RESUMO
3'-5' cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Coração Fetal/metabolismo , Diester Fosfórico Hidrolases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , AMP Cíclico , GMP Cíclico/metabolismo , Feminino , Coração Fetal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Fosfodiesterase/farmacologiaRESUMO
AIM: Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy. METHODS: Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups. RESULTS: A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]). CONCLUSION: Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.
Assuntos
Buprenorfina/efeitos adversos , Coração Fetal/efeitos dos fármacos , Antagonistas de Entorpecentes/efeitos adversos , Tratamento de Substituição de Opiáceos/efeitos adversos , Adulto , Estudos de Coortes , Feminino , Humanos , Magnetocardiografia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Gravidez , Complicações na Gravidez/tratamento farmacológico , Adulto JovemRESUMO
El diazepam (DZ) es un tranquilizante menor sintético, utilizado en pacientes con trastornos psicológicos y psiquiátricos. Es sedante, miorrelajante, anticonvulsionante y antipsicótico. El DZ atraviesa la barrera placentaria humana y la del ratón. Mujeres jóvenes que son adictas al fármaco, si se embarazan y continúan utilizándolo, sobre todo durante el primer trimestre, exponen a sus hijos a presentar alteraciones psicomotoras. El propósito de este trabajo fue investigar si el DZ administrado durante la gestación,induce alteraciones ultraestructurales del miocardio fetal de ratón. El grupo (DZ) de hembras gestantes deratón de la cepa CD-1 fue tratado con dosis únicas diarias de 1,0 mg/kg/pc/sc del día 6 al 17 y un grupo (C)que recibió solución salina. El día 18 las hembras de ambos grupos se anestesiaron, los fetos se perfundieron por vía intracardiaca con paraformaldehído al 1 % y glutaraldehido al 2,5 %, se les extrajo el corazón, se disecó el atrio, se fijó en OsO4 al 1 % y se incluyó en resina epóxica. Los cortes finos se contrastaron conacetato de uranilo y citrato de plomo y se observaron en un microscopio electrónico de transmisión. En los miocitos de los fetos del grupo DZ las sarcómeras del miocardio compacto tenían menor longitud que las del grupo C. Se observaron zonas con miofibrillas desorganizadas. El retículo sarcoplásmico de algunos miocitos presentaba cisternas distendidas y fragmentadas, mitocondrias alteradas y se observaron abundantes polirribosomas. Los cambios podrían deberse al efecto del DZ sobre la síntesis de actina y miosina pesada y sobre los organelos citoplásmicos, mediados por receptores benzodiazepínicos periféricos presentes en la membrana externa de las mitocondrias y asociados a canales de calcio dependientes de voltaje. Las alteraciones ultraestructurales del miocardio atrial de fetos de ratones expuestos in utero a DZ podrían tener efectos posnatales.
Diazepam (DZ) is a syntheticminor tranquilizer, used in patients with psychologicaland psychiatric disorders. It is a relaxing sedative,anticonvulsant and antipsychotic. DZ crosses thehuman placental barrier in mouse. Young women who are addicted to the drug, if they become pregnantand continue to use it, particularly during the firsttrimester, expose their children to psychomotor disorders. The purpose of this study was to investigate whether DZ administered during pregnancy induces ultrastructural alterations of fetal mouse myocardium.The group (DZ) of pregnant female mice of the CD-1strain was treated with a single daily dose of 1.0 mg/ kg / pc / sc of day 6 to 17 and a group (C) that received saline solution. On day 18 females of bothgroups were anesthetized, the fetuses were perfusedby intracardiac route with 1 % paraformaldehyde and 2.5 % glutaraldehyde, the heart was removed, theatrium was dissected, fixed in 1 % OsO4, it wasimmersed in epoxy resin. The fine sections werecontrasted with uranyl acetate and lead citrate and observed in a transmission electron microscope. Inthe myocytes of the fetuses of the DZ group, the sarcomers of the compact myocardium were shorter than those of the C group. Areas with disorganized myofibrils were observed. The sarcoplasmic reticulumof some myocytes had distended and fragmented 996cisterns, altered mitochondria, and abundant polyribosomes were observed. The changes may bedue to the effect of DZ on the synthesis of actin and heavy myosin and on cytoplasmic organelles mediatedby peripheral benzodiazepine receptors present onthe outer membrane of the mitochondria and associated with voltage-dependent calcium channels.Ultrastructural alterations of the atrial myocardium of fetuses of mice exposed to DZ in utero may have postnatal effects.
Assuntos
Animais , Gravidez , Camundongos , Diazepam/toxicidade , Coração Fetal/efeitos dos fármacos , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/ultraestrutura , Benzodiazepinas/toxicidade , Coração Fetal/ultraestruturaRESUMO
A G1P0 woman with aortic coarctation and mitral valve stenosis underwent endovascular aortic repair with continuous fetal monitoring during the 20th week of pregnancy. On tracheal extubation, an episode of fetal asystole followed by fetal bradycardia was identified. Ephedrine, nitroglycerin, and terbutaline were administered for intrauterine fetal resuscitation. Subsequently, the patient developed hypertension and pulmonary edema, which were treated with furosemide and noninvasive positive pressure ventilation. The fetal heart rate normalized. We conclude that intraoperative monitoring of a previable fetus may aid in optimizing maternal hemodynamics. Before performing interventional procedures in pregnant women, a multidisciplinary team should discuss the goals of neonatal care should adverse fetal events be detected.
Assuntos
Coartação Aórtica/cirurgia , Coração Fetal/fisiopatologia , Parada Cardíaca/tratamento farmacológico , Estenose da Valva Mitral/cirurgia , Complicações Cardiovasculares na Gravidez/cirurgia , Adulto , Feminino , Coração Fetal/efeitos dos fármacos , Monitorização Fetal , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Frequência Cardíaca Fetal/efeitos dos fármacos , Humanos , Gravidez , Segundo Trimestre da Gravidez , Procedimentos Cirúrgicos Vasculares/efeitos adversosRESUMO
The aim of this study was to evaluate the effects of maternal nicotine exposure on heart morphology and fibrosis in rat offspring. Nicotine was administered to pregnant Sprague-Dawley rats by using a subcutaneous osmotic mini-pump at a dose of 6 mg/kg/day from Gestational Days 7-21 or Gestational Day 7 to Postnatal Day 14. A control group received an equal volume of saline by the same route as nicotine. Rats born to prenatal nicotine-treated dams exhibited significantly greater cell width of cardiomyocytes, fewer cardiomyocyte nuclei number, higher ß-myosin heavy chain and transforming growth factor (TGF-ß1) expression, and higher collagen deposition in heart compared with rats born to normal saline-treated dams on Postnatal Days 7 and 21. Postnatal nicotine exposure further enhances these effects. We conclude that TGF-ß1 may be involved in the pathogenesis of cardiac remodeling induced by maternal nicotine exposure during gestation and lactation in rat offspring.
Assuntos
Coração Fetal/efeitos dos fármacos , Exposição Materna , Nicotina/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Colágeno/metabolismo , Feminino , Coração Fetal/patologia , Lactação , Cadeias Pesadas de Miosina/análise , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/análiseRESUMO
In the first two-thirds of gestation, ovine fetal cardiomyocytes undergo mitosis to increase cardiac mass and accommodate fetal growth. Thereafter, some myocytes continue to proliferate while others mature and terminally differentiate into binucleated cells. At term (145 days gestational age; dGA) about 60% of cardiomyocytes become binucleated and exit the cell cycle under hormonal control. Rising thyroid hormone (T3) levels near term (135 dGA) inhibit proliferation and stimulate maturation. However, the degree to which intracellular signaling patterns change with age in response to T3 is unknown. We hypothesized that in vitro activation of ERK, Akt, and p70(S6K) by two regulators of cardiomyocyte cell cycle activity, T3 and insulin like growth factor-1 (IGF-1), would be similar in cardiomyocytes at gestational ages 100 and 135 dGA. IGF-1 and T3 each independently stimulated phosphorylation of ERK, Akt, and p70(S6K) in cells at both ages. In the younger mononucleated myocytes, the phosphorylation of ERK and Akt was reduced in the presence of IGF-1 and T3. However, the same hormone combination led to a dramatic twofold increase in the phosphorylation of these signaling proteins in the 135 dGA cardiomyocytes-even in cells that were not proliferating. In the older cells, both mono- and binucleated cells were affected. In conclusion, fetal ovine cardiomyocytes undergo profound maturation-related changes in signaling in response to T3 and IGF-1, but not to either factor alone. Differences in age-related response are likely to be related to milestones in fetal cardiac development as the myocardium prepares for ex utero life.
Assuntos
Coração Fetal/metabolismo , Sistema de Sinalização das MAP Quinases , Miócitos Cardíacos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Proliferação de Células , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Coração Fetal/citologia , Coração Fetal/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Ovinos , Hormônios Tireóideos/farmacologiaRESUMO
Prenatal alcohol exposure leads to congenital heart abnormal development, its mechanisms are still unknown. Recent reports have associated alcohol exposure with histone H3 acetylation. In the present study, we have performed the experiments to test the hypothesis that histone H3K14 acetylation is the key role in the fetal heart leads to over-expression of cardiac specific genes DHAND and EHAND caused by prenatal alcohol exposure. Seventy pregnant C57BL/6 mice were divided randomly into seven groups (n=10). They were the untreated group, dimethyl sulfoxide group, alcohol exposure group, curcumin treatment group, both alcohol and curcumin treatment group, SAHA treatment group, both alcohol and SAHA treatment group. Fetal mouse hearts were collected on embryonic day 14.5. The changes of HATs activities, the acetylation levels of histone H3K14 (H3K14ac), the expression levels of cardiac specific genes DHAND and EHAND, and structure of chromatin were determined. Our data indicates that curcumin and SAHA significantly reduces and increases the activities of HATs and the levels of histone H3K14ac in fetal hearts, respectively. The expression of DHAND and EHAND is significantly down-regulated and up-regulated in the groups treated with curcumin and SAHA. Furthermore, our results from ChIP assays have shown that the histone H3K14ac connects with the DHAND and EHAND genes are significantly inhibited by curcumin and simulated by SAHA. Our study suggests that prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing H3K14ac in mice.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Etanol , Transtornos do Espectro Alcoólico Fetal/enzimologia , Coração Fetal/metabolismo , Histonas/metabolismo , Acetilação , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Sítios de Ligação , Imunoprecipitação da Cromatina , Feminino , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/genética , Coração Fetal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Regiões Promotoras Genéticas , Regulação para CimaRESUMO
Intrauterine growth restriction (IUGR) is associated with impaired cardiac function in childhood and is linked to short- and long-term morbidities. Placental dysfunction underlies most IUGR, and causes fetal oxidative stress which may impact on cardiac development. Accordingly, we investigated whether antenatal melatonin treatment, which possesses antioxidant properties, may afford cardiovascular protection in these vulnerable fetuses. IUGR was induced in sheep fetuses using single umbilical artery ligation on day 105-110 of pregnancy (term 147). Study 1: melatonin (2 mg h(-1)) was administered i.v. to ewes on days 5 and 6 after surgery. On day 7 fetal heart function was assessed using a Langendorff apparatus. Study 2: a lower dose of melatonin (0.25 mg h(-1)) was administered continuously following IUGR induction and the ewes gave birth normally at term. Lambs were killed when 24 h old and coronary vessels studied. Melatonin significantly improved fetal oxygenation in vivo. Contractile function in the right ventricle and coronary flow were enhanced by melatonin. Ischaemia-reperfusion-induced infarct area was 3-fold greater in IUGR hearts than in controls and this increase was prevented by melatonin. In isolated neonatal coronary arteries, endothelium-dependent nitric oxide (NO) bioavailability was reduced in IUGR, and was rescued by modest melatonin treatment. Melatonin exposure also induced the emergence of an indomethacin-sensitive vasodilation. IUGR caused marked stiffening of the coronary artery and this was prevented by melatonin. Maternal melatonin treatment reduces fetal hypoxaemia, improves heart function and coronary blood flow and rescues cardio-coronary deficit induced by IUGR.
Assuntos
Cardiotônicos/uso terapêutico , Retardo do Crescimento Fetal/tratamento farmacológico , Coração Fetal/efeitos dos fármacos , Melatonina/uso terapêutico , Animais , Cardiotônicos/farmacologia , Circulação Coronária/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Coração Fetal/fisiopatologia , Troca Materno-Fetal , Melatonina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Gravidez , Ovinos , Rigidez Vascular/efeitos dos fármacosRESUMO
Carbon nanoparticles, with their high biocompatibility and low toxicity, have recently been considered for biomedical applications, including antiangiogenic therapy. Critical to normal development and tumor formation, angiogenesis is the process of forming capillary blood vessels from preexisting vessels. In the present study, we evaluated the effects of diamond and graphite nanoparticles on the development of chicken embryos, as well as vascularization of the chorioallantoic membrane and heart at the morphological and molecular level. Nanoparticles did not affect either body/heart weight or serum indices of the embryos' health. However, vascularization of the heart and the density of branched vessels were significantly reduced after treatment with diamond nanoparticles and, to a lesser extent, graphite nanoparticles. Application of nanoparticles significantly downregulated gene and protein expression of the proangiogenic basic fibroblast growth factor, indicating that both diamond and graphite nanoparticles inhibit angiogenesis.
Assuntos
Carbono/administração & dosagem , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/fisiologia , Coração Fetal/efeitos dos fármacos , Coração Fetal/fisiologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Nanopartículas/administração & dosagem , Animais , Embrião de Galinha , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologiaRESUMO
BACKGROUND: Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. CONCLUSIONS/SIGNIFICANCE: Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.
Assuntos
Autoanticorpos/imunologia , Canais de Cálcio Tipo T/imunologia , Epitopos/imunologia , Bloqueio Cardíaco/congênito , Sequência de Aminoácidos , Animais , Nó Atrioventricular/efeitos dos fármacos , Nó Atrioventricular/metabolismo , Autoanticorpos/sangue , Autoantígenos/imunologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/genética , Mapeamento de Epitopos , Espaço Extracelular , Feminino , Coração Fetal/efeitos dos fármacos , Coração Fetal/imunologia , Coração Fetal/metabolismo , Expressão Gênica , Bloqueio Cardíaco/genética , Bloqueio Cardíaco/imunologia , Humanos , Masculino , Troca Materno-Fetal/imunologia , Camundongos , Dados de Sequência Molecular , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Peptídeos/imunologia , Gravidez , CoelhosRESUMO
The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 µg·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 µg·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females.
Assuntos
Metilação de DNA/efeitos dos fármacos , Dietilestilbestrol/toxicidade , Coração Fetal/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Função Ventricular Esquerda/efeitos dos fármacos , Fatores Etários , Animais , Sequência de Bases , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Calsequestrina/genética , Calsequestrina/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A , Feminino , Coração Fetal/crescimento & desenvolvimento , Coração Fetal/metabolismo , Regulação da Expressão Gênica , Idade Gestacional , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Gravidez , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Comportamento Sedentário , Fatores Sexuais , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/metabolismo , Natação , Ultrassonografia , Remodelação Ventricular/efeitos dos fármacosRESUMO
We have previously found that modest chronic increases in maternal cortisol result in an enlarged fetal heart. To explore the mechanisms of this effect, we used intrapericardial infusions of a mineralocorticoid receptor (MR) antagonist (canrenoate) or of a glucocorticoid receptor (GR) antagonist (mifepristone) in the fetus during maternal infusion of cortisol (1 mg·kg⻹·day⻹). We have shown that the MR antagonist blocked the increase in fetal heart weight and in wall thickness resulting from maternal cortisol infusion. In the current study we extended those studies and found that cortisol increased Ki67 staining in both ventricles, indicating cell proliferation, but also increased active caspase-3 staining in cells of the conduction pathway in the septum and subendocardial layers of the left ventricle, suggesting increased apoptosis in Purkinje fibers. The MR antagonist blocked the increase in cell proliferation, whereas the GR antagonist blocked the increased apoptosis in Purkinje fibers. We also found evidence of activation of caspase-3 in c-kit-positive cells, suggesting apoptosis in stem cell populations in the ventricle. These studies suggest a potentially important role of corticosteroids in the terminal remodeling of the late gestation fetal heart and suggest a mechanism for the cardiac enlargement with excess corticosteroid exposure.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Coração Fetal/efeitos dos fármacos , Hidrocortisona/farmacologia , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/efeitos dos fármacos , Animais , Ácido Canrenoico/farmacologia , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Caspase 3/metabolismo , Feminino , Coração Fetal/metabolismo , Coração Fetal/patologia , Idade Gestacional , Hidrocortisona/administração & dosagem , Hidrocortisona/toxicidade , Infusões Intravenosas , Antígeno Ki-67/metabolismo , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Gravidez , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/metabolismo , Ramos Subendocárdicos/patologia , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Ovinos , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/patologiaRESUMO
Anthracyclines are used to treat cancers during the second and third trimester of pregnancy. The chemotherapeutic effect of anthracyclines is associated with a dose- and time-dependent cardiotoxicity that is well described for infants and adults. However, data regarding fetal anthracycline-related cardiotoxicity after administration of chemotherapeutics during pregnancy are limited. In this study, we analyzed the acute effect of doxorubicin, an anthracycline derivative, on fetal and maternal rat myocardium. We injected 10 or 20 mg/kg i.v. doxorubicin to pregnant Wistar rats at day 18 of pregnancy; age-matched pregnant rats injected with physiologic saline served as controls. Maternal echocardiography and fetal Doppler scanning were performed before the injection and before sacrifice. Cesarean operation was performed at day 19 or 20, and maternal and fetal blood samples and heart biopsies were collected to measure apoptosis, the impact on cell proliferation, and structural cardiac damage. Acute maternal cardiotoxicity is associated with loss of body weight, moderately deteriorated left ventricular function, induction of apoptosis, and a decrease in cell turnover. Despite a 30% lower fetal body weight and elevated plasma B-type natriuretic peptide concentrations after doxorubicin administration, the fetal hearts had intact microstructure, an unaltered number of apoptotic cells, and preserved cell proliferation compared with controls. Our study suggests that acute treatment using anthracyclines during pregnancy impairs maternal cardiac function, whereas fetal hearts are protected.
Assuntos
Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/farmacocinética , Doxorrubicina/toxicidade , Coração Fetal/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Fator Natriurético Atrial/metabolismo , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Ecocardiografia , Feminino , Cardiopatias/diagnóstico por imagem , Marcação In Situ das Extremidades Cortadas , Injeções Intravenosas , Troca Materno-Fetal , Miocárdio/metabolismo , Miosinas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Gravidez , RNA/biossíntese , RNA/genética , Ratos , Ratos Wistar , Transcrição Gênica/efeitos dos fármacosRESUMO
Chemotherapy and especially anthracyclines are associated to cardiotoxicity. To assess this potential risk during pregnancy a clinical case-control trial was conducted. Maternal cardiac function, fetal Doppler and fetal cardiac function were evaluated before and after chemotherapy. Maternal cardiac function was assessed by echocardiography before and after the third cycle of anthracyclines and compared with a control group of 10 non-pregnant women matched for age, type of cancer and anthracycline treatment. Ten fetuses exposed to chemotherapy were compared with 10 control fetuses matched for gestational age and gender. Biometry, amniotic fluid index, fetal Doppler and cardiac function were assessed before and after each cycle of chemotherapy. In all, 108 fetal ultrasounds scans were performed before and after 36 cycles of chemotherapy. Anthracycline exposure did not result in acute maternal and fetal cardiac dysfunction in this small cohort study.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Coração Fetal/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Complicações Cardiovasculares na Gravidez/induzido quimicamente , Bélgica , Estudos de Casos e Controles , Feminino , Coração Fetal/diagnóstico por imagem , Humanos , Recém-Nascido , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Resultado da Gravidez , Estudos Prospectivos , Ultrassonografia Pré-NatalRESUMO
OBJECTIVE: To study the consequences of glucocorticoid treatment in fetal growth restriction (FGR) on cardiac function. SETTING: Laboratory. SAMPLE: Sheep. METHODS: Growth restriction was induced in sheep fetuses using single umbilical artery ligation (SUAL) on days 105-110 of gestation (term 147). Control fetuses were not ligated. Betamethasone (BM) (11.4 mg intramuscularly) or saline was administered to ewes on days 5 and 6 after surgery. Ewes were anaesthetised on day 7, the fetuses were removed, and their hearts were mounted on a Langendorff apparatus. Balloon catheters were inserted into the right and left ventricles. OUTCOME MEASURES: Ventricular contractile function and infarct area following ischaemia/reperfusion. RESULTS: The SUAL resulted in FGR (body weight 77% of control). The FGR was associated with increases in basal left ventricular pressure development and rates of contraction and relaxation. Right ventricular contraction was unaffected. Following brief ischaemia/reperfusion, the infarct area in FGR hearts was increased four-fold compared with controls. Antenatal BM resulted in a proportional increase in heart size and coronary flow, especially in FGR fetuses, and left ventricular pressure and heart rate responses to ß-adrenoceptor activation were increased. CONCLUSIONS: Fetal hearts rapidly adapt to FGR to maintain substrate delivery to the brain and heart. The FGR greatly enhanced the area of ischaemia, with implications for susceptibility in postnatal life. Antenatal BM treatment does not interfere with these cardiac changes but appears to increase left ventricle ß-adrenoceptor responsiveness, which may render the offspring vulnerable to subsequent cardiac dysfunction.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Betametasona/farmacologia , Retardo do Crescimento Fetal/fisiopatologia , Coração Fetal/efeitos dos fármacos , Glucocorticoides/farmacologia , Adaptação Fisiológica/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Análise de Variância , Animais , Betametasona/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Feminino , Coração Fetal/fisiologia , Glucocorticoides/administração & dosagem , Frequência Cardíaca Fetal/efeitos dos fármacos , Isoproterenol/farmacologia , Ligadura , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/embriologia , Carneiro Doméstico , Artérias Umbilicais , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacosRESUMO
AIMS: Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A(2A) receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period. MATERIAL AND METHODS: Gestational-day-11.5 pregnant mice were exposed to hypoxia (45 s duration followed by 10 min of recovery and repeated 3 times) while simultaneously monitoring maternal and fetal CO using high-resolution echocardiography. RESULTS: Following maternal hypoxia exposure, maternal CO transiently decreased and then returned to pre-hypoxia baseline values. In contrast to a uniform maternal cardiac response to each exposure to hypoxia, the fetal CO recovery time to the baseline decreased, and CO rebounded above baseline following the second and third episodes of maternal hypoxia. Maternal caffeine treatment inhibited the fetal CO recovery to maternal hypoxia by lengthening the time to CO recovery and eliminating the CO rebound post-recovery. Selective treatment with an adenosine A(2A) receptor antagonist, but not an adenosine A(1) receptor antagonist, reproduced the altered fetal CO response to maternal hypoxia created by caffeine exposure. CONCLUSIONS: Results suggest an additive negative effect of maternal caffeine on the fetal CV response to acute maternal hypoxia, potentially mediated via adenosine A(2A) receptor inhibition during primary cardiovascular morphogenesis.
Assuntos
Cafeína/efeitos adversos , Coração Fetal/efeitos dos fármacos , Hipóxia , Complicações na Gravidez , Antagonistas de Receptores Purinérgicos P1/efeitos adversos , Animais , Feminino , Frequência Cardíaca Fetal/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos , Organogênese , Gravidez , Volume Sistólico/efeitos dos fármacosRESUMO
OBJECTIVE: The co-occurrence of cancer and pregnancy is more frequently diagnosed. The effects of cancer treatment on maternal and fetal outcomes are less well known. The cardiotoxic effects of chemotherapy are a specific concern for the mother and fetus. We wanted to review the existing literature, mainly consisting of case reports, case studies, and retrospective data. RESULTS: Maternal effects Overall, the published data indicate that pregnancy is not an independent risk factor influencing cancer survival. There is no indirect evidence for an increased risk for maternal chemotherapy-related cardiotoxicity. Fetal effects During the first trimester chemotherapy needs to be avoided because of teratogenic risks. The risks of chemotherapy during the second and third trimester are more controversial. It has been associated with intrauterine growth restriction and preterm delivery in some studies, while others did not find the same effect. Cardiotoxic fetal effects have been reported despite the limited transplacental passage of chemotherapy. In most patients this was transient and long-term data are generally reassuring. CONCLUSION: A specific strategy for monitoring fetal and maternal chemotherapy-induced cardiotoxicity is suggested. Prospective data are needed on the long-term effects of chemotherapy in both mother and child.
Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxinas/efeitos adversos , Doenças Fetais/etiologia , Coração Fetal/efeitos dos fármacos , Coração/efeitos dos fármacos , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Antraciclinas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Gravidez , TrastuzumabRESUMO
The longevity gene clk-1/coq7 encodes an enzyme that is essential for the biosynthesis of coenzyme Q (CoQ) in mitochondria and regulates the lifespan and behavioral timing in Caenorhabditis elegans and the chronological lifespan in fission yeast. However, whether the mammalian clk-1/coq7 ortholog (clk-1) regulates these phenotypes in mammals remains to be fully evaluated due to the embryonic lethality of clk-1-deficient (clk-1(-/-)) mice. To investigate whether clk-1 regulates biological functions, such as growth and heartbeat, through CoQ in mouse embryos, we cultivated the cells and hearts of clk-1(-/-) mouse embryos at embryonic day 10.5 (E10.5) for at least 10 days in the presence of fetal bovine serum. In embryonic cells, cardiomyocytes, and hearts, the growth and heart rates were significantly slowed in clk-1(-/-) compared with wild-type or heterozygous mouse tissues. Moreover, frequent apoptosis and a significant reduction in mitochondrial functions, including membrane potential and ATP production, were observed in the clk-1(-/-) cells and hearts. The slowed growth and heart rates and the reduced mitochondrial function of clk-1(-/-) embryonic cells and hearts in culture were almost completely rescued by the administration of exogenous CoQ(10). The results indicate that clk-1 regulates growth and heart rates through CoQ-mediated mitochondrial functions in mouse embryos.
Assuntos
Coração Fetal/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Tirosina Quinases/fisiologia , Ubiquinona/análogos & derivados , Vitaminas/farmacologia , Trifosfato de Adenosina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Coração Fetal/enzimologia , Coração Fetal/crescimento & desenvolvimento , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Knockout , Mitocôndrias/enzimologia , Mitocôndrias/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Técnicas de Cultura de Órgãos , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Tirosina Quinases/deficiência , Ubiquinona/administração & dosagem , Ubiquinona/farmacologia , Vitaminas/administração & dosagemRESUMO
OBJECTIVE: To test the hypothesis that maternal restriction of polyphenol-rich foods (PRF), which, like non-steroidal anti-inflammatory drugs (NSAID), inhibit prostaglandin synthesis in the third trimester, reverse fetal ductal constriction (DC). STUDY DESIGN: An open clinical trial of 51 third trimester fetuses with DC with no history of NSAID intake was designed. All mothers were submitted to a food frequency questionnaire and were oriented to withdrawl PRF, being reassessed after 3 weeks. Doppler parameters were assessed before and after discontinuation of these substances. A control group of 26 third trimester normal fetuses, with no ductus arteriosus (DA) constriction, in which no dietary intervention was offered, was reviewed after 3 weeks. Student's t-test and Wilcoxon's test were used. RESULT: Mean gestational age was 32±3 weeks (28 to 37 weeks). After discontinuation of PRF (≥3 weeks), 48/51 fetuses (96%) showed complete reversal of DC, with decrease in mean ductal systolic velocity (1.74±0.20 m s(-1) to 1.31±0.34 m s(-1), P<0.001), mean diastolic velocity (0.33±0.09 m s(-1) to 0.21±0.07 m s(-1), P<0.001) and mean right to left ventricular dimension ratio (1.37±0.26 to 1.12±0.17, P<0.001) and increase in mean ductal pulsatility index (PI) (1.98±0.36 to 2.46±0.23, P<0.001). Median daily maternal consumption of PRF was 286 mg per day and decreased after orientation to 0 mg per day, P<0.001. In the control group, with GA of 32±4 w (29-37 w), there was no significant differences in median daily maternal consumption of PRF, mean ductal systolic velocitiy, diastolic velocity, PI and right ventricular to left ventricular diameter ratio (RV/LV) ratio. CONCLUSION: Reduction of maternal PRF intake during pregnancy, especially in the third trimester, is followed by complete reversal of DC (wide open DA), which may influence maternal dietary habits in late pregnancy.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Canal Arterial/efeitos dos fármacos , Coração Fetal/efeitos dos fármacos , Polifenóis/farmacologia , Adolescente , Adulto , Velocidade do Fluxo Sanguíneo , Constrição Patológica , Canal Arterial/diagnóstico por imagem , Canal Arterial/patologia , Feminino , Coração Fetal/diagnóstico por imagem , Humanos , Gravidez , Complicações na Gravidez , Terceiro Trimestre da Gravidez , Inquéritos e Questionários , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
This study tested the hypothesis that maternal nicotine ingestion increases matrix metalloproteinase (MMP) expression in fetal hearts, which is mediated by the generation of reactive oxygen species. Timed pregnant guinea pigs were administered either water alone, nicotine (200 µg/mL), N-acetylcysteine (NAC), or nicotine plus NAC in their drinking water for 10 days at 52-day gestation (term = 65 days). Near-term (62 days), anesthetized fetuses were extracted, hearts were excised, and left cardiac ventricles snap frozen for analysis of MMP-2/-9/-13 protein and activity levels. Interstitial collagens were identified by Picrosirius red stain to assess changes in the extracellular matrix. Prenatal nicotine increased active MMP-2 forms and interstitial collagen but had no effect on either pro- or active MMP-9 or MMP-13 forms. In the presence of nicotine, NAC decreased active MMP-2 protein levels and reversed the nicotine-induced increase in collagen staining. We conclude that prenatal nicotine alters MMP-2 expression in fetal hearts that may be mediated by reactive oxygen species generation.