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1.
J Urol ; 205(1): 68-77, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32856981

RESUMO

PURPOSE: Encrustation is a common phenomenon that can occur following placement of a ureteral stent into the urinary tract, and it can lead to serious complications. The following review addresses the mechanism of encrustation, the management of these stents and the newest technology developed to mitigate this issue. MATERIALS AND METHODS: We performed a comprehensive literature search on stent encrustation including peer-reviewed publications, public product listings, and material on current and future stent technology. RESULTS: The mechanism of encrustation is complex and multifaceted, including dwell time, patient specific risk factors, conditioning film formation, biofilm formation and mineral deposition. Several technological developments in stent materials and coatings may have a role in reducing the risk of stent encrustation. It is important to identify the extent of stent encrustation and plan treatment strategies accordingly. We propose a novel treatment algorithm for the management encrusted ureteral stents. CONCLUSIONS: The ubiquity of ureteral stents in urology practice mandates updated knowledge about the prevention of stent encrustation, identification of high risk patients and preparedness for removal using multimodal techniques.


Assuntos
Calcinose/cirurgia , Remoção de Dispositivo/métodos , Complicações Pós-Operatórias/cirurgia , Stents/efeitos adversos , Ureter/cirurgia , Calcinose/epidemiologia , Calcinose/etiologia , Calcinose/prevenção & controle , Cistoscopia , Dilatação/efeitos adversos , Dilatação/instrumentação , Humanos , Litotripsia , Masculino , Nefrostomia Percutânea , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Desenho de Prótese , Fatores de Risco , Tecnologia , Tomografia Computadorizada por Raios X , Ultrassonografia , Ureter/diagnóstico por imagem , Ureter/microbiologia , Ureter/patologia , Obstrução Ureteral/cirurgia , Ureterolitíase/etiologia , Ureterolitíase/prevenção & controle
2.
Cardiovasc Eng Technol ; 11(3): 316-327, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32356274

RESUMO

PURPOSE: Fibrocalcific aortic valve disease (CAVD) is caused by the deposition of calcific nodules in the aortic valve leaflets, resulting in progressive loss of function that ultimately requires surgical intervention. This process is actively mediated by the resident valvular interstitial cells (VICs), which, in response to oxidized lipids, transition from a quiescent to an osteoblast-like state. The purpose of this study was to examine if the ryanodine receptor, an intracellular calcium channel, could be therapeutically targeted to prevent this phenotypic conversion. METHODS: The expression of the ryanodine receptor in porcine aortic VICs was characterized by qRT-PCR and immunofluorescence. Next, the VICs were exposed to lysophosphatidylcholine, an oxidized lipid commonly found in low-density lipoprotein, while the activity of the ryanodine receptor was modulated with ryanodine. The cultures were analyzed for markers of cellular mineralization, alkaline phosphatase activity, proliferation, and apoptosis. RESULTS: Porcine aortic VICs predominantly express isoform 3 of the ryanodine receptors, and this protein mediates the cellular response to LPC. Exposure to LPC caused elevated intracellular calcium concentration in VICs, raised levels of alkaline phosphatase activity, and increased calcific nodule formation, but these changes were reversed when the activity of the ryanodine receptor was blocked. CONCLUSIONS: Our findings suggest blocking the activity of the ryanodine receptor can attenuate the valvular mineralization caused by LPC. We conclude that oxidized lipids, such as LPC, play an important role in the development and progression of CAVD and that the ryanodine receptor is a promising target for pharmacological intervention.


Assuntos
Valva Aórtica/efeitos dos fármacos , Calcinose/induzido quimicamente , Agonistas dos Canais de Cálcio/toxicidade , Cálcio/metabolismo , Lisofosfatidilcolinas/toxicidade , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Apoptose/efeitos dos fármacos , Calcinose/metabolismo , Calcinose/patologia , Calcinose/prevenção & controle , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Sus scrofa
3.
Phytother Res ; 34(8): 2074-2081, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32189385

RESUMO

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 , Curcumina/farmacologia , Cardiopatias Congênitas , Doenças das Valvas Cardíacas , Humanos
4.
BMC Cardiovasc Disord ; 20(1): 39, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000687

RESUMO

BACKGROUND: Although mineral metabolism disorder influences cardiac valvular calcification (CVC), few previous studies have examined the effects of non-calcium-containing and calcium-containing phosphate binders on CVC in maintenance hemodialysis patients. The aim of the present study was to compare the effects of lanthanum carbonate (LC) with calcium carbonate (CC) on the progression of CVC in patients who initiated maintenance hemodialysis and to investigate clinical factors related to CVC. METHODS: The current study included 50 subjects (mean age 65 years, 72% males) from our previous randomized controlled trial (LC group, N = 24; CC group, N = 26). CVC was evaluated as CVC score (CVCS) using echocardiography at baseline and 18 months after initiation of hemodialysis. We compared CVCS and the changes between the two groups. We also analyzed the associations between CVCS and any other clinical factors including arterial plaque score (PS) and serum phosphorus levels. RESULTS: Baseline characteristics of study participants including CVCS were almost comparable between the two groups. At 18 months, there were no significant differences in mineral metabolic markers or CVCS between the two groups, and CVCS were significantly correlated with PS (r = 0.39, p < 0.01). Furthermore, changes in CVCS were significantly correlated with average phosphorus levels (r = 0.36, p < 0.05), which were significantly higher in high serum phosphorus and high PS group compared to low serum phosphorus and low PS group (p < 0.05). CONCLUSIONS: In the present study, there were no significant differences between LC and CC with regard to progression of CVC. However, serum phosphorus levels and arterial plaque seem to be important for the progression and formation of CVC in hemodialysis patients.


Assuntos
Calcinose/prevenção & controle , Carbonato de Cálcio/uso terapêutico , Quelantes/uso terapêutico , Doenças das Valvas Cardíacas/prevenção & controle , Nefropatias/terapia , Lantânio/uso terapêutico , Diálise Renal , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Calcinose/sangue , Calcinose/diagnóstico por imagem , Calcinose/etiologia , Carbonato de Cálcio/efeitos adversos , Quelantes/efeitos adversos , Progressão da Doença , Feminino , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/etiologia , Humanos , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/diagnóstico , Lantânio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fósforo/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
5.
Nephrol Dial Transplant ; 35(3): 495-502, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31738424

RESUMO

BACKGROUND: Cardiovascular morbidity and mortality is high in patients starting dialysis and could be related to modifications of calcification inducers and inhibitors by dialysis, promoting cardiovascular events. The impact of dialysis initiation on serum calcification propensity evolution and arterial stiffness is unknown. We therefore prospectively determined the evolution of the one-half maximal transition time (T50) value and its main determinants as well as pulse wave velocity over the first 3 months of dialysis initiation. METHODS: We analysed the evolution of T50, fetuin-A and mineral metabolism parameters before dialysis initiation (M0) and monthly until Month 3 (M3) in incident patients starting haemodialysis (HD) or peritoneal dialysis (PD) in two tertiary Swiss university hospitals. Arterial stiffness was assessed by pulse tonometry at M0 and M3 and biological parameters were compared between M0 and M3 and before/after HD. Linear mixed models were used to assess parameter evolution over time, taking into account repeated measures and other influencing variables. RESULTS: Forty-six patients on HD and 12 on PD were followed. Among them, 45 were male (78%) with a median age of 67 years (25th-75th quartile range 54-77). T50 significantly increased between M0 and M3 from 183 (120-266) to 246 min (175-330) (P < 0.001). Fetuin-A, calcium and magnesium also increased while phosphate decreased. Factors associated with T50 changes over time were fetuin-A, phosphate and magnesium (P < 0.001). Fetuin-A changes were associated with inflammation-related factors (albumin, C-reactive protein) but not calcium and phosphate levels. Arterial stiffness was not significantly modified over 3 months. PD and HD initiation showed similar trends. CONCLUSIONS: Dialysis initiation significantly improves calcification propensity and fetuin-A levels. These modifications do not explain the high mortality related to dialysis initiation. The clinical relevance of using T50 values to initiate dialysis awaits further studies.


Assuntos
Calcificação Fisiológica/fisiologia , Calcinose/prevenção & controle , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Proteína C-Reativa/metabolismo , Calcinose/sangue , Feminino , Humanos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Estudos Prospectivos
6.
Cardiovasc Res ; 116(5): 983-994, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393559

RESUMO

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 scrofa
7.
Proc Natl Acad Sci U S A ; 116(47): 23698-23704, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690656

RESUMO

Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson-Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/metabolismo , Fosfatase Alcalina/fisiologia , Doenças da Aorta/prevenção & controle , Apirase/antagonistas & inibidores , Calcinose/prevenção & controle , Difosfatos/metabolismo , Levamisol/uso terapêutico , Progéria/tratamento farmacológico , Pirofosfatases/antagonistas & inibidores , Trifosfato de Adenosina/uso terapêutico , Fosfatase Alcalina/antagonistas & inibidores , Animais , Antígenos CD/fisiologia , Doenças da Aorta/enzimologia , Apirase/deficiência , Apirase/fisiologia , Calcinose/enzimologia , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Lamina Tipo A/genética , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Miócitos de Músculo Liso/metabolismo , Diester Fosfórico Hidrolases/deficiência , Diester Fosfórico Hidrolases/fisiologia , Progéria/genética , Progéria/metabolismo , Progéria/patologia , Pirofosfatases/deficiência , Pirofosfatases/fisiologia , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase em Tempo Real
8.
Exp Mol Med ; 51(7): 79, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292436

RESUMO

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 , Fosfatos/efeitos adversos , Suínos , Fatores de Transcrição de p300-CBP/antagonistas & inibidores
9.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340541

RESUMO

Apoptotic cell death is usually a response to the cell's microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities.


Assuntos
Lesão Renal Aguda/metabolismo , Proteínas Reguladoras de Apoptose/genética , Calcinose/metabolismo , Células Epiteliais/metabolismo , Rim/metabolismo , Necrose/metabolismo , Traumatismo por Reperfusão/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/classificação , Proteínas Reguladoras de Apoptose/metabolismo , Calcinose/genética , Calcinose/patologia , Calcinose/prevenção & controle , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação da Expressão Gênica , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Morte Celular Imunogênica/genética , Rim/efeitos dos fármacos , Rim/patologia , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/efeitos dos fármacos , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria/genética , Necroptose/efeitos dos fármacos , Necroptose/genética , Necrose/genética , Necrose/patologia , Necrose/prevenção & controle , Substâncias Protetoras/farmacologia , Piroptose/efeitos dos fármacos , Piroptose/genética , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
10.
Curr Opin Cardiol ; 34(5): 514-518, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31261178

RESUMO

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.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Lipoproteína(a)/sangue , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/prevenção & controle , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/prevenção & controle , Calcinose/sangue , Calcinose/prevenção & controle , Cardiologia , Doença das Coronárias/sangue , Doença das Coronárias/prevenção & controle , Humanos , Medicina Preventiva , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/prevenção & controle
11.
Heart Lung Circ ; 28(9): 1310-1319, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31266725

RESUMO

Degenerative or fibrocalcific aortic stenosis (AS) is now the most common native valvular heart disease assessed and managed by cardiologists in developed countries. Transthoracic echocardiography remains the quintessential imaging modality for the non-invasive characterisation of AS due to its widespread availability, superior assessment of flow haemodynamics, and a wealth of prognostic data accumulated over decades of clinical utility and research applications. With expanding technologies and increasing availability of treatment options such as transcatheter aortic valve replacements, in addition to conventional surgical approaches, accurate and precise assessment of AS severity is critical to guide decisions for and timing of interventions. Despite clear guideline echocardiographic parameters demarcating severe AS, discrepancies between transvalvular velocities, gradients, and calculated valve areas are commonly encountered in clinical practice. This often results in diagnostically challenging cases with significant implications. Greater emphasis must be placed on the quality of performance of basic two dimensional (2D) and Doppler measurements (attention to detail ensuring accuracy and precision), incorporating ancillary haemodynamic surrogates, understanding study- or patient-specific confounders, and recognising the role and limitations of stress echocardiography in the subgroups of low-flow low-gradient AS. A multiparametric approach, along with the incorporation of multimodality imaging (cardiac computed tomography or magnetic resonance imaging) in certain scenarios, is now mandatory to avoid incorrect misclassification of severe AS. This is essential to ensure appropriate selection of patients who would most benefit from interventions on the aortic valve to relieve the afterload mismatch resulting from truly severe valvular stenosis.


Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Calcinose/diagnóstico por imagem , Calcinose/fisiopatologia , Ecocardiografia sob Estresse , Ecocardiografia , Hemodinâmica , Imagem Multimodal , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/terapia , Calcinose/prevenção & controle , Calcinose/terapia , Humanos , Substituição da Valva Aórtica Transcateter
12.
J Card Surg ; 34(10): 895-900, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31269321

RESUMO

BACKGROUND AND AIM OF THE STUDY: Glutaraldehyde (Glut) fixed bioprosthetic valves fail due to progressive dystrophic calcification. Many treatments have been proposed to eliminate calcification but none have been entirely successful. Calcitonin (CT) and sodium bisulfite (BSF) have recently been introduced as independent anticalcification reagents. It is postulated that their combined effect, along with the addition of the detergent Tween 80 and alcohol at 37°C, may efficiently minimize tissue calcification due to aldehyde adduct formation and elimination of lipids. MATERIAL AND METHODS: Three groups were created from porcine aortic leaflets: group I (Glut only), group II (Glut with 1% CT, 12.5% BSF, and 1.2% Tween 80 at 37°C), and group III (Glut with 1% CT, 10% BSF, 1.2% Tween 80, and 20% alcohol at 37°C). All tissues were implanted subdermally in three sets of eight (group I), six (group II), and five (group III) Wistar rats. After 4 months, the tissues were retrieved and lyophilized at -40°C at 100 mm Hg. The calcium was measured with a flat atomic absorption technique. RESULTS: The preimplantation calcium (Ca) concentration in mg Ca/gram of tissue was 1.79 ± 0.14 in group I, 1.65 ± 0.28 in group II, and 0.72 ± 0.79 in group III (P = ns). After 4 months, the Ca concentration was 277.55 ± 32.52, 103.54 ± 5.39 (P < .001) and 42.02 ± 15.63 (P < .001), respectively. There was also a significant difference (P < .001) between groups II and III. CONCLUSION: The combination of CT and BSF along with the detergent Tween 80 and alcohol at 37°C mitigates the calcification efficiently as compared to Glut treatment only.


Assuntos
Anticoagulantes/uso terapêutico , Bioprótese , Calcinose/prevenção & controle , Doenças das Valvas Cardíacas/prevenção & controle , Próteses Valvulares Cardíacas , Guias de Prática Clínica como Assunto , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar , Suínos
13.
Kidney Blood Press Res ; 44(2): 188-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31067546

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and metabolic acidosis might accelerate vascular calcification. The T50 calcification inhibition test (T50-test) is a global functional test analyzing the overall propensity of calcification in serum, and low T50-time is associated with progressive aortic stiffening and with all-cause mortality in non-dialysis CKD, dialysis, and transplant patients. Low serum bicarbonate is associated with a short T50-time and alkali supplementation could be a simple modifier of calcification propensity. The aim of this study was to investigate the short-term effect of oral sodium bicarbonate supplementation on T50-time in CKD patients. MATERIAL AND METHODS: The SoBic-study is an ongoing randomized-controlled trial in CKD-G3 and G4 patients with chronic metabolic acidosis (serum HCO3- ≤21 mmol/L), in which patients are randomized to either achieve serum HCO3- levels of 24 ± 1 mmol/L (intervention group) or 20 ± 1 mmol/L (rescue group). The effect of bicarbonate treatment on T50-time was assessed. RESULTS: The study cohort consisted of 35 (14 female) patients aged 57 (±15) years, and 18 were randomized to the intervention group. The mean T50-time was 275 (± 64) min. After 4 weeks, the mean change of T50-time was 4 (±69) min in the intervention group and 18 min (±56) in the rescue group (ß = -25; 95% CI: -71 to 22; p = 0.298). Moreover, change of serum bicarbonate in individual patients was not associated with change in T50-time, analyzed by regression analysis. Change of serum phosphate had a significant impact on change of T50-time (ß = -145; 95% CI: -237 to -52). CONCLUSION: Oral sodium bicarbonate supplementation showed no effect on T50-time in acidotic CKD patients.


Assuntos
Acidose/tratamento farmacológico , Calcinose/prevenção & controle , Insuficiência Renal Crônica/tratamento farmacológico , Bicarbonato de Sódio/administração & dosagem , Adulto , Idoso , Calcinose/sangue , Calcinose/tratamento farmacológico , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bicarbonato de Sódio/farmacologia , Bicarbonato de Sódio/uso terapêutico , Rigidez Vascular/efeitos dos fármacos
14.
Phytother Res ; 33(6): 1717-1725, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016813

RESUMO

Inflammation is considered to be one of the initial critical factors in the occurrence of calcific heart valve disease. This study was to prove Nobiletin (NBT) inhibits inflammation-caused calcification of human valve interstitial cells (hVICs) and to elucidate the involved molecular mechanisms. Tumor necrosis factor-alpha (TNF-α)-induced hVICs were treated with or without NBT. Cell growth and calcification of hVICs were assessed. RNA sequencing was utilized to investigate the gene expression changes. Molecular target prediction and docking assay were further performed. NBT interfered with hVIC growth under TNF-α condition in a dose-dependent manner also presented a gradual decrease of positive Alizarin Red S staining, down-regulation of BMP2, and RUNX2 gene expression. Based on the global gene expression cluster, control and TNF-α plus NBT group showed a high similarity versus TNF-α only group. After Venn interaction of differential expression genes (DEGs), 2,236 common DEGs were identified to display different biological functions and signaling pathways. ABCG2 and AKR1B1 were further selected as prediction targets of NBT involved in RELA, TNF, BMP2, RUNX2, etc. interactions in mediating hVIC calcification. The results show that NBT is a natural product to prevent the occurrence of heart valve calcification.


Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Calcinose/prevenção & controle , Flavonas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Flavonas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/prevenção & controle , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/efeitos adversos
16.
J Thorac Cardiovasc Surg ; 158(3): 731-741.e1, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30738596

RESUMO

OBJECTIVE: There are pathophysiologic similarities between calcification and atherosclerosis because both are the product of an active inflammatory process. The aim of the study was to examine the effects of statin treatment on calcification in commercially available bioprosthetic heart valves. METHODS: Twenty Sprague-Dawley rats were fed a high-fat diet to induce hypercholesterolemia during 4 weeks. They were randomly divided into 2 groups according to statin intake (control, n = 10: high-fat diet/statin; n = 10: high-fat diet with statin). Four commercially available tissue valve (Magna Perimount, Carpentier-Edwards, Irvine, Calif; Hancock, Medtronic, Minneapolis, Minn; Mitroflow, LivaNova, London, England; and Trifecta, St Jude Medical, St Paul, Minn) cusp samples (total 320) were implanted in rat dorsal subcutis at 4 weeks. After implantation, rosuvastatin was administered daily to the statin group. The cusps were explanted at 12 weeks, and calcium levels were determined by atomic absorption spectroscopy. Western blotting, histologic, and immunohistochemical analyses were conducted to identify the anticalcification mechanism of the statin. RESULTS: The mean calcium level in the control group was significantly higher than in the statin group (P < .01) for all tissue valves (Magna Perimount: 2.67 ± 0.26 mg/g vs 1.31 ± 0.40 mg/g; Hancock: 2.70 ± 0.57 mg/g vs 1.53 ± 0.34 mg/g; Mitroflow: 2.39 ± 0.71 mg/g vs 1.26 ± 0.38 mg/g; Trifecta: 2.54 ± 0.42 mg/g vs 1.63 ± 0.72 mg/g). Inflammatory cell infiltration and interleukin-6 and bone morphogenetic protein 2 expressions were significantly reduced in the statin group. CONCLUSIONS: Statin treatment significantly attenuated bioprosthetic heart valve calcification associated with decreasing the levels of interleukin-6 and bone morphogenetic protein 2. Thus, statin treatment might be helpful for the longevity of bioprosthetic heart valves.


Assuntos
Bioprótese , Calcinose/prevenção & controle , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Falha de Prótese , Rosuvastatina Cálcica/farmacologia , Animais , Biomarcadores/sangue , Proteína Morfogenética Óssea 2/metabolismo , Calcinose/etiologia , Calcinose/metabolismo , Calcinose/patologia , Cálcio/metabolismo , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Implante de Prótese de Valva Cardíaca/efeitos adversos , Hipercolesterolemia/sangue , Interleucina-6/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
17.
Atherosclerosis ; 281: 25-30, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30616181

RESUMO

A large number of epidemiological studies in ethnically diverse populations show that lipoprotein(a) [Lp(a)] levels above 30-50 mg/dL are significantly associated with calcific aortic valve stenosis, although less so in African Americans. Patients with heterozygous familial hypercholesterolemia (he-FH) have a marked lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) level, and the prevalence of aortic valve calcification (AVC) is at least two-fold higher among adult he-FH patients compared with healthy controls. Additionally, Lp(a) levels above 50 mg/dL were recently found to be an independent risk factor for AVC among asymptomatic statin-treated he-FH patients. Given that worldwide an estimated 1.4 billion people have an Lp(a) level over 50 mg/dL, and that one out of 250 individuals has he-FH, then globally about 5 million he-FH patients should have an Lp(a) level higher than 50 mg/dL. However, because Lp(a) levels are, on average, significantly higher in he-FH patients than the general population, the actual number of he-FH patients with such high Lp(a) levels must be even higher. We proposed recently that Lp(a) life-years is a useful metric of cumulative burden of risk for atherosclerotic cardiovascular disease (ASCVD), and now posit that this metric may be extended to the development of AVC. The Lp(a) life-years illustrates the age-dependent exposure to a given Lp(a) level (years x mg/dL). Effective novel pharmacotherapies using apo(a) antisense oligonucleotides (ASOs) or small interfering RNA (siRNA)-based therapies targeting the hepatic expression of apo(a) offer unprecedented potential for significant reduction in the cumulative exposure of the aortic valves to Lp(a), and need to be tested in controlled clinical trials on the progression of AVC.


Assuntos
Estenose da Valva Aórtica/epidemiologia , Valva Aórtica/patologia , Calcinose/epidemiologia , Hiperlipoproteinemia Tipo II/sangue , Lipoproteína(a)/sangue , Adulto , Idoso , Animais , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/prevenção & controle , Biomarcadores/sangue , Calcinose/diagnóstico por imagem , Calcinose/prevenção & controle , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Regulação para Cima
18.
Nat Rev Cardiol ; 16(5): 305-318, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30675027

RESUMO

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)-Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.


Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doença da Artéria Coronariana , Lipoproteína(a)/metabolismo , Fosfolipídeos/metabolismo , Calcificação Vascular/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Calcinose/metabolismo , Calcinose/prevenção & controle , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Descoberta de Drogas , Humanos , Oxirredução
20.
Biochem Biophys Res Commun ; 516(3): 1026-1032, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-28342871

RESUMO

Cartilage endplate (CEP) cell calcification and apoptosis play a vital role in the intervertebral disc degeneration (IVDD). Oxidative stress is a key factor in inducing programmed cell death and cartilage calcification. However, the cell death and calcification of cartilage endplate cells under oxidative stress have never been described. The present study investigated the apoptosis and calcification in the cartilage endplate cell under oxidative stress induced by H2O2 to understand the underlying mechanism of IVDD. The cartilage endplate cells isolated from human lumbar discs were subjected to different concentrations of H2O2 for various time periods. The cell viability was determined by CCK-8 assay, whereas Western blot, immunofluorescence, and Alcian blue, Alizarin red, and Von Kossa staining evaluated the apoptosis and calcification. The level of mitochondria-specific reactive oxygen species (ROS) was quantified with an oxygen radical-sensitive probe-MitoSOX. The potential signaling pathways were investigated by Western blot after the addition of N-acetyl-l-cysteine (NAC). We found that the oxidative stress induced by H2O2 increased the apoptosis and subsequently the calcification in the cartilage endplate cells through the ROS/p38/ERK/p65 pathway. The apoptosis and the calcification of the cartilage endplate cells induced by H2O2 can be abolished by NAC. These results suggested that regulating the apoptosis and the calcification in the cartilage endplate cells under oxidative stress should be advantageous for the survival of cells and might delay the process of disc degeneration.


Assuntos
Apoptose , Condrócitos/metabolismo , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Calcinose/induzido quimicamente , Calcinose/metabolismo , Calcinose/prevenção & controle , Cartilagem/citologia , Cartilagem/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Disco Intervertebral/citologia , Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Oxidantes/farmacologia
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