Published online before print September 10, 2007, doi: 10.1161/HYPERTENSIONAHA.107.095216
(Hypertension. 2007;50:904.)
© 2007 American Heart Association, Inc.
Original Articles |
Chronic Baroreceptor Activation Enhances Survival in Dogs With Pacing-Induced Heart Failure
From the Department of Cellular and Integrative Physiology (I.H.Z., J.F.H., K.G.C., B.A.H., N.R.A.), University of Nebraska Medical Center, Omaha; CVRx, Inc (R.K., D.J.S., M.A.R.), Maple Grove, Minn; North Memorial Medical Center (E.D.I.), Robbinsdale, Minn; and the Department of Pharmacology (J.D.P.), Midwestern University, Downers Grove, Ill.
Correspondence to Irving H. Zucker, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850. E-mail izucker{at}unmc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Much of the current pharmacological therapy for chronic heart failure targets neurohormonal activation. In spite of recent advances in drug therapy, the mortality rate for chronic heart failure remains high. Activation of the carotid baroreceptor (BR) reduces sympathetic outflow and augments vagal tone. We investigated the effect of chronic activation of the carotid BR on hemodynamic and neurohormonal parameters and on mortality in dogs with chronic heart failure. Fifteen dogs were instrumented to record hemodynamics. Electrodes were applied around the carotid sinuses to allow for activation of the BR. After 2 weeks of pacing (250 bpm), electrical carotid BR activation was initiated in 7 dogs and continued for the remainder of the study. The start of BR activation was used as a time reference point for the remaining 8 control dogs that did not receive BR activation. Survival was significantly greater for dogs undergoing carotid BR activation compared with control dogs (68.1±7.4 versus 37.3±3.2 days, respectively; P<0.01), although arterial pressure, resting heart rate, and left ventricular pressure were not different over time in BR-activated versus control dogs. Plasma norepinephrine was lower in dogs receiving BR activation therapy 31 days after the start of BR activation (401.9±151.5 versus 1121.9±389.1 pg/mL in dogs not receiving activation therapy; P<0.05). Plasma angiotensin II increased less in dogs receiving activation therapy (plasma angiotensin II increased by 157.4±58.6 pg/mL in control dogs versus 10.1±14.0 pg/mL in dogs receiving activation therapy; P<0.02). We conclude that chronic activation of the carotid BR improves survival and suppresses neurohormonal activation in chronic heart failure.
Key Words: baroreflex • carotid sinus • sympathetic nerve activity • nerve stimulation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The role of autonomic activation in the setting of chronic heart failure (CHF) is well established and is the target of modern pharmacotherapy of CHF.1–4 Chronic increases in sympathetic function and activation of the renin-angiotensin II (Ang II)-aldosterone system are especially disadvantageous in the setting of CHF. The intense vasoconstrictor tone provided by increases in sympathetic outflow, along with activation of the renin-Ang II-aldosterone system, the vasopressin system, and the endothelin-1 system, may largely be responsible for peripheral organ dysfunction and damage in the setting of CHF. The prevailing dogma concerning the mechanism of sympathohumoral excitation in CHF is that the arterial and cardiopulmonary reflexes, which normally are inhibitory to these systems, have a reduced sensitivity and thereby allow neurohumoral outflow to proceed unchecked.5–12 Eckberg et al11 originally documented depressed arterial baroreflex control of heart rate in patients with heart failure. This finding has been corroborated many times for both HR and sympathetic outflow in humans and animals with CHF.13 Reflexes emanating from cardiac vagal sensory endings have also been shown to be depressed in the CHF state.14–17 There is little doubt that baroreflex function is depressed in CHF.6,10,13 This depression is a function of both baroreceptor abnormalities and changes in central neuronal signal processing.
Interestingly, there is evidence that augmentation of baroreflex function is capable of reducing sympathetic tone in humans with heart failure.18,19 These investigators demonstrated an inotropic independent enhancement in arterial baroreflex function after administration of cardiac glycosides to patients with heart failure. Animal experiments have demonstrated an excitatory effect of cardiac glycosides on baroreceptor discharge in normal and heart failure animals.20,21 These studies suggest that augmentation of a depressed baroreflex in the CHF state may be capable of reversing some of the neurohumoral excitation in this syndrome. Recent failures of other pharmacological treatments in CHF22,23 point to an urgent need for the development of other therapies.
Traditionally, it has been well accepted that the BR is involved in short-term regulation and that, with chronic changes in blood pressure, the BR will reset to the prevailing pressure. However, an emerging body of evidence indicates that arterial baroreflexes do not completely reset in response to long-term alterations in arterial pressure.24–26 As a result, arterial baroreflexes appear to have a sustained influence on sympathetic activity. Thrasher demonstrated that chronic unloading of the carotid baroreceptors in dogs produced sustained hypertension (7 days) associated with sodium retention and increases in plasma renin activity and heart rate.26 Such responses indicated sustained increases in sympathetic activity to the heart and kidneys, responses that also occur in CHF. In recent studies the idea of chronic stimulation of the carotid baroreceptors has gained attention as a therapeutic modality for the treatment of drug-resistant hypertension.27,28 Earlier studies had evaluated carotid sinus nerve stimulation in humans and animals as a therapy for hypertension and intractable angina.29–32 However, chronic baroreflex stimulation has never been evaluated in the setting of CHF. Therefore, in the present study, we hypothesized that chronic carotid sinus stimulation in the setting of CHF would reduce sympathetic outflow and have beneficial effects on cardiac function and survival.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
All of the experiments were carried out on male dogs weighing between 21 and 25 kg. All of the procedures were approved by the University of Nebraska Medical Center Institutional Animal Care and Use Committee and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Animals were housed in runs and subjected to a 12-hour light cycle. They were fed 2 cans of food per day (738 g; 0.21% sodium; 0.20% potassium) and allowed water ad libitum.
Heart Failure Model
The model of chronic tachycardia as described in previous studies from this laboratory was used to produce CHF.8,33,34 Dogs were instrumented with a left ventricular pacing electrode secured to an external pacing unit. At the same time, a Data Sciences Incradio telemetry transducer was implanted (Model TL 11 M3-D70 PCTP) with catheters implanted into the left ventricle and aorta for the measurement of left ventricular pressure, arterial pressure and left ventricular dp/dtmax. Electrodes were also secured to the ventricular surface for recording the ECG. Approximately 4 weeks after the thoracotomy, when the dogs were eating and drinking normally and had normal hemodynamics, ventricular pacing was commenced at a rate of 250 bpm. The clinical status (weight, signs of pulmonary and peripheral edema, and general level of activity) of each dog was evaluated daily. Furthermore, dogs were evaluated by echocardiography and hemodynamic monitoring (see below) on a weekly basis.
Carotid Sinus Stimulation
Stimulation of the carotid sinus baroreceptors was carried out as previously described.27 Two weeks after the thoracic instrumentation, stimulating electrodes were implanted circumferentially around both carotid sinuses. The electrodes were tunneled beneath the skin and attached to a programmable carotid sinus stimulator (Rheos, CVRx, Inc). The efficacy of the stimulation and proper placement of the electrodes were confirmed by the blood pressure- and heart rate-lowering responses during activation at the time of surgery. Several days after recovery from surgery, the response to carotid sinus stimulation was again determined in the conscious state. This was done several times over the subsequent week to insure a stable response. It has been shown that there is a linear stimulus response relationship between stimulus amplitude (voltage) and the fall in arterial pressure27 over the range of 4.5 to 7.5 volts. However, because there is some variability in the sensitivity to stimulation because of electrode placement or intrinsic differences in the carotid sinus architecture, we tested each dog for its sensitivity beginning at 1 week after electrode implantation. Over a 2- to 3-day period, we established the level of stimulation necessary to decrease arterial pressure by 10 to 15 mm Hg. We stimulated each dog at the predetermined voltage with 0.5- to 1.0-ms2 wave pulses at 50 to 100 Hz. The duty cycle for stimulation included continuous trains of pulses for 9 minutes and then off for 1 minute. This duty cycle was chosen to avoid the possibility that baroreceptors may undergo chronic resetting without a short period in which they were not stimulated. Figure S1 (see online supplemental data at http://hyper.ahajournals.org) shows a representative tracing of the arterial pressure and heart rate responses to bilateral carotid sinus stimulation in a conscious dog 2 weeks after electrode implantation.
Echocardiography
With the dogs lying on their left side on a laboratory table in a quiet, dimly lit room, echocardiographic measurements were made with an Acuson Sequoia 512 C echocardiograph using a 5-MHz probe. Left ventricular function was determined by the measurement of LV end diastolic diameter and end systolic diameter. Derived parameters were diastolic volume, systolic volume, fractional shortening, and ejection fraction.
Plasma Ang II and Norepinephrine
The protocol for Ang II extraction from plasma samples was essentially similar to that described by Raff et al35; however, we have modified the protocols for final sample preparation and the assay, which has resulted in a significant improvement of the assay. The protocol has been optimized and verified by spiking plasma samples with known and unknown amounts of pure Ang II. The sensitivity of the assay is 2 pg per tube.
Plasma norepinephrine was measured using the radioenzymatic technique as described by Peuler and Johnson36 and obtained in kit form (Amersham Biosciences). The technicians carrying out these assays were blinded to the animals that they were obtained from.
Protocol
Figure 1 summarizes the experimental protocol used in these studies. In brief, after recovery from the carotid electrode and stimulator surgery, baseline hemodynamic measurements and plasma samples were taken with the dogs lying quietly on a laboratory table in the conscious state. On day –14, cardiac pacing was initiated at a rate of 250 bpm. Pacing continued until the demise of the dogs. After 2 weeks (day 0) of pacing, dogs were divided into 2 groups. In one group, carotid sinus stimulation was initiated. The other group was treated in a similar fashion, but no carotid sinus stimulation was carried out. Hemodynamic measurements and blood sampling were then carried out twice per week for the remainder of the experiment. All of the hemodynamic measurements and blood sampling took place after the cardiac pacemaker had been turned of for 
20 minutes.
|
Statistical Analysis
All of the data are expressed at mean±SEM. Group differences were determined with a Student’s t test. Differences within a group across time were determined with a 1-way ANOVA for repeated measures when the numbers were similar. A P<0.05 was assumed to be statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Parameters
Seventeen dogs were included in this study. One dog in the stimulated group was eliminated from the data after carotid sinus stimulation, because we could not confirm continuous carotid sinus stimulation. However, this dog’s baseline data have been included. Because the survival of dogs in each group was different, the numbers for various time points are different, being greatest in the earlier time periods. The Table shows baseline hemodynamic parameters measured in the conscious state before either chronic pacing or carotid stimulation was initiated. The only significant difference was a slightly higher mean arterial pressure in the stimulated group. Table S1 shows the baseline echocardiographic data from stimulated and nonstimulated dogs. No significant differences were noted.
|
Hemodynamic Responses in Carotid Sinus-Stimulated and Nonstimulated Dogs
Hemodynamic parameters were recorded twice per week with the dogs resting in the laboratory after turning off the pacemaker for 
20 minutes. Figures 2 and 3
show the time course for changes in left ventricular end diastolic pressure, left ventricular dp/dtmax, mean arterial pressure, and HR in the 2 groups of dogs. With the exception of a slightly greater increase in left ventricular end diastolic pressure in the nonstimulated group, there were no significant differences in the other hemodynamic parameters measured. The changes in ejection fraction and fractional shortening are shown in Figure 4. As was the case for the other parameters, these echo-based parameters were also not different between stimulated and nonstimulated groups over time. Left ventricular diameters and volumes progressively increased equivalently in both groups (data not shown).
|
|
|
Plasma Norepinephrine
Baseline plasma norepinephrine averaged 288.5±75.5 pg/mL in 7 dogs from the nonstimulated group and 338.0±104.0 pg/mL in 7 dogs from the stimulated group, and they were not significantly different from each other. As shown in Figure 5, the changes in plasma norepinephrine after chronic pacing were marked in the nonstimulated group but remained low in the stimulated group until almost 10 weeks of pacing. After pacing in the nonstimulated group, norepinephrine was highly variable but increased to a peak of 1121.9±389.1 pg/mL at 31 days after the initiation of pacing. The changes in plasma norepinephrine at days 24 to 42 in the stimulated group were significantly lower compared with the nonstimulated group.
|
) in carotid sinus-stimulated and nonstimulated dogs. Solid arrow denotes the time that carotid sinus stimulation was initiated. *P<0.05.
Plasma Ang II
Baseline plasma Ang II taken before ventricular pacing was initiated at an average of 43.3±14.5 pg/mL in the nonstimulated group and 60.0±14.5 pg/mL in the stimulated group. These differences were not significantly different from each other. Figure 6 shows the changes in plasma Ang II on a weekly basis after the initiation of chronic pacing in each group. As was the case for norepinephrine, Ang II remained at baseline in the carotid sinus-stimulated group until very late in the course of pacing, whereas it increased significantly at 35 days of pacing in the nonstimulated group, reaching 198.4±63.0 pg/mL at this time point.
|
Survival
Dogs in both groups were paced until they either died or they were moribund (eg, would not stand, eat, drink, etc) and were euthanized. Two dogs in the nonstimulated group and 1 dog in the stimulated group were euthanized. The mean survival rate after the initiation of pacing was 37.3±3.2 days in the nonstimulated group versus 68.1±7.4 days in the stimulated group (P<0.01). A Kaplan-Meier plot of the percentage of survival versus time is shown in Figure 7. Nonstimulated dogs started to die as early as 22 days after pacing compared with the stimulated group, where the first dog died at 37 days. In the nonstimulated group, no dogs survived past 49 days after ventricular pacing. The longest survivor in the stimulated group was 91 days. For those dogs that succumbed to their heart failure, the exact cause of death cannot easily be determined. Hemodynamic parameters but not waveform data were recorded continuously; therefore, it is difficult to determine whether an arrhythmia or pump failure with resulting pulmonary edema caused their demise. On postmortem inspection, all of the dogs showed signs of pulmonary edema and ascites.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Short-term regulation of sympathetic outflow is determined to a large degree by the arterial baroreflex. There is, however, a good deal of controversy as to the role of the arterial baroreflex in regulating chronic changes in sympathetic outflow, especially in disease states, such as hypertension and heart failure,26,27,37,38 where sympathoexcitation is an important component.39,40 Although disagreement remains as to the long-term contribution of abnormal baroreflex function in CHF,12,33,41 there is a general consensus that arterial baroreflex function is depressed in the setting of CHF.6,11,13 Because the arterial baroreflex is a sympathoinhibitory negative feedback system, it was of interest to determine the effects of augmentation of baroreflex function in CHF. In the current study we observed significant reductions in sympathetic function and a dramatic enhancement in survival in a canine model of pacing-induced CHF. Survival was increased in spite of the fact that ventricular function did not appear to be enhanced in dogs subjected to chronic stimulation of the carotid baroreceptors.
The use of carotid sinus nerve stimulation for the treatment of hypertension and intractable angina was described in humans and animals >40 years ago.29,42–44 Although these early studies demonstrated the efficacy of this technique, it was abandoned because of limitations of implantable medical devices of that era, as well as because of improved pharmacological therapy becoming widely available. A renewed interest in carotid sinus stimulation has been generated by the development of a programmable device currently being tested for treatment of severe drug-resistant hypertension in humans. Using this device (Rheos System, CVRx, Inc), arterial pressure was chronically lowered in normotensive dogs with various forms of chronic hypertension. Lohmeier et al45,46 showed a sustained suppression of plasma norepinephrine, renin, and arterial pressure during 1 week of carotid sinus stimulation in both normal and hypertensive dogs. It is of interest to speculate why the carotid sinus-stimulated dogs in this study did not exhibit a further fall in arterial pressure compared with their nonstimulated counterparts. The model used in these experiments is substantially different than the normal or hypertensive models used by Lohmeier et al.45,46 One characteristic of the pacing model is hypotension as a result of a decrease in cardiac function. This occurred equally in both stimulated and nonstimulated dogs. Most likely it is difficult to observe a further decrease in arterial pressure, which would be superimposed on a hypotensive phenomenon. Furthermore, it must be remembered that the data obtained by Lohmeier et al45,46 were obtained during carotid sinus stimulation, whereas in our data, the stimulator was turned off during data acquisition. Sato et al47 demonstrated the use of a servo control system to regulate sympathetic outflow and arterial pressure in rats with baroreflex dysfunction in CHF. Therefore, because these neurohumoral changes would typically result in a favorable response to treatment in CHF, we set out to determine whether baroreceptor stimulation was effective in reducing mortality in the CHF state. Our data clearly demonstrate an improved survival in the group receiving carotid sinus stimulation in this pacing model of CHF.
Mechanisms for Enhanced Survival During Baroreflex Stimulation
Although the present study cannot definitively determine the mechanisms for enhanced survival in CHF dogs subjected to carotid sinus stimulation, several potential possibilities may be put forth. First, chronic increases in sympathetic outflow, especially to the heart and kidneys, can impair organ function.38,48 Indeed, cardiac sympathetic function is a prime target for therapy in the use of ß-adrenergic blockers in heart failure. However, in the present study, there were no differences in cardiac function between the stimulated and nonstimulated dogs. Therefore, it is unlikely that the beneficial effect of carotid sinus stimulation was mediated by a major influence of reducing cardiac sympathetic nerve activity or enhancing cardiac vagal outflow. It should be noted however, that Sabbah et al49 have recently reported an increase in ejection fraction after prolonged BR activation in a coronary embolization model. In this model, ejection fraction was reduced to 
25% compared with 40% using the pacing model described in the current study. The lack of an effect of BR activation on ventricular function in the present study suggests that, at least in this model of CHF, the beneficial effects of this intervention may be mediated by important peripheral adjustments. If we assume that the maintenance of low levels of plasma norepinephrine in stimulated dogs reflects a global reduction in sympathetic outflow, then it is possible that peripheral organ function is maintained for a longer period of time in the stimulated dogs (eg, maintenance of renal function).
Another potential mechanism for the beneficial effects of this therapy is a reduction in plasma Ang II. Although there was a good deal of variability in these data, in general Ang II increased at an earlier time point in nonstimulated dogs than in the stimulated dogs. This coincided with the survival profiles of the nonstimulated dogs compared with the carotid-stimulated dogs. Again, suppression of Ang II generation and Ang II receptor blockade has become mainstream therapy for the treatment of patients with CHF. Providing a stimulus that keeps Ang II low should contribute to a reduction in vascular resistance and extracellular volume and should reduce the mitogenic effects of Ang II, which may attenuate the remodeling process.50,51 What is not clear from these studies is whether the prevention of Ang II from rising in the stimulated dogs depends on a reduction in renal sympathetic nerve activity or whether the reduction in Ang II contributes to the reduced central sympathetic outflow, a phenomenon for which a large amount of evidence exists.52–55
Finally, there may be additional neurohumoral and peripheral mechanisms involved in the salutary effects of carotid sinus stimulation. For instance, it is theoretically possible that a reduction in plasma norepinephrine and Ang II would lead to enhanced endothelial function,51,56 thus enhancing regional perfusion to critical vascular beds.
Limitations of Carotid Sinus Stimulation
Because arterial baroreflex function is impaired in CHF, it is widely accepted that this depression contributes at some point to neurohumoral activation.12 In the present study, baroreceptor activation was performed using field stimulation of the carotid sinus wall. Although this technique avoids dissection and direct stimulation of the carotid sinus nerve, it could potentially activate chemoreceptors. Because the response to carotid sinus stimulation is acutely dominated by a fall in blood pressure and heart rate, it is unlikely that chemoreceptor stimulation contributed in a major way to the effects of carotid sinus stimulation in these experiments. Ventilation was not measured.
Earlier studies in humans and animals in which the carotid sinus nerve was stimulated showed repeated hypotensive effects for periods of up to several years.57 In animal experiments, Lohmeier et al27 showed sustained hypotensive, norepinephrine, and renin effects over a stimulation period of 1 week using the same Rheos system as that used in the present study. Based on the suppression of plasma norepinephrine in carotid sinus-stimulated dogs, the present study provides evidence of sustained baroreflex augmentation for periods of 
3 months.
The efficacy of this technique in humans with CHF will have to wait for appropriate clinical trials. However, this device has been implanted in patients with drug-resistant hypertension in clinical trials in Europe (DeBut-HT)58 and North America (Rheos). In these studies, the device evoked reductions in arterial pressure for prolonged periods of time. Although implantation of this device involves a surgical procedure, it is more robust and less invasive than the device reported in the late 196’s and early 1970s, where carotid sinus nerve dissection was necessary. It remains to be seen whether unilateral stimulation is as effective as bilateral stimulation. If so, this would further enhance the acceptability of this device as an adjunctive therapy for CHF.
Perspectives
Chronic carotid sinus stimulation in dogs with pacing-induced CHF-reduced neurohumoral excitation and dramatically increased survival. This occurred in spite of little change in ventricular function. Although targeting sympathetic nerve activity in CHF appears to be logical and is, to a large degree, mainstream therapy, it remains unclear whether suppression of sympathetic support in CHF is beneficial. For instance, in the Moxonidine Congestive Heart Failure Trial, which was designed to evaluate the role of central imidazoline receptor stimulation with moxonidine on survival, a surprise increase in mortality was observed. This was associated with an 18.8% decrease in plasma norepinephrine.22 This suppression of plasma norepinephrine may have been larger than is therapeutically necessary. In the present study, plasma norepinephrine was prevented from rising during ventricular pacing and the development of CHF but never went below baseline. Although the 2 situations are not completely comparable, the use of BR activation may provide significant advantages in the control of the level of sympathoinhibition. These data suggest that the beneficial effects of carotid sinus stimulation may be attributable more to peripheral vascular and/or neurohumoral inhibition than to cardiac benefits. Furthermore, they suggest that carotid sinus stimulation may be a beneficial therapy for patients with CHF in addition to patients with drug-resistant hypertension.
|
Acknowledgments |
|---|
We gratefully thank Pamela Curry and Phyllis Anding for their expert technical assistance.
Source of Funding
This study was supported by a grant from CVRx, Inc, Maple Grove, Minn.
Disclosures
I.H.Z. is a member of the scientific advisory board of CVRx, Inc. The remaining authors report no conflicts.
Received May 24, 2007; first decision June 16, 2007; accepted August 17, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Esler M, Kaye D, Lambert G, Esler D, Jennings G Adrenergic nervous system in heart failure. Am J Cardiol. 1997; 80: 7L–14L.[CrossRef][Medline] [Order article via Infotrieve]
2. Francis GS, McDonald KM, Cohn JN. Neurohumoral activation in preclinical heart failure: remodeling and the potential for intervention. Circulation. 1993; 87 (suppl 4): IV90–IV96.[Medline] [Order article via Infotrieve]
3. McMurray JJV. Major ß blocker mortality trials in chronic heart failure: a critical review. Heart. 1999; 82: 14–22.
4. Packer M. Beta-blockade in heart failure. Basic concepts and clinical results. Am J Hypertens. 1998; 11: 23S–37S.[CrossRef][Medline] [Order article via Infotrieve]
5. Ferguson DW, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J Am Coll Cardiol. 1990; 16: 1125–1134.[Abstract]
6. Mancia G, Seravalle G, Giannattasio C, Bossi M, Preti L, Cattaneo BM, Grassi G. Reflex cardiovascular control in congestive heart failure. Am J Cardiol. 1992; 69: 17G–23G.[Medline] [Order article via Infotrieve]
7. Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S, Giannattasio C, Del Bo A, Sala C, Bolla GB, Pozzi M, Mancia G. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation. 1995; 92: 3206–3211.
8. Wang W, Chen J-S, Zucker IH. Carotid sinus baroreceptor reflex in dogs with experimental heart failure. Circ Res. 1991; 68: 1294–1301.
9. Ellenbogen KA, Mohanty PK, Szentpetery S, Thames MD. Arterial baroreflex abnormalities in heart failure. Reversal after orthotopic cardiac transplantation. Circulation. 1989; 79: 51–58.
10. Creager MA. Baroreceptor reflex function in congestive heart failure. Am J Cardiol. 1992; 69: 10G–6G.[Medline] [Order article via Infotrieve]
11. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med. 1971; 285: 877–883.[Medline] [Order article via Infotrieve]
12. Mancia G. Sympathetic activation in congestive heart failure. Europ Heart J. 1990; 11 (suppl A): 3–11.
13. Zucker IH, Wang W, Brändle M, Schultz HD, Patel KP. Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovas Dis. 1995; 37: 397–414.[CrossRef][Medline] [Order article via Infotrieve]
14. Brändle M, Wang W, Zucker IH. Ventricular mechanoreflex and chemoreflex alterations in chronic heart failure. Circ Res. 1994; 74: 262–270.
15. Zucker IH, Gorman AJ, Cornish KG, Lang M. Impaired atrial receptor modulation of renal nerve activity in dogs with chronic volume overload. Cardiovas Res. 1985; 19: 411–418.[Medline] [Order article via Infotrieve]
16. Dibner-Dunlap ME, Smith ML, Kinugawa T, Thames MD. Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure. J Am Coll Cardiol. 1996; 27: 358–364.[Abstract]
17. Kinugawa T, Dibner-Dunlap ME, Sica DA, Thames MD. Treatment with enalapril fails to prevent impaired cardiopulmonary baroreflex control in dogs with left ventricular dysfunction. J Card Failure. 1995; 1: 381–389.[Medline] [Order article via Infotrieve]
18. Ferguson DW. Digitalis and baroreflexes in heart failure. Trends Cardiovasc Med. 1992; 2: 21–26.[CrossRef]
19. Ferguson DW. Digitalis and neurohormonal abnormalities in heart failure and implications for therapy. Am J Cardiol. 1992; 69: 24G–33G.[CrossRef][Medline] [Order article via Infotrieve]
20. Wang W, Chen J-S, Zucker IH. Postexcitatory depression of baroreceptors in dogs with experimental heart failure. Am J Physiol Heart Circ Physiol. 1991; 260: H1160–H1165.
21. Quest JA, Gillis RA. Effect of digitalis on carotid sinus baroreceptor activity. Circ Res. 1974; 357: 247–255.
22. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ. Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail. 2003; 5: 659–667.
23. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, Van Velduisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004; 109: 1594–1602.
24. Lohmeier TE, Hildebrandt DA, Warren S, May P, Cunningham JT. Recent insights into the interactions between the baroreflex and the kidneys in hypertension. Am J Physiol Regul Integ Comp Physiol. 2005; 288: R228–R236.
25. Lohmeier TE. The sympathetic nervous system and long-term blood pressure regulation. Am J Hypertens. 2001; 14: 147S–154S.[CrossRef][Medline] [Order article via Infotrieve]
26. Thrasher TN. Unloading arterial baroreceptors causes neurogenic hypertension. Am J Physiol Regul Integ Comp Physiol. 2002; 282: R1044–R1053.
27. Lohmeier TE, Irwin ED, Rossing MA, Serdar DJ, Kieval RS. Prolonged activation of the baroreflex produces sustained hypotension. Hypertension. 2004; 43: 306–311.
28. Lohmeier TE, Hildebrandt DA, Dwyer TM, Barrett AM, Irwin ED, Rossing MA, Kieval RS. Renal denervation does not abolish sustained baroreflex-mediated reductions in arterial pressure. Hypertension. 2007; 49: 373–379.
29. Braunwald E, Epstein SE, Glick G, Wechsler AS, Braunwald NS. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. N Engl J Med. 1967; 277: 1278–1283.[Medline] [Order article via Infotrieve]
30. Braunwald NS, Epstein SE, Braunwald E. Carotid sinus nerve stimulation for the treatment of intractable angina pectoris: surgical technique. Ann Surg. 1970; 172: 870–876.[Medline] [Order article via Infotrieve]
31. Epstein SE, Beiser GD, Goldstein RE, Redwood D, Rosing DR, Glick G, Wechsler AS, Stampfer M, Cohen LS, Reis RL, Braunwald NS. Treatment of angina pectoris by electrical stimulation of the carotid-sinus nerves. Results in 17 patients with severe angina. N Engl J Med. 1969; 280: 971–978.[Medline] [Order article via Infotrieve]
32. Brest AN, Wiener L, Bachrach B. Bilateral carotid sinus nerve stimulation in the treatment of hypertension. Am J Cardiol. 1972; 29: 821–825.[CrossRef][Medline] [Order article via Infotrieve]
33. Brändle M, Patel K, Wang W, Zucker IH. Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sino-aortic denervated dogs. J Appl Physiol. 1996; 81: 1855–1862.
34. Brändle M, Wang W, Zucker IH. Hemodynamic correlates of baroreflex impairment in experimental canine heart failure. Basic Res Cardiol. 1996; 91: 147–154.[CrossRef][Medline] [Order article via Infotrieve]
35. Raff H, Maselli J, Reid IA. Correlation of plasma angiotensin II concentration and plasma renin activity during acute hypoxia in dogs. Clin Exp Pharmacol Physiol. 1985; 12: 91–94.[Medline] [Order article via Infotrieve]
36. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci. 1977; 21: 625–636.[CrossRef][Medline] [Order article via Infotrieve]
37. Cowley AW Jr, Liard JF, Guyton AC. Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res. 1973; 32: 564–576.
38. Ito CS, Scher AM. Hypertension following arterial baroreceptor denervation in the unanesthetized dog. Circ Res. 1981; 48: 576–591.
39. Esler MD, Lambert GW, Ferrier C, Kaye DM, Wallin BG, Kalff V, Kelly MJ, Jennings GL. Central nervous system noradrenergic control of sympathetic outflow in normotensive and hypertensive humans. Clin Exp Hypertens. 1995; 17: 409–423.[CrossRef][Medline] [Order article via Infotrieve]
40. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, Hastings J, Aggarwal A, Esler MD. Sympathetic augmentation in hypertension - role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension. 2004; 43: 169–175.
41. Levett JM, Marinelli CC, Lund DD, Pardini BJ, Nader S, Scott BD, Augelli NV, Kerber RE, Schmid PG Jr. Effects of ß-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 1994; 266: H468–H475.
42. Bilgutay AM, Lillehei CW. Surgical treatment of hypertension with reference to baropacing. Am J Cardiol. 1966; 17: 663–667.[CrossRef][Medline] [Order article via Infotrieve]
43. Schwartz SI, Griffith LSC, Neistadt A, Hagfors N. Chronic carotid sinus nerve stimulation in the treatment of essential hypertension. Am J Surgery. 1967; 114: 5–15.[CrossRef][Medline] [Order article via Infotrieve]
44. Neistadt A, Schwartz SI. Effects of electrical stimulation of the carotid sinus nerve in reversal of experimentally induced hypertension. Surgery. 1967; 61: 923–931.[Medline] [Order article via Infotrieve]
45. Lohmeier TE, Dwyer TM, Hildebrandt DA, Irwin ED, Rossing MA, Serdar DJ, Kieval RS. Influence of prolonged baroreflex activation on arterial pressure in angiotensin hypertension. Hypertension. 2005; 46: 1194–1200.
46. Lohmeier TE, Dwyer TM, Irwin ED, Rossing MA, Kieval RS. Prolonged activation of the baroreflex abolishes obesity-induced hypertension. Hypertension. 2007; 49: 1307–1314.
47. Sato T, Kawada T, Sugimachi M, Sunagawa K. Bionic technology revitalizes native baroreflex function in rats with baroreflex failure. Circulation. 2002; 106: 730–734.
48. Ruffolo RR Jr, Feuerstein GZ, Ohlstein EH. Recent observations with beta-adrenoceptor blockade. Beneficial effects in hypertension and heart failure. Am J Hypertens. 1998; 11: 9S–14S.[CrossRef][Medline] [Order article via Infotrieve]
49. Sabbah HN, Irwin ED, Serdar DJ, Sharov VG, Rossing MA, Kieval RS. Chronic electrical activation of the carotid baroreflex improves left ventricular systolic and diastolic function in dogs with advanced heart failure. Circulation. 2005; 112 (suppl II): II-557. Abstract.
50. Higashi T, Kobayashi N, Hara K, Shirataki H, Matsuoka H. Effects of angiotensin II type 1 receptor antagonist on nitric oxide synthase expression and myocardial remodeling in Goldblatt hypertensive rats. J Cardiov Pharmacol. 2000; 35: 564–571.[CrossRef][Medline] [Order article via Infotrieve]
51. Touyz RM. Reactive oxygen species and angiotensin II signaling in vascular cells – implications in cardiovascular disease. Braz J Med Biol Res. 2004; 37: 1263–1273.[Medline] [Order article via Infotrieve]
52. Head GA, Saigusa T, Mayorov DN. Angiotensin and baroreflex control of the circulation. Braz J Med Biol Res. 2002; 35: 1047–1059.[Medline] [Order article via Infotrieve]
53. Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol Endocrinol Metab. 1992; 262: E763–E778.
54. Saavedra JM. Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol. 2005; 25: 485–512.[CrossRef][Medline] [Order article via Infotrieve]
55. Zucker IH. Novel mechanisms of sympathetic regulation in chronic heart failure. Hypertension. 2006; 48: 1005–1011.
56. Nishida Y, Ding J, Zhou M-S, Chex Q-H, Murakami H, Wu X-Z, Kosaka H. Role of nitric oxide in vascular hyper-responsiveness to norepinephrine in hypertensive Dahl rats. J Hypertens. 1999; 16: 1611–1618.[CrossRef]
57. Peters TK, Koralewski H, Zerbst EW. The evolution strategy-A search strategy used in individual optimization of electrical parameters for therapeutic carotid sinus nerve stimulation. IEEE Trans Biomed Engin. 1989; 36: 668–675.[CrossRef][Medline] [Order article via Infotrieve]
58. de Leeuw PW, Kroon AA, Scheffers I, Tordoir J, Schmidli J, Mohaupt M, Allemann Y, Jordan J, Engeli S, Liebeskind U, Luft F, Eckert S, Hansky B, Kieval R, Cody R, Rossing M, Irwin E, Peters T. Baroreflex hypertension therapy with a chronically implanted system: Preliminary efficacy and safety results from the Rheos DEBuT-HT study in patients with resistant hypertension. J Hypertens. 2006; 24: S300–S301.
This article has been cited by other articles:
 |
|
 |
|
  H. Zheng, Y.-F. Li, W. Wang, and K. P. Patel Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2009; 297(5): R1364 - R1374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. H. Zucker, H. D. Schultz, K. P. Patel, W. Wang, and L. Gao Regulation of central angiotensin type 1 receptors and sympathetic outflow in heart failure Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1557 - H1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Wustmann, J. P. Kucera, I. Scheffers, M. Mohaupt, A. A. Kroon, P. W. de Leeuw, J. Schmidli, Y. Allemann, and E. Delacretaz Effects of Chronic Baroreceptor Stimulation on the Autonomic Cardiovascular Regulation in Patients With Drug-Resistant Arterial Hypertension Hypertension, September 1, 2009; 54(3): 530 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Floras Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J. Am. Coll. Cardiol., July 28, 2009; 54(5): 375 - 385. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||