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Randomized, double-blinded, controlled trial of the effects of coenzyme Q10 supplementation on plasma coenzyme Q10 concentration in dogs with myxomatous mitral valve disease

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  • 1 Small Animal Clinic, University of Ljubljana, 1000 Ljubljana, Slovenia.
  • | 2 Institute of Food Safety, Feed and Environment, University of Ljubljana, 1000 Ljubljana, Slovenia.

Abstract

OBJECTIVE

To determine the dose of coenzyme Q10 (CoQ10) needed to achieve at least a 3-fold increase in plasma CoQ10 concentration in dogs with myxomatous mitral valve disease (MMVD) and congestive heart failure (CHF).

ANIMALS

18 dogs with CHF due to MMVD and 12 healthy dogs.

PROCEDURES

In a randomized, double-blinded, controlled trial, dogs with MMVD were given 50 or 100 mg of water-soluble CoQ10 (ubiquinone; total daily dose, 100 mg [n = 5] or 200 mg [6]) or a placebo (7), PO, twice a day for 2 weeks in addition to regular cardiac treatment. Plasma CoQ10 concentration was measured in dogs with MMVD before (baseline) and at various time points after supplementation began and in healthy dogs once. Concentrations were compared among and within groups.

RESULTS

No significant difference in median baseline plasma CoQ10 concentration was detected between healthy dogs and dogs with MMVD. Fold increases in plasma CoQ10 concentrations ranged from 1.7 to 4.7 and 3.2 to 6.8 for individual dogs in the 100-mg and 200-mg groups, respectively. The change in plasma CoQ10 concentration after supplementation began was significantly higher than in the placebo group at 4 hours and 1 and 2 weeks for dogs in the 200-mg group and at 1 and 2 weeks for dogs in the 100-mg group.

CONCLUSIONS AND CLINICAL RELEVANCE

A daily CoQ10 dose of 200 mg was sufficient to achieve at least a 3-fold increase in plasma CoQ10 concentration and may be used in CoQ10 supplementation studies involving dogs with CHF due to MMVD.

Abstract

OBJECTIVE

To determine the dose of coenzyme Q10 (CoQ10) needed to achieve at least a 3-fold increase in plasma CoQ10 concentration in dogs with myxomatous mitral valve disease (MMVD) and congestive heart failure (CHF).

ANIMALS

18 dogs with CHF due to MMVD and 12 healthy dogs.

PROCEDURES

In a randomized, double-blinded, controlled trial, dogs with MMVD were given 50 or 100 mg of water-soluble CoQ10 (ubiquinone; total daily dose, 100 mg [n = 5] or 200 mg [6]) or a placebo (7), PO, twice a day for 2 weeks in addition to regular cardiac treatment. Plasma CoQ10 concentration was measured in dogs with MMVD before (baseline) and at various time points after supplementation began and in healthy dogs once. Concentrations were compared among and within groups.

RESULTS

No significant difference in median baseline plasma CoQ10 concentration was detected between healthy dogs and dogs with MMVD. Fold increases in plasma CoQ10 concentrations ranged from 1.7 to 4.7 and 3.2 to 6.8 for individual dogs in the 100-mg and 200-mg groups, respectively. The change in plasma CoQ10 concentration after supplementation began was significantly higher than in the placebo group at 4 hours and 1 and 2 weeks for dogs in the 200-mg group and at 1 and 2 weeks for dogs in the 100-mg group.

CONCLUSIONS AND CLINICAL RELEVANCE

A daily CoQ10 dose of 200 mg was sufficient to achieve at least a 3-fold increase in plasma CoQ10 concentration and may be used in CoQ10 supplementation studies involving dogs with CHF due to MMVD.

Introduction

Coenzyme Q10, also known as ubiquinone, is the only lipid-soluble antioxidant synthesized endogenously in humans and other animals and is an essential electron and proton carrier in the mitochondrial respiratory chain.1–3 This coenzyme is present in both reduced (CoQ10H2 or ubiquinol) and oxidized (CoQ10 or ubiquinone) forms, with the reduced form having antioxidant properties. In its reduced form, CoQ10 effectively regenerates other antioxidants such as vitamin E and ascorbate.1 Coenzyme Q10 can also be found in certain foods and may be used as a nutritional supplement for humans with cardiovascular and other diseases (eg, neurodegenerative and neuromuscular disorders, mitochondrial cytopathy, diabetes, cancer, and periodontal disease) as well as for the elderly.4–6

In humans, plasma and myocardial CoQ10 deficiencies increase with the severity of heart failure.7 Moreover, a low plasma CoQ10 concentration independently predicts death in those with chronic heart failure.8 Indeed, a meta-analysis9 of clinical trials revealed that humans with heart failure receiving CoQ10 supplementation had a lower mortality rate and greater improvement in exercise capacity than did their placebo-treated counterparts.9 Numerous studies of the effects of CoQ10 supplementation have been conducted in humans with cardiovascular diseases, and several of them show clinical benefits.6,10,11,12,13 Coenzyme Q10 supplementation improved left ventricular systolic function in humans with advanced CHF in 1 study,14 and the investigators suggested that at least a 3-fold increase in baseline plasma CoQ10 concentration is necessary for the biological effects of CoQ10 supplementation to be appreciated.14

In contrast, studies of CoQ10 supplementation in dogs with cardiovascular disease are lacking. In the only study15 we identified of CoQ10 supplementation in dogs with naturally acquired heart disease, a daily dose of 200 mg was used. Research in human medicine suggests that the effectiveness of CoQ10 supplementation in the treatment of cardiovascular diseases increases as the dose increases and that the widely used dose of 100 mg/d is suboptimal.16 To our knowledge, no dose-evaluation studies have been conducted in dogs, and the dose required to achieve a 3-fold increase in plasma CoQ10 concentration in dogs is unknown. Therefore, the goal of the study reported here was to determine the dose of CoQ10 (ubiquinone) sufficient to achieve a 3-fold increase in plasma CoQ10 concentration in dogs with CHF due to MMVD.

Materials and Methods

Animals

Dogs presented for cardiac examination (ie, cardiac patients) or health assessment (control dogs) to the Small Animal Clinic of the University of Ljubljana from November 2018 to April 2019 were recruited for the study by 2 of the authors (ADP and ND). During this recruitment period, 90 dogs with cardiovascular disease and 28 healthy dogs were assessed for eligibility. For all dogs, owners completed a questionnaire regarding their dog's diet, including any nutritional supplements and treats and any medications administered.

Only dogs with stable CHF and MMVD (ACVIM classification stages C and D17) that were already receiving long-term treatment for heart failure were eligible for inclusion in the MMVD group. The diagnosis of MMVD was based on results of clinical examination, echocardiography, and thoracic radiography, with all assessments performed by an experienced veterinary cardiologist (ADP). Dogs were excluded from this group if they had ACVIM stage B1 or B2 MMVD, unstable CHF, untreated CHF, or comorbidities (including concomitant systemic disease); had received any nutritional supplements within the past month or any medications not related to CHF treatment; or were very small or had other characteristics that caused difficulty in blood sample collection and potential compromise of the dog's status. Only healthy dogs of small or medium breeds that were > 5 years of age were eligible for inclusion in the control group. Healthy was defined on the basis of results of clinical examination, echocardiography, CBC, WBC differential count, and serum biochemical analysis.

Owner consent was obtained for all included dogs. All procedures complied with applicable Slovenian governmental regulations (Animal Protection Act, the Official Gazette of the Republic of Slovenia, 43/2007).

Study design

In a randomized, double-blinded, controlled trial, dogs with MMVD were randomly assigned to 3 subgroups (2 CoQ10 groups and 1 placebo group) by an individual (ANS) uninvolved in patient assessment, diagnostic procedures, treatment, supplement administration, or plasma CoQ10 concentration measurements. Dogs assigned to the CoQ10 groups received CoQ10,a PO, in an amount (1.333 or 2.667 g) calculated to provide a total daily dose of 100 or 200 mg of CoQ10, divided into 50 or 100 mg twice a day for 2 weeks in addition to their regular cardiac treatment. Dogs in the placebo group received the placebo, PO, at the same frequency and for the same duration as the CoQ10 groups. To ensure blinding, treatments were prepared in syringes (2 syringes/d) containing a water-soluble form of CoQ10a (ubiquinone; 7.5% water suspension of CoQ10b in the form of an inclusion complex with β-cyclodextrin produced in accordance with a previously filed patent18) or color-matched placeboc (a solution of methylcellulose [1.5%] and yellow food coloring) and packaged in sequentially numbered sealed bags by the same individual who performed the randomization. Dog owners, veterinarians, and those performing plasma CoQ10 concentration measurements were blinded to the study treatment. Owners were instructed to administer the packaged treatments, PO, twice a day (in the morning and in the evening) for 2 weeks.

Jugular or cephalic venous blood samples for plasma CoQ10 measurements in dogs with MMVD were collected into tubes containing lithium heparin before (baseline) and at 4 hours and 1 and 2 weeks after study treatment began and 1 week after the last dose was administered. Blood samples were similarly collected once from healthy dogs. Food was withheld from all dogs for 12 hours prior to sample collection. Collected samples were immediately centrifuged at 1,500 × g for 15 minutes at 4°C. Plasma was separated and immediately stored at −80°C until analysis.

Determination of plasma CoQ10 concentrations

To determine plasma total CoQ10 concentration, a modified procedure including oxidation with 1,4-benzoquinoned was used.19,20 Each plasma sample was thawed at room temperature (approx 21°C). A 100-μL portion was transferred to a 1.5-mL microcentrifuge tube, and 100 μL of 1,4-benzoquinoned in 1-propanold (0.4 mg/mL) was added. Samples were vortexed and incubated at room temperature for 15 minutes to achieve complete oxidation of CoQ10. Sample components were precipitated with 400 μL of 1-propanol.d Tubes were capped, vortexed well, and centrifuged for 5 minutes at 10,000 × g and 4°C. The supernatant was transferred to vials.

Measurement of CoQ10 concentrations was performed by use of matrix-matched calibration. The concentration range for the calibration curve was 10 to 4,000 ng of CoQ10/mL. This analysis was performed on a liquid chromatography–tandem mass spectrometry system.e Chromatographic separation was performed at 40°C on a C18 (1.7 μm; 2.1 × 50 mm) column.f The mobile phase consisted of an 80:20:0.1 mixture of acetonitriled:2-propanold:formic acidg in isocratic elution mode. Flow rate and injection volume were 0.4 mL/min and 7.5 μL, respectively. Multiple reaction monitoring transitions at an m/z of 863.8 to 197.1 and of 882.8 to 81.0 were chosen for the determination of CoQ10.

Statistical analysis

Data were analyzed with statistical software.h,i To test whether the data were normally distributed, histograms were generated and the Shapiro-Wilk test was performed. On the basis of the findings, parametric tests or nonparametric tests were used to compare data among and within groups of dogs. Accordingly, 1-way ANOVA with the post hoc Tukey honestly significant difference test and independent t test were used for comparisons involving body weight and age. The Wilcoxon rank sum test was used to compare baseline plasma CoQ10 concentration between all MMVD patients and healthy dogs. The Kruskal-Wallis test followed by pairwise Wilcoxon rank sum tests was used to compare baseline plasma CoQ10 concentrations between all 4 groups of dogs and to compare values between the 3 MMVD subgroups at each of the 5 blood sample collection times.

Differences (changes) from baseline in plasma CoQ10 concentrations at each time point after supplementation began were calculated for each MMVD group and compared among groups with the Kruskal-Wallis test followed by pairwise Wilcoxon rank sum tests to detect differences between particular group pairs. Within-group analyses included a comparison of plasma CoQ10 concentration between baseline and subsequent time points with the Wilcoxon signed rank test. In both sets of analyses, P values were adjusted for multiple comparisons by means of the Benjamini-Hochberg correction, except for within-group comparisons for the 200-mg group whereby all P values were the same and the Bonferroni correction was used instead. Values of P < 0.05 were considered significant.

Results

Of the 90 cardiac patients assessed during the recruitment period, 71 dogs either did not meet the inclusion criteria (n = 66) or had owners who declined participation (5). Of the 28 healthy dogs considered for the control group, 16 were excluded because of subclinical heart disease (n = 13) or other reasons (3). Consequently, 19 client-owned dogs with CHF due to MMVD and 12 client-owned healthy control dogs > 5 years of age were included in the study. Six dogs with MMVD received CoQ10 at a total daily dose of 100 mg, 6 received CoQ10 at a total daily dose of 200 mg, and 7 received the placebo. One dog in the 100-mg group was excluded from the statistical analysis owing to antimicrobial treatment that began on the fourth day of CoQ10 supplementation, leaving 5 dogs in that group.

Healthy dogs included 7 mixed-breed dogs, 3 Shih Tzus, 1 Yorkshire Terrier, and 1 Tibetan Spaniel. Dogs with MMVD included 4 mixed-breed dogs, 3 Pekingese, 2 Shih Tzus, 2 Miniature Poodles, and 1 each of Miniature Pinscher, English Cocker Spaniel, Airedale Terrier, Pomeranian, Coton de Tulear, Cavalier King Charles Spaniel, and Whippet. Sixteen of these 18 dogs had ACVIM stage C MMVD and 2 had stage D MMVD. All dogs with MMVD were clinically stable and not in active CHF. Treatments included furosemide or torasemide, angiotensin-converting enzyme inhibitors, spironolactone, and pimobendan as well as digoxin and diltiazem (n = 1 dog), theophylline and a fluticasone inhalant (1), and potassium chloride (1).

Dogs assigned to the 100-mg group had a higher mean body weight than did those assigned to the 200-mg group, but this difference was not significant (Table 1). Furthermore, no significant differences in mean body weight or age were identified between the 3 MMVD subgroups or in body weight between all dogs with MMVD and healthy dogs. Although all healthy dogs were > 5 years of age, the mean age of those dogs was significantly less than the mean age of all dogs with MMVD.

Table 1

Characteristics of dogs with CHF due to MMVD before receiving water-soluble CoQ10 (total daily dose of 100 or 200 mg) or a placebo, PO, for 2 weeks in addition to their regular cardiac treatment and of healthy control dogs.

CharacteristicAll dogs with MMVD (n = 18)100 mg (n = 5)200 mg (n = 6)Placebo (n = 7)Healthy dogs (n = 12)
Sex (female/male)7/112/32/43/46/6
Age (y)11.6 ± 0.5* (8.6–16.8)11.7 ± 1.0* (8.7–14.6)10.9 ± 0.2* (10.7–11.8)12.2 ± 1.0* (8.6–16.8)7.9 ± 0.6 (5.0–11.4)
Body weight (kg)9.4 ± 1.2 (4.4–20.5)12.1 ± 2.9 (5.6–20.5)5.8 ± 0.6 (4.4–8.0)10.4 ± 1.6 (6.7–18.0)8.3 ± 1.2 (2.8–13.5)

Values for age and body weight represent mean ± SEM (range).

Mean value differs significantly (P < 0.05) from that of healthy dogs.

Median plasma CoQ10 concentration for the 12 healthy dogs was 0.095 mg/L (interquartile [25th to 75th percentile] range, 0.070 to 0.143 mg/L). Plasma CoQ10 concentrations at the various time points were summarized for dogs with MMVD (Table 2; Supplementary Figure S1, available at: avmajournals.avma.org/doi/suppl/10.2460/ajvr.82.4.280). No significant differences in baseline plasma CoQ10 concentration were identified among the dog groups. After 2 weeks of CoQ10 supplementation, plasma CoQ10 concentrations increased significantly from baseline values in the 100-mg and 200-mg groups, whereas they remained unchanged in the placebo group. After 2 weeks of CoQ10 supplementation, the fold increase in plasma CoQ10 concentration for individual dogs ranged from 1.7 to 4.7 and 3.2 to 6.8 in the 100-mg and 200-mg groups, respectively. In the 200-mg group, median plasma CoQ10 concentration was significantly greater than at baseline at 4 hours and 1, 2, and 3 weeks after supplementation began without adjustment of P values; however, significant differences in plasma CoQ10 concentrations were no longer significant after adjustment for multiple comparisons. On the other hand, in the 100-mg group, no significant differences were observed between baseline and any subsequent plasma CoQ10 concentrations. In the placebo group, plasma CoQ10 concentration remained fairly constant regardless of time point.

Table 2

Median (interquartile [25th to 75th percentile] range) plasma CoQ10 concentrations (mg/L) for the dogs with MMVD represented in Table 1 before (baseline) and at various time points during and after 2 weeks of daily CoQ10 supplementation.

GroupBaseline4 hours1 week2 weeks3 weeks
100 mg0.154 (0.062–0.367)0.165 (0.146–0.340)0.527* (0.219–1.06)0.402* (0.219–0.942)0.190 (0.077–0.373)
200 mg0.091 (0.042–0.178)0.185* (0.098–0.292)0.324* (0.134–0.520)0.384* (0.165–0.710)0.148 (0.075–0.211)
Placebo0.106 (0.100–0.161)0.107 (0.092–0.189)0.109 (0.085–0.207)0.106 (0.094–0.224)0.106 (0.088–0.193)

Within a group, the change (ie, difference) in this value from the baseline value differs significantly (P < 0.05) from the corresponding change for the placebo group.

Median plasma CoQ10 concentration did not differ between the 3 MMVD subgroups at any time point. However, the change in plasma CoQ10 concentration after supplementation began was significantly higher than it was in the placebo group at 4 hours and 1 and 2 weeks for dogs in the 200-mg group and at 1 and 2 weeks for dogs in the 100-mg group.

Discussion

In the present study, a total daily CoQ10 dose of 200 mg administered PO was found to be sufficient to achieve a 3-fold increase in plasma CoQ10 concentration in every dog with CHF due to MMVD after 2 weeks of supplementation.

Coenzyme Q10 is widely used as a nutritional supplement for humans with cardiovascular disease,6,9,12 with reported daily doses ranging from 100 to 300 mg.6,21 Although CoQ10 has also been drawing attention as a nutritional supplement for dogs with heart disease, to the authors’ knowledge only 2 reports15,22 exist of CoQ10 supplementation in dogs with heart disease, with 1 report22 involving dogs with experimentally induced CHF. For dogs with CHF due to MMVD in the present study, the total daily CoQ10 doses of 100 and 200 mg were chosen on the basis of data from the veterinary literature23 and a bioavailability study.24

Coenzyme Q10 is a lipophilic compound that is practically insoluble in water. Because of the hydrophobicity and large molecular weight of CoQ10, absorption of CoQ10 within the gastrointestinal tract when administered PO is slow and limited, resulting in poor bioavailability.25 Several solubilized formulations of CoQ10 have been developed to enable better absorption and, thus, enhanced bioavailability.10,18,26,27 However, the bioavailability of CoQ10 in these formulations varies greatly in humans and dogs.6,10,24,26,27,28,29 The bioavailability of the water-soluble CoQ10 formulation used in the present study was shown in healthy Beagles to be better than that of an oil-based form.24 Similarly, Zaghloul et al29 demonstrated that soft gelatin capsules containing watermiscible CoQ10 formulations (ubiquinone and ubiquinol) are superior to powder-filled formulations with regard to their biopharmaceutical characteristics in healthy dogs. Furthermore, Zmitek et al27 showed that the same water-soluble formulation of CoQ10 used in our study achieved greater bioavailability in healthy men than did soft gelatin capsules containing CoQ10 in soybean oil.

Our results indicated that a total daily CoQ10 dose of 200 mg resulted in at least a 3-fold increase in plasma CoQ10 concentration in every dog in that group after 2 weeks of CoQ10 supplementation. Furthermore, median plasma CoQ10 concentration was significantly higher than at baseline 1 week after administration ceased. These results suggested that a daily dose of 200 mg would be appropriate for use in supplementation studies involving dogs with CHF due to MMVD. In a previous study22 involving dogs with experimentally induced CHF, CoQ10 administered at 10 mg/kg/d, PO, for 6 weeks resulted in a significant increase in serum CoQ10 concentration; however, myocardial CoQ10 concentrations were similar to those of healthy dogs. The investigators also noted lower filling pressures and less myocardial hypertrophy in CoQ10-treated dogs.22 In another study15 involving dogs with naturally acquired MMVD, twice-daily administration of CoQ10 at 100 mg, PO, for 28 days resulted in significantly higher fractional shortening and ejection fraction in dogs weighing < 6 kg; however, these 2 measures of systolic function can be misleading indogs with MMVD because of increased preload and reduced afterload. As a consequence of these changes in filling pressures, fractional shortening and ejection fraction can be unremarkable to increased in the presence of weakened myocardial systolic function.30 Plasma CoQ10 concentration was not measured, and control dogs were not included in that study.15 A crossover pharmacokinetics study31 involving 19 Cavalier King Charles Spaniels with MMVD revealed a significant increase in plasma CoQ10 concentration following administration of CoQ10 dissolved in vegetable oil, PO, twice daily for 3 weeks. Nevertheless, whether a 3-fold increase in a plasma CoQ10 concentration was achieved in all included dogs is unclear.

Plasma and myocardial tissue CoQ10 deficiencies have been identified in human cardiac patients.7,32 In the present study, baseline plasma CoQ10 concentrations in most dogs with MMVD were similar to those of healthy dogs, which is in accordance with the results from the previous study33 of CoQ10 concentration in dogs with various cardiovascular diseases. Nevertheless, we are aware of no long-term, placebo-controlled clinical trials of the effects of CoQ10 supplementation on the course of cardiovascular disease in dogs. Therefore, further investigation is warranted into the possible effects of CoQ10 supplementation in dogs with different cardiovascular diseases.

The present study had some limitations, including the small number of dogs in the MMVD subgroups, which might have affected the precision of our estimates of mean plasma CoQ10 concentration in these groups. An additional limitation might be that the doses chosen for CoQ10 supplementation were not based on dog body weight as suggested by Tachampa et al.15 Although no significant difference in mean body weight was found between MMVD subgroups, the low sample sizes may have limited our ability to detect such differences. Regardless of these limitations, we found no significant difference in median plasma CoQ10 concentrations between dogs with CHF due to MMVD and healthy dogs, and we found that a daily CoQ10 dose of 200 mg was sufficient to achieve at least a 3-fold increase in plasma CoQ10 concentration, suggesting this dose may be used in CoQ10 supplementation studies involving similar dogs.

Acknowledgments

Supported by the Slovenian Research Agency (research program P4-0053). Funding sources did not have any involvement in the study design, data analysis and interpretation, or the writing and publication of the manuscript.

The authors declare that there were no conflicts of interest.

Presented as an abstract at the ACVIM Forum On-Demand, June 2020.

Abbreviations

ACVIM

American College of Veterinary Internal Medicine

CHF

Congestive heart failure

CoQ10

Coenzyme Q10

MMVD

Myxomatous mitral valve disease

Footnotes

a.

Q10Vital liquid, Valens, Šenčur, Slovenia.

b.

Ubidecarenone, Xiamen Kingdomway Group Co Xiamen, China.

c.

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.

d.

Sigma-Aldrich Co, St Louis, Mo.

e.

Acquity LC-MS-MS system equipped with Xevo TQ detector, Waters, Milford, Mass.

f.

UPLC BEH C18 column, Waters, Milford, Mass.

g.

Merck & Co, Burlington, Mass.

h.

SPSS, version 24.0, IBM Corp, Chicago, Ill.

i.

The R Project for Statistical Computing stats and ggplot, R version 4.0.0, The R Foundation, Vienna, Austria.

References

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Supplementary Materials

Contributor Notes

Address correspondence to Dr. Nemec Svete (alenka.nemecsvete@vf.uni-lj.si).