Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs (original) (raw)
Related papers
Circulation Research, 1993
Peripheral vasodilator responsiveness was examined in pacing-induced heart failure (HF) in 11 conscious dogs chronically instrumented for measurement of systemic (total peripheral resistance [TPR]) and local (iliac blood flow) vascular resistance. Dose responses to isoproterenol (ISO), acetylcholine (ACh), and nitroglycerin (NTG) were examined in the same dogs before pacing (control) and after 4 to 7 weeks of rapid ventricular pacing, which induced congestive HF, characterized by increased left ventricular end-diastolic pressure (6.7 +/- 0.4 [control] versus 28 +/- 1.5 [HF] mm Hg) and decreased cardiac output (-30 +/- 5%) and left ventricular dP/dt (-53 +/- 3%), as well as ascites and peripheral edema. In the control state, TPR fell by 57 +/- 2% in response to ISO (100 ng/kg), by 61 +/- 3% in response to ACh (3 micrograms/kg), and by 55 +/- 2% in response to NTG (10 micrograms/kg). In HF, smaller decreases (P < .05) in TPR were observed with the same doses of ISO (-50 +/- 2%) and...
American Journal of Veterinary Research, 2002
Objective—To describe neuroendocrine responses that develop in dogs subjected to prolonged periods of ventricular pacing. Animals—14 adult male hound-type dogs. Procedure—Samples were obtained and neuroendocrine responses measured before (baseline) and after 3 periods of ventricular pacing. A pacemaker was used to induce heart rates of 180, 200, and 220 beats/min (BPM). Each heart rate was maintained for 3 weeks before increasing to the next rate. Atrial natriuretic peptide, antidiuretic hormone, aldosterone, norepinephrine, epinephrine, and dopamine concentrations and plasma renin activity were measured. Severity of left ventricular compromise was estimated. Results—Shortening fraction decreased significantly with increasing heart rates (mean ± SE, 35.5 ± 1.4, 25.0 ± 1.4, 19.5 ± 1.9, and 12.2 ± 2.3 for baseline, 180 BPM, 200 BPM, and 220 BPM, respectively). Atrial natriuretic peptide concentrations increased significantly at 180 BPM (44.1 ± 3.0 pg/mL) and 200 BPM (54.8 ± 5.5 pg/mL)...
2000
Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is reduced by beta-adrenergic blockade, indicate the clinical relevance of heart failure neuroscience research. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with the application of isotope dilution methods for measuring cardiac norepinephrine release to plasma indicating that in untreated patients cardiac norepinephrine spillover is increased as much as 50-fold, similar to levels of release seen in the healthy heart during near maximal exercise. This preferential activation of the cardiac sympathetic out¯ow contributes to arrhythmia development and to progressive deterioration of the myocardium, and has been linked to mortality in both mild and severe cardiac failure. Although the central nervous system mechanisms involved in the sympathetic nervous activation at present remain uncertain, increased intracardiac diastolic pressure seems to be one peripheral re¯ex stimulus, and increased forebrain norepinephrine turnover an important central mechanism. Additional neurophysiological abnormalities present in the failing human heart include release of the sympathetic cotransmitters, epinephrine and neuropeptide Y, at high levels more typical of their release during exercise in healthy subjects, and the possible presynaptic augmentation of norepinephrine release from the cardiac sympathetic nerves by the regionally released epinephrine. Following on the demonstrable bene®t of beta-adrenergic blockade in heart failure, additional antiadrenergic measures (central suppression of sympathetic out¯ow with imidazoline binding agents such as clonidine, blocking of norepinephrine synthesis by dopamine-b-hydroxylase inhibition, antagonism of neuropeptide Y) are now under active investigation.
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.
failuredysfunction in conscious dogs with heart Time course of sympathovagal imbalance and left
2015
To elucidate the time course of sympathovagal balance and its relationship to left ventricular function in heart failure, we serially evaluated left ventricular contractility and relaxation and autonomic tone in 11 conscious dogs with tachycardiainduced heart failure. We determined a dynamic map of sympathetic and parasympathetic modulation by power spectral analysis of heart rate variability. The left ventricular peak ϩdP/dt substantially fell from 3,364 Ϯ 338 to 1,959 Ϯ 318 mmHg/s (P Ͻ 0.05) on the third day and declined gradually to 1,783 Ϯ 312 mmHg/s at 2 wk of rapid ventricular pacing. In contrast, the time constant of left ventricular pressure decay and end-diastolic pressure increased gradually from 25 Ϯ 4 to 47 Ϯ 5 ms (P Ͻ 0.05) and from 10 Ϯ 2 to 21 Ϯ 3 mmHg (P Ͻ 0.05), respectively, at 2 wk of pacing. The high-frequency component (0.15-1.0 Hz), a marker of parasympathetic modulation, decreased from 1,928 Ϯ 1,914 to 62 Ϯ 68 ϫ 10 3 ms 2 (P Ͻ 0.05) on the third day and further to 9 Ϯ 12 ϫ 10 3 ms 2 (P Ͻ 0.05) at 2 wk. Similar to the time course of left ventricular diastolic dysfunction, plasma norepinephrine levels and the ratio of low (0.05-to 0.15-Hz)-to highfrequency component increased progressively from 135 Ϯ 50 to 532 Ϯ 186 pg/ml (P Ͻ 0.05) and from 0.06 Ϯ 0.06 to 1.12 Ϯ 1.01 (P Ͻ 0.05), respectively, at 2 wk of pacing. These cardiac and autonomic dysfunctions recovered gradually toward the normal values at 2 wk after cessation of pacing. Thus a parallel decline in left ventricular contractility with parasympathetic influence and a parallel progression in left ventricular diastolic dysfunction with sympathoexcitation suggest a close relationship between cardiac dysfunction and autonomic dysregulation during development of heart failure.
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.)
Neural regulation of sympathetic nerve activity in heart failure
Progress in Cardiovascular Diseases, 1995
One of the hallmarks of chronic congestive heart failure is an increase in sympathetic tone to the peripheral circulation and to the heart. A correlation between plasma norepinephrine and the severity of the heart failure state has been demonstrated. One mechanism that has been proposed t O account for this sympathoexcitation is a depression in the baroreflex and, Perhaps, cardiac reflex control of sympathetic nerve activity. This review summarizes work from several laboratories, including our own, that documents a depressed baroreflex control of heart rate and sympathetic nerve activity in both animals and humans with heart failure. The mechanism of the de-pressed baroreflex most likely is caused by reduced baroreceptor sensitivity as well as enhanced input to the central nervous system from cardiac receptors that are ChemOsensitive. Although sympathetic tone and arterial baroreflex sensitivity are altered in heart failure, there have been no studies showing a cause.andeffect relationship. Increases in plasma norepinephrine are similar in baroreceptor-denervated and intact dogs paced into heart failure. This latter observation calls into question the traditional concept of baroreceptormediated increases in sympathetic tone in heart failure.
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.