Coenzyme Q10 for Heart Disease
By Dónal P. O'Mathùna, PhD. Dr. O'Mathùna is Senior Lecturer in Ethics, Decision-Making, and Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
Coenzyme q10 (coq10) has been recommended for a wide range of cardiac conditions. Heart disease remains a significant cause of morbidity and mortality, in spite of recent progress in some areas (heart disease will be used here broadly to include heart failure, arteriosclerosis, ischemic heart disease, cardiomyopathy, hypertension, and other cardiac problems1). In a variety of patients with heart disease, serum CoQ10 levels have been found to be significantly lower compared to healthy controls, suggesting that a deficiency may exist due to insufficient intake.2 Studies have found that CoQ10 levels decrease as the severity of heart disease increases.1 Because of these associations between heart disease and CoQ10 levels, use of CoQ10 supplements has become widespread.2 Various trade sources list it as having the third highest sales levels among non-herbal supplements, falling behind only glucosamine and essential fatty acids. Clinicians should be aware of the evidence currently available on CoQ10 and heart disease as many patients already may be using it or considering doing so.
Biochemistry
Coenzyme Q is the name given to a group of compounds containing a ring structure and a long chain made up of repeating five-carbon sections called isoprenoid units.3 The coenzyme Q found in humans contains 10 isoprenoid units, hence the name coenzyme Q10, or CoQ10. It is also called ubiquinone because it is ubiquitous, being found in all eukaryotic cells.1 It is an essential cofactor in the electron transport chain (ETC) and a potent antioxidant.3 It carries out both roles within mitochondria, the "power houses" of all cells. CoQ10 is highly lipid-soluble and lodges within the lipid layers of the inner membranes of mitochondria. CoQ10 is especially important in cardiac muscle because energy requirements are high and therefore the cells contain many mitochondria.4
Mechanism of Action
Mitochondria replenish the chemical energy of cells by generating a molecule called adenosine triphosphate (ATP) via the ETC. CoQ10 plays a vital role in a number of complexes involved in this process.3 Administration of CoQ10 has been proposed to help in heart disease by improving cardiac bioenergetics.1 CoQ10 is a more powerful antioxidant than vitamin E and may be beneficial in cardiovascular damage caused by free radicals and superoxide.5 CoQ10 stabilizes membranes, and in particular stabilizes calcium and other ion channels.1 This may prevent the depletion of metabolites necessary for the production of ATP. In addition, since CoQ10 levels are depleted with heart disease, supplementation may be beneficial via other mechanisms that have not yet been elucidated.
Clinical Studies
CoQ10 was discovered in 1957 and by the 1980s was being used in studies involving heart failure patients.6 The results of early clinical research were highly encouraging, but most of these studies were observational in design. Randomized controlled trials (RCTs) then were conducted, but tended to have small numbers of participants and to reach contradictory conclusions. A meta-analysis published in 2006 included 11 RCTs with a total of 277 heart failure patients.2 A statistically significant increase in ejection fraction of 3.7% was found between those taking CoQ10 and controls (P < 0.00001). This is about half the improvement found with other heart failure medications. A sub-group analysis found that patients taking CoQ10 along with ACE inhibitors had no increase in ejection fraction; those taking CoQ10 who did not concurrently take ACE inhibitors had a 6.7% increase in ejection fraction. The reviewers concluded that the two substances should not be taken together, but that CoQ10 may be an option for patients intolerant to ACE inhibitors. Further analysis found that patients with more severe heart failure (New York Heart Association [NYHA] class III and IV) had greater improvements than those with class I and II.
a.Cochrane Collaboration systematic review currently is being conducted to provide an updated evaluation of the evidence regarding heart failure.7 One of the challenges in this area is that to detect differences in relatively infrequent events (like death), very large numbers of participants would be needed. Some have estimated it would take at least 2,000 patients per group.6 Given the costs of such a trial, one with several hundred patients is more realistic. An international, multicenter RCT is being conducted with more than 500 patients with NYHA class III and IV chronic heart failure.4 Called the Q-SYMBIO (Symptoms, Biomarker status (BNP), and Long-term Outcome) trial, its results should be available in the near future and will provide the best evidence to date on the long-term effectiveness of CoQ10 for heart failure patients.
The impact of CoQ10 on hypertension was reviewed in 2007.8 The review included 12 studies, although most of them were observational studies with no control group. In that meta-analysis, the pooled results, from 362 patients, demonstrated that CoQ10 supplementation produced a reduction of up to 17 mmHg in systolic and 10 mmHg in diastolic blood pressure.
Including such divergent study designs in a meta-analysis is questionable. A 2009 Cochrane systematic review of CoQ10 for hypertension included only RCTs.9 Three were identified, with a total of 96 patients. Statistically significant reductions in both systolic (11 mmHg) and diastolic (7 mmHg) blood pressures were found. The reviewers stated that this would indicate that CoQ10 was "a remarkably effective antihypertensive agent"if the results "are true." They were concerned at the very high risk of bias in the studies stemming from their small size and unclear descriptions of their methods. In addition, the lead author on one of the studies has been investigated for scientific misconduct, leading BMJ and Lancet to publish "expressions of concern" about his work.10 Others have concluded that large RCTs are needed in this area to provide high-quality evidence to guide hypertension patients and their clinicians.6
Because of its antioxidant properties, CoQ10 also has been used for the prevention and treatment of cardiovascular disease. A 2003 AHRQ Evidence Report/Technology Assessment identified 54 studies on a variety of cardiovascular outcomes and markers.11 Many of these were preclinical studies, enrolled small numbers of patients, or were of short duration. The authors limited their analysis to RCTs measuring clinical outcomes with at least 60 patients and at least 6 months of follow-up. This led to discussion of 6 studies. The two earliest studies found significant benefit for those taking CoQ10, but both studies had serious methodological flaws. The four subsequent studies reported either no benefits or clinically small improvements. The report concluded that use of CoQ10 supplements in patients with cardiovascular disease was "an open question, with neither convincing evidence supporting nor refuting evidence of benefit or harm."
a.series of RCTs has examined the impact of statins (HMG CoA reductase inhibitors) on CoQ10 metabolism.6 The majority of these showed that plasma CoQ10 levels were lower when people took statins. This is believed to arise because statin inhibition of cholesterol synthesis also inhibits CoQ10 synthesis. Concerns have been raised that reduction in CoQ10 may account for muscle complaints and myopathies, which are an adverse effect reported for statins.12 However, this remains an unproven hypothesis in part because while statins reduce circulating CoQ10 levels, reductions in muscle tissue levels have not been reported.3 Small studies comparing the rate of muscle pain in people taking statins alone or statins plus CoQ10 have produced contradictory results. An RCT with 80 patients is currently examining this issue.3
Adverse Effects
One of the attractive aspects of CoQ10 administration is that few adverse effects are reported. It is widely acknowledged as having an excellent safety profile.4 Up to 1,200 mg per day is viewed as safe, although most studies tend to use 100-300 mg per day.3 Some studies have reported mild adverse effects, primarily gastrointestinal disturbances.
CoQ10 is chemically similar to vitamin K and may have pro-coagulant activity. A small number of cases have reported decreased effectiveness of warfarin when CoQ10 was taken concomitantly.13 Thus, caution is warranted if those taking warfarin start taking CoQ10.
Formulation
CoQ10 supplements are most commonly formulated as oil-based capsules because of the highly lipophilic nature of CoQ10. This leads to its absorption being poor, highly variable, and strongly dependent on the contents of the stomach. Nanoparticular, solubilized, and emulsified formulations are available and have better bioavailability than capsules or powders.3 More recent studies have found that higher serum levels are reached when ubiquinol is administered rather than ubiquinone.1 Ubiquinol is the reduced form of CoQ10 and believed to be the active antioxidant in the body.6 This form is absorbed eight times better than ubiquinone.1
Conclusion
The rationale for CoQ10 supplementation is clearly established biochemically. CoQ10 has a number of actions in the body that would be beneficial in the prevention and treatment of heart disease. However, the results from controlled clinical trials have not been as uniformly beneficial as was originally expected. Meta-analyses have generally found evidence of some benefit from CoQ10 supplementation. However, most of the studies to date have had small numbers of participants and other methodological weaknesses. Concerns also have been raised about the lack of detail on the CoQ10 formulation used and plasma levels attained in some studies. The concern is that some studies may have used formulations with poor bioavailability. Newer formulations and larger RCTs currently being conducted should help to give more conclusive evidence on the therapeutic potential of CoQ10 supplements.
Recommendation
Given the lack of adverse effects, CoQ10 can be recommended for some patients with heart disease. Although the evidence is inconsistent, beneficial effects on various cardiac parameters have been found. However, careful monitoring is essential, especially as many heart patients are likely to be taking other medications. Those taking ACE inhibitors may not derive any additional benefit from co-administration of CoQ10. Some uncertainty remains about the effectiveness of CoQ10 in heart disease, but a number of large RCTs are currently being conducted. As their results become available, greater confidence will be possible on precisely which types of conditions are most likely to be improved by CoQ10 supplementation. Further evidence is also needed on the best formulations and dosage regimens for various conditions.
References
1. Kumar A, wt al. Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. Pharmacol Ther 2009;124:259-268.
2. Sander S, et al. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail 2006;12:464-472.
3. Villalba JM, et al. Therapeutic use of coenzyme Q10 and coenzyme Q10-related compounds and formulations. Expert Opin Investig Drugs 2010;19:535-554.
4. Molyneux SL, et al. Coenzyme Q10; an adjunctive therapy for congestive heart failure? N Z Med J 2009;122:74-79.
5. Playford DA, et al. Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes. Atherosclerosis 2003;168:169-179.
6. Pepe S, et al. Coenzyme Q10 in cardiovascular disease. Mitochondrion 2007:7S:S154-S167.
7. Madmani ME, et al. Coenzyme Q10 for heart failure (Protocol). Cochrane Database Systematic Rev 2010; Issue 9. Art. No.: CD008684.
8. Rosenfeldt FL, et al. Coenzyme Q10 in the treatment of hypertension: A meta-analysis of the clinical trials. J Hum Hypertens 2007;21:297-306.
9. Ho MJ, et al. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Systematic Rev 2009, Issue 4. Art. No.: CD007435.
10. Mann J. The Indo-Mediterranean diet revisited. Lancet 2005;366:353-354.
11. Shekelle P, et al. Effect of supplemental antioxidants vitamin C, vitamin E, and coenzyme Q10 for the prevention and treatment of cardiovascular disease. Evidence Report/Technology Assessment, number 83. 2003. Available at: www.ahrq.gov/downloads/pub/evidence/pdf/antioxcard/aoxcard.pdf. Accessed February 4, 2011.
12. Chatzizisis YS, et al. Risk factors and drug interactions predisposing to statin-induced myopathy: Implications for risk assessment, prevention and treatment. Drug Saf 2010;33:171-187.
13. Singh U, et al. Coenzyme Q10 supplementation and heart failure. Nutr Rev 2007;65:286-293.
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