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Clin Biochem Rev. May 2008; 29(2): 71–82.
PMCID: PMC2533152

Coenzyme Q10: Is There a Clinical Role and a Case for Measurement?

Abstract

Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ10 supplements are available over the counter from health food shops and pharmacies. CoQ10 deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson’s disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ10 concentrations. The case for measurement of plasma CoQ10 is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ10 supplementation plasma CoQ10 levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ10 absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ10 has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ10 does indeed have an important clinical role and in particular, whether there is a case for measurement.

Introduction

CoQ10, a 1,4-benzoquinone with a 50-carbon isoprenoid side chain, was first isolated from beef heart mitochondria by Frederick Crane of Wisconsin, USA, in 1957.1 Various CoQ homologues, containing different numbers of isoprenoid units in the sidechain, exist and both CoQ9 and CoQ10 are present in human plasma. The latter is the dominant homologue.2 CoQ10 is present in the body in both the reduced (ubiquinol, CoQ10H2) and oxidised (ubiquinone, CoQ10) forms. Oxidised CoQ10 is reduced to CoQ10H2 in the mitochondria by flavoenzymes including mitochondrial succinate dehydrogenase and NADH dehydrogenase.3 CoQ10 is lipophilic and transported in lipoprotein particles in the circulation. It is not surprising therefore that plasma CoQ10 correlates positively with plasma total cholesterol and LDL-cholesterol.411 CoQ is synthesised in the body, and is also obtained from the diet, with meat products being the largest source in the normal diet.12

CoQ10 is an essential cofactor in mitochondrial oxidative phosphorylation, and is necessary for ATP production (Figure 1). In this role, CoQ10 acts as a mobile electron carrier, transferring electrons from complex I (NADH coenzyme Q reductase) to complex III (cytochrome bc1 complex) or from complex II (succinate dehydrogenase) to complex III. The reduced form of CoQ10 is also an antioxidant, and is the only endogenously synthesised lipophilic antioxidant. It can act as an antioxidant directly, protecting biological membranes against oxidation,13 as well as inhibiting the peroxidation of lipoprotein lipids present in the circulation.14 Indeed, supplementation with exogenous CoQ10 has been shown to lead to an increase in the CoQ10H2 content of LDL, and a decrease of their peroxidisability.15 As an antioxidant, CoQ10H2 may also have a role recycling α-tocopherol, as reviewed by Sohal.16

Figure 1
The mitochondrial electron transport chain. NADH = nicotinamide adenine dinucleotide, Q = CoQ10, C = cytochrome C, Fe-S = iron-sulfur clusters, C1 = cytochrome C1, b = cytochrome b, a1-Cu = copper associated with cyctochrome a1, ADP = adenosine diphosphate, ...

Measurement of CoQ10

Methodological Aspects

CoQ10 is almost always measured by high performance liquid chromatography (HPLC) after extraction from plasma or tissue. Because of the highly hydrophobic nature of CoQ10, it is usually separated on a highly hydrophobic reverse-phase column such as a C18-column with a high carbon load, with a mobile phase based on lower alcohols, sometimes with hexane or heptane included.

Extraction

Although some older methods use two-phase extraction systems, with combinations of hexane and lower alcohols, protein precipitation and extraction with 1-propanol is simple, more direct, and is now the method of choice. To obtain quantitative extraction the ratio of the volume of propanol to plasma or tissue should be greater than 5.7

Detection

Electrochemical detection is the most sensitive and selective detection method,17 and allows measurement of both ubiquinone and ubiquinol in the same plasma sample. Electrochemical detection is also sensitive enough to detect CoQ9 in human plasma simultaneously with CoQ10.2 Tandem mass spectrometric detection has been used,18 but since the ubiquinones and ubiquinols of both CoQ9 and CoQ10 give the same fragmentation ions there is no obvious advantage compared with electrochemical detection.

Internal Standards

When simple liquid-liquid extraction of CoQ10 from plasma is achieved using 1-propanol, recovery is approximately 100% and it is questionable whether an internal standard is necessary. The most commonly used internal standard for measurement of CoQ10 is CoQ9, however since CoQ9 is found endogenously in human plasma, it is not an ideal internal standard.2

Percentage of Reduced CoQ of total CoQ10

CoQ10H2 is rapidly oxidised to CoQ10 by oxygen, hence measuring it in plasma specimens is demanding. The percentage CoQ10H2 of total CoQ10 in plasma has been reported variously from 51 to 96%,7,8,1927 and it is presumed that this discrepancy is due to a variable conversion of CoQ10H2 to CoQ10 before analysis. To maintain the endogenous CoQ10H2 it is necessary to employ meticulous pre-analytical sample handling, processing blood samples rapidly and freezing plasma to −80 °C. Therefore it is not practicable to offer the routine analysis of the percentage of CoQ10H2 in the total CoQ10 as a clinical diagnostic test.

Plasma and Tissue CoQ10

Measurement of both plasma20,28 and tissue CoQ10 has been reported.29 However, the relationship between plasma and tissue CoQ10 levels is not yet clear, and plasma levels should only be regarded as a surrogate for tissue,30 and in particular mitochondrial levels, where any therapeutic effect of CoQ10 may be expected to be most important. The primary problem with measuring tissue levels is access to tissue samples. Blood cells have been used for estimates of CoQ10 in tissues.31 CoQ10 content of blood mononuclear cells was shown to correlate with skeletal muscle CoQ in unsupplemented subjects whereas the plasma concentrations did not.32 There would appear to be no clinical value in measuring erythrocyte CoQ10, but there may be a possible case for considering its measurement in platelets or other mitochondria-containing blood cells, though pertinent reference ranges would need to be established.

Reference Interval

It has been well established that the adult reference interval for plasma or serum CoQ10 is approximately 0.5 – 1.7 μmol/L.4,26,33,34 Because plasma CoQ10 and lipid concentrations correlate strongly, it has been proposed that lipids should be considered when measuring plasma CoQ10,5,9 and the ratio of CoQ10 to total- or LDL-cholesterol reported.

Factors Affecting Plasma CoQ10 Concentration

Whether there is a gender difference in CoQ10 levels is controversial, with both a significant difference4,6,35 and no difference19,33,36 being reported. Although there was a significant gender difference in both total CoQ10 and the CoQ10 to total cholesterol ratio, we found no basis for stratification of the total CoQ10 reference interval for gender according to the Harris and Boyd criteria.4,37

The effect of ageing on CoQ10 is unclear, with reports that CoQ10 correlates positively with age, an association which disappears when total cholesterol is included in multivariate analysis,4,10 or conversely that there is no association between CoQ10 and age.35,38 Clinically healthy infants (1–12 months) and preschoolers (1–6 years) have been shown to have significantly higher total CoQ10 than school aged children (6– 15 years) (median CoQ10 0.98, 1.0 and 0.81, respectively).39 The ratio of CoQ10 to total cholesterol was significantly higher in the infants compared to the elder subgroups.39 Furthermore, Menke et al. reported that infants in the first to fourth month of age have significantly lower total CoQ10 than subgroups of infants aged five to eight, or nine to twelve months.39 CoQ10 has been shown to correlate positively with BMI.4,6,10,35,40

There is substantial evidence that plasma CoQ10 is reduced by the cholesterol lowering medication HMG-CoA reductase inhibitors (statins). This is not surprising, since both CoQ10 and cholesterol are synthesised by the mevalonate pathway (Figure 2). Numerous studies have demonstrated reductions of up to 54% in plasma/serum CoQ10 concentrations following statin therapy.41,42 The magnitude of the statin-induced depletion of CoQ10 levels has been shown to be dose related,43 and is reversible on cessation of statin therapy.44 It is possible the reduction in circulating CoQ10 may reflect decreased LDL-cholesterol concentrations. However, several studies have reported a lower CoQ10 to LDL-cholesterol ratio after statin treatment,43,45,46 suggesting CoQ10 depletion may not only be due to a reduction in LDL-cholesterol carriers, although this has not been consistently shown in all trials.44,47,48

Figure 2
The mevalonate pathway. Inhibition by HMGCoA reductase by statins leads to depletion in products of the pathway including cholesterol and possibly CoQ10.

Circulating concentrations of CoQ10 do not necessarily reflect tissue CoQ10 concentrations, and clinical studies evaluating the effect of statin treatment on skeletal muscle CoQ levels are contradictory. In an early trial, four weeks of simvastatin (20 mg/day) produced a 47% increase in muscle CoQ10 concentrations,48 and six months of treatment with 20 mg/day of simvastatin gave a similar result.47 One trial comparing the effect of eight weeks of simvastatin 80 mg/day, atorvastatin 40 mg/day, or placebo on muscle CoQ10 levels, reported a 34% reduction in those treated with simvastatin.49 However, in a recent study there was no significant difference in the mean intramuscular CoQ10 concentration in patients with statin-related myopathy compared to controls.50

Several studies have shown that supplementation with oral CoQ10 can restore plasma CoQ10 levels in patients receiving statin therapy.5153 The long-term effect of statin-induced plasma CoQ10 decreases, especially considering the increasingly popular intensive lipid lowering via statins, is not yet clear, and should be monitored.

CoQ10 Supplementation

There are many different brands of CoQ10 supplement available, and their formulations can differ widely in respect to whether they contain reduced or oxidised CoQ10, whether they are dry powder capsules or CoQ10 dispersed in oil, and whether they contain surfactants and emulsifiers, such as lecithin and polysorbate 80 to improve absorption. There is a significant difference in bioavailability of the various brands and formulations of CoQ10 supplement.54 The majority of bioavailability studies have focussed on plasma CoQ10 levels rather than the mitochondrion, however new analogues have been developed with a view to enhanced mitochondrial uptake, including mitoquinone-Q (Mito-Q)55. These drugs are currently under investigation. Moreover, there is also a significant difference in absorption of CoQ10 from supplements between individuals.36,40,54,5658 These two points highlight the need for measurement of plasma CoQ10 concentrations during supplementation, to monitor efficacy.

Biological Variation, Reference Change Value, and Index of Individuality

Biological variation quantifies changes in the concentration of an analyte over time. For CoQ10, the CoQ10 to LDL-cholesterol ratio, and the CoQ10 to total cholesterol ratio in healthy young males, the intra-individual variation is 12, 15 and 14%, respectively, and the inter-individual variation is 29, 26, and 18%, respectively.4 From this biological variation data the reference change value (RCV), an estimate of the percentage change required in the concentration of an analyte for the change to be (at a specified probability) likely to be due to something other than normal biological variation, can be calculated. The RCV for a 95% significant change in CoQ10 is 35%, and for a 99% significant change is 46%.4 An index of individuality (II) (intra-individual variation/inter-individual variation), which numerically determines whether reference intervals are of use when determining whether a change in the concentration of an analyte is significant or not, can also be calculated. When the II is high (>1.4) reference intervals are helpful, but when the II is low (<0.6) a clinically significant change in the concentration of the analyte can occur, while the concentration still remains within the reference interval. The II for CoQ10 is 0.42, which is low. Thus many individuals can experience a significant reduction in plasma CoQ10, and others a significant increase, while their values remain within the reference interval.4

Clinical Aspects of CoQ10

Primary CoQ10 Deficiency

Ogashara et al. described the first patients (two sisters) with primary CoQ10 deficiency in 1989.59 The patients, aged 12 and 14, had progressive muscle weakness, abnormal fatigue, and central nervous system dysfunction from early childhood. The CoQ10 concentration in their muscles was markedly decreased, being about 5% of normal, but was normal in serum and cultured fibroblasts.59 It was concluded that the primary defect in these sisters probably involved a tissue-specific isozyme in the CoQ10 synthetic pathway of muscle and brain, and both patients improved remarkably with oral CoQ10.59

In 2000, Rötig reported a much more dramatic variant of CoQ10 deficiency, which presented as infantile mitochondrial encephalomyopathy (a CoQ10 biosynthetic defect) with widespread CoQ10 deficiency and nephritic syndrome.60 In 2007, Mollet and colleagues documented molecular defects in three of the nine genes required for CoQ10 biosynthesis, all of which are associated with early and severe clinical presentations.61

CoQ10 deficiency can be classified into four major clinical categories as below, probably representing a mixture of primary and secondary CoQ10 deficiency.

  1. Myopathy with recurrent myoglobinuria and CNS involvement
  2. Cerebellar ataxia with variable CNS involvement
  3. Isolated myopathy
  4. Infantile mitochondrial encephalomyopathy

The most severe, and earliest presenting variant of CoQ10 deficiency is infantile mitochondrial encephalomyopathy, which occurs due to defects in CoQ10 biosynthesis.

More recently, genetic defects in steps of CoQ10 biosynthesis have been characterised (CoQ2, PDSS1, PDSS2) with the likelihood that other steps will also be shown to be implicated in clinical disorders and with the corollary that CoQ10 supplementation may confer clinical benefit.62 Exogenous CoQ10 supplementation has been shown to lead to improvements in the status of patients with CoQ10 deficiency.59,60,6365

CoQ10 and Statin Myopathy

The underlying pathophysiology of statin-induced myopathy is unknown, but one postulated mechanism is mitochondrial dysfunction through depletion of CoQ10,66 since CoQ10 is an essential cofactor in the mitochondrial electron transport chain67 (Figure 1) and mitochondria are essential for normal muscle function. Post-marketing studies have indicated up to 13.6% of statin treated patients experience some degree of myopathy,68 and as targets for cholesterol reduction become progressively lower, necessitating higher statin doses, the risk of side effects, particularly myopathies, has increased.69,70

A small number of studies have provided some evidence of impaired mitochondrial function in statin-induced myopathy. De Pinieux et al. observed significant elevations in the lactate to pyruvate ratio, an indirect marker of mitochondrial dysfunction, in statin-treated hypercholesterolaemic patients compared to untreated patients (p<0.02) and controls (p<0.001).45 Additionally, four case reports of statin induced myopathy, despite normal creatine kinase levels, demonstrated increased intramuscular lipid, diminished cytochrome oxidase staining and ragged red muscle fibres in muscle biopsy samples, findings consistent with mitochondrial dysfunction.71 These abnormalities resolved following discontinuation of statin therapy in the three patients who had repeat biopsies. In contrast, a study by Lamperti et al. revealed that only 2 of 18 muscle biopsies taken from patients with statin-induced myopathy showed evidence of mitochondrial dysfunction, along with mildly decreased intramuscular CoQ10 levels.50

To date, only two randomised trials have investigated the effect of CoQ10 administration on statin-induced myalgia, with contrasting results.72,73 In the first study, Caso et al. reported a 40% reduction in myopathic pain (p<0.001) after 30 days of 100 mg/day of CoQ10 supplementation compared with no change following 400 IU/day of vitamin E in patients with statin-related myopathy on concurrent statin treatment.72 This trial lacked a placebo-control design and patients were not on a standardised dose or type of statin. In the second study, we randomised 44 patients with prior statin-induced myalgia to treatment with 200 mg/day of CoQ10 or placebo for 12 weeks in combination with upward dose titration of simvastatin at 10 mg/day, doubling every 4 weeks if tolerated to a maximum of 40 mg/day.73 Plasma CoQ10 increased with supplementation, but there were no significant differences in the myalgia score change (median 6.0 vs 2.3, p = 0.63), in the number of patients who tolerated 40 mg/day simvastatin (CoQ10 16/22 (73%) vs 13/22 (59%), p = 0.34); or in the number remaining on any simvastatin dose (16/22 (73%) vs 18/22 (82%), p=0.47), between statin and CoQ10 therapy and statin alone.

Adequately powered randomised controlled trials are now required to establish if there is a role for CoQ10 supplementation in reducing or eliminating statin myopathy. Considerations for such trials should include clearly defined myopathy by statin withdraw and re-challenge, initiation of CoQ prior to statin therapy, a more objective myopathic pain score and muscle biopsy studies.

An important factor contributing to statin related myopathy may be genetic susceptibility to muscle disorders and underlying metabolic myopathies. Oh et al. reported a 2.33–2.58 fold increase in the relative risk of statin intolerance associated with polymorphisms in the CoQ2 gene.74 Furthermore, Vladutiu et al. observed a four-fold increase in mutant alleles of common mutations for three metabolic myopathies: carnitine palmitoyltransferase II deficiency, McArdle’s disease and myoadenylate deaminase deficiency, in individuals with primarily statin-induced myopathies.75 Individuals with mutations for underlying metabolic myopathies may therefore represent a subgroup of the statin-treated population for whom CoQ10 may be more likely to confer a clinical benefit. More recently the CYP2D6*4 polymorphism, which reduces statin metabolism, has been linked to statin-induced muscle effects.76 Improved identification and detection of relevant susceptibility genotypes may allow CoQ10 to be more appropriately targeted in patients with statin-myalgia, leading to a further enhanced safety profile for statins.

CoQ10 and Heart Failure

Given the importance of CoQ10 in mitochondrial electron transport and ATP synthesis, its depletion has been postulated to compromise myocardial energy generation and lead to “energy starvation” of the myocardium, considered to be a pathogenic mechanism of chronic heart failure (CHF).77 Recent evidence suggests a role for CoQ10 as a predictor of outcomes and also as an adjunctive clinical therapy and supplementation is routine in some countries, such as Japan.77

Myocardial depletion of CoQ10 has been demonstrated in heart failure and the severity of the deficiency has been found to correlate with the severity of symptoms, with patients in NYHA class IV having significantly lower CoQ10 in endomyocardial biopsy samples than those in NYHA class I.30 This myocardial CoQ10 deficiency in patients with cardiomyopathy was also reversed by CoQ10 therapy.30

An interesting observation is that total cholesterol is related to survival in CHF.78,79 In the study of Rauchhaus et al. serum total cholesterol was independently associated with total mortality in a CHF cohort, with increasing total serum cholesterol predicting survival (hazard ratio 0.64, 95% CI 0.48 to 0.86), independent of the aetiology of CHF, age, left ventricular ejection fraction and exercise capacity.78 Postulated mechanisms for this association were that cholesterol may be limiting lipopolysaccharide-induced production of cytokines and that high cholesterol may provide “greater metabolic reserve” to deal with the CHF syndrome. The authors did not, however, make reference to CoQ10, which is known to correlate with plasma total and LDL-cholesterol concentration,4 and which could be postulated to explain the worse outcomes seen in patients with low cholesterol in CHF patients. Cardiac cachexia (lean tissue wasting associated with heart failure) was not thought to be an important mechanism, given that lipid levels were no different between patients with and without cachexia and that survival was independent of the presence of cachexia.78

In a recent observational study, we showed that CoQ10 levels, but not statin therapy (known to lower CoQ10 in heart failure41) were an independent predictor of total mortality in an observational study of 236 subjects with heart failure.80 We were unable to confirm that cholesterol was associated with survival in this cohort,80 although our patients were older and followed for longer than the cohort of Rauchhaus et al.78

Meta-analyses of CoQ10 supplementation in CHF have been undertaken.81,82 Soja and Mortensen81 reviewed eight double-blind placebo-controlled studies and reported a significant improvement in stroke volume, ejection fraction, cardiac output, cardiac index and end diastolic volume index, as a consequence of CoQ10 supplementation.8390 In a more recent meta-analysis, Sander et al. reviewed eleven studies,82 ten that evaluated ejection fraction83,85-87,9095 and two that evaluated cardiac output89,91 with CoQ10 doses ranging from 60–200 mg/day and treatment periods ranging from 1–6 months. Overall, a 3.7% (95%CI 1.59–5.77) net improvement in the ejection fraction was found, and cardiac output was increased on average of 0.28 L/minute (95%CI 0.03–0.53).82

An international, randomised, double-blind multi-centre intervention study, “Q-SYMBIO” has been initiated with CoQ10 supplementation in CHF patients and focus on symptoms, biomarker status (BNP) and long-term outcomes.77 This study is expected to report in 2009. Coupled with the findings of the meta-analyses81,82 a positive result to Q-SYMBIO may be expected to increase the acceptance of CoQ10 as an adjunctive therapy in addition to the current medical strategies.

Interest has recently focussed on whether statins may confer benefit or not in patients with CHF, given the likely underlying ischemic aetiology in many patients.96 However, the Controlled Rosuvastatin Multinational Trial in heart Failure (CORONA) investigators failed to show a reduction in major vascular events in older patients with systolic heart failure.97 One explanation for this may be the reduction in CoQ10, as we have shown to occur in patients with non-ischaemic heart failure.41 We showed that 40 mg atorvastatin led to a 33% reduction in CoQ10 levels in non-ischaemic heart failure subjects, though this did not compromise improvements in endothelial function.41 A significant association (r = −0.585, p = 0.011), between CoQ10 reductions and improvement in endothelial function as measured in the resistance arteries with forearm plethysmography suggested that the improvement in endothelial function with atorvastatin therapy is mediated by “non-lipid pleiotropic” pathways. This study indicates a role of CoQ10 as a potential surrogate marker for improvement in endothelial function in resistance vessels.

Given these observations and the complex interplay of cholesterol, statin therapy and clinical outcomes in heart failure, future trials incorporating a CoQ10 supplementation arm together with statin may be expected to confer improved clinical outcomes that CORONA did not show.97

We have shown that CoQ10 predicts mortality in heart failure, and in all of the intervention trials undertaken to date, those achieving higher plasma CoQ10 levels showed better clinical outcomes.77 Hence there may be a case for measurement of plasma CoQ10 levels, in order to identify those subjects at increased risk of mortality and who might benefit from CoQ10 intervention.80

CoQ10 and Hypertension

A recent meta-analysis of CoQ10 in the treatment of hypertension (12 clinical trials, 362 patients) concluded that, in hypertensive patients, CoQ10 has the potential to lower systolic and diastolic blood pressure, without significant side effects.98 A blood pressure lowering effect of CoQ10 was found across three types of studies including randomised controlled, crossover, and open label. Decreases in systolic blood pressure ranged from 11 to 17 mmHg and in diastolic blood pressure from 8 to 10 mmHg.98 In three of the 12 studies CoQ10 was given in addition to existing anti-hypertensive medication, and in one of these more than 50% of the patients were able to cease taking at least one anti-hypertensive medication during the trial.98 The antihypertensive effect of CoQ10 occurs gradually over several months, and the CoQ10 dose required for effectiveness varies between patients.99

The mechanism for the hypotensive action of CoQ10 may be through CoQ10H2 acting as an antioxidant, decreasing the oxidative stress known to occur in hypertension.98 In this role, CoQ10H2 may counteract vasoconstriction resulting from impaired ability of the endothelium to induce nitric oxide mediated relaxation of underlying smooth muscle.98

Further studies on the role of CoQ10 as an antihypertensive agent are required, with double-blind, randomised, placebo control, and adequate supplementation for efficacy which will require analysis of plasma CoQ10 levels.

CoQ10 and Type 2 Diabetes and Insulin Resistance

A growing body of evidence indicates that oxidative stress plays a critical role in the pathogenesis of type 2 diabetes mellitus and its complications.100 CoQ10 deficiency in type 2 diabetes results from impaired mitochondrial substrate metabolism,101 and increased oxidative stress.100 In diabetes, CoQ10 deficiency is thought to contribute to endothelial dysfunction, and may also be linked to impaired beta-cell function and the development of insulin resistance.102 Low plasma CoQ10 concentrations have been negatively correlated with poor glycaemic control and diabetic complications.103 Since CoQ10 plays an important role in the mitochondrial electron transport chain, and as a potent antioxidant, oral supplementation may be an attractive therapy in type 2 diabetes. Accordingly, a number of clinical trials have shown that CoQ10 can improve glycaemic control,104,105 and lower plasma insulin;104 although these findings are inconsistent with other studies. In addition, several trials have demonstrated a significant blood pressure lowering effect of CoQ10 in patients with type 2 diabetes.104,105 Furthermore, Watts et al. reported an improvement in endothelial function of conduit arteries (i.e. flow mediated dilation of the brachial artery) following 12 weeks of oral CoQ10 therapy in dyslipidemic patients with type 2 diabetes.106 Conversely, two further trials in type 2 diabetic patients failed to show any improvement in microcirculatory function with CoQ10 monotherapy, suggesting that the effect of CoQ10 may be specific to the vascular bed.107,108 Playford et al. did however, observe a significant increase in endothelium-dependent microcirculatory perfusion in type 2 diabetes, with combined CoQ10 and fenofibrate therapy, suggesting that CoQ10 may have the potential to augment the benefits of PPAR-α agonists on vascular function.107 CoQ10 supplementation may also enhance the ability of other anti-atherogenic agents such as statins.102 Further studies, including clinical outcome trials are required to confirm whether there is a role for CoQ10 in treatment of diabetes and its complications.

CoQ10 and Malignancy

CoQ10 may have a role as adjunctive therapy in cancer. In the 1990s there were reports describing regression of metastases in breast cancer patients,109 and suggested CoQ10 deficiency in cancer patients.110 More recently, patients with melanoma were found to have significantly lower plasma CoQ10 levels than controls, and patients who developed metastases had significantly lower plasma CoQ10 compared to those in the metastasis-free subgroup, such that plasma CoQ10 concentrations were a significant predictor of metastasis.111 Co-supplementation of CoQ10 (100 mg/day), riboflavin (10 mg/day) and niacin (50 mg/day) in postmenopausal breast cancer patients treated with Tamoxifen (10 mg twice daily) counteracted Tamoxifen-induced hyperlipidaemia to normal levels.112 It has also been suggested that CoQ10 may protect the heart from anthracycline-induced cardiotoxicity,113 and additionally that it may stimulate the immune system.114 However, there are some concerns regarding CoQ10 supplementation in cancer patients receiving some other anti-cancer treatments, for example, Brea-Calvo et al. found an increased concentration of CoQ10 (due to increased biosynthesis) in cancer cell lines after chemotherapy treatment with camptothecin, etoposide, doxorubicin and methotrexate.115 Inhibition of CoQ10 biosynthesis enhanced camptothecin cytotoxicity, suggesting that CoQ10 increase is implicated in the cellular defence under chemotherapy treatment, and may contribute to cell survival.115 Further research into the use of CoQ10 as an adjuvant treatment in cancer is therefore required.

CoQ10 and Parkinson’s Disease

Parkinson’s disease (PD) is a degenerative neurological disorder characterised by tremor, rigidity and slowness of movement, believed to result from a progressive loss of dopaminergic neurons in the substantia nigra.116 Although the pathological cause of PD is not well understood, mitochondrial dysfunction and oxidative stress are key features of this disorder. Initial evidence implicating mitochondrial respiratory chain dysfunction in PD came from findings that the mitochondrial complex I inhibitor MPTP induces a parkinsonian syndrome.117 Subsequent investigations have demonstrated reduced activity of complex I in platelet mitochondria of PD patients,118 and also in the substantia nigra, but not other areas of the brain in individuals with PD.119 CoQ10 concentrations in platelet mitochondria have been shown to be significantly lower in PD patients compared to matched controls and to correlate with complex I and II/III activity, suggesting that CoQ10 depletion may contribute to cellular dysfunction in PD.120 Furthermore, the CoQ10 ratio of the oxidised to the reduced form is elevated in parkinsonian patients, suggesting increased oxidative stress in PD.121 Taken together, these findings and the dual function of CoQ10 as both an electron acceptor for complexes I and II and a potent antioxidant,67 provide support for the idea that CoQ10 may be a therapeutic strategy in PD. Oral CoQ10 administration in PD patients has been shown to increase plasma CoQ10 levels,122 and has been reported to be safe and well tolerated,122126 at doses as high as 2400 mg.124 Shults et al. investigated the effects of CoQ10 in early PD and found that 1,200 mg/day of CoQ10 slows the progressive deterioration of functions in PD as indicated by the total Unified Parkinson Disease Rating Scale (UPDRS), although it did not affect the UPDRS motor score or postpone the onset of symptomatic therapy.123 In addition, CoQ10 at a dose of 1,200 mg/day was associated with improved complex I activity in this trial.123 Another trial demonstrated improved motor function in patients with early PD following six months of treatment with up to 1,500 mg/day of CoQ10,127 however this study was not placebo controlled. In contrast, other trials have failed to demonstrate significant beneficial effects of CoQ10 in either early PD patients or in those receiving symptomatic therapy.124126 Large phase III trials are needed to confirm the positive findings of the study by Shults et al.123 and planning is currently underway for one such trial in patients with early PD.128 It is anticipated that 600 patients will be randomised to 1,200, or 2,400 mg CoQ10/day or placebo for a 16 month follow-up period, with a primary outcome of the change in total UPDRS or to the need for symptomatic therapy. The findings from this trial may help establish whether CoQ10 is an appropriate neuroprotective agent for PD.

Conclusions

CoQ10 deficiency has been implicated in several clinical disorders and in some areas there is a rationale for supplementation therapy. The case for measurement of CoQ10 is related to the relationship between levels and outcomes, as in CHF, where it may identify individuals most likely to benefit from supplementation therapy. Where supplementation is occurring plasma CoQ10 levels should be monitored to ensure efficacy, especially given the variable bioavailability between commercial formulations and known inter-individual variation in CoQ10 absorption.54 Furthermore, an understanding of biological variation, the reference change and least significant change values are important to determine whether a significant change has occurred, whether a reduction, for example as a result of statin therapy or an increase, with supplementation. Emerging evidence will determine whether CoQ10 does indeed have an important clinical role and in particular, whether there is a case for measurement.

Acknowledgements

Dr Molyneux is a post-doctoral fellow supported by the National Heart Foundation of New Zealand.

Footnotes

Competing Interests: None declared.

References

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