RESUMEN
Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and the activin receptor-like kinase 1 (ALK1) gene have been reported in heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH). However, the relation between clinical characteristics and each gene mutation in IPAH and HPAH is still unclear, especially in childhood. The aim of this study was to determine, in a retrospective study, the influence and clinical outcomes of gene mutations in childhood IPAH and HPAH. Fifty-four patients with IPAH or HPAH whose onset of disease was at <16 years of age were included. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared in BMPR2 and ALK1 mutation carriers and noncarriers. Overall 5-year survival for all patients was 76%. Eighteen BMPR2 mutation carriers and 7 ALK1 mutation carriers were detected in the 54 patients with childhood IPAH or HPAH. Five-year survival was lower in BMPR2 mutation carriers than mutation noncarriers (55% vs 90%, hazard ratio 12.54, p = 0.0003). ALK1 mutation carriers also had a tendency to have worse outcome than mutation noncarriers (5-year survival rate 64%, hazard ratio 5.14, p = 0.1205). In conclusion, patients with childhood IPAH or HPAH with BMPR2 mutation have the poorest clinical outcomes. ALK1 mutation carriers tended to have worse outcomes than mutation noncarriers. It is important to consider aggressive treatment for BMPR2 or ALK1 mutation carriers.
Asunto(s)
Receptores de Activinas Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Hipertensión Pulmonar/genética , Mutación/genética , Adolescente , Niño , Preescolar , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/mortalidad , Masculino , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: Indomethacin is used to close the patent ductus arteriosus in premature infants and for tocolysis of preterm labor. Clinically and experimentally, early in utero exposure to indomethacin induces the paradoxical delay of postnatal closure of the ductus arteriosus. OBJECTIVES: To clarify the pharmacological nature of the delay of closure of the ductus arteriosus in the rat. METHODS: We studied early in utero exposure to indomethacin (dose and timing) in addition to other drugs, inducing a delay in postnatal ductal closure. Pregnant rats at near term were studied by cesarean section on gestational day 21 (D21), incubated in room air at 33 degrees C, followed by rapid whole-body freezing. RESULTS: The delay in closure of the ductus arteriosus was dose dependent. A large dose of indomethacin (10 mg/kg) 1 or 2 days before birth induced a delay of 3-4 times. A timing study revealed maximum delay with administration of indomethacin 2 days before birth and minimum delay with administration 5 days before. Aspirin, ibuprofen, the selective COX1 inhibitor SC 560, the selective COX2 inhibitor rofecoxib and a prostaglandin EP(4) receptor blocker, ONO-208, all delayed neonatal ductal closure following maternal administration on D19 and D20. CONCLUSIONS: The delay by indomethacin was dose dependent. The maximum delay was induced by 2 doses of 10 mg/kg indomethacin on D19 and D20. The delay was induced by a decreased stimulus to the prostaglandin EP(4) receptor system in the last 2 days in utero. The delay was temporary with recovery 3 days or more after exposure.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Conducto Arterioso Permeable/inducido químicamente , Conducto Arterial/efectos de los fármacos , Indometacina/farmacología , Animales , Animales Recién Nacidos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Aspirina/administración & dosificación , Aspirina/farmacología , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/sangre , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Conducto Arterial/anomalías , Conducto Arterioso Permeable/embriología , Conducto Arterioso Permeable/patología , Femenino , Feto/anomalías , Feto/efectos de los fármacos , Edad Gestacional , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacología , Indometacina/administración & dosificación , Indometacina/sangre , Masculino , Exposición Materna , Embarazo , Pirazoles/administración & dosificación , Pirazoles/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND: Mutations of the bone morphogenetic protein receptor II gene (BMPR2), and 1 mutation of the activin receptor-like kinase 1 gene (ALK1) have been reported in patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: A genomic study of ALK1 and BMPR2 was conducted in 21 PAH probands under 16 years of age to study the relationship between the clinical features of the patients and these genes. In all 4 familial aggregates of PAH, 3 ALK1 or 1 BMPR2 mutations were identified. Among 17 probands aged between 4 and 14 years with idiopathic PAH, 2 ALK1 mutations (2/17: 11.8%) and 3 BMPR2 mutations (3/17: 17.6%; 5 mutations in total: 5/17: 29.4%) were found. CONCLUSION: Each proband with the ALK1 mutation developed PAH, as did the probands with the BMPR2 mutation. Hence, it is proposed that ALK1 plays as notable a role as BMPR2 in the etiology of PAH. Furthermore, asymptomatic carriers with the ALK1 mutation within the serine - threonine kinase domain are at risk of developing PAH and hereditary hemorrhagic telangiectasia, so close follow-up is recommended for those individuals.
Asunto(s)
Receptores de Activinas Tipo II/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Hipertensión Pulmonar/genética , Mutación , Adolescente , Determinación de la Edad por el Esqueleto , Niño , Preescolar , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Masculino , Linaje , Proteínas Serina-Treonina Quinasas/genética , Arteria Pulmonar/fisiopatología , Telangiectasia Hemorrágica Hereditaria/genéticaRESUMEN
BACKGROUND: Alpha-human atrial natriuretic peptide (hANP) reportedly increases in premature infants with patent ductus arteriosus (PDA). OBJECTIVES: To clarify a possible hANP effect to reopen the postnatal ductus, we studied in vivo reopening of the postnatal DA by a recombinant hANP, carperitide, in rats. METHODS: Near-term rat pups were incubated at 33 degrees C following caesarean section. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. The DA constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 min (fetal state) and 60 min after birth. hANP concentration in the pup blood and the ductus-dilating effect of hANP were studied by subcutaneous injection of hANP at 60 min after birth, and by measurement 7, 15, 30 and 60 min later. RESULTS: The peak hANP concentration was 790 pg/ml at 7 min with 1 mg/kg, which is similar to the level seen in preterm infants with symptomatic PDA. hANP dilated the postnatal ductus dose dependently and maximally at 7 min after injection. hANP dilated the postnatal constricted ductus completely to 0.79 mm in diameter with a large dose (10 mg/kg) and to 0.55 mm with 1 mg/kg. CONCLUSIONS: hANP reopens the constricted postnatal DA dose dependently in rats. The increased hANP, accompanying premature PDA, may delay closure of the DA.
Asunto(s)
Factor Natriurético Atrial/farmacología , Dilatación , Conducto Arterioso Permeable , Conducto Arterial/efectos de los fármacos , Animales , Animales Recién Nacidos , Factor Natriurético Atrial/sangre , Criopreservación , Relación Dosis-Respuesta a Droga , Conducto Arterial/embriología , Conducto Arterial/patología , Conducto Arterioso Permeable/patología , Conducto Arterioso Permeable/fisiopatología , Secciones por Congelación , Inyecciones Subcutáneas , Modelos Animales , Ratas , Ratas Wistar , Proteínas RecombinantesRESUMEN
Oxygen-sensitive, voltage-gated potassium channels (Kv) may contribute to the determination of the membrane potential in smooth muscle cells of the ductus arteriosus (DA), and thus to regulation of contractile tone in response to oxygen. Developmental changes in Kv during gestation may be related to closure of the DA after birth. This study investigated developmental changes in the expression of Kv in the DA and compared it with that of the pulmonary artery (PA) and the aorta (Ao). The DA, PA, and Ao were isolated from fetal rats at days 19 and 21 of gestation (term: 21.5 days). The expression of Kv1.2, Kv1.5, Kv2.1, and Kv3.1, putative oxygen-sensitive Kv channels that open in response to oxygen, was evaluated at both the mRNA and protein levels, using quantitative real-time polymerase chain reaction and immunohistochemistry. In the Kv family studied, Kv1.5 mRNA was expressed most abundantly in the DA, PA, and Ao in both day-19 and day-21 fetuses. Although the expression levels of Kv1.2, Kv1.5, Kv2.1, and Kv3.1 did not change much with development in the PA and Ao, in the DA they decreased with development. The decrease in the expression of Kv channels may enhance DA closure after birth by eliminating the opening of Kv channels when oxygen increases.
Asunto(s)
Conducto Arterial/embriología , Feto/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Animales , Conducto Arterial/metabolismo , Femenino , Inmunohistoquímica , Reacción en Cadena de la Polimerasa , Embarazo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
We studied the transplacental ductal constrictive effects of a selective cyclooxygenase (COX)-1 inhibitor (SC560), six selective COX-2 inhibitors including rofecoxib, and a non-selective COX inhibitor (indomethacin). Each drug was administered to the pregnant rats, and fetal ductus arteriosus (DA) was studied with a whole-body freezing method. The inner diameter ratio of the DA to the main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean+/-S.E.M.) in controls. Every drug constricted the DA dose-dependently. In preterm rats on the 19th day of gestation, 10mg/kg of SC560, rofecoxib and indomethacin caused ductal constriction, with DA/PA reduced to 0.76+/-0.02, 0.80+/-0.03 and 0.75+/-0.02, respectively. In near-term on the 21st day, 10mg/kg of them caused ductal constriction, with DA/PA to 0.74+/-0.04, 0.26+/-0.02 and 0.33+/-0.05. In conclusion, both COX-1 and COX-2 selective inhibitors constrict fetal DA. They are not better alternatives for the fetus than non-selective COX inhibitors for tocolysis.
Asunto(s)
Inhibidores de la Ciclooxigenasa/efectos adversos , Conducto Arterioso Permeable/fisiopatología , Enfermedades Fetales/fisiopatología , Tocólisis/efectos adversos , Vasoconstricción/efectos de los fármacos , Animales , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Relación Dosis-Respuesta a Droga , Conducto Arterioso Permeable/inducido químicamente , Conducto Arterioso Permeable/enzimología , Femenino , Enfermedades Fetales/inducido químicamente , Enfermedades Fetales/enzimología , Feto/anomalías , Feto/enzimología , Feto/patología , Feto/fisiopatología , Embarazo , Ratas , Ratas WistarRESUMEN
The voltage-gated potassium channels (Kv) are partially responsible for the contraction/relaxation of blood vessels in response to changes in the Po(2) level. The present study determined the expression of Kvbeta1 and four oxygen-sensitive Kvalpha subunits (Kv1.2, Kv1.5, Kv2.1, and Kv9.3) in the ductus arteriosus (DA), the aorta (Ao), and the pulmonary artery (PA) in porcine neonates immediately after birth. We cloned three Kvbeta1 transcript variants (Kvbeta1.2, Kvbeta1.3, and Kvbeta1.4), Kv1.2, Kv1.5, and Kv9.3 from piglets. Three Kvbeta1 transcripts, Kv1.2, Kv1.5, and Kv9.3, encode predicted proteins of 401, 408, 202, 499, 600, and 491 residues. These Kv showed a high degree of sequence conservation with the corresponding Kv in human. Northern and quantitative real-time PCR (qr-PCR) analyses showed that Kvbeta1.2 expression was high in the DA and Ao but low in the PA. Kv1.5 expression was high in the Ao and PA but low in the DA. Expression of Kvbeta1.3, Kvbeta1.4, Kv1.2, Kv2.1, and Kv9.3 was low in these blood vessels. The inactivation property of Kvbeta1.2 against Kv1.5 was confirmed using Xenopus laevis oocytes. Our findings suggest that the molecular basis for the differential electrophysiological characteristics including opposing response to oxygen in the DA and the PA are partially due to diversity in expression of Kv1.5 and Kvbeta1.2 subunits. The high expression of Kvbeta1.2 and relatively low expression of Kv1.5 in the DA might be partially responsible for the ductal closure after birth.
Asunto(s)
Conducto Arterial/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Secuencia de Bases , Northern Blotting , Bovinos , Clonación Molecular , ADN Complementario , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Canales de Potasio con Entrada de Voltaje/química , Canales de Potasio con Entrada de Voltaje/genética , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Clinically, it appears that phosphodiesterase 3 (PDE 3) inhibitors, which are used for acute cardiac failure in premature infants, dilate the ductus arteriosus (DA). OBJECTIVES: To clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm fetal rats, in in vivo studies. METHODS: The in vivo ductal diameter of rat pups and fetuses was measured using a rapid whole-body freezing method, by cutting on a freezing microtome and measuring with a microscope and micrometer. Eight to twenty pups and fetuses were studied in each group. Milrinone and amrinone (specific inhibitors of PDE 3) were injected into 1-hour-old pups and the DA was studied 0.5 and 1 h later. The differential effects of these PDE 3 inhibitors on the near-term and preterm ductus were studied by injecting indomethacin (10 mg/kg) and PDE 3 inhibitors into 21D (21st day of pregnancy: term-21.5 days) and 19D dams and studying the fetal ductus 4 and 8 h later. RESULTS: Milrinone and amrinone dilated the postnatal ductus dose-dependently. Large doses of these drugs dilated it completely, and clinically equivalent doses dilated it minimally. Milrinone and amrinone prevented constriction of the fetal ductus by indomethacin. Their ductus-dilating effects were more potent in the preterm than in the near-term fetuses, and clinically equivalent doses of these PDE 3 inhibitors dilated preterm ductus completely. CONCLUSION: In rats, PDE 3 inhibitors reopen the constricted postnatal DA slightly. PDE 3 inhibitors dilate the fetal DA constricted with indomethacin effectively and more sensitively in preterm than in near-term fetuses.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Conducto Arterial/efectos de los fármacos , Conducto Arterial/enzimología , Inhibidores de Proteínas Quinasas/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Animales , Animales Recién Nacidos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Conducto Arterial/embriología , Conducto Arterial/crecimiento & desarrollo , Conducto Arterioso Permeable/tratamiento farmacológico , Femenino , Indometacina/farmacología , Milrinona/farmacología , Embarazo , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas , Ratas WistarRESUMEN
Prostaglandin E1 is used to reopen the constricted ductus arteriosus in neonates with ductus-dependent circulation. To clarify possible prostanoid receptor agonists that can reopen the neonatal ductus with fewer side effects, we studied in vivo reopening of the neonatal ductus arteriosus by AE1-329, a prostanoid EP4-receptor agonist, in the rat. Neonatal rats were incubated at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. Intraesophageal pressure was measured with a Millar micro-tip transducer. The ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 and 60 min after birth. PGE1 and AE1-329, injected subcutaneously at 60 min after birth, dilated the ductus dose-dependently. Thirty minutes after injection of 10 ng/g of PGE1 and AE1-329, the ductus diameter was 0.52 and 0.65 mm, respectively. The ductus-dilating effect of PGE1 was maximal at 15-30 min, and disappeared at 2 h. The ductus-dilating effect of AE1-329 was prolonged, the ductus was widely open at 6 h, and closed at 12 h after injection of 10 ng/g AE1-329. AE1-259-01 (EP2 agonist) (100 ng/g) did not dilate the neonatal ductus. Respiration was depressed by PGE1, but not by AE1-329. These results indicate the major role of EP4 in the neonatal ductus and that AE1-329, an EP4 agonist, can be used to dilate the neonatal constricted ductus without the side effects shown by EP3, including apnea.
Asunto(s)
Alprostadil/farmacología , Animales Recién Nacidos , Conducto Arterial/efectos de los fármacos , Receptores de Prostaglandina E/agonistas , Animales , Femenino , Embarazo , Ratas , Ratas Wistar , Subtipo EP4 de Receptores de Prostaglandina ERESUMEN
Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.
Asunto(s)
Conducto Arterial/efectos de los fármacos , Feto/efectos de los fármacos , Naftalenos/farmacología , Fenilbutiratos/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacos , Animales , Animales Recién Nacidos , Conducto Arterial/fisiopatología , Feto/fisiopatología , Ratas , Subtipo EP4 de Receptores de Prostaglandina ERESUMEN
Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.
Asunto(s)
Proteínas de Unión al ADN/genética , Defectos del Tabique Interatrial/genética , Proteínas de Homeodominio/genética , Mutación , Factores de Transcripción/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Factor de Transcripción GATA4 , Defectos del Tabique Interatrial/patología , Proteína Homeótica Nkx-2.5 , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Literatura de Revisión como AsuntoRESUMEN
A recent in vitro study showed that sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted ductus arteriosus of neonatal rabbits. We studied the in vivo ductus-dilating effects of sildenafil in fetal and neonatal rats. Ductus diameters were measured with whole-body freezing and cutting on a freezing microtome. Indomethacin (10 mg/kg) constricted the fetal ductus severely at 4 and 8 h after orogastric administration to the dams. Sildenafil, administered orogastrically and simultaneously with indomethacin, dilated the near-term fetal [21 fetal days (FD)] ductus constricted by indomethacin completely with 1 mg/kg at 8 h after administration. The preterm fetal ductus was more sensitive to sildenafil at 19FD. The ductus constricted rapidly after birth, and the ductal diameter was only 10% of the fetal diameter at 1 h after birth. The ductus-dilating effect of sildenafil was studied by i.p. injection at 1 h after birth, and the ductus diameter was studied 30 and 60 min later. Sildenafil dilated the neonatal constricted ductus moderately with a massive dose (100 mg/kg) and only minimally with 1 mg/kg. In conclusion, sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted fetal ductus completely at 8 h with 1 mg/kg in the near-term fetus and completely with a smaller dose (0.1 mg/kg) in the preterm fetus. However, sildenafil dilated the neonatal constricted ductus only moderately with large doses and minimally with 1 mg/kg. Probably, sildenafil is useful clinically for treating idiopathic and secondary fetal ductal constriction and not useful for dilation of the neonatal constricted ductus.
Asunto(s)
Conducto Arterial/efectos de los fármacos , Conducto Arterial/patología , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Antiinflamatorios no Esteroideos/farmacología , Peso Corporal , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Congelación , Indometacina/farmacología , Piperazinas/farmacología , Prostaglandinas E/metabolismo , Purinas , Ratas , Ratas Wistar , Citrato de Sildenafil , Sulfonas , Factores de TiempoRESUMEN
BACKGROUND: To find a better treatment for patent ductus arteriosus (PDA) in premature infants, the present study investigated the synergism of clinical doses of dexamethasone, indomethacin, and rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the fetal ductus arteriosus (DA) in rats. METHODS AND RESULTS: Dexamethasone (0.3 mg/kg), indomethacin (0.3 mg/kg), and rofecoxib (0.3 mg/kg), alone or in combination, were administered to preterm (d19) and near-term (d21) fetal rats. The ratio of the inner diameter of the DA to that of the main pulmonary artery (PA) (DA/PA) was studied at 2, 4 and 8 h after drug administration, using a rapid whole-body freezing method. In near-term rats, the combined administration of dexamethasone and indomethacin caused severe constriction, with a DA/PA ratio of 0.52+/-0.08 at 8 h, whereas the DA/PA ratios were 0.83+/-0.03 and 0.90+/-0.02 with dexamethasone and indomethacin, respectively. Combined administration of dexamethasone and rofecoxib also caused severe constriction, with a DA/PA ratio of 0.64+/-0.07 at 8 h, compared with the DA/PA ratio of 0.92+/-0.03 with rofecoxib alone. CONCLUSIONS: Combined therapy may be an option in the medical management of PDA in premature infants before considering surgical treatment.
Asunto(s)
Antiinflamatorios/administración & dosificación , Conducto Arterial/efectos de los fármacos , Feto/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Animales , Dexametasona/administración & dosificación , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Conducto Arterial/fisiología , Conducto Arterioso Permeable/tratamiento farmacológico , Feto/irrigación sanguínea , Indometacina/administración & dosificación , Lactonas/administración & dosificación , Modelos Animales , Ratas , Ratas Wistar , Sulfonas/administración & dosificaciónRESUMEN
The phenotypic expression of cardiomyopathy is greatly influenced by extrinsic factors other than intrinsic genetic defects, such as environmental stress. Exercise is assumed to be an important extrinsic factor, since sudden death is sometimes seen during exercise in young patients with hypertrophic cardiomyopathy (HCM). However, the long-term effects of mild exercise on phenotypic expression in cardiomyopathy remain unclear. To evaluate the effects of exercise performed during infancy or adolescence in cardiomyopathic patients, cardiomyopathic Syrian hamsters (BIO14.6) were subjected to swimming. BIO14.6 and age-matched congenic normal hamsters (CN) as controls were divided into three groups: sedentary (Sed), and trained during infancy (Inf) and during adolescence (Ado). Histological and biochemical analysis of 41-week-old hamsters revealed that (1) the relative level of beta-myosin heavy chain mRNA was significantly lower in the Inf group than in the Sed and Ado groups of BIO14.6. The level in the Inf group of BIO14.6 was compatible with that in the age-matched Sed group of the CN strain; (2) in BIO14.6, degenerative mitochondrial change in the cardiomyocytes was not seen in the Inf group while it was common in the Sed and Ado groups; (3) calcineurin phosphatase activity in the swimming group in 10-week-old CN was significantly higher than that of the age-matched sedentary group, and was as much as that of the swimming and sedentary groups in 10- and 41-week-old BIO14.6.
Asunto(s)
Cardiomiopatía Hipertrófica/metabolismo , Ventrículos Cardíacos/fisiopatología , Condicionamiento Físico Animal/fisiología , Natación , Factores de Edad , Animales , Peso Corporal , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Tamaño de la Célula , Cricetinae , Modelos Animales de Enfermedad , Ventrículos Cardíacos/química , Técnicas In Vitro , Mesocricetus , Miocardio/química , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Cadenas Pesadas de Miosina/genética , Tamaño de los Órganos , Monoéster Fosfórico Hidrolasas/metabolismo , ARN Mensajero/análisis , ARN Mensajero/genética , Natación/fisiología , Factores de Tiempo , Función Ventricular , Miosinas Ventriculares/genéticaRESUMEN
Diabetes was reported to be associated with a mitochondrial (mt) DNA mutation at 3243 and variants at 1310, 1438, 3290, 3316, 3394, 12,026, 15,927, and 16,189. Among these mtDNA abnormalities, those at 3243, 3316, 15,927, and 16,189 were also suggested to cause cardiomyopathies. We investigated the prevalence of such mtDNA abnormalities in 68 diabetic patients with LV hypertrophy (LVH), 100 without LVH, and 100 controls. Among the 9 mtDNA abnormalities, those at 3243, 3316, and 15,927 tended to be more prevalent in diabetic patients with LVH than in those without LVH (1%, 1%, and 4% vs. 0%, 0%, and 0%). Notably, the variant at 16,189 was more prevalent in diabetic patients with LVH than without LVH (46% vs. 24%, [Formula: see text] ). The odds ratio for LVH was 3.0 (95% CI, 1.5-6.1) for the 16,189 variant. A common mtDNA variant at 16,189 was found to be associated with LVH in diabetic patients.
Asunto(s)
ADN Mitocondrial/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/genética , Análisis Mutacional de ADN , ADN Mitocondrial/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Pruebas Genéticas , Variación Genética , Humanos , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Del22q11.2 syndrome is the most frequent known chromosomal microdeletion syndrome, with an incidence of 1 in 4000-5000 livebirths. It is characterised by a 3-Mb deletion on chromosome 22q11.2, cardiac abnormalities, T-cell deficits, cleft palate facial anomalies, and hypocalcaemia. At least 30 genes have been mapped to the deleted region. However, the association of these genes with the cause of this syndrome is not clearly understood. METHODS: To test for the chromosomal deletion at 22q11.2, we did fluorescence in-situ hybridisation analysis with ten probes on 22q11.2 in 235 unrelated patients with clinically diagnosed del22q11.2 syndrome. To investigate mutations in the coding sequence of TBX1, we also did genetic analysis in 13 patients from ten families who have the 22q11.2 syndrome phenotype but no detectable deletion of 22q11.2. FINDINGS: 96% (225 of 235) of patients had a defined 1.5-3-Mb deletion at 22q11.2. We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome. We did not record these three mutations in 555 healthy controls (1110 chromosomes; p<0.0001). INTERPRETATION: Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q11.2 syndrome. Therefore, we conclude that TBX1 is a major genetic determinant of the del22q11.2 syndrome.
Asunto(s)
Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/genética , Eliminación de Gen , Proteínas de Dominio T Box/genética , Anomalías Múltiples/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Mutación , FenotipoRESUMEN
Phospholamban is an endogenous inhibitor of sarcoplasmic reticulum calcium ATPase and plays a prime role in cardiac contractility and relaxation. Phospholamban may be a candidate gene responsible for cardiomyopathy. We investigated genome sequence of phospholamban in patients with cardiomyopathy. PCR-based direct sequence was performed for the promoter region and the whole coding region of phospholamban in 87 hypertrophic, 10 dilated, and 2 restricted cardiomyopathic patients. We found a heterozygous single nucleotide transition from A to G at -77-bp upstream of the transcription start site in the phospholamban promoter region of one patient with familial hypertrophic cardiomyopathy. This nucleotide change was not found in 296 control subjects. Using neonatal rat cardiomyocytes, the mutation, -77A-->G, increased the phospholamban promoter activity. No nucleotide change in the phospholamban coding region was found in 99 patients with cardiomyopathy. We suspect that the mutation plays an important role in the development of hypertrophic cardiomyopathy.
Asunto(s)
Proteínas de Unión al Calcio/genética , Cardiomiopatía Hipertrófica/genética , Predisposición Genética a la Enfermedad , Mutación , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , Cardiomiopatía Hipertrófica/diagnóstico , Humanos , Ratas , Activación TranscripcionalRESUMEN
Lectin-like oxidized low-density lipoprotein receptor (LOX-1/OLR1) has been suggested to play a role in the progression of atherogenesis. We analyzed the OLR1 gene and found a single nucleotide polymorphism (SNP), G501C, in patients with ischemic heart disease from a single family, which resulted in the missense mutation of K167N in LOX-1 protein. We compared the group of patients with myocardial infarction (MI) (n=102) with a group of clinically healthy subjects (n=102), and found that the MI group had a significantly high frequency of 501G/C+501C/C (38.2%) compared with the healthy group (17.6%; p<0.002). The odds ratio for the risk of MI associated with the 501G/C+501C/C genotype was 2.89 (95% CI, 1.51-5.53). These findings suggest that OLR1 or a neighboring gene linked with G501C SNP is important for the incidence of MI. Manipulating LOX-1 activity might be a useful therapeutic and preventative approach for coronary artery disease, especially for individuals with the G501C genotype of OLR1.
Asunto(s)
Infarto del Miocardio/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Metabolismo de los Lípidos , Masculino , Mutación , Mutación Missense , Oportunidad Relativa , Linaje , Polimorfismo de Nucleótido Simple , Polimorfismo Conformacional Retorcido-Simple , Receptores de LDL Oxidadas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Receptores Depuradores de Clase ERESUMEN
PURPOSE: To elucidate whether thrombocytopenia in 22q11.2 deletion syndrome patients is associated with the hemizygosity of glycoprotein Ib-beta and to clarify the correlation of phenotype and genotype of this gene in 22q11.2 deletion syndrome patients with thrombocytopenia. METHODS: Platelet number, mean platelet volume, platelet agglutination, and the protein level of glycoprotein Ib-beta were measured in 22q11.2 deletion syndrome patients and controls. Phenotypes other than that of thrombocytopenia were also analyzed in these patients. RESULTS: The 22q11.2 deletion syndrome patients with thrombocytopenia had a larger mean platelet volume, lower agglutination to ristocetin, and lower protein level of glycoprotein Ib-beta than control patients. The 22q11.2 deletion syndrome patients with thrombocytopenia showed an increased risk of developing schizophrenia. CONCLUSIONS: Thrombocytopenia in 22q11.2 deletion syndrome patients is associated with decreased expression of glycoprotein Ib-beta because of the hemizygosity. 22q11.2 deletion syndrome patients with thrombocytopenia require total management, especially for schizophrenia.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22 , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Trombocitopenia/genética , Adolescente , Adulto , Western Blotting , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Fenotipo , Recuento de Plaquetas , Análisis de Secuencia de ADN , Trombocitopenia/sangreRESUMEN
The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied the preventive effect of a dual ET receptor antagonist (bosentan) and a selective ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near-term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal ductus was constricted by four medications: orogastric administration of indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1, 10, or 100 mg/kg) was injected intraperitoneally either simultaneously with indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally simultaneously with indomethacin. After maternal atlas dislocation, cesarean section, fetal whole-body freezing, and cutting on the freezing microtome, measurements were made of the inner diameters of the ductus, main pulmonary artery, and ascending aorta. Bosentan blocked fetal ductal constriction by indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal constriction was nearly completely blocked by simultaneously administered 100 mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan) and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus arteriosus induced by ductus-constricting agents in rats, indicating that ET and ET-A receptors are essential in fetal ductal constriction.