RESUMEN
Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals.
Asunto(s)
Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , División Celular , Eosinófilos/patología , Inmunización , Animales , Bradicardia/complicaciones , Bradicardia/inmunología , Bradicardia/patología , Bradicardia/fisiopatología , Bromodesoxiuridina/metabolismo , Hiperreactividad Bronquial/sangre , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstricción/efectos de los fármacos , División Celular/efectos de los fármacos , Estimulación Eléctrica , Eosinófilos/efectos de los fármacos , Etanercept/farmacología , Femenino , Cobayas , Linfocitos/efectos de los fármacos , Linfocitos/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Cloruro de Metacolina/farmacología , Monocitos/efectos de los fármacos , Monocitos/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Ozono , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiopatologíaRESUMEN
Fingolimod is a an oral disease modifying drug for relapsing remitting multiple sclerosis (MS) preventing egress of B and T cells from lymph nodes. Relevant first dose adverse events include bradycardia and atrioventricular conduction slowing. Cardiac side effects of fingolimod and combinational pharmacotherapy including duloxetine and tolterodine were monitored in mice of different age using implantable ECG telemetric systems. Cardiac tissue was assessed for S1P-receptor subtype (1 and 3), and for GIRK1 expression. Fingolimod led to a significant heart rate reduction within 60 min, which returned to baseline values within 24 h. In older mice bradycardia was more pronounced compared to younger mice. Atrioventricular conduction was not affected. Older mice showed a higher S1PR3 expression in a naïve state and receptor expression was reduced after fingolimod administration. Combination with duloxetine or tolterodine alleviated fingolimod induced heart rate decrease. Our data provide preclinical evidence that negative chronotropic effects of fingolimod might be age dependent, possibly due to an altered expression and internalization of cardiac S1PR3 in older animals. This data could be relevant for future clinical monitoring and patient selection in the aging MS population. Combinational therapies of fingolimod and duloxetine or tolterodine are well tolerated and safe without an increased risk for pronounced bradycardia or arrhythmia.
Asunto(s)
Envejecimiento/efectos de los fármacos , Bradicardia/inducido químicamente , Clorhidrato de Fingolimod/administración & dosificación , Clorhidrato de Fingolimod/efectos adversos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Envejecimiento/inmunología , Envejecimiento/metabolismo , Animales , Bradicardia/inmunología , Bradicardia/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Quimioterapia Combinada , Femenino , Ratones , Ratones Endogámicos C57BL , Telemetría/métodosRESUMEN
Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin's direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Regulación de la Temperatura Corporal/efectos de los fármacos , Bradicardia/tratamiento farmacológico , Orexinas/farmacología , Choque Séptico/tratamiento farmacológico , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Regulación de la Temperatura Corporal/inmunología , Bradicardia/inducido químicamente , Bradicardia/inmunología , Bradicardia/mortalidad , Quimiocina CCL3/antagonistas & inhibidores , Quimiocina CCL3/genética , Quimiocina CCL3/inmunología , Quimiocina CCL4/antagonistas & inhibidores , Quimiocina CCL4/genética , Quimiocina CCL4/inmunología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Inyecciones Subcutáneas , Interferón gamma/antagonistas & inhibidores , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-17/inmunología , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Choque Séptico/inducido químicamente , Choque Séptico/inmunología , Choque Séptico/mortalidad , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
OBJECTIVE: To clarify the current situation concerning drug fever (DF) in Japan, we retrospectively analyzed patients undergoing infectious disease consultation at our institution. METHODS: Between April 2014 and May 2015, we extracted the records of DF patients from among 388 patients who had obtained infectious disease consultations in Kurume University Hospital. We reviewed their medical charts and summarized the characteristics of DF. RESULTS: This study included the records of 16 patients. Clinical signs (relative bradycardia, the duration of the drug administration before becoming febrile, and the interval between the discontinuation of a drug and the alleviation of a fever), and laboratory tests (varied white blood cell count, low level of C-reactive protein, and a mild elevation of transaminases) were compatible with those from previous reports. Among the drug-confirmed cases, five involved the use of glycopeptides (vancomycin: 3, teicoplanin: 2), which were considered to be uncommon causes, and the another five cases involved the use of ß-lactams. In addition, the procalcitonin levels were either negative or low (≤0.25 ng/mL) in 10 of the 11 procalcitonin-measured cases. CONCLUSION: Our findings demonstrated that glycopeptides, similar to ß-lactams, may be the origin of DF. Furthermore, procalcitonin may be helpful in the diagnosis of DF, but only in combination with other detailed examinations.
Asunto(s)
Antibacterianos/efectos adversos , Bradicardia/inducido químicamente , Enfermedades Transmisibles/tratamiento farmacológico , Fiebre/inducido químicamente , Adulto , Anciano , Antibacterianos/administración & dosificación , Biomarcadores/sangre , Bradicardia/inmunología , Proteína C-Reactiva/metabolismo , Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina , Enfermedades Transmisibles/inmunología , Femenino , Fiebre/inmunología , Hospitales Universitarios , Humanos , Japón/epidemiología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Precursores de Proteínas/sangre , Derivación y Consulta , Estudios RetrospectivosRESUMEN
Persistent fetal bradycardia in early pregnancy is a rare finding and indicates towards congenital heart block. This is commonly associated with positive maternal anti-Ro/anti-La antibodies. A case of an asymptomatic primigravida with persistent fetal bradycardia on routine antenatal ultrasound is reported with special emphasis on its management options.
Asunto(s)
Autoanticuerpos/inmunología , Bradicardia/etiología , Bloqueo Cardíaco/congénito , Complicaciones del Embarazo/inmunología , Adulto , Anticuerpos Antinucleares/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Bradicardia/diagnóstico por imagen , Bradicardia/inmunología , Ecocardiografía/métodos , Femenino , Bloqueo Cardíaco/diagnóstico , Bloqueo Cardíaco/inmunología , Frecuencia Cardíaca Fetal , Humanos , Embarazo , Complicaciones del Embarazo/diagnóstico por imagenRESUMEN
The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.
Asunto(s)
Presión Arterial , Barorreflejo , Bradicardia/metabolismo , Sistema Cardiovascular/inervación , Inmunidad Innata , Taquicardia/metabolismo , Receptor Toll-Like 9/metabolismo , Nervio Vago/metabolismo , Animales , Derivados de Atropina , Conducta Animal , Bradicardia/inducido químicamente , Bradicardia/genética , Bradicardia/inmunología , Bradicardia/fisiopatología , Sistema Cardiovascular/inmunología , Condicionamiento Psicológico , Modelos Animales de Enfermedad , Miedo , Frecuencia Cardíaca , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Propranolol , Transducción de Señal , Taquicardia/inducido químicamente , Taquicardia/genética , Taquicardia/inmunología , Taquicardia/fisiopatología , Factores de Tiempo , Receptor Toll-Like 9/deficiencia , Receptor Toll-Like 9/genética , Nervio Vago/inmunología , Nervio Vago/fisiopatologíaRESUMEN
IMPORTANCE: Voltage-gated potassium channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. OBSERVATIONS: Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. CONCLUSIONS AND RELEVANCE: Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Bradicardia/inmunología , Encefalitis/inmunología , Marcapaso Artificial , Síntomas Prodrómicos , Proteínas/inmunología , Amnesia/etiología , Amnesia/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/patología , Bradicardia/etiología , Bradicardia/terapia , Encéfalo/patología , Encefalitis/complicaciones , Encefalitis/patología , Femenino , Humanos , Hiponatremia/etiología , Hiponatremia/inmunología , Péptidos y Proteínas de Señalización Intracelular , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Canales de Potasio con Entrada de Voltaje , Convulsiones/etiología , Convulsiones/inmunologíaRESUMEN
The aims of this study were to evaluate the effects of nandrolone (ND) on cardiac inflammatory cytokines, ACE activity, troponin I, and the sensitivity of the Bezold-Jarisch reflex (BJR). Male Wistar rats were administered either ND (20 mg/kg; DECA) or vehicle (control animals; CONT) for 4 weeks. BJR was analyzed by measuring the bradycardia and hypotension responses elicited by serotonin administration (2-32 µg/kg). Mean arterial pressure (MAP) was assessed and myocyte hypertrophy was determined by the heart weight/body weight ratio and by morphometric analysis. Matrix collagen deposition was assessed by histological analysis of the picrosirius red-stained samples. Mesenteric vascular reactivity was performed and central venous pressure (CVP) evaluated. Cardiac inflammatory cytokine levels and angiotensin-converting enzyme (ACE) activity were studied as well the biomarker of cardiac lesion, troponin I. DECA group showed enhancement of matrix type I collagen deposition (p < 0.01) and cardiac ACE activity (p < 0.01) compared with the CONT. Interleukin (IL)-10 was reduced (p < 0.01) and pro-inflammatory cytokines (TNF-α and IL-6; p < 0.01) were increased in the DECA group compared with CONT. Cardiac injury was observed in the DECA group shown by the reduction in cardiac troponin I (p < 0.01) compared with the CONT group. Animals in the DECA group also developed myocyte hypertrophy and reduction of BJR sensitivity. The MAP of animals treated with ND reached hypertensive levels (p < 0.01; compared with CONT). No changes in CVP and vascular reactivity were observed in both experimental groups. We conclude that high doses of ND elicit cardiotoxic effects with cardiac remodelling and injury. Cardiac changes reduce the BJR sensitivity. Together, these abnormalities contributed to the development of hypertension in animals in the DECA group.
Asunto(s)
Anabolizantes/efectos adversos , Bradicardia/fisiopatología , Hipertensión/fisiopatología , Nandrolona/análogos & derivados , Reflejo/efectos de los fármacos , Síndromes de la Apnea del Sueño/fisiopatología , Animales , Presión Arterial/efectos de los fármacos , Bradicardia/etiología , Bradicardia/inmunología , Expresión Génica/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/etiología , Hipertensión/inmunología , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucina-6/biosíntesis , Interleucina-6/inmunología , Masculino , Nandrolona/efectos adversos , Nandrolona Decanoato , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Wistar , Serotonina/farmacología , Síndromes de la Apnea del Sueño/etiología , Síndromes de la Apnea del Sueño/inmunología , Troponina I/genética , Troponina I/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Differences in the pools of 10 cytokine were found in blood samples from the caudal vein of mice with normal and abnormal heart rhythm. Both groups were albino mice bred by us and differing from mdx albino mice by the absence of mutation in muscular dystrophin gene. Mice with normal heart rhythm had low IL-17 content and elevated concentrations of proinflammatory cytokines IL-6 and IL-1α in comparison with the normal (according to published data). In mice with bradyarrhythmias, increased blood levels of IL-10, IL-6, IL-5, IL-2, IL-1α, IL-17, IL-4, TNF-α, and granulocyte-macrophage colony-stimulating factor were detected. The relative content of IL-4 and IL-17 in the total cytokine pool increased. The lifespan of mice with bradyarrhythmias and cytokine hyperexpression was shorter by 2-3 months in comparison with mice without heart rhythm disturbances and moderate changes in the cytokine pool.
Asunto(s)
Bradicardia/sangre , Citocinas/sangre , Frecuencia Cardíaca/fisiología , Animales , Bradicardia/inmunología , Bradicardia/fisiopatología , Citocinas/inmunología , Distrofina/genética , Electrocardiografía , Femenino , Frecuencia Cardíaca/inmunología , Longevidad , Masculino , Ratones , Ratones Noqueados , MutaciónRESUMEN
OBJECTIVE: To study the clinical course and outcome of fetal sinus bradycardia (SB) due to maternal antibody-induced sinus node dysfunction. METHODS: We reviewed the maternal, prenatal, and postnatal findings of fetuses with SB associated with elevated maternal anti-SSA/Ro and anti-SSB/La antibodies. RESULTS: Of the 6 cases diagnosed prenatally, 3 had isolated SB persisting after birth and had a good prognosis. Three fetuses with SB and severe myocardial involvement (congenital complete heart block and/or endocardial fibroelastosis) succumbed in utero in spite of treatment. Postmortem histopathology in 1 fetus showed inflammatory destruction of the sinus and atrioventricular nodes. SB was detected incidentally in a 7-year-old girl. She had intermittent heart block with progressive sinus arrest requiring permanent pacemaker. CONCLUSION: Fetal SB associated with maternal autoantibodies may persist in childhood, with a good prognosis in the absence of widespread cardiac involvement.
Asunto(s)
Anticuerpos Antinucleares/inmunología , Bradicardia/inmunología , Feto/inmunología , Feto/fisiopatología , Embarazo/inmunología , Síndrome del Seno Enfermo/inmunología , Adulto , Autoantígenos/inmunología , Bradicardia/fisiopatología , Niño , Preescolar , Femenino , Feto/patología , Bloqueo Cardíaco/congénito , Bloqueo Cardíaco/inmunología , Bloqueo Cardíaco/fisiopatología , Humanos , Ribonucleoproteínas/inmunología , Síndrome del Seno Enfermo/fisiopatología , Antígeno SS-BRESUMEN
Perfusion of human foetal heart with anti-Ro/SSA antibodies induces transient heart block. Anti-Ro/SSA antibodies may cross-react with T- and L-type calcium channels, and anti-p200 antibodies may cause calcium to accumulate in rat heart cells. These actions may explain a direct electrophysiological effect of these antibodies. Congenital complete heart block is the more severe manifestation of so-called "Neonatal Lupus". In clinical practice, it is important to distinguish in utero complete versus incomplete atrioventricular (AV) block, as complete AV block to date is irreversible, while incomplete AV block has been shown to be potentially reversible after fluorinated steroid therapy. Another issue is the definition of congenital AV block, as cardiologists have considered congenital blocks detected months or years after birth. We propose as congenital blocks detected in utero or within the neonatal period (0-27 days after birth). The possible detection of first degree AV block in utero, with different techniques, might be a promising tool to assess the effects of these antibodies. Other arrhythmias have been described in NL or have been linked to anti-Ro/SSA antibodies: first degree AV block, in utero and after birth, second degree (i.e. incomplete block), sinus bradycardia and QT prolongation, both in infants and in adults, ventricular arrhythmias (in adults). Overall, these arrhythmias have not a clinical relevance, but are important for research purposes.
Asunto(s)
Arritmias Cardíacas/etiología , Enfermedades del Recién Nacido/etiología , Lupus Eritematoso Sistémico/congénito , Lupus Eritematoso Sistémico/complicaciones , Animales , Arritmias Cardíacas/congénito , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/inmunología , Arritmias Cardíacas/fisiopatología , Bloqueo Atrioventricular/congénito , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/etiología , Bloqueo Atrioventricular/inmunología , Bloqueo Atrioventricular/fisiopatología , Bradicardia/congénito , Bradicardia/etiología , Bradicardia/inmunología , Bradicardia/fisiopatología , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/inmunología , Enfermedades del Recién Nacido/fisiopatología , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/etiología , Síndrome de QT Prolongado/inmunología , Síndrome de QT Prolongado/fisiopatología , Lupus Eritematoso Sistémico/inmunologíaAsunto(s)
Enfermedades del Sistema Nervioso Autónomo/inmunología , Bradicardia/inmunología , Síndrome de Miller Fisher/complicaciones , Síndrome de Miller Fisher/inmunología , Oftalmoplejía/complicaciones , Oftalmoplejía/inmunología , Enfermedad Aguda , Adulto , Autoanticuerpos/sangre , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/virología , Blefaroptosis/inmunología , Blefaroptosis/fisiopatología , Bradicardia/fisiopatología , Bradicardia/virología , Enfermedades de los Nervios Craneales/complicaciones , Enfermedades de los Nervios Craneales/inmunología , Enfermedades de los Nervios Craneales/fisiopatología , Nervios Craneales/inmunología , Nervios Craneales/patología , Nervios Craneales/fisiopatología , Diplopía/inmunología , Diplopía/fisiopatología , Progresión de la Enfermedad , Diagnóstico Precoz , Gangliósidos/inmunología , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Síndrome de Miller Fisher/fisiopatología , Enfermedades del Nervio Oculomotor/complicaciones , Enfermedades del Nervio Oculomotor/inmunología , Enfermedades del Nervio Oculomotor/fisiopatología , Oftalmoplejía/virología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología , Resultado del Tratamiento , Enfermedades del Nervio Vago/inmunología , Enfermedades del Nervio Vago/fisiopatología , Enfermedades del Nervio Vago/virología , Virosis/complicaciones , Virosis/inmunologíaRESUMEN
INTRODUCTION: Premature infants should be vaccinated at the appropriate vaccinating age, without correcting for their gestational week and regardless of their weight. Uncertainty with regard to possible severe adverse events exists among physicians. METHODS: In all, 473 patients with a birth weight under 1500 g were included in a prospective observational study for adverse events that included cardiorespiratory events, local reactions and fever. Three vaccination combinations were used at different time periods. RESULTS: The median birth weight was 910 (375 to 1495) g. Gestational week at birth was 27.6 (22.6 to 34.3). At the time of vaccination, the gestational week was 37.4 (31.5 to 48.3). The frequency of adverse events for local reactions/fever was 2.8% and for apnea/bradycardia it was 10.8%. Apnea appeared significantly more often in children who were younger at the time of immunization. This is in concordance with the fact that they were also younger at birth. If apnea appeared, the chance of the development of bradycardia had an odds ratio of 6.4 (3.2:13.0). Children with higher-grade hemorrhages and/or with periventricular leukomalacia did not experience more adverse events, except fever. CONCLUSION: Timely vaccination of premature infants with a birth weight under 1500 g is safe, but the occurrence of cardiorespiratory events is related to earlier gestational week.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Edad Gestacional , Esquemas de Inmunización , Inmunización/efectos adversos , Recién Nacido de muy Bajo Peso/inmunología , Apnea/inmunología , Bradicardia/inmunología , Fiebre/inmunología , Humanos , Lactante , Recién Nacido , Oportunidad Relativa , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: To study anti-Ro/La-negative congenital heart block (CHB). METHODS: Forty-five fetuses with CHB were evaluated by analysis of anti-Ro/La antibodies using sensitive laboratory methods. RESULTS: There were 9 cases of anti-Ro/La-negative CHB; 3 died (33.3%). Only 3 (33.3%) were complete in utero and 5 (55.5%) were unstable. No specific etiology was diagnosed. Six infants (66.6%) were given pacemakers. There were 36 cases of anti-Ro/La-positive CHB. All except 2 infants (94.4%) had complete atrioventricular block in utero. Ten died (27.8%), one (2.7%) developed severe dilated cardiomyopathy, and 26 (72.2%) were given pacemakers. CONCLUSION: Nine of the 45 consecutive CHB cases (20%) were anti-Ro/La-negative with no known cause. They were less stable and complete than the anti-Ro/La positive cases.
Asunto(s)
Anticuerpos Antinucleares/sangre , Bloqueo Atrioventricular/inmunología , Autoantígenos/inmunología , Complicaciones del Embarazo/inmunología , Ribonucleoproteínas/inmunología , Bloqueo Atrioventricular/congénito , Bloqueo Atrioventricular/mortalidad , Bradicardia/congénito , Bradicardia/inmunología , Bradicardia/mortalidad , Cardiomiopatía Dilatada/inmunología , Cardiomiopatía Dilatada/mortalidad , Femenino , Humanos , Recién Nacido , Masculino , Morbilidad , Embarazo , Diagnóstico Prenatal , Estudios Seroepidemiológicos , Antígeno SS-BRESUMEN
Although anticholinergic therapy inhibits bronchoconstriction in asthmatic patients and antigen-challenged animals, administration of atropine 1 h before antigen challenge significantly potentiates airway hyperreactivity and eosinophil activation measured 24 h later. This potentiation in airway hyperreactivity is related to increased eosinophil activation and is mediated at the level of the airway nerves. Since eosinophils produce nerve growth factor (NGF), which is known to play a role in antigen-induced airway hyperreactivity, we tested whether NGF mediates atropine-enhanced, antigen challenge-induced hyperreactivity. Antibody to NGF (Ab NGF) was administered to sensitized guinea pigs with and without atropine pretreatment (1 mg/kg iv) 1 h before challenge. At 24 h after challenge, animals were anesthetized, vagotomized, paralyzed, and ventilated. Electrical stimulation of both vagus nerves caused bronchoconstriction that was increased in challenged animals. Atropine pretreatment potentiated antigen challenge-induced hyperreactivity. Ab NGF did not affect eosinophils or inflammatory cells in any group, nor did it prevent hyperreactivity in challenged animals that were not pretreated with atropine. However, Ab NGF did prevent atropine-enhanced, antigen challenge-induced hyperreactivity and eosinophil activation (assessed by immunohistochemistry). This effect was specific to NGF, since animals given control IgG remained hyperreactive. These data suggest that anticholinergic therapy amplifies eosinophil interactions with airway nerves via NGF. Therefore, therapeutic strategies that target both eosinophil activation and NGF-mediated inflammatory processes in allergic asthma are likely to be beneficial.
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Antígenos/farmacología , Atropina/farmacología , Hiperreactividad Bronquial/inmunología , Broncodilatadores/farmacología , Eosinófilos/inmunología , Factor de Crecimiento Nervioso/metabolismo , Animales , Antígenos/inmunología , Asma/inducido químicamente , Asma/inmunología , Asma/fisiopatología , Presión Sanguínea/efectos de los fármacos , Bradicardia/inducido químicamente , Bradicardia/inmunología , Bradicardia/fisiopatología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/fisiopatología , Broncoconstricción/efectos de los fármacos , Broncoconstricción/inmunología , Estimulación Eléctrica , Femenino , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/inmunología , Factor de Crecimiento Nervioso/inmunología , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Sistema Nervioso Parasimpático/inmunología , Receptor Muscarínico M2/fisiología , Organismos Libres de Patógenos Específicos , Vagotomía , Nervio Vago/fisiologíaRESUMEN
BACKGROUND: Congenital heart block (CHB) is an autoimmune disease that affects fetuses/infants born to mothers with anti-Ro/La antibodies (positive IgG). Although the hallmark of CHB is complete atrioventricular block, sinus bradycardia has been reported recently in animal models of CHB. Interestingly, knockout of the neuroendocrine alpha1D Ca channel in mice results in significant sinus bradycardia and atrioventricular block, a phenotype reminiscent to that seen in CHB. Here, we tested the hypothesis that the alpha1D Ca channel is a novel target for positive IgG. METHODS AND RESULTS: Reverse transcription-polymerase chain reaction, confocal indirect immunostaining, and Western blot data established the expression of the alpha1D Ca channel in the human fetal heart. The effect of positive IgG on alpha1D Ca current (I(Ca-L)) was characterized in heterologous expression systems (tsA201 cells and Xenopus oocytes) because of the unavailability of alpha1D-specific modulators. alpha1D I(Ca-L) activated at negative potentials (between -60 and -50 mV). Positive IgG inhibited alpha1D I(Ca-L) in both expression systems. This inhibition was rescued by a Ca channel activator, Bay K8644. No effect on alpha1D I(Ca-L) was observed with negative IgG and denatured positive IgG. Western blot data showed that positive IgG binds directly to alpha1D Ca channel protein. CONCLUSIONS: The data are the first to demonstrate (1) expression of the alpha1D Ca channel in human fetal heart, (2) inhibition of alpha1D I(Ca-L) by positive IgG, and (3) direct cross-reactivity of positive IgG with the alpha1D Ca channel protein. Given that alpha1D I(Ca-L) activates at voltages within the pacemaker's diastolic depolarization, inhibition of alpha1D I(Ca-L) in part may account for autoimmune-associated sinus bradycardia. In addition, Bay K8644 rescue of alpha1D I(Ca-L) inhibition opens new directions in the development of pharmacotherapeutic approaches in the management of CHB.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Bradicardia/etiología , Canales de Calcio Tipo L/fisiología , Animales , Autoanticuerpos , Bradicardia/inmunología , Calcio/metabolismo , Canales de Calcio Tipo L/análisis , Canales de Calcio Tipo L/genética , Línea Celular , Electrofisiología , Feto/citología , Corazón/fisiopatología , Humanos , Inmunoglobulina G/inmunología , Miocitos Cardíacos/química , Miocitos Cardíacos/fisiología , ARN Mensajero/análisis , Conejos , Nodo Sinoatrial/fisiopatología , Transducción GenéticaRESUMEN
Apart from complete and incomplete congenital heart block (CHB), new cardiac manifestations related to anti-SSA/Ro antibodies have been reported in children born to mothers bearing these antibodies. These manifestations include transient fetal first-degree heart block, prolongation of corrected QT (QTc) interval, sinus bradycardia, late-onset cardiomyopathy, endocardial fibroelastosis and cardiac malformations. Anti-SSA/Ro antibodies are not considered pathogenic to the adult heart, but a prolongation of the QTc interval has recently been reported in adult patients and is still a matter of debate. Treatment of CHB is not well established and needs to be assessed carefully. The risks and benefits of prenatal fluorinated steroids are discussed.
Asunto(s)
Anticuerpos Antinucleares/inmunología , Electrocardiografía , Cardiopatías/etiología , Inmunidad Materno-Adquirida , Miocardio/patología , Adulto , Edad de Inicio , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Betametasona/uso terapéutico , Bradicardia/etiología , Bradicardia/inmunología , Cardiomiopatías/epidemiología , Cardiomiopatías/etiología , Cardiomiopatías/inmunología , Niño , Preescolar , Ensayos Clínicos como Asunto , Dexametasona/uso terapéutico , Fibroelastosis Endocárdica/etiología , Fibroelastosis Endocárdica/inmunología , Femenino , Corazón Fetal/inmunología , Corazón Fetal/patología , Corazón Fetal/fisiopatología , Bloqueo Cardíaco/congénito , Bloqueo Cardíaco/tratamiento farmacológico , Bloqueo Cardíaco/etiología , Bloqueo Cardíaco/inmunología , Cardiopatías Congénitas/etiología , Cardiopatías Congénitas/inmunología , Cardiopatías/congénito , Cardiopatías/inmunología , Cardiopatías/fisiopatología , Humanos , Lactante , Recién Nacido , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/inmunología , Lupus Eritematoso Sistémico/congénito , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/inmunología , Masculino , Estudios Multicéntricos como Asunto , Miocardio/inmunología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/inmunología , Estudios ProspectivosRESUMEN
Congenital heart block (CHB) associated with maternal anti-SSA/SSB antibodies: a report of four cases. CHB detected in utero is strongly associated with maternal antibodies to SSA (Ro) and SSB (La). Their pathogenic role in the development of CHB has been established in several studies. The mothers of affected infants frequently had autoimmune disease (systemic lupus erythematosus, Sjögren's syndrome) or were entirely asymptomatic. It is very difficult to identify pregnant asymptomatic mothers carrying anti-SSA/SSB antibodies. We report four cases of infants born to asymptomatic mothers with anti-SSA/SSB antibodies, three of them developed isolated congenital cardiac heart block and one with no evidence of CHB. All three CHB are detected during pregnancy between 16 and 24 weeks of gestation. All maternal sera contained antibodies to SSA alone or the both SSA and SSB. Three of four subsequent pregnancies were complicated by heart block. One child affected died in utero. While the two other newborns with CHB required pacemaker insertion during the first 3 months of life. Although the association of anti-SSA/SSB with CHB is widely accepted, the precise mechanism by which these antibodies cause cardiac conduction abnormalities remains to be defined. Antibodies to SSA/SSB have been proposed to be a serologic marker for neonatal lupus syndrome and CHB. Fetal and neonatal diseases are presumed to be due to the transplacental passage of these IgG autoantibodies from the mother into the fetal circulation. Since these antibodies may have a pathogenic role in CHB, screening of infants with isolated CHB or neonatal lupus and their mothers for the presence of anti-SSA and anti-SSB is strongly recommended.
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Anticuerpos Antinucleares/inmunología , Autoantígenos , Enfermedades Autoinmunes/inmunología , Bloqueo Cardíaco/congénito , Inmunidad Materno-Adquirida , Isoanticuerpos/inmunología , Complicaciones del Embarazo/inmunología , ARN Citoplasmático Pequeño , Ribonucleoproteínas/inmunología , Adulto , Bradicardia/embriología , Bradicardia/inmunología , Estimulación Cardíaca Artificial , Femenino , Muerte Fetal/etiología , Enfermedades Fetales/inmunología , Corazón Fetal/inmunología , Corazón Fetal/patología , Bloqueo Cardíaco/inmunología , Bloqueo Cardíaco/terapia , Humanos , Recién Nacido , Masculino , Embarazo , Antígeno SS-BRESUMEN
Congenital heart block (CHB) is a conduction abnormality characterized by complete atrioventricular (AV) block. CHB affects fetuses and/or newborn of mothers with autoantibodies reactive with ribonucleoproteins 48-kDa SSB/La, 52-kDa SSA/Ro, and 60-kDa SSA/Ro. We recently established animal models of CHB and reported, for the first time, significant sinus bradycardia preceding AV block. This unexpected observation implies that the spectrum of conduction abnormalities extends beyond the AV node to also affect the SA node. To test this hypothesis, we investigated the functional basis of this sinus bradycardia by characterizing the effects of antibodies from mothers with CHB children (positive IgG) on ionic currents that are known to significantly contribute to spontaneous pacing in SA node cells. We recorded L- (I(Ca.L)) and T- (I(Ca.T)) type Ca2+, delayed rectifier K+ (I(K)), hyperpolarization-activated (I(f)) currents, and action potentials (APs) from young rabbit SA node cells. We demonstrated that positive IgG significantly inhibited both I(Ca.T) and I(Ca.L) and induced sinus bradycardia but did not affect I(f) and I(K). Normal IgG from mothers with healthy children did not affect all the currents studied and APs. These results establish that IgG from mothers with CHB children causes substantial inhibition of I(Ca.T) and I(Ca.L), two important pacemaker currents in rabbit SA node cells and point to both I(Ca.T) and I(Ca.L) as major players in the ionic mechanism by which maternal antibodies induce sinus bradycardia in CHB. These novel findings have important clinical significance and suggest that sinus bradycardia may be a potential marker in the detection and prevention of CHB. The full text of this article is available online at http://circres.ahajournals.org
Asunto(s)
Anticuerpos Antinucleares/farmacología , Arritmia Sinusal/fisiopatología , Autoantígenos , Bradicardia/fisiopatología , Bloqueo Cardíaco/fisiopatología , Inmunoglobulina G/farmacología , ARN Citoplasmático Pequeño , Nodo Sinoatrial/fisiopatología , Potenciales de Acción , Adulto , Animales , Anticuerpos Antinucleares/inmunología , Arritmia Sinusal/etiología , Arritmia Sinusal/inmunología , Bradicardia/etiología , Bradicardia/inmunología , Calcio/metabolismo , Canales de Calcio Tipo L/efectos de los fármacos , Canales de Calcio Tipo L/fisiología , Canales de Calcio Tipo T/efectos de los fármacos , Canales de Calcio Tipo T/fisiología , Femenino , Bloqueo Cardíaco/complicaciones , Bloqueo Cardíaco/congénito , Bloqueo Cardíaco/inmunología , Humanos , Inmunidad Materno-Adquirida , Inmunoglobulina G/inmunología , Transporte Iónico/efectos de los fármacos , Embarazo , Conejos , Ribonucleoproteínas/inmunología , Nodo Sinoatrial/patología , Antígeno SS-BRESUMEN
Congenital heart block (CHB) is associated with high mortality and affects children of mothers with autoantibodies (IgG) to ribonucleoproteins SSB/La and SSA/Ro. IgG from mothers of children with CHB (positive IgG) was used to assess activation patterns in both the right atrium (RA) and right ventricle (RV) of Langendorff-perfused young rabbit hearts. Optical action potentials (AP) were obtained by using a 124-site photodiode array with 4-[-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium. Optical APs were recorded to simultaneously image activation patterns from the RA and RV. Perfusion of positive IgG (800--1,200 micro resulted in sinus bradycardia and varying degrees of heart block. Activation maps revealed marked conduction delay at the sinoatrial junction but only minor changes in overall atrial and ventricular activation patterns. No conduction disturbances were seen in the presence of IgG from mothers with healthy children. In conclusion, besides atrioventricular (AV) block, positive IgG induces sinus bradycardia. These results establish that the sequelae of CHB are associated with impaired intrasinus and/or sinoatrial conduction. The findings raise the possibility that sinus bradycardia in the developing heart may indicate the potential for AV conduction disturbances.