ubiquinone and Cardiomyopathies

Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant.

Topics: Ataxia; Cardiomyopathies; Epilepsy; Female; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Muscle Weakness; Mutation; Pregnancy; Ubiquinone

The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further.. To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months.. On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies.. We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months.. Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria.. We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between. Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.

Topics: Adolescent; Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiovascular Agents; Child; Disease Progression; Eplerenone; Human Growth Hormone; Humans; Lisinopril; Losartan; Male; Muscular Dystrophy, Duchenne; Non-Randomized Controlled Trials as Topic; Perindopril; Placebos; Randomized Controlled Trials as Topic; Stroke Volume; Ubiquinone; Young Adult

Several reports in the literature describe the effects of low-dose (5 mg/kg/day) idebenone in significantly reducing cardiac hypertrophy in patients with Friedreich ataxia. However, the effects of idebenone on neurological function have not been reliably determined in these studies; when neurological parameters were reported, results were often inconclusive, usually because of subject heterogeneity and lack of adequate statistical power. In two of these studies, some patients showed beneficial effects of idebenone on their cardiomyopathy only when the dose was increased, prompting the systematic investigation of higher doses of idebenone. Following a phase 1 dose escalation study, a phase 2 tolerability and efficacy trial with low, intermediate, and high doses of idebenone was conducted. The results suggested that treatment with intermediate- and high-dose idebenone had beneficial effects on neurological symptoms. On the basis of these results, two phase 3 trials have been initiated, one in the United States with young ambulatory patients and one in Europe without limits on age and disease severity.

Topics: Antioxidants; Cardiomyopathies; Clinical Protocols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Friedreich Ataxia; Humans; Nervous System Diseases; Ubiquinone

Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non-lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.

Topics: Anti-Arrhythmia Agents; Anti-Inflammatory Agents; Antioxidants; Autonomic Agents; Cardiomyopathies; Cytokines; Drug Evaluation; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy; Lipoproteins; Myocardial Ischemia; Myocardium; Neovascularization, Pathologic; Neurotransmitter Agents; Selenoproteins; Treatment Outcome; Ubiquinone; Ventricular Remodeling

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol concentrations. Although generally safe, they have been associated with a variety of myopathic complaints. Statins block production of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone or coenzyme Q10 (CoQ10). This fact, plus the role of CoQ10 in mitochondrial energy production, has prompted the hypothesis that statin-induced CoQ10 deficiency is involved in the pathogenesis of statin myopathy. We identified English language articles relating statin treatment and CoQ10 levels via a PubMed search through August 2006. Abstracts were reviewed and articles addressing the relationship between statin treatment and CoQ10 levels were examined in detail. Statin treatment reduces circulating levels of CoQ10. The effect of statin therapy on intramuscular levels of CoQ10 is not clear, and data on intramuscular CoQ10 levels in symptomatic patients with statin-associated myopathy are scarce. Mitochondrial function may be impaired by statin therapy, and this effect may be exacerbated by exercise. Supplementation can raise the circulating levels of CoQ10, but data on the effect of CoQ10 supplementation on myopathic symptoms are scarce and contradictory. We conclude that there is insufficient evidence to prove the etiologic role of CoQ10 deficiency in statin-associated myopathy and that large, well-designed clinical trials are required to address this issue. The routine use of CoQ10 cannot be recommended in statin-treated patients. Nevertheless, there are no known risks to this supplement and there is some anecdotal and preliminary trial evidence of its effectiveness. Consequently, CoQ10 can be tested in patients requiring statin treatment, who develop statin myalgia, and who cannot be satisfactorily treated with other agents. Some patients may respond, if only via a placebo effect.

Topics: Cardiomyopathies; Coenzymes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mitochondria; Muscle, Skeletal; Ubiquinone

Topics: Animals; Cardiomyopathies; Clinical Trials as Topic; Coenzymes; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Stunning; Myocardium; Oils; Pravastatin; Simvastatin; Solubility; Ubiquinone; Water

Pediatric cardiomyopathy (PCM) represents a group of rare and heterogeneous disorders that often results in death. While there is a large body of literature on adult cardiomyopathy, all of the information is not necessarily relevant to children with PCM. About 40% of children who present with symptomatic cardiomyopathy are reported to receive a heart transplant or die within the first two years of life. In spite of some of the advances in the management of PCM, the data shows that the time to transplantation or death has not improved during the past 35 years. Coenzyme Q10 is a vitamin-like nutrient that has a fundamental role in mitochondrial function, especially as it relates to the production of energy (ATP) and also as an antioxidant. Based upon the biochemical rationale and a large body of data on patients with adult cardiomyopathy, heart failure, and mitochondrial diseases with heart involvement, a role for coenzyme Q10 therapy in PCM patients is indicated, and preliminary results are promising. Additional studies on the potential usefulness of coenzyme Q10 supplementation as an adjunct to conventional therapy in PCM, particularly in children with dilated cardiomyopathy, are therefore warranted.

Topics: Cardiomyopathies; Coenzymes; Dietary Supplements; Humans; Infant; Ubiquinone

Preclinical and clinical studies suggest that anthracycline-induced cardiotoxicity can be prevented by administering coenzyme Q10 during cancer chemotherapy that includes drugs such as doxorubicin and daunorubicin. Studies further suggest that coenzyme Q10 does not interfere with the antineoplastic action of anthracyclines and might even enhance their anticancer effects. Preventing cardiotoxicity might allow for escalation of the anthracycline dose, which would further enhance the anticancer effects. Based on clinical investigation, although limited, a cumulative dose of doxorubicin of up to 900 mg/m2, and possibly higher, can be administered safely during chemotherapy as long as coenzyme Q10 is administered concurrently. The etiology of the dose-limiting cardiomyopathy that is induced by anthracyclines can be explained by irreversible damage to heart cell mitochondria, which differ from mitochondria of other cells in that they possess a unique enzyme on the inner mitochondrial membrane. This enzyme reduces anthracyclines to their semiquinones, resulting in severe oxidative stress, disruption of mitochondrial energetics, and irreversible damage to mitochondrial DNA. Damage to mitochondrial DNA blocks the regenerative capability of the organelle and ultimately leads to apoptosis or necrosis of myocytes. Coenzyme Q10, an essential component of the electron transport system and a potent intracellular antioxidant, appears to prevent damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Cardiomyopathies; Coenzymes; Cytoprotection; Dose-Response Relationship, Drug; Drug Therapy, Combination; Heart; Heart Failure; Humans; Mitochondria, Heart; Neoplasms; Ubiquinone

The anthracycline antibiotic adriamycin (doxorubicin) is one of the most effective chemotherapeutic agents against a wide variety of cancers. However, its use is seriously limited by the development in the heart of acute and chronic toxic effects. Mechanisms of action and toxicity of adriamycin are briefly revised in this review. Among followed strategies to attenuate adriamycin toxicity are dosage optimisation, synthesis and use of analogues or combined therapy with antioxidants. The most promising results come from the combination of the drug delivery together with an antioxidant in order to reduce oxidative stress. Many antioxidants have been assayed with very different results. Among these molecules, metal ions chelators and low-molecular-mass agents that scavenge reactive oxygen species and that are synthesised in vivo have been widely studied. However, the present review will be exclusively focused on the antioxidants that are derived from the diet, in particular the role of vitamin E, vitamin C, vitamin A, coenzyme Q, flavonoids, antioxidant components of virgin olive oil and selenium.

Topics: Animals; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cardiomyopathies; Curcuma; DNA Damage; Doxorubicin; Female; Flavonoids; Humans; Olive Oil; Phenols; Plant Oils; Polymers; Rats; Reactive Oxygen Species; Selenium; Ubiquinone; Vitamin A; Vitamin E

This article provides a comprehensive review of 30 years of research on the use of coenzyme Q10 in prevention and treatment of cardiovascular disease. This endogenous antioxidant has potential for use in prevention and treatment of cardiovascular disease, particularly hypertension, hyperlipidemia, coronary artery disease, and heart failure. It appears that levels of coenzyme Q10 are decreased during therapy with HMG-CoA reductase inhibitors, gemfibrozil, Adriamycin, and certain beta blockers. Further clinical trials are warranted, but because of its low toxicity it may be appropriate to recommend coenzyme Q10 to select patients as an adjunct to conventional treatment.

Topics: Animals; Cardiomyopathies; Cardiovascular Diseases; Complementary Therapies; Coronary Disease; Heart Failure; Humans; Hypertension; Myocardial Infarction; Ubiquinone

beta-Methyl-p-(123I)-iodophenyl pentadecanoic acid (BMIPP) is one of the branched-chain free fatty acids, which has suitable characteristics for myocardial SPECT because of higher uptake and longer retention in the myocardium. Recent advances of BMIPP myocardial SPECT for evaluating cardiomyopathy were reviewed. BMIPP defects were observed in 80% patients with hypertrophic cardiomyopathy (HCM). Moreover, BMIPP uptake was reduced at sites that corresponded with hypertrophic areas, where thallium uptake was increased. The correlations between severity score and septal wall thickness and LV function were better with BMIPP SPECT, suggesting that BMIPP is more suitable for the assessment of myocardial integrity in HCM. The dissociation between BMIPP and thallium defects was not observed frequently in dilated cardiomyopathy (DCM). We carried out BMIPP myocardial SPECT to evaluate the therapeutic effects of co-enzyme Q10 on DCM patients. Hearts to the mediastinum ratio and BMIPP defect scores were significantly decreased after co-enzyme Q10 treatment. BMIPP myocardial SPECT was confirmed to be sensitive in evaluating the therapeutic effect for the perspective of metabolic SPECT imaging. Recently, a lack of myocardial uptake of BMIPP has been found in a small subset of patients (0.3%-1.2%). Cardiac radionuclide imaging using BMIPP and 18F-FDG were performed on patients with type I CD36 deficiency. The percent dose uptake of 18F-FDG was significantly higher than in normal controls. CD functions as a major myocardial long-chain fatty acid transporter and its absence may lead to a compensatory upregulation of myocardial glucose uptake. An increased frequency of CD36 deficiency was demonstrated in cardiomyopathy. Therefore, fatty acid transport proteins and their related gene defects in relation to BMIPP uptake may become an important issue in the future.

Topics: Antioxidants; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; CD36 Antigens; Coenzymes; Fatty Acids; Humans; Iodine Radioisotopes; Iodobenzenes; Tomography, Emission-Computed, Single-Photon; Ubiquinone

The biochemical and genetic analysis served as the basis for the definition of the following mitochondrial diseases (mt diseases) and the diseases of the mitochondrial deoxyribonucleic acid (mtDNA diseases): mitochondrial myopathy, encephalomyopathy, and cardiomyopathy. The therapy of mitochondrial diseases (in both practice and experiment) belongs to the current trends of research.. The study does not present any new experimental results but in their literary review the authors indicate: a) new trend in biochemical studies of mitochondrial diseases, b) some current knowledge on mtDNA diseases, c) the current trend of mitochondrial disease "redox therapy" by CoQ10, d) significance of the therapeutic task of CoQ10 in four experimental models of the myocardial mitochondria impairment (by ageing, smoking, alcohol, ischemia).. The authors indicate a new perspective for the studies of mitochondrial diseases (mt diseases) and the diseases of the mitochondrial deoxyribonucleic acid (mtDNA diseases) and their therapy not only under experimental conditions, but also in the blood and bioptic samples of patients. (Tab. 3, Fig. 2, Ref. 43.)

Topics: Animals; Cardiomyopathies; Humans; Mitochondria; Mitochondrial Myopathies; Ubiquinone

Many antioxidants have been suggested as potential treatments for Friedreich ataxia, but have not been tested in clinical trials. We found that a majority of patients in our cohort already use such antioxidants, including idebenone, which is not available at a pharmaceutical grade in the United States. Younger age, cardiomyopathy and shorter GAA repeat length were independent predictors of idebenone use, but no factors predicted use of other antioxidants. This confirms that non-prescription antioxidant use represents a major confounder to formal trials of existing and novel agents for Friedreich ataxia.

Topics: Adolescent; Adult; Age Factors; Age of Onset; Antioxidants; Cardiomyopathies; Clinical Trials as Topic; Cohort Studies; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Mitochondria; Nonprescription Drugs; Oxidative Stress; Patient Selection; Placebo Effect; Self Medication; Trinucleotide Repeat Expansion; Ubiquinone

Friedreich ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.

Topics: Antioxidants; Benzoquinones; Cardiomyopathies; Cross-Over Studies; Echocardiography; Female; Friedreich Ataxia; Humans; Magnetic Resonance Spectroscopy; Male; Mitochondria; Muscle, Skeletal; Radionuclide Imaging; Ubiquinone

Two groups of children with acute lymphoblastic leukemia or non-Hodgkin lymphoma, treated with anthracyclines (ANT), were studied: group I, consisting of 10 patients, with coenzyme Q10 (CoQ) therapy; group II, consisting of 10 patients without CoQ therapy. The ANT cumulative dose was 240 +/- 20.0 mg/m2 in group I and 252.0 +/- 20.1 mg/m2 in group II. Echocardiographic study was performed at the beginning, at the cumulative dose of 180 mg/m2 and at the end of therapy with ANT. Percentage left ventricular fractional shortening (%LVFS) decreased from baseline (40.36 +/- 4.6) to end value (35.82 +/- 5.02) (P < 0.05) in group I; %LVFS decreased from baseline (39.89 +/- 4.37) to end value (33.43 +/- 3.46) (P < 0.002) in group II. Interventricular septum wall thickening decreased only in group II from baseline (46.10 +/- 10.1) to end therapy (27.00 +/- 18.54) (P < 0.01). Septum wall motion abnormalities were detected only in 2 patients of group II. These data demonstrate a protective effect of CoQ on cardiac function during therapy with ANT.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Child; Coenzymes; Daunorubicin; Echocardiography; Humans; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors; Treatment Outcome; Ubiquinone; Ventricular Function, Left

Coenzyme Q10 (CoQ10) is a natural and essential cofactor in the heart. It is the primary redox coupler in the respiratory chain, a potent free radical scavenger, and a superoxide inhibitor. In this study the myocardial protective effects of CoQ10 were determined in high-risk (n = 10) patients during heart surgery compared to that found in placebo controls (n = 10). In both groups, there was a blood CoQ10 deficiency (< 0.6 microgram/ml), low cardiac index (CI < 2.4 l/m2 per minute), and low left ventricular ejection fraction (LVEF < 35%) before treatment. CoQ10 (100 mg per day) was given orally for 14 days before and 30 days after surgery. Presurgical CoQ10 treatment significantly (P < 0.01) improved blood and myocardial CoQ10 and myocardial ATP compared to that found in the control group. Cardiac functions (CI and LVEF) were improved but not significantly. After cardiac cooling, rewarming, and reperfusion; blood and tissue CoQ10 and tissue ATP levels were maintained in the normal ranges in the CoQ10 patients. Cardiac pumping (CI) and LVEF were significantly (P < 0.01) improved. The recovery course was short (3-5 days) and uncomplicated. In the control group blood and tissue CoQ10, tissue ATP levels, and cardiac functions were depressed after surgery. The recovery course was long (15-30 days) and complicated. Positive relationships between blood and myocardial CoQ10, myocardial ATP, cardiac function, and the postoperative recovery time and course found in both study groups show the therapeutic benefits of CoQ10 in preserving the myocardium during heart surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Cardiomyopathies; Coenzymes; Combined Modality Therapy; Double-Blind Method; Female; Heart Function Tests; Humans; Male; Risk Factors; Ubiquinone

Coenzyme Q10 (CoQ10) is indispensable in mitochondrial bioenergetics and for human life to exist. 88/115 patients completed a trial of therapy with CoQ10 for cardiomyopathy. Patients were selected on the basis of clinical criteria, X-rays, electrocardiograms, echocardiography, and coronary angiography. Responses were monitored by ejection fractions, cardiac output, and improvements in functional classifications (NYHA). Of the 88 patients 75%-85% showed statistically significant increases in two monitored cardiac parameters. Patients with the lowest ejection fractions (approx. 10%-30%) showed the highest increases (115 delta %-210 delta %) and those with higher ejection fractions (50%-80%) showed increases of approx. 10 delta %-25 delta % on therapy. By functional classification, 17/21 in class IV, 52/62 in class III, and 4/5 in class II improved to lower classes. Clinical responses appeared over variable times, and are presumably based on mechanisms of DNA-RNA-protein synthesis of apoenzymes which restore levels of CoQ10 enzymes in a deficiency state. 10/21 (48%) of patients in class IV, 26/62 (42%) in class III, and 2/5 (40%) in class II had exceptionally low control blood levels of CoQ10. Clinical responses on therapy with CoQ10 appear maximal with blood levels of approx. 2.5 micrograms CoQ10/ml and higher during therapy.

Topics: Adult; Aged; Aged, 80 and over; Cardiac Output; Cardiomyopathies; Cardiomyopathy, Dilated; Clinical Trials as Topic; Coenzymes; Coronary Disease; Female; Heart Failure; Humans; Male; Middle Aged; Stroke Volume; Ubiquinone

Nineteen patients with chronic myocardial disease (NYHA Classes III and IV) were given Coenzyme Q10 in a controlled double-blind cross-over study. All had either low or borderline levels of CoQ10 in their blood, and showed a significant change into the normal range with oral CoQ10 replacement. Eighteen patients reported improvement in activity tolerance with replacement therapy. Combined clinical observations, stroke volume measured by impedance cardiography, and ejection fractions calculated from systolic time intervals, all showed significant improvement in parallel with CoQ10 administration. This application of the principles of bioenergetics introduces a promising new dimension to the study and treatment of the complex problem of myocardial failure.

Topics: Cardiomyopathies; Chronic Disease; Coenzymes; Double-Blind Method; Electrocardiography; Humans; Random Allocation; Stroke Volume; Ubiquinone

Coenzyme Q10 (CoQ10), a biochemically established redox component of respiration including the coupled mechanisms of electron transfer and oxidative phosphorylation, is naturally present in the human myocardium. A double-blind and double-crossover trial has been conducted by administering CoQ10 and a matching placebo orally to two groups of patients having class III or IV cardiomyopathy (classification according to criteria of the New York Heart Association). Group A received CoQ10 and then placebo; group B received placebo and then CoQ10. Blood levels of CoQ10 and cardiac function were determined at 0 and 4 weeks (control stabilization period) and at 16 and 28 weeks (after the 12-week CoQ/placebo-treatment periods). For group A, significant increases in CoQ10 blood levels and cardiac function occurred during CoQ10 treatment and then decreased during crossover to placebo. For group B, there was no change in CoQ10 blood levels and cardiac function during placebo treatment, but increases in both parameters occurred in crossover to CoQ10. These patients, steadily worsening and expected to die within 2 years under conventional therapy, generally showed an extraordinary clinical improvement, indicating that CoQ10 therapy might extend the lives of such patients. This improvement could be due to correction of a myocardial deficiency of CoQ10 and to enhanced synthesis of CoQ10-requiring enzymes.

Topics: Adult; Aged; Cardiomyopathies; Coenzymes; Double-Blind Method; Female; Humans; Male; Middle Aged; Stroke Volume; Ubiquinone

Mitochondrial dysfunction plays a key role in the development of heart failure, but targeted therapeutic interventions remain elusive. Previous studies have shown coenzyme Q10 (CoQ10) insufficiency in patients with heart disease with undefined mechanism and modest effectiveness of CoQ10 supplement therapy. Using 2 transgenic mouse models of cardiomyopathy owing to cardiac overexpression of Mst1 (Mst1-TG) or β 2 -adrenoceptor (β 2 AR-TG), we studied changes in cardiac CoQ10 content and alterations in CoQ10 biosynthesis genes. We also studied in Mst1-TG mice effects of CoQ10, delivered by oral or injection regimens, on both cardiac CoQ10 content and cardiomyopathy phenotypes. High performance liquid chromatography and RNA sequencing revealed in both models significant reduction in cardiac content of CoQ10 and downregulation of most genes encoding CoQ10 biosynthesis enzymes. Mst1-TG mice with 70% reduction in cardiac CoQ10 were treated with CoQ10 either by oral gavage or i.p. injection for 4-8 weeks. Oral regimens failed in increasing cardiac CoQ10 content, whereas injection regimen effectively restored the cardiac CoQ10 level in a time-dependent manner. However, CoQ10 restoration in Mst1-TG mice did not correct mitochondrial dysfunction measured by energy metabolism, downregulated expression of marker proteins, and oxidative stress nor to preserve cardiac contractile function. In conclusion, mouse models of cardiomyopathy exhibited myocardial CoQ10 deficiency likely due to suppressed endogenous synthesis of CoQ10. In contrast to ineffectiveness of oral administration, CoQ10 administration by injection regimen in cardiomyopathy mice restored cardiac CoQ10 content, which, however, failed in achieving detectable efficacy at molecular and global functional levels.

Topics: Animals; Cardiomyopathies; Heart; Mice; Mice, Transgenic; Ubiquinone

We report a 19-month-old patient with cardiomyopathy as the first presenting feature of primary COQ10 deficiency-6. This case expands the phenotypic spectrum of this disorder. Furthermore, it shows that genetic testing for primary COQ10 deficiency should be considered in patients with pediatric-onset cardiomyopathy as it can guide treatment options.

Topics: Ataxia; Cardiomyopathies; Humans; Infant; Mitochondrial Diseases; Muscle Weakness; Mutation; Ubiquinone

In the present study, we investigated the cardioprotective effects of coenzyme Q10 (Q10) against doxorubicin (DOXO) induced cardiomyopathy. Twenty adult rats were distributed in four experimental groups: group 1 received NaCl 0.9% at 1 ml/day for 14 days; group 2 received Q10 at 1 mg/kg/day for 14 days; group 3 received initial 7 days of treatment with NaCl 0.9% followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of NaCl; and group 4 received initial 7 days of Q10 1 mg/kg/day, followed by a single dose of doxorubicin (12.5 mg/kg IP) and another 7 days of Q10. At the end of 14 days, systolic, diastolic and mean blood pressure, electrocardiogram (ECG), complete blood count, and serum biochemical profile were evaluated. We also analyzed heart histological and ultrastructure analysis, and estimated heart's oxidative stress and lipid peroxidation. DOXO administration altered ECG, with increase heart rate, P-wave duration, PR interval duration, and T-wave amplitude. All the parameters were significantly reduced following Q10 treatment. DOXO also caused increase in CK, CK-MB, LDH, and urea levels, which were not mitigated by Q10 treatment. However, Q10 reduced oxidative stress by interfering with superoxide dismutase, significantly decreasing lipid peroxidation in heart tissue. DOXO administration also leads to several histological and ultrastructure alterations including cardiomyocyte degeneration and intense intracelullar autophagosomes, all minimized by Q10 treatment. Q10 treatment prevented the ECG changes, minimized oxidative stress, lipid peroxidation, and DOXO-induced heart tissue alterations. Our findings suggest that pre- and post-treatment with Q10 exerts potential cardioprotective effect against the DOX-induced cardiotoxicity.

Topics: Animals; Antioxidants; Cardiomyopathies; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Lipid Peroxidation; Myocytes, Cardiac; Oxidative Stress; Rats, Wistar; Ubiquinone

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.

Topics: Acidosis; Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases; Adrenergic beta-Antagonists; Amino Acid Metabolism, Inborn Errors; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Carvedilol; Drug Therapy, Combination; Female; Humans; Infant, Newborn; Mitochondrial Diseases; Muscle Weakness; Prognosis; Pyruvates; Ubiquinone; Vitamins

Heart failure (HF) is rapidly increasing in incidence and is often present in patients receiving long-term statin therapy.. To test whether or not patients with HF on long-term statin therapy respond to discontinuation of statin therapy and initiation of coenzyme Q. Baseline and follow-up physical examination findings, symptom scores, echocardiograms, and plasma CoQ. Of 142 identified patients with HF, 94% presented with preserved ejection fraction (EF) and 6% presented with reduced EF (< 50%). After a mean follow-up of 2.8 years, New York Heart Association class 1 increased from 8% to 79% (p < 0.0001). In patients with preserved EF, 34% had normalization of diastolic function and 25% showed improvement (p < 0.0001). In patients with reduced EF at baseline, the EF improved from a mean of 35% to 47% (p = 0.02). Statin-attributable symptoms including fatigue, muscle weakness, myalgias, memory loss, and peripheral neuropathy improved (p < 0.01). The 1-year mortality was 0%, and the 3-year mortality was 3%.. In patients receiving long-term statin therapy, statin-associated cardiomyopathy may develop that responds safely to statin treatment discontinuation and CoQ

Topics: Aged; Cardiomyopathies; Cholesterol; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Stroke Volume; Ubiquinone; Vitamin E

Q10 is a powerful antioxidant often used in medical nutritional supplements for cancer treatment. This study determined whether Q10 could effectively prevent cardio-toxicity caused by doxorubicin treatment. Four week old SD rats were segregated into groups namely control, doxorubicin group (challenged with doxorubicin), Dox + Q10 group (with doxorubicin challenge and oral Q10 treatment), and Q10 group (with oral Q10 treatment). Doxorubicin groups received IP doxorubicin (2.5 mg/kg) every 3 days and Q10 groups received Q10 (10 mg/kg) every day. Three weeks of doxorubicin challenge caused significant reduction in heart weight, disarray in cardiomyocyte arrangement, elevation of collagen accumulation, enhancement of fibrosis and cell death associated proteins, and inhibition of survival proteins. However, Q10 effectively protected cardiomyocytes and ameliorated fibrosis and cell death induced by doxorubicin. Q10 is, therefore, evidently a potential drug to prevent heart damage caused by doxorubicin. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 679-689, 2017.

Topics: Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cardiomyopathies; Cardiotonic Agents; Cell Survival; Doxorubicin; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Ubiquinone

Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative to citrate synthase (0.012, reference range 0.014-0.034). Myocardial CoQ10 was markedly decreased (224pmol/mg, reference range 942-2738), with a marginally decreased white blood cell level (34pmol/mg reference range 37-133). The dose of CoQ10 was increased from 1.5 to 25mg/kg/day. Cardiomyopathy slowly improved allowing removal of the external mechanical cardiac support after 67days. We demonstrate for the first time low myocardial CoQ10 in cardiomyopathy in PA, highlighting secondary mitochondrial impairment as a relevant causative mechanism. According to these findings, a high-dose CoQ10 supplementation could be a potential adjuvant therapeutic to be considered in PA-related cardiomyopathy.

Topics: Adolescent; Biopsy; Cardiomyopathies; Humans; Infant; Male; Mitochondria; Myocardium; Propionic Acidemia; Treatment Outcome; Ubiquinone; Vitamins

Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare.. To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel.. Description of a series.. Academic research.. Six patients with FAexdel and 46 patients with typical FA.. FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification.. We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA.. Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis.

Topics: Adult; Antioxidants; Cardiomyopathies; Disease Progression; Electromyography; Exons; Family Health; Female; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Magnetic Resonance Imaging; Male; Middle Aged; Sequence Deletion; Trinucleotide Repeat Expansion; Ubiquinone

Cardiomyopathy is reflected in a deterioration of heart function, increased risk of developing arrhythmias, and the potential for sudden cardiac death. The use of enhanced external counterpulsation has been recommended for treating chronic stable angina in high-risk surgical patients. Furthermore, cells require adequate levels of adenosine triphosphate for the maintenance of integrity and function. Lower myocardial levels of adenosine triphosphate are commonly found with ischemia and heart failure. d-Ribose, a natural occurring carbohydrate, enhances the regeneration of adenosine triphosphate levels and improves diastolic function following ischemia.. We present a patient with cardiomyopathy and marked reduced cardiac function.. This patient underwent enhanced external counterpulsation and metabolic supplementation, including d-ribose, and achieved a significant functional improvement.

Topics: Aged; Cardiomyopathies; Combined Modality Therapy; Counterpulsation; Dietary Supplements; Echocardiography; Heart Failure; Humans; Male; Myocardial Contraction; Quality of Life; Ribose; Treatment Outcome; Ubiquinone; Vitamins

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.

Topics: Animals; Apoptosis; Body Weight; Cardiomyopathies; Cardiotonic Agents; Doxorubicin; Electron Spin Resonance Spectroscopy; Electron Transport Complex IV; Endomyocardial Fibrosis; Heart; Heme; Male; Mitochondria, Heart; Myocardium; Organophosphorus Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; Ubiquinone

The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1-4 Hz). In the range of frequency of 1-4 Hz also CoQ10 and omega-3 significantly (p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+ T') and peak rate of tension fall (-T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects.

Topics: Animals; Cardiomyopathies; Cardiomyopathy, Dilated; Carnitine; Cricetinae; Fatty Acids, Omega-3; Male; Mesocricetus; Models, Animal; Myocardial Contraction; Papillary Muscles; Stimulation, Chemical; Ubiquinone

Topics: Aged; Biopsy; Carbazoles; Cardiomyopathies; Carvedilol; Coenzymes; Coronary Angiography; Enalapril; Female; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnetic Resonance Imaging; Mitochondria, Heart; Mitochondrial Diseases; Propanolamines; Ubiquinone

Topics: Cardiomyopathies; Coenzymes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Placebo Effect; Treatment Outcome; Ubiquinone

Fifty consecutive new cardiology clinic patients who were on statin drug therapy (for an average of 28 months) on their initial visit were evaluated for possible adverse statin effects (myalgia, fatigue, dyspnea, memory loss, and peripheral neuropathy). All patients discontinued statin therapy due to side effects and began supplemental CoQ(10) at an average of 240 mg/day upon initial visit. Patients have been followed for an average of 22 months with 84% of the patients followed now for more than 12 months. The prevalence of patient symptoms on initial visit and on most recent follow-up demonstrated a decrease in fatigue from 84% to 16%, myalgia from 64% to 6%, dyspnea from 58% to 12%, memory loss from 8% to 4% and peripheral neuropathy from 10% to 2%. There were two deaths from lung cancer and one death from aortic stenosis with no strokes or myocardial infarctions. Measurements of heart function either improved or remained stable in the majority of patients. We conclude that statin-related side effects, including statin cardiomyopathy, are far more common than previously published and are reversible with the combination of statin discontinuation and supplemental CoQ(10). We saw no adverse consequences from statin discontinuation.

Topics: Adult; Aged; Aged, 80 and over; Anticholesteremic Agents; Cardiomyopathies; Coenzymes; Dyspnea; Fatigue; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Memory Disorders; Middle Aged; Muscular Diseases; Pain; Peripheral Nervous System Diseases; Prospective Studies; Ubiquinone

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I-III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.

Topics: Adult; Antioxidants; Benzoquinones; Biopsy; Cardiomyopathies; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Female; Humans; Mitochondrial Myopathies; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Oxidoreductases; Succinate Dehydrogenase; Ubiquinone

Topics: Antioxidants; Cardiomyopathies; Female; Humans; Middle Aged; Ubiquinone

Cardiomyopathic hamsters develop heart disease early in life, which leads to congestive heart failure and death as these hamsters age. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce ubiquinone concentrations and to deteriorate myocardial function in humans and in experimental animals. HMG-CoA reductase inhibitors differ regarding their ability to penetrate extrahepatic tissues. As a consequence, lovastatin inhibits cholesterol biosynthesis at least 100-fold more effectively than pravastatin in extrahepatic cells. We examined the effect of lovastatin and pravastatin (approximately 10 mg per kilogram of body weight and per day mixed in the diet) compared with controls on the lifespan of cardiomyopathic hamsters (BIO 8262 strain) in the heart-failure period. In male hamsters, neither lovastatin nor pravastatin significantly affected survival. In female hamsters, lovastatin reduced median survival time from 89 days (control animals) to 30 days (P <.05); pravastatin (median survival, 115 days) had no statistically significant effect. We conclude that lovastatin, but not pravastatin, at a daily dose of 10 mg per kilogram of body weight significantly increases the mortality of cardiomyopathic hamsters. This effect may be the result of inhibition of myocardial ubiquinone supply.

Topics: Administration, Oral; Animals; Anticholesteremic Agents; Cardiomyopathies; Cricetinae; Disease Models, Animal; Female; Lovastatin; Male; Pravastatin; Sex Factors; Survival Analysis; Ubiquinone

Topics: Anticoagulants; Antioxidants; Blood Coagulation Disorders; Cardiomyopathies; Coenzymes; Drug Interactions; Humans; Male; Middle Aged; Ubiquinone; Warfarin

Consistent with the postulated role of oxidative stress in the etiology of late diabetic complications, pharmacological interventions based on biological antioxidants have been suggested. The aim of the present study was to investigate the effect of dietary supplementation with the pyridoindole antioxidant stobadine on the myocardial antioxidant status and ultrastructure of streptozotocin-diabetic rats. Diabetic male Wistar rats were fed for 32 weeks a standard diet or a diet supplemented with stobadine (0.05% w/w). Control rats received a standard diet or stobadine-supplemented diet (0.16% w/w). Plasma levels of glucose, cholesterol and triglycerides were increased significantly by diabetes. Activities of superoxide dismutase and catalase were markedly elevated in the diabetic myocardium. Myocardial levels of conjugated dienes increased after eight months of diabetes, in spite of significantly increased myocardial alpha-tocopherol and coenzyme Q9 content. The long-term treatment of diabetic animals with stobadine (i) reduced plasma cholesterol and triglyceride levels yet left the severe hyperglycemia unaffected, (ii) reduced oxidative damage of myocardial tissue as measured by conjugated dienes, (iii) reversed myocardial levels of alpha-tocopherol and coenzyme Q9 to near control values, (iv) reduced elevated activity of superoxide dismutase in the diabetic myocardium, and (v) attenuated angiopathic and atherogenic processes in the myocardium as assessed by electron microscopy examination. These results are in accordance with the postulated prooxidant role of chronic hyperglycemia and provide further evidence that development of pathological changes in diabetic myocardium is amenable to pharmacological intervention by biological antioxidants.

Topics: Animals; Anti-Arrhythmia Agents; Antioxidants; Blood Glucose; Body Weight; Carbolines; Cardiomyopathies; Catalase; Cholesterol; Diabetes Mellitus, Experimental; Drinking; Eating; Glutathione Peroxidase; Heart; Male; Myocardium; Oxidation-Reduction; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Triglycerides; Ubiquinone; Vitamin E

Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia.. Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily).. Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g).. Our in-vitro data suggest that both iron chelators and antioxidant drugs that may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.

Topics: Adult; Antioxidants; Benzoquinones; Cardiac Volume; Cardiomyopathies; Child; Electron Transport Complex II; Female; Friedreich Ataxia; Humans; Iron Chelating Agents; Male; Multienzyme Complexes; Myocardium; Oxidoreductases; Succinate Dehydrogenase; Ubiquinone

The aim of the study was to show whether the ACE inhibitor captopril is able to protect the heart against the deleterious effect of passive cigarette smoking on left ventricular mitochondria. Four groups of rabbits were investigated: control (C), passive smoking of three cigarettes twice daily/30 minutes (S), control + captopril (7.5 mg/kg body weight twice daily) (Cap), and smoking + captopril (SCap) as in group 2 and 3. Three weeks lasting passive smoking impaired oxidative phosphorylation, diminished cytochrome oxidase activity and increased the mitochondrial F1-ATPase protein concentration. Moreover, the level of coenzyme Q10 (CoQ10) and coenzyme Q9 were decreased. Simultaneous treatment with captopril prevented partly the decrease of CoQ10 level, deterioration of oxidative phosphorylation, diminution of cytochrome oxidase activity and enhancement of F1-ATPase level. We conclude that captopril protected the myocardium against the harmful effect of passive smoking in rabbits.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cardiomyopathies; Coenzymes; Electron Transport; Electron Transport Complex IV; Energy Metabolism; Heart Ventricles; Mitochondria, Heart; Mitochondrial Myopathies; Oxidative Phosphorylation; Proton-Translocating ATPases; Rabbits; Tobacco Smoke Pollution; Ubiquinone

Coenzyme Q10 and alpha-tocopherol concentrations were assessed in 28 endomyocardial biopsies from 22 patients and in 61 blood samples from 31 patients after heart transplantation with histologically confirmed signs of rejection. The values were compared to the group of 14 patients with cardiomyopathies of unclear etiology as candidates for heart transplantation. Blood analyses were also compared with 50 healthy persons. Myocardial and blood coenzyme Q10 concentrations were already significantly decreased in the incipient phase of rejection (degree 0-1) and also in rejection phase 1 and 2. In patients without rejection signs myocardial and blood coenzyme Q10 values were similar to those of cardiomyopathic patients. No significant differences were found in alpha-tocopherol concentrations in relation to signs of rejection. Increased plasma lipid peroxidation quantified as malondialdehyde production was detected in all groups of transplanted patients. The results contribute to the explanation of some pathobiochemical mechanisms participating in the rejection development of the transplanted heart.

Topics: Adult; Biopsy; Cardiomyopathies; Coenzymes; Endocardium; Female; Graft Rejection; Heart Transplantation; Humans; Male; Malondialdehyde; Middle Aged; Myocardium; Osmolar Concentration; Postoperative Period; Reference Values; Ubiquinone; Vitamin E

Mitochondrial cardiomyopathies are being studied as metabolic diseases of the cardiac muscle which represents a new approach in metabolic studies. The development of mitochondrial diseases is concomited by an impairment in complexes of mitochondrial respiratory chain, which so far could have been possibly studied exclusively on experimental animals. The method of skinned? fibers enables to measure the pathobiochemical processes in mitochondria in a small amount of bioptic myocardial tissue of patients.. The study is aimed at: applying the method of skinned fibers in biopsy of myocardium in patients, trying to localize the impaired loci of the mitochondrial respiratory chains, prospective early and fast assessment of the diagnosis of mitochondrial cardiomyopathy in patients.. The study brings the first information on the possibility of performing more value measurements of mitochondrial respiratory chains per one bioptic sample from the myocardium in patients. The preliminary results indicate to the prospective possibility of early and fast assessment of the diagnosis of mitochondrial cardio(myo)pathies. The presented results require complementary studies involving the development of "mitochondrial medicine".

Topics: Biopsy; Cardiomyopathies; Flavin-Adenine Dinucleotide; Humans; In Vitro Techniques; Mitochondria, Heart; Mitochondrial Myopathies; Myocardium; NAD; Oxygen Consumption; Ubiquinone

The coenzyme Q10 (ubiquinone) plays an important role in bioenergetic conditions in myocardiac cells and together with alpha-tocopherol they act as endogenous antioxidants. Decreased levels in coenzyme Q10 were confirmed in some types of cardiomyopathies and in failing myocardium. Insufficiency of E vitamin is a risk factor in cardiovascular diseases. The study investigates the levels of coenzyme Q10 and alpha-tocopherol in the blood and in bioptic samples of the myocardium in patients with cardiopathies of unknown origin and it is aimed at their application as an auxiliary diagnostic method. The authors have introduced a method of coenzyme Q10 and alpha-tocopherol assessment from the bioptic samples of the myocardium, from the blood and plasma of these patients by means of high-performance liquid chromatography (HPLC). The authors detected decreased levels of coenzyme Q10 in the myocardium and blood of patients with cardiopathies. The dependence on the functional state of the myocardium according to NYHA was not confirmed due to the small number of patients. The plasmatic alpha-tocopherol levels decreased in dependence on the severeness of the disease. A more significant dependence was detected between the levels of alpha-tocopherol in the myocardium and its functional state. The average myocardial level of alpha-tocopherol in patients of the NYHA II group was almost ten-fold higher than in the NYHA II group. The gained results appoint to the meaning of investigation of the coenzyme Q10 and alpha-tocopherol in patients with cardiopathies of unknown origin and give a hint of prospective possibilities for application in the diagnosis assessment.

Topics: Cardiomyopathies; Chromatography, High Pressure Liquid; Humans; Myocardium; Ubiquinone; Vitamin E

Pathobiochemical mechanisms which participate in the rejection of transplanted heart are not fully clarified. A significant role in this process can be played by endogenous antioxidants, especially coenzyme Q10 which aside from its antioxidative properties is inevitable for cellular bioenergy. The authors investigated the concentration of Q10 alpha-tocopherol in endomyocardial biopsies in the blood in 11 patients from 1 to 9 years of age after transplantation of the heart (HTx-pat) examined in UKVCH in Bratislava who were compared with the group of 13 patients with cardiopathies of unclear origin (KPNP-pat) as possible candidates for transplantation. They detected a decreased concentration of coenzyme Q10 in the myocardium and blood of HTx-patients. Levels of alpha-to-copherol in the myocardium were identical in both groups, in plasma they were higher in patients after HTx. The authors suppose that the levels of coenzyme Q10 in patients after HTx can be influenced by an increased production of free oxygen radicals during rejection episodes, as well as immunosuppressive therapy, and indicate to the possible consequences of this decrease. The presented results provide the first information on the levels of coenzyme Q14 and alpha-tocopherol in patients after transplantation of the heart, registered and controlled in the Slovak Republic. They can contribute to the clarification of some pathobiochemical mechanisms of rejection, respectively to their therapeutic effect. (Fig. 2, Ref. 16.).

Topics: Antioxidants; Cardiomyopathies; Coenzymes; Heart Transplantation; Humans; Ubiquinone; Vitamin E

Overt mitochondrial diseases associated with mitochondrial DNA mutations are characterized by a decline in mitochondrial respiratory function. Similarly, a progressive decline in mitochondrial respiratory function associated with mitochondrial DNA mutations is clearly evidenced in aged human subjects. This communication is concerned with the development of a rat model for the study of bioenergy decline associated with the ageing process and overt mitochondrial diseases. The model involves the treatment of young rats with AZT to induce skeletal and cardiac myopathies. It has shown that there is a decline in soleus muscle function in vivo and that this decline is mirrored in the capacity of heart sub-mitochondrial particles to maintain bioenergy function. Coenzyme Q10 and several analogs were administered with AZT as potential therapeutics for the re-energization of affected tissues. Coenzyme Q10 and especially decyl Q were found to be therapeutically beneficial by both in vivo improvement in soleus muscle function and in vitro cardiac mitochondrial membrane potential capacity. Sub-mitochondrial particles were also prepared from heart mitochondria of young and aged rats. The particles prepared from the aged rats were found to have a decreased ability to maintain membrane potential as compared to those derived from the young rats.

Topics: Animals; Cardiomyopathies; Coenzymes; Humans; Mitochondria, Heart; Mitochondrial Myopathies; Muscle, Skeletal; Oxidation-Reduction; Rats; Submitochondrial Particles; Ubiquinone; Zidovudine

Symptoms of fatigue and activity impairment, atypical precordial pain, and cardiac arrhythmia frequently precede by years the development of congestive heart failure. Of 115 patients with these symptoms, 60 were diagnosed as having hypertensive cardiovascular disease, 27 mitral valve prolapse syndrome, and 28 chronic fatigue syndrome. These symptoms are common with diastolic dysfunction, and diastolic function is energy dependent. All patients had blood pressure, clinical status, coenzyme Q10 (CoQ10) blood levels and echocardiographic measurement of diastolic function, systolic function, and myocardial thickness recorded before and after CoQ10 replacement. At control, 63 patients were functional class III and 54 class II; all showed diastolic dysfunction; the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%, and 7% showed significant myocardial hypertrophy, and 87%, 30%, and 11% had elevated blood pressure readings in hypertensive disease, mitral valve prolapse and chronic fatigue syndrome respectively. Except for higher blood pressure levels and more myocardial thickening in the hypertensive patients, there was little difference between the three groups. CoQ10 administration resulted in improvement in all; reduction in high blood pressure in 80%, and improvement in diastolic function in all patients with follow-up echocardiograms to date; a reduction in myocardial thickness in 53% of hypertensives and 36% of the combined prolapse and fatigue syndrome groups; and a reduced fractional shortening in those high at control and an increase in those initially low.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Cardiomyopathies; Coenzymes; Diastole; Energy Metabolism; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Ubiquinone

This study was undertaken to determine if long-term oral administration of lovastatin (50 mg/kg per day) or fenofibrate (200 mg/kg per day) was affecting ubiquinone levels in the heart and the liver of cardiomyopathic hamsters. After 23 weeks of treatment, ubiquinone concentrations (CoQ9 + CoQ10) and ubiquinone ratio (CoQ10/CoQ9) were determined in the heart and in the liver. Our results indicate that lovastatin significantly decreased ubiquinone concentrations in the heart (-33%, P < 0.01) but not in the liver (-23%, NS) when compared to controls, whereas fenofibrate did not alter these parameters. Ubiquinone homologues were not equally decreased during lovastatin treatment: the ratio between CoQ10 and CoQ9 was significantly lowered in the heart (-33%, P < 0.001) and in the liver (-75%, P < 0.001) of lovastatin-treated animals. These results suggest that 3-hydroxymethylglutaryl-coenzyme A reductase inhibition (HMG-CoARI) associated with lovastatin treatment in cardiomyopathic hamsters is more marked in the liver than in the heart, while ubiquinone concentrations are more decreased in cardiac than in hepatic tissues. Our data also showed that fenofibrate had no effect on ubiquinone levels.

Topics: Animals; Body Weight; Cardiomyopathies; Cricetinae; Female; Fenofibrate; Heart; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Lovastatin; Male; Mesocricetus; Myocardium; Ubiquinone

Topics: Adolescent; Adult; Cardiomyopathies; Child; Circadian Rhythm; Coenzymes; Female; Graft Rejection; Heart Transplantation; Humans; Male; Middle Aged; Myocardial Ischemia; Physical Exertion; Reference Values; Ubiquinone

Twenty years of international open and seven double blind trials established the efficacy and safety of coenzyme Q10 (CoQ10) to treat patients in heart failure. In the U.S., ca. 20,000 patients under 65 years are eligible for transplants, but donors are less than 1/10th of those eligible, and there are many more such patients over 65, both eligible and ineligible. We treated eleven exemplary transplant candidates with CoQ10; all improved; three improved from Class IV to Class I; four improved from Classes III-IV to Class II; and two improved from Class III to Class I or II. After CoQ10, some patients required no conventional drugs and had no limitation in lifestyle. The marked improvement is based upon correcting myocardial deficiencies of CoQ10 which improve mitochondrial bioenergetics and cardiac performance. These case histories, and very substantial background proof of efficacy and safety, justify treating with CoQ10 patients in failure awaiting transplantation.

Topics: Adult; Aged; Cardiomyopathies; Cardiomyopathy, Dilated; Coenzymes; Female; Heart Transplantation; Humans; Male; Middle Aged; Ubiquinone

Coenzyme Q10 (10 mg/kg/day) or digoxin (2 micrograms/kg/day) was given orally to cardiomyopathic hamsters (BIO 14.6) for 8 weeks from 12 weeks of age. The left ventricular weight per gram of body weight (mg/g) was lower (p less than 0.01) in the coenzyme Q10 group (3.09 +/- 0.13) than in the digoxin (3.32 +/- 0.20) and control (3.44 +/- 0.14) groups. Left ventricular function was evaluated in isovolumically beating hearts. Left ventricular developed pressure (63 +/- 5 vs. 54 +/- 10 mmHg, p less than 0.05), -dP/dt (1385 +/- 100 vs. 1211 +/- 136 mmHg/sec, p less than 0.05), and -dP/dt (1068 +/- 126 vs. 896 +/- 141 mmHg/sec, p less than 0.05) were greater in the coenzyme Q10 than in the control group. The time constant of left ventricular relaxation was shorter in the coenzyme Q10 group than in the control group (25 +/- 3 vs. 28 +/- 3 msec, p less than 0.05). By contrast, in the digoxin group, the indices of left ventricular function did not differ from the control group. These results suggest that coenzyme Q10, but not digoxin, attenuated disease progression and preserved left ventricular function in cardiomyopathic hamsters.

Topics: Animals; Body Weight; Cardiac Volume; Cardiomyopathies; Cricetinae; Digoxin; In Vitro Techniques; Mesocricetus; Myocardial Contraction; Ubiquinone; Ventricular Function, Left

One hundred and forty-three cases of chronic, stable, non-secondary, non-hypertrophic cardiomyopathy, 98% of whom were in NYHA Classes III and IV, were given 100 mg of coenzyme Q10 orally in addition to their conventional medical programme in an open-label long-term study. Blood CoQ10 levels, clinical status, myocardial function and survival have been recorded now for almost 6 years. Mean control/CoQ10 levels of 0.85 micrograms/ml rose to 2 micrograms/ml in 3 months and remained stable at that level. Mean ejection fraction of 44% measured by systolic time interval analysis rose to 60% within 6 months and stabilized at that level with 84% of patients showing statistically significant improvement. Eighty-five percent of patients improved by one or two NYHA Classes. Survival figures were encouraging with an 11.1% mortality in 12 months and 17.8% mortality in 24 months, comparing favourably with several reports in the literature. There was no positive evidence of toxicity or intolerance in a total of 368.9 patient-years of exposure. Coenzyme Q10 is safe and effective long-term therapy for chronic cardiomyopathy.

Topics: Adult; Aged; Cardiomyopathies; Coenzymes; Drug Therapy, Combination; Female; Humans; Longitudinal Studies; Male; Middle Aged; Stroke Volume; Survival Rate; Ubiquinone

The rate of irreversible loss of mitochondrial phosphorylating respiratory function with NAD-linked substrates during zero flow myocardial autolysis at 37 degrees C was gradual and relatively linear with time, progressing at about 1% of the control activity per minute. State 3 respiratory rates and initial rates of inner membrane potential development dropped off in close parallel with one another as well as with NADH-coenzyme Q (CoQ) reductase activity, suggesting that oxygen uptake as well as membrane potential development were rate limited by the increasing impairment of electron flow through complex I. Although the initial rate of membrane potential development dropped off gradually, the time course for the loss of the ability to ultimately develop and hold a full potential was slower still, there being only a moderate impairment of this ability at 80 min of autolysis. This sustained ability to develop and hold a membrane potential after more than 1 h of autolysis suggested that inner membrane leakiness contributed little or not at all to the functional impairment observed. The irreversible loss of mitochondrial inner membrane competence emerged in these studies as a relatively late development in the sequence of cellular alterations which characterize the myocardial ischemic process.

Topics: Animals; Autolysis; Cardiomyopathies; Dogs; Enzyme Activation; Female; Male; Membrane Potentials; Mitochondria, Heart; NAD; Phosphorylation; Time Factors; Ubiquinone

The tissue levels of coenzyme Q10 (CoQ10) in endomyocardial biopsy samples and blood from 43 patients with cardiomyopathy were determined by steps of extraction, purification, and HPLC. The biopsy samples were obtained from the patients after a routine heart catheterization. Six patients were of class I, 18 of class II, 11 of class III, and 8 of class IV (classified according to guidelines of the New York Heart Association). True control biopsies of healthy hearts are not available for ethical reasons, but the data of the four classes by severity of disease may be justifiably compared. Patients of class IV had lower (P less than 0.01) levels of CoQ10 than those of class I. Patients of classes III and IV had a lower (P less than 0.0001) level than those of classes I and II. Biopsy samples were obtained from five patients after treatment with CoQ10 for 2-8 months. The increases of CoQ10 levels ranged from 20% to 85%; the mean value was higher (P less than 0.02) than before treatment. Blood deficiencies also increase with severity of disease, but not as markedly as for the biopsies. These data reveal a myocardial deficiency of CoQ10, which is higher with increasing severity of disease and is reduced by therapy. This biochemistry correlates with the effective treatment of cardiomyopathy with CoQ10.

Topics: Biopsy; Cardiomyopathies; Coenzymes; Humans; Myocardium; Ubiquinone

Topics: Animals; Cardiomyopathies; Coenzymes; Female; Isoproterenol; Male; Mitochondria, Heart; Myocardium; Necrosis; Rats; Ubiquinone

Adriamycin (ADR), one of the anthracycline derivatives, has the most strong cardiotoxicity. We studied the cardiotoxicity caused by ADR in New Zealand white rabbits and its protection by the medication of CoQ10. The findings of ECG and the myocardial tissue examined by the electron microscope showed the effectiveness of the injection of CoQ10 to prevent the cardiotoxicity caused by ADR. The concomitant injection of CoQ10 dissolved in saline was tried in patients with various kinds of neoplasm who were given more than 200 mg of ADR or DM. Only one patient showed the ST-T change. On the contrary, 3 of patients given more than 200 mg ADR or DM alone showed abnormal change of ECG.

Topics: Acute Disease; Adult; Aged; Animals; Arrhythmias, Cardiac; Cardiomyopathies; Coenzymes; Doxorubicin; Electrocardiography; Female; Heart; Humans; Leukemia; Lymphoma; Male; Middle Aged; Rabbits; Ubiquinone

Histochemical alterations of acute and chronic doxorubicin (DOX) cardiotoxicity in the mouse were assessed by the localization of succinate dehydrogenase (SDH), coenzyme Q10 (CoQ), cytochrome oxidase (COX), creatine phosphokinase (CPK), lactate dehydrogenase (LDH), reduced glutathione (GSH), and intracellular calcium. Isolated myocytes intensely stained for calcium were found at 72 and 120 h under the acute protocol; altered staining patterns of SDH, CoQ, and COX, were evident at 120 h. Chronically, two patterns of intracellular calcium staining were evident: (1) intensely stained myocytes as found in the acute protocol; and (2) multiple discrete intracellular deposits suggestive of mitochondrial localization. Altered staining patterns of SDH, CoQ, COX, CPK, and LDH under the chronic protocol were only seen after abnormal staining was evident in trichrome stained sections. The presence of characteristic vacuolated myocardial cells in both acute and chronic protocols was confirmed by one micron epon-embedded toluidine blue stained sections and electron microscopy. These histochemical findings suggest that DOX alters the functional integrity of mitochondrial respiratory chain enzymes in the myocardial cell.

Topics: Animals; Calcium; Cardiomyopathies; Creatine Kinase; Dose-Response Relationship, Drug; Doxorubicin; Enzymes; Glutathione; L-Lactate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Mitochondria, Heart; Myocardium; Oxidation-Reduction; Succinate Dehydrogenase; Ubiquinone

Topics: Animals; Cardiomyopathies; Cytochromes; Isoproterenol; Lipid Peroxides; Mitochondria, Heart; Oxygen Consumption; Rats; Ubiquinone

Pretreatment of Swiss Webster mice with coenzyme Q10 (CoQ) markedly reduced the lethality of the antitumor antibiotic anthramycin as well as its ability to decrease ventricular weights. In tumor-bearing mice CoQ pretreatment did not produce any consistent alteration of radioactivity levels in blood, heart, tumor, lungs, kidneys, liver, muscles, brain, or spleen after [15-3H]anthramycin administration. Gross alterations in anthramycin distribution is probably not the mechanism by which CoQ alters the cardiotoxicity and lethality of anthramycin.

Topics: Animals; Anthramycin; Benzodiazepinones; Cardiomyopathies; Heart Ventricles; Male; Mice; Organ Size; Time Factors; Tissue Distribution; Ubiquinone

Topics: Animals; Cardiomyopathies; Doxorubicin; Male; Rabbits; Time Factors; Ubiquinone

Topics: Animals; Cardiomyopathies; Doxorubicin; Myocardium; Rabbits; Ubiquinone; Verapamil