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 , HumanosRESUMO
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 , VitóriaRESUMO
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/fisiologiaRESUMO
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 , VasodilatadoresRESUMO
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 TratamentoRESUMO
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
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 , TransgenesRESUMO
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/biossínteseRESUMO
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/fisiologiaRESUMO
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 , PosturaRESUMO
Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P<0.05). In a rat model of CHF, a 40% reduction (P<0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (P<0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 micromol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at http://www.circresaha.org.
Assuntos
Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de Crescimento Neural/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Adulto , Animais , Células Cultivadas , Regulação para Baixo , Humanos , Pessoa de Meia-Idade , Fator de Crescimento Neural/efeitos dos fármacos , Fator de Crescimento Neural/genética , Norepinefrina/farmacologia , Prazosina/farmacologia , Proteína Quinase C/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Sprague-DawleyAssuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Insuficiência Cardíaca/terapia , Animais , Circulação Coronária , Modelos Animais de Doenças , Vetores Genéticos/genética , Insuficiência Cardíaca/fisiopatologia , OvinosRESUMO
BACKGROUND: The clinical features of congestive heart failure (CHF) result from a complex interaction between reduced ventricular function, neurohormonal activation, and impaired endothelial function. Although endothelial dysfunction has been well documented, the mechanisms that contribute to this abnormality remain unknown. Recent studies, however, indicate a potential therapeutic role for supplemental L-arginine, suggesting the presence of an underlying disorder of L-arginine metabolism. METHODS AND RESULTS: We used 2 complementary approaches to assess L-arginine transport in control subjects and patients with CHF. During a steady-state intra-arterial infusion of [(3)H]L-arginine (100 nCi/min), forearm clearance of [(3)H]L-arginine was significantly reduced in CHF patients compared with forearm kinetics in control subjects (64+/-2 versus 133+/-14 mL/min, P=0.002). In conjunction with this, [(3)H]L-arginine uptake by peripheral blood mononuclear cells (PBMCs) was also substantially reduced in heart failure patients compared with controls (V(max) 10. 1+/-1.3 versus 49.8+/-7.1 pmol/10(5) cells per 5 minutes, P<0.001). In association with this finding, we observed a 76% (P<0.01) reduction in mRNA expression for the cationic amino acid transporter CAT-1, as assessed by ribonuclease protection assay. CONCLUSIONS: These data document both in vivo and in vitro evidence for a marked depression of L-arginine transport in human CHF and therefore provide an explanation for the restorative actions of supplemental L-arginine on vascular function in CHF.
Assuntos
Arginina/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Adulto , Sistemas de Transporte de Aminoácidos Básicos , Arginina/sangue , Transporte Biológico , Proteínas de Transporte/genética , Antebraço/irrigação sanguínea , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Pessoa de Meia-Idade , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de Tempo , TrítioRESUMO
BACKGROUND: Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood. METHODS AND RESULTS: In the present study, we examined the effect of short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3 to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although total systemic norepinephrine spillover was unchanged. CONCLUSION: The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
Assuntos
Insuficiência Cardíaca/terapia , Coração/fisiopatologia , Respiração com Pressão Positiva , Sistema Nervoso Simpático/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Norepinefrina/metabolismoRESUMO
OBJECTIVES: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF). BACKGROUND: We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF. METHODS: We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP). RESULTS: SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001). CONCLUSIONS: There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Nitroprussiato/farmacologia , Norepinefrina/sangue , Pressorreceptores/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Feminino , Insuficiência Cardíaca/sangue , Humanos , Hipertensão Pulmonar/sangue , Masculino , Pessoa de Meia-Idade , DescansoRESUMO
OBJECTIVES: The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF). BACKGROUND: Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release. METHODS: Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 microg and 0.48 microg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics. RESULTS: Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004). CONCLUSIONS: Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Pré-Sinápticos/fisiologia , Idoso , Clonidina/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Pré-Sinápticos/efeitos dos fármacosRESUMO
OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.
Assuntos
Antagonistas Adrenérgicos/administração & dosagem , Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas Adrenérgicos/efeitos adversos , Adulto , Idoso , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Catecolaminas/sangue , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVES: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. BACKGROUND: Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. METHODS: Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. RESULTS: Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. CONCLUSIONS: Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.
Assuntos
Encéfalo/metabolismo , Insuficiência Cardíaca/fisiopatologia , Coração/inervação , Norepinefrina/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Di-Hidroxifenilalanina/metabolismo , Insuficiência Cardíaca/etiologia , Humanos , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Neuropeptídeo Y/metabolismo , Pressão Propulsora Pulmonar/fisiologia , TermodiluiçãoRESUMO
OBJECTIVES: We sought to examine the efficacy of dietary supplementation of L-arginine on endothelium-dependent vasodilation in patients with congestive heart failure. BACKGROUND: Endothelial dysfunction, as evidenced by a diminished response to such vasodilators as acetylcholine, is well defined in patients with heart failure. These responses are improved by intraarterial infusion with L-arginine. Because L-arginine is a semi-essential amino acid, we investigated the effects of dietary L-arginine on endothelium-dependent vasodilation in these patients. METHODS: Twenty patients with heart failure (New York Heart Association functional class III/IV, mean [+/- SE] age 51.3 +/- 1.7 years) and seven healthy control subjects (mean age 52.6 +/- 3.3 years) were studied. All patients continued taking their usual treatment. Responses to acetylcholine and sodium nitroprusside were determined using forearm plethysmography. Patients with heart failure received either L-arginine (20 g/day every day for 28 days) or placebo (vehicle syrup in equal amounts) in a double-blind protocol. The calculated power of the study was between 62% and 80% to detect a 30% to 40% change in area under the dose-response (forearm vascular resistance) curve. RESULTS: Responses to acetylcholine, but not to sodium nitroprusside, were significantly attenuated in patients with heart failure compared with control subjects (mean area under curve [AUC], control subjects vs. patients with heart failure: 1,125.4 +/- 164.5 vs. 617.3 +/- 116.6 U, p < 0.05, by Student t test). A significant increase in urea and aspartate transaminase levels in patients receiving active L-arginine treatment was observed. Responses to acetylcholine (AUC; before vs. after L-arginine: 641.5 +/- 126.7 vs. 695.9 +/- 151.9 U) and sodium nitroprusside were not affected by either L-arginine or placebo. CONCLUSIONS: Endothelial dysfunction was apparent in patients with heart failure despite rigorous vasoactive treatment. Oral administration with L-arginine was ineffective in influencing endothelial function in these patients.
Assuntos
Arginina/administração & dosagem , Artérias/fisiopatologia , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Resistência Vascular/efeitos dos fármacos , Adulto , Dieta , Endotélio Vascular/efeitos dos fármacos , Feminino , Antebraço/irrigação sanguínea , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects. BACKGROUND: Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown. METHODS: We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose. RESULTS: Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01). CONCLUSIONS: Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.