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The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q 10 . A review of animal and human publications
Abstract
The depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials. This drug-induced nutrient deficiency is dose related and more notable in settings of pre-existing CoQ10 deficiency such as in the elderly and in heart failure. Statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.
... This naturally occurring compound is ubiquitous in nature; thus, it is also known as ubiquinone. Coenzyme Q 10 exists in three oxidation states: the fully reduced ubiquinol form (CoQ 10 H 2 ), the radical semiquinone intermediate (CoQ 10 H . ), and the fully oxidized ubiquinone form (CoQ 10 ; Figure 1). Although similar in structure to some vitamins (eg, vitamin K), CoQ 10 is not a vitamin since it is synthesized in the body, whereas vitamins must be obtained from the diet. ...
... Coenzyme Q 10 exists in three oxidation states: the fully reduced ubiquinol form (CoQ 10 H 2 ), the radical semiquinone intermediate (CoQ 10 H . ), and the fully oxidized ubiquinone form (CoQ 10 ; Figure 1). Although similar in structure to some vitamins (eg, vitamin K), CoQ 10 is not a vitamin since it is synthesized in the body, whereas vitamins must be obtained from the diet. ...
... In its reduced form, ubiquinol, it is itself a potent lipophilic antioxidant and can recycle and regenerate other antioxidants in the body. Numerous other functions of CoQ 10 have been described, such as cell signaling, gene expression, and membrane stabilization. 2 ...
Coenzyme Q10 (CoQ10) is among the most widely used dietary and nutritional supplements on the market. CoQ10 has several fundamental properties that may be beneficial in several clinical situations. This article reviews the pertinent chemical, metabolic, and physiologic properties of CoQ10 and the scientific data and clinical trials that address its use in two common clinical settings: statin-associated myopathy syndrome (SAMS) and congestive heart failure (CHF). Although clinical trials of CoQ10 in SAMS have conflicting conclusions, the weight of the evidence, as seen in meta-analyses, supports the use of CoQ10 in SAMS overall. In CHF, there is a lack of large-scale randomized clinical trial data regarding the use of statins in patients receiving contemporary treatment. However, one relatively recent randomized clinical trial, Q-SYMBIO, suggests an adjunctive role for CoQ10 in CHF. Recommendations regarding the use of CoQ10 in these clinical situations are presented.
... Reports started to emerge in the early 1990s showing that statin treatment was associated with a significant reduction in CoQ10 levels (e.g., 29% reduction with 80 mg/day lovastatin and 20% reduction with 40 mg/day pravastatin) in a dose-dependent manner in both animal studies and human experiments recruiting healthy volunteers or patients with hypercholesterolemia [35]. This decrease in CoQ10 parallelled the decline of cholesterol and it was eventually detected with every statin tested [30,36]. The reduction in plasma CoQ10 was proportionally greater than the reduction in LDL-C in some studies [37], while it was similar in others [18]. ...
... Importantly, it was also shown that CoQ10 supplementation could completely prevent CoQ10 depletion. In humans, the statin-induced CoQ10 depletion is thought to be well tolerated in younger, healthy patients, especially in the short term, but in patients with preexisting heart disease or acute cardiac injury, there is reasonable evidence to support a detrimental effect [36]. Our patients were relatively young (48.7 ± 6.0 years of age) and this must be taken into consideration when interpreting our results. ...
Coenzyme Q10 (CoQ10) plays a crucial role in facilitating electron transport during oxidative phosphorylation, thus contributing to cellular energy production. Statin treatment causes a decrease in CoQ10 levels in muscle tissue as well as in serum, which may contribute to the musculoskeletal side effects. Therefore, we aimed to assess the effect of newly initiated statin treatment on serum CoQ10 levels after acute ST-elevation myocardial infarction (STEMI) and the correlation of CoQ10 levels with key biomarkers of subclinical or clinically overt myopathy. In this study, we enrolled 67 non-diabetic, statin-naïve early-onset STEMI patients with preserved renal function. Plasma CoQ10 level was determined by ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC/MS-MS), while the myopathy marker serum fatty acid-binding protein 3 (FABP3) level was measured with enzyme-linked immunosorbent assay (ELISA) at hospital admission and after 3 months of statin treatment. The treatment significantly decreased the plasma CoQ10 (by 43%) and FABP3 levels (by 79%) as well as total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B100 (ApoB100), and oxidized LDL (oxLDL) levels. The change in CoQ10 level showed significant positive correlations with the changes in total cholesterol, LDL-C, ApoB100, and oxLDL levels, while it did not correlate with the change in FABP3 level. Our results prove the CoQ10-reducing effect of statin treatment and demonstrate its lipid-lowering efficacy but contradict the role of CoQ10 reduction in statin-induced myopathy.
... One example is its co-administration with HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) inhibitors, widely used cholesterol-lowering drugs otherwise known as statins. HMGR catalyzes the formation of mevalonic acid, the precursor for cholesterol and CoQ 10 biosyntheses [27]. Patients using statins show lower blood levels of CoQ 10 , and this justifies the need for CoQ 10 supplementation to reduce the cardiomyopathy risk associated with statin use [27][28][29][30]. ...
... HMGR catalyzes the formation of mevalonic acid, the precursor for cholesterol and CoQ 10 biosyntheses [27]. Patients using statins show lower blood levels of CoQ 10 , and this justifies the need for CoQ 10 supplementation to reduce the cardiomyopathy risk associated with statin use [27][28][29][30]. The presence of CoQ 10 is however implicated in resistance to chemotherapeutic drugs, and this calls for caution in administering CoQ 10 alongside certain agents [31,32]. ...
Coenzyme Q10 (CoQ10), a benzoquinone present in most organisms, plays an important role in the electron-transport chain, and its deficiency is associated with various neuropathies and muscular disorders. CoQ10 is the only lipid-soluble antioxidant found in humans, and for this, it is gaining popularity in the cosmetic and healthcare industries. To meet the growing demand for CoQ10, there has been considerable interest in ways to enhance its production, the most effective of which remains microbial fermentation. Previous attempts to increase CoQ10 production to an industrial scale have thus far conformed to the strategies used in typical metabolic engineering endeavors. However, the emergence of new tools in the expanding field of synthetic biology has provided a suite of possibilities that extend beyond the traditional modes of metabolic engineering. In this review, we cover the various strategies currently undertaken to upscale CoQ10 production, and discuss some of the potential novel areas for future research.
... This study identified a novel frameshift mutation in the HMGCR gene that is associated with unresponsiveness to atorvastatin in DM2 patients. The presence of this mutation may lead to the production of truncated HMG-CoA reductase proteins, potentially impairing the drug's efficacy in lowering cholesterol levels 47 . These findings align with previous research suggesting genetic factors play a crucial role in statin responsiveness 48 . ...
Dyslipidemia, an imbalance in blood lipid levels, is a frequent complication of type 2 diabetes mellitus (DM2) and heightens the risk of cardiovascular diseases (CVDs). Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, are potent competitive inhibitors that reduce plasma cholesterol levels. However, individual responses to statins can vary markedly, possibly due to genetic variations in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. This study aimed to investigate the pharmacogenetic relationship between the HMGCR gene and hypercholesterolemia in type 2 diabetes mellitus patients who respond differently to atorvastatin, as well as in healthy individuals. Ninety participants were involved, including sixty with type 2 diabetes mellitus and hypercholesterolemia, and thirty healthy individuals. They were randomly assigned to three groups: responsive (received atorvastatin 40 mg), non-responsive (also received atorvastatin 40 mg), and control. Both responsive and non-responsive groups underwent fasting. Biochemical tests were conducted, followed by genetic analysis to identify mutations in the HMGCR gene. The effects of statins in each group were assessed using analysis of variance (ANOVA) and post hoc Tukey’s Honestly Significant Difference (HSD) analysis. Atorvastatin 40 mg was administered to assess its efficacy in reducing cholesterol levels in patients with hypercholesterolemia and type 2 diabetes mellitus. The control group exhibited similar cholesterol levels to the responsive group (cholesterol < 200 mg/dl). However, both control and responsive groups significantly differed from the non-responsive group, which had markedly elevated cholesterol levels (> 240 mg/dl). Genetic analysis revealed a cytosine nucleotide insertion in the catalytic domain of the HMGCR gene in only two non-responsive participants to atorvastatin 40 mg therapy. These two patients showed non-responsiveness to atorvastatin 40 mg due to a genetic mutation in the HMGCR gene. This mutation altered the amino acid sequence in the flap domain, replacing isoleucine with a stop codon. As a result, translation was prematurely terminated, leading to the production of truncated proteins.
... The reason for its inclusion was the evidence that most patients with statinassociated muscle symptoms (SAMS)-included in the broader concept of statin-induced myopathy-show overt coenzyme Q10 reduction in blood and muscle samples. [57][58][59] That evidence has led to several clinical trials designed to clarify whether Q10 supplementation could be useful to treat SAMS, although contradictory results show that the effect remains controversial. [60][61][62][63] Whether a coenzyme Q10 deficit is directly pathogenic is not known. ...
Background and Objectives
Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype.
Methods
Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis–related genes and high-resolution human leukocyte antigen (HLA) typing were performed.
Results
Patients, aged 3–25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls.
Discussion
WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis–related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.
... enzyme, which is involved in the synthesis of CoQ10 in the body (Nawarskas, 2005), by reducing the transfer of CoQ10 in the plasma following a decrease in the level of LDL as a carrier of CoQ10 (Marcoff & Thompson, 2007), and also by reducing its bioavailability (Potgieter et al., 2013). Therefore, these people may have seen better effects by increasing their serum CoQ10 levels after taking CoQ10 supplements (Langsjoen & Langsjoen, 2003). ...
Coenzyme Q10 is a potent antioxidant and is necessary for energy production in mitochondria. Clinical data have suggested that coenzyme Q10 (CoQ10) has some beneficial effects on liver function. However, these results are equivocal. This systematic review and meta‐analysis aimed to clarify the effect of coenzyme Q10 supplementation on the serum concentration of liver function enzymes. We searched the online databases using relevant keywords up to April 2022. Randomized clinical trials (RCTs) investigating the effect of CoQ10, compared with a control group, on serum concentrations of liver enzymes were included. We found a significant reduction following supplementation with CoQ10 on serum concentrations of alanine aminotransferase (ALT) based on 15 effect sizes from 13 RCTs (weighted mean difference [WMD] = −5.33 IU/L; 95% CI: −10.63, −0.03; p = .04), aspartate aminotransferase (AST) based on 15 effect sizes from 13 RCTs (WMD = −4.91 IU/L; 95% CI: −9.35, −0.47; p = .03) and gamma‐glutamyl transferase (GGT) based on eight effect sizes from six RCTs (WMD = −8.07 IU/L; 95% CI: −12.82, −3.32; p = .001; I ² = 91.6%). However, we found no significant effects of CoQ10 supplementation on alkaline phosphatase concentration (WMD = 1.10 IU/L; 95% CI: −5.98, 8.18; p = .76). CoQ10 supplementation significantly improves circulating ALT, AST, and GGT levels; therefore, it might positively affect liver function. Further high‐quality RCTs with more extended intervention periods and larger sample sizes are recommended to confirm our results.
... Mitochondrial dysfunction and oxidative stress are also very likely to contribute to cognitive disturbances. Statins inhibit the synthesis of mevalonate, which serves to produce both cholesterol and coenzyme Q10 [88]. Coenzyme Q10 is essential for the normal functioning of mitochondria and the production of adenine triphosphate (ATP), which is why statin-induced coenzyme Q10 depletion has been thought to be involved in excessive fatigue and myopathies [89]. ...
Statin therapy has been extensively evaluated and shown to reduce the incidence of new or recurrent vascular events, ischemic stroke included. As a consequence, each published guideline pushes for lower low-density cholesterol levels in the population at large, recommending increased statin doses and/or adding new cholesterol-lowering molecules. Neurologists find it sometimes difficult to apply these guidelines, having to confront situations such as (1) ischemic strokes, mainly cardioembolic ones, in patients with already low LDL-cholesterol levels; (2) myasthenic patients, whose lifespan has been extended by available treatment, and whose age and cholesterol levels put them at risk for ischemic stroke; (3) patients with myotonic dystrophy, whose disease often associates diabetes mellitus and heart conduction defects, and in whom blood cholesterol management is also not settled. As such, further trials are needed to address these issues.
... Statins are the most common pharmacological intervention option for cholesterol regulation. They are inhibitors of hydroxyl methylglutaryl-coenzyme-A (HMG-CoA), the key catalytic enzymes in the rate-limiting step of cholesterol biosynthesis 42 . PGE2 synthesis is governed by COX-2, and PGE2 interacts with the E prostanoid receptor (EPR) to activate downstream signals. ...
Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer adaptive immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs involving lipid modulations have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.
... In fact, statin-related myopathy has been reported to be associated with muscular mitochondrial dysfunction [39,40]. Mechanism(s) by which statins cause these muscular side effects has not been fully elucidated, however, other studies have reported that the depletion of CoQ 10 , which is also produced via the cholesterol metabolic pathway, might be the potential mechanism [41,42]. Although not completely understood, the depletion of CoQ 10 with regular statin intake could be related to the continued rise in CVD-related deaths in some patients. ...
Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitably process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevaonate pathway like farnesyl pyrophosphate and coenzyme Q10 (CoQ10). The latter is by far the most important co-factor and co-enzyme required for effeicient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ10 has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia. Thus, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintatinin CoQ10 levels in conditions of dyslipidemia. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review explores the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway. More importantly, the ability of these compounds to block cholesterol while maintaining CoQ10 biosynthesis to protect against the destructive complications of dyslipidemia.
... On the other hand, high cholesterol levels are associated with an increased risk of Alzheimer's disease [97,98]. In this case, the protective effect of statins would be attributed to the pleiotropic effects of these drugs (reduced endothelial dysfunction, increased endothelial nitric oxide production, anti-inflammatory, antioxidant, and antithrombotic properties, vascular generation and other angioprotective properties) [99,100]. ...
Atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality are decreasing in high-income countries, but ASCVD remains the leading cause of morbidity and mortality in high-income countries. Over the past few decades, major risk factors for ASCVD, including LDL cholesterol (LDL-C), have been identified. Statins are the drug of choice for patients at increased risk of ASCVD and remain one of the most commonly used and effective drugs for reducing LDL cholesterol and the risk of mortality and coronary artery disease in high-risk groups. Unfortunately, doctors tend to under-prescribe or under-dose these drugs, mostly out of fear of side effects. The latest guidelines emphasize that treatment intensity should increase with increasing cardiovascular risk and that the decision to initiate intervention remains a matter of individual consideration and shared decision-making. The purpose of this review was to analyze the indications for initiation or continuation of statin therapy in different categories of patient with high cardiovascular risk, considering their complexity and comorbidities in order to personalize treatment.
... The administration of CoQ10 has been suggested to prevent and treat statin-induced myopathy. In fact, Langsjoen and Langsjoen (2003) recommended to use supplemental CoQ10 with all HMG-CoA reductase inhibitors, since its increased potency or dose could result in a more severe CoQ10 depletion, leading to an increased likelihood of heart muscle function impairment. Caso, Kelly, McNurlan, and Lawson (2007) and Littlefield, Beckstrand, and Luthy (2014) reported that CoQ10 supplementation (30 to 200 mg/day) may decrease muscular pain associated with statin treatment, offering an alternative to treatment discontinuation. ...
World population growth and aging are posing unprecedented challenges in sustaining the health of 9.1 billion people that will be occupying the planet by 2050. Although noncommunicable diseases such as cardiovascular and neurodegenerative diseases, cancer, and diabetes are among the top 10 global causes of death, they can be prevented by risk factor reduction, early detection, and adequate treatment. Since a healthy diet along with dietary supplementation could play an important role to reduce morbidity and cut off its associated health care costs, research in the food and nutrition area is required to find solutions to global challenges affecting health.
As a result of the healthy living trend, dietary supplements category is growing fast, leading to an urgent need for dietitians, physicians, and policy makers to broaden the scientific evidence on the efficacy and safety of a wide range of active ingredients. Coenzyme Q10 (CoQ10), as the third most consumed dietary supplement, and as a potential candidate for the treatment of various noncommunicable diseases that are among the global top 10 causes of death, has gained interest over years. Scientific evidence regarding mainly CoQ10 efficacy and safety, as well as formulation challenges, is addressed in this review.
... The commonly prescribed cholesterol-lowering medications known as statins are primarily indicated for atherosclerotic cardiovascular disease management and risk reduction. 1 Statins impact cholesterol metabolism via the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis that catalyzes the conversion of HMG-CoA to mevalonic acid in the mevalonate (MVA) pathway. 2 A recent, thorough review by Collins et al. 3 reports that, among clinicians, the cause of adverse effects of statins on muscle cells are still unknown, although much of the evidence points to alterations in mitochondria. To that end, the MVA pathway also results in the synthesis of important isoprenoids, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP); precursors of cholesterol and other products that regulate numerous cellular functions. ...
Simvastatin, a commonly used cholesterol‐lowering drug, inhibits the mevalonate pathway involved in the synthesis of the mitochondrial electron carrier Coenzyme Q10, as well as other bioenergetics substrates. The purpose of this study was to investigate simvastatin exposure on mitochondrial respiration, metabolic fuel preferences, and glucose utilization. We hypothesized that simvastatin at a non‐cytotoxic dose will impair energy metabolism in human neuroblastoma cells. SK‐N‐AS cells were exposed at acute and chronic time points and evaluated in a Seahorse XF analyzer, revealing decreased mitochondrial and glycolytic parameters. Flow cytometry showed a significant induction of apoptosis in simvastatin‐treated cells at 48 hours. Finally, multiple techniques were used to show that simvastatin‐mediated impairment of bioenergetics is more complex than CoQ10 depletion or hampered glucose uptake. Therefore, the data reported here represents a biphasic hit to mitochondria followed by reduction in glucose and glutamine metabolism in neuroblastoma; adding mechanism to potential pleotropic effects of statins.
... Coenzyme Q10 lowers lipoprotein(a) and improves dyslipidemia medicine [91,92]. ...
... 3 The impairment of mitochondrial energy production by low levels of myocardial coenzyme Q10 (CoQ10) 4 and statin-induced depletion of CoQ10 have been described. 5 A clinical trial of 14 patients with hypercholesterolemia treated with 20 mg of atorvastatin for 6 months documented the development of diastolic dysfunction in 10 of the 14 patients that was reversed with CoQ10 supplementation at 300 mg/d. 6 Our hypothesis is that statin-induced CoQ10 depletion may cause impairment in diastolic function and that the widespread use of statin therapy, particularly in elderly individuals, may be a contributor to the increasing incidence of HF. ...
Context
Heart failure (HF) is rapidly increasing in incidence and is often present in patients receiving long-term statin therapy.
Objective
To test whether or not patients with HF on long-term statin therapy respond to discontinuation of statin therapy and initiation of coenzyme Q10 (CoQ10) supplementation.
Design
We prospectively identified patients receiving long-term statin therapy in whom HF developed in the absence of any identifiable cause. Treatment consisted of simultaneous statin therapy discontinuation and CoQ10 supplementation (average dosage = 300 mg/d).
Main Outcome Measures
Baseline and follow-up physical examination findings, symptom scores, echocardiograms, and plasma CoQ10 and cholesterol levels.
Results
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%.
Conclusion
In patients receiving long-term statin therapy, statin-associated cardiomyopathy may develop that responds safely to statin treatment discontinuation and CoQ10 supplementation. Statin-associated cardiomyopathy may be a contributing factor to the current increasing prevalence of HF with preserved EF.
... It also makes the injured myocardium more susceptible to ischemia, accelerating the process of HF [13,35]. Inadequate micronutrients may be intensified by medical interventions such as cholesterol-lowering HMG-CoA reductase inhibitors exacerbate present nutritional deficiency and limiting long-term treatment success [36][37][38][39][40][41]. However, plasma concentration of micronutrient compounds may not reflect tissue levels because of large transmembrane cellular gradients [42][43][44][45][46]. ...
The increasing recognition of deficiency of certain essential micronutrients in the failing heart suggests that they may be involved in the pathogenesis of nutritional deficiency cardiomyopathy (NDCM) and ultimately heart failure (HF). Chronic deficits in thiamine, carnitine, selenium, niacin, taurine and Coenzyme Q10 in the myocardial tissues have already been associated with alterations in myocardial energy production, calcium balance or oxidative defences. These pathologic changes may lead to metabolic or myocardial remodelling progressing into NDCM. Due to the severity of potential outcomes of untreated NDCM, it is important for cardiologists to have a good understanding of NDCM. More importantly, NDCM is a treatable phenotype of dilated or hypertrophic cardiomyopathy (CM). Early detection and prompt initiation of nutrient supplementation therapy (NST) has the potential to reverse pathologic myocardial changes and resolve cardiac symptoms. However, current expert consensus guidelines on the treatment of HF do not expressly recommend or are conspicuously silent about the use of NST possibly attributable to inconsistent findings by several small-scale trials and the lack of reliable data by large-scale randomized clinical trials. This review summarizes the existing published data about NDCM with an emphasis on the specific aetiologic micronutrients deficiencies, including their pathophysiology, manifestation, diagnosis and clinical management. This review also identifies gaps in current studies and areas of limited knowledge to move forward with research to fill these critical gaps in knowledge.
... Leakage of oxygen and high energy electrons from mitochondria is a primary source of oxidative stress in cells and is increased when key protective nutrients are lacking. 78 The role of mitochondrial damage in aging and chronic disease, including neurodegenerative disease, is now well established. 127 Flavonoid capacity to support mitochondrial function could, therefore, provide critical neuroprotective effects that can positively influence health outcomes in chronic glaucoma. ...
Current treatment strategies for glaucoma are limited to halting disease progression and do not restore lost visual function. Intraocular pressure is the main risk factor for glaucoma, and intraocular pressure–lowering treatment remains the mainstay of glaucoma treatment, but even successful intraocular pressure reduction does not stop the progression of glaucoma in all patients. We review the literature to determine whether nutritional interventions intended to prevent or delay the progression of glaucoma could prove to be a valuable addition to the mainstay of glaucoma therapy. A total of 33 intervention trials were included in this review, including 21 randomized controlled trials. These suggest that flavonoids exert a beneficial effect in glaucoma, particularly in terms of improving ocular blood flow and potentially slowing progression of visual field loss. In addition, supplements containing forskolin have consistently demonstrated the capacity to reduce intraocular pressure beyond the levels achieved with traditional therapy alone; however, despite the strong theoretical rationale and initial clinical evidence for the beneficial effect of dietary supplementation as an adjunct therapy for glaucoma, the evidence is not conclusive. More and better quality research is required to evaluate the role of nutritional supplementation in glaucoma.
... A szubsztitúció megszakítása után mintegy 33 órával a plazmaszint csökkenni kezdett, de egy hónappal később még mindig 74%-kal volt magasabb a kiindulási értéknél, sőt a kiindulási plazmaszint csak 6 hónappal később tért vissza (22). Legtöbb CoQ 10 -et a marha és disznó belsőségek, a szardínia és a vörös húsú halak, az olajok és az olajos magvak tartalmazzák, a táplálékkal bevihető mennyiséget azonban csak napi 3-5 mg-ra becsülik (18,19,23). Mivel a CoQ 10 veleszületett hiányállapotai kedvezően reagáltak a molekula szubsztitúciójára, a kutatók figyelme arra irányult, hogy milyen más kórfolyamatokban lehetne kedvező hatást elérni a CoQ 10 pótlásával. ...
... This effect is harmful to patients with heart failure [109]. That fact was proved in many clinical studies [98,[110][111][112][113][114][115]. In such a way, it was concluded that it is better to administrate CoQ 10 supplementation simultaneously with statin therapy to avoid myopathic side effects. ...
The burden of cardiovascular and metabolic diseases is increasing with every year. Although the management of these conditions has improved greatly over the years it is still far from perfect. With all of this in mind, there is a need for new methods of prophylaxis and treatment. Coenzyme Q10 (CoQ10) is an essential compound of the human body. There is growing evidence that CoQ10 is tightly linked to cardiometabolic disorders. Its supplementation can be useful in a variety of chronic and acute disorders. This review analyses the role of CoQ10 in hypertension, ischemic heart disease, myocardial infarction, heart failure, viral myocarditis, cardiomyopathies, cardiac toxicity, dyslipidemia, obesity, type 2 diabetes mellitus, metabolic syndrome, cardiac procedures and resuscitation.
... They have been widely used in atherosclerosis treatment for many years. While their actual effect has come under increasing scrutiny in recent years (62), statins remain an effective HMG-CoA reductase inhibitor. Atorvastatin can normalize T cell signaling and reduce the production of IL-10 and IL 6 by inhibiting cholesterol biosynthesis and reducing cholesterol levels in the T cell membrane (42). ...
Compartmentalization and spatial control of biochemical reactions is the foundation of cell-based life on earth. The lipid bilayer system employed by eukaryote cells not only keeps them separate from the environment but also provides a platform for key receptors to sense and interact with outside factors. Arguably one of the cell types most reliant on interactions of this kind, immune cells depend on their membrane to keep functioning properly. In this review, the influence of variation in cholesterol levels, a key component of lipid bilayer stability, on T cells will be discussed in detail. In comparison to other cells, T cells must be able to undergo rapid activation followed by proliferation. Furthermore, receptor colocalization is an important mechanism in this activation process. The impact of cholesterol availability on the processes of T cell proliferation and receptor sensitivity, as well as its potential for immunomodulation in disease treatment will be considered.
... On the other side, statins-induced systemic HMG-CoA reductase inhibition has been shown to reduce levels of farnesyl pyrophosphate, the intermediate product of the mevalonate cycle, leading to coenzyme Q10 (CoQ10, ubiquinone) and dilicol depletion. 20 CoQ10 is a lipid-soluble endogenous proenzyme with established implication in oxidative phosphorylation and energy metabolism as well as the antioxidant defense system. While CoQ10 supplementation was soon recognized to improve statins-induced myopathy, 21 recent investigations suggest that coenzyme Q10 might be also a promising prescription for neurodegenerative disorders like Parkinson's disease. ...
Objectives:
Coenzyme Q10 (CoQ10, ubiquinone) stands among the safest supplements in the elderly to protect against cardiovascular disorders. Noteworthy, CoQ10 deficiency is common in many surviving stroke patients as they are mostly prescribed statins for the secondary prevention of stroke incidence lifelong. Accordingly, the current study aims to experimentally examine whether CoQ10 supplementation in animals receiving atorvastatin may affect acute stroke-induced injury.
Methods:
Adult rats underwent transient middle cerebral artery occlusion after atorvastatin pretreatment (5 or 10 mg/ kg/day; po; 30 days) with or without CoQ10 (200 mg/kg/day). After 24 hours ischemic/reperfusion injury, animals were subjected to functional assessments followed by cerebral molecular and histological to detect inflammation, apoptosis and oxidative stress.
Results:
Animals dosed with 10 mg/kg presented the worst neurological function and brain damage in the acute phase of stroke injury. CoQ10 supplementation efficiently improved functional deficit and cerebral infarction in all stroke animals, particularly those exhibiting statin toxicity. Such benefits were associated with remarkable anti-inflammatory and anti-apoptotic effects, based on the analyzed tumor necrosis factor-a, interleukin-6, Bax/Bcl2 and cleaved caspase 3/9 immunoblots. Importantly, our fluoro-jade staining data indicated CoQ10 may revert the stroke-induced neurodegeneration. No parallel alteration was detected in stroke-induced oxidative stress as determined by malondialdehyde and 8-oxo-2'-deoxyguanosine levels.
Discussion:
These data suggest that all stroke animals may benefit from CoQ10 administration through modulating inflammatory and degenerative pathways. This study provides empirical evidence for potential advantages of CoQ10 supplementation in atorvastatin-receiving patients which may not shadow its antioxidant properties.
... This leakage increases when key nutrients/protective molecules are missing, such as the dose-dependent depletion of CoQ 10 in patients taking statin drugs-a problem that has been known for a long time. 7 Note in Figure 3 that the highenergy electrons are transported between the various mitochondrial complexes by CoQ 10 . Many factors are associated with increased damage to the mitochondria. ...
... This eventually ends up in a marked deficit resulting in a suboptimal Q10 levels, being underlined by the fact that mostly in every chronic ailment there is a significant deficit in Q10-levels. In this context it is also noteworthy that any patient taking a statin drug for high cholesterol levels, because of the blockade of the enzyme HMG-CoA reductase, this ultimately will endup in a deficit of the coenzyme Q10, as both have an upstream common pathway, which is blocked by the statin drug resulting in a cholesterollowering effect but also in an insufficient manufacture of the vital coenzyme Q10 [1,2]. Because of such HMG CoA reductase inhibition, endogenous biosynthesis of the essential co-factor coenzyme Q10, required for energy production, often is associated with impairment of organ function such as the myocardium, the liver, the brain, and/or the musculature. ...
... This eventually ends up in a marked deficit resulting in a suboptimal Q10 levels, being underlined by the fact that mostly in every chronic ailment there is a significant deficit in Q10-levels. In this context it is also noteworthy that any patient taking a statin drug for high cholesterol levels, because of the blockade of the enzyme HMG-CoA reductase, this ultimately will endup in a deficit of the coenzyme Q10, as both have an upstream common pathway, which is blocked by the statin drug resulting in a cholesterollowering effect but also in an insufficient manufacture of the vital coenzyme Q10 [1,2]. Because of such HMG CoA reductase inhibition, endogenous biosynthesis of the essential co-factor coenzyme Q10, required for energy production, often is associated with impairment of organ function such as the myocardium, the liver, the brain, and/or the musculature. ...
... That is, nearly all subacute animal studies so far have considered a maximum of 14 days long treatment prior to experimental stroke which might not be long enough for all isoprenoid effectors being affected. This might be exemplified considering that statins serve antioxidant effects in as early as hours to days (Hong et al. 2006), while it takes weeks to significantly reduce systemic Coenzyme Q10 levels (Langsjoen and Langsjoen 2003) and about 10 months to ameliorate AD pathology (Kurata et al. 2015). ...
Statins are widely used in high-risk patients to reduce the stroke incidence. However, little has been investigated about the impact of chronic pretreatment with statins on cerebral ischemic insult following defined arterial occlusion. To address this in experimental rats, in the present work, atorvastatin was orally dosed for 1 month to evaluate the outcomes of the subsequent occlusive stroke induced by middle cerebral artery occlusion (MCAO). Our data was suggestive of potential escalating impact of chronic atorvastatin (Atv; 10 mg/kg) on neurological function, but not infarct volume. According to our immunoblotting data, such escalations were consistent with the prominent rise in TNF-α and IL-6 which paralleled with augmented Bax/Bcl2 ratio and Caspase-9 activation; however, these were not enough to worsen acute neurodegeneration determined by Fluoro Jade B staining. Noteworthy, such deteriorating effects were also partly detected in non-ischemic animals. Conclusively, our data are indicative of cerebral proinflammatory effects of chronic Atv which might overwhelm the beneficial pliotropic of the drug and predispose animals’ brain to ischemic insult. Further studies on different statins with discrete pharmacokinetic properties are highly suggested to precisely explore stroke outcomes following long term prophylactic treatment particularly in primates.
... The postulation that statins can cause cognitive decline is based on the fact that lipophilic statins like atorvastatin and simvastatin show increased crossing of the blood-brain barrier compared to hydrophilic statins (for example, pravastatin and rosuvastatin). Two possible mechanisms are proposed: (1) the reduced availability of cholesterol caused by statins might impair the integrity of the neuronal and glial cell membrane, resulting in slowed conduction of neuronal impulses [6]; and (2) the reduced re-myelination and reduction in coenzyme Q10 levels impairs mitochondrial function and may lead to an increase in oxidative stress [7,8]. However, in a study investigating the long-term effects of treatment with pravastatin and atorvastatin in adult rats, pravastatin tended to impair learning, implying an impact on working memory and object recognition memory that was reversible on discontinuation, whereas atorvastatin did not impair either task. ...
Background
Simvastatin is commonly prescribed for hypercholesterolemia to reduce vascular risk in patients. Some of these patients have dementia with cognitive defects of several domains. Although protective effects seem to be present, there is emerging evidence that statins cause cognitive impairment.The role of cholesterol in cognitive function is complex. This is reflected in the effects that statins show on cognition functions. The reduction in cholesterol levels seen with statins is effective in improving learning and memory in some patients. However, there is emerging evidence that statins may worsen cognitive function. Similarly, there are major concerns over whether statins alleviate or worsen cognitive problems. The correlation between cholesterol levels and cognitive function is still controversial, mainly due to a lack of robust evidence. Case presentationWe report the cases of two Asian patients who developed cognitive deficits after starting simvastatin. A 32-year-old man and a 54-year-old woman developed different but clear cognitive deficits that reversed after stopping simvastatin. Conclusions
The possibility of new-onset cognitive dysfunction and the deterioration of existing cognitive deficits should be considered when prescribing simvastatin to patients.
... Therefore, supplementation with Coenzyme Q10 and Ubiquinol could act as an adjunctive therapy for this disease at all stages. In healthy individuals, blood plasma levels of Coenzyme Q10 are about 1.0 +/-0.2 mg/l, whereas in certain diseases levels of close to 0.6 mg/l or even lower are found (8). CoQ10 is naturally synthesized in all human tissues, and in healthy young people, normal levels are maintained by biosynthesis combined with Coenzyme Q10 intake from the diet. ...
Coenzyme Q10 (also known as Ubiquinone) and its active form, Ubiquinol, are essential for the body's energy production processes, including those which take place in the heart. Thus, a deficiency of heart and blood CoQ10 could be a risk factor for the development of cardiovascular diseases. The latest advance in supplemental Coenzyme Q10 is the reduced, active form Ubiquinol. While traditional, oxidized CoQ10 has to be converted into Ubiquinol before it works in the body, Ubiquinol can work quickly and directly without such conversion. It is effective at lower dosages. Ubiquinol daily doses range from 100 to 600 mg and can increase blood plasma levels of CoQ10 to more than 3.5 mg/l, which is the level required by patients with severe heart problems for improving heart function. Clinical studies support the safety of Ubiquinol in CHF patients and demonstrate that Ubiquinol is more effective than oxidized Coenzyme Q10.
... [28] Patients receiving statin show lower levels of plasma CoQ10, Therefore, statin treatment may cause a CoQ10 deficiency. [29] Studies have consistently demonstrated that statin therapy decreases circulating CoQ10 concentrations. [30] According to Chapidze et al., [31] treatment with CoQ10 in a patient with ischemic heart disease, is associated with its potential independent role in lowering the markers of oxidative stress and decreasing the total cholesterol/HDL-C ratio. ...
The present investigation was aimed to improve the inflammatory factors and lipoproteins concentration in patients with myocardial infarction (MI) by supplementation with coenzyme Q10 (CoQ10).
In a double-blind, placebo-controlled study, we measured serum concentrations of one soluble cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1]), serum concentration of intereukin-6 (IL-6) and lipid profiles (high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], total cholesterol and triglyceride [TG]) in CoQ10 supplementation group (n = 26) compared with placebo group (n = 26) in hyperlipidemic patients with MI. Fifty-two patients were randomized to receive 200 mg/day of CoQ10 or placebo for 12 weeks.
There were no significant differences for serum LDL-C, total cholesterol, and TG between two mentioned groups after the intervention. A significant enhancement in serum HDL-C level was observed between groups after the intervention (55.46 ± 6.87 and 44.07 ± 6.99 mg/dl in CoQ10 and placebo groups, respectively P < 0.001). Concentrations of ICAM-1 (415.03 ± 96.89 and 453.38 ± 0.7 ng/dl CoQ10 and placebo groups, respectively, P = 0.001) and IL-6 (11 ± 9.57 and 12.55 ± 8.76 pg/ml CoQ10 and placebo groups, respectively P = 0.001) in serum were significantly decreased in CoQ10 group.
Supplementation with CoQ10 in hyperlipidemic patients with MI that have statin therapy has beneficial effects on their aspects of health.
Lipids a source of energy and can also be stored in body cells for proper cellular functions. Defects in lipid metabolism can lead to a wide range of metabolic disorders. A number of risk factors are generally responsible for the dysregulation of lipid metabolism and subsequently the development of metabolic diseases. In this chapter, the pathophysiology of several lipid-metabolism-related diseases has been discussed, and the therapeutic potential of different phytochemicals or plant-derived phytonutrients in managing these disorders are highlighted. There are several medicinal secondary metabolites, which could be highly significant to manage the lipid profile and prevent the development of serious outcomes of lipid-metabolism abnormalities such as hyperchylomicronemia, hypercholesterolemia, atherosclerosis, cancer, obesity, insulin sensitivity, and resistance. Many phytonutrients isolated from fruits, vegetables, and plant sources have presented their broad spectrum of medicinal activities to modulate metabolic processes and are also involved in lipid metabolism and the management of cholesterol levels in body. Bioactive compounds such as small molecular phytonutrients from natural sources have suggested prospective treatments against lipid-metabolism-related abnormalities and have been defined in this chapter. Considering diverse physiochemical properties and therapeutic value of phytonutrients, it is highly recommended to introduce more vegetables, and fruits in the dietary regimen to intake food containing fewer fats and high fibers so that it could significantly aid the management of lipid-metabolism-related diseases.
The elaboration of therapeutic protocols using natural compounds can help in improving the outcomes of many human conditions such as malignant disorders, neurodegenerative diseases, and systemic disorders. Recently, the attention of scientists was more focused on nutraceuticals as potential candidates that can be administered in the management strategy of various pathologies. This rise in nutraceutical applications is due to their relative safety and their pleiotropic effects. Several studies suggest the use of dietary regimens and food-derived substances for the prevention and treatment of many metabolic disorders that affect the central nervous system. The neuroprotective actions offered by these substances are mediated by their pertinent antiapoptotic, antiinflammatory, and antioxidative potentials. Some compounds may also intervene in the promotion of individuals’ health via the regulation of the process of autophagy and via the enhancement of the functionality of intracellular organelles such as mitochondria. Furthermore, healthy diet and the use of dietary supplements can directly influence the functions and the progeny of neural stem cells and the metabolism of microglial cells and can influence the polarization of macrophages in the nervous tissue resulting in better outcomes in some pathologic situations. In this chapter, we review the different roles and applications of nutraceuticals in the treatment of the major brain disorders that can affect human beings.
Metabolic diseases are devastating abnormalities that address human lives toward death if they are not correctly managed. Obesity and diabetes mellitus are the prime factors that induce insulin resistance to signaling pathways and increase the risk of cardiovascular diseases. Phytonutrients are the biologically active agents derived from natural sources such as vegetables, fruits, grains, cereals, and medicinal plants, and present the ability to boost the immune system of patients with metabolic disease and also enhance the conditions by the management of lipid profiles, insulin resistance and glucose homeostasis, and chemopreventive events in case of cancer disease. This chapter highlights some phytonutrients that may have issues with the gene and produce healthy and unhealthy interactions. However, the interaction between genetic and environmental factors such as intake of particular healthy and sufficient diet plans with a good lifestyle encourages the development and pathogenesis of diseases of polygenic dietary components. Phytonutrients are critical tools for the modulation of gene expressions involved in signaling pathways and phenotypes linked with metabolic diseases. It is also noted that human health is also affected by dietary nutrients having carcinogens and aflatoxin attached with them and influence the genetic variants. As the knowledge of carcinogen and anticarcinogen increases, nutritional science leads to promising therapeutics for cancer management by healthy diet plans. This chapter has depicted essential aspects of phytonutrients and their interactions with genes in metabolic disease prevention and treatments.
In spite of the advanced researches, preventive measures, and treatment options, cancer remains a growing ailment all over the world and its prevalence is estimated to increase in future. Cellular metabolic alterations have been documented as a hallmark of cancer. Metabolic regulation is an intricately coupled process whose deregulation leads to tumor progression as well as metastasis. In order to thrive in the living system, cancer cells adapt different metabolic pathways (bioenergetics and biosynthesis). They replenish their metabolic demands by switching from normal metabolism to cancer metabolism by the process of metabolic rewiring. Recent researches suggest that starving cancer cells by the use of nontoxic chemical entities can give promising results regarding cancer proliferation. Natural products, especially those of plant origin, offer different chemical scaffolds to target cancer via modulation of multiple cell signaling cascades. Phytonutrients, the secondary metabolites from the plants, constitute edible phytochemicals which are abundantly found in vegetables, whole grains, and fruits. The growing numbers of evidences suggest that phytonutrients exhibit anticancer as well as chemopreventive activities of these bioactive molecules against several cancers by targeting the various significant enzymes of glycolysis, the PPP pathway, TCA cycle, and serine metabolism. This book chapter presents an update for the scientific community about targeting the cancer metabolism by phytonutrients. The alterations in the cancer metabolism in the context of bioenergetics, biosynthesis, and mitochondrial functions have been discussed while presenting the impact of phytonutrients as modulators of potential metabolic effectors in the cancer metabolism.
Mitochondria are the main organelles responsible for generating cellular energy. The common symptom of mitochondrial disorders is extreme fatigue. The lowered mitochondrial activity owing to lack of chemical transmembrane capacity, changes in the electron transport chain’s function, the maintenance of the inner mitochondrial membrane’s electrical and decrease in essential metabolites transport to the mitochondria. The change in mitochondrial activity is brought about by the reduction of adenosine-5′-triphosphate (ATP) and oxidative phosphorylation. The mitochondrial activity needs regular replacement of natural phytochemicals and supplementations that help to maintain the energy level. The efficacy of oral alternative nutrients like reduced nicotinamide adenine dinucleotide (NADH), alpha-lipoic acid, coenzyme Q10, alpha-lipoic acid carnitine, membrane phospholipids, and other supplements was evaluated in clinical studies and were found effective against mitochondrial disorders. Combinations of these supplements can substantially alleviate weakness and other symptoms associated with mitochondrial disorders in patients. The frequent intake of these nutrients can also help to reduce the onset of various neurological disorders along with mitochondrial dysfunction. These results have significant effects on the welfare of both the civilian and military communities.
Introduction
Findings on the association between statin therapy and Parkinson's disease (PD) occurrence have been inconsistent. This study aimed to identify the association between statin use and PD in participants with a history of hyperlipidemia or blood cholesterol >200 in a Korean population to exclude nonstatin users owing to normal lipid values.
Methods
We conducted a nested case-control analysis using the Korean National Health Insurance Service-National Sample Cohort assessed between 2002 and 2015. We identified 3026 PD cases. A total of 12,104 controls were then individually matched by age, sex, income, and region of residence at a ratio of 1:4. Potential confounders comprised basic demographic factors, lifestyle factors, various medical conditions and comorbidities. A conditional/unconditional logistic regression method was applied.
Results
Compared with statin use for <6 months, adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for 6–12 months of statin use and ≥12 months of statin use were 1.03 (0.92–1.15) and 1.61 (1.35–1.93) after adjustment for confounders, respectively (P = 0.664 and P < 0.001). In analyses according to statin solubility, only the association between lipophilic statin use for ≥12 months and PD maintained statistical significance, with an aOR of 1.64 (95% CI = 1.34–2.01, P < 0.001). These relations were consistent in subgroup analyses by covariates.
Conclusions
Statin use for more than 12 months was associated with a higher probability of PD in the Korean population with hyperlipidemia. This probability was significant for lipophilic statins but not hydrophilic statins.
Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood.
Background. Left ventricular remodeling (LVR) that frequently occurs after acute myocardial infarction (AMI) is associated with an increased risk of heart failure and cardiovascular death. Although several risk factors have been identified, there is still no marker in clinical use to predict LVR. Plasma level of Coenzyme Q10 (CoQ10), that plays a key role in mitochondrial energy production and as an antioxidant, seems to be negatively correlated with left ventricular function after AMI.
Objective. The goal of our study was to determine whether the plasma CoQ10 baseline concentrations at time of the ST-elevation myocardial infarction (STEMI) could predict LVR at 6 months follow-up.
Methods. Sixty-eight patients who were admitted to hospital for STEMI and successfully revascularized with primary percutaneous coronary intervention (PPCI) were recruited. All patients underwent a 3D-echocardiography examination within the first 4 days after PPCI and 6 months later then divided in 2 groups based on the presence or not of LVR. Plasma CoQ10 level at the time of PPCI was determined using high performance liquid chromatography-tandem mass spectrometry (HPLC/MSMS).
Results. While we found similar plasma CoQ10 concentrations compared to other studies, no association was evidenced between CoQ10 levels and LVR (p=0.89).
Conclusion. We found no evidence for using plasma CoQ10 concentration as an early prediction marker of LVR after STEMI.
Coenzyme Q10 (CoQ10) is a naturally occurring compound that is found in animals and all humans. It has a fundamental role in cellular energy production. Although it is produced in the body, tissue deficiency can occur due to medications such as statins, which inhibit the mevalonate pathway. The clinical syndromes of statin-associated muscle symptoms (SAMS) and some of the features observed in patients with heart failure (HF) may be related to blood and tissue deficiency of CoQ10. Numerous clinical trials of CoQ10 in SAMS have yielded conflicting results. Yet, the weight of evidence as reflected in meta-analyses supports the use of exogenous CoQ10 in SAMS. In patients with HF, large-scale randomized clinical trials are lacking, although one relatively contemporary trial, Q-SYMBIO, suggests an adjunctive role for CoQ10. The possibility that statin-related CoQ10 deficiency may play a role in patients with diastolic HF is an intriguing hypothesis that warrants further exploration.
The Introduction is spot on: “”Science can be a force for good, and it has enhanced our lives in countless ways, but even a cursory look at the 20th century shows that what passes for science can be detrimental” (p. 1).
The last decade saw major advances in understanding the metabolism of Coenzyme A (CoA) thioesters (acyl-CoAs) and related inborn errors (CoA metabolic diseases, CAMDs). For diagnosis, acylcarnitines and organic acids, both derived from acyl-CoAs, are excellent markers of most CAMDs. Clinically, each CAMD is unique but strikingly, three main patterns emerge: first, systemic decompensations with combinations of acidosis, ketosis, hypoglycemia, hyperammonemia and fatty liver; second, neurological episodes, particularly acute "stroke-like" episodes, often involving the basal ganglia but sometimes cerebral cortex, brainstem or optic nerves and third, especially in CAMDs of long chain fatty acyl-CoA metabolism, lipid myopathy, cardiomyopathy and arrhythmia. Some patients develop signs from more than one category. The pathophysiology of CAMDs is not precisely understood. Available data suggest that signs may result from CoA sequestration, toxicity and redistribution (CASTOR) in the mitochondrial matrix has been suggested to play a role. This predicts that most CAMDs cause deficiency of CoA, limiting mitochondrial energy production, and that toxic effects from the abnormal accumulation of acyl-CoAs and from extramitochondrial functions of acetyl-CoA may also contribute. Recent progress includes the following. (1) Direct measurements of tissue acyl-CoAs in mammalian models of CAMDs have been related to clinical features. (2) Inborn errors of CoA biosynthesis were shown to cause clinical changes similar to those of inborn errors of acyl-CoA degradation. (3) CoA levels in cells can be influenced pharmacologically. (4) Roles for acetyl-CoA are increasingly identified in all cell compartments. (5) Nonenzymatic acyl-CoA-mediated acylation of intracellular proteins occurs in mammalian tissues and is increased in CAMDs.
Background
Previous studies have demonstrated a possible association between the induction of coenzyme Q10 (CoQ10) after statin treatment and statin‐induced myopathy. However, whether CoQ10 supplementation ameliorates statin‐induced myopathy remains unclear.
Methods and Results
PubMed, EMBASE, and Cochrane Library were searched to identify randomized controlled trials investigating the effect of CoQ10 on statin‐induced myopathy. We calculated the pooled weighted mean difference (WMD) using a fixed‐effect model and a random‐effect model to assess the effects of CoQ10 supplementation on statin‐associated muscle symptoms and plasma creatine kinase. The methodological quality of the studies was determined, according to the Cochrane Handbook. Publication bias was evaluated by a funnel plot, Egger regression test, and the Begg‐Mazumdar correlation test. Twelve randomized controlled trials with a total of 575 patients were enrolled; of them, 294 patients were in the CoQ10 supplementation group and 281 were in the placebo group. Compared with placebo, CoQ10 supplementation ameliorated statin‐associated muscle symptoms, such as muscle pain (WMD, −1.60; 95% confidence interval [CI], −1.75 to −1.44; P<0.001), muscle weakness (WMD, −2.28; 95% CI, −2.79 to −1.77; P=0.006), muscle cramp (WMD, −1.78; 95% CI, −2.31 to −1.24; P<0.001), and muscle tiredness (WMD, −1.75; 95% CI, −2.31 to −1.19; P<0.001), whereas no reduction in the plasma creatine kinase level was observed after CoQ10 supplementation (WMD, 0.09; 95% CI, −0.06 to 0.24; P=0.23).
Conclusions
CoQ10 supplementation ameliorated statin‐associated muscle symptoms, implying that CoQ10 supplementation may be a complementary approach to manage statin‐induced myopathy.
Coenzyme Q 10 (CoQ 10 ) is a vitamin-like substance that plays a key role in the metabolic process, supplying all cells with energy. Tissues with a high energy requirement, such as the heart, are particularly dependent on maintaining an adequate supply of CoQ 10 for normal functioning. Deficiency of CoQ 10 has been identified as a risk factor for a variety of disorders, including cardiovascular and neurological diseases. The objective of this article is therefore to provide a brief overview of the pharmacology of CoQ 10 , with particular emphasis on its role in the prevention and treatment of cardiovascular disorders.
Congestive heart failure (CHF) is the inability of the heart to pump blood effectively throughout the body. Such dysfunction may concern myocardial contractility, the ventricular preload, the end-diastolic volume, an obstacle to cardiac ejection, or excessive afterload and heart rate. The main causes of heart failure are long-term hypertension, previous myocardial infarction, disorders of the heart valves, cardiomyopathies, and chronic lung disease. A condition of compensation can be precipitated by some aggravating factors such as increased metabolic demand, as in the case of thyrotoxicosis, anemia, arteriovenous shunt, fever, fluid overload, increased sodium intake, environmental temperature that is too high or too low, renal or hepatic failure, respiratory insufficiency, emotional stress, pregnancy, obesity, arrhythmias, pulmonary embolism, alcohol ingestion, nutrient deficiency, uncontrolled hypertensive states, and beta-blockers, anti-arrhythmic drugs, and sodium-retaining drugs such as steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) [1].
Background
Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately.
Objectives
To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype.
Methods
Cardiovascular risk was quantified using the QRISK2 calculator (high ?20%, medium ?10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment.
Results
In 2909 individuals with recent-onset PD, the mean age was 67.5?years (SD 9.3), 63.5% were men and the mean disease duration was 1.3?years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD.
Conclusions
Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment.
Trial registration number
GN11NE062, NCT02881099.
Low-molecular-weight aldehydes (glyoxal, methylglyoxal) generated on autooxidation of glucose under conditions of carbonyl stress react much less actively with amino groups of L-lysine and ε-amino groups of lysine residues of apoprotein B-100 in human blood plasma low density lipoproteins (LDL) than their structural analogs - malonic dialdehyde (MDA) resulting on free radical oxidation of lipids under conditions of oxidative stress. Using the methods of EPR spectroscopy and lucigenin-dependent chemiluminescence, it has been shown that non-enzymatic generation of free radicals including superoxide anion radical takes place during the interaction of L-lysine with methylglyoxal at physiological pH values. In the course of analogous reaction of L-lysine with MDA, the formation of organic free radicals or superoxide radical was not observed. Glyoxal-modified LDL aggregate in the incubation medium with a significantly higher rate than LDL modified by MDA, and MDA-modified LDL are markedly more poorly absorbed by cultured human macrophages and significantly more slowly eliminated from the rat bloodstream upon intravenous injection. Studies on kinetics of free radical oxidation of rat liver membrane phospholipids have shown that ubiquinol Q10 is the most active lipid-soluble natural antioxidant, and suppression of ubiquinol Q10 biosynthesis by β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors (statins) is accompanied by intensification of lipid peroxidation in rat liver biomembranes as well as in LDL of human blood plasma. Injection of ubiquinone Q10 protects the human blood plasma LDL against oxidation and prevents oxidative stress-induced damages to rat myocardium. A unified molecular mechanism of atherogenic action of carbonyl-modified LDL in disorders of lipid and carbohydrate metabolism is discussed.
Coenzyme Q (CoQ), a lipophilic substituted benzoquinone present in all cells. Besides its fundamental role of an electron carrier associated with energy production in the respiratory chain, CoQ has two other functions in mitochondria. It is an essential factor in activation of protein uncoupling and it controls permeability of transition pores. Moreover, it participates in extramitochondrial electron transport in plasma membranes and lysosomes, controls physicochemical properties of membranes, and is the only endogenous lipid antioxidant. Its pro-oxidant role consists in generating the major superoxide radical/H2O2 second-messenger system. Biosynthesis of CoQ proceeds in every cell, small amounts of CoQ can be obtained from diet. CoQ is also available as a dietary supplement. It shows minimal toxicity, excellent tolerance, and no significant side effects. Its beneficial effects are largely attributed to its essential role in cellular bioenergetics and antioxidant properties. Supplementation of CoQ can improve conditions of a wide range of pathological states. Some forms of mitochondrial CoQ deficiency respond well to its oral administration. Recent meta-analysis of tests for hypertension is also promising. This review summarizes the current knowledge of the therapeutic efficacy of CoQ in various diseases.
Lovastatin is clinically used to treat patients with hypercholesterolemia and successfully lowers cholesterol levels. The mechanism of action of lovastatin is inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme involved in the biosynthesis of cholesterol from acetyl-CoA. Inhibition of this enzyme could also inhibit the intrinsic biosynthesis of coenzyme Q10 (CoQ10), but there have not been definitive data on whether lovastatin reduces levels of CoQ10 as it does cholesterol. The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQ10, this reduction would constitute a new risk of cardiac disease, since it is established that CoQ10 is indispensable for cardiac function. We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosynthesis of CoQ10. One protocol was done on rats, and is reported in the preceding paper [Willis, R. A., Folkers, K., Tucker, J. L., Ye, C.-Q., Xia, L.-J. & Tamagawa, H. (1990) Proc. Natl. Acad. Sci. USA 87, 8928-8930]. The other two protocols are reported here. One involved patients in a hospital, and the other involved a volunteer who permitted extraordinary monitoring of CoQ10 and cholesterol levels and cardiac function. All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10. The five hospitalized patients, 43-72 years old, revealed increased cardiac disease from lovastatin, which was life-threatening for patients having class IV cardiomyopathy before lovastatin or after taking lovastatin. Oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presumably can be caused by the lovastatin-induced deficiency of CoQ10.
Lovastatin is used for the treatment of hypercholesterolemia. It functions by inhibiting the enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34), that is required for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid. Since biosynthesis of both cholesterol and coenzyme Q (CoQ) requires mevalonic acid as a precursor, it was considered that lovastatin therapy would also result in a lowering of cellular CoQ levels. This study was conducted to determine whether lovastatin treatment does decrease CoQ levels and whether such decreases can be prevented by CoQ supplementation. Forty-five adult male Holtzman rats were randomly assigned to one of three treatment groups. Controls were fed ground laboratory rat chow ad libitum. The other two groups were fed ground laboratory rat chow containing 400 mg of lovastatin per kg of diet ad libitum. One of the lovastatin-fed groups received CoQ10 (15 mg per kg of body weight) daily via stomach intubation. After 4 weeks, samples of heart, liver, and blood were analyzed for CoQ concentrations. Results indicated that CoQ concentrations in all tissues analyzed were decreased in lovastatin-treated rats. Lovastatin-treated animals that were supplemented with CoQ10 had blood, heart, and liver CoQ10 concentrations that approximated or exceeded those of control animals. It is concluded that lovastatin does indeed lower tissue concentrations of CoQ and that a return to normal can be achieved by supplementation with CoQ.
Plasma coenzyme Q (CoQ) was measured in 20 hyperlipidaemic patients treated with diet and simvastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase); 22 hyperlipidaemic patients treated with diet with alone; and 20 normal controls. Patients treated with simvastatin had a significantly lower plasma CoQ and CoQ: cholesterol ratio than either patients receiving diet alone or normal controls. Use of simvastatin was inversely and independently correlated with both CoQ (p < 0.0001) and CoQ: cholesterol ratio (p < 0.01). There was a significant inverse association between CoQ and dose of simvastatin (p < 0.001). It is concluded that simvastatin may lower the plasma CoQ concentration and this may be greater than the reduction in cholesterol. The possible adverse effect of simvastatin on the metabolism of CoQ may be clinically important and requires further study.
2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMG-CoA reductase expression, generating a synergistic, self-limited negative regulatory loop. Hence, the pharmacological properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol. It was safe in hamsters, squirrel monkeys and Göttingen minipigs at pharmacologically active doses, lowering LDL approximately 60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071, up to approximately 20 micrograms/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself. In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.
Cytochrome b5 reductase purified from liver plasma membrane reduces coenzyme Q (CoQ) in reconstituted liposomes in the absence of cytochrome b5. Both CoQ and its reductase are responsible for the reduction of the ascorbate free radical at the cell surface. Thus, NADH-CoQ reductase represents a partial reaction of NADH-AFR reductase in the plasma membrane. Cytochrome b5 reductase maintains CoQ and ascorbate in their reduced state to support antioxidations. Reduced CoQ prevents lipid peroxidation in liposomes and plasma membranes. Also, oxidized CoQ can prevent lipid peroxidations in the presence of cytochrome b5 reductase and NADH. Addition of CoQ to intact cells prevents serum withdrawal-induced lipid peroxidation and apoptosis. The prevention of apoptosis by CoQ is independent of the bcl-2 protein content in the cell. Antioxidants that act at the plasma membrane as CoQ and ascorbate would represent a first barrier to protect lipids from oxidative stress and subsequent apoptosis. Cytochrome b5 reductase is then an enzyme leading this function at the plasma membrane. These data support the idea that when the plasma membrane barrier fails, bcl-2 protein would be required to prevent cell death.
A randomized, double-masked, placebo-controlled cross-over trial was carried out to evaluate whether ubiquinone supplementation (180 mg daily) corrects impaired defence against initiation of oxidation of low density lipoprotein (LDL) related to effective (60 mg daily) lovastatin treatment. Nineteen men with coronary heart disease and hypercholesterolemia received lovastatin with or without ubiquinone during 6-week periods after wash-out. The depletion times for LDL ubiquinol and reduced alpha-tocopherol were determined during oxidation induced by 2,2-azobis(2,4-dimethylvaleronitrile) (AMVN). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated diene formation. Compared to mere lovastatin therapy, ubiquinone supplementation lead to a 4.4-fold concentration of LDL ubiquinol (P < 0.0001). In spite of the 49% lengthening in depletion time (P < 0.0001) of LDL ubiquinol, the lag time in copper-mediated oxidation increased only by 5% (P = 0.02). Ubiquinone loading had no statistically significant effect on LDL alpha-tocopherol redox kinetics during high radical flux ex vivo. The faster depletion of LDL ubiquinol and shortened lag time in conjugated diene formation during high-dose lovastatin therapy may, at least partially, be restored with ubiquinone supplementation. However, the observed improvement in LDL antioxidative capacity was scarce, and the clinical relevance of ubiquinone supplementation during statin therapy remains open.
Today there is an increasing tendency to treat hypercholesterolemia aggressively; hence, the greater worldwide use of cholesterol-lowering agents such as the statins. Statins are very potent inhibitors of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis at the mevalonate level. This effect is not selective, however, and results in the inhibition of several nonsterol isoprenoid end-products, including coenzyme Q(10) (CoQ(10), ubiquinone). The CoQ(10)-lowering effect of statins is very well documented and should be a matter of concern for clinicians. CoQ(10), a fat-soluble quinone, functions as an electron carrier in oxidative phosphorylation in mammalian mitochondria, a stabilizer of cell membranes, and a potent scavenger of free radicals, thus preventing lipid peroxidation. CoQ(10)-deficiency states are described and are associated with many diseases, primarily cardiovascular. Many clinical trials demonstrate this relationship and also the effectiveness of CoQ(10) therapy. Ironically, the attempt to reduce cardiovascular morbidity and mortality with statins is partially negated by lowering the CoQ(10) level, which is essential for optimal cellular function. Some of the side effects that result from statin treatment (eg, myopathies) also indicate a more general mitochondrial injury, These observations suggest that during extended therapy with statins, CoQ(10) supplementation should be considered to support cellular bioenergetic demand as well as minimize potential lipid peroxidative insult.
Plasma membranes isolated from K562 cells contain an NADH-ascorbate free radical reductase activity and intact cells show the capacity to reduce the rate of chemical oxidation of ascorbate leading to its stabilization at the extracellular space. Both activities are stimulated by CoQ10 and inhibited by capsaicin and dicumarol. A 34-kDa protein (p34) isolated from pig liver plasma membrane, displaying NADH-CoQ10 reductase activity and its internal sequence being identical to cytochrome b
5 reductase, increases the NADH-ascorbate free radical reductase activity of K562 cells plasma membranes. Also, the incorporation of this protein into K562 cells by p34-reconstituted liposomes also increased the stabilization of ascorbate by these cells. TPA-induced differentiation of K562 cells increases ascorbate stabilization by whole cells and both NADH-ascorbate free radical reductase and CoQ10 content in isolated plasma membranes. We show here the role of CoQ10 and its NADH-dependent reductase in both plasma membrane NADH-ascorbate free radical reductase and ascorbate stabilization by K562 cells. These data support the idea that besides intracellular cytochrome b
5-dependent ascorbate regeneration, the extracellular stabilization of ascorbate is mediated by CoQ10 and its NADH-dependent reductase.
Potential ubiquinone (CoQ10; a natural fermentation product) toxicity was assessed in rats administered CoQ(10) by oral gavage for 1 year at 100, 300, 600, and 1200 mg/(kg day). No adverse changes in mortality, clinical signs, body weight, food consumption, or clinical pathology results occurred. CoQ(10) had elimination half-lives ranging from 10.7 to 15.2 h. At 1200 mg/(kg day), a high incidence of orange, granular, lumenal exudate in nasal turbinates occurred; microscopically, findings similar to those in the turbinates were occasionally observed in small granulomas within lung alveoli. A dose-related increased incidence of vacuolated macrophages (mesenteric lymph nodes) and vacuolated hepatic periportal cells was noted. Neither were associated with tissue damage or organ dysfunction, so they were not considered to be adverse. The nasal turbinate and lung findings were probably secondary to incidental exposure to crystallized test material. Overall, CoQ(10) was well tolerated by male and female rats at dose levels up to 1200 mg/(kg day).
A double-blinded, placebo-controlled cross-over trial was carried out with 27 hypercholesterolemic men with coronary heart disease. During the 6-week treatment period lovastatin (60 mg/day) decreased fasting serum LDL cholesterol by 45%, LDL phosphorus by 38% and apoB by 33%. Ubiquinol content diminished by 13% as measured per LDL phosphorus. When LDL was oxidized ex vivo with AMVN both LDL ubiquinol and α-tocopherol were exhausted faster after lovastatin treatment compared to placebo, by 24% (P
The inferior recovery of cardiac function after interventional cardiac procedures in elderly patients compared to younger patients suggests that the aged myocardium is more sensitive to stress. We report two studies that demonstrate an age-related deficit in myocardial performance after aerobic and ischemic stress and the capacity of CoQ10 treatment to correct age-specific diminished recovery of function. In Study 1 the functional recovery of young (4 mo) and senescent (35 mo) isolated working rat hearts after aerobic stress produced by rapid electrical pacing was examined. After pacing, the senescent hearts, compared to young, showed reduced recovery of pre-stress work performance. CoQ10 pretreatment (daily intraperitoneal injections of 4 mg/kg CoQ10 for 6 weeks) in senescent hearts improved their recovery to match that of young hearts. Study 2 tested whether the capacity of human atrial trabeculae (obtained during surgery) to recover contractile function, following ischemic stress in vitro (60 min), is decreased with age and whether this decrease can be reversed by CoQ10. Trabeculae from older individuals (> or = 70 yr) showed reduced recovery of developed force after simulated ischemia compared to younger counterparts (< 70 yr). Notably, this age-associated effect was prevented in trabeculae pretreated in vitro (30 min at 24 degrees C) with CoQ10 (400 MicroM). We measured significantly lower CoQ10 content in trabeculae from > or = 70 yr patients. In vitro pretreatment raised trabecular CoQ10 content to similar levels in all groups. We conclude that, compared to younger counterparts, the senescent myocardium of rats and humans has a reduced capacity to tolerate ischemic or aerobic stress and recover pre-stress contractile performance, however, this reduction is attenuated by CoQ10 pretreatment.
Summary Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50–150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%. Moreover, we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.
The vitamin-like nutrient CoQ10 (ubiquinone), discovered in 1957 and first used in human illness in 1967, has a crucial role in cellular ATP production as the coenzyme for mitochondrial complexes I, II and III. CoQ10 is also a lipid soluble antioxidant with cell protective effects. The past 30 years of clinical study have focused on congestive heart failure, ischaemic heart disease, angina, and myocardial protection during open-heart surgery. Measurably low blood and tissue levels of CoQ10 are evident in heart failure and may be normalised with oral CoQ10 supplementation, which has in turn been associated with measurable clinical improvement. Benefits observed in angina as well as objective measurement of ischaemia are believed to be related to both the bioenergetic and antioxidant properties of CoQ10 Recent studies of CoQ10 supplementation during open heart surgery showing an improvement in postoperative recovery have suggested a myocardial protective effect. The growing appreciation of the clinical relevance of CoQ10 depletion has caused concern over the CoQ10-lowering effect of the increasingly more potent and popular HMG-CoA reductase inhibitors (statins). Overall, CoQ10 appears to be a unique addition to standard medical therapy for cardiovascular disease.
The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (>3.5 μg/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.
The object of this paper is to help to evolve a conceptual framework suitable for exploring and explaining the mechanisms of protonmotive cytochrome systems.A review of some of the knowledge of the kinetic and equilibrium behaviour of the classical cytochrome systems of mitochondria indicates that the simple redox loop concept is not adequate for building a realistic conceptual model. In particular, the remarkable behaviour of the components of the cytochrome b-c1 complex, which has long been regarded as puzzling, cannot be explained on the basis of simple redox loop formulations. However, the newly introduced concepts of the protonmotive ubiquinone cycle, or Q cycle, and of the cyclic loop 2–3 system, which represent developments of the redox loop concept, are shown to provide a promising basis for the evolution of a satisfactory theory.The mechanism of the Q cycle is discussed and developed in the light of experimental knowledge of classical mitochondrial cytochrome systems. The possible operation of a Q cycle in chloroplasts and bacteria is briefly discussed, and attention is drawn to bacterial cytochrome systems that appear to be organized as simple redox loops rather than as cyclic systems.Some aspects of notions of direct chemiosmotic coupling and indirect conformational coupling are compared in the context of research strategy.
Rats were treated with mevinolin by intraperitoneal injection (15 days) or dietary administration (30 days). The cholesterol, dolichol, dolichyl phosphate and ubiquinone contents of the liver, brain, heart, muscle and blood were then investigated. The cholesterol contents of these organs did not change significantly, with the exception of muscle. Intraperitoneal administration of the drug increases the amount of dolichol in liver, muscle and blood and decreases the dolichyl-P amount in muscle. The same treatment increases the level of ubiquinone in muscle and blood and decreases this value in liver and heart. Oral administration decreases dolichol, dolichyl-P and ubiquinone levels in heart and muscle, while in liver the dolichol level is elevated and ubiquinone level lowered. In brain the amount of dolichyl-P is increased. Intraperitoneal injection of mevinolin also modifies the liver dolichol and dolichyl-P isoprenoid pattern, with an increase in shorter chain polyisoprenes. The levels of dolichol and ubiquinone in the blood do not follow the changes observed in other tissues. Incorporation of [3H]acetate into cholesterol by liver slices prepared from mevinolin-treated rats exhibited an increase, whereas in brain no change was seen. Labeling of dolichol and ubiquinone was increased in both liver and brain, but incorporation into dolichyl phosphate remained relatively stable. The results indicate that mevinolin affects not only HMG-CoA reductase but, to some extent, also affects certain of the peripheral enzymes, resulting in considerable effects on the various mevalonate pathway lipids.
The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.
The neutral and phospholipid compositions of various regions of the human brain were analyzed using autopsy material covering the life period between 33 and 92 years of age. The protein content was also measured and, on a weight basis, this content is unchanged in the cerebellum, pons, and medulla oblongata, whereas in the 90-year-old group it decreases in the hippocampus, gray matter, and nucleus caudatus. In white matter, the protein content decreases continuously with age. The phospholipid composition is characteristic of the region investigated, but remains unchanged during aging. The total phospholipid content exhibits only a 5-10% decrease in the oldest age group. The content of dolichol and its polyisoprenoid pattern are also characteristic of the region analyzed. Between 33 and 92 years of age, the amount of dolichol in all portions of the brain increases three- to fourfold, but the isoprenoid pattern remains constant. The level of dolichyl-P varies between different regions, but only a moderate increase is seen with age. Ubiquinone content is highest in the nucleus caudatus, gray matter, and hippocampus, and in all areas this content is decreased to a great extent in the oldest age groups. All regions of the human brain are rich in cholesterol, but alterations in the amount of this lipid are highly variable during aging, ranging from no change to a 40% decrease.
Coenzyme Q10 (CoQ10) occurs in the mitochondria of human cells. It is 2,3-dimethoxy-5-methyl-6-decaprenyl-l,4-benzoquinone and functions as a cofactor in several enzyme systems related to energy conversion. As such, it is essential for human life to exist. Since mitochondria are very abundant in myocardial cells and because of their huge energy needs, a deficiency of CoQ10 could have a particularly severe effect on myocardial function.In 1981 we chose cardiomyopathy for clinical study because it has been a disease of unknown cause, which has been apparently limited to the myocardium and has been without effective treatment. A short-term doubleblind cross-over study of 19 patients with cardiomyopathy (New York Heart Association classes III and IV) was completed in 1982. Control subjects' CoQ10 levels that were in the deficiency range were increased into the normal range by oral replacement therapy. This paralleled significant improvement in myocardial function and clinical status. There was no intolerance of the treatment.1A long-term open-label study was begun in November 1982 with the goal of determining if tolerance of CoQ10 and clinical improvement were maintained over long periods of time. From our observations with untreated control subjects in the short-term study and those of Mortensen et al,2 we thought it improper to use untreated control subjects in a long-term study. Myocardial function entails active energy input in both the contracting and relaxing phases, which may not be equally involved in clinical heart disease. Since precise measurement of each phase of myocardial function remains developmental, long-term survival figures could be finite and meaningful.
The levels of cholesterol, ubiquinone, dolichol, dolichyl-P, and total phospholipids in human lung, heart, spleen, liver, kidney, pancreas, and adrenal from individuals from one-day-old to 81 years of age were investigated and compared with the corresponding organs from 2 to 300 day-old rats. The amount of cholesterol in human tissues did not change significantly during aging, but the level of this lipid in the rat was moderately elevated in the organs of the oldest animals. In human pancreas and adrenal the ubiquinone content was highest at one year of age, whereas in other organs the corresponding peak value was at 20 years of age, and was followed by a continuous decrease upon further aging. A similar pattern was observed in the rats, with the highest concentration of ubiquinone being observed at 30 days of age. Dolichol levels in human tissues increase with aging, but they increase to very different extents. In the lungs this increase is seven-fold, and in the pancreas it is 150-fold. The elevation in the dolichol contents of rat tissues ranges from 20 to 30-fold in our material. In contrast, the levels of the phosphorylated derivative of dolichol increased to a more limited extent, i.e., 2 to 6-fold in human tissues and even less in the rat. These results demonstrate that the levels of a number of lipids in human and rat organs are modified in a characteristic manner during the life-span. This is in contrast to phospholipids, which constitute the bulk of the cellular lipid mass.
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.
The interaction between ubiquinones and vitamin E was studied in the inner membranes of rat liver mitochondria, liposomes and human erythrocyte plasma membranes. Free radicals were produced by addition of exogenous oxidants, and their reaction with chromanols and ubiquinone was followed by ESR and HPLC. Membranes were made deficient in ubiquinone but sufficient in alpha-tocopherol and were reconstituted with added ubiquinone. With these membrane preparations it was shown that (i) in the inner mitochondrial membranes there is a requirements for ubiquinone in the enzymatic recycling of vitamin E; (ii) succinate-ubiquinone reductase incorporated in liposomes cannot protect vitamin E in the absence of ubiquinone and (iii) in human erythrocyte plasma membranes protection against the loss of vitamin E can be provided by NADH-cytochrome-b5-dependent enzymatic recycling. We conclude that ubiquinonols (ubisemiquinones) reduce vitamin E through electron transport.
Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales 77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.
Alcohol metabolism may result in oxidant stress and free radical injury through a variety of mechanisms. Lovastatin may also produce oxidant stress by reducing levels of an endogenous antioxidant, coenzyme Q (CoQ). The separate and combined effects of ethanol, 20 EN% in a total liquid diet, and lovastatin, 67 mg/kg diet, on alpha-tocopherol, retinol palmitate, CoQ9 and thiobarbituric acid reactive (TBAR) material in liver from rats were determined. The effect of exogenous CoQ10 on these treatment groups was also determined. Food consumption, weight gain, liver lipid and TBAR material were similar between treatment groups. Compared to control animals, ethanol reduced retinol palmitate significantly, from 143 to 90 micrograms/g wet weight. Lovastatin had no effect on retinal palmitate nor did it act additively with ethanol. Ethanol decreased liver alpha-tocopherol from 28 to 12 micrograms/g wet weight and lovastatin diminished it to 12 micrograms; no additive effect was evident. Ethanol had no effect, but lovastatin decreased CoQ9 from 83 to 55 micrograms/g wet weight. Supplementation with CoQ10 did not modulate the effect of ethanol on retinal palmitate, but it did reverse the effect of lovastatin on CoQ9. Supplementary CoQ10 did not alter control levels of alpha-tocopherol, but it appeared to reverse most of the decrease in alpha-tocopherol attributable to ethanol or lovastatin separately. It only partially reversed the effect of ethanol and lovastatin combined on alpha-tocopherol, however. As expected, lovastatin had no effect on CoQ10 levels in supplemented animals. Ethanol, either separately or in combination with lovastatin, diminished liver stores of CoQ10 by almost 40%. We conclude that 20 EN% ethanol given in a liquid diet for 5 weeks is sufficient to lower retinol palmitate and that lovastatin reduces CoQ9. Both diminish alpha-tocopherol, an effect largely overcome by CoQ10 supplementation with either drug alone, but not with the combination. Since many individuals chronically consume the levels of ethanol represented by this experiment, and since a certain number of those also take lovastatin, further research into the possible clinical significance of these observations is warranted.
Over an eight year period (1985-1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q10 (CoQ10) to their medical regimens. Doses of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Treatment was primarily guided by the patient's clinical response. In many instances, CoQ10 levels were employed with the aim of producing a whole blood level greater than or equal to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes. Patients were divided into six diagnostic categories: ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary diastolic dysfunction (PDD), hypertension (HTN), mitral valve prolapse (MVP) and valvular heart disease (VHD). For the entire group and for each diagnostic category, we evaluated clinical response according to the New York Heart Association (NYHA) functional scale, and found significant improvement. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented using the following echocardiographic parameters: left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Before treatment with CoQ10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy.
Ubiquinone is a carrier of the mitochondrial respiratory chain which regulates oxidative phosphorylation: it also acts as a membrane stabilizer preventing lipid peroxidation. In man the quinone ring originates from tyrosine, while the formation of the polyisoprenoid lateral chain starts from acetyl CoA and proceeds through mevalonate and isopentenylpyrophosphate; this biosynthetic pathway is the same as the cholesterol one. We therefore performed this study to evaluate whether statins (hypocholesterolemic drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase) modify blood levels of ubiquinone. Thirty unrelated outpatients with primary hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 3-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, and at 45 and 90 days: total plasma cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Apo A1, Apo B and CoQ10 in plasma and in platelets. In the S group, there was a marked decrease in total cholesterol low-density lipoprotein-cholesterol and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of plasma CoQ10 (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg).(ABSTRACT TRUNCATED AT 250 WORDS)
Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.
Lovastatin, a cholesterol-lowering drug, decreased plasma cholesterol and cardiac tissue coenzyme Q10 levels in guinea pigs given 20 mg per kg body weight twice a day. Plasma cholesterol levels were reduced 40% in animals 2 to 4 months of age and 61% in animals 2 years of age. Coenzyme Q10 values in cardiac muscle and cardiac mitochondria of the treated, older group were decreased 31% and 37%, respectively. A significant decrease was not observed in coenzyme Q10 levels of the younger animal group. The potential to phosphorylate ADP to ATP driven by pyruvate-malate and succinate oxidation was decreased 43% and 45%, respectively, for cardiac mitochondria from the treated, 2-year-old animals. A decrease in phosphorylation potential was not observed for the younger group. The respiratory burst of leukocytes isolated from the intraperitoneal cavities of the treated, older animals was decreased 67%, while leukocytes isolated directly from their blood was decreased 76% (Diebold, B., Bhagavan, N. and Guillory, R. (1991) FASEB J. 5, A1203). In contrast to the intact leukocytes, the superoxide production of the cell-free systems prepared from leukocytes isolated from treated and untreated animals did not differ significantly. These observations suggest that in vivo lovastatin may not directly affect the leukocyte superoxide generating system, but may influence it indirectly possibly by modifying the lipid content of the membrane.
Ubiquinone (coenzyme Q), in addition to its function as an electron and proton carrier in mitochondrial and bacterial electron transport linked to ATP synthesis, acts in its reduced form (ubiquinol) as an antioxidant, preventing the initiation and/or propagation of lipid peroxidation in biological membranes and in serum low-density lipoprotein. The antioxidant activity of ubiquinol is independent of the effect of vitamin E, which acts as a chain-breaking antioxidant inhibiting the propagation of lipid peroxidation. In addition, ubiquinol can efficiently sustain the effect of vitamin E by regenerating the vitamin from the tocopheroxyl radical, which otherwise must rely on water-soluble agents such as ascorbate (vitamin C). Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo, and for which there exist enzymic mechanisms that can regenerate the antioxidant from its oxidized form resulting from its inhibitory effect of lipid peroxidation. These features, together with its high degree of hydrophobicity and its widespread occurrence in biological membranes and in low-density lipoprotein, suggest an important role of ubiquinol in cellular defense against oxidative damage. Degenerative diseases and aging may bc
1 manifestations of a decreased capacity to maintain adequate ubiquinol levels.
The improved cardiac function in patients with congestive heart failure treated with coenzyme Q10 supports the hypothesis that this condition is characterized by mitochondrial dysfunction and energy starvation, so that it may be ameliorated by coenzyme Q10 supplementation. However, the main clinical problems in patients with congestive heart failure are the frequent need of hospitalization and the high incidence of life-threatening arrhythmias, pulmonary edema, and other serious complications. Thus, we studied the influence of coenzyme Q10 long-term treatment on these events in patients with chronic congestive heart failure (New York Heart Association functional class III and IV) receiving conventional treatment for heart failure. They were randomly assigned to receive either placebo (n = 322, mean age 67 years, range 30-88 years) or coenzyme Q10 (n = 319, mean age 67 years, range 26-89 years) at the dosage of 2 mg/kg per day in a 1-year double-blind trial. The number of patients who required hospitalization for worsening heart failure was smaller in the coenzyme Q10 treated group (n = 73) than in the control group (n = 118, P < 0.001). Similarly, the episodes of pulmonary edema or cardiac asthma were reduced in the control group (20 versus 51 and 97 versus 198, respectively; both P < 0.001) as compared to the placebo group. Our results demonstrate that the addition of coenzyme Q10 to conventional therapy significantly reduces hospitalization for worsening of heart failure and the incidence of serious complications in patients with chronic congestive heart failure.
This multicenter study evaluated the efficacy and tolerability of coenzyme Q10 in 1715 outpatients with chronic heart failure (New York Heart Association classes II and III), stabilized with standard therapy for 3 months. The patients were treated with coenzyme Q10 at a daily dose of 50 mg for 4 weeks, in addition to receiving conventional therapy. The efficacy of coenzyme Q10 was assessed by an open study that evaluated the improvement in clinical signs and symptoms of heart failure. After the baseline evaluation the subjects were seen on days 15 and 30. The intensity of signs and symptoms was assessed by a semiquantitative 4-point scale. Our results demonstrate that the administration of coenzyme Q10 in association with standard therapy improves dyspnea at rest, exertional dyspnea, palpitations, cyanosis, hepatomegaly, pulmonary rales, ankle edema, heart rate, and systolic and diastolic blood pressure in patients with stabilized heart failure. The rate of improvement and the low number of side effects in this large group of patients demonstrate that despite some methodological limitations in the study design and the short period of treatment (4 weeks) coenzyme Q10 given at a daily dose of 50 mg led to an improvement in the signs and symptoms of heart failure and in the quality of life.
This study was undertaken to evaluate the potential of HMG-CoA reductase inhibitors, pravastatin sodium (hereafter abbreviated to pravastatin) and simvastatin, for induction of myopathy and influence on the ubiquinone content of skeletal and cardiac muscles and other tissues in the rabbit. Both drugs were administered orally to New Zealand White rabbits (n = 5) at the dose of 50 mg/kg per day for 14 days. Serum cholesterol levels in the pravastatin- and simvastatin-treated groups were reduced significantly by 47% an 58% on day 14 (P < 0.05), respectively, as compared with the control group, but the difference between the two treatment groups was not significant. In animals of the simvastatin-treated group, abnormal elevations of creatine kinase (CK) and lactate dehydrogenase (LDH) levels were observed, in association with severe lesions in skeletal muscles, but not cardiac muscle. The ubiquinone content in skeletal muscle in this treatment group was not affected, even in the muscles that had severe lesions, whereas that in liver and cardiac muscle was significantly reduced compared with the control group. The results suggest that there is no direct correlation between myopathy and the decrease of ubiquinone content in skeletal muscles. In contrast, the animals in the pravastatin-treated group did not show any changes in CK and LDH levels, ubiquinone content in liver and muscles, or in histopathological features of muscle fibers. The difference between the adverse effects seen with the two drugs could be attributed to physicochemical properties: simvastatin permeates the plasma membrane because of its hydrophobic nature, whereas pravastatin does not, because it is hydrophilic.
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.
Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.
Effects of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, pravastatin and simvastatin, on the myocardial level of coenzyme Q 10 , and on mitochrondrial respiration were examined in dogs
Either vehicle (control), pravastatin (4 mg kg ⁻¹ day ⁻¹ ), or simvastatin (2 mg kg ⁻¹ day ⁻¹ ) was administered orally for 3 weeks. First, the myocardial tissue level of coenzyme Q 10 was determined in the 3 groups. Second, ischaemia was induced by ligating the left anterior descending coronary artery (LAD) in anaesthetized open chest dogs, pretreated with the inhibitors. After 30 min of ischaemia, nonischaemic and ischaemic myocardium were removed from the left circumflex and LAD regions, respectively, and immediately used for isolation of mitochondria. The mitochondrial respiration was determined by polarography, with glutamate and succinate used as substrates
Simvastatin significantly decreased the myocardial level of coenzyme Q 10 , but pravastatin did not
Ischaemia decreased the mitochondrial respiratory control index (RCI) in both groups. Significant differences in RCI between nonischaemic and ischaemic myocardium were observed in the control and simvastatin‐treated groups
Only in the simvastatin‐treated group did ischaemia significantly decrease the ADP/O ratio, determined with succinate
The present results indicate that simvastatin but not pravastatin may cause worsening of the myocardial mitochondrial respiration during ischaemia, probably because of reduction of the myocardial coenzyme Q 10 level.
It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.
1Statins inhibit synthesis of mevalonate, a precursor of ubiquinone that is a central compound of the mitochondrial respiratory chain. The main adverse effect of statins is a toxic myopathy possibly related to mitochondrial dysfunction.
2This study was designed to evaluate the effect of lipid-lowering drugs on ubiquinone (coenzyme Q10) serum level and on mitochondrial function assessed by blood lactate/pyruvate ratio.
3Eighty hypercholesterolaemic patients (40 treated by statins, 20 treated by fibrates, and 20 untreated patients, all 80 having total cholesterol levels >6.0 mmol l−1) and 20 healthy controls were included. Ubiquinone serum level and blood lactate/pyruvate ratio used as a test for mitochondrial dysfunction were evaluated in all subjects.
4Lactate/pyruvate ratios were significantly higher in patients treated by statins than in untreated hypercholesterolaemic patients or in healthy controls (P<0.05 and P<0.001). The difference was not significant between fibrate-treated patients and untreated patients.
5Ubiquinone serum levels were lower in statin-treated patients (0.75 mg l−1±0.04) than in untreated hypercholesterolaemic patients (0.95 mg l−1±0.09; P<0.05).
6We conclude that statin therapy can be associated with high blood lactate/pyruvate ratio suggestive of mitochondrial dysfunction. It is uncertain to what extent low serum levels of ubiquinone could explain the mitochondrial dysfunction.
A double-blinded, placebo-controlled cross-over trial was carried out with 27 hypercholesterolemic men with coronary heart disease. During the 6-week treatment period lovastatin (60 mg/day) decreased fasting serum LDL cholesterol by 45%, LDL phosphorus by 38% and apoB by 33%. Ubiquinol content diminished by 13% as measured per LDL phosphorus. When LDL was oxidized ex vivo with AMVN both LDL ubiquinol and alpha-tocopherol were exhausted faster after lovastatin treatment compared to placebo, by 24% (P < 0.005) and 36% (P < 0.0001), respectively. Lag time in copper-induced oxidation of LDL decreased by 7% (P < 0.01). This suggests diminished antioxidant-dependent resistance of LDL to the early phase of oxidative stress.
Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.
Coenzyme Q10 in its reduced form, ubiquinol-10, although present in LDL at concentrations considerably lower than that of alpha-tocopherol, exerts a potent antioxidant action in this class of lipoproteins. Previous studies indicated that the content of CoQ10 is the lowest in the densest subfraction of LDL, i.e. LDL3, which is commonly regarded as the most peroxidizable and atherogenic one. These levels were associated with the highest levels of hydroperoxides detectable in the three subclasses. Enrichment of LDL with CoQ10, by means of exogenous supplementation, resulted in a significant increase of CoQ10 in LDL, mainly in LDL3, and in a lower extent of peroxidizability. Spontaneous oxidation of ubiquinol was monitored in plasma and in LDL of unsupplemented and of supplemented subjects and the time-course of oxidation was found considerably slower in CoQ10-enriched LDL. The lagphase of conjugated dienes formation upon induced oxidation was significantly correlated with the absolute content of ubiquinol-10. Distribution of CoQ10 among different classes of plasma lipoproteins was also studied: about 60% of plasma CoQ10 was found associated with LDL.
Coenzyme Q10 (Ubidecarenone) is marketed as a dietary supplement. Drug interaction between coenzyme Q10 and warfarin has previously been reported. In the present case, a 72-year-old female treated with warfarin showed less responsiveness to warfarin than previously. It appeared she had taken coenzyme Q10, and when this was stopped, her responsiveness to warfarin was the same as before. Coenzyme Q10 is chemically similar to K-vitamins, which may explain the interaction with warfarin. Patients in treatment with warfarin should be aware of the possible risk of treatment failure when taking coenzyme Q10. The need for questioning patients concerning not only medications but also use of dietary supplements and alternative medications is emphasised.
A combination of electrophysiological, pathological, and biochemical studies were performed in myopathy induced by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Simvastatin (a lipophilic inhibitor) or pravastatin (a hydrophilic inhibitor) were administered by gavage to rabbits. In Group I (simvastatin-treated group, 50 mg/kg/day for 4 weeks), four rabbits showed muscle necrosis and high serum creatine kinase (CK) levels, and all six rabbits showed electrical myotonia. In Group II (pravastatin-treated group, 100 mg/kg/day for 4 weeks), no rabbit showed either condition. In Group III (pravastatin-treated group, 200 mg/kg/day for 3 weeks plus 300 mg/kg/day for 3 weeks), one rabbit showed muscle necrosis and high serum CK level and two rabbits showed electrical myotonia. The pathological findings were muscle fiber necrosis and degeneration with increased acid phosphatase activity by light microscopy, autophagic vacuoles and mitochondrial swelling, and disruption and hypercontraction of myofibrils by electron microscopy. Ubiquinone content decreased in skeletal muscle by 22 to 36% in Group I, by 18 to 52% in Group II, and by 49 to 72% in Group III. However, mitochondrial enzyme activities of respiratory chain were normal in all groups. These results indicate that myopathy was not induced by a secondary dysfunction of mitochondrial respiration due to low ubiquinone levels.
We examined effects of pravastatin on age-related changes in mitochondrial function in rats. Decline in the activity of complex I of the mitochondrial electron transport chain was observed in diaphragm and psoai major in rats aged 35 and 55 weeks, and that of complex IV in rats aged 55 weeks. Pravastatin accelerated significantly age-related decline in the activity of complex I of diaphragm mitochondria, though pravastatin did not show significant effect on normally observed age-associated decline in the activities of complex IV of psoai major and diaphragm mitochondria. Aging effect on mitochondrial respiratory function was not observed on heart muscle and liver in rats up to 55 weeks old, and pravastatin did not effect significantly heart and liver mitochondrial respiratory function. From these results, careful clinical examination on respiratory muscle function should be necessary in patients treated with pravastatin particularly in elderly patients.
Previous studies suggested that certain lipid-lowering drugs such as statins suppress ubiquinone, affect mitochondrial function, and may have deleterious effect on skeletal or cardiac muscles with potentially serious clinical consequences, especially in patients with established coronary heart disease and left ventricular dysfunction. In this double-blind study, we assessed the effects of 20 mg simvastatin (S, n = 32) or 200 mg micronized fenofibrate (F, n = 32, control group) on rest and exercise left ventricular function in hypercholesterolemic survivors of a previous Q-wave acute myocardial infarction. Left ventricular radionuclide imaging was performed at rest and during submaximal exercise and global and segmental (nine segment regional wall-motion score) ejection fractions were measured before treatment and 12 weeks later. Serum ubiquinone was reduced after treatment (p = 0.03) in the S but not the F group, whereas total and low-density lipoprotein (LDL) cholesterol were significantly reduced in both groups. Before treatment, mean global ejection fraction was 52.1+/-12.2% and 49.3+/-11.8% at rest in F and S patients, respectively, and increased (56.0+/-13.7% in F and 52.1+/-12.9% in S) at peak exercise (no difference between groups). After treatment, the increase in ejection fraction tended to be lower in S (0) than in F (+3.8%) but not significantly. However, ejection fraction at rest increased after treatment in S (p = 0.009) but not in F. Subgroup analyses indicated that the improvement in rest ejection fraction in S was essentially observed in patients with ejection fraction <40% (n = 8, +6%), whereas it was stable in patients with ejection fraction >40% (+1.8%). Finally, the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment. Mean maximal exercise load (113+/-23 watts in F vs. 104+/-27 W in S before treatment) was not modified by the treatment (111+/-21 and 104+/-27 W). Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise. The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size.
Wirkung der Therapie mit 3-Hydroxy-3-methylglutaryl-Coenzym-A-Reduktase- Hemmern auf das Serum-Coenzym Q10 bei Diabetikern
Die Konzentration von Serum-Coenzym Q1o (CoQ1o: 2-(3,7,11,15,19,23,27,31,35,39-Decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzochinon, CAS 303-98-0) und der Cholesterinspiegel wurden bestimmt, urn die Wirkung der Cholesterin-senkenden Therapie bei Patienten mit nicht insulinabhängigem Diabetes mellitus (noninsulin-dependent diabetes mellitus, NIDDM) zu untersuchen. 20 gesunde Probanden, 97 NIDDM-Patienten sowie 2 Patienten mit familiärer Hypercholesterinämie nahmen an der Studie teil. Bei keiner Versuchsperson lag eine erkennbare Herzinsuffizienz oder eine andere Herzerkrankung vor. Die durchschnittliche Serum-CoQ10-Konzentration war bei Diabetikern mit normalem Cholesterinspiegel signifikant (p 0,01) niedriger, und zwar mit oder ohne Verabreichung von 3-Hydroxy-3-methylglutaryl-Coenzym-A-Reduktase-Inhibitoren (HMG-CoA RI) wie Simvastatin (normal: 0,91 ± 0,26 (Mittelwert ± SD) 1⁻¹; Diabetiker mit HMG-CoA RI: 0,63 ± 0,19; Diabetiker ohne HMG-CoA RI: 0,66 ± 0,21). Bei Diabetikern mit Hypercholesterinämie war die CoQ10- Konzentration höher (1,37 ± 0,48, p < 0,001). Durch Simvastatin oder die Apherese von Lipoproteinen geringer Dichte sank mit dem Cholesterin- Spiegel auch die Serum-CoQ10- Konzentration. Die orale Verabreichung von CoQ10 an Diabetiker, die mit HMG-CoA RI behandelt wurden, erhöhte sich die Serum-CoQlo-Konzentration signifikant (p < 0,001) von 0,81 ± 0,24 auf 1,47 ± 0,44 1⁻¹, ohne den Cholesterinspiegel zu verändern. Das kardiothorakale Verhältnis ging dadurch signifikant (p < 0,03) von 51,4 ± 5,l auf 49,2 ± 4,7% zurück. Dies läßt darauf schließen, daß der Serum-CoQ10-Spiegel bei NIDDM-Patienten vermindert ist und vermutlich bei der subklinischen diabetischen Kardiomyopathie eine Rolle spielt; dem kann durch Verabreichung von CoQ10 entgegengewirkt werden.