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Marat Fudim - One of the best experts on this subject based on the ideXlab platform.
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surgical ablation of the right greater Splanchnic Nerve for the treatment of heart failure with preserved ejection fraction first in human clinical trial
European Journal of Heart Failure, 2021Co-Authors: Filip Malek, Marat Fudim, Piotr Gajewski, Robert Zymlinski, Dariusz Janczak, Mariusz Chabowski, Tomas Martinca, Petr Neužil, Jan Biegus, Martin MatesAbstract:Aims Inappropriate control of blood volume redistribution may be a mechanism responsible for exercise intolerance in heart failure with preserved ejection fraction (HFpEF). We propose to address this underlying pathophysiology with selective blockade of sympathetic signalling to the Splanchnic circulation by surgical ablation of the right greater Splanchnic Nerve (GSN). Methods and results In a single-arm, prospective, two-centre trial, 10 patients with HFpEF (50% male, mean age 70 ± 3 years) all with New York Heart Association (NYHA) class III, left ventricular ejection fraction >40%, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry, underwent ablation of the right GSN via thoracoscopic surgery. Patients were evaluated at baseline, 1, 3, 6 and 12 months after the procedure. The primary endpoint was a reduction in exercise PCWP at 3 months. There were no adverse events related to the blockade of the Nerve during 12-month follow-up but three patients had significant peri-procedural adverse events related to the surgical procedure itself. At 3 months post-GSN ablation, patients demonstrated a reduction in 20 W exercise PCWP when compared to baseline [-4.5 mmHg (95% confidence interval, CI -14 to -2); P = 0.0059], which carried over to peak exercise [-5 mmHg (95% CI -11 to 0; P = 0.016). At 12 months, improvements were seen in NYHA class [3 (3) vs. 2 (1, 2); P = 0.0039] and quality of life assessed with the Minnesota Living with Heart Failure Questionnaire [60 (51, 71) vs. 22 (16, 27); P = 0.0039]. Conclusion In this first-in-human study, GSN ablation in HFpEF proved to be feasible, with a suggestion of reduced cardiac filling pressure during exercise, improved quality of life and exercise capacity.
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Splanchnic Nerve modulation in heart failure mechanistic overview initial clinical experience and safety considerations
European Journal of Heart Failure, 2021Co-Authors: Marat Fudim, Manesh R Patel, Adrian F Hernandez, Daniel Burkhoff, Michael G. Felker, Piotr P Ponikowski, Mark E Dunlap, Paul A Sobotka, Jeroen Molinger, Sheldon E LitwinAbstract:Volume recruitment from the Splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater Splanchnic Nerve (GSN) could have significant benefits in some patients with heart failure (HF) by reducing cardiac filling pressures and improvement in exercise capacity. However, to date the long-term safety of Splanchnic Nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.
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Splanchnic Nerve block mediated changes in stressed blood volume in heart failure
Jacc-Heart Failure, 2021Co-Authors: Marat Fudim, Manesh R Patel, Richard L Boortzmarx, Barry A Borlaug, Adam D Devore, Arun Ganesh, Cynthia L Green, Renato D Lopes, Robert J Mentz, Chetan B PatelAbstract:Abstract Objectives The authors estimated changes of stressed blood volume (SBV) induced by Splanchnic Nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF). Background The Splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB. Methods We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (Splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (Splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight. Results Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p Conclusions The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407 ; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151 )
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Splanchnic Nerve block for chronic heart failure
Jacc-Heart Failure, 2020Co-Authors: Marat Fudim, Richard L Boortzmarx, Adam D Devore, Arun Ganesh, Chetan B Patel, Joseph G Rogers, Aubrie Coburn, Inneke Johnson, Amanda Paul, Brian CoyneAbstract:Abstract Objectives We hypothesized that Splanchnic Nerve blockade (SNB) would attenuate increased exercise-induced cardiac filling pressures in patients with chronic HF. Background Chronic heart failure (HF) is characterized by limited exercise capacity driven in part by an excessive elevation of cardiac filling pressures. Methods This is a prospective, open-label, single-arm interventional study in chronic HF patients. Eligible patients had a wedge pressure ≥15 mm Hg at rest or ≥25 mm Hg with exercise on baseline right heart catheterization. Patients underwent cardiopulmonary exercise testing with invasive hemodynamic assessment, followed by percutaneous SNB with ropivacaine. Results Nineteen patients were enrolled, 15 of whom underwent SNB. The average age was 58 ± 13 years, 7 (47%) patients were women and 6 (40%) were black. Left ventricular ejection fraction was ≤35% in 14 (93%) patients. No procedural complications were encountered. SNB reduced mean pulmonary arterial pressure at peak exercise from 54.1 ± 14.4 (pre-SNB) to 45.8 ± 17.7 mm Hg (p Conclusions SNB reduced resting and exercise-induced pulmonary arterial and wedge pressure with favorable effects on cardiac output and exercise capacity. Continued efforts to investigate short- and long-term effects of SNB in chronic HF are warranted. Clinical Trials Registration (Abdominal Nerve Blockade in Chronic Heart Failure; NCT03453151)
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Increasing Blood Pressure by Greater Splanchnic Nerve Stimulation: a Feasibility Study
Journal of Cardiovascular Translational Research, 2020Co-Authors: Anisha Bapna, Zoar J Engelman, Christopher Adin, Marat FudimAbstract:The Splanchnic vascular compartment is the major reservoir for intravascular blood volume, and dysregulation of the compartment was implicated in a series of cardiovascular conditions. We explored feasibility and effectiveness of an implantable cuff system on the greater Splanchnic Nerve (GSN) in healthy canines for short- and long-term neuromodulation to affect the circulation. Five mongrel hounds underwent minimally invasive right-sided unilateral GSN cuff placement. All animals underwent same day GSN stimulation and repeat stimulation at 9–30 days. Stimulation parameter optimization was conducted both acutely and chronically. Parameters ranged from 1–250 Hz, 0.25 mA–35 mA, 0.1–0.5 ms, and 30-s pulse duration. Two animals were survived for 9 days and 3 animals for 30 days. Stimulation of the right GSN increased mean arterial blood pressure by 36.9 mmHg ± 13.4 ( p < 0.0001), central venous pressure by 6.9 mmHg ± 1.7 ( p < 0.0001), and mean pulmonary arterial pressure by 6.3 mmHg ± 2.0 ( p < 0.0001). Peak effects were observed within 30 s, and magnitude of effects was comparable between stimulation cycles ( p = 0.4). Stimulation-induced changes in hemodynamics were independent of afferent Nerve fibers (pain response) or the adrenal gland. Necropsy showed no evidence of Nerve damage on histologic studies up to 30 days after implantation. GSN stimulation via an implanted Nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The neuromodulation cuff was well tolerated and elicited a response up to 30 days after implantation. The clinical application of GSN stimulation as a tool to change central and peripheral cardiovascular hemodynamics needs to be explored.
Nathalie C Guerineau - One of the best experts on this subject based on the ideXlab platform.
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cholinergic and peptidergic neurotransmission in the adrenal medulla a dynamic control of stimulus secretion coupling
Iubmb Life, 2020Co-Authors: Nathalie C GuerineauAbstract:Synaptic neurotransmission at the Splanchnic Nerve-chromaffin cell synapse is a chief element of the stimulus-secretion coupling in the adrenal medullary tissue, managing and regulating the secretion of catecholamines. Making the state of play more intricate than initially envisioned, the synaptic vesicles of Nerve terminals innervating the medulla contain various compounds, including various neurotransmitters and neuropeptides. Under basal conditions associated with a low Splanchnic Nerve discharge rate, neurotransmission is ensured by the synaptic release of the primary neurotransmitter acetylcholine (ACh). Under sustained and repetitive stimulations of the Splanchnic Nerve, as triggered in response to stressors, the synaptic release of neuropeptides, such as the pituitary adenylate cyclase-activating polypeptide PACAP, supplants ACh release. The anatomical and functional changes that occur presynaptically at the preganglionic Splanchnic Nerve, combined with changes occurring postsynaptically at nicotinic acetylcholine receptors (nAChRs), confer the adrenomedullary synapses a solid and persistent aptitude to functional remodeling, from birth to aging. The present review focuses on the composite cholinergic and noncholinergic nature of neurotransmission occurring at the Splanchnic Nerve-chromaffin cell synapse and its remodeling in response to physiological or pathological stimuli.
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THE JOURNAL OF CELL BIOLOGY
2013Co-Authors: Agnès O. Martin, Gérard Alonso, Nathalie C GuerineauAbstract:In contrast to its well-established actions as an organizer of synaptic differentiation at the neuromuscular junction, the proteoglycan agrin is still in search of a function in the nervous system. Here, we report an entirely unanticipated role for agrin in the dual modulation of electrical and chemical intercellular communication that occurs during the critical period of synapse formation. When applied at the developing Splanchnic Nerve– chromaffin cell cholinergic synapse in rat adrenal acute slices, agrin rapidly modified cell-to-cell communicatio
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Developmental and stress-induced remodeling of cell-cell communication in the adrenal medullary tissue.
Cellular and Molecular Neurobiology, 2010Co-Authors: Nathalie C Guerineau, Michel G DesarménienAbstract:The adrenal medullary tissue contributes to maintain body homeostasis in reaction to stressful environmental changes via the release of catecholamines into the blood circulation in response to Splanchnic Nerve activation. Accordingly, chromaffin cell stimulus-secretion coupling undergoes temporally restricted periods of anatomo- functional remodeling in response to prevailing hormonal requirements of the organism. The postnatal development of the adrenal medulla and response to stress are remarkable physiological situations in which the stimulus- secretion coupling is critically affected. Catecholamine secretion from rat chromaffin cells is under a dual control involving an incoming initial command arising from the sympathetic nervous system that releases acetylcholine at the Splanchnic Nerve terminal-chromaffin cell synapses and a local gap junction-mediated intercellular communication. Interestingly, these two communication pathways are functionally interconnected within the gland and exhibit coordinated plasticity mechanisms. This article reviews the physiological and molecular evidence that the adrenal medullary tissue displays anatomical and functional adaptative remodeling of cell-cell communications upon physiological (postnatal development) and/or physiopathological (stress) situations associated with specific needs in circulating catecholamine levels.
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functional characterization of α9 containing cholinergic nicotinic receptors in the rat adrenal medulla implication in stress induced functional plasticity
The Journal of Neuroscience, 2010Co-Authors: Claude Colomer, Luis Alcides Olivosore, Anne Vincent, Michael J Mcintosh, Antonio R Artalejo, Nathalie C GuerineauAbstract:An increase in circulating adrenal catecholamine levels constitutes one of the mechanisms whereby organisms cope with stress. Accordingly, stimulus-secretion coupling within the stressed adrenal medullary tissue undergoes persistent remodeling. In particular, cholinergic synaptic neurotransmission between Splanchnic Nerve terminals and chromaffin cells is upregulated in stressed rats. Since synaptic transmission is mainly supported by activation of postsynaptic neuronal acetylcholine nicotinic receptors (nAChRs), we focused our study on the role of alpha9-containing nAChRs, which have been recently described in chromaffin cells. Taking advantage of their specific blockade by the alpha-conotoxin RgIA (alpha-RgIA), we unveil novel functional roles for these receptors in the stimulus-secretion coupling of the medulla. First, we show that in rat acute adrenal slices, alpha9-containing nAChRs codistribute with synaptophysin and significantly contribute to EPSCs. Second, we show that these receptors are involved in the tonic inhibitory control exerted by cholinergic activity on gap junctional coupling between chromaffin cells, as evidenced by an increased Lucifer yellow diffusion within the medulla in alpha-RgIA-treated slices. Third, we unexpectedly found that alpha9-containing nAChRs dominantly (>70%) contribute to acetylcholine-induced current in cold-stressed rats, whereas alpha3 nAChRs are the main contributing channels in unstressed animals. Consistently, expression levels of alpha9 nAChR transcript and protein are overexpressed in cold-stressed rats. As a functional relevance, we propose that upregulation of alpha9-containing nAChR channels and ensuing dominant contribution in cholinergic signaling may be one of the mechanisms whereby adrenal medullary tissue appropriately adapts to increased Splanchnic Nerve electrical discharges occurring in stressful situations.
Peng Li - One of the best experts on this subject based on the ideXlab platform.
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caudal ventrolateral medulla mediates the depressor response elicited by the greater Splanchnic Nerve afferent stimulation in rats
Neuroscience Letters, 2002Co-Authors: Yingjie Peng, Qianling Gong, Ning Wang, Peng LiAbstract:Caudal ventrolateral medulla (CVLM) plays an important role in the regulation of reflex cardiovascular activity. In the present study, the possible involvement of the CVLM in mediating the depressor response elicited by the greater Splanchnic Nerve (GSPL) afferent stimulation was explored in rats anesthetized with urethane and alpha-chloralose. Microinjection of lidocaine, and the glutamate receptor antagonists, kynurenic acid and 2-amino-7-phosphonolieptanoic acid, into the CVLM significantly blocked the depressor response induced by the GSPL afferent stimulation. Electrical stimulation of the GSPL inputs excited 48 of 75 CVLM neurons tested (64%). Sixteen out of 21 excited CVLM neurons tested received baroreceptor inputs. Coherence analysis revealed a strong cardiac-related rhythm in the discharges of 11 out of these 21 excited neurons. These results suggest the involvement of CVLM neurons and activation of glutamate receptors in the CVLM in mediating the depressor response induced by the GSPL afferent stimulation in rats.
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gabaa receptors in the rostral ventrolateral medulla mediate the depressor response induced by stimulation of the greater Splanchnic Nerve afferent fibres in rats
Neuroscience Letters, 1998Co-Authors: Yingjie Peng, Qianling Gong, Peng LiAbstract:Abstract Experiments have been carried out to investigate the chemical substrate in the rostral ventrolateral medulla (RVLM) underlying the depressor responses induced by activation of the greater Splanchnic Nerve (GSPL) afferent fibres of the rat. In anaesthetised rats with urethane and alpha-chloralose, microinjection of bicuculline, a GABA A receptor antagonist, into the RVLM, attenuated largely the depressor responses elicited by electrical stimulation of the GSPL afferent fibres, while strychnine or saline had no effect. In 18 RVLM neurons (including seven identified cardiovascular neurons), iontophoresis of bicuculline also significantly blocked the inhibition evoked by stimulation of the GSPL afferent inputs. We suggest that the depressor responses induced by stimulation of the GSPL afferent fibres involve a GABA A -receptor-mediated mechanism in the RVLM in rats.
Yingjie Peng - One of the best experts on this subject based on the ideXlab platform.
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caudal ventrolateral medulla mediates the depressor response elicited by the greater Splanchnic Nerve afferent stimulation in rats
Neuroscience Letters, 2002Co-Authors: Yingjie Peng, Qianling Gong, Ning Wang, Peng LiAbstract:Caudal ventrolateral medulla (CVLM) plays an important role in the regulation of reflex cardiovascular activity. In the present study, the possible involvement of the CVLM in mediating the depressor response elicited by the greater Splanchnic Nerve (GSPL) afferent stimulation was explored in rats anesthetized with urethane and alpha-chloralose. Microinjection of lidocaine, and the glutamate receptor antagonists, kynurenic acid and 2-amino-7-phosphonolieptanoic acid, into the CVLM significantly blocked the depressor response induced by the GSPL afferent stimulation. Electrical stimulation of the GSPL inputs excited 48 of 75 CVLM neurons tested (64%). Sixteen out of 21 excited CVLM neurons tested received baroreceptor inputs. Coherence analysis revealed a strong cardiac-related rhythm in the discharges of 11 out of these 21 excited neurons. These results suggest the involvement of CVLM neurons and activation of glutamate receptors in the CVLM in mediating the depressor response induced by the GSPL afferent stimulation in rats.
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gabaa receptors in the rostral ventrolateral medulla mediate the depressor response induced by stimulation of the greater Splanchnic Nerve afferent fibres in rats
Neuroscience Letters, 1998Co-Authors: Yingjie Peng, Qianling Gong, Peng LiAbstract:Abstract Experiments have been carried out to investigate the chemical substrate in the rostral ventrolateral medulla (RVLM) underlying the depressor responses induced by activation of the greater Splanchnic Nerve (GSPL) afferent fibres of the rat. In anaesthetised rats with urethane and alpha-chloralose, microinjection of bicuculline, a GABA A receptor antagonist, into the RVLM, attenuated largely the depressor responses elicited by electrical stimulation of the GSPL afferent fibres, while strychnine or saline had no effect. In 18 RVLM neurons (including seven identified cardiovascular neurons), iontophoresis of bicuculline also significantly blocked the inhibition evoked by stimulation of the GSPL afferent inputs. We suggest that the depressor responses induced by stimulation of the GSPL afferent fibres involve a GABA A -receptor-mediated mechanism in the RVLM in rats.
Manesh R Patel - One of the best experts on this subject based on the ideXlab platform.
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Splanchnic Nerve modulation in heart failure mechanistic overview initial clinical experience and safety considerations
European Journal of Heart Failure, 2021Co-Authors: Marat Fudim, Manesh R Patel, Adrian F Hernandez, Daniel Burkhoff, Michael G. Felker, Piotr P Ponikowski, Mark E Dunlap, Paul A Sobotka, Jeroen Molinger, Sheldon E LitwinAbstract:Volume recruitment from the Splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater Splanchnic Nerve (GSN) could have significant benefits in some patients with heart failure (HF) by reducing cardiac filling pressures and improvement in exercise capacity. However, to date the long-term safety of Splanchnic Nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.
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Splanchnic Nerve block mediated changes in stressed blood volume in heart failure
Jacc-Heart Failure, 2021Co-Authors: Marat Fudim, Manesh R Patel, Richard L Boortzmarx, Barry A Borlaug, Adam D Devore, Arun Ganesh, Cynthia L Green, Renato D Lopes, Robert J Mentz, Chetan B PatelAbstract:Abstract Objectives The authors estimated changes of stressed blood volume (SBV) induced by Splanchnic Nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF). Background The Splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB. Methods We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (Splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (Splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight. Results Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p Conclusions The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407 ; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151 )
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Splanchnic Nerve block for acute heart failure
Circulation, 2018Co-Authors: Marat Fudim, Richard L Boortzmarx, Arun Ganesh, Cynthia L Green, Schuyler W Jones, Adrian F Hernandez, Manesh R PatelAbstract:The abdominal vascular compartment is the main storage of intravascular blood volume, and decreased abdominal vascular capacitance has been proposed as a major contributor to the complex pathophysiology of heart failure (HF) in animals and humans. 1, 2 In HF, as a result of neurohormonal imbalance, the vascular capacitance ("storage-space") is decreased and acute sympathetic Nerve activation can result in acute volume redistribution 3 from the abdominal compartment to the thoracic compartment (heart and lungs), which increases intra-cardiac pressures and precipitates HF symptoms (Figure 1A). The sympathetic nervous system controls the Splanchnic compartment via branches from the sympathetic thoracic ganglia (T6 through T11). 4 We have identified the Splanchnic Nerves as a potential target for treating HF.