RESUMEN

OBJECTIVE: The role of atherosclerosis in the acute coronary syndromes (ACS) that occur in patients with rheumatoid arthritis (RA) has not been quantified in detail. We undertook this study to determine the extent to which ACS are associated with carotid atherosclerosis in RA. METHODS: We prospectively ascertained ACS, defined as myocardial infarction, unstable angina, cardiac arrest, or death due to ischemic heart disease, in an RA cohort. We measured carotid atherosclerosis using high-resolution ultrasound. We used Cox proportional hazards models to estimate the association between ACS and atherosclerosis, adjusting for demographic features, cardiovascular (CV) risk factors, and RA manifestations. RESULTS: We performed carotid ultrasound on 636 patients whom we followed up for 3,402 person-years. During this time, 84 patients experienced 121 new or recurrent ACS events, a rate of 3.5 ACS events per 100 patient-years (95% confidence interval [95% CI] 3.0-4.3). Among the 599 patients without a history of ACS, 66 incident ACS events occurred over 3,085 person-years, an incidence of 2.1 ACS events per 100 person-years (95% CI 1.7-2.7). The incidence of new ACS events per 100 patient-years was 1.1 (95% CI 0.6-1.7) among patients without plaque, 2.5 (95% CI 1.7-3.8) among patients with unilateral plaque, and 4.3 (95% CI 2.9-6.3) among patients with bilateral plaque. Covariates associated with incident ACS events independent of atherosclerosis included male sex, diabetes mellitus, and a cumulative glucocorticoid dose of ≥ 20 gm. CONCLUSION: Atherosclerosis is strongly associated with ACS in RA. RA patients with carotid plaque, multiple CV risk factors (particularly diabetes mellitus or hypertension), many swollen joints, and a high cumulative dose of glucocorticoids, as well as RA patients who are men, are at high risk of ACS.

Asunto(s)

Síndrome Coronario Agudo/etiología , Artritis Reumatoide/complicaciones , Aterosclerosis/complicaciones , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/complicaciones , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/epidemiología , Adulto , Anciano , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/epidemiología , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/epidemiología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Ultrasonografía

RESUMEN

BACKGROUND: The effect of moderate left ventricular systolic dysfunction (LVSD) on ventricular/vascular coupling and the aortic pressure waveform (AoPW) has been well described, but the effect of severe LVSD has not. METHODS AND RESULTS: We used noninvasive, high-fidelity tonometry of the radial artery and a mathematical transfer function to generate the AoPW in 25 treated patients with LVSD (mean LV ejection fraction, 24+/-8.8%; range, 11% to 40%; 21 patients <30%). Pulse wave analysis of the AoPW was used to characterize ventricular/vascular coupling and compared with pulse wave analysis performed in 25 normal subjects matched for age, gender, height, body mass index, and heart rate. Measurements obtained using pulse wave analysis in LVSD patients indicated features of poor LV stroke performance and also reduced indices of arterial stiffness: increased travel time of the pressure wave (147+/-10 ms versus 132+/-21 ms; P<0.001); decreased systolic duration of reflected wave (134+/-24 ms versus 167+/-26 ms; P<0.001); ejection duration (277+/-22 ms versus 299+/-25 ms; P<0.008); percent systolic duration (32+/-5.3% versus 35+/-4.0%; P<0.02); aortic systolic pressure (100+/-16 mm Hg versus 121+/-16 mm Hg; P<0.001); unaugmented pressure (24+/-6.3 mm Hg versus 32+/-6.4 mm Hg; P<0.001); augmented pressure (4.8+/-3.1 mm Hg versus 9.6+/-4.5 mm Hg; P<0.001); pulse pressure (28+/-7.4 mm Hg versus 42+/-9.5 mm Hg; P<0.001); augmentation index (12+/-6.6% versus 23+/-7.6%; P<0.006); wasted LV effort (5.3+/-2.8x10(2) dyne sec/cm(2) versus 17+/-10x10(2) dyne sec/cm(2); P<0.001); systolic pressure time index (17+/-4.1x10(2) mm Hg-sec/min versus 23+/-4.2x10(2) mm Hg sec/min; P<0.001); and pressure systolic area (383+/-121 mm Hg sec/min versus 666+/-150 mm Hg sec/min; P<0.001). CONCLUSIONS: Severe LVSD causes measurable changes in the AoPW. Standardization of AoPW findings in LVSD patients may allow for the clinical use of radial artery pulse wave analysis to noninvasively determine the severity of dysfunction and aid in logical therapy.

Asunto(s)

Hemodinámica , Disfunción Ventricular Izquierda/fisiopatología , Anciano , Aorta , Presión Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Arteria Radial , Índice de Severidad de la Enfermedad

RESUMEN

Interleukin (IL)-18 is a cardiotropic proinflammatory cytokine chronically elevated in the serum of patients with cardiac hypertrophy (LVH). The purpose of this study was to examine the role of IL-18 in pressure-overload hypertrophy using wild type (WT) and IL-18 -/- (null) mice. Adult male C57Bl/6 mice underwent transaortic constriction (TAC) for 7days or sham surgery. Heart weight/body weight ratios showed blunted hypertrophy in IL-18 null TAC mice compared to WT TAC animals. Microarray analyses indicated differential expression of hypertrophy-related genes in WT versus IL-18 nulls. Northern, Western, and EMSA analyses showed Akt and GATA4 were increased in WT but unchanged in IL-18 null mice. Our results demonstrate blunted hypertrophy with reduced expression of contractile-, hypertrophy-, and remodeling-associated genes following pressure overload in IL-18 null mice, and suggest that IL-18 plays a critical role in the hypertrophic response.

Asunto(s)

Cardiomegalia/genética , Cardiomegalia/fisiopatología , Hipertensión/metabolismo , Interleucina-18/deficiencia , Interleucina-18/genética , Animales , Aorta/cirugía , Hipertensión/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados

RESUMEN

Patients with rheumatoid arthritis (RA) are predisposed to atherosclerosis and cardiovascular disease. This is thought to be caused in part, by exposure to chronic systemic inflammation during the course of the disease. We hypothesized that RA disease duration augments the effect of age on atherosclerosis. We measured the carotid artery intima-media thickness (IMT) in 631 consecutive RA patients. We ascertained age, sex and disease duration, established CV risk factors, RA clinical manifestations and markers of inflammation. We used multivariable regression to model IMT, with age as the independent variable. We then added RA duration quartile x age interaction terms to estimate the IMT-age relationship within RA duration strata. We found that the rate at which the IMT increased per unit of age steepened in proportion to the RA duration, from 0.154 mm/10 years among patients with RA for 7 years or less, to 0.295 mm/10 years among patients with RA for 20 years or more (P

Asunto(s)

Artritis Reumatoide/complicaciones , Aterosclerosis , Enfermedades de las Arterias Carótidas , Arteria Carótida Interna/patología , Túnica Íntima/patología , Túnica Media/patología , Adulto , Factores de Edad , Anciano , Aterosclerosis/complicaciones , Aterosclerosis/patología , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Interna/diagnóstico por imagen , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Túnica Íntima/diagnóstico por imagen , Túnica Media/diagnóstico por imagen , Ultrasonografía

RESUMEN

Macrophages have the potential to deliver therapeutic genes to many target tissues. Macrophage-specific synthetic promoters (SPs) generated by random ligation of myeloid/macrophage cis elements had activity up to 100-fold that of a native macrophage promoter in macrophage cell lines, but were minimally active in nonmyeloid cells. Mouse bone marrow cells (BMCs) transduced ex vivo with lentivectors expressing green fluorescent protein (GFP) driven either by an SP (SP-GFP) or a cytomegalovirus (CMV) promoter (CMV-GFP) were used for syngeneic transplantation of lethally irradiated mice. Blood leukocytes showed stable GFP expression for up to 15 months after transplantation. SP-GFP expression was selective for CD11b+ macrophages, whereas CMV-GFP expression was observed in erythrocytes, as well as in both CD11b+ and CD11b- leukocytes. Furthermore, SP-GFP expression was much stronger than CMV-GFP expression in CD11b+ macrophages. apoE-/- BMCs transduced with the lentiviral vector encoding human apoE were used to transplant apoE-/- mice. Macrophage expression of apoE from 10 to 26 weeks of age significantly reduced atherosclerotic lesions in recipient apoE-/- mice. Thus, the novel SPs, especially when combined with lentivectors, are useful for macrophage-specific delivery of therapeutic genes.

Asunto(s)

Terapia Genética , Macrófagos Peritoneales/citología , Regiones Promotoras Genéticas , Animales , Apolipoproteínas E/biosíntesis , Apolipoproteínas E/genética , Aterosclerosis/terapia , Secuencia de Bases , Western Blotting , Médula Ósea/metabolismo , Línea Celular , Cartilla de ADN , Femenino , Citometría de Flujo , Vectores Genéticos , Humanos , Lentivirus/genética , Ratones , Ratones Endogámicos C57BL

RESUMEN

The objective of this study was to assess whether educational attainment moderates outcomes in the intervention group in a trial of disease management in heart failure (HF). Data were collected from a sample of 654 patients enrolled in the disease management arm of a community- based study of HF patients. The full sample was used to analyze two primary outcomes- all-cause mortality and cardiac event-free survival. Two other primary outcomes- rates of HF-related emergency department (ED) visits and inpatient admissions-and secondary outcomes (patient self-confidence in managing HF symptoms and daily dietary sodium intake in milligrams) were analyzed in a smaller sample of 602 patients who completed at least 6 months of disease management. One-way analysis of variance and chi (2) tests were used to assess differences in baseline demographic and clinical characteristics. Survival analyses were conducted with proportional hazards regression, while negative binomial regression was used to assess educational differences in ED usage and inpatient admissions. Repeated measures analysis of variance models were used to assess whether secondary outcomes differed across educational strata and/or over time. All outcome analyses were adjusted for confounders. Patients with the least education fared the poorest for all-cause mortality, but education- related differences failed to achieve statistical significance. No education-related differences were observed for cardiac event-free survival, or for the rates of inpatient admission and ED usage. For secondary outcomes, sodium intake differed significantly by education (p = 0.04), with the largest drop (-838 mg/day) observed in the least well-educated group. Confidence increased an approximately equal amount (2.1-3.0 points on a 100-point scale) across all educational strata (p = ns). Low educational attainment may not be a barrier to effective disease management.

Asunto(s)

Manejo de la Enfermedad , Escolaridad , Insuficiencia Cardíaca/terapia , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Texas , Resultado del Tratamiento

RESUMEN

Conductance measurements for generation of an instantaneous left ventricular (LV) volume signal in the mouse are limited, because the volume signal is a combination of blood and LV muscle, and only the blood signal is desired. We have developed a conductance system that operates at two simultaneous frequencies to identify and remove the myocardial contribution to the instantaneous volume signal. This system is based on the observation that myocardial resistivity varies with frequency, whereas blood resistivity does not. For calculation of LV blood volume with the dual-frequency conductance system in mice, in vivo murine myocardial resistivity was measured and combined with an analytic approach. The goals of the present study were to identify and minimize the sources of error in the measurement of myocardial resistivity to enhance the accuracy of the dual-frequency conductance system. We extended these findings to a gene-altered mouse model to determine the impact of measured myocardial resistivity on the calculation of LV pressure-volume relations. We examined the impact of temperature, timing of the measurement during the cardiac cycle, breeding strain, anisotropy, and intrameasurement and interanimal variability on the measurement of intact murine myocardial resistivity. Applying this knowledge to diabetic and nondiabetic 11- and 20- to 24-wk-old mice, we demonstrated differences in myocardial resistivity at low frequencies, enhancement of LV systolic function at 11 wk and LV dilation at 20-24 wk, and histological and electron-microscopic studies demonstrating greater glycogen deposition in the diabetic mice. This study demonstrated the accurate technique of measuring myocardial resistivity and its impact on the determination of LV pressure-volume relations in gene-altered mice.

Asunto(s)

Sistema de Conducción Cardíaco/fisiología , Corazón/fisiología , Contracción Miocárdica/fisiología , Resistencia Vascular/fisiología , Función Ventricular Izquierda/fisiología , Animales , Volumen Sanguíneo/genética , Volumen Sanguíneo/fisiología , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Electrofisiología , Femenino , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Contracción Miocárdica/genética , Miocardio/patología , Temperatura , Resistencia Vascular/genética , Función Ventricular Izquierda/genética

Asunto(s)

Cardiopatías/diagnóstico , Pericardio/patología , Taponamiento Cardíaco/diagnóstico , Taponamiento Cardíaco/patología , Taponamiento Cardíaco/terapia , Diagnóstico por Imagen , Cardiopatías/terapia , Humanos , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/patología , Derrame Pericárdico/terapia , Pericarditis/diagnóstico , Pericarditis/patología , Pericarditis/terapia

Asunto(s)

Antagonistas Adrenérgicos beta/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Anciano , Humanos , Disfunción Ventricular Izquierda/tratamiento farmacológico

RESUMEN

The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) antagonizes the pro-survival signaling of Akt and promotes cell death. Previously, we demonstrated that IL-18 induced apoptosis in human cardiac microvascular endothelial cells (HCMEC). Here we have investigated the role of PTEN in this response. Our results demonstrate that IL-18 reduced phospho-Akt and bcl-2 levels, stimulated NF-kappaB activation, and induced PTEN-promoter-reporter activity, mRNA expression, and protein levels in HCMEC. IL-18-mediated PTEN transcription was enhanced by ectopic expression of wild type p65, but inhibited by dominant negative (dn) IkappaB-alpha, dnp65, and dnIKKbeta. Furthermore, overexpression of constitutively active Akt and wild type bcl-2 blocked IL-18-mediated cell death. While forced expression of PTEN potentiated, expression of catalytically inactive PTEN attenuated IL-18-mediated cell death. IL-18-induced activation of NF-kappaB and PTEN upregulation were mediated by p38MAPK. Together, these studies demonstrate a novel signal transduction pathway involving p38MAPK-NF-kappaB-PTEN in IL-18-mediated HCMEC death, and identify IL-18 as potential therapeutic target to inhibit or reduce myocardial inflammation and injury.

Asunto(s)

Apoptosis/fisiología , Células Endoteliales/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacología , FN-kappa B/metabolismo , Fosfohidrolasa PTEN/metabolismo , Transducción de Señal/fisiología , Apoptosis/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

BACKGROUND: Disease management programs are reported to improve clinical and quality-of-life outcomes while simultaneously lowering healthcare costs. OBJECTIVE: To examine the effectiveness of disease management in improving health-related quality of life (HRQL) among patients with heart failure beyond 12 months. METHODS: A total of 1069 community-dwelling patients 18 years and older in South Texas with echocardiographic evidence of congestive heart failure were randomly assigned to disease management, augmented disease management, and control groups. They were followed up 18 months. Patients in the control group received usual care. Patients in the intervention groups were assigned a registered nurse as a disease manager who performed telephonic patient education and medication management. Health-related quality-of-life data (based on the Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]) were collected 4 times, at 6-month intervals. RESULTS: Disease management has a limited effect on HRQL. Analysis of the SF-36 health transition measure showed a positive effect of the intervention on self-reported improvement in health at 6 months and at 12 months (P = .04 and P = .004, respectively). However, no effect of disease management was observed across any of the SF-36 components. Women and patients with diastolic heart failure had poorer HRQL scores. CONCLUSIONS: Participation in disease management has little effect on HRQL outcomes in congestive heart failure. Beneficial effects on the SF-36 scale scores seen at 6 and 12 months were not sustained. Therefore, it is unclear whether disease management can provide long-term improvement in HRQL for patients with congestive heart failure.

Asunto(s)

Manejo de la Enfermedad , Insuficiencia Cardíaca/fisiopatología , Calidad de Vida , Anciano , Anciano de 80 o más Años , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Texas

RESUMEN

OBJECTIVE: To estimate the contribution of cardiovascular (CV) risk factors and rheumatoid arthritis (RA) disease manifestations to atherosclerosis in RA. METHODS: We used high-resolution carotid ultrasound to measure the carotid intima-media thickness (IMT) and plaque in 631 RA patients. Using R(2) measures from multivariable models, we estimated the contribution of demographic characteristics (age, sex, and ethnic group), CV risk factors (diabetes mellitus, hypercholesterolemia, cigarette smoking, hypertension, and body mass index, and RA manifestations (joint tenderness, swelling, and deformity, nodules, erythrocyte sedimentation rate [ESR], C-reactive protein, rheumatoid factor, the HLA-DRB1 shared epitope, and cumulative glucocorticoid dose) to each of the outcomes. Estimates were obtained in the full sample, and within strata defined by age, sex, and ethnic group. We tested for interaction between CV risk factors and RA manifestations. RESULTS: The contribution of demographic factors, CV risk factors, and RA manifestations to IMT and plaque R(2) varied depending on the patients' age stratum. Demographic features explained 11-16% of IMT variance, CV risk factors explained 4%-12%, and RA manifestations explained 1-6%. The greatest contribution of RA manifestations occurred in the youngest age group, while that of CV risk factors occurred in the older age groups. Results for carotid plaque were similar. There was a significant interaction between the number of CV risk factors present and the ESR, suggesting that the ESR's effect on IMT varied according to the number of CV risk factors. CONCLUSION: Both established CV risk factors and manifestations of RA inflammation contribute significantly to carotid atherosclerosis in RA, and may modify one another's effects. These findings may have implications regarding the prevention of atherosclerosis in RA.

Asunto(s)

Artritis Reumatoide/complicaciones , Aterosclerosis/etiología , Enfermedades de las Arterias Carótidas/etiología , Artritis Reumatoide/epidemiología , Artritis Reumatoide/patología , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/epidemiología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Texas/epidemiología , Túnica Íntima/diagnóstico por imagen , Ultrasonografía

RESUMEN

We recently demonstrated that the chemokine CXCL16 is expressed in aortic smooth muscle cells (ASMC) and induces ASMC adhesion and proliferation (Chandrasekar, B., Bysani, S., and Mummidi, S. (2004) J. Biol. Chem. 279, 3188-3196). Here we reort that interleukin (IL)-18 positively regulates CXCL16 transcription in rat ASMC. We characterized the cis-regulatory region of CXCL16 and identified a functional activator protein-1 (AP-1) binding motif. Deletion or mutation of this site attenuated IL-18-mediated CXCL16 promoter activity. Gel shift, supershift, and chromatin immunoprecipitation assays confirmed AP-1-dependent CXCL16 expression. CXCL16 promoter-reporter activity was increased by constitutively active c-Fos and c-Jun and decreased by dominant negative or antisense c-Fos and c-Jun. Src kinase inhibitors PP1 and PP2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002, Akt inhibitor, the c-Jun N-terminal kinase (JNK) inhibitor SP600125, antisense JNK and dominant negative MyD88, interleukin-1 receptor-associated kinase (IRAK)-1, IRAK4, and phosphatidylinositol 3-kinase expression all attenuated IL-18-mediated AP-1 binding and reporter activity, CXCL16 promoter-reporter activity, and CXCL16 expression. Thus IL-18 induced CXCL16 expression via a MyD88 --> IRAK1-IRAK4-TRAF6 (tumor necrosis factor receptor-associated factor 6) --> c-Src--> PI3K --> Akt --> JNK --> AP-1 pathway. Importantly, IL-18 stimulated ASMC proliferation in a CXCL16-dependent manner. These data provide for the first time a mechanism of IL-18-mediated CXCL16 gene transcription and CXCL16-dependent ASMC proliferation and suggest a role for IL-18-CXCL16 cross-talk in atherogenesis and restenosis following angioplasty.

Asunto(s)

Antígenos de Diferenciación/fisiología , Aorta/metabolismo , Quimiocinas CXC/biosíntesis , Regulación de la Expresión Génica , Interleucina-18/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Proteínas de la Membrana/biosíntesis , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Quinasas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Receptores Inmunológicos/biosíntesis , Receptores Inmunológicos/fisiología , Factor 6 Asociado a Receptor de TNF/fisiología , Factor de Transcripción AP-1/fisiología , Proteínas Adaptadoras Transductoras de Señales , Secuencias de Aminoácidos , Animales , Antígenos de Diferenciación/metabolismo , Apoptosis , Secuencia de Bases , Proteína Tirosina Quinasa CSK , Adhesión Celular , Proliferación Celular , Quimiocinas CXC/metabolismo , Dactinomicina/farmacología , Relación Dosis-Respuesta a Droga , Elementos de Facilitación Genéticos , Inhibidores Enzimáticos/farmacología , Genes Dominantes , Quinasas Asociadas a Receptores de Interleucina-1 , Interleucina-18/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas de la Membrana/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Modelos Genéticos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Factor 88 de Diferenciación Mieloide , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Interferente Pequeño/metabolismo , Ratas , Receptores Inmunológicos/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Factores de Tiempo , Factor de Transcripción AP-1/metabolismo , Familia-src Quinasas

RESUMEN

Stimulated production of reactive oxygen species (ROS) by plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidases (Nox) in non-phagocytic cells regulates a number of biological processes including growth, vessel tone, and oxygen sensing. The purpose of this study was to investigate H(2)O(2)-stimulated ROS production in primary adult cardiac fibroblasts (CF). Results demonstrate that CF express an H(2)O(2)-inducible oxidant generating system that is inhibitable by diphenylene iodonium (DPI) and sensitive to antioxidants. In addition to H(2)O(2), generation of ROS was stimulated potently by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and arachidonic acid (AA) in a protein kinase C-independent manner. Pretreatment with arachidonyl trifluoromethyl ketone was nearly as effective as DPI at reducing H(2)O(2)- and OAG-stimulated oxidant generation indicating a central role for phospholipase A(2) (PLA(2)) in this signaling pathway. Co-stimulation with H(2)O(2) and OAG did not increase ROS generation as compared to OAG alone suggesting both agonists signal through a shared, rate-limited enzymatic pathway involving PLA(2). Co-stimulation with H(2)O(2) and AA had additive effects indicating these two agonists stimulate oxidant production through a parallel activation pathway. Reverse transcriptase-coupled polymerase chain reaction and Western blotting demonstrate primary cardiac fibroblasts express transcripts and protein for Nox4, p22, p47, and p67 phox. Transfections with Nox4 small inhibitory ribonucleic acid oligonucleotides or p22 phox antisense oligonucleotides significantly downregulated stimulated Nox activity. Inhibitors of nitric oxide synthases were without effect. We conclude adult CF express Nox4/p22 phox-containing oxidant generating complex activated by H(2)O(2), OAG, and AA through a pathway that requires activation of PLA(2).

Asunto(s)

Envejecimiento/fisiología , Ácido Araquidónico/biosíntesis , Peróxido de Hidrógeno/farmacología , Miocardio/citología , NADPH Oxidasas/metabolismo , Fosfolipasas A/metabolismo , Animales , Antioxidantes/metabolismo , Ácido Araquidónico/metabolismo , Células Cultivadas , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Masculino , NADPH Oxidasa 4 , NADPH Oxidasas/genética , Fosfolipasas A2 , ARN Interferente Pequeño , Ratas , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

BACKGROUND: Because of the prevalence and expense of congestive heart failure (CHF), significant efforts have been made to develop disease management (DM) programs that will improve clinical and financial outcomes. The effectiveness of such programs in a large, heterogeneous population of CHF patients remains unknown. METHODS AND RESULTS: We randomized 1069 patients (aged 70.9+/-10.3 years) with systolic (ejection fraction 35+/-9%) or echocardiographically confirmed diastolic heart failure (HF) to assess telephonic DM over an 18-month period. Data were collected at baseline and at 6-month intervals. Survival analysis was performed by Kaplan-Meier and Cox regression methods. Healthcare utilization was defined after extensive record review, with an attempt to account for all inpatient and outpatient visits, medications, and diagnostic tests. We obtained data on 92% of the patients, from nearly 53,000 health-related encounters. Total cost per patient was defined by adding estimated costs for the observed encounters, excluding the cost of the DM. Kaplan-Meier analysis showed that DM patients had a reduced mortality rate (P=0.037), with DM patients surviving an average of 76 days longer than controls. Subgroup analysis showed that DM had beneficial outcomes in patients with systolic HF (hazard ratio 0.62; P=0.040), which was more pronounced in NYHA classes III and IV. Although improvements in NYHA class were more likely with DM (P<0.001), 6-minute walk data from 217 patients in whom data were available at each visit showed no significant benefit from DM (P=0.08). Total and CHF-related healthcare utilization, including medications, office or emergency department visits, procedures, or hospitalizations, was not decreased by DM. Repeated-measures ANOVA for cost by group showed no significant differences, even in the higher NYHA class groups. CONCLUSIONS: Participation in DM resulted in a significant survival benefit, most notably in symptomatic systolic HF patients. Although DM was associated with improved NYHA class, 6-minute walk test results did not improve. Healthcare utilization was not reduced by DM, and it conferred no cost savings. DM in HF results in improved life expectancy but does not improve objective measures of functional capacity and does not reduce cost.

Asunto(s)

Atención a la Salud/métodos , Insuficiencia Cardíaca/economía , Insuficiencia Cardíaca/prevención & control , Anciano , Análisis Costo-Beneficio , Atención a la Salud/economía , Diástole , Manejo de la Enfermedad , Determinación de Punto Final , Femenino , Servicios de Salud/estadística & datos numéricos , Insuficiencia Cardíaca/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Esperanza de Vida , Masculino , Sistemas de Registros Médicos Computarizados , Grupo de Atención al Paciente , Educación del Paciente como Asunto , Tasa de Supervivencia , Sístole

RESUMEN

Reperfusion of ischemic myocardium (I/R) is associated with local release of a brief pulse of reactive oxygen species. The purpose of this study was to determine the effects of brief H2O2 stimulation on primary adult cardiac fibroblast phenotype. We demonstrate that brief H2O2 exposure results in transient phosphorylations of p38 and ERK which peaked by 15 min. Proliferation was minimally affected by either H2O2 or MAPK inhibition. Pretreatment with SB203580 or U0126 revealed that p38 enhances or maintains migration rates while ERK retarded migration. Peroxide exposure increased necrosis from 4% at baseline to >12% while reducing apoptosis by 3.5-fold. p38 inhibition resulted in increased necrosis and apoptosis while ERK inhibition had minimal effects. In conclusion, primary adult cardiac fibroblasts exposed to brief H2O2 exhibit an altered phenotype characterized by reduced migration and apoptosis and increased necrosis resulting, in part, from the differential effects of p38 and ERK signaling.

Asunto(s)

Fibroblastos/fisiología , Miocardio/citología , Estrés Oxidativo , Animales , Apoptosis , División Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Cinética , Sistema de Señalización de MAP Quinasas , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Oxidantes/farmacología , Ratas , Ratas Endogámicas WKY

RESUMEN

It is unclear whether the increase in availability of substrates for energy production in diabetes can lead to enhanced systolic function early in the disease, before the onset of structural changes to the myocardium. To examine this issue, BKS.Cg-m +/+ Lepr db (db/db) mice with type 2 diabetes and wild type controls had left ventricular pressure-volume relationships determined in situ. We demonstrated that the db/db mice, when compared to their wild type controls, generated greater left ventricular pressure and an enhancement of left ventricular systolic function based on enhanced power/EDV, positive dP/dt, preload recruitable stroke work, dP/dt--EDV relationship, and curvilinear end-systolic elastance. This enhancement in systolic function occurred despite the db/db mice having greater body weight, but similar preload (end-diastolic volume) and afterload (effective arterial elastance). We postulate that the previously described enhancement in renal glomerular filtration rate seen early in type 2 diabetes may be in part due to enhanced left ventricular systolic function early in this disease.

Asunto(s)

Diabetes Mellitus Tipo 2/fisiopatología , Función Ventricular Izquierda/fisiología , Animales , Peso Corporal , Modelos Animales de Enfermedad , Femenino , Hemodinámica/fisiología , Ratones , Ratones Mutantes , Sístole , Factores de Tiempo

RESUMEN

We describe an unusual presentation of congenital heart disease mimicking preeclampsia in a young, gravid girl. The diagnosis of Shone's complex was confirmed by echocardiography. This complex is manifested by multiple levels of obstruction involving the left side of the heart and the systemic circulation. It is extremely rare, especially in pregnant adolescents. We briefly describe the patient's clinical history, physical examination, and treatment, as well as our clinical decisions regarding her case. The discussion focuses on the spectrum of findings in Shone's complex and the physiologic impact of therapy on this patient.

Asunto(s)

Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/diagnóstico , Preeclampsia/diagnóstico , Preeclampsia/etiología , Adolescente , Diagnóstico Diferencial , Femenino , Humanos , Embarazo

RESUMEN

OBJECTIVE: To examine the relationship between markers of systemic inflammation and carotid atherosclerosis in patients with rheumatoid arthritis (RA) and healthy controls. METHODS: Carotid artery intima-media thickness (IMT) and carotid plaque were measured using high-resolution B-mode ultrasound in 204 patients with RA, ages 40-85, and 102 age- and sex-matched healthy persons. No subject in either group had ever smoked cigarettes. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to measure systemic inflammation. The relationship of the carotid artery IMT and carotid plaque to inflammation markers was examined, adjusting for age, sex, RA versus control status, and the cardiovascular (CV) risk factors hypercholesterolemia, systolic blood pressure, diabetes mellitus, and body mass index (BMI). RESULTS: A significant linear trend for increased carotid artery IMT was associated with increasing ESR and CRP categories (r = 0.16, P = 0.004 for ESR, and r = 0.13, P = 0.02 for CRP). These trends did not differ among RA cases and controls, and were independent of age, sex, and CV risk factors. The difference in carotid artery IMT between the lowest and highest categories of ESR was 0.221 mm (95% confidence interval [95% CI] 0.767-1.020, P = 0.02). The difference between extreme CRP categories was 0.275 mm (95% CI 0.039-0.509, P = 0.02). Both remained significant after CV risk factor adjustment. Carotid plaque displayed a similar relationship to markers of inflammation. CONCLUSION: Increased carotid artery IMT and the presence of carotid plaque are associated with markers of systemic inflammation in patients with RA and in healthy subjects. This observation is consistent with hypotheses that assign a role to systemic inflammation in atherosclerosis, and may have implications regarding RA and other chronic inflammatory diseases.

Asunto(s)

Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/epidemiología , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Enfermedades de las Arterias Carótidas/epidemiología , Arteria Carótida Común/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Túnica Íntima/diagnóstico por imagen , Ultrasonografía

RESUMEN

BACKGROUND: It has been hypothesized that because of its rapid heart rate, the intact murine heart functions near maximal contractility in the basal state. If this hypothesis is correct, then the fast and slow components of myocardial length-dependent activation should be blunted compared with larger mammals. METHODS AND RESULTS: Mice (n=24) were anesthetized, and via an open chest, LV pressure-volume relationships were determined by a dual-frequency conductance catheter system. Baseline pressure-volume relationships were determined during transient occlusion of the inferior vena cava, and repeat measurements were made after 1 (n=10) and 7 (n=21) minutes of sustained aortic occlusion. Control experiments were performed in a subset of mice (n=3). For baseline to 1 minute, an increase in afterload (maximal pressure 95+/-9 to 126+/-7 mm Hg; P<0.001) and effective arterial elastance (5.9+/-3.1 to 9.2+/-3.9 mm Hg/microl; P<0.001) resulted in an increase in end-diastolic volume (31+/-8 to 35+/-9 microL; P<0.001). The result was maintenance of stroke volume (17+/-6 to 15+/-6; P=NS) owing to an increase in contractility (leftward shift in V100 [the volume of end-systolic elastance at 100 mm Hg], 24+/-9 to 16+/-5 microL; P<0.001). No additional augmentation of systolic function was found at 7 minutes. CONCLUSIONS: This study demonstrates that the fast phase of length-dependent activation is intact but not the slow phase, consistent with murine myocardium functioning near maximal contractility in the basal state.

Asunto(s)

Corazón/fisiología , Contracción Miocárdica/fisiología , Animales , Aorta/fisiología , Presión Sanguínea/fisiología , Volumen Cardíaco/fisiología , Diástole/fisiología , Femenino , Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Ratones , Especificidad de la Especie , Volumen Sistólico/fisiología , Sístole/fisiología , Vena Cava Inferior/fisiología , Función Ventricular Izquierda/fisiología