RESUMEN
INTRODUCTION: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. METHODS: We analyzed data from two separate experiments where swine were subjected to lethal insults. Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. RESULTS: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.
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Lesión Renal Aguda/prevención & control , Hemorragia/complicaciones , Inhibidores de Histona Desacetilasas/uso terapéutico , Traumatismo Múltiple/complicaciones , Ácido Valproico/uso terapéutico , Lesión Renal Aguda/sangre , Lesión Renal Aguda/etiología , Animales , Creatinina/sangre , Evaluación Preclínica de Medicamentos , Hemorragia/sangre , Hemorragia/mortalidad , Inhibidores de Histona Desacetilasas/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Lipocalina 2/sangre , Traumatismo Múltiple/sangre , Traumatismo Múltiple/mortalidad , Proteoma/efectos de los fármacos , Porcinos , Ácido Valproico/farmacologíaRESUMEN
Rationale: Prone positioning is an appealing therapeutic strategy for nonintubated hypoxic patients with coronavirus disease (COVID-19), but its effectiveness remains to be established in randomized controlled trials. Objectives: To identify contextual factors relevant to the conduct of a definitive clinical trial evaluating a prone positioning strategy for nonintubated hypoxic patients with COVID-19. Methods: We conducted a cluster randomized pilot trial at a quaternary care teaching hospital. Five inpatient medical service teams were randomly allocated to two treatment arms: 1) usual care (UC), consisting of current, standard management of hypoxia and COVID-19; or 2) the Awake Prone Positioning Strategy (APPS) plus UC. Included patients had positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing or suspected COVID-19 pneumonia and oxygen saturation less than 93% or new oxygen requirement of 3 L per minute or greater and no contraindications to prone positioning. Oxygenation measures were collected within 48 hours of eligibility and included nadir oxygen saturation to fraction of inspired oxygen (S/F) ratio and time spent with S/F ratio less than 315. Concurrently, we conducted an embedded implementation evaluation using semistructured interviews with clinician and patient participants to determine contextual factors relevant to the successful conduct of a future clinical trial. The primary outcomes were drawn from an implementation science framework including acceptability, adoption, appropriateness, effectiveness, equity, feasibility, fidelity, and penetration. Results: Forty patients were included in the cluster randomized trial. Patients in the UC group (n = 13) had a median nadir S/F ratio over the 48-hour study period of 216 (95% confidence interval [95% CI], 95-303) versus 253 (95% CI, 197-267) in the APPS group (n = 27). Patients in the UC group spent 42 hours (95% CI, 13-47) of the 48-hour study period with an S/F ratio below 315 versus 20 hours (95% CI, 6-39) for patients in the APPS group. Mixed-methods analyses uncovered several barriers relevant to the conduct of a successful definitive randomized controlled trial, including low adherence to prone positioning, large differences between physician-recommended and patient-tolerated prone durations, and diffusion of prone positioning into usual care. Conclusions: A definitive trial evaluating the effect of prone positioning in nonintubated patients with COVID-19 is warranted, but several barriers must be addressed to ensure that the results of such a trial are informative and readily translated into practice.
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COVID-19 , Vigilia , Humanos , Hipoxia/terapia , Proyectos Piloto , Posición Prona , SARS-CoV-2RESUMEN
During construction of several gene deletion mutants in Lactococcus lactis MG1363 which involved a high-temperature (37.5°C) incubation step, additional spontaneous mutations were observed which resulted in stable heat resistance and in some cases salt-hypersensitive phenotypes. Whole-genome sequencing of one strain which was both heat resistant and salt hypersensitive, followed by PCR and sequencing of four other mutants which shared these phenotypes, revealed independent mutations in llmg_1816 in all cases. This gene encodes a membrane-bound stress signaling protein of the GdpP family, members of which exhibit cyclic dimeric AMP (c-di-AMP)-specific phosphodiesterase activity. Mutations were predicted to lead to single amino acid substitutions or protein truncations. An independent llmg_1816 mutant (Δ1816), created using a suicide vector, also displayed heat resistance and salt hypersensitivity phenotypes which could be restored to wild-type levels following plasmid excision. L. lactis Δ1816 also displayed improved growth in response to sublethal concentrations of penicillin G. High-temperature incubation of a wild-type industrial L. lactis strain also resulted in spontaneous mutation of llmg_1816 and heat-resistant and salt-hypersensitive phenotypes, suggesting that this is not a strain-specific phenomenon and that it is independent of a plasmid integration event. Acidification of milk by the llmg_1816-altered strain was inhibited by lower salt concentrations than the parent strain. This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity.
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Lactococcus lactis/genética , Lactococcus lactis/fisiología , Mutación , Hidrolasas Diéster Fosfóricas/genética , Secuencia de Bases , Fosfatos de Dinucleósidos/metabolismo , Eliminación de Gen , Genoma Bacteriano , Calor , Lactococcus lactis/crecimiento & desarrollo , Hidrolasas Diéster Fosfóricas/metabolismo , Salinidad , Análisis de Secuencia de ADN , Transducción de Señal , Cloruro de Sodio/metabolismo , Estrés FisiológicoRESUMEN
OBJECTIVE: We have previously demonstrated that pretreatment and posttreatment of animals with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can improve survival in a mouse model of lipopolysaccharide (LPS)-induced severe shock. This study was designed to assess whether SAHA affects LPS/Toll-like receptor 4 signaling through acetylation of heat shock protein 90 (HSP90) and degradation of its client protein interleukin-1 receptor-associated kinase 1 (IRAK1). METHODS: RAW264.7 cells were exposed to LPS (1 µg/mL) for 2 h, followed by treatment with SAHA (10 µM) or geldanamycin (3 µM), an inhibitor of HSP90. Sham (no SAHA, no LPS) macrophages served as a control. The cells were harvested at different time points, and time zero served as the reference point. RESULTS: LPS dramatically increased protein expression of myeloid differentiation factor 88 and IRAK1, and stimulated nuclear translocation of nuclear factor κB, leading to an increases of gene expression and protein production of tumor necrosis factor α and interleukin-6. Treatment with SAHA significantly attenuated these LPS-stimulated alterations. LPS or SAHA did not change the levels of HSP90 protein, but immunoprecipitation studies demonstrated that SAHA treatment enhanced acetylation of HSP90, and increased the dissociation of IRAK1, compared to the LPS control. CONCLUSIONS: SAHA suppresses LPS/Toll-like receptor 4 signaling in LPS-stimulated macrophages through multiple potential mechanisms. It inhibits the function of HSP90 through hyperacetylation of the chaperone protein, which results in dissociation and degradation of the client protein IRAK1 and, at least in part, leads to a decrease in nuclear translocation of nuclear factor κB and attenuation of key proinflammatory cytokine expression.
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Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/fisiología , Transporte Activo de Núcleo Celular , Animales , Células Cultivadas , Proteínas HSP90 de Choque Térmico/análisis , Quinasas Asociadas a Receptores de Interleucina-1/análisis , Interleucina-6/análisis , Interleucina-6/genética , Macrófagos/metabolismo , Ratones , Factor 88 de Diferenciación Mieloide/análisis , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/genética , VorinostatAsunto(s)
Alpinia/química , Alcoholes Bencílicos/farmacología , Membrana Celular/efectos de los fármacos , Ácidos Grasos/química , Staphylococcus aureus/efectos de los fármacos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Alcoholes Bencílicos/aislamiento & purificación , Membrana Celular/química , Regulación Bacteriana de la Expresión Génica , Genes Bacterianos , Microscopía Electrónica de Rastreo , Staphylococcus aureus/genética , Staphylococcus aureus/ultraestructura , Estrés FisiológicoRESUMEN
BACKGROUND: Cycle length (CL) increases as ventricular fibrillation (VF) progresses. OBJECTIVE: The purpose of this study was to test the hypotheses that increased CL is due to increased diastolic interval (DI), not increased action potential duration (APD), and that the DI increase is not solely due to increased postrepolarization refractoriness. METHODS: In 10 swine, VF was recorded for 20 minutes using a floating microelectrode through a hole in a 504-electrode epicardial plaque. Mean APD, DI, action potential amplitude (APA), maximum change in voltage during the AP upstroke (V(max)), and CL were calculated from the floating microelectrode recordings each minute of VF. The refractory period was estimated from the minimum DI (DI(min)). In two animals, rapid pacing was performed to gauge refractoriness. RESULTS: As VF progressed, CL, DI, and DI(min) increased (P <.05), whereas APD, V(max), and APA decreased (P <.05). At 20 minutes, DI(min) was not different from mean DI at VF onset. Pacing captured, but 53% of paced wavefronts blocked within the plaque. CONCLUSION: Increasing CL in VF is due to increased DI and not APD, which shortens. The increase in DI(min) over time is much less than the increase in mean DI, indicating that the myocardium is excitable during much of the DI. This finding, along with the ability to pace at a CL shorter than the native VF CL and the poor paced wavefront propagation, suggests that the increase in DI is due not only to increased postrepolarization refractoriness but also to poor wavefront propagation because of decreased APA and V(max) secondary to global ischemia caused by VF.
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Potenciales de Acción , Diástole , Fibrilación Ventricular/fisiopatología , Animales , Estimulación Cardíaca Artificial , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Sistema de Conducción Cardíaco/fisiopatología , Microelectrodos , Contracción Miocárdica , Sus scrofaRESUMEN
BACKGROUND: Knowledge of the shock potential gradient (nablaV) and postshock activation is limited to internal defibrillation of short-duration ventricular fibrillation (SDVF). OBJECTIVE: The purpose of this study was to determine these variables after external defibrillation of long-duration VF (LDVF). METHODS: In six pigs, 115-20 plunge needles with three to six electrodes each were inserted to record throughout both ventricles. After the chest was closed, the biphasic defibrillation threshold (DFT) was determined after 20 seconds of SDVF with external defibrillation pads. After 7 minutes of LDVF, defibrillation shocks that were less than or equal to the SDVF DFT strength were given. RESULTS: For DFT shocks (1632 +/- 429 V), the maximum minus minimum ventricular voltage (160 +/- 100 V) was 9.8% of the shock voltage. Maximum cardiac nablaV (28.7 +/- 17 V/cm) was 4.7 +/- 2.0 times the minimum nablaV (6.2 +/- 3.5 V/cm). Although LDVF did not increase the DFT in five of the six pigs, it significantly lengthened the time to earliest postshock activation following defibrillation (1.6 +/- 2.2 seconds for SDVF and 4.9 +/- 4.3 seconds for LDVF). After LDVF, 1.3 +/- 0.8 episodes of spontaneous refibrillation occurred per animal, but there was no refibrillation after SDVF. CONCLUSION: Compared with previous studies of internal defibrillation, during external defibrillation much less of the shock voltage appears across the heart and the shock field is much more even; however, the minimum nablaV is similar. Compared with external defibrillation of SDVF, the biphasic external DFT for LDVF is not increased; however, time to earliest postshock activation triples. Refibrillation is common after LDVF but not after SDVF in these normal hearts, indicating that LDVF by itself can cause refibrillation without requiring preexisting heart disease.
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Cardioversión Eléctrica , Potenciales de la Membrana/fisiología , Fibrilación Ventricular/fisiopatología , Fibrilación Ventricular/terapia , Animales , Mapeo del Potencial de Superficie Corporal , Porcinos , Factores de TiempoRESUMEN
Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution (n = 6) or normal Tyrode solution as a control (n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 x 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 +/- 1.5 vs. 9.2 +/- 3.2 min, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excitable, but only short episodes of VF could be reinduced. Endocardial activation rates were similar during the first 2 min of LDVF for Lugol-ablated and control hearts but were significantly slower in Lugol hearts by 3 min. In control hearts, the endocardium activated more rapidly than the epicardium after 4 min of LDVF with wave fronts propagating most often from the endocardium to epicardium. No difference in transmural activation rate or wave front direction was observed in Lugol hearts. Ablation of the subendocardium hastens VF spontaneous termination and alters VF activation sequences, suggesting that Purkinje fibers are important in the maintenance of LDVF.
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Endocardio/efectos de los fármacos , Yoduros/farmacología , Ramos Subendocárdicos/efectos de los fármacos , Fibrilación Ventricular/fisiopatología , Potenciales de Acción , Animales , Mapeo del Potencial de Superficie Corporal , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Perros , Endocardio/fisiopatología , Técnicas In Vitro , Ramos Subendocárdicos/fisiopatología , Factores de TiempoRESUMEN
BACKGROUND: Interest in combining antiarrhythmic drugs has been prompted by the lack of efficacy of monotherapies and the toxicity resulting from high doses of individual agents. OBJECTIVES: We tested the hypothesis that procainamide and sotalol combined have greater beneficial effects on restitution, on the dispersion of refractoriness, and on decreasing the complexity of ventricular fibrillation (VF) than either drug alone. METHODS: Six open-chest pigs received intravenous procainamide (15 mg/kg load and 50 microg/kg/min maintenance) followed by sotalol (1.5 mg/kg). Another six pigs received sotalol first and procainamide second. Before drugs and after each drug, 20-second episodes of electrically induced VF were recorded from a 21 x 24 unipolar electrode plaque (2 mm spacing) sutured on the lateral posterior left ventricular epicardium. Restitution properties and dispersion of refractoriness were estimated from activation recovery intervals during pacing. RESULTS: The combination of the two drugs reduced the maximum slope of the restitution curve and during VF reduced the number of wavefronts, the activation rate, the percentage of wavefront families exhibiting reentry, and the conduction velocity more than either drug alone. In addition, in the group that received sotalol first, both drugs together reduced the SD and the coefficient of variation of the spatial dispersion of refractoriness compared with baseline. CONCLUSIONS: Procainamide and sotalol combined have greater beneficial effects on restitution properties, dispersion of refractoriness, and the complexity of VF than either drug alone compared with baseline.
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Electrocardiografía/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Procainamida/administración & dosificación , Sotalol/administración & dosificación , Fibrilación Ventricular/tratamiento farmacológico , Fibrilación Ventricular/fisiopatología , Animales , Antiarrítmicos/administración & dosificación , Quimioterapia Combinada , Sistema de Conducción Cardíaco/efectos de los fármacos , Inyecciones Intramusculares , Periodo Refractario Electrofisiológico/efectos de los fármacos , Porcinos , Resultado del TratamientoRESUMEN
BACKGROUND: Acute ischemia causes myriad changes including increased catecholamines. We tested the hypothesis that elevated catecholamines alone are arrhythmogenic. METHODS AND RESULTS: A 504 electrode sock was placed over both ventricles in six open-chest pigs. During control infusion of saline through a catheter in the left anterior descending coronary artery (LAD), no sustained arrhythmias occurred, and the refractory period estimated by the activation recovery interval (ARI) was 175 +/- 14 ms in the LAD bed below the catheter. After infusion of isoproterenol at 0.1 microg/kg/min through the catheter, the ARI in this bed was significantly reduced to 109 +/- 10 ms. A sharp gradient of refractoriness of 43 +/- 10 ms was at the border of the perfused bed. Sustained monomorphic ventricular tachycardia occurred after drug infusion in the perfused bed or near its boundary in all animals with a cycle length of 329 +/- 26 ms and a focal origin. The maximum slope of the ARI restitution curve at the focal origins of the tachyarrhythmias was always <1 (0.62 +/- 0.15). Similar results with a focal arrhythmia origin occurred in two additional pigs in which intramural mapping was performed with 36 plunge needle electrodes in the left ventricular perfused bed. CONCLUSION: Regional elevation of a catecholamine, which is one of the alterations produced by acute ischemia, can by itself cause tachyarrhythmias. These arrhythmias are closely associated with a shortened refractory period and a large gradient of the spatial distribution of refractoriness but not with a steep restitution curve.
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Catecolaminas/administración & dosificación , Fibrilación Ventricular/inducido químicamente , Fibrilación Ventricular/fisiopatología , Animales , Femenino , Infusiones Intraarteriales , Masculino , Porcinos , Fibrilación Ventricular/diagnósticoRESUMEN
In this paper, we document a fabrication process that yields linear arrays of rectangular platinum black electrodes spaced 25 mum apart with edge-to-edge separation of 20 microm. The spatial arrangement is therefore sufficiently fine to insure stimulation and recording within cardiac tissue space constants, as six electrodes with dimensions of either 5 x 100 microm2, 5 x 250 microm2, or 5 x 500 microm2 were positioned in a 130-microm2 span in the arrays. Despite the small electrode sizes and available surface areas, favorable impedance characteristics were identifed. Averages ranged from 111 kOmega to 146 kOmega at 0.5 Hz and from 14 kOmega 39 kOmega at 500 Hz. Differences in impedances between the electrode sizes tested were small. Potential differences (deltaphis) recorded using the two central electrodes during stimulation with combinations at separations of only 75 microm, 100 microm, and 125 microm had low signal noise. As a preliminary test of the use of these arrays for possible application to impedance measurements in cardiac tissue, the deltaphis recorded during stimulation were compared to deltaphis obtained from finite-difference simulations using an isotropic volume conductor model. Anticipated decays in deltaphi with widening electrode separation identified in those simulations matched the decays in the recorded deltaphis closely. These findings are significant because they suggest intracellular and interstitial microimpedance mesurements in heart experiments will be straightforward.
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Estimulación Eléctrica/instrumentación , Electrocardiografía/instrumentación , Electrodos Implantados , Sistema de Conducción Cardíaco/fisiología , Microelectrodos , Marcapaso Artificial , Pletismografía de Impedancia/instrumentación , Estimulación Eléctrica/métodos , Electrocardiografía/métodos , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , Pletismografía de Impedancia/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Measurements of intramural membrane potential (Vm) would greatly increase knowledge of cardiac arrhythmias and defibrillation. Optrodes offer the possibility for three-dimensional Vm mapping, but their signal quality has been inadequate. OBJECTIVE: The purpose of this work was to improve optrode signal quality and use optrodes to measure intramural distribution of action potentials and shock-induced Vm changes in porcine hearts. METHODS: Optrodes were made from seven optical fibers 225 or 325 microm in diameter. Fiber ends were polished at a 45 degrees angle, which improved light collection and allowed their insertion without a needle. Fluorescent measurements were performed in isolated porcine hearts perfused with Tyrode's solution or blood using Vm-sensitive dye RH-237 and a 200-W Hg/Xe lamp. RESULTS: The signal-to-noise ratio for 325-microm fibers was 44 +/- 23 in blood-perfused hearts (n = 5) and 106 +/- 45 in Tyrode's-perfused hearts (n = 3), which represents an approximately four-fold improvement over previously reported data. There was close correspondence between optical and electrical measurements of activation times and action potential duration (APD). No significant intramural APD gradients were observed at cycle lengths up to 4 s and in the presence of dofetilide or d-sotalol. Application of shocks (5-50 V/cm) produced large intramural Vm changes (up to approximately 200% action potential amplitude), possibly reflecting a combined effect of tissue discontinuities and optrode geometry. CONCLUSIONS: A substantial improvement of optrode signal quality was achieved. Optical measurements of APD and activation times matched electrical measurements. Optrode measurements revealed no significant intramural APD gradients. Application of shocks caused large intramural Vm changes that could be influenced by the optrode geometry.
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Potenciales de Acción/fisiología , Estimulación Cardíaca Artificial , Cardioversión Eléctrica , Tecnología de Fibra Óptica/instrumentación , Corazón/inervación , Animales , Electrocardiografía , Potenciales de la Membrana/fisiología , Fibras Ópticas , Proyectos Piloto , PorcinosRESUMEN
BACKGROUND: Humans are more similar in transmural Purkinje and cardiac ion channel distributions to dogs than pigs. The Purkinje network in pigs is transmural but confined to the endocardium in dogs. Little is known about intramural activation during long-duration ventricular fibrillation (LDVF) given these differences. We tested the hypothesis that the transmural activation sequence is similar in sinus rhythm (SR) and LDVF in dogs as well as pigs, but different between species. METHODS AND RESULTS: In six pigs and seven dogs, 50-60 plunge needles (six electrodes, 2-mm spacing) were placed throughout the left ventricle. Unipolar recordings were made for >10 minutes of LDVF. SR and LDVF activation times were grouped into waves by linking activations along each needle. Origin (earliest activation) and propagation direction were determined for each wave. The mean wave origin was significantly more endocardial in dogs than pigs for SR and 1 through 10 minutes of LDVF. Predominant propagation direction in LDVF and SR was endocardial to epicardial in dogs, but the opposite or equal in both directions in pigs. Fastest activation rate was epicardial in pigs, but endocardial in dogs with an increasing endocardial-to-epicardial activation rate gradient as LDVF progressed in dogs but not pigs. CONCLUSIONS: The transmural activation sequence in SR and LDVF is markedly different between pigs and dogs. These differences may be related to differences in Purkinje fiber and ion channel distributions and suggest that dogs are a better model for investigating activation sequences during LDVF, given the similarities with humans.
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Sistema de Conducción Cardíaco/fisiopatología , Ventrículos Cardíacos/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Fibrilación Ventricular/fisiopatología , Animales , Perros , Especificidad de la Especie , Porcinos , Disfunción Ventricular Izquierda/etiología , Fibrilación Ventricular/complicacionesRESUMEN
During ventricular fibrillation (VF) only 39% of the variation in action potential duration (APD) is accounted for by the previous diastolic interval [DI((n-1))], i.e., restitution, and the previous APD [APD((n-1))], i.e., memory. We tested the hypothesis that a characteristic of the AP upstroke, the maximum rate of depolarization (V(max)), also helps account for its APD. A floating microelectrode was used to make transmembrane recordings at 16,000 samples/s from the anterior left ventricular wall during four 20-s episodes of VF in each of six pigs. V(max), time from V(max) to 60% repolarization (APD(60)), and DI were calculated throughout all episodes. Stepwise linear regression was used to determine how well each APD(60) (APD(60n)) was predicted by V(max) of that AP, the four previous DIs (n-1, n - 2, n - 3, n - 4), and the three previous APD(60)s (n-1, n - 2, n - 3). V(max) entered in the regression equation significantly more often (86% of VF episodes) than either APD((n-1)) (47% of episodes) or DI((n-1)) (58% of episodes). When these three variables entered first or second, their coefficients were almost always positive, consistent with a longer APD associated with 1) a larger V(max), 2) a longer APD((n-1)), and 3) a longer DI((n-1)). R(2) of the regression for all entered variables was 0.51 +/- 0.01 (mean +/- SD). During the first 20 s of VF in swine, V(max) is a more important determinant of APD than the previous DI (restitution) or the previous APD (memory). All variables together account for only one-half of APD variation during VF.
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Potenciales de Acción , Sistema de Conducción Cardíaco/fisiopatología , Fibrilación Ventricular/fisiopatología , Animales , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Electrocardiografía , Electrodos Implantados , Ventrículos Cardíacos/fisiopatología , Modelos Lineales , Modelos Cardiovasculares , Proyectos de Investigación , Porcinos , Factores de TiempoRESUMEN
BACKGROUND: The roles of Purkinje fibers (PFs) and focal wave fronts, if any, in the maintenance of ventricular fibrillation (VF) are unknown. If PFs are involved in VF maintenance, it should be possible to map wave fronts propagating from PFs into the working ventricular myocardium during VF. If wave fronts ever arise focally during VF, it should be possible to map them appearing de novo. METHODS AND RESULTS: Six canine hearts were isolated, and the left main coronary artery was cannulated and perfused. The left ventricular cavity was exposed, which allowed direct endocardial mapping of the anterior papillary muscle insertion. Nonperfused VF was induced, and 6 segments of data, each 5 seconds long, were analyzed during 10 minutes of VF. During 36 segments of data that were analyzed, 1018 PF or focal wave fronts of activation were identified. In 534 wave fronts, activation was mapped propagating from working ventricular myocardium to PF. In 142 wave fronts, activation was mapped propagating from PF to working ventricular myocardium. In 342 wave fronts, activation was mapped arising focally. More than 1 of these 3 patterns could occur in the same wave front. CONCLUSIONS: PFs are highly active throughout the first 10 minutes of VF. In addition to retrograde propagation from the working ventricular myocardium to PFs, antegrade propagation occurs from PFs to working ventricular myocardium, which suggests PFs are important in VF maintenance. Prior plunge needle recordings in dogs indicate activation propagates from the endocardium toward the epicardium after 1 minute of VF, which suggests that focal sites on the endocardium may represent foci and not breakthrough. If so, in addition to reentry, abnormal automaticity or triggered activity may also occur during VF.
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Modelos Animales de Enfermedad , Ramos Subendocárdicos/fisiología , Fibrilación Ventricular/fisiopatología , Potenciales de Acción/fisiología , Animales , Perros , Corazón/fisiología , Ramos Subendocárdicos/patologíaRESUMEN
BACKGROUND: Earliest recorded postshock myocardial activations in pigs originate in the subepicardium of the apex and lateral free wall of the left ventricle (LV) 30-90 ms after the shock. OBJECTIVE: The purpose of this study was to determine whether the Purkinje system is a candidate for the source of postshock activations by performing endocardial and transmural postshock activation mapping. METHODS: In five pigs, 32 plunge needles with 12 electrodes (1-mm spacing) were inserted into the LV apex and lateral free wall. Up to 70 plunge needles with six electrodes (2-mm spacing) were spread throughout the remainder of the LV, while 9-12 plunge needles with four electrodes (2-mm spacing) were inserted into the right ventricle. A basket catheter with 32 bipolar recording sites was inserted into the LV. Defibrillation-threshold (DFT)-level shocks were delivered during 10 episodes of electrically induced ventricular fibrillation. Electrograms of postshock activation cycles were analyzed for Purkinje and myocardial activations. RESULTS: Purkinje activations were recorded before local myocardial activation in 9% of basket electrograms and in 15% of plunge needles during the first postshock activation cycle. Purkinje activations were identified during the first and subsequent several postshock activation cycles in at least one basket and one needle electrogram in 96% and 98% of defibrillation episodes, respectively. CONCLUSIONS: The Purkinje system is active during the early postshock activation cycles after DFT-level shocks. Further studies are required to determine whether activation initiates in the Purkinje system or whether it is activated by the myocardium or by Purkinje-myocardial junctional cells.
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Mapeo del Potencial de Superficie Corporal , Cardioversión Eléctrica , Endocardio/inervación , Sistema de Conducción Cardíaco/fisiopatología , Ventrículos Cardíacos/fisiopatología , Miocardio , Ramos Subendocárdicos , Fibrilación Ventricular/fisiopatología , Animales , Electrodos , Porcinos , Factores de TiempoRESUMEN
We have developed an eight-channel telemetry system for studying experimental models of chronic cardiovascular disease. The system is an extension of a previous device that has been miniaturized, reduced in power consumption and provided with increased functionality. We added sensors for ventricular dimension, and coronary artery blood flow and arterial blood pressure that are suitable for use with the system. The telemetry system consists of a front end, a backpack and a host PC. The front end is a watertight stainless steel case with all sensor electronics sealed inside; it acquires dimension, flow, pressure and five cardiac electrograms from selected locations on the heart. The backpack includes a control unit, Bluetooth radio, and batteries. The control unit digitizes eight channels of data from the front end and forwards them to the host PC via Bluetooth link. The host PC has a receiving Bluetooth radio and Labview programs to store and display data. The whole system was successfully tested on the bench and in an animal model. This telemetry system will greatly enhance the ability to study events leading to spontaneous sudden cardiac arrest.
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Enfermedades Cardiovasculares/diagnóstico , Telemetría/instrumentación , Animales , Muerte Súbita Cardíaca , Electrofisiología , Implantes Experimentales , PorcinosRESUMEN
We have previously shown that left-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. To test our hypothesis that right-sided vagus nerve stimulation will also abort seizure activity, we have initiated seizures in the spinal cord and then performed right-sided vagus nerve stimulation in an animal model. Four pigs were anesthetized and placed in the lateral position and a small laminectomy performed in the lumbar region. Topical penicillin, a known epileptogenic drug to the cerebral cortex and spinal cord, was next applied to the dorsal surface of the exposed cord. With the exception of the control animal, once seizure activity was discernible via motor convulsion or increased electrical activity, the right vagus nerve previously isolated in the neck was stimulated. Following multiple stimulations of the vagus nerve and with seizure activity confirmed, the cord was transected in the midthoracic region and vagus nerve stimulation performed. Right-sided vagus nerve stimulation resulted in cessation of spinal cord seizure activity in all animals. Transection of the spinal cord superior to the site of seizure induction resulted in the ineffectiveness of vagus nerve stimulation in causing cessation of seizure activity in all study animals. As with left-sided vagus nerve stimulation, right-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. Additionally, the effects of right-sided vagus nerve stimulation on induced spinal cord seizures involve descending spinal pathways. These data may aid in the development of alternative mechanisms for electrical stimulation for patients with medically intractable seizures and add to our knowledge regarding the mechanism for seizure cessation following peripheral nerve stimulation.
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Convulsiones/metabolismo , Médula Espinal/metabolismo , Nervio Vago/fisiología , Animales , Masculino , Porcinos/metabolismoRESUMEN
The prospect of biological attacks is a growing strategic threat. Covert aerosol attacks inside a building are of particular concern. In the summer of 2005, the Center for Biosecurity of the University of Pittsburgh Medical Center convened a Working Group to determine what steps could be taken to reduce the risk of exposure of building occupants after an aerosol release of a biological weapon. The Working Group was composed of subject matter experts in air filtration, building ventilation and pressurization, air conditioning and air distribution, biosecurity, building design and operation, building decontamination and restoration, economics, medicine, public health, and public policy. The group focused on functions of the heating, ventilation, and air conditioning systems in commercial or public buildings that could reduce the risk of exposure to deleterious aerosols following biological attacks. The Working Group's recommendations for building owners are based on the use of currently available, off-the-shelf technologies. These recommendations are modest in expense and could be implemented immediately. It is also the Working Group's judgment that the commitment and stewardship of a lead government agency is essential to secure the necessary financial and human resources and to plan and build a comprehensive, effective program to reduce exposure to aerosolized infectious agents in buildings.
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Microbiología del Aire , Contaminación del Aire Interior/prevención & control , Bioterrorismo/prevención & control , Control de Enfermedades Transmisibles/métodos , Planificación en Desastres , Ambiente Controlado , Gestión de Riesgos/métodos , Comités Consultivos , Aerosoles/toxicidad , Aire Acondicionado/instrumentación , Comercio/normas , Filtración/instrumentación , Calefacción/instrumentación , Humanos , Liderazgo , Pennsylvania , Instalaciones Públicas/normas , Ventilación/instrumentaciónRESUMEN
INTRODUCTION: Patients with bradycardia can have severe tachyarrhythmias but it is unclear whether bradycardia alone can induce arrhythmias or whether an additional substrate is necessary. While several animal models of ventricular tachycardia (VT) exist, no model has been reported to mimic the clinical condition of spontaneous VT and sudden cardiac death (SCD) in the presence of bradycardia and chronic myocardial infarction (MI) in large animals without manipulation of the autonomic nervous system. We tested the hypothesis that MI and bradycardia cause more spontaneous sustained VT than does bradycardia alone. METHODS AND RESULTS: Sheep (42-56 kg) underwent atrioventricular (AV) node catheter ablation alone (n = 5) or AV node ablation and 150 minutes of angioplasty balloon occlusion of the left anterior descending coronary artery (n = 9). An implantable cardioverter defibrillator delivered rescue shocks and demand pacing at 90 beats per minute for the first week and at 40 beats per minute thereafter. Electrograms were continuously radiotelemetered and recorded for 6 weeks. Acute post-MI VT disappeared by day 4. The sudden bradycardia on day 8 triggered numerous premature ventricular contractions (PVCs) and episodes of sustained VT lasting >30 seconds during the next 5 weeks. There were 43 episodes of sustained VT and no spontaneous ventricular fibrillation (VF) with bradycardia alone. However, in the presence of both MI and bradycardia there were 970 episodes of VT/VF (P < 0.05) and three deaths at days 13, 15, and 34. The average 24-hour count of PVCs was similar at day 7 between the two groups but by days 11 and 40, the PVC counts were 35 times and 4 times greater, respectively, in the presence of bradycardia and chronic MI compared to bradycardia alone. No significant difference in the incidence of PVCs was detected because of large individual variation between the two groups (P = 0.21). A high PVC count did not appear to predict SCD. CONCLUSION: The combination of MI and bradycardia secondary to AV node ablation in sheep produces a higher incidence of VT than bradycardia alone, suggesting that this preparation can serve as a model for the study of VT and sudden cardiac death.