Crystal

Vasquez NFSC440: Advanced Human Nutrition Evidence Analysis Assignment: Final December 11, 2012 Evidence Question: What is the relationship between coenzyme Q10 intake and inflammatory markers? Lee B, Huang Y, Chen S, Lin P. Effects of coenzyme Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in patients with coronary artery disease. J Nutr. 2012; 28:767-772 Shargorodsky M, Debby O, Matas Z, Zimlichman R. Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. Nutr Metab. 2010; 7:55 Gokbel H, Gergerlioglu H, Okudan N, Gul I, Buyukbas S, Belviranli M. Effects of coenzyme Q10 supplementation on plasma adiponectin, interleukin-6, and tumor necrosis factor- levels in men. J Med Food. 2010; 13:216-218 Senes M, Erbay A, Yilmaz F, et al. Coenzyme Q10 and high-sensitivity C-reactive protein in ischemic and idiopathic dilated cardiomyopathy. Clin Chem Lab Med. 2008; 46(3):382-386

What is the relationship between coenzyme Q10 intake and inflammatory markers?
RCTs with subjects with CAD or risk factors for CAD In a randomized, parallel, placebo-controlled study, Lee et al (2012) examined 40 patients with coronary artery disease from a teaching hospital in central Taiwan over a 12-week period and found that following coenzyme Q10 supplementation at a dose of 150mg (n=14) decreased inflammatory markers IL-6 by 14% (r=-.25, p=0.03) in patients with CVD verses the coenzyme Q10 supplementation of 60mg (n=14) and a placebo (n=12). Coenzyme Q10 supplementation had no significant effect on homocysteine levels. Supplementation groups and placebo group were well matched at baseline; participants of this study were not taking statins, vitamins or hormone therapy. Limitations of this study included small sample size and reporting of results was limited (a graph was provided, however, numerical data was not provided). Further studies are necessary to determine effects of higher dosage coenzyme Q10 supplementation on patients with CVD. In a randomized, placebo-controlled trial, Shargorodsky et al (2010) examined 66 patients (33 patients in the supplementation group and 33 in the placebo group) with at least two CVD risk factors from E. Wolfson Medical Center Outpatient Clinic and found that after 6- months of antioxidant supplementation (500mg/day vitamin C, 200 iu/day vitamin E, 60mg/d coenzyme Q10, 100 mcg/d selenium) arterial elasticity index increased (LAEI 12.7 4.7 / SAEI 4.7 2.7) and blood pressure lowered (136.122.3/75.0 2.3), however there were no significant changes in CRP levels. Baseline data for the supplementation group LAEI 11.04.4, SAEI 3.3 1.9, and blood pressure 145.2 25.4/78.4 11.7. Participants of the study were similar in all aspects of health, except baseline HDL % was higher in the placebo group. Limitations of the study included activity level and dietary habits of the participants; also description of how blood plasma levels were measured was missing from the study. RCT with sedentary but healthy subjects In a randomized, double blind, crossover trial, Gokbel et al (2010) examined 14 healthy, nonsmoking, sedentary men and found that after 8-weeks of coenzyme Q10 supplementation of 100mg/day or placebo there was no significant effect on inflammatory markers adiponectin and TNF-. IL-6 levels increased (baseline level 100.913.0 pg/ml) in both the supplementation group (124.9 36.0pg/ml) and placebo group (133.8 38.2 pg/ml), no explanation was given as to why IL-6 levels increased in both group. Other limitations to the study included defining healthy and sedentary, CoQ10 plasma levels were not measured prior to the start of the study and lifestyle habits and age of participants was not mentioned. Cross sectional study of patients with cardiomyopathy In a cross-sectional study, Senes et al (2008) studied levels of plasma antioxidants in patients with ischemic dilated cardiomyopathy (ISCMP) (n=17) or idiopathic dilated cardiomyopathy (IDCMP) (n=11), control group included patients who had been

hospitalized for chest pain with normal coronary arteries and were without heart failure (n=28) and found that the patients with ISCMP or IDCMP had decreased antioxidant status compared to patients without cardiomyopathy (CMP). They found no significant differences between the ISCMP groups and IDCMP groups. Levels of coenzyme Q10 in the CMP groups were 411g 38 g verses the control group 544g 33g. There was a negative relationship between CoQ10 levels and Hs-CRP in the CMP group (r=-0.387, p=0.003). It was determined that patients with CMP have lower antioxidant status and CoQ10 can be used as biomarkers. Limitations of this study include: small sample size, supplements taken by participants, and age range did of participants did not closely match the age range of the controlled group. Cross-sectional studies do not allow for cause and effect. Conclusion Findings on coenzyme Q10 supplementation in patients with CVD and CVD risk factors are mixed. However, it appears that higher dosages (150mg/day) may slightly decrease (14%) inflammatory marker interleukin-6 after 12-weeks supplementation. One trial using lower doses (100 mg/day) for 8 weeks showed no change in TNF- and IL-6. It is difficult to know the exact effect of lower dosages of Q10 (60mg/day), when combined with other antioxidants, though it appeared that this dosage has no effect. There are weak correlations of Q10 supplementation on IL-6 levels (-.25) and on CRP levels (-.38). Grade II: Fair

Citation

AND Evidence Analysis Worksheet Lee B, Huang Y, Chen S, Lin P. Effects of coenzyme Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in patients with coronary artery disease. J Nutr. 2012; 28:767-772 Randomized controlled trial (RCT) A To assess the influence that coenzyme Q10 has on inflammatory markers in patients with coronary artery disease Patients having at least 50% stenosis of one major coronary artery by cardiac catheterization Patients that had percutaneous transluminal coronary angioplasty Patients with diabetes, liver or renal disease Patients taking statins or vitamin supplements Study design: randomized, parallel, placebo-controlled study Recruitment: patients with CAD (coronary artery disease) from teaching hospital in central Taiwan 51 subjects participated, 4 of whom were postmenopausal women (who were not taking hormonal supplements) Intervention: Placebo group (n=14), 60mg/d Q10-supplementation group (n=19), and 150mg/d Q-10-supplementation group (n=18) 12-weeks, one capsule per day Information measured at baseline: age, blood pressure, smoking habits, body weight, height and BMI Outcome measurement: Blood samples obtained prior to supplementation and again after 12weeks of supplementation Subjects analyzed: placebo group (n=12), 60mg/d Q-10 group (n=14), 150mg/d Q-10 group (n=14) (decrease in number of subjects due to discontinuation from intervention) Fasting venous blood samples were taken, measured using chemical assays at baseline and analyzed for: Independent variable: plasma coenzyme Q10 Dependent variables hs-CRP plasma interleukin-6 level (IL-6) plasma homocysteine plasma malaondialdehyde (MDA) superoxide dismutase (SOD) Control variables: serum urea nitrogen serum creatinine total cholesterol

Study Design Class Research Purpose Inclusion Criteria

Exclusion Criteria Description of Study Protocol

Data Collection Summary

Summary of Results

triacyglycerol low-density lipoprotein high-density lipoprotein Statistic methods used: Differences between groups: Tukey post hoc test Data within each group: paired t test Relation of coenzyme Q10 concentration to inflammatory markers and MDA/SOD levels, before and after supplementation: Pearson productmoment correlation There was no significant difference between participants in age, BMI, blood pressure, anthropometric measurements, hematologic entities and smoking habits between the three intervention groups. After 12-week intervention plasma coenzyme Q10 levels significantly increased at 60mg/d and 150mg/d dosages, but not in the placebo group. In the in the Q10-150 mg/d group only, Inflammatory marker IL-6 significantly decreased at week 12 MDA levels were significantly lower at week 12 SOD activity increased in the Q10-60mg/l group and Q10-150mg/d group at week 12. SOD levels lowered significantly in the placebo group at week 12. No significant change in any of the three groups in homocysteine and Hs-CRP levels. Correlations between coenzyme Q10 plasma levels and inflammatory markers (Significant data reported for participants receiving supplementation, P value <0.05) Before supplementation: IL-6 had a negative correlation with coenzyme Q10 levels (r = -.25, P = 0.03) After 12-weeks of supplementation: MDA had a negative correlation with coenzyme Q10 levels (r= -.35, P<0.01) SOD had a positive correlation with coenzyme Q10 levels (r= .52, P<0.01) Coenzyme Q10 supplementation of 150 mg may decrease the inflammatory marker IL-6 by 14 % in patients with CAD. However, there is no significant correlation between coenzyme Q10 supplementation and homocysteine levels. Concerns that affect study validity and generalizability: Dietary patterns of subjects (past and present), Past activity levels of patients Severity of patients CVD Length of time since surgery Strengths: Good background information on the role of coenzyme Q10 in

Author Conclusion Reviewer Comments

introduction. Good explanation of inflammatory markers in discussion. Weaknesses/Limitations: Reminding patients to check that all pills were gone every 4 weeks monitored compliance. However, it does not mention if all subjects analyzed complied 100% of the study. 8 subjects discontinued the intervention, but the reason was not stated. 3 subjects from were excluded from analysis, but the reason was not stated. A graph of results was provided, however, actual results from blood test of coenzyme Q10 plasma levels, hs-CRP, IL-6, homocysteine, MDA, and SOD levels was not provided. Funding source: National Science Council, Taiwan

Citation

Study Design Class Research Purpose Inclusion Criteria

Exclusion Criteria Description of Study Protocol

AND Evidence Analysis Worksheet Gokbel H, Gergerlioglu H, Okudan N, Gul I, Buyukbas S, Belviranli M. Effects of coenzyme Q10 supplementation on plasma adiponectin, interleukin-6, and tumor necrosis factor- levels in men. J Med Food. 2010; 13:216-218 Randomized Crossover Trial A To determine the effects of Coenzyme Q10 supplementation on plasma levels of inflammatory markers in sedentary men. Male Healthy Non-Smoking Sedentary None mentioned Study design: randomized, double-blind, crossover trial Subjects: 14 healthy, nonsmoking, sedentary men Blood samples collected from all participants prior to start of study Participants randomly assigned into two groups One group received 100 mg/day of coenzyme Q10 (n=7) Other group received a placebo (n=7) After 8 weeks, another blood sample was collected After a 4-week washout period, group that received supplementation was given a placebo and placebo group was given coenzyme Q10 supplements. After 8 weeks, another blood sample was collected Prior to each blood sampling, body weight and fat percentage of each participant was measured Blood samples were taken and analyzed using ELISA kits Independent variable: Co-Q10 supplementation Dependent variables: Adiponectin IL-6 TNF- Control variables: Body weight Body fat percentage Statistic methods used: All data presented as SD values IL-6 and TNF- assessed by Wilcoxons signed-rank test Adiponectin levels assessed by t test

Data Collection Summary

Summary of Results

Body Weight & Body Fat Percentage of Participants Beginning Placebo CoQ10 Body Weight 72.2 13.0 73.0 13.5 73.3 13.7 (kg) Body Fat 13.9 4.5 14.2 4.7 14.3 4.8 Percentage (%) No significant difference in body weight or body fat percentage among participants. Values of Blood Plasma Levels Beginning Placebo CoQ10 Adiponectin 37.9 2.1 37.6 2.6 38.3 1.5 (g/mL) IL-6 (pg/mL) 100.9 13.0 133.8 38.2* 124.9 36.0* TNF- (pg/mL) 1.09 0.14 1.05 0.05 1.10 0.16 CoQ10 and placebo supplementation had no significant effect on adiponectin levels or TNF- levels IL-6 levels were significantly increased in both CoQ10 supplementation and placebo supplementation. * = Significant value Mean SD values (n=14) Values of P <.05 considered significant

Author Coenzyme Q10 supplementation does not effect the plasma levels of Conclusion adiponectin, IL-6, and TNF- in sedentary men. Reviewer Concerns that affect study validity and generalizability: Comments Small sample size Note strengths and Age of participants unclear limitations of the study (beyond Strengths: what appears in the Study was done on healthy participants, rather than patients who have study). Indentify been diagnosed with CVD. concerns that Study design (randomized, double-blind, crossover trial) affect study validity and Weaknesses/Limitations: generalizability. Definition of sedentary also unclear does this mean no activity or Funding source low activity, also what about lifestyle activity (for example: construction worker vs. office worker) Definition of healthy was not stated Dietary patterns of men prior to and during supplementation CoQ10 status of participants was not measured before starting supplementation. No explanation given as to why IL-6 levels increased in both groups. Funding source: not mentioned, however article states, no competing financial interests exist.

Citation

Study Design Class Research Purpose

Inclusion Criteria

Exclusion Criteria

Description of Study Protocol

AND Evidence Analysis Worksheet Shargorodsky M, Debby O, Matas Z, Zimlichman R. Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. Nutr Metab. 2010; 7:55 Randomized controlled trial (RCT) A To assess the effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial elasticity, inflammatory and metabolic measures in patients with multiple cardiovascular risk factors Patients having at least two of the following cardiovascular risk factors o Hypertension o Diabetes o Low HDL cholesterol levels o Current cigarette smoking Patients with a history of unstable angina, MI, CVA or surgery within the past 6 months Unbalanced endocrine disease or any disease that might affect absorption of medications Patients with plasma creatinine >2mg/dl Elevation of liver enzymes more than twice the upper normal limit Patients with electrolyte abnormalities Study Design: Randomized, placebo-controlled trial Recruitment: 70 patients were recruited from E. Wolfson Medical Center Outpatient Clinic having 2 or more risk factors for CVD (see above) Screening procedures: physical exam, blood chemistry, complete blood count, urinalysis and electrocardiogram Intervention: Group 1 (n=36) received oral daily supplementation of vitamin C (500 mg), vitamin E (200 iu), coenzyme Q10 (60 mg) and selenium (100 mcg). Group 2 (n=34) received a placebo. 6 months, two capsules per day Measured at Baseline: age, sex, BMI, status of above risk factors for CVD, dyslipidemia, obesity, family history of IHD, concomitant medication, endothelin levels Patients were stabilized on their previous medical treatments Patients concomitant medications were kept stable Outcome measurement: Blood pressure, arterial elasticity measurements and blood samples obtained prior to supplementation and after 6-months of supplementation Independent variable: supplementation of vitamin C, vitamin E, coenzyme Q10 and selenium.

Data Collection Summary

Dependent variables (Measured at baseline, 3-month and 6-months): Blood pressure LAEI (large arterial elasticity index) SAEI (small arterial elasticity index) SVR (systemic vascular resistance) Arterial compliance measures were measured using a pressure transducer amplifier system. Measurements taken after an overnight fast and before blood sampling between 8-10 am in a quiet temperature controlled room. Dependent variables (Measured at baseline and 6-months): Fasting glucose HbA Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Hs-CRP Homocysteine Renin Aldosterone Urine cathacholamines Blood was analyzed using standard methods. Statistic methods used: Descriptive statics calculated and reported as mean standard deviation for continuous variables (arterial compliance parameters, biochemistry data) Normalcy of distribution of continuous variables using KolmogorovSmirnov test Frequency distributions for categorical variables T-test for independent samples to compare continuous variables by treatment group Categorical variables compared by treatment group using chi square test General linear modeling used to compare post-treatment continuous variables All tests two-sided, significant P <0.05 Supplementation and placebo groups are similar in age, sex, BMI, presence of CVD risk factors, baseline blood pressure, baseline arterial elasticity parameters, and concomitant medications were similarly distributed. The placebo group had higher baseline HDL% and higher baseline triglycerides at the beginning of the trial. After 6-month supplementation, the following significantly improved in the group receiving antioxidant supplementation:

Summary of Results

Author Conclusion Reviewer Comments

o Systolic BP lowered: 145.2 25.4 to 136.1 22.3 (p-value 0.001) o Diastolic BP were lowered: 78.4 11.7 to 75.0 12.3 (p-value 0.034) o LAEI increased: 11.0 4.4 to 12.7 4.7 (p-value 0.006) o SAEI increased: 3.3 1.9 to 4.7 2.7 (p-value 0.0001) o HbA1C decreased: 7.08 1.69 to 6.33 2.3 (p-value 0.022) o HDL% increased: 22.1 4 to 26.2 10 (p-value 0.022) After 6-month supplementation, there were no significant changes in humoral factors or inflammatory markers No significant changes in placebo group Antioxidant supplementation increased arterial elasticity index and lowered blood pressure in patients with multiple CVD risk factors. There was a beneficial effect on glucose levels and lipid metabolism. Concerns that affect study validity and generalizability: Dietary patterns of subjects Activity levels of subjects Strengths: Good explanation of the individual antioxidants and previous findings regarding effects of individual supplementation of antioxidants in the discussion Detailed explanation of how arterial elasticity measurements were taken Weaknesses/Limitations: Description of blood test methods were not described Funding source: not listed

AND Evidence Analysis Worksheet Citation Senes M, Erbay A, Yilmaz F, et al. Coenzyme Q10 and high-sensitivity Creactive protein in ischemic and idiopathic dilated cardiomyopathy. Clin Chem Lab Med. 2008; 46(3):382-386 Study Design Cross-sectional study Class D Research Purpose Study the levels of plasma antioxidants, such as CoQ10, albumin and total thiol groups in patients with ischemic and idiopathic dilated cardiomyopathy. Inclusion Criteria Patients with cardiomyopathy o Ischemic dilated cardiomyopathy (ISCMP) o Idiopathic dilated cardiomyopathy (IDCMP) o All patients had dilated CMP o All patients had coronary angiography in the last 6 months Control Group o Patients who were hospitalized for chest pain with normal coronary arteries and without heart failure Exclusion Patients who had evidence of: hypertension, rheumatic, congenital, Criteria infectious, pericardial disease, valvular heart disease, mitral valve prolapse, or hypertrophic CMP, clinical signs of acute ischemia or angina were excluded. Description of ISCMP group included patients that had an obstruction of >70% in one Study Protocol or more of the epicardial coronary arteries o n=17 o Ages 18-76 years o 14 men and 3 women o 2 patients taken statins IDCMP group had no obstruction or an obstruction of <50% o n=11 o Ages 18-69 o 7 men and 4 women o No underlying cause that could lead to CMP o 2 patients taking statins Control group o n=28 o Ages 30-71 o 12 men and 16 women o 6 patients taking statins Physical exam and anamnesis, radiological exam, biochemical and hematologic tests performed on all patients. Severity of heart failure was assessed All patients taking medications

Data Collection Summary

Independent variable: Patients cardiomyopathy status Dependent variables: CoQ10 T-SH Albumin Uric Acid Total bilirubin hs-CRP Fibrinogen Total cholesterol Triglyceride HDL-cholesterol LDL-cholesterol Urea Creatinine Hemoglobin Hematocrit Blood was drawn in the morning of the second day of hospitalization in the patient group Blood was drawn in the morning of the second day of coronary angiography in the control group Venous blood samples were drawn from antecubial vein into o Vacutainer tubes with serum separator gel o Citrate-containing tubes o Whole blood tubes with EDTA Samples were processed immediately o Sera was separated and aliquoted o Albumin, uric acid, urea, creatinine, total bilirubin and lipid profile (cholesterol, triglycerides, HDL, LDL) was done on a Modular D+P analyzer o T-SH concentrations were determined based on reactions between SH groups and Ellmans reagent o CoQ10 concentration determined with isoctatic HPLC system o Measured as oxidized Q10 o Hs-CRP concentrations measured by Immage nephelometer o Plasma fibrinogen concentrations by Dade Behring reagents o Hemocrit and Hemoglobin levels with Coulter LH 70 hematology analyzer

Statistic methods used: Equality of variances controlled by Levenes test Differences between groups compared using Mann-Whitney test P-value of <0.05 considered significant

Summary of Results

Author Conclusion Reviewer Comments

There were no significant differences between the ISCMP group and the IDCMP group except: Creatinine 12711 (ISCMP) and 8815 (IDCMP) (p=0.008) In the CMP groups verses the control group the following was higher: Urea 26.5 2.8 (CMP) and 12.1 0 (Control) (P-value <0.01) Creatinine 112 10 (CMP and 70 3 (Control) (P-value <0.01) Uric acid 552 45 (CMP) and 355 13 (Control) (P-value <0.01) Inflammatory markers o Hs-CRP30.1 8.5 (CMP) and 4.0 0.7 (Control) (P-value <0.01) o Fibrinogen 3.74 0.20 (CMP) and 3.21 0.12 (Control) (P-value <0.05) The CMP groups had decreased levels of the following compared to the control group: CoQ10 411 38 (CMP) and 544 33 (Control) (P-value <0.05) Albumin 34.2 1.0 (CMP) and 43.40.6 (Control) (P-value <0.01) T-SH 297 15 (CMP) and 354 12 (Control) (P-value <0.01) Cholesterol 3.580.22 (CMP) and 4.700.44 (Control) (P-value <0.05) o HDL 0.900.05 (CMP) and 1.100.05 (Control) (P-value <0.05) o LDL 2.220.18 (CMP) and 2.820.17 (Control) (P-value <0.01) Triglycerides 1.010.07 (CMP) and 1.490.13 (Control) (P-value <0.05) Negative correlations were found between CoQ10 levels and Hs-CRP (r= -0.387, p=0.003) Evidence of decreased antioxidant status was determined in patients with CMP with vascular inflammation. CoQ10, T-SH, albumin, hs-CRP and fibrinogen are biomarkers, which can be used to access antioxidant status of patients and inflammation in patients with CHF. Concerns that affect study validity and generalizability: Small sample size Dietary patterns of subjects or control group was not mentioned Activity level of subjects and control group was not mentioned Week study design: Does disease state cause decreased CoQ levels and increased CRP levels or increased CoQ levels? Strengths: Good explanation of how factors were measured to allow for reproduction of study Weaknesses/Limitations: Range of sex and age of participants was large (18-76) and did not closely match control group (30-71). Status of a healthy 18 year old could vary compared to a 30 year old. Cross-sectional analysis does not allow for cause and effect Study lists medications, but not supplements (if any) taken by participants Funding source: not listed