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Die in der Literatur kontrovers diskutierte klinische Evidenz für eine intensivierte präoperative Statintherapie bei herzchirurgischen Patienten scheint einen Einfluss auf den postoperativen Verlauf nach Herzoperation mit Herz-Lungenmaschine zu haben; insbesondere auf die Reduktion von Mortalität, Schlaganfall, Ausbildung von postoperativem Vorhofflimmern und systemischer Inflammation. Jedoch konnte bisher nicht nachgewiesen werden, ob die beobachtete systemische Inflammation anhand erhöhter Inflammationsmarker eine klinische Relevanz nach sich zieht. Daher untersuchten wir den Einfluss der Statintherapie auf die postoperative Hämodynamik vor dem Hintergrund, dass die systemische Inflammation reduziert wird. Es wurden 478 Patienten mit herzchirurgischen Eingriffen mittels Herz-Lungenmaschine zwischen 2005 und 2006 in die klinisch retrospektive Studie eingeschlossen. Diese wurden in zwei Gruppen eingeteilt: Mit Statintherapie (n=276; Statingruppe) und Patienten ohne Statintherapie (n=202; Nicht-Statingruppe). Präoperative und intraoperative Daten, sowie der postoperative Verlauf wurden untersucht. Es zeigte sich kein Unterschied im SAPS II Score, APACHE II Score, RIFLE Score, in der Liegedauer auf der Intensivstation, sowie in der Dauer des Krankenhausaufenthaltes. Das postoperative Vorhofflimmern war ebenfalls unbeeinflusst. In der Nicht-Statingruppe zeigte das erweiterte hämodynamische Monitoring lediglich für den SVRI (systemischer Gefäßwiderstandsindex) signifikant erhöhte Werte (882±206 vs. 1050±501 dyn*s*cm-5*m-2, p=0.022), wobei jedoch der Inotropikaverbrauch nicht unterschiedlich war. Die Gesamt-Mortalität unterschied sich in den beiden Gruppen nicht. Die perioperative Statintherapie bei Patienten mit herzchirurgischen Eingriffen mittels Herz-Lungenmaschine zeigte auf die postoperative Hämodynamik sowie auf den postoperativen Verlauf keinen klinisch relevanten Effekt.

The purpose of this project was to develop a practice guideline for screening patients at risk for cardiovascular disease, educate the staff at the site about the guideline, and implement the guideline at a primary care clinic. The intention was to identify and treat patients at risk for cardiovascular disease to prevent occurrence of heart disease. Cardiovascular disease includes hypertension, coronary heart disease, heart failure, and stroke. Coronary heart disease is one of the leading causes of death in the Western world. The local practice problem and focus of this project was underprescribed statin therapy for patients at risk for developing heart disease at a clinic in the southern United States. The practice-focused question that guided this project explored whether an evidence-based clinical guideline that might impact the prescription of statins for the prevention of cardiovascular disease would be approved for implementation in a primary care clinic serving adult and geriatric patients. The appraisal of guidelines for research and evaluation and the Fineout-Overholt model were used to guide this project. Sources of evidence to meet the purpose of this project were obtained from the literature and scholarly articles. The results of the presentation to the expert panel indicated that this clinical practice guideline would be implemented at the project site and would be used by nurse practitioners and physicians. The implications of this project for positive social change might include improved management of patients who are at risk for heart disease and a decrease in premature deaths related to cardiovascular disease.

Huntington’s disease (HD) is a heritable, neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. The progressive disease is caused by an unstable CAG expansion within the gene that normally encodes for the huntingtin protein (Htt). The expanded mutant form of Htt (mHtt) is expressed ubiquitously throughout patients’ bodies; however, neuronal degeneration is prominent only in the corpus striatum and, to a lesser extent, the cortex. The Ras homolog Rhes is also preferentially localized to the striatum. The putative co-factor Rhes has been shown to act with mHtt to cause neuronal death. Simvastatin, a lipid lowering drug, and zoledronate, a nitrogen bisphosphonate, act on the mevalonate pathway, which gives both Rhes and its target cells, binding sites. The current study aimed to interrupt the mevalonate pathway and inactivate, via de-prenylation, Rhes in CD-1 mice exposed to 3-nitroproprionic acid, a neurotoxin that mimics HD mitochondrial dysfunction and striatal degeneration. Results suggest that drug treatment does not rescue motor impairments and may potentiate 3-NP damage. The persistent motor deficits are discussed in relation to possible Rhes de-prenylation.

A doença cardiovascular é a principal causa de morte no mundo ocidental e as estatinas são os medicamentos mais prescritos para prevenção e tratamento. Apesar de serem os fármacos mais prescritos, ainda são subutilizados, tendo como principal causa de interrupção do tratamento a miopatia. Entre os mecanismos envolvidos na fisiopatologia da miotoxicidade, a deficiência da coenzima Q10 vem sendo apontada como a principal responsável deste efeito colateral. A creatinofosfoquinase (CPK) é um biomarcador de gravidade dos danos musculares sendo utilizado de rotina na prática clínica. Contudo, seus níveis podem estar normais ou aumentados em pacientes em uso de estatinas e apresentando sintomas musculares. Sendo assim, a espectroscopia do hidrogênio por ressonância magnética (EHRM) poderia auxiliar no diagnóstico da toxicidade muscular causada pelas estatinas, através de um estudo metabólico de alterações decorrentes dos vários mecanismos envolvidos isolados ou associados. O objetivo deste estudo é avaliar as concentrações das gorduras intramiocelulares (IMCL) e extramiocelulares (EMCL), creatina total (Cr total) e trimetilamina (TMA), nos músculos tibial anterior e sóleo, nos pacientes em uso de estatina e com sintomas musculares e comparar com indivíduos hipercolesterolêmicos (LDL>=160mg/dL) e normocolesterolêmicos (LDL<160mg/dL), ambos sem tratamento. Também avaliar o efeito da redução do colesterol plasmático (após três meses de tratamento com estatinas) nas concentrações de gorduras IMCL e EMCL. Além disso, fazer uma correlação entre os níveis de CPK destes pacientes com as variáveis da espectroscopia. Noventa e um pacientes (média de 44 anos, 54 mulheres e 37 homens) foram submetidos à coleta de sangue para avaliação do perfil lipídico, TGO, TGP, CPK, TSH, T4 livre, creatinina e glicemia, e H-MRS para avaliação dos metabólitos IMCL, EMCL, Cr total e TMA. Os pacientes foram divididos em três grupos: grupo 1 (pacientes com LDL-C<160mg/dL, sem uso de medicação hipolipemiante) n=49, grupo 2 (pacientes em uso de estatina e apresentando sintomas musculares) n=18 e grupo 3 (pacientes com LDL-C>=160mg/dL, sem uso de estatina) n=24. Os pacientes do grupo 3 foram submetidos à coleta de sangue e a EHRM em dois momentos: antes e três meses após o tratamento com sinvastatina 20mg. Os exames foram realizados utilizando o aparelho de ressonância magnética SIGNA 1,5 T (Tesla) (General Electric, Milwaukee, WI, USA) e as imagens foram analisadas e processadas automaticamente utilizando o programa LCModel versão 6.2 (http://s-provencher.com/). Foram obtidos 115 exames de espectroscopia. Os pacientes do grupo 2 (55±9 anos) eram mais velhos do que os dos grupos 1 (38±11 anos) e 3 (48±9 anos) respectivamente, p<0,001. Houve diferença significante entre os grupos, pré-tratamento, em relação ao colesterol total, LDL-colesterol, triglicérides e TGO (p<0,001). Não foi observada diferença significante nos níveis de CPK entre os grupos 1, 2 e 3 (p=NS). No grupo 3, houve redução significante nos níveis de colesterol total, LDL-C e triglicérides após tratamento com estatina (p<0,05). Não houve diferença significante entre as variáveis IMCL, EMCL, Cr total e TMA, assim como suas razões entre os grupos avaliados e no grupo 3 antes e após o tratamento com estatinas (p=NS).Em relação aos valores de CPK e os resultados encontrados nas espectroscopias dos pacientes do grupo 2, observamos uma correlação positiva e significante entre a análise sérica da CPK e a razão da gordura IMCL e creatina total no músculo tibial anterior (r=0,253; p=0,018). A EHRM é um exame factível para ser utilizado na prática clínica, porém não foi possível demonstrar alterações nas concentrações dos metabólitos nos músculos tibial anterior e sóleo entre os grupos estudados. Os achados de correlações entre a CPK e a razão da gordura IMCL e creatina total podem sugerir uma manifestação precoce de toxicidade muscular causada pelas estatinas, em pacientes com sintomas musculares. / Cardiovascular disease is the leading cause of death in the western world and statins are the most prescribed medications for prevention and treatment. Despite being the most prescribed drugs, they are still under-used. The main cause of interruption of statin treatment is myopathy. Among the mechanisms involved in the pathophysiology of myotoxicity, deficiency of coenzyme Q10 has been described as the main cause of this side effect. Creatine kinase (CK) is a biomarker for severity of muscle damage, but its levels may be normal or increased in patients on statin use and muscle symptoms. Thus, proton magnetic resonance spectroscopy (H-MRS) could assist in the diagnosis of muscle toxicity caused by statins, through a study of the metabolic changes. The aim of this study is to evaluate the concentrations of intramyocellular (IMCL) and extramyocellular lipids (EMCL), total creatine and trimethylamine (TMA), on tibialis anterior and soleus muscles in patients on statin use and muscle symptoms and compare with hypercholesterolemic subjects (LDL >= 160mg/dL) and normal subjects (LDL<160mg/dL), both without treatment. Also, the effect on LDL serum levels (after three month statin treatment), and concentrations of IMCL and EMCL lipids. In addition, make a correlation between the levels of CK and the variables of spectroscopy. Ninety-one patients (mean age=44, 54 women and 37 men) were submitted to blood sampling for evaluation of serum total cholesterol, LDL-C, HDL-C, triglycerides, AST, ALT, CK, glucose, TSH and creatinine, and H-MRS for evaluation of metabolites, IMCL and EMCL lipids, total creatine and TMA. Patients were divided in 3 groups: 1 (patients with LDL-C<160mg/dL, without statin use) n=49, 2 (patients on statin use and muscle symptoms) n=18 and 3 (patients with LDL-C>=160mg/dL, without statin use) n=24.Group 3 were subjected to blood sampling and the H-MRS on two occasions: before and three months after treatment with simvastatin 20 mg. The tests were carried out in a MRI SIGNA 1.5 Tesla (General Electric, Milwaukee, WI, USA) magnet and the images were processed automatically using the software LCModel version 6.2 (http://s-provencher.com/). From the 91 study subjects a total of 115 H-MRS scans were performed. Patients in group 2 (age 55.0 ± 9.0 years) were older, respectively, than in groups 3 (48.0 ± 9.0 years) and 1 (38.0 ± 11.0 years), p<0.001. There was a statistically significant difference between the groups before treatment in relation to the total cholesterol, LDL-cholesterol, triglycerides and AST (p<0.001). There were no significant differences on plasma CK levels, in patients presenting muscle symptoms (p=NS). In Group 3, there was significant reduction in levels of total cholesterol, LDL-C and triglycerides after treatment with statin (p<0.05).There were no significant differences regarding median IMCL variables, EMCL, total creatine and TMA, in the tibialis anterior and soleus muscles as well as their ratios among the three groups and after group 3 three month treatment (p=NS). A significant and positive correlation (r=0.253, p=0.018), was found in group 2 between serum CK and the ratio of intramyocellular and total creatine in tibialis anterior muscle. H-MRS is a feasible exam to be used in clinical practice; however it has not been possible to demonstrate changes in concentrations of the metabolites in the tibialis anterior and soleus muscles. The findings of correlations between CK and intramyocellular and total creatine may suggest an early manifestation of muscle toxicity caused by statins in patients with muscle symptoms.

The isoprenoid biosynthetic pathway is targeted in the treatment of several diseases, including hypercholesteremia and bone related disorders. Farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) are isoprenoid biosynthetic pathway intermediates that are utilized during post-translational modification of proteins termed farnesylation and geranylgeranylation, respectively, together known as prenylation. The Ras and Rho GTPase family members are examples of proteins that are prenylated. Prenylation is essential for proper membrane localization and function of these small GTPases. Activating mutations or over-expression of these proteins promote oncogenic events, such as increased proliferation and migration. Studies have demonstrated that farnesyl transferase inhibitors and geranylgeranyl transferase inhibitors possess anti-cancer effects in humans and animal models of cancer, respectively. An alternative way to impair protein prenylation is through the depletion of FPP and GGPP. Statins and nitrogenous bisphosphonates (NBPs) deplete FPP and GGPP leading to impaired protein prenylation by inhibiting HMG-CoA Reductase (HMGCR) and FPP synthase (FDPS), respectively. These drugs have been shown to induce apoptosis, inhibit cancer cell migration, and induce cell cycle arrest. The anti-cancer effects of statins and NBPs can be prevented by GGPP addition, suggesting that GGPP depletion may be the mechanism by which these agents interfere with cancer cell survival. We and our collaborators have developed bisphosphonate inhibitors of GGPP synthase (GGDPS), an enzyme that produces GGPP from the substrates FPP and isopentenyl pyrophosphate. The goal of this research was to identify novel GGDPS inhibitors and to assess the effects of specific inhibition of GGDPS on cancer cell survival and function. Two aromatic bisphosphonates were identified as potent inhibitors of GGDPS in enzyme and cellular assays. Apoptosis hallmarks such as PARP cleavage and DNA fragmentation demonstrated that GGDPS inhibition induces apoptosis in K562 chronic myeloid leukemia cells through GGPP depletion and FPP accumulation. Isobologram analysis and enhanced impairment of protein geranylgeranylation showed that GGDPS inhibition is synergistic with the inhibition of HMGCR. Migration assays, transwell assay and large scale digital cell analysis system microscopy, demonstrated that GGDPS inhibition interferes with MDA-MB-231 breast cancer cell migration. Increased LC3-II expression showed that FDPS and GGDPS inhibition induces autophagy in PC3 prostate and MDA-MB-231 breast cancer cells. Inhibition of autophagy enhances the toxic effects of GGDPS inhibition as measured by MTT assay. Propidium iodine staining of DNA and immunostaining of cell cycle proteins such as p27 did not show significant effects of GGDPS inhibition on cell cycle progression. Importantly, exogenous addition of GGPP prevented most of the effects observed with GGDPS inhibition, suggesting specific inhibition of GGDPS by our bisphosphonate inhibitors. The data obtained herein suggest that GGDPS can be targeted to interfere with the progression of cancer cells.

The work detailed in this dissertation has an overarching theme of modulating microglia activation in both in vivo and in vitro models relevant to AD. The premise is that understanding microglia function in this context may lead to a better understanding of AD pathogenesis and thus to effective therapeutic interventions. In chapter 3, we employ a well-defined model of microglia activation whereby the intraperitoneal delivery of LPS results in CNS microglia activation and TNF-α production. Having previously identified that CD45 signaling pathways antagonized microglia TNF-α production in vitro and given that immunotherapy with anti-CD45 antibodies are already in clinical trials for both the treatment of malignant disorders as well as for tolerance induction following organ transplants, we investigated whether microglial CD45 could be a relevant molecular target in the opposition of microglia activation in vivo. Given that a number of epidemiological studies have shown an inverse correlation between the use of statins (a class of drugs that were initially described as specific inhibitors of cholesterol biosynthesis) and the incidence of Alzheimer's disease (Wolozin, 2000; Simon 2002; Zamrini, 2004); in chapter 4, we employed one of the most prescribed statins, lovastatin in our microglia activation paradigm. Interestingly, we show that statins only inhibit the enzyme HMG-CoA (the rate limiting step of cholesterol biosynthesis) but that they also display pleiotrophic effects including the inhibition of CD40 expression. Given the role of CD40 in microglia activation and its potential role in AD pathogenesis, we investigated whether lovastatin's protection in AD might be derived from effects on microglia function as governed by the CD40 pathway. In chapter 5, we provide evident for a model of microglia activation that addresses some of the current controversies concerning the role of microglia cells in AD pathogenesis. The model suggests that microglia cells exist in a number of distinct activation states, in one such state that we denote the "phagocytic state"; microglia function to clear cellular debris or foreign invaders or in the case of AD to remove β-amyloid/Aβ peptides. However, in response to certain co-stimuli (i.e. CD40 activation) these microglia take the form of an "antigen presenting cell" (APC) whereby they lose their phagocytic capacity in lieu of cytokine production and thus potential contributing to AD pathogenesis.

Coronary heart disease (CHD) remains the single leading cause of natural death worldwide. Despite significant advances in the diagnosis and treatment, CHD accounts for 1 out of every 6 deaths in the United States. Myocardial infarct (MI) as a result of CHD causes irreversible damage to the heart through the loss of viable myocardial tissue. Patients surviving the initial MI are at risk of developing heart failure due to lost contractile function and adverse cardiac remodeling. Improvement in the survival rates for MI have led to an increase in the incidence of heart failure, affecting approximately 5 million people in the United States. Although treatment of heart failure has improved, the mortality rates of heart failure remain high with 1 in 5 dying within the first year of diagnosis and 50% dying within 5 years. The cost of caring for heart failure patients ranks number one in Medicare. Oxidative stress plays an important role in the etiology and pathophysiology of CHD and heart failure. The transcription factor Nrf2 is a master regulator of cellular antioxidant defense mechanisms, controlling the expression of numerous antioxidant and detoxification genes through the Antioxidant Response Element (ARE) in the promoter regions. The cytoprotective effects of Nrf2 have been demonstrated in a variety of organs and disease states; however, the role of Nrf2 in the heart and heart disease has not been defined. The work presented here defines roles of Nrf2 in limiting cardiac injury and the progression to heart failure (Chapter II), protecting cardiac myocytes from oxidative stress through the preservation of mitochondria (Chapter III), and mediating the infarct reducing effects of statins, one of the most prescribed pharmacological agent (Chapter IV). In order to investigate a role of Nrf2 in the pathology of ischemic injury in the heart, a mouse model of ischemia and myocardial infarct by occlusion of the left anterior descending coronary artery was used. Nrf2 knockout mice subjected to ischemia/reperfusion injury experienced a larger infarct size than wild-type mice. Furthermore, mice lacking Nrf2 experienced a higher mortality rate and an accelerated progression to heart failure, indicated by severely compromised contractile function and reduced cardiac output, within 10 days following an MI. Morphological examination revealed maladaptive remodeling, including myocyte hypertrophy, heart enlargement, and dilated left ventricle, in Nrf2 KO mice that was absent in WT mice. Analysis of cardiac function by echocardiogram revealed increased left ventricular mass, increased systolic volume, decreased fraction shortening, reduced ejection fraction, and decreased cardiac output in Nrf2 KO mice. Nrf2 KO mice also demonstrated expression of biomarkers of heart failure, such as expression of fetal gene program, with elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. Interestingly, a lack of immune cell infiltrate and myofibroblasts as well as a deficiency in collagen deposition were observed in the infarcted region of hearts from Nrf2 KO mice. These data indicate that Nrf2 plays an important role in protecting the myocardium from ischemic injury and the progression to heart failure. Lack of Nrf2 response results in deficiency of wound healing and instead initiation of maladaptive remodeling, leading to heart failure. Mitochondria are key sources of reactive oxygen species (ROS) generation, as well as important targets for ROS-induced cell injury. Cardiac myocytes have the highest content of mitochondria among all cell types and can be particularly susceptible to mitochondrial dysfunction due to the high metabolic demand associated with the contractile function of the heart. With cardiomyocytes (CMCs) isolated from neonatal rats and kept under tissue culture conditions, mitochondria exist in elaborated networks. Such networks were replaced by predominately individual punctate mitochondria 24 hours after exposure to a sublethal dose of H₂O₂. Mitochondrial morphology was altered with membrane swelling and disorganization of inner cristae with areas of condensation. Disrupted mitochondrial morphology was associated with a loss of membrane potential and decreased expression of mitochondrial proteins involved in the electron transport chain, such as cytochrome b and cytochrome c. Nrf2 overexpression prevented H₂O₂ from inducing morphological changes in mitochondria and the reduction of cytochrome b and cytochrome c expresssion. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation as measured by carbonyl formation. Instead, we found that Nrf2 localizes to the outer mitochondrial membrane, suggesting a direct role of Nrf2 in mitochondrial protection. As further evidence of a direct role in mitochondrial protection, a cell-free system of mitochondria isolated from the myocardium of Nrf2 knockout mice were more sensitive to permeability transition, an indicator of mitochondrial dysfunction. Combined, these data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria. In the clinic, statins are now commonly administered for patients experiencing MI or CHD. Statins have become mainstays in the treatment of hypercholesterolemia and atherosclerosis as inhibitors of the rate limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition, statins have been shown to elicit pleiotropic effects, including plaque stabilization, maintenance of endothelial function, anti-inflammatory actions, and antioxidant capabilities, independent of effects on cholesterol synthesis. Recently, these pleiotropic effects have been implicated in providing acute protection against ischemia and reperfusion injury, which has led to the use of high dose statins clinically before revascularization of an ischemic event. I have found that administration of atorvastatin in mice induced Nrf2 protein levels in the heart, brain, lung, and liver. While atorvastatin reduced infarct size following an MI in wild-type mice, this protective effect was lost in mice lacking Nrf2. Failure of atorvastatin to protect against MI in Nrf2 knockout mice indicates that Nrf2 plays a critical role in mediating the protective effects of acute statin treatment. Nrf2 induction by statins is a novel discovery. In order to understand the mechanism of such statin effect, I used an in vitro cell system, in which a variety of statins, atorvastatin, simvastatin, lovastatin, and pravastatin, were found to elevate Nrf2 protein levels. Elevation of Nrf2 by statins was independent of increased protein stability or transcriptional regulation. Instead, statins increased Nrf2 mRNA association with ribosomal complexes and induced Nrf2 protein through a translational mechanism. Recruitment of Nrf2 mRNA to ribosomes and induction of Nrf2 protein was dependent on activation of PI3 kinase. These studies provide evidence that Nrf2 plays a critical role in protecting cardiac myocytes and the heart from oxidative stress and MI. In the absence of Nrf2, mice experienced worse cardiac injury following MI and quickly advanced to heart failure. Mechanistically, this work has identified a novel role of Nrf2 in preserving mitochondrial morphology and integrity during oxidative stress through a direct interaction with the outer mitochondrial membrane. Finally, a newly defined role of Nrf2 induction by statins in mediating protection against MI by acute statin therapy indicates that modulation of Nrf2 may represent a viable pharmacological target for cardiac protection in humans.

abstract: Cancer is a heterogeneous disease with discrete oncogenic mechanisms. P53 mutation is the most common oncogenic mutation in many cancers including breast cancer. This dissertation focuses on fundamental genetic alterations enforced by p53 mutation as an indirect target. p53 mutation upregulates the mevalonate pathway genes altering cholesterol biosynthesis and prenylation. Prenylation, a lipid modification, is required for small GTPases signaling cascades. Project 1 demonstrates that prenylation inhibition can specifically target cells harboring p53 mutation resulting in reduced tumor proliferation and migration. Mutating p53 is associated with Ras and RhoA activation and statin prevents this activity by inhibiting prenylation. Ras-related pathway genes were selected from the transcriptomic analysis for evaluating correlation to statin sensitivity. A gene signature of seventeen genes and TP53 genotype (referred to as MPR signature) is generated to predict response to statins. MPR signature is validated through two datasets of drug screening in cell lines. As advancements in targeted gene modification are rising, the CRISPR-Cas9 technology has emerged as a new cancer therapeutic strategy. One of the important risk factors in gene therapy is the immune recognition of the exogenous therapeutic tool, resulting in obstruction of treatment and possibly serious health consequences. Project 2 describes a method development that can potentially improve the safety and efficacy of gene-targeting proteins. A cohort of 155 healthy individuals was screened for pre-existing B cell and T cell immune response to the S. pyogenes Cas9 protein. We detected antibodies against Cas9 in more than 10% of the healthy population and identified two immunodominant T cell epitopes of this protein. A de-immunized Cas9 that maintains the wild-type functionality was engineered by mutating the identified T cell epitopes. The gene signature and method described here have the potential to improve strategies for genome-driven tumor targeting. / Dissertation/Thesis / Doctoral Dissertation Chemistry 2017

Sammanfattning Bakgrund:Koenzym Q10 (Q10) syntetiseras i kroppen och återfinns med de högsta koncentrationerna i hjärta, lever och immunförsvarets celler. Det har en viktig roll när det agerar transportör av elektroner i andningskedjan. Q10 har även antioxiderande egenskaper, stärker cellmembran och motverkar fettsyraoxidation i mitokondrien och cellmembran. Nyare studier visar att ett tillskott av Q10 även förbättrar symptomen vid kronisk hjärtsvikt och minskar kardiovaskulära händelser.Vid förhöjda blodfetter är det mest använda läkemedlet statiner. De hämmar kolesterolsyntesen i levern och de påverkar även syntesen av Q10 vilken också sker mevalonatvägen. En av de vanligaste biverkningarna vid statinbehandling är muskelbesvären myopati och myalgi. Studier visar att dåligt fungerande mitokondrier och reducering av Q10 i serum kan relateras till statinbehandling. Syfte:Syftet med detta arbete har varit att undersöka om ett tillskott av Q10 har någon reducerande effekt på smärtan vid statininducerad myopati (SIM).  Metod:Denna litteraturstudie baserades på sex vetenskapliga artiklar sökta via PubMed. Studierna skulle vara randomiserade, dubbelblinda kliniska studier gjorda på människor. Av sökningens 10 träffar erhölls 6 artiklar vilka var relevanta för att besvara denna studiens frågeställning. Resultat:Resultatet visade att Q10 inte har någon större effekt på smärtan vid SIM. Endast 2 av 6 studier visar att Q10 har en god effekt.  Slutsats: För att kunna dra slutsats om Q10 har effekt eller inte vid SIM behövs fler randomiserade placebokontrollerade studier med jämförbara grupper och fler antal deltagare.