Coenzyme Q10 (CoQ) has long been utilized as a cardioprotective drug treating myocardial ischemic heart disease, heart failure, and cardiotoxic chemical intoxication. As a member of the mitochondrial electron transfer chain, CoQ is directly involved in energy transduction and aerobic ATP production; it transports electrons in the respiratory chain and couples the respiratory chain to oxidative phosphorylation.1,2 In addition, CoQ is a powerful antioxidant not only within the mitochondria but also in other organelle membranes containing CoQ.3 It is now apparent that reactive oxygen species (ROS) are a common mediator of cytotoxic stress. The biochemical mechanisms underlying the toxicity of ROS are their ability to peroxidize membrane phospholipids with unsaturated free fatty acid and interaction with certain sulfhydryl proteins essential for maintaining normal cell function. The net result of free radical-induced damage appears to be altered membrane function and structure. Eventually, the altered handling of ionic gradients results in intracellular calcium overload leading to activation of calcium-dependent degradation enzymes such as calcium-activated neutral proteases and phospholipases, wasting of energy by activating calcium-dependent ATPase, and mitochondrial dysfunction due to energy-dependent uptake of calcium by mitochondria. Accumulation of calcium in the mitochondrial matrix above the critical level results in the activation of cell death cascade as will be discussed later.
The rationale for employing ROS scavengers in the face of ischemia and reperfusion is based on the fact that ischemia and reperfusion increase free radical generation and that an antioxidative defense system is compromised during these periods. Several animal studies support the theory of ROS-induced myocardial damage during ischemia and reperfusion. Myocardial reperfusion has been shown to increase ROS generation.4-6 On the other hand, the activity of superoxide dismutase and glutathione peroxidase is reduced and cellular glutathione is depleted during myocardial ischemia and reperfusion.7,8 Pretreat-ment of animals with ROS scavengers has been demonstrated to reduce myocardial injury and improve cardiac function during reperfusion.9-11 Likewise, the studies examining CoQ as a therapeutic agent indicate that its major action in protecting the heart from reperfusion damage is primarily derived from antioxidation. The feasibility of CoQ treatment has been supported by several studies. The level of endogenous CoQ decreases during reperfusion, and administration of CoQ increased mitochondrial CoQ level and inhibited its reduction during reperfusion.12,13 Biosynthesis of CoQ after reperfusion is impaired especially in aged animals.14 Finally, mitochondrial CoQ content is decreased after simulated reperfusion associated with free radical generation.15
Myocardial protection by exogenous CoQ was first reported by Nayler.16 She demonstrated that rat hearts pretreated with CoQ had significantly less depletion of ATP and less severe ultrastructural changes compared to controls after postischemic reperfusion. Since then, numerous animal studies have been performed using CoQ as a cardioprotectant and most of them have proven that exogenous CoQ is useful in myocardial protection. The beneficial effects of CoQ on myocardial energy metabolism have been most convincingly demonstrated in global ischemia models. CoQ treatment was capable of increasing myocardial high energy phosphate compounds following reperfusion 17,18 and improving left ventricular function.19 Animal studies of acute myocardual infarction also have shown improvement of left ventricular function and inhibition of ultrastructural deterioration after acute occlusion of coronary arteries by preischemic intravenous administration of CoQ in rats and dogs.20,21 However, it has been shown that acute administration of CoQ failed to reduce infarct size after acute coronary artery occlusion and reperfusion in rabbits.22 The reason for this apparent discrepancy is unknown, but may be related to differences in species and in parameters of myocardial protection. In contrast, Ferrara and coworkers reported that after 4 weeks of dietary supplementation with CoQ10, tissue concentration of CoQ10 was elevated by 22%, and oxidative stress was significantly suppressed.23 Morita and coworkers showed that administration of CoQ 10 before the onset of reoxygenation on cardiopulmonary bypass reduced oxygen-mediated myocardial injury and attenuated myocardial injury after cardiopulmonary bypass in pigs.24 In a recent study, a group of pigs were fed coenzyme Q10 supplements with their regular diets for 30 days while another group of pigs were fed a regular diet supplemented with a placebo for the same time period and served as controls. At the end of 30 days, isolated in situ pig hearts were prepared and hearts perfused with a cardiopulmonary pump system. Each heart was subjected to 15 minutes of regional ischemia by snaring LAD followed by 60 minutes of hypothermic cardiople-gic global ischemia and 60 minutes of normothermic reperfusion. Contractile function was evaluated by measuring left ventricular developed pressure (LVDP) at preischemic baseline and during reperfusion. Blood perfusate was collected at the preischemic baseline and during reperfusion to estimate creatine kinase (CK) and malonaldehyde (MDA) contents. At the end of the experiments, myocardial infarct size was measured by TTC staining methods. Separate groups of pigs (CoQ10-fed and unfed) were used to assess CoQ10 content. The CoQ10 fed group revealed higher content of CoQ 10 (21.5 ± 0.7 vs. 28.0 ± 0.5 pg/g heart) indicating bioavailability of CoQ10 in heart. Postischemic left ventricular contractile function was better recovered in the CoQ10 group as compared with the control group of pigs. For example, at the end of 2 hours of reperfusion, developed pressure (DP) (92 ± 3.9 vs. 131 ± 4.2 mmHg) and maximum first derivative of DP (LVmaaxdp/dt) (1110 ± 98 vs. 1976 ± 85 mmHg/sec) were higher for the hearts of CoQ10-fed pigs. CoQ10-fed pigs revealed smaller myocardial infarctions and lesser CK release from the coronary effluent compared to those for the non-CoQ10-fed animals. The CoQ10 group of pigs demonstrated lesser amounts of MDA in the coronary effluent and a higher content of antioxidant reserve in the heart. The results of this study demonstrated that nutritional supplementation of CoQ10 could render the hearts resistant to ischemic reperfusion injury probably by reducing the oxidative stress.
The effects of CoQ on patients with ischemic heart disease have been investigated. Hiasa et al.23 evaluated exercise tolerance in a placebo-controlled trial utilizing intravenous administration of CoQ 1.5 mg/kg once daily for 7 days versus placebo in 18 patients with chronic stable angina. The mean exercise time in the CoQ group at day 7 had significantly increased compared to placebo treatment, suggesting that CoQ treatment induced tolerance to myocardial ischemia. Randomized, double-blind placebo-controlled trials of oral administration of CoQ have confirmed the effectiveness of CoQ in improving anginal episodes, arrhythmias, and left ventricular function in patients with acute myocardial infarction.24 The potential benefit of long-term oral administration of CoQ has emerged from the clinical trial for patients with chronic heart failure. CoQ is deficient in patients with congestive heart failure25 and supplimentation of CoQ benefits such patients.26 The efficacy of long-term CoQ treatment on cardiac function and myocardial energy metabolism has been confirmed experimentally in rats with chronic heart failure.27 CoQ has been employed in treatment for adriamycin cardiotoxicity. Many years ago, adriamycin, an anthoracycline, and mixed quinoid and hydroquinoid compounds were shown to have inhibitory effects on CoQ enzyme systems28 and several experimental studies demonstrated that exogenous CoQ prevented adriamycin-induced myocardial damage.29,30 CoQ has also been employed in attempts to improve postischemic cardiac function in open heart surgery. Either oral administration for 7 days before surgery or intravenous administration 30 minutes before cardiopulmonary bypass was shown to be effective in mitigating postoperative pump failure.31,32 Another study,33 however, failed to demonstrate myocardial protection during cardiac operations by short-term oral supplementation with CoQ. The differences of effectiveness by exogenous CoQ may in part be due to its hydrophobic nature, which prevents CoQ from gaining access to intracellular organelles where CoQ exerts cytoprotective action. Perhaps optimal tissue distribution of CoQ requires several days by oral administration, but can be shortened by intravenous treatment of liposomal form of CoQ. Cardioprotective effects of CoQ are not confined to cardiomyocytes, but are also beneficial in improving coronary endothelial function.34 Protection of both cardiomyocytes and endothelial cells from reperfusion injury could synergistically enhance the recovery of myocardial function during reperfusion. In summary, although there is some controversy on the efficacy of CoQ in treating cardiovascular diseases, the prevailing opinion suggests that CoQ may have a potential role in protecting myocardium from energy depletion and ROS overproducing events.
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