title: Statins in heart failure--With preserved and reduced ejection fraction. An update.
abstract: HMG-CoA reductase inhibitors or statins beyond their lipid lowering properties and mevalonate inhibition exert also their actions through a multiplicity of mechanisms. In heart failure (HF) the inhibition of isoprenoid intermediates and small GTPases, which control cellular function such as cell shape, secretion and proliferation, is of clinical significance. Statins share also the peroxisome proliferator-activated receptor pathway and inactivate extracellular-signal-regulated kinase phosphorylation suppressing inflammatory cascade. By down-regulating Rho/Rho kinase signaling pathways, statins increase the stability of eNOS mRNA and induce activation of eNOS through phosphatidylinositol 3-kinase/Akt/eNOS pathway restoring endothelial function. Statins change also myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channel activity and inhibit sympathetic nerve activity suppressing arrhythmogenesis. Less documented evidence proposes also that statins have anti-hypertrophic effects - through p21ras/mitogen activated protein kinase pathway - which modulate synthesis of matrix metalloproteinases and procollagen 1 expression affecting interstitial fibrosis and diastolic dysfunction. Clinical studies have partly confirmed the experimental findings and despite current guidelines new evidence supports the notion that statins can be beneficial in some cases of HF. In subjects with diastolic HF, moderately impaired systolic function, low b-type natriuretic peptide levels, exacerbated inflammatory response and mild interstitial fibrosis evidence supports that statins can favorably affect the outcome. Under the lights of this evidence in this review article we discuss the current knowledge on the mechanisms of statins' actions and we link current experimental and clinical data to further understand the possible impact of statins' treatment on HF syndrome.
authors.affiliation: 1st Cardiology Department, University of Athens Medical School, "Hippokration" Hospital, Athens, Greece. Electronic address: drtousoulis@hotmail.com.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tousoulis
authors.affiliation: 1st Cardiology Department, University of Athens Medical School, "Hippokration" Hospital, Athens, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Oikonomou
authors.affiliation: 1st Cardiology Department, University of Athens Medical School, "Hippokration" Hospital, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Siasos
authors.affiliation: 1st Cardiology Department, University of Athens Medical School, "Hippokration" Hospital, Athens, Greece.
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Stefanadis
mesh_terms: D006321:Heart / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009206:Myocardium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013318:Stroke Volume / Q000187:drug effects* / Q000502:physiology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: C reactive protein; CAD; CRP; Diastolic function; EF; ERK; HF; HMG-CoA reductase inhibitors; Heart failure; IL-; Inflammation; LV; MMPs; Mortality; NADPH; NF-κΒ; NO; PRAP; Statins; TNFα; coronary artery disease; eNOS; ejection fraction; endothelial NO synthase; extracellular-signal-regulated kinase; heart failure; interleukin; left ventricle; matrix metalloproteinases; nicotinamide adenine dinucleotide phosphate; nitric oxide; nuclear factor Kappa B; peroxisome proliferator-activated receptor; tumor necrosis factor alpha