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1.
EBioMedicine ; 52: 102365, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31447395

RESUMO

BACKGROUND: Total liquid ventilation (TLV) of the lungs could provide radically new benefits in critically ill patients requiring lung lavage or ultra-fast cooling after cardiac arrest. It consists in an initial filling of the lungs with perfluorocarbons and subsequent tidal ventilation using a dedicated liquid ventilator. Here, we propose a new paradigm for a lung-conservative TLV using pulmonary volumes of perfluorocarbons below functional residual capacity (FRC). METHODS AND FINDINGS: Using a dedicated technology, we showed that perfluorocarbon end-expiratory volumes could be maintained below expected FRC and lead to better respiratory recovery, preserved lung structure and accelerated evaporation of liquid residues as compared to complete lung filling in piglets. Such TLV below FRC prevented volutrauma through preservation of alveolar recruitment reserve. When used with temperature-controlled perfluorocarbons, this lung-conservative approach provided neuroprotective ultra-fast cooling in a model of hypoxic-ischemic encephalopathy. The scale-up and automating of the technology confirmed that incomplete initial lung filling during TLV was beneficial in human adult-sized pigs, despite larger size and maturity of the lungs. Our results were confirmed in aged non-human primates, confirming the safety of this lung-conservative approach. INTERPRETATION: This study demonstrated that TLV with an accurate control of perfluorocarbon volume below FRC could provide the full potential of TLV in an innovative and safe manner. This constitutes a new paradigm through the tidal liquid ventilation of incompletely filled lungs, which strongly differs from the previously known TLV approach, opening promising perspectives for a safer clinical translation. FUND: ANR (COOLIVENT), FRM (DBS20140930781), SATT IdfInnov (project 273).


Assuntos
Ventilação Líquida/métodos , Pulmão , Reabilitação , Animais , Biópsia , Cuidados Críticos , Fluorocarbonos/administração & dosagem , Hipotermia Induzida , Imuno-Histoquímica , Ventilação Líquida/instrumentação , Macaca fascicularis , Recuperação de Função Fisiológica , Reabilitação/instrumentação , Reabilitação/métodos , Testes de Função Respiratória , Suínos , Tomografia Computadorizada por Raios X
2.
Front Physiol ; 9: 1723, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555353

RESUMO

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume (p = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs (p = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% (p = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship (p = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography.

3.
Ann Intensive Care ; 8(1): 57, 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-29721820

RESUMO

BACKGROUND: Ultrafast cooling by total liquid ventilation (TLV) provides potent cardio- and neuroprotection after experimental cardiac arrest. However, this was evaluated in animals with no initial lung injury, whereas out-of-hospital cardiac arrest is frequently associated with early-onset pneumonia, which may lead to acute respiratory distress syndrome (ARDS). Here, our objective was to determine whether hypothermic TLV could be safe or even beneficial in an aspiration-associated ARDS animal model. METHODS: ARDS was induced in anesthetized rabbits through a two-hits model including the intra-tracheal administration of a pH = 1 solution mimicking gastric content and subsequent gaseous non-protective ventilation during 90 min (tidal volume [Vt] = 10 ml/kg with positive end-expiration pressure [PEEP] = 0 cmH2O). After this initial period, animals either received lung protective gas ventilation (LPV; Vt = 8 ml/kg and PEEP = 5 cmH2O) under normothermic conditions, or hypothermic TLV (TLV; Vt = 8 ml/kg and end-expiratory volume = 15 ml/kg). Both strategies were applied for 120 min with a continuous monitoring of respiratory and cardiovascular parameters. Animals were then euthanized for pulmonary histological analyses. RESULTS: Eight rabbits were included in each group. Before randomization, all animals elicited ARDS with arterial oxygen partial pressure over inhaled oxygen fraction ratios (PaO2/FiO2) below 100 mmHg, as well as decreased lung compliance. After randomization, body temperature rapidly decreased in TLV versus LPV group (32.6 ± 0.6 vs. 38.2 ± 0.4 °C after 15 min). Static lung compliance and gas exchanges were not significantly different in the TLV versus LPV group (PaO2/FiO2 = 62 ± 4 vs. 52 ± 8 mmHg at the end of the procedure, respectively). Mean arterial pressure and arterial bicarbonates levels were significantly higher in TLV versus LPV. Histological analysis also showed significantly lower inflammation in TLV versus LPV group (median histological score = 3 vs. 4.5/5, respectively; p = 0.03). CONCLUSION: Hypothermic TLV can be safely induced in rabbits during aspiration-associated ARDS. It modified neither gas exchanges nor respiratory mechanics but reduced lung inflammation and hemodynamic failure in comparison with LPV. Since hypothermic TLV was previously shown to provide neuro- and cardio protective effects after cardiac arrest, these findings suggest a possible use of TLV in the settings of cardiac arrest-associated ARDS.

4.
PLoS One ; 13(1): e0191885, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29377922

RESUMO

BACKGROUND: Filling the lung with dense liquid perfluorocarbons during total liquid ventilation (TLV) might compress the myocardium, a plausible explanation for the instability occasionally reported with this technique. Our objective is to assess the impacts of TLV on the cardiovascular system, particularly left ventricular diastolic function, in an ovine model of neonatal respiratory distress syndrome. METHOD: Eight newborns lambs, 3.0 ± 0.4 days (3.2 ± 0.3kg) were used in this crossover experimental study. Animals were intubated, anesthetized and paralyzed. Catheters were inserted in the femoral and pulmonary arteries. A high-fidelity pressure catheter was inserted into the left ventricle. Surfactant deficiency was induced by repeated lung lavages with normal saline. TLV was then conducted for 2 hours using a liquid ventilator prototype. Thoracic echocardiography and cardiac output assessment by thermodilution were performed before and during TLV. RESULTS: Left ventricular end diastolic pressure (LVEDP) (9.3 ± 2.1 vs. 9.2 ± 2.4mmHg, p = 0.89) and dimension (1.90 ± 0.09 vs. 1.86 ± 0.12cm, p = 0.72), negative dP/dt (-2589 ± 691 vs. -3115 ± 866mmHg/s, p = 0.50) and cardiac output (436 ± 28 vs. 481 ± 59ml/kg/min, p = 0.26) were not affected by TLV initiation. Left ventricular relaxation time constant (tau) slightly increased from 21.5 ± 3.3 to 24.9 ± 3.7ms (p = 0.03). Mean arterial systemic (48 ± 6 vs. 53 ± 7mmHg, p = 0.38) and pulmonary pressures (31.3 ± 2.5 vs. 30.4 ± 2.3mmHg, p = 0.61) were stable. As expected, the inspiratory phase of liquid cycling exhibited a small but significant effect on most variables (i.e. central venous pressure +2.6 ± 0.5mmHg, p = 0.001; LVEDP +1.18 ± 0.12mmHg, p<0.001). CONCLUSIONS: TLV was well tolerated in our neonatal lamb model of severe respiratory distress syndrome and had limited impact on left ventricle diastolic function when compared to conventional mechanical ventilation.


Assuntos
Diástole , Modelos Animais de Doenças , Ventilação Líquida/métodos , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Função Ventricular Esquerda , Animais , Animais Recém-Nascidos , Fluorocarbonos/farmacocinética , Hidrocarbonetos Bromados , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Ovinos
5.
IEEE Trans Biomed Eng ; 64(12): 2760-2770, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28237918

RESUMO

GOAL: Recent preclinical studies have shown that therapeutic hypothermia induced in less than 30 min by total liquid ventilation (TLV) strongly improves the survival rate after cardiac arrest. When the lung is ventilated with a breathable perfluorocarbon liquid, the inspired perfluorocarbon allows us to control efficiently the cooling process of the organs. While TLV can rapidly cool animals, the cooling speed in humans remains unknown. The objective is to predict the efficiency and safety of ultrafast cooling by TLV in adult humans. METHODS: It is based on a previously published thermal model of ovines in TLV and the design of a direct optimal controller to compute the inspired perfluorocarbon temperature profile. The experimental results in an adult sheep are presented. The thermal model of sheep is subsequently projected to a human model to simulate the optimal hypothermia induction and its sensitivity to physiological parameter uncertainties. RESULTS: The results in the sheep showed that the computed inspired perfluorocarbon temperature command can avoid arterial temperature undershoot. The projection to humans revealed that mild hypothermia should be ultrafast (reached in fewer than 3 min (-72 °C/h) for the brain and 20 min (-10 °C/h) for the entire body). CONCLUSION: The projection to human model allows concluding that therapeutic hypothermia induction by TLV can be ultrafast and safe. SIGNIFICANCE: This study is the first to simulate ultrafast cooling by TLV in a human model and is a strong motivation to translate TLV to humans to improve the quality of life of postcardiac arrest patients.


Assuntos
Fluorocarbonos , Hipotermia Induzida/métodos , Ventilação Líquida/métodos , Adulto , Animais , Encéfalo/fisiologia , Simulação por Computador , Fluorocarbonos/administração & dosagem , Fluorocarbonos/uso terapêutico , Parada Cardíaca/terapia , Humanos , Pulmão/fisiologia , Modelos Biológicos , Ovinos , Temperatura
6.
Cryobiology ; 73(1): 99-101, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27242031

RESUMO

Ultra-fast cooling for mild therapeutic hypothermia (MTH) has several potential applications, including prevention of post-cardiac arrest syndrome. Ultra-fast MTH by total liquid ventilation (TLV) entails the sudden filling of the lungs with a cold perfluorocarbon liquid and its subsequent use to perform TLV. The present physiological study was aimed at assessing whether pulmonary and systemic hemodynamics as well as lung mechanics are significantly altered during this procedure. Pulmonary and systemic arterial pressures, cardiac output as well as airway resistance and respiratory system compliance were measured during ultra-fast MTH by TLV followed by rewarming and normothermia in six healthy juvenile lambs. Results show that none of the studied variables were altered upon varying the perfluorocarbon temperature from 12 to 41 °C. It is concluded that ultra-fast MTH by TLV does not have any deleterious effect on hemodynamics or lung mechanics in healthy juvenile lambs.


Assuntos
Hemodinâmica/fisiologia , Hipotermia Induzida/métodos , Ventilação Líquida/métodos , Mecânica Respiratória/fisiologia , Animais , Fluorocarbonos/farmacologia , Ovinos , Carneiro Doméstico
7.
IEEE Trans Biomed Eng ; 63(7): 1483-91, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26552070

RESUMO

BACKGROUND: Total liquid ventilation (TLV) consists in filling the lungs with a perfluorocarbon (PFC) and using a liquid ventilator to ensure a tidal volume of oxygenated, CO 2 -free and temperature-controlled PFC. Having a much higher thermal capacity than air, liquid PFCs assume that the filled lungs become an efficient heat exchanger with pulmonary circulation. OBJECTIVE: The objective of the present study was the development and validation of a parametric lumped thermal model of a subject in TLV. METHODS: The lungs were modeled as one compartment in which the control volume varied as a function of the tidal volume. The heat transfer in the body was modeled as seven parallel compartments representing organs and tissues. The thermal model of the lungs and body was validated with two groups of lambs of different ages and weights (newborn and juvenile) undergoing an ultrafast mild therapeutic hypothermia induction by TLV. RESULTS: The model error on all animals yielded a small mean error of -0.1 ±0.4  (°)C for the femoral artery and 0.0 ±0.1   (°)C for the pulmonary artery. CONCLUSION: The resulting experimental validation attests that the model provided an accurate estimation of the systemic arterial temperature and the venous return temperature. SIGNIFICANCE: This comprehensive thermal model of the lungs and body has the advantage of closely modeling the rapid thermal dynamics in TLV. The model can explain how the time to achieve mild hypothermia between newborn and juvenile lambs remained similar despite of highly different physiological and ventilatory parameters. The strength of the model is its strong relationship with the physiological parameters of the subjects, which suggests its suitability for projection to humans.


Assuntos
Hipotermia Induzida/métodos , Ventilação Líquida/métodos , Modelos Biológicos , Animais , Animais Recém-Nascidos , Temperatura Corporal/fisiologia , Pulmão/fisiologia , Reprodutibilidade dos Testes , Ovinos
8.
Annu Int Conf IEEE Eng Med Biol Soc ; 2016: 2704-2707, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28268879

RESUMO

Mild hypothermia is well known for its therapeutic value in cardio- and neuroprotection. Many recent experimental studies have shown that the swiftness of the cooling offered by total liquid ventilation (TLV) holds great promise in achieving maximal therapeutic effect. TLV is an emerging ventilation technique in which the lungs are filled with breathable liquids, namely perfluorocarbons (PFCs). A liquid ventilator ensures subject ventilation by periodically renewing a volume of oxygenated, CO2-free and temperature-controlled breathable PFC. The substantial difference between breathing air and liquid is related to the fact that PFCs have over 500 times the volumetric thermal capacity of air 100% relative humidity. The PFC-filled lungs thus turn into an efficient heat exchanger with pulmonary circulation. The objective of the present study was to compute a posteriori the optimal inspired PFC temperature for ultrafast induction of mild hypothermia by TLV in a juvenile lamb experimentation using direct optimal control. The continuous time model and the discretized cycle-by-cycle model are presented. The control objectives of the direct optimal control are also presented and the results are compared with experimental data in order to validate the improved control performances. The computed direct optimal control showed that the inspired PFC temperature command can be improved to avoid temperature undershoots without altering the cooling performances.


Assuntos
Fluorocarbonos/uso terapêutico , Hipotermia Induzida , Ventilação Líquida/métodos , Animais , Humanos , Ovinos , Temperatura
9.
Crit Care Med ; 43(10): e420-30, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26110489

RESUMO

OBJECTIVES: Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits. DESIGN: Randomized animal study. SETTING: Academic research laboratory. SUBJECTS: New Zealand Rabbits. INTERVENTIONS: Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12). MEASUREMENTS AND MAIN RESULTS: Ultrafast cooling with total liquid ventilation (32 °C within 5 min in the esophagus) dramatically attenuated the post-cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1ß, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32 °C within 90-120 min in the esophagus), providing none of the above-mentioned systemic or organ protection. CONCLUSIONS: Ultrafast cooling by total liquid ventilation limits the post-cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response.


Assuntos
Encefalopatias/etiologia , Encefalopatias/prevenção & controle , Parada Cardíaca/complicações , Hipotermia Induzida , Ventilação Líquida , Animais , Asfixia/complicações , Barreira Hematoencefálica , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Hemodinâmica , Hipotermia Induzida/métodos , Ventilação Líquida/métodos , Masculino , Coelhos , Distribuição Aleatória , Sepse/fisiopatologia
10.
Annu Int Conf IEEE Eng Med Biol Soc ; 2015: 1695-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26736603

RESUMO

Total liquid ventilation (TLV) is an emerging mechanical ventilation technique. In this technique, the lungs are filled with liquid perfluorocarbons (PFC) and a liquid ventilator assures ventilation by periodically renewing a volume of oxygenated, CO2 freed and temperature controlled PFC. A huge difference between conventional mechanical ventilation and TLV relates to the fact that PFCs are about 1500 times denser than air. Thus, the PFCs filled lungs turn into an efficient heat exchanger with the circulating blood. One of the most appealing utilization of the lungs as a heat exchanger in TLV is for ultrafast induction of mild therapeutic hypothermia (MTH) for neuroprotection and cardioprotection after ischemia-reperfusion injuries. This study aimed to perform ultrafast MTH induction by TLV in animals up to 25 kg, then perform a fast post-hypothermic rewarming while maintaining proper ventilation. A thermal model of the lamb and liquid ventilator was developed to predict the dynamic and the control strategy to adopt for MTH induction. Two juvenile lambs were instrumented with temperature sensors in the femoral artery, pulmonary artery, oesophagus, right eardrum and rectum. After stabilization in conventional mechanical ventilation, TLV was initiated with ultrafast MTH induction, followed by posthypothermic rewarming. Preliminary results in the two juvenile lambs reveal that the liquid ventilator Inolivent-6.0 can induce MTH by TLV in less than 2.5 min for systemic arterial blood and in less than 10 min for venous return, esophagus and eardrum. Rectal temperature reached MTH in respectively 19.4 and 17.0 min for both lambs. Experimental results were consistent with the model predictions. Moreover, blood gas analysis exhibited that the gas exchange in the lungs was maintained adequately for the entire experiments.


Assuntos
Fluorocarbonos , Hipotermia Induzida/instrumentação , Animais , Temperatura Corporal , Hipotermia Induzida/métodos , Ventilação Líquida , Masculino , Monitorização Fisiológica , Respiração Artificial/instrumentação , Respiração Artificial/métodos , Carneiro Doméstico , Ventiladores Mecânicos
11.
IEEE Trans Biomed Eng ; 61(12): 2859-68, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24960422

RESUMO

In total liquid ventilation (TLV), the lungs are filled with a breathable liquid perfluorocarbon (PFC) while a liquid ventilator ensures proper gas exchange by renewal of a tidal volume of oxygenated and temperature-controlled PFC. Given the rapid changes in core body temperature generated by TLV using the lung has a heat exchanger, it is crucial to have accurate and reliable core body temperature monitoring and control. This study presents the design of a virtual lung temperature sensor to control core temperature. In the first step, the virtual sensor, using expired PFC to estimate lung temperature noninvasively, was validated both in vitro and in vivo. The virtual lung temperature was then used to rapidly and automatically control core temperature. Experimentations were performed using the Inolivent-5.0 liquid ventilator with a feedback controller to modulate inspired PFC temperature thereby controlling lung temperature. The in vivo experimental protocol was conducted on seven newborn lambs instrumented with temperature sensors at the femoral artery, pulmonary artery, oesophagus, right ear drum, and rectum. After stabilization in conventional mechanical ventilation, TLV was initiated with fast hypothermia induction, followed by slow posthypothermic rewarming for 1 h, then by fast rewarming to normothermia and finally a second fast hypothermia induction phase. Results showed that the virtual lung temperature was able to provide an accurate estimation of systemic arterial temperature. Results also demonstrate that TLV can precisely control core body temperature and can be favorably compared to extracorporeal circulation in terms of speed.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Ventilação Líquida/instrumentação , Ventilação Líquida/métodos , Termografia/instrumentação , Termografia/métodos , Interface Usuário-Computador , Ar Condicionado/instrumentação , Ar Condicionado/métodos , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Retroalimentação , Retroalimentação Fisiológica/fisiologia , Calefação/instrumentação , Calefação/métodos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Ovinos , Terapia Assistida por Computador/instrumentação , Terapia Assistida por Computador/métodos
12.
Artigo em Inglês | MEDLINE | ID: mdl-24110548

RESUMO

Mild therapeutic hypothermia (MTH) consists in cooling the body temperature of a patient to between 32 and 34 °C. This technique helps to preserve tissues and neurological functions in multi-organ failure by preventing ischemic injury. Total liquid ventilation (TLV) ensures gas exchange in the lungs with a liquid, typically perfluorocarbon (PFC). A liquid ventilator is responsible for ensuring cyclic renewal of tidal volume of oxygenated and temperature-controlled PFC. Hence, TLV using the lung as a heat exchanger and PFC as a heat carrier allows ultra fast cooling of the whole body which can help improve outcome after ischemic injuries. The present study was aimed to evaluate the control performance and safety of automated ultrarapid MTH induction by TLV. Experimentation was conducted using the Inolivent-5.0 liquid ventilator equipped with a PFC treatment unit that allows PFC cooling and heating from the flow of energy carrier water inside a double wall installed on an oxygenator. A water circulating bath is used to manage water temperature. A feedback controller was developed to modulate inspired PFC temperature and control body temperature. Such a controller is important since, with MTH induction, heart temperature should not reach 28 °C because of a high risk of fibrillation. The in vivo experimental protocol was conducted on a male newborn lamb of 4.7 kg which, after anesthetization, was submitted to conventional gas ventilation and instrumented with temperature sensors at the femoral artery, oesophagus, right ear drum and rectum. After stabilization, TLV was initiated with fast automated MTH induction to 33.5 °C until stabilization of all temperatures. MTH could be reached safely in 3 minutes at the femoral artery, in 3.6 minutes at the esophagus, in 7.7 minutes at the eardrum and in 15 minutes at the rectum. All temperatures were stable at 33.5 ± 0.5 °C within 15 minutes. The present results reveal that ultra-fast MTH induction by TLV with Inolivent-5.0 is safe for the heart while maintaining esophageal and arterial temperature over 32.6 °C.


Assuntos
Hipotermia Induzida/instrumentação , Animais , Temperatura Corporal , Humanos , Hipotermia Induzida/métodos , Ventilação Líquida , Masculino , Ovinos , Ventiladores Mecânicos
13.
Proc Natl Acad Sci U S A ; 107(45): 19356-61, 2010 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-20974940

RESUMO

In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.


Assuntos
Septo Interatrial/citologia , Endocárdio/citologia , Fator de Transcrição GATA4/fisiologia , Cardiopatias/congênito , Óxido Nítrico Sintase Tipo III/fisiologia , Proteínas com Domínio T/fisiologia , Animais , Septo Interatrial/patologia , Sobrevivência Celular , Endocárdio/patologia , Haploinsuficiência , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Camundongos , Fenótipo , Proteínas com Domínio T/análise
14.
EMBO J ; 25(21): 5201-13, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17053787

RESUMO

In humans, congenital heart defects occur in 1-2% of live birth, but the molecular mechanisms and causative genes remain unidentified in the majority of cases. We have uncovered a novel transcription pathway important for heart morphogenesis. We report that KLF13, a member of the Krüppel-like family of zinc-finger proteins, is expressed predominantly in the heart, binds evolutionarily conserved regulatory elements on cardiac promoters and activates cardiac transcription. KLF13 is conserved across species and knockdown of KLF13 in Xenopus embryos leads to atrial septal defects and hypotrabeculation similar to those observed in humans or mice with hypomorphic GATA-4 alleles. Physical and functional interaction with GATA-4, a dosage-sensitive cardiac regulator, provides a mechanistic explanation for KLF13 action in the heart. The data demonstrate that KLF13 is an important component of the transcription network required for heart development and suggest that KLF13 is a GATA-4 modifier; by analogy to other GATA-4 collaborators, mutations in KLF13 may be causative for congenital human heart disease.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Coração/embriologia , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas de Xenopus/metabolismo , Alelos , Animais , Fator de Transcrição GATA4/genética , Dosagem de Genes , Regulação da Expressão Gênica no Desenvolvimento/genética , Comunicação Interatrial/embriologia , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Mutação , Miocárdio/patologia , Células NIH 3T3 , Transcrição Gênica/genética , Proteínas de Xenopus/genética , Xenopus laevis
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