RESUMEN
COVID-19 pandemic and subsequent lockdowns created a global public health crisis generating mental health problems including social isolation, stress, and anxiety especially for persons with dementia and their carers. This article reports on the use of digital technology to maintain social connectivity via a virtual group session that focused on the topic of "what is home." Participants in this session included 16 day-care center clients representing an immigrant community identified with mild to moderate cognitive impairment. A trained psychodrama therapist conducted the virtual group meeting based on five key techniques: spectrogram, role reversal, doubling, mirroring, and soliloquy. The NVivo software was used for the qualitative analysis of the transcribed video recording to identify key themes based on grounded theory methodology. Zooming from home, clients engaged in significant social interaction. Findings of the NVivo analysis identified the following themes of "what is home": Emotions and home, Home is family, Home is community, and Reminiscence (with objects and traditions). Findings suggest that digital interactive technologies, like Zoom, enhance social connectivity thus mitigating the negative impact of social isolation for persons with dementia especially during pandemic lockdowns. Our pilot findings based on virtual group meetings from home demonstrate that participants can express significant emotive capacity and enhanced connectivity with one another despite a diagnosis of mild to moderate dementia. While larger studies are needed to confirm these findings, we suggest that this methodology may be used to support persons with dementia not only in times of pandemics but also as an addition to other community and home care services. Changes in reimbursement policies to include these innovative home services may be helpful in building more resilient communities for the more highly vulnerable populations.
Asunto(s)
COVID-19 , Demencia , Psicodrama , Cuidadores , Control de Enfermedades Transmisibles , Demencia/epidemiología , Humanos , Pandemias , SARS-CoV-2RESUMEN
Utilization management strategies, including prior authorization, are commonly used to facilitate safe and guideline-adherent provision of new, individualized, and potentially costly cardiovascular therapies. However, as currently deployed, these approaches encumber multiple stakeholders. Patients are discouraged by barriers to appropriate access; clinicians are frustrated by the time, money, and resources required for prior authorizations, the frequent rejections, and the perception of being excluded from the decision-making process; and payers are weary of the intensive effort to design and administer increasingly complex prior authorization systems to balance value and appropriate use of these treatments. These issues highlight an opportunity to collectively reimagine utilization management as a transparent and collaborative system. This would benefit the entire healthcare ecosystem, especially in light of the shift to value-based payment. This article describes the efforts and vision of the multistakeholder Prior Authorization Learning Collaborative of the Value in Healthcare Initiative, a partnership between the American Heart Association and the Robert J. Margolis, MD, Center for Health Policy at Duke University. We outline how healthcare organizations can take greater utilization management responsibility under value-based contracting, especially under different state policies and local contexts. Even with reduced payer-mandated prior authorization in these arrangements, payers and healthcare organizations will have a continued shared need for utilization management. We present options for streamlining these programs, such as gold carding and electronic and automated prior authorization processes. Throughout the article, we weave in examples from cardiovascular care when possible. Although reimagining prior authorization requires collective action by all stakeholders, it may significantly reduce administrative burden for clinicians and payers while improving outcomes for patients.
Asunto(s)
Enfermedades Cardiovasculares/economía , Enfermedades Cardiovasculares/terapia , Prestación Integrada de Atención de Salud , Costos de la Atención en Salud , Autorización Previa/economía , Seguro de Salud Basado en Valor/economía , Compra Basada en Calidad/economía , Enfermedades Cardiovasculares/diagnóstico , Toma de Decisiones Clínicas , Análisis Costo-Beneficio , Prestación Integrada de Atención de Salud/economía , Prestación Integrada de Atención de Salud/organización & administración , Humanos , Innovación Organizacional , Formulación de Políticas , Autorización Previa/organización & administración , Mejoramiento de la Calidad/economía , Indicadores de Calidad de la Atención de Salud/economía , Participación de los Interesados , Seguro de Salud Basado en Valor/organización & administración , Compra Basada en Calidad/organización & administraciónRESUMEN
Heart failure (HF) is a leading cause of hospitalizations and readmissions in the United States. Particularly among the elderly, its prevalence and costs continue to rise, making it a significant population health issue. Despite tremendous progress in improving HF care and examples of innovation in care redesign, the quality of HF care varies greatly across the country. One major challenge underpinning these issues is the current payment system, which is largely based on fee-for-service reimbursement, leads to uncoordinated, fragmented, and low-quality HF care. While the payment landscape is changing, with an increasing proportion of all healthcare dollars flowing through value-based payment models, no longitudinal models currently focus on chronic HF care. Episode-based payment models for HF hospitalization have yielded limited success and have little ability to prevent early chronic disease from progressing to later stages. The available literature suggests that primary care-based longitudinal payment models have indirectly improved HF care quality and cardiovascular care costs, but these models are not focused on addressing patients' longitudinal chronic disease needs. This article describes the efforts and vision of the multi-stakeholder Value-Based Models Learning Collaborative of The Value in Healthcare Initiative, a collaboration of the American Heart Association and the Robert J. Margolis, MD, Center for Health Policy at Duke University. The Learning Collaborative developed a framework for a HF value-based payment model with a longitudinal focus on disease management (to reduce adverse clinical outcomes and disease progression among patients with stage C HF) and prevention (an optional track to prevent high-risk stage B pre-HF from progressing to stage C). The model is designed to be compatible with prevalent payment models and reforms being implemented today. Barriers to success and strategies for implementation to aid payers, regulators, clinicians, and others in developing a pilot are discussed.
Asunto(s)
Prestación Integrada de Atención de Salud/economía , Costos de la Atención en Salud , Insuficiencia Cardíaca/economía , Insuficiencia Cardíaca/terapia , Evaluación de Procesos y Resultados en Atención de Salud/economía , Seguro de Salud Basado en Valor/economía , Compra Basada en Calidad/economía , Ahorro de Costo , Análisis Costo-Beneficio , Costos de Hospital , Humanos , Modelos Económicos , Readmisión del Paciente , Mejoramiento de la Calidad/economía , Indicadores de Calidad de la Atención de Salud/economía , Participación de los Interesados , Factores de Tiempo , Resultado del TratamientoRESUMEN
Background Fish oil is among the most common natural supplements for treatment of hypertriglyceridemia or prevention of cardiovascular disease. However, concerns about theoretical bleeding risk have led to recommendations that patients should stop taking fish oil before surgery or delay in elective procedures for patients taking fish oil by some health care professionals. Methods and Results We tested the effect of fish oil supplementation on perioperative bleeding in a multinational, placebo-controlled trial involving 1516 patients who were randomized to perioperative fish oil (eicosapentaenoic acid+docosahexaenoic acid; 8-10 g for 2-5 days preoperatively, and then 2 g/d postoperatively) or placebo. Primary outcome was major perioperative bleeding as defined by the Bleeding Academic Research Consortium. Secondary outcomes include perioperative bleeding per thrombolysis in myocardial infarction and International Society on Thrombosis and Hemostasis definitions, chest tube output, and total units of blood transfused. Participants' mean (SD) age was 63 (13) years, and planned surgery included coronary artery bypass graft (52%) and valve surgery (50%). The primary outcome occurred in 92 patients (6.1%). Compared with placebo, risk of Bleeding Academic Research Consortium bleeding was not higher in the fish oil group: odds ratio, 0.81; 95% CI, 0.53-1.24; absolute risk difference, 1.1% lower (95% CI, -3.0% to 1.8%). Similar findings were seen for secondary bleeding definitions. The total units of blood transfused were significantly lower in the fish oil group compared with placebo (mean, 1.61 versus 1.92; P<0.001). Evaluating achieved plasma phospholipid omega-3 polyunsaturated fatty acids levels with supplementation (on the morning of surgery), higher levels were associated with lower risk of Bleeding Academic Research Consortium bleeding, with substantially lower risk in the third (odds ratio, 0.30 [95% CI, 0.11-0.78]) and fourth (0.36 [95% CI, 0.15-0.87]) quartiles, compared with the lowest quartile. Conclusions Fish oil supplementation did not increase perioperative bleeding and reduced the number of blood transfusions. Higher achieved n-3-PUFA levels were associated with lower risk of bleeding. These novel findings support the need for reconsideration of current recommendations to stop fish oil or delay procedures before cardiac surgery. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00970489.
Asunto(s)
Puente de Arteria Coronaria , Aceites de Pescado/uso terapéutico , Hemorragia Posoperatoria/prevención & control , Anciano , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , RiesgoRESUMEN
Background: Cognitive decline has been reported following cardiac surgery, leading to great interest in interventions to minimize its occurrence. Long-chain n-3 (ω-3) polyunsaturated fatty acids (PUFAs) have been associated with less cognitive decline in observational studies, yet no trials have tested the effects of n-3 PUFAs on cognitive decline after surgery. Objective: We sought to determine whether perioperative n-3 PUFA supplementation reduces postoperative cognitive decline in patients postcardiac surgery. Methods: The study comprised a randomized, double-blind, placebo-controlled, multicenter, clinical trial conducted on cardiac surgery recipients at 9 tertiary care medical centers across the United States. Patients were randomly assigned to receive fish oil (1-g capsules containing ≥840 mg n-3 PUFAs as ethyl esters) or placebo, with preoperative loading of 8-10 g over 2-5 d followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Global cognition was assessed using in-person testing over 30 d with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (primary outcome), Mini-Mental State Exam (secondary outcome), and Trails A and B (secondary outcome) tests. All end points were prespecified. Statistical methods were employed, including descriptive statistics, logistic regression, and various sensitivity analyses. Results: A total of 320 US patients were enrolled in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Cognitive Trial (OCT), a substudy of OPERA. The median age was 62 y (IQR 53, 70 y). No differences in global cognition were observed between placebo and fish oil groups at day 30 (P = 0.32) for the primary outcome, a composite neuropsychological RBANS score. The population demonstrated resolution of initial 4-d cognitive decline back to baseline function by 30 d on the RBANS. Conclusion: Perioperative supplementation with n-3 PUFAs in cardiac surgical patients did not influence cognition ≤30 d after discharge. Modern anesthetic, surgical, and postoperative care may be mitigating previously observed long-term declines in cognitive function following cardiac surgery. This trial was registered at clinicaltrials.gov as NCT00970489.
Asunto(s)
Cognición/efectos de los fármacos , Disfunción Cognitiva , Suplementos Dietéticos , Aceites de Pescado/farmacología , Cardiopatías/cirugía , Atención Perioperativa , Complicaciones Posoperatorias , Anciano , Fibrilación Atrial , Disfunción Cognitiva/etiología , Disfunción Cognitiva/rehabilitación , Método Doble Ciego , Ácidos Grasos Omega-3/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
IMPORTANCE: Statins affect several mechanisms underlying acute kidney injury (AKI). OBJECTIVE: To test the hypothesis that short-term high-dose perioperative atorvastatin would reduce AKI following cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Double-blinded, placebo-controlled, randomized clinical trial of adult cardiac surgery patients conducted from November 2009 to October 2014 at Vanderbilt University Medical Center. INTERVENTIONS: Patients naive to statin treatment (n = 199) were randomly assigned 80 mg of atorvastatin the day before surgery, 40 mg of atorvastatin the morning of surgery, and 40 mg of atorvastatin daily following surgery (n = 102) or matching placebo (n = 97). Patients already taking a statin prior to study enrollment (n = 416) continued taking the preenrollment statin until the day of surgery, were randomly assigned 80 mg of atorvastatin the morning of surgery and 40 mg of atorvastatin the morning after (n = 206) or matching placebo (n = 210), and resumed taking the previously prescribed statin on postoperative day 2. MAIN OUTCOMES AND MEASURES: Acute kidney injury defined as an increase of 0.3 mg/dL in serum creatinine concentration within 48 hours of surgery (Acute Kidney Injury Network criteria). RESULTS: The data and safety monitoring board recommended stopping the group naive to statin treatment due to increased AKI among these participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) receiving atorvastatin. The board later recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] were women; 202 [32.8%] had diabetes) completed the study. Among all participants (n = 615), AKI occurred in 64 of 308 (20.8%) in the atorvastatin group vs 60 of 307 (19.5%) in the placebo group (relative risk [RR], 1.06 [95% CI, 0.78 to 1.46]; P = .75). Among patients naive to statin treatment (n = 199), AKI occurred in 22 of 102 (21.6%) in the atorvastatin group vs 13 of 97 (13.4%) in the placebo group (RR, 1.61 [0.86 to 3.01]; P = .15) and serum creatinine concentration increased by a median of 0.11 mg/dL (10th-90th percentile, -0.11 to 0.56 mg/dL) in the atorvastatin group vs by a median of 0.05 mg/dL (10th-90th percentile, -0.12 to 0.33 mg/dL) in the placebo group (mean difference, 0.08 mg/dL [95% CI, 0.01 to 0.15 mg/dL]; P = .007). Among patients already taking a statin (n = 416), AKI occurred in 42 of 206 (20.4%) in the atorvastatin group vs 47 of 210 (22.4%) in the placebo group (RR, 0.91 [0.63 to 1.32]; P = .63). CONCLUSIONS AND RELEVANCE: Among patients undergoing cardiac surgery, high-dose perioperative atorvastatin treatment compared with placebo did not reduce the risk of AKI overall, among patients naive to treatment with statins, or in patients already taking a statin. These results do not support the initiation of statin therapy to prevent AKI following cardiac surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00791648.
Asunto(s)
Lesión Renal Aguda/prevención & control , Atorvastatina/administración & dosificación , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lesión Renal Aguda/sangre , Lesión Renal Aguda/etiología , Anciano , Anciano de 80 o más Años , Aspartato Aminotransferasas/sangre , Atorvastatina/efectos adversos , Creatinina/sangre , Método Doble Ciego , Esquema de Medicación , Femenino , Tasa de Filtración Glomerular , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Masculino , Cumplimiento de la Medicación/estadística & datos numéricos , Persona de Mediana Edad , Complicaciones Posoperatorias , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: Animal study results point to oxidative stress as a key mechanism triggering postoperative atrial fibrillation (PoAF), yet the extent to which specific biomarkers of oxidative stress might relate to PoAF risk in humans remains speculative. METHODS AND RESULTS: We assessed the association of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans, and F3-isoprostanes) in plasma and urine, with incident PoAF among 551 cardiac surgery patients. Biomarkers were measured at enrollment, the end of surgery, and postoperative day 2. PoAF lasting ≥30 seconds was confirmed with rhythm strip or electrocardiography and centrally adjudicated. Outcomes were assessed until hospital discharge or postoperative day 10, whichever occurred first. Urine level of each oxidative stress biomarker rose at the end of surgery (2- to 3-fold over baseline, P<0.001) and subsequently declined to concentrations comparable to baseline by postoperative day 2. In contrast, plasma concentrations remained relatively stable throughout the perioperative course. Urine F2-isoprostanes and isofurans at the end of surgery were 20% and 50% higher in subjects who developed PoAF (P≤0.009). While baseline biomarker levels did not associate significantly with PoAF, end of surgery and postoperative day 2 isoprostanes and isofurans demonstrated relatively linear associations with PoAF. For example, the end of surgery extreme quartile multivariate adjusted OR (95% CI) for urine isofurans and F3-isoprostanes were 1.95 (1.05 to 3.62; P for trend=0.01) and 2.10 (1.04 to 2.25, P for trend=0.04), respectively. The associations of biomarkers with PoAF varied little by demographics, surgery type, and medication use (P≥0.29 for each). CONCLUSIONS: These novel results add to accumulating evidence supporting the likely key pathogenic role of elevated oxidative stress in PoAF. CLINICAL TRIAL REGISTRATION: URL: Clinicaltrials.gov Unique identifier: NCT00970489.
Asunto(s)
Fibrilación Atrial/epidemiología , Fibrilación Atrial/prevención & control , Biomarcadores/sangre , Ácidos Grasos Omega-3/uso terapéutico , Estrés Oxidativo , Complicaciones Posoperatorias/prevención & control , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Grasas Insaturadas en la Dieta/uso terapéutico , Electrocardiografía , F2-Isoprostanos/sangre , Ácidos Grasos Omega-3/administración & dosificación , Femenino , Humanos , Incidencia , Isoprostanos/sangre , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/dietoterapia , Periodo Posoperatorio , Resultado del TratamientoRESUMEN
BACKGROUND: Long-chain polyunsaturated omega-3 fatty acids (n-3 PUFA) demonstrated antiarrhythmic potential in experimental studies. In a large multinational randomized trial (OPERA), perioperative fish oil supplementation did not reduce the risk of postoperative atrial fibrillation (PoAF) in cardiac surgery patients. However, whether presupplementation habitual plasma phospholipid n-3 PUFA, or achieved or change in n-3 PUFA level postsupplementation are associated with lower risk of PoAF is unknown. METHODS AND RESULTS: In 564 subjects undergoing cardiac surgery between August 2010 and June 2012 in 28 centers across 3 countries, plasma phospholipid levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were measured at enrollment and again on the morning of cardiac surgery following fish oil or placebo supplementation (10 g over 3 to 5 days, or 8 g over 2 days). The primary endpoint was incident PoAF lasting ≥ 30 seconds, centrally adjudicated, and confirmed by rhythm strip or ECG. Secondary endpoints included sustained (≥ 1 hour), symptomatic, or treated PoAF; the time to first PoAF; and the number of PoAF episodes per patient. PoAF outcomes were assessed until hospital discharge or postoperative day 10, whichever occurred first. Relative to the baseline, fish oil supplementation increased phospholipid concentrations of EPA (+142%), DPA (+13%), and DHA (+22%) (P < 0.001 each). Substantial interindividual variability was observed for change in total n-3 PUFA (range = -0.7% to 7.5% after 5 days of supplementation). Neither individual nor total circulating n-3 PUFA levels at enrollment, morning of surgery, or change between these time points were associated with risk of PoAF. The multivariable-adjusted OR (95% CI) across increasing quartiles of total n-3 PUFA at enrollment were 1.0, 1.06 (0.60 to 1.90), 1.35 (0.76 to 2.38), and 1.19 (0.64 to 2.20); and for changes in n-3 PUFA between enrollment and the morning of surgery were 1.0, 0.78 (0.44 to 1.39), 0.89 (0.51 to 1.55), and 1.01 (0.58 to 1.75). In stratified analysis, demographic, medication, and cardiac parameters did not significantly modify these associations. Findings were similar for secondary PoAF endpoints. CONCLUSIONS: Among patients undergoing cardiac surgery, neither higher habitual circulating n-3 PUFA levels, nor achieved levels or changes following short-term fish oil supplementation are associated with risk of PoAF.
Asunto(s)
Fibrilación Atrial/sangre , Fibrilación Atrial/epidemiología , Procedimientos Quirúrgicos Cardíacos , Suplementos Dietéticos , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Ácidos Grasos Insaturados/sangre , Aceites de Pescado , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/epidemiología , Anciano , Femenino , Aceites de Pescado/administración & dosificación , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: The incidence of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema is increased in patients with seasonal allergies. OBJECTIVE: We tested the hypothesis that patients with ACE inhibitor-associated angioedema present during months when pollen counts are increased. METHODS: Cohort analysis examined the month of presentation of ACE inhibitor-associated angioedema and pollen counts in the ambulatory and hospital setting. Patients with ACE inhibitor-associated angioedema were ascertained through (1) an observational study of patients presenting to Vanderbilt University Medical Center, (2) patients presenting to the Marshfield Clinic and participating in the Marshfield Clinic Personalized Medicine Research Project, and (3) patients enrolled in The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Measurements include date of presentation of ACE inhibitor-associated angioedema, population exposure to ACE inhibitor by date, and local pollen counts by date. RESULTS: At Vanderbilt, the rate of angioedema was significantly associated with tree pollen months (P = .01 from χ(2) test). When separate analyses were conducted in patients with a history of seasonal allergies and patients without, the rate of ACE inhibitor-associated angioedema was increased during tree pollen months only in patients with a history of seasonal allergies (P = .002). In Marshfield, the rate of angioedema was significantly associated with ragweed pollen months (P = .025). In ONTARGET, a positive trend was observed between the ACE inhibitor-associated angioedema rate and grass season, although it was not statistically significant (P = .057). CONCLUSIONS: Patients with ACE inhibitor-associated angioedema are more likely to present with this adverse drug event during months when pollen counts are increased.
Asunto(s)
Alérgenos/inmunología , Angioedema/inducido químicamente , Angioedema/epidemiología , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Polen/inmunología , Rinitis Alérgica Estacional/epidemiología , Adulto , Anciano , Ambrosia/inmunología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Malezas/inmunología , Poaceae/inmunología , Árboles/inmunologíaRESUMEN
Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.
Asunto(s)
Bradiquinina/farmacología , Endotelio Vascular/metabolismo , Glucosa/metabolismo , Óxido Nítrico/fisiología , Obesidad/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Adulto , Aspirina/farmacología , Bradiquinina/fisiología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/farmacología , Femenino , Antebrazo/irrigación sanguínea , Humanos , Masculino , Óxido Nítrico/biosíntesis , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Obesidad/enzimología , Obesidad/fisiopatología , Flujo Sanguíneo Regional/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , omega-N-Metilarginina/farmacologíaRESUMEN
OBJECTIVE: To test the hypothesis that pharmacological plasminogen activator inhibitor (PAI)-1 inhibition protects against renin-angiotensin-aldosterone system-induced cardiovascular injury, the effect of a novel orally active small-molecule PAI-1 inhibitor, PAI-039, was examined in a mouse model of angiotensin (Ang) II-induced vascular remodeling and cardiac fibrosis. METHODS AND RESULTS: Uninephrectomized male C57BL/6J mice were randomized to vehicle subcutaneus, Ang II (1 mug/h) subcutaneous, vehicle+PAI-039 (1 mg/g chow), or Ang II+PAI-039 during high-salt intake for 8 weeks. Ang II caused significant medial, adventitial, and aortic wall thickening compared with vehicle. PAI-039 attenuated Ang II-induced aortic remodeling without altering the pressor response to Ang II. Ang II increased heart/body weight ratio and cardiac fibrosis. PAI-039 did not attenuate the effect of Ang II on cardiac hypertrophy and increased fibrosis. The effect of PAI-039 on Ang II/salt-induced aortic remodeling and cardiac fibrosis was comparable to the effect of genetic PAI-1 deficiency. Ang II increased aortic mRNA expression of PAI-1, collagen I, collagen III, fibronectin, osteopontin, monocyte chemoattractant protein-1, and F4/80; PAI-039 significantly decreased the Ang II-induced increase in aortic osteopontin expression at 8 weeks. CONCLUSIONS: This study demonstrates that pharmacological inhibition of PAI-1 protects against Ang II-induced aortic remodeling. Future studies are needed to determine whether the interactive effect of Ang II/salt and reduced PAI-1 activity on cardiac fibrosis is species-specific. In this study, the effect of pharmacological PAI-1 inhibition in a mouse model of Ang II-induced vascular remodeling and cardiac fibrosis was examined. PAI-1 inhibition significantly attenuated Ang II-induced aortic medial and wall thickening, but not cardiac hypertrophy, and enhanced Ang II/salt-induced cardiac fibrosis.