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1.
Am Heart J ; 218: 110-122, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31726314

RESUMO

BACKGROUND: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. METHODS: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. RESULTS: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. CONCLUSIONS: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

2.
Am Heart J ; 165(3): 344-53.e1, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23453103

RESUMO

Percutaneous coronary intervention (PCI) is an integral part of the treatment of coronary artery disease. The most common complication of PCI, bleeding, typically occurs at the vascular access site and is associated with short-term and long-term morbidity and mortality. Periprocedural bleeding also represents the primary safety concern of concomitant antithrombotic therapies essential for PCI success. Use of radial access for PCI reduces procedural bleeding and hence may change the risk profile and net clinical benefit of these drugs. This new drug-device safety interaction creates opportunities to advance the safe and effective use of antithrombotic agents during PCI. In June 2010 and March 2011, leaders from government, academia, professional societies, device manufacturing, and pharmaceutical industries convened for 2 think tank meetings. Titled TREAT I and II, these forums examined approaches to improve the overall safety of PCI by optimizing strategies for antithrombotic drug use and radial artery access. This article summarizes the content and proceedings of these sessions.


Assuntos
Doença da Artéria Coronariana/cirurgia , Fibrinolíticos/administração & dosagem , Intervenção Coronária Percutânea/métodos , Hemorragia Pós-Operatória/etiologia , Artéria Radial/cirurgia , Fibrinolíticos/efeitos adversos , Humanos , Intervenção Coronária Percutânea/efeitos adversos
4.
Am Heart J ; 160(4): 619-26, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20934554

RESUMO

Although several randomized clinical trials have demonstrated the safety and efficacy of catheter ablation of atrial fibrillation (AF) in experienced centers, the outcomes of this procedure in routine clinical practice and in patients with persistent and long-standing persistent AF remain uncertain. Brisk adoption of this therapy by physicians with diverse training and experience highlights potential concerns regarding the safety and effectiveness of this procedure. Some of these concerns could be addressed by a national registry of AF ablation procedures such as the Safety of Atrial Fibrillation Ablation Registry Initiative that was initially proposed at a Cardiac Safety Research Consortium Think Tank meeting in April 2009. In January 2010, the Cardiac Safety Research Consortium, in collaboration with the Duke Clinical Research Institute, the US Food and Drug Administration, the American College of Cardiology, and the Heart Rhythm Society, held a follow-up meeting of experts in the field to review the construct and progress to date. Other participants included the National Heart, Lung, and Blood Institute; the Centers for Medicare and Medicaid Services; the Agency for Healthcare Research and Quality; the AdvaMed AF working group; and additional industry representatives. This article summarizes the discussions that occurred at the meeting of the state of the Safety of Atrial Fibrillation Ablation Registry Initiative, the identification of a clear pathway for its implementation, and the exploration of solutions to potential issues in the execution of this registry.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/normas , Procedimentos Clínicos/organização & administração , Sistema de Registros , Gestão da Segurança/organização & administração , Humanos , Relações Interprofissionais , Estados Unidos
5.
Am Heart J ; 159(1): 17-24, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20102862

RESUMO

Atrial fibrillation (AF) is a major public health problem in the United States that is associated with increased mortality and morbidity. Of the therapeutic modalities available to treat AF, the use of percutaneous catheter ablation of AF is expanding rapidly. Randomized clinical trials examining the efficacy and safety of AF ablation are currently underway; however, such trials can only partially determine the safety and durability of the effect of the procedure in routine clinical practice, in more complex patients, and over a broader range of techniques and operator experience. These limitations of randomized trials of AF ablation, particularly with regard to safety issues, could be addressed using a synergistically structured national registry, which is the intention of the SAFARI. To facilitate discussions about objectives, challenges, and steps for such a registry, the Cardiac Safety Research Consortium and the Duke Clinical Research Institute, Durham, NC, in collaboration with the US Food and Drug Administration, the American College of Cardiology, and the Heart Rhythm Society, organized a Think Tank meeting of experts in the field. Other participants included the National Heart, Lung and Blood Institute, the Centers for Medicare and Medicaid Services, the Agency for Healthcare Research and Quality, the Society of Thoracic Surgeons, the AdvaMed AF working group, and additional industry representatives. The meeting took place on April 27 to 28, 2009, at the US Food and Drug Administration headquarters in Silver Spring, MD. This article summarizes the issues and directions presented and discussed at the meeting.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Procedimentos Clínicos , Sistema de Registros , Fibrilação Atrial/mortalidade , Feminino , Humanos , Relações Interprofissionais , Masculino , Gestão da Segurança , Estados Unidos
6.
Am J Physiol Heart Circ Physiol ; 294(1): H41-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17982010

RESUMO

Discordant action potential alternans creates large gradients of refractoriness, which are thought to be the mechanisms linking T-wave alternans to cardiac arrhythmogenesis. Since intercellular coupling acts to maintain synchronization of repolarization between cells, we hypothesized that intercellular uncoupling, such as during ischemia, would initiate discordant alternans and that restoration of intercellular coupling by the gap junction opener rotigaptide may provide a novel approach for suppressing arrhythmogenic discordant alternans. Optical mapping was used to record action potentials from ventricular epicardium of Langendorff-perfused guinea pig hearts. Threshold for spatially synchronized (i.e., concordant) alternans and discordant alternans was determined by increasing heart rate step-wise during 1) baseline, 2) treatment with rotigaptide or vehicle, and 3) global low-flow ischemia + rotigaptide or vehicle. Ischemia reduced the threshold for concordant alternans in both groups from 362 +/- 8 to 305 +/- 9 beats/min (P < 0.01) and for discordant alternans from 423 +/- 6 to 381 +/- 7 beats/min (P < 0.01). Interestingly, rotigaptide also increased the threshold for discordant alternans relative to vehicle both before (438 +/- 7 vs. 407 +/- 8 beats/min, P < 0.05) and during (394 +/- 7 vs. 364 +/- 9 beats/min, P < 0.05) ischemia. Rotigaptide increased conduction velocity and prevented conduction slowing and dispersion of repolarization during ischemia. Confocal immunofluorescence revealed that total connexin43 quantity and cellular distribution were unchanged before or after low-flow ischemia, with and without rotigaptide. However, connexin43 dephosphorylation in response to low-flow ischemia was significantly prevented by rotigaptide (15.9 +/- 7.0 vs. 0.3 +/- 6.4%, P < 0.001). These data suggest that intercellular uncoupling plays an important role in the transition from concordant to discordant alternans. By suppressing discordant alternans, repolarization gradients, and connexinx43 dephosphorylation, rotigaptide may protect against ischemia-induced arrhythmias. Drugs that selectively open gap junctions offer a novel strategy for antiarrhythmic therapy.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Junções Comunicantes/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Isquemia Miocárdica/complicações , Oligopeptídeos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Estimulação Cardíaca Artificial/efeitos adversos , Conexina 43/metabolismo , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Junções Comunicantes/metabolismo , Cobaias , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatologia , Oligopeptídeos/uso terapêutico , Fosforilação , Fatores de Tempo
7.
Cardiovasc Res ; 67(3): 539-47, 2005 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15913582

RESUMO

OBJECTIVE: We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43). METHODS: Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage. RESULTS: Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping. CONCLUSIONS: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.


Assuntos
Cardiomiopatias/metabolismo , Desmina/genética , Junções Comunicantes/química , Mutação , Contração Miocárdica , Miócitos Cardíacos/química , Animais , Cardiomiopatias/fisiopatologia , Desmina/análise , Desmina/metabolismo , Eletrofisiologia , Junções Comunicantes/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Modelos Animais , Miócitos Cardíacos/metabolismo
8.
J Biol Chem ; 279(15): 15330-8, 2004 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-14742426

RESUMO

The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), has been implicated in the process of cardiac hypertrophy and apoptosis, yet the specific roles of JNK in heart failure are unclear. To determine the effects of JNK activation in intact heart, we established transgenic animals using a Cre/loxP-mediated gene switch approach to achieve targeted expression of an upstream activator, mitogen-activated protein kinase kinase 7 (D) (MKK7D), in ventricular myocytes. MKK7D expression led to significant JNK activation, robust induction of the fetal gene program, and contractile dysfunction. The animals died approximately 7 weeks after birth with signs of congestive heart failure. Doppler mode echocardiography revealed a marked stiffening of JNK-activated hearts that was associated with the remodeling of specific extracellular matrix components. Gene expression analysis of MKK7D hearts revealed up-regulation of transforming growth factor beta signaling, offering a potential molecular mechanism underlying changes in extracellular matrix composition. In addition, we demonstrated that JNK activation led to specific loss of connexin 43 protein and gap junctions without affecting the expression or localization of other key intercalated disc proteins. This specific and localized gap junction remodeling resulted in significant slowing of ventricular electrical conduction in JNK-activated hearts. These results represent the first characterization of JNK-mediated cardiac pathology in vivo and support an important role for JNK signaling in specific aspects of cardiac remodeling in the pathogenesis of cardiac disease.


Assuntos
Cardiomiopatias/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Proteínas Quinases Ativadas por Mitógeno/química , Animais , Animais Geneticamente Modificados , Apoptose , Conexina 43/metabolismo , Ecocardiografia , Condutividade Elétrica , Eletrocardiografia , Ativação Enzimática , Matriz Extracelular/metabolismo , Junções Comunicantes , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde , Coração/fisiologia , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Luminescentes/metabolismo , Pulmão/metabolismo , MAP Quinase Quinase 7 , Camundongos , Camundongos Transgênicos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Tamanho do Órgão , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Transgenes , Regulação para Cima
9.
Circulation ; 108(25): 3157-63, 2003 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-14656916

RESUMO

BACKGROUND: Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart. METHODS AND RESULTS: High-resolution optical mapping was used to measure conduction velocity (CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline (pH 7.4) and during 45 minutes of perfusion with acidotic (pH 6.0) Tyrode's solution with (n=8) and without (control, n=7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1+/-0.1 to 16.8+/-0.2 cm/s, P<0.0001) and longitudinal (47.2+/-2.4 to 33.2+/-4.8 cm/s, P<0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na+ current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound's action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 (6.7+/-0.8 ms) compared with controls (9.7+/-3.1 ms, P<0.05), presumably by enhancing cell-to-cell coupling. CONCLUSIONS: These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.


Assuntos
Antiarrítmicos/farmacologia , Junções Comunicantes/efeitos dos fármacos , Coração/efeitos dos fármacos , Oligopeptídeos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Mapeamento Potencial de Superfície Corporal , Células Cultivadas , Sistemas de Liberação de Medicamentos , Condutividade Elétrica , Junções Comunicantes/fisiologia , Cobaias , Coração/fisiologia , Concentração de Íons de Hidrogênio , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Técnicas de Cultura de Órgãos
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