A Clinical Study of the Effect of Coenzyme Q on Congestive Heart Failure

Transcription

1 A Clinical Study of the Effect of Coenzyme Q on Congestive Heart Failure Taro ISHIYAMA, M.D., Yoshiharu MORITA, M.D., Seiichi TOYAMA, M.D.,* Toru YAMAGAMI, M.D.,* Nozomu TSUKAMOTO, M.D.,** Noboru WADA, M.D.,*** Masaaki OHKUBO, M.D.,*** and Yuichi YAMAMURA, M.D. SUMMARY Expecting activation of myocardial energy liberation, coenzyme Q was applied as a treatment to 55 patients suffering from congestive heart failure. Daily doses of 50 to 100mg of coenzyme Q7 were injected intravenously in 21 cases for 3 to 35 days. Daily doses of 60mg of coenzyme Q7 were administered perorally in 17 cases for 14 to 196 days. Daily doses of 30mg of coenzyme Q10 were administered perorally in 17 cases for 7 to 182 days. Clinical effects were evaluated within 4 weeks by the criteria using a scoring method of severity of congestive heart failure which was devised by the authors. In summary a certain effect was found in 20 cases and a mild effect was observed in 29 cases. No significant changes were observed in heart rate and blood pressure. Exanthema appeared in 2 patients of the group of coenzyme Q7 intravenous injection. In conclusion the therapeutic effect of coenzyme Q was thought to be mild but stable in supplement to digitalis therapy in cases of congestive heart failure. Additional Indexing Words: Activation of myocardial energy liberation Coenzyme Q7 and Q10 Intravenous injection Peroral administration A scoring method to evaluate severity of congestive heart failure ECENTLY clinical application of substances affecting to myocardial energy metabolism such as vitamin B complexes, adenosine triphosphate or its precursors, cytochrome C, and some metabolites has revealed a certain effect in therapeutics of cardiac diseases. Coenzyme Q was isolated by Crane and his coworkers and it was evidenced to localize mainly in mitochondria of subcellular fraction and to play an important role in oxidative From the Third Department of Internal Medicine, Osaka University Medical School, Osaka. *The Center for Adult Diseases, Osaka **Department of Internal Medicine, Nishinomiya City Central Hospital, Nishinomiya ***Kobe Shosei Hospital, Kobe Received for publication April 19,

2 Vol.17 No.1 ISHIYAMA, ET AL. 33 phosphorylation in the electron transfer system.1) Therefore it was expected to reveal a same kind of effect in biomedical or clinical field. Although actions of these substances administered exogenously are difficult to prove directly in clinical cases, the effect of these substances on cardiac dysfunctions is able to be evaluated clinically. In congestive heart failure myocardial energy liberation is considered to be impaired secondarily because of continuous relative reduction of coronary blood supply as well as relative increase of oxygen demand. It is expected that exogenous coenzyme Q acts a role of trigger to activate deteriorated mitochondrial energy liberation. This expected action is thought to reveal a different kind of effect when compared with that of digitalis or diuretics. According to the above-mentioned concept, a clinical trial was attempted to apply coenzyme Q to cases of congestive heart failure. SUBJECTS AND METHODS Subjects were 21 inpatients and 34 outpatients suffering from congestive heart failure. Underlying diseases were valvular diseases, congenital heart diseases, hypertension, arteriosclerosis, pulmonary diseases, and primary myocardial diseases. Classifications of cardiac function before the treatment were the second grade of NYHA in almost all cases and the third grade in a few cases. Preceding the start of the treatment, all patients were observed at least 1 week either without medication or continuing the same medication hitherto. Table I. A Proposed Scoring Method of Severity of Congestive Heart Failure

3 34 EFFECT OF COENZYME Q ON CONGESTIVE HEART FAILURE Jap. Heart J. January, 1976 Subjects were divided into the following 3 groups according to the difference of the treatment: Intravenous coenzyme Q7 group: included 21 inpatients. The grade of congestive heart failure was more severe in average in this group than the other 2 groups. Daily doses of 50 to 100mg of coenzyme Q7 was injected intravenously for 3 to 35 days. Table II. Results of Treatment: *Prescription was not changed from at least one week before the start of the treatment until sufficiency, MI: mitral insufficiency, AI: aortic insufficiency.

4 Vol.17 ISHIYAMA, ET AL. 35 No.1 Peroral coenzyme Q7 group: included 17 outpatients. Coenzyme Q7 was administered perorally 50 to 100mg daily to all cases except 1 case for 14 to 196 days. Peroral coenzyme Q10 group: included 17 outpatients. Coenzyme Q10 was administered perorally 30mg daily to all cases for 7 to 182 days. Subjects were classified randomly into the 2 peroral groups. Although combined use of other drugs was not restricted, alternation of prescrip- Intravenous Coenzyme Q7 Group the judgment of effects, **fb: finger breadth, MS: mitral stenosis, MSI: mitral stenoin-

5 36 EFFECT OF COENZYME Q ON CONGESTIVE HEART FAILURE Jap. Heart J. January, 1976 tion was prohibited strictly since 1 week before the start of the treatment until the date of evaluation of the effect. The effect was judged within 4 weeks after the start of the treatment, because such substances as coenzyme Q were considered to reveal metabolic action more slowly than other prevalent drugs which had a certain pharmacological action. A scoring method devised by the authors was adopted in order to evaluate the effect. Symptoms and signs of congestive heart failure were graded and assigned scores as shown in Table I. Severity of congestive heart failure in individual cases was expressed quantitatively by the total scores of each symptoms and signs. Differences of the total scores before the treatment and the total scores after the treatment were evaluated as follows: (TOTAL SCOREbefore treatment)-(total SCOREafter treatment) 4 as "effective", 3 (TOTAL SCOREbefore treatment)-(total SCOREafter treatment) 1 as "mildly effective", and (TOTAL SCOREbefore treatment)-(total SCOREafter treatment) 0 as "ineffective". Heart rate and blood pressure were also checked before and after the treatment. Daily amount of urine was recorded on the all inpatients. RESULTS 1. Intravenous Coenzyme Q7 Group Results were summarized in Table II. "Effectives" were found in 10 Fig.1. Changes of heart rate before and after the treatment.

6 Vol.17 No.1 ISHIYAMA, ET AL. 37 cases. "Mildly effectives" were in 7 cases, and" ineffectives" were in 4 cases. As shown in Fig.1, changes of heart rate showed no consistent tendency after the treatment. Changes of blood pressure were not remarkable. Fig.2. Changes of daily amount of urine before and after the treatment in cases of the inpatients (intravenous coenzyme Q7 group). Fig.3. Changes of total scores of severity of congestive heart failure before and after the treatment. The thick lines represent changes of the mean total scores before and after treatments.

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9 40 EFFECT OF COENZYME Q ON CONGESTIVE HEART FAILURE Jap. Heart J. January, 1976 Fig.2 shows changes of the daily amount of urine before and after the treatment. More than half cases showed increases in daily amount of urine. Changes of the total score of congestive heart failure were shown in Fig.3. Improvement of the total score was dominant. In 2 cases, itching exanthema was observed during the treatment but was not so severe. It disappeared easily by interruption of the treatment. 2. Peroral Coenzyme Q7 Group Results were summarized in Table III. "Effectives" were found in 7 cases, "mildly effectives" were in 8 cases, and "ineffectives" were in 2 cases. As shown in Fig.1, many cases showed decreased heart rate after the treatment. Changes of blood pressure were not remarkable. Changes of the total score were shown in Fig. 3. Although subjects were all outpatients and the total score before the treatment (mean }standard deviation=3.6 } 1.7) were lower as a whole than those of the intravenous coenzyme Q7 group (mean }standard deviation=6.2 }2.8) (p<0.005), improvement of the total score was dominant and many cases showed disappearance of symptoms and signs. This figure suggested that peroral administeration of coenzyme Q7 was effective in mild cases suffering from congestive heart failure. All cases showed no side effect. 3. Peroral Coenzyme Q10 Group Results were summarized in Table IV. "Effectives" were found in 3 cases, "mildly effectives" were in 14 cases, and "ineffectives" were not found. As shown in Fig.1, many cases showed decreased heart rate afte the treatment, but not remarkably. Changes of blood pressure were also not remarkable. Changes of the total score were shown in Fig.3. Although subjects were all outpatients and the total score before the treatment (mean } standard deviation=3.2 }2.1) were also low, improvement of the total score was dominant and no significant difference was evidenced with the improvement of the total score of the peroral coenzyme Q7 group. All cases showed no side effect. DISCUSSION Coenzyme Q is known to be a member in the electron transfer system and is said to participate in electron transfer between flavoprotein and cytochromes. It distributes widely in animals, plants, and microorganisms. It is found abundantly in liver and heart mitochondria. However, exogenous addition of this substance was thought to reveal a trigger effect to activate

10 Vol.17 No.1 ISHIYAMA, ET AL. 41 myocardial energy liberation according to the following observations. Fahre et al2) reported that coenzyme Q inhibited the biosynthesis of aldosterone. In the authors' basic study3) uncoupling of oxidative phosphorylation of impaired canine heart mitochondria was improved to some extent by addition of coenzyme Q into the mitochondrial suspension in vitro. Folkers et al4) measured the activity of succinate dehydrogenase-coenzyme Q10 reductase system of biopsy specimens of the human heart. The specific activity of this enzyme system from some patients under cardiac surgery showed substantial increases in activity on the addition of exogenous coenzyme Q. Clinical effects of coenzyme Q on congestive heart failure will be explained from the above-mentioned mechanisms. Therefore coenzyme Q will be expected to reveal a different mode of action from digitalis or diuretics. It is desirable to combine this substance with digitalis and/or diuretics in the therapy of congestive heart failure. Therapeutic effect is most expected in cases with ischemic heart disease, in cases of recurrent relapses, in cases with chronic heart diseases and in senile cases, because in these cases myocardial energy liberation is believed to be deteriorated in addition to impaired myocardial energy utilization. Quantitative evaluation of severity of congestive heart failure is in general a difficult problem. The scoring method adopted here might involve some problems such as inadequacies of symptoms and signs and difficulties to assign a certain score. But informations adopted here were all easy for physicians to examine even on outpatients without any specific facilities or technics. In this study coenzyme Q was indicated in most of the cases at a stage of mild and stable congestive heart failure which had been achieved by the use of digitalis and/or diuretics. Another indication selected in this study was mild cases to whom any medication had not been applied yet. The reason is that coenzyme Q could not be expected to substitute digitalis or diuretics but to have supplementary effect to these drugs, because the mode of action of coenzyme Q is thought to be activation of myocardial energy metabolism and the secondary effect to activate cardiac dynamics is probably mild and the appearance of effects is possibly later than any other drugs having pharmacological actions. Thus the authors evaluated effects somewhat later at a period within 4 weeks after the start of the treatment. Among 3 groups the intravenous coenzyme Q7 group showed relatively higher total scores. In this group improvement of the total scores was as same as those of the other 2 groups, suggesting that it was difficult for this substance to expect complete disappearance of symptoms and signs of rather severe congestive heart failure. Reversely in the group of peroral coenzyme

11 42 EFFECT OF COENZYME Q ON CONGESTIVE HEART FAILURE Jap. Heart J. January, 1976 Q7 or Q10, most of the cases showed low total score before the treatment and many cases revealed complete disappearance of symptoms and signs. In this study the authors had an opportunity to test clinical effects of 2 different kinds of coenzyme Q, that is, coenzyme Q7 and coenzyme Q10. Numbers of isoprenoid side chains (n) are different in species, n=7 is of microorganism and n=10 is of human being. The authors had arbitrarily chosen daily doses of 60mg of coenzyme Q7 and 30mg of coenzyme Q10. So far as peroral administration was made to cases of congestive heart failure, the effects were different between 60mg of coenzyme Q7 and 30mg of coenzyme Q10. This was partly because of the criteria of judgment adopted here, because mild cases with total score 3 before the start of the treatment were never judged as "effectives" but "mildly effectives" even when symptoms and signs of congestive heart failure had completely disappeared. Difference of the doses might also influence partly to the difference of the effects. From the standpoint of the changes of the total score shown in Fig.3, however, there was no significant difference between the latter 2 groups. Finally the long term application of coenzyme Q did not reveal any severe side effect. In conclusion it is thought that administration of coenzyme Q is an effective strategy to cure congestive heart failure of mild cases from the standpoint of the different mode of action from digitalis or diuretics. REFERENCES 1. Crane FL, Hatefi Y, Lester RL, Widemer C: Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 25: 220, Fahre LF Jr, Banks RC, Mclsaac W, Farrel G: Effects of ubiquinone and related substances on secretion of aldosterone and cortisol. Am J Physiol 208: 1275, Yamamura Y, Ishiyama T, Morita Y, Yamagami T: Therapeutics of congestive heart failure from the standpoint of myocardial energy metabolism. Sogorinsho 16: 1564, 1967 (in Japanese) 4. Folkers K, Littarru GP, Ho L, Runge TM, Havanonda S, Cooley D: Evidence for a deficiency of Coenzyme Q22 in human heart disease. Internat J Vit Res 40: 380, 1970