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BACKGROUND: Whether a conservative strategy of medical therapy alone or a strategy of medical therapy plus invasive treatment is more beneficial in older adults with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. METHODS: We conducted a prospective, multicenter, randomized trial involving patients 75 years of age or older with NSTEMI at 48 sites in the United Kingdom. The patients were assigned in a 1:1 ratio to a conservative strategy of the best available medical therapy or an invasive strategy of coronary angiography and revascularization plus the best available medical therapy. Patients who were frail or had a high burden of coexisting conditions were eligible. The primary outcome was a composite of death from cardiovascular causes (cardiovascular death) or nonfatal myocardial infarction assessed in a time-to-event analysis. RESULTS: A total of 1518 patients underwent randomization; 753 patients were assigned to the invasive-strategy group and 765 to the conservative-strategy group. The mean age of the patients was 82 years, 45% were women, and 32% were frail. A primary-outcome event occurred in 193 patients (25.6%) in the invasive-strategy group and 201 patients (26.3%) in the conservative-strategy group (hazard ratio, 0.94; 95% confidence interval [CI], 0.77 to 1.14; P = 0.53) over a median follow-up of 4.1 years. Cardiovascular death occurred in 15.8% of the patients in the invasive-strategy group and 14.2% of the patients in the conservative-strategy group (hazard ratio, 1.11; 95% CI, 0.86 to 1.44). Nonfatal myocardial infarction occurred in 11.7% in the invasive-strategy group and 15.0% in the conservative-strategy group (hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications occurred in less than 1% of the patients. CONCLUSIONS: In older adults with NSTEMI, an invasive strategy did not result in a significantly lower risk of cardiovascular death or nonfatal myocardial infarction (the composite primary outcome) than a conservative strategy over a median follow-up of 4.1 years. (Funded by the British Heart Foundation; BHF SENIOR-RITA ISRCTN Registry number, ISRCTN11343602.).
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AIMS: Fractional flow reserve (FFRCT) using computed tomography coronary angiography (CTCA) determines both the presence of coronary artery disease and vessel-specific ischaemia. We tested whether an evaluation strategy based on FFRCT would improve economic and clinical outcomes compared with standard care. METHODS AND RESULTS: Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with CTCA with selective FFRCT (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months. Secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Randomized groups were similar at baseline. Most patients had an initial CTCA: 439 (63%) in the standard group vs. 674 (96%) in the experimental group, 254 of whom (38%) underwent FFRCT. Mean total cardiac costs were higher by £114 (+8%) in the experimental group, with a 95% confidence interval from -£112 (-8%) to +£337 (+23%), though the difference was not significant (P = 0.10). Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group) and angina and quality of life improved to a similar degree over follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01). CONCLUSION: A strategy of CTCA with selective FFRCT in patients with stable angina did not differ significantly from standard clinical care pathways in cost or clinical outcomes, but did reduce the use of invasive coronary angiography.
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Angina Estable , Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Reserva del Flujo Fraccional Miocárdico , Angina Estable/diagnóstico por imagen , Angina Estable/terapia , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Vasos Coronarios , Humanos , Valor Predictivo de las Pruebas , Calidad de VidaRESUMEN
There is growing empirical support for the benefits of developing psychological capital (PsyCap), and the effectiveness of PsyCap interventions (PCIs) in the workplace. However, to-date, PCI delivery modes have not been compared. The first study in this article compares a face-to-face to an online PCI. The second study compares an online PCI to a micro-learning PCI utilizing a mobile application. Results from 228 participants assessed three times (before, immediately after, and six weeks after PCI completion) support the effectiveness and comparability of the three delivery modes, but also highlight notable advantages for online and micro-learning.
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BACKGROUND: The aim of the study is to determine whether performing endovascular aortic aneurysm repair (EVAR) in a dedicated vascular hybrid operating room (OR) is associated with a decreased patient radiation and contrast dose compared with mobile C-arm imaging in a conventional OR. METHODS: This is a retrospective study of patients undergoing standard EVAR from 2009-2016. "Standard EVAR" was defined as the elective EVAR performed with bifurcated graft for infrarenal aneurysm with no iliac aneurysms. Patients were divided into 2 groups. Group 1 included EVARs performed in conventional theater with a mobile C-arm (January 2009 to June 2012) and group 2 EVARs performed in the dedicated vascular hybrid OR (July 2012 to December 2016). Data collected included patient demographics, aneurysm diameter, neck length, radiation dose, screening time, and contrast use of each patient. RESULTS: There were 286 patients, 78 and 208 patients in group 1 and 2, respectively. There was no difference in age (77.6 years [76.3-78.9] vs. 76.6 years [75.9-77.9], P > 0.05), body mass index (26.5 kg/m2 [25.1-28.0] vs. 27.9 kg/m2 [27.1-28.7] P > 0.05), and mean aneurysm diameter (6.48 cms [6.13-6.82] vs. 6.81 cms [6.0-7.7], P > 0.05) between groups. Patients in group 2 received approximately half the mean radiation dose (16,807 cGy cm2 [±11,078] vs. 8,233 cGy cm2 [±7,471], P < 0.001), shorter fluoroscopy time (36.02 min [±21.3] vs. 26.96 min [±19], P = 0.001), and less contrast use (114 mls [±44.2] vs. 158 mls [±63.9], P < 0.001). CONCLUSIONS: Performing EVAR in a dedicated vascular Hybrid OR may be associated with a lower patient radiation dose, shorter screening time, and less contrast use than performing EVAR in a conventional OR.
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Aneurisma de la Aorta/cirugía , Aortografía , Implantación de Prótesis Vascular , Angiografía por Tomografía Computarizada , Medios de Contraste/administración & dosificación , Procedimientos Endovasculares , Quirófanos , Dosis de Radiación , Exposición a la Radiación , Radiografía Intervencional , Anciano , Aneurisma de la Aorta/diagnóstico por imagen , Aortografía/efectos adversos , Prótesis Vascular , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/instrumentación , Angiografía por Tomografía Computarizada/efectos adversos , Medios de Contraste/efectos adversos , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/instrumentación , Inglaterra , Femenino , Hospitales Generales , Humanos , Masculino , Valor Predictivo de las Pruebas , Exposición a la Radiación/efectos adversos , Exposición a la Radiación/prevención & control , Radiografía Intervencional/efectos adversos , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Stents , Resultado del TratamientoRESUMEN
Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/sangre , Células Neoplásicas Circulantes , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Recuento de Células , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Antígenos Comunes de Leucocito/sangre , Neoplasias Pulmonares/patología , Masculino , Microfluídica , Persona de Mediana Edad , Mutación , Nanotecnología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de la Célula IndividualRESUMEN
Background: Normal saline (NS) has been the choice fluid for volume resuscitation in diabetic ketoacidosis (DKA) for decades. Large volume resuscitation with NS can lead to hyperchloremic metabolic acidosis and is associated with a higher incidence of major adverse kidney events compared to balanced fluids (BF). Objective: Compare safety and effectiveness of fluid resuscitation with BF vs NS in adult patients with DKA. Methods: Single-center retrospective cohort study evaluated patients who received NS or BF for DKA treatment between July 2020 and August 2021. Primary endpoint was time to DKA resolution. Secondary endpoints included time to anion gap ≤12, HCO3 ≥15 and ≥18 mmol/L, acute kidney injury, and hospital and intensive care unit length of stay. Results: 110 patients were included (NS 55% (n = 60), BF 45% (n = 50)). Time to DKA resolution was faster in patients who received BF vs NS (13 (10 - 19) hours vs 17 (11 - 25) hours, P = 0.02). Treatment with NS was associated with a longer time to resolution of DKA when adjusted for initial bicarbonate and AKI at admission. Conclusion: BF was associated with a shorter time to DKA resolution compared to NS.
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Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
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BACKGROUND: FFRCT assesses the functional significance of lesions seen on CTCA, and may be a more efficient approach to chest pain evaluation. The FORECAST randomized trial found no significant difference in costs within the UK National Health Service, but implications for US costs are unknown. The purpose of this study was to compare costs in the FORECAST trial based on US healthcare cost weights, and to evaluate factors affecting costs. METHODS: Patients with stable chest pain were randomized either to the experimental strategy (CTCA with selective FFRCT), or to standard clinical pathways. Pre-randomization, the treating clinician declared the planned initial test. The primary outcome was nine-month cardiovascular care costs. RESULTS: Planned initial tests were CTCA in 912 patients (65%), stress testing in 393 (28%), and invasive angiography in 94 (7%). Mean US costs did not differ overall between the experimental strategy and standard care (cost difference +7% (+$324), CI -12% to +26%, p â= â0.49). Costs were 4% lower with the experimental strategy in the planned invasive angiography stratum (p for interaction â= â0.66). Baseline factors independently associated with costs were older age (+43%), male sex (+55%), diabetes (+37%), hypertension (+61%), hyperlipidemia (+94%), prior angina (+24%), and planned invasive angiography (+160%). Post-randomization cost drivers were coronary revascularization (+348%), invasive angiography (267%), and number of tests (+35%). CONCLUSIONS: Initial evaluation of chest pain using CTCA with FFRCT had similar US costs as standard care pathways. Costs were increased by baseline coronary risk factors and planned invasive angiography, and post-randomization invasive procedures and the number of tests. Registration at ClinicalTrials.gov (NCT03187639).
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Enfermedad de la Arteria Coronaria , Reserva del Flujo Fraccional Miocárdico , Humanos , Masculino , Angiografía Coronaria/métodos , Medicina Estatal , Valor Predictivo de las Pruebas , Angina de Pecho/terapia , Angiografía por Tomografía Computarizada/métodosRESUMEN
OBJECTIVE: Being able to predict a patient's life expectancy can help doctors and patients prioritize treatments and supportive care. For predicting life expectancy, physicians have been shown to outperform traditional models that use only a few predictor variables. It is possible that a machine learning model that uses many predictor variables and diverse data sources from the electronic medical record can improve on physicians' performance. For patients with metastatic cancer, we compared accuracy of life expectancy predictions by the treating physician, a machine learning model, and a traditional model. MATERIALS AND METHODS: A machine learning model was trained using 14 600 metastatic cancer patients' data to predict each patient's distribution of survival time. Data sources included note text, laboratory values, and vital signs. From 2015-2016, 899 patients receiving radiotherapy for metastatic cancer were enrolled in a study in which their radiation oncologist estimated life expectancy. Survival predictions were also made by the machine learning model and a traditional model using only performance status. Performance was assessed with area under the curve for 1-year survival and calibration plots. RESULTS: The radiotherapy study included 1190 treatment courses in 899 patients. A total of 879 treatment courses in 685 patients were included in this analysis. Median overall survival was 11.7 months. Physicians, machine learning model, and traditional model had area under the curve for 1-year survival of 0.72 (95% CI 0.63-0.81), 0.77 (0.73-0.81), and 0.68 (0.65-0.71), respectively. CONCLUSIONS: The machine learning model's predictions were more accurate than those of the treating physician or a traditional model.
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Aprendizaje Automático , Metástasis de la Neoplasia/radioterapia , Pronóstico , Oncólogos de Radiación , Anciano , Área Bajo la Curva , Registros Electrónicos de Salud , Femenino , Humanos , Estimación de Kaplan-Meier , Esperanza de Vida , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Curva ROCRESUMEN
OBJECTIVE: Patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction with cardiogenic shock (CS) are often treated with intra-aortic balloon pump counterpulsation (IABP), even though the evidence to support this is limited. We determined whether IABP as an addition to PCI-centered therapy ameliorates multiorgan dysfunction syndrome (MODS) in patients with acute myocardial infarction complicated by CS. DESIGN: A prospective, randomized, controlled, open-label clinical trial recruiting patients between March 2003 and June 2004 (ClinicalTrials.gov ID NCT00469248). SETTING: Tertiary care university hospital. PATIENTS AND INTERVENTIONS: Forty-five consecutive patients with AMI and CS undergoing PCI were randomized to treatment with or without IABP. MEASUREMENTS AND MAIN RESULTS: Acute Physiology and Chronic Health Evaluation (APACHE) II scores (primary outcome measure), hemodynamic values, inflammatory markers, and plasma brain natriuretic peptide (BNP) levels (secondary outcomes) were collected over 4 days from randomization. The prospective hypothesis was that adding IABP therapy to "standard care" would improve CS-triggered MODS. The addition of IABP to standard therapy did not result in a significant improvement in MODS (measured by serial APACHE II scoring over 4 days). IABP use had no significant effect on cardiac index or systemic inflammatory activation, although BNP levels were significantly lower in IABP-treated patients. Initial and serial APACHE II scoring correlated with mortality better than cardiac index, systemic inflammatory state, and BNP levels in this group of patients. Nonsurvivors had significantly higher initial APACHE II scores (29.9 +/- 2.88) than survivors (18.1 +/- 1.66, p < .05). Nevertheless, discrepancies among patients within the groups cannot be ruled out and might interfere with our results. CONCLUSIONS: In this randomized trial addressing addition of IABP in CS patients, mechanical support was associated only with modest effects on reduction of APACHE II score as a marker of severity of disease, improvement of cardiac index, reduction of inflammatory state, or reduction of BNP biomarker status compared with medical therapy alone. However, the limitations of our present trial preclude any definitive conclusion, but request for a larger prospective, randomized, multicentered trial with mortality as primary end point.
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Contrapulsador Intraaórtico/métodos , Insuficiencia Multiorgánica/prevención & control , Infarto del Miocardio/mortalidad , Infarto del Miocardio/cirugía , Choque Cardiogénico/mortalidad , Choque Cardiogénico/cirugía , APACHE , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Terapia Combinada , Angiografía Coronaria , Contrapulsación/métodos , Enfermedad Crítica/mortalidad , Enfermedad Crítica/terapia , Electrocardiografía , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Probabilidad , Estudios Prospectivos , Medición de Riesgo , Factores Sexuales , Choque Cardiogénico/complicaciones , Choque Cardiogénico/diagnóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: This prospective study aimed to determine the accuracy of radiation oncologists in predicting the survival of patients with metastatic disease receiving radiation therapy and to understand factors associated with their accuracy. METHODS AND MATERIALS: This single-institution study surveyed 22 attending radiation oncologists to estimate patient survival. Survival predictions were defined as accurate if the observed survival (OS) was within the correct survival prediction category (0-6 months, >6-12 months, >12-24 months, and >24 months). The physicians made survival estimates for each course of radiation, yielding 877 analyzable predictions for 689 unique patients. Data analysis included Stuart's Tau C, logistic regression models, ordinal logistic regression models, and stepwise selection to examine variable interactions. RESULTS: Of the 877 radiation oncologists' predictions, 39.7% were accurate, 26.5% were underestimations, and 33.9% were overestimations. Stuart's Tau C showed low correlation between OS and survival estimates (0.3499), consistent with the inaccuracy reported in the literature. However, results showed less systematic overprediction than reported in the literature. Karnofsky performance status was the most significant predictor of accuracy, with greater accuracy for patients with shorter OS. Estimates were also more accurate for patients with lower Karnofsky performance status. Accuracy by patient age varied by primary site and race. Physician years of experience did not correlate with accuracy. CONCLUSIONS: The sampled radiation oncologists have a 40% accuracy in predicting patient survival. Future investigation should explore how survival estimates influence treatment decisions and how to improve survival prediction accuracy.
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Esperanza de Vida , Neoplasias/mortalidad , Oncólogos de Radiación , Anciano , Competencia Clínica , Exactitud de los Datos , Femenino , Predicción , Humanos , Estado de Ejecución de Karnofsky/estadística & datos numéricos , Modelos Logísticos , Masculino , Metástasis de la Neoplasia , Neoplasias/patología , Neoplasias/radioterapia , Estudios Prospectivos , Oncólogos de Radiación/estadística & datos numéricos , Análisis de Supervivencia , Cuidado Terminal , Factores de TiempoRESUMEN
OBJECTIVES: Levosimendan improves left ventricular hemodynamic function in patients with cardiogenic shock. However, its impact on right ventricular performance has not been determined. We compared the hemodynamic effects of levosimendan on left and right ventricular function in patients with intractable cardiogenic shock following myocardial infarction. DESIGN: Observational hemodynamic study. SETTING: Tertiary care center university hospital. PATIENTS: Fifty-six patients with cardiogenic shock secondary to myocardial infarction were treated with percutaneous revascularization (including intra-aortic balloon pump when appropriate) and commenced on conventional inotropic therapy. INTERVENTION: Twenty-five consecutive patients with cardiogenic shock due to myocardial infarction who had not improved sufficiently with conventional therapy (including dobutamine and norepinephrine) received levosimendan (as a bolus of 12 microg/kg per minute for 10 mins then 0.1 microg/kg per minute--0.2 mug/kg per minute) as "bail-out" therapy for 24 hrs while invasive hemodynamic parameters were recorded. MEASUREMENTS AND MAIN RESULTS: Levosimendan therapy was associated with a significant increase in cardiac index from 2.1 +/- 0.1 to 3.0 +/- 0.2 L x min x m (p < .01). In addition, levosimendan enhanced right ventricular cardiac power index (0.14 +/- 0.19 to 0.18W +/- 0.12, p < .001), while pulmonary vascular resistance fell from 227.7 +/- 94.5 to 178.1 +/- 62.3 dyne x s x cm (p = .002). No significant change in central venous pressure or mean pulmonary artery pressure was observed. The observed hemodynamic improvement was sustained after the levosimendan infusion was stopped. CONCLUSIONS: Levosimendan infusion for cardiogenic shock following acute myocardial infarction improved hemodynamic parameters of right ventricular performance. Furthermore, we describe the use of right ventricular cardiac power index as a hemodynamic parameter of right ventricular performance.
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Hidrazonas/farmacología , Infarto del Miocardio/complicaciones , Piridazinas/farmacología , Choque Cardiogénico/tratamiento farmacológico , Choque Cardiogénico/etiología , Vasodilatadores/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Hemodinámica/efectos de los fármacos , Humanos , Persona de Mediana Edad , Infarto del Miocardio/fisiopatología , Choque Cardiogénico/fisiopatología , SimendánRESUMEN
Hydrogen sulfide is a key gasotransmitter for plants and has been shown to greatly increase their growth and survival in the presence of environmental stressors. Current methods for slowly releasing hydrogen sulfide use chemicals, such as GYY-4137, but these result in the release of chemicals not found in the environment, and chemicals used may lack structures that can be readily tuned to affect the rate of release of hydrogen sulfide. In this article, we describe the synthesis and slow release of hydrogen sulfide from dialkyldithiophosphates, which are a new set of hydrogen sulfide releasing chemicals that can be used in agriculture. The rates of hydrolysis of dibutyldithiophosphate and GYY-4137 were measured in water at 85 °C and compared with each other to investigate their differences. GYY-4137 is widely used as a chemical that slowly releases H2S, but its rate of release was not previously quantified. The release of hydrogen sulfide in water at room temperature was measured for a series of dialkyldithiophosphates using a hydrogen sulfide electrode. It was shown that the structure of the dialkyldithiophosphate affected the amount of hydrogen sulfide released. The final degradation products of dibutyldithiophosphate were shown to be phosphoric acid and butanol, which are chemicals found in the environment. This result was notable because it demonstrated that dialkyldithiophosphates degrade to safe, natural chemicals that will not pollute the environment. To demonstrate that dialkyldithiophosphates have potential applications in agriculture, maize was grown for 4.5 weeks after exposure to 1-200 mg of dibutyldithiophosphate, and the weight of corn plants increased by up to 39% at low loadings of dibutyldithiophosphate.
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Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Sulfuro de Hidrógeno/química , Sulfuro de Hidrógeno/farmacología , Organotiofosfatos/química , Zea mays/efectos de los fármacos , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Hidrólisis , Morfolinas/química , Compuestos Organotiofosforados/química , Zea mays/crecimiento & desarrolloRESUMEN
AIMS: There are limited data on aspirin (ASA) desensitization for patients with coronary disease. We present our experience with a rapid nurse-led oral desensitization regimen in patients with aspirin sensitivity undergoing coronary angiography. METHODS: This single-center retrospective observational study includes patients with a history of ASA sensitivity undergoing coronary angiography with intent to perform percutaneous coronary intervention (PCI). RESULTS: Between January 2012 and January 2017, 24 patients undergoing coronary angiography for stable coronary disease (7 cases) or acute coronary syndromes (non-ST-segment myocardial infarction [NSTEMI; 8 cases], STEMI [9 cases]) underwent aspirin desensitization having reported previous reactions to aspirin. At initial presentation, previous sensitivity reactions were reported as: mucocutaneous reactions in 17 patients (urticaria in 3 [13%], nonurticarial rash in 6 [25%], angio-oedema in 8 [33%]), respiratory sensitivity in 4 (17%), and systemic anaphylactoid reactions in 3 (13%). Seventeen (71%) patients underwent PCI. Desensitization was acutely successful in 22 (92%) patients and unsuccessful in 2 (8%) patients who both had a single short-lived episode of acute bronchospasm treated successfully with nebulized salbutamol. Fifteen successfully desensitized patients completed 12 months of aspirin; no patient had recurrent hypersensitivity reaction. Aspirin was stopped prior to 12 months in 7 patients (replaced by warfarin [1 case], no antiplatelet or single antiplatelet clinically indicated and clopidogrel chosen [4 cases], patient choice without evidence of recurrent hypersensitivity [1 case], and death due to cardiogenic shock following STEMI [1 case]). CONCLUSION: A rapid aspirin desensitization protocol is safe and effective across a broad spectrum of hypersensitivity reactions and clinical presentations.
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Síndrome Coronario Agudo/terapia , Aspirina/administración & dosificación , Desensibilización Inmunológica , Hipersensibilidad a las Drogas/prevención & control , Infarto del Miocardio sin Elevación del ST/terapia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/administración & dosificación , Infarto del Miocardio con Elevación del ST/terapia , Síndrome Coronario Agudo/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Aspirina/inmunología , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/enfermería , Hipersensibilidad a las Drogas/diagnóstico , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio sin Elevación del ST/diagnóstico por imagen , Intervención Coronaria Percutánea/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/inmunología , Estudios Retrospectivos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Reperfusion injury of ischemic myocardium has been attributed to neutrophil infiltration, inflammatory activation and cardiac necrosis/apoptosis. Serine protease inhibition with aprotinin is cardioprotective, but the mechanism is unknown. METHODS AND RESULTS: We studied aprotinin in a rat model of myocardial ischemia for 20 minutes and reperfusion for 20 minutes, 8 hours or 24 hours. Aprotinin (20,000 IU/kg) given 5 minutes before reperfusion significantly reduced leukocyte accumulation (P<0.01), myocardial injury (determined by CK depletion, P<0.01) and myocyte apoptosis (P<0.05) compared with vehicle treated rats. Differential gene expression analysis showed myocardial ischemia plus reperfusion increased expression of proinflammatory genes like P-selectin, E-selectin, intercellular adhesion molecule, tumor necrosis factor-alpha, tumor necrosis factor-alpha receptor, interleukin-6, monocyte chemoattractant protein-1, p53, and Fas (CD59). Aprotinin before reperfusion suppressed expression of these inflammatory genes. Finally, differential protein expression analysis demonstrated increased intercellular adhesion molecule-1, tumor necrosis factor-alpha, and p53 after myocardial ischemia plus reperfusion, and this effect was diminished by aprotinin. CONCLUSIONS: We demonstrated myocardial ischemia plus reperfusion induced leukocyte accumulation, inflammation, gene expression, protein expression and finally tissue injury and showed aprotinin limiting reperfusion injury through each of these stages, even after 24 hours of reperfusion. This effect seems partly attributable to suppression of proinflammatory genes and leukocyte accumulation. This work casts further light on the complex signaling of ischemia and reperfusion.
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Aprotinina/uso terapéutico , Regulación de la Expresión Génica/fisiología , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Biosíntesis de Proteínas/fisiología , Animales , Aprotinina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Reperfusión Miocárdica/métodos , Daño por Reperfusión Miocárdica/prevención & control , Biosíntesis de Proteínas/efectos de los fármacos , RatasRESUMEN
Bivalirudin, a direct thrombin inhibitor binds specifically and reversibly to both fibrin-bound and unbound thrombin. Bivalirudin is approved for use as an anticoagulant in patients undergoing percutaneous coronary intervention. The OASIS-5 trial presented a significant increase in cardiac catheter thrombosis for the pentasaccharid fondaparinux compared to enoxaparin. Catheter thrombosis has never been reported in any trial using bivalirudin. Our study compared the development of catheter thrombosis for bivalirudin, enoxaparin, and unfractionated heparin in a controlled in-vitro environment. Ten healthy male volunteers were pretreated with aspirin 500 mg 2 hours before venesection of 50 ml of blood. The seven groups of anticoagulant combinations tested were: UFH, UFH + eptifibatide, enoxaparin, enoxaparin + eptifibatide, bivalirudin bolus, bivalirudin + eptifibatide, bivalirudin bolus + continuous infusion. The blood/anticoagulant mix continuously circulated through a cardiac guiding catheter for 60 minutes or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy was used to quantify the degree of erythrocyte, platelet and fibrin deposition. Following anticoagulation with bolus dose bivalirudin, the catheter was invariably occluded with thrombus after 33 minutes of circulation. However, a continuous infusion of Bivalirudin prevented the development of occlusive catheter thrombosis. In the bolus bivalirudin group the mean thrombus weight was significantly greater than in all other groups (p-value < 0.01 in all analyses). Bivalirudin given as a bolus was not sufficient to prevent cardiac catheter thrombosis in our in-vitro study. However, a continuous infusion of bivalirudin had similar anti-thrombotic efficacy compared to other treatment strategies.
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Anticoagulantes/farmacología , Cateterismo Cardíaco/efectos adversos , Enoxaparina/farmacología , Heparina/farmacología , Hirudinas/farmacología , Fragmentos de Péptidos/farmacología , Trombosis/prevención & control , Aspirina/administración & dosificación , Eptifibatida , Eritrocitos/patología , Fibrina/metabolismo , Fibrinolíticos/administración & dosificación , Heparina/análogos & derivados , Humanos , Técnicas In Vitro , Masculino , Microscopía Electrónica de Rastreo , Péptidos/farmacología , Perfusión , Inhibidores de Agregación Plaquetaria/farmacología , Proteínas Recombinantes/farmacología , Trombosis/patologíaRESUMEN
Bacterial toxins cause cardiac dysfunction and death through an inflammatory process, but the mechanism remains unclear. Simvastatin is recognized as having anti-inflammatory properties beyond its lipid-lowering effects. We examined Staphylococcus aureus alpha-toxin in isolated heart and in vivo models and tested simvastatin's effects in sepsis. Isolated Langendorff-perfused rat hearts were exposed to a recirculating perfusate containing alpha-toxin (0.5 microg mL(-1)). Compared with controls, there was a significant increase in coronary perfusion pressure and fall in myocardial performance. Significant increases in p53 expression and apoptosis (1.3 +/- 0.5 to 7.1 +/- 1.4 terminal deoxynucleaotidyl transferase nick end labeling-positive cells; P < 0.05) compared with controls were observed, but markers of necrosis were similar. In parallel experiments, anaesthetized rats receiving alpha-toxin (40 microg kg(-1), i.v.) had in vivo hemodynamic parameters and serum markers of necrosis monitored for 4 h before the hearts were analyzed for histological change, p53 expression, and apoptosis. Over 4 h, alpha-toxin exposure produced substantial hemodynamic effects. In addition, p53 expression (0.2 +/- 0.2 to 7.1 +/- 0.5 p53-positive myocytes; P < 0.05), TNF-alpha levels, the degree of apoptosis, and markers of necrosis were all significantly increased compared with control animals. Pretreatment with simvastatin protected against alpha-toxin-induced sepsis associated with reduced p53, TNF-alpha, apoptosis, and necrosis. We found significant changes in systemic hemodynamics, coronary perfusion pressure, myocardial function, and increased p53 expression with apoptosis due to bacterial exotoxin. In vivo changes were significantly inhibited by pretreatment with simvastatin. We provide novel evidence for the mechanisms by which septicemia causes myocardial depression and hint at a potential role for simvastatin as an inhibitor of apoptosis in sepsis.
Asunto(s)
Apoptosis/efectos de los fármacos , Cardiomiopatías/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Simvastatina/uso terapéutico , Animales , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , Exotoxinas/toxicidad , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hemodinámica/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Miocardio/metabolismo , Miocardio/patología , Necrosis , Ratas , Sepsis/inducido químicamente , Sepsis/complicaciones , Factor de Necrosis Tumoral alfa/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Animal data strongly support a role for inflammation in myocardial ischemia reperfusion injury. Attempts at cardioprotection by immunomodulation (such as with the specific C5 antibody pexelizumab) in humans have been disappointing. We hypothesized that a broader spectrum antiinflammatory agent might yield successful cardioprotection. The serine protease inhibitor nafamostat (FUT-175), which is already in clinical use, is a potent antiinflammatory synthetic serine protease inhibitor with anticomplement activity that we tested in a well-established rabbit model of 1 hour of myocardial ischemia followed by 3 hours of reperfusion. Compared to vehicle-treated animals, nafamostat (1 mg/kg of body weight) administered 5 minutes before reperfusion significantly reduced myocardial injury assessed by plasma creatine kinase activity (38.1 +/- 6.0 versus 57.9 +/- 3.7I U/g protein; P < 0.05) and myocardial necrosis (23.6 +/- 3.1% versus 35.7 +/- 1.0%; P < 0.05) as well as myocardial leukocyte accumulation (P < 0.05). In parallel in vitro studies, Nafamostat was a significantly more potent broad spectrum complement suppressor than C1 inhibitor. Nafamostat appears to have capability as an inhibitor of both complement pathways and as a broad-spectrum antiinflammatory agent by virtue of its serine protease inhibition. Administration of nafamostat before myocardial reperfusion after ischemia produced significant, dose-dependent cardioprotection. Reduced leukocyte accumulation and complement activity seem involved in the mechanism of this cardioprotective effect.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Activación de Complemento/efectos de los fármacos , Guanidinas/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Inhibidores de Serina Proteinasa/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/farmacología , Benzamidinas , Proteína Inhibidora del Complemento C1/farmacología , Proteína Inhibidora del Complemento C1/uso terapéutico , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Vía Alternativa del Complemento/efectos de los fármacos , Vía Clásica del Complemento/efectos de los fármacos , Creatina Quinasa/metabolismo , Guanidinas/administración & dosificación , Guanidinas/farmacología , Hemodinámica , Humanos , Inmunohistoquímica , Masculino , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Necrosis , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Conejos , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/farmacologíaRESUMEN
BACKGROUND: The Organization to Assess Strategies in Acute Ischemic Syndromes trials showed that fondaparinux (fonda) is at least as effective and safe as unfractionated heparin (UFH) and enoxaparin (enoxa) in acute coronary syndromes. Unexpectedly, there was an increase in catheter-related thrombus formation during percutaneous coronary interventions in fonda-treated patients. METHODS: Ten healthy male volunteers were pretreated with aspirin 500 mg 2 h before venesection of 50 ml of blood. Eight groups of anticoagulant (combinations) were tested and volunteers donated blood eight times, thus, acting as their own controls. The groups were UFH, UFH+eptifibatide, enoxa, enoxa+eptifibatide, fonda, fonda+eptifibatide, fonda+(half-therapeutic) UFH, and fonda+eptifibatide+(half-therapeutic) UFH. The blood/anticoagulant mix was kept at 37 degrees C and continuously circulated through a guiding catheter for 60 min or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy of the catheter lining was used to quantify the degree of erythrocyte and fibrin deposition. RESULTS: Despite fonda anticoagulation, catheters were invariably occluded by thrombus before the 60 min perfusion period had elapsed. Thrombotic catheter occlusion occurred even with higher fonda concentrations and combined fonda/eptifibatide use. All other combinations (including fonda and half-therapeutic UFH) ensured catheter patency for 60 min. Furthermore, thrombus weight and the cell/fibrinogen counts were significantly increased in fonda and fonda+eptifibatide compared with other treatment groups. CONCLUSION: Treatment with fonda, even in combination with eptifibatide, was not sufficient to prevent cardiac catheter thrombus development in our in-vitro study. However, the combination of fonda with 'half' therapeutic dosages of UFH were as efficient as other treatment strategies in preventing thrombus formation.
Asunto(s)
Cateterismo Cardíaco/efectos de los fármacos , Fibrinolíticos/farmacología , Trombosis/prevención & control , Enoxaparina/farmacología , Fondaparinux , Heparina/farmacología , Humanos , Técnicas In Vitro , Masculino , Microscopía Electrónica , Polisacáridos/farmacologíaRESUMEN
Hydrogen sulfide (H2S) is a key gasotransmitter in agriculture and has been reported to increase the growth of plants in the first two weeks and to mitigate the effects of environmental stressors. GYY-4137 is widely used in these studies because it slowly releases H2S, but there is disagreement as to whether it requires enzymes to release H2S. In this article we describe the release of H2S in water without enzymes and that it releases H2S faster in organic solvents than in water or when mixed in topsoil. Furthermore, we describe the long-term effect of dosing pea, radish, and lettuce plants with GYY-4137 for up to six weeks. The effect of GYY-4137 on plant growth for six weeks was either positive or negative depending on the loading of GYY-4137 and how it was applied to plants. The addition of GYY-4137 to lettuce plants via potting mix resulted in reduced growth and death of the plants. In contrast, application of GYY-4137 to the leaves of lettuce plants increased the harvest weight of the leaves by up to 86%. Our results demonstrate that GYY-4137 can have a positive, important effect on the growth of plants but that this effect is dependent on several factors.