Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease

doi:10.1016/j.atherosclerosis.2011.02.050

Atherosclerosis

Volume 217, Issue 1, July 2011, Pages 158-164

https://doi.org/10.1016/j.atherosclerosis.2011.02.050 Get rights and content

Abstract

Background

Coenzyme Q10 levels are low in patients with coronary artery disease (CAD), and increasing or preserving coenzyme Q10 could be a beneficial strategy. Exercise and statins improve high-density lipoprotein cholesterol (HDL-C) levels. However, statins inhibit coenzyme Q10 biosynthesis, and the combination of statins with coenzyme Q10 supplementation increases HDL-C compared to statins alone. We compared the effects of two statins (rosuvastatin and atorvastatin) combined with exercise on coenzyme Q10 and HDL-C levels in CAD patients.

Methods

After randomizing 28 CAD patients to rosuvastatin (n = 14) and atorvastatin (n = 14) groups, patients performed weekly in-hospital aerobic exercise and daily home exercise for 20 weeks. We measured serum lipids, ubiquinol, and exercise capacity.

Results

Both statins equally improved exercise capacity and lowered low-density lipoprotein cholesterol and triglyceride levels. Rosuvastatin significantly increased HDL-C (rosuvastatin, +12 ± 9 mg/dL [+30%], atorvastatin, +5 ± 5 mg/dL [+13%], p = 0.014) and apolipoprotein A1 (ApoA1) (rosuvastatin, +28.3 ± 20.7 mg/dL, atorvastatin, +13.4 ± 12.0 mg/dL, p = 0.030) compared to atorvastatin. Atorvastatin significantly decreased serum ubiquinol (731 ± 238 to 547 ± 219 nmol/L, p = 0.001), but rosuvastatin (680 ± 233 to 668 ± 299 nmol/L, p = 0.834) did not. There was a significant positive correlation between changes in ubiquinol and ApoA1 (r = 0.518, p = 0.005). Multivariate regression analysis showed that changes in ubiquinol correlated significantly with changes in ApoA1 after adjusting for age, sex, body mass index, and smoking (β = 0.502, p = 0.008).

Conclusions

Compared to atorvastatin, rosuvastatin combined with exercise significantly preserved ubiquinol levels associated with an increase in HDL-C. Rosuvastatin with regular exercise could be beneficial for CAD patients.

Introduction

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase; statin) to lower levels of low-density lipoprotein cholesterol (LDL-C) is an established strategy for reducing cardiovascular events [1]. Coenzyme Q10 (CoQ10) levels decrease in all organs with aging [2] and are lower in patients with heart failure and ischemic heart disease [3], [4] than in health individuals. Increasing or preserving CoQ10 levels could be a beneficial strategy in treating atherosclerosis [5]. Statins decrease the biosynthesis of CoQ10, and the combination of a statin with CoQ10 supplementation has been reported to raise high-density lipoprotein cholesterol (HDL-C) levels [5], [6]. Thus, the effect of statins on serum CoQ10 levels may lead to changes in HDL-C levels. Despite intensive therapy to lower LDL-C to target levels, a residual risk of cardiovascular events still remains [7]. One of the causes of residual risk is low levels of HDL-C; therefore, other therapies to increase HDL are required and have been investigated [8]. However, there are a few practical options, such as cholesterol ester transfer protein inhibitors, for raising HDL-C [9].

Exercise intervention should be recommended for patients with coronary artery disease (CAD) because the importance of exercise has been demonstrated in recent clinical practice [10]. Exercise therapy is effective and beneficial in improving cardiometabolic risk factors and cardiopulmonary function in patients with CAD, even after optimal medical treatment [11], [12]. Because exercise [13] and statin treatment [14] have been shown to increase HDL-C levels, the combination of statin and regular exercise could help further reduce the residual cardiovascular risk. However, the synergistic effects of combining statin treatment and exercise on CoQ10 and HDL-C levels in patients with CAD are not well examined. The aim of the present study was to determine the beneficial effects of statin therapy (rosuvastatin or atorvastatin) combined with regular exercise on CoQ10 and HDL-C levels in patients with CAD.

Section snippets

Study population

This was a prospective, open labeled randomized trial. Twenty-eight Japanese CAD patients with a history of myocardial infarction, angina pectoris, or 50% or more stenosis in at least one major coronary artery were included. The eligibility criterion is also included age from 20 to 89 years, regardless of sex. The exclusion criteria were the following: inability to exercise, history of poor pulmonary function, lung disease, and history of severe hepatic and renal disturbances. The protocol was

Baseline characteristics

Twenty-eight CAD patients (mean age 67 ± 11 years, 75% male, mean LVEF 60.5 ± 7.9%) were included. There were no significant differences in sex, age, medication use and other traditional risk factors between the two groups at study entry (Table 1). There were no patients having other cardiovascular drugs, analgesics, dietary and vitamin supplements in both groups. The baseline lipid profile, serum ubiquinol, $peak- \dot{V} O_{2}$ (Table 2), and cardiac function on echocardiography (Table 1) were not

Discussion

The present study demonstrated that the combination of rosuvastatin and exercise significantly preserved CoQ10 levels associated with an increase in HDL-C levels compared to atorvastatin and exercise in patients with CAD.

Reducing LDL-C with a statin is an established strategy to reduce cardiovascular events. Increasing HDL-C in addition to lowering LDL-C has the potential to reduce residual cardiovascular risk, because HDL-C is an independent inverse predictor of cardiovascular disease [18],

Conclusions

The present study investigated the effects of combining rosuvastatin or atorvastatin with exercise on serum CoQ10 and HDL-C levels in patients with CAD and showed that the combination of rosuvastatin and exercise successfully preserved serum ubiquinol levels associated with a significant increase in HDL levels, compared to atorvastatin. Rosuvastatin combined with regular exercise could prevent cardiovascular events and reduce residual cardiovascular risk in CAD patients. Further large clinical

Funding sources

This study was supported by a grant (No. C22590786 for S. Sugiyama) from the Ministry of Education, Science, and Culture in Japan and by the Advanced Education Program for Integrated Clinical, Basic and Social Medicine, Graduate School of Medical Sciences, Kumamoto University (Program for Enhancing Systematic Education in Graduate Schools, MEXT, Japan).

Disclosures

None.

Acknowledgments

We would like to thank Mari Hamada (Registered instructor of cardiac rehabilitation), Yurie Katayama (Rehabilitation staff), Ayako Satoda (Cardiopulmonary exercise test analyzer), Tomoko Horikawa (Medical sonographer), Yuko Sakamoto (Medical technologist), Motoki Kamura and Yukari Fukushima (Pharmacists), Kyoko Hirai and Manabu Kinoshita (Clinical Research Center staff), and Haruna Toyama for their support during the study.

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Cerebral Malaria (CM) is associated with the complex neurological syndrome, whose pathology is mediated by severe inflammatory processes following infection with Plasmodium falciparum. Coenzyme-Q₁₀ (Co-Q₁₀) is a potent anti-inflammatory, anti-oxidant, and anti-apoptotic agent with numerous clinical applications. The aim of this study was to elucidate the role of oral administration of Co-Q₁₀ on the initiation or regulation of inflammatory immune response during experimental cerebral malaria (ECM). For this purpose, the pre-clinical effect of Co-Q₁₀ was evaluated in C57BL/6 J mice infected with Plasmodium berghei ANKA (PbA). Treatment with Co-Q₁₀ resulted in the reduction of infiltrating parasite load, greatly improved the survival rate of PbA-infected mice that occurred independent of parasitaemia and prevented PbA-induced disruption of the blood-brain barrier (BBB) integrity. Exposure to Co-Q₁₀ resulted in the reduction of infiltration of effector CD8 + T cells in the brain and secretion of cytolytic Granzyme B molecules. Notably, Co-Q₁₀-treated mice had reduced levels of CD8 +T cell chemokines CXCR3, CCR2, and CCR5 in the brain following PbA-infection. Brain tissue analysis showed a reduction in the levels of inflammatory mediators TNF- α, CCL3, and RANTES in Co-Q₁₀ administered mice. In addition, Co-Q₁₀ modulated the differentiation and maturation of both splenic and brain dendritic cells and cross-presentation (CD8α+DCs) during ECM. Remarkably, Co-Q₁₀ was very effective in decreasing levels of CD86, MHC-II, and CD40 in macrophages associated with ECM pathology. Exposure to Co-Q₁₀ resulted in increased expression levels of Arginase-1 and Ym1/chitinase 3–like 3, which is linked to ECM protection. Furthermore, Co-Q₁₀ supplementation prevented PbA-induced depletion of Arginase and CD206 mannose receptor levels. Co-Q₁₀ abrogated PbA-driven elevation in pro-inflammatory cytokines IL-1β, IL-18, and IL-6 levels. In conclusion, the oral supplementation with Co-Q₁₀ decelerates the occurrence of ECM by preventing lethal inflammatory immune responses and dampening genes associated with inflammation and immune-pathology during ECM, and offers an inimitable opening for developing an anti-inflammatory agent against cerebral malaria.
Oral administration of Coenzyme Q <inf>10</inf> protects mice against oxidative stress and neuro-inflammation during experimental cerebral malaria
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Coenzyme Q10 is an essential cofactor in the bioenergetics reactions and a powerful antioxidant that acts against oxidative stress [66,67], and a regulator of gene expression [68]. These roles has resulted in Coenzyme Q10 being investigated for treatment of neurodegenerative disorders, diabetes mellitus, and cardiovascular diseases [69–71]. Despite this remarkable observation, there exists no data on the role of CoQ10 during ECM.
In animal model of experimental cerebral malaria (ECM), the genesis of neuropathology is associated with oxidative stress and inflammatory mediators. There is limited progress in the development of new approaches to the treatment of cerebral malaria. Here, we tested whether oral supplementation of Coenzyme Q₁₀ (CoQ₁₀) would offer protection against oxidative stress and brain associated inflammation following Plasmodium berghei ANKA (PbA) infection in C57BL/6 J mouse model. For this purpose, one group of C57BL/6 mice was used as control; second group of mice were orally supplemented with 200 mg/kg CoQ₁₀ and then infected with PbA and the third group was PbA infected alone. Clinical, biochemical, immunoblot and immunological features of ECM was monitored. We observed that oral administration of CoQ₁₀ for 1 month and after PbA infection was able to improve survival, significantly reduced oedema, TNF-α and MIP-1β gene expression in brain samples in PbA infected mice. The result also shows the ability of CoQ₁₀ to reduce cholesterol and triglycerides lipids, levels of matrix metalloproteinases-9, angiopoietin-2 and angiopoietin-1 in the brain. In addition, CoQ₁₀ was very effective in decreasing NF-κB phosphorylation. Furthermore, CoQ₁₀ supplementation abrogated Malondialdehyde, and 8-OHDG and restored cellular glutathione. These results constitute the first demonstration that oral supplementation of CoQ₁₀ can protect mice against PbA induced oxidative stress and neuro-inflammation usually observed in ECM. Thus, the need to study CoQ₁₀ as a candidate of antioxidant and immunomodulatory molecule in ECM and testing it in clinical studies either alone or in combination with antimalaria regimens to provide insight into a potential translatable therapy.
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Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI).
Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with ¹²³⁻I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and ²⁰¹⁻thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR−AAI) × 100/AAR (%)].
Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (−37.6% ± 17.2%) and atorvastatin (−32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (−53.3% ± 48.8% versus −13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01).
Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C.
Clinical trial registration: URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893.
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Stock combination simvastatin Sigma (St. Louis, MO) and ubiquinol from General Nutrition Center (Pittsburg, PA) was dissolved in dimethyl sulfoxide (DMSO) to make treatment solutions; with final concentration of DMSO 0.1% for all treatments. Cells were treated with 5 µM or 10 µM simvastatin as previously performed (Araki et al., 2012) with or without ubiquinol at either 0.5 µM or 1 µM (roughly physiological serum concentrations [0.5–0.8 nM]) and incubated for 24 h or 48 h as described above (Toyama et al., 2011). PGC-1α mRNA expression was quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).
Statin medications diminish cholesterol biosynthesis and are commonly prescribed to reduce cardiovascular disease. Statins also reduce production of ubiquinol, a vital component of mitochondrial energy production; ubiquinol reduction may contribute to rhabdomyolysis. Human rhabdomyosarcoma cells were treated with either ethanol and dimethyl sulfoxide (DMSO) control, or simvastatin at 5 µM or 10 µM, or simvastatin at 5 µM with ubiquinol at 0.5 µM or 1.0 µM for 24 h or 48 h. PGC-1α RNA levels were determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mitochondrial content was determined using flow cytometry and immunocytochemistry. Metabolism was determined by quantification of extracellular acidification rate and oxygen consumption rate. Treatment of human rhabdomyosarcoma cells with simvastatin significantly reduced oxidative, total metabolism, and cellular ATP content in a time- and dose-dependent manner which was rescued by concurrent treatment with ubiquinol. Treatment with simvastatin significantly reduced mitochondrial content as well as cell viability which were both rescued by simultaneous treatment with ubiquinol. This work demonstrates that the addition of ubiquinol to current statin treatment regimens may protect muscle cells from myopathies.

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Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Baseline characteristics

Discussion

Conclusions

Funding sources

Disclosures

Acknowledgments

J Am Coll Cardiol

J Cardiol

Am J Med

J Lipid Res

Anal Biochem

Am J Med

Lancet

Eur J Pharmacol

Biochem Pharmacol

Intensive lipid lowering with atorvastatin in patients with stable coronary disease

N Engl J Med

Age-related changes in the lipid compositions of rat and human tissues

Lipids

Coenzyme Q10 and exercise training in chronic heart failure

Eur Heart J

Ratio of low-density lipoprotein cholesterol to ubiquinone as a coronary risk factor

N Engl J Med

Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction

Mol Cell Biochem

Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study

Atherosclerosis