RESUMO
Calcific Aortic Valve Disease (CAVD) is a fibrocalcific disease. Lipoproteins and oxidized phospholipids play a substantial role in CAVD; the level of Lp(a) has been shown to accelerate the progression of valve calcification. Indeed, oxidized phospholipids carried by Lp(a) into the aortic valve stimulate endothelial dysfunction and promote inflammation. Inflammation and growth factors actively promote the synthesis of the extracellular matrix (ECM) and trigger an osteogenic program. The accumulation of ECM proteins promotes lipid adhesion to valve tissue, which could initiate the osteogenic program in interstitial valve cells. Statin treatment has been shown to have the ability to diminish the death rate in subjects with atherosclerotic impediments by decreasing the serum LDL cholesterol levels. However, the use of HMG-CoA inhibitors (statins) as cholesterol-lowering therapy did not significantly reduce the progression or the severity of aortic valve calcification. However, new clinical trials targeting Lp(a) or PCSK9 are showing promising results in reducing the severity of aortic stenosis. In this review, we discuss the implication of lipids in aortic valve calcification and the current findings on the effect of lipid-lowering therapy in aortic stenosis.
RESUMO
BACKGROUND: Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis. METHODS: Rats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls. RESULTS: The bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31. CONCLUSIONS: SPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.
Assuntos
Adrenomedulina/análogos & derivados , Bleomicina/toxicidade , Endotélio Vascular/metabolismo , Hipertensão Pulmonar/metabolismo , Fragmentos de Peptídeos/metabolismo , Fibrose Pulmonar/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adrenomedulina/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Endotélio Vascular/diagnóstico por imagem , Endotélio Vascular/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico por imagem , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Compostos Radiofarmacêuticos/metabolismo , Ratos , Ratos WistarRESUMO
AIMS: Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model. METHODS AND RESULTS: HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-ß), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation. CONCLUSIONS: PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-ß, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.
Assuntos
Acetatos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Pulmonar/prevenção & controle , Hipertrofia Ventricular Direita/prevenção & controle , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Células Cultivadas , Modelos Animais de Doenças , Endotelina-1/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Fosforilação , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/fisiopatologia , Ratos Wistar , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/metabolismo , Disfunção Ventricular Direita/fisiopatologiaRESUMO
AIMS: Calcific aortic valve stenosis (CAVS) is characterized by a fibrocalcific process. Studies have shown an association between CAVS and the activation of platelets. It is believed that shear stress associated with CAVS promotes the activation of platelets. However, whether platelets actively participate to the mineralization of the aortic valve (AV) and the progression of CAVS is presently unknown. To identify the role of platelets into the pathobiology of CAVS. METHODS AND RESULTS: Explanted control non-mineralized and mineralized AVs were examined by scanning electron microscope (SEM) for the presence of activated platelets. In-depth functional assays were carried out with isolated human valve interstitial cells (VICs) and platelets as well as in LDLR-/- apoB100/100 IGFII (IGFII) mice. Scanning electron microscope and immunogold markings for glycoprotein IIb/IIIa (GPIIb/IIIa) revealed the presence of platelet aggregates with fibrin in endothelium-denuded areas of CAVS. In isolated VICs, collagen-activated platelets induced an osteogenic programme. Platelet-derived adenosine diphosphate induced the release of autotaxin (ATX) by VICs. The binding of ATX to GPIIb/IIIa of platelets generated lysophosphatidic acid (LysoPA) with pro-osteogenic properties. In IGFII mice with CAVS, platelet aggregates were found at the surface of AVs. Administration of activated platelets to IGFII mice accelerated the development of CAVS by 2.1-fold, whereas a treatment with Ki16425, an antagonist of LysoPA receptors, prevented platelet-induced mineralization of the AV and the progression of CAVS. CONCLUSIONS: These findings suggest a novel role for platelets in the progression of CAVS.
Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/patologia , Plaquetas/metabolismo , Calcinose/metabolismo , Osteogênese , Animais , Valva Aórtica/metabolismo , Valva Aórtica/ultraestrutura , Apolipoproteína B-100/metabolismo , Progressão da Doença , Humanos , Integrina beta3/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos , Microscopia Eletrônica de Varredura/métodos , Diester Fosfórico Hidrolases/metabolismo , Glicoproteína IIb da Membrana de Plaquetas/metabolismoRESUMO
INTRODUCTION: Aortic valve bioprostheses, which do not mandate chronic anticoagulation, are prone to structural valve degeneration (SVD). The processes involved in SVD are likely multifactorial. We hypothesized that inflammation and macrophage activation could be involved in SVD. METHODS: In 203 patients with an aortic valve bioprosthesis, we evaluated the association between the macrophage activation marker soluble CD14 (sCD14) and SVD. RESULTS: After a mean follow-up of 8⯱â¯3â¯years, 42 (21%) patients developed SVD. Patients with SVD had higher peak (44⯱â¯13â¯mmHg vs. 25⯱â¯12â¯mmHg, pâ¯<â¯.0001) and mean (24⯱â¯7â¯mmHg vs. 12⯱â¯5â¯mmHg, pâ¯<â¯.0001) transprosthetic gradients. On univariable analysis, low-density lipoprotein cholesterol (LDL) and sCD14 were associated with SVD. After correction for covariates, sCD14 (OR: 1.12, 95%CI: 1.02-1.23, pâ¯=â¯.01) remained independently associated with SVD. In turn, sCD14 was associated with the HOMA index and high-density lipoprotein (HDL) level. Patients with a metabolic syndrome (MetS) had higher level of sCD14. In a model corrected for age, sex, HOMA and HDL, the MetS remained independently associated with sCD14 levels (ßâ¯=â¯0.65, SEâ¯=â¯0.30, pâ¯=â¯.03). CONCLUSION: Circulating level of sCD14 is an independent predictor of SVD. In turn, patients with MetS have higher sCD14 levels.