][15][16][17][18] In a case-control study, hospitalized patients with HF had lower mtDNA-CN in peripheral blood compared to controls without HF, and when HF cases were followed up, those with lower mtDNA-CN had a higher risk of cardiovascular death and rehospitalization compared to those with higher mtDNA-CN. 19 In small case-control studies, depletion of mtDNA in heart tissue samples was associated with HF.…”

Peripheral Blood Mononuclear Cells and Platelets Mitochondrial Dysfunction, Oxidative Stress, and Circulating mtDNA in Cardiovascular Diseases

“…When mtDNA damage occurs, it results in mitochondrial dysfunction, inflammation, and cell senescence participating in the pathogenesis of CVDs and atherosclerosis. The mtDNA copy number might reflect the level of mtDNA damage, potentially being a biomarker of mitochondrial function and a predictor of CVDs' risk and prognosis [77,79,81].…”

Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution

“…Cellular coordination of mtDNA content is a dynamic and tightly regulated process (Li et al 2005;Scarpulla 2006;Wu et al 2006); however, the mechanisms by which mtDNA copy number is monitored and controlled are not well understood (Moraes 2001;Clay Montier et al 2009;Klingbeil and Shapiro 2009). In addition, alterations in mtDNA levels often accompany key pathophysiological changes during the transition from healthy to diseased states (Butow and Avadhani 2004), and a number of age-related diseases correlate with mtDNA abundance, including cardiovascular disease (Yue et al 2018), type 2 diabetes (Malik et al 2009;Monickaraj et al 2012), cancer (Afrifa et al 2018), and dementia (Rice et al 2014;Pyle et al 2016). Furthermore, mtDNA levels in peripheral blood mononuclear cells (PBMCs) gradually decrease during aging and are associated with health status among the elderly (Mengel-From et al 2014;Wachsmuth et al 2016), suggesting that mtDNA may be a biomarker of biological (not chronological) age and disease exposure (Pieters et al 2015;Qiu et al 2015;Tyrka et al 2015).…”