Assuntos
Doenças Cardiovasculares/terapia , Reforma dos Serviços de Saúde/legislação & jurisprudência , Política de Saúde/legislação & jurisprudência , Patient Protection and Affordable Care Act/legislação & jurisprudência , Formulação de Políticas , Saúde da Mulher/legislação & jurisprudência , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Feminino , Regulamentação Governamental , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde/legislação & jurisprudência , Humanos , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Informed consent is the cornerstone for protection of human subjects in clinical trials. However, a growing body of evidence suggests that reform of the informed consent process in the United States is needed. METHODS: The Clinical Trials Transformation Initiative conducted interviews with 25 experienced observers of the informed consent process to identify limitations and actionable recommendations for change. RESULTS: There was broad consensus that current practices often fail to meet the ethical obligation to inform potential research participants during the informed consent process. The most frequent single recommendation, which would affect all participants in federally regulated clinical research, was reform of the informed consent document. The interviews also identified the need for reform of clinical research review by institutional review boards, including transitioning to a single institutional review board for multi-site trials. CONCLUSION: The consensus recommendations from the interviewees provide a framework for meaningful change in the informed consent process. Although some proposed changes are feasible for rapid implementation, others such as substantive reform of the informed consent document may require change in federal regulations.
Assuntos
Comitês Consultivos , Pesquisa Biomédica/ética , Consentimento Livre e Esclarecido/normas , Consenso , Humanos , Consentimento Livre e Esclarecido/ética , Entrevistas como Assunto , Pesquisa Qualitativa , Estados UnidosRESUMO
The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.
Assuntos
Pressão Sanguínea/fisiologia , Cardiomegalia/genética , Cardiomegalia/patologia , Hipertensão/patologia , Miócitos Cardíacos/patologia , Receptor Tipo 2 de Angiotensina/genética , Animais , Fator Natriurético Atrial/metabolismo , Northern Blotting , Western Blotting , Colágeno/metabolismo , Hipertensão/genética , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor Tipo 2 de Angiotensina/fisiologia , Análise de Sobrevida , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVE: To develop a model to predict stroke-free survival and mortality over a multiyear time frame for a trial-excluded population of medically managed asymptomatic patients with significant carotid artery stenosis. METHODS: We calibrated, validated, and applied a Monte Carlo microsimulation model. For calibration we adjusted general-population mortality and stroke risks to capture these risks specific to asymptomatic carotid stenosis patients. For validation, we compared model-predicted and actual stroke-free survival curves and stroke counts from a population of comparable patients. For application, the validated model predicted stroke-free survival for a hypothetical medically managed arm of a recent single-arm carotid revascularization trial. RESULTS: For each month in the 60-month time frame, the model-predicted and actual calibration trial stroke-free survival curves were not statistically different (P > 0.62). In validation, the calibrated model's stroke-free survival curvematched the actual curve from an independent population; beyond 24 months, the model-predicted and actual curves were not statistically different (P > 0.32). We also compared model-predicted and actual number of strokes from the independent trial. The model predicted 187.25 strokes (95% confidence interval 161.49-213.01), while the actual number was 171.6, within 1.22 standard deviations of the simulated mean. CONCLUSIONS: Given the absence of medically managed populations in recent carotid stenosis trials, our model can estimate stroke-free survival and mortality data for these patients. The model may also estimate the effectiveness of novel medical and procedural therapies for stroke prevention. These effectiveness estimates can inform the development of policies, guidelines, or cost-effectiveness analyses when only single-arm trial data exist.
Assuntos
Estenose das Carótidas/diagnóstico , Simulação por Computador , Indicadores Básicos de Saúde , Acidente Vascular Cerebral/prevenção & controle , Calibragem , Estenose das Carótidas/complicações , Intervalo Livre de Doença , Humanos , Método de Monte Carlo , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND: Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the "dose" of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers. METHODS AND RESULTS: A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression. I(HCN2) was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic pacemakers. Studies encompassed 6 weeks. I(HCN2) for all cells was 32.1+/-1.3 pA/pF (mean+/-SE) at -150 mV. Pacemaker function in intact dogs required 10 to 12 days to fully stabilize and persisted consistently through day 42 in dogs receiving > or =700,000 hMSCs (approximately 40% of which carried current). Rhythms were catecholamine responsive. Tissues from animals killed at 42 days manifested neither apoptosis nor humoral or cellular rejection. CONCLUSIONS: hMSCs provide a means for administering catecholamine-responsive biological pacemakers that function stably for 6 weeks and manifest no cellular or humoral rejection at that time. Cell doses >700,000 are sufficient for pacemaking when administered to left ventricular myocardium.
Assuntos
Coração/fisiologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Adulto , Animais , Células Cultivadas , Cães , Condutividade Elétrica , Eletrocardiografia , Epinefrina/farmacologia , Bloqueio Cardíaco/fisiopatologia , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Canais Iônicos/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Técnicas de Patch-Clamp , Canais de Potássio , Transfecção , Transplante HeterólogoAssuntos
Desfibriladores Implantáveis , Revelação , Vigilância de Produtos Comercializados , Qualidade de Produtos para o Consumidor/legislação & jurisprudência , Desfibriladores Implantáveis/efeitos adversos , Desfibriladores Implantáveis/economia , Aprovação de Equipamentos/legislação & jurisprudência , Revelação/legislação & jurisprudência , Falha de Equipamento , Segurança de Equipamentos , Humanos , Indústrias/legislação & jurisprudência , Notificação de Abuso , Rotulagem de Produtos/legislação & jurisprudência , Risco , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
Public registration of clinical trials is fundamentally important to the integrity of the medical device development process. In addition to fulfilling obligations to those study volunteers, a complete record of trial results provides the general public, clinical community, and medical device manufacturers with a more accurate understanding as to how a specific therapeutic should be used. Although the issues associated with public disclosure of clinical trials are similar to the pharmaceutical industries, the iterative nature of device development introduces differences in what type of information needs to be disclosed during development and commercialization. The Second Dartmouth Device Development Symposium (3D2) held in October 2004 brought together thought leaders representing many of the stakeholders associated with medical device development. This consensus document arising from the proceedings of the 3D2 is offered to provide background to these issues and recommend pathways to implementation of device trial registration.
Assuntos
Ensaios Clínicos como Assunto , Equipamentos e Provisões/normas , Sistema de Registros , HumanosAssuntos
Doenças Cardiovasculares/diagnóstico , Competência Clínica/normas , Coração/diagnóstico por imagem , Angiografia por Ressonância Magnética/normas , Imageamento por Ressonância Magnética/normas , Privilégios do Corpo Clínico/normas , Tomografia Computadorizada por Raios X/normas , American Heart Association , Cardiologia/normas , Angiografia Coronária/normas , Credenciamento/normas , Educação Médica Continuada , Humanos , Imageamento por Ressonância Magnética/métodos , Doses de Radiação , Sociedades Médicas , Tomografia Computadorizada por Raios X/métodos , Estados UnidosRESUMO
Neuregulins and their erbB receptors are essential for cardiac development and postulated to be cardioprotective in the presence of injury in the postnatal heart. We tested the hypothesis that the development of doxorubicin-induced cardiotoxicity in vivo is more severe in mice with heterozygous knockout of the neuregulin-1 gene (NRG-1(+/-)) compared with wild-type mice (WT). Three-month old NRG-1(+/-) and WT mice were injected with a single dose of doxorubicin (20 mg/kg ip). Survival was analyzed by the Kaplan-Meier approach. Left ventricular (LV) function and signaling pathways were analyzed 4 days after treatment. Fifteen days after treatment, survival was significantly lower in doxorubicin-treated NRG-1(+/-) mice (NRG-1(+/-)-Dox) compared with doxorubicin-treated WT mice (WT-Dox) (15% vs. 33%, P < 0.01). LV mass was significantly lower in NRG-1(+/-)-Dox but not in WT-Dox compared with nontreated animals. LV systolic pressure and LV midwall fractional shortening were significantly lower in NRG-1(+/-)-Dox compared with WT-Dox mice. LV protein levels of NRG-1, erbB2, and erbB4 receptors were similar in WT-Dox and NRG-1(+/-)-Dox mice. However, levels of phosphorylated erbB2, Akt, and ERK-1/2 were significantly decreased in NRG-1(+/-)-Dox compared with WT-Dox mice. A significant decrease in phosphorylated P70S6K levels was also observed in NRG-1(+/-)-Dox compared with nontreated NRG-1(+/-) mice. These results demonstrate that heterozygous knockout of the neuregulin-1 gene worsens survival and LV function in the presence of doxorubicin-induced cardiac injury in vivo. This is associated with the depression of activation of the erbB2 receptor as well as Akt, p70S6K, and ERK-1/2 pathways.
Assuntos
Baixo Débito Cardíaco/induzido quimicamente , Baixo Débito Cardíaco/fisiopatologia , Doxorrubicina , Neuregulina-1/deficiência , Animais , Baixo Débito Cardíaco/diagnóstico por imagem , Baixo Débito Cardíaco/patologia , Ecocardiografia , Receptores ErbB/metabolismo , Hemodinâmica , Heterozigoto , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Knockout , Miocárdio/patologia , Neuregulina-1/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-4 , Índice de Gravidade de Doença , Transdução de Sinais , Análise de SobrevidaAssuntos
Procedimentos Cirúrgicos Cardíacos , Competência Clínica/normas , Fluoroscopia , Privilégios do Corpo Clínico/normas , Radiologia Intervencionista , Anormalidades Induzidas por Radiação/etiologia , Anormalidades Induzidas por Radiação/prevenção & controle , Adolescente , Adulto , Cinerradiografia/efeitos adversos , Cinerradiografia/instrumentação , Cinerradiografia/métodos , Cinerradiografia/normas , Currículo/normas , Medicina Baseada em Evidências , Prova Pericial , Feminino , Fluoroscopia/efeitos adversos , Fluoroscopia/instrumentação , Fluoroscopia/métodos , Fluoroscopia/normas , Física Médica , Humanos , Consentimento Livre e Esclarecido/normas , Masculino , Pessoa de Meia-Idade , Gravidez , Doses de Radiação , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Radiodermite/etiologia , Radiodermite/prevenção & controle , Radiologia Intervencionista/instrumentação , Radiologia Intervencionista/métodos , Radiologia Intervencionista/normas , Radiometria , Risco , Raios XRESUMO
ANG II type 2 receptor (AT(2)) is upregulated in failing hearts, but its effect on myocyte contractile function is not known. We measured fractional cell shortening and intracellular Ca(2+) concentration transients in left ventricular myocytes derived from transgenic mice in which ventricle-specific expression of AT(2) was driven by the myosin light chain 2v promoter. Confocal microscopy studies confirmed upregulation of AT(2) in the ventricular myocytes and partial colocalization of AT(2) with AT(1). Three components of contractile performance were studied. First, baseline measurements (0.5 Hz, 1.5 mmol/l extracellular Ca(2+) concentration, 25 degrees C) and study of contractile reserve at faster pacing rates (1-5 Hz) revealed Ca(2+)-dependent contractile dysfunction in myocytes from AT(2) transgenic mice. Comparison of two transgenic lines suggested a dose-dependent relationship between magnitude of contractile dysfunction and level of AT(2) expression. Second, activity of the Na(+)/H(+) exchanger, a dominant transporter that regulates beat-to-beat intracellular pH, was impaired in the transgenic myocytes. Third, the inotropic response to beta-adrenergic versus ANG II stimulation differed. Both lines showed impaired contractile response to beta-adrenergic stimulation. ANG II elicited an increase in contractility and intracellular Ca(2+) in wild-type myocytes but caused a negative inotropic effect in myocytes from AT(2) transgenic mice. In contrast with beta-adrenergic response, the depressed response to ANG II was related to level of AT(2) overexpression. The depressed response to ANG II was also present in myocytes from young transgenic mice before development of heart failure. Thus chronic overexpression of AT(2) has the potential to cause Ca(2+)- and pH-dependent contractile dysfunction in ventricular myocytes, as well as loss of the inotropic response to ANG II.
Assuntos
Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Cloreto de Amônio/farmacologia , Angiotensina II/farmacologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Cardiotônicos/farmacologia , Ventrículos do Coração , Concentração de Íons de Hidrogênio , Isoproterenol/farmacologia , Camundongos , Camundongos Transgênicos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Concentração Osmolar , Receptor Tipo 1 de Angiotensina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Fatores de TempoAssuntos
Cardiologia , Doenças Cardiovasculares/diagnóstico por imagem , Competência Clínica , Técnicas Eletrofisiológicas Cardíacas , Fluoroscopia , Radiologia Intervencionista , Cardiologia/educação , Cardiologia/normas , Cinerradiografia , Relação Dose-Resposta a Droga , Técnicas Eletrofisiológicas Cardíacas/normas , Feminino , Fluoroscopia/normas , Cardiopatias/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Consentimento Livre e Esclarecido , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Radiologia Intervencionista/normas , RiscoRESUMO
BACKGROUND: Clinical and experimental studies suggest that aldosterone modulates myocardial hypertrophy. From in vivo studies, it is not possible to distinguish between direct actions on myocyte growth and effects of mechanical load. In this study we tested the hypothesis that aldosterone induces myocyte hypertrophy in low-density, serum-free cultures of neonatal rat ventricular myocytes. METHODS AND RESULTS: Hypertrophy was quantified by [(14)C]-phenylalanine incorporation and confocal microscopic assessment of myocyte surface area. Aldosterone caused a 27% increase in protein incorporation (EC(50) = 40 nmol/L) and a 29% increase in myocyte surface area compared with the vehicle control. This response was associated with increased mRNA levels of atrial natriuretic factor, alpha- and beta-myosin heavy chain measured by RNase protection assay, and it was suppressed by the mineralocorticoid receptor blocker spironolactone. Analysis of early signaling events showed that aldosterone stimulation acutely translocated protein kinase C (PKC)-alpha to the membrane fraction and increased the levels of phosphorylated ERK1/2 and JNK. PD 98059, an inhibitor of the ERK activator MEK (mitogen-activated protein kinase kinase) and bisindolylmaleimide I, an inhibitor of PKC activation, each blocked aldosterone-stimulated hypertrophy. CONCLUSION: Aldosterone directly stimulates hypertrophy in neonatal rat ventricular myocytes. The growth response is dependent on the mineralocorticoid receptor and is associated with activation of ERK, JNK, and PKC-alpha.
Assuntos
Aldosterona/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Aldosterona/administração & dosagem , Animais , Animais Recém-Nascidos , Células Cultivadas , Meios de Cultura Livres de Soro , Dexametasona/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Glucocorticoides/farmacologia , Antagonistas de Hormônios/farmacologia , Hipertrofia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Microscopia Confocal , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteína Quinase C/fisiologia , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/fisiologia , Espironolactona/farmacologiaRESUMO
PURPOSE: To examine the effects of a 12-week tai chi program on quality of life and exercise capacity in patients with heart failure. METHODS: Thirty patients with chronic stable heart failure and left ventricular ejection fraction < or =40% (mean [+/- SD] age, 64 +/- 13 years; mean baseline ejection fraction, 23% +/- 7%; median New York Heart Association class, 2 [range, 1 to 4]) were randomly assigned to receive usual care (n = 15), which included pharmacologic therapy and dietary and exercise counseling, or 12 weeks of tai chi training (n = 15) in addition to usual care. Tai chi training consisted of a 1-hour class held twice weekly. Primary outcomes included quality of life and exercise capacity. Secondary outcomes included serum B-type natriuretic peptide and plasma catecholamine levels. For 3 control patients with missing data items at 12 weeks, previous values were carried forward. RESULTS: At 12 weeks, patients in the tai chi group showed improved quality-of-life scores (mean between-group difference in change, -25 points, P = 0.001), increased distance walked in 6 minutes (135 meters, P = 0.001), and decreased serum B-type natriuretic peptide levels (-138 pg/mL, P = 0.03) compared with patients in the control group. A trend towards improvement was seen in peak oxygen uptake. No differences were detected in catecholamine levels. CONCLUSION: Tai chi may be a beneficial adjunctive treatment that enhances quality of life and functional capacity in patients with chronic heart failure who are already receiving standard medical therapy.
Assuntos
Insuficiência Cardíaca/terapia , Tai Chi Chuan/métodos , Idoso , Fármacos Cardiovasculares/uso terapêutico , Doença Crônica , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Norepinefrina/sangue , Consumo de Oxigênio , Qualidade de Vida , Inquéritos e QuestionáriosAssuntos
Comitês Consultivos , Doenças Cardiovasculares/terapia , Ensaios Clínicos como Assunto/legislação & jurisprudência , Conflito de Interesses/legislação & jurisprudência , Ética Médica , Sociedades Médicas , Coleta de Dados/estatística & dados numéricos , Humanos , Projetos de Pesquisa , Estados UnidosRESUMO
Glycolysis increases in hypertrophied hearts but the mechanisms are unknown. We studied the regulation of glycolysis in hearts with pressure-overload LV hypertrophy (LVH), a model that showed marked increases in the rates of glycolysis (by 2-fold) and insulin-independent glucose uptake (by 3-fold). Although the V(max) of the key glycolytic enzymes was unchanged in this model, concentrations of free ADP, free AMP, inorganic phosphate (P(i)), and fructose-2,6-bisphosphate (F-2,6-P2), all activators of the rate-limiting enzyme phosphofructokinase (PFK), were increased (up to 10-fold). Concentrations of the inhibitors of PFK, ATP, citrate, and H+ were unaltered in LVH. Thus, our findings show that increased glucose entry and activation of the rate-limiting enzyme PFK both contribute to increased flux through the glycolytic pathway in hypertrophied hearts. Moreover, our results also suggest that these changes can be explained by increased intracellular free [ADP] and [AMP], due to decreased energy reserve in LVH, activating the AMP-activated protein kinase cascade. This, in turn, results in enhanced synthesis of F-2,6-P2 and increased sarcolemma localization of glucose transporters, leading to coordinated increases in glucose transport and activation of PFK.
Assuntos
Glicólise/fisiologia , Hipertrofia Ventricular Esquerda/metabolismo , Proteínas Quinases Ativadas por AMP , Animais , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Glucose/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Complexos Multienzimáticos/metabolismo , Consumo de Oxigênio , Fosfofrutoquinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Neuregulins are required for maintenance of acetylcholine receptor-inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances beta-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1+/-) and examined the effects of beta-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol. METHODS AND RESULTS: We evaluated contraction and intracellular Ca2+ transients ([Ca2+]i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1+/- and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25 degrees C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca2+]i were not different between WT and NRG-1+/- mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca2+]i in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca2+]i, and cAMP levels. In NRG-1+/- myocytes, carbachol did not attenuate either FS or peak-systolic [Ca2+]i, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M2 receptors or G protein Galpha(i1,2), Galpha(i3), and Galpha(o) subunits. CONCLUSIONS: Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance beta-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.