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Integrina alfa4/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfocitos B/efectos de los fármacos , Tiofenos/química , Urea/análogos & derivados , Animales , Antineoplásicos/química , Técnicas de Cocultivo , Resistencia a Antineoplásicos , Humanos , Inflamación , Leucemia/tratamiento farmacológico , Ratones , Trasplante de Neoplasias , Células Precursoras de Linfocitos B/citología , Células del Estroma/citología , Tiofenos/administración & dosificación , Urea/administración & dosificación , Urea/químicaRESUMEN
Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/ß- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.
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Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Fragmentos de Péptidos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinonas/farmacología , Sialoglicoproteínas/metabolismo , beta Catenina/metabolismo , Animales , Asparaginasa/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dexametasona/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/genética , Sialoglicoproteínas/antagonistas & inhibidores , Sialoglicoproteínas/genética , Survivin , Vincristina/farmacología , Vía de Señalización Wnt , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: CRT causes reduction in MR due to left ventricular (LV) remodelling, but determinants of clinically meaningful MR reduction acutely after CRT have not been evaluated. OBJECTIVES: We evaluated echocardiographic predictors of significant reduction in functional mitral regurgitation (MR) by cardiac resynchronisation treatment (CRT). METHODS: 35 patients with >or= moderate to severe MR underwent CRT for presence of electrical and/or mechanical dyssynchrony. Significant reduction in MR post-CRT was defined as reduction to less than moderate MR (MR jet area/left atrial area <25%, group 1) on follow-up echocardiogram at 1.7 (SD 2.8) months post-CRT. RESULTS: Significant MR reduction of 62% (28%) from baseline MR occurred in 18 patients vs 22% (16%) in the remaining patients (group 2), p<0.01). Follow-up left ventricular ejection fraction (LVEF) was 0.43 (0.09) in group 1 patients vs 0.29% (0.1%) in group 2 patients (p<0.001). On multivariate analysis, time to peak strain in the mid inferior segment was the only significant predictor of MR reduction post-CRT (p = 0.008, OR = 1.023 (CI 1.006 to 1.041). The sensitivity and specificity of the combined variable of time to peak strain of >400 ms in the mid inferior segment and peak negative strain of >or=9% and 8% in the basal and mid posterior segments, respectively, to predict follow-up MR was 88% and 93% respectively and positive and negative predictive value was 94% and 87%. CONCLUSION: In patients with cardiomyopathy and significant MR, the presence of delayed longitudinal strain in the mid inferior LV segment along with preserved negative systolic strain in the basal and mid posterior segments predicts substantial reduction in MR post-CRT.
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Arritmias Cardíacas/terapia , Estimulación Cardíaca Artificial , Insuficiencia de la Válvula Mitral/terapia , Adulto , Anciano , Arritmias Cardíacas/etiología , Ecocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Estudios Prospectivos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Adulto JovenRESUMEN
BACKGROUND: Human mesenchymal stem cells (MSC) possess powerful ex vivo expansion and versatile differentiation potential, placing themselves at the forefront of the field of stem cell-based therapy and transplantation. Of high clinical relevance is the endothelial differentiation potential of MSC, which can be used to treat various forms of ischemic vascular disease. METHODS: We investigated whether human umbilical cord blood (UCB)-derived MSC are able to differentiate in vitro along an endothelial lineage, by using flow cytometry, RT-PCR and immunofluorescence analyzes, as well as an Ab array method. RESULTS: When the cells were incubated for up to 3 weeks in the presence of VEGF, EGF and hydrocortisone, they began to express a variety of endothelial lineage surface markers, such as Flk-1, Flt-1, VE-Cadherin, vWF, VCAM-1, Tie-1 and Tie-2, and to secrete a specific set of cytokines. Differentiated cells were also found to be able to uptake low-density lipoprotein and form a tubular network structure. DISCUSSION: These observations have led us to conclude that UCB-derived MSC retain endothelial potential that is suitable for basic and clinical studies aimed at the development of vasculature-directed regenerative medicine.
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Diferenciación Celular/fisiología , Células Endoteliales/citología , Sangre Fetal/citología , Células Madre Mesenquimatosas/citología , Antígenos CD/análisis , Cadherinas/análisis , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Células Endoteliales/química , Células Endoteliales/fisiología , Factor de Crecimiento Epidérmico/farmacología , Expresión Génica/genética , Humanos , Hidrocortisona/farmacología , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Lipoproteínas LDL/farmacocinética , Células Madre Mesenquimatosas/química , Células Madre Mesenquimatosas/metabolismo , Neovascularización Fisiológica , Receptor TIE-1/genética , Receptor TIE-2/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Molécula 1 de Adhesión Celular Vascular/análisis , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/análisis , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Factor de von Willebrand/análisisAsunto(s)
Antiarrítmicos/efectos adversos , Arritmias Cardíacas/terapia , Desfibriladores Implantables , Campos Electromagnéticos/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Marcapaso Artificial , Cardioversión Eléctrica , Electrofisiología , Humanos , Imagen por Resonancia Magnética , Miocardio/metabolismo , TeléfonoRESUMEN
OBJECTIVES: The study was performed to document that atrioventricular node reciprocating tachycardia (AVNRT) can be associated with eccentric retrograde left-sided activation, masquerading as tachycardia using a left accessory pathway. BACKGROUND: The eccentric retrograde left-sided activation during tachycardia is thought to be diagnostic of the presence of a left free wall accessory pathway. However, it is not known whether AVNRT can occur with eccentric retrograde left-sided activation. METHODS: We studied 356 patients with AVNRT who underwent catheter ablation. Retrograde atrial activation during tachycardia and ventricular pacing were determined by intracardiac recordings, including the use of a decapolar coronary sinus catheter. RESULTS: The retrograde atrial activation was eccentric in 20 patients (6%). Eight of these patients had the earliest retrograde atrial activation recorded in the lateral coronary sinus leads, and 12 had the earliest retrograde atrial activation recorded in the posterior coronary sinus leads, with the most proximal coronary sinus electrode pair straddling the coronary sinus orifice. These tachycardias were either the fast-slow or the slow-slow form of AVNRT. The slow-fast form of AVNRT was also inducible in 17 of the 20 patients. Successful ablation of the slow pathway in the right atrial septum near the coronary sinus ostium prevented the induction and clinical recurrence of reciprocating tachycardia in all patients. CONCLUSIONS: Atypical AVNRT with eccentric retrograde left-sided activation was demonstrated in 6% of all patients with AVNRT masquerading as tachycardia using a left-sided accessory pathway. Ablation of the slow pathway at the posterior aspects of the right atrial septum resulted in a cure in these patients.
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Sistema de Conducción Cardíaco , Taquicardia por Reentrada en el Nodo Atrioventricular/diagnóstico , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Taquicardia/fisiopatología , Adulto , Anciano , Ablación por Catéter , Diagnóstico Diferencial , Electrocardiografía , Femenino , Atrios Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Taquicardia/diagnóstico , Taquicardia/terapia , Taquicardia por Reentrada en el Nodo Atrioventricular/terapiaRESUMEN
BACKGROUND: A patient-specific measure of defibrillation efficacy that requires a minimum number of ventricular fibrillation (VF) episodes would be valuable for programming implantable cardioverter-defibrillators (ICDs). The upper limit of vulnerability (ULV) is the weakest shock strength at or above which VF is not induced when a stimulus is delivered during the vulnerable phase of the cardiac cycle. It correlates with the defibrillation threshold (DFT) and can be determined with a single episode of VF. The objective of this study was to test the hypothesis that ICDs programmed on the basis of the ULV convert spontaneous ICD-detected VF reliably. METHODS AND RESULTS: We studied 100 consecutive patients at ICD implantation and during follow-up of 20 +/- 7 months. At implantation, the ULV and DFT were determined, and the ICD system was tested at a shock strength equal to the ULV + 3 J. During follow-up, the strength of the first shock was programmed to the ULV + 5 J for arrhythmias detected in the VF zone (cycle length < 292 +/- 17 ms). We reviewed stored detection intervals and electrograms from spontaneous episodes of ICD-detected VF to determine the success rate for appropriate first shocks. The programmed first-shock strength was 17.5 +/- 5.2 J. During follow-up, there were 120 appropriate first shocks in 37 patients. The arrhythmia was rapid monomorphic ventricular tachycardia (VT) in 70% of episodes (31 patients), VF in 11% (13 patients), polymorphic VT in 1%, and unclassified in 17% (15 patients). The first shock was successful in 119 of 120 episodes (99%; 95% CI, 93% to 100%). One unclassified episode required two shocks. No patient had syncope associated with an ICD shock or arrhythmic death. CONCLUSIONS: ICD shocks can be programmed on the basis of the ULV, a measurement made in regular rhythm, without a direct measure of defibrillation efficacy.
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Desfibriladores Implantables , Programas Informáticos , Taquicardia Ventricular/terapia , Fibrilación Ventricular/terapia , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/fisiopatologíaRESUMEN
INTRODUCTION: The upper limit of vulnerability (ULV) is the shock strength at or above which ventricular fibrillation cannot be induced when delivered in the vulnerable period. It correlates acutely with the acute defibrillation threshold (DFT) and can be determined with a single episode of fibrillation. The goal of this prospective study was to determine the relationship between the ULV and the chronic DFT. METHODS AND RESULTS: We studied 40 patients at, and 3 months after, implantation of transvenous cardioverter defibrillators. The ULV was defined as the weakest biphasic shock that failed to induce fibrillation when delivered 0, 20, and 40 msec before the peak of the T wave. patients were classified as clinically stable or unstable based on prospectively defined criteria. There were no significant differences between the group means for the acute and chronic determinations of ULV (13.5 +/- 5.3 J vs 12.4 +/- 6.8 J, P = 0.25) and DFT (10.1 +/- 5.0 J vs 9.9 +/- 5.7 J, P = 0.74). Five patients (15%) were classified as unstable. The strength of the correlation between acute ULV and acute DFT (r = 0.74, P < 0.001) was similar to that between the chronic ULV and chronic DFT (r = 0.82, P < 0.001). There was a correlation between the change in ULV from acute to chronic and the corresponding change in DFT (r = 0.67, P < 0.001). The chronic DFT was less than the acute ULV +3 J in all 35 stable patients, but it was greater in 2 of 5 unstable patients (P = 0.04). CONCLUSIONS: The strength of the correlation between the chronic ULV and the chronic DFT is comparable to that between the acute ULV and the acute DFT. Temporal changes in the ULV predict temporal changes in the DFT. In clinically stable patients, a defibrillation safety margin of 3 J above the acute ULV proved an adequate chronic safety margin.
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Desfibriladores Implantables , Cardioversión Eléctrica/métodos , Taquicardia Ventricular/terapia , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Taquicardia Ventricular/fisiopatologíaRESUMEN
INTRODUCTION: Shocks during the vulnerable period of the cardiac cycle induce ventricular fibrillation (VF) if their strength is above the VF threshold (VFT) and less than the upper limit of vulnerability (ULV). However, the range of shock strengths that constitutes the vulnerable zone and the corresponding range of coupling intervals have not been defined in humans. The ULV has been proposed as a measure of defibrillation because it correlates with the defibrillation threshold (DFT), but the optimal coupling interval for identifying it is unknown. METHODS AND RESULTS: We studied 14 patients at implants of transvenous cardioverter defibrillators. The DFT was defined as the weakest shock that defibrillated after 10 seconds of VF. The ULV was defined as the weakest shock that did not induce VF when given at 0, 20, and 40 msec before the peak of the T wave or 20 msec after the peak in ventricular paced rhythm at a cycle length of 500 msec. The VFT was defined as the weakest shock that induced VF at any of the same four intervals. To identify the upper and lower boundaries of the vulnerable zone, we determined the shock strengths required to induce VF at all four intervals for weak shocks near the VFT and strong shocks near the ULV. The VFT was 72 +/- 42 V, and the ULV was 411 +/- V. In all patients, a shock strength of 200 V exceeded the VFT and was less than the ULV. The coupling interval at the ULV was 19+/- 11 msec shorter than the coupling interval at the VFT (P < 0.001). The vulnerable zone showed a sharp peak at the ULV and a less distinct nadir at the VFT. A 20-msec error in the interval at which the ULV was measured could have resulted in underestimating it by a maximum of 95 +/- 31 V. The weakest shock that did not induce VF was greater for the shortest interval tested than for the longest interval at both the upper boundary (356 +/- 108 V vs 280 +/- 78 V; P < 0.01) and lower boundary (136 +/- 68 msec vs 100 +/- 65 msec; P < 0.05). CONCLUSIONS: The human vulnerable zone is not symmetric with respect to a single coupling interval, but slants from the upper left to lower right. Small differences in the coupling interval at which the ULV is determined or use of the coupling interval at the VFT to determine the ULV may result in significant variations in its measured value. An efficient strategy for inducing VF would begin by delivering a 200-V shock at a coupling interval 10 msec before the peak of the T wave.
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Cardioversión Eléctrica , Fibrilación Ventricular/fisiopatología , Fibrilación Ventricular/terapia , Anciano , Recolección de Datos , Electrodos , Electrochoque , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
This report describes a percutaneous, transaxillary approach for implanting permanent pacemakers in the retropectoral space. This approach was used in 17 patients; indications for the procedure included the need to find a new implantation site in patients with infections and multiple previous pacemaker pocket sites (2 patients), emaciation and absence of sufficient adipose tissue (4 patients), and cosmetic considerations (11 patients). No complications were encountered during the implantation and the results were uniformly excellent in all patients. The pacemaker was "invisible" in each case. We conclude that a percutaneous approach for implanting permanent pacemakers in the retropectoral region is safe and feasible. This approach is likely to be applicable to the implantation of transvenous antitachycardia devices.
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Estimulación Cardíaca Artificial/métodos , Marcapaso Artificial , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético , Selección de Paciente , TóraxRESUMEN
A new 83 cm3 implantable cardioverter-defibrillator (ICD) designed for pectoral implantation has been implanted most frequently using right ventricular and superior vena cava (RV-->SVC) electrodes; a patch electrode (RV-->patch + SVC) has been added when necessary to decrease the defibrillation threshold (DFT). The goal of this prospective study was to compare biphasic waveform DFTs for 3 electrode configurations: RV-->patch, RV-->SVC, and RV-->patch + SVC in 25 consecutive patients. The patch was positioned in a left retro-pectoral pocket, and the SVC electrode was positioned with the tip at the junction of the SVC and innominate vein. In the first 15 patients, all 3 electrode configurations were tested in random order; in the last 10 patients, only the RV-->patch and RV-->patch + SVC configurations were tested. In the first 15 patients, the stored-energy DFT for the RV-->SVC configuration (15.2 +/- 7.7 J) was higher (p < 0.001) than the DFT for the RV-->patch configuration (11.3 +/- 6.2 J) and the RV-->patch + SVC configuration (10.0 +/- 5.8 J). For all 25 patients, the DFT was lower for the RV-->patch + SVC configuration (9.7 +/- 5.1 J) than for the RV-->patch configuration (12.4 +/- 6.6 J, p = 0.005). The pathway resistance was highest for the RV-->patch configuration (72 +/- 9 omega), lower for the RV-->SVC configuration (63 +/- 6 omega, p < 0.01), and lowest for the RV-->patch + SVC configuration (46 +/- 3 omega, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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Desfibriladores Implantables , Anciano , Interpretación Estadística de Datos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculos Pectorales , Volumen Sistólico , Taquicardia Ventricular/terapia , Fibrilación Ventricular/terapiaRESUMEN
BACKGROUND: The upper limit of vulnerability is the stimulus strength above which electrical stimulation cannot induce ventricular fibrillation even when the stimulus occurs during the vulnerable period of the cardiac cycle. The purpose of this study was to test the hypothesis that the upper limit of vulnerability can accurately predict the defibrillation threshold in patients undergoing implantable cardioverter-defibrillator (ICD) implantation using nonthoracotomy lead systems. METHODS AND RESULTS: We studied 77 patients at the time of ICD implantation. Multiple endocardial-endocardial and endocardial-subcutaneous shock pathways were used. Two different protocols were used to test the upper limit of vulnerability. In protocol 1 (n = 17), the upper limit of vulnerability was tested with two shocks on the peak or the up-slope of the T wave of paced rhythm. The shocks were given randomly either at the peak and 20 milliseconds before the peak of T wave (n = 7) or at 20 and 40 milliseconds before the peak of T wave (n = 10). In protocol 2 (n = 60), the upper limit of vulnerability was tested with three shocks delivered at 0, 20, and 40 milliseconds before the peak of the T wave. The weakest shock that failed to induce ventricular fibrillation by a 5-J step-down or step-up method was defined as the upper limit of vulnerability. The defibrillation threshold was also determined by a 5-J step-down or step-up method. In protocol 1, the upper limit of vulnerability (9 +/- 6 J) was significantly lower than the defibrillation threshold (13 +/- 7 J) with a correlation coefficient of .87 and P < .001. In protocol 2, the upper limit of vulnerability (13 +/- 6 J) was not significantly different from the defibrillation threshold (13 +/- 6 J) with a correlation coefficient of .85 and P < .001. In 45 of the 60 patients, the upper limit of vulnerability was < or = 15 J; all had a defibrillation threshold of < or = 20 J. In 51 of the 60 patients, the upper limit of vulnerability was within 5 J of the defibrillation threshold. The upper limit of vulnerability overestimated the defibrillation threshold by > 10 J in 8 patients and underestimated the defibrillation threshold by > 10 J in only 1 patient. The overestimation and underestimation occurred only in patients with the upper limit of vulnerability > 15 J. CONCLUSIONS: When tested with three shocks on and before the peak of the T wave, the upper limit of vulnerability accurately predicted the defibrillation threshold in patients undergoing ICD implantation using nonthoracotomy lead systems. This method required either one or no episodes of ventricular fibrillation in most patients.
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Cardioversión Eléctrica , Anciano , Amiodarona/farmacología , Desfibriladores Implantables , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Little is known about the transmyocardial impedance during internal ventricular defibrillation. In a canine model, using high rate on-line digitization, random shock delivery, and titanium electrodes, we determined the relationship among voltage, current, and impedance, delivered energy, and defibrillation success within the individual and within successive defibrillation shocks. Impedance decreased with repeated defibrillation in 10 of 11 dogs. Impedance always increased during trapezoidal discharges, whereas voltage decreased. Impedance was lower with high energy-voltage shocks in all dogs. Visually, voltage and current waveform did not show a phase shift. There was no difference in the total energy delivered and the energy converted into heat by the resistive part of the impedance. With a formula valid only for resistive loads, the capacitance of the defibrillator was calculated to be within the measurement accuracy and tolerance of the factory-provided value of 132 microF. Polarization voltage was consistently observed. Thus the transmyocardial impedance during defibrillation is primarily resistive, nonlinear voltage dependent, and declines with successive shocks. Defibrillation success was not influenced by these phenomena.
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Cardioversión Eléctrica , Corazón/fisiopatología , Animales , Perros , Conductividad Eléctrica , Cardioversión Eléctrica/métodos , Femenino , Masculino , Modelos Cardiovasculares , Probabilidad , Resultado del TratamientoRESUMEN
OBJECTIVES: The goal of this study was to determine the incidence and clinical significance of underdetection in 125 patients treated with a tiered-therapy cardioverter-defibrillator, the Medtronic PCD. BACKGROUND: Underdetection, distinct from undersensing, is a unique, potential complication of new algorithms that enhance specificity in tiered-therapy cardioverter-defibrillators. These algorithms may delay or prevent recognition of ventricular tachycardia even though electrograms are sensed accurately and RR intervals meet the programmed interval criterion. METHODS: Underdetection was defined as delay in detection > 5 s at electrophysiologic study or symptomatic delay or detection failure at follow-up of 15 +/- 8 months. RESULTS: We identified six specific mechanisms of underdetection caused by algorithms to discriminate sustained ventricular tachycardia from sinus tachycardia, atrial fibrillation, ventricular fibrillation and nonsustained ventricular tachycardia. Underdetection caused detection delays in 13 (1.9%) of 677 induced ventricular tachyarrhythmia episodes in 12 patients (9.6%). During follow-up, underdetection occurred in 7 (9.9%) of 71 patients in whom ventricular tachycardia therapies were programmed. Failure to detect ventricular tachycardia occurred in 6 (0.6%) of 988 spontaneous ventricular tachycardia episodes in four patients (5.6%); 2 episodes required external cardioversion. After defibrillator reprogramming, underdetection did not occur. CONCLUSIONS: Algorithms to enhance specificity cause underdetection of ventricular tachycardia in a significant minority of patients with tiered-therapy cardioverter-defibrillators. Optimal programming can minimize underdetection.
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Algoritmos , Desfibriladores Implantables , Taquicardia Ventricular/diagnóstico , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Taquicardia Ventricular/terapiaRESUMEN
The effects of applied voltage and phase of respiration on impedance of pathways used by implantable cardioverter-defibrillators were investigated. Patients were studied at implantation of cardioverter-defibrillators using epicardial (n = 12) or transvenous and subcutaneous (SQ) (n = 30) electrodes. Transvenous-SQ pathways were right ventricular cathode to SQ anode and coronary sinus cathode to SQ anode. Transvenous-transvenous pathways were right ventricle to coronary sinus and right ventricle to superior vena cava. Patients with nonthoracotomy electrode systems were studied at end-expiration and end-inspiration. Five shocks of 65 to 745 V (0.2 to 34 J) were given in random order in sinus rhythm. Over this range, end-expiratory impedance decreased monotonically for all pathways. This effect was greatest for transvenous-SQ pathways (13 +/- 3% to 17 +/- 4%, p < 0.001), intermediate for transvenous-transvenous pathways (5 +/- 4% to 8 +/- 5%, p < 0.001), and least for epicardial pathways (3 +/- 3%, p = 0.006). Paired data in inspiration and expiration showed that inspiration increased impedance in transvenous-SQ pathways (p < 0.001) but not in transvenous-transvenous pathways. Further, the effects of respiration and voltage on impedance in transvenous-SQ pathways were interactive (p < 0.001): Inspiration increased voltage-dependence of impedance. The magnitude of the inverse relationship between voltage and impedance depends on type of defibrillation pathway. The effect of respiration on impedance suggests that voltage-dependence of impedance is greatest in the lungs. These findings have potential relevance for intraoperative testing of cardioverter-defibrillators and selection of pathways for low-energy cardioversion.
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Cardioversión Eléctrica , Impedancia Eléctrica , Respiración/fisiología , Anciano , Análisis de Varianza , Desfibriladores Implantables , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , ToracotomíaRESUMEN
BACKGROUND: In the canine model, an upper limit of shock strength exists that can induce ventricular fibrillation during the vulnerable period of the cardiac cycle. This shock strength (the upper limit of vulnerability) closely correlates with the defibrillation threshold and supports the "upper limit of vulnerability" hypothesis of defibrillation. It is not known whether an upper limit of vulnerability exists in humans or whether this limit correlates with the defibrillation threshold. METHODS AND RESULTS: In 13 patients undergoing implantable cardioverter-defibrillator implantation, the shock strengths associated with a 50% probability of reaching the upper limit of vulnerability (ULV50) and a 50% probability of reaching the defibrillation threshold (DFT50) were determined by the up-down algorithm. The ULV50 was determined only for the mid-upslope of the positive T waves and for the mid-downslope of the negative T waves. No major complications occurred during surgery. An upper limit of vulnerability was demonstrated in each patient. The ULV50 was 300 +/- 138 V or 6.8 +/- 5.8 J, which was significantly lower than the DFT50 of 347 +/- 167 V (p = 0.038) or 9.1 +/- 7.3 J (p = 0.013). The correlation between the ULV50 and the DFT50 was significant (r = 0.90, p < 0.001 for voltage; r = 0.93, p < 0.001 for energy). CONCLUSIONS: An upper limit of vulnerability is present in humans. There is a significant correlation between the ULV50 and the DFT50, and the ULV50 is significantly lower than the DFT50.
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Algoritmos , Desfibriladores Implantables , Cardioversión Eléctrica , Sistema de Conducción Cardíaco/fisiopatología , Fibrilación Ventricular/prevención & control , Estimulación Cardíaca Artificial , Muerte Súbita Cardíaca/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Taquicardia Ventricular/terapia , Fibrilación Ventricular/etiología , Fibrilación Ventricular/fisiopatologíaRESUMEN
OBJECTIVE: This study was conducted to assess the utility of clinical variables in predicting the inducibility of sustained ventricular arrhythmias in a heterogeneous group of patients undergoing programmed ventricular stimulation. METHODS: Variables were considered in a simulated chronologic order to determine the incremental information added by the signal-averaged electrocardiogram (ECG) and left ventricular ejection fraction. All patients undergoing baseline programmed ventricular stimulation for induction of ventricular tachyarrhythmia during a 30-month period were included in the study. Fourteen historical, ECG, signal-averaged ECG and left ventricular wall motion variables were evaluated for their ability in predicting inducibility of a sustained ventricular arrhythmia, a "positive" event, at programmed ventricular stimulation. RESULTS: On univariate analysis of the clinical variables, comparison between patients with positive or negative results showed significant differences in 10 of the 14 clinical variables: major cardiac diagnosis, history of ventricular tachycardia, myocardial infarction by history or ECG, all five signal-averaged ECG variables, left ventricular ejection fraction and presence of left ventricular aneurysm. On multivariate analysis, five independent variables were determined to be important: history of ventricular tachycardia, historical or ECG evidence of myocardial infarction, history of loss of consciousness, filtered QRS duration on the signal-averaged ECG and left ventricular ejection fraction. However, with sequential multivariate analysis, a model based only on historical and conventional ECG data was found to do as well as a model that included signal-averaged ECG and left ventricular ejection fraction data. CONCLUSIONS: Routinely available noninvasive historical, ECG, signal-averaged ECG and left ventricular wall motion variables can be used to accurately predict the outcome of programmed ventricular stimulation. The majority of the predictive power was obtained with the routine model, using only historical and ECG data. The signal-averaged ECG and left ventricular wall motion analysis added no significant incremental information.
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Arritmias Cardíacas/epidemiología , Estimulación Cardíaca Artificial , Técnicas de Apoyo para la Decisión , Taquicardia/epidemiología , Anciano , Arritmias Cardíacas/diagnóstico , Electrocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Curva ROC , Factores de Riesgo , Procesamiento de Señales Asistido por Computador , Volumen Sistólico , Taquicardia/diagnósticoRESUMEN
Although amiodarone is an effective drug for the treatment of life-threatening ventricular arrhythmias, no standard oral loading dose protocol has been defined, and patients often undergo prolonged hospitalization for amiodarone loading. High dose (greater than 1,800 mg/day) oral loading has usually been reserved for unstable patients with incessant ventricular tachyarrhythmias. The current study was designed to 1) examine the clinical and electrophysiologic effects of a high dose oral amiodarone loading regimen in more stable patients; and 2) ascertain its safety and tolerance, possibly allowing shortened amiodarone loading periods and potentially decreased length of hospital stay. The study group included 16 patients with a history of recurrent ventricular arrhythmias and decreased left ventricular function, who were refractory to prior antiarrhythmic drug therapy. The oral loading protocol was 50 mg/kg per day of amiodarone for 3 days, then 30 mg/kg per day for 2 days, followed by maintenance therapy of 300 to 400 mg twice daily. Electrophysiologic testing was performed at baseline, on days 1 and 5 and during week 6. Amiodarone and desethylamiodarone levels were measured and symptoms monitored. Clinically, the high dose loading protocol was well tolerated in 15 of the 16 patients. Arrhythmias were rendered noninducible by day 1 in three patients and remained noninducible throughout the study period in two of the three. The remaining patients continued to have inducible ventricular tachycardia. Ventricular tachycardia cycle length and right ventricular effective refractory period both progressively increased significantly over baseline, starting on day 1. The 15 patients who remained in the study had no significant side effects during the loading period.(ABSTRACT TRUNCATED AT 250 WORDS)
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Amiodarona/administración & dosificación , Administración Oral , Amiodarona/efectos adversos , Amiodarona/análogos & derivados , Amiodarona/sangre , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Tolerancia a Medicamentos , Electrofisiología , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia , Taquicardia/sangre , Taquicardia/tratamiento farmacológico , Taquicardia/fisiopatología , Factores de TiempoRESUMEN
The relation between ventricular late potentials and the occurrence of acute (in-hospital) and hyperacute (before hospital admission) ventricular tachycardia or fibrillation was studied in 281 consecutive patients with uninterrupted acute myocardial infarction. The prevalence of late potentials was significantly higher in patients with than without ventricular tachycardia/fibrillation (65 vs 22%; p less than 0.01). These relations persisted among patients with left bundle branch block, although a different definition was used for identifying late potentials in these patients. Multivariate analysis showed that presence of late potentials and peak creatine kinase enzyme level were the only 2 independent variables associated with early ventricular tachycardia/fibrillation. Total in-hospital mortality, as well as in-hospital cardiac mortality, was significantly higher among patients with than without acute ventricular tachycardia/fibrillation. However, at 1 year, mortality rates did not differ between the 2 groups. The following conclusions were drawn from this study: (1) Late potentials are closely related to ventricular tachycardia/fibrillation in hyperacute and acute phases of infarction. (2) Presence of left bundle branch block does not mitigate against the finding of late potentials in these patients. (3) Early ventricular tachycardia/fibrillation in acute infarction is related to large infarctions and to a high in-hospital mortality rate.