Reduction In Sympathetic Nerve Activity Research Articles

Renal nerves in physiology, pathophysiology and interoception.

Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.

Effect of pulmonary vein isolation on left atrial remodeling and muscle sympathetic nerve activity in patients with atrial fibrillation

Abstract Background Catheter ablation (CA) for atrial fibrillation (AF) improves left ventricular function and induces left atrium reverse remodeling (LARR). CA is also associated with the modulation of ganglionated plexi in the left atrium (LA), including stretch-sensitive sympathetic and parasympathetic nerve mechanoreceptors. Increased filling pressure and enlargement of LA stimulate stretch-sensitive sympathetic nerve mechanoreceptors in heart failure, which contribute augmented sympathetic nerve activity. However, little is known about an effect of CA on the interaction between the changes of LARR and sympathetic nerve activity. Purpose To test the hypothesis that CA induce the reduction in sympathetic nerve activity in accordance with LARR in patients with atrial fibrillation. Methods This study was conducted as a retrospective, observational study. Twenty-eight AF patients (65.4±12.1 years old) were included in this study. We measured mean blood pressure (BP), heart rate (HR), brain natriuretic peptide (BNP), and direct recording of muscle sympathetic nerve activity (MSNA) using microneurography technique before and 12 weeks after CA. Echocardiogram was also performed to assess LARR and left ventricular function. To evaluate the interaction between LARR and MSNA, AF patients were divided into two groups by presence (LARR group; n=18) and absence (no LARR group; n=10) of LARR according to left atrium volume index (LAVi) following CA. Results No significant differences were observed at baseline in BP, MSNA and LAVi between two groups. BP did not change significantly after CA in both groups. HR significantly increased in the LARR group (63.1±5.7 vs 69.9±7.8, p<0.01) compared to no LARR group. CA significantly reduced MSNA in the LARR group (37.8±10.1 vs 24.9±8.8 bursts/min, p<0.01), but there was no significant change in the no LARR group. The septal E/e' ratio (11.3±3.8 vs 9.8±2.9, p<0.05), left ventricular end-systolic volume index (LVESVi) (24.4±11.9 vs 19.6±7.8 ml/m2, p<0.05) and Ln BNP (4.0±1.2 vs 3.3±1.0 log/pg/ml, p<0.05) were also significantly improved in the LARR group. On the other hand, in the no LARR group, there were no significancy in the changes of the septal E/e' ratio, LVESVi and Ln BNP. LVEF was not significantly changed in both two groups. Conclusion Our study shows CA reduced MSNA accompanied by LARR in AF patients. The reduction in MSNA, septal E/e' ratio, LVESVi and Ln BNP were all more pronounced in the LARR group compared to the no LARR group. These findings suggest that LARR is associated with the reduction in MSNA in AF patients, which was attributed to CA-induced modulation of stretch-sensitive sympathetic nerve mechanoreceptors. Funding Acknowledgement Type of funding sources: None.

Use of Alpha 2 Agonist in Septic Shock: A Case Report

In this case study the aim is to highlight the role of Alpha-2 agonists to reduce vasopressor requirements in septic shock. In fact the case presented to us is an 11-month-old child admitted for burns on the whole body. The usual treatment does not seem to be very effective, so the hospital's medical team decided to inject him with a α 2-adrenoceptor agonists: Remarkable results have emerged at the end of this treatment. It has been proven that Clonidine reduces sympathetic nerve activity to the heart and vasculature by a direct central action, which is its main mechanism of action as an antihypertensive drug. With reductions in sympathetic nerve activity to other organs, this is likely associated with a decrease in plasma catecholamines concentrations. This substance has a special mechanism which has proven a succes in septic shock.

The dynamic activity of C1 neurons determines the level of blood pressure during hemorrhage in freely behaving rats

Background Adrenergic neurons in the rostral ventrolateral medulla (RVLM), called C1 neurons, regulate vasomotor sympathetic nerve activity (SNA) and blood pressure (BP), and are thought to contribute to BP homeostasis during hemorrhage. In unanesthetized rats, hemorrhage has two sequential phases: 1) compensated, when SNA is markedly elevated and BP is maintained at nearly normal levels and 2) decompensated, when SNA is suppressed, and BP falls dramatically. We hypothesize that dynamic changes in C1 neuron activity determines the level of SNA and BP during hemorrhage. Aim To measure C1 neuron activity during hypotensive hemorrhage in non-anesthetized freely behaving rats. Methods The real-time activity of C1 neurons was monitored using a genetically encoded calcium indicator, jGCaMP7s, with in vivo fiber photometry in non-anesthetized rats. A virus carrying a Cre-dependent GCaMP7 transgene (pGP-AAV1-syn-FLEX-jGCaMP7s-WPRE) was injected in the RVLM of adult female and male Th-Cre rats and an optic fiber was implanted at the site of injection. Four weeks later, rats were instrumented for BP measurements and vascular access for blood withdrawal. The next day, the activity of C1 neurons was measured while the rats were subjected to a controlled hypotensive hemorrhage (18 ml/kg of blood withdrawal over 20 minutes, rate 0.3-0.5 ml/min). Isosbestic-corrected fluorescence (DF/F0) is expressed as a Z-score based on a baseline recording period expressed as mean ± SD. Tests include Student's t-test or repeated measures one-way ANOVA. Differences were considered significant at p<0.05. Results Four weeks after the injection, GCaMP7 was expressed selectively in C1 neurons (76 ± 12 % of GCaMP7-positive neurons expressed tyrosine hydroxylase and PNMT). Transient hypotension induced by intravenous sodium nitroprusside (SNP) activated C1 neurons (from -0.3 ± 0.6 to 11.3 ± 4 A.U., p=0.0002, n=8), whereas elevations in BP induced by intravenous phenylephrine (PE) did not consistently reduce C1 neuron activity (from 0.1 ± 0.3 to -0.9 ± 2.3 A.U., p=0.343, n=7). During hemorrhage, the activity of C1 neurons increases during the compensated phase (when BP is stable despite the blood loss) in relation to the pre-hemorrhage period (from 0.17 ± 0.8 to 5.2 ± 2.1 A.U., p=0.0006, n=8). At the onset of the decompensated phase, the activity of C1 neurons drops dramatically in relation to the compensated phase (from 5.2 ± 2.1 to 2.9 ± 2.8 A.U., p=0.0017, n=8). Conclusions Our results indicate that C1 neurons have low resting activity and are very sensitive to hypotension in quite awake freely behaving rats. And the activation of C1 neurons is critical for BP stability during compensated hemorrhage and their inhibition contributes to the reduction in SNA and hypotension during decompensated hemorrhage.

Abstract 16157: Catheter Ablation Induces an Increase in Heart Rate With Discordant With a Decrease in Sympathetic Nerve Activity in Patients With Paroxysmal Atrial Fibrillation

Background/Introduction: Paroxysmal atrial fibrillation (PAF) is the most common arrhythmia and catheter ablation (CA) is selected with the aim of rhythm control. CA was reported to increase heart rate (HR), which explains the modulation on the cardiac autonomic nervous system. However, little is known about the relationship between heart rate, sympathetic nerve activity and parasympathetic nerve activity in patient with PAF. Purpose: The purpose of this study was to evaluate the effect of CA on direct recording of muscle sympathetic nerve activity (MSNA) and heart rate variability (HRV), and these influences on HR. Methods: This study was conducted as a prospective, observational study. Patients with PAF who were scheduled for CA were enrolled. We measured blood pressure, HR, body weight, brain natriuretic peptide (BNP), echocardiogram parameters, high frequency component as cardiac parasympathetic nerve activity and low frequency component as cardiac sympathetic nerve activity in HRV, and MSNA before and 12 weeks after CA. Results: 21 PAF patients participated in this study. After CA, E/e’ and Ln BNP were significantly reduced(10.6±2.9 to 9.2±2.6, p&lt;0.05. 3.8±1.3 to 3.3±1.6 log/pg/ml, p&lt;0.05, respectively) while no significant changes were observed in EF, SV, left atrial diameter, left ventricular end diastolic and systolic diameters. HR was significantly increased (61.3±7.8 to 71.1±7.6 beats/min, p&lt;0.05, respectively). However, the MSNA burst incidence and frequency were significantly decreased (65.4±12.6 to 41.3±13.4 bursts/100beats, p&lt;0.01, n=21. 39.8±8.8 to 28.1±9.6 bursts/min, p&lt;0.01, n=21. respectively). Also, the reduction in MSNA burst frequency was correlated with the increase in HR (r=0.57, 95%CI 0.183-0.804, p=0.00702). Ln Low frequency component in HRV was significantly decreased (5.72±1.75 to 3.85±2.13 log/ms 2 , p&lt;0.05, n=12), but Ln high frequency (HF) component was not changed . No significant relationship observed between increased HR and HF component. Conclusion: CA induced paradoxical increasing heart rate with the reduction in sympathetic nerve activity in patient with PAF. These findings suggest that CA might modulate autonomic interaction between sinus nodes and in left atrium with denervated in ganglionated plexi.

Artificial Co 2 -water Immersion Facilitates Recovery From Muscle Fatigue Caused By High Intensity Anaerobic Exercise

In response to the CO2-water (CO2≥1000 ppm) immersion, the reduction of sympathetic nerve activity may imply the facilitation of muscle fatigue recovery. PURPOSE: In the present study, we investigated whether the whole body bath with CO2-water influences recovery of the muscle fatigue after high intensity exercise. METHODS: The healthy male college students (n=6, 18-21yrs, 171.3±6.7cm, 73.6±13.0kg) participated in this study. The cycle ergometer work tests lasting 30 seconds were used to estimate anaerobic power with leg pedaling exercises. Exercise loads of the tests were 0.075kp per body weight. Anaerobic power was determined by measuring the highest power output during 30 seconds. Core temperature (CoreT) and ECG were recorded continuously throughout the experiment. The subjects performed 30-s maximal pedaling exercise, and took bath in tap- or CO2-water at 35 °C for 10 minute after exercise. Subjective thermal sensation (TS) in the body bath was also recorded. Vastus lateralis (VL) dominant muscle hardness using the elastography. , muscle pain by visual analog scale (VAS), and blood lactate (BLa) and were evaluated at pre- and immediately after-exercise, and at 10 min after exercise. RESULTS: The strain ratio (SR) between the VL and a reference material was calculated. TS in the CO2-water was significantly higher than in the tap-water (tap-water vs. CO2-water, -0.17±0.76 vs. 1.17±0.41, p<0.01). At 10 min in recovery, in the CO2-water compared with the tap-water, SR significantly decreased quicker (0.49±0.25 vs. 0.91±0.25, p<0.01). However, there was no significant difference in CoreT, BLa and VAS between these two water kinds. CONCLUSIONS: We reported previously that the muscle blood flow in the immersed part was larger in CO2-water than tap-water of a same temperature. In addition to a local effect of CO2, suppression of muscular sympathetic activity may also contribute to the increase in local blood flow. Facilitation of muscle hardness recovery shown in this study might be caused by the increased muscle blood flow. The present results suggested that CO2-water immersion may contribute to rapid recovery from the muscular hardness induced by high intensity exercise.

1141-P: Effects of SGLT2 Inhibitors on Nighttime Sympathetic Nerve Activity, Heart Rate, Blood Pressure Variability, and Glycemic Variability in Type 2 Diabetic Patients

Objective: SGLT2 inhibitors (SGLT2i) were examined for their effects on nighttime sympathetic nerve activity in type 2 diabetic patients. Methods: A total of 15 type 2 diabetic outpatients with poor glycemic and body weight control despite conventional antidiabetic therapy (HbA1c, 7.7 ± 1.1%; BMI, 27.6 ± 3.8 kg/m2) were given dapagliflozin (Dapa) 5 mg/day for 3 months. Patients were compared before and 3 months after Dapa treatment for Low frequency/High frequency (LF/HF) ratios at 5-minute intervals as index of sympathetic verve activity through spectrum analysis of heart rate variability, blood pressure (BP) variability at 30-minute intervals, glucose variability at 5-minute intervals using concurrent Holter electrocardiogram, ambulatory blood pressure monitoring, and continuous glucose monitoring. Blood samples were drawn from these patients after 30 minutes of bed rest before and 3 months after Dapa treatment to measure their plasma catecholamine values. Outcome measures of the study included the area under the curve for LF/HF ratios (AUC-LF/HF ratio), mean BP values during sleep, extent of nighttime BP dip, and mean glucose/SD of glucose values during sleep. Results: HbA1c and body weight were significantly decreased with Dapa. Again, the nighttime AUC-LF/HF ratio and plasma noradrenalin values, as well as the heart rate, systolic BP (SBP) and diastolic BP (DBP) values during the same hours, were significantly decreased, and the extent of nighttime BP dip was also significantly increased, in those achieving weight reductions with Dapa. In contrast, these findings were not observed in 3 patients failing to achieve weight reductions with Dapa. Conclusions: Study results suggest that reductions in sympathetic nerve activity associated with the SGLT2i treatment may be closely associated with SGLT2i-mediated weight reductions. Disclosure T. Onishi: None. Y. Shioda: None. Y. Mori: None.

Effects of arm cranking exercise on muscle oxygenation between active and inactive muscles in people with spinal cord injury

Objective: We investigated the effects of the incremental arm-cranking exercise (ACE) on tissue oxygen saturation (StO2) between active and inactive muscles, and the relationship between peak oxygen uptake (VO2peak) and changes in the StO2 in inactive muscles. Design: Observational study. Setting: Community-based supervised intervention. Participants: The participants were individuals with motor and sensory complete spinal cord injury (complete SCI; n = 8) and motor complete but sensory incomplete SCI (incomplete SCI; n = 8), and able-bodied (AB) individuals (n = 8) matched for age, height, and body mass index. Intervention: The ACE was performed at a rate increasing by 10 watts min−1 until exhaustion. Outcome Measures: VO2peak, heart rate (HR), and StO2. Results: While VO2peak was similar among the groups, peak HR was significantly higher in both SCI groups than in the AB (P < 0.05). In active muscles (biceps brachii), no differences in the StO2 were observed among the groups (P > 0.05). In inactive muscles (vastus lateralis), the StO2 in the AB and the incomplete SCI began to decrease at approximately 40% of the peak work rate; however, they remained unchanged in the complete SCI. The reductions in StO2 in the AB were significantly greater than in the incomplete SCI. Conclusions: These results suggest that sympathetic vasoconstriction occurred in the incomplete SCI and AB, although it did not occur in the complete SCI, probably due to a reduction in sympathetic nerve activity. Sympathetic vasoconstriction in inactive muscles may not contribute to an individual’s VO2peak regardless of their group.

Postexercise Intracranial Hypotension

Arterial hypotension, minutes to hours after exercise, is a well described phenomenon. The drop in mean arterial blood pressure (MAP) likely results from a combination of sustained vasodilation of the previously active muscles, centrally mediated reduction in sympathetic nervous activity and resetting of thermo-, chemo-, and baroreceptors. Despite decreased MAP, cerebral blood flow is generally well maintained. PURPOSE: To characterize effects of moderate aerobic exercise on intracranial pressure (ICP) as a mechanism for maintaining cerebral perfusion pressure during and following exercise. METHODS: Sixteen healthy volunteers completed 30-min exercise at 70% estimated VO2-max on an upright ergonomic bicycle followed by a one-hour recovery phase in supine position. MAP, heart rate, stroke volume, and total peripheral resistance (TPR) were recorded continuously (Nexfin). In 15 subjects (8 female, 20±2 years, height 169±10 cm, weight 64±12 kg) ICP was estimated non-invasively by evoked tympanic membrane displacement (Cerebral Cochlea Fluid Pressure device). Invasive parenchymal ICP recordings were performed in one, cerebrally intact, former patient (male, 74 years, 176 cm, 80 kg) via a permanently implanted tip-transducer telemetric ICP-sensor (Neurovent-P-tele). RESULTS: 30 min moderate exercise did not increase ICP (-6.1mmHg during seated rest vs -6.8mmHg during exercise). Invasive (N=1) and non-invasive (N=15) ICP recordings followed the same trend, demonstrating a 52.8±22.9% (P<0.005) decrease immediately postexercise and graduate returned to baseline (fig). ICP was correlated to MAP (r2=0.8, P<0.05) and TPR (r2=0.9, P<0.005) DISCUSSION: Postexercise decrease in ICP is a potential factor for maintaining cerebral perfusion pressure during arterial hypotension. Future analysis and ongoing trials are stratifying these responses according to responsiveness, gender and age. Supported by Novo Nordic Foundation (NNF150C0019196)

Renal sympathetic nerve activation via α2-adrenergic receptors in chronic kidney disease progression.

Chronic kidney disease (CKD) is increasing worldwide without an effective therapeutic strategy. Sympathetic nerve activation is implicated in CKD progression, as well as cardiovascular dysfunction. Renal denervation is beneficial for controlling blood pressure (BP) and improving renal function through reduction of sympathetic nerve activity in patients with resistant hypertension and CKD. Sympathetic neurotransmitter norepinephrine (NE) via adrenergic receptor (AR) signaling has been implicated in tissue homeostasis and various disease progressions, including CKD. Increased plasma NE level is a predictor of survival and the incidence of cardiovascular events in patients with end-stage renal disease, as well as future renal injury in subjects with normal BP and renal function. Our recent data demonstrate that NE derived from renal nerves causes renal inflammation and fibrosis progression through alpha-2 adrenergic receptors (α2-AR) in renal fibrosis models independent of BP. Sympathetic nerve activation-associated molecular mechanisms and signals seem to be critical for the development and progression of CKD, but the exact role of sympathetic nerve activation in CKD progression remains undefined. This review explores the current knowledge of NE-α2-AR signaling in renal diseases and offers prospective views on developing therapeutic strategies targeting NE-AR signaling in CKD progression.

Increased excitatory regulation of the hypothalamic paraventricular nucleus and circulating vasopressin results in the hypertension observed in polycystic kidney disease.

Hypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD). We examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat. Bilateral PVN inhibition with muscimol reduced SBP further in urethane-anaesthetized adult LPK rats than in control Lewis rats (-43 ± 4 vs. -18 ± 3 mmHg; P < 0.0001, n = 14), but was not associated with a greater reduction in sympathetic nerve activity (SNA) or improvement in HR or SNA baroreflex function. Blockade of ionotropic glutamatergic input to the PVN with kynurenic acid also reduced SBP (P < 0.001), but not SNA, further in both adult and juvenile LPK rats. No differences in AMPA or NMDA receptor mRNA expression were noted. Systemic V1A receptor antagonism using OPC-21268 reduced SBP in adult LPK rats only (P < 0.001) and had no effect on the depressor response to PVN inhibition (P = 0.39). Combined peripheral V1A receptor antagonism and PVN inhibition, however, normalized SBP in adult LPK rats (122 ± 11 vs. 115 ± 6 mmHg; LPK vs. Lewis, P > 0.05, n = 10). Our data show that in the LPK rat model of PKD, hypertension is contributed to by increased PVN neuronal activity and, through an independent mechanism, systemic V1A receptor activation. Treatments that reduce PVN neuronal activity and/or inhibit peripheral V1A receptors may provide novel treatment strategies to ameliorate hypertension in individuals with PKD and limit overall disease progression.

Sinoaortic denervation attenuates vasopressin-induced hypothermia and reduction of sympathetic nerve activity innervating brown adipose tissue in rats

It is well known that sympathetic nerve activity innervating brown adipose tissue (BAT sympathetic nerve activity) plays an important role in BAT thermogenesis. We have found that peripheral administration of arginine vasopressin (AVP) induced hypothermia by reduced thermogenesis in BAT. However, little is known about AVP-induced hypothermic response and its relationship with BAT sympathetic nerve activity. Because increases in baroreceptor inputs inhibit peripheral sympathetic nervous activity, we hypothesized that AVP-induced hypothermia is related to baroreceptor reflex suppression of BAT sympathetic nerve activity. To test this hypothesis, Male Sprague-Dawley rats were subjected to sinoaortic denervation or sham denervation, and implanted with radiotelemetry transmitters to assess the effects of peripheral administration of AVP on BAT sympathetic nerve activity, core and BAT temperatures. In sham-operated rats, an intraperitoneal (i.p.) injection of 10µg/kg AVP led to a significant decrease in core and BAT temperatures. However, sinoaortic denervation significantly reduced the fall of core and BAT temperatures induced by AVP, compared with levels in sham-operated rats. AVP (10µg/kg i.p.) rapidly decreased BAT sympathetic nerve activity in control and sham-operated rats, with the greatest levels of suppression occurring at 35min and these lowest levels attained were with 30.6% and 29.24%, respectively. Furthermore, we found that sinoaortic denervation attenuated the suppressive effects of AVP (10µg/kg i.p.) on BAT sympathetic nerve activity. The greatest level of suppression was only 20.8% occurring at 35min after AVP. Therefore, these results indicate that the hypothermic effects of peripheral administration of AVP are partially mediated by the arterial baroreceptor reflex suppression of BAT sympathetic nerve activity and BAT thermogenesis.

Open-loop characteristics of the arterial baroreflex after blockade of unmyelinated baroreceptors with resiniferatoxin.

Arterial baroreceptors can be divided into two categories dependent on whether their axons are myelinated (A-fiber) or unmyelinated (C-fiber). We investigated the effect of periaxonal resiniferatoxin (RTX), a blocker of C-fiber baroreceptor activity, on the open-loop static characteristics of the arterial baroreflex. The baroreceptor region of the right aortic depressor nerve was isolated, and intra-baroreceptor region pressure (BRP) was changed from 60 to 180 mm Hg in 10 anesthetized Sprague-Dawley rats. Open-loop static characteristics of the neural arc from BRP to efferent sympathetic nerve activity (SNA), peripheral arc from SNA to arterial pressure (AP), and total reflex arc from BRP to AP were estimated. Although blocking C-fiber activity with RTX resulted in a lower response range (33.7±4.6% and 49.4±4.8%, P<0.01) and higher minimum SNA (78.0±4.7% and 53.6±5.0%, P<0.001) of the steady-state neural arc, the peak SNA response to BRP was greater at a BRP of 160 mm Hg (-37.87±5.83% and -26.28±4.90%, P=0.01). RTX also resulted in a lower response range (27.8±5.0 mm Hg and 40.9±5.2 mm Hg, P<0.01) and higher minimum AP (92.4±4.7 mm Hg and 79.1±4.9 mm Hg, P<0.001) of the total reflex arc. Despite these changes, the maximum slope of the neural arc and the maximum gain of the total reflex arc did not differ significantly after RTX. These data suggest that A-fiber baroreceptors can regulate AP and maintain the maximum gain when systemic AP is around the normal operating range. In contrast, C-fiber baroreceptors are critically important for reductions in SNA and AP when systemic AP is raised above the normal operating range.

(148) - Restoration of Pulsatile Flow Leads to a Reduction in Sympathetic Nerve Activity Among Patients With Continuous-Flow Left Ventricular Assist Devices

s S63 Results: Twenty-seven patients met inclusion criteria and had hemodynamic measures both preand post-LVAD. Results are outlined in the table below. All LVADs were implanted via median sternotomy. As expected, measures of RV load (pulmonary vascular resistance, pulmonary vascular compliance (CPA), and effective arterial elastance (Ea)) were lower on initial post-LVAD hemodynamic assessment (mean 67 days). Pulmonary capillary wedge pressure (PCWP) also significantly declined yet right atrial pressure (RAP) remained unchanged. Therefore, the RAP:PCWP ratio increased (0.52 vs. 0.86, p< 0.001). Two novel hemodynamic parameters that quantify RV adaptation to load conditions worsened after implant: CPA x RAP (22.6 vs 30.2, p= 0.04) and Ea/RAP (0.20 vs. 0.11, p< 0.001). At the 18-36 month hemodynamic assessment (mean 730 days), RA:PCWP ratio, CPA x RAP, and EA/ RAP significantly improved compared to the initial post-LVAD assessment suggesting improvement in RV function. Including only those patients with 18-36 month follow-up data (n= 9) yielded similar results. Conclusion: Although the RV is unloaded with LVAD implantation, RV function and its ability to accommodate afterload worsens during the perioperative time period. Over time, however, RV function appears to recover to near pre-LVAD baseline. Table 1. Hemodynamic measurements pre-LVAD, 0-6 months and 18-36 months postLVAD Pre-implant 0-6 months 18-36 months p value (pre vs 0-6 mo) p value (0-6 vs 18-36 mo) All Patients (N) 27 27 9 Right Atrial Pressure (RAP) (mmHg) 13 ± 8 11 ± 6 7 ± 4 0.61 0.09 Pulmonary Capillary Wedge Pressure (PCWP) (mmHg) 23 ± 10 13 ± 7 12 ± 6 < 0.001 0.73 RAP to PCWP Ratio 0.52 ± 0.17 0.86 ± 0.26 0.60 ± 0.21 < 0.001 0.01 Cardiac index (L/min/m2) 1.7 ± 0.4 2.4 ± 0.6 2.6 ± 0.2 < 0.001 0.47 Pulmonary Vascular Resistance (PVR) (Wood Units) 3.2 ± 1.8 2.4 ± 1.2 1.2 ± 0.3 0.07 0.002 Compliance (SV/PP) (mL/mmHg) 2.5 ± 1.7 3.1 ± 1.3 2.3 ± 1.1 0.03 0.13 Effective Arterial Elastance (Ea) (mmHg/mL) 1.2 ± 0.7 0.7 ± 0.3 0.9 ± 0.4 0.005 0.2 Compliance * RAP 22.6 ± 11.5 30.2 ± 14.3 15.0 ± 9.0 0.04 0.006 Ea/RAP 0.20 ± 0.24 0.11 ± 0.17 0.15 ± 0.05 < 0.001 0.002 Only subjects with data at 18-36 months (N) 9 9 9 Right Atrial Pressure (RAP) (mmHg) 11 ± 5 9 ± 5 7 ± 4 0.34 0.56 Pulmonary Capillary Wedge Pressure (PCWP) (mmHg) 22 ± 8 10 ± 6 12 ± 6 0.004 0.55 RAP to PCWP Ratio 0.49 ± 0.12 0.82 ± 0.26 0.60 ± 0.21 0.004 0.07 Pulmonary Vascular Resistance (PVR) (Wood Units) 2.3 ± 0.8 1.7 ± 0.8 1.2 ± 0.3 0.16 0.29 Compliance (SV/PP) (mL/ mmHg) 2.7 ± 1.3 4.1 ± 1.5 2.3 ± 1.1 0.04 0.01 Effective Arterial Elastance (Ea) (mmHg/mL) 0.9 ± 0.4 0.5 ± 0.3 0.9± 0.4 0.01 0.008 Compliance * RAP 25.1 ± 12.8 28.8 ± 14.4 15.0 ± 9.0 0.59 0.029 Ea/RAP 0.18 ± 0.11 0.08 ± 0.05 0.15 ± 0.05 0.02 0.02 responses to step changes (200-400 RPM) in CF-LVAD pump speed from a maximum of 10,580±60 RPM to a minimum of 8,580±440 RPM. Results: A representative tracing is displayed in Figure 1. Reductions in pump speed led to increases in pulsatility as determined by pulse pressure (high v. low speed: 17±7 v. 26±13 mmHg, P< 0.05) and pulsatility index (4.3±1.0 v. 6.1±0.7 units, P< 0.05). Both mean arterial pressure (MAP) and LVAD flow decreased during reductions in speed (MAP: 89±11 v. 75±13 mmHg; flow 5.8±1.1 v. 4.4±0.5 L/min, P< 0.05 for all comparisons). MSNA decreased during reductions in pump speed (45±17 v. 35±18 bursts/min, P< 0.05) despite the reduction in MAP. MSNA was inversely related to pulse pressure, even after adjustment for MAP (Figure 2). Conclusion: Restoration of pulsatile flow reduces the heightened SNA present in patients with CF-LVADs, likely through a baroreceptor-mediated pathway. Further study is needed to determine whether reduction of SNA in this setting leads to improved outcomes.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity.

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Mindfulness meditation lowers muscle sympathetic nerve activity and blood pressure in African-American males with chronic kidney disease.

Mindfulness meditation (MM) is a stress-reduction technique that may have real biological effects on hemodynamics but has never previously been tested in chronic kidney disease (CKD) patients. In addition, the mechanisms underlying the potential blood pressure (BP)-lowering effects of MM are unknown. We sought to determine whether MM acutely lowers BP in CKD patients, and whether these hemodynamic changes are mediated by a reduction in sympathetic nerve activity. In 15 hypertensive African-American (AA) males with CKD, we conducted a randomized, crossover study in which participants underwent 14 min of MM or 14 min of BP education (control intervention) during two separate random-order study visits. Muscle sympathetic nerve activity (MSNA), beat-to-beat arterial BP, heart rate (HR), and respiratory rate (RR) were continuously measured at baseline and during each intervention. A subset had a third study visit to undergo controlled breathing (CB) to determine whether a reduction in RR alone was sufficient in exacting hemodynamic changes. We observed a significantly greater reduction in systolic BP, diastolic BP, mean arterial pressure, and HR, as well as a significantly greater reduction in MSNA, during MM compared with the control intervention. Participants had a significantly lower RR during MM; however, in contrast to MM, CB alone did not reduce BP, HR, or MSNA. MM acutely lowers BP and HR in AA males with hypertensive CKD, and these hemodynamic effects may be mediated by a reduction in sympathetic nerve activity. RR is significantly lower during MM, but CB alone without concomitant meditation does not acutely alter hemodynamics or sympathetic activity in CKD.

Obstructive sleep apnea and insight into mechanisms of sympathetic overactivity

Nearly two decades ago, we evaluated ten patients with obstructive sleep apnea (OSA). We determined that alarming nocturnal oscillations in arterial pressure and sympathetic nerve activity (SNA) were caused by regulatory coupling and neural interactions among SNA, apnea, and ventilation. Patients with OSA exhibited high levels of SNA when awake, during normal ventilation, and during normoxia, which contributed to hypertension and organ damage. Additionally, we achieved a beneficial and potentially lifesaving reduction in SNA through the application of continuous positive airway pressure (CPAP), which remains a primary therapeutic approach for patients with OSA. With these results in hindsight, we herein discuss three concepts with functional and therapeutic relevance to the integrative neurobiology of autonomic cardiovascular control and to the mechanisms involved in excessive sympathoexcitation in OSA.

Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius

Adult obese Zucker rats (OZR; >12 wk) develop elevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with impaired baroreflexes compared with adult lean Zucker rats (LZR) and juvenile OZR (6-7 wk). In adult OZR, baroreceptor afferent nerves respond normally to changes in MAP, whereas electrical stimulation of baroreceptor afferent fibers produces smaller reductions in SNA and MAP compared with LZR. We hypothesized that impaired baroreflexes in OZR are linked to reduced activation of brain stem sites that mediate baroreflexes. In conscious adult rats, a hydralazine (HDZ)-induced reduction in MAP evoked tachycardia that was initially blunted in OZR, but equivalent to LZR within 5 min. In agreement, HDZ-induced expression of c-Fos in the rostral ventrolateral medulla (RVLM) was comparable between groups. In contrast, phenylephrine (PE)-induced rise in MAP evoked markedly attenuated bradycardia with dramatically reduced c-Fos expression in the nucleus tractus solitarius (NTS) of adult OZR compared with LZR. However, in juvenile rats, PE-induced hypertension evoked comparable bradycardia in OZR and LZR with similar or augmented c-Fos expression in NTS of the OZR. In urethane-anesthetized rats, microinjections of glutamate into NTS evoked equivalent decreases in SNA, heart rate (HR), and MAP in juvenile OZR and LZR, but attenuated decreases in SNA and MAP in adult OZR. In contrast, microinjections of glutamate into the caudal ventrolateral medulla, a target of barosensitive NTS neurons, evoked comparable decreases in SNA, HR, and MAP in adult OZR and LZR. These data suggest that OZR develop impaired glutamatergic activation of the NTS, which likely contributes to attenuated baroreflexes in adult OZR.

Infliximab, a TNF-α inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients

Tumour necrosis factor-alpha (TNF-α) is an important mediator in the pathogenesis of rheumatoid arthritis (RA) and hypertension. TNF-α inhibitors improve clinical symptoms and inhibit joint destruction in RA, but their effect on blood pressure (BP) has not been fully investigated. We measured 24-h BP using an ambulatory BP monitor in 16 RA patients treated with a TNF-α inhibitor, infliximab, to investigate its influence on BP and its association with the regulatory factors of BP and renin-angiotensin-aldosterone and sympathetic nervous systems. Infliximab significantly reduced the 24-h systolic BP (SBP) from 127.4±21.8 to 120.1±23.4 mm Hg (P<0.0001). Particularly, morning BP (0600-0800 h) decreased from 129.7±19.7 to 116.9±13.4 mm Hg (P<0.0001), and daytime BP decreased from 131.8±15.1 to 122.5±13.7 mm Hg (P<0.0001). Infliximab significantly reduced the plasma level of norepinephrine and plasma renin activity (PRA) (from 347.5±180.7 to 283.0±181.8 pg ml(-1) and 2.6±2.7 to 2.1±2.9 ng ml(-1) h(-1), respectively) but did not significantly reduce the plasma levels of dopamine and epinephrine. The reduction in morning SBP correlated with the reduction in the norepinephrine level (P<0.05) but not with that in PRA and inflammatory parameters related to RA. This study shows the effect of infliximab on ambulatory BP, especially daytime BP, which may be partly accounted for by the reduction of sympathetic nerve activity after infliximab treatment.

Reduced sympathetic activity in idiopathic rapid-eye-movement sleep behavior disorder and Parkinson's disease

More than 50% of patients with idiopathic REM sleep behavior disorder (iRBD) will develop Parkinson's disease or Lewy body dementia. In a previous study, we found attenuated heart rate responses in iRBD and Parkinson's disease patients during sleep. The current study aimed to evaluate heart rate variability further in order to identify possible changes in these components during wakefulness and sleep in patients with iRBD and Parkinson's disease. We evaluated heart rate variability in 5-minute electrocardiography segments from wakefulness, and non-REM and REM sleep in 11 iRBD patients and 23 Parkinson's disease patients, and compared these with 10 control subjects. Patients with iRBD had attenuated sympathetic nervous system activity compared with controls and this was more pronounced in patients with Parkinson's disease. The cardiac parasympathetic nervous system seems to be relatively well preserved in patients with iRBD and Parkinson's disease. The progressive reduction of sympathetic nervous activity is in line with the postganglionic sympathetic nervous dysfunction seen in early Parkinson's disease.