Measurement of Sympathetic Nervous System Activity in Heart Failure: The Role of Norepinephrine Kinetics (original) (raw)
Related papers
Journal of the American College of Cardiology, 1994
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, heal udynamic variables and central nervous system catech trine rely use on cardiac sympathetic tone. Backgmmnd. Although head failure is generally accompanied by symp,%thoexcitation, the integrity of cardiac sympathetic nerve fuadion in hod failure remains controversial, particularly in relstflon to nerve firing activity and to the capacity of sympathetic nerves to recapture pore pinephrive. Additionally, the location of the affirrent and central neural pathways implicated in heart failure-Induced sympathoexcitation remains unclear. Whodh InulkArv,er techniques were applied in 41 patients with severe head failure and IS 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 Inessured to study the central noudrenergle control of sympathetic outflow. The development of congestive heart failure is accompanied by activation of a variety of neural and hormonal counterregulatory systems. These include the sympathetic nervous system (1-4) and the renin-angiotensin-aldosterone axis (5-7), with accompanying increased release of vasopressin (8) and endothelin (9). Evidence for activation of the sympathetic nervous system in heart failure includes increased plasma norepineph-From the Alfred and Baker Medical Unit. Baker Medical Research Institute. Melbourne and
Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy
Circulation Research, 2013
Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that become activated in the syndrome to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to push the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF, along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart. (Circ Res. 2013;113:739-753.)
Neurohumoral activation in heart failure: the role of adrenergic receptors
Anais da Academia Brasileira de Ciências, 2006
Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.
Mitigation of beta 1- and/or beta 2-adrenoceptor function in human heart failure
British Journal of Clinical Pharmacology, 1990
Patients with congestive heart failure (CHF) have an elevated activity of the sympathoadrenal system. We have investigated several aspects of P-adrenoceptor desensitization in such patients. 2 The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2-values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF.
Adverse consequences of high sympathetic nervous activity in the failing human heart
Journal of the American College of Cardiology, 1995
In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. Background. Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. Methods. Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9-+ 0.9% [mean _+ SE]) were studied prospectively. In addition to the compilation of a bemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. Results. The mean follow-up period of the study group was 7-1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 "¢-37 vs. 105-+ 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capil. lary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepi. nephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study, Conclusions. These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.
International Journal of Cardiology, 2006
Background: h-adrenergic receptor antagonism with drugs like carvedilol slows the progression of heart failure by an undefined mechanism. 123 I-metaiodobenzylguanidine (MIBG) is an analog of norepinephrine used to study cardiac sympathetic function. Methods and results: In this double-blind randomized, placebo-controlled study, we used MIBG imaging to evaluate the effect of carvedilol (n = 15) or placebo (n = 7) on neuronal norepinephrine reuptake in patients with heart failure due to idiopathic dilated cardiomyopathy, with LVEF less than 35% and functional class II or III. The drug was begun at 6.25 mg b.i.d. and titrated up to 25 mg t.i.d, as tolerated. Thorax planar scintigraphy images were obtained 15 min (Initial) and 4 h (Late) after MIBG injection at baseline (t 0 ) as well as 2 months (t 1 ) and 6 months (t 2 ) after drug initiation. The multifarious statistical technique of profile analysis was applied and p V 0.05 was considered significant. The heart/mediastinum MIBG uptake (H/M ratio) was calculated from these images. On the Initial images, the H/M ratio was 1.64 F 0.24 (t 0 ), 1.71 F 0.21 (t 1 ), and 1.87 F 0.34 (t 2 ) in the carvedilol group and 1.68 F 0.42 (t 0 ), 1.81 F 0.45 (t 1 ), and 1.69 F 0.44 (t 2 ) in controls ( p = 0.0455). On the Late images, the H/M ratio was 1.39 F 0.24 (t 0 ), 1.53 F 0.23 (t 1 ), and 1.64 F 0.36 (t 2 ) in the carvedilol group, and 1.49 F 0.45 (t 0 ), 1.53 F 0.47 (t 1 ), and 1.47 F 0.41 (t 2 ) in controls ( p = 0.0513). Conclusion: Compared with placebo, the addition of carvedilol to existing heart failure treatment incites the reverse remodeling of cardiac sympathetic nervous system function. D
Journal of the American College of Cardiology, 2001
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 g and 0.48 g/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 Ͻ 0.05, p Ͻ 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 ϭ 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.
Adrenal adrenoceptors in heart failure
Frontiers in Physiology, 2014
Heart failure (HF) is a chronic clinical syndrome characterized by the reduction in left ventricular (LV) function and it represents one of the most important causes of morbidity and mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Sympathetic outflow, characterized by increased circulating catecholamines (CA) biosynthesis and secretion, is peculiar in HF and sympatholytic treatments (as β-blockers) are presently being used for the treatment of this disease. Adrenal gland secretes Epinephrine (80%) and Norepinephrine (20%) in response to acetylcholine stimulation of nicotinic cholinergic receptors on the chromaffin cell membranes. This process is regulated by adrenergic receptors (ARs): α2ARs inhibit CA release through coupling to inhibitory Gi-proteins, and βARs (mainly β2ARs) stimulate CA release through coupling to stimulatory Gs-proteins. All ARs are G-protein-coupled receptors (GPCRs) and GPCR kinases (GRKs) regulate their signaling and function. Adrenal GRK2-mediated α2AR desensitization and downregulation are increased in HF and seem to be a fundamental regulator of CA secretion from the adrenal gland. Consequently, restoration of adrenal α2AR signaling through the inhibition of GRK2 is a fascinating sympatholytic therapeutic strategy for chronic HF. This strategy could have several significant advantages over existing HF pharmacotherapies minimizing side-effects on extra-cardiac tissues and reducing the chronic activation of the renin-angiotensin-aldosterone and endothelin systems. The role of adrenal ARs in regulation of sympathetic hyperactivity opens interesting perspectives in understanding HF pathophysiology and in the identification of new therapeutic targets.
The sympathetic nervous system in chronic heart failure
Progress in Cardiovascular Diseases, 1998
The sympathetic nervous system plays a pivotal role in the natural history of chronic heart failure (CHF). There is early activation of cardiac adrenergic drive, which is followed by an increasing magnitude of generalized sympathetic activation, with worsening heart failure. The adverse consequences predominate over the short-term compensatory effects and are mediated through downregulation of 13-receptor function and harmful biological effects on the cardiomyocyte, p-blockers exert a beneficial effect on the natural history of CHF by attenuating the negative biological effects, restoring homogeneity of contractile/relaxant mechanisms, and reducing the risk of myocardial ischemia and arrhythmias. After pioneering work conducted over 20 years ago, numerous studies have shown the beneficial effects of IS-blockade on left ventricular function, and survival, morbidity, and mortality rates in CHR Large-scale trials are underway to determine the overall benefits of p-blockade in heart failure.
Regional Sympathetic Effects of Low-Dose Clonidine in Heart Failure
Hypertension, 2003
This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 μg/kg of clonidine resulted in a fall in cardiac (326±73 to 160±40 pmol/min, P <0.001), renal (2.5±0.6 to 1.5±0.3 nmol/min, P =0.01), and global norepinephrine spillover (4.0±0.6 to 3.1±0.5 nmol/min, P <0.01), with a significantly dispr...