RESUMO
Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leucocyte antigen (HLA) loci have also been reported to be associated with KD, but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 White patients with KD and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I = 97.5%, class II = 96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C*15 (z = +2.19, P = 0.03) and under-transmission of HLA-B*44 (z = -2.49, P = 0.01) alleles from parents to patients with KD. HLA-B*44 has been associated with KD in other smaller studies, and both HLA-C*15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family-based information is a powerful approach. However, studies with larger sample sizes are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Síndrome de Linfonodos Mucocutâneos/genética , Polimorfismo de Nucleotídeo Único , Alelos , Família , Feminino , Frequência do Gene , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/imunologiaRESUMO
Kawasaki disease (KD) is a diffuse and acute small-vessel vasculitis observed in children, and has genetic and autoimmune components. We genotyped 112 case-parent trios of European decent (confirmed by ancestry informative markers) using the immunoChip array, and performed association analyses with susceptibility to KD and intravenous immunoglobulin (IVIG) non-response. KD susceptibility was assessed using the transmission disequilibrium test, whereas IVIG non-response was evaluated using multivariable logistic regression analysis. We replicated single-nucleotide polymorphisms (SNPs) in three gene regions (FCGR, CD40/CDH22 and HLA-DQB2/HLA-DOB) that have been previously associated with KD and provide support to other findings of several novel SNPs in genes with a potential pathway in KD pathogenesis. SNP rs838143 in the 3'-untranslated region of the FUT1 gene (2.7 × 10(-5)) and rs9847915 in the intergenic region of LOC730109 | BRD7P2 (6.81 × 10(-7)) were the top hits for KD susceptibility in additive and dominant models, respectively. The top hits for IVIG responsiveness were rs1200332 in the intergenic region of BAZ1A | C14orf19 (1.4 × 10(-4)) and rs4889606 in the intron of the STX1B gene (6.95 × 10(-5)) in additive and dominant models, respectively. Our study suggests that genes and biological pathways involved in autoimmune diseases have an important role in the pathogenesis of KD and IVIG response mechanism.
Assuntos
Predisposição Genética para Doença/genética , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/genética , Regiões 3' não Traduzidas/genética , Criança , Pré-Escolar , Feminino , Fucosiltransferases/genética , Predisposição Genética para Doença/etnologia , Genótipo , Técnicas de Genotipagem/métodos , Humanos , Lactente , Íntrons/genética , Modelos Logísticos , Masculino , Síndrome de Linfonodos Mucocutâneos/etnologia , Análise Multivariada , Núcleo Familiar , Polimorfismo de Nucleotídeo Único , Sintaxina 1/genética , Resultado do Tratamento , Estados Unidos , População Branca/genética , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
This study examines adaptations in myocardial cytosolic phosphate content and buffering capacity that occur in vivo as a function of development. Phosphate metabolites were monitored in an open chest sheep preparation using a 31P magnetic resonance surface coil over the left ventricle. Newborn lambs (aged 4-9 d, n = 5) underwent exchange transfusion with adult blood to reduce blood-borne 2,3-diphosphoglycerate contamination of the heart monophosphate and phosphomonoester resonances, thus allowing determination of these phosphate concentrations. The blood-exchanged newborns and mature controls (aged 30-60 d, n = 5) were infused with 0.4 N hydrochloric acid to decrease pH from greater than 7.35 to less than 7.00. Simultaneously, intracellular and extracellular pH were determined from the chemical shifts of the respective phosphate peaks and compared to arterial blood pH. Findings were as follows: (a) diphosphoglycerate contribution to the cardiac spectrum was found to be negligible, (b) significant decreases in cytosolic phosphate (P less than 0.03) and phosphomonoester (P less than 0.01) content occurred with maturation, and (c) large decreases in extracellular pH (greater than 0.5 U) in both groups were similarly associated with only small changes in intracellular pH (less than 0.1 U). Change in cytosolic phosphate content implies that alterations occur in the phosphorylation potential with resulting effects on regulation of myocardial respiration, and cardiac energetics.
Assuntos
Concentração de Íons de Hidrogênio , Miocárdio/metabolismo , Fosfatos/metabolismo , 2,3-Difosfoglicerato , Equilíbrio Ácido-Base , Acidose/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos/metabolismo , Transfusão de Sangue , Citosol/metabolismo , Ácidos Difosfoglicéricos/metabolismo , Hemodinâmica , Espectroscopia de Ressonância Magnética , OvinosRESUMO
This study examines the role of phosphate metabolites in the regulation of mitochondrial oxygen consumption of the heart in vivo as a function of development. We used an open chest lamb/sheep preparation in which myocardial oxygen consumption (MVO2) was monitored via an extracorporeal shunt from the coronary sinus. Phosphate metabolites were monitored simultaneously using 31P nuclear magnetic resonance with a surface coil overlying the left ventricle. Graded infusions of epinephrine were used to increase MVO2 in both neonatal lambs (age 5-12 d, n = 8), and mature sheep (26-86 d, n = 6). The maximal increase in MVO2 achieved was 220 +/- 38% in the newborns and 350 +/- 66% in the mature animals. Associated with these increases in MVO2 in the newborn lambs are significant (P less than 0.001) decreases in PCr/ATP, and increases in calculated ADP and intracellular Pi. This was in contrast to the mature sheep, in which there were no significant changes in PCr/ATP, ADP, or Pi. In conclusion, we find that (a) there are changes in PCr/ATP, Pi, and ADP in newborn animals with moderate increases in work that are not apparent in mature animals of the same species and (b) that these changes suggest that cytosolic ATP hydrolysis products may be more important in regulation of myocardial energy metabolism in the newborn than in the adult.
Assuntos
Miocárdio/metabolismo , Consumo de Oxigênio , Fosfatos/metabolismo , Trifosfato de Adenosina/metabolismo , Envelhecimento , Animais , Animais Recém-Nascidos , Epinefrina/farmacologia , Coração/efeitos dos fármacos , Fosfocreatina/metabolismo , OvinosRESUMO
This study investigates the relation between myocardial oxygen consumption (MVO2), function, and high energy phosphates during severe hypoxia and reoxygenation in sheep in vivo. Graded hypoxia was performed in open-chested sheep to adjust PO2 to values where rapid depletion of energy stores occurred. Highly time-resolved 31P nuclear magnetic resonance spectroscopy enabled monitoring of myocardial phosphates throughout hypoxia and recovery with simultaneous MVO2 measurement. Sheep undergoing graded hypoxia (n = 5) with an arterial PO2 nadir of 13.4 +/- 0.5 mmHg, demonstrated maintained rates of oxygen consumption with large changes in coronary flow as phosphocreatine (PCr) decreased within 4 min to 40 +/- 7% of baseline. ATP utilization rate increased simultaneously 59 +/- 20%. Recovery was accompanied by marked increases in MVO2 from 2.0 +/- 0.5 to 7.2 +/- 1.9 mumol/g per min, while PCr recovery rate was 4.3 +/- 0.6 mumol/g per min. ATP decreased to 75 +/- 6% of baseline during severe hypoxia and did not recover. Sheep (n = 5) which underwent moderate hypoxia (PO2 maintained 25-35 mmHg for 10 min) did not demonstrate change in PCr or ATP. Functional and work assessment (n = 4) revealed that cardiac power increased during the graded hypoxia and was maintained through early reoxygenation. These studies show that (a) MVO2 does not decrease during oxygen deprivation in vivo despite marked and rapid decreases in high energy phosphates; (b) contractile function during hypoxia in vivo does not decrease during periods of PCr depletion and intracellular phosphate accumulation, and this may be related to marked increases in circulating catecholamines during global hypoxia. The measured creatine rephosphorylation rate is 34 +/- 11% of predicted (P < 0.01) calculated from reoxygenation parameters, which indicates that some mitochondrial respiratory uncoupling also occurs during the rephosphorylation period.
Assuntos
Trifosfato de Adenosina/metabolismo , Metabolismo Energético , Hemodinâmica , Hipóxia/metabolismo , Miocárdio/metabolismo , Consumo de Oxigênio , Fosfocreatina/metabolismo , Animais , Pressão Sanguínea , Débito Cardíaco , Circulação Coronária , Dopamina/sangue , Epinefrina/sangue , Frequência Cardíaca , Concentração de Íons de Hidrogênio , Lactatos/metabolismo , Espectroscopia de Ressonância Magnética , Norepinefrina/sangue , Oxigênio/sangue , Pressão Parcial , Fósforo , Ovinos , Função Ventricular EsquerdaRESUMO
Unidirectional myocardial ATP synthesis, P(i)-->ATP flux, was studied in vivo using 31P magnetization transfer techniques in intact sheep hearts (n = 5) which were functioning aerobically. Myocardial oxygen consumption (MVO) expressed as mu moles of oxygen atoms/gm/min was estimated using linear regression analysis of data derived from sheep (n = 23), which had undergone continuous MVO measurement during graded stepups in epinephrine induced work loads. During the saturation transfer experiment, epinephrine, beginning at 1 microgram/kg per min was infused to achieve a higher steady-state work load and level of MVO. The unidirectional P(i)-->ATP flux was found to increase significantly (P < 0.05) during increases in rate pressure product and MVO. These data show that the unidirectional P(i)-->ATP flux is at least 3-times higher than the peak ATP synthesis rate, achieved through oxidative phosphorylation in these experiments, and more than a magnitude higher than the peak ATP synthesis rate through glycolysis. Therefore, forward P(i)-->ATP flux through glycolysis is the major contributor to the measured P(i)-->ATP flux and these ATP producing bidirectional glycolytic reactions are in a near equilibrium state. Furthermore, delta P(i)-->ATP/delta MVO, 2.70 +/- 0.29 (S.E.) elicited during epinephrine infusion is similar to classically derived P:O values, indicating that most of the change in unidirectional flux is due to oxidative phosphorylation and that minimal disturbance in the glycolytic near equilibrium occurs under these conditions.
Assuntos
Trifosfato de Adenosina/metabolismo , Miocárdio/metabolismo , Fosfatos/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Glicólise , Hemodinâmica , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Consumo de Oxigênio , OvinosRESUMO
BACKGROUND: The signal transduction mechanism linking mitochondrial ATP synthesis with cytosolic ATP utilization in heart changes during postnatal development in vivo. This maturational process occurs in parallel with accumulation of mitochondrial adenine nucleotide translocator (ANT), which provides a possible site for respiratory control. We postulated that thyroid hormone regulates these maturational processes. METHODS AND RESULTS: We used (31)P MR spectroscopy to determine the relationship between myocardial high-energy phosphates, phosphocreatine, and ADP and oxygen consumption (MVO(2)) during epinephrine stimulation in 32- to 40-day-old lambs thyroidectomized after birth (THY) and age-matched controls. Steady-state protein and mRNA levels for ANT isoforms and beta-F(1)-ATPase were assessed from left ventricular tissues by Western and Northern blotting. With greater doses of epinephrine, THY attained lower peak MVO(2) than controls (P:<0.05). Controls maintained high-energy phosphate levels, unlike THY, which demonstrated significantly decreased phosphocreatine/ATP and increased cytosolic ADP despite lower peak MVO(2). No significant differences in beta-F(1)-ATPase protein or mRNA occurred between groups. However, ANT isoform mRNA levels were 2-fold greater and protein levels 4-fold greater in control hearts. CONCLUSIONS: These data imply that the maturational shift away from ADP-mediated respiratory control is regulated by thyroid hormone in vivo. Specific thyroid-modulated increases in ANT mRNA and protein imply that this regulation occurs in part at a pretranslational level.
Assuntos
Animais Recém-Nascidos/fisiologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Miocárdio/metabolismo , Fenômenos Fisiológicos Respiratórios , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Difosfato de Adenosina/metabolismo , Animais , Northern Blotting , Western Blotting , Hemodinâmica , Concentração de Íons de Hidrogênio , Líquido Intracelular/enzimologia , Líquido Intracelular/metabolismo , Isoenzimas/metabolismo , Espectroscopia de Ressonância Magnética , Miocárdio/enzimologia , Consumo de Oxigênio , Fosfocreatina/metabolismo , ATPases Translocadoras de Prótons/metabolismo , RNA Mensageiro/metabolismo , Ovinos , Tireoidectomia , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
OBJECTIVES: We sought to prospectively determine the incidence and clinical significance of major coronary artery anomalies in asymptomatic children using transthoracic two-dimensional echocardiography. BACKGROUND: Anomalous origins of the left main coronary artery (ALMCA) from the right sinus of Valsalva or anomalous origins the right coronary artery (ARCA) from the left sinus are rarely diagnosed in children and can cause sudden death, especially in young athletes. Because most patients are asymptomatic, the diagnosis is often made post mortem. No study to date has prospectively identified anomalous coronary arteries in asymptomatic children in the general population. METHODS: After serendipitously identifying an index case with ALMCA, we examined proximal coronary artery anatomy in children with otherwise anatomically normal hearts who were referred for echocardiography. In those diagnosed with ALMCA or ARCA, we performed further tests. RESULTS: Within a three-year period, echocardiograms were obtained in 2,388 children and adolescents. Four children (0.17%) were identified with anomalous origin of their coronary arteries, and angiograms, exercise perfusion studies and/or stress tests were then performed. One ARCA patient had decreased perfusion in the right coronary artery (RCA) perfusion area and showed ventricular ectopy on electrocardiogram (ECG) at rest that diminished but did not resolve with exercise. A second patient with ALMCA had atrial tachycardia immediately after exercise, with inferior and lateral ischemic changes on ECG and frequent junctional and/or ventricular premature complexes both at rest and recovery. CONCLUSIONS: This study demonstrates that although anomalous origins of coronary arteries are rare in asymptomatic children, the prevalence is greater than that found in other prospective studies. Ischemia can occur with both ALMCA and ARCA even though patients remain asymptomatic. Because of the high risk of sudden cardiac death, aggressive surgical management and close follow-up are necessary.
Assuntos
Anomalias dos Vasos Coronários/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Angiografia Coronária , Anomalias dos Vasos Coronários/epidemiologia , Estudos Transversais , Ecocardiografia , Eletrocardiografia , Teste de Esforço , Feminino , Humanos , Lactente , Masculino , Washington/epidemiologiaRESUMO
OBJECTIVES: This study was conducted to test hypotheses stating that: 1) altered signaling for mitochondrial membrane proteins occurs during postinfarction remodeling, and 2) successful myocardial adaptation relates to promotion of specific mitochondrial membrane components. BACKGROUND: Abnormalities in high-energy phosphate content and limitations in adenosine 5'-triphosphate (ATP) synthesis rate occur during the transition to contractile failure from compensatory remodeling after left ventricular infarction. The adenine nucleotide translocator (ANT) and F1-ATPase respectively regulate mitochondrial adenosine 5'-diphosphate (ADP)/ATP exchange and ADP-phosphorylation, which are key components of high-energy phosphate metabolism. METHODS: Steady-state mRNA and protein expression for ANT isoform1 and the beta subunit of the F1-ATPase (betaF1) were analyzed in myocardium remote from the infarction zone eight weeks after left circumflex coronary artery ligation in pigs, demonstrating either successful left ventricular remodeling (LVR, n = 8) or congestive heart failure (CHF, n = 4) as determined by clinical and contractile performance parameters. RESULTS: Substantial reductions in steady-state mRNA expression for ANT1 and betaF1 relative to normal (n = 8) occur in CHF, p < 0.01, but not in LVR. Relative expression for both proteins coordinated with their respective steady-state mRNA levels; CHF at 40% normal, p < 0.05 for ANT and 70% normal for betaF1, p < 0.05. CONCLUSIONS: Maintained signaling for major mitochondrial membrane proteins occurs in association with successful remodeling and adaptation after infarction. Reduced expression of these proteins relates to limited ATP synthesis capacity and high energy phosphate kinetic abnormalities previously demonstrated in CHF. These findings imply that mitochondrial processes participate in myocardial remodeling after infarction.
Assuntos
Insuficiência Cardíaca/genética , Mitocôndrias Cardíacas/metabolismo , Translocases Mitocondriais de ADP e ATP/genética , ATPases Translocadoras de Prótons/genética , Transdução de Sinais , Remodelação Ventricular , Animais , Biomarcadores , Northern Blotting , Western Blotting , Progressão da Doença , Expressão Gênica , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Contração Miocárdica , ATPases Translocadoras de Prótons/metabolismo , RNA Mensageiro/biossíntese , SuínosRESUMO
A 14 month old boy with suprasystemic right ventricular pressure secondary to pulmonary valvular stenosis and anular size of 10 mm underwent percutaneous balloon valvuloplasty with a 12 mm balloon. Right ventricular pressure almost doubled after valvuloplasty and the electrocardiogram revealed development of severe right ventricular strain. Both findings persisted on the following day. A postvalvuloplasty right ventriculogram demonstrated a severe systolic infundibular obstruction not present before. The patient underwent surgical relief of infundibular obstruction; successful opening of the pulmonary valve by the balloon valvuloplasty was observed. It is concluded that a balloon size 20% larger than anular size can be safe in human subjects and that infundibular obstruction may appear or even worsen after balloon valvuloplasty. Such an obstruction may be related to the severity of pulmonary valvular obstruction and a hypercontractile infundibulum.
Assuntos
Angioplastia com Balão/efeitos adversos , Contração Miocárdica , Estenose da Valva Pulmonar/terapia , Constrição Patológica/etiologia , Constrição Patológica/terapia , Ventrículos do Coração/fisiopatologia , Humanos , Lactente , Masculino , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Estenose da Valva Pulmonar/fisiopatologiaRESUMO
UNLABELLED: The purpose of this study was to measure myocardial buffering capacity and adenosine triphosphate utilization rates in the newborn animal in vivo during hypothermic circulatory arrest and recovery. METHODS: These studies were performed with 31P magnetic resonance spectroscopic techniques, which supplied a 12- to 16-second time resolution, to monitor intracellular pH and phosphocreatine and adenosine triphosphate levels. All experiments were performed with a radiofrequency surface coil on the pericardium with the sheep centered inside a 4.7 T magnet. Newborn sheep (n = 5, aged 16 days +/- 2.4 standard error) were supported by cardiopulmonary bypass, cooled to 20 degrees C, and subjected to 20 minutes of circulatory arrest. RESULTS: During early ischemia, phosphocreatine hydrolysis progressed at a linear rate, 1.2 +/- 0.05 mumol/gm per minute, and was accompanied by intracellular alkalinization. Myocardial buffering capacity calculated from delta pH/delta phosphocreatine equals 25 +/- 3 mueq gm-1 delta pH-1, a value similar to that obtained from perfused heart studies. After the initial 4 minutes in ischemia, the decrease in phosphocreatine hydrolysis was accompanied by intracellular acidification, which is likely due to late induction of anaerobic metabolism. CONCLUSIONS: In these studies, early phosphocreatine hydrolysis rate is nearly equivalent to adenosine triphosphate utilization rate. During the early period of ischemia phosphocreatine hydrolysis serves a buffering function and is associated with intracellular alkalinization. These techniques and measurements can be used to compare effects of myocardial preservation techniques on intracellular pH and adenosine triphosphate kinetics.
Assuntos
Trifosfato de Adenosina/metabolismo , Parada Cardíaca Induzida , Hipotermia Induzida , Miocárdio/metabolismo , Animais , Animais Recém-Nascidos , Glicólise , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , OvinosRESUMO
OBJECTIVE: Cardiopulmonary bypass suppresses circulating thyroid hormone levels. Although acute triiodothyronine repletion has been evaluated in adult patients after cardiopulmonary bypass, triiodothyronine pharmacokinetics and effects have not previously been studied in infants undergoing operations for congenital heart disease. We hypothesized that triiodothyronine deficiency in the developing heart after bypass may adversely affect cardiac function reserve postoperatively. METHODS: Infants less than 1 year old undergoing ventricular septal defect or tetralogy of Fallot repair were randomized into 2 groups. Group T (n = 7) received triiodothyronine (0.4 microg/kg) immediately before the start of cardiopulmonary bypass and again with myocardial reperfusion. Control (NT, n = 7) patients received saline solution placebo or no treatment. RESULTS: These groups underwent similar ischemic and bypass times and received similar quantities of inotropic agents after the operation. The NT group demonstrated significant depression in circulating levels, compared with prebypass levels, for free triiodothyronine and total triiodothyronine at 1, 24, and 72 hours after bypass. Group T demonstrated similar low thyroxine values, but free and total triiodothyronine levels were maintained at prebypass levels for 24 hours and remained elevated over those of group NT (P <.05) at 72 hours. Heart rate was transiently elevated in group T compared with group NT (P <.05), and peak systolic pressure-rate product increased after 6 hours. CONCLUSION: These data imply that (1) triiodothyronine in the prescribed dose prevents circulating triiodothyronine deficiencies and (2) triiodothyronine repletion promotes elevation in heart rate without concomitant decrease in systemic blood pressure. Elevation of peak systolic pressure-rate product implies that triiodothyronine repletion improves myocardial oxygen consumption and may enhance cardiac function reserve after cardiopulmonary bypass in infants.
Assuntos
Ponte Cardiopulmonar , Cardiopatias Congênitas/cirurgia , Tri-Iodotironina/metabolismo , Comunicação Interventricular/cirurgia , Hemodinâmica , Humanos , Lactente , Estudos Prospectivos , Tetralogia de Fallot/cirurgia , Tri-Iodotironina/uso terapêuticoRESUMO
OBJECTIVES: The pH of cardioplegic solutions is postulated to affect myocardial protection during neonatal hypothermic circulatory arrest. Neither optimization of cardioplegic pH nor its influence on intracellular pH during hypothermic circulatory arrest has been previously studied in vivo. Thus we examined the effects of the pH of cardioplegic solutions on postischemic cardiac function in vivo, including two possible operative mechanisms: (1) reduction in adenosine triphosphate use and depletion of high-energy phosphate stores or (2) reduction of H+ flux during reperfusion, or both. METHODS: Dynamic 31P spectroscopy was used to measure rates of adenosine triphosphate use, high-energy phosphate depletion, cytosolic acidification during hypothermic circulatory arrest, and phosphocreatine repletion and realkalinization during reperfusion. Neonatal pigs in three groups (n = 8 each)--group A, acidic cardioplegia (pH = 6.8); group B, basic cardioplegia (pH = 7.8); and group N, no cardioplegia--underwent hypothermia at 20 degrees C with 60 minutes of hypothermic cardioplegia followed by reperfusion. RESULTS: Recoveries of peak elastance, stroke work, and diastolic stiffness were superior in group B. Indices of ischemic adenosine triphosphate use, initial phosphocreatine depletion rate, and tau, the exponential decay half-time, were not different among groups. Peak [H+] in group A (end-ischemia) was significantly elevated over that of group B. The realkalinization rate was reduced in group B compared with that in groups A (p = 0.015) and N (p = 0.035), with no difference between groups A and N (p = 0.3). Cytosolic realkalinization rate was markedly reduced and the half-time of [H+] decay was increased during reperfusion in group B. CONCLUSIONS: Superior postischemic cardiac function in group B is not related to alterations in ischemic adenosine triphosphate use or high-energy store depletion, but may be due to slowing in H+ efflux during reperfusion, which should reduce Ca++ and Na+ influx.
Assuntos
Soluções Cardioplégicas/química , Parada Cardíaca Induzida , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Soluções Cardioplégicas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Hipotermia Induzida , Canais Iônicos/metabolismo , Espectroscopia de Ressonância Magnética , Traumatismo por Reperfusão Miocárdica/metabolismo , Fosfocreatina/metabolismo , SuínosRESUMO
Two-dimensional phase contrast magnetic resonance angiography (MRA) was used to image alterations in cranial blood flow induced by changes in arterial PCO2 in an animal model. MRA was performed on five sheep; 64 acquisitions were obtained in each of three flow encode directions using a 256 x 256 matrix. Sheep were intubated and ventilated with oxygen and 1.5% halothane to prevent any movement. Femoral arterial cannulation was performed to monitor arterial blood gases and pressure. The sheep was secured in a cradle with its head and neck in a 6-inch imaging coil within the 26-cm-clear bore. Images were obtained during separate physiologic states, which were induced by changes in ventilatory parameters. These were normocapnia (PCO2 35-45 mm Hg), hypercapnia (greater than 90-130 mm Hg), and hypercapnia with superimposed hypoxia. Comparisons of images were performed using both a video flashback mode and image subtraction. The authors noted that 1) both venous and arterial flow velocity qualitatively increased during hypercapnia; 2) in addition to change in the caliber of blood vessels, redistribution of blood flow within the cranium could be demonstrated during the PCO2 changes; and 3) blood was directed away from superficial structures and toward the brain during superimposed hypoxia. MRA, previously used to show steady-state cranial flow also can demonstrate flow responses to physiologic stimuli.
Assuntos
Dióxido de Carbono/sangue , Circulação Cerebrovascular/fisiologia , Imageamento por Ressonância Magnética , Animais , Pressão Parcial , OvinosRESUMO
Studies were performed to determine the pH relationships among the extracellular, intracellular, and arterial blood compartments in the brain in vivo. Resolution of the extracellular monophosphate resonance peak from the intracellular peak in 31P nuclear magnetic resonance (NMR) spectra of sheep brain with the calvarium intact enabled pH measurement in these respective compartments. Sheep were then subjected to both hyper- and hypoventilation, which resulted in a wide range of arterial PCO2 and pH values. Linear regression analysis of pH in these compartments yielded slopes of 0.56 +/- 0.05 for extracellular pH (pHe) vs. arterial pH, 0.43 +/- 0.078 for intracellular pH (pHi) vs. pHe, and 0.23 +/- 0.056 for pHi vs. arterial pH. These data indicate that CO2 buffering capacity is different and decreases from the intracellular to extracellular to arterial blood compartments. Separation of the extracellular space from the vascular space may be a function of the blood-brain barrier, which contributes to the buffering capability of the extracellular compartment. A marked decrease in the pH gradient between the extracellular and intracellular space occurs during hypercarbia and may influence mechanisms of central respiratory control.
Assuntos
Encéfalo/metabolismo , Hipercapnia/metabolismo , Hipocapnia/metabolismo , Animais , Espaço Extracelular/metabolismo , Concentração de Íons de Hidrogênio , Líquido Intracelular/metabolismo , Espectroscopia de Ressonância Magnética , OvinosRESUMO
Since 1983 we have performed electrophysiologic studies in 6 patients who had previously undergone repair of an ostium primum atrioventricular septal defect. Information obtained during electrophysiologic studies was crucial in guiding appropriate pacemaker therapy in these patients. As judged from the resting electrocardiogram, sinus or junctional bradycardia was present in 3/6, atrial flutter / fibrillation in 2/6, and paced rhythm in 2 patients who had had ventricular pacemakers implanted for complete atrioventricular block. During maximal exercise testing 4 patients had reduced heart rates; 2 had sudden drops in heart rate at 1 min postexercise; 1 patient had exercise induced ventricular bigeminy; and 1 patient with atrial flutter and 2: 1-4: 1 block at rest developed 1: 1 conduction during Stage II with an effective ventricular rate of 220/min. During electrophysiologic studies, the maximum corrected sinus node recovery time was abnormal in five of the six, ranging from 410 to 5630 msec. There was no spontaneous atrial rhythm in the other patient. Complete atrioventricular block was present in 2 patients while the atrioventricular Wenckebach phenomenon occurred abnormally at atrial pacing cycle lengths greater than 450 msec in 2 others. Supraventricular tachycardia or atrial flutter/fibrillation, was either spontaneous or induced in 2/6 patients, while ventricular tachycardia was induced in 1/3 patients who underwent programmed ventricular stimulation. Electrophysiologic studies were important in unmasking severe sinus node disease in 3 patients and atrioventricular node disease in 2. We therefore recommend that electrophysiologic studies be strongly considered as part of the evaluation of conduction abnormalities following repair of ostium primum atrioventricular septal defect.
Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Defeitos dos Septos Cardíacos/fisiopatologia , Adolescente , Adulto , Arritmias Cardíacas/etiologia , Nó Atrioventricular/fisiopatologia , Estimulação Cardíaca Artificial , Criança , Pré-Escolar , Eletrocardiografia , Defeitos dos Septos Cardíacos/cirurgia , Humanos , Complicações Pós-Operatórias , Taquicardia/fisiopatologiaRESUMO
At the current state of the art, cardiothoracic MR angiography offers the clinician information that is supplemental to that provided by other noninvasive imaging techniques. Indeed, in some areas MR angiography will likely surpass currently used methods as the technique of choice. Specifically, measurement of cardiac output, pulmonary blood flow, and lung perfusion can be performed relatively accurately and simply during a brief MR examination. Both standard spin-echo and angiographic evaluation of the thoracic aorta provide qualitative images with superior resolution. Additionally, development of pulmonary artery angiography is progressing rapidly and may soon be clinically useful. Phase incoherence caused by complex flow and resulting in a signal void is useful for location and qualitative assessment of abnormal flow jets induced by stenoses. However, this phenomenon represents the major limitation to quantitative assessment of flow abnormalities. Methods to increase signal to noise and/or reduce phase incoherence must be developed before MR angiography can be used effectively to assess abnormal flow conditions.
Assuntos
Doenças Cardiovasculares/diagnóstico , Vasos Coronários/patologia , Imageamento por Ressonância Magnética/métodos , Artéria Pulmonar/patologia , Humanos , Aumento da Imagem/métodosRESUMO
We quantified high-energy phosphate metabolites in hypertensive hypertrophied and normal myocardium and monitored temporal changes using the non-invasive 31P nuclear magnetic resonance (NMR) spectroscopy. Hearts from 18 month spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) were perfused with a phosphate-free buffer at 10 cc/min per g and paced at 240 beats/min on a modified Langendorff apparatus. Perfusion pressure, left ventricular pressure (LVP) and dP/dt were recorded and successive 31P NMR spectra were collected during a 24-min baseline period (oxygenated buffer), anoxia (N2-bubbled and glucose-free buffer) until a 70% fall in LVP occurred, and recovery. An aminomethylphosphonate standard, located within the LVP balloon, permitted absolute quantification of myocardial phosphate moieties (including inorganic phosphate (Pi), creatine phosphate (CP) and ATP). During perfusion, SHR hearts demonstrated higher coronary resistance but no significant differences in LVP or dP/dt. Spontaneously hypertensive rat hearts had lower CP, ATP and CP/Pi ratio and showed a faster fall in cardiac function during anoxia, associated with parallel rates of changes in the phosphate moieties.
Assuntos
Metabolismo Energético , Hipertensão/metabolismo , Animais , Coração/fisiopatologia , Hipóxia/fisiopatologia , Espectroscopia de Ressonância Magnética , Masculino , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Fósforo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYAssuntos
Relógios Biológicos/fisiologia , Ritmo Circadiano/fisiologia , Proteínas de Drosophila , Proteínas do Olho , Regulação da Expressão Gênica/fisiologia , Coração/fisiologia , Células Fotorreceptoras de Invertebrados , Fatores de Transcrição ARNTL , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Proteínas CLOCK , Cardiomegalia/fisiopatologia , Proteínas de Ciclo Celular , Criptocromos , Drosophila , Retroalimentação Fisiológica/fisiologia , Flavoproteínas/genética , Flavoproteínas/metabolismo , Camundongos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , NAD/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Circadianas Period , Ratos , Receptores Acoplados a Proteínas G , Transativadores/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The role of creatine kinase in regulation of myocardial respiration was studied in vivo as a function of maturation. Unidirectional creatine kinase flux (JCK), phosphocreatine to gamma-ATP, was measured in newborn lambs (age 3-9 days, n = 8) and mature sheep (age 30-60 days, n = 6) using 31P saturation transfer techniques, and total creatine kinase activity was measured using standard methods. Myocardial oxygen consumption (MVO2) was measured simultaneously via an extracorporeal shunt from the coronary sinus as cardiac work was increased via epinephrine (1-3 micrograms.kg-1.min-1). Findings were as follows: 1) baseline newborn JCK was markedly lower than in mature sheep despite higher levels of MVO2, and this could be related to a decrease in total creatine kinase activity; 2) JCK was substantially higher than the rate of ATP synthesis in both groups at baseline rates of oxygen consumption; and 3) JCK decreased significantly in newborns during increases in MVO2, whereas there was no change in flux rate in the mature sheep during even larger relative changes in work and oxygen consumption. These data imply that creatine kinase does not limit oxidative phosphorylation. However, this enzyme system probably maintains at least an indirect role in respiratory control that is a function of the myocardial developmental state.