Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms?

Muntean, Daniela-Lucia; Thompson, Paul D.; Catapano, Alberico L.; Stasiołek, Mariusz; Fabiś, Jarosław; Muntner, Paul; Şerban, Corina; Banach, Maciej

doi:10.1016/j.drudis.2016.09.001

Cited by 74 publications

(54 citation statements)

References 124 publications

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“…The strengths of the current study include measuring vitamin D levels in patients before and after statin and placebo therapy, and confirming SAMS with a cross-over, placebo-controlled study design. This confirmation protocol yielded a similar percent of patients testing positive for SAMS as a recent clinical trial utilizing an almost identical design (14), but nonetheless the lack of sensitive biomarkers for SAMS still limits conclusive diagnostic capabilities (33). …”

Section: Discussionmentioning

confidence: 94%

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

et al. 2017

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Background and aims Low vitamin D (VITD) may contribute to statin-associated muscle symptoms (SAMS). We examined the influence of baseline and change in VITD in patients with verified SAMS. Methods SAMS was verified in 120 patients with prior statin muscle complaints using 8-week randomized, double-blind crossover trials of simvastatin (SIMVA) 20 mg/d and placebo. 25 (OH)vitamin D was measured at each phase of the trial. Results Forty-three patients (35.8%) experienced muscle pain on SIMVA but not placebo, exhibiting confirmed SAMS. VITD (mean ± standard deviation) prior to SIMVA treatment were not different between patients who did (31.7 ± 12.1 ng/mL, n=43) or did not (31.6 ± 10.3 ng/mL, n=77) develop SAMS and did not predict SAMS (p=0.96). The change in VITD with SIMVA treatment was not different between patients with and without SAMS (0.3 ± 5.9 vs. 0.2±8.3 ng/mL, respectively) and did not predict SAMS (p=0.96). The proportion of patients classified as VITD deficient (<20 ng/mL) did not differ between patients with (n=16) and without (n=10) SAMS (χ2=1.45; p=0.23), nor did the proportion of patients classified as VITD insufficient (<30 ng/mL) (n=42 vs. 48; χ2<0.01 and p=0.94). Both baseline and on-statin VITD were inversely related to the change in creatine kinase (CK) with statin therapy (p=0.01 and 0.02, respectively), independent of SAMS (p=0.36 and 0.35). Conclusions Baseline VITD, VITD deficiency/insufficiency and changes in VITD with statin therapy do not predict SAMS in patients with rigorously verified SAMS. However, low VITD may exacerbate statin-induced muscle injury and could contribute to SAMS development with a longer duration of statin treatment.

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Section: Discussionmentioning

confidence: 94%

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

et al. 2017

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“…The use of more biomarkers is warranted for diagnosis, as this allows to reduce possible errors. This can be important for clinicians who must decide whether or not continue statin therapy in patients presenting myalgia, so to avoid the risk of life-threatening rhabdomyolysis (Gluba-Brzozka et al, 2016; Muntean et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

Risk of Myopathy in Patients in Therapy with Statins: Identification of Biological Markers in a Pilot Study

et al. 2017

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Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. Our previous preclinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl). An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability. These effects can be detrimental for muscle function leading to drug-induced myopathy. Our goal is to study the causes of statin-induced muscle side effects in patients at the aim to identify biological markers useful to prevent and counteract statin-induced muscle damage. We examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs. Western Blot (WB) analysis showed a 40% reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type. Real-time PCR analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting post-transcriptional modification. The mRNA expression of a series of genes was also evaluated. MuRF-1 was increased in accord with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit. Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation. In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration. Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggests mitochondrial biogenesis. Thus, the reduction of ClC-1 protein and consequent sarcolemma hyperexcitability together with energy deficiency appear to be among the most important alterations to be associated with statin-related risk of myopathy in humans. Thus, it may be important to avoid statin treatment in pathologies characterized by energy deficit and chloride channel malfunction. This study validates the measure of ClC-1 expression as a reliable clinical test for assessing statin-dependent risk of myopathy.

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“…But a considerable number of patients throughout the world are intolerant to statins due to the adverse events just like myopathy and hepatotoxicity [29, 30]. Previous study revealed many best-selling and commonly taken drugs (including statins) target genes were rhythmic expressions which controlled by core clock genes [31].…”

Section: Discussionmentioning

confidence: 99%

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells

Lin

Tang

et al. 2017

Lipids Health Dis

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BackgroundThe clock genes are involved in regulating cardiovascular functions, and their expression disorders would lead to circadian rhythm disruptions of clock-controlled genes (CCGs), resulting in atherosclerotic plaque formation and rupture. Our previous study revealed the rhythmic expression of clock genes were attenuated in human plaque-derived vascular smooth muscle cells (PVSMCs), but failed to detect the downstream CCGs expressions and the underlying molecular mechanism. In this study, we examined the difference of CCGs rhythmic expression between human normal carotid VSMCs (NVSMCs) and PVSMCs. Furthermore, we compared the cholesterol and triglycerides levels between two groups and the link to clock genes and CCGs expressions.MethodsSeven health donors’ normal carotids and 19 carotid plaques yielded viable cultured NVSMCs and PVSMCs. The expression levels of target genes were measured by quantitative real-time PCR and Western-blot. The intracellular cholesterol and triglycerides levels were measured by kits.ResultThe circadian expressions of apoptosis-related genes and fibrinolytic-related genes were disordered. Besides, the cholesterol levels were significant higher in PVSMCs. After treated with cholesterol or oxidized low density lipoprotein (ox-LDL), the expressions of clock genes were inhibited; and the rhythmic expressions of clock genes, apoptosis-related genes and fibrinolytic-related genes were disturbed in NVSMCs, which were similar to PVSMCs.ConclusionThe results suggested that intracellular high cholesterol content of PVSMCs would lead to the disorders of clock genes and CCGs rhythmic expressions. And further studies should be conducted to demonstrate the specific molecular mechanisms involved.

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Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms?

Cited by 74 publications

References 124 publications

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

Risk of Myopathy in Patients in Therapy with Statins: Identification of Biological Markers in a Pilot Study

Intracellular high cholesterol content disorders the clock genes, apoptosis-related genes and fibrinolytic-related genes rhythmic expressions in human plaque-derived vascular smooth muscle cells

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