@article{3021241,
    title = "Statins’ Withdrawal Induces Atherosclerotic Plaque Destabilization in Animal Model—A “Rebound” Stimulation of Inflammation",
    author = "Stasinopoulou, M. and Kadoglou, N.P.E. and Christodoulou, E. and Paronis, E. and Kostomitsopoulos, N.G. and Valsami, G. and Liapis, C.D. and Kakisis, J.",
    journal = "Journal of Cardiovascular Pharmacology and Therapeutics",
    year = "2019",
    volume = "24",
    number = "4",
    pages = "377-386",
    publisher = "SAGE Publications Ltd",
    issn = "1074-2484, 1940-4034",
    doi = "10.1177/1074248419838499",
    keywords = "atorvastatin;  biological marker;  collagen;  gelatinase B;  hydroxymethylglutaryl coenzyme A reductase inhibitor;  monocyte chemotactic protein 1;  stromelysin;  tumor necrosis factor;  antiinflammatory agent;  atorvastatin;  autacoid;  collagen;  hydroxymethylglutaryl coenzyme A reductase inhibitor, animal experiment;  animal model;  animal tissue;  antiinflammatory activity;  aortic tissue;  apolipoprotein E knockout mouse;  Article;  atherosclerotic plaque;  concentration (parameter);  connective tissue;  controlled study;  drug effect;  drug withdrawal;  immunohistochemistry;  lipid diet;  macrophage;  male;  mouse;  nonhuman;  priority journal;  random sample;  tissue section;  animal;  aorta;  aortic disease;  atherosclerosis;  disease exacerbation;  disease model;  drug administration;  drug effect;  genetics;  human;  metabolism;  pathology;  rupture;  signal transduction;  time factor, Animals;  Anti-Inflammatory Agents;  Aorta;  Aortic Diseases;  Atherosclerosis;  Atorvastatin;  Collagen;  Disease Models, Animal;  Disease Progression;  Drug Administration Schedule;  Humans;  Hydroxymethylglutaryl-CoA Reductase Inhibitors;  Inflammation Mediators;  Mice, Knockout, ApoE;  Plaque, Atherosclerotic;  Rupture, Spontaneous;  Signal Transduction;  Time Factors",
    abstract = "Background: To evaluate the impact of atorvastatin discontinuation on the progression and stability of atherosclerotic plaques in a valid animal model of atherosclerosis. Methods: Seventy ApoE−/− male mice fed with high-fat diet were randomly assigned into: (1) long-term intervention groups: (i) ATL, received atorvastatin for 12 weeks, (ii) CO-12W, control received vehicle for 12 weeks, (iii) ATW-6W, received atorvastatin for 6 weeks which was withdrawn for another 6 weeks. (2) Short-term intervention groups: (i) ATS received atorvastatin for 6 weeks, (ii) CO-6W, control receiving vehicle for 6 weeks, (iii) ATW-3D, ATW-7D, received atorvastatin for 6 weeks which was withdrawn for 3 days and 7 days, respectively. Daily dosage of atorvastatin was 20 mg/kg. Mice were killed and aortic samples were obtained for histological evaluation. Results: Long-term atorvastatin treatment (ATL) induced atherosclerosis regression and stabilization compared to control (P <.05). Atorvastatin’s withdrawal was associated with acute (ATW-3D) reduction in connective tissue and collagen contents within plaques compared to ATS (P <.05). Those changes were almost restored after a while (ATW-7D) and started appearing again after longer cessation (ATW-6W). Moreover, atorvastatin withdrawal induced shortly (ATW-3D) a peak in inflammatory markers (macrophages, MCP-1, tumor necrosis factor-α) and matrix metalloproteinases (MMP-3, MMP-9) concentrations within plaques, which sustained but to a lesser extent along time (ATW-7D, ATW-6W). Conclusion: Short-term withdrawal of atorvastatin seems to compromise its antiatherosclerotic effects, leading to an unstable phenotype of the atherosclerotic lesions and a rebound increase in inflammatory mediators. The clinical relevance of our findings requires further investigation. © The Author(s) 2019."
}