Coenzyme Qlo: The Prophylactic Effect on Low Cardiac Output Following Cardiac Valve Replacement

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1 Coenzyme Qlo: The Prophylactic Effect on Low Cardiac Output Following Cardiac Valve Replacement Jiro Tanaka, M.D., Ryuji Tominaga, M.D., Mochikazu Yoshitoshi, M.D., Kanji Matsui, M.D., Masataka Komori, M.D., Akira Sese, M.D., Hisataka Yasui, M.D., and Kouichi Tokunaga, M.D. ABSTRACT A randomized, prospective study of the effectiveness of preoperative administration of coenzyme Qlo on the prophylaxis of postoperative low cardiac output state was performed in 5 patients with acquired valvular diseases necessitating valve replacement. There were patients in the treatment group and in the control group. Patients in the treatment group received 3 to 6 mg of coenzyme Qlo orally for six days before operation. Preoperative clinical variables, operative procedures, total cardiopulmonary bypass time, and aortic cross-clamping time were similar for the two groups. Postoperatively, mild to severe low cardiac output state developed in 8 of 5 patients (56%) and necessitated the administration of considerable amounts of inotropic agent. The treatment group showed a significantly lower incidence of low cardiac output state during the recovery period than the control group (p <.5). These results suggest that preoperative administration of coenzyme Qlo will increase the tolerance of human hearts to ischemia during aortic cross-clamping. Although the incidence of postoperative low cardiac output state appears to be decreasing because of technical improvements in openheart operations, especially intraoperative myocardial protection, it is still a major cause of early death following cardiac operation [l,. The occurrence of low cardiac output state is related, in part, to the preoperative functional state of the patient's heart [l,. For prevention of this state, therefore, it is important to im- From the Division of Cardiovascular Surgery, Research Institute of Angiocardiology and Cardiovascular Clinics, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Accepted for publication Mar, 98. Address reprint requests to Dr. Tanaka, Division of Cardiovascular Surgery, Research Institute of Angiocardiology and Cardiovascular Clinics, Faculty of Medicine, Kyushu University, 3--, Maidashi, Higashi-ku, Fukuoka 8, Japan. prove the preoperative cardiac function as much as possible as well as assure myocardial protection from ischemic injury during aortic cross-clamping. Coenzyme Ql is a naturally existing component of the mitochondria electron-transfer processes of respiration and coupled oxidative phosphorylation. A deficiency of this coenzyme has been found in diseased human hearts [3]. The therapeutic administration of coenzyme Qlo is reported to be effective in improving the condition of patients with congestive heart failure [4, 5. In addition, recent studies have shown the efficacy of coenzyme Ql administration for preventing acute ischemic injury in myocardium of experimental animals [6-8. Thus it is likely that coenzyme Qlo may be useful for prophylaxis of postoperative low cardiac output state following open-heart operation. However, there has been no clinical report to this effect. The present study was undertaken in a clinical setting to evaluate the possible prophylactic effect of coenzyme Qlo on postoperative low cardiac output state. Low cardiac output state was assessed by vasopressor dependence. Material and Methods Fifty patients admitted to Kyushu University Hospital for operation because of acquired valvular lesions were randomly assigned by hospital number to one of two groups. Excluded from this study were patients who did not undergo valve replacement, who were in New York Heart Association Functional Class I or IV, and who had hypertension. The study began in November, 978, and terminated in June, 98. Since coenzyme Qlo* was officially approved by the Ministry of Health and Welfare as an inotropic agent for congestive heart failure prior to 'Neuquinon; Eisai Pharmaceutical Corp., Tokyo, Japan by The Society of Thoracic Surgeons

2 46 The Annals of Thoracic Surgery Vol33 No February 98 Table. Preoperative Clinical Variables" Variable Group Group Significance No. of patients Malelfemale ratio Age (yr) NYHA Class Cardiothoracic ratio Systolic PAP LVEDP Cardiac index k. 65. k k k. 3. k k.8.4 k. 63. k k k. 3. k. "Where applicable, data are shown as mean f standard error of the mean. NYHA = New York Heart Association; PAP = pulmonary artery pressure; LVEDP = left ventricular end-diastolic pressure; = not significant. the beginning of this study, there was no need for informed consent. Patients in Group received 3 to 6 mg of coenzyme Qlo orally for six days prior to operation (treatment group), and patients in Group did not (control group). Group received coenzyme Qlo treatment in the ward after admission to the hospital. Only one of us (J. T.) knew the purpose of this study. No appreciable side-effects were found in any patient after administration of coenzyme QlW All patients had been on a regimen of digitalis or diuretics or both preoperatively. The groups were similar in age, sex, and preoperative hemodynamic values, including left ventricular end-diastolic pressure, systolic pulmonary artery pressure, and cardiac index (Table ). There was no significant difference in New York Heart Association Functional Class or cardiothoracic ratio preoperatively between the two groups. The cardiac operations and the postoperative management were performed by the same group of surgeons, who were unaware of which patient had received which treatment. A median sternotomy was utilized in all patients, and open-heart operation was done under cardiopulmonary bypass (CPB) with moderate hypothermia. The mitral valve was approached through a left atrial incision immediately posterior to the interatrial groove. The aortic valve was exposed through a low oblique aortotomy. The left ventricle was vented transapically. In all patients myocardial protection during aortic cross-clamping was assured by the combination of topical cooling of the heart with iced Table. Operative Procedures Procedure Group Group Total MVR + TVP MVR AVR AVR + MVR AVR + MVR + TVP AVR + MVP AVR + MVR +TvR Total MVR = mitral valve replacement; TVP = tricuspid valve plasty; AVR = aortic valve replacement; MVP = mitral valve plasty; TVR = tricuspid valve replacement. saline solution, and cardioplegia with 5 ml of cold 5% glucose solution containing 3 meq per liter of potassium chloride, units per liter of insulin,.6 mm per liter of calcium gluconate, and sodium bicarbonate, ph 7.8. Additional perfusions of 5 ml per kilogram of body weight of the same cardioplegic solution were done every to 3 minutes during cross-clamping. Operative procedures were performed similarly in the two patient groups (Table ). After cessation of CPB, left atrial pressure was monitored to maintain radial artery pressure appropriately. Bradycardia was managed using temporarily placed myocardial electrodes and pacemaker. Blood gas analysis and determination of serum levels of potassium and calcium ions were frequently carried out, and abnormalities, if present, were corrected 5

3 47 Tanaka et al: Coenzyme Qlo and Low Cardiac Output Table 3. Postoperative Low-Output State and Clinical Variablesa LOW- NO. of Record- Systemic Arterial Pressure (mm Hg) Output Patients ing State (YO) Time Systolic Diastolic Mean None (44) CPB 7.4 k f f. Mild (4) CPB 85. f 4.b " 63.9 f.8d DOP 76.7 f.4d d 58.8 f.9d Severe 6 (3) CPB 78.6 f.4d 53.3 k.' 6.4 f.4d DOP 74.9 f.6d 5.6 f.8d 58.3 f.9d Pulse Pressure (mm HE) f.7' 6.8 f.5d 4. f.4d." 3. f.4"' Left Atrial Mean Pressure (mm H d 6.4 f. 9. f. 8.8 f.. f f.9 Heart Rate (bpm) 8.5 f f f f 3. "Where applicable, data are shown as mean? standard error of the mean. b.c.dstatistical significance between none and mild classification of low-output state or between none and severe: "p <.5; 'p <.; "p <.. e,fstatistical significance between mild and severe classification of low-output state: 'p <., <.5. CPB = immediately after coming off cardiopulmonary bypass; DOP = beginning of intravenous drip of dopamine. promptly. Nevertheless, when hypotension of less than 85 mm Hg of radial artery pressure with elevated left atrial pressure continued, low cardiac output state was considered. Dopamine is the preferred drug for management of this state. The dosage was adjusted to the minimal one that would achieve the desired effect. Severity of low cardiac output state was graded according to the dosage of dopamine needed to overcome it in the postoperative period: "severe" if the average dose for the initial twelve hours was greater than 5 pglkglmin; "mild" if it was less than 5 pglkglmin; and "none" if the patient required no vasoactive drug at any time. Statistical analyses were performed by Student's t test or chi-square analysis. Results There were no deaths, and all patients are alive and well. However, as the patients were weaned from CPB and followed in the recovery period, some required administration of considerable amounts of dopamine because of low cardiac output state: 4% were in the mild category and 3%, severe (Table 3). The average dose of dopamine for the first twelve hours was 3.35 k.79 pglkglmin (mean f standard error of the mean) for mild low cardiac output state and 8.4 f.57 pglkglmin for the severe state. Also in Table 3 are the hernodynamic data obtained immediately after the patient came off CPB or at the beginning of the intravenous drip of dopamine. Patients without low cardiac output state showed good, stable hemodynamics immediately after cessation of CPB. In contrast, systemic arterial pressures in patients with low cardiac output remained low. Pulse pressure, believed to correlate with cardiac output, showed statistical significance between the two groups of patients ( p <., none versus mild low cardiac output state; p <., none versus severe low-output state; p <., mild versus severe low-output state). Left atrial pressures in patients with low cardiac output state were higher than in those without, although they failed to reach statistical significance. Heart rate was not significantly different between the patient groups. Hemodynamic data obtained at the beginning of dopamine administration worsened, and highly significant differences were shown in pulse pressures among the patient groups ( p <., none versus mild lowoutput state, and none versus severe lowoutput state; p <.5, mild versus severe low-output state). During recovery in the intensive care unit, patients with low cardiac output state required higher left atrial mean pressure to maintain stable hemodynamics than patients without this condition despite continuous administration of dopamine (6.5 k. mm Hg in patients without low cardiac output state and 9.9 f. mm Hg in those in mild or severe low-output state, p <.5; the highest value of left atrial mean pressure recorded during recovery was

4 48 The Annals of Thoracic Surgery Vol 33 No February 98 UI c. C.- c c) * n - c 8 t possible to explain the cause of low cardiac out- EEZI LOS yes 5 put state to be merely a prolonged aortic cross- L.S no clamping time. Pretreatment of patients with coenzyme Qlo did affect the incidence of postoperative low cardiac output state (Table 4). The total duration of CPB time and aortic cross-clamping time were not significantly different between Group (coenzyme Qlo) and Group (control). However, the incidence of low cardiac output state 6o 6o 9o lzo Duration of aortic cross-clamping (min) Fig. Incidence of postoperative low cardiac output state (LOS) in 5 patients having valve replacement as related to aortic cross-clamping time. There is no direct correlation between the cross-clamp time and the occurrence of low-output state. collected for individuals, and the average in each group was obtained). The difference of the mean values of aortic cross-clamping time between patients with and those without low cardiac output state failed to reach significance; 7.8 f 7.8 minutes and 9.6 f. minutes, respectively. The incidence of postoperative low cardiac output state in relation to aortic cross-clamping time is illustrated in Figure l. One patient with an aortic cross-clamping time of 98 minutes and who underwent triple-valve replacement and enlargement of a small aortic annulus with a Dacron patch, required neither an inotropic nor a pressor agent during recovery. On the contrary, a patient with a cross-clamp time of 43 minutes and who had isolated mitral valve replacement, required more than 5 pglkglmin of dopamine for more than twelve hours. Thus, it seems im- 55 loo 'lo "lo in Group was significantly lower than in Group (p <.5). The occurrence of severe low cardiac output state, especially, was different (p <.4). A review Of the incidence Of dopamine support postoperatively correlated with the duration of aortic cross-c~amping tirne demonstrates only a small and insignificant increase with prolongation of cross-clamping in Group (Fig ), but the increase is significant in Group ; that is, all of the patients who had more than minutes of cross-clamp time fell into low cardiac output state, while 35% of patients with a cross-clamp time of less than minutes required no vasopressor agents. Again, the incidence of severe low cardiac output state in Group patients was significantly lower than in Group patients, regardless of the duration of aortic cross-clamping. In Group, the percent of patients with severe low cardiac output state was more than twice that in Group during the corresponding time periods. Comment The results of the present study suggest that preoperative administration of coenzyme Q can increase the tolerance of human hearts to Table 4. Effect of Preoperative Administration of Coenzyme Qlo and the Incidence of Postoperative Low-Output State Aortic Low-Output State CPB Time Cross-clamp Group (min) Timea (min) Mild Severe Total (%) (n = ) 65.4 k f (4) (9-475) (43-98) (n = ) 45.9 f f. 6 8 (7) (98-63) (6-) Significance p <.4 p <.5 adata are shown as mean k standard error of the mean. Range is given in parentheses. CPB = cardiopulmonary bypass; = not significant.

5 49 Tanaka et al: Coenzyme Q, and Low Cardiac Output No L O S Mild L S Severe LOS Group Group :$a n: 7 n: n: > Duration of aortic cross-clamping (min) Fig. Pretreatment with coenzyme Ql,and incidence of postoperative low cardiac output state (LOS). There is a small increase in the incidence of low-output state associated with prolongation of aortic cross-clamping time in treated patients (Group ) and a significant increase in controls (Group ). Note the difference in the incidence of severe low-output state in corresponding time periods between the two groups. ischemia, as indicated by a significantly lowered incidence of low cardiac output state following open-heart operation necessitating administration of considerable amounts of inotropic agent. The cause of low-output state immediately after open-heart operation is thought to be hemorrhagic myocardial damage due to prolonged subendocardial ischemia of the hypertrophied left ventricle during CPB, aortic cross-clamping, and reperfusion [9-. The onset of this complication remains serious because of the lowered hemodynamic state and the following acute renal failure [3, 4. The preoperative functional state of the patient s heart [l, and the adequacy of intraoperative myocardial protection against ischemia [5] are known to affect the incidence of low cardiac output state. A report by Engelman and coworkers [6] in 98 suggests that patients with valvular disease have greater intrinsic myocardial dysfunction preoperatively than patients with other kinds of heart disease, and that the myocardial hypertrophy of valvular disease is prone to intraoperative subendocardial ischemic injury, resulting in low cardiac output state during recovery. More than half of our patients who underwent valve replacement had low cardiac output postoperatively. The duration of ischemic arrest seemed to have no direct correlation with the occurrence of this state, especially in the group treated with coenzyme Qlo. This is consistent with the report of Engelman and colleagues [6]. Therefore, it seems apparent that low cardiac output state relates more to the magnitude of myocardial preservation during ischemia than to total duration of ischemic arrest. The patients given coenzyme Q,o treatment experienced low cardiac output, especially the severe form, less frequently than the controls. As we did not carry out biopsy of myocardium at operation, we cannot offer evidence that hearts were deficient in the coenzyme or that treatment with coenzyme Q,,, actually increased myocardial stores of the coenzyme. However, in 97 Folkers and co-workers [3] determined the level of the coenzyme in heart tissue obtained at operation. They reported that 83% of 66 cardiac patients showed varying deficiencies of the coenzyme. It has been demonstrated that orally administered coenzyme QIo appears in heart tissue [7]. In addition, there are several reports that this coenzyme has positive inotropic action for congestive heart failure [4, 5. On the basis of these considerations, it is probable that preoperative administration of coenzyme Q offered more adequate myocardial preservation during ischemic arrest than did hypothermic cardioplegia and topical cooling alone. In biochemistry, it is accepted in general that coenzyme Qlo is a naturally occurring component of the respiratory chain localized in mitochondria and links the flavoprotein to cytochrome b. Previous studies have shown the beneficial effect of coenzyme Qlo on congestive heart failure [4, 5. However, the administration period of coenzyme Qlo in our study seems too short to improve the patient s preoperative cardiac function [4]. Recently, coenzyme Qlo has been found to have a protective effect on myocardial structure and function during acute ischemia and reperfusion [6-8. Abe and coworkers [7 and Jennings [8 reported that the rate of degradation of myocardial adenosine triphosphate (ATP) during an episode of total ischemia was slowed in animals treated with the coenzyme. Nayler [8 found that pretreatment with coenzyme Qlo gave rabbit hearts an

6 5 The Annals of Thoracic Surgery Vol33 No February 98 increased protection against the deleterious effects of ischemia and reperfusion. This protection was accompanied by a maintenance of the oxidative-phosphorylating and ATP-generating capacities of the mitochondria, and the absence of mitochondrial Ca++ overload. This coenzyme may have a membrane-stabilizing effect resembling that of an alpha-tocopherol, since it has been shown that reduced coenzyme Qlo functions as a potent antioxidant against lipid peroxidation in myocardial mitochondrial membrane [9,. We believe that the fundamental components of myocardial protection are hypothermia and the suspension of contractile activity. In fact, the combination of topical cooling and potassium cardioplegia at this institution, as in many others, allows us to operate in a quiet, flaccid, bloodless field with confidence that the heart is protected to some extent during aortic crossclamping. However, to extend the upper limit of safe cross-clamping time, methods having additive protection should be sought. This is very important when we treat patients with long-standing acquired valvular disease necessitating valve replacement. Coenzyme Qlo is the only mobile component of the respiratory chain in mitochondria, and thus, a deficiency in the amount of the coenzyme could occur in diseased hearts [3]. Although the mode of action of coenzyme Qlo is not entirely clear, this preliminary work on human hearts strongly supports the previous work in animals regarding its protective effect on myocardial ischemic changes. Coenzyme Qlo is neither a protein nor a foreign substance. Therefore, neither anaphylactic nor other serious side-effects can be expected. Some gastrointestinal side-effects were encountered in the administration of a maximum daily dose of 3 mg in 5,43 patients: epigastral discomfort in patients (.39'/), loss of appetite in (.3%), nausea in 8 (.6%), and diarrhea in 6 (.%).* We believe the results of the administration of coenzyme Qlo to patients having open-heart operation merit evaluation of its prophylactic benefit on myocardial damage during ischemic arrest and reperfusion. 'Tanaka J et al: Unpublished data, 98 References. Appelbaum A, Kouchoukos NT, Blackstone EH, et al: Early risks of open heart surgery for mitral valve disease. Am J Cardiol 37:, 976. Salomon NW, Stinson EB, Griepp RB, Shumway NE: Patient-related risk factors as predictors of results following isolated mitral valve replacement. Ann Thorac Surg 4:59, Folkers K, Littarru GP, Ho L, et al: Evidence for a deficiency of coenzyme Ql in human heart disease. Int J Vitaminforsch 4:38, Ishiyama T, Morita Y, Toyama S, et al: A clinical study of the effect of coenzyme Q on congestive heart failure. Jpn Heart J 7:3, Yamamura Y: Clinical status of coenzyme Q and prospects. In Folkers K, Yamamura Y (eds): Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the International Symposium on Coenzyme Q, Lake Yamanaka, Japan, Sept 976. Amsterdam, Oxford, New York, Elsevier, 977, pp Matsunaga H, Matsumoto H, Yoshitake T, et al: Protection of cardiac muscle in surgery. In Yamamura Y, Folkers K, Ito Y (eds): Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the Second International Symposium on Coenzyme Q, Tokyo, Japan, Sept 9-3, 979. Amsterdam, New York, Oxford, ElsevierlNorth- Holland, 98, vol, pp Abe T, Okamoto F, Chiba M, et al: Myocardial protection with coenzyme Q,,, during two hours of aortic cross-clamping: evaluation from the aspects of high-energy phosphates and lactate in the myocardium. In Yamamura Y, Folkers K, Ito Y (eds): Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the Second International Symposium on Coenzyme Q, Tokyo, Japan, Sept 9-3, 979. Amsterdam, New York, Oxford, ElsevierlNorth-Holland, 98, vol, pp Nayler WG: The use of coenzyme Q,,, to protect ischemic heart muscle. In Yamamura Y, Folkers K, Ito Y (eds): Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the Second International Symposium on Coenzyme Q, Tokyo, Japan, Sept 9-3, 979. Amsterdam, New York, Oxford, ElsevierlNorth-Holland, 98, vol, pp Taber RE, Morales AR, Fine G: Myocardial necrosis and the postoperative low-cardiac-output syndrome. Ann Thorac Surg 4:, 967. Najafi H, Henson D, Dye WS, et al: Left ventricular hemorrhagic necrosis. Ann Thorac Surg 7:55, 969. Buckberg GD, Towers 8, Paglia DE, et al: Subendocardia ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 64:669, 97. Buckberg GD: Left ventricular subendocardial necrosis (collective review). Ann Thorac Surg 4:379, 977

7 5 Tanaka et al: Coenzyme Qlo and Low Cardiac Output 3. Abel RM, Buckley MJ, Austen WG, et al: Etiology, incidence, and prognosis of renal failure following cardiac operations: results of a prospective analysis of 5 consecutive patients. J Thorac Cardiovasc Surg 7:33, Tanaka J, Yasui H, Nakano E, et al: Predisposing factors of renal dysfunction following total correction of tetralogy of Fallot in the adult. J Thorac Cardiovasc Surg 8:35, Cunningham JN Jr, Adams PX, Knopp EA, et al: Preservation of ATP, ultrastructure, and ventricular function after aortic cross-clamping and reperfusion. J Thorac Cardiovasc Surg 78:78, Engelman RM, Rousou JH, Vertrees RA, et al: Safety of prolonged ischemic arrest using hypothermic cardioplegia. J Thorac Cardiovasc Surg 79:75, Fujita T, Matsuura T, Takamatsu T, et al: Studies on metabolism of ubiquinone-: I. Mainly absorption, tissue distribution and excretion in rats and rabbits (English abstract). Oyo Yakuri 6:695, Jennings RB: Discussion of Abe et a [7] 9. Mellors A, Tappel AL: The inhibition of mitochondrial peroxidation by ubiquinone and ubiquinol. J Biol Chem 4:4353, 966. Takeshige K, Takayanagi R, Minakami S: Reduced coenzyme Q,,, as an antioxidant of lipid peroxidation in bovine heart mitochondria. In Yamamura Y, Folkers K, Ito Y (eds): Biomedical and Clinical Aspects of Coenzyme Q: Proceedings of the Second International Symposium on Coenzyme Q, Tokyo, Japan, Sept 9-3, 979. Amsterdam, New York, Oxford, ElseviedNorth- Holland, 98, vol, pp 5-6 Notice from the American Board of Thoracic Surgery The American Board of Thoracic Surgery now A candidate applying for admission to the requires that candidates pass both the written 983 certifying examination must fulfill all the and oral portions of the certifying examination. requirements for the Board in force at the time In 98 and thereafter, a written examination the application is received. will be given prior to the oral examination. It Please address all communications to the will be necessary to pass the written examina- American Board of Thoracic Surgery, 464 E tion before the oral examination can be taken. Seven Mile Road, Detroit, MI 485. The closing date for registration for 983 is August,98. The exact times and places of these examinations will be announced later.