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Pharmacological Reports : PR 2011Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for... (Review)
Review
Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.
Topics: Animals; Creatine Kinase; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Muscular Diseases; Myositis; Rhabdomyolysis
PubMed: 22001973
DOI: 10.1016/s1734-1140(11)70601-6 -
Journal of Neuromuscular Diseases 2018Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of... (Review)
Review
Anti-HMGCR myopathy was first recognized and characterized in patients with a history of statin exposure and immune-mediated necrotizing myopathy. After the discovery of anti-HMGCR autoantibodies, several international groups identified and characterized more patients, expanding the phenotypic spectrum of this disease to include pediatric patients and young adults without statin exposure and those with a chronic myopathy resembling limb-girdle muscular dystrophy. We provide a summary of clinical findings, pathologic features, muscle imaging, and immunogenetic risk factors of the disease. We also discuss the current treatment strategies and approaches to monitoring the therapeutic response. Lastly, we briefly summarize the current understanding of the pathophysiology of the disease and postulate a model for autoimmunity initiation and propagation in this disease.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Muscular Diseases; Myositis
PubMed: 29480216
DOI: 10.3233/JND-170282 -
International Journal of Molecular... Oct 2021Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the... (Review)
Review
Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.
Topics: Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Muscular Diseases; Prevalence
PubMed: 34769118
DOI: 10.3390/ijms222111687 -
Arquivos de Neuro-psiquiatria May 2022Idiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of... (Review)
Review
Idiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of acute or subacute onset of proximal weakness. Extramuscular manifestations may occur, including involvement of the lungs, skin, and joints. Classically, the diagnosis used to be made based on the creatine kinase level increase, abnormalities in electroneuromyography and presence of inflammatory infiltrates in the muscle biopsy. Recently, the importance of autoantibodies has increased, and now they may be identified in more than half of IIM patients. The continuous clinicoseropathological improvement in IIM knowledge has changed the way we see these patients and how we classify them. In the past, only polymyositis, dermatomyositis and inclusion body myopathy were described. Currently, immune-mediated necrotizing myopathy, overlap myositis and antisynthetase syndrome have been considered the most common forms of IIM in clinical practice, increasing the spectrum of classification. Patients previously considered to have polymyositis, in fact have these other forms of seropositive IIM. In this article, we reviewed the new concepts of classification, a practical way to make the diagnosis and how to plan the treatment of patients suffering from IIM.
Topics: Autoantibodies; Dermatomyositis; Humans; Muscular Diseases; Myositis; Neurologists; Polymyositis
PubMed: 35976321
DOI: 10.1590/0004-282X-ANP-2022-S131 -
International Journal of Molecular... Mar 2023Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and... (Review)
Review
Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, and , are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients' derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies.
Topics: Humans; Collagen Type VI; Muscular Dystrophies; Muscular Diseases; Contracture; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital
PubMed: 36982167
DOI: 10.3390/ijms24065095 -
Journal of Atherosclerosis and... Mar 2019Statins are the main treatment for hypercholesterolemia and the cornerstone of atherosclerotic cardiovascular disease prevention. Many patients taking statins report... (Review)
Review
Statins are the main treatment for hypercholesterolemia and the cornerstone of atherosclerotic cardiovascular disease prevention. Many patients taking statins report muscle-related symptoms, one of the most important causes of statin treatment discontinuation, which is associated with an increased risk of cardiovascular events. Therefore, it is important to identify patients who are truly statin intolerant to avoid unnecessary discontinuation of this beneficial treatment. Some studies indicate that not all muscle complaints are caused by statins, and most patients can tolerate a statin upon re-challenge, down-titration of dose, or switching to another statin. In this paper, we review the definitions of statin intolerance and approaches to reducing cardiovascular risk among individuals reporting statin-associated muscle symptoms.
Topics: Animals; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemias; Muscular Diseases
PubMed: 30662020
DOI: 10.5551/jat.RV17030 -
Neurotherapeutics : the Journal of the... Oct 2018Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been... (Review)
Review
Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core-rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.
Topics: Animals; Humans; Muscular Diseases; Ryanodine Receptor Calcium Release Channel
PubMed: 30406384
DOI: 10.1007/s13311-018-00677-1 -
Physiological Reviews Jul 2015Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term... (Review)
Review
Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.
Topics: Animals; Biomechanical Phenomena; Critical Illness; Disease Models, Animal; Energy Metabolism; Excitation Contraction Coupling; Humans; Inflammation Mediators; Intensive Care Units; Ion Channels; Mechanotransduction, Cellular; Molecular Motor Proteins; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Polyneuropathies; Predictive Value of Tests; Risk Factors
PubMed: 26133937
DOI: 10.1152/physrev.00028.2014 -
Neurologic Clinics Aug 2014Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical... (Review)
Review
Myopathies are a heterogeneous group of disorders that can be challenging to diagnose. This review provides a diagnostic approach based predominantly on the clinical history and neurologic examination. Laboratory testing that can be used to confirm the suspected diagnosis based on this pattern recognition approach is also discussed. Careful consideration of the distribution of muscle weakness and attention to common patterns of involvement in the context of other aspects of the neurologic examination and laboratory evaluation should assist the clinician in making a timely and accurate diagnosis and can sometimes minimize the expense of further testing.
Topics: Humans; Medical History Taking; Muscular Diseases; Neurologic Examination
PubMed: 25037080
DOI: 10.1016/j.ncl.2014.04.008 -
Orphanet Journal of Rare Diseases Aug 2013RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated...
BACKGROUND
RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.
METHODS
In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.
RESULTS
Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.
CONCLUSIONS
These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.
Topics: Cohort Studies; Female; Genes, Recessive; Genetic Association Studies; Humans; Male; Muscular Diseases; Mutation; Ryanodine Receptor Calcium Release Channel; Severity of Illness Index
PubMed: 23919265
DOI: 10.1186/1750-1172-8-117