RESUMO
OBJECTIVES: This study aimed to assess the impact of stent optimization by NC-balloon postdilatation (PD) during primary-PCI for STEMI with the use of coronary physiology and intracoronary imaging. METHODS: This was a prospective observational study (ClinicalTrials.gov:NCT02788396). Optical coherence tomography (OCT) and physiological measurements were performed immediately before and after PD with the operators blinded to all measurements. The index of microcirculatory resistance (IMR), coronary flow reserve (CFR) and fractional flow reserve (FFR) were measured. OCT analysis was performed for assessment of stent expansion, malapposition, in-stent plaque-thrombus prolapse (PTP) and stent-edge dissections (SED). The change in IMR before and after PD as a measure of microvascular injury was the primary objective of the study. RESULTS: Thirty-two STEMI patients undergoing primary-PCI had physiological measurements before and after PD. All patients received second-generation DES (diameter 3.1 ± 0.5 mm, length 29.9 ± 10.7 mm) and postdilatation with NC-balloons (diameter 3.6 ± 0.6 mm, inflation pressure 19.3 ± 2.0 atm). IMR (44.9 ± 25.6 vs. 48.8 ± 34.2, p = 0.26) and CFR (1.60 ± 0.89 vs. 1.58 ± 0.71, p = 0.87) did not change, while FFR increased after PD (0.91 ± 0.08 vs. 0.93 ± 0.06, p = 0.037). At an individual patient level, IMR increased in half of the cases. PD improved significantly absolute and relative stent expansion, reduced malapposition, and increased PTP. There was no difference in clinically relevant SED. CONCLUSION: In this exploratory, hypothesis-generating study, postdilatation during primary-PCI for STEMI improved stent expansion, apposition and post-PCI FFR, without a significant effect on coronary microcirculation overall. Nevertheless, IMR increased in a group of patients and larger studies are warranted to explore predictors of microcirculatory response to postdilatation.
Assuntos
Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Angiografia Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Humanos , Microcirculação , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Stents , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
OBJECTIVES: We sought to evaluate mortality predictors and the role of new-generation drug-eluting stents (NG-DES) in stent thrombosis (ST) management. BACKGROUND: No data are available regarding the outcome of patients with ST after interventional management that includes exclusively NG-DES. METHODS: Patients with definite ST of DES or BMS who underwent urgent/emergent angiography between 2015 and 2018 at our institution were considered for the study. After excluding patients who achieved TIMI-flow<2 after intervention or received an old-generation stent, 131 patients were included. Management classification was stent or non-stent treatment (medical management, thromboaspiration, balloon-angioplasty). Follow-up was performed to document all-cause death (ACD) and target-lesion-revascularization (TLR) that was used for censorship. RESULTS: Mode of presentation was STEMI in 88% and UA/NSTEMI in 12%. Type of ST was early, late, and very late in 11, 4, and 85%, respectively. Eighty four patients received stent and 47 non-stent treatment. After 926 ± 34 days, 21 ACDs, 7 TLRs and no cases of definite, recurrent ST were observed. Univariate predictors of in-hospital mortality were LVEF and presentation with shock or cardiac arrest. For patients discharged alive, non-stent treatment (HR 4.2, p = .01), TIMI-2 flow (HR 7.4, p = .002) and GFR < 60 mL/min (HR 3.8, p = .01) were independent predictors of ACD. The stent-treatment group had significantly better ACD-free survival after discharge, both unadjusted (p = .022) and adjusted (p = .018). CONCLUSIONS: After ST management, different predictors were observed for in-hospital mortality and mortality in patients discharged alive. The better outcome with NG-DES treatment is a novel observation, warranting further studies to elucidate if it is associated with stent-related or patient-related factors.
Assuntos
Angioplastia Coronária com Balão , Fármacos Cardiovasculares/uso terapêutico , Trombose Coronária/terapia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Trombectomia , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/mortalidade , Fármacos Cardiovasculares/efeitos adversos , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Trombose Coronária/mortalidade , Inglaterra , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Desenho de Prótese , Recidiva , Sistema de Registros , Retratamento , Medição de Risco , Fatores de Risco , Trombectomia/efeitos adversos , Trombectomia/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the immediate and short term impact of right coronary artery (RCA) chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) upon collateral donor vessel fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). BACKGROUND: CTO PCI influences collateral donor vessel physiology, making the indication and/or timing of donor vessel revascularization difficult to determine. METHODS: In patients with RCA CTO, FFR, iFR, and collateral function index (FFRcoll ) were measured in LAD and LCx pre-CTO PCI, immediately post and at 4 month follow-up. RESULTS: 34 patients underwent successful PCI. In the predominant donor vessel immediately post PCI, FFR, and FFRcoll did not change (0.76 ± 0.12 to 0.75 ± 0.13, P = 0.267 and 0.31 ± 0.10 vs. 0.34 ± 0.11, P = 0.078), but iFR increased significantly (0.86 ± 0.10 to 0.88 ± 0.10, P = 0.012). At follow-up, there was a significant increase in predominant donor FFR and iFR (0.76 ± 0.12 to 0.79 ± 0.11, P = 0.047 and 0.86 ± 0.10 to 0.90 ± 0.07, P = 0.003), accompanied by a significant reduction in FFRcoll (0.31 ± 0.10 to 0.18 ± 0.07 P < 0.0001). These changes resulted in a reclassification of the predominant donor vessel from ischemic to nonischemic in 18% (FFR) and 25% (iFR) of the cases, respectively. CONCLUSIONS: Successful recanalization of an RCA CTO resulted in a modest but statistically significant increase in the predominant donor vessel immediately post CTO PCI in the case of iFR and at 4-month follow-up for FFR and iFR compared to pre-PCI with a concomitant reduction in collateral function.
Assuntos
Angina Estável/terapia , Cateterismo Cardíaco , Circulação Colateral , Oclusão Coronária/terapia , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Idoso , Angina Estável/diagnóstico , Angina Estável/fisiopatologia , Doença Crônica , Tomada de Decisão Clínica , Angiografia Coronária , Oclusão Coronária/diagnóstico , Oclusão Coronária/fisiopatologia , Stents Farmacológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Frailty, a state of increased vulnerability to adverse health outcomes, has garnered significant attention in research and clinical practice. Existing constructs aggregate clinical features or health deficits into a single score. While simple and interpretable, this approach may overlook the complexity of frailty and not capture the full range of variation between individuals. METHODS: Exploratory factor analysis was used to infer latent dimensions of a frailty index constructed using survey data from the English Longitudinal Study of Ageing, wave 9. The dataset included 58 self-reported health deficits in a representative sample of community-dwelling adults aged 65+ (N=4971). Deficits encompassed chronic disease, general health status, mobility, independence with activities of daily living, psychological well-being, memory and cognition. Multiple linear regression examined associations with CASP-19 quality of life scores. RESULTS: Factor analysis revealed four frailty subdimensions. Based on the component deficits with the highest loading values, these factors were labelled 'mobility impairment and physical morbidity', 'difficulties in daily activities', 'mental health' and 'disorientation in time'. The four subdimensions were a better predictor of quality of life than frailty index scores. CONCLUSIONS: Distinct subdimensions of frailty can be identified from standard index scores. A decomposed approach to understanding frailty has a potential to provide a more nuanced understanding of an individual's state of health across multiple deficits.
Assuntos
Atividades Cotidianas , Idoso Fragilizado , Fragilidade , Avaliação Geriátrica , Qualidade de Vida , Humanos , Idoso , Feminino , Masculino , Estudos Longitudinais , Idoso Fragilizado/psicologia , Idoso Fragilizado/estatística & dados numéricos , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Envelhecimento/psicologia , Inglaterra , Análise Fatorial , Nível de Saúde , Vida Independente , Saúde MentalRESUMO
Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1-positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Delta1-9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.
Assuntos
Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Prolactina/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Sequência de Bases , Proliferação de Células , Primers do DNA/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/terapia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Prolactina/genética , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Ratos , Receptores da Prolactina/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Distribuição TecidualRESUMO
BACKGROUND: Randomised studies of percutaneous coronary intervention (PCI) in patients with chronic total occlusion (CTO) have shown inconsistent outcomes, suggesting incomplete understanding of this cohort and their coronary physiology. To address this shortcoming, we designed a prospective observational study to measure the recovery of absolute coronary blood flow following successful CTO PCI Aims: We sought to identify patient and procedural characteristics associated with a favourable physiological outcome after CTO PCI. METHODS: Consecutive patients with a CTO subtending viable myocardium underwent PCI utilising contemporary techniques and the hybrid algorithm. Immediately after PCI, and at 3-month follow-up, physiological measurements were performed utilising continuous thermodilution. RESULTS: A total of 81 patients were included with a mean age of 63.6±8.9 years, and 66 (81.5%) were male. Physiological measurements of absolute coronary blood flow in the CTO vessel increased by 30% (p<0.001) and microvascular resistance reduced by 16% (p<0.001) from immediately post-CTO PCI to follow-up assessment. Fractional flow reserve increased by 0.02 (p=0.015) in the same period. Prior coronary artery bypass graft (CABG) and a higher estimated glomerular filtration rate (eGFR) were associated with a larger change in absolute flow. An extraplaque strategy was associated with a smaller change in absolute flow. CONCLUSIONS: Post-CTO PCI, there is a continued augmentation in absolute coronary blood flow and reduction in microvascular resistance from baseline to follow-up at 3 months. Prior CABG and a higher baseline eGFR were predictors of a larger change in absolute coronary flow, whilst an extraplaque final wire path strategy predicted a smaller change. Lastly, the patient characteristics and comorbidities had a larger influence than procedural factors on the observed change in absolute flow.
Assuntos
Oclusão Coronária , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Resultado do Tratamento , Oclusão Coronária/cirurgia , Intervenção Coronária Percutânea/métodos , Angiografia Coronária , Miocárdio , Doença Crônica , Fatores de RiscoRESUMO
The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1(-/-) myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.
Assuntos
Músculo Esquelético/metabolismo , Proteínas Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/fisiologia , Animais , Atrofia , Peso Corporal , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Colágeno/farmacologia , Combinação de Medicamentos , Deleção de Genes , Vetores Genéticos , Genótipo , Proteínas de Fluorescência Verde/metabolismo , Homozigoto , Humanos , Immunoblotting , Laminina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Músculos/patologia , Plasmídeos/metabolismo , Ligação Proteica , Proteoglicanas/farmacologia , Retroviridae/genética , Transdução de Sinais , Somatomedinas/metabolismo , Serina-Treonina Quinases TOR , Fatores de Tempo , TransfecçãoRESUMO
BACKGROUND: Contemporary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) incorporates wire escalation and dissection/re-entry recanalisation strategies. AIMS: The purpose of the study was to investigate changes in collateral function after CTO PCI and to identify whether the mode of successful recanalisation influences collateral function regression. METHODS: Patients scheduled for elective CTO PCI with evidence of viability in the CTO territory by noninvasive imaging were included in this study. After successful CTO PCI, the aortic pressure (Pa) and distal coronary artery wedge pressure (Pw) during balloon occlusion were measured, both in a resting state and during infusion of intravenous adenosine, allowing the calculation of the pressure-derived collateral pressure index at rest and hyperaemia (CPIrest and the collateral fractional flow reserve [FFRcoll], respectively). Measurements were repeated 3 months later during angiographic follow-up. RESULTS: Eighty-one patients had physiological measurements at baseline and follow-up. In the final cohort the mean age was 64 years and 82% were male. The mean maximal stent diameter and total stent length were 3.2±0.5 mm and 68±31 mm, respectively. Successful strategies were antegrade wiring (64.2%), antegrade dissection re-entry (8.6%), and retrograde dissection re-entry (27.1%). Between the index procedure and follow-up, wedge pressure decreased from 34±11 mmHg to 21±8.5 mmHg (p<0.01), respectively. FFRcoll changed from 0.34±0.11 to 0.19±0.09 (p<0.01) at follow-up and CPIrest from 0.40±0.14 to 0.17±0.09 (p<0.01). Absolute maximum collateral flow decreased from 55±32 ml/min directly after PCI to 38±24 ml/min (p<0.01). There was no relation between the recanalisation technique and changes in FFRcoll. CONCLUSIONS: There was a significant reduction in collateral flow over time, independent of the recanalisation technique.
Assuntos
Oclusão Coronária , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Crônica , Angiografia Coronária , Oclusão Coronária/cirurgia , Intervenção Coronária Percutânea/métodos , Resultado do TratamentoRESUMO
OBJECTIVE: The impact of adjunctive manual thrombus aspiration (TA) in patients with stent thrombosis (ST) treated with percutaneous intervention has not been evaluated in the current era of potent P2Y12 agents and new-generation drug-eluting stents. We sought to assess the effect of TA using data from a large contemporary registry. METHODS: The study population was derived from the Essex ST Investigation Registry (ESTHIR), which contains all consecutive cases of angiographically determined definite ST undergoing interventional treatment in a tertiary cardiac centre between November 2015 and June 2018. Propensity score matching was performed to match patients who underwent TA (TA group) to those who did not (n-TA group). The study endpoints were final TIMI flow and survival free of cardiovascular death (CD) or target lesion revascularisation (TLR). RESULTS: A total of 128 ST patients were included in the present analysis. The mean age was 65 ± 11 years, and 84% were male. About 90% of the patients presented with STEMI, and 85% had very late ST. Seventy-two patients (56%) underwent TA. After propensity score matching, 30 patients were included in each study group. A higher rate of final TIMI III flow was observed in the TA group (TA vs n-TA group, 100% vs 83%), but this difference did not reach statistical significance (p = 0.052). At 1000 days of follow-up, survival free of CD or TLR was not different between the two groups (p = 0.8). CONCLUSION: In a propensity-matched population of ST patients undergoing PCI in a contemporary setting, TA was not associated with improved final TIMI flow or long-term cardiovascular outcomes.
Assuntos
Trombose Coronária , Stents Farmacológicos , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Trombose , Idoso , Angiografia Coronária , Trombose Coronária/terapia , Stents Farmacológicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Sucção , Trombectomia/efeitos adversos , Trombose/epidemiologia , Trombose/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Fractional flow reserve (FFR) assessment of remote arteries, in the context of a bystander chronic total occlusion (CTO), can lead to false positive results. Adenosine stress cardiovascular magnetic resonance (CMR) evaluates perfusion defects across the entire myocardium and may therefore be a reliable tool in the work-up of remote lesions in CTO patients. The IMPACT-CTO study investigated donor artery invasive physiology before, immediately post, and at 4 months following right coronary artery (RCA) CTO percutaneous coronary intervention (PCI). The aim of this subanalysis was to assess the concordance between baseline perfusion CMR and serial FFR evaluation of left anterior descending artery (LAD) ischemia in patients from the IMPACT-CTO study. METHODS: Baseline adenosine stress CMR examinations from 26 patients were analyzed for qualitative evidence of LAD ischemia. The results were correlated with the serial LAD FFR measurements. RESULTS: The present findings demonstrated that before RCA CTO PCI, there was 62% agreement between perfusion CMR and FFR (ischemic threshold £ 0.8) in the assessment of LAD ischemia (k = 0.29; fair concordance). At 4 months after revascularization, there was 77% agreement (k = 0.52; moderate concordance) between the index CMR assessment of LAD ischemia and the follow-up LAD FFR. Concordance was improved at a LAD FFR ischemic threshold of £ 0.75. CONCLUSIONS: In this hypothesis generating study, baseline CMR assessment of LAD ischemia correlated better with the 4 months LAD FFR data (threshold £ 0.8) as compared to the FFR measurements taken prior to RCA CTO revascularization.
Assuntos
Oclusão Coronária , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Adenosina , Angiografia Coronária , Oclusão Coronária/diagnóstico , Oclusão Coronária/cirurgia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , PerfusãoRESUMO
We report the first crystal structure of a 1:2 hormone.receptor complex that involves prolactin (PRL) as the ligand, at 3.8-A resolution. Stable ternary complexes were obtained by generating affinity-matured PRL variants harboring an N-terminal tail from ovine placental lactogen, a closely related PRL receptor (PRLR) ligand. This structure allows one to draw up an exhaustive inventory of the residues involved at the PRL.PRLR site 2 interface, consistent with all previously reported site-directed mutagenesis data. We propose, with this description, an interaction model involving three structural components of PRL site 2 ("three-pin plug"): the conserved glycine 129 of helix alpha3, the hydrogen bond network involving surrounding residues (glycine cavity), and the N terminus. The model provides a molecular basis for the properties of the different PRL analogs designed to date, including PRLR antagonists. Finally, comparison of our 1:2 PRL.PRLR(2) structure with those of free PRL and its 1:1 complex indicates that the structure of PRL undergoes significant changes when binding the first, but not the second receptor. This suggests that the second PRLR moiety adapts to the 1:1 complex rather than the opposite. In conclusion, this structure will be a useful guiding tool for further investigations of the molecular mechanisms involved in PRLR dimerization and activation, as well as for the optimization of PRLR antagonists, an emerging class of compounds with high therapeutic potential against breast and prostate cancer.
Assuntos
Prolactina/química , Prolactina/genética , Receptores da Prolactina/química , Receptores da Prolactina/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia , Dimerização , Desenho de Fármacos , Glicina/metabolismo , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Lactogênio Placentário/química , Lactogênio Placentário/genética , Prolactina/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Receptores da Prolactina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Ovinos , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Difração de Raios XRESUMO
There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)-->Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlR(I146L)), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlR(I146L) in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Fibroadenoma/genética , Fibroadenoma/metabolismo , Mutação de Sentido Incorreto , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Adulto , Estudos de Casos e Controles , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Éxons/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Humanos , Imuno-Histoquímica , Estudos Prospectivos , Receptores da Prolactina/agonistas , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/farmacologiaRESUMO
AIM: We sought to investigate the impact of IVUS use on chronic total occlusion (CTO) PCI using data from a contemporary registry of consecutive patients and applying a propensity score matching analysis. METHODS AND RESULTS: We evaluated 514 successful CTO-PCIs, median age: 67 years (IQR: 58-73), 83.5% males. IVUS-guided PCI was performed in 184 (35.8%) of cases. After using 1:1 propensity matching score analysis, two groups of 182 patients each (IVUS-guided vs. angiography-guided CTO-PCI group) were produced to form the study population. In the IVUS-guided group the median maximum stent diameter was larger and the median total stented segment was longer compared to the angiography-guided group [(3.5 mm, IQR: 3.0-4.0 vs. 3.2 mm, IQR: 3.0-3.5, p < 0.001) and (60.0 mm, IQR: 38.0-91.3 vs. 38.0 mm, IQR: 32.0-70.5, p < 0.001), respectively]. In the IVUS-guided group, retrograde recanalization was more frequently encountered compared to the angiography-guided PCI group (30.2% vs. 20.9%, p = 0.04). Procedural time was significantly longer in the IVUS-guided group, without any difference in fluoroscopy time, radiation dose and contrast volume. Multivariate linear regression analysis showed that IVUS use was the strongest independent factor associated with larger maximum diameter stents (p < 0.001) and a strong independent predictor for total stented segment length during CTO-PCI (p < 0.001). Up to 8 years follow-up, there was no difference in the incidence of the composite endpoint of all-cause death, cardiac death, myocardial infarction and target vessel revascularization between the IVUS-guided PCI and the angiography-guided PCI groups (hazard ratio: 13.7% vs. 15.9%, respectively, log-rank: p = 0.67, median follow-up time: 49.0 months, IQR: 33.0-67.0). CONCLUSIONS: Use of IVUS in CTO-PCI was associated with larger stent diameter and longer stented segments. Despite more frequent use of IVUS in retrograde CTO-PCI, there was no difference in long-term adverse events between IVUS and angiography CTO-PCI groups; nevertheless, the study was not powered to assess clinical outcomes.
Assuntos
Oclusão Coronária , Stents Farmacológicos , Intervenção Coronária Percutânea , Idoso , Angiografia Coronária , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/cirurgia , Feminino , Humanos , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
OBJECTIVES: Adenosine hyperemia is an integral component of the physiological assessment of obstructive coronary artery disease in patients with chronic coronary syndrome (CCS). The aim of this study was to compare systemic, coronary and microcirculatory hemodynamics between intravenous (IV) adenosine hyperemia versus physical exercise stress in patients with CCS and coronary stenosis. METHODS: Twenty-three patients (mean age, 60.6 ± 8.1 years) with CCS and single-vessel coronary stenosis underwent cardiac catheterization. Continuous trans-stenotic coronary pressure-flow measurements were performed during: i) IV adenosine hyperemia, and ii) physical exercise using a catheter-table-mounted supine ergometer. Systemic, coronary and microcirculatory hemodynamic responses were compared between IV adenosine and exercise stimuli. RESULTS: Mean stenosis diameter was 74.6% ± 10.4. Median (interquartile range) FFR was 0.54 (0.44-0.72). At adenosine hyperemia versus exercise stress, mean aortic pressure (Pa, 91 ± 16 mmHg vs 99 ± 15 mmHg, p < 0.0001), distal coronary pressure (Pd, 58 ± 21 mmHg vs 69 ± 24 mmHg, p < 0.0001), trans-stenotic pressure ratio (Pd/Pa, 0.63 ± 0.18 vs 0.69 ± 0.19, p < 0.0001), microvascular resistance (MR, 2.9 ± 2.2 mmHg.cm-1.sec-1 vs 4.2 ± 1.7 mmHg.cm-1.sec-1, p = 0.001), heart rate (HR, 80 ± 15 bpm vs 85 ± 21 bpm, p = 0.02) and rate-pressure product (RPP, 7522 ± 2335 vs 9077 ± 3200, p = 0.0001) were all lower. Conversely, coronary flow velocity (APV, 23.7 ± 9.5 cm/s vs 18.5 ± 6.8 cm/s, p = 0.02) was higher. Additionally, temporal changes in Pa, Pd, Pd/Pa, MR, HR, RPP and APV during IV adenosine hyperemia versus exercise were all significantly different (p < 0.05 for all). CONCLUSIONS: In patients with CCS and coronary stenosis, invasive hemodynamic responses differed markedly between IV adenosine hyperemia versus physical exercise stress. These differences were observed across systemic, coronary and microcirculatory hemodynamics.
Assuntos
Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Hiperemia , Adenosina/farmacologia , Idoso , Cateterismo Cardíaco , Estenose Coronária/diagnóstico por imagem , Vasos Coronários , Exercício Físico , Hemodinâmica , Humanos , Microcirculação , Pessoa de Meia-Idade , Síndrome , Vasodilatadores/farmacologiaRESUMO
Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval.
Assuntos
Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Vias Neurais/metabolismo , Percepção Espacial/fisiologia , Animais , Anisomicina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Vias Neurais/efeitos dos fármacos , Testes Neuropsicológicos , Orientação/efeitos dos fármacos , Orientação/fisiologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Percepção Espacial/efeitos dos fármacosRESUMO
The serotonergic (5-hydroxytryptamine; 5-HT) dysfunction found in depression may affect not only brain function (mood) but also cerebrovascular control. Similar, but possibly occult, disturbances may also be induced by 3,4-methylenedioxymethamphetamine-induced neurotoxicity (MDMA, or "ecstasy"). Acute tryptophan depletion (ATD) is widely used to identify vulnerability to depression, and we hypothesized that repeated MDMA administration would increase the sensitivity of rats to this acute serotonergic challenge. In this study, male Wistar rats were injected with MDMA (20 mg kg(-1), twice daily for 4 days) and challenged 3 weeks later with ATD, induced by intragastric administration of a nutritional mixture with tryptophan (TRP) removed. Cerebral metabolism (CMRG) and blood flow (CBF) were measured in parallel groups of animals following ATD by using quantitative [(14)C]2-deoxyglucose and [(14)C]iodoantipyrine autoradiographic techniques, respectively. A significant reduction in paroxetine binding to 5-HT transporter sites in MDMA-treated rats indicated 5HT terminal depletion, whereas the plasma TRP/sum large neutral amino acids ratio was reduced by 40% following ATD. Under all experimental conditions, the normal close correlation between CBF and metabolic demand was maintained. However, a global analysis of all brain regions revealed a significant decrease in the overall ratio of CBF to CMRG after ATD in control animals, whereas a higher ratio was observed after ATD in the MDMA-treated group. This increase in blood flow relative to cerebral metabolism suggests an ATD-induced loss of cerebrovascular tone in MDMA-treated animals that could have pathophysiological consequences and might conceivably contribute to the behavioral dysfunction of depression.
Assuntos
Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/metabolismo , Transtorno Depressivo/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Serotonina/deficiência , Triptofano/deficiência , Animais , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Transtornos Cerebrovasculares/fisiopatologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Hiperemia/induzido quimicamente , Hiperemia/metabolismo , Hiperemia/fisiopatologia , Masculino , Paroxetina/metabolismo , Ratos , Ratos Wistar , Serotoninérgicos/toxicidade , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
AIMS: We sought to compare the efficiency of the novel EuroCTO (CASTLE) score with the commonly used Multicentre CTO Registry in Japan (J-CTO) score in predicting procedural success of percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTOs). METHODS AND RESULTS: We evaluated 660 consecutive CTO PCIs (mean age 66±11 years, 84% male). The mean J-CTO and EuroCTO (CASTLE) scores were 1.86±1.2 and 1.74±1.2, respectively. Antegrade wire escalation, antegrade dissection re-entry and retrograde approach were used in 82%, 14% and 37% of cases, respectively. Receiver operating characteristic analysis demonstrated equal overall discriminatory capacity between the two scores (AUC 0.698, 95% CI: 0.653-0.742, p<0.001 for J-CTO vs AUC 0.676, 95% CI: 0.627-0.725, p<0.001 for EuroCTO; AUC difference: 0.022, p=0.5). However, for more complex procedures (J-CTO ≥3 or EuroCTO [CASTLE] ≥4]), the predictive capacity of the EuroCTO (CASTLE) score appeared superior (AUC 0.588, 95% CI: 0.509-0.668, p=0.03 for EuroCTO [CASTLE] score vs AUC 0.473, 95% CI: 0.393-0.553, p=NS for the J-CTO score, AUC difference: 0.115, p=0.04). CONCLUSIONS: In this study, the novel EuroCTO (CASTLE) score was comparable to the J-CTO score in predicting CTO PCI outcome with a superior discriminatory capacity for the more complex cases.
Assuntos
Oclusão Coronária/cirurgia , Intervenção Coronária Percutânea , Sistema de Registros , Idoso , Doença Crônica , Angiografia Coronária , Oclusão Coronária/diagnóstico , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/mortalidade , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Background This study aimed to investigate longitudinal physiological changes in the recanalized coronary chronic total occlusion (CTO) vessel and its dependent myocardium after successful percutaneous coronary intervention (PCI). Methods and Results In this pilot study, 25 patients scheduled for elective CTO PCI with viable myocardium and angiographically visible collaterals were included. Absolute coronary blood flow and absolute microvascular resistance were measured invasively using continuous thermodilution. Measurements were performed immediately after successful CTO PCI and at short-term follow-up. In a subgroup of patients, physiological measurements were performed at the predominant donor vessel before CTO PCI, immediately afterwards, and at follow-up. Absolute coronary blood flow in the recanalized CTO artery increased from 148±53 mL/min immediately after PCI to 221±77 mL/min at follow-up (P<0.001). In agreement, absolute resistance in the myocardial territory perfused by the CTO artery, decreased from 545±255 Wood units immediately after the procedure to 387±128 Wood units at follow-up (P=0.014). There were no significant changes in the absolute coronary blood flow and resistance in the predominant donor between baseline and follow-up. Positive remodeling of the distal CTO vessel with an increase in lumen diameter was observed. Conclusions After successful CTO PCI, blood flow in the recanalized artery and microvascular function of the dependent myocardium are not immediately normal but recover over time.
Assuntos
Circulação Coronária , Oclusão Coronária/terapia , Vasos Coronários/fisiopatologia , Microcirculação , Intervenção Coronária Percutânea , Resistência Vascular , Idoso , Velocidade do Fluxo Sanguíneo , Doença Crônica , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Projetos Piloto , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do TratamentoRESUMO
The corpus luteum (CL) plays a central role in the maintenance of pregnancy in rodents, mainly by secreting progesterone. Female mice lacking prolactin (PRL) receptor (R) are sterile due to a failure of embryo implantation, which is a consequence of decreased luteinizing hormone (LH) receptor expression in the CL and inadequate levels of progesterone. We attempted to treat PRLR(-/-) females with human chorionic gonadotropin (hCG) and showed a de novo expression of LHR mRNA in the corpora lutea. Binding analysis confirmed that the LHR in hCG-treated PRLR(-/-) animals was functional. This was accompanied with increased expression of steroidogenic enzymes involved in progesterone synthesis. Despite these effects, no embryo implantation was observed because of high expression of 20alpha-hydroxysteroid dehydrogenase. To better appreciate the molecular mechanisms underlying maintenance of the CL, a series of mRNA expression-profiling experiments was performed on isolated corpora lutea of PRLR(-/-) and hCG-treated PRLR(-/-) mice. This approach revealed several novel candidate genes with potentially pivotal roles in ovarian function, among them, p27, VE-cadherin, Pten, and sFRP-4, a member of the Wnt/frizzled family. This study showed the differential role of PRL and LH in CL function and identified new targets of these hormones in luteal cells.
Assuntos
Manutenção do Corpo Lúteo/genética , Regulação da Expressão Gênica , Hormônio Luteinizante/fisiologia , Prolactina/fisiologia , Animais , Gonadotropina Coriônica/farmacologia , Corpo Lúteo/efeitos dos fármacos , Corpo Lúteo/metabolismo , Corpo Lúteo/fisiologia , Manutenção do Corpo Lúteo/sangue , Manutenção do Corpo Lúteo/efeitos dos fármacos , Manutenção do Corpo Lúteo/metabolismo , Feminino , Fertilidade/efeitos dos fármacos , Fertilidade/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Luteinizante/farmacologia , Masculino , Camundongos , Camundongos Knockout , Ovário/anatomia & histologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Gravidez , Progesterona/sangue , Prolactina/farmacologia , Receptores do LH/genética , Receptores do LH/metabolismo , Receptores da Prolactina/genéticaRESUMO
There is a large body of literature showing that prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Delta1-9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients.