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Coenzyme Q10 and Cardiovascular Disease: A Review

Sarter, Barbara PhD

The Journal of Cardiovascular Nursing: July 2002 - Volume 16 - Issue 4 - p 9-20
Alternative Medicines for Cardiovascular Diseases
Free

This article provides a comprehensive review of 30 years of research on the use of coenzyme Q10 in prevention and treatment of cardiovascular disease. This endogenous antioxidant has potential for use in prevention and treatment of cardiovascular disease, particularly hypertension, hyperlipidemia, coronary artery disease, and heart failure. It appears that levels of coenzyme Q10 are decreased during therapy with HMG-CoA reductase inhibitors, gemfibrozil, Adriamycin, and certain beta blockers. Further clinical trials are warranted, but because of its low toxicity it may be appropriate to recommend coenzyme Q10 to select patients as an adjunct to conventional treatment.

Associate Professor; Department of Nursing; University of Southern California; Los Angeles, California

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INTRODUCTION

Coenzyme Q10 (CoQ10, or ubiquinone) was discovered in 1957. This naturally occurring molecule has been the subject of extensive research in Japan as well as in the United States, Europe, and India. The Japanese government approved it in 1974 for treatment of congestive heart failure. Coenzyme Q10 is a well-known and widely utilized substance in the complementary and alternative medicine community. It is advocated as a supplement to promote cardiovascular health; it also is used in the treatment of cancer, gum disease, and other conditions that are felt to benefit from antioxidant supplementation.1 This research review focuses only on studies relating to its use in the prevention and treatment of cardiovascular disease. It discusses nursing implications, focusing on how patients should be counseled if they are using coenzyme Q10 as an adjunct in the treatment of heart disease.

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OVERVIEW OF PHYSIOLOGIC MECHANISM OF ACTION

Coenzyme Q10 is an obligatory member of the respiratory chain in the mitochondria of all cells. Therefore, it is an essential ingredient in the formation of adenosine triphosphate (ATP), the source of energy in most cellular processes. It also is one of two endogenous antioxidants within the low-density lipoprotein (LDL) molecule (the other is vitamin E).2 Therefore, in addition to its role in mitochondrial energy production, it is part of a network of antioxidants that delay or prevent the oxidation of membrane-bound lipid peroxide free radicals.3 This role has important clinical implications, for it is oxidation of lipids that contributes to the pathogenesis of atherosclerosis. One study4 concluded that ubiquinol-10 protected LDL-cholesterol more efficiently against lipid peroxidation than did vitamin E, suggesting that it is a powerful antioxidant that may be useful in the prevention of heart disease.

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CoQ10 DEFICIENCY IN CARDIOVASCULAR DISEASE

There are several steps necessary in order to determine whether an oral supplement can be of clinical benefit. Establishing the presence of a deficit of the substance in question in certain disease states is one such step. Early studies documented a deficiency of coenzyme Q10 in patients with a variety of cardiovascular disorders. One study5 showed that myocardial deficiencies of CoQ10 were present in the majority of patients with aortic and mitral valve disease, diabetic cardiomyopathy, and congenital valvular defects. The same researcher reported in a later study6 that patients in a general cardiology practice had a significantly lower level of serum CoQ10 than a comparison group of young healthy college students. In one study,7 approximately 75% of patients undergoing cardiac surgery had low levels of CoQ10, and concentrations declined in blood and myocardium in correlation with increasing severity of disease.

Circulating levels of CoQ10 have been shown to be significantly lower in rats with ischemic heart disease.8 NADH-coenzyme Q10 reductase, a reduced form of coenzyme Q10 in the inner mitochondrial membrane, is impaired early during ischemia and has been shown to be one of the mitochondrial components most sensitive to ischemia.9 Myocardial coenzyme Q10 radical has been shown to be low in conditions of prolonged ischemia and in myocardial tissue reperfused after 50 minutes.10 One study11 took muscle biopsies from the vastus lateralis of seven males with effort angina. Muscle coenzyme Q10 depletion in the subjects appeared to be related to the formation of molecular oxygen and free-radical formation, and then caused severe trauma to the slow twitch muscle fibers and the mitochondria. The researchers speculated that similar pathology occurs in the myocardium.

Hanaki et al12 compared 245 normal subjects with 72 patients with ischemic heart disease or ischemic changes on electrocardiograph (ECG). In the ischemic group, plasma total and LDL and triglyceride levels were higher and the plasma coenzyme Q10 level was lower than in the normal subjects (p < .01). The ratios of total cholesterol to high-density lipoprotein (HDL) and of LDL to coenzyme Q10 also were higher. There was a greater difference between the LDL/coenzyme Q10 ratio than in the total cholesterol/HDL ratio. The researchers suggested that the LDL/coenzyme Q10 ratio might be a sensitive indicator of risk of atherosclerosis.

Coenzyme Q10 levels are decreased in the myocardium of patients with idiopathic dilated cardiomyopathy13 and post-myocardial infarction. Yamagami et al14 suggested that severe coenzyme Q10 deficiency accompanies the well-known myocardial enzymatic disorder that occurs after myocardial infarction. It has been proposed that the impaired function of mitochondria may be due to lipid peroxidation of the complex in which coenzyme Q10 is present, resulting in a loss of coenzyme Q10.15 Conflicting results have been found in studies examining plasma coenzyme Q10 levels in patients with hyperlipidemia or atherosclerosis. Kontush et al16 measured plasma coenzyme Q10 in 38 hyperlipidemic and 30 healthy subjects. Coenzyme Q10 levels were lower in hyperlipidemic subjects than in controls (p < .001). There was a negative correlation between coenzyme Q10 and plasma triglycerides. Coenzyme Q10 levels were most reduced among smokers. The researchers suggested that plasma coenzyme Q10 might be a sensitive indicator of oxidative stress and early oxidative damage in humans. However, a more recent study17 comparing 71 male patients with severe coronary artery disease with 69 males without carotid artery plaques concluded that differences in coenzyme Q10 concentrations and coenzyme Q10/LDL ratios of the two groups were not significant. This same study confirmed the observation that plasma coenzyme Q10 is lower in hyperlipidemic but not in coronary artery disease patients. Other researchers18 also have questioned the value of plasma coenzyme Q10 levels as a marker for cardiovascular disease.

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SERUM AND TISSUE LEVELS AFTER ORAL SUPPLEMENTATION

The next step in evaluating clinical utility of a supplement is to assess if oral administration leads to increases in target tissue levels. Many studies have demonstrated consistently that oral supplementation with coenzyme Q10 does raise serum and myocardial levels of this substance. Folkers et al13 reported that oral administration of 100 mg/day for 2 to 8 months led to an increase in myocardial levels of 20% to 85% in patients with cardiomyopathy and myocardial coenzyme Q10 deficiency. Nakamura et al19 demonstrated that exogenous administration of coenzyme Q10 resulted in its transfer in an intact form to the inner membrane of rat mitochondria, where it serves as a co-factor in the electron transport chain. Another study20 demonstrated that 300 mg/day of coenzyme Q10 orally in preoperative cardiac patients for 7 days resulted in substantial increases of this substance in myocardial membranes.

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THERAPEUTIC BENEFIT IN HYPERTENSION

In studies involving animal models of hypertension, orally administered coenzyme Q10 has been shown to significantly reduce blood pressure.21-24 Human studies have been open label and non-controlled, but have suggested that coenzyme Q10 of varying dosage results in lowered need for medication25,26 and significant reductions in blood pressure.27 This last study showed a significant reduction in peripheral resistance but no change in plasma renin, serum/urine sodium and potassium, or urinary aldosterone. The doses used ranged from 100 to 225 mg/day, and the treatment period was from 4.4 to 10 months in these human studies. More recently, Singh et al28 conducted a randomized, double-blind trial among patients receiving antihypertensive medication and presenting with coronary artery disease. The treatment group received 60 mg of coenzyme Q10 twice daily for 8 weeks. At the end of the treatment period, the coenzyme Q10 group showed reductions in blood pressure, plasma insulin, glucose, and several lipid compounds.

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THERAPEUTIC BENEFIT IN CORONARY ARTERY DISEASE

Animal studies

In Japan a series of several international biannual symposia on the biomedical and clinical aspects of coenzyme Q10 have been conducted. At the second of these symposia, many animal studies examining the effect of coenzyme Q10 on myocardial function during conditions of severe ischemia were reported. Most dog studies used intravenous doses of 10 mg/kg of coenzyme Q10 before induction of cardiac ischemia. Researchers reported significant reductions in action potential duration,29 increases in resting tensions,29 improvement in functional recovery after cardiac arrest,30 higher levels of energy-rich phosphate compounds,31,32 lower levels of lactate accumulation,33 and lower arrhythmogenicity34 in pretreated myocardia. Another study35 suggests that pretreatment with coenzyme Q10 might suppress myocardial ischemia and cardiac dysfunction produced by noradrenaline and adrenaline in dogs with moderate or severe coronary constriction.

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Human studies

Fewer human studies have been conducted on the use of coenzyme Q10 in coronary artery disease. A dose of 300 mg/day for 7 days was shown to improve myocardial efficiency as measured by consumption of oxygen per unit ATP formed (n 5 10, p < .05).20 In another double-blind crossover study, 12 patients with stable angina were randomly assigned to treatment or placebo groups each for 4 weeks. Coenzyme Q10 at a dose of 150 mg/day significantly increased treadmill exercise tolerance and the time to ST-segment depression. Though not statistically significant, there also was a 53% reduction in frequency of angina and a 54% reduction in number of nitroglycerin tablets used during the treatment phase.36

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THERAPEUTIC BENEFIT IN MYOCARDIAL INFARCTION

Animal studies

Studies conducted on anesthetized dogs have provided support for the use of coenzyme Q10 to minimize myocardial damage after experimentally induced infarction. Coenzyme Q10 appears to reduce the area of infarction, decrease the severity of degeneration and necrosis, and increase the levels of the H unit of LDL.37 It has been shown to protect the phospholipid bilayer structure of the myocardial cell membrane38 and to allow immediate functional recovery of the myocardium after reperfusion.39 Another study40 showed that intravenous coenzyme Q10 during experimentally induced ischemic cardiac arrest resulted in improved myocardial oxygen utilization and accelerated recovery of myocardial energy consumption after reperfusion.

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Human studies

One randomized, double-blind, placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction used oral treatment with coenzyme Q10 (120 mg/day for 28 days) after acute myocardial infarction.41 The researchers noted a significant (p < .05) reduction in angina, total arrhythmias, and left ventricular dysfunction. They also found a significant (p < .02) reduction in total cardiac events (15% versus 30%). Indicators of oxidative stress decreased and levels of vitamins A, E, C, and beta-carotene increased in the treated group. The researchers concluded that coenzyme Q10 might provide rapid protective effects in patients with acute myocardial infarction if administered within 3 days of symptom onset.

Another double-blind, placebo-controlled trial of selenium plus coenzyme Q10 examined 61 patients admitted with acute myocardial infarction and symptom duration of less than 6 hours. The treatment group (n 5 32) received 550 mcg selenium on admission, then 100 mg coenzyme Q10 daily plus 100 mcg selenium daily for a period of 1 year. There was a reduced concentration of CPK-mb and ASAT in the treatment group during the acute phase. None of the treatment group showed QT prolongation, whereas 40% of the controls had the QT interval prolonged more that 440 msec (p < .001). During the 1-year follow-up, six of the controls died from re-infarction whereas one patient from the treatment group died from non-cardiac causes.42

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THERAPEUTIC BENEFIT IN CONGESTIVE HEART FAILURE

Human studies

An early, open-label, uncontrolled Japanese study with human subjects43 treated 17 patients with congestive heart failure using 30 mg/day of coenzyme Q10. The researchers reported that all the patients improved and that 53% were asymptomatic after 4 weeks of treatment. Other studies on the effect of coenzyme Q10 on cardiac function indicate that coenzyme Q10 may improve myocardial metabolic function in congestive heart failure.44 Another open-label, uncontrolled study provided 12 patients with congestive heart failure resistant to usual therapy 100 mg/day of coenzyme Q10 for 7 months. Two thirds showed improvement by subjective data and physical examination after a mean of 30 days. All who improved experienced relapses after withdrawal of the supplement, and improvement in symptoms after resumption of the coenzyme Q10.45

In a small, randomized, blinded trial in which 17 patients with congestive heart failure received either taurine or 30 mg/day of coenzyme Q10, 71% of the coenzyme Q10 group was judged to be generally improved after 6 weeks. However, there were no significant improvements in outcomes measured by M-mode echocardiography.46 An Italian multicenter trial47 of coenzyme Q10 enrolled 2,664 patients of New York Heart Association (NYHA) functional class II or III in an open, noncomparative post-marketing study. For 3 months, patients took 50 to 100 mg/day of coenzyme Q10. Subjective and physical examination results rated on a Likert scale after 3 months indicated the following percentages of improvement: cyanosis, 78.1; edema, 78.6; rales, 77.8; hepatomegaly, 49.3; jugular reflux, 71.8; dyspnea, 52.7; palpitations, 75.4; sweating, 79.8; insomnia, 62.8; vertigo, 73.1; and nocturia, 53.6. Notably, 54% of patients had improvements in at least three symptoms.

Another longer-term, multicenter, randomized study48 provided coenzyme Q10 at a level of 2 mg/kg/day for 1 year to 643 patients with NYHA class III or IV heart failure. In this double-blind, placebo-controlled study the number of hospitalizations for deterioration was significantly less in the treatment group (p < .001). The complications of pulmonary edema/cardiac asthma also were significantly reduced (p < .001) in the treatment group. Another study49 examined myocardial diastolic dysfunction in patients at high risk for development of congestive heart failure, treating them with coenzyme Q10. All 115 patients had symptoms of fatigue/activity impairment, atypical precordial pain, and cardiac arrhythmia. Sixty had hypertensive cardiovascular disease, 27 had mitral valve prolapse, and 28 had chronic fatigue syndrome; 63 were NYHA class III and 54 were class II. Coenzyme Q10 administration resulted in improvement in all patients' subjective symptoms, a reduction in blood pressure in 80% of subjects, and improvement in diastolic function in all. There was a reduction in myocardial thickness in 53% of hypertensives and 36% of the other two groups and a reduced fractional shortening in those high at control and an increase in those low at control.

A study50 reported in 1999 used pre- and post-treatment right heart catheterization to measure the response of 22 NYHA class II and III patients to either coenzyme Q10 100 mg twice daily or placebo for 2 weeks. In the treatment group, stroke volume at rest and after 3 minutes of exercise improved significantly, pulmonary artery pressure at rest decreased significantly, and pulmonary capillary wedge pressure at rest and exercise decreased significantly at 1 minute. More recently, a double-blind, controlled trial51 randomized 55 patients with NYHA class III and IV heart failure receiving standard treatment to receive 200 mg/day of coenzyme Q10 or placebo. Ejection fraction, peak oxygen consumption, and exercise duration were unchanged in both groups after 6 months. A subsequent commentary by Sinatra,52 a well-known advocate of complementary therapies in the treatment of heart disease, said the study period was too short and the dose of coenzyme Q10 was too low for patients in class III and IV. He said that, for this group of patients, reported blood levels of coenzyme Q10 were not optimal and needed to be higher. He also suggested that beta blockers, which were administered to more than 75% of the patients, may interfere with coenzyme Q10-dependent enzymes.

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THERAPEUTIC BENEFIT IN CARDIOMYOPATHY

Several studies have suggested that coenzyme Q10 may be of benefit in treatment of patients with cardiomyopathy, especially idiopathic dilated type. A double-blind, crossover trial53 provided 19 patients with cardiomyopathy (NYHA class III and IV) 100 mg/day of coenzyme Q10 or placebo for 12 weeks. There was a significant increase in cardiac stroke volume and ejection fraction in the treatment group. Eighteen subjects reported subjective improvement in physical activity tolerance when taking coenzyme Q10. The same group reported two later studies in which long-term treatment was provided for up to 66 months. In the group treated for up to 24 months, 75% to 85% of those treated showed significant improvement in at least two of three parameters of cardiac function (ejection fraction, cardiac output, NYHA class); 80% moved into a higher level of functioning.54 In the group of class III and IV patients treated for up to 66 months, mean ejection fraction increased from 41 to 59 (p < .001) after 6 months and then remained stable. Notably, 84% of these patients were still alive after 2 years.55 In an open protocol56 treating patients with cardiomyopathy 100 mg coenzyme Q10 daily, nearly two thirds of subjects showed clinical improvement. However, another double-blind, crossover trial57 placed 30 patients with cardiomyopathy on oral coenzyme Q10 and placebo, each for 3 months. Echocardiographic indices and the Minnesota "Living with Heart Failure" quality-of-life questionnaire were the outcomes studied. The researchers reported no significant differences in response to coenzyme Q10 treatment.

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DRUG-INDUCED CARDIOMYOPATHY

A substantial body of research has demonstrated the effectiveness of coenzyme Q10 in reducing adriamycin-induced cardiomyopathy. It has been shown to prevent ECG and histologic cardiac damage58 and to restore impairment of myocardial contractility.59,60 It also has been reported to increase the antitumor effect of adriamycin61 and to allow higher doses of the drug to be safely administered.62 Lower myocardial coenzyme Q10 levels than controls have been demonstrated in cancer patients receiving adriamycin, and coenzyme Q10 depletion appears to be related to the cardiac impairment often experienced in these patients.63

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DRUG-INDUCED DEPRESSION OF COENZYME Q10 LEVELS

Certain drugs used to treat hyperlipidemia and hypertension appear to possibly lower coenzyme Q10 levels. Studies in this area have been small and weakly designed, but results are worthy of notice. One small study64 in which patients served as their own controls showed that hospitalized patients with congestive heart failure had increased cardiac disease and decreased coenzyme Q10 levels when lovastatin was added to their regimen. Oral administration of coenzyme Q10 was accompanied by an improvement in cardiac function. Another study65 of 19 patients with coronary artery disease and hypercholesterolemia receiving lovastatin showed a minor improvement (p < .02) in LDL oxidative capacity when they were given 180 mg/day of coenzyme Q10. However, a small study66 published in 2001 found no difference in coenzyme Q10 levels from baseline after 4 weeks of pravastatin or atorvastatin therapy in 12 healthy subjects. It also appears that gemfibrozil may decrease coenzyme Q10 levels67 and that propanolol and metoprolol may inhibit coenzyme Q10-dependent enzymes.68

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CAN COENZYME Q10 BE RECOMMENDED FOR PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE?

It appears that coenzyme Q10 may be of benefit in a variety of clinical situations. It may have a role in the prevention of cardiovascular disease because of its role in preventing LDL oxidation, though this role requires further research. It appears that this substance is deficient in many patients with a variety of cardiovascular disorders, and that some of them—particularly those with coronary artery disease, heart failure, and cardiomyopathy—may benefit from its ability to enhance the efficiency of myocardial energy production. It also seems warranted to use it as a routine supplement during therapy with adriamycin, for it has been shown in many studies to reduce the serious cardiomyopathy associated with this agent. HMG-CoA reductase inhibitors, gemfibrozil, and certain beta blockers appear to deplete levels of coenzyme Q10. Studies are needed to explore whether this results in any adverse clinical outcomes and whether supplementation is beneficial for these patients. In general, much of the research on coenzyme Q10 does not meet the rigorous standards that would conclusively validate its results. But its potential appears significant, and toxicity is low. For patients who are interested in supplements to enhance cardiovascular health, it may be an appropriate recommendation.

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NURSING IMPLICATIONS

The nurse working with the patient who is using complementary therapies has many responsibilities. He or she must serve as an advocate, supporting the patient's right to making informed self-care decisions. The nurse should be familiar with the research that supports the use of a given therapy; its mechanism of action, indications, and contraindications; potential benefits and risks; as well as interactions with drugs and other mainstream therapies. Fortunately, there are many excellent resources now available that provide health care practitioners with reliable, research-based information in all of these areas. One of the most highly respected sources for research-based information on nutritional supplements is the on-line Natural Medicines Comprehensive Database,69 updated daily. The following guidelines for coenzyme Q10 therapy are derived from this resource.

The dosage of coenzyme Q10 may safely range from 25 to 100 mg three times daily, with higher doses reserved for those with active disease and under medical supervision. No significant toxicities have been reported at this dosage range in studies lasting up to 1 year. To minimize the possibility of mild gastrointestinal discomfort, daily doses larger than 100 mg should be divided. CoQ10 formulated in soybean oil appears to have superior bioavailability compared with other formulations. The nurse can advise patients to look for products that provide coenzyme Q10 in an oil-based formula. Coenzyme Q10 may work synergistically with antihypertensive and glucose-lowering drugs, so patients and prescribers should be aware of this possibility and monitor appropriately. As indicated in the research review, HMG-coenzyme A reductase inhibitors, beta blockers, and some antidiabetic agents may lower levels of coenzyme Q10, but the clinical significance of this is yet to be determined.

Coenzyme Q10 is one of the most popular supplements purchased in the United States by individuals at risk for or diagnosed with cardiovascular disease. The nurse can serve as an advocate in the use of complementary therapies such as this only if he or she becomes familiar with the large body of research that has been conducted on thousands of nutritional supplements. This advocacy role is extremely important in the current health care climate in which self-selected supplements are freely available to patients. Hopefully this article will contribute to a scientific knowledgebase for one complementary adjunct to care in cardiovascular nursing.

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Keywords:

cardiomyopathy; coenzyme Q10; coenzyme Q10 antioxidants; complementary therapies; coronary artery disease; heart failure

Copyright © 2002 by Aspen Publishers, Inc.