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Artigo em Inglês | MEDLINE | ID: mdl-32053090


BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. OBJECTIVE: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. METHODS: We performed a narrative review of the PCSK9 inhibitor class of drugs Results: Current data indicates that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. CONCLUSION: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Post-marketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

J Hypertens ; 34(3): 452-63; discussion 463, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26682783


OBJECTIVES: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. METHODS: Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18-32  µm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. RESULTS: EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels. CONCLUSION: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function.

Arteríolas/fisiopatologia , Fatores Biológicos/metabolismo , Dieta Hiperlipídica , Artérias Mesentéricas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , RNA Mensageiro/metabolismo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Dieta , Regulação para Baixo , Feminino , Hipertensão , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Óxido Nítrico , Óxido Nítrico Sintase Tipo III/genética , Norepinefrina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia