This study investigates the effects of prolonged simvastatin exposure on coenzyme Q9/10 (CoQ9/10) levels, an essential component of antioxidant defense, in cultured cardiac cells. Statins, commonly used to manage dyslipidemia and reduce cardiovascular risk, may impair mitochondrial function, but their impact on CoQ10 depletion and oxidative stress is not well understood. We examined the influence of simvastatin on mitochondrial oxidative capacity, reactive oxygen species (ROS) production, and CoQ9/10 status at concentrations of 0.3, 0.6, 1.25, 2.5, 5, 10, and 20 μM, over durations of 24, 48, and 72 h. Using an in vitro model of cultured H9c2 cardiomyoblasts, our results showed that short-term exposure (24 h) at lower concentrations (<5 μM) enhanced cytosolic and mitochondrial ROS levels without affecting mitochondrial function or CoQ9/10 status. However, prolonged exposure to higher concentrations (≥10 μM for >48 h) resulted in impaired mitochondrial oxidative capacity, indicated by increased proton leak and elevated ROS levels, which were followed by significantly reduced cell viability. These findings suggest that prolonged, high-dose simvastatin exposure may disrupt the oxidative balance of CoQ9/10, leading to myocardial injury. This research addresses a gap in understanding the long-term effects of statins on mitochondrial health and underscores the need for further studies to optimize statin therapy and minimize adverse effects on myocardial function.

Cardiovascular drugs are widely used for the prevention and treatment of various cardiac and vascular disorders. However, some of these drugs can also cause adverse effects on the kidney, leading to acute or chronic renal dysfunction, electrolyte imbalances, and increased mortality. The mechanisms of drug-induced renal toxicity vary depending on the type and class of the drug, the dose and duration of exposure, and the patient's characteristics and comorbidities. In this review, we summarize the current knowledge on the renal effects of some common cardiovascular drugs, such as diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, antiplatelet agents, anticoagulants, and statins and proton-pump inhibitors. We also discuss the clinical implications and management strategies for preventing or minimizing drug-induced nephrotoxicity, as well as the potential role of oxidative stress in its pathogenesis.

Coenzyme Q10 (CoQ10) is a critical component of the mitochondrial respiratory chain. CoQ10 deficiencies cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ10 involvement in several biological processes. One such process is cholesterol homeostasis, since CoQ10 is synthesized through the mevalonate pathway, which also produces cholesterol. To elucidate the role of lipid dysfunction in the pathogenesis of CoQ10 deficiency, we investigated lipid metabolism in human CoQ10 deficient iPSCs-derived neurons, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway. We show that CoQ10 deficiency causes alterations in cholesterol homeostasis, fatty acids oxidation, phospholipids and sphingolipids synthesis in neurons. These alterations depend on the molecular defect, and on the residual CoQ10 levels. Our results imply that CoQ10 deficiencies can induce pathology by altering lipid homeostasis and the composition of cellular membranes. These findings provide further understanding of the mechanisms underlying CoQ10 deficiency and point to potential novel therapeutic targets.

Cancer remains one of the leading causes of the death of individuals globally. Conventional treatment techniques like chemotherapy and radiation often suffer various drawbacks like toxicity and drug resistance. The study of cell death has been predominantly focused on classical forms like apoptosis, but the role of metal ions in governing controlled cell death is a fascinating and less explored area. Metal-mediated controlled cell death is a process where metal triggers cell death via a unique mechanism. Nanomaterial-based strategies have gained attention for their ability to deliver precise therapeutic agents while also triggering Regulated Cell Death (RCD) mechanisms in cancer cells. The recently discovered metal-mediated controlled cell death techniques like cuproptosis and ferroptosis can be used in cancer treatment as they can be used selectively for the treatment of drug-resistant cancer. Nano material-based delivery system can also be used for the precise delivery of the drug to the targeted sites. In this review, we have given some idea about the mechanism of metal-mediated controlled cell death techniques (ferroptosis and cuproptosis) and how we can initiate controlled cell deaths using nanomaterials for cancer treatment.

Cardiac surgery-related acute kidney injury (CS-AKI) is a decrease in kidney function after open-heart surgery, affecting up to 50% of patients. The pathophysiology of CS-AKI involves ischemia-reperfusion injury, inflammation, and oxidative stress. Ubiquinone is a potent antioxidant, and we hypothesized that it could decrease both the incidence and severity of CS-AKI. The intervention group received ubiquinone (8 mg/kg/day) divided into three daily doses, while the control group received a placebo. The primary outcome was the incidence of CS-AKI, which was manifested as an increase in creatinine ≥26.5 µmol/L or a urine output below 0.5 mL/kg/h for 6 h. Out of 73 patients, 39.7% (N = 29) developed CS-AKI, including 35.3% of the ubiquinone group and 43.6% of the placebo group (X2(1,N = 73) = 0.4931, p = 0.4825). The secondary outcomes revealed that the ubiquinone group experienced reduced postoperative bleeding, with a median (IQR) drainage of 320 mL (230-415) compared to the drainage of 420 mL (242.5-747.5) in the placebo group (t(35.84) = 2.055, p = 0.047). The median hs-TnI level in the ubiquinone group was 239.5 ng/mL (113.25-382.75) after surgery compared to a level of 366 (234.5-672.5) ng/mL in the placebo group (p = 0.024). In conclusion, there was no significant difference in the incidence of CS-AKI between groups. Postoperative hs-TnI and bleeding were significantly reduced among patients receiving ubiquinone.

Statin therapy is associated with an increased risk of new-onset diabetes (NOD), possibly due to a reduction in coenzyme Q10 (CoQ10) levels as a result of statin use. This study aimed to investigate the relationship between exogenous CoQ10 supplementation and the development of NOD.

This study included 4394 participants from the National Health and Nutrition Examination Survey (NHANES). Baseline characteristics were compared between those with and without NOD and between those with and without CoQ10. Univariate logistic regression was performed to identify factors associated with NOD. Two models were used for confounding factors, including demographics and various covariates. Multifactor logistic regression further assessed the association between CoQ10 supplementation and NOD. Additionally, restricted cubic spline (RCS) analysis was conducted to evaluate the potential nonlinear relationship between daily CoQ10 dose and NOD.

Univariate logistic regression showed an association between CoQ10 supplementation and a reduced risk of NOD (odds ratio [OR] = 0.323, 95% confidence interval [CI] 0.157-0.668, p = 0.003), which remained significant after adjustments in model 1 (OR = 0.344, 95% CI 0.160-0.737, p = 0.006) and model 2 (OR = 0.232, 95% CI 0.057-0.942, p = 0.041). There was no evidence of a linear association between daily CoQ10 dose and NOD in logistic regression analysis (OR = 0.999, 95% CI 0.994-1.004, p = 0.720), and no evidence of a nonlinear correlation in the RCS analysis (p > 0.05).

CoQ10 supplementation in individuals taking statins was associated with a reduced risk of NOD, and this association was independent of the CoQ10 dose.

The brain contains many interconnected and complex cellular and molecular mechanisms. Injury to the brain causes permanent dysfunctions in these mechanisms. So, it continues to be an area where surgical intervention cannot be performed except for the removal of tumors and the repair of some aneurysms. Some agents that can cross the blood-brain barrier and reach neurons show neuroprotective effects in the brain due to their anti-apoptotic, anti-inflammatory and antioxidant properties. In particular, some agents act by reducing or modulating the accumulation of protein aggregates in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and prion disease) caused by protein accumulation. Substrate accumulation causes increased oxidative stress and stimulates the brain's immune cells, microglia, and astrocytes, to secrete proinflammatory cytokines. Long-term or chronic neuroinflammatory response triggers apoptosis. Brain damage is observed with neuronal apoptosis and brain functions are impaired. This situation negatively affects processes such as motor movements, memory, perception, and learning. Neuroprotective agents prevent apoptosis by modulating molecules that play a role in apoptosis. In addition, they can improve impaired brain functions by supporting neuroplasticity and neurogenesis. Due to the important roles that these agents play in central nervous system damage or neurodegenerative diseases, it is important to elucidate many mechanisms. This review provides an overview of the mechanisms of flavonoids, which constitute a large part of the agents with neuroprotective effects, as well as vitamins, neurotransmitters, hormones, amino acids, and their derivatives. It is thought that understanding these mechanisms will enable the development of new therapeutic agents and different treatment strategies.

The success of statin therapy in reducing cardiovascular morbidity and mortality is contrasted by the skeletal muscle complaints, which often leads to nonadherence. Previous studies have shown that inhibition of mitochondrial function plays a key role in statin intolerance. Recently, it was found that statins may also influence energy metabolism in cardiomyocytes. This study assessed the effects of statin use on cardiac muscle ex vivo from patients using atorvastatin, rosuvastatin, simvastatin or pravastatin and controls.

Cardiac tissue and skeletal muscle tissue were harvested during open heart surgery after patients provided written informed consent. Patients included were undergoing cardiac surgery and either taking statins (atorvastatin, rosuvastatin, simvastatin or pravastatin) or without statin therapy (controls). Contractile behaviour of cardiac auricles was tested in an ex vivo set-up and cellular respiration of both cardiac and skeletal muscle tissue samples was measured using an Oxygraph-2k. Finally, statin acid and lactone concentrations were quantified in cardiac and skeletal homogenates by LC-MS/MS.

Fatty acid oxidation and mitochondrial complex I and II activity were reduced in cardiac muscle, while contractile function remained unaffected. Inhibition of mitochondrial complex III by statins, as previously described, was confirmed in skeletal muscle when compared to control samples, but not observed in cardiac tissue. Statin concentrations determined in skeletal muscle tissue and cardiac muscle tissue were comparable.

Statins reduce skeletal and cardiac muscle cell respiration without significantly affecting cardiac contractility.

Drug-induced liver injury (DILI) continues to be a major concern in clinical practice, thus necessitating a need for novel therapeutic approaches to alleviate its impact on hepatic function. This review investigates the therapeutic potential of nutraceuticals against DILI, focusing on examining the underlying molecular mechanisms and cellular pathways. In preclinical and clinical studies, nutraceuticals, such as silymarin, curcumin, and N-acetylcysteine, have demonstrated remarkable efficacy in attenuating liver injury induced by diverse pharmaceutical agents. The molecular mechanisms underlying these hepatoprotective effects involve modulation of oxidative stress, inflammation, and apoptotic pathways. Furthermore, this review examines cellular routes affected by these nutritional components focusing on their influence on hepatocytes, Kupffer cells, and stellate cells. Key evidence highlights that autophagy modulation as well as unfolded protein response are essential cellular processes through which nutraceuticals exert their cytoprotective functions. In conclusion, nutraceuticals are emerging as promising therapeutic agents for mitigating DILI, by targeting different molecular pathways along with cell processes involved in it concurrently.

COQ8A plays an important role in the biosynthesis of coenzyme Q10 (CoQ10), and variations in COQ8A gene are associated with primary CoQ10 deficiency-4 (COQ10D4), also known as COQ8A-ataxia. The current understanding of the association between the specific variant type, the severity of CoQ10 deficiency, and the degree of oxidative stress in individuals with primary CoQ10 deficiencies remains uncertain. Here we provide a comprehensive analysis of the clinical and genetic characteristics of an 18-year-old patient with COQ8A-ataxia, who exhibited novel compound heterozygous variants (c.1904_1906del and c.637C > T) in the COQ8A gene. These variants reduced the expression levels of COQ8A and mitochondrial proteins in the patient's muscle and skin fibroblast samples, contributed to mitochondrial respiration deficiency, increased ROS production and altered mitochondrial membrane potential. It is worth noting that the optimal treatment for COQ8A-ataxia remains uncertain. Presently, therapy consists of CoQ10 supplementation, however, it did not yield significant improvement in our patient's symptoms. Additionally, we reviewed the response of CoQ10 supplementation and evolution of patients in previous literatures in detail. We found that only half of patients could got notable improvement in ataxia. This research aims to expand the genotype-phenotype spectrum of COQ10D4, address discrepancies in previous reviews regarding the effectiveness of CoQ10 in these disorders, and help to establish a standardized treatment protocol for COQ8A-ataxia.

Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid side chain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) but is also required for several other crucial cellular processes. In fact, CoQ appears to be central to the entire redox balance of the cell. Remarkably, its structure and therefore its properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox-active molecule in the ETC and other enzymatic systems, its role as a prooxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common, as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.

Development and aging significantly impact the cellular levels of Coenzyme Q (CoQ), which is associated with both pathological and physiological conditions. Aim of this study was to describe the CoQ status throughout the lifetime of Drosophila melanogaster, a well-established model in aging studies. CoQ9 and CoQ distribution was analysed across different body segments and various life stages in both male and female flies. The results indicate that CoQ9 is the predominant isoform in every phase of flies' life cycle, with the highest concentrations observed in the thorax. We noted distinct trends in CoQ distribution during aging, which varied according to sex and body segments (head, thorax, and abdomen). Supplementation with two concentrations of CoQ9 and CoQ10 (15 μM and 75 μM) for 2 weeks induced a segment- and sex-specific CoQ uptake. Although 75 μM CoQ10 was more effective in modulating the CoQ status, lifelong treatment with this concentration did not affect the longevity of the flies.

Efavirenz, tenofovir, rifampicin, simvastatin, lamotrigine and clarithromycin are known potential mitochondrial toxicants. Mitochondrial toxicity has been reported to disrupt the chain of events in the insulin signalling pathway. Considering the upward trajectory of diabetes mellitus prevalence, studies which seek to uncover probable risk factors for developing diabetes should be encouraged. This study aimed to evaluate the intracellular mechanisms leading to the development of insulin resistance in the presence of various conventional pharmacological agents reported as potential mitochondrial toxicants in skeletal muscle cell line. Differentiated C2C12 preparations were exposed to multiple concentrations of efavirenz, tenofovir, rifampicin, simvastatin, lamotrigine, and clarithromycin, separately. Glucose handling was evaluated by observing the changes in insulin-stimulated glucose uptake and assessing the changes in GLUT4 translocation, GLUT4 expression and Akt expression. The changes in mitochondrial function were evaluated by assessing mitochondrial membrane integrity, cellular ATP production, generation of intracellular reactive oxygen species, expression of tafazzin and quantification of medium malonaldehyde. Insulin stimulated glucose uptake was perturbed in C2C12 pre-treated with potential mitotoxicants. Additionally, ATP synthesis, alterations in mitochondrial membrane potential, excessive accumulation of ROS and malonaldehyde were observed in the presence of potential mitotoxicants. Particularly, we observed suppression of proteins involved in the insulin signalling pathway and maintenance of mitochondrial function namely GLUT4, Akt and tafazzin. Mitochondrial toxicants can potentially induce insulin resistance emanating from mitochondrial dysfunction. These new findings will contribute to the understanding of underlying mechanisms involved in the development of insulin resistance linked to mitochondrial dysfunction.

Dysfunctional mitochondria have been linked to the pathogenesis of obesity-associated metabolic diseases. Excessive energy intake impairs mitochondrial biogenesis and function, decreasing adenosine-5'-triphosphate production and negatively impacting metabolically active tissues such as adipose tissue, skeletal muscle, and the liver. Compromised mitochondrial function disturbs lipid metabolism and increases reactive oxygen species production in these tissues, contributing to the development of insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease. Recent studies have demonstrated the therapeutic potential of bioactive food components, such as resveratrol, quercetin, coenzyme Q10, curcumin, and astaxanthin, by enhancing mitochondrial function. This review provides an overview of the current understanding of how these bioactive compounds ameliorate mitochondrial dysfunction to mitigate obesity-associated metabolic diseases.

Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype.

Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed.

Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls.

WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.

Several studies have reported that pravastatin can mitigate the progression of kidney disease, but limited evidence exists regarding its effects on kidney function in Asian patients. This multicenter prospective observational study aimed to assess the effect of pravastatin on kidney function in Korean patients with dyslipidemia and type 2 diabetes mellitus (T2DM) in clinical practice.

This 48-week prospective multicenter study included 2604 of 2997 eligible patients with dyslipidemia and T2DM who had available estimated glomerular filtration rate (eGFR) measurements. The primary endpoint was eGFR percent change at week 24 from baseline. We also assessed secondary endpoints, which included percent changes in eGFR at weeks 12 and 48 from baseline, as well as changes in eGFR, metabolic profiles (lipid and glycemic levels) at 12, 24, and 48 weeks from baseline, and safety.

We noted a significant improvement in eGFR, with mean percent changes of 2.5%, 2.5%, and 3.0% at 12, 24, and 48 weeks, respectively (all adjusted p < 0.05). The eGFR percent changes significantly increased in subgroups with baseline eGFR 30-90 mL/min/1.73 m2, glycated hemoglobin (HbA1c) ≥ 7 at baseline, no hypertension history, T2DM duration > 5 years, or previous statin therapy. Lipid profiles were improved and remained stable throughout the study, and interestingly, fasting glucose and HbA1c were improved at 24 weeks.

Our findings suggest that pravastatin may have potential benefits for improving eGFR in Korean patients with dyslipidemia and T2DM. This could make it a preferable treatment option for patients with reduced kidney function.

NCT05107063 submitted October 27, 2021.

Statins are among the most widely prescribed drugs for treating dyslipidemia and reducing the incidence of heart disease and stroke. However, they come with a wide range of side effects, from myopathy to necrotizing rhabdomyolysis, as well as diabetes, hepatotoxicity, and sleep problems. The most common side effect of statins is statin-induced myopathy, often leading to discontinuation of statin therapy and noncompliance in many patients. This study aims to assess the effectiveness of coenzyme Q10 (CoQ10) supplementation as a treatment for patients with statin-induced myopathy. This systematic review was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. Relevant studies were identified through searches of Medline, PMC, PubMed, Science Direct, and Google Scholar. Only randomized control trials and meta-analyses of oral CoQ10 supplementation versus placebo in adults with statin-associated myalgia were included. The risk of bias was assessed using the Cochrane Risk of Bias tool (The Cochrane Collaboration, London, England, UK) and the measurement tool for the "assessment of multiple systematic reviews" (AMSTAR tool). Out of 5,000 records identified, only five were selected for this review: one meta-analysis and four randomized controlled trials. All of these studies were conducted between 2010 and 2023, involving a total of 800 patients. All randomized controlled trials showed improvement in statin-associated myopathy with CoQ10 supplementation, along with or without a reduced dosage of statins, without any notable side effects of CoQ10. Therefore, it can be deduced that CoQ10 supplementation significantly ameliorates statin-induced musculoskeletal symptoms.

Statins represent the primary therapy for combatting hypercholesterolemia and reducing mortality from cardiovascular events. Despite their pleiotropic effects in lowering cholesterol synthesis, circulating cholesterol, as well as reducing the risk of other systemic diseases, statins have adverse events in a small, but significant, population of treated patients. The most prominent of these adverse effects is statin-induced myopathy, which lacks precise definition but is characterised by elevations in the muscle enzyme creatine kinase alongside musculoskeletal complaints, including pain, weakness and fatigue. The exact aetiology of statin-induced myopathy remains to be elucidated, although impaired mitochondrial function is thought to be an important underlying cause. This may result from or be the consequence of several factors including statin-induced inhibition of coenzyme Q10 (CoQ10) biosynthesis, impaired Ca2+ signalling and modified reactive oxygen species (ROS) generation. The purpose of this review article is to provide an update on the information available linking statin therapy with mitochondrial dysfunction and to outline any mechanistic insights, which may be beneficial in the future treatment of myopathic adverse events.

Statins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and β-hydroxy-β-methylbutyrate (HMB), however, little is known about the changes in the metabolism of leucine and its metabolites in response to statins.

We aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA).

12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine), along with their respective keto acids and HMB.

We found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB.

Our study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.

An integral component of the practice of medicine is focused on the initiation of medications, based on clinical practice guidelines and underlying trial evidence, which usually test the addition of novel medications intended for life-long use in short-term clinical trials. Much less attention is given to the question of medication discontinuation, especially after a lengthy period of treatment, during which patients age gets older and diseases may either progress or new diseases may emerge. Given the paucity of data, clinical practice guidelines offer little to no guidance on when and how to deprescribe cardiovascular medications. Such decisions are often left to the discretion of clinicians, who, together with their patients, express concern of potential adverse effects of medication discontinuation. Even in the absence of adverse effects, the continuation of medications without any proven effect may cause harm due to drug-drug interactions, the emergence of polypharmacy, and additional preventable spending to already strained health systems. Herein, several cardiovascular medications or medication classes are discussed that in the opinion of this author group should generally be discontinued, either for the prevention of potential harm, for a lack of benefit, or for the availability of better alternatives.

Immune-mediated necrotizing myopathy (IMNM) is a form of statin myopathy characterized by the presence of antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti HMGCR).

The aim of this study was to investigate the relationship between the different statins and the risk of IMNM.

A two-time approach was used. First, we performed a descriptive analysis of the French national pharmacovigilance database (FNPV) for the period from 1985 to december2020. To identify relevant cases, we used Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) related to IMNM. We performed a quantitative and qualitative review of individual case safety reports (ICSRs) recorded in the french vigilance spontaneous reporting system. In a second time, we performed a comparative analysis with the World Health Organization global individual case safety reports database (Vigibase). The association between IMNM and statins exposure was assessed by calculating the reporting odds ratio (ROR) and its 95% confidence interval.

After analysis, a total of 25 ICSRs were related to IMNM in the FNPV. The suspected statins were atorvastatin (n=21), simvastatin (n=2), pravastatin (n=1) and rosuvastatin (n=1). In Vigibase, 567 notifications were identified. A significant ROR value was found for atorvastatin, pitavastatin, simvastatin, pravastatin and rosuvastatin.

Atorvastatin presents the highest risk of IMNM. Our data suggest that the occurrence of IMNM is a class effect.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia, insulin resistance, and insufficient insulin secretion. Sarcopenia, as a new complication of diabetes, is characterized by the loss of muscle mass and the progressive decline of muscle strength and function in T2DM patients, which has a serious impact on the physical and mental health of patients. Insulin resistance, mitochondrial dysfunction, and chronic inflammation are common mechanisms of diabetes and sarcopenia. Reasonable exercise training, nutrition supplement, and drug intervention may improve the quality of life of patients with diabetes combined with sarcopenia. This article reviews the relevant factors and management measures of sarcopenia in T2DM patients, in order to achieve early detection, diagnosis, and intervention.

With the rapid development of new generations of antitumor therapies, the average survival time of cancer patients is expected to be continuously prolonged. However, these therapies often lead to cardiotoxicity, resulting in a growing number of tumor survivors with cardiovascular disease. Therefore, a new interdisciplinary subspecialty called "cardio-oncology" has emerged, aiming to detect and treat cardiovascular diseases associated with tumors and antitumor therapies. Recent studies have highlighted the role of ferroptosis in both cardiovascular and neoplastic diseases. The balance between intracellular oxidative stress and antioxidant defense is crucial in regulating ferroptosis. Tumor cells can evade ferroptosis by upregulating multiple antioxidant defense pathways, while many antitumor therapies rely on downregulating antioxidant defense and promoting ferroptosis in cancer cells. Unfortunately, these ferroptosis-inducing antitumor therapies often lack tissue specificity and can also cause injury to the heart, resulting in ferroptosis-induced cardiotoxicity. A range of cardioprotective agents exert cardioprotective effects by inhibiting ferroptosis. However, these cardioprotective agents might diminish the efficacy of antitumor treatment due to their antiferroptotic effects. Most current research on ferroptosis only focuses on either tumor treatment or heart protection but rarely considers both in concert. Therefore, further research is needed to study how to protect the heart during antitumor therapies by regulating ferroptosis. In this review, we summarized the role of ferroptosis in the treatment of neoplastic diseases and cardiovascular diseases and also attempted to propose further research directions for ferroptosis in the field of cardio-oncology.

The objective of this article is to evaluate near-infrared spectroscopy (NIRS), a non-invasive technique to assess tissue oxygenation and mitochondrial function, as a diagnostic tool for statin-associated muscle symptoms (SAMS).

We verified SAMS in 39 statin-treated patients (23 women) using a double-blind, placebo-controlled, cross-over protocol. Subjects with suspected SAMS were randomised to simvastatin 20 mg/day or placebo for 8 weeks, followed by a 4-week no treatment period and then assigned to the alternative treatment, either simvastatin or placebo. Tissue oxygenation was measured before and after each statin or placebo treatment using NIRS during handgrip exercise at increasing intensities of maximal voluntary contraction (MVC).

44% (n=17) of patients were confirmed as having SAMS (11 women) because they reported discomfort only during simvastatin treatment. There were no significant differences in percent change in tissue oxygenation in placebo versus statin at all % MVCs in all subjects. The percent change in tissue oxygenation also did not differ significantly between confirmed and unconfirmed SAMS subjects on statin (-2.4% vs -2.4%, respectively) or placebo treatment (-1.1% vs -9%, respectively). The percent change in tissue oxygenation was reduced after placebo therapy in unconfirmed SAMS subjects (-10.2%) (p≤0.01) suggesting potential measurement variability.

NIRS in the forearm cannot differentiate between confirmed and unconfirmed SAMS, but further research is needed to assess the usability of NIRS as a diagnostic tool for SAMS.

NCT03653663.

BACKGROUNDWhile the benefits of statin therapy on atherosclerotic cardiovascular disease are clear, patients often experience mild to moderate skeletal myopathic symptoms, the mechanism for which is unknown. This study investigated the potential effect of high-dose atorvastatin therapy on skeletal muscle mitochondrial function and whole-body aerobic capacity in humans.METHODSEight overweight (BMI, 31.9 ± 2.0) but otherwise healthy sedentary adults (4 females, 4 males) were studied before (day 0) and 14, 28, and 56 days after initiating atorvastatin (80 mg/d) therapy.RESULTSMaximal ADP-stimulated respiration, measured in permeabilized fiber bundles from muscle biopsies taken at each time point, declined gradually over the course of atorvastatin treatment, resulting in > 30% loss of skeletal muscle mitochondrial oxidative phosphorylation capacity by day 56. Indices of in vivo muscle oxidative capacity (via near-infrared spectroscopy) decreased by 23% to 45%. In whole muscle homogenates from day 0 biopsies, atorvastatin inhibited complex III activity at midmicromolar concentrations, whereas complex IV activity was inhibited at low nanomolar concentrations.CONCLUSIONThese findings demonstrate that high-dose atorvastatin treatment elicits a striking progressive decline in skeletal muscle mitochondrial respiratory capacity, highlighting the need for longer-term dose-response studies in different patient populations to thoroughly define the effect of statin therapy on skeletal muscle health.FUNDINGNIH R01 AR071263.

Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.

In a recent study, we have shown that atorvastatin is clinically safe for dermatomyositis (DM) and antisynthetase syndrome (ASS) patients with dyslipidemia. Herein, we showed in an unprecedented way, the safety of atorvastatin on the muscular tissues of these patients.

Transcriptome analysis was performed on samples of the vastus lateralis muscle obtained at baseline and after 12 weeks of atorvastatin (20 mg/day) intervention in DM or ASS patients with dyslipidemia [6DM and 5ASS received atorvastatin, and 2DM and 3ASS received placebo]. The results were analyzed considering differences in expression fold change before and after treatment. Histological and histochemical analyses were also performed.

In both groups, no significant changes were observed in genes related to the mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways. Histological analysis showed a slight variability in the fiber size that was preserved after the intervention. In addition, the mosaic of muscle fibers was preserved in the internal architecture of the fibers and all histological regions. No fiber necrosis or atrophy, focal failures, subsarcolemmal accumulation, lipids, areas of fibrosis, or alterations in mitochondrial activity were observed. All muscle fibers were labeled for MHC I.

Atorvastatin did not promote significant changes in the expression of genes related to mitochondrial, oxidative, insulin, lipid, and fibrogenic pathways in the muscle tissues of DM and ASS patients with dyslipidemia. Atorvastatin did not also promote histological and histochemical changes in muscle tissues. Our results reinforce the safety of the administration of atorvastatin to treat dyslipidemia in patients with DM and ASS.

Atherosclerosis is the build-up of fatty deposits in the arteries, which is the main underlying cause of cardiovascular diseases and the leading cause of global morbidity and mortality. Current pharmaceutical treatment options are unable to effectively treat the plaque in the later stages of the disease. Instead, they are aimed at resolving the risk factors. Nanomaterials and nanoparticle-mediated therapies have become increasingly popular for the treatment of atherosclerosis due to their targeted and controlled release of therapeutics. In this review, we discuss different types of therapeutics used to treat this disease and focus on the different nanomaterial strategies employed for the delivery of these drugs, enabling the effective and efficient resolution of the atherosclerotic plaque. The ideal nanomaterial strategy for each drug type (e.g. statins, nucleic acids, small molecule drugs, peptides) will be comprehensively discussed.

Coenzyme Q10 is a potent antioxidant and is necessary for energy production in mitochondria. Clinical data have suggested that coenzyme Q10 (CoQ10) has some beneficial effects on liver function. However, these results are equivocal. This systematic review and meta-analysis aimed to clarify the effect of coenzyme Q10 supplementation on the serum concentration of liver function enzymes. We searched the online databases using relevant keywords up to April 2022. Randomized clinical trials (RCTs) investigating the effect of CoQ10, compared with a control group, on serum concentrations of liver enzymes were included. We found a significant reduction following supplementation with CoQ10 on serum concentrations of alanine aminotransferase (ALT) based on 15 effect sizes from 13 RCTs (weighted mean difference [WMD] = -5.33 IU/L; 95% CI: -10.63, -0.03; p = .04), aspartate aminotransferase (AST) based on 15 effect sizes from 13 RCTs (WMD = -4.91 IU/L; 95% CI: -9.35, -0.47; p = .03) and gamma-glutamyl transferase (GGT) based on eight effect sizes from six RCTs (WMD = -8.07 IU/L; 95% CI: -12.82, -3.32; p = .001; I 2 = 91.6%). However, we found no significant effects of CoQ10 supplementation on alkaline phosphatase concentration (WMD = 1.10 IU/L; 95% CI: -5.98, 8.18; p = .76). CoQ10 supplementation significantly improves circulating ALT, AST, and GGT levels; therefore, it might positively affect liver function. Further high-quality RCTs with more extended intervention periods and larger sample sizes are recommended to confirm our results.

Humans operating in extreme environments often conduct their operations at the edges of the limits of human performance. Sometimes, they are required to push these limits to previously unattained levels. As a result, their margins for error in execution are much smaller than that found in the general public. These same small margins for error that impact execution may also impact risk, safety, health, and even survival. Thus, humans operating in extreme environments have a need for greater refinement in their preparation, training, fitness, and medical care. Precision medicine (PM) is uniquely suited to address the needs of those engaged in these extreme operations because of its depth of molecular analysis, derived precision countermeasures, and ability to match each individual (and his or her specific molecular phenotype) with any given operating context (environment). Herein, we present an overview of a systems approach to PM in extreme environments, which affords clinicians one method to contextualize the inputs, processes, and outputs that can form the basis of a formal practice. For the sake of brevity, this overview is focused on molecular dynamics, while providing only a brief introduction to the also important physiologic and behavioral phenotypes in PM. Moreover, rather than a full review, it highlights important concepts, while using only selected citations to illustrate those concepts. It further explores, by demonstration, the basic principles of using functionally characterized molecular networks to guide the practical application of PM in extreme environments. At its core, PM in extreme environments is about attention to incremental gains and losses in molecular network efficiency that can scale to produce notable changes in health and performance. The aim of this overview is to provide a conceptual overview of one approach to PM in extreme environments, coupled with a selected suite of practical considerations for molecular profiling and countermeasures.

Ηypercholesterolemia/hyperlipidemia in conjunction with oxidative stress and inflammatory processes contribute synergistically to the pathogenesis of atherosclerosis. We hereby evaluated the antiatherosclerotic effect of the multi-target derivative 4-methyl-2-(10H-phenothiazin-3-yl)morpholin-2-ol hydrobromide 1 in apoE^-/- mice; compound 1 is a potent antihyperlipidemic agent acting through Squalene Synthase inhibition, while it has exhibited an outstanding antioxidant and anti-inflammatory activity in various experimental animal models. The new analogue was evaluated in terms of its antiatherosclerotic/antioxidant effect in the ApoE^-/- transgenic mouse model. Its toxicity profile was also assessed by measuring the levels of four sensitive indicators of liver toxicity. Prolonged administration of 1 in ApoE^-/- mice fed with a western-type (wt) diet efficiently reduced the aortic atheromatic lesions, an effect that took place through a cholesterol lowering independent manner. In addition, 1 displayed a significant reduction not only of glucose but also of oxidative stress levels, while it did not cause any toxicity. To the best of our knowledge this is the first time that the antiatherosclerotic effect of a Squalene Synthase inhibitor is studied in this specific atherosclerosis mouse model. As a result, compound 1 may serve as a promising starting point towards developing new bioactive analogues against the onset and subsequent development of atherosclerosis.

Diabetes is one of the most common chronic ailments; its incidence has reached epidemic proportions in the 21st century. Diabetes significantly increases micro and macrovascular complications, which are effectively managed with statins. Therefore, statins' pharmacokinetics, pharmacodynamics, and pharmacogenetics have been extensively studied. Although statins act as a keystone in preventing cardiovascular complications, at the same time, they pose a threat to the quality of life of diabetics due to the resulting muscular side effects. This article summarizes the prevalence, clinical manifestations, pathophysiology, and risk factors of statin-induced myopathy in diabetic patients. Among the diverse predisposing risk factors, the primary variables identified for causing myopathy in diabetic patients include age, gender, ethnicity, duration and severity of illness, comorbid conditions, level of physical activity, alcohol use, cholecalciferol (vitamin D3) levels, type and dose of statins, and anti-diabetic drugs or other drugs used concomitantly. In addition, cardiovascular risk quotients also potentially impact diabetic patients making them more vulnerable to developing myopathy from statins. Therefore, this study highlights the importance of managing statin-associated myopathic side effects by providing consensus guidelines on diagnostic, monitoring, and treatment strategies. We also discussed statins' prognostic value in reducing cardiovascular events in diabetic individuals.

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.

Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitable process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevalonate pathway like farnesyl pyrophosphate and coenzyme Q₁₀ (CoQ₁₀). The latter is by far the most important co-factor and co-enzyme required for efficient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ₁₀ has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia.. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintaining CoQ₁₀ levels in conditions of dyslipidemia. Furthermore, this review disscusses the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway, more importantly, their ability to block cholesterol while maintaining CoQ₁₀ biosynthesis to protect against the destructive complications of dyslipidemia.

Previous meta-analyses have suggested that the effects of coenzyme Q10 (CoQ10) on lipid profiles remain debatable. Additionally, no meta-analysis has explored the optimal intake of CoQ10 for attenuating lipid profiles in adults.

This study conducted a meta-analysis to determine the effects of CoQ10 on lipid profiles and assess their dose-response relationships in adults.

Databases (Web of Science, PubMed/Medline, Embase, and the Cochrane Library) were systematically searched until August 10, 2022. The random effects model was used to calculate the mean differences (MDs) and 95% CI for changes in circulating lipid profiles. The novel single-stage restricted cubic spline regression model was applied to explore nonlinear dose-response relationships.

Fifty randomized controlled trials with a total of 2794 participants were included in the qualitative synthesis. The pooled analysis revealed that CoQ10 supplementation significantly reduced total cholesterol (TC) (MD -5.53 mg/dL; 95% CI -8.40, -2.66; I2 = 70%), low-density lipoprotein cholesterol (LDL-C) (MD -3.03 mg/dL; 95% CI -5.25, -0.81; I2 = 54%), and triglycerides (TGs) (MD -9.06 mg/dL; 95% CI -14.04, -4.08; I2 = 65%) and increased high-density lipoprotein cholesterol (HDL-C) (MD 0.83 mg/dL; 95% CI 0.01, 1.65; I2 = 82%). The dose-response analysis showed an inverse J-shaped nonlinear pattern between CoQ10 supplementation and TC in which 400-500 mg/day CoQ10 largely reduced TC (χ2 = 48.54, P < .01).

CoQ10 supplementation decreased the TC, LDL-C, and TG levels, and increased HDL-C levels in adults, and the dosage of 400 to 500 mg/day achieved the greatest effect on TC.

The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, ClC-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle ClC-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored ClC-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered ClC-a expression. Taken together, these results may indicate the potential role of ClC-a inhibition in statin-associated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.