coenzyme q10 and its role in heart disease

J. Clin. Biochem. Nutr., 26, 109-118, 1999

Coenzyme Q10 and Its Role in Heart Disease

Ram B. SINGH,1,* Mohammad A. NIAZ,2 Shanti S. RASTOGI,2

and Satya P. VERMA2

1 Heart Research Laboratory, Medical Hospital and Research Centre, Moradabad, India

2I ndraprastha Appolo Hospital, New Delhi, India

Summary Coenzyme Q10 (CoQ10) deficiency has been observed in apparently healthy subjects as well as in patients with congestive heart failure, angina pectoris, coronary artery disease, cardiomyopathy, hyper-tension, mitral valve prolapse and after coronary revascularization. CoQ10 bolsters the synthesis of ATP and inhibits free radical damage, hence is useful in preventing cellular damage during ischaemia-reper-fusion injury. The clinical benefits are mainly due to its ability to improve energy production, antioxidant activity, and membrane stabiliz-ing properties. Several small scale studies indicate that coenzyme Q could be useful in patients with congestive heart failure, angina pectoris, cardiomyopathy, coronary artery disease, acute myocardial infarction and in the preservation of myocardium. CoQ10 may also decrease lipo-

protein (a) and plasma insulin. CoQ10 is normally present in the low-density lipoprotein cholesterol fraction and inhibits its oxidation indicat-ing that it can inhibit atherosclerosis. It can also regenerate vitamin E. CoQ10 is known for producing minor gastrointestinal discomfort and elevation in SCOT and LDH when used.

Key Words: ubiquinone, coronary artery disease, hypertension, heart

failure, cardiomyopathy, myocardial infarction

Coenzyme Q10 (CoQ10, ubiquinone) is present in almost every plant and animal cell [1-3]. It is naturally present in foods and is synthesized in all body tissues. The biosynthesis of CoQ10 from the amino acid tyrosine is a multistage

process requiring at least eight vitamins and several trace elements [1-3]. CoQ10 is a coenzyme for at least three mitochondrial enzymes (complex I, II

and III) as well as enzymes in other parts of the cell [2]. These enzymes are concerned with oxidative phosphorylation pathway and thus are essential for the synthesis of ATP which is essential for cell function [2]. It may be useful in

preventing cellular damage during myocardial ischaemia and reperfusion.

* To whom correspondence should be addressed .

109

110 R.B. SINGH et al.

The clinical benefits of CoQlo are mainly due to its ability to improve energy

production, antioxidant activity and membrane stabilizing properties [1-3]. These effects are beneficial in the prevention and treatment of heart disease. The antiox-idant activity confers protection against lipid peroxidation and it works together with vitamin E in prevention of damage to lipid membranes and plasma lipids [4]. Treatment with CoQlo may offer significant protection against atherosclerosis by

preventing lipid peroxide formation and oxidation of low density lipoprotein (LDL) cholesterol [5-7]. It may have some ability to maintain the integrity of myocardial calcium ion channels and potassium channels during ischaemic insults. CoQlo might therefore activate potassium channels similar to nicorandil and modulate calcium channels resulting into decreased cellular calcium and improved cardiac integrity during ischaemia [S]. Reduction in cytoplasmic cal-cium may be associated with hyperpolarization of cell membrane which may mediate vasorelaxation and decrease in cell damage. There is evidence that free redicals play an important role in cardiac damage that occurs during myocardial ischaemia and reperfusion [9, 10]. Free radicals are molecules containing an unpaired electron in the outer orbit rendering it chemically active. If a free radical reacts with a nonradical species, another free radical is produced. This property of self perpetuation enables free radicals to initiate and perpetuate chain reactions. Superoxide anion (O2), hydroxyl radical, hydrogen peroxide and nitric oxide are major species of free radicals which are produced during ischaemia [11, 12].

During myocardial ischaemia, oxygen is the major source of free radicals. ATP is catabolized to adenosine, inosine and hypoxanthine which are oxidants. In addition, xanthine dehydrogenase is selectively converted into xanthine oxidase via limited protolysis or by oxidation of the thiol groups. Oxygen combines with hypoxanthine in the presence of xanthine oxidase reperfusion which generates superoxide anion and other free radicals. Neutrophil is another potential source of free radicals due to the activation of NADPH oxidase [2]. This enzyme system

produces superoxide radical. Mitochondria is the third source of free radicals during myocardial ischaemia.

Electrons can leak out of the mitochondrion [3] via pathways involving NADP dehydrogenase and ubisemiquinone and produce superoxide radical. Lipid

peroxidase and hydroperoxidase present in the cell membrane lipids are activated during ischaemia which release arachidonic acid. Arachinonate in turn accelerates the production and perpetuation of free radicals due to actions of cyclooxygenase and lipooxygenase. Release of free iron and copper during ischaemia also cause the

production of hydroxyl radicals [1-3]. These multiple mechanisms involved in the production of free radicals can result in damage to the cell membrane. As a result, there may occur a handling of calcium gradients, activation of calcium dependent

phospholipases, protein kinases, contractile elements and accumulation of mito-chondrial calcium leading to further cellular damage and necrosis. There is evidence that treatment with endogenous free radical scavengers such as superoxide dismutase and catalase can enhance cardiac function during ischaemia [1].

J. Clin. Biochem. Nutr.

UBIQUINONE AND HEART DISEASE ill

CoQ10 protects ischaemic tissue from reperfusion damage by its antioxidant membrane stabilizing property and free radical scavenging activity. Further, ubiquinone provides protection to myocardium by preventing oxidation of LDL cholesterol. These actions provide the rationale for the experimental and clinical use of coenzyme Q in cardiovascular disease [1-3]. These actions are similar to angiotensin converting enzyme, ACE-inhibitors and potassium channel activators. It is possible that there is "in vivo" reduction of CoQ4 to its reduced quniol form. This short, side chain quinol might act as a radical scavenging antioxidant by donating phenolic hydrogen to peroxyl radicals [101. The other possible antiox-idant action may be in the capacity of ubiquinols to reduce the rx-tocopheryl radical, thus allowing regeneration of the active form of vitamin E. The possible mechanisms of action of CoQ10 have been summarized in Table 1.

CLINICAL USES OF CoQ10 IN CARDIAC DISORDERS

Majority of the patients with heart diseases have CoQ10 deficiency (Table 2). The deficiency of CoQra and experimental observations of myocardial protection during ischaemia [10] by CoQ10 reasonably constitutes one of the sound reasons for the therapeutic use of CoQra in human heart disease. Indications for CoQ10 administration are growing gradually (Table 3).

CoQ10 therapy in heart diseases has been shown to improve cardiac energetics in the form of higher ejection fraction, improvement in clinical manifestations, decreased levels of serum catecholamines, better work capacity, decreased fre-

quency of hospitalization, and prolonged survival [13-23]. Congestive heart failure. There is maximum scientific evidence to indicate

that heart failure is the main indication for CoQ10 therapy. In 1984, Mortensen et al. [23] reported that patients in NYHA classes III and IV showed diminished contents of cardiac CoQ10 when compared to patients in classes I and II. It is

possible that there may be an impairment of CoQ10 biosynthesis or accelerated catabolism or both causing a deficiency. Increased antioxidant commitment of CoQ may somehow lead to accelerated consumption and therefore deficiency. It is

Table 1. Possible mechanisms of action of CoQra.

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possible that exogenous CoQ administration may increase the velocity of electron transfer, especially when endogenous pool is diminished as in cases of higher levels of lipid peroxidation.

In one study [21] involving 79 patients with heart failure, a double blind crossover trial showed CoQ1Q-associated improvement in physical performance and exercise capacity. In another double blind trial [22] involved 33 centers, comprising 641 patients; of these 319 were administered CoQ1o and 322 placebo for 12 months. Although deaths were (16 vs. 21) not significantly less, incidence of acute pulmonary oedema, arrhythmias, hospitalizations and incidence of classes III and IV heart failure, were significantly lower in the CoQ1o group. Clinical benefit score [1-3] was much higher in the treatment group. In another double blind and controlled study, treatment with CoQ1o was associated with significant reduction in catecholamines with clinical improvement in the intervention group compared to control group in a group of elderly heart failure patients [20]. How-ever a German double blind study [24] showed no benefit of CoQ1o in patients with well preserved cardiac function. In a long-term randomized survival study involving 90 patients with congestive heart failure, treatment with 100 mg/day of CoQ1o showed significant benefit compared to control group during a follow-up of 8 years [25].

In congestive heart failure due to coronary artery disease (CAD), there may be an ischaemia-reperfusion induced free radical stress in conjunction with higher serum catecholamines [26]. Higher sympathetic activity and catecholamines in heart failure may be associated with a deficiency of endogenoss antioxidants catalase and superoxide dismutase, glutathione as well as antioxidant vitamins A, E and C and /l-carotene which further enhance the oxidative stress. These bio-chemical abnormalities may be associated with worsening of heart failure. In experimental animals an improved myocardial redox state with long-term antiox-idant therapy has been shown to modulate the development and progression of heart failure [26]. This study provides further proof to the rationale regarding the use of antioxidants in heart failure. Carvedilol which is an antioxidant and

f3-blocker has also been found to retard heart failure indicating that decrease in

Table 2, Cardiovascular diseases asso-

ciated with COQIO deficiency.Table 3. Potential therapeutic uses of

CoQio.


UBIQUINONE AND HEART DISEASE 113

oxidative stress and sympathetic activity may benefit in heart failure [26]. CoQro has been also successfully used in patients with refractory heart failure [3, 27]. According to the metaanalysis of randomized trials published between 1984-1994, only 8 out of 14 studies met the inclusion criteria [28]. These studies comprised of a total of 356 patients. Treatment with CoQro was consistent with improvement in stroke volume, injection fraction, cardiac output, cardiac index and end diasbolic volume index compared to control group.

Cardiomyopathy. It is not clear whether CoQro deficiency is the cause or effect of cardiomyopathy [17-23] . Tissue levels of CoQ10 was significantly lower among NYHA class IV subjects of cardiomyopathy compared to classes I and II subjects [3]. Greater the deficiency of CoQro better the response to treatment with CoQ10 indicated cardiomyopathy. Significant improvement was noted in patients with dilated cardiomyopathy with classes III and IV heart failure in a randomized double blind study when they were administered CoQ10 [13] . In other studies, treatment with coenzyme has also shown benefits in patients with cardiomyopathy

[17-24]. Myocardial preservation and intervention. There is evidence that prior CoQ10 therapy provides protection against ischaemic reperfusion [1-3] . A role of CoQro in preserving ischaemic myocardium was thus observed in a rabbit heart model of ischaemia and reperfusion [1]. Myocardium pretreated with CoQro was relatively protected against both structural and functional changes induced by ischaemia and reperfusion. The animals pretreated with CoQro were able to maintain oxidative phosphorylation and cellular ATP generating capacity and showed that cellular and mitochondrial calcium overload was prevented by

pretreatment with CoQ1Q. The clinical and metabolic beneficial effects were similar in magnitude to those seen with propranolol and verapamil [1]. CoQro has been demonstrated to protect both Ca dependent and Na-K dependent ATPase activity. The effectiveness of CoQro in preventing low cardiac output states following cardiac surgery was compared in a randomized study in humans [29]. Judy et al.

[29] demonstrated myocardial preservation by prior treatment with CoQro for 15 days before heart surgery.

Cardiac arrhythmias. In experimental coronary artery ischaemia, pretreat-ment with CoQ10 increased the ventricular fibrillation threshold while minimizing the impairment in contractility and myocardial stunning [30]. The antiarrhythmic effect of CoQro has been studied in several experiments. Treatment with CoQ10 was associated with prolongation of action potential duration in right ventricular

papillary muscles. Clinical studies on the role of CoQ10 in patients with ventricular ectopic

activity indicate that 20-25% of patients respond to treatment with this agent [1, 2]. These studies also showed a consistent effect of CoQ in shortening the QT interval including QTc. CoQro may have similar effect on QT interval in patients receiving psychotropic agents.

Angina pectoris and CAD. Since CoQro can protect against ischaemia, it is

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possible that it can be a potential antianginal drug indicating its use in CAD. At least five double blind, controlled intervention trials have been published to demonstrate the role of CoQ10 in CAD [14-18]. Kamikawa et al. [14] administer-ed oral CoQ10 (150 mg/day in three daily doses) or placebo for 4 weeks in 12

patients with chronic stable angina. This was followed by a crossover to the opposing treatment regimen for another 4 weeks. Exercise time and time to onset of 1 mm electrocardiographic ST-depression were significantly increased in the CoQ10 group compared to placebo group. Schardt et al. [15] compared the effect of 600 mg/day of oral CoQ10 with placebo and the combination of pindolol (7.5 mg/day) and isosobidedinitrate (30 mg/day) in 15 patients with chronic stable angina. Treatment with CoQ10 was associated with a significant reduction in cumulative exercise-induced ST-segment depression compared to placebo but no difference was noted compared to conventional antianginal drugs. There was a significant reduction in exercise systolic blood pressure in the CoQ10 in doses of 150 or 300 mg/day. CoQ10 monotherapy caused an increase in exercise duration to onset of angina of 70 s in the 300 mg group and 65 s in the 150 mg group at the end of first week and of 140 and 127 s respectively by week 4. There was a 60% decrease in the frequency of anginal attacks in the 150 mg group. In post infarction patients

[17], treatment with CoQ10 caused a significant beneficial effect on work capacity and significantly lower level of malondialdehyde in the treatment group compared to placebo. In one 58 year old patient with diabetes mellitus and refractory unstable angina, addition of CoQ10 (60 mg/day) to treatment with nitrates and calcium blockers was associated with exercise tolerance and relief in angina within 2 weeks, although no response was observed during the last 4 weeks with conven-tional drugs [3].

In a randomized, double blind trial [31] involving 144 patients with acute myocardial infarction (AMI), treatment with CoQ10 (60 mg twice daily) was associated with significant decrease in arrhythmias, angina pectoris and heart enlargement in the CoQ10 group than placebo after 4 weeks of trial. Non-fatal infarction and cardiac deaths were significantly lower in the CoQ10 group compar-ed to control group (15% vs. 30.9%, p<0.02).

Hypertension. CoQ10 deficiency has been found to be associated with hyper-tension and its supplemental use (102 mg/kg/day) is reported to lower blood

pressure [1-3]. Fihirdi et al. [32] also studied the role of CoQ10 in hypertension and reported a decrease in total peripheral resistance which may be due to improvement in arterior smooth muscle cell metabolism. In a recent study by Langsjoen et al. [33] involving 109 patients with known essential hypertension, CoQ10 (225 mg/day average) was administered to achieve serum level of 2 pg/ml, in conjunction with anti-hypertensive drugs. There was a need to withdraw one to three drugs in 51% of patients. The decrease in systolic blood pressure was from 159 to 147 mmHg, and in diastolic blood pressure was from 94 to 85 mmHg. A further study [20] showed that CoQ10 causes a significant decrease in serum catecholamines, which possibly reduce peripheral vascular resistance. The avail-



able data indicate that a double-blind randomized study should be conducted with higher doses (100-200 mg/day) of CoQ10 with a long-term follow-up.

Mitral valve prolapse. Mitral valve prolapse may also be associated with CoQ10 deficiency [ 1 ] . Clinical studies suggest that CoQ10 may improve cardiac

performance under exercise conditions in patients with mitral valve prolapse. Adriamycin myocardial toxicity. Adriamycin, an anthracycline and mixed

quinoid and hydroquinoid compound may have inhibition effects on CoQ10 enzyme systems [ 1 ] . Repletion with CoQ10 can prevent the inhibition of CoQ10 enzymes in mitochondrial preparations. In several other experimental studies, the role of exogenous CoQ10 in preventing adriamycin toxicity was corroborated [ 1]. Clinical studies also showed a beneficial effect on systolic time intervals of

pretreatment with CoQ10 (a manifestation of adriamycin toxicity) in cancer patients. In a randomized [34] and controlled study involving 20 patients with cancer, 10 were supplemented with 200 mg/day of CoQ10 for a duration of treat-ment with anthracyclins. Echo-cardiographic monitoring showed protective effects on the left ventricular contractile function in the form of less decrease in injection fraction and of shortening fraction in the CoQ10 group compared to control subjects. It is possible that CoQ10 therapy causes repletion of a CoQ10 deficiency induced by adriamycin and inhibits adriamycin induced lipid peroxidation and free radical generation.

Plasma lipoproteins. In one in vitro experiment [5], it has been demonstrated that following exposure to free radical source (Azo compounds) LDL deployed their antioxidant reserve which were consumed while inhibiting the oxidative attack. When LDL depleted of ascorbic acid was exposed to free radical source,

peroxidation was remained under control as long as some ubiquinol was present. These findings suggest that ubiquinol as an antioxidant may be more efficient than tocopherol and carotenoids in preventing the oxidation of LDL.

A double blind controlled study [5] in patients with hypercholesterolemia showed that treatment with HMGCoA reductase (lovastatin) was associated with significantly lower plasma level of CoQ10 compared to placebo [35]. The decrease in CoQ10 appears to be due to the fact that cholesterol and CoQ10 share the same biosynthetic pathway. These findings were confirmed in a crossover trial with CoQ10 and HMGCoA inhibitors [3G]. This study showed a decrease in CoQ10 in

plasma as well as in platelets which was prevented by concomitant administration of CoQlo. In one experimental study, Singh et al. [37] demonstrated that lova-statin has a modest antioxidant activity which may be similar to fluvastatin. Despite a reduction in CoQ1o, induced by statins, oxidation of LDL is inhibited by the statins resulting into no serious adverse effect of CoQ10 deficiency. However treatment of hypercholesterolemia with HMGCoA reductase inhibitors in con-

junction with CoQ10 may provide greater benefit in the regression of coronary atherosclerosis and prevention of cardiac events. We also observed in a substudy that CoQ10 treatment may be associated with significant reduction in plasma lipoprotein (a) and insulin levels in patients with acute coronary syndrome [38,

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39]. A recent study [40] has reported that CoQio can inhibit human vitronectin receptor expression.

THERAPEUTIC DOSAGE

In different clinical situations, the evidence indicates that therapeutic dosage varies between 30-300 mg/day in two to three divided doses. The optimal doses in heart disease appear to be 50 to 100 mg/day or 2-3 mg/kg body weight. Long-term follow-up studies in a large number of subjects would be necessary to demonstrate the exact therapeutic dosage of CoQ10 in heart disease.

CONCLUSION

In brief, CoQio is still in an investigational stage. It is sold as a health product in the United States (Tishcon Corporation, Westbury, NY, USA) and its therapeu-tic usage can not be patented, hence drug industry is not interested in research on CoQio. The most intriguing property of CoQio is its potential ability to protect and

preserve ischaemic myocardium. However no randomized controlled intervention trial exists on its use in decreasing myocardial infarction size. Only in two studies

[37, 41], CoQ10 has been used in the prevention of complications in patients with AMI. In AMI, ischaemic reperfusion injury is an important determinant of complications and hence CoQro should be administered as soon as possible on suspicion of infarction, preferably intravenously, before the thrombolytic agents to achieve maximum protection. Since the drug has no side effects, it is not justified to waste time in taking ethical approval for conduction trials with CoQio.

REFERENCES

1. Greenberg, S., and Frishman, W.H. (1990): Coenzyme Q10. A new drug for cardio-vascular disease. J. Clin. Pharmacol., 30, 596-608.

2. Ernster, L., and Dallner, G. (1995): Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys. Acta, 1271, 195-204.

3. Singh, R.B., Niaz, M.A., Rastogi, V., and Rastogi, S.S. (1998): Coenzyme Q in cardiovascular disease. JAPI, 46, 299-306.

4. Kagan, V., and Packer, L. (1993): Electron transport regenerates vitamin E in mitochondria and microsomes via ubiquinone: An antioxidant duet, in Free Radicals and Antioxidants and Nutrition, ed. by Corongni, F., Banni, S., Desai, M.A., and Rice-Evans, C., Richelieu

Press, London, pp. 27-36. 5. Stoeker, R., Bowry, W.V., and Frei, B. (1991): Ubiquinol-10 protects human low density

lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc. Natl. Acad. Sci. U.S.A., 88, 1646-1650.

6. Merati, G., Pasquali, P., Vergani, C., and Landi, L. (1992): Antioxidant activity of ubiquinone-3 in human low density lipoprotein. Free Radical Res. Commun., 16, 11-17.

7. Mohr, D., Bowry, V.W., and Stocker, R. (1992): Dietary supplementation with CoQ10 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, 1126, 247-254. 8. Esconde, D., and Cavero, I. (1992): Potassium channel openers: Moving towards cardio-

protection via strengthening of a natural mechanism. Trends Pharmacol. Sci.,13, 269-272. 9. Sundarroa, M., and Quinn, P. (1986): Proton magnetic resonance spectroscopic studies of

the interaction of ubiquinone-10 with phospholipid membranes. Int. J. Biochem.,155, 353- 358.

10. Niki, E. (1993): Chemistry and biochemistry of vitamin E and coenzyme Q as antioxidants, in Free Radicals and Antioxidants in Nutrition, ed. by Corongiu, F., Banni, S., Desai,

N.M.A., and Rice-Evans, C., Richelieu Press, London, pp. 13-25. 11. Grech, E.D., Jackson, M., and Ramsdale, D.R. (1995): Reperfusion injury after acute

myocardial infarction. Br. Med. J., 310, 477-478. 12. Singh, R.B., and Niaz, M.A. (1996): Antioxidants, oxidants and free radical stress in

cardiovascular disease. J. Assoc. Physicians India, 44, 43-48. 13. Langsjoen; P.H., Vadhanavikit, S., and Folkers, K. (1984): Effective treatment with coen-

zyme Q10 of patients with myocardial disease classes III and IV, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 4, ed. by Folkers, K., and Yamamura, Y., Elsevier, Amster- dam, pp. 325-339.

14. Kamikawa, T., Kobayashi, A., Yamashita, T., Hayashi, H., and Yamasaki, N. (1985): Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am. J. Cardiol., 56, 247-251.

15. Schardt, F., Welzel, D., Schess, W., and Toda, K. (1986): Effect of coenzyme Q10 on ischaemia-induced ST-segment depression: A double blind placebo controlled crossover

study, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 5, ed. by Folkers, K., and Yamamura, Y., Elsevier, Amsterdam, pp. 385-394.

16. Mazzola, C., Guffanti, E.E., Vaccarella, A., Meregalli, M., Colmago, R., Ferrario, N., Cantoni, V., and Marcherri, G. (1987): Noninvasive assessment of coenzyme Q10 in patients

with chronic stable effort angina and moderate heart failure. Curr. They: Res., 41, 923-930. 17. Rosi, E., Lombardo, A., Testa, M., Lippa, S., Oradei, A., Littarru, G.P., Lucente, M.,

Coppola, E., and Manzoli, U. (1991): Coenzyme Q10 in ischaemic cardiopathy, in Bio- medical and Clinical Aspects of Coenzyme Q, ed. by Folkers, K., Littarru, G.P., and Yamagami, T., Elsevier, Amsterdam, pp. 321-326.

18. Wilson, M.E., Frishman, W.H., Giles, T., Sethi, G., Greenberg, S.M., and Brackett, D.J. (1991): Coenzyme Q10 therapy and exercise duration in stable angina, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 6, ed. by Folkers, K., Littarru, G.P., and Yamagami,

T., Elsevier, Amsterdam, pp. 339-348. 19. Bresolin, N., Moroni, I., Angilini, C., Doriguzzic, C., Castelli, E., Banfi, P., Liciardelic, L.,

Carenzi, A., Comi, G., and Scarlato, G. (1991): Ubiquinone treatment in patients with mitochondrial myopathies: The first double blind trial, in Biomedical and Clinical Aspects

of Coenzyme Q, Vol. 6, ed. by Folkers, K., Littarru, G.P., and Yamagami, T., Elsevier, Amsterdam, pp. 397-405.

20. Ursini, F., Gambini, C., Paciaroni, E., and Littarni, G.P. (1.991): Coenzyme Q10 treatment of heart failure in elderly: Preliminary results, in Biomedical and Clinical Aspects of

Coenzyme Q, Vol. 6, ed. by Folkers, K., Littarru, G.P., and Yamagami, T., Elsevier, Amsterdam, pp. 473-480.

21. Hofman-Bang, C., Rehnqvist, N., Swedberg, K., and Astrom, H. (1992): Coenzyme Q10 as an adjunctive in treatment in congestive heart failure. J. Am. Coil. Cardiol., 19 (Suppl.),

774-776. 22. Morisco, C., Trimarco, B., and Condorelli, M. (1993): Effect of coenzyme Q10 therapy in

patients with congestive heart failure: A long term multicentre randomized study. Clin. Invest., 71 (Suppl.), 134-136.

23. Mortensen, S.A., Vadhanavikit, S., and Folkers, K. (1984): Apparent effectiveness of coenzyme Q10 (CoQ) to treat patients with cardiomyopathy and CoQ levels in blood and

endomyocardial biopsies, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 4, ed. by Folkers, K., and Yamagami, T., Elsevier, Amsterdam, pp. 391-402.

Vol. 26, No. 2, 1999


24. Permanetter, B., Rossy, W., Weingartner, R., Baner, R., Seidi, K.F., Klein, G., and von Wirksamkeit, F. (1989): Coenzyme Q10 (Ubiquinone) bei der iangzeitbehandlung der dilatativen kardiomyopathie. Z. Kardiol., 78, 360-365.

25. Judy, W.V., Folkers, K., and Hall, J.H. (1991): Improved long-term survival in coenzyme

Q10 treated congestive heart failure patients compared to conventionally treated patients, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 6, ed. by Folkers, K., Littarru, G.P.,

and Yamagami, T., Elsevier, Amsterdam, pp. 291-298. 26. Dhalla, N.S., Hill, M.F., and Singal, P.K. (1996): Role of oxidative stress in transition of

hypertrophy to heart failure. J. Am. Coll. Cardiol., 28, 506-514. 27. Sinatra, S.T. (1997): Refractory congestive heart failure successfully managed with high dose

coenzyme Q10 administration. Mol. Aspects Med., 18, 299-305. 28. Soja, A.M., and Mortensen, S.A. (1997): Treatment of congestive heart failure with coen-

zyme Q10 illuminated by meta-analysis of clinical trials. Mol. Aspects Med., 18, 159-168. 29. Judy, W.V., Stogsdill, W.W., and Folkers, K. (1993): Myocardial preservation by therapy

with coenzyme Q10 during heart surgery. Clin. Invest., 71 (Suppl.), 155-161. 30. Takasawa, K., Fuse, K., Konishi, T., and Watanabe, Y. (1991): Prevention of premature

ventricular contractions with CoQ10 after coronary artery bypass grafting, in Biomedical and Clinical Aspects of Coenzyme Q, Vol. 6, ed. by Folkers, K., Littarru, G.P., and

Yamagami, T., Elsevier, Amsterdam, pp. 357-359. 31. Singh, R.B., Wander, G.S., Rastogi, A., Shukla, P.K., Mittal, A., Sharma, J.P., Mehrotra, S.

K., and Kapoor, R. (1998): Randomized, double blind, placebo controlled trial of coenzyme Q10 in patients with acute myocardial infarction. Cardiovasc. Drugs Ther., 12, 347-353.

32. Fihirdi, B., Vsnyini, G., Oradei, A., Biusi, G., Guarino, G.C., Brocchi, A., Bellandi, F., Mancini, M., and Littarru, G.P. (1994): Coenzyme Q10 in essential hypertension. Mol.

Aspects Med., 15 (Suppl.), 275-283. 33. Langsjoen, P., Wills, R., and Folkers, K. (1994): Treatment of essential hypertension with

coenzyme Q10. Mol. Aspects Med., 15 (Suppl.), 265-272. 34. Iarussi, D., Auricchio, U., Murano, A., Giuliano, M., Di Tullio, M.T., and Iacono, A.

(1994): Protective effect of coenzyme Q on anthracyclines cardiotoxicity: Control study in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Mol. Aspects

Med., 15 (Suppl.), 207-212. 35. Ghirlanda, G., Oradei, A., Manto, A., Lippa, S., Uccioli, L., Caputo, S., Greco, A.V., and

Littarru, G.P. (1993): Evidence of plasma CoQ10 lowering effect by HMG-CoA reductase inhibitors: A double blind placebo controlled. J Clin. Pharmacol., 33, 226-229.

36. Bargossi, A.M., Battino, M., Gaddi, A., Fiorella, P.L., Grossi, G., Barozzi, G., Di Giulio, R., Descovich, G., Sassi, S., Genova, M.L., and Lenaz, G. (1994): Exogenous CoQ10 preserves

plasma ubiquinone levels in patients treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Int. J. Clin. Lab. Res., 24, 171-176.

37. Singh, R.B., Singh, N.K., Rastogi, S.S., Wander, G.S., Aslam, M., Onouchi, Z., and Kummerow, R.A. (1997): Antioxidant effects of lovastatin and vitamin E on experimental

atherosclerosis in rabbits. Cardiovasc. Drugs Ther., 11, 575-580. 38. Singh, R.B., Chopra, R.K., Niaz, M.A., and Kapoor, R. (1999): Serum concentration of

lipoprotein (a) decreases on treatment with hydro-soluble coenzyme Q10 in patients with acute coronary artery disease. Discovery of a new role. Int. J. Cardiol., 68, 23-29.

39. Singh, R.B., Niaz, M.A., Rastogi, S.S., Shukla, P.K., and Thakur, A.S. (1999): Effect of hydrosoluble coenzyme Q10 on blood pressures, and insulin resistance in hypertensive

patients with eoronary artery disease. J. Hum. Hyperten., 13, 203-208. 40. Serebruamy, V.L., Ordonez, J.V., Herzog, W.R., Rohde, M., Mortensen, S.A., Folkers, K.,

and Gurbel, P.A. (1997): Dietary coenzyme Q10 supplementation alters platelet size and inhibits human vitronectin (CD51/CD61) receptor expression. J. Cardiovasc. Pharmacol.,

29, 16-22. 41. Kuklinski, B., Weissenbacher, E., and Fahnrich, A. (1994): Coenzyme Q10 and antioxidants

in acute myocardial infarction. Mol. Aspects Med., 15 (Suppl.), 143-147.


coenzyme q10 and its role in heart disease

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