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J Thorac Cardiovasc Surg 1994;107:242-247
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES |
Kaohsiung, Taiwan
From the Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical College, Kaohsiung, Taiwan.
Received for publication Oct. 22, 1992. Accepted for publication April 16, 1993. Address for reprints: Ying-Fu Chen, MD, Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical College, 100 Shih-Chuan 1st Rd., Kaohsiung, Taiwan.
Abstract
A prospective, randomized, double-blind trial assigned 11 patients to receive coenzyme Q10 and 11 to receive none. Patients pretreated with coenzyme Q10 had a lower left atrial pressure and a lesser incidence of low cardiac output. They also had a wider pulse pressure. The right and left ventricular myocardial ultrastructure was better preserved in patients receiving preoperative treatment with coenzyme Q10. There was no demonstrable benefit to the atrial myocardium. (J THORAC CARDIOVASC SURG 1994;107:242-7)
Coenzyme Q10 (CoQ10), also known as ubiquinone, is a naturally occurring substance that is an essential component of the mitochondrial respiratory chain where aerobic energy is produced.
1 In 1970, Folkers and associates 2 demonstrated a deficiency of this coenzyme in the myocardium of patients with various cardiac disorders. Subsequent reports described the results of myocardial biopsy studies from patients having cardiac operation 3, 4 and blood sample studies from over 1000 patients with general cardiac disease 5; these studies showed significantly lower levels of endogenous CoQ10 in patients with heart failure than in normal subjects. CoQ10 is the only mobile electron carrier in the lipid phase of the mitochondrial electron-transfer process of respiration and, coupled phosphorylation, has been widely established. 6 Nayler, 7 in 1980, was the first to suggest a role for CoQ10 in preserving the ischemic myocardium. She studied New Zealand rabbit hearts rendered ischemic and then reperfused with or without prior treatment with CoQ10. The results showed that the myocardium pretreated with CoQ10 was relatively protected against both structural and functional changes induced by ischemia and reperfusion. A randomized, prospective study of the effectiveness of preoperative administration of CoQ10 on the prophylaxis of postoperative low cardiac output state suggested that low output syndrome was less prevalent among patients undergoing elective cardiac operations who had received this compound orally for 1 week before the operation than among patients not receiving this compound. 8 Therefore, this agent may be expected to be useful for myocardial energy metabolism during induced ischemia.
The objective of this prospective, randomized, double-blind study was to evaluate whether the preoperative administration of CoQ10 could have a beneficial effect on myocardial preservation.
PATIENTS AND METHODS
A prospective, randomized, double-blind study was designed to determine whether preoperative administration of CoQ10 (Eisai Pharmaceutical Corp., Tokyo, Japan) could improve the effectiveness of myocardial preservation. There were 11 patients in the coenzyme group and 11 patients in the control group. Patients in the coenzyme group received 150 to 200 mg of CoQ10 orally per day for 5 to 7 days before the operation. Altogether, 1000 mg was given to each patient. Patients in the control group did not receive CoQ10. The two groups were comparable with regard to sex, age, preoperative cardiothoracic ratio, New York Heart Association functional class, and ventricular function (Table I). There were also no significant differences in ischemic time, cardiopulmonary bypass time, and systemic hypothermia. Each operation was performed by the same cardiac team. Cardiopulmonary bypass was accomplished by double venous cannulation with snares placed on the superior and inferior venae cavae. Immediately after aortic crossclamping, blood cardioplegic solution, 15 ml/kg body weight, was infused into the aortic root. Additional cardioplegic solution (7.5 ml/kg) was administered every 30 minutes or if electromechanical activity returned. The composition of blood cardioplegic solutions used was as reported previously. 9 Moderate systemic hypothermia was induced with the heat exchanger of the extracorporeal circuit. External topical hypothermia was induced by pouring iced slush on the heart.
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Hemodynamic measurements.
The analysis of hemodynamic measurements included systemic arterial pressure, pulse pressure, left atrial pressure, heart rate, and frequency of low cardiac output. Presence of low cardiac output was defined as the need for inotropic support (dopamine hydrochloride > 6 µg/kg per minute) for more than 12 hours to keep systemic blood pressure above 90 mm Hg after optimized filling pressures.
Ultrastructural studies.
Two serial specimens (preischemic and ischemic) were obtained from the right atrium, right ventricle, and left ventricle of each patient in both groups. The first specimen was taken before aortic crossclamping as a control sample; the second specimen was obtained at the end of ischemia. The right and left ventricular muscle biopsy samples were obtained by direct puncture of the right ventricular free wall and the left ventricular apex with a disposable Travenol biopsy needle (Tru-Cut; Baxter Healthcare Corp., Deerfield, Ill.). A total of 132 biopsy specimens were obtained from these 22 patients.
Each specimen was fixed for 1
hours in paraformaldehyde and 2.5% glutaraldehyde in cacodylate buffer solution, 0.1 mmol/L. The specimen was washed several times with cold phosphate buffer solution, 0.1 mmol/L, for 1 hours and then dehydrated with graded ethyl alcohol. Subsequently, the specimen was embedded in epoxy resin and sectioned after dealcoholization with propylene oxide. Finally, it was stained with uranyl acetate and lead citrate and examined with an electron microscope (Hitachi H-500; Hitachi Ltd., Tokyo, Japan).
Twelve electron micrographs were obtained for each of the 132 biopsy specimens. The initial magnification of the electron micrographs was 8,000x to 12,000x. Forty to 50 randomly selected mitochondria from each electron micrograph were graded in terms of ischemic injury. Thus a total of 500 mitochondria in each biopsy were assessed.
Each mitochondrion was assigned a grade on a scale of 0 to 4, as follows 10:
Finally, the average score for 500 mitochondria from each biopsy specimen was calculated.
Statistical analysis.
The data were analyzed by nonpaired and paired Student's t tests or 
2 analysis. Values were considered significant if the probability values were less than or equal to 0.05.
RESULTS
Postoperative clinical parameters.
All patients in both groups did well and were discharged from the hospital after the operation. There were no complications resulting from the myocardial biopsies. Table II summarizes the hemodynamic parameters obtained after the patients returned to the intensive care unit until 8 AM on the first postoperative day. No statistically significant differences were found between the two groups with regard to systemic arterial pressure and heart rate. The group of patients without pretreatment with CoQ10 had a higher left atrial pressure (11.7 ± 3.4 mm Hg) than the group with pretreatment with CoQ10 (9.1 ± 3.3 mm Hg), although the difference failed to reach statistical significance. The frequency of low cardiac output tended to be higher in the group of patients without pretreatment with CoQ10, but the difference was not statistically significant. An evaluation of pulse pressure, admittedly correlated with cardiac output, showed a statistically significant difference between the two groups of patients (p < 0.005).
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Table III shows the mitochondrial score of the right atrial, right ventricular, and left ventricular myocardium in patients without CoQ10 pretreatment. In the right atrium, the average mitochondrial score rose from 0.474 ± 0.177 in the preischemic stage to 2.276 ± 0.350 in the ischemic stage. The difference was highly significant (p < 0.0005). In the right ventricle, the score was 0.401 ± 0.226 in the preischemic stage and 1.290 ± 0.522 after ischemia. The difference was also highly significant (p < 0.0005). In the left ventricle, the score was 0.434 ± 0.221 before ischemia and 1.319 ± 0.650 after ischemia. Again, the difference was highly significant (p < 0.0005). On the other hand, both the right ventricular and left ventricular myocardium were better preserved than the right atrial myocardium (2.276 ± 0.350 versus 1.290 ± 0.522, p < 0.0005; 2.276 ± 0.350 versus 1.319 ± 0.650, p < 0.0005). Table IV presents the mitochondrial score of right atrial, right ventricular, and left ventricular myocardium in patients treated with CoQ10. In the right atrium, the mitochondrial score was 0.406 ± 0.251 before ischemia and 2.412 ± 0.717 after ischemia, a difference that was significant (p < 0.0005). The mitochondrial score for the right ventricle was elevated from 0.273 ± 0.215 of preischemia to only 0.783 ± 0.615, but the difference was still statistically significant (p < 0.005). In the left ventricle, the score was 0.256 ± 0.146 in the preischemic stage and 0.664 ± 0.619 in the ischemic stage, again a significant difference (p < 0.005). Likewise, both the right ventricular and left ventricular myocardium had lesser ischemic injury than the right atrial myocardium (2.412 ± 0.717 versus 0.783 ± 0.615, p < 0.0005; 2.412 ± 0.717 versus 0.664 ± 0.619, p < 0.0005). Table V summarizes the comparison of the mitochondrial score for the right atrial, right ventricular, and left ventricular myocardium in patients treated with or without CoQ10. The right and left ventricular myocardial ultrastructure were better preserved in the group of patients treated with CoQ10 before the operation than in the group of patients without preoperative administration of CoQ10. The difference between ischemic values for the right ventricles treated with CoQ10 and those not treated with CoQ10 was statistically significant (p < 0.05). The difference was statistically significant as well for the left ventricle (p < 0.05). As can be seen in Table V, no demonstrable benefit could be found in the CoQ10-treated atrial myocardium in comparison with that of the group of patients without CoQ10 pretreatment.
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Postoperative clinical parameters.
This study suggests that preoperative treatment with CoQ10 may improve hemodynamics. Low cardiac output after cardiopulmonary bypass reflects preexisting ventricular dysfunction and inadequacy of myocardial preservation. In this study, patients without pretreatment with CoQ10 more frequently required inotropic support for low cardiac output syndrome and tended to have higher left atrial pressure. Despite this, there was no statistically significant difference. In addition, an increased pulse pressure usually results from an increase in stroke volume and cardiac output. The group of patients pretreated with CoQ10 had a wider pulse pressure than the group of patients not pretreated with CoQ10 (p < 0.005). These results imply better cardiac function in patients pretreated with CoQ10.
Ultrastructural studies.
Our results clearly show poorer preservation of atrial myocardium than ventricular myocardium, regardless of whether CoQ10 pretreatment was given or not. These findings are compatible with our previous ultrastructural studies. 11, 12 Why might hypothermic cardioplegia cause such disproportionate effectiveness of myocardial preservation between the atrial myocardium and ventricular myocardium? Three possible explanations are proposed. First, the position of the right atrium is relatively higher than that of either ventricle, so that the right atrium is frequently excluded from topical ice cooling 9 with resultant differential cooling of theatrial septum (25.9° C) and ventricular septum (15.7° C). 13 Our recent work 14 has also demonstrated uneven myocardial hypothermia among the three cardiac chambers (right atrium, right ventricle, and left ventricle) during cardioplegic arrest in 55 consecutive patients. The right atrium had a higher temperature (19.1° ± 4.1° C) than the right ventricle (12.7° ± 4.8° C) or the left ventricle (7.3° ± 3.4° C). The importance of profound hypothermia in protecting the myocardium during cardioplegic arrest is well known. In fact, hypothermic cardioplegia has two protective components—hypothermia and cardioplegia—and their effects are additive 15. Comparison of the efficacy of hypothermia alone and chemical cardioplegia alone reveals that hypothermia has a more powerful protective action. 16 Because the right atrium has the highest temperature, 14 it is reasonable to expect poorer preservation of the right atrial myocardium than the ventricular myocardium, as this study demonstrated. Second, noncoronary collateral blood flow may affect myocardial preservation, Brazier, Hottenrott, and Buckberg 17 found that the highest proportion of noncoronary collateral blood flow during aortic crossclamping was always delivered to the atria, which receive up to 30% of their normal blood supply from noncoronary collateral circulation. This noncoronary collateral flow often causes early washout of the cardioplegic solution, which may explain why electromechanical activity is often encountered during the period of cardioplegic arrest. 18 Third, there is a differential delivery of the cardioplegic solution; all regions of the atria receive approximately half as much cardioplegic solution per gram of tissue as the ventricles do. 13
Of great significance, right and left ventricular myocardial preservation was more effective in the group of patients receiving preoperative treatment with CoQ10 than in the group of patients without preoperative administration of CoQ10. Low cardiac output syndrome after cardiac surgery has been found to be less prevalent after pretreatment of the patient with CoQ10. 8 Ohhara and associates 19 reported that pretreatment with CoQ10 preserved myocardial stores of both adenosine triphosphate (ATP) and total adenine nucleotides during ischemia and restored better mechanical function in the isolated perfused rat heart. Mori and Mohri 20 also demonstrated that the addition of CoQ10 to potassium cardioplegic solutions resulted in improved myocardial stores of ATP and creatine phosphate (CP) and a low level of lactate during induced ischemia and reperfusion. Okamoto and Buckberg 21 confirmed that CoQ10-treated hearts did recover more ATP, CP, and total adenine nucleotides in all myocardial layers and showed more contractile reserve than untreated hearts. Higher tissue ATP and CP levels in CoQ10-treated hearts suggest that CoQ10 allows for better protection of the metabolic processes responsible for maintaining oxidative phosphorylation and the cellular ATP-generating capacity and indicate that this salutary effect contributes to improved high-energy phosphate production.
As can be seen in 
Table V, no demonstrable benefit could be found in the CoQ10-treated atrial myocardium. It is puzzling that the CoQ10-treated heart could display such an advantage for the ventricular myocardium but have no concurrent advantage for the atrial myocardium. What possible mechanism lies behind this? Okamoto and colleagues 21 attest that the myocardial contractile reserve was better preserved in hearts receiving blood cardioplegic solution without CoQ10 than in those receiving CoQ10 alone. Therefore, they suggested that the role of CoQ10 in avoiding reperfusion damage is supportive rather than primary. Our previous work demonstrated significantly poorer preservation of the right atrium than of the right and left ventricles. 11, 12 Thus we hypothesized that the benefits to the preservation of the atrial myocardium in patients treated with CoQ10 depend on the severity of the ischemic injury of the atrial myocardium during the ischemic stage: the more severe the ischemic injury, the less effective the treatment. The results of this study suggest that CoQ10 is a potentially useful additive for improving myocardial preservation during the stage of limited ischemic injury. Too severe ischemic injury exceeds the ability of CoQ10 to protect. This finding is compatible with the experiments described by Okamoto and colleagues, 21which disclosed the role of CoQ10 in preventing reperfusion damage as being additive rather than primary.
On the other hand, CoQ10 is also known to have antioxidant and membrane stabilizing properties. 6 Through its antioxidant capacity, CoQ10 would act as an oxygen radical scavenger during the reperfusion stage. In addition, exogenous CoQ10 has been shown to be inhibitory to the cellular phospholipases responsible for degrading cell membranes during postischemic reperfusion periods. 22 These are other properties of CoQ10 that may allow it to protect the ischemic myocardium by reducing reperfusion injury.
In summary, this study shows that pretreatment with CoQ10 yields favorable hemodynamics. Likewise, according to ultrastructural studies based on grading of ischemic injury, an additional effectiveness of myocardial preservation on ventricular myocardium could be demonstrated. However, there is no similar protective effect on the atrial myocardium.
We are grateful to Wen-Jiun Lin for her secretarial assistance in the preparation of the manuscript.
References
This article has been cited by other articles:
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  F. Rosenfeldt, S. Marasco, W. Lyon, M. Wowk, F. Sheeran, M. Bailey, D. Esmore, B. Davis, A. Pick, M. Rabinov, et al. Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue J. Thorac. Cardiovasc. Surg., January 1, 2005; 129(1): 25 - 32. [Abstract] [Full Text] [PDF]
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 D. P. Taggart, M. Jenkins, J. Hooper, L. Hadjinikolas, M. Kemp, D. Hue, and G. Bennett Effects of Short-Term Supplementation With Coenzyme Q10 on Myocardial Protection During Cardiac Operations Ann. Thorac. Surg., March 1, 1996; 61(3): 829 - 833. [Abstract] [Full Text]
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