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Stability issues in membrane-free coacervates have been addressed with coating strategies, but these approaches often compromise the permeability of the coacervate. Here we report a facile approach to maintain both stability and permeability using tannic acid and then demonstrate the value of this approach in enzyme-triggered drug release. First, we develop size-tunable coacervates via self-assembly of heparin glycosaminoglycan with tyrosine and arginine-based peptides. A thrombin-recognition site within the peptide building block results in heparin release upon thrombin proteolysis. Notably, polyphenols are integrated within the nano-coacervates to improve stability in biofluids. Phenolic crosslinking at the liquid-liquid interface enables nano-coacervates to maintain exceptional structural integrity across various environments. We discover a pivotal polyphenol threshold for preserving enzymatic activity alongside enhanced stability. The disassembly rate of the nano-coacervates increases as a function of thrombin activity, thus preventing a coagulation cascade. This polyphenol-based approach not only improves stability but also opens the way for applications in biomedicine, protease sensing, and bio-responsive drug delivery.
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Sistemas de Liberação de Medicamentos , Polifenóis , Taninos , Trombina , Polifenóis/química , Trombina/metabolismo , Trombina/química , Humanos , Taninos/química , Heparina/química , Liberação Controlada de Fármacos , Peptídeos/química , Peptídeos/metabolismo , ProteóliseRESUMO
Chronic wounds and amputations are common in chronic kidney disease patients needing hemodialysis (HD). HD is often complicated by drops in blood pressure (BP) called intra-dialytic hypotension. Whether intra-dialytic hypotension is associated with detectable changes in foot perfusion, a risk factor for wound formation and impaired healing remains unknown. Photoacoustic (PA) imaging is ideally suited to study perfusion changes. We scanned the feet of 20 HD and 11 healthy subjects. HD patients were scanned before and after a dialysis session whereas healthy subjects were scanned twice at rest and once after a 10 min exercise period while BP was elevated. Healthy (r = 0.70, p < 0.0001) and HD subjects (r = 0.43, p < 0.01) showed a significant correlation between PA intensity and systolic BP. Furthermore, HD cohort showed a significantly reduced PA response to changes in BP compared to the healthy controls (p < 0.0001), showing that PA can monitor hemodynamic changes due to changes in BP.
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Chronic wounds are a major health problem that cause the medical infrastructure billions of dollars every year. Chronic wounds are often difficult to heal and cause significant discomfort. Although wound specialists have numerous therapeutic modalities at their disposal, tools that could three dimensional-map wound bed physiology and guide therapy do not exist. Visual cues are the current standard but are limited to surface assessment; clinicians rely on experience to predict response to therapy. Photoacoustic (PA) ultrasound (US) is a non-invasive, hybrid imaging modality that can solve these major limitations. PA relies on the contrast generated by haemoglobin in blood which allows it to map local angiogenesis, tissue perfusion and oxygen saturation-all critical parameters for wound healing. This work evaluates the use of PA-US to monitor angiogenesis and stratify patients responding versus not-responding to therapy. We imaged 19 patients with 22 wounds once a week for at least 3 weeks. Our findings suggest that PA imaging directly visualises angiogenesis. Patients responding to therapy showed clear signs of angiogenesis and an increased rate of PA increase (p = 0.002). These responders had a significant and negative correlation between PA intensity and wound size. Hypertension was correlated to impaired angiogenesis in non-responsive patients. The rate of PA increase and hence the rate of angiogenesis was able to predict healing times within 30 days from the start of monitoring (power = 88%, alpha = 0.05). This early response detection system could help inform management and treatment strategies while improving outcomes and reducing costs.
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Neovascularização Patológica , Cicatrização , Humanos , Morfogênese , Ultrassonografia , Cicatrização/fisiologiaRESUMO
The transmission of SARS-CoV-2 coronavirus has led to the COVID-19 pandemic. Nucleic acid testing while specific has limitations for mass surveillance. One alternative is the main protease (Mpro ) due to its functional importance in mediating the viral life cycle. Here, we describe a combination of modular substrate and gold colloids to detect Mpro via visual readout. The strategy involves zwitterionic peptide that carries opposite charges at the C-/N-terminus to exploit the specific recognition by Mpro . Autolytic cleavage releases a positively charged moiety that assembles the nanoparticles with rapid color changes (t<10â min). We determine a limit of detection for Mpro in breath condensate matrices <10â nM. We further assayed ten COVID-negative subjects and found no false-positive result. In the light of simplicity, our test for viral protease is not limited to an equipped laboratory, but also is amenable to integrating as portable point-of-care devices including those on face-coverings.
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COVID-19/diagnóstico , Proteases 3C de Coronavírus/metabolismo , Peptídeos/metabolismo , SARS-CoV-2/metabolismo , Biomarcadores/metabolismo , Testes Respiratórios , COVID-19/virologia , Colorimetria/métodos , Humanos , Limite de Detecção , ProteóliseRESUMO
There is a need for surveillance of COVID-19 to identify individuals infected with SARS-CoV-2 coronavirus. Although specific, nucleic acid testing has limitations in terms of point-of-care testing. One potential alternative is the nonstructural protease (nsp5, also known as Mpro/3CLpro) implicated in SARS-CoV-2 viral replication but not incorporated into virions. Here, we report a divalent substrate with a novel design, (Cys)2-(AA)x-(Asp)3, to interface gold colloids in the specific presence of Mpro leading to a rapid and colorimetric readout. Citrate- and tris(2-carboxyethyl)phosphine (TCEP)-AuNPs were identified as the best reporter out of the 17 ligated nanoparticles. Furthermore, we empirically determined the effects of varying cysteine valence and biological media on the sensor specificity and sensitivity. The divalent peptide was specific to Mpro, that is, there was no response when tested with other proteins or enzymes. Furthermore, the Mpro detection limits in Tris buffer and exhaled breath matrices are 12.2 and 18.9 nM, respectively, which are comparable to other reported methods (i.e., at low nanomolar concentrations) yet with a rapid and visual readout. These results from our work would provide informative rationales to design a practical and noninvasive alternative for COVID-19 diagnostic testing-the presence of viral proteases in biofluids is validated.
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Facemasks in congregate settings prevent the transmission of SARS-CoV-2 and help control the ongoing COVID-19 global pandemic because face coverings can arrest transmission of respiratory droplets. While many groups have studied face coverings as personal protective equipment, these respiratory droplets can also serve as a diagnostic fluid to report on health state; surprisingly, studies of face coverings from this perspective are quite limited. Here, we determined the concentration and distribution of aerosolized saliva (via α-amylase levels) captured on various face coverings. Our results showed that α-amylase accumulated on face coverings in a time-dependent way albeit at different levels, e.g., neck gaiters and surgical masks captured about 3-fold more α-amylase than cloth masks and N95 respirators. In addition, the saliva aerosols were primarily detected on the inner layer of multilayered face coverings. We also found that the distribution of salivary droplets on the mask correlated with the morphologies of face coverings as well as their coherence to the face curvature. These findings motivated us to extend this work and build multifunctional sensing strips capable of detecting biomarkers in situ to create "smart" masks. The work highlights that face coverings are promising platforms for biofluid collection and colorimetric biosensing, which bode well for developing surveillance tools for airborne diseases.
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COVID-19 , Saliva , Aerossóis , Humanos , Máscaras , SARS-CoV-2RESUMO
Chronic wounds can be difficult to heal and are often accompanied by pain and discomfort. Multiple skin substitutes or cellularized/tissue-based skin products have been used in an attempt to facilitate closure of complex wounds. Allografts from cadaveric sources have been a viable option in achieving such closure. However, early assessment of graft incorporation has been difficult clinically, often with delayed evidence of failure. Visual cues to assess graft integrity have been limited and remain largely superficial at the skin surface. Furthermore, currently used optical imaging techniques can penetrate only a few millimeters deep into tissue. Ultrasound (US) imaging offers a potential solution to address this limitation. This work evaluates the use of US to monitor wound healing and allograft integration. We used a commercially available dual-mode (US and photoacoustic) scanner operating only in US mode. We compared the reported wound size from the clinic with the size measured using US in 45 patients. Two patients from this cohort received an allogenic skin graft and underwent multiple US scans over a 110-d period. All data were processed by two independent analysts; one of them was blinded to the study. We measured change in US intensity and wound contraction as a function of time. Our results revealed a strong correlation (R2 = 0.81, p < 0.0001) between clinically and US-measured wound sizes. Wound contraction >91% was seen in both patients after skin grafting. An inverse relationship between wound size and US intensity (R2 = 0.77, p < 0 .0001) indicated that the echogenicity of the wound bed increases as healthy cells infiltrate the allograft matrix, regenerating and leading to healthy tissue and re-epithelization. This work indicates that US can be used to measure wound size and visualize tissue regeneration during the healing process.
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Sistemas Automatizados de Assistência Junto ao Leito , Transplante de Pele , Humanos , Pele/diagnóstico por imagem , Ultrassonografia , CicatrizaçãoRESUMO
BACKGROUND: Ticagrelor presents less thrombotic risk compared to clopidogrel in acute coronary syndromes. However, its role in dual antiplatelet therapy (DAPT)-naive patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous intervention (PCI) remains unclear, including uncertainty in the method of conversion to clopidogrel for adequate coverage without increased bleeding risk. OBJECTIVE: Determine the safety and efficacy of ticagrelor loading and transitioning to clopidogrel in patients with SIHD undergoing elective PCI. METHODS: This is a retrospective cohort review of patients with SIHD who underwent elective PCI. The Switch Rx patients were treated with ticagrelor immediately before PCI, converted to clopidogrel 300 mg the day after, and discharged with clopidogrel 75 mg daily. Standard Rx patients, who received a clopidogrel load and received clopidogrel 75 mg daily after the procedure, were analyzed as a matched comparator cohort. The safety outcomes were any bleeding event at 24 hours and 30 days. The efficacy outcomes included major adverse cardiac events (MACE) at 24 hours and 30 days. RESULTS: Five Switch Rx patients (n = 54) experienced bleeding academic research consortium type I bleeding within 24 hours, with no subsequent bleeding observed out to 30 days. When comparing the Switch Rx patients (n = 39) to their matched Standard Rx cohort (n = 39), no MACEs occurred within 30 days and there were no significant differences in safety and efficacy outcomes. CONCLUSION: In DAPT-naive patients undergoing elective PCI for SIHD, a strategy of in-lab ticagrelor transitioning to clopidogrel with a 300-mg load was not associated with increased bleeding or other adverse events.
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Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/cirurgia , Clopidogrel/efeitos adversos , Humanos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Retrospectivos , Ticagrelor , Resultado do TratamentoRESUMO
BACKGROUND: Pre-procedural anemia is associated with increased bleeding and mortality post-percutaneous coronary intervention (PCI). The effect of trans-radial PCI (TR-PCI) in improving outcomes compared to trans-femoral PCI (TF-PCI) in anemic patients is not known. OBJECTIVE: The aim of this study was to evaluate the association between arterial access site (radial versus femoral) and outcomes in anemic Veterans undergoing PCI. METHODS: Patients with baseline anemia, undergoing PCI at Veterans Affairs (VA) facilities between 2009 and 2015, were divided into two groups based on primary radial or femoral access. The association between anemia and access site with in-hospital and one-year adverse outcomes was evaluated using multivariable analysis. RESULTS: 7330 veterans were included in the analysis, with 1712 (23%) treated via radial access. Baseline anemia was independently associated with in-hospital major bleeding (OR 3.8, 95% CI 2.5-5.6 for moderate anemia, OR 18.6, 95% CI 11.6-29.7 for severe anemia), and in-hospital mortality (OR 3.2, 95% CI 1.8-5.8 for moderate anemia, OR 7.9, 95% CI 3.7-16.8 for severe anemia). Anemia was also associated with increased one-year MACE and mortality. PCI performed via radial access was not associated with different outcomes compared with femoral access in the presence of anemia. Comparable results were noted when analysis was restricted to only patients with acute coronary syndrome (ACS). CONCLUSIONS: Moderate and severe anemia were strongly associated with increased in-hospital and one-year mortality in a large healthcare system, though there was no interaction between arterial access site for PCI and clinical outcomes among patients with moderate or severe anemia.
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Anemia/epidemiologia , Cateterismo Periférico , Doença da Artéria Coronariana/terapia , Artéria Femoral , Hemorragia/epidemiologia , Intervenção Coronária Percutânea , Artéria Radial , Idoso , Anemia/diagnóstico , Anemia/mortalidade , Cateterismo Periférico/efeitos adversos , Cateterismo Periférico/mortalidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Feminino , Hemorragia/mortalidade , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Punções , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , United States Department of Veterans Affairs , Serviços de Saúde para Veteranos MilitaresRESUMO
The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization. The FLOURISH study is designed to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. The FLOURISH study is a double-blind, placebo-controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one-time IC administration of RT-100 (1012 vp) or placebo in a 1:1 ratio. Subjects will be 18-80 years of age, on optimal standard of care HF therapy with LVEF ≥10% and ≤35% by echocardiogram, and will undergo IC administration of RT-100 vs. placebo on Day 1. Follow-up study visits will be performed at Weeks 1 and 4, and Months 3, 6, and 12. Patients will be followed for an additional 36 months for safety assessments with telephone contact at Months 24, 36, and 48. The primary objective is to determine the efficacy of IC RT-100 vs. placebo in reducing the event rate of all (first and repeat) HF hospitalizations occurring from baseline to 12 months. The secondary objectives are to determine the efficacy of IC RT-100 on CV death, all cause death, and all HF events and in improving NYHA functional classification. Exploratory endpoints will include echocardiographic parameters of left ventricular systolic and diastolic function, HF symptoms and physical limitations, 6-minute walking distance, Borg dyspnea score, and NT-proBNP levels. The FLOURISH study, which received fast track designation from the Food and Drug Administration in December 2017, will further investigate the role of a one-time intracoronary injection of RT-100 in reducing HF hospitalizations and will serve as a registration trial (potentially pivotal investigation) for RT-100 as a treatment for HFrEF.
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Adenilil Ciclases/administração & dosagem , Ensaios Clínicos Fase III como Assunto/métodos , Técnicas de Transferência de Genes , Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Volume Sistólico/fisiologia , Adenovírus Humanos , Vasos Coronários , Insuficiência Cardíaca/fisiopatologia , Humanos , Injeções Intra-Arteriais , Função Ventricular Esquerda/fisiologiaRESUMO
Despite improvements in drug and device therapy for heart failure, hospitalization rates and mortality have changed little in the past decade. Randomized clinical trials using gene transfer to improve function of the failing heart are the focus of this review. Four randomized clinical trials of gene transfer in heart failure with reduced ejection fraction (HFrEF) have been published. Each enrolled patients with stable symptomatic HFrEF and used either intracoronary delivery of a virus vector or endocardial injection of a plasmid. The initial CUPID trial randomized 14 subjects to placebo and 25 subjects to escalating doses of adeno-associated virus type 1 encoding sarcoplasmic reticulum calcium ATPase (AAV1.SERCA2a). AAV1.SERCA2a was well tolerated, and the high-dose group met a 6 month composite endpoint. In the subsequent CUPID-2 study, 243 subjects received either placebo or the high dose of AAV1.SERCA2a. AAV1.SERCA2a administration, while safe, failed to meet the primary or any secondary endpoints. STOP-HF used plasmid endocardial injection of stromal cell-derived factor-1 to promote stem-cell recruitment. In a 93-subject trial of patients with ischemic etiology heart failure, the primary endpoint (symptoms and 6 min walk distance) failed, but subgroup analyses showed improvements in subjects with the lowest ejection fractions. A fourth trial randomized 14 subjects to placebo and 42 subjects to escalating doses of adenovirus-5 encoding adenylyl cyclase 6 (Ad5.hAC6). There were no safety concerns, and patients in the two highest dose groups (combined) showed improvements in left ventricular function (left ventricular ejection fraction and -dP/dt). The safety data from four randomized clinical trials of gene transfer in patients with symptomatic HFrEF suggest that this approach can be conducted with acceptable risk, despite invasive delivery techniques in a high-risk population. Additional trials are necessary before the approach can be endorsed for clinical practice.
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Técnicas de Transferência de Genes/tendências , Terapia Genética , Insuficiência Cardíaca/terapia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/uso terapêutico , Dependovirus , Feminino , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Parvovirinae/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genéticaRESUMO
Methods commonly used clinically to assess cardiac function in patients with heart failure include ejection fraction (EF), exercise treadmill testing (ETT), and symptom evaluation. Although these approaches are useful in evaluating patients with heart failure, there are at times substantial mismatches between individual assessments. For example, ETT results are often discordant with EF, and patients with minimal symptoms sometimes have surprisingly low EFs. To better define the relationship of these methods of assessment, we studied 56 patients with heart failure with reduced EF (HFrEF) who underwent measurement of ETT duration, EF by echocardiography, quantitative symptom evaluation, and LV peak dP/dt (rate of left ventricular pressure development and decline, measured invasively). Correlations were determined among these four tests in order to assess the relationship of EF, ETT, and symptoms against LV peak dP/dt. In addition, we sought to determine whether EF, ETT, and symptoms correlated with each other. Overall, correlations were poor. Only 15 of 63 total correlations (24%) were significant (p < 0.05). EF correlated most closely with LV peak -dP/dt. Linear regression analysis indicated that EF, ETT, and symptoms taken together predicted LV peak dP/dt better than any one measure alone. We conclude that clinical tests used to assess LV function in patients with HFrEF may not be as accurate or correlate as well as expected. All three clinical measures considered together may be the best representation of cardiac function in HFrEF patients currently available.
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Insuficiência Cardíaca/diagnóstico , Ecocardiografia , Teste de Esforço , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Volume SistólicoRESUMO
IMPORTANCE: Gene transfer has rarely been tested in randomized clinical trials. OBJECTIVE: To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization. INTERVENTIONS: Intracoronary administration of Ad5.hAC6 (3.2 × 109 to 1012 virus particles) or placebo. MAIN OUTCOMES AND MEASURES: Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4 + 5). RESULTS: Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P = .27; 12 weeks, P = .47, respectively). The D4 + 5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n = 21; P < .004), but not 12 weeks (+3.0 [2.4] EF units; n = 21; P = .16). Placebo participants showed no increase in EF at 4 weeks or 12 weeks. Exercise duration showed no between-group differences (4-week change from baseline: placebo, 27 [36] seconds; D4 + 5, 44 [25] seconds; P = .27; 12-week change from baseline: placebo, 44 [28] seconds; D4 + 5, 58 [29 seconds, P = .47). AC6 gene transfer increased basal left ventricular peak -dP/dt (4-week change from baseline: placebo, +93 [51] mm Hg/s; D4 + 5, -39 [33] mm Hg/s; placebo [n = 21]; P < .03); AC6 did not increase arrhythmias. The admission rate for patients with heart failure was 9.5% (4 of 42) in the AC6 group and 28.6% (4 of 14) in the placebo group (relative risk, 0.33 [95% CI, 0.08-1.36]; P = .10). CONCLUSIONS AND RELEVANCE: AC6 gene transfer safely increased LV function beyond standard heart failure therapy, attainable with one-time administration. Larger trials are warranted. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00787059.
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Adenoviridae/genética , Adenilil Ciclases/administração & dosagem , Técnicas de Transferência de Genes/tendências , Terapia Genética/métodos , Insuficiência Cardíaca/diagnóstico , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Adenilil Ciclases/uso terapêutico , Idoso , Cateterismo Cardíaco/métodos , Ecocardiografia , Teste de Esforço/métodos , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Resultado do Tratamento , Estados Unidos/epidemiologiaAssuntos
Angioplastia Coronária com Balão/instrumentação , Aneurisma da Aorta Torácica/complicações , Dissecção Aórtica/complicações , Oclusão Coronária/terapia , Infarto do Miocárdio/terapia , Idoso de 80 Anos ou mais , Dissecção Aórtica/patologia , Aorta/patologia , Aneurisma da Aorta Torácica/patologia , Angiografia Coronária/instrumentação , Oclusão Coronária/etiologia , Oclusão Coronária/patologia , Vasos Coronários/patologia , Humanos , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Seio Aórtico/patologia , Stents , Tomografia Computadorizada Espiral/instrumentaçãoRESUMO
OBJECTIVES: We evaluated the efficacy and safety of prasugrel and clopidogrel in the setting of a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND: Prasugrel reduced cardiovascular events as compared with clopidogrel in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) but with increased bleeding. METHODS: Researchers in the TRITON-TIMI 38 randomized 13,608 subjects with acute coronary syndrome undergoing percutaneous coronary intervention to prasugrel versus clopidogrel. The use of a GP IIb/IIIa inhibitor was at the physician's discretion. For the current analysis, end points were examined at 30 days and were stratified by use of a GP IIb/IIIa inhibitor. RESULTS: A total of 7,414 subjects (54.5%) received a GP IIb/IIIa inhibitor during their index hospitalization. There was a consistent benefit of prasugrel over clopidogrel for reducing cardiovascular death, myocardial infarction, or stroke in patients who did (hazard ratio: 0.76; 95% confidence interval: 0.64 to 0.90) or did not receive a GP IIb/IIIa inhibitor (hazard ratio: 0.78; 95% confidence interval: 0.63 to 0.97, p(interaction) = 0.83). Prasugrel significantly reduced myocardial infarction, urgent revascularization, and stent thrombosis irrespective of GP IIb/IIIa inhibitor use. Although subjects treated with a GP IIb/IIIa inhibitor had greater rates of bleeding, the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor (p(interaction) = 0.19). CONCLUSIONS: Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used. The use of a GP IIb/IIIa inhibitor does not accentuate the relative risk of bleeding with prasugrel as compared with clopidogrel.
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Síndrome Coronariana Aguda/terapia , Angioplastia Coronária com Balão , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2 , Tiofenos/uso terapêutico , Síndrome Coronariana Aguda/complicações , Idoso , Clopidogrel , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Cloridrato de Prasugrel , Stents , Acidente Vascular Cerebral/prevenção & controle , Tiofenos/administração & dosagem , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêuticoRESUMO
OBJECTIVES: This study sought to determine the factors associated with suboptimal platelet inhibition (PI) with single- and double-bolus eptifibatide during percutaneous coronary intervention (PCI). BACKGROUND: Although PI > or = 95% measured 10 min after glycoprotein IIb/IIIa inhibitor therapy is associated with improved outcomes following PCI, this level of PI often is not achieved. METHODS: We prospectively studied 150 patients undergoing PCI with single-bolus eptifibatide (180 microg/kg) (n = 100) and double-bolus eptifibatide (180 microg/kg administered 10 min apart) (n = 50) followed by standard infusion (2 microg/kg/min). Measuring platelet aggregation at baseline and at 10 min and 30 to 45 min after eptifibatide bolus, patients were classified as optimal responders (OPT) (> or =95% PI) or suboptimal responders (sub-OPT) (<95% PI) based on 10-min PI after final bolus. RESULTS: Suboptimal PI was achieved in 61% of patients with single-bolus eptifibatide and in 36% with double-bolus eptifibatide. In the single-bolus group, sub-OPT had higher fibrinogen levels (324 +/- 85 mg/dl vs. 259 +/- 49 mg/dl, p = 0.0002), platelet counts (221 +/- 70 vs. 186 +/- 47, p = 0.008), and white blood cell counts (7.7 +/- 2.3 vs. 6.6 +/- 1.9, p = 0.02). In the double-bolus group, sub-OPT also had higher fibrinogen levels (324 +/- 68 mg/dl vs. 278 +/- 53 mg/dl, p = 0.01) and were more likely to be smokers (38.9% vs. 9.4%, p = 0.01). Multivariable analysis showed that fibrinogen level was the only independent predictor of suboptimal PI, with fibrinogen cutoffs at 375 and 325 mg/dl predicting suboptimal PI (single-bolus: 100% and 90.0%, respectively; double-bolus: 100% and 60%, respectively) with both doses. CONCLUSIONS: During PCI, both single- and double-bolus eptifibatide provide suboptimal PI in a substantial proportion of patients. A fibrinogen level >375 mg/dl is a strong predictor of suboptimal PI.
Assuntos
Angioplastia Coronária com Balão , Fibrinogênio/metabolismo , Peptídeos/administração & dosagem , Idoso , Testes de Coagulação Sanguínea , Eptifibatida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/fisiologia , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
UNLABELLED: Many cardiologists consider it reasonable to assume in clinical practice that percutaneous coronary intervention using drug-eluting stents ought to be considered equivalent, if not superior, to bypass surgery. In the absence of a definitive clinical trial to support this view, how should the prudent, cutting-edge cardiologist proceed? OBJECTIVES: This study assessed the geographical differences in target vessel revascularization (TVR) after percutaneous coronary intervention (PCI) in the Prevention of Restenosis With Tranilast and its Outcomes (PRESTO) trial. BACKGROUND: An aggressive approach to PCI is more common in the U.S. than in other countries. The impact of this approach on restenosis outcomes has not been studied. METHODS: Using the PRESTO trial, we compared nine-month ischemic TVR after PCI in U.S.-treated patients (n = 5,026) with rates in other countries (n = 6,458). We defined TVR as repeat intervention for chest pain/positive stress test. Additionally, angiographic restenosis (> or =50% narrowing or > or =50% loss of gain at nine-month follow-up) was compared between U.S. and non-U.S. patients within the prespecified angiographic subset (n = 2,823). Regression models were developed to adjust for clinical and lesion-related characteristics. RESULTS: Higher rates of TVR (18% vs. 11%), and angiographic restenosis (65% vs. 48%) were observed in patients treated in the U.S. as compared with the other patients (p < 0.01 for both comparisons). Patients treated in the U.S. were more likely to be female, diabetic, not currently smoking, to have unstable angina, and to have a prior PCI. In U.S. patients, lesions tended to be longer, but less likely to be American College of Cardiology/American Heart Association class C. After adjusting for clinical and angiographic variables, PCI in the U.S. was still associated with increased angiographic restenosis and ischemic TVR. CONCLUSIONS: Angiographic restenosis and ischemia-driven TVR rates were higher in patients treated in the U.S. The difference could only partially be explained by the higher prevalence of measured adverse clinical and angiographic features.
Assuntos
Angioplastia Coronária com Balão , Anti-Inflamatórios não Esteroides/uso terapêutico , Reestenose Coronária/terapia , ortoaminobenzoatos/uso terapêutico , Austrália , Canadá , Angiografia Coronária , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/prevenção & controle , Europa (Continente) , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Retratamento , África do Sul , Resultado do Tratamento , Estados UnidosAssuntos
Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Sirolimo/administração & dosagem , Stents , Vasoconstrição , Vasos Coronários/fisiopatologia , Endotélio Vascular/fisiopatologia , Exercício Físico/fisiologia , Humanos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
OBJECTIVES: The aim of the present study was to determine the rates of target vessel revascularization (TVR) and to determine predictors of TVR from clinical and angiographic variables available in the Prevention of Restenosis With Tranilast and its Outcomes (PRESTO) database. BACKGROUND: The rates of TVR after percutaneous revascularization procedures, and its prediction with available clinical and angiographic variables, is less well known. METHODS: We studied nine-month TVR in 11,484 patients enrolled in the PRESTO trial. Clinical, lesion-related, and procedural characteristics were analyzed in a logistic regression model. Study data were divided at random into an 80% training set on which the models were developed and a 20% hold-out set on which the model properties were evaluated. RESULTS: A total of 14% (n = 1,609) had ischemic TVR. Clinical variables with increased risk for TVR included younger age; hypertension; diabetes mellitus; nonsmokers; unstable angina; previous coronary artery bypass grafting; peripheral vascular disease; procedure- and lesion-related such as ostial location, multilesion angioplasty, location in the left anterior descending artery, length > or =20 mm, in-stent restenosis at baseline, and use of rotablator. There was significant increase in the risk of ischemic TVR at U.S. treatment sites. Smoking and stent placement were associated with lower risk of ischemic TVR. The mean area (+/- SD) under the receiver-operating characteristic curve of the bootstrap samples was 0.66, indicating a modest ability of the model to discriminate patients who needed TVR on follow-up. CONCLUSIONS: Despite being the largest prospective trial designed to test restenosis, the discriminatory ability of the clinical and angiographic variables to predict TVR is modest.
Assuntos
Angioplastia Coronária com Balão , Estenose Coronária/terapia , Isquemia Miocárdica/etiologia , Complicações Pós-Operatórias , Idoso , Ensaios Clínicos Controlados como Assunto , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reoperação , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Restenosis prediction from published studies is hampered by inadequate sample size and incomplete angiographic follow-up. The prediction of restenosis with the existing variables is poor. The aim of the present study was to include the clinical and angiographic variables commonly associated with angiographic restenosis and develop a prediction model for restenosis from the PRESTO database. METHODS AND RESULTS: This study included 1312 patients with a single lesion enrolled in the angiographic substudy of the PRESTO trial. We constructed 2 risk scores. The first used preprocedural variables (female gender, vessel size [< or =2.5 mm, 2.5 to 3 mm, 3 to 3.5 mm, 3.5 to 4 mm, >4 mm], lesion length >20 mm, diabetes, smoking status, type C lesion, any previous percutaneous coronary intervention [PCI], and unstable angina) derived from previous studies. Estimated restenosis rates and corresponding variability for each possible level of the resultant risk score were obtained via bootstrapping techniques. The area under the receiver-operator characteristic (ROC) curve was 0.63, indicating modest discriminatory ability to predict restenosis. The second approach constructed a multiple logistic regression model considering significant univariate clinical and angiographic predictors of restenosis identified from the PRESTO database (treated diabetes mellitus, nonsmoker, vessel size, lesion length, American College of Cardiology/American Heart Association type C lesion, ostial location, and previous PCI). The area under the ROC curve for this risk score was also 0.63. CONCLUSIONS: The preprocedural clinical and angiographic variables from available studies and from the PRESTO trial have only modest predictive ability for restenosis after PCI.