Prepared by: Hemmi N. Bhagavan, PhD, FACN, Lancaster , PA 17602, May 27, 2003
CONCLUSIONS:
There is sound scientific rationale for an important role for coenzyme Q10 in the maintenance of cardiovascular health in general and in the management of heart disease and in particular heart failure. Review of published literature in peer-reviewed journals on the use of coenzyme Q10 as an adjunct to conventional therapy in patients with congestive heart failure and cardiomyopathy shows that there is strong evidence in favor of significant clinical improvement with coenzyme Q10 supplementation. As a naturally-occurring nutrient that is produced in the body, coenzyme Q10 has an excellent safety record and no side effects. Therefore, coenzyme Q10 supplementation as supportive therapy for patients with or at risk for congestive heart failure or cardiomyopathy is justified and appropriate, since it can afford significant clinical benefit to the patients. Furthermore, by improving heart function and the quality of life in these patients, and by reducing the number of hospitalizations, coenzyme Q10 supplementation also has the potential to reduce overall healthcare costs.
The weight of the evidence based upon an objective assessment of available scientific literature supports the following proposed health claims for coenzyme Q10:
- Coenzyme Q10 supplementation may help reduce the risk for congestive heart failure and cardiomyopathy.
- Coenzyme Q10 supplementation may help reduce the risk for heart failure.
- Coenzyme Q10 supplementation may help reduce the risk for certain types of heart diseases.
- Coenzyme Q10 supplementation may help reduce the risk for certain types of heart diseases such as congestive heart failure and cardiomyopathy.
- Coenzyme Q10 supplementation, as an adjunct to standard medical therapy, may help reduce the risk for certain types of heart diseases such as congestive heart failure and cardiomyopathy.
Introduction
Coenzyme Q10 (CoQ10) belongs to the homologous series of compounds called coenzyme Q that share the same basic ring structure but differ in the length of the isoprenoid side chain. Because of their wide and ubiquitous distribution in nature, these compounds are also called ubiquinones . CoQ10 stands for CoQ with 10 isoprene units in the side chain and it is the form present in humans and several other species. CoQ compounds play an essential role in the production of cellular energy in most aerobic organisms, from humans to plants and bacteria (Bliznakov, 1987; Ernster and Dallner, 1995; Crane 2001).
CoQ10 was first discovered and isolated in pure form from bovine heart mitochondria in 1957 by Dr. Fred Crane at the University of Wisconsin (Crane et al, 1957). Identification of the chemical structure and synthesis of CoQ10 was accomplished by Dr. Karl Folkers and his group at Merck in 1958 (Wolf et al, 1958). CoQ10 is a quinone with a structure similar to that of vitamin K, and is present in high concentrations in the mitochondria. Mitochondria are the fuel cells in each and every cell in the body where biological energy is produced. Research conducted during 1960s and 1970s clearly established the role of CoQ10 as a key component of the mitochondrial electron transport system (also known as the respiratory chain) where biological energy in the form of ATP (adenosine triphosphate) is produced. CoQ10 serves as the critical cofactor for at least three mitochondrial enzymes (called complexes I, II and III) that play a vital role in the electron transport chain (in a process known as oxidative phosphorylation). CoQ10 functions as the only non-protein component of the electron transport chain enabling the transfer of electrons between the donor and recipient molecules. Thus, CoQ10 plays an essential role in the synthesis of ATP, the energy that drives all cellular activities and without which cells cease to function (Crane, 2001). In addition to this role, CoQ10 is also an essential fat-soluble redox agent and an antioxidant (in its reduced form as ubiquinol) and furthermore, it can regenerate and recycle other antioxidants. CoQ10 is also a membrane stabilizer. Among the other functions of CoQ10 are cell signaling and gene expression (Ernster and Dallner, 1995; Rauchova et al, 1995; Crane, 2000; Crane 2001).
Although CoQ10 is sometimes referred to as a vitamin, by strict definition it does not meet the necessary criteria on one count. CoQ10 is an endogenous compound that is synthesized in our body, unlike vitamins that must be derived from exogenous sources. However, CoQ10 qualifies as a “conditionally essential nutrient”, since its production in the body cannot meet the needs under certain conditions. For instance, data show that CoQ10 production in the body slows down as we age, staring from the 20s. There are other conditions under which CoQ10 status is known to be compromised. Those tissues and organs with high-energy requirements such as the heart, liver, skeletal muscle pancreas, and kidney are ones most readily affected when CoQ10 supply becomes limiting (Ernster and Dallner, 1995).
CoQ10 for heart failure (cardiomyopathy and congestive heart failure)
The rationale for the use of CoQ10 in heart disease in general and particularly in heart failure lies in the fact that CoQ10 plays a pivotal role in the bioenergetics of the heart muscle as a cofactor in mitochondrial ATP production. This bioenergetic effect of CoQ10 is of fundamental importance in its clinical application, particularly as it relates to cells with exceedingly high metabolic demands such as the cardiac myocytes. It is also a potent antioxidant, a feature that has important implications in heart function, and especially under conditions of ischemia-reperfusion injury to the myocardium. The role of free radicals and their destructive potential in cell injury and in cell death in settings of ischemia and reperfusion are now well recognized. The antioxidant properties of CoQ10 and its localization within the mitochondria, a major source of free radicals, make it an obvious candidate for a potential therapeutic agent in these situations. Protection of LDL from oxidation is another important antioxidant function of CoQ10 that has an important bearing in maintaining cardiovascular health (Mohr et al, 1992; Ernster and Dallner, 1995; Rauchova et al, 1995; Alleva et al, 1997; Crane 2000, 2001).
Congestive heart failure (CHF) and cardiomyopathy are still among the major causes of morbidity and mortality in the US . The primary biochemical basis for the use of CoQ10 in the treatment of heart failure is defective bioenergetics, specifically availability of ATP that plays a central role in regulating myocardial contractility (Bashore et al, 1987; Rengo et al, 1993). A significant correlation has been demonstrated in the diseased heart between ATP content and systolic and diastolic left ventricular indices. Myocardial deficiency of CoQ10 has also been documented in patients with cardiomyopathy which serves to explain the underlying energy deficit in the heart muscle leading to impaired function (Folkers et al, 1985), and there is clear-cut evidence to show that CoQ10 acts at the mitochondrial level to improve the efficiency of energy production in human heart tissue (Rosenfeldt et al, 2002). Another interesting mechanism by which CoQ10 may aid heart function in CHF patients is by way of its inotropic action (Greenberg and Frishman, 1990). Such action increases the contractile force of the heart to improve cardiac output.
Pioneering studies on the efficacy of CoQ10 supplementation in patients with heart failure were carried out in Japan in the 1960s (Yamamura, 1977). S ince these early investigations, there has been a slow but steady accumulation of clinical experience worldwide with the use of CoQ10 as adjunct therapy in patients with various types of heart disease for over three decades. I n addition to numerous open-label studies, there have been over 15 randomized controlled clinical trials with both primary and secondary forms of heart failure. Furthermore, data from a large number of laboratory and preclinical studies using various animal models are also available that document the efficacy and safety of coenzyme Q10 in patients with heart failure, and heart disease in general (Linnane et al, 1995; Rosenfeldt et al, 2002).
The very first controlled randomized trials on CHF and cardiomyopathy were also carried out in Japan in 1972, and significant clinical improvement according to New York Heart Association (NYHA) classification was documented in CHF patients treated with a daily dose of 30 mg CoQ10 (Hashiba et al, 1972; Iwabuchi et al, 1972; cited by Langsjoen and Langsjoen, 1999). In the USA, pioneering research on the use of CoQ10 in heart disease was led by the late Dr. Karl Folkers in the 1960s, and the first report documenting a deficiency of CoQ10 in heart disease appeared in 1970 (Folkers et al, 1970). Dr. Folkers made invaluable contributions in this area in collaboration with Langsjoen and numerous other scientists (Folkers et al, 1985; Langsjoen et al, 1985; Langsjoen and Langsjoen, 1999).
Controlled clinical trials
There have been at least 15 randomized controlled clinical trials with a total of about 1400 patients on the efficacy of oral CoQ10 supplementation as adjunct therapy in heart failure that have demonstrated significant clinical improvement (Table 1). Furthermore, a meta-analyses of the controlled clinical trials in heart failure conducted during the years 1986-1995 was made in 1997 (Soja and Mortensen, 1997). Eight of the 14 trials met the inclusion criteria for reliable meta-analyses, and seven out the eight studies documented significant improvement in various parameters of heart function in patients with CHF of varying etiologies (idiopathic dilated, ischemia, hypertension, valvular heart disease, and congenital heart disease). Significant functional improvement was evident specifically with respect to stroke volume, cardiac output, cardiac index, and end-diastolic volume in patients treated with CoQ10.
The very first double-blind placebo-controlled trial in the USA was reported in 1985 that involved 19 heart failure patients, NYHA class II and IV, receiving either 100 mg of CoQ10 per day or placebo for three month periods in a cross-over design (Langsjoen et al, 1985). CoQ10 was administered as an adjunct to standard medical therapy. Assessment of clinical improvement included ejection fraction by impedence cardiography that showed a highly significant increase, concomitant with significant functional improvement. This was followed by three additional trials in 1986 using the same dosage of CoQ10 that confirmed and extended the clinical efficacy of CoQ10 in heart failure patients (VanFraechem et al, 1986; Judy et al, 1986a, 1986b). In 1990, Oda documented normalization of load-induced cardiac dysfunction in 40 patients with mitral valve prolapse using a dose of 3.1-3.4 mg CoQ10 per kg per day in a double-blind placebo-controlled trial (Oda, 1990). This was followed by two other double-blind studies, one involving 20 patients with ischemic cardiomyopathy receiving 200 mg CoQ10 per day for three months (Rossi et al, 1991) and the other with 20 patients with ischemic cardiomyopathy or dilated cardiomyopathy (NYAS class II and III) on 100 mg CoQ10 per day (Poggesi, 1991). Significant clinical improvements were seen in both studies, particularly with respect to exercise tolerance and left ventricular function. Similarly, Rengo et al (1993) documented significant improvements in clinical and echocardiographic parameters of cardiac performance, quality of life and tolerance in 60 patients with heart failure treated with 100 mg of CoQ10 per day for seven months.
The largest controlled trial to date was reported in 1993 that involved a total of 641 CHF patients (Morisco et al, 1993). This was a double-blind placebo-controlled study with NYHA class III and IV patients using a dose of 2 mg CoQ10 per kg per day or placebo for one year that documented a highly significant reduction (33%) in the number of hospital admissions ( p < 0.001). In addition, there were significant improvements in arrhythmias and episodes of pulmonary edema, associated with a low mortality rate in the treated group. The improvement in the overall quality of life of patients along with the reduction in hospitalizations in the CoQ10 group ( p < 0.01) also translates into highly significant savings in health care costs. This study was followed by a small double-blind cross-over trial by the same investigators where a noninvasive technique called radionuclide scanning was employed to examine changes in ejection fraction, stroke volume and cardiac output in chronic heart failure patients. Significant improvements were documented in all these measures in patients treated with 150 mg of CoQ10 per day for four weeks (Morisco et al, 1994). Following this study, data from another controlled trial was reported where 79 patients with severe chronic CHF were treated with CoQ10, 100 mg per day for three months, using a double-blind cross-over design (Hofman-Bang et al, 1995) and significant improvements in volume load ejection fraction, arteriovenous oxygen difference and quality of life assessment were documented. In a more recent controlled trial with 22 CHF patients (NYHA class II and III) treated with 200 mg of CoQ10 per day for three months, a marked improvement in left ventricular ejection fraction was demonstrated (Munkholm et al, 1999). It should be emphasized here that in all these clinical trials, CoQ10 was used as an adjunct to conventional therapy for heart failure.
Open label clinical trials
Among the open label trials are two very large multicenter studies. One involved 1715 patients with heart failure (NYHA class II and III) in 378 centers, which had been stabilized with standard therapy for three months (Lampertico and Comis, 1993). This was a short-term study where the efficacy and safety of CoQ10 supplementation as adjunct therapy at a daily dose of 50 mg for four weeks was evaluated. The results demonstrated that CoQ10 supplementation significantly improved various measures such as dyspnea, palpitations, cyanosis, hepatomegaly, ankle edema, heart rate, and systolic and diastolic blood pressure in patients with stabilized heart failure. It was concluded that CoQ10 supplementation leads to improvements in the signs and symptoms of heart failure and in the quality of life. According to the authors, CoQ10 represents a new therapeutic modality in the treatment of cardiac diseases. The second large scale open label study, the largest to date, was similar in design and it involved a total of 2664 patients with CHF, NYHA class II and III, in 173 centers who received an average of 100 mg of CoQ10 as adjunct therapy for three months (Baggio et al, 1993; 1994). Clinical and laboratory measurements were made at entry and at the end of three months. Significant improvements in clinical signs and symptoms of the disease were observed, particularly with respect to cyanosis, edema, jugular reflux, pulmonary rate, dyspnea, arrhythmia and palpitations, and in the overall quality of life. In a longer-term trial, the improvement in ejection fraction in heart failure patients (NYHA class II-IV) associated with CoQ10 treatment was maintained at three years (Langsjoen et al, 1990a). In a longer-term trial, 143 patients with chronic, stable, non-hypertrophic cardimyopathy (98% in NYHA class III and IV) were treated with 100 mg CoQ10 per day as an adjunct to standard therapy for six years. Most patients (85%) improved one or two NYHA classes, and there was a significant improvement in ejection fraction (from 44% to 60%) in 84% of patients within six months and remained stabilized at that level. A comparison with patients on conventional therapy alone showed a reduction in mortality rate with CoQ10, and no side effects attributable to CoQ10 supplementation (Langsjoen et al, 1990b).
Another open label study that is cited often involved 126 patients in NYHA class II-IV heart failure who were treated with 100 mg CoQ10 a day for six months (Langsjoen et al, 1990). Blood CoQ10 levels rose to about 2 mcg/mL by three months and remained stable thereafter. The ejection fraction, assessed from systolic time intervals, increased from 41% at control to 59% at six months that was highly significant. Two-year survival was 84% as compared with 50% in similar groups of controls, again a highly significant observation. In a larger study, data on 424 patients with heart disease including ischemic cardiomyopathy, dilated cardiomyopathy, primary diastolic dysfunction, hypertensive heart disease, and valvular heart disease, treated with an average dose of 240 mg CoQ10 per day and followed up to eight years, showed significant improvements in NYHA functional classification, myocardial function and an average of 50% reduction in concomitant drug therapy (Langsjoen et al, 1994). Myocardial function showed an improvement within a month following CoQ10 treatment and reached a maximum by six months, and this improvement was sustained in a majority of patients. Withdrawal of CoQ10 therapy resulted in a measurable decline in myocardial function within one month and a return to pretreatment values within three to six months. This observation on relapse following cessation of CoQ10 therapy is consistent with data from several other trials (Mortensen et al, 1986; Mortensen, 1993; Lampertico and Comis, 1993). The fact that CoQ10 supplementation resulted in about 50% reduction in concomitant therapy in this study is in itself a very important finding.
The therapeutic efficacy of CoQ10 in patients with dilated cardiomyopathy (DCM) was examined in one study using a daily dose of 100 mg CoQ10 (Manzoli et al, 1990). Improvements in various clinical parameters and in NYHA class were documented in 47% of patients. Patients with lower myocardial CoQ10 levels at baseline appeared to show a better response to CoQ10 treatment. These data again indicate that DCM may be reversible, and that CoQ10 is an efficacious aid in the traditional treatment of chronic heart failure. In a more recent study, the potential clinical benefit of CoQ10 in 17 patients with CHF was examined, and the data showed significant functional, clinical and hemodynamic improvements after four months of treatment (Sacher et al, 1997). It should be noted again here that in all these studies CoQ10 was used as an adjunct to standard medical therapy. Therefore, although there were no control groups in these open-label trials, the fact that the patients continued to receive conventional therapy during the course of Co10 supplementation makes a strong case for the therapeutic role of CoQ10. There are numerous other open trials reported in the literature similarly documenting the beneficial effect of adjunctive CoQ10 therapy in patients with heart failure and other cardiovascular diseases.
Controlled clinical trials with “neutral” results
There were three controlled trials with heart failure patients treated with CoQ10 as adjunct therapy that did not yield positive results (Table 2). The results were neutral in that no benefit with CoQ10 supplementation over and above that obtained with conventional therapy was observed, and the possible reasons for the lack of benefit of CoQ10 need to be addressed. Features common to these three studies that may have contributed to the neutral results are: small sample size (underpowered trials), severity and duration of the disease, relatively low dosage of CoQ10, duration of treatment, and either lack of measurement of plasma CoQ10 levels or inadequate plasma CoQ10 levels following CoQ10 supplementation. One study that is often quoted in the CoQ10 literature involved 25 patients with IDCM (idiopathic dilated cardiomyopathy) with normal coronary anatomy (Permanetter et al, 1992). No significant improvement in exercise tolerance or myocardial function could be demonstrated after four months of treatment with CoQ10 at 100 mg per day. Most of the earlier trials where a positive response was seen involved patients with heart failure due to ischemic heart disease and other etiologies, and the data show that these diseases to be more responsive to CoQ10 treatment than IDCM. More importantly, plasma CoQ10 levels were not measured in this study, and it is not known and unlikely that therapeutic plasma levels (at least 2.0-2.5 mcg/mL and preferably above 3.5 mcg/mL) were achieved in these patients at the dose employed (Langsjoen et al, 1988; Sinatra, 1997; Langsjoen and Langsjoen, 1998, 1999). Furthermore, the duration of IDCM prior to entry into the study is an important factor and this was not indicated in this report. Patients who are treated with CoQ10 shortly after diagnosis of dilated cardiomyopathy are known to show the greatest degree of improvement as opposed to those with long-standing disease, presumably due to gradual loss of myocytes (Langsjoen and Langsjoen, 1999). In other studies, IDCM patients treated with the same dose of CoQ10 have shown sustained clinical improvement (Mortensen et al, 1985; Langsjoen et al, 1990). It is interesting to note here that the authors state in their discussion that “a possible explanation for the differing results could be that the patients taking part in the study of Langsjoen et al (1985) were in a worse clinical condition. The therapeutic effect might depend on the severity of heart failure”.
The second neutral trial was a double-blind study with 30 patients for three-month, followed by crossover (Watson et al, 1999). The patients were not classified according to NYHA scale, and seemingly at late-stage disease, and no significant improvement was observed in left ventricular function with CoQ10 (100 mg per day). Plasma CoQ10 was measured which showed a doubling to only about 1.75 mcg/mL that is well below the range that is considered to be necessary for therapeutic benefit (Langsjoen et al, 1988; Sinatra, 1997; Langjoen and Langsjoen, 1998, 1999).
The third neutral study involved 55 patients with CHF (NYHA class III and IV) receiving CoQ10 (200 mg per day) or placebo for six months using a randomized double-blind design (Khatta et al, 2000). The shortcomings in this study include a lack of information on the duration of the disease, an important factor affecting the outcome. The authors’ conclusions are heavily dependent on three outliers who did not conform to the patterns of response observed for the rest of the patients. Only half of the patients in the treatment group achieved a therapeutic response in serum CoQ10 level, and this indicates a compliance problem. Nevertheless, it is interesting to note that the majority of patients showing a significant increase in serum CoQ10 also had a positive clinical response (increase in peak oxygen consumption). Statistical power is another issue here and the authors themselves point out in their discussion that the apparent lack of beneficial effect of CoQ10 may have been due to the relatively small sample size in their study.
Thus, it appears that the observed lack of beneficial effect of CoQ10 as an adjunct to standard medical therapy could have been due to any one or a combination of factors such as statistical power, duration and severity of heart disease, CoQ10 dosage, duration of treatment, and plasma CoQ10 levels. One other variable that is rarely considered in this context is the bioavailability of the formulations used. Recent studies have shown vast differences in bioavailability between the “solubilized” and powder-based formulations of CoQ10, as reflected in plasma CoQ10 levels (Chopra et al, 1998).
Following a recent review of 34 controlled trials including the neutral study by Permanetter et al (1992), and several open-label and long-term studies, Langsjoen and Langsjoen (1999) concluded that there is strong evidence to show CoQ10 alters the naturally history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease by the maintenance of optimal cellular and mitochondrial function. The benefits of CoQ10 supplementation are not due solely to a correction of deficiency, since clinical improvements are frequently seen in patients with “normal” plasma CoQ10 levels. Thus, optimum clinical benefit may require plasma CoQ10 values over and above the “normal” range so as to enhance tissue uptake and stimulate mitochondrial bioenergetics. It has become clear in recent years that the ischemic cardiomyopathy patients with viable although weak myocytes, often show the most dramatic improvements with supplemental CoQ10 and this is perhaps related to the large free radical burden in ischemic tissue. Furthermore, the duration of idiopathic dilated cardiomyopathy prior to CoQ10 supplementation is an important factor in so much as those patients treated shortly after the diagnosis show the greatest response as opposed to those with long-standing disease who frequently show minimal changes that is presumably related to the gradual loss of myocytes with an increasingly thin and fibrotic myocardium (Langsjoen and Langsjoen, 1998.1999). In this context, it is very interesting to note that in a cross-sectional study of 94 hospital patients over the age of 50 years, those with low serum CoQ10/cholesterol ratios showed increased risk of CHF or severe myalgia or died within a six-month follow-up period (Jameson, 1993).
Safety of CoQ10
CoQ10 has an excellent safety record. It should be noted that CoQ10 is not a foreign substance but a naturally occurring nutrient that is synthesized in the body. Long-term safety of high dose CoQ10 supplementation has been very well documented in both animals and humans (Langsjoen et al, 1990; Lampertico and Comis, 1993; Baggio et al, 1993, 1994; Sinatra, 1998; Williams et al, 1999). The only side effects reported in a very small number of subjects are mild symptoms such as nausea and stomach upset. Daily dosage for up to eight years has not revealed any adverse effects and thus confirms the safety profile of CoQ10 in human subjects (Langsjoen et al, 1990a, 1990b, 1994; Overvad et al, 1999).
Summary and conclusions
There is sound scientific rationale for an important role for coenzyme Q10 in cardiovascular health, particularly with respect to congestive heart failure and cardiomyopathy. In addition to its critical role in energy production in the mitochondria, coenzyme Q10 is also an important antioxidant. Published data in peer-reviewed journals on the use of coenzyme Q10 as an adjunct to standard medical therapy in both controlled and open-label studies provide strong evidence in support of significant clinical improvement with coenzyme Q10 supplementation in heart failure patients. It is important to recognize that coenzyme Q10 is a naturally occurring nutrient that is synthesized in the body, and it has an excellent safety record. Therefore, the use of coenzyme Q10 as an adjunct to conventional therapy in patients with congestive heart failure and cardiomyopathy can be readily justified. Coenzyme Q10 has the potential to improve and strengthen cardiac function and the quality of life, and reduce the number of hospitalizations of heart failure patients, and thus, coenzyme Q10 supplementation can also help reduce overall healthcare costs.
The weight of the evidence based upon an objective assessment of all available scientific literature supports the following proposed health claim statements for coenzyme Q10:
– Coenzyme Q10 supplementation may help reduce the risk for congestive heart failure and cardiomyopathy.
– Coenzyme Q10 supplementation may help reduce the risk for heart failure.
– Coenzyme Q10 supplementation may help reduce the risk for certain types of heart diseases.
– Coenzyme Q10 supplementation may help reduce the risk for certain types of heart diseases such as congestive heart failure and cardiomyopathy.
– Coenzyme Q10 supplementation, as an adjunct to standard medical therapy, may help reduce the risk for certain types of heart diseases such as congestive heart failure and cardiomyopathy.
BIBLIOGRAPHY
Alleva R, Tomasetti M, Bompadre S, Littarru GP. Oxidation of LDL and their subfractions: kinetic aspects and CoQ10 content. Molecular Aspects of Medicine, 1997;18 (Suppl):S105-12.
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators. Clin Investig 1993;71(8 Suppl):S145-9
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heartfailure. CoQ10 Drug Surveillance Investigators.Mol Aspects Med 1994;15 (Suppl):S287-94.
Bashore TM, Magorien DJ, Letterio J, Shaffer P, Unverferth DV. Histologic and biomedical correlates of left ventricular chamber dynamics in man. J Am Coll Med 1987;9: 734-42.
Bliznakov EG. The Miracle Nutrient Coenzyme Q10 . Bantam Books, New York, 1987.
Chopra RK, Goldman R, Sinatra ST, Bhagavan HN. Relative bioavailability of coenzyme Q10 formulations in human subjects. Int J Vit Nutr Res 1998;68:109-113.
Crane FL. New functions for coenzyme Q. Protoplasma , 213, 127, 2000.
Crane F L. Biochemical functions of coenzyme Q10 ,J Am Coll Nutr 2001;20,591-8.
Crane FL, Hatefi Y, Lester RL, Widmer C. Isolation of a quinone from beef heart mitochondria.
Biochim Biophys Acta 1957;25:220-1.
Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, Cooley D. Evidence for a deficiency of coenzyme Q10 in human heart disease. Int Z Vitaminforsch 1970;40:380-90.
Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci U S A 1985;82:901-4
Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990;30:596-608.
Judy WV, Hall JH, Toth PD, Folkers K. Long-term management of end-stage heart failure with coenzyme Q10. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986a;5:291-301.
Judy WV, Hall JH, Toth PD, Folkers K. Double-blind double- crossover study of coenzyme Q10 in heart failure. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986b;5:315-23.
Judy WV, Folkers K, Hall JH. Improved long-term survival in coenzyme Q10-treated congestve heart failure patients compared to, conventionally-treated patients. In: Folkers K, Littarru GP, Yamagami T, (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1991;6:291-8.
Hofman-Bang C, Rehnqvist N, Swedberg K, Wiklund I, Astrom H. Coenzyme Q10 as an adjunctive in the treatment of chronic congestive heart failure. J Card Fail 1995;1:101-7.
Jameson S. Statistical data support prediction of death within 6 months on low levels of coenzyme Q10 and other entities. Clin Investig 1993;71(8 Suppl):S137-9.
Khatta M, Alexander BS, Krichten CM, Fisher ML, Freudenberger R, Robinson SW, Gottlieb SS. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Int Med 2000;132:636-40.
Lampertico M, Comis S. Italian multicenter study on the efficacy and safety of coenzyme Q10 as adjunct therapy in heart failure. Clin Investig 1993;71:S129-33.
Langjoen PH, Folkers K, Lyson K, Muratsu K, Lyson T, Langsjoen P. Effective and safe therapy with coenzyme Q10 for cardiomyopathy. Klin Wochenschr 1988;66:583-90.
Langjoen PH, Folkers K, Lyson K, Muratsu K, Lyson T, Langsjoen P. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and conventional therapy. Int J Tissue React 1990;12:163-8.
Langsjoen PH, Langsjoen AM. Coenzyme Q10 in cardiovascular disease with emphasis on heart failure and myocardial ischemia. Asia Pacific Heart J 1998;7:160-8.
Langsjoen PH, Langsjoen AM. Overview of the use of coenzyme Q10 in cardiovascular disease. Biofactors 1999;9:273-84.
Langsjoen PH, Langsjoen PH, Folkers K. Long-term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1990a;65:521-3.
Langsjoen PH, Langsjoen PH, Folkers K. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React 1990b;12:169-71.
Langsjoen HA, Langsjoen PH, Langsjoen PH, Willis R, Folkers K. Usefulness of coenzyme Q10 in clinical cardiology: a long-term study. Mol Aspects Med 1994;15 (Suppl):S265- 72.
Langsjoen PH, Vadhanavikit S, Folkers K. Response of patients in class II and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10. Proc Nat Acad Sci USA 1985;82:4240-4.
Manzoli U, Rossi E, Littarru GP, Frustaci A, Lippa S, Oradei A, Aureli V. Coenzyme Q10 in dilated cardiomyopathy. Int J Tissue React 1990;12:173-8.
Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta 1992;1126:247-54.
Morisco C, Trimarco B, Condorelli M. Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. Clin Investig 1993;71 (Suppl 8):S134-6.
Morisco C, Nappi A, Argenziano L, Sarno D, Fonatana D, Imbriaco M, Nicolai E, Romano M, Rosiello G, Cuocolo A. Noninvasive evaluation of cardiac hemodynamics during exercise in patients with chronic heart failure: effects of short-term coenzyme Q10 treatment. Mol Aspects Med 1994;15 (Suppl);S155-63.
Mortensen SA. Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone). Clin Investig 1993;71(8 Suppl):S116-23.
Mortensen SA, Bouchelouche K, Muratsu K, Folkers K. Clinical decline and relapse of cardiac patients on coenzyme Q10 withdrawal. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:281-90.
Mortensen SA, Vadhanavikit S, Baandrup U, Folkers K. Long- term coenzyme Q10 therapy: A major advance in the management of resistant myocardial failure. Drugs Exptl Clin Res 1985;11:581-93.
Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors 1999;9:285-9.
Nishimura T. Beta-methyl-p-(123I)-iodophenylpentadecanoic acid single-photon emission computed tomography in cardiomyopathy. Int J Card Imaging 1999;15:41-8.
Oda T. Effect of coenzyme Q10 on load-induced cardiac dysfunction: Double-blind study and investigation of dose-response relationship. In: Lenaz G, Barnabei O, Rabbi A (Eds). Highlights in Ubiquinone Research. London, Taylor and francis, 1990;232-7.
Overvad, K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr 1999 Oct;53(10):764-70
Permanetter B, Rossy, W, Klein G, Weingartner F, Said KF, Blomer H. Ubiquinone (coenzyme Q10) in the long-term treatment of idiopathic dilated cardiomyopathy. Eur Heart J. 1992;13:1528-33.
Poggesi L, Galanti G, Comeglio M, Toncelli L, Vinci M. Effect of coenzyme Q10 on left ventricular function in patients with dilative cardiomyopathy. A medium-term randomized double-blind study versus placebo. Curr Ther Res 1991;49:878-86.
Rauchova H, Drahota Z, Lenaz, G. Function of coenzyme Q in the cell: Some biochemical and physiological properties. Physiol Rev 1995;44:209-16.
Rengo F, Abete P, Landino P, Leosco D, Covelluzzi F, Vitale D, Fedi V, Ferrara N. Role of metabolic therapy in cardiovascular disease. Clin Investig 1993;71(8 Suppl):S124- 8.
Rosenfeldt FL, Pepe S, Linnane A, Nagley P, Rowland M, Ou R, Marasco S, Lyon W. The effects of ageing on the response to cardiac surgery: protective strategies for the ageing myocardium. Biogerontology 2002;3:37-40.
Rossi E, Lombardo A, Testa M., Lippa S, Oradei A, Littarru GP,Lucente M, Coppola E, Manzoli U. Coenzyme Q10 in ischaemic cardiopathy. In: Folkers K, Yamagami T, Littarru GP. (Eds). Biomedical and Clinical aspects of Coenzyme Q. Amsterdam, Elsevier, 1991;6:321-6.
Sacher HL, Sacher ML, Landau SW, Kersten R, Dooley F, Sacher A, Sacher M, Dietrick K, Ichkhan K. The clinical and hemodynamic effects of coenzyme Q10 in congestive cardioimyopathy. Am J Ther 1997;4:66-72.
Schneeberger W, Muller-Steinwachs J, Anda LP, Fuchs W, Zilliken F, Lyson K, Muratsu K, Folkers K. A clinical double-blind and crossover trial with coenzyme Q10 on patients with cardiac disease. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:325-33.
Sinatra ST. Refractory congestive heart failure successfully managed with high dose coenzyme Q10 administration. Mol Aspects Med 1997;18:S299-305.
Sinatra ST. The Coenzyme Q10 Phenomenon. Keats Publishing, New Canaan, 1998.
Soja AM, Mortensen SA. Treatment of congestive heart failure with coenzyme Q10 illuminated by meta-analyses of clinical trials. Mol aspects Med 1997;18:S159-68.
VanFraechem JPH, Picalausa C, Folkers K. Effects of CoQ10 on physical performance and recovery in myocardial failure. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:371-7.
Watson PS, Scalia GM, Galbraith A, Burstow DJ, Bett N, Aroney CN. Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure. J Am Coll Cardiol 1999;33:1549-52.
Williams KD, Maneke JD, AbdelHameed M, Hall RL, Palmer TE, Kitano M, Hidaka T. 52-Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery. J Agric Food Chem 1999;47:3756-63.
Wolf DE, Hoffman CH, Trenner NR, Arison BH, Shunk CH, Linn BD, McPherson JF, and Folkers K. Structure studies on the coenzyme Q group. J Am Chem Soc 1958: 80:4752..
Yamamura Y. Clinical status of Coenzyme Q and prospects. In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1977;281-98.
Table 1: Controlled clinical trials on the efficacy of oral coenzyme Q10 in heart failure
Investigators
|
No. Of patients
|
Investigators
Diagnosis |
Results
|
Hashiba et al (1972)
|
197
|
CHF
|
Improved, NYHA class
|
Iwabuchi et al (1972)
|
38
|
CHF
|
Improved, NYHA class
|
Langsjoen et al (1985)
|
19
|
CHF
|
Increased EF
|
Vanfraechem et al (1986)
|
15
|
CHF
|
Increased EF, CO, SV
|
Judy et al (1986)
|
14
|
CHF
|
Increased EF, CO
|
Schneeberger et al (1986)
|
12
|
MVP,DD
|
Increased CO, SV
|
Oda (1990)
|
40
|
ICM
|
Improved DF
|
Rossi et al (1991)
|
20
|
ICM,IDCM
|
Increased ET
|
Poggesi et al (1991)
|
20
|
CHF
|
Increased EF
|
Judy et al (1991)
|
180
|
CHF
|
Increased survival
|
Rengo et al (1993)
|
60
|
CHF
|
Increased EF
|
Morisco et al (1993)
|
641
|
CHF
|
Fewer hospitalizations
|
Morisco et al (1994)
|
6
|
CHF
|
Increased EF, CO, SV
|
Hofman-Bang et al (1995)
|
79
|
CHF
|
Increased EF
|
Munkholm et al (1999)
|
22
|
CHF
|
Increased EF
|
Abbreviations: CHF – congestive heart failure, NYHA – NY Heart Association, EF – ejection fraction, CO – cardiac output, SV – stroke volume, MVP – mitral valve prolapse, DD – diastolic dysfunction, DF – diastolic function, ICM ischemic cardiomyopathy, IDCM – idiopathic dilated cardiomyopathy.
Table 2: Controlled clinical trials on the lack of efficacy of oral coenzyme Q10 in heart failure
Investigators
|
No. of patients
|
Diagnosis
|
Results
|
Permanetter et al (1992)
|
25
|
IDCM
|
No improvement
|
Watson et al (1999)
|
30
|
CHF
|
No improvement
|
Khatta et al (2000)
|
55
|
CHF
|
No improvement
|
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G.
Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators.
Clin Investig 1993;71(8 Suppl):S145-9
Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G.
Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators.
Mol Aspects Med 1994;15 (Suppl):S287-94
Bashore TM, Magorien DJ, Letterio J, Shaffer P, Unverferth DV.
Histologic and biomedical correlates of left ventricular chamber dynamics in man.
J Am Coll Med 1987;9:734-42.
Bliznakov EG.
The Miracle Nutrient Coenzyme Q10 .
Bantam Books, New York, 1987.
Chopra RK, Goldman R, Sinatra ST, Bhagavan HN.
Relative bioavailability of coenzyme Q10 formulations in human subjects.
Int J Vit Nutr Res 1998;68:109-113.
Crane FL.
New functions for coenzyme Q.
Protoplasma , 213, 127, 2000.
Crane F L.
Biochemical functions of coenzyme Q10
J Am Coll Nutr 2001;20,591-8.
Folkers K, Vadhanavikit S, Mortensen SA.
Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10.
Proc Natl Acad Sci U S A 1985;82:901-4
Greenberg S, Frishman WH.
Co-enzyme Q10: a new drug for cardiovascular disease.
J Clin Pharmacol 1990;30:596-608.
Judy WV, Hall JH, Toth PD, Folkers K.
Long-term management of end-stage heart failure with coenzyme Q10.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986a;5:291-301
Judy WV, Hall JH, Toth PD, Folkers K.
Double-blind double-crossover study of coenzyme Q10 in heart failure.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986b;5:315-23.
Judy WV, Folkers K, Hall JH.
Improved long-term survival in coenzyme Q10-treated congestive heart failure patients compared to, conventionally-treated patients.
In: Folkers K, Littarru GP, Yamagami T, (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1991;6:291-8.
Hofman-Bang C, Rehnqvist N, Swedberg K, Wiklund I, Astrom H.
Coenzyme Q10 as an adjunctive in the treatment of chronic congestive heart failure.
J Card Fail 1995;1:101-7.
Jameson S.
Statistical data support prediction of death within 6 months on low levels of coenzyme Q10 and other entities.
Clin Investig 1993;71(8 Suppl):S137-9.
Khatta M, Alexander BS, Krichten CM, Fisher ML, Freudenberger R, Robinson SW, Gottlieb SS.
The effect of coenzyme Q10 in patients with congestive heart failure.
Ann Int Med 2000;132:636-40.
Lampertico M, Comis S.
Italian multicenter study on the efficacy and safety of coenzyme Q10 as adjunct therapy in heart failure.
Clin Investig 1993;71:S129-33.
Langsjoen PH, Folkers K, Lyson K, Muratsu K, Lyson T, Langsjoen P.
Effective and safe therapy with coenzyme Q10 for cardiomyopathy.
Klin Wochenschr 1988;66:583-90.
Langsjoen PH, Folkers K, Lyson K, Muratsu K, Lyson T, Langsjoen P.
Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and conventional therapy.
Int J Tissue React 1990;12:163-8.
Langsjoen PH, Langsjoen AM.
Coenzyme Q10 in cardiovascular disease with emphasis on heart failure and myocardial ischemia.
Asia Pacific Heart J 1998;7:160-8.
Langsjoen PH, Langsjoen AM.
Overview of the use of coenzyme Q10 in cardiovascular disease.
Biofactors 1999;9:273-84.
Langsjoen PH, Langsjoen PH, Folkers K.
Long-term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy.
Am J Cardiol 1990a;65:521-3.
Langsjoen PH, Langsjoen PH, Folkers K.
A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10.
Int J Tissue React 1990b;12:169-71.
Langsjoen HA, Langsjoen PH, Langsjoen PH, Willis R, Folkers K.
Usefulness of coenzyme Q10 in clinical cardiology: a long-term study.
Mol Aspects Med 1994;15 (Suppl):S265-72.
Langsjoen PH, Vadhanavikit S, Folkers K.
Response of patients in class II and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10.
Proc Nat Acad Sci USA 1985;82:4240-4.
Manzoli U, Rossi E, Littarru GP, Frustaci A, Lippa S, Oradei A, Aureli V
Coenzyme Q10 in dilated cardiomyopathy.
Int J Tissue React 1990;12:173-8.
Morisco C, Trimarco B, Condorelli M.
Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study.
Clin Investig 1993;71 (Suppl 8):S134-6.
Morisco C, Nappi A, Argenziano L, Sarno D, Fonatana D, Imbriaco M, Nicolai E, Romano M, Rosiello G, Cuocolo A.
Noninvasive evaluation of cardiac hemodynamics during exercise in patients with chronic heart failure: effects of short-term coenzyme Q10 treatment.
Mol Aspects Med 1994;15 (Suppl);S155-63.
Mortensen SA.
Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone).
Clin Investig 1993;71(8 Suppl):S116-23.
Mortensen SA, Bouchelouche K, Muratsu K, Folkers K.
Clinical decline and relapse of cardiac patients on coenzyme Q10 withdrawal.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:281-90.
Mortensen SA, Vadhanavikit S, Baandrup U, Folkers K.
Long-term coenzyme Q10 therapy: A major advance in the management of resistant myocardial failure.
Drugs Exptl Clin Res 1985;11:581-93.
Munkholm H, Hansen HH, Rasmussen K.
Coenzyme Q10 treatment in serious heart failure.
Biofactors 1999;9:285-9.
Nishimura T.
Beta-methyl-p-(123I)-iodophenylpentadecanoic acid single-photon emission computed tomography in cardiomyopathy.
Int J Card Imaging 1999;15:41-8.
Oda T.
Effect of coenzyme Q10 on load-induced cardiac dysfunction: Double-blind study and investigation of dose-response relationship.
In: Lenaz G, Barnabei O, Rabbi A (Eds). Highlights in Ubiquinone Research. London, Taylor and francis, 1990;232-7.
Overvad, K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S.
Coenzyme Q10 in health and disease.
Eur J Clin Nutr 1999 Oct;53(10):764-70
Permanetter B, Rossy, W, Klein G, Weingartner F, Said KF, Blomer H.
Ubiquinone (coenzyme Q10) in the long-term treatment of idiopathic dilated cardiomyopathy.
Eur Heart J. 1992;13:1528-33.
Poggesi L, Galanti G, Comeglio M, Toncelli L, Vinci M.
Effect of coenzyme Q10 on left ventricular function in patients with dilative cardiomyopathy. A medium-term randomized double-blind study versus placebo.
Curr Ther Res 1991;49:878-86.
Rauchova H, Drahota Z, Lenaz, G.
Function of coenzyme Q in the cell: Some biochemical and physiological properties.
Physiol Rev 1995;44:209-16.
Rengo F, Abete P, Landino P, Leosco D, Covelluzzi F, Vitale D, Fedi V, Ferrara N.
Role of metabolic therapy in cardiovascular disease.
Clin Investig 1993;71(8 Suppl):S124-8.
Rosenfeldt FL, Pepe S, Linnane A, Nagley P, Rowland M, Ou R, Marasco S, Lyon W.
The effects of ageing on the response to cardiac surgery: protective strategies for the ageing myocardium.
Biogerontology 2002;3:37- 40.
Rossi E, Lombardo A, Testa M., Lippa S, Oradei A, Littarru GP,Lucente M, Coppola E, Manzoli U.
Coenzyme Q10 in ischaemic cardiopathy.
In: Folkers K, Yamagami T, Littarru GP. (Eds). Biomedical and Clinical aspects of Coenzyme Q. Amsterdam, Elsevier, 1991;6:321-6.
Sacher HL, Sacher ML, Landau SW, Kersten R, Dooley F, Sacher A, Sacher M, Dietrick K, Ichkhan K.
The clinical and hemodynamic effects of coenzyme Q10 in congestive cardiomyopathy.
Am J Ther 1997;4:66- 72.
Schneeberger W, Muller-Steinwachs J, Anda LP, et al.
A clinical double-blind and crossover trial with coenzyme Q10 on patients with cardiac disease.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:325-33.
Sinatra ST.
Refractory congestive heart failure successfully managed with high dose coenzyme Q10 administration.
Mol Aspects Med 1997;18:S299-305.
Soja AM, Mortensen SA.
Treatment of congestive heart failure with coenzyme Q10 illuminated by meta- analyses of clinical trials.
Mol aspects Med 1997;18:S159-68.
VanFraechem JPH, Picalausa C, Folkers K.
Effects of CoQ10 on physical performance and recovery in myocardial failure.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1986;5:371-7.
Watson PS, Scalia GM, Galbraith A, Burstow DJ, Bett N, Aroney CN.
Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure.
J Am Coll Cardiol 1999;33:1549-52.
Williams KD, Maneke JD, AbdelHameed M, Hall RL, Palmer TE, Kitano M, Hidaka T.
52-Week oral gavage chronic toxicity study with ubiquinone in rats with a 4-week recovery.
J Agric Food Chem 1999;47:3756-63.
Yamamura Y.
Clinical status of Coenzyme Q and prospects.
In: Folkers K, Yamamura Y. (Eds). Biomedical and Clinical Aspects of Coenzyme Q. Amsterdam, Elsevier, 1977;281-98.