Article

Effect of atorvastatin on left ventricular, diastolic function and ability of coenzyme Q(10) to reverse that dysfunction

Authors:
  • Peter Langsjoen MD PA, Tyler, Texas
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Abstract

This study evaluated left ventricular diastolic function with Doppler echocardiography before and after statin therapy. Statin therapy worsened diastolic parameters in most patients; coenzyme Q(10) supplementation in patients with worsening diastolic function with statin therapy improved parameters of diastolic function.

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... et al., 1997, Miyake et al., 1999, Watts et al., 1993, Passi et al., 2003, Laaksonen et al., 1995, Laaksonen et al., 1996, Palomaki et al., 1997, Palomaki et al., 1998, Bleske et al., 2001, Jula et al., 2002, Wong et al., 2001, Rundek et al., 2004 Interestingly, one study not evaluated in regard to changes in CoQ 10 levels was a study performed by Silver and Langsjoen. (Silver, et al., 2004) In this study, 14 patients received atorvastatin 20 mg/day for 3 to 6 months. From the data provided in the article by Langsjoen et al., 2005 (Table 1) baseline CoQ 10 levels were 0.99 + 0.3 ug/ml prior to atorvastatin and 1.0 + 0.4 ug/mL following atorvastatin therapy. These findings are similar to a previous study (Bleske, et al., 200 ...
... (Bleske, et al., 2001) This may also possibly explain the authors' own findings? (Silver, et al., 2004) It is likely that the reduction in CoQ 10 seen in previous studies is related to LDL reduction and not a reduction in overall cellular CoQ 10 concentrations. Another and perhaps the most significant issue is that we do not know the relationship between circulating CoQ 10 and intracellular CoQ 10 . ...
... The evidence provided by the authors appears to be based on two articles. (Miyake, et al., 1999, Silver, et al., 2004 One article demonstrated significant decrease in cardiothoracic ratios following CoQ 10 supplementation in 97 patients with non-insulin dependent diabetes mellitus receiving simvastatin therapy. (Miyake, et al) The other article by Silver et al., demonstrated improvement in diastolic function following CoQ 10 supplementation in 14 patients receiving atorvastatin therapy. ...
Article
In the paper by Langsjoen et al. (2005), they put forth the concept that HMG-CoA reductase inhibitors (statins) sig-nificantly decrease the production of cellular coenzyme Q 10 (CoQ 10) resulting in significant clinical consequences, es-pecially myocardial dysfunction. This is a good hypothesis; HMG-CoA reductase inhibition leads to a reduction in far-nestyl that is a branch point for a number of other pathways including cholesterol and CoQ 10 . It is plausible that not only cholesterol but also CoQ 10 may be reduced with the admin-istration of a statin. But, as with all good hypotheses there is an implicit promise to have clear evidence that the hypothesis is valid. There have been many good hypotheses that when tested were not valid. For example, the PROMISE trial had a good hypothesis; administration of inotropic agents to patients with poor heart function would be of benefit (The PROMISE Study Research Group, 1991). Another good hypothesis was to administer antiarrhythmic agents to patients with prema-ture ventricular arrhythmias post myocardial infarction (The CAST Investigators, 1989). We now know that these good hypotheses when tested were not valid and were in fact harm-ful. Fortunately, these hypotheses were not made standard of care before they were tested. Similar to the current hypothesis, additional data is needed before subjecting millions of patients to an unknown therapy. The data presented by Langsjoen et al., is interesting and somewhat suggestive but by no means conclusive and for the most part debatable. Langsjoen et al., shows multiple pieces of evidence that plasma levels of CoQ 10 are decreased following statin therapy. It should be noted of the 18 trials cited the authors stated that only 9 were controlled trials with one trial showing no decrease in muscle CoQ 10 and one showing no decrease in blood CoQ 10 . (Ghirlanda et al. Interestingly, one study not evaluated in regard to changes in CoQ 10 levels was a study performed by Silver and Langsjoen. (Silver, et al., 2004) In this study, 14 patients received atorvastatin 20 mg/day for 3 to 6 months. From the data provided in the article by Langsjoen et al., 2005 (Table 1) baseline CoQ 10 levels were 0.99 + 0.3 ug/ml prior to atorvastatin and 1.0 + 0.4 ug/mL following atorvastatin therapy. These findings are similar to a previous study (Bleske, et al., 2001). Despite these contradictory find-ings, including their own data, the authors implied that reduc-tion in blood levels following statin therapy is a marker for CoQ 10 depletion. To overcome this depletion, administra-tion of CoQ 10 is required. However, critical evaluation of this concept puts this recommendation into question. Low-density lipoproteins (LDL) are carrier molecules for CoQ 10 , if LDL is reduced by statin therapy it would be anticipated that CoQ 10 would also be reduced. In fact, studies have shown a strong correlation between LDL reduction and CoQ 10 levels. When this may not occur is when CoQ 10 levels are sufficiently low so that there are a sufficient number of carrier molecules avail-able. The findings observed in a previous study that demon-strated no decrease in CoQ 10 levels following statin therapy may be explained by this rationale. (Bleske, et al., 2001) This may also possibly explain the authors' own findings? (Silver, et al., 2004) It is likely that the reduction in CoQ 10 seen in previous studies is related to LDL reduction and not a re-duction in overall cellular CoQ 10 concentrations. Another and perhaps the most significant issue is that we do not know the relationship between circulating CoQ 10 and intracellular CoQ 10 . Since each cell makes CoQ 10 , blood levels may be irrelevant. Blood CoQ 10 may only reflect dietary intake. The best data so far, which were studied in humans, showed no relationship between serum CoQ 10 and muscle CoQ 10 levels following statin therapy. (Laaksonen et al., 1995) At this point in time evaluating circulating CoQ 10 levels has little or no meaning. One must have a further understanding of the rela-tionship between circulating and tissue concentrations before one uses circulating CoQ 10 (i.e. blood/serum CoQ 10) to help justify the administration of CoQ 10 .
... Foram analisados 18 trabalhos científicos envolvendo a suplementação do nutracêutico (ubiquinona ou ubiquinol) para melhora dos seguintes efeitos induzidos por estatinas: miopatias/danos musculares [2,[5][6][7][8][14][15][16][17]; disfunções ventricular/endotelial [6,18,19] e mitocondrial [8,[20][21][22]; hepatotoxicidade [7,8,15,22]; fadiga, dispneia, perda de memória e neuropatia periférica [6]; cardiomiopatia induzida por estatinas [13]; sensibilidade a insulina [23]; também, foi estudado o efeito da CoQ10 na melhora de parâmetros de performance física (aptidão cardiorrespiratória e/ou desempenho muscular) [16,24]; assim como de marcadores inflamatórios e níveis de enzimas antioxidantes em usuários de estatinas [25]. ...
... É bem consolidado que a suplementação de CoQ10, mesmo em curto prazo, eleva significativamente os níveis de ubiquinona plasmática [5,7,8,13,[16][17][18][19][20][21][22][23][24][25]. Como demonstrado por Diemen et al., que em apenas quatro semanas de suplementação, com a dosagem de 300 mg/dia já obtiveram esse resultado, ou ainda, como Zlatohlavek et al., que alcançaram o significativo aumento de 194% nos níveis séricos de CoQ10 com 60 mg/dia de ubiquinol (duas doses de 30 mg/dia) em seis meses de suplementação. ...
... Desses dez estudos, cinco encontraram resultados positivos no uso da CoQ10 para o tratamento da miopatia induzida por estatinas, isto é, redução dos sintomas miopáticos [2,5,6,15,17]. Três não encontraram resultados de melhora significativa desses sintomas ou marcadores [8,14,16] [6,19]. Os achados são semelhantes, em relação a disfunção endotelial, apesar da suplementação ter apresentado uma melhora desta disfunção em pacientes tratados com estatinas, distintos, provocando assim diferenças no efeito do fármaco. ...
Article
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Coenzyme Q10 (CoQ10), also known as ubiquinone, is an essential component of the mitochondrial respiratory chain. One of the causes of its deficiency is the chronic use of statins, a class of widely prescribed anti-cholesterolemic drugs. Its reduction can cause undesirable side effects, such as dyspnea, hepatic alterations, muscular and/or gastrointestinal symptoms, rhabdomyolysis, peripheral neuropathies, type 2 Diabetes Mellitus, among others. This literature review aimed to understand whether CoQ10 supplementation reduces the side effects caused by the use of statins, to describe them, and to indicate the safe and effective dose for the success of this nutritional strategy. This is a systematic review of the literature, which was searched in the MEDLINE/PubMed database, of studies published between 2004 and 09/2020, using the descriptors and combination Ubiquinone AND Anticholesteremic Agents and Ubiquinone AND Cholesterol. A total of 462 articles were identified, and after reading the title, abstract, and applying the exclusion criteria, 18 scientific papers were included for analysis. The studies presented varied populations and methodologies, and the methods for evaluating the results were also heterogeneous, mainly due to the variety of side effects studied. Of the 18 studies, ten (66.6%) found some benefit from supplementation. It was evidenced that the usual dose of supplementation (between 100 and 300 mg) was able to bring benefits regarding the following parameters: diastolic, endothelial, and mitochondrial function, fatigue, myopathies, dyspnea, memory loss, peripheral neuropathy, lipid profile, antioxidant and anti-inflammatory activity, and hepatotoxicity evidenced after 30 days of supplementation, and also a reduction in cardiovascular risk.
... Furthermore, up to 20% of patients treated with ACE-Is develop intolerance [49]. Numerous studies have shown coenzyme Q 10 to be safe and generally well tolerated in humans [19,20,[55][56][57][58][59][60]. Indeed, coenzyme Q 10 effectively attenuates diastolic dysfunction induced by chronic statin use in hypercholesterolemic patients [60]. ...
... Numerous studies have shown coenzyme Q 10 to be safe and generally well tolerated in humans [19,20,[55][56][57][58][59][60]. Indeed, coenzyme Q 10 effectively attenuates diastolic dysfunction induced by chronic statin use in hypercholesterolemic patients [60]. Coenzyme Q 10 appears to have fewer side effects than ACE-Is and animal studies indicate that it may also provide protection against renal dysfunction [36,54]. ...
Article
Cardiac oxidative stress is an early event associated with diabetic cardiomyopathy, triggered by hyperglycemia. We tested the hypothesis that targeting left ventricular (LV) reactive oxygen species (ROS) upregulation subsequent to hyperglycemia attenuates type 1 diabetes-induced LV remodeling and dysfunction, accompanied by attenuated pro-inflammatory markers and cardiomyocyte apoptosis. Male 6-week-old mice received either streptozotocin (55mg/kg/day for 5 days) to induce type 1 diabetes, or citrate buffer vehicle. After 4 weeks of hyperglycemia, mice were allocated to coenzyme Q10 supplementation (10mg/kg/day), treatment with the angiotensin converting-enzyme inhibitor (ACE-I) ramipril (3mg/kg/day), olive oil vehicle or untreated, for 8 weeks. Type 1 diabetes upregulated LV NADPH oxidase (Nox2, p22phox, p47phox and superoxide production), LV uncoupling protein UCP3 expression and both LV and systemic oxidative stress (LV 3-nitrotyrosine and plasma lipid peroxidation). All of these were significantly attenuated by coenzyme Q10. Coenzyme Q10 substantially limited type 1 diabetes-induced impairments in LV diastolic function (E:A ratio and deceleration time by echocardiography, LV end-diastolic pressure and LV-dP/dt by micromanometry), LV remodeling (cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis) and LV expression of pro-inflammatory mediators (tumor necrosis factor TNFα, with a similar trend for interleukin IL-1β). Coenzyme Q10 actions were independent of glycemic control, body-mass and blood pressure. Coenzyme Q10 compared favorably to improvements observed with ramipril. In summary, these data suggest coenzyme Q10 effectively targets LV ROS upregulation to limit type 1 diabetic cardiomyopathy. Coenzyme Q10 supplementation may thus represent an effective alternative to ACE-Is for the treatment of cardiac complications in type 1 diabetic patients.
... As shown by large clinical trials, reduction in total cholesterol by statins results in a significant decrease in CV events and all-cause mortality 10 . Statins can cause muscle cramps, rhabdomyolysis, and have the potential to cause or worsen congestive heart failure or diastolic dysfunction 140,141 , but these may be reversed by the administration of coenzyme Q10 140,141 . Fibrates [peroxisome proliferator-activated receptor (PPAR)-β agonists] reduce LDL-cholesterol, VLDL-cholesterol and triglycerides, and increase HDL-cholesterol; they improve insulin sensitivity. ...
... As shown by large clinical trials, reduction in total cholesterol by statins results in a significant decrease in CV events and all-cause mortality 10 . Statins can cause muscle cramps, rhabdomyolysis, and have the potential to cause or worsen congestive heart failure or diastolic dysfunction 140,141 , but these may be reversed by the administration of coenzyme Q10 140,141 . Fibrates [peroxisome proliferator-activated receptor (PPAR)-β agonists] reduce LDL-cholesterol, VLDL-cholesterol and triglycerides, and increase HDL-cholesterol; they improve insulin sensitivity. ...
... HMG-CoA reductase inhibitors (statins) reduce Co-Q10 levels in human [41,42]. Alternatively, supplementation with oral Co-Q10 can restore plasma Co-Q10 levels in patients receiving statin therapy [41][42][43]. ...
... HMG-CoA reductase inhibitors (statins) reduce Co-Q10 levels in human [41,42]. Alternatively, supplementation with oral Co-Q10 can restore plasma Co-Q10 levels in patients receiving statin therapy [41][42][43]. Statin mediated Co-Q10 depletion affects muscle function. Patients taking statin to reduce plasma lipids suffered myalgia and myopathic pain [44][45][46]. ...
Article
Full-text available
Co-enzyme Q10 (Co-Q10) is an essential component of the mitochondrial electron transport chain. Most cells are sensitive to co-enzyme Q10 (Co-Q10) deficiency. This deficiency has been implicated in several clinical disorders such as heart failure, hypertension, Parkinson’s disease and obesity. The lipid lowering drug statin inhibits conversion of HMG-CoA to mevalonate and lowers plasma Co-Q10 concentrations. However, supplementation with Co-Q10 improves the pathophysiological condition of statin therapy. Recent evidence suggests that Co-Q10 supplementation may be useful for the treatment of obesity, oxidative stress and the inflammatory process in metabolic syndrome. The anti-inflammatory response and lipid metabolizing effect of Co-Q10 is probably mediated by transcriptional regulation of inflammation and lipid metabolism. This paper reviews the evidence showing beneficial role of Co-Q10 supplementation and its potential mechanism of action on contributing factors of metabolic and cardiovascular complications.
... Second, improvements in parameters of LV diastolic function with an acute ascorbic acid infusion in postmenopausal women, but not premenopausal women, supports the notion of tonic suppression of LV diastolic function by ROS. These findings are consistent with previous investigations that showed an improvement in LV diastolic function following the chronic administration of the mitochondrial targeted antioxidant coenzyme Q 10 in patients with hypercholesterolemia and hypertrophic cardiomyopathy [36,37]. ...
... In this regard, attention has recently been focused on targeting sources of high ROS production, such as the mitochondria. Alternative mitochondria targeted antioxidant therapies (e.g., Coenzyme Q10 and MitoQ) have been increasingly investigated in populations with advanced cardiovascular disease [36,55,56] demonstrating improvements in LV function, endothelial function, and favorable cardiac remodeling. However, to our knowledge, there are no studies that have investigated the effects of mitochondrial targeted antioxidants on cardiovascular function in postmenopausal women, acutely or chronically, making it an attractive area of research for studying alternative methods of attenuating the decline in cardiovascular function with aging in women. ...
Article
Objectives: We tested the hypothesis that oxidative stress contributes to reductions in left ventricular diastolic (LV) function in estrogen-deficient postmenopausal women, related in part to reduced nitric oxide (NO) bioavailability. Study design: LV diastolic function - recorded using transthoracic echocardiography and determined as the peak early (E) to late (A) mitral inflow velocity ratio and the E to peak early (e') mitral annular velocity ratio - and brachial artery flow mediated dilation (FMD), a biomarker of NO bioavailability, were measured during acute systemic infusions of saline (control) and ascorbic acid (experimental model to decrease oxidative stress) in healthy premenopausal women (N=14, 18-40 years) and postmenopausal women (N=23, 45-75 years). Results: The E/A ratio was lower (1.16[1.06-1.33] vs 1.65[1.5-2.3]; median[interquartile range]) and the E/e' ratio was elevated (8.8[7.6-9.9] vs. 6.6[5.5-7.3]) in postmenopausal compared with premenopausal women, indicating reduced LV diastolic function. E/A and E/e' were correlated with FMD (r=0.54 and r=-0.59, respectively, both P<0.01). Ascorbic acid infusion improved both FMD (5.4±2.0% to 7.8±2.6%) and E/e' (to 8.1[7.2-9.7], P=0.01) in postmenopausal women but not in premenopausal women. Ascorbic acid did not change E/A in either group. Conclusion: The current study provides evidence that oxidative stress contributes to reduced LV diastolic function in estrogen-deficient postmenopausal women, possibly by reducing the availability of NO.
... Cardiovascular function is a primary contributor to exercise capacity and it is impaired in people with T2D, providing a logical potential cause of the impaired cardiorespiratory fitness of T2D. In previous studies, supplementation with antioxidants has augmented cardiac function [13][14][15][16] and vasodilation [17][18][19] which may impact tissue oxygen delivery in both central and peripheral circulations and affect the utilization of oxygen during exercise. However, to date we have not determined the isolated effects of cardiovascular function, per se, on cardiorespiratory fitness in persons with T2D. ...
... In cardiac myocytes, a decrease in nitric oxide disrupts calcium kinetics [33] and impairs cardiac relaxation [34]. Previous investigations have also demonstrated improved cardiac function with acute [16] and chronic [13][14][15] antioxidant therapy administration. Thus, it is possible that the beneficial effect of vitamin C on diastolic function in this study was through modulation of oxidant burden. ...
Article
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Background People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. Methods Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m²) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m²) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. Results Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E’ (P < 0.01), but did not change RH (P = 0.92), or VO2peak (P = 0.33) in any participants. Conclusion Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets. Trial registration NCT00786019. Prospectively registered May 2008
... Because the heart is a muscle, it is plausible that heart muscle weakness could arise from long-term statin usage. Indeed, atorvastatin has been shown to impair ventricular diastolic heart performance [72], and low cholesterol levels were also found to be associated with greater 12-month mortality risk in patients with chronic heart failure [62]. Furthermore, CoQ10 supplementation has been shown to improve cardiac function [57,86]. ...
... Heart failure was also much more common in the statin drug branch, consistent with the findings of Silver et al. [72]. ...
Article
We address the problem of information accessibility for patients concerned about, pharmaceutical drug side effects and experiences. We create a new corpus of online patient-provided drug reviews and present our initial experiments on that corpus. We detect biases in term distributions that show a statistically significant association between a class of cholesterol-lowering drugs called statins, and a wide range of alarming disorders, including depression, memory loss, and heart failure. We also develop an initial language model for speech recognition in the medical domain, with transcribed data on sample patient comments collected with Amazon Mechanical Turk. Our findings show that patient-reported drug experiences have great potential to empower consumers to make more informed decisions about medical drugs, and our methods will be used to increase information accessibility for consumers.
... In 2004 Silver et al. documented the development of left ventricular diastolic dysfunction in fourteen patients treated with 20 mg atorvastatin per day. This diastolic dysfunction was found to be reversible upon CoQ 10 supplementation while the patients stayed on the statin therapy [74]. ...
... Statin cardiomyopathy (SCM) can be defined as an impairment in heart muscle function consequent to statin drug therapy not explainable by any other pathophysiology. The first study that recognized statin-induced impairment in heart muscle function in previously healthy individuals was published in 2004 [74]. This study was unique in that it demonstrated that a relatively low dose of statin could over a relatively short period of time cause significant impairment in previously normal myocardial function. ...
Chapter
HMG-CoA reductase inhibitors, a class of drugs commonly referred to as statins, decrease the cellular production of mevalonate which is necessary in the biosynthesis of cholesterol, statins’ intended target. An often overlooked consequence of the mechanism of statin action is that they unavoidably diminish all downstream biosynthetic products in the mevalonate pathway, which includes coenzyme Q10 (CoQ10), dolichol, and a family of isoprenoids including selenoproteins and heme A. This collateral damage affects numerous aspects of cell physiology – not only disrupting all cholesterol-related functions, but severely impairing CoQ10 related mitochondrial ATP production, mitochondrial DNA protection by CoQ10, and the viable process of cell division. While the biochemical implications of this pathway suppression were well understood in the 1980s, in the 1990s the clinical characteristics of statin adverse effects became more narrowly viewed in terms of only cholesterol reduction and CoQ10 depletion. By and large, the potential adverse consequences of decreasing cholesterol were ignored or viewed as inconsequential in comparison to the perceived benefit of cholesterol lowering on human health. Over the following 20 years, a number of studies have focused on CoQ10 depletion and on the ability of supplemental CoQ10 to either prevent or diminish these statin adverse effects. Unfortunately, it has become increasingly evident that such an amelioration of CoQ10 depletion in the setting of statin use has only a palliative effect on skeletal and cardiac myopathy.
... It has been suggested that fatigue, muscle pain, and weakness with statin use are related to a deficiency in coenzyme Q10. Interestingly, in patients with normal cardiac function, who received 20 mg of atorvastatin, 70 % developed diastolic dysfunction that was reversible with CoQ10 supplementation [51]. ...
Article
Full-text available
Heart failure affects 5.1 million people in the USA annually. It accounts for a frequent cause of hospitalizations and disability. Patients with congestive heart failure have lower plasma levels of CoQ10, which is an independent predictor of mortality in this patient population. It has been hypothesized that a deficiency of CoQ10 can play a role in the development and worsening of heart failure, and that oral supplementation can possibly improve symptoms and survival in these patients. Based on previous small studies and meta-analyses, the use of CoQ10 in heart failure suggested an improvement ejection fraction, stroke volume, cardiac output, and cardiac index with CoQ10 supplementation, however most of these small studies appeared to be underpowered to result in any significant data. The results of the recent Q-SYMBIO trial demonstrated an improvement in heart failure symptoms with a significant reduction in major adverse cardiovascular events and mortality.
... 15 Administration of CoQ10 increases CoQ10 blood levels in patients treated with statins. [16][17][18][19] However, these studies were based on relatively small sample sizes. Therefore, the precise effect(s) of CoQ10 supplementation has not been established. ...
Article
Objective To evaluate the efficacy of coenzyme Q10 (CoQ10) supplementation on statin-induced myopathy. Participants and Methods We searched the MEDLINE, Cochrane Library, Scopus, and EMBASE databases (November 1, 1987, to May 1, 2014) to identify randomized controlled trials investigating the impact of CoQ10 on muscle pain and plasma creatine kinase (CK) activity as 2 measures of statin-induced myalgia. Two independent reviewers extracted data on study characteristics, methods, and outcomes. Results We included 6 studies with 302 patients receiving statin therapy: 5 studies with 226 participants evaluated the effect of CoQ10 supplementation on plasma CK activity, and 5 studies (4 used in the CK analysis and 1 other study) with 253 participants were included to assess the effect of CoQ10 supplementation on muscle pain. Compared with the control group, plasma CK activity was increased after CoQ10 supplementation, but this change was not significant (mean difference, 11.69 U/L [to convert to μkat/L, multiply by 0.0167]; 95% CI, –14.25 to 37.63 U/L; P=.38). Likewise, CoQ10 supplementation had no significant effect on muscle pain despite a trend toward a decrease (standardized mean difference, –0.53; 95% CI, –1.33 to 0.28; P=.20). No dose-effect association between changes in plasma CK activity (slope, –0.001; 95% CI, –0.004 to 0.001; P=.33) or in the indices of muscle pain (slope, 0.002; 95% CI, –0.005 to 0.010; P=.67) and administered doses of CoQ10 were observed. Conclusion The results of this meta-analysis of available randomized controlled trials do not suggest any significant benefit of CoQ10 supplementation in improving statin-induced myopathy. Larger, well-designed trials are necessary to confirm the findings from this meta-analysis.
... Thus, it is not surprising that the supplementation with CoQ10 to prevent or treat statin-induced myopathy revealed contradictory results. Some studies showed that CoQ10 administration can increase CoQ10 blood levels in statin-treated patients [25][26][27][28]. Two studies on the frequency of myopathic symptoms reported improvement of statin-related muscle complaints upon CoQ10 (240 mg/day) coadministration in patients with gastric adenocarcinoma treated with high-dose lovastatin (35-45 mg/kg/day) [29,30]. ...
Article
Background: Statins inhibit hydroxymethylglutaryl-coenzyme A reductase, decrease plasma low-density lipoprotein cholesterol and reduce cardiovascular morbidity and mortality. They can also exert adverse effects, mostly affecting skeletal muscle, ranging from mild myalgia to rhabdomyolysis. Materials and methods: Based on a PubMed search until December 2014, this review summarizes studies on statin effects on muscle mitochondrial morphology and function in the context of myopathy. Results: Possible mechanisms of statin-induced myopathy include lower cholesterol synthesis and production of prenylated proteins, reduced dolichols and increased atrogin-1 expression. Statin-treated patients frequently feature decreased muscle coenzyme Q10 (CoQ10) contents, suggesting that statins might impair mitochondrial function. In cell cultures, statins diminish muscle oxygen consumption, promote mitochondrial permeability transient pore opening and generate apoptotic proteins. Animal models confirm the statin-induced decrease in muscle CoQ10, but reveal no changes in mitochondrial enzyme activities. Human studies yield contradictory results, with decreased CoQ10, elevated lipids, decreased enzyme activities in muscle and impaired maximal oxygen uptake in several but not all studies. Some patients are susceptible to statin-induced myopathy due to variations in genes encoding proteins involved in statin uptake and biotransformation such as the solute carrier organic anion transporter family member 1B1 (SLCO1B1) or cytochrome P450 (CYP2D6, CYP3A4, CYP3A5). Carriers for carnitine palmitoyltransferase II deficiency and McArdle disease also present with higher prevalence of statin-induced myopathy. Conclusions: Despite the widespread use of statins, the pathogenesis of statin-induced myopathy remains unclear, requiring prospective randomized controlled trials with intensive phenotyping also for identifying strategies for its risk assessment, prevention and treatment.
... Ubiquinone is a powerful intra-cellular antioxidant and an integral component of the mitochondrial respiratory chain. Very low levels of ubiquinone have been associated with statin-induced rhabdomyolysis (27) and, possibly, cardiac dysfunction (45,46). Statin pharmacokinetics are significantly altered in the critically ill due to changes in protein binding, hepatic metabolism and renal excretion, resulting in significantly higher plasma levels than those found in the general population (28). ...
Article
Statins may offer protective effects in sepsis through anti-inflammatory, mitochondrial protection and other actions. We thus evaluated the effects of simvastatin on survival, organ and mitochondrial function, tissue and plasma ubiquinone levels and liver transcriptomics in a 3-day rat model of sepsis. Comparisons of rat plasma simvastatin and ubiquinone levels were made against levels sampled in blood from patients with acute lung injury (ALI) enrolled into a trial of statin therapy. Animals received simvastatin by gavage either pre- or post-induction of faecal peritonitis. Control septic animals received vehicle alone. 72-hour survival was significantly greater in statin pre-treated animals (43.7%) compared to both their statin post-treated (12.5%) and control septic (25%) counterparts (p<0.05). Sepsis-induced biochemical derangements in liver and kidney improved with statin therapy, particularly when given pre-insult. Both simvastatin pre- and post-treatment prevented the fall in mitochondrial oxygen consumption in muscle fibers taken from septic animals at 24 hours. This beneficial effect was paralleled by recovery of genes related to fatty acid metabolism. Simvastatin pre-treatment resulted in a significant decrease in myocardial ubiquinone. Patients with ALI had a marked variation in plasma simvastatin acid levels however their ubiquinone/LDL cholesterol ratio did not differ regardless of whether they were receiving statin or placebo. In summary, despite protective effects seen with statin treatment given both pre- and post-insult, survival benefit was only seen with pre-treatment, reflecting experiences in patient studies.
... 165 This may also be why statins can worsen congestive heart failure. 166 Statins are such powerful suppressors of the immune system 167 that they are being tested and considered for use in organ transplant immunosuppressive chemotherapy 168 , 169 and for autoimmune diseases. 170 , 171 , 172 Most things that suppress the immune system leave way for the development of cancer: ...
... Flavonoids are known to regulate cholesterol production and exert a potent hypocholesterolemic effect via suppression of the HMG-CoA reductase enzyme. 17 Unlike statin drugs, which reduce the activity of the HMG-CoA reductase enzyme [18]. ...
Article
Full-text available
Vitex agnus castus widely use worldwide and traditionally used in Iraq for gynaecological issues. Extensive search has been done on this herb revealed that this herb has potential anti-angiogenesis activity. The objective of this study is to find the extent of herb safety, to be formulated later; and use by people as an anti angiogenic drug. Methanol extracts which showed potential anti-angiogenic activity has been tested against two animal species mice and rats for testing its safety. Toxicity of the extract was evaluated in Swiss albino mice by feeding the animals with serial doses of the extract between 1.0 to 20.0 g/kg body weight orally and observed continuously for the first 4 h and every hourly for the next 24 h, then 6 hourly for 48 h (72 h, acute toxicity) results collected after two weeks. Rats were also fed with 5000mg/kg extract The toxicity in the animals was carried out by assessing the effects on biochemical parameters, body weight and histopathological study for liver, heart, lung, stomach, spleen, sex organs for both male and female, and renal organs following oral administration of methanol extract. The median acute toxicity value (LD 50) of Vitex agnus castus leaves methanol extract was found to be 17.21g/kg body weight. The extract reduced cholesterol level significantly. Other biochemical finding show no significant different in comparison to control. The body weight was observed in all the groups treated with the extract. No significant weight changes occur throughout the study. The LD 50 value indicated the drug to be quite safe in one dose treatment. The study also showed that the extract had good hypolipidemic effects.
... [29][30][31][32] Several studies have demonstrated a relationship between statin use and reduced blood CoQ10 levels, however evidence of the same relationship in muscle levels of CoQ10 is less consistent; in one report CoQ10 levels were only reduced at high therapeutic doses of specific statins, such as simvastatin and atorvastatin. 33 CoQ10 administration can increase blood CoQ10 levels in patients treated with statins, [34][35][36][37] and may also reduce symptoms of statin-induced myopathy in patients treated with massive statin doses. [38][39][40] In our patient the start of CoQ10 corresponded with a fall in CK levels from 113 228 to 269 IU/L over 9 days. ...
Article
Full-text available
We describe a case of extreme mixed overdose of calcium channel blockers, β-blockers and statins. The patient was successfully treated with aggressive resuscitation including cardiac pacing and multiorgan support, glucagon and high-dose insulin for toxicity related to calcium channel blockade and β-blockade, and ubiquinone for treating severe presumed statin-induced rhabdomyolysis and muscle weakness.
... However, data on intramuscular CoQ 10 levels in patients symptomatic for statin-associated myopathy are scarce and inconsistent (Laaksonen et al. 1995;Paiva et al. 2005), thus its direct association with myopathy remains controversial (Marcoff and Thompson 2007). Inevitably, CoQ 10 supplementation has been shown to reverse statin-induced decreases in plasma CoQ 10 concentrations in patients (Bargossi et al. 1994;Silver et al. 2004;Mabuchi et al. 2005), but the evidence its effects on tissue levels and myopathic symptoms are contentious (Ghirlanda et al. 1993). Approximately half of the body's CoQ 10 is obtained through dietary fat ingestion, whereas the remainder results from endogenous synthesis, and it is uncertain whether its extracellular supply via the circulation influences the intracellular levels (Niklowitz et al. 2007). ...
Article
Statins are the first line treatment for the management of hyperlipidemia. However, the primary adverse effect limiting their use is myopathy. This study examines the efficacy and safety of red yeast rice (RYR), a source of natural statins, as compared with atorvastatin, which is the most widely used synthetic statin. Statin interference with the endogenous synthesis of coenzyme Q10 (CoQ10) prompted the hypothesis that its deficiency may be implicated in the pathogenesis of statin-associated myopathy. Hence, the effects of combination of CoQ10 with either statin have been evaluated. Rats were rendered hyperlipidemic through feeding them a high-fat diet for 90 days, during the last 30 days of the diet they were treated daily with either atorvastatin, RYR, CoQ10, or combined regimens. Lipid profile, liver function tests, and creatine kinase were monitored after 15 and 30 days of drug treatments. Heart contents of CoQ9 and CoQ10 were assessed and histopathological examination of the liver and aortic wall was performed. RYR and CoQ10 had the advantage over atorvastatin in that they lower cholesterol without elevating creatine kinase, a hallmark of myopathy. RYR maintained normal levels of heart ubiquinones, which are essential components for energy production in muscles. In conclusion, RYR and CoQ10 may offer alternatives to overcome atorvastatin-associated myopathy.
... Flavonoids are known to regulate cholesterol production and exert a potent hypocholesterolemic effect via suppression of the HMG-CoA reductase enzyme. 17 Unlike statin drugs, which reduce the activity of the HMG-CoA reductase enzyme [18]. ...
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Vitex agnus castus widely use worldwide and traditionally used in Iraq for gynaecological issues. Extensive search has been done on this herb revealed that this herb has potential anti-angiogenesis activity. The objective of this study is to find the extent of herb safety, to be formulated later; and use by people as an anti angiogenic drug. Methanol extracts which showed potential antiangiogenic activity has been tested against two animal species mice and rats for testing its safety. Toxicity of the extract was evaluated in Swiss albino mice by feeding the animals with serial doses of the extract between 1.0 to 20.0 g/kg body weight orally and observed continuously for the first 4 h and every hourly for the next 24 h, then 6 hourly for 48 h (72 h, acute toxicity) results collected after two weeks. Rats were also fed with 5000mg/kg extract The toxicity in the animals was carried out by assessing the effects on biochemical parameters, body weight and histopathological study for liver, heart, lung, stomach, spleen, sex organs for both male and female, and renal organs following oral administration of methanol extract. The median acute toxicity value (LD50) of Vitex agnus castus leaves methanol extract was found to be 17.21g/kg body weight. The extract reduced cholesterol level significantly. Other biochemical finding show no significant different in comparison to control. The body weight was observed in all the groups treated with the extract. No significant weight changes occur throughout the study. The LD50 value indicated the drug to be quite safe in one dose treatment. The study also showed that the extract had good hypolipidemic effects.
... In some case reports, it has been suggested that there is a decrease in cardiac function after initiating statin therapy [7,8]. Decreased coenzyme Q10 (CoQ10) has been held responsible for deteriorating diastolic parameters in statin therapy [9]. CoQ10 is an antioxidant molecule which plays a vital role in mitochondrial ATP synthesis [10]. ...
Article
Atorvastatin is a statin derivated hypolipidemic drug used in the treatment of hyperlipidemia. High-dose atorvastatin has been shown to significantly reduce adenosine triphosphate (ATP) levels in the heart tissue. Reduction of ATP by atorvastatin causes increased production of reactive oxygen species (ROS), decreased antioxidants, subsequent cell membrane and mitochondrial damage. The present study aimed to biochemically investigate the protective effect of ATP against possible cardiac damage caused by high dose atorvastatin in rats. Male Wistar rats were divided into atorvastatin (ATR), atorvastatin+ATP (AAT) and healthy control (HG) groups. ATP at a 25 mg/kg dose was injected intraperitoneally (ip) to the AAT (n-6) group. 0.9% NaCl as solvent was applied to the ATR (n-6) and HG (n-6) groups by the same route. Afterward, atorvastatin was administered orally at a dose of 20 mg/kg to the AAT and ATR groups. This procedure was repeated once daily for four weeks. At the end of this period, blood samples were taken into tubes to analyze troponin-I (TP-I) by cardiac puncture before animals were sacrificed with high-dose anesthesia. In addition, heart tissues were removed and malondialdehyde (MDA), total glutathione (tGSH), total oxidant (TOS) and total antioxidant (TAS) levels were measured. Biochemical test results showed that in the heart tissues of the ATR group, the oxidative parameters MDA and TOS significantly increased, while the antioxidant parameters tGSH and TAS significantly decreased compared to AAT and HG. Atorvastatin alone administration significantly increased blood TP-I levels, a marker of cardiac tissue damage. However, ATP administration to AAT group animals brought oxidative parameter levels closer to HG, despite high-dose atorvastatin treatment. In addition, the significant decrease in antioxidant levels was prevented by ATP application. High doses of atorvastatin can cause heart damage. ATP treatment was able to prevent atorvastatin-induced oxidative heart damage.
... Silver and colleagues documented systematic impairment of diastolic ventricular function in stable outpatients being started on atorvastatin therapy for hyperlipidemia (Silver et al., 2004). The authors postulate that sensitive diastolic markers may represent early biomarkers for impairment of left ventricular function and found reversal of these abnormalities in the patients after supplemental CoQ 10 at 300 mg per day was added to their atorvastatin therapy. ...
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Statins are drugs of known efficacy in the treatment of hypercholesterolemia and are tolerated by most patients. Although rhabdomyolysis is rare, muscle complaints with normal CK levels are common resulting in decreased patient compliance. Owing to the common biosynthetic pathway, coenzyme Q10 (CoQ10) levels are decreased by statins. As far as plasma levels of CoQ10 are concerned, there is no doubt that they are decreased in the course of statin treatment as evident from numerous animal and clinical studies. It is less clear to what extent statin treatment affects tissue levels of CoQ10; in fact while several animal studies confirm this data, the findings are not as numerous regarding human tissues. Some papers indicate that CoQ10 depletion during statin therapy might be associatied with subclinical cardiomyopathy and this situation is reversed upon CoQ10 treatment. We hypothesize that in some conditions where other CoQ10 impoverishing situations exist treatment with statins may impair plasma and tissue levels of CoQ10. Physicians should be aware of this drug-nutrient interaction and be vigilant to the possibility that statin drugs have the potential to cause or to worsen CHF. We support supplemental CoQ10 at the dose of 200-400 mg/day inpatients on statin therapy.
... It is predominantly found in high-energy-demanding tissues, such as the heart (Ernster and Dallner, 1995). Ubiquinone levels were previously shown to increase in response to endurance exercise in cardiac and skeletal muscles of rats (Beyer et al., 1984;Zoladz et al., 2016), and coenzyme-Q10 supplementation was beneficial in settings of diabetic cardiomyopathy in mice (Huynh et al., 2012) and heart failure patients (Langsjoen et al., 1997;Sander et al., 2006;Silver et al., 2004). ...
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Exercise-induced heart growth provides protection against cardiovascular disease, whereas disease-induced heart growth leads to heart failure. These distinct forms of growth are associated with different molecular profiles (e.g., mRNAs, non-coding RNAs, and proteins), and targeting differentially regulated genes has therapeutic potential for heart failure. The effects of exercise on the cardiac and circulating lipidomes in comparison to disease are unclear. Lipidomic profiling was performed on hearts and plasma of mice subjected to swim endurance training or a cardiac disease model (moderate or severe pressure overload). Several sphingolipid species and phospholipids containing omega-3/6 fatty acids were distinctly altered in heart and/or plasma with exercise versus pressure overload. A subset of lipids was validated in an independent mouse model with heart failure and atrial fibrillation. This study highlights the adaptations that occur to lipid profiles in response to endurance training versus pathology and provides a resource to investigate potential therapeutic targets and biomarkers.
... 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. We postulate the existence of a clinical entity designated statin-associated cardiomyopathy (SACM), which can be defined as an impairment in heart muscle function secondary to statin drug therapy of a severity sufficient to cause HF. ...
Article
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, symp¬tom scores, echocardiograms, and plasma CoQ10 and cholesterol levels. Results: Of 142 identified patients with HF, 94% presented with preserved ejection frac¬tion (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 cardiomy¬opathy 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.
... Furthermore, the ALLHAT-LLT trial showed that pravastatin did not reduce either all-cause mortality or coronary heart disease in older persons with well-controlled hypertension [58]. Fourth, the observed associations between comorbidities like stroke, TIA, dementia and PAD and less statin use could possibly be explained by the higher risk of adverse effects [50,[59][60][61], the limited effect of statins in people with these conditions [62,63] and possibly the greater risk of drug errors in people with cognitive problems. Other interesting associations between less statin use and cancer and more statin use and paralysis should be confirmed by further research. ...
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Background The current study evaluated time trends of statin use and incidence of recurrent CVD in secondary prevention from 1999 to 2013 and investigated which factors were associated with statin use in secondary prevention. Methods Intego is a primary care registration network with 111 general practitioners working in 48 practices in Flanders, Belgium. This retrospective registry-based study included patients aged 50 years or older with a history of CVD. The time trends of statin use and incidence of recurrent CVD in secondary prevention were determined by using a joinpoint regression analysis. Multivariable mixed-effect logistic regression analysis was used to assess factors associated with statin use in patients in secondary prevention in 2013. Results The overall prevalence of statin use increased and showed two trends: a sharp increase from 1999 to 2005 (annual percentage change (APC) 25.4%) and a weaker increase from 2005 to 2013 (APC 3.7%). The average increase in statin use was the highest in patients aged 80 and older. Patients aged 70–79 years received the most statins. Men used more statins than women did, but both genders showed similar time trends. The incidence of CVD decreased by an average APC of 3.9%. There were no differences between men and women and between different age groups. A significant decrease was only observed in older patients without statins prescribed. In 2013, 61% of the patients in secondary prevention did not receive a statin. The absence of other secondary preventive medication was strongly associated with less statin use. Gender, age and comorbidity were associated with statin use to a lesser degree. Conclusions The prevalence of statin use in secondary prevention increased strongly from 1999 to 2013. Less than 50% of patients with a history of CVD received a statin in 2013. Especially patients who did not receive other secondary preventive medication were more likely to not receive a statin. Despite the strong increase in statin use, there was only a small decrease in the incidence of recurrent CVD, and this occurred mainly in older patients without statins prescribed.
... A recent study demonstrated that, in rats, only 3% of orally administered CoQ 10 can be absorbed [8]. Supplementation with enhanced bioavailability of CoQ 10 formulation has been thought to be more beneficial, especially for situations in which adequate CoQ 10 production is adversely affected [9]. Several advancements have been made to enhance the bioavailability of CoQ 10 using various approaches like size reduction, solubility enhancement (by solid dispersion, prodrug, complexation, ionization) and use of novel drug carriers such as liposomes, microspheres, nanoparticles, nanoemulsions, and self-emulsifying systems [10]. ...
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Background/aims: Coenzyme Q10 (CoQ10), is a promising antioxidant; however, low bioavailability owing to lipid-solubility is a limiting factor. We developed water-soluble CoQ10 (CoQ10-W) and compared its effects with conventional lipid-soluble CoQ10 (CoQ10-L) in an experimental model of chronic tacrolimus (Tac) nephropathy. Methods: CoQ10-W was developed from a glycyrrhizic-carnitine mixed layer CoQ10 micelle based on acyltransferases. Chronic nephropathy was induced in rats with 28-day Tac treatment; they were concomitantly treated with CoQ10-L or CoQ10-W. CoQ10 level in plasma and kidney were measured using liquid chromatography-mass spectrometry. CoQ10-W and CoQ10-L effects on Tac-induced nephropathy were assessed in terms of renal function, histopathology, oxidative stress, and apoptotic cell death. Their effects on cell viability and reactive oxygen species (ROS) production were assessed in cultured proximal tubular cells, human kidney 2 (HK-2) cells. Results: The plasma CoQ10 level was significantly higher in the CoQ10-W group than in the CoQ10-L group. Tac treatment caused renal dysfunction, typical pathologic lesions, and oxidative stress markers. Serum creatinine was restored in the Tac + CoQ10-L or CoQ10-W groups compared with that in the Tac group. CoQ10-W administration reduced oxidative stress and apoptosis markers. Mitochondrial ultrastructure assessment revealed that the addition of CoQ10-L or CoQ10-W with Tac increased mitochondrial size and number than Tac treatment alone. In vitro investigations revealed that both CoQ10-L and CoQ10-W improved cell viability and reduced ROS production in the Tac-induced HK-2 cell injury. Conclusions: CoQ10-W has a better therapeutic effect in Tac-induced renal injury than conventional CoQ10-L, possibly associated with improved CoQ10 bioavailability.
... The magnitude of the reduction of CoQ10 in combination with statins has been shown to be dose related and reversible with the cessation of treatment. It has been hypothesized that this reduction may be the cause of the adverse effects of statins, and CoQ10 supplementation during treatment with statins could be a possible mediator treatment as long as it is properly monitored [27,28] (see Fig. 3). ...
Article
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Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain responsible for different functions, among them its action as an antioxidant compound. Low CoQ10 levels are related to inflammatory processes and oxidative stress, factors implicated in atherosclerosis, obesity, nonalcoholic fatty liver (NAFLD), as well as metabolic syndrome (MS). MS is a disease characterized by cardiovascular risk factors linked to obesity, dyslipidemia and hyperglycemia. NAFLD is recognized as a hepatic manifestation of MS and, together with the latter, has a high incidence in the world population. Recent investigations have underscored the positive effects of CoQ10 supplementation on the treatment of obesity, oxidative stress, MS, and NAFLD. The objective of the present study was to analyze the evidence of the effects of CoQ10 supplementation on MS and NAFLD and to provide a general view of the mechanisms of action of CoQ10 in both diseases.
... 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. ...
Article
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.
... In a previous study, however, 44 patients suffering from statin-induced myalgia saw no improvement in their conditions after receiving CoQ 10 for 3 months (Young et al., 2007). Other studies have determined that CoQ 10 supplementation improves endothelial dysfunction in type 2 diabetic patients treated with statins (Hamilton et al., 2009) and can reverse the worsening of the diastolic function induced by statins (Silver et al., 2004). ...
Article
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Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
... However, some previous studies suggest that statins may also worsen cardiac function. In a very small trial, 14 patients without previous myocardial function and heart failure were given 20 mg of atorvastatin per day [26]. A total of 10 patients showed a worsening of diastolic ventricular function (e.g. ...
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Background: Exercise and statins reduce cardiovascular disease (CVD). Exercise capacity may be assessed using cardiopulmonary exercise testing (CPET). Whether statin medication is associated with CPET parameters is unclear. We investigated if statins are related with exercise capacity during CPET in the general population. Methods: Cross-sectional data of two independent cohorts of the Study of Health in Pomerania (SHIP) were merged (n = 3,500; 50% males). Oxygen consumption (VO2) at peak exercise (VO2peak) and anaerobic threshold (VO2@AT) was assessed during symptom-limited CPET. Two linear regression models related VO2peak with statin usage were calculated. Model 1 adjusted for age, sex, previous myocardial infarction, and physical inactivity and model 2 additionally for body mass index, smoking, hypertension, diabetes and estimated glomerular filtration rate. Propensity score matching was used for validation. Results: Statin usage was associated with lower VO2peak (no statin: 2336; 95%-confidence interval [CI]: 2287-2,385 vs. statin 2090; 95%-CI: 2,031-2149 ml/min; P < .0001) and VO2@AT (no statin: 1,172; 95%-CI: 1,142-1,202 vs. statin: 1,111; 95%-CI: 1,075-1,147 ml/min; P = .0061) in males but not females (VO2peak: no statin: 1,467; 95%-CI: 1,417-1,517 vs. statin: 1,503; 95%-CI: 1,426-1,579 ml/min; P = 1.00 and VO2@AT: no statin: 854; 95%-CI: 824-885 vs. statin 864; 95%-CI: 817-911 ml/min; P = 1.00). Model 2 revealed similar results. Propensity scores analysis confirmed the results. Conclusion: In the general population present statin medication was related with impaired exercise capacity in males but not females. Sex specific effects of statins on cardiopulmonary exercise capacity deserve further research.
... With reference to improved diastolic function, a 6 month treatment with rosuvastatin has been shown to significantly reduce the Tei index, a parameter which incorporates myocardial relaxation time, in patients without evidence of coronary artery disease (Talini et al., 2008). By contrast, other work has shown that 70% of naïve patients without overt cardiac dysfunction who were given atorvastatin for up to 6 months developed worsening diastolic function (defined as a 10% change in three echocardiographic indices of diastolic performance) (Silver et al., 2004). In both these studies, individuals were hypercholesterolemic, so the impact of statin treatment on serum cholesterol must be considered. ...
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The number of people taking statins is set to increase across the globe due to recent changes in prescription guidelines. For example, half the US population over 40 is now eligible for these drugs, whether they have high serum cholesterol or not. With such development in policy comes a stronger need for understanding statins’ myriad of effects. Surprisingly little is known about possible direct actions of statins on cardiac myocytes, although claims of a direct myocardial toxicity have been made. Here we determine the impact of simvastatin administration (40 mg/kg/day) for 2 weeks in normocholesterolaemic rats on cardiac myocyte contractile function and identify an underlying mechanism. Under basal conditions, statin treatment increased the time to half (t0.5) relaxation without any effect on the magnitude of shortening, or the magnitude/kinetics of the [Ca2+]i transient. Enhanced myocyte lusitropy could be explained by a corresponding increase in phosphorylation of troponin I (TnI) at Ser23,24. Statin treatment increased expression of eNOS and Ser1177 phosphorylated eNOS, decreased expression of the NOS-inhibitory proteins caveolin 1 and 3, and increased (P=0.06) NO metabolites, consistent with enhanced NO production. It is well established that NO stimulates protein kinase G, one of the effectors of TnI phosphorylation at Ser23,24. Trends for parallel changes in phospho-TnI, phospho-eNOS and caveolin 1 expression were seen in atrial muscle from patients taking statins. Our data are consistent with a mechanism whereby chronic statin treatment enhances TnI phosphorylation and myocyte lusitropy through increased NO bioavailability. We see no evidence of impaired function with statin treatment; the changes we document at the level of the cardiac myocyte should facilitate diastolic filling and cardiac performance.
... Dyspnea, interstitial lung disease, pleural effusion are pulmonary related adverse events, reason attributed for this is statin accelerate aging effect on diaphragm mitochondrial cellular respiration affecting major muscle of breathing [175][176][177][178]. ...
Article
It is well known that by improving mitochondrial bioenergetics, Coenzyme Q10 improves the systolic function in heart failure. The aim of this study was to see whether it benefits the diastolic dysfunction in hypertrophic cardiomyopathy (HCM) cases since diastolic relaxation also requires energy like the systole. 200 mg/day of CoQ10 was added to the conventional treatment in 46 patients with HCM diagnosed clinically and by echocardiography and by excluding cases of long standing hypertension. A comparable group of 41 age/sex matched cases received only conventional therapy. There was a significant improvement in the parameters like NYHA class ≥ 1, in quality of life (QOL) on 6 minutes walk test, in diastolic dysfunction by ≥1 parameter and in MR ≥ 1 grade. Post treatment echocardiogram showed significant reduction in left ventricular outflow tract ( LVOT) gradient ≥15 mm Hg in obstructive cases (12 out of 46) in the treatment group. The mean interventricular septal thickness (IVS) showed a 22.4% reduction (p < 0.005). The mean posterior wall thickness showed a 23.1% reduction (p < 0.005). No patient in the treatment Group had ventricular tachycardia (VT) whereas 4 cases in the control group had VT. In both groups 1 patient was lost due to sudden cardiac death (SCD).
Article
Background: With the increasing use and dependence on the internet to obtain medical information and the effectiveness and attractiveness of video-based learning linked with the stressed importance on proper blood pressure measurement, the purpose of this study is to assess the scientific quality of YouTube videos that present information on blood pressure measurement. Methods: In the study, we included 99 relevant videos out of the first 500 videos returned by YouTube’s search engine in response to ‘Blood pressure measurement’ sorted by view count. We measured the scientific quality of these videos based on an 11-element skillset of blood pressure measurement. Results: The sample was found to have a mean scientific score of 4.87 (±2.28) with the most common step mentioned of the 11 being placing the cuff over a bare arm. A significant difference in mean scientific quality with source upload (p = 0.015) was found, with the highest quality for health information websites (8.6 ± 2.3). A significant correlation was found between scientific quality and duration of video (p < 0.001); however, no significant difference was found between scientific quality and view count. Conclusions: Although the YouTube content on blood pressure measurement is scientifically weak at its current state, it has the potential to greatly benefit its viewers if properly utilized. To make better use of the YouTube platform we recommend the evaluation of medical information obtained from YouTube by health professionals and organizations as well as developing and uploading medical videos themselves.
Article
HMG-CoA reductase inhibitors or statins beyond their lipid lowering properties and mevalonate inhibition exert also their actions through a multiplicity of mechanisms. In heart failure (HF) the inhibition of isoprenoid intermediates and small GTPases, which control cellular function such as cell shape, secretion and proliferation are of clinical significance. Statins share also the Peroxisome proliferator-activated receptor pathway and inactivate extracellular-signal-regulated kinase phosphorylation suppressing inflammatory cascade. By down-regulating Rho/Rho kinase signaling pathways, statins increase the stability of eNOS mRNA and induce activation of eNOS through phosphatidylinositol 3-kinase/Akt/eNOS pathway restoring endothelial function. Statins change also myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channel activity and inhibit sympathetic nerve activity suppressing arrhythmogenesis. Less documented evidence proposes also that statins have anti-hypertrophic effects-through p21ras/mitogen activated protein kinase pathway-, modulate synthesis of matrix metalloproteinases and procollagen 1 expression affecting interstitial fibrosis and diastolic dysfunction. Clinical studies have partly confirmed the experimental findings and despite current guidelines new evidence support the notion that statins can be beneficial in some cases of HF. In subjects with diastolic HF, moderately impaired systolic function, low b-type natriuretic peptides levels, exacerbated inflammatory response and mild interstitial fibrosis evidence support that statins can favorably affect the outcome. Under the lights of this evidence in this review article we discuss the current knowledge on the mechanisms of statins' actions and we link current experimental and clinical data to further understand the possible impact of statins' treatment on HF syndrome.
Article
Cardiovascular disease (CVD) is the leading cause of mortality in the Western world. The effort of research should aim at the primary prevention of CVD. Alongside statin therapy, which is maintained to be an effective method of CVD prevention, there are alternative methods such as vitamin B substitution therapy with folic acid (FA), and vitamins B12 and B6 . B-vitamins may inhibit atherogenesis by decreasing the plasma level of homocysteine (Hcy) - a suspected etiological factor for atherosclerosis -, and by other mechanisms, primarily through their antioxidant properties. Although Hcy-lowering vitamin trials have failed to demonstrate beneficial effects of B-vitamins in the prevention of CVD, a meta-analysis and stratification of a number of large vitamin trials have suggested their effectiveness in cardiovascular prevention (CVP) in some aspects. Furthermore, interpretation of the results from these large vitamin trials has been troubled by statin/aspirin therapy, which was applied along with the vitamin substitution, and FA fortification, both of which obscured the separate effects of vitamins in CVP. Recent research results have accentuated a new approach to vitamin therapy for CVP. Studies undertaken with the aim of primary prevention have shown that vitamin B substitution may be effective in the primary prevention of CVD, and may also be an option in the secondary prevention of disease if statin therapy is accompanied by serious adverse effects. Further investigations are needed to determine the validity of vitamin substitution therapy before its introduction in the protocol of CVD prevention. This article is protected by copyright. All rights reserved.
Article
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.
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Background. Cohort studies indicate that chronic anxiety, aggression and depression may be associated with neuroendocrine dysfunctions and lack of happiness which may predispose to poor social and physical health, leading to cardio-metabolic diseases (CMDs). Dopamine, serotonin, oxytocin and endorphins are the quartet neurotransmitters responsible for the happiness of the mind, which may be blunted by stress hormones released due to psychological diseases. This study aims to develop and validate a questionnaire for assessment of happiness to find out the prevalence of happiness in relation to coronary artery disease (CAD). Subjects and Methods. After written informed consent and approval from the hospital ethics committee, this cross-sectional survey was conducted at Halberg Hospital and Research Institute, Moradabad, India. All subjects, 980 urban (495 men and 485 women), 900 rural (510 men and 390 women) above 25 years of age were randomly selected and recruited from urban and rural populations. Clinical data as well as risk factors were recorded with the help of case record form and validated questionnaires. Assessment of happiness was made by a new questionnaire involving happiness of mind by including questions related to social, psychological and spiritual behaviors. Results. The prevalence of happiness was 62.4% (n = 612) among urban and 63.2% (n = 569) among rural subjects, with overall prevalence of 62.8% (n = 1,181). The prevalence of happiness was significantly greater among subjects > 45 years among both urban and rural populations compared to subjects between 25 to 45 years and the trend was significant. The overall prevalence of happiness was also significantly greater among subjects above 45 years compared to subject below 45 years of age. The prevalence of happiness overall showed a graded increase with age from 25 to 84 years in both sexes among urban and rural populations and the trends were significant (P < 0.02). The overall prevalence of tobacco intake was 16.2%, (n = 304) and alcoholism 1.96%. The frequency of tobacco intake and alcoholism were significantly lower among subjects with happiness compared to those with no happiness. However, among subjects with happiness, the frequency of moderate alcohol intake was significantly greater compared to urban subjects with no happiness. The prevalence of CAD was significantly lower among subjects with happiness Ram 280 B Singh, Agnieszka Wilczynska, Jan Fedacko et al. compared to those with no happiness, respectively both in urban (5.06 vs. 12.2%, P < 0.01) and rural populations (2.09% vs. 3.92%, P < 0.05), indicating that happiness may be protective against CAD. There were no gender differences in happiness. Conclusions. It is possible that this modified questionnaire can be successfully used for assessment of happiness rates in urban and rural areas of north India. The questionnaire allowed us to identify overall 63.2% (n = 569) subjects with happiness, including 62.4 % among urban and 63.2% (n = 569) among rural subjects. Moderate intake of alcohol may be in favor of happiness. Happiness may be protective against CAD. Further analysis is necessary to verify our findings. Keywords: Western diet, sedentary behavior, mastication, cardiovascular diseases.
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Background: Statins have well-known benefits in the prevention of cardiovascular disease, however, 7-29% of patients develop muscle side effects and up to 0.5% develop severe symptoms. Mitochondrial dysfunction has been associated with severe statin-induced myopathy (SM); however, there is a paucity of systematic studies in affected individuals. Objectives: The goal of this study was to combine clinical and laboratory features with quantitative biochemical and histopathologic studies of skeletal muscle biopsies from SM cases to determine what proportion could be attributed to mitochondrial dysfunction and how many of these had primary respiratory chain defects. Methods: A retrospective analysis was performed on patient records derived from 279 SM patients whose muscle biopsies were referred to our clinical diagnostic laboratory for analysis. Clinical, histopathologic and biochemical features were compared with two myopathic control groups unexposed to statins: individuals with idiopathic mitochondrial myopathy (MMP; n = 94) and with unknown metabolic myopathy (UMP; n = 86); normal controls were unavailable for this record review study. Results: More SM patients had significantly elevated plasma CK than in the other two groups (p < 0.01). A subset of SM patients (67 of 279; 24%) had histopathologic and/or electron microscopic (EM) evidence for mitochondrial dysfunction in skeletal muscle; more cases were identified by EM than by histochemical analysis. Of 279 cases, 29 (10%) were confirmed to have respiratory chain defects by biochemical analysis; 4 of these had mitochondrial abnormalities by EM. An additional 20 cases had mitochondrial abnormalities by EM without a biochemical diagnosis. Conclusions: Both primary and secondary mitochondrial dysfunction was found in subsets of SM patients. The fact that respiratory chain defects were not found in most cases with histopathologic mitochondrial abnormalities does not rule out primary mitochondrial disease in these cases, however, it is more likely that secondary effects on mitochondrial structure and function have occurred; molecular analysis may be helpful only in a small number of cases.
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The current study aimed to test the profile of serum lipids, phospholipase D (PLD) activity, and CD59 expression pattern in rat hepatocellular carcinoma (HCC) after therapeutic treatment with Coenzyme Q10 (CoQ10). Three rat groups were allocated as normal control, untreated HCC, and treated HCC (HCC + CoQ10). The levels of serum α‐fetoprotein (AFP) and tumour necrosis factor (TNF)‐α were assessed using enzyme‐linked immunosorbent assay (ELISA), while proliferating cell nuclear antigen (PCNA) was detected using immunohistochemistry (IHC). Serum lipids, classical (CH50), and alternative (APH50) pathways of complement activation, the liver cell HMG‐CoA reductase (HMGCR), and PLD activities were assayed colorimetrically. The protein expression of CD59, scavenger receptor class B type 1 (SRB1), B cell lymphoma‐2 (Bcl2), and cleaved Caspase‐3 (Casp‐3) were detected using western blotting, while the level of serum CD59 (sCD59) was assessed using dot‐blot. CoQ10 reduced the cell proliferation, histological alterations, and the levels of AFP and TNF‐α but increased lipids, CH50, and sCD59 in serum. In the liver cell, CoQ10 decreased and increased PLD and HMGCR enzyme activities, respectively. In addition, reduction of liver CD59, Bcl2, and SRB1 vs increased cleaved Casp‐3 expressions was observed. Statistical correlation indicated an inverse relationship between CH50 and each of CD59 expression and PLD activity after treatment with CoQ10. In conclusion, CoQ10 could protect against rat HCC through increased lipids and the reduction of CD59 expression and PLD activity. Significance of the study To our knowledge, this study is the first to describe the attenuating effect of antitumour natural product like Coenzyme Q10 (CoQ10) via the reduction of CD59 expression and phospholipase D (PLD) activity. This illustrates the important role of CD59 and PLD in relation to lipids in cancer prevention.
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One of the most frequent causes of hospital admissions in older adults is the devastating condition known as congestive heart failure. Characterized by disabling symptoms of difficulty breathing, fatigue, and swelling of the extremities, congestive heart failure also increases the risk of early demise. Fortunately, scientists have discovered that the mitochondrial energizer coenzyme Q10 (CoQ10) can offer powerful assistance to those challenged with congestive heart failure, improving the heart's pumping ability and even reducing the need for medications. Since CoQ10 levels are depleted by aging and statin medications and tend to be low in those with congestive heart failure, achieving optimal blood levels of CoQ10 may be an important strategy for safeguarding cardiac health. What is CoQ10? It has been 50 years since Fred Crane discovered CoQ10 in 1957.1 Since that time, scientists have discovered what this extraordinary molecule is and what it does in settings of both health and disease. It is important to clarify that a coenzyme should not be confused with an enzyme (a protein that accelerates a biochemical reaction). A coenzyme is a simple molecule (many vitamins are coenzymes) that is essential for the normal function of specific enzyme systems in our cells. Coenzyme Q10 is the cofactor or coenzyme for three large enzyme systems that are essential for 90% of cellular energy production. Because the heart muscle uses more energy than any other tissue and normally has the highest concentration of CoQ10, it is very sensitive to CoQ10 deficiency. Coenzyme Q10 is well established to be a clinically relevant first-line antioxidant in our defense system against excess oxidative stress. It is the only fat-soluble antioxidant that is synthesized by our body and is capable of regeneration back to its reduced or antioxidant form through normal cellular enzyme systems. Its location in the lipid mitochondrial membranes is particularly important, as mitochondria are the major site of free-radical production, and CoQ10 is an excellent free-radical scavenger.
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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.
In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and 'heme A', and thereby ATP generation. Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated.
Article
Coenzyme Q10 (CoQ10) is a vitamin-like substance that plays a key role in the metabolic process that supplies all cells with energy. Tissues with a high energy requirement, such as the heart, are particularly dependent on maintaining an adequate supply of CoQ10 for normal functioning. Deficiency of CoQ10 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 CoQ10, with particular emphasis on its role in the prevention and treatment of cardiovascular disorders.
Article
Coenzyme Q (CoQ) is an essential lipid of cells present in all cellular compartments. The functions of CoQ in mitochondrial respiration and as an antioxidant are established, although the lipid likely has additional, presently unknown, roles. While the therapeutic utility of CoQ10 supplements is recognized in the rare cases of primary CoQ10 deficiencies, a potential role for CoQ10 supplements in cardiovascular disease, particularly heart failure, has also been studied for over 40 years. This review summarizes our current knowledge in these areas derived from animal studies and human trials. Current evidence for a benefit of CoQ10 supplements in diseases other than primary CoQ10 deficiencies is insufficient. Expected final online publication date for the Annual Review of Nutrition Volume 35 is July 17, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.
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Background: Heart failure (HF) is currently a major concern for the middle-aged and elderly. Some studies have suggested the beneficial effects of coenzyme Q10 (CoQ10) on clinical symptoms and echocardiographic indices in patients with HF. Reduced selenium, a cofactor in the activation of CoQ10 levels, has also been found in HF. The present study evaluated the effects of the combination of CoQ10 and selenium on patients with HF. Methods: This randomized, double-blind, clinical trial was conducted on New York Heart Association (NYHA) class II and III patients. The subjects were randomly allocated to intervention and control groups (n = 32 each). A questionnaire containing demographic characteristics, history of diseases, consumed medications, and NYHA class was filled out prior to the intervention. Echocardiography (the Simpson method) was also performed to determine the left ventricular ejection fraction (LVEF) and the myocardial performance index (MPI). The intervention group then received 90 mg of CoQ10 and 200 μg of selenium per day for 3 months. The control group consumed placebos with an identical appearance during the same period. The NYHA class, LVEF, and MPI were reevaluated after the intervention. Results: Two subjects from the intervention group and one from the control group were excluded during the course of the study. The two groups had no significant differences in terms of age, gender, history of diseases, consumed medications, and baseline NYHA class, LVEF, and MPI. However, intervention significantly improved the NYHA class, LVEF, and MPI. According to the analysis of covariance (ANCOVA) adjusted for age, gender, and baseline characteristics, the intervention improved the LV function indices in patients with HF. Conclusion: Based on our findings, combination therapy with selenium and CoQ10 led to clinical improvement and enhanced LV function indices in patients with HF. Further clinical trials with larger sample sizes and longer follow-up periods can clarify the appropriateness of adding these supplements to the treatment protocols for HF.
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Coenzyme Q10 (CoQ10) is a vitamin-like substance, and a natural intermediate of electron transport chain (ETC) of mitochondria which can accepts and donates electrons from complex I and complex II. CoQ10 shares a biosynthetic pathway with cholesterol and dolichol thus it can be a potential target of the widely available lipid-lowering drugs. The lipid lowering drugs such as statins, are widely administered to individuals who have high cholesterol levels. This article reviews the a) clinical benefits of CoQ10 b) association between administration of statin and CoQ10 deficiency and c) involvement of CoQ10 in statin-associated myopathy.
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In spite of the unequivocal efficacy of statins in reducing primary and secondary cardiovascular (CV) events, the use of these drugs in a considerable number of patients is limited because of statin intolerance, mainly statin-associated muscle symptoms (SAMS). SAMS encompass a broad spectrum of clinical presentations, including mild muscular aching and other types of myalgias, myopathy with the significant elevation of creatine kinase, and the rare but life-threatening rhabdomyolysis. Among several pathophysiologic mechanisms of SAMS, mitochondrial dysfunction is thought to be one of the main one. Curcumin is the polyphenolic ingredient of Curcuma longa L., which has various pharmacological properties against a vast range of diseases. Curcumin has several mechanisms of actions relevant to the treatment of SAMS. These effects include the capacity to prevent and reduce delayed onset muscle soreness by blocking the nuclear factor (NF)-кB inflammatory pathway, attenuation of muscular atrophy, enhancement of muscle fiber regeneration following injury, analgesic and antioxidant effects. Curcumin can also increase the levels of cyclic adenosine monophosphate (cAMP), which leads to an increase in the number of mitochondrial DNA duplicates in skeletal muscle cells. Finally, owing to its essential lipid-modifying properties, curcumin might serve as an adjunct to statin therapy in patients with SAMS, allowing for effective lowering of low-density lipoprotein cholesterol and possibly for statin dose reduction. Owing to the paucity of effective treatments, and the safety of curcumin in clinical practice, proof-of-concept trials are recommended to assess the potential benefit of this phytochemical in the treatment of SAMS.
Article
Clinical trials demonstrated that statin therapy is associated with a significant reduction in cardiovascular morbidity and mortality when used for either primary or secondary prevention of cardiovascular events. Several studies have shown that statins, having an important effect in the prevention of acute coronary syndromes, are also able to prevent heart failure (HF) in patients with coronary artery disease. This review summarizes the experimental and clinical evidence regarding the role of statins in the management of HF.
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Background: Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. Patients−Methods: To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C Main Outcome Measures: Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. Results: The mean dosage of atorvastatin was 24 mg/day. This statin reduced total cholesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quality-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p Conclusions: Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.
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Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80 mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C <100 mg/dl (2.6 mmol/l). All patients were followed up for a mean period of 3 years. Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. The mean dosage of atorvastatin was 24 mg/day. This statin reduced total chlesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quaility-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p < 0.0001. In detail, atorvastatin reduced, in comparison to 'usual' care, total mortality (RR 0.57, CI 0.39-0.78, p = 0.0021), coronary mortality (RR 0.53, CI 0.29-0.74, p = 0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71, p < 0.0001), and stroke (RR 0.53, CI 0.30-0.82, p = 0.034). All subgroups of patients (women, those with diabetes mellitus, arterial hypertension, age 60 to 75 years, congestive heart failure, recent unstable angina or prior revascularisation) benefited from treatment with atorvastatin. Withdrawal of patients because of side-effects from the atorvastatin group was low (0.75%) and similar to that of the 'usual' care group (0.4%). Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.
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Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely used for the treatment of hypercholesterolemia and coronary heart disease and for the prevention of stroke. There have been various adverse effects, most commonly affecting muscle and ranging from myalgia to rhabdomyolysis. These adverse effects may be due to a coenzyme Q(10) (CoQ(10)) deficiency because inhibition of cholesterol biosynthesis also inhibits the synthesis of CoQ(10). To measure CoQ(10) levels in blood from hypercholesterolemic subjects before and after exposure to atorvastatin calcium, 80 mg/d, for 14 and 30 days. Prospective blinded study of the effects of short-term exposure to atorvastatin on blood levels of CoQ(10). Stroke center at an academic tertiary care hospital. Patients We examined a cohort of 34 subjects eligible for statin treatment according to National Cholesterol Education Program: Adult Treatment Panel III criteria. The mean +/- SD blood concentration of CoQ(10) was 1.26 +/- 0.47 micro g/mL at baseline, and decreased to 0.62 +/- 0.39 micro g/mL after 30 days of atorvastatin therapy (P<.001). A significant decrease was already detectable after 14 days of treatment (P<.001). Even brief exposure to atorvastatin causes a marked decrease in blood CoQ(10) concentration. Widespread inhibition of CoQ(10) synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, myalgia, and myoglobinuria.
Article
Background: The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. Methods: Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. Findings: Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. Interpretation: The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.
Article
Unlabelled: Load-induced cardiac dysfunction (LCD), in which a supernormal left ventricular (LV) systolic performance at rest decreases due to an afterload challenge, usually occurs among children with mitral valve prolapse (MVP). However, diastolic performance is also important because relaxation, like contraction, is based on a process that requires energy. The aim of this study was to examine LV diastolic response patterns to stress in patients with LCD before and after coenzyme Q10 (CoQ) therapy and in controls. The D-E slope, E-F slope and maximal diastolic endocardial velocity were used as echographic diastolic indices. Thirty subjects, aged 9-16 years, were divided into four groups: group 1, 10 normals; group 2, 10 patients with LCD; group 3, the same 10 as in group 2, who recovered with CoQ, 3.0-3.4 mg/kg/day for 7 days; group 4, 10 asymptomatic children with MVP. The heart rate, both at rest and during handgrip (HG), showed little intergroup difference. Only in group 2, were the ejection fraction and all the diastolic indices greater than in the other groups, but these became subnormal with HG. In the other groups, these indices increased with HG to a similar extent, although resting values were smaller than in group 2. In conclusion: (1) in normal hearts and in hearts with LCD, diastolic performance mimicked systolic performance both in resting and loading conditions; (2) CoQ improved not only the load-induced systolic but also the diastolic dysfunctions in a similar time-course, and (3) mechanical stiffness of the cardiac tissue may not be a cause of load-induced diastolic dysfunction, because the dysfunction was quickly resolved with CoQ therapy. CoQ may be a key substance which affects a common bioenergetic process in contraction and relaxation, to keep these functions normal.
Article
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)
Article
Symptoms of fatigue and activity impairment, atypical precordial pain, and cardiac arrhythmia frequently precede by years the development of congestive heart failure. Of 115 patients with these symptoms, 60 were diagnosed as having hypertensive cardiovascular disease, 27 mitral valve prolapse syndrome, and 28 chronic fatigue syndrome. These symptoms are common with diastolic dysfunction, and diastolic function is energy dependent. All patients had blood pressure, clinical status, coenzyme Q10 (CoQ10) blood levels and echocardiographic measurement of diastolic function, systolic function, and myocardial thickness recorded before and after CoQ10 replacement. At control, 63 patients were functional class III and 54 class II; all showed diastolic dysfunction; the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%, and 7% showed significant myocardial hypertrophy, and 87%, 30%, and 11% had elevated blood pressure readings in hypertensive disease, mitral valve prolapse and chronic fatigue syndrome respectively. Except for higher blood pressure levels and more myocardial thickening in the hypertensive patients, there was little difference between the three groups. CoQ10 administration resulted in improvement in all; reduction in high blood pressure in 80%, and improvement in diastolic function in all patients with follow-up echocardiograms to date; a reduction in myocardial thickness in 53% of hypertensives and 36% of the combined prolapse and fatigue syndrome groups; and a reduced fractional shortening in those high at control and an increase in those initially low.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
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.
Article
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.
Article
Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are of proven clinical benefit in coronary heart disease, at least in those patients who do not have overt chronic heart failure (CHF). However, as there have been no prospective clinical trials of statins in CHF patients, the question arises as to whether the benefits observed in the absence of CHF can be necessarily inferred in those patients in whom CHF is established. In this review, the evidence base stating support of the use of statins in CHF is presented, as well as theoretical considerations as to why these agents may not necessarily be of benefit in this setting. The beneficial potential of statins clearly relates to their plaque stabilization properties and associated improvements in endothelial function, which together should reduce the risk of further infarction and, perhaps, the ischemic burden on the failing ventricle. Furthermore, these agents may have beneficial effects independent of lipid lowering. These include actions on neoangiogenesis, downregulation of AT(1) receptors, inhibition of proinflammatory cytokine activity and favorable modulation of the autonomic nervous system. The potential adverse effects of statins in CHF include reduction in levels of coenzyme Q10 (which may further exacerbate oxidative stress in CHF) and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins entering the circulation via the gut. In support of these possibilities are epidemiologic data linking a lower serum cholesterol with a poorer prognosis in CHF. These uncertainties indicate the need for a definitive outcome trial to assess the efficacy and safety of statins in CHF, despite their current widespread, non-evidence based use in this population.
Article
An improvement in myocardial longitudinal systolic velocities, assessed by pulsed-wave tissue Doppler imaging during low-dose dobutamine infusion, was observed at 6-month follow-up after 6 months of treatment with atorvastatin. Our findings indicate a favorable effect of atorvastatin on contractile reserve, possibly through an enhancement of flow-dependent coronary dilatation during stress.
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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.
Treatment with From the Division of General Internal Medicine and Health Care Research Cleveland, Ohio; Innovative Data Resources, Asheville, North Carolina; and GlaxoSmithKline, King of Prussia, Pennsylvania. Dr. Frolkis's address is: University Hospitals of Cleveland
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Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG. Treatment with From the Division of General Internal Medicine and Health Care Research, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio; Innovative Data Resources, Asheville, North Carolina; and GlaxoSmithKline, King of Prussia, Pennsylvania. Dr. Frolkis's address is: University Hospitals of Cleveland, Lakeside 3574, 11100 Euclid Avenue, Cleveland, Ohio 44106. E-mail: jpf4@po.cwru.edu. Manuscript received March 11, 2004; revised manuscript received and accepted July 14, 2004. 1310 ©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matter The American Journal of Cardiology Vol. 94 November 15, 2004 doi:10.1016/j.amjcard.2004.07.122
The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10
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