RESUMO
Degenerative calcific aortic valve stenosis (CAVS) is a chronic disease whose prevalence has increased over the last decade because of the aging of the general population. CAVS pathogenesis is characterized by complex molecular and cellular mechanisms that promote valve fibro-calcific remodeling. During the first phase, referred to as initiation, the valve undergoes collagen deposition and lipid and immune cell infiltration due to mechanical stress. Subsequently, during the progression phase, the aortic valve undergoes chronic remodeling through osteogenic and myofibroblastic differentiation of interstitial cells and matrix calcification. Knowledge of the mechanisms underlying CAVS development supports the resort to potential therapeutic strategies that interfere with fibro-calcific progression. Currently, no medical therapy has demonstrated the ability to significantly prevent CAVS development or slow its progression. The only treatment available in symptomatic severe stenosis is surgical or percutaneous aortic valve replacement. The aim of this review is to highlight the pathophysiological mechanisms involved in CAVS pathogenesis and progression and to discuss potential pharmacological treatments able to inhibit the main pathophysiological mechanisms of CAVS, including lipid-lowering treatment with lipoprotein(a) as emergent therapeutic target.
Assuntos
Estenose da Valva Aórtica , Calcinose , Humanos , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Calcinose/tratamento farmacológico , Calcinose/prevenção & controle , LipídeosRESUMO
Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. Age and congenital bicuspid aortic valve morphology are important and unalterable risk factors for CAVD, whereas additional risk is conferred by elevated blood pressure and plasma lipoprotein(a) levels and the presence of obesity and diabetes mellitus, which are modifiable factors. Genetic and molecular studies have identified that the NOTCH, WNT-ß-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD. Although no medical therapy is effective for reducing or preventing the progression of CAVD, studies have started to identify actionable targets.
Assuntos
Estenose da Valva Aórtica , Calcinose , Humanos , Valva Aórtica , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/metabolismo , Calcinose/prevenção & controle , Calcinose/genéticaRESUMO
The objective of this study was to test the hypothesis that targeting sclerostin would accelerate the progression of aortic valve stenosis. Sclerostin (mouse gene, Sost) is a secreted glycoprotein that acts as a potent regulator of bone remodeling. Antibody therapy targeting sclerostin is approved for osteoporosis but results from a stage III clinical trial showed multiple off-target cardiovascular effects. Wild-type (WT, Sost+/+) and Sost-gene knockout-expression (Null, Sost-/-) mice were generated and maintained to 12 mo of age on a high-cholesterol diet to induce aortic valve stenosis. Mice were examined by echocardiography, histology, and RNAseq. Immortalized valve interstitial cells were developed from each genotype for in vitro studies. Null mice developed a bone overgrowth phenotype, similar to patients with sclerosteosis. Surprisingly, however, WT mice developed hemodynamic signs of aortic valve stenosis, whereas Null mice were unchanged. WT mice had thicker aortic valve leaflets and higher amounts of α-smooth muscle actin, a marker myofibroblast activation and dystrophic calcification, with very little evidence of Runx2 expression, a marker of osteogenic calcification. RNAseq analysis of aortic roots indicated the HOX family of transcription factors was significantly upregulated in Null mice, and valve interstitial cells from Null animals were enriched with Hoxa1, Hoxb2, and Hoxd3 subtypes with downregulated Hoxa7. In addition, Null valve interstitial cells were shown to be less contractile than their WT counterparts. Contrary to our hypothesis, sclerostin targeting prevented hallmarks of aortic valve stenosis and indicates that targeted antibody treatments for osteoporosis may be beneficial for these patients regarding aortic stenosis.NEW & NOTEWORTHY We have found that genetic ablation of the Sost gene (protein: sclerostin) prevents aortic valve stenosis in aged, Western diet mice. This is a new role for sclerostin in the cardiovascular system. To the knowledge of the authors, this is one of the first studies directly manipulating sclerostin in a cardiovascular disease model and the first to specifically study the aortic valve. We also provide a potential new role for Hox genes in cardiovascular disease, noting pan-Hox upregulation in the aortic roots of sclerostin genetic knockouts. The role of Hox genes in postnatal cardiovascular health and disease is another burgeoning field of study to which this article contributes.
Assuntos
Estenose da Valva Aórtica , Calcinose , Osteoporose , Camundongos , Animais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/diagnóstico , Valva Aórtica/metabolismo , Camundongos Knockout , Calcinose/genética , Calcinose/prevenção & controle , Osteoporose/metabolismo , Osteoporose/patologiaRESUMO
AIMS: Tetrahydrobiopterin (BH4) is a critical determinant of the biological function of endothelial nitric oxide synthase. The present study was to investigate the role of valvular endothelial cell (VEC)-derived BH4 in aortic valve calcification. METHODS AND RESULTS: Plasma and aortic valve BH4 concentrations and the BH4:BH2 ratio were significantly lower in calcific aortic valve disease patients than in controls. There was a significant decrease of the two key enzymes of BH4 biosynthesis, guanosine 5'-triphosphate cyclohydrolase I (GCH1) and dihydrofolate reductase (DHFR), in calcified aortic valves compared with the normal ones. Endothelial cell-specific deficiency of Gch1 in Apoe-/- (Apoe-/-Gch1fl/flTie2Cre) mice showed a marked increase in transvalvular peak jet velocity, calcium deposition, runt-related transcription factor 2 (Runx2), dihydroethidium (DHE), and 3-nitrotyrosine (3-NT) levels in aortic valve leaflets compared with Apoe-/-Gch1fl/fl mice after a 24-week western diet (WD) challenge. Oxidized LDL (ox-LDL) induced osteoblastic differentiation of valvular interstitial cells (VICs) co-cultured with either si-GCH1- or si-DHFR-transfected VECs, while the effects could be abolished by BH4 supplementation. Deficiency of BH4 in VECs caused peroxynitrite formation increase and 3-NT protein increase under ox-LDL stimulation in VICs. SIN-1, the peroxynitrite generator, significantly up-regulated alkaline phosphatase (ALP) and Runx2 expression in VICs via tyrosine nitration of dynamin-related protein 1 (DRP1) at Y628. Finally, folic acid (FA) significantly attenuated aortic valve calcification in WD-fed Apoe-/- mice through increasing DHFR and salvaging BH4 biosynthesis. CONCLUSION: The reduction in endothelial-dependent BH4 levels promoted peroxynitrite formation, which subsequently resulted in DRP1 tyrosine nitration and osteoblastic differentiation of VICs, thereby leading to aortic valve calcification. Supplementation of FA in diet attenuated hypercholesterolaemia-induced aortic valve calcification by salvaging BH4 bioavailability.
Assuntos
Estenose da Valva Aórtica , Calcinose , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Apolipoproteínas E/metabolismo , Biopterinas/análogos & derivados , Calcinose/metabolismo , Calcinose/prevenção & controle , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células Endoteliais/metabolismo , GTP Cicloidrolase/metabolismo , Humanos , Camundongos , Ácido Peroxinitroso/metabolismo , Tirosina/metabolismoRESUMO
OBJECTIVES: To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC. METHODS: We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC. RESULTS: The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (ß 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase). CONCLUSIONS: Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Hiperlipoproteinemias , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Lipoproteína(a) , Idoso , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Estenose da Valva Aórtica/prevenção & controle , Calcinose/sangue , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Calcinose/prevenção & controle , Estudos de Coortes , Correlação de Dados , Progressão da Doença , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/tratamento farmacológico , Hiperlipoproteinemias/epidemiologia , Lipoproteína(a)/sangue , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores/métodos , Tomografia Computadorizada Multidetectores/estatística & dados numéricos , Países Baixos/epidemiologia , Prevalência , Tempo para o TratamentoAssuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Hiperlipoproteinemias , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Lipoproteína(a) , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/prevenção & controle , Calcinose/sangue , Calcinose/diagnóstico , Calcinose/prevenção & controle , Progressão da Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/tratamento farmacológico , Lipoproteína(a)/sangue , Lipoproteína(a)/metabolismo , Seleção de Pacientes , Prevenção Secundária/ética , Prevenção Secundária/métodos , Tempo para o TratamentoRESUMO
Aortic stenosis is one of the most common cardiovascular diseases in the world. Extensive work on the underlying pathophysiology responsible for calcific aortic valve disease and its progression to aortic stenosis has described a complex process involving inflammation, lipid deposition, mineralisation, and genetic factors such as elevated lipoprotein(a). With the advancement of gene silencing technology and development of novel therapeutic agents, we may now be closer than ever to having medical therapies that prevent, or at least slow the progression of aortic stenosis. In this review, we highlight the pathophysiology and risk factors of calcific aortic valve disease, along with current, potential, and emerging novel medical therapies. We also provide potential explanations for the failure of statin trials and suggest new avenues for research and new randomised trials in this area.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Conduta do Tratamento Medicamentoso/tendências , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/etiologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/terapia , Calcinose/etiologia , Calcinose/metabolismo , Calcinose/prevenção & controle , Calcinose/terapia , Progressão da Doença , Drogas em Investigação/farmacologia , Terapia Genética/métodos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologiaRESUMO
[Figure: see text].
Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Calcinose/prevenção & controle , Hidrazinas/uso terapêutico , Triazóis/uso terapêutico , Animais , Estenose da Valva Aórtica/tratamento farmacológico , Proteína Axina/metabolismo , Fator de Ligação a CCAAT , Calcinose/tratamento farmacológico , Reposicionamento de Medicamentos , Carioferinas/antagonistas & inibidores , Proteínas Klotho , Camundongos , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Via de Sinalização Wnt , Proteína Exportina 1Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Lipoproteína(a)/sangue , Fatores de Risco de Doenças Cardíacas , Estenose da Valva Aórtica/prevenção & controle , Doença da Artéria Coronariana/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Acidente Vascular Cerebral/prevenção & controleAssuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Calcinose/prevenção & controle , Inibidores da Dipeptidil Peptidase IV , Implante de Prótese de Valva Cardíaca/métodos , Administração dos Cuidados ao Paciente , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/classificação , Inibidores da Dipeptidil Peptidase IV/farmacologia , Progressão da Doença , Cardiopatias/terapia , Humanos , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/normas , Seleção de Pacientes , Medição de Risco , Índice de Gravidade de Doença , Tempo para o Tratamento/ética , Tempo para o Tratamento/normas , Conduta Expectante/métodosRESUMO
Atherosclerosis is the condition of narrowing of arteries due to plaque buildup on the artery walls. Aortic valve calcification (AVC) is one of the reasons of atherosclerosis which leads to narrowing at the opening of the aortic valve which is commonly referred as Aortic valve stenosis (AS). The Rosuvastatin-chitosan (ROS-chitosan) nanoparticles were prepared using ionotropic gelation method. Nanoparticulate formulation was optimized by 3 factor, 2 level full factorial design to find the effect of independent variables on particle size and percentage encapsulation efficiency. Particle size, encapsulation efficiency, scanning electron microscopy, in vitro drug release of nanoparticles was determined. The adult male rabbit of 4-5 months old were chosen for the study. Hypercholesterolemia was induced in experimental animals by administering diet with Cholesterol and Cholic acid (1.25 % and 0.5% respectively.) Blood lipid profile, interleukin 6 levels and histopathological study was performed. Rosuvastatin was found to be significantly effective in lowering the blood lipid levels. It helps to attenuate atherosclerosis as well as calcification of various valve tissues in experimental animals.
Assuntos
Anticolesterolemiantes/farmacologia , Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Aterosclerose/tratamento farmacológico , Calcinose/prevenção & controle , Portadores de Fármacos , Hipercolesterolemia/tratamento farmacológico , Rosuvastatina Cálcica/farmacologia , Animais , Anticolesterolemiantes/sangue , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/induzido quimicamente , Aterosclerose/sangue , Aterosclerose/induzido quimicamente , Biomarcadores/sangue , Calcinose/sangue , Calcinose/induzido quimicamente , Cálcio/sangue , Quitosana/química , Colesterol/administração & dosagem , Colesterol/efeitos adversos , Colesterol/sangue , LDL-Colesterol/sangue , Ácido Cólico/administração & dosagem , Ácido Cólico/efeitos adversos , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Hipercolesterolemia/sangue , Hipercolesterolemia/induzido quimicamente , Interleucina-6/sangue , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Tamanho da Partícula , Coelhos , Rosuvastatina Cálcica/sangue , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression. METHODS: Out of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as 'favourable'. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%). RESULTS: Maximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007). CONCLUSIONS: DPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.
Assuntos
Aorta/fisiopatologia , Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Calcinose/prevenção & controle , Inibidores da Dipeptidil Peptidase IV , Ecocardiografia/métodos , Idoso , Animais , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/tratamento farmacológico , Estenose da Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/classificação , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Modelos Animais de Doenças , Progressão da Doença , Monitoramento de Medicamentos/métodos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Masculino , Ratos , Índice de Gravidade de Doença , Resultado do TratamentoAssuntos
Estenose da Valva Aórtica/prevenção & controle , Terapia de Alvo Molecular , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Solidão , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/terapia , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/fisiopatologia , Cardiopatia Reumática/terapia , Medição de RiscoRESUMO
AIMS: The aim of this study was to evaluate the feasibility, efficacy and safety of the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) technique during transcatheter aortic valve implantation (TAVI) in an initial cohort at a single European centre. METHODS AND RESULTS: Between August 2018 and March 2020, BASILICA was attempted in 23 leaflets in 21 consecutive patients undergoing TAVI (age 78±6 years, 52% female). The index procedure was performed for 21 degenerated bioprosthetic leaflets (90%, 9.2±2.6 years after implantation) and two native leaflets (10%). BASILICA was performed for a single leaflet in 19 (90%) patients and for both leaflets in two (10%) patients. The median total procedure time was 82 (interquartile range [IQR] 70-131) minutes, and BASILICA time (sheath-in to laceration) was 45 (IQR 35-67) minutes. A cerebral embolic protection device was used in 20 (95%) patients. BASILICA was feasible in all but one patient (95%) and resulted in effective prevention of coronary obstruction in 19 patients (90%). One patient developed a non-flow-limiting ostial lesion after BASILICA and TAVI, and was treated by additional coronary stenting. No mortality or stroke was observed up to 30 days. CONCLUSIONS: The feasibility, efficacy and safety of BASILICA in this early single-centre experience were consistent with the initial proof-of-concept reports. Further validation by ongoing multicentre registries remains warranted.
Assuntos
Estenose da Valva Aórtica , Oclusão Coronária , Dispositivos de Proteção Embólica , Próteses Valvulares Cardíacas , Lacerações , Substituição da Valva Aórtica Transcateter , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Substituição da Valva Aórtica Transcateter/métodos , Resultado do TratamentoRESUMO
The osteogenic differentiation of human aortic valve interstitial cells (hVICs) is the key cellular mechanism of calcified aortic valve disease (CAVD). This study aimed to explore how curcumin (CCM) inhibits the osteogenic differentiation of hVICs and elucidate the molecular mechanisms involved. In this study, CCM inhibited the osteogenic differentiation of hVICs under osteogenic medium (OM) conditions by reversing the OM-induced increase in calcified nodule formation and osteogenesis-specific markers (ALP and Runx2). RNA sequencing identified 475 common differentially expressed genes with Venn diagrams of the different groups. Kyoto Encyclopedia of Genes and Genomes enrichment revealed that the CCM inhibition of hVIC osteogenic differentiation was enriched in the NF-κB, PI3K-AKT, TNF, Jak-STAT, and MAPK signaling pathways. In addition, CCM suppressed the phosphorylation of ERK, IκBα, AKT, and interfered with the translocation of P65 into the cell nucleus in hVICs under OM culture conditions. In conclusion, CCM inhibited the osteogenic differentiation of hVICs via interfering with the activation of NF-κB/AKT/ERK signaling pathways. Our findings provide novel insights into a critical role for CCM in CAVD progression and shed new light on CCM-directed therapeutics for CAVD.
Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Calcinose/prevenção & controle , Curcumina/química , Curcumina/uso terapêutico , NF-kappa B/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Valva Aórtica/efeitos dos fármacos , Doença da Válvula Aórtica Bicúspide , Curcumina/farmacologia , Cardiopatias Congênitas , Doenças das Valvas Cardíacas , HumanosAssuntos
Estenose da Valva Aórtica/etiologia , Transplante de Coração , Complicações Pós-Operatórias/etiologia , Fatores Etários , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/cirurgia , Ecocardiografia , Humanos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/cirurgia , Índice de Gravidade de Doença , Doadores de Tecidos , Tomografia Computadorizada por Raios X , Substituição da Valva Aórtica TranscateterAssuntos
Estenose da Valva Aórtica/prevenção & controle , Aterosclerose/prevenção & controle , Idoso , Estenose da Valva Aórtica/etiologia , Aterosclerose/etiologia , Progressão da Doença , Feminino , Hemoglobinas Glicadas/análise , Humanos , Japão , Lipídeos/sangue , Masculino , Estudos Prospectivos , Fatores de RiscoRESUMO
AIMS: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS. METHODS AND RESULTS: We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3' untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions. CONCLUSION: miR-34a plays an important role in the development of CAVS via Notch1-Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.
Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/prevenção & controle , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos/metabolismo , Receptor Notch1/metabolismo , Idoso , Animais , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Oligonucleotídeos/genética , Osteogênese , Receptor Notch1/genética , Transdução de Sinais , Sus scrofaRESUMO
Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients.
Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/patologia , Benzoatos/farmacologia , Calcinose/prevenção & controle , Histonas/metabolismo , Pirazóis/farmacologia , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação/efeitos dos fármacos , Animais , Valva Aórtica/efeitos dos fármacos , Estenose da Valva Aórtica/induzido quimicamente , Estenose da Valva Aórtica/patologia , Calcinose/induzido quimicamente , Calcinose/patologia , Cálcio/efeitos adversos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrobenzenos , Fosfatos/efeitos adversos , Pirazolonas , Suínos , Fatores de Transcrição de p300-CBP/antagonistas & inibidoresRESUMO
PURPOSE OF REVIEW: The purpose of this review is to highlight our emerging understanding of lipoprotein(a) [Lp(a)]'s role in atherosclerotic cardiovascular disease (ASCVD), its structure-function relationship, and promising developments within the therapeutic pipeline. RECENT FINDINGS: Elevated levels of Lp(a) are strongly associated with an increased risk of coronary heart disease, calcific aortic valve stenosis, and ischemic stroke. With circulating levels almost exclusively genetically mediated, increased levels of Lp(a) contribute significantly to the residual cardiovascular disease risk in individuals with otherwise well controlled risk factors. The unique structure of Lp(a) - comprised of a genetically heterogeneous apolipoprotein(a) molecule bound to an LDL-like moiety - provides insight into its pathogenic role in cardiovascular disease and also complicates its accurate measurement. Emerging therapies targeting the apolipoprotein(a) component of Lp(a) have the potential to revolutionize the management of individuals with elevated Lp(a). SUMMARY: With promising therapies on the horizon, there has been a renewed focus on the role of Lp(a) in ASCVD. Given Lp(a)'s strong and independent association with key cardiovascular outcomes, it is hopeful that these promising targeted therapies will add another therapeutic option for the prevention of cardiovascular disease.