RESUMEN
BACKGROUND: Electronic health records (EHRs) offer the opportunity to transform quality improvement by using clinical data for comparing hospital performance without the burden of chart abstraction. However, current performance measures using EHRs are lacking. METHODS: With support from the Centers for Medicare & Medicaid Services (CMS), we developed an outcome measure of hospital risk-standardized 30-day mortality rates for patients with acute myocardial infarction for use with EHR data. As no appropriate source of EHR data are currently available, we merged clinical registry data from the Action Registry-Get With The Guidelines with claims data from CMS to develop the risk model (2009 data for development, 2010 data for validation). We selected candidate variables that could be feasibly extracted from current EHRs and do not require changes to standard clinical practice or data collection. We used logistic regression with stepwise selection and bootstrapping simulation for model development. RESULTS: The final risk model included 5 variables available on presentation: age, heart rate, systolic blood pressure, troponin ratio, and creatinine level. The area under the receiver operating characteristic curve was 0.78. Hospital risk-standardized mortality rates ranged from 9.6% to 13.1%, with a median of 10.7%. The odds of mortality for a high-mortality hospital (+1 SD) were 1.37 times those for a low-mortality hospital (-1 SD). CONCLUSIONS: This measure represents the first outcome measure endorsed by the National Quality Forum for public reporting of hospital quality based on clinical data in the EHR. By being compatible with current clinical practice and existing EHR systems, this measure is a model for future quality improvement measures.
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Registros Electrónicos de Salud , Hospitales/estadística & datos numéricos , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , Evaluación de Resultado en la Atención de Salud , Anciano , Centers for Medicare and Medicaid Services, U.S. , Femenino , Mortalidad Hospitalaria , Humanos , Revisión de Utilización de Seguros , Masculino , Modelos Estadísticos , Mejoramiento de la Calidad , Sistema de Registros , Medición de Riesgo , Estados UnidosRESUMEN
OBJECTIVES: This study sought to determine the use of intravenous fluids in the early care of patients with acute decompensated heart failure (HF) who are treated with loop diuretics. BACKGROUND: Intravenous fluids are routinely provided to many hospitalized patients. METHODS: We conducted a retrospective cohort study of patients admitted with HF to 346 hospitals from 2009 to 2010. We assessed the use of intravenous fluids during the first 2 days of hospitalization. We determined the frequency of adverse in-hospital outcomes. We assessed variation in the use of intravenous fluids across hospitals and patient groups. RESULTS: Among 131,430 hospitalizations for HF, 13,806 (11%) were in patients treated with intravenous fluids during the first 2 days. The median volume of administered fluid was 1,000 ml (interquartile range: 1,000 to 2,000 ml), and the most commonly used fluids were normal saline (80%) and half-normal saline (12%). Demographic characteristics and comorbidities were similar in hospitalizations in which patients did and did not receive fluids. Patients who were treated with intravenous fluids had higher rates of subsequent critical care admission (5.7% vs. 3.8%; p < 0.0001), intubation (1.4% vs. 1.0%; p = 0.0012), renal replacement therapy (0.6% vs. 0.3%; p < 0.0001), and hospital death (3.3% vs. 1.8%; p < 0.0001) compared with those who received only diuretics. The proportion of hospitalizations that used fluid treatment varied widely across hospitals (range: 0% to 71%; median: 12.5%). CONCLUSIONS: Many patients who are hospitalized with HF and receive diuretics also receive intravenous fluids during their early inpatient care, and the proportion varies among hospitals. Such practice is associated with worse outcomes and warrants further investigation.
Asunto(s)
Fluidoterapia , Insuficiencia Cardíaca/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Insuficiencia Cardíaca/epidemiología , Mortalidad Hospitalaria , Hospitalización , Humanos , Infusiones Intravenosas , Unidades de Cuidados Intensivos/estadística & datos numéricos , Intubación Intratraqueal/estadística & datos numéricos , Soluciones Isotónicas/uso terapéutico , Masculino , Persona de Mediana Edad , Terapia de Reemplazo Renal/estadística & datos numéricos , Estudios Retrospectivos , Solución de Ringer , Solución Salina Hipertónica/uso terapéutico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Existing publicly reported readmission measures are condition-specific, representing less than 20% of adult hospitalizations. An all-condition measure may better measure quality and promote innovation. OBJECTIVE: To develop an all-condition, hospital-wide readmission measure. DESIGN: Measure development study. SETTING: 4821 U.S. hospitals. PATIENTS: Medicare fee-for-service beneficiaries aged 65 years or older. MEASUREMENTS: Hospital-level, risk-standardized unplanned readmissions within 30 days of discharge. The measure uses Medicare fee-for-service claims and is a composite of 5 specialty-based, risk-standardized rates for medicine, surgery/gynecology, cardiorespiratory, cardiovascular, and neurology cohorts. The 2007-2008 admissions were randomly split for development and validation. Models were adjusted for age, principal diagnosis, and comorbid conditions. Calibration in Medicare and all-payer data was examined, and hospital rankings in the development and validation samples were compared. RESULTS: The development data set contained 8 018 949 admissions associated with 1 276 165 unplanned readmissions (15.9%). The median hospital risk-standardized unplanned readmission rate was 15.8 (range, 11.6 to 21.9). The 5 specialty cohort models accurately predicted readmission risk in both Medicare and all-payer data sets for average-risk patients but slightly overestimated readmission risk at the extremes. Overall hospital risk-standardized readmission rates did not differ statistically in the split samples (P = 0.71 for difference in rank), and 76% of hospitals' validation-set rankings were within 2 deciles of the development rank (24% were more than 2 deciles). Of hospitals ranking in the top or bottom deciles, 90% remained within 2 deciles (10% were more than 2 deciles) and 82% remained within 1 decile (18% were more than 1 decile). LIMITATION: Risk adjustment was limited to that available in claims data. CONCLUSION: A claims-based, hospital-wide unplanned readmission measure for profiling hospitals produced reasonably consistent results in different data sets and was similarly calibrated in both Medicare and all-payer data. PRIMARY FUNDING SOURCE: Centers for Medicare & Medicaid Services.
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Hospitales/normas , Revisión de Utilización de Seguros , Readmisión del Paciente , Anciano , Planes de Aranceles por Servicios , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Medicare , Readmisión del Paciente/estadística & datos numéricos , Mejoramiento de la Calidad , Ajuste de Riesgo , Estados UnidosRESUMEN
BACKGROUND: Prior claims analyses suggest that the use of intravenous inotropic therapy for patients hospitalized with heart failure varies substantially by hospital. Whether differences in the clinical characteristics of the patients explain observed differences in the use of inotropic therapy is not known. METHODS AND RESULTS: We sought to characterize institutional variation in inotrope use among patients hospitalized with heart failure before and after accounting for clinical factors of patients. Hierarchical generalized linear regression models estimated risk-standardized hospital-level rates of inotrope use within 209 hospitals participating in Get With The Guidelines-Heart Failure (GWTG-HF) registry between 2005 and 2011. The association between risk-standardized rates of inotrope use and clinical outcomes was determined. Overall, an inotropic agent was administered in 7691 of 126 564 (6.1%) heart failure hospitalizations: dobutamine 43%, dopamine 24%, milrinone 17%, or a combination 16%. Patterns of inotrope use were stable during the 7-year study period. Use of inotropes varied significantly between hospitals even after accounting for patient and hospital characteristics (median risk-standardized hospital rate, 5.9%; interquartile range, 3.7%-8.6%; range, 1.3%-32.9%). After adjusting for case-mix and hospital structural differences, model intraclass correlation indicated that 21% of the observed variation in inotrope use was potentially attributable to random hospital effects (ie, institutional preferences). Hospitals with higher risk-standardized inotrope use had modestly longer risk-standardized length of stay (P=0.005) but had no difference in risk-standardized inpatient mortality (P=0.12). CONCLUSIONS: Use of intravenous inotropic agents during hospitalization for heart failure varies significantly among US hospitals even after accounting for patient and hospital factors.
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Cardiotónicos/administración & dosificación , Adhesión a Directriz , Insuficiencia Cardíaca/tratamiento farmacológico , Hospitales/normas , Pacientes Internos , Evaluación de Resultado en la Atención de Salud , Pautas de la Práctica en Medicina , Anciano , Estudios Transversales , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/mortalidad , Mortalidad Hospitalaria/tendencias , Humanos , Infusiones Intravenosas , Tiempo de Internación/tendencias , Masculino , Sistema de Registros , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiologíaRESUMEN
The authors developed 8 measures of waste associated with cardiac procedures to assist hospitals in comparing their performance with peer facilities. Measure selection was based on review of the research literature, clinical guidelines, and consultation with key stakeholders. Development and validation used the data from 261 hospitals in a split-sample design. Measures were risk adjusted using Premier's CareScience methodologies or mean peer value based on Medicare Severity Diagnosis-Related Group assignment. High variability was found in resource utilization across facilities. Validation of the measures using item-to-total correlations (range = 0.27-0.78), Cronbach α (.88), and Spearman rank correlation (0.92) showed high reliability and discriminatory power. Because of the level of variability observed among hospitals, this study suggests that there is opportunity for facilities to design successful waste reduction programs targeting cardiac-device procedures.
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Enfermedades Cardiovasculares/terapia , Costos de Hospital , Procedimientos Innecesarios/economía , Bases de Datos Factuales , Eficiencia Organizacional/economía , Equipos y Suministros/economía , Recursos en Salud/estadística & datos numéricos , Administradores de Hospital , Hospitales Generales/economía , Humanos , Cuerpo Médico de Hospitales , Investigación Cualitativa , Garantía de la Calidad de Atención de Salud/métodos , Estados UnidosRESUMEN
BACKGROUND: Because relative value unit (RVU)-based costs vary across hospitals, it is difficult to use them to compare hospital utilization. OBJECTIVE: To compare estimates of hospital utilization using RVU-based costs and standardized costs. DESIGN: Retrospective cohort. SETTING AND PATIENTS: Years 2009 to 2010 heart failure hospitalizations in a large, detailed hospital billing database that contains an itemized log of costs incurred during hospitalization. INTERVENTION: We assigned every item in the database with a standardized cost that was consistent for that item across all hospitals. MEASUREMENTS: Standardized costs of hospitalization versus RVU-based costs of hospitalization. RESULTS: We identified 234 hospitals with 165,647 heart failure hospitalizations. We observed variation in the RVU-based cost for a uniform "basket of goods" (10th percentile cost $1,552; 90th percentile cost of $3,967). The interquartile ratio (Q75/Q25) of the RVU-based costs of a hospitalization was 1.35 but fell to 1.26 after costs were standardized, suggesting that the use of standardized costs can reduce the "noise" due to differences in overhead and other fixed costs. Forty-six (20%) hospitals had reported costs of hospitalizations exceeding standardized costs (indicating that reported costs inflated apparent utilization); 42 hospitals (17%) had reported costs that were less than standardized costs (indicating that reported costs underestimated utilization). CONCLUSIONS: Standardized costs are a novel method for comparing utilization across hospitals and reduce variation observed with RVU-based costs. They have the potential to help hospitals understand how they use resources compared to their peers and will facilitate research comparing the effectiveness of higher and lower utilization.
Asunto(s)
Insuficiencia Cardíaca/economía , Costos de Hospital , Hospitalización/economía , Escalas de Valor Relativo , Estudios de Cohortes , Estudios Transversales , Insuficiencia Cardíaca/terapia , Humanos , Estudios RetrospectivosAsunto(s)
Furosemida/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Sulfonamidas/uso terapéutico , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Torasemida , Resultado del TratamientoRESUMEN
OBJECTIVES: This study sought to determine hospital patterns of change in use of nesiritide over a 6-year period after publications of safety concerns in 2005 and to identify hospital characteristics associated with these patterns. BACKGROUND: The changing nature of medical evidence often requires a change in practice. Nesiritide was commercialized in 2001 for early relief of dyspnea in patients with decompensated heart failure. In 2005, concerns about its safety led to recommendations to restrict its use. Little is known about how hospitals responded to this information. METHODS: We analyzed data from the Premier database, including 403 hospitals contributing 813,783 hospitalizations with heart failure from 2005 to 2010. We applied a growth mixture modeling approach to hospital-level, risk-standardized, quarterly use rates of nesiritide to distinguish hospital groups on the basis of their patterns of change in use. RESULTS: The proportion of hospitalizations using nesiritide declined from 15.4% in 2005 to 1.2% in 2010. The level and speed of change varied markedly among hospitals. After adjusting for differences in patient characteristics across hospitals and years, we identified 3 distinct groups of hospitals: "low users," "fast de-adopters," and "slow de-adopters." In multivariate regression analysis, these groups did not differ in traditional hospital characteristics, such as size, urban setting, or teaching status. CONCLUSIONS: We identified 3 distinct hospital groups characterized by their patterns of change in nesiritide use. These trajectory curves can provide hospitals with important feedback on how fast and effectively they react to new information compared with other hospitals. Uncovering factors that promote organizational learning requires further research.
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Utilización de Medicamentos/estadística & datos numéricos , Insuficiencia Cardíaca/tratamiento farmacológico , Natriuréticos/efectos adversos , Péptido Natriurético Encefálico/efectos adversos , Sistemas de Registro de Reacción Adversa a Medicamentos , Hospitalización , Hospitales , HumanosRESUMEN
OBJECTIVES: This study sought to determine hospital variation in the use of positive inotropic agents in patients with heart failure. BACKGROUND: Clinical guidelines recommend targeted use of positive inotropic agents in highly selected patients, but data are limited and the recommendations are not specific. METHODS: We analyzed data from 376 hospitals including 189,948 hospitalizations for heart failure from 2009 through 2010. We used hierarchical logistic regression models to estimate hospital-level risk-standardized rates of inotrope use and risk-standardized in-hospital mortality rates. RESULTS: The risk-standardized rates of inotrope use ranged across hospitals from 0.9% to 44.6% (median: 6.3%, interquartile range: 4.3% to 9.2%). We identified various hospital patterns based on the type of agents: dobutamine-predominant (29% of hospitals), dopamine-predominant (25%), milrinone-predominant (1%), mixed dobutamine and dopamine pattern (32%), and mixed pattern including all 3 agents (13%). When studying the factors associated with interhospital variation, the best model performance was with the hierarchical generalized linear models that adjusted for patient case mix and an individual hospital effect (receiver operating characteristic curves from 0.77 to 0.88). The intraclass correlation coefficients of the hierarchical generalized linear models (0.113 for any inotrope) indicated that a noteworthy proportion of the observed variation was related to an individual institutional effect. Hospital rates or patterns of use were not associated with differences in length of stay or risk-standardized mortality rates. CONCLUSIONS: We found marked differences in the use of inotropic agents for heart failure patients among a diverse group of hospitals. This variability, occurring in the context of little clinical evidence, indicates an urgent need to define the appropriate use of these medications.
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Cardiotónicos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hospitales/normas , Estudios Transversales , Insuficiencia Cardíaca/mortalidad , Mortalidad Hospitalaria/tendencias , Humanos , Tiempo de Internación/tendencias , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Estados Unidos/epidemiologíaRESUMEN
Mammalian target of rapamycin (mTOR) activity is regulated by assembly of two functionally distinct complexes, mTORC1 and mTORC2. In syndecan-4 (S4) null endothelial cells, mTORC2 activity is reduced, resulting in decreased Akt activation, while mTORC1 activity is increased. Levels of rictor, mLST8, and mSin-1 are unchanged in total cell lysates but decreased in the rafts of S4(-/-) endothelial cells, as is the level of PKCalpha. Expression of myristoylated-PKCalpha in S4(-/-) cells restores rictor, mLST8, and mSin-1 presence in the rafts and rescues Akt phosphorylation. PKCalpha knockdown mimics the effect of S4 deletion on mTORC2 localization and Akt activation. Reduced mTORC2 activity in S4(-/-) endothelial cells results in decreased FoxO1/3a and eNOS phosphorylation, decreased endothelial cell size, and increased arterial blood pressure in S4(-/-) mice. Thus, S4-dependent targeting of PKCalpha to the plasma membrane is required for recruitment of mTORC2 components to the rafts and Akt activation.
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Proteína Quinasa C-alfa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sindecano-4/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Transporte Biológico Activo , Línea Celular , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Activación Enzimática/efectos de los fármacos , Sustancias de Crecimiento/farmacología , Microdominios de Membrana/metabolismo , Ratones , Ratones Noqueados , Modelos Biológicos , Sindecano-4/deficiencia , Sindecano-4/genéticaRESUMEN
The possibility of reconstituting the damaged heart has introduced a new paradigm in cardiovascular biology and created the potential for a new therapeutic approach in the cardiovascular field, where there is a compelling need for innovative treatments. While the results of animal and early clinical studies are encouraging, the more direct use of cell-based therapies in patients is still long-reached. Gaps in our basic understanding of mechanisms, lack of important randomized, double blind, and controlled clinical trials, as well as technology development for cell production are among challenges to be overcome before full translation of cell based therapies in clinical arena. This review focuses on summarizing the latest knowledge in stem cell therapy for cardiovascular diseases.
RESUMEN
Endothelial nitric oxide synthase (eNOS) plays an important role in control of vascular tone and angiogenesis among other functions. Its regulation is complex and has not been fully established. Several studies have emphasized the importance of phosphorylation in the regulation of eNOS activity. Although it is commonly accepted that protein kinase C (PKC) signaling inhibits eNOS activity by phosphorylating Thr497 and dephosphorylating Ser1179, the distinct role of different PKC isoforms has not been studied so far. The PKC family comprises roughly 12 different isozymes that activate distinct downstream pathways. The present study was designed to investigate the role of PKCalpha isoform in regulation of eNOS activity. Overexpression of PKCalpha in primary endothelial cells was associated with increased eNOS-Ser1179 phosphorylation and increased NO production. Inhibition of PKCalpha activity either by siRNA transfection or by overexpression of a dominant negative mutant resulted in a marked decrease in FGF2-induced Ser1179 phosphorylation and NO production. In vivo, PKCalpha transduction in rat femoral arteries resulted in a significant increase in the resting blood flow that was suppressed by treatment with L-NAME, an eNOS inhibitor. In conclusion, these data demonstrate for the first time that PKCalpha stimulates NO production in endothelial cells and plays a role in regulation of blood flow in vivo.
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Células Endoteliales/metabolismo , Óxido Nítrico Sintasa/metabolismo , Proteína Quinasa C/fisiología , Animales , Bovinos , Células Cultivadas , Activación Enzimática , Humanos , Masculino , Ratones , Ratones Noqueados , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Fosforilación , Proteína Quinasa C-alfa , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Proteínas Proto-Oncogénicas c-akt , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo RegionalRESUMEN
Protein kinase Balpha (PKBalpha/Akt-1) is a key mediator of multiple signaling pathways involved in angiogenesis, cell proliferation and apoptosis among others. The unphosphorylated form of Akt-1 is virtually inactive and its full activation requires two phosphatidylinositol-3,4,5-triphosphate-dependent phosphorylation events, Thr308 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser473 by an undefined kinase that has been termed PDK2. Recent studies have suggested that the Ser473 kinase is a plasma membrane raft-associated kinase. In this study we show that protein kinase Calpha (PKCalpha) translocates to the membrane rafts in response to insulin growth factor-1 (IGF-1) stimulation. Overexpression of PKCalpha increases Ser473 phosphorylation and Akt-1 activity, while inhibition of its activity or expression decreases IGF-1-dependent activation of Akt-1. Furthermore, in vitro, in the presence of phospholipids and calcium, PKCalpha directly phosphorylates Akt-1 at the Ser473 site. We conclude, therefore, that PKCalpha regulates Akt-1 activity via Ser473 phosphorylation and may function as PDK2 in endothelial cells.
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Células Endoteliales/enzimología , Factor I del Crecimiento Similar a la Insulina/farmacología , Proteína Quinasa C/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Serina/metabolismo , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Animales , Activación Enzimática , Microdominios de Membrana , Fosforilación , Proteína Quinasa C-alfa , Proteínas Proto-Oncogénicas c-akt , Ratas , Transducción de SeñalRESUMEN
Syndecan-4 is one of the principal heparan sulfate-carrying proteins on the cell surface. Unlike other members of syndecan family, syndecan-4 mediates phosphatidylinositol 4,5-bisphosphate 2 (PIP(2))-dependent PKC-alpha activation, and overexpression of syndecan-4 in vitro results in enhanced FGF2 signaling. The present study was designed to test the functional effect of increased syndecan-4 expression in endothelial cells in transgenic mice. Several transgenic mice lines expressing syndecan-4 cDNA under control of human endothelial nitric oxide (NO) synthase (eNOS) promoter were generated. Exogenous syndecan-4 was mainly expressed in the heart, brain, and lungs. In particular, the heart demonstrated the greatest increase in the ratio of transgenic-to-native syndecan-4 gene expression. Vessels from the eNOS-syndecan-4 mice demonstrated more pronounced vasodilation to FGF2 but not to VEGF-A(165), sodium nitroprusside, and A 23187 compared with wild-type mice. To elucidate the mechanism of this effect, we measured NO release from primary cardiac endothelial cells isolated from transgenic or wild-type adult mice. Cells from the eNOS-syndecan-4 transgenic mice had a significant increase in FGF2- and VEGF-A(165)-induced NO release compared with endothelial cells from the wild-type mice. However, the absolute magnitude of this increase was higher for FGF2 than VEGF-A(165). In conclusion, enhanced syndecan-4 expression in mouse cardiac endothelial cells results in preferential augmentation of FGF2 but not VEGF-A(165)-induced NO release.
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Factor 2 de Crecimiento de Fibroblastos/farmacología , Glicoproteínas de Membrana/fisiología , Proteoglicanos/fisiología , Transducción de Señal/efectos de los fármacos , Animales , Northern Blotting , Circulación Coronaria/efectos de los fármacos , Factores de Crecimiento Endotelial/farmacología , Endotelio Vascular/fisiología , Regulación de la Expresión Génica/fisiología , Humanos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfocinas/farmacología , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , Microcirculación/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Proteoglicanos/genética , Sindecano-4 , Transgenes , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used alpha-myosin heavy chain (MHC) promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alpha MHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 microg/mL) administration despite similar expression levels of NO synthase genes II and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from alpha MHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice. At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alpha MHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP-induced vasomotion. The vasomotor activity of the endothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators and point to a novel role of the HS matrix in regulation of microvascular homeostasis.