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ORIGINAL ARTICLE
Effect of Coenzyme Q10 on the Incidence of Atrial Fibrillation in Patients With Heart Failure Qingyan Zhao, MD, PhD,* A. Hafid Kebbati, MD, PhD,* Yuguo Zhang, MBchB,† Yanhong Tang, MD, PhD,* Emmy Okello, MBChB,* and Congxin Huang, MD, PhD* Background: There is mounting evidence to support the influence of inflammation and oxidative stress in the pathogenesis of atrial fibrillation (AF) and heart failure (HF). The efficacy of coenzymeQ10 (CoQ10), an antioxidant used as an adjunct treatment in patients with AF and HF, remains less well established. Methods: Consecutive patients with HF were randomized and divided into 2 groups: the CoQ10 group (combined administration of common drugs and CoQ10) and the control group (administration of common drugs). Ambulatory electrocardiogram Holter monitoring (24 hours), Doppler echocardiography, and evaluation of inflammatory cytokines were performed before treatment and 6 and 12 months after treatment. Results: One hundred two patients (72 male and 30 female patients), with ages ranging from 45 to 82 years (mean age, 62.3 years), were examined. There was significant reduction in the level of malondialdehyde (3.9 ± 0.7 vs 2.5 ± 0.6 ng/mL; 3.9 ± 0.7 vs 2.3 ± 0.5 ng/mL, P < 0.05) in the CoQ10 group, whereas there was no significant difference (3.3 ± 0.8 vs 2.9 ± 0.8 ng/mL; 3.3 ± 0.8 vs 2.9 ± 0.5 ng/mL) in the control group after 6 and 12 months. Three patients (6.3%) in the CoQ10 group and 12 patients (22.2%) in the control group had episodes of AF after 12 months’ treatment (P = 0.02). Four patients with AF in the control group went through the third Holter recording. Conclusions: CoenzymeQ10 as adjuvant treatment in patients with HF may attenuate the incidence of AF. The mechanisms of the effect perhaps have relation with the reduced levels of malondialdehyde. Key Words: atrial fibrillation, coenzymeq10, heart failure, oxidative stress (J Investig Med 2015;63: 735–739)
I
n recent years, atrial fibrillation (AF) has increasingly become a focus of attention because it remains the most encountered arrhythmia in clinical practice and a major cause of morbidity and mortality.1,2 The fundamental mechanisms underlying AF have long been debated. However, to this day, the mechanisms have not been elucidated. There is an increasing body of evidence linking inflammation and oxidative stress to a broad spectrum of cardiovascular conditions, such as heart failure (HF), coronary artery disease, and hypertension.3–5 In addition, there are emerging data to support the association between inflammation and AF.6,7 This has created exciting potential opportunities to target inflammatory and oxidative stress processes for the prevention of AF and HF. From the Departments of *Cardiology and †Ultrasonography, Renmin Hospital of Wuhan University, Wuchang, Wuhan, People’s Republic of China. Received July 16, 2014, and in revised form March 16, 2015. Accepted for publication March 24, 2015. Reprints: Congxin Huang, MD, PhD, Cardiovascular Research Institute of Wuhan Unviersity, Renmin Hospital of Wuhan University, 238Jiefang Rd, Wuchang, Wuhan City, 430060, People’s Republic of China. E-mail: [email protected]. The authors have no conflicts of interest to disclose. Disclosures: None Q.Z. and A.H.K. are co–first authors. Copyright © 2015 by The American Federation for Medical Research ISSN: 1081-5589 DOI: 10.1097/JIM.0000000000000202
Studies have shown that coenzyme Q10 (CoQ10) plays a central role in mitochondrial oxidative phosphorylation and has an important effect on cellular adenosine triphosphate production.8 Normally, with increasing age and HF, the concentration of Q10 in the heart has been shown to fall considerably. Several observational and controlled prospective trials have demonstrated the efficacy of CoQ10 as adjunctive treatment of HF.9–11 However, whether chronic treatment with CoQ10 has an impact on the occurrence of AF remains unanswered. The objectives of the present study are first to assess the effects of CoQ10 on the occurrence of AF in the patients with HF and finally to evaluate the relation between the occurrence of AF and the inflammatory cytokines markers.
METHODS Patients This study has been performed with the subjects’ written informed consent. One hundred twenty-eight consecutive patients (90 men and 38 women, aged 60 ± 4 years) with HF of nonischemic origin were included in this study. Eligibility criteria included New York Heart Association functional status II-IV, left ventricular ejection fraction (LVEF) less than 40%, and patients needed to be on stable standard HF for 3 to 6 months before the study. Patients were excluded if they had AF before the study or renal or liver dysfunction. In addition, patients with acute HF, acute coronary syndrome, or HF of ischemic origin were also excluded from the study. Patients underwent a standard clinical examination and investigation including a standard 12-lead electrocardiogram (ECG), echocardiography, complete blood counts, electrolyte analysis, chest radiographs, and liver and renal function tests.
Study Design After the baseline evaluation, the patients were randomized and divided into 2 groups in a double-blind fashion and prospectively studied: the CoQ10 group (CoQ10: 30 mg/d, n = 62) and the control group (n = 66). The patients, physicians, echocardiography staff, laboratory, and the statistician were all blinded to the study. A 24-hour continuous ambulatory ECG monitoring, echocardiography, and checking of blood samples for high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and malondialdehyde (MDA) were performed on every patient, at study enrollment and after 6 and 12 months (the study end). Patients returned for 6- and 12-month follow-up evaluations, with phone calls every 2 weeks to ensure drug compliance.
Ambulatory ECG Holter Monitoring A 24-hour continuous ambulatory ECG monitoring was performed on every patient on 3 occasions: at the beginning of the study (days 1–7), after 6 months (days 185–192), and after
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TABLE 1. Clinical Characteristics of the Patients Control Group CoQ10 Group Patients Sex, male/female Age, y Hypertension Diabetes Hyperlipidemia LVEF, % LVED, mm LAD, mm Medication Digitalis ACE inhibitors AT1 blockers β-Blockers Calcium-channel blockers Dihydropyridines Nondihydropyridines Diuretics Nitrates Statins
P
54 38/16 62 ± 6 18 24 23 36 ± 4 60 ± 6 37 ± 4
48 34/14 63 ± 7 14 20 24 38 ± 3 58 ± 7 38 ± 3
1.00 0.44 0.68 0.84 0.55 0.08 0.17 0.16
30 32 22 50
24 28 20 47
0.69 1.00 1.00 0.37
12 8 50 5 54
8 10 42 6 48
0.62 0.45 0.22 0.75 —
Values are mean ± SD or number of patients. LAD indicates left atrial diameter; AT, angiotensin receptor.
12 months (days 362–369). The Holter monitoring was digitally recorded using Mars 3000 (Milwaukee, WI). After visual scrutiny and verification, all episodes meeting the criteria were manually measured and logged. Loss of P wave and irregular narrow ventricular rhythm for 30 seconds or more were regarded as an episode of AF.
Echocardiography and Laboratory Measurements Transthoracic Doppler echocardiography was performed using Vivid7 (GE, Wauwatosa, WI). The left ventricular enddiastolic diameter (LVED) and left atrial end-diastolic diameter were measured by conventional 2-dimensional parasternal longaxis view of the left heart. The LVEF was measured according to the biplane Simpson rule. Results were taken in triplicate and
averaged. The images were reviewed by an independent echocardiography expert. Four milliliters of venous blood was collected in EDTA Vacutainers in the morning after an overnight fast and centrifuged at 3000 revolutions per minute, for 10 minutes at 4°C (Avanti J-E; Beckman Coulter, Inc., Brea, CA). The serum was separated and kept in micro-tubes and stored at –80°C until assay. Proinflammatory markers TNF-α and IL-6 were measured using commercially available enzyme-linked immunosorbent assay kits (eBioscience, San Diego, CA). High-sensitivity C-reactive protein was measured using immunoprecipitation technique. Malondialdehyde was measured using rat anti-human immunoassay enzyme-linked immunosorbent assay (Adliattrem; Cusabio, Wuhan, Hubei, China). The proposal was approved by the university research and ethics committee. The study participants were handled according to the Declaration of Helsinki.
Statistical Analysis Continuous data are expressed as the mean ± SEM, and SPSS statistical software was used for the analysis. Statistical comparisons were made using analysis of variance. Paired and unpaired comparisons were conducted using the Student t test. Statistical significance was assumed if P < 0.05.
RESULTS Baseline Characteristics Patients (n = 128) with HF of nonischemic origin were enrolled in the study. Fourteen patients (8 patients in the control group and 6 patients in the CoQ10 group) died during follow-up and were excluded. Twelve patients were lost because their treatment was stopped by physicians at a local hospital. One hundred two patients (72 male and 30 female patients), with ages ranging from 45 to 82 years (mean age, 62.3 years), were examined, and their data were used to analyze the results. Baseline clinical data for these patients are summarized in Table 1. There was no difference between the 2 study groups at baseline.
Recording of AF The first, second, and third Holter recordings were performed in 128, 113, and 102 patients, respectively. Among the 113 patients who received their second Holter recordings, 58 patients were in the control group, and 55 patients were in the CoQ10 group.
FIGURE 1. Changes of hs-CRP in the 2 groups. There was a significant reduction in the level of hs-CRP after 6 and 12 months of treatment in the 2 groups.
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CoQ10 and Heart Failure
FIGURE 2. Changes of IL-6, TNF-α, and MDA in the 2 groups. Results showed that there was a significant reduction in the levels of IL-6 and TNF-α after 6 and 12 months of treatment in the 2 groups. There were no significant changes in the level of MDA after 6 and 12 months of treatment in the control group. However, the level of MDA decreased after 6 and 12 months of treatment in the CoQ10 group.
Among the 102 patients who received their third Holter recordings, 54 patients were in the control group, and 48 patients were in the CoQ10 group. In the second Holter recording, AF was recorded in 6 patients: 2 patients in the CoQ10 group and 4 patients in the control group (all the 6 patients had self-limited AF). In the third Holter recording, AF was recorded in 15 patients: 3 patients in the CoQ10 group (All the 3 patients had self-limited AF) and 12 patients in the control group (8 patients had self-limited AF, and 4 patients with AF went through the Holter recording). The incidence of AF was lower in the CoQ10 group than in the control group after 12 months. (6.3% vs 22.2%; P = 0.02).
MDA (3.9 ± 0.7 vs 2.5 ± 0.6 ng/mL) after 6 months of treatment. Furthermore, there was a significant increase in LVEF and a significant reduction in the LVED. However, the changes in LVEF and LVED have no significant difference after 6 and 12 months (Tables 2 and 3).
DISCUSSION
In the control group, the cohort of patients had significant reductions in hs-CRP (4.3 ± 2.6 vs 3.4 ± 1.8 mg/L, P < 0.05) (Fig. 1), TNF-α (3.3 ± 1.3 vs 2.2 ± 1.3 ng/mL, P < 0.05) (Fig. 2), improvement in LVEF (36 ± 4% vs 41 ± 6%, P < 0.05), and a decrease in LVED (60 ± 5 vs 55 ± 4 mm, P < 0.05) after 6 months’ treatment (Tables 2 and 3). There was a significant decrease in the level of IL-6 (3.5 ± 1.6 vs 2.5 ± 1.3 mg/L, P < 0.05) but no significant changes in the level of MDA (3.3 ± 0.8 vs 2.9 ± 0.5 mg/L, P > 0.05) (Fig. 2). Furthermore, compared with that after 6 months, the reductions in inflammatory markers (hs-CRP: 3.4 ± 1.8 vs 3.3 ± 1.3 mg/L; TNF-α: 2.2 ± 1.2 vs 2.1 ± 1.5 ng/mL; IL-6: 2.5 ± 1.3 vs 2.3 ± 1.5 mg/L; MDA: 2.9 ± 0.7 vs 2.8 ± 0.7 mg/L, P > 0.05) and LVED have no significant difference after 12 months. In the CoQ10 group, there was a significant reduction in the level of TNF-α (3.5 ± 1.2 vs 1.8 ± 0.9 ng/mL), IL-6 (3.4 ± 1.2 vs 2.4 ± 1.1 ng/mL), hs- CRP (4.2 ± 2.5 vs 2.0 ± 1.9 mg/L), and
The novel finding of the present study indicates that the oral CoQ10 supplementation in patients with HF had lower incidence of AF. These results suggest that long-term oral CoQ10 attenuates AF vulnerability in patients with HF. Atrial fibrillation and HF are 2 increasingly common cardiac disorders with a growing prevalence in the overall population.12 Atrial fibrillation is a common atrial arrhythmia in patients with HF caused by left ventricular dysfunction and is associated with significant morbidity and possibly increased mortality rates.13,14 The mechanisms by which HF promotes AF are incompletely understood. Studies have shown that their interaction involves complex ultrastructural, electrophysiologic, and neurohormonal processes that go beyond mere sharing of mutual risk factors.15 Clinical studies have shown that inflammation is an independent risk factor for the initiation and maintenance of AF.16 Furthermore, patients with HF remain plagued by a poor prognosis that is thought to be linked to underlying inflammation and oxidative stress. Chronic inflammation in HF is associated with raised circulating level of inflammatory cytokines. In addition to inflammation, HF is a high oxidative stress state in which high reactive oxygen species levels have been shown to correlate with depressed cardiac function.17 There is evidence supporting some of the drug therapies, such as the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and statins, which might
TABLE 2. Changes of LVEF in the 2 Groups (%, Mean ± SD)
TABLE 3. Changes of LVED in the 2 Groups (mm, Mean ± SD)
Changes of Inflammatory Markers and Echocardiography Measurements
Control Group (n = 54) CoQ10 Group (n = 48) Before treatment After 6 mo After 12 mo
36 ± 4* 41 ± 6 43 ± 5
*P < 0.05 vs after 6 and 12 months’ treatment.
37 ± 4* 44 ± 7 46 ± 6
Control Group (n = 54) CoQ10 Group (n = 48) Before treatment After 6 mo After 12 mo
60 ± 5* 55 ± 4 54 ± 4
58 ± 4* 54 ± 9 53 ± 3
*P < 0.05 vs after 6 and 12 months’ treatment.
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be efficacious in the prevention of AF and beneficial for HF by modulating inflammatory pathways.18,19 CoenzymeQ10 is found in the highest concentration in the human myocardium, where it is involved in mitochondrial oxidative phosphorylation, resulting in adenosine triphosphate production, an important process for high energy requiring organs such as the heart.20 In addition, CoQ10 is involved in free radical scavenging, an effect that is linked to the increase in the level of SOD. The antioxidant CoQ10, which is found to have lower levels in HF patients, has been shown in recent studies to boost plasma ubiquinone levels when supplemented orally. The return to normal physiological levels of ubiquinone resulted in various dose-dependent actions in the heart including improvement in LVEF, reduction in LVED, and generally faster symptom improvement in patients with HF.21,22 However, the effect of combined administration of common drugs and CoQ10 on HF with AF has not been elucidated. In the present study, we observed that administration of common drugs (statins, ACE inhibitors, etc) could reduce the serum TNF and hs-CRP levels, but the level of MDA had no significant change after treatment. CoenzymeQ10 as adjuvant treatment not only reduced the levels of TNF and hs-CRP, but also reduced the level of MDA. Malondialdehyde is one of the small-molecular-weight fragments that occur when polyunsaturated fatty acids undergo oxidative stress by free radicals. Malondialdehyde itself may result in additional structural or functional damage because of its high chemical reactivity. In human beings, a previous study demonstrated higher levels of plasma MDA in HF patients.23 In this study, we found that the incidence of AF was lower in the CoQ10 group than in the control group after 12 months, and the level of MDA was lower in this group. The results indicate that CoQ10 as adjuvant treatment has the beneficial effect of reducing the occurrence of AF in patients with HF by reducing the serum MDA level. There is now compelling evidence that statins therapy may attenuate the effect of inflammation, and several studies showed favorable effects of statins to reduce the incidence of AF.24 Most of the early studies on statins/CoQ10 interactions focused on the effect of statins on CoQ10 levels, and its relationship with statins induced myopathy.25,26 Almost one half of the studies found that statins significantly decreased CoQ10 levels.27,28 In our study, our results showed that CoQ10 as adjuvant treatment is more efficacious than statins alone. Although CoQ10 as adjuvant treatment reduced the levels of inflammatory cytokines markers after 6 months, there was no difference in the incidence of AF. After 12 months, incidence of AF in CoQ10 group was higher than in the control group. This result implied that HF patients could benefit from long-term use of CoQ10 because it reduces the occurrence of AF.
Limitations Our study has several limitations. Before and after follow-up, AF was identified by Holter. The diagnosis could have been missed in some patients with transient episodes of AF. This would have confounded the results and lowered the AF estimates. However, the method for identified AF using Holter is a better approach and is introduced in many international electrophysiological centers. Furthermore, the sample size was relatively small. Thus, further studies in a larger group of patients are needed to confirm these findings.
CONCLUSIONS The present study suggests that CoQ10 as adjuvant treatment attenuates the incidence of AF. The mechanisms of the effect perhaps have relation with the reduced levels of MDA.
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REFERENCES 1. Nattel S, Opie LH. Controversies in atrial fibrillation. Lancet. 2006;367: 262–272. 2. Beyerbach DM, Zipes DP. Mortality as an endpoint in atrial fibrillation. Heart Rhythm. 2004;1:B8–B18. 3. Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996;93:704–711. 4. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143. 5. Nadar S, Blann AD, Lip GY. Endothelial dysfunction: methods of assessment and application to hypertension. Curr Pharm Des. 2004;10: 3591–3605. 6. Boos CJ, Lip GY. The role of inflammation in atrial fibrillation. Int J Clin Pract. 2005;59:870–872. 7. Engelmann MD, Svendsen JH. Inflammation in the genesis and perpetuation of atrial fibrillation. Eur Heart J. 2005;26:2083–2092. 8. Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001; 20:591–598. 9. Tran MT, Mitchell TM, Kennedy DT, et al. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy. 2001; 21:797–806. 10. Okello E, Jiang X, Mohamed S, et al. Combined statin/coenzyme Q10 as adjunctive treatment of chronic heart failure. Med Hypotheses. 2009;73: 306–308. 11. McCarty MF. Practical prevention of cardiac remodeling and atrial fibrillation with full-spectrum antioxidant therapy and ancillary strategies. Med Hypotheses. 2010;75:141–147. 12. Wang TJ, Larson MG, Levy D, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003;107:2920–2925. 13. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol. 2003;91:2D–8D. 14. Hynes BJ, Luck JC, Wolbrette DL, et al. Atrial fibrillation in patients with heart failure. Curr Opin Cardiol. 2003;18:32–38. 15. Deedwania PC, Lardizabal JA. Atrial fibrillation in heart failure: a comprehensive review. Am J Med. 2010;123:198–204. 16. Korantzopoulos P, Kolettis TM, Kountouris E. Inflammation and anti-inflammatory interventions in atrial fibrillation. Int J Cardiol. 2005; 104(3):361–362. 17. Tanaka T, Tsutamoto T, Nishiyama K, et al. Impact of oxidative stress on plasma adiponectin in patients with chronic heart failure. Circ J. 2008;72: 563–568. 18. Kumagai K, Nakashima H, Urata H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2197–2204. 19. Fazio G, Amoroso GR, Barbaro G, et al. The role of statins in preventing the progression of congestive heart failure in patients with metabolic syndrome. Curr Pharm Des. 2008;14:2605–2612. 20. Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol. 1998;31: 1352–1356. 21. Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators. 2Mol Aspects Med. 1994;15 Suppl:s287–s294. 22. Mortensen SA, Vadhanavikit S, Muratsu K, et al. Coenzyme Q10: clinical benefits with biochemical correlate suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue React. 1990;12: 155–162.
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23. Belch JJ, Bridges AB, Scott N, et al. Oxygen free radicals and congestive heart failure. Br Heart J. 1991;65:245–248. 24. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol. 2003;92:1343–1345. 25. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993;33: 226–229.
CoQ10 and Heart Failure
26. Bliznakov EG, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): a critical overview. Adv Ther. 1998;15:218–228. 27. Rundek T, Naini A, Sacco R, et al. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol. 2004;61:889–892. 28. Hargreaves IP, Duncan AJ, Heales SJ, et al. The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Saf. 2005;28:659–676.
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Effect of Coenzyme Q10 on the Incidence of Atrial Fibrillation in Patients With Heart Failure Qingyan Zhao, A. Hafid Kebbati, Yuguo Zhang, Yanhong Tang, Emmy Okello and Congxin Huang J Investig Med 2015 63: 735-739
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ORIGINAL ARTICLE
Effect of Coenzyme Q10 on the Incidence of Atrial Fibrillation in Patients With Heart Failure Qingyan Zhao, MD, PhD,* A. Hafid Kebbati, MD, PhD,* Yuguo Zhang, MBchB,† Yanhong Tang, MD, PhD,* Emmy Okello, MBChB,* and Congxin Huang, MD, PhD* Background: There is mounting evidence to support the influence of inflammation and oxidative stress in the pathogenesis of atrial fibrillation (AF) and heart failure (HF). The efficacy of coenzymeQ10 (CoQ10), an antioxidant used as an adjunct treatment in patients with AF and HF, remains less well established. Methods: Consecutive patients with HF were randomized and divided into 2 groups: the CoQ10 group (combined administration of common drugs and CoQ10) and the control group (administration of common drugs). Ambulatory electrocardiogram Holter monitoring (24 hours), Doppler echocardiography, and evaluation of inflammatory cytokines were performed before treatment and 6 and 12 months after treatment. Results: One hundred two patients (72 male and 30 female patients), with ages ranging from 45 to 82 years (mean age, 62.3 years), were examined. There was significant reduction in the level of malondialdehyde (3.9 ± 0.7 vs 2.5 ± 0.6 ng/mL; 3.9 ± 0.7 vs 2.3 ± 0.5 ng/mL, P < 0.05) in the CoQ10 group, whereas there was no significant difference (3.3 ± 0.8 vs 2.9 ± 0.8 ng/mL; 3.3 ± 0.8 vs 2.9 ± 0.5 ng/mL) in the control group after 6 and 12 months. Three patients (6.3%) in the CoQ10 group and 12 patients (22.2%) in the control group had episodes of AF after 12 months’ treatment (P = 0.02). Four patients with AF in the control group went through the third Holter recording. Conclusions: CoenzymeQ10 as adjuvant treatment in patients with HF may attenuate the incidence of AF. The mechanisms of the effect perhaps have relation with the reduced levels of malondialdehyde. Key Words: atrial fibrillation, coenzymeq10, heart failure, oxidative stress (J Investig Med 2015;63: 735–739)
I
n recent years, atrial fibrillation (AF) has increasingly become a focus of attention because it remains the most encountered arrhythmia in clinical practice and a major cause of morbidity and mortality.1,2 The fundamental mechanisms underlying AF have long been debated. However, to this day, the mechanisms have not been elucidated. There is an increasing body of evidence linking inflammation and oxidative stress to a broad spectrum of cardiovascular conditions, such as heart failure (HF), coronary artery disease, and hypertension.3–5 In addition, there are emerging data to support the association between inflammation and AF.6,7 This has created exciting potential opportunities to target inflammatory and oxidative stress processes for the prevention of AF and HF. From the Departments of *Cardiology and †Ultrasonography, Renmin Hospital of Wuhan University, Wuchang, Wuhan, People’s Republic of China. Received July 16, 2014, and in revised form March 16, 2015. Accepted for publication March 24, 2015. Reprints: Congxin Huang, MD, PhD, Cardiovascular Research Institute of Wuhan Unviersity, Renmin Hospital of Wuhan University, 238Jiefang Rd, Wuchang, Wuhan City, 430060, People’s Republic of China. E-mail: [email protected]. The authors have no conflicts of interest to disclose. Disclosures: None Q.Z. and A.H.K. are co–first authors. Copyright © 2015 by The American Federation for Medical Research ISSN: 1081-5589 DOI: 10.1097/JIM.0000000000000202
Studies have shown that coenzyme Q10 (CoQ10) plays a central role in mitochondrial oxidative phosphorylation and has an important effect on cellular adenosine triphosphate production.8 Normally, with increasing age and HF, the concentration of Q10 in the heart has been shown to fall considerably. Several observational and controlled prospective trials have demonstrated the efficacy of CoQ10 as adjunctive treatment of HF.9–11 However, whether chronic treatment with CoQ10 has an impact on the occurrence of AF remains unanswered. The objectives of the present study are first to assess the effects of CoQ10 on the occurrence of AF in the patients with HF and finally to evaluate the relation between the occurrence of AF and the inflammatory cytokines markers.
METHODS Patients This study has been performed with the subjects’ written informed consent. One hundred twenty-eight consecutive patients (90 men and 38 women, aged 60 ± 4 years) with HF of nonischemic origin were included in this study. Eligibility criteria included New York Heart Association functional status II-IV, left ventricular ejection fraction (LVEF) less than 40%, and patients needed to be on stable standard HF for 3 to 6 months before the study. Patients were excluded if they had AF before the study or renal or liver dysfunction. In addition, patients with acute HF, acute coronary syndrome, or HF of ischemic origin were also excluded from the study. Patients underwent a standard clinical examination and investigation including a standard 12-lead electrocardiogram (ECG), echocardiography, complete blood counts, electrolyte analysis, chest radiographs, and liver and renal function tests.
Study Design After the baseline evaluation, the patients were randomized and divided into 2 groups in a double-blind fashion and prospectively studied: the CoQ10 group (CoQ10: 30 mg/d, n = 62) and the control group (n = 66). The patients, physicians, echocardiography staff, laboratory, and the statistician were all blinded to the study. A 24-hour continuous ambulatory ECG monitoring, echocardiography, and checking of blood samples for high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and malondialdehyde (MDA) were performed on every patient, at study enrollment and after 6 and 12 months (the study end). Patients returned for 6- and 12-month follow-up evaluations, with phone calls every 2 weeks to ensure drug compliance.
Ambulatory ECG Holter Monitoring A 24-hour continuous ambulatory ECG monitoring was performed on every patient on 3 occasions: at the beginning of the study (days 1–7), after 6 months (days 185–192), and after
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TABLE 1. Clinical Characteristics of the Patients Control Group CoQ10 Group Patients Sex, male/female Age, y Hypertension Diabetes Hyperlipidemia LVEF, % LVED, mm LAD, mm Medication Digitalis ACE inhibitors AT1 blockers β-Blockers Calcium-channel blockers Dihydropyridines Nondihydropyridines Diuretics Nitrates Statins
P
54 38/16 62 ± 6 18 24 23 36 ± 4 60 ± 6 37 ± 4
48 34/14 63 ± 7 14 20 24 38 ± 3 58 ± 7 38 ± 3
1.00 0.44 0.68 0.84 0.55 0.08 0.17 0.16
30 32 22 50
24 28 20 47
0.69 1.00 1.00 0.37
12 8 50 5 54
8 10 42 6 48
0.62 0.45 0.22 0.75 —
Values are mean ± SD or number of patients. LAD indicates left atrial diameter; AT, angiotensin receptor.
12 months (days 362–369). The Holter monitoring was digitally recorded using Mars 3000 (Milwaukee, WI). After visual scrutiny and verification, all episodes meeting the criteria were manually measured and logged. Loss of P wave and irregular narrow ventricular rhythm for 30 seconds or more were regarded as an episode of AF.
Echocardiography and Laboratory Measurements Transthoracic Doppler echocardiography was performed using Vivid7 (GE, Wauwatosa, WI). The left ventricular enddiastolic diameter (LVED) and left atrial end-diastolic diameter were measured by conventional 2-dimensional parasternal longaxis view of the left heart. The LVEF was measured according to the biplane Simpson rule. Results were taken in triplicate and
averaged. The images were reviewed by an independent echocardiography expert. Four milliliters of venous blood was collected in EDTA Vacutainers in the morning after an overnight fast and centrifuged at 3000 revolutions per minute, for 10 minutes at 4°C (Avanti J-E; Beckman Coulter, Inc., Brea, CA). The serum was separated and kept in micro-tubes and stored at –80°C until assay. Proinflammatory markers TNF-α and IL-6 were measured using commercially available enzyme-linked immunosorbent assay kits (eBioscience, San Diego, CA). High-sensitivity C-reactive protein was measured using immunoprecipitation technique. Malondialdehyde was measured using rat anti-human immunoassay enzyme-linked immunosorbent assay (Adliattrem; Cusabio, Wuhan, Hubei, China). The proposal was approved by the university research and ethics committee. The study participants were handled according to the Declaration of Helsinki.
Statistical Analysis Continuous data are expressed as the mean ± SEM, and SPSS statistical software was used for the analysis. Statistical comparisons were made using analysis of variance. Paired and unpaired comparisons were conducted using the Student t test. Statistical significance was assumed if P < 0.05.
RESULTS Baseline Characteristics Patients (n = 128) with HF of nonischemic origin were enrolled in the study. Fourteen patients (8 patients in the control group and 6 patients in the CoQ10 group) died during follow-up and were excluded. Twelve patients were lost because their treatment was stopped by physicians at a local hospital. One hundred two patients (72 male and 30 female patients), with ages ranging from 45 to 82 years (mean age, 62.3 years), were examined, and their data were used to analyze the results. Baseline clinical data for these patients are summarized in Table 1. There was no difference between the 2 study groups at baseline.
Recording of AF The first, second, and third Holter recordings were performed in 128, 113, and 102 patients, respectively. Among the 113 patients who received their second Holter recordings, 58 patients were in the control group, and 55 patients were in the CoQ10 group.
FIGURE 1. Changes of hs-CRP in the 2 groups. There was a significant reduction in the level of hs-CRP after 6 and 12 months of treatment in the 2 groups.
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CoQ10 and Heart Failure
FIGURE 2. Changes of IL-6, TNF-α, and MDA in the 2 groups. Results showed that there was a significant reduction in the levels of IL-6 and TNF-α after 6 and 12 months of treatment in the 2 groups. There were no significant changes in the level of MDA after 6 and 12 months of treatment in the control group. However, the level of MDA decreased after 6 and 12 months of treatment in the CoQ10 group.
Among the 102 patients who received their third Holter recordings, 54 patients were in the control group, and 48 patients were in the CoQ10 group. In the second Holter recording, AF was recorded in 6 patients: 2 patients in the CoQ10 group and 4 patients in the control group (all the 6 patients had self-limited AF). In the third Holter recording, AF was recorded in 15 patients: 3 patients in the CoQ10 group (All the 3 patients had self-limited AF) and 12 patients in the control group (8 patients had self-limited AF, and 4 patients with AF went through the Holter recording). The incidence of AF was lower in the CoQ10 group than in the control group after 12 months. (6.3% vs 22.2%; P = 0.02).
MDA (3.9 ± 0.7 vs 2.5 ± 0.6 ng/mL) after 6 months of treatment. Furthermore, there was a significant increase in LVEF and a significant reduction in the LVED. However, the changes in LVEF and LVED have no significant difference after 6 and 12 months (Tables 2 and 3).
DISCUSSION
In the control group, the cohort of patients had significant reductions in hs-CRP (4.3 ± 2.6 vs 3.4 ± 1.8 mg/L, P < 0.05) (Fig. 1), TNF-α (3.3 ± 1.3 vs 2.2 ± 1.3 ng/mL, P < 0.05) (Fig. 2), improvement in LVEF (36 ± 4% vs 41 ± 6%, P < 0.05), and a decrease in LVED (60 ± 5 vs 55 ± 4 mm, P < 0.05) after 6 months’ treatment (Tables 2 and 3). There was a significant decrease in the level of IL-6 (3.5 ± 1.6 vs 2.5 ± 1.3 mg/L, P < 0.05) but no significant changes in the level of MDA (3.3 ± 0.8 vs 2.9 ± 0.5 mg/L, P > 0.05) (Fig. 2). Furthermore, compared with that after 6 months, the reductions in inflammatory markers (hs-CRP: 3.4 ± 1.8 vs 3.3 ± 1.3 mg/L; TNF-α: 2.2 ± 1.2 vs 2.1 ± 1.5 ng/mL; IL-6: 2.5 ± 1.3 vs 2.3 ± 1.5 mg/L; MDA: 2.9 ± 0.7 vs 2.8 ± 0.7 mg/L, P > 0.05) and LVED have no significant difference after 12 months. In the CoQ10 group, there was a significant reduction in the level of TNF-α (3.5 ± 1.2 vs 1.8 ± 0.9 ng/mL), IL-6 (3.4 ± 1.2 vs 2.4 ± 1.1 ng/mL), hs- CRP (4.2 ± 2.5 vs 2.0 ± 1.9 mg/L), and
The novel finding of the present study indicates that the oral CoQ10 supplementation in patients with HF had lower incidence of AF. These results suggest that long-term oral CoQ10 attenuates AF vulnerability in patients with HF. Atrial fibrillation and HF are 2 increasingly common cardiac disorders with a growing prevalence in the overall population.12 Atrial fibrillation is a common atrial arrhythmia in patients with HF caused by left ventricular dysfunction and is associated with significant morbidity and possibly increased mortality rates.13,14 The mechanisms by which HF promotes AF are incompletely understood. Studies have shown that their interaction involves complex ultrastructural, electrophysiologic, and neurohormonal processes that go beyond mere sharing of mutual risk factors.15 Clinical studies have shown that inflammation is an independent risk factor for the initiation and maintenance of AF.16 Furthermore, patients with HF remain plagued by a poor prognosis that is thought to be linked to underlying inflammation and oxidative stress. Chronic inflammation in HF is associated with raised circulating level of inflammatory cytokines. In addition to inflammation, HF is a high oxidative stress state in which high reactive oxygen species levels have been shown to correlate with depressed cardiac function.17 There is evidence supporting some of the drug therapies, such as the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and statins, which might
TABLE 2. Changes of LVEF in the 2 Groups (%, Mean ± SD)
TABLE 3. Changes of LVED in the 2 Groups (mm, Mean ± SD)
Changes of Inflammatory Markers and Echocardiography Measurements
Control Group (n = 54) CoQ10 Group (n = 48) Before treatment After 6 mo After 12 mo
36 ± 4* 41 ± 6 43 ± 5
*P < 0.05 vs after 6 and 12 months’ treatment.
37 ± 4* 44 ± 7 46 ± 6
Control Group (n = 54) CoQ10 Group (n = 48) Before treatment After 6 mo After 12 mo
60 ± 5* 55 ± 4 54 ± 4
58 ± 4* 54 ± 9 53 ± 3
*P < 0.05 vs after 6 and 12 months’ treatment.
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Zhao et al
be efficacious in the prevention of AF and beneficial for HF by modulating inflammatory pathways.18,19 CoenzymeQ10 is found in the highest concentration in the human myocardium, where it is involved in mitochondrial oxidative phosphorylation, resulting in adenosine triphosphate production, an important process for high energy requiring organs such as the heart.20 In addition, CoQ10 is involved in free radical scavenging, an effect that is linked to the increase in the level of SOD. The antioxidant CoQ10, which is found to have lower levels in HF patients, has been shown in recent studies to boost plasma ubiquinone levels when supplemented orally. The return to normal physiological levels of ubiquinone resulted in various dose-dependent actions in the heart including improvement in LVEF, reduction in LVED, and generally faster symptom improvement in patients with HF.21,22 However, the effect of combined administration of common drugs and CoQ10 on HF with AF has not been elucidated. In the present study, we observed that administration of common drugs (statins, ACE inhibitors, etc) could reduce the serum TNF and hs-CRP levels, but the level of MDA had no significant change after treatment. CoenzymeQ10 as adjuvant treatment not only reduced the levels of TNF and hs-CRP, but also reduced the level of MDA. Malondialdehyde is one of the small-molecular-weight fragments that occur when polyunsaturated fatty acids undergo oxidative stress by free radicals. Malondialdehyde itself may result in additional structural or functional damage because of its high chemical reactivity. In human beings, a previous study demonstrated higher levels of plasma MDA in HF patients.23 In this study, we found that the incidence of AF was lower in the CoQ10 group than in the control group after 12 months, and the level of MDA was lower in this group. The results indicate that CoQ10 as adjuvant treatment has the beneficial effect of reducing the occurrence of AF in patients with HF by reducing the serum MDA level. There is now compelling evidence that statins therapy may attenuate the effect of inflammation, and several studies showed favorable effects of statins to reduce the incidence of AF.24 Most of the early studies on statins/CoQ10 interactions focused on the effect of statins on CoQ10 levels, and its relationship with statins induced myopathy.25,26 Almost one half of the studies found that statins significantly decreased CoQ10 levels.27,28 In our study, our results showed that CoQ10 as adjuvant treatment is more efficacious than statins alone. Although CoQ10 as adjuvant treatment reduced the levels of inflammatory cytokines markers after 6 months, there was no difference in the incidence of AF. After 12 months, incidence of AF in CoQ10 group was higher than in the control group. This result implied that HF patients could benefit from long-term use of CoQ10 because it reduces the occurrence of AF.
Limitations Our study has several limitations. Before and after follow-up, AF was identified by Holter. The diagnosis could have been missed in some patients with transient episodes of AF. This would have confounded the results and lowered the AF estimates. However, the method for identified AF using Holter is a better approach and is introduced in many international electrophysiological centers. Furthermore, the sample size was relatively small. Thus, further studies in a larger group of patients are needed to confirm these findings.
CONCLUSIONS The present study suggests that CoQ10 as adjuvant treatment attenuates the incidence of AF. The mechanisms of the effect perhaps have relation with the reduced levels of MDA.
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CoQ10 and Heart Failure
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Effect of Coenzyme Q10 on the Incidence of Atrial Fibrillation in Patients With Heart Failure Qingyan Zhao, A. Hafid Kebbati, Yuguo Zhang, Yanhong Tang, Emmy Okello and Congxin Huang J Investig Med 2015 63: 735-739
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