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1.
Curr Heart Fail Rep ; 17(2): 34-42, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32112345

RESUMO

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (DHF) makes up more than half of all congestive heart failure presentations (CHF). With an ageing population, the case load and the financial burden is projected to increase, even to epidemic proportions. CHF hospitalizations add too much of the financial and infrastructure strain. Unlike systolic heart failure (SHF), much is still either uncertain or unknown. Specifically, in epidemiology, the disease burden is established; however, risk factors and pathophysiological associations are less clear; diagnostic tools are based on rigid parameters without the ability to accurately monitor treatments effects and disease progression; finally, therapeutics are similar to SHF but without prognostic data for efficacy. RECENT FINDINGS: The last several years have seen guidelines changing to account for greater epidemiological observations. Most of these remain general observation of shortness of breath symptom matched to static echocardiographic parameters. The introduction of exercise diastolic stress test has been welcome and warrants greater focus. HFpEF is likely to see new thinking in the coming decades. This review provides some of perspective on this topic.


Assuntos
Insuficiência Cardíaca Diastólica/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Ecocardiografia , Teste de Esforço , Insuficiência Cardíaca Diastólica/diagnóstico , Humanos
2.
Clin Pharmacol Ther ; 102(2): 228-237, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28466986

RESUMO

Heart failure (HF) with preserved ejection fraction (HFPEF) is responsible for half of all HF cases and will be the most common form of HF within the next 5 years. Previous studies of pharmacological agents in HFPEF have proved neutral or negative, in part due to phenotypic heterogeneity and complex underlying mechanisms. This review summarizes the key molecular and cellular pathways characterized in HFPEF as well as current and future therapies that target these mechanisms.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Animais , Sistemas de Liberação de Medicamentos/tendências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Volume Sistólico/fisiologia
3.
Intern Med J ; 46(6): 723-7, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26929061

RESUMO

BACKGROUND: Methamphetamine abuse is a growing public health problem, and increasing numbers of patients are admitted with methamphetamine-associated cardiomyopathy (MAC). AIM: We sought to characterise the patterns of this disease and identify predictors of recovery. METHODS: We retrospectively studied consecutive patients diagnosed with MAC between January 2006 and July 2015. RESULTS: We identified 20 patients (14 males, 6 females) with mean age 35 ± 9 years. Most had very severe systolic dysfunction (mean left ventricular ejection fraction (LVEF) 19.7 ± 11.4%) at presentation with 14 requiring inotropes and 5 requiring mechanical support. The pattern of systolic dysfunction was global in 14 patients, while 6 patients had a 'reverse Takotsubo' (RT) pattern with severely hypokinetic basal-mid segments and apical preservation. RT patients were predominantly female, had a short history of methamphetamine abuse and had higher cardiac enzyme levels. Patients with global dysfunction tended to have mid-wall fibrosis on cardiac magnetic resonance imaging. On follow-up transthoracic echocardiography, 6 out of 19 (32%) had normalisation of LVEF (LVEF ≥ 50%) within 6 weeks. Smaller left ventricular and left atrial size, shorter duration of methamphetamine use and RT pattern appeared to predict early recovery. CONCLUSION: A subset of MAC patients, particularly those with a RT pattern and lesser ventricular dilatation have the potential for early recovery of ventricular function. By contrast, those with evidence of myocardial fibrosis and ventricular enlargement have limited scope for recovery.


Assuntos
Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico por imagem , Metanfetamina/efeitos adversos , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Adulto , Cardiomiopatias/induzido quimicamente , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Miocárdio/patologia , Estudos Retrospectivos , Volume Sistólico , Vitória
4.
Acta Physiol (Oxf) ; 212(1): 39-48, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25041756

RESUMO

AIM: Hypertension is a major clinical complication of obesity. Our previous studies show that abnormal uptake of the nitric oxide precursor L-arginine, via the cationic amino acid transporter-1 (CAT1), contributes to endothelial dysfunction in cardiovascular disease. In this study, we tested the hypothesis that abnormal L-arginine transport may be a key mediator of obesity-induced hypertension. METHODS: Mean arterial pressure (MAP) was monitored by telemetry in conscious wild-type (WT; n = 13) mice, and transgenic mice with endothelial-specific overexpression of CAT1 (CAT+; n = 14) fed a normal or a high fat diet for 20 weeks. Renal angiotensin II (Ang II), CAT1 mRNA and plasma nitrate/nitrite levels were then quantified. In conjunction, plasma nitrate/nitrite levels were assessed in obese normotensive (n = 15) and obese hypertensive subjects (n = 15). RESULTS: Both genotypes of mice developed obesity when fed a high fat diet (P ≤ 0.002). Fat fed WT mice had 13% greater MAP and 78% greater renal Ang II content, 42% lesser renal CAT1 mRNA levels and 42% lesser plasma nitrate/nitrite levels, than WT mice fed a normal fat diet (P ≤ 0.02). In contrast, none of these variables were significantly altered by high fat feeding in CAT+ mice (P ≥ 0.36). Plasma nitrate/nitrite levels were 17% less in obese hypertensives compared with obese normotensives (P = 0.02). CONCLUSION: Collectively, these data indicate that obesity-induced down-regulation of CAT1 expression and subsequent reduced bioavailability of nitric oxide may contribute to the development of obesity-induced hypertension.


Assuntos
Arginina/metabolismo , Canais de Cálcio/metabolismo , Células Endoteliais/metabolismo , Hipertensão/etiologia , Obesidade/complicações , Canais de Cátion TRPV/metabolismo , Idoso , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Obesidade/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Acta Physiol (Oxf) ; 210(4): 845-53, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24428817

RESUMO

AIM: Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial l-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension. METHODS: Wild-type mice (WT; n = 9) and endothelial CAT1 overexpressing (CAT+) mice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA; 30 mg kg(-1) day(-1) ; 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2 -isoprostane levels. RESULTS: Basal MAP was less in CAT+ (92 ± 2 mmHg; n = 6) than in WT (98 ± 2 mmHg; n = 9; P < 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 ± 0.5%; P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2 -isoprostane levels (by 67 ± 11%; P = 0.05) in WT but not in CAT+. Total renal F2 -isoprostane levels were greater during DETCA infusion in WT (by 72%; P < 0.001), but not in CAT+, compared to appropriate controls. CONCLUSION: Augmented endothelial l-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.


Assuntos
Pressão Sanguínea/fisiologia , Canais de Cálcio/metabolismo , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/fisiologia , Superóxido Dismutase/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Canais de Cálcio/genética , Estradiol/análogos & derivados , Estradiol/farmacologia , Isoprostanos , Rim/metabolismo , Camundongos , Estresse Oxidativo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Canais de Cátion TRPV/genética
6.
Intern Med J ; 42(11): 1173-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22757740

RESUMO

The mortality rate post admission to hospital after successful resuscitation from out-of-hospital cardiac arrest is high, with significant variation between regions and individual institutions. While prehospital factors such as age, bystander cardiopulmonary resuscitation and total cardiac arrest time are known to influence outcome, several aspects of post-resuscitative care including therapeutic hypothermia, coronary intervention and goal-directed therapy may also influence patient survival. Regional systems of care have improved provider experience and patient outcomes for those with ST elevation myocardial infarction and life-threatening traumatic injury. In particular, hospital factors such as hospital size and interventional cardiac care capabilities have been found to influence patient mortality. This paper reviews the evidence supporting the possible development and implementation of Australian cardiac arrest centres.


Assuntos
Institutos de Cardiologia/provisão & distribuição , Parada Cardíaca Extra-Hospitalar/terapia , Suporte Vital Cardíaco Avançado/educação , Suporte Vital Cardíaco Avançado/estatística & dados numéricos , Assistência ao Convalescente/organização & administração , Austrália/epidemiologia , Institutos de Cardiologia/organização & administração , Institutos de Cardiologia/estatística & dados numéricos , Reanimação Cardiopulmonar , Atenção à Saúde/estatística & dados numéricos , Gerenciamento Clínico , Serviços Médicos de Emergência/métodos , Serviços Médicos de Emergência/estatística & dados numéricos , Objetivos , Humanos , Hipotermia Induzida/estatística & dados numéricos , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/mortalidade , Comunicação Interdisciplinar , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/mortalidade , Revascularização Miocárdica/estatística & dados numéricos , Parada Cardíaca Extra-Hospitalar/etiologia , Parada Cardíaca Extra-Hospitalar/mortalidade , Equipe de Assistência ao Paciente , Sistema de Registros , Resultado do Tratamento
7.
Am J Physiol Renal Physiol ; 302(12): F1554-62, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22442214

RESUMO

Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 µmol·kg(-1)·min(-1); 30 min) and subsequent superimposition of l-arginine (100 µmol·kg(-1)·min(-1); 30 min), the NO synthase inhibitor N(G)-nitro-l-arginine (2.4 mg/kg; iv bolus), and the NO donor sodium nitroprusside (0.24 µg·kg(-1)·min(-1)) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM; P = 0.004). l-Lysine tended to reduce medullary perfusion (-15 ± 7%; P = 0.07) and reduced medullary NO concentration (-9 ± 3%; P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l-[(3)H]arginine transport was less in SHR compared with SD rats (P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney.


Assuntos
Arginina/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Animais , Transporte Biológico , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Lisina/farmacologia , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia
8.
Br J Pharmacol ; 166(7): 2015-23, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22288373

RESUMO

BACKGROUND AND PURPOSE: Nitrate tolerance, the loss of vascular responsiveness with continued use of nitrates, remains incompletely understood and is a limitation of these therapeutic agents. Vascular superoxide, generated by uncoupled endothelial NOS (eNOS), may play a role. As arginase competes with eNOS for L-arginine and may exacerbate the production of reactive oxygen species (ROS), we hypothesized that arginase inhibition might reduce nitrate tolerance. EXPERIMENTAL APPROACH: Vasodilator responses were measured in aorta from C57Bl/6 and arginase II knockout (argII -/-) mice using myography. Uncoupling of eNOS, determined as eNOS monomer : dimer ratio, was assessed using low-temperature SDS-PAGE and ROS levels were measured using L-012 and lucigenin-enhanced chemiluminescence. KEY RESULTS: Repeated application of glyceryl trinitrate (GTN) on aorta isolated from C57Bl/6 mice produced a 32-fold rightward shift of the concentration-response curve. However this rightward shift (or resultant tolerance) was not observed in the presence of the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC; 100 µM) nor in aorta isolated from argII -/- mice. Similar findings were obtained after inducing nitrate tolerance in vivo. Repeated administration of GTN in human umbilical vein endothelial cells induced uncoupling of eNOS from its dimeric state and increased ROS levels, which were reduced with arginase inhibition and exogenous L-arginine. Aortae from GTN tolerant C57Bl/6 mice exhibited increased arginase activity and ROS production, whereas vessels from argII -/- mice did not. CONCLUSION AND IMPLICATIONS: Arginase II removal prevents nitrate tolerance. This may be due to decreased uncoupling of eNOS and consequent ROS production.


Assuntos
Arginase/antagonistas & inibidores , Tolerância a Medicamentos , Nitroglicerina/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Arginase/genética , Arginase/metabolismo , Arginina/metabolismo , Ácidos Borônicos/farmacologia , Tolerância a Medicamentos/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Intern Med J ; 42(1): 7-17, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21999843

RESUMO

Cardiac magnetic resonance imaging (CMR) has matured into a robust, accurate and highly reproducible imaging modality for the assessment of cardiac function and ischaemic heart disease. The unique physical properties of CMR permit depiction of pathology-specific tissue contrast based on differences in tissue composition, such as myocardial oedema, necrosis and fibrosis. This can be imaged at high spatial resolution allowing characterisation of the acuity of an ischaemic event, the presence and extent of myocardial ischaemia, necrosis and viability. Prognostically important information obtained from CMR evaluation of ischaemic heart disease, such as left ventricular ejection fraction, infarct size and transmurality, infarct location and the presence of intraventricular mechanical dyssynchrony may be used to guide coronary revascularisation, device and medical therapies.


Assuntos
Imageamento por Ressonância Magnética , Isquemia Miocárdica/diagnóstico , Síndrome Coronariana Aguda/diagnóstico , Adenosina , Meios de Contraste , Circulação Coronária , Desfibriladores Implantáveis , Edema Cardíaco/diagnóstico , Edema Cardíaco/etiologia , Edema Cardíaco/patologia , Gadolínio , Testes de Função Cardíaca/instrumentação , Testes de Função Cardíaca/métodos , Humanos , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Microcirculação , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/patologia , Isquemia Miocárdica/patologia , Revascularização Miocárdica , Tamanho do Órgão , Cuidados Pré-Operatórios , Reprodutibilidade dos Testes , Vasodilatadores
11.
Am J Transplant ; 9(1): 140-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18976296

RESUMO

Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group; however, their effectiveness remains unclear. We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI. Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 +/- 0.34 mL/s vs. 1.00 +/- 0.54 mL/s, p < 0.05) but not the CNI (1.32 +/- 0.54 mL/s vs. 1.36 +/- 0.53 mL/s, p = ns) or CNI+PSI (1.20 +/- 0.24 mL/s vs. 1.20 +/- 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (

Assuntos
Transplante de Coração , Imunossupressores/uso terapêutico , Adulto , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Creatinina/urina , Infecções por Citomegalovirus/prevenção & controle , Feminino , Rejeição de Enxerto , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
12.
Gene Ther ; 15(23): 1550-7, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18650850

RESUMO

Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max); low dose -220+/-70, P>0.05; medium dose 125+/-53, P<0.05; high dose 287+/-104, P<0.05) and echocardiographically (fractional shortening: low dose -3+/-2, P>0.05; medium dose 1+/-2, P>0.05; high dose 6.5+/-3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Miocárdio/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Estimulação Cardíaca Artificial , Circulação Coronária , Dependovirus/genética , Relação Dose-Resposta a Droga , Ecocardiografia , Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Fígado/virologia , Pulmão/virologia , Modelos Animais , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/análise , Distribuição Aleatória , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/sangue , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Ovinos , Tempo , Transdução Genética/métodos , Transgenes
13.
Pharmacol Ther ; 116(3): 428-36, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17915331

RESUMO

The amino acid l-arginine participates in a variety of key biochemical and physiological activities, including its well-recognized role as the key substrate for nitric oxide (NO) biosynthesis. The current review describes the cellular influences on arginine metabolism with particular focus on the transport of l-arginine in the endothelium. It details the processes by which intracellular and extracellular levels of l-arginine may influence nitric oxide production and further documents the imbalance that is evident in various cardiovascular disease states. In man, impairment of l-arginine transport has been observed in hypertension, heart failure, and renal disease, and it may thus be a relevant therapeutic target for rectification of nitric oxide pathogenesis in these conditions.


Assuntos
Sistemas de Transporte de Aminoácidos Básicos/antagonistas & inibidores , Arginina/metabolismo , Doenças Cardiovasculares/metabolismo , Animais , Transporte Biológico , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Cinética , Óxido Nítrico/biossíntese
14.
J Mol Cell Cardiol ; 42(6): 1119-28, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17490678

RESUMO

Reactive oxygen species such as superoxide are implicated in cardiac hypertrophy, but their contribution to the cardiac complications of insulin resistance is unresolved. We tested the hypothesis that the antioxidant tempol attenuates cardiac hypertrophy in insulin-resistant mice. Mice with cardiac GLUT4 deletion (GLUT4-knockout), superimposed on global GLUT4 suppression (GLUT4-knockdown) were administered tempol for 4 weeks. Age-matched GLUT4-knockdown littermates were used as controls (14 mice/group). GLUT4-knockout mice exhibited marked cardiac hypertrophy: heart to body weight ratio was increased 61+/-7% and expression of the hypertrophic genes beta-myosin heavy chain and B-type natriuretic peptide (BNP) were elevated 5.5+/-0.7- and 6.2+/-1.5-fold relative to control, respectively. Pro-fibrotic pro-collagen III expression was also higher (3.8+/-0.7-fold) in the GLUT4-knockout myocardium (all p<0.001). Both gp91(phox) and Nox1 subunits of NADPH oxidase were also upregulated, 4.9+/-1.2- and 9.3+/-2.8-fold (both p<0.01). Tempol treatment significantly attenuated all of these abnormalities in GLUT4-knockout mice. Heart to body weight ratio was decreased, as was fold expression of beta-myosin heavy chain (to 3.8+/-0.8), BNP (to 2.5+/-0.5), pro-collagen III (to 1.9+/-0.4), gp91(phox) (to 0.9+/-0.3) and Nox1 (to 2.3+/-0.1, all p<0.05 versus untreated GLUT4-knockout mice). In addition, tempol upregulated ventricular expression of both thioredoxin-2 (confirming an antioxidant action) and glycogen synthase kinase-3beta (GSK-3beta). Tempol did not elicit any other significant changes in control mice. Cardiac superoxide generation, however, was not altered by GLUT4-knockout or tempol. In conclusion, tempol treatment reduced morphological and molecular evidence of cardiac hypertrophy in the GLUT4-knockout insulin-resistant mouse in vivo, even at doses insufficient to lower cardiac superoxide. Parallel reductions in pro-collagen III and NADPH oxidase have important implications for our understanding of the molecular basis of cardiac hypertrophy in the setting of insulin resistance. Antioxidants may offer new alternatives in this disorder.


Assuntos
Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Óxidos N-Cíclicos/farmacologia , Transportador de Glucose Tipo 4/deficiência , Resistência à Insulina/genética , Animais , Feminino , Transportador de Glucose Tipo 4/genética , Masculino , Camundongos , Camundongos Knockout , Marcadores de Spin
15.
Intern Med J ; 36(2): 114-23, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16472265

RESUMO

Heart failure (HF) is increasingly common and, despite advances in pharmacotherapeutic management, often progresses. Progression is marked by structural and electrical changes-remodelling. In approximately one-third of patients, ventricular dilatation is accompanied by intraventricular conduction delays, most commonly the left bundle branch block (LBBB). The presence of LBBB is associated with mechanical dyssynchrony of the heart. Cardiac resynchronisation therapy (CRT), the use of special pacemakers with or without implantable cardioverter defibrillators, aims to resynchronise the failing heart, improving myocardial contraction without increased energetics. Several, large, randomised clinical trials have now established the benefit of CRT in a select group of HF patients, providing functional and, recently shown, mortality benefits. However, a substantial proportion of patients are considered non-responders to CRT, and studies are now underway to identify the patients most likely to respond to CRT.


Assuntos
Estimulação Cardíaca Artificial/métodos , Insuficiência Cardíaca/terapia , Animais , Progressão da Doença , Insuficiência Cardíaca/fisiopatologia , Humanos , Contração Miocárdica/fisiologia , Resultado do Tratamento
16.
Eur J Heart Fail ; 8(3): 263-9, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16309956

RESUMO

BACKGROUND: The determinants of release of brain natriuretic peptide (BNP) in heart failure (HF) are incompletely understood, particularly, the effect of heart rhythm and haemodynamic stress. AIMS: To investigate the effect of haemodynamic stress on cardiac BNP release in HF and differentiate this response for atrial fibrillation (AF) and sinus rhythm (SR). METHODS: In 18 HF patients (ejection fraction<40%, 9 in AF and 9 in SR) haemodynamics and BNP levels were measured from arterial and coronary sinus samples at baseline, after 10 min of 20 degrees passive head up tilt (HUT) and after 10 min of isometric handgrip (IHG) exercise. From these data, we calculated a transcardiac BNP gradient and compared results between the AF and SR cohort. RESULTS: During haemodynamic stress in both groups, there were no significance differences in left sided filling pressures. At baseline, there were no differences in BNP measurements between the SR and AF group. The transcardiac BNP gradient increased significantly in the SR (p=0.02) but not the AF cohort, after HUT. During IHG exercise, there was a significant decrease in cardiac BNP release in the AF cohort (p=0.03) but not the SR cohort. CONCLUSION: These data imply in HF, cardiac rhythm influences cardiac BNP release in response to haemodynamic stress.


Assuntos
Fibrilação Atrial/metabolismo , Pressão Sanguínea , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Idoso , Exercício Físico , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Postura
17.
Eur Respir J ; 23(5): 735-40, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15176689

RESUMO

Previous small-scale studies of the effect of sleep-disordered breathing (SDB) on prognosis in congestive heart failure (CHF) are either lacking or conflicting. The aim of this study was to assess the impact of the presence and type of SDB on mortality in a patient group with severe CHF referred to a specialised heart failure centre. Out of 78 patients ((mean +/- SD) 53 +/- 9 yrs, left ventricular ejection fraction 19.9 +/- 7.2% and pulmonary capillary wedge pressure 16.5 +/- 8.3 mmHg) followed-up over a median period of 52 months, 29% had no apnoea (CHF-N), 28% had obstructive sleep apnoea (CHF-OSA) and 42% had central sleep apnoea (CHF-CSA). At 52 months, their overall mortality was 40%, and combined mortality and transplantation was 72%. Mortality rates were similar between the three apnoea groups. Survivors had a similar prevalence of SDB (71%) as the nonsurvivors (70%). Although a significant increase in mortality was evident at 500 days in those patients with either CHF-SDB or CHF-CSA as compared with CHF-N, this was not significant at final follow-up (52 months) using Kaplan Meier analysis. Multivariate analysis identified transplantation but not SDB type or severity as a significant predictor of survival. In conclusion, sleep-disordered breathing impacts upon early (500 day), but not long-term (52 month), mortality in a specialised heart failure centre.


Assuntos
Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/mortalidade , Síndromes da Apneia do Sono/complicações , Adulto , Estudos de Casos e Controles , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Pressão Propulsora Pulmonar , Índice de Gravidade de Doença , Apneia do Sono Tipo Central/complicações , Apneia Obstrutiva do Sono/complicações , Volume Sistólico , Análise de Sobrevida
18.
Am J Physiol Heart Circ Physiol ; 287(3): H1179-85, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15072955

RESUMO

The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI2), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI2 of IP and EP1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 microM) virtually abolished the increase in [3H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 microM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 microM) in the presence of the EP1 antagonist AH-6809 (3 microM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% (P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 microM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.


Assuntos
Cardiomegalia/prevenção & controle , AMP Cíclico/metabolismo , Epoprostenol/análogos & derivados , Miócitos Cardíacos/metabolismo , Receptores de Prostaglandina/metabolismo , Transdução de Sinais , Angiotensina II , Animais , Biomarcadores/análise , Cardiomegalia/induzido quimicamente , Endotelina-1 , Epoprostenol/farmacologia , Iloprosta/farmacologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Epoprostenol
19.
Lancet ; 360(9348): 1840-2, 2002 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-12480364

RESUMO

Alterations in monoaminergic neurotransmission in the brain are thought to underlie seasonal variations in mood, behaviour, and affective disorders. We took blood samples from internal jugular veins in 101 healthy men, to assess the relation between concentration of serotonin metabolite in these samples and weather conditions and season. We showed that turnover of serotonin by the brain was lowest in winter (p=0.013). Moreover, the rate of production of serotonin by the brain was directly related to the prevailing duration of bright sunlight (r=0.294, p=0.010), and rose rapidly with increased luminosity. Our findings are further evidence for the notion that changes in release of serotonin by the brain underlie mood seasonality and seasonal affective disorder.


Assuntos
Encéfalo/metabolismo , Estações do Ano , Serotonina/biossíntese , Luz Solar , Adolescente , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade
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