RESUMO
OBJECTIVE: The aims of this study are to determine the incidence of congenital heart block (CHB) in the Japanese population and identify maternal factors predicting fetal CHB in anti-Ro/SSA antibody positive pregnancy. METHODS: A retrospective study was performed using 52,147 clinical records of pregnancies followed in a single center. For 183 anti-Ro/SSA antibody-positive women, anti-Ro52 and Ro60 antibodies were measured, and the odds of CHB in relation to maternal clinical features were calculated by multivariate analysis. The receiver-operating characteristic (ROC) curves for predicting CHB were constructed for the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies. RESULTS: Fetal CHB occurred in two pregnancies among those without known risks such as positive anti-Ro/SSA antibody or previous CHB-affected pregnancy, suggesting an incidence similar to that in Caucasian populations. As for the anti-Ro/SSA antibody positive pregnancies, the titers of anti-Ro/SSA, anti-Ro52 and anti-Ro60 antibodies were independent risk factors for fetal CHB and the use of corticosteroids before 18 gestational weeks was an independent protective factor. The area under the ROC was 0.84, 0.73 and 0.74 for anti-Ro52, anti-Ro60 and anti-Ro/SSA antibodies, respectively. CONCLUSION: CHB occurred in two among approximately 50,000 pregnancies without known risks such as positive anti-Ro/SSA antibody or previous delivery of CHB-affected babies. Measurement of anti-Ro52 antibody levels may be helpful in extracting a risk group of delivering CHB infants in the anti-Ro/SSA antibody positive pregnancy.
Assuntos
Anticorpos Antinucleares/sangue , Doenças Fetais/sangue , Bloqueio Cardíaco/congênito , Adulto , Biomarcadores/sangue , Feminino , Doenças Fetais/epidemiologia , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/epidemiologia , Humanos , Incidência , Masculino , Gravidez , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVES: At the moment there are no standard guidelines for the treatment of autoimmune congenital heart block (CHB). We set out to carry out a prospective cohort study to evaluate the benefits, limits, and safety of a combined therapy protocol to treat antibody-related CHB. METHODS: Twelve consecutive pregnant patients positive to anti-SSA/Ro ± anti-SSB/La antibodies in whom CHB was detected were prospectively evaluated from 2009 to 2014. The treatment protocol consisted of: weekly plasmapheresis, fortnightly intravenous immunoglobulins (IVIG), and daily 4 mg betamethasone from CHB detection until delivery; IVIG was administered to the neonates soon after birth. RESULTS: At the time CHB was detected, six of the foetuses presented atrioventricular blocks of 2(nd) degree type and six of 3(rd) degree type. Two of the foetuses with a 2(nd) degree block reverted to a 1st degree block and one to a normal atrioventricular conduction. The condition was stable throughout the pregnancy in the other three cases of 2(nd) degree block. All six 3(rd) degree blocks were stable during pregnancy and confirmed at birth. After a mean of 37.6 months ± 19.6 SD post-birth, the infants with 1st, normal sinus rhythm, and 2(nd) degree blocks at birth were all found to be stable. During the follow-up (29 months ± 19.8 SD), pacemakers were implanted in three of the six infants with 3(rd) degree blocks. CONCLUSIONS: This combined therapy seems to be effective and safe in treating 2(nd) degree CHB, while its efficacy in treating 3rd degree CHB remains to be established.
Assuntos
Doenças Autoimunes/terapia , Betametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Bloqueio Cardíaco/congênito , Imunoglobulinas Intravenosas/administração & dosagem , Plasmaferese , Adulto , Anticorpos Antinucleares/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Betametasona/efeitos adversos , Biomarcadores/sangue , Terapia Combinada , Esquema de Medicação , Quimioterapia Combinada , Ecocardiografia Doppler , Feminino , Idade Gestacional , Glucocorticoides/efeitos adversos , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/imunologia , Bloqueio Cardíaco/terapia , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Recém-Nascido , Masculino , Plasmaferese/efeitos adversos , Gravidez , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia Pré-Natal/métodosRESUMO
BACKGROUND: Pregnant women positive for 52- and 60-kDa anti-Ro/SSA and anti-La/SSB antibodies can suffer from congenital heart block (CHB), a passively acquired autoimmune disease. STUDY DESIGN AND METHODS: We evaluated the efficacy of plasma exchange (PE) in removing 52- and 60-kDa anti-Ro/SSA and anti-La/SSB antibodies in pregnant women with CHB treated with a combined therapy including PE, intravenous immunoglobulins, and steroids. Antibody levels were monitored in 10 consecutive pregnant women diagnosed with CHB and prospectively followed between 2009 and 2013. Assaying was performed using a homemade enzyme-linked immunosorbent assay test on blood samples collected immediately before and after PE sessions. RESULTS: A significant decrease in mean post-PE antibody levels was noted in all the cases examined. An analysis of antibody level trends in the samples collected before PE sessions showed that there was a steady, significant decrease in 90% of the patients with 52-kDa anti-Ro/SSA, in 80% of those with 60-kDa anti-Ro/SSA antibodies, and in 100% of those with anti-La/SSB antibodies. CONCLUSION: This study demonstrates that PE is effective in removing antibodies linked to the pathogenesis of CHB. PE treatment was found to have a long-term efficacy in all the women positive for anti-La/SSB antibodies and in most of the women positive for 52- and 60-kDa anti-Ro/SSA antibodies. It is interesting that the significant, immediate, and long-term fall in antibody levels that was observed in these patients took place in all the women whose CHB was reversed. This finding could give PE an important role in the treatment of CHB.
Assuntos
Autoanticorpos/sangue , Bloqueio Cardíaco/congênito , Troca Plasmática , Complicações na Gravidez , Adulto , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/terapia , Humanos , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/terapiaRESUMO
OBJECTIVES: To verify the association between the presence of specific anti-52 Ro/SSA-p200 antibodies and congenital heart block (CHB). METHODS: 207 pregnant Italian women carrying anti-Ro/SSA Ab were retrospectively evaluated. Anti-p200 Ab were investigated in the mothers' sera by ELISA (Euro-Diagnostica,Wieslab SS-A p200). RESULTS: CHB occurred in 42 children (34 complete CHB), whereas 165 were not affected. All CHB cases were previously identified with an ELISA screening for anti-Ro/SSA 60 kD Ab. Anti-p200 Ab were more frequently positive (81.0% vs. 59.1%, p=0.013) and at a higher titer in CHB mothers (Absorbance ratio: 2.030 (0.208-4.052) vs. 0.925 (0.200-3.816); p=0.017). This association was maintained even when the 42 mothers of children with CHB were compared with a control group matched for age and diagnosis (80.9% vs. 50.0%; p=0.006). The presence of anti-p200 Ab provided an odds ratio (OR) for CHB of 2.98 (CI: 1.30-6.83), which was higher than that of other variables, such as maternal disease and other antibody specificities. CHB risk significantly decreased in the absence of this fine specificity (OR:0.34, CI: 0.15-0.77). However, while the negative predictive value related to anti-Ro/SSA 60 kD Ab ELISA was 100%, almost 20% of mothers negative for anti-p200 Ab delivered babies with CHB. CONCLUSIONS: Anti-p200 antibodies seem to be associated with CHB with a higher probability than anti-Ro/SSA Ab, and therefore may be an additional test to identify mothers at higher risk to deliver affected children. An ELISA screening for anti-Ro/SSA 60 kD Ab is nevertheless mandatory given the probability of developing CHB also in the absence of anti-p200 Ab.
Assuntos
Anticorpos Antinucleares/sangue , Bloqueio Cardíaco/congênito , Fragmentos de Peptídeos/imunologia , Ribonucleoproteínas/imunologia , Adulto , Biomarcadores/sangue , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/imunologia , Humanos , Itália , Troca Materno-Fetal , Razão de Chances , Valor Preditivo dos Testes , Gravidez , Estudos Retrospectivos , Fatores de RiscoRESUMO
Despite advances in device closure for atrial septal defect, post-closure heart failure remains a clinical problem in adult patients but is seen only rarely in children. An eight-year-old boy, who had been followed by a local pediatrician with the diagnosis of diabetes mellitus and congenital heart disease, was consulted to us for cardiac re-evaluation. Electrocardiography demonstrated absent P waves, and echocardiography revealed enlargement of the right ventricle and both atria and secundum atrial septal defect. With the diagnosis of atrial standstill, secundum atrial septal defect and thiamine-responsive megaloblastic anemia, acute heart failure developed after transvenous closure of the atrial septal defect, which improved dramatically with thiamine and supportive treatment.
Assuntos
Anemia Megaloblástica/complicações , Anemia Megaloblástica/tratamento farmacológico , Cardiomiopatias/complicações , Doenças Genéticas Inatas/complicações , Átrios do Coração/anormalidades , Bloqueio Cardíaco/complicações , Insuficiência Cardíaca/complicações , Comunicação Interatrial/cirurgia , Tiamina/uso terapêutico , Cardiomiopatias/sangue , Criança , Doenças Genéticas Inatas/sangue , Bloqueio Cardíaco/sangue , Insuficiência Cardíaca/sangue , Comunicação Interatrial/sangue , Comunicação Interatrial/complicações , Humanos , MasculinoRESUMO
While mainly based on the use of fluorinated steroids, there is no standard management of anti-Ro/La-related congenital heart block (CHB). This is a report concerning two consecutive cases of anti-Ro/La-related second-degree block treated with betamethasone (4 mg/day), weekly plasmapheresis, and intravenous immunoglobulins (IVIGs; 1 g/kg) administered every 15 days, a therapy that was begun shortly after CHB was detected and continued until delivery. The newborns were also treated with IVIG (1 g/kg) soon after birth and continued fortnightly until the anti-Ro/La antibody levels became undetectable. In both cases second-degree AV block reverted to a stable sinus rhythm with a first-degree atrioventricular (AV) block. Moreover, there was no recurrence of CHB when therapy was suspended, as confirmed by a 29 month and an eight month follow-up, respectively.
Assuntos
Anticorpos Antinucleares/sangue , Betametasona/uso terapêutico , Bloqueio Cardíaco/congênito , Imunoglobulinas Intravenosas/uso terapêutico , Plasmaferese , Adulto , Terapia Combinada , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/imunologia , Bloqueio Cardíaco/terapia , Humanos , Recém-Nascido , Gravidez , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Considerable proportion of patients does not respond to the cardiac resynchronization therapy (CRT). This study investigated clinical relevance of left ventricular electrode local electrogram delay from the beginning of QRS (QLV). We hypothesized that longer QLV indicating more optimal lead placement in the late activated regions is associated with the higher probability of positive CRT response. METHODS: We conducted a retrospective, single-centre analysis of 161 consecutive patients with heart failure and LBBB or nonspecific intraventricular conduction delay (IVCD) treated with CRT. We routinely intend to implant the LV lead in a region with long QLV. Clinical response to CRT, left ventricular (LV) reverse remodelling (i.e. decrease in LV end-systolic diameter - LVESD ≥10%) and reduction in plasma level of NT-proBNP >30% at 12-month post-implant were the study endpoints. We analyzed association between pre-implant variables and the study endpoints. RESULTS: Clinical CRT response rate reached 58%, 84% and 92% in the lowest (≤105 ms), middle (106-130 ms) and the highest (>130 ms) QLV tertile (p < 0.0001), respectively. Longer QRS duration (p = 0.002), smaller LVESD and a non-ischemic cardiomyopathy (both p = 0.02) were also univariately associated with positive clinical CRT response. In a multivariate analysis, QLV remained the strongest predictor of clinical CRT response (p < 0.00001), followed by LVESD (p = 0.01) and etiology of LV dysfunction (p = 0.04). Comparable predictive power of QLV for LV reverse remodelling and NT-proBNP response rates was observed. CONCLUSION: LV lead position assessed by duration of the QLV interval was found the strongest independent predictor of beneficial clinical response to CRT.
Assuntos
Dispositivos de Terapia de Ressincronização Cardíaca , Terapia de Ressincronização Cardíaca , Técnicas Eletrofisiológicas Cardíacas , Bloqueio Cardíaco/terapia , Insuficiência Cardíaca/terapia , Função Ventricular Esquerda , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bloqueio de Ramo/fisiopatologia , Bloqueio de Ramo/terapia , Terapia de Ressincronização Cardíaca/efeitos adversos , Distribuição de Qui-Quadrado , República Tcheca , Desenho de Equipamento , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/fisiopatologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Remodelação VentricularRESUMO
Congenital heart block (CHB) is an autoimmune disease associated with autoantibodies against intracellular ribonucleoproteins SSB/La and SSA/Ro. The hallmark of CHB is complete atrioventricular block. We have recently established that anti-SSA/Ro -SSB/La autoantibodies inhibit alpha(1D) L-type Ca current, I(Ca-L), and cross-react with the alpha(1D) Ca channel protein. This study aims at identifying the possible binding sites on alpha(1D) protein for autoantibodies from sera of mothers with CHB children. GST fusion proteins of the extracellular regions between the transmembrane segments (S5-S6) of each of the four alpha(1D) Ca channel protein domains I-IV were prepared and tested for reactivity with sera from mothers with CHB children and controls using ELISA. Sera containing anti-Ro/La autoantibodies from 118 mothers with CHB children and from 15 mothers with anti-Ro/La autoantibodies but have healthy children, and from 28 healthy mothers without anti-Ro/La autoantibodies and healthy children were evaluated. Seventeen of 118 (14.4%) sera from mothers with CHB children reacted with the extracellular loop of domain I S5-S6 region (E1). In contrast, only 2 of 28 (7%) of sera from healthy mothers (-anti-Ro/La) and healthy children reacted with E1 loop and none (0 of 15) of sera from healthy mothers (+anti-Ro/La) and healthy children reacted with the E1 loop. Preincubation of E1 loop with the positive sera decreased the O.D reading establishing the specificity of the response. Electrophysiological characterization of the ELISA positive sera and purified IgG showed inhibition (44.1% and 49.8%, respectively) of the alpha(1D) I(Ca-L) expressed in tsA201 cells. The inhibition was abolished when the sera were pre-incubated with E1 fusion protein. The results identified the extracellular loop of domain I S5-S6 of L-type Ca channel alpha(1D) subunit as a target for autoantibodies from a subset of mothers with CHB children. This novel finding provides insights into the potential development of therapeutic peptides that could bind to the pathogenic antibodies and prevent CHB.
Assuntos
Autoanticorpos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Bloqueio Cardíaco/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Autoanticorpos/sangue , Autoantígenos/imunologia , Bloqueadores dos Canais de Cálcio/sangue , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/imunologia , Desenho de Fármacos , Mapeamento de Epitopos , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/prevenção & controle , Humanos , Gravidez , Conformação Proteica , Engenharia de Proteínas , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Ribonucleoproteínas/imunologia , Antígeno SS-BRESUMO
OBJECTIVE: In utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment. METHODS: Blood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays. RESULTS: We observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma. CONCLUSIONS: Ro/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.
Assuntos
Anticorpos Antinucleares/imunologia , Bloqueio Cardíaco/congênito , Interferon Tipo I/imunologia , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Casos e Controles , Ecocardiografia Doppler , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/embriologia , Bloqueio Cardíaco/imunologia , Humanos , Recém-Nascido , Interferon Tipo I/sangue , Masculino , Troca Materno-Fetal/imunologia , Gravidez , Complicações na Gravidez/imunologia , Doenças Reumáticas/imunologia , Suécia , Transcriptoma , Adulto JovemAssuntos
Feto , Bloqueio Cardíaco/diagnóstico , Adulto , Autoanticorpos/sangue , Bradicardia/sangue , Bradicardia/diagnóstico , Bradicardia/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Bloqueio Cardíaco/sangue , Humanos , Marca-Passo Artificial , Cuidado Pré-Natal , Resultado do TratamentoRESUMO
OBJECTIVES: Myocardial asynchrony in postinfarction patients with intraventricular conduction defects (IVCD) may influence plasma levels of B-type natriuretic peptide (BNP). The aim of the study is to evaluate asynchrony parameters in postinfarction patients with IVCD and to define the relationship between plasma levels of BNP and echocardiographic parameters of asynchrony. METHODS: The study included 158 patients 6 months after myocardial infarction (MI): 126 patients with IVCD and 32 patients without IVCD. Plasma levels of BNP were measured using an immunoenzymatic method. Left ventricular (LV) function was evaluated in echocardiography. RESULTS: In patients with post-MI IVCD, the mean plasma level of BNP was 280.2 +/- 340.2 versus 181.7 +/- 270.4 pg/ml (p < 0.001) and they had significantly higher parameters of interventricular asynchrony as compared with subjects without postinfarction IVCD. Multifactorial regression analysis showed that in patients with an ejection fraction (EF) > or =50%, interventricular asynchrony and intraventricular delay significantly influenced the BNP level. In patients with an EF <50%, BNP levels were correlated with the magnitude of the EF. CONCLUSION: Plasma levels of BNP 6 months after MI depend not only on parameters of LV function but also on LV asynchrony and may serve as its marker in patients with IVCD and preserved LV systolic function.
Assuntos
Biomarcadores/sangue , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/etiologia , Infarto do Miocárdio/complicações , Peptídeo Natriurético Encefálico/sangue , Idoso , Ecocardiografia , Feminino , Bloqueio Cardíaco/diagnóstico por imagem , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Função Ventricular EsquerdaRESUMO
Congenital heart block (CHB) is an autoantibody mediated disorder presumably caused by placental transmission of maternal autoantibodies to Ro/SSA 52 kd, p200, Ro/SSA 60 kd, La/SSB ribonucleoproteins. This study investigated the clinical significance of isolated anti-Ro/SSA 52 kd, anti-p200, anti-Ro/SSA 60 kd, and anti-La/SSB antibodies in positive pregnant patients. One hundred sixty-three pregnant women positive to anti-Ro/SSA 52 kd and/or anti-Ro/SSA 60 kd and/or anti-La/SSB antibodies were prospectively enrolled in the study. Anti-Ro52, anti-Ro60, anti-p200, and anti-La antibodies were assayed using home-made ELISA assays. Isolated antibody positivity was found in 25 women (15.3%), while multiple antibody positivity in 138 (84.7%). Twenty-four developed CHB, and the 139 had a favorable pregnancy outcome. The prevalence of isolated anti-Ro/SSA 60 kd antibodies was significantly higher (p < 0.046) as the prevalence of lower mean antibody titers (p < 0.0001) in the later group. Confirmation of these results by large-scale studies could lead clinicians to recommend less stringent fetal echocardiography monitoring in women with isolated anti-Ro/SSA 60 kd antibodies.
Assuntos
Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Bloqueio Cardíaco/congênito , Complicações Cardiovasculares na Gravidez , Adulto , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/epidemiologia , Bloqueio Cardíaco/imunologia , Humanos , Incidência , Recém-Nascido , Itália/epidemiologia , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND: Myxedema coma (MC), a medical emergency defined as severe hypothyroidism leading to altered mental status, is more common in older women with hypothyroidism. METHODS/RESULTS: A 7-year-old Caucasian male with chromosome 1q deletion presented with altered mental status preceded by milestone regression. His presenting labs results were: thyroid-stimulating hormone (TSH) 0.501 µIU/ml and free thyroxine (T4) <0.5 ng/dl. His morning cortisol level was 8.1 µg/dl with repeat testing, while TSH was 1.119 µIU/ml and free T4 was 0.5 ng/dl. Low-dose cosyntropin test showed baseline and peak cortisol levels of 1.9 and 16 µg/dl, respectively. Aside from altered mental status, heart block was present in addition to hypothermia and hypercarbia. Diffuse cerebral cortical and corpus callosum atrophy were seen on MRI. An intravenous (i.v.) stress dose of hydrocortisone was administered for 24 h prior to an i.v. loading dose of levothyroxine. His activity level subsequently returned to baseline within 48 h after treatment had been initiated. CONCLUSION: Though MC is rare, occurring mainly with noncompliance in primary hypothyroidism, it may occur at the diagnosis of secondary hypothyroidism. Based on features like hypothermia, hypoventilation, and cardiovascular instability occurring in the setting of central hypothyroidism, it should be suspected and managed urgently in order to avert the associated high mortality resulting from treatment delays.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Hipotireoidismo Congênito , Transtornos Mentais , Agenesia do Corpo Caloso/sangue , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Córtex Cerebral/anormalidades , Criança , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , Corpo Caloso/patologia , Cortisona/administração & dosagem , Cortisona/sangue , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/genética , Bloqueio Cardíaco/patologia , Humanos , Hipotermia/sangue , Hipotermia/genética , Hipotermia/patologia , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/genética , Transtornos Mentais/patologia , Tireotropina/sangue , Tiroxina/sangueRESUMO
BACKGROUND: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. AIMS: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. METHODS AND RESULTS: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and alphaB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. CONCLUSIONS: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.
Assuntos
Cardiomiopatia Restritiva/genética , Desmina/genética , Bloqueio Cardíaco/genética , Adolescente , Adulto , Anticorpos/metabolismo , Biópsia , Cardiomiopatia Restritiva/sangue , Análise Mutacional de DNA , Desmina/sangue , Desmina/imunologia , Endocárdio/patologia , Feminino , Bloqueio Cardíaco/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miocárdio/metabolismo , Miocárdio/patologia , Linhagem , Fenótipo , Análise de Sequência , Cadeia B de alfa-Cristalina/genéticaRESUMO
BACKGROUND: It is a widely held view that congenital heart block (CHB) is caused by the transplacental transfer of maternal autoantibodies (anti-SSA/Ro and/or anti-SSB/La) into the fetal circulation. To test this hypothesis and to reproduce human CHB, an experimental mouse model (BALB/c) was developed by passive transfer of human autoantibodies into pregnant mice. METHODS AND RESULTS: Timed pregnant mice (n=54) were injected with a single intravenous bolus of purified IgG containing human anti-SSA/Ro and anti-SSB/La antibodies from mothers of children with CHB. To parallel the "window period" of susceptibility to CHB in humans, 3 groups of mice were used: 8, 11, and 16 days of gestation. Within each group, we tested 10, 25, 50, and 100 microg of IgG. At delivery, ECGs were recorded and analyzed for conduction abnormalities. Bradycardia and PR interval were significantly increased in 8-, 11-, and 16-day gestational groups when compared with controls (P<0.05). QRS duration was not significantly different between all groups. Antibody levels measured by ELISA in both mothers and their offspring confirmed the transplacental transfer of the human antibodies to the pups. CONCLUSIONS: The passive transfer model demonstrated bradycardia, first-degree but not complete atrioventricular block in pups. The greater percentage and degree of bradycardia and PR prolongation in the 11-day mouse group correlates with the "window period" of susceptibility observed in humans. The high incidence of bradycardia suggests possible sinoatrial node involvement. All together, these data provide relevant insights into the pathogenesis of CHB.
Assuntos
Animais Recém-Nascidos/fisiologia , Eletrocardiografia , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/congênito , Coração/fisiopatologia , Imunoglobulina G/fisiologia , Prenhez/fisiologia , Animais , Animais Recém-Nascidos/imunologia , Anticorpos Antinucleares/análise , Anticorpos Antinucleares/fisiologia , Bradicardia/etiologia , Bradicardia/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Feminino , Bloqueio Cardíaco/genética , Humanos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , Mães , GravidezRESUMO
OBJECTIVES: We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and protein expression. BACKGROUND: It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects. METHODS: The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal controls included eight heart donor biopsies for tissue studies and 107 subjects for LMNA gene studies. RESULTS: Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at 1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with AVB (5/15: 33%). The LMNA expression of the myocyte nuclei was reduced or absent. Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes. None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls. CONCLUSIONS: The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation.
Assuntos
Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Genes Dominantes/genética , Bloqueio Cardíaco/complicações , Bloqueio Cardíaco/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Fatores Etários , Idoso , Cardiomiopatia Dilatada/sangue , Criança , Proteção da Criança , Pré-Escolar , Creatina Quinase/sangue , Creatina Quinase/genética , Saúde da Família , Feminino , Seguimentos , Bloqueio Cardíaco/sangue , Humanos , Lamina Tipo A , Laminas , Masculino , Pessoa de Meia-Idade , Mutação/genética , Miocárdio/citologia , Miocárdio/patologia , Linhagem , Fenótipo , Polimorfismo Genético/genética , Valor Preditivo dos Testes , PrevalênciaRESUMO
To elucidate the genesis and effect of fascicular block, 131 patients with acute Q-wave anteroseptal infarction were studied. Thirty-seven patients had new onset of fascicular block in the coronary care unit. The hospital mortality rate was 16%. Multivariate analysis was performed to determine the important variables related to the occurrence of fascicular block and hospital mortality based on 17 clinical variables obtained at the time of hospital admission. Serum potassium level and heart rate were the significant factors predicting the occurrence of fascicular block, whereas cardiac output and arterial oxygen tension were important for hospital mortality. Therefore, not only the rise in the heart rate but also the effect of the serum potassium level on the conduction system are independent factors related to the occurrence of fascicular block, and fascicular block in itself has no significant influence on the hospital mortality.
Assuntos
Bloqueio Cardíaco/etiologia , Infarto do Miocárdio/complicações , Idoso , Arritmias Cardíacas/etiologia , Fibrilação Atrial/etiologia , Cateterismo de Swan-Ganz , Eletrocardiografia , Feminino , Bloqueio Cardíaco/sangue , Bloqueio Cardíaco/fisiopatologia , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Infarto do Miocárdio/sangue , Potássio/sangueRESUMO
We describe three elderly patients with Brugada-type electrocardiographic abnormalities unmasked by a high plasma concentration of the Class IC antiarrhythmic drug pilsicainide, caused by renal dysfunction. The electrocardiograms showed right bundle branch block pattern and ST segment elevation in the precordial leads in patients 1 and 2, and a polymorphic wide QRS wave in patient 3. The serum concentrations of pilsicainide were 2.85, 2.50, and 4.18 microg/ml, which were much higher than the therapeutic range (0.16-0.24 microg/ml). Withdrawal of the drug reversed the electrocardiographic changes. Careful observation is necessary to avoid life-threatening arrhythmias whenever pilsicainide is administered to elderly patients.
Assuntos
Antiarrítmicos/uso terapêutico , Eletrocardiografia , Falência Renal Crônica/complicações , Lidocaína/análogos & derivados , Lidocaína/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/sangue , Bloqueio Cardíaco/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/fisiopatologia , Lidocaína/sangue , MasculinoRESUMO
A 76-year-old woman was referred to our hospital for unresponsiveness and hypotension. She had developed constipation that had led to ileus and had received 34 g of magnesium citrate (Magcolol P) orally the day before. She was lethargic, her blood pressure was less than 50 mmHg, and electrocardiogram (ECG) revealed sinus arrest with junctional escape rhythm. Her serum concentration of magnesium (Mg) was markedly elevated (16.6 mg/dl =13.7 mEq/l). Emergency colonoscopy revealed ischemic colitis. As her condition ameliorated, her renal function returned to normal. Hence, the present case suggests that severe hypermagnesemia can occur in the absence of pre-existing renal dysfunction in elderly patients with gastrointestinal diseases.