RESUMO
Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.
Assuntos
Relógios Circadianos , Insuficiência Cardíaca , Animais , Humanos , Ritmo Circadiano , Coração , Insuficiência Cardíaca/terapia , Biologia , Relógios Circadianos/fisiologiaRESUMO
The temporal dynamics in biological systems displays a wide range of behaviors, from periodic oscillations, as in rhythms, bursts, long-range (fractal) correlations, chaotic dynamics up to brown and white noise. Herein, we propose a comprehensive analytical strategy for identifying, representing, and analyzing biological time series, focusing on two strongly linked dynamics: periodic (oscillatory) rhythms and chaos. Understanding the underlying temporal dynamics of a system is of fundamental importance; however, it presents methodological challenges due to intrinsic characteristics, among them the presence of noise or trends, and distinct dynamics at different time scales given by molecular, dcellular, organ, and organism levels of organization. For example, in locomotion circadian and ultradian rhythms coexist with fractal dynamics at faster time scales. We propose and describe the use of a combined approach employing different analytical methodologies to synergize their strengths and mitigate their weaknesses. Specifically, we describe advantages and caveats to consider for applying probability distribution, autocorrelation analysis, phase space reconstruction, Lyapunov exponent estimation as well as different analyses such as harmonic, namely, power spectrum; continuous wavelet transforms; synchrosqueezing transform; and wavelet coherence. Computational harmonic analysis is proposed as an analytical framework for using different types of wavelet analyses. We show that when the correct wavelet analysis is applied, the complexity in the statistical properties, including temporal scales, present in time series of signals, can be unveiled and modeled. Our chapter showcase two specific examples where an in-depth analysis of rhythms and chaos is performed: (1) locomotor and food intake rhythms over a 42-day period of mice subjected to different feeding regimes; and (2) chaotic calcium dynamics in a computational model of mitochondrial function.
Assuntos
Locomoção , Análise de Ondaletas , Animais , Biologia , Fractais , CamundongosRESUMO
OBJECTIVE: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes (Clock, Bmal1) and genes involved in lipid metabolism (Pgc1a, Pparg, Ucp2) through nutrient-sensing pathways (Sirt1, Ampk, Nampt) in peripheral tissues. METHODS: Rats were grouped according to food access: Control group (CG, food ad libitum), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. RESULTS: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a, Pparg, and Ucp2 but not Ampk and Nampt. CONCLUSION: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.
Assuntos
Hipotálamo , Fígado , Animais , Ritmo Circadiano , Metabolismo dos Lipídeos , Fígado/metabolismo , Nutrientes , RatosRESUMO
In animals, circadian clocks impose a daily rhythmicity to many behaviors and physiological processes. At the molecular level, circadian rhythms are driven by intracellular transcriptional/translational feedback loops (TTFL). Interestingly, emerging evidence indicates that they can also be modulated by multiple signaling pathways. Among these, Ca2+ signaling plays a key role in regulating the molecular rhythms of clock genes and of the resulting circadian behavior. In addition, the application of in vivo imaging approaches has revealed that Ca2+ is fundamental to the synchronization of the neuronal networks that make up circadian pacemakers. Conversely, the activity of circadian clocks may influence Ca2+ signaling. For instance, several genes that encode Ca2+ channels and Ca2+-binding proteins display a rhythmic expression, and a disruption of this cycling affects circadian function, underscoring their reciprocal relationship. Here, we review recent advances in our understanding of how Ca2+ signaling both modulates and is modulated by circadian clocks, focusing on the regulatory mechanisms described in Drosophila and mice. In particular, we examine findings related to the oscillations in intracellular Ca2+ levels in circadian pacemakers and how they are regulated by canonical clock genes, neuropeptides, and light stimuli. In addition, we discuss how Ca2+ rhythms and their associated signaling pathways modulate clock gene expression at the transcriptional and post-translational levels. We also review evidence based on transcriptomic analyzes that suggests that mammalian Ca2+ channels and transporters (e.g., ryanodine receptor, ip3r, serca, L- and T-type Ca2+ channels) as well as Ca2+-binding proteins (e.g., camk, cask, and calcineurin) show rhythmic expression in the central brain clock and in peripheral tissues such as the heart and skeletal muscles. Finally, we discuss how the discovery that Ca2+ signaling is regulated by the circadian clock could influence the efficacy of pharmacotherapy and the outcomes of clinical interventions.
RESUMO
ABSTRACT Objective: Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes ( Clock, Bmal1 ) and genes involved in lipid metabolism ( Pgc1a, Pparg, Ucp2 ) through nutrient-sensing pathways ( Sirt1, Ampk, Nampt ) in peripheral tissues. Materials and methods: Rats were grouped according to food access: Control group (CG, food ad libitum ), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. Results: In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a , Pparg , and Ucp2 but not Ampk and Nampt . Conclusion: Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.
Assuntos
Animais , Ratos , Hipotálamo , Fígado/metabolismo , Nutrientes , Ritmo Circadiano , Metabolismo dos LipídeosRESUMO
RESUMEN El nodo sinusal constituye el marcapasos fisiológico del corazón. Diferentes estados fisiopatológicos conducen a una reducción de su función, lo que es llamado en la clínica, disfunción sinusal. Sin embargo, para la mejor comprensión de su estado de enfermedad se requiere dilucidar cómo opera en condiciones normales. Las nuevas evidencias señalan que el automatismo del nodo sinusal se produce por la interacción del reloj de membrana y el reloj de calcio, lo que le confiere un fuerte carácter que lo protege contra fallas de funcionamiento. Se presentan las evidencias actuales sobre la sincronía celular dentro del nodo sinusal, así como la forma de propagación eléctrica y el acoplamiento fuente-sumidero. Además, se describen recientes hallazgos anatómicos e histológicos.
ABSTRACT The sinus node is the physiological pacemaker of the heart. Different pathophysiological conditions lead to a reduction of its function, which is clinically called sinus dysfunction. However, for a better understanding of its disease state, it is necessary to elucidate how it works under normal conditions. New evidences indicate that the automatism of the sinus node is produced by the interaction of the membrane clock and the calcium clock, which gives it a strong character that protects it against malfunctions. Current evidences on cell synchrony within the sinus node are presented, as well as the form of electrical propagation and the source-sink coupling. In addition, recent anatomical and histological findings are described.
Assuntos
Nó Sinoatrial , Relógios Biológicos , Eletrofisiologia CardíacaRESUMO
Fundamento: en los últimos años el implante de marcapasos permanente se ha convertido en un procedimiento seguro con bajo índice de complicaciones pero cuando estas se presentan, pueden ocasionar un desenlace fatal en la vida del paciente debido a la disfunción del dispositivo. Objetivo: analizar el diagnóstico tardío del desplazamiento del electrodo de marcapasos permanente en una paciente. Caso clínico: paciente de 68 años de edad, con historia de hipertensión arterial de alrededor de 25 años de evolución, con tratamiento diario de amlodipino e hidroclorotiazida de 10 y 25 mg, respectivamente. Hacía cinco años se le había implantado un marcapasos permanente, por bloqueo auriculoventricular de tercer grado y síncope, con buena evolución y sin complicaciones al alta hospitalaria. A los cuatro meses de operada presentó otro síncope y acudió a consulta de programación de marcapasos, sin problemas con la estimulación del dispositivo. Continuó con mareos y pérdida del conocimiento, por lo que recurrió a las consultas programadas de seguimiento especializado. Finalmente se le diagnostica el desplazamiento del electrodo, se reinterviene y se coloca un nuevo cable. En el seguimiento posterior no presento más síncope ni mareos. Conclusiones: el método clínico constituye el elemento principal para el diagnóstico de complicaciones en el seguimiento de pacientes con marcapasos permanentes, aun así un solo medio diagnóstico no es suficiente para descartar la misma, por lo que se deben utilizar otros medios diagnósticos.
Background: in the last years, the placement of permanent pacemakers has become a safe procedure with low rates of complications; however, when these complications present they can cause a fatal end for patients due to the dysfunction of the device. Objective: to analyze the late diagnosis of displacement of the electrode in the permanent pacemaker of a patient. Clinical case: a sixty-six-year-old female patient with a history of high blood pressure of 25 years of evolution. The patient was under a daily treatment with amlodipine and hydrochlorothiazide, 10 and 25 mg respectively. Five years ago, because of third-degree atrioventricular block and syncope, she underwent the implantation of a permanent pacemaker. The patient had a good progress and no complications when discharged from the hospital. Four months after the operation she presented syncope and went to the pacemaker program consultation; there were no problems with the stimulation of the device. She continued presenting dizziness and loss of consciousness so she went to the specialized programmed follow-up consultations. Finally, the patient is diagnosed with displacement of the electrode. She underwent another procedure to place a new lead. She did not present dizziness or syncope in the follow-up. Conclusions: the clinical method is the main element for the diagnosis of complications in the follow-up of patients with permanent pacemakers; still, only one diagnosis element is not enough to discard the problem so is necessary to use other diagnostic means.
RESUMO
La dexmedetomidina (DXM) es un agonista selectivo de los receptores alfa 2 preganglionares, que actúa tanto en el sistema nervioso central como en el periférico. Desde su incursión en la práctica médica, ha sido utilizada satisfactoriamente en un amplio espectro de procedimientos anestésicos, que van desde sedación hasta intervenciones bajo anestesia general. Dentro de sus principales ventajas se encuentran la estabilidad hemodinámica y la mínima depresión respiratoria. Este artículo describe una terapia de resincronización cardiaca exitosa a través de la implantación deun marcapasos biventricular en un paciente hemodinámicamenteinestable, bajo sedación con DXM y midazolam a bajas dosis.
Dexmedetomidine (DXM) is a selective 2-adrenoreceptor agonist acting over both the central and peripheral nervous system. Since it became available for medical application, DXM has been satisfactorily used for a broad spectrum of anesthetic procedures, ranging from sedation to interventions under general anesthesia. Its key advantages include its hemodynamic stability and minimal respiratory depression. This articleprovides a description of a successful cardiac resynchronization therapy implanting a biventricular pacemaker in a hemodynamically unstable patient under DXM and low-dose midazolamsedation.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Amiodarona , Relógios Biológicos , Dexmedetomidina , Medidas de Segurança , SegurançaRESUMO
Exfoliated epithelial cells represent valuable source of information on the physiopathological state of the mucosa. However, the interpretation of data obtained from exfoliated cells is complicated by the conditions of isolation as well as the health of the subject. Exfoliation is either: a) a natural loss of body cells implying a molecular signal related to the turnover of terminally differentiated cells and to the progressive mobilization of proliferative as well as stem cells or b) the result of manual exfoliation by applying mechanical constraints like scraping. Depending on the methodology of isolation, exfoliated epithelial cells are believed to be either in apoptosis or in anoïkis. Most studies are using microscopic examination to demonstrate the presence of typical cells along with measurements on a limited number of biomarkers. Only few studies using proteomics or transcriptomics are available and they open discussion about tissue references and normalization. The main advantage of measures realized on exfoliated epithelial cells is that they are strictly non-invasive and open the possibility to evaluate maturation of gastric and intestinal tissues in long-term experiments performed on the same animal or in translational research on samples recovered from preterm infants.
Células epiteliais exfoliadas são uma fonte de informação valiosa sobre o estado fisiológico da mucosa. Contudo, a interpretação dos dados obtidos de células exfoliadas é complicado pelas condições de isolamento e da saúde do sujeito. A exfoliação é: a) uma perda natural de células implicando um sinal molecular relacionado ao turnover terminal de células diferenciadas e à progressiva mobilização de células proliferativas e de células tronco ou b) o resultado de aplicação de fatores mecânicos como raspagem. Dependendo do método de islolamento, acredita-se que podem estar em apoptose ou em anoikis. A maior parte dos estudos tem utilizado exame microscópico para demonstrar a presença de células típicas com medições sobre um número limitado de biomarcadores. Apenas uns poucos estudos usando proteômica ou transcriptômica estão disponíveis e discutem sobre referenciais de tecidos e normalização. A principal vantagem de medidas realizadas em células epiteliais exfoliadas é que elas são estritamente não invasivas e abertas à possibilidade de avaliar a maturação de tecidos gástricos e intestinais em experimentos de longo prazo feitos no mesmo animal ou em pesquisas translacionais com amostras obtidas de crianças pré-termo.
Assuntos
Humanos , Recém-Nascido , Células Epiteliais , Recém-Nascido Prematuro , Trato Gastrointestinal/patologiaRESUMO
¿Cuál es la naturaleza del reloj biológico que determina el envejecimiento de las células? ¿De qué manera se explica la génesis de las enfermedades asociadas con el envejecimiento? Las anteriores son sólo algunas de las preguntas cuya respuesta puede ser hallada en el marco del modus operandi de la dupla telómeros-telomerasa, convertida en objeto de estudio para un sinnúmero de hombres y mujeres de ciencia, desde los pioneros Hermann Müller y Bárbara McClintock hasta los más recientes Jack Szostak, Elizabeth Blackburn y Carol Greider, entre otros.
What is the nature of the biological clock that determines the cells aging? What is the way to explain the genesis of diseases associated in aging? The above are only some of the questions whose answer could be found within the modus operandi frame of the telomere-telomerase pair, which had become in objective of study for a number of science men and women since the pioneers Hermann Müller and Barbara McClintock, until the most recent Jack Szostak, Elizabeth Blackburn and Carol Greider, among others.