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2.
J Cardiovasc Electrophysiol ; 27(1): 120-4, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26511459

RESUMO

We present three cases within 11 months at a single institution of sustained VT that fell below the programmed detection rate of the patients' implantable cardioverter-defibrillators (ICDs), two of which continued until converting to an agonal VF that did not meet criteria for detection, and a third case that could not be successfully defibrillated after a prolonged period of VT. These episodes may be under-recognized due to the dependence of device diagnostic storage on programming and the post-mortem effort that is often required to review these events. Some patients, likely those with the most advanced heart failure, may not tolerate sustained ventricular tachycardia (VT) and may even die from ventricular arrhythmias without ever having a rhythm that meets detection criteria in a ventricular fibrillation (VF) zone.


Assuntos
Morte Súbita Cardíaca/etiologia , Cardioversão Elétrica/instrumentação , Taquicardia Ventricular/terapia , Idoso , Causas de Morte , Desfibriladores Implantáveis , Eletrocardiografia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Falha de Tratamento
3.
J Cardiovasc Electrophysiol ; 26(10): 1111-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26222980

RESUMO

INTRODUCTION: Cardiac implantable electronic device (CIED) infections are potentially preventable complications associated with high morbidity, mortality, and cost. A recently developed bio-absorbable antibacterial envelope (TYRX™-A) might prevent CIED infections in high-risk subjects. However, data regarding safety and efficacy have not been published. METHODS AND RESULTS: In a single-center retrospective cohort study, we compared the prevalence of CIED infections among subjects with ≥2 risk factors treated with the TYRX™-A envelope (N = 135), the nonabsorbable TYRX™ envelope (N = 353), and controls who did not receive an envelope (N = 636). Infection was ascertained by individual chart review. The mean (95% confidence interval) number of risk factors was 3.08 (2.84-3.32) for TYRX™-A, 3.20 (3.07-3.34) for TYRX™, and 3.09 (2.99-3.20) for controls, P = 0.3. After a minimum 300 days follow-up, the prevalence of CIED infection was 0 (0%) for TYRX™-A, 1 (0.3%) for TYRX™, and 20 (3.1%) for controls (P = 1 for TYRX™-A vs. TYRX™, P = 0.03 for TYRX™-A vs. controls, and P = 0.002 for TYRX™ vs. controls). In a propensity score-matched cohort of 316 recipients of either envelope and 316 controls, the prevalence of infection was 0 (0%) and 9 (2.8%), respectively, P = 0.004. When limited to 122 TYRX™-A recipients and 122 propensity-matched controls, the prevalence of CIED infections was 0 (0%) and 5 (4.1%), respectively, P = 0.024. CONCLUSIONS: Among high-risk subjects, the TYRX™-A bio-absorbable envelope was associated with a very low prevalence of CIED related infections that was comparable to that seen with the nonabsorbable envelope.


Assuntos
Antibacterianos/administração & dosagem , Desfibriladores Implantáveis/estatística & dados numéricos , Implantes de Medicamento/administração & dosagem , Marca-Passo Artificial/estatística & dados numéricos , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/prevenção & controle , Implantes Absorvíveis/estatística & dados numéricos , Idoso , Causalidade , Estudos de Coortes , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Infecções Relacionadas à Prótese/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida , Tennessee/epidemiologia , Resultado do Tratamento
4.
Am J Physiol Cell Physiol ; 306(1): C19-27, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24196528

RESUMO

A constant provision of ATP is of necessity for cardiac contraction. As the heart progresses toward failure following a myocardial infarction (MI), it undergoes metabolic alterations that have the potential to compromise the ability to meet energetic demands. This study evaluated the efficacy of mesenchymal stem cell (MSC) transplantation into the infarcted heart to minimize impairments in the metabolic processes that contribute to energy provision. Seven and twenty-eight days following the MI and MSC transplantation, MSC administration minimized cardiac systolic dysfunction. Hyperinsulinemic-euglycemic clamps, coupled with 2-[(14)C]deoxyglucose administration, were employed to assess systemic insulin sensitivity and tissue-specific, insulin-mediated glucose uptake 36 days following the MI in the conscious, unrestrained, C57BL/6 mouse. The improved systolic performance in MSC-treated mice was associated with a preservation of in vivo insulin-stimulated cardiac glucose uptake. Conserved glucose uptake in the heart was linked to the ability of the MSC treatment to diminish the decline in insulin signaling as assessed by Akt phosphorylation. The MSC treatment also sustained mitochondrial content, ADP-stimulated oxygen flux, and mitochondrial oxidative phosphorylation efficiency in the heart. Maintenance of mitochondrial function and density was accompanied by preserved peroxisome proliferator-activated receptor-γ coactivator-1α, a master regulator of mitochondrial biogenesis. These studies provide insight into mechanisms of action that lead to an enhanced energetic state in the infarcted heart following MSC transplantation that may assist in energy provision and dampen cardiac dysfunction.


Assuntos
Difosfato de Adenosina/farmacologia , Glucose/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/cirurgia , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia
5.
J Cardiovasc Electrophysiol ; 25(1): 36-42, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24028661

RESUMO

INTRODUCTION: The FDA has issued class I advisories for Medtronic Sprint Fidelis(®) and St. Jude Medical Riata(TM) ICD lead families. Transvenous Riata(TM) ICD lead extraction is typically considered higher risk than Fidelis(®) extraction, based on longer duration from implant, presence of externalized conductors and lack of silicone backfill in the SVC and RV coils. However, published data comparing procedural outcomes between these leads are limited. METHODS: Records were reviewed for all patients undergoing transvenous extraction of Sprint Fidelis(®) or Riata(TM) ICD leads at the Vanderbilt Heart and Vascular Institute from July 2006 to April 2013 to ascertain indication for extraction, procedural details, complications, and 30-day mortality. RESULTS: There were significant differences between those undergoing extraction of a Sprint Fidelis(®) (n = 145) or Riata(TM) lead (n = 47). In the Riata(TM) group, device-related endocarditis was a more common indication for extraction, the mean duration of implant was longer, and larger excimer laser sheaths were required. Lead malfunction was a more common indication in the Fidelis(®) group. There were no statistically significant differences in median procedure duration, procedural success (97.9% vs 95.7%, P = 0.41), median length of hospital stay (1 day vs 1 day, P = 0.23), procedural complication rate (5.5% vs 10.6%, P = 0.23) or 30-day mortality (2.1% vs 2.1%, P = 0.98). Analyses excluding patients with device infection revealed similar results. CONCLUSION: Despite differences in baseline characteristics, this study indicates that Medtronic Sprint Fidelis(®) and St. Jude Riata(TM) ICD leads have similar procedural outcomes with transvenous lead extraction.


Assuntos
Desfibriladores Implantáveis/efeitos adversos , Remoção de Dispositivo/mortalidade , Remoção de Dispositivo/métodos , Eletrodos Implantados/efeitos adversos , Desfibriladores Implantáveis/microbiologia , Eletrodos Implantados/microbiologia , Endocardite/diagnóstico , Endocardite/mortalidade , Endocardite/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Retrospectivos , Resultado do Tratamento
6.
Cardiovasc Diabetol ; 12: 128, 2013 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-24007410

RESUMO

BACKGROUND: This study aimed to evaluate the efficacy of mesenchymal stem cell (MSC) transplantation to mitigate abnormalities in cardiac-specific and systemic metabolism mediated by a combination of a myocardial infarction and diet-induced insulin resistance. METHODS: C57BL/6 mice were high-fat fed for eight weeks prior to induction of a myocardial infarction via chronic ligation of the left anterior descending coronary artery. MSCs were administered directly after myocardial infarction induction through a single intramyocardial injection. Echocardiography was performed prior to the myocardial infarction as well as seven and 28 days post-myocardial infarction. Hyperinsulinemic-euglycemic clamps coupled with 2-[14C]deoxyglucose were employed 36 days post-myocardial infarction (13 weeks of high-fat feeding) to assess systemic insulin sensitivity and insulin-mediated, tissue-specific glucose uptake in the conscious, unrestrained mouse. High-resolution respirometry was utilized to evaluate cardiac mitochondrial function in saponin-permeabilized cardiac fibers. RESULTS: MSC administration minimized the decline in ejection fraction following the myocardial infarction. The greater systolic function in MSC-treated mice was associated with increased in vivo cardiac glucose uptake and enhanced mitochondrial oxidative phosphorylation efficiency. MSC therapy promoted reductions in fasting arterial glucose and fatty acid concentrations. Additionally, glucose uptake in peripheral tissues including skeletal muscle and adipose tissue was elevated in MSC-treated mice. Enhanced glucose uptake in these tissues was associated with improved insulin signalling as assessed by Akt phosphorylation and prevention of a decline in GLUT4 often associated with high-fat feeding. CONCLUSIONS: These studies provide insight into the utility of MSC transplantation as a metabolic therapy that extends beyond the heart exerting beneficial systemic effects on insulin action.


Assuntos
Dieta Hiperlipídica , Metabolismo Energético , Resistência à Insulina , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/cirurgia , Miocárdio/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Ácidos Graxos/sangue , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/metabolismo , Músculo Esquelético/metabolismo , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Fosforilação Oxidativa , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recuperação de Função Fisiológica , Volume Sistólico , Sístole , Fatores de Tempo
7.
Dis Model Mech ; 5(4): 468-80, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22563055

RESUMO

CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs.


Assuntos
Cardiomiopatia Dilatada/patologia , Proteínas Cromossômicas não Histona/deficiência , Deleção de Genes , Proteínas dos Microfilamentos/deficiência , Microtúbulos/metabolismo , Envelhecimento/patologia , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Cardiomiopatia Dilatada/genética , Anormalidades Cardiovasculares/embriologia , Anormalidades Cardiovasculares/patologia , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Costâmeros/metabolismo , Fibrose , Perfilação da Expressão Gênica , Coração/embriologia , Integrases/metabolismo , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Especificidade de Órgãos , Ligação Proteica , Transcrição Genética , Troponina T/metabolismo
8.
Heart Rhythm ; 9(8): 1218-24, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22449742

RESUMO

BACKGROUND: Inside-out abrasion with externalization of sensing ring or high-voltage cables in St Jude Medical Riata implantable cardioverter-defibrillator leads has been reported. The prevalence of extruded cables, rate of electrical abnormalities, and predictors of failure in Riata leads are unknown. OBJECTIVES: To estimate the incidence of lead failure in the St Jude Medical Riata implantable cardioverter-defibrillator leads and to propose a standard for the fluoroscopic assessment of insulation breakdown. METHODS: Patients undergoing cine-fluoroscopy on Riata implantable cardioverter-defibrillator leads at our institution before January 25, 2012, were included (n = 87). Leads were graded as types 0-3 (0 = normal, 1 = abnormal conductor spacing, 2 ≤1 cm cable extrusion, 3 = >1 cm length extrusion). Comparison to extracted leads (n = 15) was documented. Device interrogation data were used for electrical analysis. RESULTS: The mean time from implant was 5.9 ± 3.45 years. Structural lead failure with externalized cables was seen in 33.3% (29 of 87) of the patients. Thirty-one percent (9 of 29) of the leads with exposed cables showed electrical failure, and 29.7% (19 of 64) of the leads with normal electrical data contained externalized cables. Time from implant ≥5 years predicted structural lead failure (P < 0.05). X-ray grade compared with extracted leads demonstrated a sensitivity and specificity of 86% and 100%, respectively. CONCLUSIONS: Cine-fluoroscopy using a simple scale correlated with the structural integrity of extracted Riata leads. A high percentage of leads with extrusion showed electrical failure. Leads ≥5 years from implant showed a high rate of externalized cables. A large independent multicenter study to determine the prevalence and clinical sequelae of Riata lead failures is warranted.


Assuntos
Desfibriladores Implantáveis , Eletrodos Implantados , Análise de Falha de Equipamento , Desfibriladores Implantáveis/efeitos adversos , Condutividade Elétrica , Falha de Equipamento , Fluoroscopia , Humanos , Prevalência , Retirada de Dispositivo Médico Baseada em Segurança , Silicones
10.
Heart Rhythm ; 9(5): 717-20, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22172318

RESUMO

BACKGROUND: Predictable progression to battery depletion is necessary for device management in patients with pacemakers or implantable cardioverter-defibrillators, particularly in patients who either are pacemaker dependent or have required implantable cardioverter-defibrillator therapies. OBJECTIVE: To determine the incidence and characteristics of unexpected battery depletion in patients implanted with a cardiac resynchronization therapy - defibrillator (CRT-D) device. METHODS: All patients with a St Jude Atlas+ HF or Atlas II HF CRT-D device implanted between 2004 and 2007 at the Massachusetts General Hospital and the Nashville VA Medical Center (Vanderbilt University) were studied. All patients with early generator depletion (transition of generator voltage above specified elective replacement indicator [ERI] to end of life [EOL] in less than 90 days) were evaluated further. RESULTS: Eight cases (mean age 69.6 ± 9 years) with abrupt battery depletion were identified among 191 patients (4.2%) implanted with a St Jude Atlas CRT-D device. The longevity of 8 premature depletion devices was 46.4 ± 10 months (median 45 months). The battery voltage in these 8 devices decreased from a mean of 2.48 ± 0.03 V (above ERI) to 2.3 ± 0.08 V (below ERI) over 33.3 ± 23 days (range 1-59 days; median 38.5 days). One device reached EOL status within 1 day of having battery voltage above ERI and another device within 12 days. CONCLUSION: The incidence of abrupt battery depletion was 4.2% in patients implanted with a St Jude Atlas CRT-D device. No common mechanism has been identified for this failure. Close monitoring of battery voltage and timely generator replacement are required in patients with these devices.


Assuntos
Desfibriladores Implantáveis/estatística & dados numéricos , Fontes de Energia Elétrica/estatística & dados numéricos , Falha de Equipamento/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Pessoa de Meia-Idade
11.
Am J Physiol Endocrinol Metab ; 302(2): E163-72, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21971524

RESUMO

Intense interest has been focused on cell-based therapy for the infarcted heart given that stem cells have exhibited the ability to reduce infarct size and mitigate cardiac dysfunction. Despite this, it is unknown whether mesenchymal stem cell (MSC) therapy can prevent metabolic remodeling following a myocardial infarction (MI). This study examines the ability of MSCs to rescue the infarcted heart from perturbed substrate uptake in vivo. C57BL/6 mice underwent chronic ligation of the left anterior descending coronary artery to induce a MI. Echocardiography was performed on conscious mice at baseline as well as 7 and 23 days post-MI. Twenty-eight days following the ligation procedure, hyperinsulinemic euglycemic clamps assessed in vivo insulin sensitivity. Isotopic tracer administration evaluated whole body, peripheral tissue, and cardiac-specific glucose and fatty acid utilization. To gain insight into the mechanisms by which MSCs modulate metabolism, mitochondrial function was assessed by high-resolution respirometry using permeabilized cardiac fibers. Data show that MSC transplantation preserves insulin-stimulated fatty acid uptake in the peri-infarct region (4.25 ± 0.64 vs. 2.57 ± 0.34 vs. 3.89 ± 0.54 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05) and prevents increases in glucose uptake in the remote left ventricle (3.11 ± 0.43 vs. 3.81 ± 0.79 vs. 6.36 ± 1.08 µmol·100 g(-1)·min(-1), SHAM vs. MI + PBS vs. MI + MSC; P < 0.05). This was associated with an enhanced efficiency of mitochondrial oxidative phosphorylation with a respiratory control ratio of 3.36 ± 0.18 in MSC-treated cardiac fibers vs. 2.57 ± 0.14 in the infarct-only fibers (P < 0.05). In conclusion, MSC therapy exhibits the potential to rescue the heart from metabolic aberrations following a MI. Restoration of metabolic flexibility is important given the metabolic demands of the heart and the role of energetics in the progression to heart failure.


Assuntos
Metabolismo Energético/fisiologia , Transplante de Células-Tronco Mesenquimais , Mitocôndrias/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Remodelação Ventricular/fisiologia , Animais , Coração/fisiopatologia , Camundongos , Mitocôndrias/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Fosforilação/fisiologia
12.
Cardiology ; 119(1): 47-53, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21822014

RESUMO

Most sudden cardiac deaths in young athletes are caused by previously undetected inherited cardiac diseases. Here, we report a case of a young male athlete in whom a presumptive diagnosis of hypertrophic cardiomyopathy (HCM) was made following a near sudden cardiac death. Although his imaging studies initially suggested HCM, a detailed clinical and genetic evaluation of the patient and his asymptomatic father led to the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in both. DNA sequencing revealed that each individual was heterozygous for two rare variants in the PKP2 and DSC2 genes, both of which were previously shown to be associated with ARVD and to encode desmosomal proteins, i.e. the previously reported splicing variant c2489 + 1A > G in the PKP2 gene and the novel p.I109M variant in the DSC2 gene. Imaging and electrophysiologic studies further supported a diagnosis of ARVD in the father. This case highlights the importance of detailed clinical evaluation and genetic testing of family members when dealing with sudden cardiac death or unexplained cardiomyopathies in the young.


Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico , Desmocolinas/genética , Placofilinas/genética , Displasia Arritmogênica Ventricular Direita/genética , Cardiomiopatia Hipertrófica/diagnóstico , Morte Súbita Cardíaca , Diagnóstico Diferencial , Eletrocardiografia , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Esportes , Adulto Jovem
14.
Heart Rhythm ; 6(5): 619-24, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19389648

RESUMO

BACKGROUND: Increased rates of complications related to the use of small-diameter implantable cardioverter-defibrillator (ICD) leads have been reported. Lead design and engineering aimed at reducing ICD lead diameter may increase associated subacute complications, including cardiac perforation, lead dislodgement, or lead failure. OBJECTIVE: The purpose of this study was to determine whether lead caliber altered the risk of perforation, lead dislodgement, or lead failure in a single center. METHODS: All patients with right ventricular (RV) ICD lead implantation at Vanderbilt University and VA-Nashville Medical Center between January 1, 2007, and August 31, 2007, were included in this study. Leads implanted during this period were the Riata 1580, Riata ST 7000 (St. Jude Medical, St. Paul, MN), Sprint Fidelis 6949, and Sprint Quattro 6947 (Medtronic, Minneapolis, MN). Information was collected retrospectively. RESULTS: A total of 305 ICD leads were implanted (138 small diameter, 167 standard diameter) during the study period. Failure was defined as development of high pacing threshold, marked sensing change, cardiac perforation, or development of extracardiac stimulation. A total of 11 lead failures occurred in the small-diameter lead group, versus one in the standard group. Implantation of a small-diameter lead (Riata 1580, Riata ST 7000, or Sprint Fidelis 6949) was associated with a significant increase in failure rate, 8.0% versus 0.6% (P = .0008) compared with standard-size leads (Sprint Quattro 6947). CONCLUSIONS: Subacute lead-related complications were more likely with use of small-diameter ICD leads (Riata 1580, Riata ST 7000, Sprint Fidelis 6949) than with with standard-caliber ICD leads (Sprint Quattro 6947).


Assuntos
Desfibriladores Implantáveis/efeitos adversos , Cardioversão Elétrica/instrumentação , Insuficiência Cardíaca/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Falha de Equipamento , Seguimentos , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia Torácica , Estudos Retrospectivos , Fatores de Tempo
15.
Biochim Biophys Acta ; 1782(10): 586-92, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18692568

RESUMO

Insulin resistance is characterized by elevated rates of cardiac fatty acid utilization resulting in reduced efficiency and cardiomyopathy. One potential therapeutic approach is to limit the uptake and oxidation of fatty acids. The aims of this study were to determine whether a quantitative reduction in heart-type fatty acid binding protein (FABP3) normalizes cardiac substrate utilization without altering cardiac function. Transgenic (FABP3(+/-)) and wild-type (WT) littermates were studied following low fat (LF) or high fat (HF) diets, with HF resulting in obese, insulin-resistant mice. Cardiovascular function (systolic blood pressure, % fractional shortening) and heart dimension were measured at weaning and every month afterward for 3 mo. During this period cardiovascular function was the same independent of genotype and diet. Catheters were surgically implanted in the carotid artery and jugular vein for sampling and infusions in mice at 4 mo of age. Following 5 d recovery, mice underwent either a saline infusion or a hyperinsulinemic-euglycemic clamp (4 mU kg(-1) min(-1)). Indices of long chain fatty acid and glucose utilization (R(f), R(g); mumol g wet weight(-1) min(-1)) were obtained using 2-deoxy[(3)H]glucose and [(125)I]-15-rho-iodophenyl)-3-R,S-methylpentadecanoic acid. FABP3(+/-) had enhanced cardiac R(g) compared with WT during saline infusion in both LF and HF. FABP3(+/-) abrogated the HF-induced decrement in insulin-stimulated cardiac R(g). On a HF diet, FABP(+/-) but not WT had an increased reliance on fatty acids (R(f)) during insulin stimulation. In conclusion, cardiac insulin resistance and glucose uptake is largely corrected by a reduction in FABP3 in vivo without contemporaneous deleterious effects on cardiac function.


Assuntos
Proteínas de Ligação a Ácido Graxo/metabolismo , Resistência à Insulina/fisiologia , Miocárdio/metabolismo , Animais , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Peso Corporal , Dieta com Restrição de Gorduras , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Coração/efeitos dos fármacos , Coração/fisiopatologia , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Função Ventricular/fisiologia
16.
Lipids ; 43(8): 703-11, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18481132

RESUMO

Insulin resistance is characterized by increased metabolic uptake of fatty acids. Accordingly, techniques to examine in vivo shifts in fatty acid metabolism are of value in both clinical and experimental settings. Partially metabolizable long chain fatty acid (LCFA) tracers have been recently developed and employed for this purpose: [9,10-3H]-(R)-2-bromopalmitate ([3H]-BROMO) and [125I]-15-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid ([125I]-BMIPP). These analogues are taken up like native fatty acids, but once inside the cell do not directly enter beta-oxidation. Rather, they become trapped in the slower processes of omega and alpha-oxidation. Study aims were to (1) simultaneously assess and compare [3H]-BROMO and [125I]-BMIPP and (2) determine if tracer breakdown is affected by elevated metabolic demands. Catheters were implanted in a carotid artery and jugular vein of Sprague-Dawley rats. Following 5 days recovery, fasted animals (5 h) underwent a rest (n = 8) or exercise (n = 8) (0.6 mi/h) protocol. An instantaneous bolus containing both [3H]-BROMO and [125I]-BMIPP was administered to determine LCFA uptake. No significant difference between [125I]-BMIPP and [3H]-BROMO uptake was found in cardiac or skeletal muscle during rest or exercise. In liver, rates of uptake were more than doubled with [3H]-BROMO compared to [125I]-BMIPP. Analysis of tracer conversion by TLC demonstrated no difference at rest. Exercise resulted in greater metabolism and excretion of tracers with approximately 37% and approximately 53% of [125I]-BMIPP and [3H]-BROMO present in conversion products at 40 min. In conclusion, [3H]-BROMO and [125I]-BMIPP are indistinguishable for the determination of tissue kinetics at rest in skeletal and cardiac muscle. Exercise preferentially exacerbates the breakdown of [3H]-BROMO, making [125I]-BMIPP the analogue of choice for prolonged (>30 min) experimental protocols with elevated metabolic demands.


Assuntos
Compostos de Bromo/metabolismo , Ácidos Graxos/metabolismo , Iodobenzenos/metabolismo , Palmitatos/metabolismo , Animais , Compostos de Bromo/farmacocinética , Ácidos Graxos/farmacocinética , Radioisótopos do Iodo , Iodobenzenos/farmacocinética , Masculino , Especificidade de Órgãos , Palmitatos/farmacocinética , Ratos , Ratos Sprague-Dawley , Trítio
17.
J Am Soc Hypertens ; 2(5): 355-65, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19727429

RESUMO

BACKGROUND: No reduction in either coronary mortality or sudden cardiac death (SCD) has been demonstrated in overviews of randomized trials of treatment of hypertension with diuretics. METHODS: An overview was conducted of coronary mortality and SCD in randomized controlled antihypertensive trials in which an epithelial sodium channel (ENaC) inhibitor/ hydrochlorthiazide (HCTZ) combination was used. Secondarily, an analogous overview in which thiazide diuretic was used alone was performed. Randomized trials that used an ENaC inhibitor/ HCTZ combination (or, alternatively, thiazide diuretic alone) were identified from previous meta-analyses, searches of PubMed, search of the Cochrane Clinical Trials database, and review of publications that addressed the consequences of treating hypertension. Trials in which participants were randomized to either an ENaC inhibitor combined with a thiazide diuretic (or to a thiazide diuretic alone) or to control treatment for at least one year and in which coronary mortality was reported were included. Numbers of events in individual trials were abstracted independently by 2 authors. RESULTS: Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination. The odds ratio (OR) for coronary mortality was 0.59 (95% confidence interval [CI] 0.44, 0.78) and for SCD was 0.60 (95% CI 0.38, 0.94). In contrast, an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality (OR 0.94; 95% CI 0.81, 1.09) or SCD (OR 1.27; 95% CI 0.93, 1.75). CONCLUSIONS: Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD.

18.
Diabetes ; 56(10): 2476-84, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17639019

RESUMO

OBJECTIVE: Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU x kg(-1) x min(-1)) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS: C57BL/6J mice with (HK(+/-)) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n = 8-10 mice/group). 2-deoxy[(3)H]glucose was used to measure R(g), an index of MGU. RESULTS: Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK(+/-)). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by approximately 25% with either high-fat feeding or partial HK II knockout alone but by >50% when the two were combined. Insulin-stimulated R(g) was modestly impaired by high-fat feeding and partial HK II knockout independently ( approximately 15-20%) but markedly reduced by the two together ( approximately 40-50%). Exercise-stimulated R(g) was reduced by approximately 50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two. CONCLUSIONS: In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat-fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions.


Assuntos
Glucose/metabolismo , Hexoquinase/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Tecido Adiposo/enzimologia , Animais , Transporte Biológico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Técnica Clamp de Glucose , Hexoquinase/deficiência , Hiperinsulinismo , Insulina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/enzimologia , Miocárdio/enzimologia , Fosforilação , Resistência Física , Esforço Físico , Valores de Referência
19.
J Physiol ; 582(Pt 2): 801-12, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17495042

RESUMO

The absence of GLUT4 severely impairs basal glucose uptake in vivo, but does not alter glucose homeostasis or circulating insulin. Glucose uptake in isolated contracting skeletal muscle (MGU) is also impaired by the absence of GLUT4, and onset of muscle fatigue is hastened. Whether the body can compensate and preserve glucose homeostasis during exercise, as it does in the basal state, is unknown. One aim was to test the effectiveness of glucoregulatory compensation for the absence of GLUT4 in vivo. The absence of GLUT4 was also used to further define the role of hexokinase (HK) II, which catalyses glucose phosphorylation after it is transported in the cell. HK II increases MGU during exercise, as well as exercise endurance. In the absence of GLUT4, HK II expression will not affect MGU. A second aim was to test whether, in the absence of GLUT4, HK II retains its ability to increase exercise endurance. Wild-type (WT), GLUT4 null (GLUT4(-/-)), and GLUT4 null overexpressing HK II (GLUT4(-/-)HK(Tg)) mice were studied using a catheterized mouse model that allows blood sampling and isotope infusions during treadmill exercise. The impaired capacity of working muscle to take up glucose in GLUT4(-/-) is partially offset by an exaggerated increase in the glucagon: insulin ratio, increased liver glucose production, hyperglycaemia, and a greater capillary density in order to increase the delivery of glucose to the exercising muscle of GLUT4(-/-). Hearts of GLUT4(-/-) also exhibited a compensatory increase in HK II expression and a paradoxical increase in glucose uptake. Exercise tolerance was reduced in GLUT4(-/-) compared to WT. As expected, MGU in GLUT4(-/-)HK(Tg) was the same as in GLUT4(-/-). However, HK II overexpression retained its ability to increase exercise endurance. In conclusion, unlike the basal state where glucose homeostasis is preserved, hyperglycaemia results during exercise in GLUT4(-/-) due to a robust stimulation of liver glucose release in the face of severe impairments in MGU. Finally, studies in GLUT4(-/-)HK(Tg) show that HK II improves exercise tolerance, independent of its effects on MGU.


Assuntos
Transportador de Glucose Tipo 4/deficiência , Glucose/metabolismo , Músculo Esquelético/metabolismo , Resistência Física , Animais , Hexoquinase/genética , Hexoquinase/metabolismo , Hiperglicemia/etiologia , Cinética , Fígado/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/fisiologia , Contração Muscular/fisiologia , Músculo Esquelético/fisiologia , Miocárdio/metabolismo , Resistência Física/fisiologia
20.
Echocardiography ; 24(1): 83-9, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17214630

RESUMO

Ventricular dysfunction remains a hallmark of most cardiac disease. The mouse has become an essential model system for cardiovascular biology, and echocardiography an established tool in the study of normal and genetically altered mice. This review describes the measurement of ventricular function, most often left ventricular function, by echocardiographic methods in mice. Technical limitations related to the small size and rapid heart rate in the mouse initially argued for the performance of echocardiography under anesthesia. More recently, higher frame rates and smaller probes operating at higher frequencies have facilitated imaging of conscious mice in some, but not all, experimental protocols and conditions. Ventricular function may be qualitatively and quantitatively evaluated under both conditions. Particular detail is provided for measurement under conscious conditions, and measurement under conscious and sedated or anesthestized conditions are contrasted. Normal values for echocardiographic indices for the common C57BL/6 strain are provided. Diastolic dysfunction is a critical pathophysiologic component of many disease states, and progress in the echocardiographic evaluation of diastolic function is discussed. Finally, echocardiography exists among several competing imaging technologies, and these alternatives are compared.


Assuntos
Ecocardiografia/métodos , Modelos Animais , Função Ventricular/fisiologia , Adrenérgicos , Anestésicos/administração & dosagem , Animais , Técnicas de Diagnóstico por Radioisótopos , Diástole , Ecocardiografia/efeitos dos fármacos , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Valores de Referência
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