By PETER H. LANGSJOEN, M.D., F.A.C.C.

CoQ10 is known to be highly concentrated in heart muscle cells due to the high energy requirements of this cell type. For the past 14 years, the great bulk of clinical work with CoQ10 has focused on heart disease. Specifically, congestive heart failure (from a wide variety of causes) has been strongly correlated with significantly low blood and tissue levels of CoQ10 (15). The severity of heart failure correlates with the severity of CoQ10 deficiency (16). This CoQ10 deficiency may well be a primary etiologic factor in some types of heart muscle dysfunction while in others it may be a secondary phenomenon. Whether primary, secondary or both, this deficiency of CoQ10 appears to be a major treatable factor in the otherwise inexorable progression of heart failure. Pioneering trials of CoQ10 in heart failure involved primarily patients with dilated weak heart muscle of unknown cause (idiopathic dilated cardiomyopathy). 

CoQ10 was added to standard treatments for heart failure such as fluid pills (diuretics), digitalis preparations (Lanoxin), and ACE inhibitors. Several trials involved the comparison between supplemental CoQ10 and placebo on heart function as measured by echocardiography. CoQ10 was given orally in divided doses as a dry tablet chewed with a fat containing food or an oil based gel cap swallowed at mealtime. Heart function, as indicated by the fraction of blood pumped out of the heart with each beat (the ejection fraction), showed a gradual and sustained improvement in tempo with a gradual and sustained improvement in patients' symptoms of fatigue, dyspnea, chest pain, and palpitations. The degree of improvement was occasionally dramatic with some patients developing a normal heart size and function on CoQ10 alone. 

Most of these dramatic cases were patients who began CoQ10 shortly after the onset of congestive heart failure. Patients with more established disease frequently showed clear improvement but not a return to normal heart size and function. Internationally, there have been at least nine placebo controlled studies on the treatment of heart disease with CoQ10: two in Japan, two in the United States, two in Italy, two in Germany, and one in Sweden (17,18,19,20,21,22,23,24,25). All nine of these studies have confirmed the effectiveness of CoQ10 as well as its remarkable safety. There have now been eight international symposia on the biomedical and clinical aspects of CoQ10 (from 1976 through 1993 (26,27,28,29,30,31,32,33)). 

These eight symposia comprised over 300 papers presented by approximately 200 different physicians and scientists from 18 different countries. The majority of these scientific papers were Japanese (34%), with American (26%), Italian (20%) and the remaining 20% from Sweden, Denmark, Germany, United Kingdom, Belgium, Australia, Austria, France, India, Korea, Netherlands, Poland, Switzerland, USSR, and Finland. The majority of the clinical studies concerned the treatment of heart disease and were remarkably consistent in their conclusions: that treatment with CoQ10 significantly improved heart muscle function while producing no adverse effects or drug interactions. It should be mentioned that a slight decrease in the effectiveness of the blood thinner, coumadin, was noted in a case by a Norwegian clinician (34). 

This possible drug - CoQ10 interaction has not been observed by other investigators even when using much higher doses of CoQ10 for up to seven years and involving 25 patients treated with coumadin concomitantly with CoQ10 (this is still, as of this date, unpublished data). The efficacy and safety of CoQ10 in the treatment of congestive heart failure, whether related to primary cardiomyopathies or secondary forms of heart failure, appears to be well established (35,36,37,38,39,40,41,42). The largest study to date is the Italian multicenter trial, by Baggio et al., involving 2664 patients with heart failure (43). The most recent work in heart failure examined the effect of CoQ10 on diastolic dysfunction, one of the earliest identifiable signs of myocardial failure that is often found in mitral valve prolapse, hypertensive heart disease and certain fatigue syndromes (44,45). Diastolic dysfunction might be considered the common denominator and a basic cause of symptoms in these three diagnostic groups of disease. Diastole is the filling phase of the cardiac cycle. Diastolic function has a larger cellular energy requirement than the systolic contraction and, therefore, the process of diastolic relaxation is more highly energy dependent and thus more highly dependent on CoQ10. In simpler terms, it takes more energy to fill the heart than to empty it. Diastolic dysfunction is a stiffening of the heart muscle which interferes with the heart's ability to function as an effective pump. It is seen early in the course of many common cardiac disorders and is demonstrable by echocardiography. This stiffening returns towards normal with supplemental CoQ10 in tempo with clinical improvement. It is important to note that in all of the above clinical trials, CoQ10 was used in addition to traditional medical treatments, not to their exclusion. In one study by Langsjoen et al (46), of 109 patients with essential hypertension, 51% were able to stop between one and three antihypertensive drugs at an average of 4.4 months after starting CoQ10
treatment while the overall New York Heart Association (NYHA) functional class improved significantly from a mean of 2.40 to 1.36. Hypertension is reduced when diastolic function improves.

In another study (39), there was a gradual and sustained decrease in dosage or discontinuation of concomitant cardiovascular drug therapy: Of 424 patients with cardiovascular disease, 43% were able to stop between one and three cardiovascular drugs with CoQ10 therapy. The authors conclude that the
vitamin-like substance, CoQ10, "may be ushering in the new era of cellular/biochemical treatment of disease, complementing and extending the systems-oriented, macro and microscopic approach that has served us well to this point". 

References

1. Gian Paolo Littarru (1994) Energy and Defense. Facts and perspectives on CoenzymeQ10 in biology
and medicine. Casa Editrice Scientifica Internazionale, pp 1-91. 

2. Crane F.L., Hatefi Y., Lester R.I., Widmer C. (1957) Isolation of a quinone from beef heart
mitochondria. In: Biochimica et Biophys. Acta, vol. 25, pp 220-221. 

3. Morton R.A., Wilson G.M., Lowe J.S., Leat W.M.F. (1957) Ubiquinone. In: Chemical Industry, pp
1649. 

4. Mellors A., Tappel A.L. (1966) Quinones and quinols as inhibitors of lipid peroxidation. Lipids, vol. 1, pp 282-284. 

5. Mellors A., Tappel A.L. (1966) The inhibition of mitochondrial peroxidation by ubiquinone and ubiquinol. J. Biol. Chem., vol. 241, pp 4353-4356. 

6. Littarru G.P., Ho L., Folkers K. (1972) Deficiency of Coenzyme Q10 in human heart disease. Part I and II. In: Internat. J. Vit. Nutr. Res., 42, n. 2, 291:42, n. 3:413. 

7. Mitchell P. (1976) Possible molecular mechanisms of the protonmotive function of cytochrome systems. In: J. Theoret. Biol., vol. 62, pp 327-367. 

8. Mitchell P. (1991) The vital protonmotive role of coenzyme Q. In: Folkers K., Littarru G.P., Yamagami T. (eds) Biomedical and Clinical Aspects of Coenzyme Q, vol. 6, Elsevier, Amsterdam, pp 3-10. 

9. Mitchell P. (1988) Respiratory chain systems in theory and practice. In: Advances in Membrane Biochemistry and Bioenergetics, Kim C.H., et al. (eds), Plenum Press, New York, pp 25-52. 

10. Mitchell P. (1979) Kelin's respiratory chain concept and its chemiosmotic consequences. In: Journal Science, vol. 206, pp 1148-1159. 

11. Ernster L. (1977) Facts and ideas about the function of coenzyme Q10 in the Mitochondria. In: Folkers K., Yamamura Y. (eds) Biomedical and Clinical Aspects of Coenzyme Q. Elsevier, Amsterdam, pp 15-8. 

12. Littarru G.P., Lippa S., Oradei A., Fiorni R.M., Mazzanti L. Metabolic and diagnostic implications of blood CoQ10 levels. In: Biomedical and Clinical Aspects of Coenzyme Q, vol. 6 (1991) Folkers K., Yamagami T., and Littarru G. P. (eds) Elsevier, Amsterdam, pp 1-555. 

13. Ghirlanda G., Oradei A., Manto A., Lippa S., Uccioli L., Caputo S., Greco A.V., Littarru G.P. (1993) Evidence of Plasma CoQ10 - Lowering Effect by HMG-CoA Reductase Inhibitors: A double blind , placebo-controlled study. Clin. Pharmocol., J. 33, 3, 226-229. 

14. Folkers K., Langsjoen Per H.,Willis R., Richardson P., Xia L.,Ye C., Tamagawa H. (1990) Lovastatin decreases coenzyme Q levels in humans. Proc. Natl. Acad Sci. Vol. 87, pp.8931-8934. 

15. Folkers K., Vadhanavikit S., Mortensen S.A. (1985) Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. In: Proc. Natl. Acad. Sci., U.S.A., vol. 82(3), pp 901-904. 

16. Mortensen S.A., Vadhanavikit S., Folkers K. (1984) Deficiency of coenzyme Q10 i myocardial failure. In: Drugs Exptl. Clin. Res. X(7) 497-502. 

17. Hiasa Y., Ishida T., Maeda T., Iwanc K., Aihara T., and Mori H. (1984) Effects of coenzyme Q10 on exercise tolerance in patients with stable angina pectoris. In: Biomedical and Clinical Aspects of Coenzyme Q, vol. 3 (1981) Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, pp 291-301. 

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

19. Langsjoen Per.H., Vadhanavikit S., Folkers K. (1985) Response of patients in classes III and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10. In: Proc. Natl. Acad. of Sci., U.S.A., vol. 82, pp 4240-4244. 

20. Judy W.V., Hall J.H., Toth P.D., Folkers K. (1986) Double blind-double crossover study of coenzyme Q10 in heart failure. In: Folkers K., Yamamura Y. (eds) Biomedical and clinical aspects of coenzyme Q, vol. 5. Elsevier, Amsterdam, pp 315-323. 

21. Rossi E., Lombardo A., Testa M., Lippa S., Oradei A., Littarru G.P., Lucente M. Coppola E., Manzoli U. Coenzyme Q10 in ischaemic cardiopathy. In: Biomedical and Clinical Aspects of Coenzyme Q, vol. 6 (1991) Folkers K., Yamagami T., and Littarru G. P. (eds) Elsevier, Amsterdam, pp 321-326. 

22. Morisco C., Trimarco B., Condorelli M. Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. In: Seventh International Symposium on Biomedical and Clinical Aspects of Coenzyme Q Folkers K., Mortensen S.A., Littarru G.P., Yamagami T., and Lenaz G. (eds) The Clinical Investigator, (1993) 71:S 34-S 136. 

23. Schneeberger W., Muller-Steinwachs J., Anda L.P., Fuchs W., Zilliken F., Lyson K., Muratsu K., and Folkers K. A clinical double blind and crossover trial with coenzyme Q10 on patients with cardiac disease. In: Biomedical and Clinical Aspects of Coenzyme Q, vol. 5 (1986) Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, pp 325-333. 

24. Schardt F., Welzel D., Schiess W., and Toda K. 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. 6 (1991) Folkers K., Yamagami T., and Littarru G. P. (eds) Elsevier, Amsterdam, pp 385-403. 

25. Swedberg K., Hoffman-Berg C., Rehnqvist N., Astrom H. (1991) Coenzyme Q10 as an adjunctive in treatment of congestive heart failure. In: 64th Scientific Sessions American Heart Association, Abstract 774-6. 

26. Biomedical and Clinical Aspects of Coenzyme Q. (1977) Folkers K., Yamamura Y. (eds) Elsevier, Amsterdam, pp 1-315. 

27. Biomedical and Clinical Aspects of Coenzyme Q, Vol. 2 (1980) Yamamura Y., Folkers K., and Ito Y. (eds) Elsevier, Amsterdam, pp 1-456. 

28. Biomedical and Clinical Aspects of Coenzyme Q, Vol. 3 (1981) Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, pp 1-414. 

29. Biomedical and Clinical Aspects of Coenzyme Q , Vol. 4 (1983) Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, pp 1-432. 

30. Biomedical and Clinical Aspects of Coenzyme Q, Vol. 5 (1986) Folkers K., Yamamura Y., (eds) Elsevier, Amsterdam, pp 1-410. 

31. Biomedical and Clinical Aspects of Coenzyme Q, Vol. 6 (1991) Folkers K., Yamagami T., and Littarru G. P. (eds) Elsevier, Amsterdam, pp 1-555. 

32. Seventh International Symposium on Biomedical and Clinical Aspects of Coenzyme Q (1993) Folkers K., Mortensen S.A., Littarru G.P., Yamagami T., and Lenaz,G. (eds) The Clinical Investigator, Supplement to Vol.71 / Issue 8, pp S51-S177. 

33. Eighth International Symposium on Biomedical and Clinical Aspects of Coenzyme Q (1994) Littarru G.P., Battino M. , Folkers K. (Eds) The Molecular Aspects of Medicine, Vol. 15 (Supplement), pp S1-S294. 

34. Spigset O. (1994) Reduced effect of warfarin caused by ubidecarenone. Lancet Nov 12 Vol. 344, pp. 8933. 

35. Mortensen S.A., Vadhanavikit S., Folkers K. (1984) Deficiency of coenzyme Q10 in myocardial failure. In: Drugs Exptl. Clin. Res., vol. X(7), pp 497-502. 

36. Mortensen S.A., Vadhanavikit S., Baandrup U., Folkers K. (1985) Long term coenzyme Q10 therapy: a major advance in the management of resistant myocardial failure. In: Drugs Exp. Clin. Res., vol. 11(8), pp 581-593. 

37. Langsjoen P.H., Folkers K., Lyson K., Muratsu K., Lyson T., Langsjoen P. H. Effective and safe therapy with coenzyme Q10 for cardiomyopathy. In: Klin. Wochenschr. (1988) 66:583-593. 

38. Langsjoen P. H., Langsjoen, P. H., Folkers, K. (1989) Long term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy. In: The American Journal of Cardiology, vol. 65, pp 521 - 523. 

39. Mortensen S.A., Vadhanavikit S., Muratsu K., Folkers K. (1990) Coenzyme Q10: Clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. In: Int. J. Tissue React., vol. 12 (3), pp 155-162. 

40. Ursini T., Gambini C., Paciaroni E., and Littarru G.P. Coenzyme Q10 treatment of heart failure in the elderly: Preliminary results. In: Biomedical and Clinical Aspects of Coenzyme Q, vol. 6 (1991)
Folkers K., Yamagami T., and Littarru G. P. (eds) Elsevier, Amsterdam, pp 473-480. 

41. Poggessi L., Galanti G., Comeglio M., Toncelli L., Vinci M. (1991) Effect of coenzyme Q10 on left ventricular function in patients with dilative cardiomyopathy. Curr. Ther. Res. 49:878-886. 

42. Langsjoen H.A., Langsjoen P. H., Langsjoen P. H., Willis R., Folkers K. (1994) Usefulness of coenzyme Q10 in clinical cardiology, a long-term study. In: Eighth International Symposium on Biomedical and Clinical Aspects of Coenzyme Q, Littarru G.P., Battino M. , Folkers K. (Eds) The Molecular Aspects of Medicine, Vol. 15 (Supplement), pp S165-S175. 

43. Baggio E., Gandini R., Plancher A.C., Passeri M., Carmosino G. Italian multicenter study on safety and efficacy of coenzyme Q10 adjunctive therapy in heart failure. In: Eighth International Symposium on
Biomedical and Clinical Aspects of Coenzyme Q (1994) Littarru G.P., Battino M. , Folkers K. (Eds) The Molecular Aspects of Medicine, Vol. 15 (Supplement), pp S287-S294. 

44. Langsjoen Per H., Langsjoen Peter H., Folkers K. Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment. In: Seventh International Symposium on Biomedical and Clinical Aspects of Coenzyme Q. Folkers, K., Mortensen S.A., Littarru G.P., Yamagami T., and Lenaz G. (eds) The Clinical Investigator, (1993) 71:S 140-S 144. 

45. Oda T. Recovery of the Frank-Starling mechanism by coenzyme Q10 in patients with load-induced contractility depression. In: Eighth International Symposium on Biomedical and Clinical Aspects of Coenzyme Q (1994) The Molecular Aspects of Medicine, in print. 

46. Langsjoen P. H., Langsjoen P. H., Willis R., Folkers K. (1994) Treatment of essential hypertension with coenzyme Q10. In: Eighth International Symposium on Biomedical and Clinical Aspects of Coenzyme Q (1994) Littarru G.P., Battino M. , Folkers K. (Eds) The Molecular Aspects of Medicine, Vol. 15 (Supplement), pp S287-S294.