Background

Since the discovery of the vitamin-like nutrient coenzyme Q₁₀ (ubiquinone, CoQ₁₀) by Frederick Crane et al. in 1957 [10] and by other investigators [57], and since the first patients with heart failure were treated with coenzyme Q by Yuichi Yamamura [87-89], there has been a slow but steady accumulation of worldwide clinical experience with CoQ₁₀ in heart disease over the ensuing 30 years. CoQ₁₀ is a coenzyme for the inner mitochondrial enzyme complexes involved in oxidative phosphorylation. [44,45,49]. This bioenergetic effect of CoQ₁₀ is believed to be of fundamental importance in its clinical application, particularly as relates to cells with exceedingly high metabolic demands such as cardiac myocytes. The second fundamental property of CoQ₁₀ involves its antioxidant (free radical scavenging) functions [5,15,62,82]. CoQ₁₀ is the only known naturally occurring lipid soluble antioxidant for which the body has enzyme systems capable of regenerating the active reduced ubiquinol form [15]. CoQ₁₀ is known to be closely linked to Vitamin E and serves to regenerate the reduced (active) a-tocopherol form of Vitamin E [9]. Other aspects of CoQ₁₀ function include its involvement in extramitochondrial electron transfer, e.g. plasma membrane oxidoreductase activity [41,82], involvement in cytosolic glycolysis [41,46,48], and potential activity in both Golgi apparatus and lysosomes [11,12]. CoQ₁₀ also plays a role in improvement in membrane fluidity [42,43,62] as evidenced by a decrease in blood viscosity with CoQ₁₀ supplementation [29]. The rationale behind the use of CoQ₁₀ in heart failure has focused primarily on the correction of a measurable deficiency of CoQ₁₀ in both blood and myocardial tissue with the degree of CoQ₁₀ deficiency correlating directly with the degree of impairment in left ventricular function [55]. CoQ₁₀ supplementation corrects measurable deficiencies of CoQ₁₀ in blood and tissue [16,17,30,31,34,47,55]. Exogenous CoQ₁₀ is taken up by CoQ₁₀-deficient cells and can be demonstrated to be incorporated into the mitochondria [59]. The role of free radicals in cell injury and in cell death in settings of ischemia and reperfusion is becoming increasingly well established. CoQ₁₀'s antioxidant properties and its location within the mitochondria (the center of free radical production) make it an obvious candidate for a potential therapeutic agent in these situations [92].

Congestive Heart Failure Controlled Trials

Since the Japanese pioneering studies in the late 1960's, there have been at least 15 randomized controlled trials involving a total of 1,366 patients with both primary and secondary forms of myocardial failure. The first randomized controlled trial by Hashiba et al in 1972 involving 197 patients [21] documented significant improvement using 30 mg CoQ₁₀/day. Similar observations were made in another controlled trial by Iwabuchi et al., again using 30 mg of oral CoQ₁₀ in 38 patients with heart failure [24]. The first controlled trial in idiopathic dilated cardiomyopathy in the United States was published by Per Langsjoen in 1985 using 100 mg of CoQ₁₀ per day in 19 patients with double-blind crossover design and three month treatment periods [34]. Significant improvements were noted in ejection fraction as well as functional status. Three controlled trials in 1986 by VanFraechem et al., Judy et al. and Schneeberger et al. confirmed these findings, again using 100 mg of CoQ₁₀ per day [25,71,81]. In 1990 Oda documented normalization of load-induced cardiac dysfunction in 40 patients with mitral valve prolapse using a double blind placebo controlled design [60]. In 1991, Rossi et al. showed significant improvement in ischemic cardiomyopathy in 20 patients using 200 mg per day [68]. Poggesi et al. documented significant improvement in myocardial function in 20 patients with either ischemic or idiopathic dilated cardiomyopathies using 100 mg of CoQ₁₀ per day [65]. Judy et al. randomized 180 patients to receive either 100 mg per day of CoQ₁₀ versus placebo and noted significant improvement in long-term survival with patients followed up to eight years [26]. The only controlled study to show no benefit in heart failure was published by Permanetter et al. in 1992 [64]. This was a well designed study looking specifically at idiopathic dilated cardiomyopathy in 25 patients with documented normal coronary anatomy by cardiac catheterization. After a two month stabilization period, patients were treated with either placebo or CoQ₁₀ for a duration of four months in a double-blind crossover design. No significant improvement in exercise tolerance or measurements of myocardial function could be demonstrated. Possible reasons for the lack of therapeutic efficacy of CoQ₁₀ in this trial merit discussion. Although the 100 mg per day dose of CoQ₁₀ used in this trial was shown to give a threefold increase plasma CoQ₁₀ levels in healthy volunteers, the plasma levels in the patients during the trial were not measured and it is conceivable that many of the cardiomyopathy patients may have had poor absorption of the CoQ₁₀ and, therefore, may have had only marginal increases in their plasma Q levels. Another point is that all prior trials in heart failure involved patients with a mixture of etiologies, which frequently included patients with ischemic heart disease. It has become clear in recent years that the ischemic cardiomyopathy patients with viable but weak myocytes, often show the most dramatic improvements with supplemental CoQ₁₀ (author's observations) perhaps related to the large free radical burden in ischemic tissue. Furthermore, the duration of idiopathic dilated cardiomyopathy prior to the institution of CoQ₁₀ supplementation was not specified in this study and is of considerable importance in so much as those patients treated shortly after the diagnosis of dilated cardiomyopathy show the greatest degree of improvement as opposed to patients with long-standing dilated cardiomyopathy who frequently show minimal changes, presumably related to the gradual loss of myocytes in this disease with an increasingly thin and fibrotic myocardium. In 1993, Rengo et al. documented clinical and echocardiographic improvement in 60 patients treated with 100 mg of CoQ₁₀ for seven months [66]. The largest controlled trial to date was published in 1993 by Morisco et al, in which 641 patients were randomly assigned to receive either placebo or CoQ₁₀ at 2 mg/kg per day in a one year double-blind trial [51]. 118 patients in the controlled group required hospitalization for heart failure in the one year follow-up compared to 73 in the CoQ₁₀ treated group (P < 0.001). In addition to the obvious improvement in quality of life for these patients, the reduction in hospitalization rate has strong implications in the growing problem of health care cost containment. A year later in 1994, Morisco et al. documented significant improvements in ejection fraction, stroke volume and cardiac output as measured by radio nuclide scanning in six patients treated with 150 mg of CoQ₁₀ per day in a double-blind crossover design [52]. Lastly, in 1995, Swedberg et al. published a study on 79 patients with severe chronic congestive heart failure whose mean ejection fraction at rest was 22% +/-10% [75]. There was a slight but significant improvement in volume load ejection fraction measurement and a significant improvement in quality of life assessment. A meta analysis of controlled studies in heart failure by Soja et al. demonstrated significant improvement in measurements of cardiac function [73].

Open Label and Long Term Congestive Heart Failure Trials

Dr. Yuichi Yamamura published an excellent review of all early Japanese trials prior to 1984 [91]. By mid 1980's it became apparent that CoQ₁₀ was safe and effective in the short-term treatment of patients with heart failure. Several long-term trials were undertaken to determine if this effect would be sustained and to determine long-term safety. In 1985, Mortensen et al. observed sustained benefit and safety in idiopathic dilated cardiomyopathy on 100 mg per day of CoQ₁₀ [53]. In 1990, we published our observations on 126 patients with dilated cardiomyopathy followed for six years, again noting sustained benefit with remarkable long-term safety and lack of side effects [35]. In 1994, Baggio et al. published the largest open trial in heart failure involving 2,664 patients treated with up to 150 mg of CoQ₁₀ per day, again noting significant benefit and lack of toxicity [3]. Also, in 1994, we published observations on 424 patients with a broader spectrum of myocardial disease including ischemic cardiomyopathy, dilated cardiomyopathy, primary diastolic dysfunction, hypertensive heart disease, and valvular heart disease [37]. Patients were treated with an average of 240 mg of CoQ₁₀ per day and followed for up to eight years with mean follow-up of 18 months. We observed significant improvement in NYHA functional classification, improvement in measurements of myocardial function, an average of 50% reduction in the requirement for concomitant cardiovascular drug therapy, and a complete lack of toxicity. Myocardial function became measurably improved within one month with maximal improvement usually obtained by six months and this improvement appears to be sustained in the majority of patients. The withdrawal of CoQ₁₀ therapy resulted in a measurable decline in myocardial function within one month and a return to pretreatment measurements within three to six months. This return to baseline myocardial function after withdrawal of CoQ₁₀ therapy was also observed by Mortensen et al. [54].

Diastolic Dysfunction

After initial favorable observations in advanced congestive heart failure with predominant systolic dysfunction, our group and others began to look at earlier stages of myocardial dysfunction, specifically, diastolic dysfunction. This filling phase of the cardiac cycle involves the ATP-dependent clearance of calcium which in turn is required for the breaking of the actin-myosin binding. Diastolic dysfunction often precedes more advanced stages of congestive heart failure and is commonly seen in a wide variety of clinical syndromes, including symptomatic hypertensive heart disease with left ventricular hypertrophy, symptomatic mitral valve prolapse, hypertrophic cardiomyopathy, the aging heart, and is often seen in fatigue states such as chronic fatigue syndrome. In 1993, we published observations on 115 patients with isolated diastolic dysfunction - 60 with hypertensive heart disease, 27 with mitral valve prolapse syndrome, and 28 with chronic fatigue syndrome [36]. The administration of CoQ₁₀ resulted in improvement in diastolic function, a decrease in myocardial thickness, and an improvement in functional classification. In 1994, Oda published results on 30 patients with load-induced diastolic dysfunction and documented normalization of diastolic function in all patients after CoQ₁₀ supplementation [63]. In 1994, we published data on 109 patients with hypertensive heart disease and again noted not only improvement in NYHA functional classification and left ventricular hypertrophy, but we also observed significant improvement in diastolic function as measured by doppler echocardiography [38]. We noted improvement in blood pressure and a lessening in the requirement for antihypertensive drug therapy which occurred in tempo with the improvement in diastolic function. In 1997, we published data on seven patients with hypertrophic cardiomyopathy and again noted significant improvement in diastolic function as well as a lessening in hypertrophy and an improvement in functional status [39]. Also in 1997, we published data on 16 otherwise healthy elderly patients over the age of 80, all of whom had significant diastolic dysfunction prior to treatment and all of whom had normalization of diastolic function within three months of CoQ₁₀ supplementation [40]. In summary, there appears to be an improvement in diastolic function in all categories of cardiac disease and this improvement occurs earlier and is more consistent than improvements in systolic function. This is understandable given the frequent occurrence of permanent myocardial fibrosis in advanced idiopathic dilated cardiomyopathy and the permanent myocardial scarring seen in advanced ischemic heart disease. Diastolic dysfunction is easily identified by non-invasive techniques and appears to be readily reversible with supplemental CoQ₁₀ with gratifying clinical improvement.

Ischemic Heart Disease Controlled Trials

Controlled trials in angina did not begin until the mid 1980's with the first publication by Hiasa in 1984 in which 18 patients were randomized to receive either intravenous CoQ₁₀ or placebo [22]. The treated patients showed an increase in exercise tolerance of one stage or greater in a modified Bruce protocol as compared to no increase in exercise tolerance in the placebo group, showed less ST-segment depression with exercise and experienced less angina with no alteration in heart rate or blood pressure. A year later in 1985, Kamikawa et al. studied 12 patients with chronic stable angina in a double-blind placebo controlled randomized crossover protocol using 150 mg a day of oral CoQ₁₀ [28]. Exercise time increased significantly from 345 seconds to 406 seconds with CoQ₁₀ treatment and time until 1 mm of ST depression increased significantly from 196 seconds to 284 seconds (P < 0.01). Again, no significant alteration in heart rate or blood pressure was observed. In 1986, Schardt et al. studied 15 patients with exercise-induced angina treated with 600 mg per day of CoQ₁₀ with a placebo controlled double-blind crossover design [70]. Again, a significant decrease in ischemic ST-segment depression was noted with CoQ₁₀ treatment. Since the CoQ₁₀ treatment caused no significant alteration in heart rate or blood pressure, it was concluded that the mechanism of action was related to a direct effect on myocardial metabolism. In 1991, Wilson et al. studied 58 patients with up to 300 mg per day of CoQ₁₀ compared to placebo and again noted significant improvement in exercise duration to the onset of angina without a change in peak rate pressure product, suggesting an improvement in myocardial efficiency [84]. Also, in 1991, Serra et al. showed significant improvement in 20 patients with chronic ischemic heart disease using 60mg of CoQ₁₀ per day for 4 weeks, documenting improvements in myocardial function measurements, improved exercise capacity, and a significant reduction in the number of anginal episodes and nitrate consumption [72]. In 1994, Kuklinski et al. studied 61 patients with acute myocardial infarction, randomized to obtain either placebo or 100 mg of CoQ₁₀ with 100 microg of selenium for a period of one year [32]. The treatment group showed no prolongation of the QT-interval whereas, in the placebo group, 40% showed prolongation of the corrected QT-interval of greater than 440 milliseconds (P < 0.001). Although there were no significant differences in the acute hospitalization, the one year follow-up revealed six patients (20%) in the control group died from re-infarction, whereas one patient in the treatment group suffered a noncardiac death. The prevention of QT-interval prolongation can be explained by an enhancement in myocardial bioenergetics with an improvement in sodium potassium ATPase function, thereby optimizing membrane repolarization.

LDL Cholesterol Oxidation

The antioxidant properties of CoQ₁₀ and the fact that 60 % of CoQ₁₀ is carried in the plasma with LDL cholesterol [2], has led to investigations as to whether or not CoQ₁₀ has any clinically relevant antioxidant function in terms of decreasing the oxidation of cholesterol [23,79]. It is generally believed that the oxidation of LDL cholesterol is of primary importance in the development of atherosclerosis. In 1996 in Australia, Stocker's group showed in vitro that supplemental CoQ₁₀ prevented the pro-oxidant effect of alpha-tocopherol [78]. Supplementation with vitamin E alone resulted in an LDL which was more prone to oxidation as compared to the combination of CoQ₁₀ and vitamin E which increased the resistance to oxidation. Alleva et al. showed that supplemental CoQ₁₀ increased the amount of CoQ₁₀ in LDL (especially LDL3) and lowered the peroxidizability of the LDL. Aejmelaeus et al. documented a doubling of CoQ₁₀ content in LDL particles after CoQ₁₀ supplementation at 100 mg/day [1].

Statins and CoQ₁₀

Harry Rudney was among the first to recognize the importance of HMG-CoA reductase in the biosynthesis of CoQ₁₀. In January 1981 at the 3rd International Symposium on the Biomedical and Clinical Aspects of Coenzyme Q held in Austin, Texas, USA, he stated "... a major regulatory step in CoQ₁₀ synthesis is at the level of HMG-CoA reductase" [69]. In 1990 Willis et al. [83] studied 40 rats and demonstrated significant tissue CoQ₁₀ deficiency in heart and liver in the lovastatin treated rats which could easily be prevented by co-administration of CoQ₁₀. Later in the same year, Langsjoen et al. noted not only a decline of CoQ₁₀ blood levels, but also a significant clinical decompensation with a reduction in ejection fraction in 5 heart failure patients after the addition of lovastatin to their standard medical therapy plus 100 mg CoQ₁₀ per day [18]. This decompensation was reversed by a doubling of their CoQ₁₀ dose from 100 mg to 200 mg/day. In 1992 Ghirlanda et al. showed in a double blind controller trial in 40 hypercholesterolemic patients a 40% drop in blood CoQ₁₀ level after treatment with either pravastatin or simvastatin [19]. In 1994 Bargossi et al. randomized 30 patients to receive either 20 mg simvastatin or 20 mg simvastatin plus 100mg CoQ₁₀ and followed them for 90 days [4]. The lowering of cholesterol was significant and similar in both groups and the simultaneous CoQ₁₀ therapy prevented both the plasma and platelet CoQ₁₀ depletion induced by simvastatin administration. In 1997 Mortensen et al. observed similar reductions in serum CoQ₁₀ levels in a placebo controlled double blind trial [56]. The authors concluded that "although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of possible adverse consequences from CoQ₁₀ lowering seems important during long term therapy". Also in 1997, Palomaki et al. documented a decrease in the resistance of LDL cholesterol to oxidative stress after 6 weeks of lovastatin therapy in a double blind, placebo controlled, cross over trial on 27 hypercholesterolemic men [63]. This enhanced oxidizability of LDL cholesterol is believed to be related to a decrease in the number of molecules of CoQ₁₀ per each LDL cholesterol particle and may lessen the benefit of LDL cholesterol reduction. The CoQ₁₀ lowering effect of statins is now well established with a significant depletion in plasma and platelets in humans and with a significant depletion in blood, liver and heart in rats. Human skeletal muscle CoQ₁₀ may actually increase with statin therapy as documented by a Finnish study [33] but human heart muscle tissue CoQ₁₀ data are presently lacking and, when available, should help clarify the mechanism of clinical deterioration noted in some cardiomyopathy patients treated with statins. The concern over the long term consequences of statin-induced CoQ₁₀ deficiency is heightened by the rapidly increasing number of patients treated and the increasing dosages and potencies of the statin drugs. As the "target" or "ideal" cholesterol level is steadily lowered, the CoQ₁₀-lowering effect will be more pronounced and the potential for long term adverse health effects enhanced. Before the results of this vast human experiment become obvious over the next decade, it is incumbent upon the medical profession to more closely evaluate the clinical significance of this drug-induced CoQ₁₀ depletion. The combined use of CoQ₁₀ and statins not only prevents the depletion of CoQ₁₀, but may also enhance the benefits of the cholesterol lowering by lessening the oxidation of LDL cholesterol.

Hypertension

A tendency to decrease blood pressure in patients with established hypertension has been noted as far back as 1976 by Nagano, who studied 45 patients on 30-60 mg of CoQ₁₀ per day [58]. A year later, Yamagami published data on 29 patients using 1-2 mg of CoQ₁₀ per kg body weight per day [86]. From 1980 through 1984, three smaller studies again showed favorable improvement in hypertension with CoQ₁₀ supplementation [20,67,80] and in 1986, Yamagami evaluated 20 patients in randomized controlled fashion using 100 mg of CoQ₁₀ per day and again observed a favorable effect [86]. Further uncontrolled open studies [14,38,50] all uniformly found a favorable influence on hypertension when CoQ₁₀ supplementation was added to standard antihypertensive drug therapy. We postulate that the blood pressure lowering effect of CoQ₁₀ may in part be an indirect effect, whereby improved diastolic function leads to a lessening in the adaptive high catecholamine state of hypertensive disease. In addition, effects on vascular endothelium may be involved. It is also possible that the blood viscosity lowering effect of CoQ₁₀ may favorably influence hypertension [29].

Controlled Trials in Cardiovascular Surgery

The first controlled study evaluating the effectiveness of CoQ₁₀, administered preoperatively, was published by Tanaka et al. in 1982 [77]. Fifty patients undergoing heart valve replacement were randomized to receive either placebo or CoQ₁₀ at a dose of 30-60 mg per day for six days before surgery. The treatment group showed a significantly lower incidence of low cardiac output state during the postoperative recovery period. In 1991, Sunamori et al. studied 78 patients undergoing coronary artery bypass graft surgery [74]. Sixty of these patients were given 5 mg per/kg of CoQ₁₀ intravenously two hours prior to cardiopulmonary bypass. Postoperatively, there was a significant benefit to left ventricular stroke work index in the CoQ₁₀ treated group as compared to controls and a significant decrease in postoperative CPK MB measurements in the treated group. In 1993, Judy et al. studied 20 patients undergoing either coronary artery bypass surgery (16 patients) or combined bypass surgery with valve replacement (4 patients) [27]. Patients were randomized to receive either placebo or administration of oral 100 mg per day of CoQ₁₀ for 14 days prior to surgery and continued for 30 days postoperatively. The treatment group showed significant elevations not only in blood CoQ₁₀ level but also in myocardial tissue CoQ₁₀ content as measured in atrial appendage. Significant improvement in postoperative cardiac index and left ventricular ejection fraction were noted in the treatment group, and a significant shortening of the postoperative recovery time was observed. In 1994, Chello et al. randomized 40 patients to receive either placebo or 150 mg per day of oral CoQ₁₀ one week prior to coronary artery bypass graft surgery [6]. A significant decrease in postoperative markers of oxidative damage was observed in the treatment group with lower concentrations of coronary sinus thiobarbituric acid reactive substances, conjugated dienes and cardiac isoenzymes of creatine kinase. The treatment group also showed a significantly lower incidence of ventricular arrhythmias in the recovery period and the mean dose of dopamine required to maintain stable hemodynamics was significantly lower in the CoQ₁₀ treated group. In 1994, Chen et al. randomized 22 patients to receive either CoQ₁₀ or placebo prior to coronary artery bypass surgery and observed improvement in left atrial pressure and an improvement in the incidence of low cardiac output state in the postoperative period [8]. Right and left ventricular myocardial ultrastructure was better preserved in the CoQ₁₀ treated group as compared to placebo. In 1996, Chello randomized 30 patients to receive either placebo or 150 mg oral CoQ₁₀ for 7 days before abdominal aortic surgery and documented a significant decrease in markers of peroxidative damage in the CoQ₁₀ treated patients [7]. In 1996 Taggart et al. randomized 20 patients undergoing coronary revascularization surgery to receive either placebo or 600 mg of oral CoQ₁₀ 12 hours prior to operation with no significant effects observed, confirming the lack of acute pharmacologic or clinical changes with CoQ₁₀ [76]. Typically, oral CoQ₁₀ supplementation rarely causes measurable effect before one week and is not maximal for several months.

Conclusions

In summary, coenzyme Q₁₀ is a deceptively simple molecule which lies at the center of mitochondrial ATP production and appears to have clinically relevant antioxidant properties manifested by tissue protection in settings of ischemia and reperfusion. Congestive heart failure has served as a model for measurable deficiency of CoQ₁₀ in blood and tissue, which when corrected, results in improved myocardial function. Ischemic heart disease, anginal syndromes, and most recently the ischemia reperfusion injury of coronary revascularization has provided clear evidence of clinically relevant antioxidant cell protective effects of CoQ₁₀. Newer P31 NMR spectroscopy studies such as those conducted by Whitman's group in Philadelphia have documented enhanced cellular high energy phosphate concentrations with CoQ₁₀ supplementation in models of ischemia and reperfusion [13]. Sophisticated biochemical markers of oxidative injury are now demonstrating in-vivo the antioxidant cell protective effects of CoQ₁₀. Upon review of the 30 years of clinical publications on CoQ₁₀ and the author's own clinical experience, it is clear that there are several consistent and unique characteristics of the clinical effects of CoQ₁₀ supplementation which are worthy of discussion and may for simplicity be termed the "Q effect". The benefits of CoQ₁₀ supplementation are likely not due solely to a correction of deficiency in so far as clinical improvements are frequently seen in patients with "normal" pre-treatment CoQ₁₀ blood levels and optimum clinical benefit requires above normal CoQ₁₀ blood levels (2 to 4 times higher). High blood levels may be required to attain an elevation of tissue CoQ₁₀ levels or to rescue defective mitochondrial function perhaps by driving cytosolic glycolysis or the plasma membrane oxidoreductase or by directly enhancing the function of defective mitochondria. There is almost always a delay in the onset of clinical change of one to four weeks and a further delay in maximal clinical benefit of several months. Possible reasons for this delay include time to attain adequate tissue levels of CoQ₁₀ or time to synthesize CoQ₁₀-dependent apoenzymes. Supplemental CoQ₁₀ appears to affect much more than just cardiac myocytes and many aspects of patients' health tend to improve which cannot be explained by the observed improvement in heart function. CoQ₁₀ does not lend itself to traditional organ-specific or disease-specific strategy and requires a reassessment and a rethinking of medical theory and practice. The combination of the ready availability of pure crystalline CoQ₁₀ in quantity from the Japanese pharmaceutical industry and increasingly sophisticated and standardized methodology to directly measure CoQ₁₀ in both blood and tissue, brings us to a point where we can more readily and accurately expand upon the preceding 30 years of pioneering clinical work on this extraordinary molecule.

References

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