Mitochondrial Dysfunction Induced by Statin Contributes to Endothelial Dysfunction in Patients with Coronary Artery Disease

Abstract

Despite the use of statin therapy, a significant proportion of patients with coronary artery disease (CAD) still develop cardiovascular events. We hypothesized that development of mitochondrial dysfunction (MD) after statin therapy might be linked to endothelial dysfunction and thus limiting its beneficial effects. We studied the effect of MD on endothelial function in 119 patients with CAD on long-term statins (>1 year). Brachial artery flow-mediated dilation (FMD) was assessed by high-resolution ultrasonography and blood levels of lactate, pyruvate, fasting glucose, and lipids were measured. MD (defined by a lactate/pyruvate ratio >75th percentile of the age- and sex-matched normal controls, i.e., > or = 18) was observed in 43/119(36%) patients. There were no significant differences in age, gender, and clinical characteristics between patients with or without MD (all P > 0.05). Patients with MD received higher dose of statin (23.5 +/- 19.3 vs. 17.1 +/- 10.5 mg simvastatin-equivalent dose, P = 0.05) and had lower FMD (2.69 +/- 2.94 vs. 4.33 +/- 2.80%, P = 0.003) than those without MD. Multivariate analysis showed that statin dosage was independently associated with MD (OR:1.03, P = 0.03), and MD significantly predicted an absolute 1.36% decrease in FMD (P = 0.01). In conclusion, a significant proportion of patients with CAD on statin developed MD, which was associated with high-dose statin and with impaired FMD, suggesting that increased statin dosage may induce MD and contribute to endothelial dysfunction in patients with CAD.

Association of Lower Habitual Physical Activity Level With Mitochondrial and Endothelial Dysfunction in Patients With Stable Coronary Artery Disease

“…25 In patients with CAD, the presence of mitochondrial dysfunction has been associated with impaired endothelial function. 13 Indeed, the findings from our study indicated that mitochondrial dysfunction and its blood marker, the LP ratio, both significantly correlated with impairment of FMD. Furthermore, mitochondrial dysfunction was associated with a significant relative impairment of 26% in endothelial function, suggesting that the endothelial dysfunction related to lower PAL was at least partly mediated through the occurrence of mitochondrial dysfunction.…”

“…11, 12 Clinical studies have also demonstrated an association between mitochondrial dysfunction and impaired endothelial function in patients with CAD. 13 The lactate/pyruvate (LP) ratio is an established indirect serum marker of mitochondrial dysfunction, 13,14 as the impaired oxidative phosphorylation in the mitochondria is associated with excessive hydrolysis of ATP and production of more protons, which drives the equilibrium reaction from pyruvate to lactate, leading to an increased LP Physical Activity and Endothelial Function ratio. 13, 14 Although exercise training has been reported to augment mitochondrial content and function in human skeletal muscle, [15][16][17] there is limited evidence on whether physical activity modulates mitochondrial function in high-risk CAD patients.…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…On the other hand, high micromolar concentrations of statins, 100-to 200-fold higher than serum statin levels in patients, have been reported to induce apoptosis (Katsiki et al, 2010). Moreover, the inhibition of ubiquinone synthesis by statins, which is essential for a proper mitochondrial function, might be responsible for mitochondrial dysfunction, which has been proposed as a STATINS AND CANCER: PROS AND CONS 113 possible cause of statin-induced myopathy, suggesting the possibility of contrasting such detrimental effect with supplements of ubiquinone (Dai et al, 2010).…”

Potential Non-Hypoxic/Ischemic Causes of Increased Cerebral Interstitial Fluid Lactate/Pyruvate Ratio: A Review of Available Literature

“…Long-term statin use also can be associated with elevated blood LPR, presumably due to statins' inhibition of mevalonate synthesis. Mevalonate is a precursor of ubiquinone, which is a key component of complexes I and II of the ETC [72].…”