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1.
Eur Heart J ; 35(38): 2655-62, 2014 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-24755006

RESUMO

AIMS: We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. 'paradoxical' low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG<40 mmHg with the AVW of patients with NF and MG≥40 mmHg. METHODS AND RESULTS: We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) ≤ 35 mL/m(2)] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m(2)) with MG ≥ 40 mmHg (NF-HG group). Despite a much lower MG (29 ± 7 vs. 53 ± 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 ± 0.12 vs. 0.69 ± 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63-2.50) vs. 2.60 (1.66-3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63-2.50) vs. 2.30 (1.58-3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73-3.61) vs. 2.60 (2.10-3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non-consecutive patients (n = 150, Cohort B) with NF and concordant Doppler-echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. CONCLUSION: The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low-gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Idoso , Valva Aórtica/anormalidades , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/cirurgia , Doença da Válvula Aórtica Bicúspide , Estudos de Coortes , Ecocardiografia Doppler , Feminino , Doenças das Valvas Cardíacas/patologia , Humanos , Masculino , Valva Mitral/patologia , Tamanho do Órgão/fisiologia , Caracteres Sexuais , Volume Sistólico/fisiologia , Valva Tricúspide/patologia
2.
Eur J Pharmacol ; 689(1-3): 139-46, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22659116

RESUMO

Calcific aortic valve disease is the most common heart valve disorder. So far, there is no medical treatment for calcific aortic valve disease. The expression of ectonucleotidases, which metabolize nucleotides into phosphate products, may influence the calcification of the aortic valve. In this study, we investigated if the administration of an ectonucleotidase inhibitor, ARL67156 (6-N,N-Diethyl-D-ß,γ-dibromomethyleneATP trisodium salt), may prevent the calcification of the aortic valve in the warfarin-induced mineralization rat model. Male Wistar rats were treated with warfarin or warfarin+ARL67156 for 28 days. All rats had comprehensive Doppler-echocardiographic studies at 28 day. A gene profiling of ectonucleotidases expressed in aortas of rats was documented by quantitative real-time PCR. The amount of calcium was determined by quantitative method and von Kossa staining. Ex vivo cultures of rat aortas were also used to further assess the effect of ARL67156 on the calcifying process and Akt signaling. Mineralization of the aorta/aortic valve was documented in warfarin-treated rats and was accompanied by the development of aortic stenosis. These changes were paralleled by an increased of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). Administration of the ectonucleotidase inhibitor, ARL67156 prevented the development of aortic stenosis by lowering the level of apoptosis and mineralization of the aortic valve/aorta. In addition, ARL67156 normalized the level of pAkt, an important kinase involved in the survival pathway. Inhibition of ectonucleotidase activity prevented the development of calcific aortic valve disease in a rat model. On that account, ectonucleotidase may represent a novel target in the treatment of calcific aortic valve disease.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Estenose da Valva Aórtica/prevenção & controle , Calcinose/prevenção & controle , Pirofosfatases/antagonistas & inibidores , Varfarina/toxicidade , Adenosina Trifosfatases/farmacologia , Adenosina Trifosfatases/uso terapêutico , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/uso terapêutico , Animais , Estenose da Valva Aórtica/induzido quimicamente , Estenose da Valva Aórtica/enzimologia , Calcinose/induzido quimicamente , Calcinose/enzimologia , Masculino , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Ratos , Ratos Wistar , Resultado do Tratamento
3.
J Mol Cell Cardiol ; 52(5): 1191-202, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22366713

RESUMO

Calcific aortic valve disease (CAVD) is a disorder related to progressive mineralization of valvular tissue that is a leading cause of heart disease. Thus far, there is no medical treatment to prevent the mineralization of aortic valves. It is generally thought that pathologic mineralization is linked to apoptosis of vascular cells. However, the role of apoptosis during mineralization as well as the survival signals for valvular interstitial cells (VICs), the main cellular component of aortic valves, remains to be identified. Here, through several lines of evidence, we show that bioavailability of extracellular ATP is a signal which determines survival or apoptosis of VICs and, in doing so, plays a major role in the development of CAVD. Specifically, in CAVD and in VIC cultures undergoing mineralization, we found a high level of the ectonucleotidase ENPP1. In addition, a genetic polymorphism in the intron 9 of the ENPP1 gene was associated with CAVD in a case-control cohort as well as with mRNA expression levels of ENPP1 in aortic valves. A high level of ENPP1 in CAVD promoted apoptosis-mediated mineralization of VICs by depleting the extracellular pool of ATP. We then documented that release of ATP by VICs promoted cell survival via the P2Y(2) receptor and the PI3K/Akt signaling pathway. Hence, our results show that level of ENPP1 modulates extracellular concentration of ATP, which is an important survival signal for VICs. These findings may help to develop novel pharmacological treatment for CAVD.


Assuntos
Trifosfato de Adenosina/fisiologia , Valva Aórtica/patologia , Calcinose/metabolismo , Cardiomiopatias/metabolismo , Células Epiteliais/metabolismo , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Trifosfato de Adenosina/metabolismo , Valva Aórtica/metabolismo , Apoptose , Calcinose/patologia , Cardiomiopatias/patologia , Estudos de Casos e Controles , Células Cultivadas , Perfilação da Expressão Gênica , Estudos de Associação Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Polimorfismo de Nucleotídeo Único , Pirofosfatases/metabolismo , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/metabolismo , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Transdução de Sinais , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Análise Serial de Tecidos
4.
Am J Pathol ; 176(6): 2638-45, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20382708

RESUMO

Aortic stenosis (AS) is the most common valvular heart disease, and it is suspected that atherosclerotic mechanisms are involved in the development of this disorder. Therefore, the retention of lipids within the aortic valve may play a role in the pathobiology of AS. In this study, a gene expression microarray experiment was conducted on human aortic valves with and without AS. The expression levels of transcripts encoding proteoglycans and enzymes involved in lipid retention were compared between the two groups. The microarray results were subsequently replicated in a cohort of 87 AS valves and 36 control valves. In addition, the interaction between proteoglycan and lipid-modifying enzyme was documented in isolated valve interstitial cells (VICs). The microarray results indicated that only biglycan (BGN) and phospholipid transfer protein (PLTP) were overexpressed in the AS valves. These results were then confirmed by quantitative PCR. The immunohistochemical analysis revealed a colocalization of BGN, PLTP, and Toll-like receptor-2 (TLR 2) in AS valves. In vitro, we showed that BGN induces the production of PLTP in VICs via the stimulation of TLR 2. Thus, increased accumulation of BGN in AS valves contributes to the production of PLTP via TLR 2. These results suggest that intricate links between valve matrix proteins, inflammation, and lipid retention are involved in the pathobiology of AS.


Assuntos
Estenose da Valva Aórtica/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas de Transferência de Fosfolipídeos/metabolismo , Proteoglicanas/metabolismo , Receptor 2 Toll-Like/metabolismo , Estenose da Valva Aórtica/patologia , Biglicano , Perfilação da Expressão Gênica , Humanos , Análise em Microsséries , Proteínas de Transferência de Fosfolipídeos/genética , Receptor 2 Toll-Like/genética
5.
Int J Cardiol ; 145(3): 444-9, 2010 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19525020

RESUMO

INTRODUCTION: The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS. METHODS: In this study, 36 male patients (age: 61.5±2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines. RESULTS: Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL (r=0.4; p=0.02), AGN (r=0.41; p=0.01), and white blood cells count (r=0.33; p=0.04), whereas it was inversely related to plasma level of adiponectin (r=-.35; p=0.04). After adjustment for covariates, plasma level of ox-LDL (p=0.01) remained significantly associated with SBP (p=0.01). Within the aortic valve, expression of TNF-α was significantly associated with plasma levels of ox-LDL (r=0.58; p=0.03), Ang II (r=0.69; p=0.013), and waist circumference (r=0.60; p=0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II (r=0.51; p=0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-α. CONCLUSION: Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.


Assuntos
Angiotensina II/sangue , Estenose da Valva Aórtica/metabolismo , Lipoproteínas LDL/sangue , Miocardite/metabolismo , Pré-Hipertensão/metabolismo , Adiponectina/sangue , Angiotensina I/sangue , Angiotensinogênio/sangue , Estenose da Valva Aórtica/imunologia , Biomarcadores/sangue , Pressão Sanguínea/fisiologia , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocardite/imunologia , Estresse Oxidativo/imunologia , Pré-Hipertensão/imunologia , Sistema Renina-Angiotensina/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Circunferência da Cintura/fisiologia
6.
Circ Cardiovasc Genet ; 2(5): 489-98, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20031625

RESUMO

BACKGROUND: Calcific aortic valve stenosis (AS) is a major societal and economic burden that is rising after the current shift toward an older population. Understanding the pathobiology of AS is crucial to implementing better preventive and therapeutic options. Research conducted during the past decade clearly points to active molecular and cellular processes involved in disease pathogenesis. However, no genomic approaches were used to identify genes and pathways that are differentially regulated in aortic valves of patients with and without AS. METHODS AND RESULTS: A large-scale quantitative measurements of gene expression was performed on 5 normal and 5 AS valves using Affymetrix GeneChips. A total of 409 and 306 genes were significantly up- and downregulated in AS valves, respectively. The 2 most highly upregulated genes were matrix metalloproteinase 12 and chitinase 3-like 1. The upregulation of these 2 biologically relevant genes in AS was validated by real-time polymerase chain reaction in 38 aortic valves (12 normal and 26 AS). To provide a global biological validation of the whole-genome gene expression analysis, the microarray experiment was repeated in a second set of aortic valves with (n=5) or without (n=5) AS. There was an overrepresentation of small P values among genes claimed significant in the first microarray experiment. A total of 223 genes were replicated (P<0.05 and fold change >1.2), including matrix metalloproteinase 12 and chitinase 3-like 1. CONCLUSIONS: This study reveals many unrecognized genes potentially implicated in the pathogenesis of AS. These new genes were overlaid on known pathological pathways leading to AS to refine our molecular understanding of this disease.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/metabolismo , Calcinose/genética , Perfilação da Expressão Gênica , Idoso , Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/metabolismo , Calcinose/patologia , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos
7.
J Heart Valve Dis ; 14(3): 353-7, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15974530

RESUMO

BACKGROUND AND AIM OF THE STUDY: The calcification of heart valves is associated with valve degeneration and failure, but the mechanisms involved are poorly understood. The presence of lamellar bone has been demonstrated in calcified aortic valves. Since osseous calcification is closely associated with alkaline phosphatase (ALP) activity, it was hypothesized that ALP activity might be implicated in the calcification of isolated leaflet interstitial cells (ICs). METHODS: Human valve leaflet ICs were isolated from transplant-explanted hearts at the time of transplantation (n = 12). RESULTS: Isolated leaflet ICs expressed the fibroblast-specific antigen (100% of cells) and smooth muscle (SM) alpha-actin (70-80% of cells), but osteoblastic markers were not expressed. Cultured ICs did not calcify spontaneously, however when the growth medium was supplemented with beta-glycerophosphate (an organic phosphate) it induced the formation of calcified nodules that expressed osteonectin and ALP, but not SM alpha-actin. Beta-glycerophosphate-induced calcification of ICs showed a time-dependent effect on the calcium content of treated cells over a 14-day period. ALP activity was considerably increased in beta-glycerophosphate-treated ICs, and this correlated with the calcium content (r = 0.5: p = 0.01). Levamisol (an ALP inhibitor) inhibited the beta-glycerophosphate-induced calcification process, as well as the expression of osteoblastic differentiation markers. CONCLUSION: Isolated and cultured leaflet ICs did not calcify spontaneously, though organic phosphate induced the formation of calcified nodules that expressed osteoblastic markers. The calcification of isolated ICs was seen to be dependent on ALP activity.


Assuntos
Fosfatase Alcalina/fisiologia , Valva Aórtica/enzimologia , Calcinose/enzimologia , Doenças das Valvas Cardíacas/enzimologia , Actinas/análise , Fosfatase Alcalina/antagonistas & inibidores , Valva Aórtica/citologia , Valva Aórtica/efeitos dos fármacos , Calcinose/induzido quimicamente , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células do Tecido Conjuntivo/efeitos dos fármacos , Células do Tecido Conjuntivo/enzimologia , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Glicerofosfatos/farmacologia , Humanos , Levamisol/farmacologia , Osteoblastos/efeitos dos fármacos , Osteonectina/análise , Fatores de Tempo
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