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1.
Int J Cardiol ; 296: 98-102, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31455517

RESUMO

BACKGROUND: Predictors of heart failure (HF) hospitalization after transcatheter aortic valve implantation (TAVI) are not well defined. CAPRI is a score for predicting 1-year post-TAVI cardiovascular and all-cause mortality. The aim of the present study is to assess the prognostic significance of the CAPRI score for HF hospitalization 1 year after TAVI. METHODS AND RESULTS: CAPRI-HF is an ancillary study of the C4CAPRI trial, analyzing 409 consecutive patients treated by TAVI. The primary outcome was hospitalization for HF during the first year post-intervention. The prognostic value of the CAPRI score was assessed by multivariable analysis adjusted for diabetes, atrial fibrillation, vascular route, pacemaker implantation, post-TAVI aortic regurgitation, transfusion and pulmonary artery systolic pressure. A subanalysis focused on patients with low-gradient aortic stenosis (LGAS). At 1 year, HF hospitalization occurred in 78 (19.9%) patients. Patients with HF were more prone to have diabetes, atrial fibrillation, renal dysfunction, lower mean aortic gradient, higher logistic EuroSCORE and higher CAPRI score (p < .05 for all associations). In the multivariable analysis, CAPRI score was the sole predictor of HF: hazard ratio (HR) for each 0.1 CAPRI score increase was 1.065, 95% confidence interval (CI) 1.021-1.110. This was confirmed when adjusted for EuroSCORE: HR 1.066, 95% CI 1.024-1.110. The predictive power of the CAPRI score increased for LGAS: HR 1.098, 95% CI 1.028-1.172. CONCLUSIONS: CAPRI score helps predict HF post-TAVI. Including the score in the decision-making process may help selecting candidates for TAVI and identifying patients who need close monitoring post-procedure.

2.
Microbiol Spectr ; 7(4)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31298206

RESUMO

The type VI secretion system (T6SS) is a multiprotein machine that uses a spring-like mechanism to inject effectors into target cells. The injection apparatus is composed of a baseplate on which is built a contractile tail tube/sheath complex. The inner tube, topped by the spike complex, is propelled outside of the cell by the contraction of the sheath. The injection system is anchored to the cell envelope and oriented towards the cell exterior by a trans-envelope complex. Effectors delivered by the T6SS are loaded within the inner tube or on the spike complex and can target prokaryotic and/or eukaryotic cells. Here we summarize the structure, assembly, and mechanism of action of the T6SS. We also review the function of effectors and their mode of recruitment and delivery.

3.
Circ Cardiovasc Interv ; 12(4): e007597, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30998397

RESUMO

BACKGROUND: The durability of transcatheter aortic bioprosthetic valves is a crucial issue, but data are scarce, especially beyond 5 years of follow-up. We aimed to assess long-term (7 years) structural valve deterioration (SVD) and bioprosthetic valve failure of transcatheter aortic bioprosthetic valves. METHODS AND RESULTS: Consecutive patients with at least 5-year follow-up available undergoing transcatheter aortic valve implantation from April 2002 to December 2011 in 5 French centers were included. Incidence of SVD and bioprosthetic valve failure were defined according to newly standardized criteria of the European Association of Percutaneous Cardiovascular Interventions/European Society of Cardiology/European Association for Cardio-Thoracic Surgery and reported as cumulative incidence function to account for the competing risk of death. One thousand four hundred three consecutive patients were included with a mean age of 82.6±7.5 years and with a mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) of 21.3±7.5%. A balloon-expandable valve was used in 83.7% of cases. Survival rates were 83.5% (95% CI, 81.4%-85.5%) and 18.6% (95% CI, 15.3%-21.8%) at 1 and 7 years, respectively. Median duration of follow-up was 3.9 years. Bioprosthetic valve failure occurred in 19 patients with a 7-year cumulative incidence of 1.9% (95% CI, 1.4%-2.4%). SVD occurred in 49 patients (moderate, n=32; severe, n=17) with a 7-year cumulative incidence of moderate and severe SVD of 7.0% (95% CI, 5.6%-8.4%) and 4.2% (95% CI, 2.9%-5.5%), respectively. Five patients had aortic valve reintervention (1.0%; 95% CI, 0.4%-1.6%) including 1 case of surgical aortic valve replacement and 4 redo-transcatheter aortic valve implantation. The incidences of SVD and bioprosthetic valve failure were not significantly different between balloon and self-expandable prostheses. CONCLUSIONS: The long-term assessment of transcatheter aortic bioprosthetic valves durability is limited by the poor survival of our population beyond 5 years. Further studies are warranted, particularly in younger and lower-risk patients.

4.
EMBO J ; 38(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877094

RESUMO

Bacteria have evolved macromolecular machineries that secrete effectors and toxins to survive and thrive in diverse environments. The type VI secretion system (T6SS) is a contractile machine that is related to Myoviridae phages. It is composed of a phage tail-like structure inserted in the bacterial cell envelope by a membrane complex (MC) comprising the TssJ, TssL and TssM proteins. We previously reported the low-resolution negative-stain electron microscopy structure of the enteroaggregative Escherichia coli MC and proposed a rotational 5-fold symmetry with a TssJ:TssL:TssM stoichiometry of 2:2:2. Here, cryo-electron tomography analyses of the T6SS MC confirm the 5-fold symmetry in situ and identify the regions of the structure that insert into the bacterial membranes. A high-resolution model obtained by single-particle cryo-electron microscopy highlights new features: five additional copies of TssJ, yielding a TssJ:TssL:TssM stoichiometry of 3:2:2, an 11-residue loop in TssM, protruding inside the lumen of the MC and constituting a functionally important periplasmic gate, and hinge regions. Based on these data, we propose an updated model on MC structure and dynamics during T6SS assembly and function.

5.
J Integr Med ; 17(2): 107-114, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30792149

RESUMO

OBJECTIVE: The use of animal models of aortic stenosis (AS) remains essential to further elucidate its pathophysiology and to evaluate new therapeutic strategies. The waved-2 mouse AS model has been proposed; data have indicated that while aortic regurgitation (AR) is effectively induced, development of AS is rare. We aimed to evaluate the effect of high-fat diet (HFD) and vitamin D3 supplementation in this model. METHODS: HFD and subcutaneous vitamin D3 injections were initiated at the age of 6 weeks until the age of 6 (n = 16, 6-month treatment group) and 9 (n = 11, 9-month treatment group) months. Twelve waved-2 mice without supplementation were used as control. Echocardiography was performed at 3, 6 and 9 months. Blood serum analysis (calcium, 1,25(OH)2D3 and cholesterol), histology and immunohistochemistry (CD-31, CD-68 and osteopontin) were evaluated at the end of the experiment (6 or 9 months). RESULTS: Total cholesterol and 1,25(OH)2D3 were significantly increased relative to the control group. HFD and vitamin D3 supplementation did result in improvements to the model, since AS was only detected in 6 (15.3%) mice (2 in the 3 groups) and AR was developed in the remaining animals. Echocardiographic parameters, fibrosis, thickness, inflammation and valvular calcification, were not significantly different between the 6-month treatment and control groups. Similar results were also observed in the 9-month treatment group. CONCLUSION: These results suggest that HFD and vitamin D3 supplementation have no effect in the waved-2 mouse model. This model essentially mimics AR and rarely AS. Further studies are needed to find a reliable animal model of AS.

6.
Circ Cardiovasc Interv ; 11(11): e006927, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571207

RESUMO

BACKGROUND: The impact of preexisting left bundle branch block (LBBB) in transcatheter aortic valve replacement (TAVR) recipients is unknown. The aim of this study was to determine the impact of preexisting LBBB on clinical outcomes after TAVR. METHODS AND RESULTS: This multicenter study evaluated 3404 TAVR candidates according to the presence or absence of LBBB on baseline ECG. TAVR complications and causes of death were defined according to Valve Academic Research Consortium-2 definitions. Follow-up outpatient visits or telephone interviews were conducted at 30 days, 12 months, and yearly thereafter. Echocardiography examinations were performed at baseline, at hospital discharge, and at 1-year follow-up. Preexisting LBBB was present in 398 patients (11.7%) and was associated with an increased risk of permanent pacemaker implantation (PPI; 21.1% versus 14.8%; adjusted odds ratio, 1.51; 95% CI, 1.12-2.04) but not death (7.3% versus 5.5%; adjusted odds ratio, 1.33; 95% CI, 0.84-2.12) at 30 days. At a mean follow-up of 22±21 months, there were no differences between patients with and without preexisting LBBB in overall mortality (adjusted hazard ratio, 0.94; 95% CI, 0.75-1.18) and cardiovascular mortality (adjusted hazard ratio, 0.90; 95% CI, 0.68-1.21). In a subanalysis of 2421 patients without PPI at 30 days and with complete follow-up about the PPI, preexisting LBBB was not associated with an increased risk of PPI or sudden cardiac death. Patients with preexisting LBBB had a lower left ventricular ejection fraction (LVEF) at baseline and at 1-year follow-up ( P <0.001 for both), but those with low LVEF exhibited a similar increase in LVEF over time after TAVR compared with patients with no preexisting LBBB ( P=0.327). CONCLUSIONS: Preexisting LBBB significantly increased the risk of early (but not late) PPI after TAVR, without any significant effect on overall mortality or cardiovascular mortality. Preexisting LBBB was associated with lower LVEF pre-TAVR but did not prevent an increase in LVEF post-TAVR similar to patients without LBBB.


Assuntos
Valva Aórtica/cirurgia , Bloqueio de Ramo/terapia , Estimulação Cardíaca Artificial , Doenças das Valvas Cardíacas/cirurgia , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Brasil/epidemiologia , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/mortalidade , Bloqueio de Ramo/fisiopatologia , Canadá/epidemiologia , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/mortalidade , Ecocardiografia , Eletrocardiografia , Europa (Continente)/epidemiologia , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/mortalidade , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Masculino , Marca-Passo Artificial , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/terapia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do Tratamento
7.
Nat Microbiol ; 3(12): 1404-1416, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30323254

RESUMO

To support their growth in a competitive environment and cause pathogenesis, bacteria have evolved a broad repertoire of macromolecular machineries to deliver specific effectors and toxins. Among these multiprotein complexes, the type VI secretion system (T6SS) is a contractile nanomachine that targets both prokaryotic and eukaryotic cells. The T6SS comprises two functional subcomplexes: a bacteriophage-related tail structure anchored to the cell envelope by a membrane complex. As in other contractile injection systems, the tail is composed of an inner tube wrapped by a sheath and built on the baseplate. In the T6SS, the baseplate is not only the tail assembly platform, but also docks the tail to the membrane complex and hence serves as an evolutionary adaptor. Here we define the biogenesis pathway and report the cryo-electron microscopy (cryo-EM) structure of the wedge protein complex of the T6SS from enteroaggregative Escherichia coli (EAEC). Using an integrative approach, we unveil the molecular architecture of the whole T6SS baseplate and its interaction with the tail sheath, offering detailed insights into its biogenesis and function. We discuss architectural and mechanistic similarities but also reveal key differences with the T4 phage and Mu phage baseplates.

8.
Cancer Res ; 78(21): 6257-6267, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30135191

RESUMO

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors.Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257-67. ©2018 AACR.

9.
EuroIntervention ; 14(AB): AB64-AB73, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30158097

RESUMO

Aortic bioprostheses are increasingly used both for surgery, as an alternative to mechanical valves, and for transcatheter implantation in patients with severe aortic stenosis. Transcatheter aortic valve implantation (TAVI) has been widely adopted for the treatment of severe symptomatic aortic stenosis in elderly (>75 years) patients who are at risk for surgery and who have favourable transfemoral access. It is already under evaluation in low-risk patients. The aim of this review is to present an update on definitions and to assess the various forms of transcatheter heart valve failure and their management: structural valve deterioration, non-structural deterioration, thrombosis and endocarditis.

10.
11.
Pacing Clin Electrophysiol ; 41(9): 1178-1184, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29931693

RESUMO

BACKGROUND: One of the most frequent complications of transcatheter aortic valve implantation (TAVI) is the occurrence of atrioventricular (AV) conduction disorders secondary to AV node or His bundle injury leading to permanent pacemaker implantation (PPI). The objective was to quantify the rate of ventricular pacing (VP), according to post-TAVI indication for PPI using recorded pacemaker memory. METHODS: From October 2009 to January 2017' all patients who had PPI following TAVI performed at Rouen University Hospital were included. Indications for PPI were: ≥ 1 episode of complete atrioventricular block (CAVB) or 2:1 atrioventricular block, and new-onset persistent left bundle branch block (NOP-LBBB) with either prolonged PR interval (> 200 ms) or HV interval (>70 ms). The primary endpoint was VP percentage at the first pacemaker interrogation (a VP percentage ≥ 1% was considered as significant). RESULTS: Out of 936 TAVI patients (Sapien-3' n = 379 [Edwards Lifesciences, Irvine, CA, USA]; Sapien-XT' n = 513; CoreValve' n = 44, Medtronic, Minneapolis, MN, USA), 87 (9.3%) had PPI. Eighty of these 87 patients were followed-up and analyzed. At the first pacemaker interrogation, a significant VP percentage was observed in 60/80 followed-up patients (75%), in 46/51 patients (90.2%) implanted for CAVB, and 12/23 patients (52.2%) implanted for NOP-LBBB associated with either prolonged PR or HV interval. No clinical predictive factor of significant VP percentage was found. CONCLUSION: In the post-TAVI period, our data support PPI in patients with CAVB even if paroxysmal. Our data also suggest PPI may be considered in patients with NOP-LBBB associated with either prolonged PR or HV interval.

12.
Artigo em Inglês | MEDLINE | ID: mdl-29778857

RESUMO

OBJECTIVES: The aim of this study was to develop a new scoring system based on thoracic aortic calcification (TAC) to predict 1-year cardiovascular and all-cause mortality. BACKGROUND: A calcified aorta is often associated with poor prognosis after transcatheter aortic valve replacement (TAVR). A risk score encompassing aortic calcification may be valuable in identifying poor TAVR responders. METHODS: The C4CAPRI (4 Cities for Assessing CAlcification PRognostic Impact) multicenter study included a training cohort (1,425 patients treated using TAVR between 2010 and 2014) and a contemporary test cohort (311 patients treated in 2015). TAC was measured by computed tomography pre-TAVR. CAPRI risk scores were based on the linear predictors of Cox models including TAC in addition to comorbidities and demographic, atherosclerotic disease and cardiac function factors. CAPRI scores were constructed and tested in 2 independent cohorts. RESULTS: Cardiovascular and all-cause mortality at 1 year was 13.0% and 17.9%, respectively, in the training cohort and 8.2% and 11.8% in the test cohort. The inclusion of TAC in the model improved prediction: 1-cm3 increase in TAC was associated with a 6% increase in cardiovascular mortality and a 4% increase in all-cause mortality. The predicted and observed survival probabilities were highly correlated (slopes >0.9 for both cardiovascular and all-cause mortality). The model's predictive power was fair (AUC 68% [95% confidence interval [CI]: 64-72]) for both cardiovascular and all-cause mortality. The model performed similarly in the training and test cohorts. CONCLUSIONS: The CAPRI score, which combines the TAC variable with classical prognostic factors, is predictive of 1-year cardiovascular and all-cause mortality. Its predictive performance was confirmed in an independent contemporary cohort. CAPRI scores are highly relevant to current practice and strengthen the evidence base for decision making in valvular interventions. Its routine use may help prevent futile procedures.

13.
EuroIntervention ; 14(3): e264-e271, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29599103

RESUMO

AIMS: Durability of transcatheter aortic bioprosthetic valves remains a major issue. Standardised definitions of deterioration and failure of bioprosthetic valves have recently been proposed. The aim of this study was to assess structural transcatheter valve deterioration (SVD) and bioprosthetic valve failure (BVF) using these new definitions. METHODS AND RESULTS: All TAVI patients implanted up to September 2012 with a minimal theoretical five-year follow-up were included. Systematic clinical and echocardiographic follow-up was performed annually. New standardised definitions were used to assess durability of transcatheter aortic bioprosthetic valves. From 2002 to 2012, 378 patients were included. Mean age and logistic EuroSCORE were 83.3±6.8 years and 22.8±13.1%. Thirty-day mortality was 13.2%. Nine patients had SVD including two severe forms and two patients had definite late BVF. The incidence of SVD and BVF at eight years was 3.2% (95% CI: 1.45-6.11) and 0.58% (95% CI: 0.15-2.75), respectively. CONCLUSIONS: Even though limited by the poor survival of the very high-risk/compassionate early population, our data do not demonstrate any alarm concerning transcatheter aortic valve durability. Careful prospective assessment in younger and lower-risk patients and comparison with surgical bioprosthetic valves are required for further assessment of the long-term durability of transcatheter valves.

14.
Curr Opin Struct Biol ; 49: 77-84, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29414515

RESUMO

The Type VI secretion system (T6SS) is a dynamic nanomachine present in many Gram-negative bacteria. Using a contraction mechanism similar to that of myophages, bacteriocins or anti-feeding prophages, it injects toxic effectors into both eukaryotic and prokaryotic cells. T6SS assembles three large ensembles: the trans-membrane complex (TMC), the baseplate and the tail. Recently, the tail structure has been elucidated by cryo electron microscopy (cryoEM) in extended and contracted forms. The structure of the trans-membrane complex has been deciphered using a combination of X-ray crystallography and EM. However, the structural characterisation of the baseplate lags behind and should be the target of future studies. Finally, cryo-tomography should provide low/medium resolution maps allowing to assemble the different parts ultimately leading to a complete structural description of T6SS.

15.
J Mol Biol ; 430(7): 987-1003, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29458124

RESUMO

The type VI secretion system (T6SS) is a multiprotein complex used by bacteria to deliver effectors into target cells. The T6SS comprises a bacteriophage-like contractile tail structure anchored to the cell envelope by a membrane complex constituted of the TssJ outer-membrane lipoprotein and the TssL and TssM inner-membrane proteins. TssJ establishes contact with the periplasmic domain of TssM whereas the transmembrane segments of TssM and its cytoplasmic domain interact with TssL. TssL protrudes in the cytoplasm but is anchored by a C-terminal transmembrane helix (TMH). Here, we show that TssL TMH dimerization is required for the stability of the protein and for T6SS function. Using the TOXCAT assay and point mutations of the 23 residues of the TssL TMH, we identified Thr194 and Trp199 as necessary for TssL TMH dimerization. NMR hydrogen-deuterium exchange experiments demonstrated the existence of a dimer with the presence of Trp185 and Trp199 at the interface. A structural model based on molecular dynamic simulations shows that TssL TMH dimer formation involves π-π interactions resulting from the packing of the two Trp199 rings at the C-terminus and of the six aromatic rings of Tyr184, Trp185 and Trp188 at the N-terminus of the TMH.

16.
Opt Express ; 26(24): 31542-31553, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30650738

RESUMO

Coherent beam combining in tiled-aperture configuration is demonstrated on seven femtosecond fiber amplifiers using an interferometric phase measurement technique. The residual phase error between two fibers is as low as λ/55 RMS and a combination efficiency of 48% has been achieved. The combined pulses are compressed to 216 fs, delivering 71 W average power at a repetition rate of 55 MHz. Operating the laser system in a nonlinear regime with an estimated B-integral of 5 rad yields a combining efficiency of 45% with the same phase stability. These results pave the way to very large high-power and high energy coherent beam combining systems.

17.
JACC Cardiovasc Interv ; 10(23): 2426-2436, 2017 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-29217006

RESUMO

OBJECTIVES: The aim of this study was to assess the incidence, prognostic impact, and predictive factors of readmission for congestive heart failure (CHF) in patients with severe aortic stenosis treated by transcatheter aortic valve replacement (TAVR). BACKGROUND: TAVR is indicated in patients with severe symptomatic aortic stenosis in whom surgery is considered high risk or is contraindicated. Readmission for CHF after TAVR remains a challenge, and data on prognostic and predictive factors are lacking. METHODS: All patients who underwent TAVR from January 2010 to December 2014 were included. Follow-up was achieved for at least 1 year and included clinical and echocardiographic data. Readmission for CHF was analyzed retrospectively. RESULTS: This study included 546 patients, 534 (97.8%) of whom were implanted with balloon-expandable valves preferentially via the transfemoral approach in 87.8% of cases. After 1 year, 285 patients (52.2%) had been readmitted at least once, 132 (24.1%) for CHF. Patients readmitted for CHF had an increased risk for death (p < 0.0001) and cardiac death (p < 0.0001) compared with those not readmitted for CHF. On multivariate analysis, aortic mean gradient (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79 to 0.99; p = 0.03), post-procedural blood transfusion (HR: 2.27; 95% CI: 1.13 to 5.56; p = 0.009), severe post-procedural pulmonary hypertension (HR: 1.04; 95% CI: 1.00 to 1.07; p < 0.0001), and left atrial diameter (HR: 1.47; 95% CI: 1.08 to 2.01; p = 0.02) were independently associated with CHF readmission at 1 year. CONCLUSIONS: Readmission for CHF after TAVR was frequent and was strongly associated with 1-year mortality. Low gradient, persistent pulmonary hypertension, left atrial dilatation, and transfusions were predictive of readmission for CHF.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Insuficiência Cardíaca/epidemiologia , Readmissão do Paciente , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/fisiopatologia , Valvuloplastia com Balão/efeitos adversos , Causas de Morte , Distribuição de Qui-Quadrado , Ecocardiografia , Feminino , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/fisiopatologia , Incidência , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Razão de Chances , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do Tratamento
18.
Clin Cardiol ; 40(12): 1316-1322, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29247516

RESUMO

BACKGROUND: Coronary artery disease (CAD) is common in patients undergoing transcatheter aortic valve replacement (TAVR). However, the impact of CAD distribution before TAVR on short- and long-term prognosis remains unclear. HYPOTHESIS: We hypothesized that the long-term clinical impact differs according to CAD distribution in patients undergoing TAVR using the FRench Aortic National CoreValve and Edwards (FRANCE-2) registry. METHODS: FRANCE-2 is a national French registry including all consecutive TAVR performed between 2010 and 2012 in 34 centers. Three-year mortality was assessed in relation to CAD status. CAD was defined as at least 1 coronary stenosis >50%. RESULTS: A total of 4201 patients were enrolled in the registry. For the present analysis, we excluded patients with a history of coronary artery bypass. CAD was reported in 1252 patients (30%). Half of the patients presented with coronary multivessel disease. CAD extent was associated with an increase in cardiovascular risk profile and in logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (from 19.3% ± 12.8% to 21.9% ± 13.5%, P < 0.001). Mortality at 30 days and 3 years was 9% and 44%, respectively, in the overall population. In multivariate analyses, neither the presence nor the extent of CAD was associated with mortality at 3 years (presence of CAD, hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78-1.07). A significant lesion of the left anterior descending (LAD) was associated with higher 3-year mortality (HR: 1.42; 95% CI: 1.10-1.87). CONCLUSIONS: CAD is not associated with decreased short- and long-term survival in patients undergoing TAVR. The potential deleterious effect of LAD disease on long-term survival and the need for revascularization before or at the time of TAVR should be validated in a randomized control trial.


Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Sistema de Registros , Medição de Risco/métodos , Substituição da Valva Aórtica Transcateter , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/epidemiologia , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/cirurgia , Feminino , Seguimentos , França/epidemiologia , Humanos , Incidência , Masculino , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida/tendências , Resultado do Tratamento
19.
MBio ; 8(5)2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29042493

RESUMO

The type II secretion system (T2SS) releases large folded exoproteins across the envelope of many Gram-negative pathogens. This secretion process therefore requires specific gating, interacting, and dynamics properties mainly operated by a bipartite outer membrane channel called secretin. We have a good understanding of the structure-function relationship of the pore-forming C-terminal domain of secretins. In contrast, the high flexibility of their periplasmic N-terminal domain has been an obstacle in obtaining the detailed structural information required to uncover its molecular function. In Pseudomonas aeruginosa, the Xcp T2SS plays an important role in bacterial virulence by its capacity to deliver a large panel of toxins and degradative enzymes into the surrounding environment. Here, we revealed that the N-terminal domain of XcpQ secretin spontaneously self-assembled into a hexamer of dimers independently of its C-terminal domain. Furthermore, and by using multidisciplinary approaches, we elucidate the structural organization of the XcpQ N domain and demonstrate that secretin flexibility at interdimer interfaces is mandatory for its function.IMPORTANCE Bacterial secretins are large homooligomeric proteins constituting the outer membrane pore-forming element of several envelope-embedded nanomachines essential in bacterial survival and pathogenicity. They comprise a well-defined membrane-embedded C-terminal domain and a modular periplasmic N-terminal domain involved in substrate recruitment and connection with inner membrane components. We are studying the XcpQ secretin of the T2SS present in the pathogenic bacterium Pseudomonas aeruginosa Our data highlight the ability of the XcpQ N-terminal domain to spontaneously oligomerize into a hexamer of dimers. Further in vivo experiments revealed that this domain adopts different conformations essential for the T2SS secretion process. These findings provide new insights into the functional understanding of bacterial T2SS secretins.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Multimerização Proteica , Pseudomonas aeruginosa/metabolismo , Sistemas de Secreção Tipo II/química , Sistemas de Secreção Tipo II/metabolismo , Cristalografia por Raios X , Microscopia Eletrônica , Modelos Moleculares , Conformação Proteica
20.
Bioessays ; 39(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28817192

RESUMO

The Type VI secretion system (T6SS) is a multiprotein and mosaic apparatus that delivers protein effectors into prokaryotic or eukaryotic cells. Recent data on the enteroaggregative Escherichia coli (EAEC) T6SS have provided evidence that the TssA protein is a key component during T6SS biogenesis. The T6SS comprises a trans-envelope complex that docks the baseplate, a cytoplasmic complex that represents the assembly platform for the tail. The T6SS tail is structurally, evolutionarily and functionally similar to the contractile tails of bacteriophages. We have shown that TssA docks to the membrane complex, recruits the baseplate complex and initiates and coordinates the polymerization of the inner tube with that of the sheath. Here, we review these recent findings, discuss the variations within TssA-like proteins, speculate on the role of EAEC TssA in T6SS biogenesis and propose future research perspectives.


Assuntos
Sistemas de Secreção Tipo VI/metabolismo , Bacteriófagos/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo
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