Augmented Sympathetic Nerve Activity Research Articles

Sympathetic Neural Overdrive and Diminished Exercise Capacity in Reduced Ejection Fraction Heart Failure Related to Anthracycline- Based Chemotherapy.

Cardiotoxicity is the most worrying cardiovascular alteration in patients treated with chemotherapy. To improve the understanding regarding the cardiotoxicity, we studied whether: 1) patients with cardiac dysfunction related to anthracycline-based chemotherapy have augmented sympathetic nerve activity and decreased exercise capacity and 2) these responses are similar to those observed in patients with heart failure caused by other etiologies. Sixteen patients with heart failure with reduced ejection fraction related to anthracycline-based chemotherapy with or without chest radiation (HFrEFCA), 10 patients with heart failure with reduced ejection not related to cancer therapy (HFrEF), and 16 age-and body mass index (BMI)-matched healthy controls were studied. Left ventricular ejection fraction (LFEF, Echocardiography), peak oxygen consumption (peak V̇O2, cardiopulmonary exercise test), muscle sympathetic nerve activity (MSNA, microneurography) and forearm blood flow (FBF, venous occlusion plethysmography) were measured. We found that peak oxygen consumption peak V̇O2 and LVEF were significantly reduced in patients with HFrEFCA compared to controls (P<0.0001) but similar to those found in HFrEFCA patients. The sympathetic nerve activity burst frequency and incidence were significantly higher in patients with HFrEFCA than in controls (P<0.0001). No differences were found between HFrEF and HFrEFCA patients. Peak V̇O2 was inversely associated with MSNA burst frequency (r=-0.53, P=0.002) and burst incidence (r=-0.38, P=0.01), and directly associated with LVEF (r=0.71, P<0.0001). Taken together, we conclude that patients who develop heart failure due to anthracycline-based chemotherapy have sympathetic neural overdrive and reduced exercise capacity. In addition, these physiological changes are similar to those observed in patients with HFrEF.

Different contribution of sympathetic nerve activity to arterial velocity pulse index in hypertensive patients with and without diastolic dysfunction

Abstract Introduction Left ventricular diastolic dysfunction (LVDD) is the main cause of heart failure with preserved ejection fraction (HFpEF). LVDD is related not only to arterial stiffness but also sympathetic nerve activity (SNA). Recent study demonstrated that increased muscle sympathetic nerve activity (MSNA) may be one of contributing factor for arterial stiffness. In clinical practice, Cardio-ankle vascular index (CAVI) provides a reproducible index of arterial stiffness, independent of blood pressure (BP). Recently, Arterial Velocity pulse Index (AVI), which is an index of arterial reflected waves, have been proposed as new index of arterial stiffness. We reported that AVI was associated with MSNA in hypertensive (HT) patients. However, it is still uncertain the effect of LVDD on the association between AVI and SNA in HT patients. Thus, we tested the hypothesis that AVI would be increased and related to MSNA in HT patients with LVDD. Methods Patients with essential HT subjects were included in this study. HT was diagnosed as systolic blood pressure (SBP) ≥140mmHg or diastolic blood pressure (DBP) ≥90mmHg. Patients with secondary HT was excluded. AVI was measured from left upper arm by NAS-1000 (Nihon Koden, Japan). CAVI was measured by VaSera VS-1500A (Fukuda Denshi, Japan). Transthoracic echocardiography was performed by trained sonographers. SNA was evaluated by direct recording of MSNA from peroneal nerves. Results 25 HT patients were included (age 63±14 years, Male/Female 9/16). They were divided into two groups according to E/e' (no LVDD group, E/e' ≤9, N=12; LVDD group, E/e' &amp;gt;9, N=13). There were no significant differences between no LVDD and LVDD groups in age (63±9 vs 69±9 years p=0.205), body mass index (23±3 vs 24±4 p=0.355), BP (SBP 139±16 vs 144±20mmHg p=0.524, DBP 87±15 vs 78±14mmHg p=0.167). LV Ejection Fraction (EF) and Stroke Volume (SV) did not differ between two groups (EF 66±7 vs 69±6% p=0.471, SV 58±7 vs 62±14ml p=0.599). MSNA had tendency to increase in LVDD group compared to no LVDD group (MSNA 53±10 vs 44±12 bursts/100 heartbeats, p=0.052). Contrary to our hypothesis, AVI and CAVI did not differ between two groups (AVI 27±7 vs 29±7 p=0.398, CAVI 8.7±1.4 vs 8.6±1.4 p=0.894). However, a significant correlation was seen between AVI and MSNA in no LVDD group (r=0.57, p&amp;lt;0.05), but no correlation in LVDD group. There is no correlation between CAVI and MSNA in no LVDD and LVDD group. Significant relationship was observed between AVI and CAVI in LVDD group (r=0.61, p&amp;lt;0.05), but no relationship in no LVDD group. Conclusion AVI was significantly associated with MSNA in HT patients without LVDD, but not with LVDD. CAVI was related to AVI in HT patients with LVDD, but not without LVDD. MSNA was slightly increased in HT patients with LVDD compared to without LVDD. These results indicate that augmented SNA could contribute to the increase in arterial stiffness in HT patients without LVDD, however, this contribution might be attenuated in HT patients with LVDD. Funding Acknowledgement Type of funding sources: None.

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&amp;lt;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&amp;lt;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&amp;lt;0.05), left ventricular end-systolic volume index (LVESVi) (24.4±11.9 vs 19.6±7.8 ml/m2, p&amp;lt;0.05) and Ln BNP (4.0±1.2 vs 3.3±1.0 log/pg/ml, p&amp;lt;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.

Sublingual Nitroglycerin Acutely Alters Cardiovagal and Sympathetic Baroreflex Sensitivity in Healthy Humans

Augmented sympathetic nerve activity (SNA) and impaired baroreflex sensitivity (BRS) are important therapeutic targets in patients with cardiovascular diseases. Nitroglycerin (glyceryl trinitrate, GTN) is a vasodilator, widely used in patients with coronary artery diseases, however, the effects of GTN on SNA and BRS are incompletely understood. Importantly, the acute effects of GTN on SNA and BRS are not clear. Additionally, there are no reports evaluating both the sympathetic BRS (SBRS) and cardiovagal BRS (CBRS) responses to the administration of sublingual GTN. The purpose of this study was to assess the acute effects of GTN on muscle sympathetic nerve activity (MSNA), SBRS and CBRS in healthy subjects. We hypothesized that sublingual GTN would rapidly modulate sympathetic and cardiovagal BRS and thus increase MSNA in healthy subjects. Ten (9M, 1F) healthy subjects (60 ± 2 yrs) without medications were examined. Beat-to-beat heart rate (HR), arterial pressure (AP) and MSNA were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated by analyzing the relationship between spontaneous variations in diastolic AP and MSNA. CBRS was assessed with the sequence technique. Every 2 min HR, AP and MSNA data were recorded and compared. SBRS and CBRS were assessed during baseline, and during min 3-6 (Post A) and 7-10 min (Post B) after GTN administration. Compared to baseline, mean AP did not significantly change during Post A (baseline, 98.5 ± 1.8 to 95.6 ± 2.3 mmHg, P = 0.423) but decreased during Post B (91.9 ± 2.2 mmHg, P < 0.05). MSNA increased significantly by min 2 after GTN and remained significantly elevated during both the Post A and Post B periods (31.2 ± 4.0 to 48.2 ± 4.4, and 47.5 ± 4.2; bursts/min, both P < 0.05). Compared to baseline, during the Post A and Post B periods CBRS decreased significantly (12.9 ± 1.6 to 7.1 ± 1.0, and 6.4 ± 0.6; ms･mmHg-1, both P < 0.05), while SBRS increased significantly (0.8 ± 0.2 to 1.5 ± 0.2, and 1.8 ± 0.3; units･beat-1･mmHg-1, both P < 0.05). The SBRS operating point was also reset and shifted to upward during both the Post A and Post B periods. The results show that a clinical sublingual dose of GTN attenuated the CBRS and raised the SBRS with an upward shift of the operating point, resulting in augmented MSNA. Whether these acute changes in MSNA and BRS with GTN in the absence of changes in BP can evoke adverse sequelae in patients with atherosclerosis is unknown. These findings have never been reported before. These factors should be considered by clinicians as they use this agent.

TNF-α-induced sympathetic excitation requires EGFR and ERK1/2 signaling in cardiovascular regulatory regions of the forebrain.

Peripherally or centrally administered TNF-α elicits a prolonged sympathetically mediated pressor response, but the underlying molecular mechanisms are unknown. Activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cardiovascular regions of the brain has recently been recognized as a key mediator of sympathetic excitation, and ERK1/2 signaling is induced by activation of epidermal growth factor receptor (EGFR) tyrosine kinase activity. The present study examined the role of EGFR and ERK1/2 signaling in the sympathetic response to TNF-α. In urethane-anesthetized rats, intracarotid artery injection of TNF-α increased phosphorylation of EGFR and ERK1/2 in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN); upregulated the gene expression of excitatory mediators in SFO and PVN; and increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA). A continuous intracerebroventricular infusion of the selective EGFR tyrosine kinase inhibitor AG1478 or the ERK1/2 inhibitor PD98059 significantly attenuated these responses. Bilateral PVN microinjections of TNF-α also increased phosphorylated ERK1/2 and the gene expression of excitatory mediators in PVN, along with increases in BP, HR, and RSNA, and these responses were substantially reduced by prior bilateral PVN microinjections of AG1478. These results identify activation of EGFR in cardiovascular regulatory regions of the forebrain as an important molecular mediator of TNF-α-driven sympatho-excitatory responses and suggest that EGFR activation of the ERK1/2 signaling pathway plays an essential role. These mechanisms likely contribute to sympathetic excitation in pathophysiological states like heart failure and hypertension, in which circulating and brain TNF-α levels are increased.NEW & NOTEWORTHY Proinflammatory cytokines contribute to the augmented sympathetic nerve activity in hypertension and heart failure, but the central mechanisms involved are largely unknown. The present study reveals that TNF-α transactivates EGFR in the subfornical organ and the hypothalamic paraventricular nucleus to initiate ERK1/2 signaling, upregulate the gene expression of excitatory mediators, and increase sympathetic nerve activity. These findings identify EGFR as a gateway to sympathetic excitation and a potential target for intervention in cardiovascular disease states.

Abstract 16604: Significant Correlation Between Arterial Velocity Pulse Index and Muscle Sympathetic Nerve Activity in Hypertensive Patients

Introduction: Augmented sympathetic nerve activity (SNA) in hypertension (HT) is regarded as a therapeutic target, but there is few non-invasive markers to evaluate SNA in clinical practice. It is reported to associate with SNA which increased arterial reflected wave plays the important role in disease progression in HT, and it is reported to associate with SNA. Recently, Arterial Velocity Pulse Index (AVI) are developed as an index of arterial reflected waves, however the relationship between AVI and SNA is still uncertain. Methods: Patients with essential HT and matched non-hypertensive control subjects were included in this study. HT was diagnosed as systolic blood pressure (SBP) ≧ 140 mmHg or diastolic blood pressure (DBP) ≧ 90 mmHg. Patients with secondary HT was excluded. AVI was measured from left upper arm by NAS-1000 (Nihon Koden, Japan). SNA was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) from peroneal nerves. Results: 50 HT patients and 50 control subjects were included. Age, SBP and DBP were significantly increased in HT group compared to control (Age 63±14 vs 42±16 years, p&lt;0.001; SBP 144±16 vs 115±9 mmHg, p&lt;0.001; DBP 80±14 vs 67±9 mmHg, p&lt;0.001). MSNA and AVI were significantly increased in HT group compared to control (MSNA 34±10 vs 25±8 bursts/min, p&lt;0.05; AVI 28±9 vs 17±5, p&lt;0.05). In univariate analysis, AVI was significantly correlated with MSNA, age, and SBP in HT group. However, no significant relationship was observed between AVI and MSNA in multivariate analysis. Therefore, HT group was divided into two groups according to their severity (group 1, SBP&lt;160mmHg, N=30; group 2, SBP&gt;160 mmHg, N=20). AVI in group 1 showed significantly correlation with MSNA (r=0.49, p&lt;0.05), but no correlation was seen in group 2. Conclusions: AVI was significantly increased in patients with HT compared to control, and AVI is significantly associated with MSNA in HT patients with SBP&lt;160mmHg. These results indicate that AVI is helpful to estimate augmented SNA in patients with mild or moderate hypertension. Further study is warranted to exam the relationship AVI and SNA in reality.

Different prognosis between severe and very severe obstructive sleep apnea patients; Five year outcomes

BackgroundObstructive sleep apnea (OSA) is characterized by augmented sympathetic nerve activity. In our previous study, patients with OSA and an apnea-hyperpnea index (AHI)>55events/h showed increased single-unit muscle sympathetic nerve activity compared to patients with OSA and AHI of 30–55events/h. However, the prognostic impact in these patients remains unclear. MethodsNinety-one OSA patients were included. All patients who had indication for continuous positive airway pressure (CPAP) were treated with CPAP. Patients were divided into three groups: mild/moderate OSA (S), AHI<30events/h (n=44); severe OSA (SS), AHI 30–55events/h (n=29); and very severe OSA (VSS), AHI>55events/h (n=18). The primary endpoint was a composite outcome composed of death, cardiovascular events, stroke, and heart failure with hospitalization. ResultsIn the 5-year follow-up, the primary event rate in the SS group [3 events (7%)] was the same as that in the S group [3 events (10%)]. However, the VSS group showed a significantly higher primary event rate among the three groups [6 events (33%), p<0.05]. In Cox regression analysis, the VSS group had the highest hazard ratio compared to other risk factors. ConclusionsCPAP was effective for preventing cardiovascular disease in patients with severe OSA, however patients with very severe OSA still had a high event rate, indicating that CPAP treatment might be insufficient to reduce the OSA-related risk burden in patients with very severe OSA. Additional systemic medical treatment for CPAP might be needed in patients with very severe OSA.

Effects of Obesity and Sleep Apnea on Sympathetic Neural Activity during Early Pregnancy in Humans: A Pilot Study

Maternal obesity is a major risk factor for adverse pregnancy outcomes and this increased risk is attributed, at least in part, to obstructive sleep apnea (OSA; defined as an Apnea and Hypopnea Index ≥5). However, whether obesity and OSA increase the risk of adverse outcomes through sympathetic neural mechanisms is unknown. We hypothesized that obese women with OSA would have augmented sympathetic nerve activity during pregnancy.Twenty‐five women within 10 weeks of gestation were studied; 13 of them were normal‐weight (BMI 18.5–24.9 kg/m2) while 12 were obese (BMI ≥30 kg/m2). Home‐based sleep testing was performed using a portable device (WatchPat) and 24‐hour ambulatory blood pressure (BP) was monitored in all subjects. Muscle sympathetic nerve activity (MSNA), beta‐by‐beat BP, and heart rate were continuously recorded during supine rest in our laboratory.We found that obese pregnant women had higher 24‐hour systolic (mean±SD; 129±13 vs 108±5 mmHg, P&lt;0.001) and diastolic (72±9 vs 62±4 mmHg, P=0.0013) BP compared with normal‐weight pregnant women. Resting MSNA trended to be greater in obese than normal‐weight women (burst frequency: 31±20 vs 19±7 bursts/min, P=0.063; burst incidence: 40±26 vs 26±10 bursts/100 heartbeats, P=0.108; total activity: 358±283 vs 189±95 a.u./min, P=0.075). Preliminary data showed that among obese pregnant women, those with OSA (n=3) had much higher systolic (140±8 vs 125±12 mmHg)and diastolic (82±3 vs 69±8 mmHg) BP compared to those without OSA. In addition, MSNA appeared to be greater in obese women with OSA versus those without OSA (57±12 vs 20±10 bursts/min; 72±21 vs 26±11 bursts/100 heartbeats).These preliminary results indicate that obesity and OSA may be associated with augmented sympathetic activity and elevated blood pressure early on during pregnancy, leading to the development of adverse maternal‐fetal outcomes.Support or Funding InformationSupported by the NIH R01 grant (HL142605).24 hour ambulatory blood pressure was greater in obese pregnant women with sleep apnea than pregnant women with obesity only.Figure 1Impact of sleep apnea and maternal obesity on resting MSNA during early pregnancy.Figure 2

Effects of Central Intervention of Tumor Necrosis Factor‐α Converting Enzyme (TACE) on Neuroinflammation and Cardiac Function in Heart Failure

Central nervous system inflammation has been implicated in the neurohumoral activation and disease progression in experimental animal models of heart failure (HF). The pro‐inflammatory cytokine tumor necrosis factor‐α (TNF‐α) increases in cardiovascular/autonomic brain regions including the paraventricular nucleus of the hypothalamus (PVN) and subfornical organ (SFO), and contributes significantly to the augmented sympathetic nerve activity in HF. TNF‐α is initially synthesized as a membrane bound protein that is proteolytically cleaved by TNF‐α converting enzyme (TACE), also known as a disintegrin and metalloprotease 17 (ADAM17), to become the fully functional inflammatory mediator. Our previous study demonstrated that TACE has elevated expression in the PVN and SFO and mediates TNF‐α‐induced sympathetic excitation and hemodynamic responses in HF rats. However, whether inhibition of TACE in the brain has a protective effect on central inflammation and cardiac function in HF remains unclear. We hypothesized that inhibition of TACE activity in the brain reduces central inflammation and improves left ventricular (LV) function during HF. Adult male Sprague‐Dawley rats were studied 4–5 weeks after induction of HF by coronary artery ligation. TACE activity was chronically inhibited specifically in the brain by infusion of the TACE inhibitor TAPI‐1 (30μg/day) via an osmotic minipump connected to an intracerebroventricular (ICV) cannula. Treatment with TAPI‐1 or vehicle began immediately following the myocardial infarction. At the end of experiments, LV function was assessed by echocardiography and tissues were collected for molecular analysis. In HF rats‐treated with TAPI‐1, the LV ejection fraction (26.8±0.9% vs 34.8±6.4%) was improved, although this did not reach statistical significance vs. HF treated with vehicle. Wet lung weight to body weight ratio also showed a trend towards being improved in TAPI‐1 treated animals (6.3±0.3mg/g vs. 4.8±0.4mg/g, vehicle vs. TAPI‐1, p=0.32). Additionally, TAPI‐1 treatment significantly decreased mRNA levels of proinflammatory mediators including TNF‐α, IL‐1β, and TACE in the SFO (TNF‐α: 0.28±0.10, p&lt;0.05; IL1‐β: 0.25±0.11, p&gt;0.05; TACE: 0.68±0.14, p&lt;0.05, fold change vs. vehicle) and resulted in a trend toward reduced levels of these measurements in the PVN (TNF‐α: 0.52±0.13, p=0.24; IL1‐β: 0.58±0.11, p=0.21; TACE: 0.87±0.11, p=0.43, fold change vs. vehicle). TNF‐α expression was also reduced in both the superior cervical (0.35±0.07, p&lt;0.05, fold change vs. vehicle) and stellate ganglia (0.44±0.14, p&lt;0.05 fold change vs. vehicle). Taken together, these data suggest that central inhibition of TACE activity diminishes the inflammatory state in the brain and improve cardiac function in HF.

Renal iodine123-metaiodobenzylguanidine scintigraphy relates to muscle sympathetic nervous activity in heart failure with reduced ejection fraction.

Renal denervation is effective for modulating augmented sympathetic nerve activity (SNA) in heart failure with reduced ejection fraction (HFrEF). We have demonstrated that renal iodine123-metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with muscle sympathetic nerve activity (MSNA) in patients with hypertension. However, it is unclear whether renal 123I-MIBG scintigraphy is useful for assessment of SNA in HFrEF. The study population consisted of 24 HFrEF patients and 11 healthy subjects as controls. Patients with HFrEF underwent 123I-MIBG scintigraphy and hemodynamics using a Swan-Ganz catheter (SGC). HFrEF was defined as echocardiography with left ventricular ejection fraction (LVEF)<50%. MSNA was measured from the peroneal nerve for direct evaluation of SNA. Renal 123I-MIBG scintigraphy was performed simultaneously with cardiac scintigraphy. The early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rate (WR) were calculated. LVEFs were 35%±11% in patients with HFrEF and 63%±10% in the controls (p<0.01). The WR of cardiac 123I-MIBG showed no relation to MSNA, but was related to stroke volume (r=0.45, p<0.05). In contrast, the WR of renal 123I-MIBG scintigraphy (average of both sides) showed a strong correlation with MSNA (BI, r=0.70, p<0.01; BF, r=0.66, p<0.01); however, no significant correlations were detected between renal 123I-MIBG scintigraphy and SGC results. The WR of renal 123I-MIBG scintigraphy may reflect MSNA. Further studies are needed to clarify the relationship between renal 123I-MIBG imaging and renal SNA.

1417Effect of sodium glucose cotransporter 2 inhibitor on sympathetic nerve activity in type 2 diabetes mellitus patients

Abstract Background Diabetes mellitus (DM) is a well-known risk factor for cardiovascular diseases. Augmented sympathetic nerve activity plays an important role in the progressive worsening disease severity. Most of anti-diabetic drugs were demonstrated to not only decrease blood glucose, but also increase sympathetic nerve activity. Recently, it has been reported that sodium glucose cotransporter 2 (SGLT2) inhibitor has beneficial effects on cardiovascular events in spite of the decrease in blood glucose in type 2 DM patients. The underlying mechanisms remain speculative; however, it is assumed that SGLT2 inhibitor would improve sympathetic nerve activity in type 2 DM patients. Purpose The purpose of this study was to evaluate the effect of SGLT2 inhibitor on sympathetic nerve activity in type 2 DM patients. Methods This study was designed as the prospective single-arm study. Type2 DM patients whose HbA1c &gt;7.0% with at least one atherosclerotic risk factors (Hypertension, obesity, smoking history, aging ...) were included. Patients who had renal failure (eGFR&lt;45ml/min/1.73m2) or high age patients (&gt;80 years old) were excluded. We measured blood glucose, HbA1c and blood insulin concentration at baseline and 12 weeks after treatment of dapagliflozin (5mg/day). Muscle sympathetic nerve activity (MSNA) was applied to scrutinize accurate sympathetic nerve activity in type 2 DM patients. Also, baroreflex sensitivity was calculated by examining the relationship between MSNA and beat to beat diastolic blood pressure. Results Eleven type2 DM patients were included in this study. Body mass index, blood pressure, HbA1c and blood insulin concentration tended to decrease at 12weeks after dapagliflozin (body mass index: 27.2±6.3 vs. 24.9±3.2 kg/m2. systolic blood pressure: 121±12.3 vs. 118±13.6 mmHg. diastolic blood pressure: 74.3±6.3 vs. 72.5±7.6 mmHg. HbA1c: 7.6±0.3 vs. 7.2±0.7%. insulin: 9.7±7.2 vs. 8.8±5.1 μU/ml). Dapagliflozin significantly decrease MSNA and heart rate compared to baseline (46.7±7.5 vs. 38.6±6.9 bursts/minute, P&lt;0.05. Heart rate: 80.6±8.5 vs. 72.8±7.4 beats per minute, P&lt;0.05). However, there is no interaction between the reduction in MSNA and baroreflex sensitivity or insulin resistance. 12 weeks administration decreased MSNA Conclusion Our data demonstrated that dapagliflozin significantly decreased MSNA and HR beyond the lowering effect of blood glucose in type2 DM patients. These results indicate the favorable effect of SGLT2 inhibitor might be, in part, attributed to the improvement in sympathetic nerve activity.

Muscle metaboreflex modulation of post‐exercise heart rate kinetics

A delay in the post‐exercise recovery heart rate is a strong predictor of mortality that may be mediated by autonomic nervous system dysfunction (e.g., impaired parasympathetic reactivation and/or augmented sympathetic nerve activity, SNA). We tested the hypothesis that augmented SNA during exercise recovery would delay the rate of post‐exercise heart rate decay compared to a control condition (CTL). Twenty‐two healthy adults (13 f; 22 ± 2 yrs; peak VO2 = 47 ± 7.4 mL/kg/min; BMI = 23.4 kg/m2) performed heavy‐intensity exercise above the ventilatory threshold at 90 ± 6% peak heart rate for 5 min during CTL (no SNA augmentation) and during an experimental (EXP) condition. The EXP condition entailed SNA augmentation via the muscle metaboreflex following 2 min of bilateral isometric handgrip exercise at 30–40% maximal voluntary contraction during cycle ergometry exercise. Bilateral circulatory occlusion was performed during the last 1 min of exercise and continued during 4 min of recovery. Post‐exercise heart rate kinetics were analyzed using paired t‐tests and significant differences were determined when P &lt; 0.05. There was no difference in end‐exercise heart rate (last 1 min) between CTL (159 ± 3 beats/min) and EXP (158 ± 3 beats/min, P = 0.592), amplitude of heart rate recovery between CTL (−61 ± 2 beats/min) and EXP (−64 ± 2 beats/min, P = 0.178), or end recovery heart rate between CTL (98 ± 3 beats/min) and EXP (94 ± 3 beats/min, P = 0.068). There was a significant difference in heart rate kinetics between CTL (57 ± 3 s) and EXP (69 ± 5 s, P = 0.009). These findings suggest that augmented SNA may modulate a delay in the recovery time for heart rate following heavy intensity exercise.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A16563 Sympathetic Innervation Promotes Bone Marrow Homing of Specific CD8+ Effector Memory T Cells in Hypertension

Objectives: We have recently identified a critical role of effector memory T lymphocytes (TEM cells) in the hypertension and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge, TEM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and can be reactivated upon re-exposure to the hypertensive stimulus. In this study, we hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension-specific TEM cells in the BM. Methods: We performed unilateral superior cervical ganglionectomy (SCGx) in mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To study enhanced local sympathetic nerve activity in BM observed in hypertension, excitatory DREADD was transduced in the SCG on one side of mice by microinjection of AAV vector. Results: To determine the changes of T cells in the BM that were specific to hypertension, 5 × 10^6 BM cells were isolated from either the SCGx or control limbs, and co-cultured with 0.5 × 10^6 splenic dendritic cells isolated from another Ang II-infused mouse. We found 30% less CD8+ T cell proliferation in the SCGx BM compared to control side but no difference in CD4+ T cells. Mice with DREADD expression in SCG received 10^7 pan-T cells adoptively transferred from hypertensive donors, and the specific ligand for DREADD was given in drinking water for 7 days. Augmented sympathetic nerve activity in BM led to ∼50% increase in the CD8+ TEM homing compared to baseline level. Conclusion: Sympathetic nerves play a crucial role in memory T cell trafficking, and this likely contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension.

Abstract P290: Central Angiotensin II and Interleukin-1©¬ Upregulate Brain Tumor Necrosis Factor-¥å Converting Enzyme in the Rat

Tumor necrosis factor-α (TNF-α) converting enzyme (TACE/ADAM17) proteolytically cleaves the extracellular domain of transmembrane TNF-α to release the soluble form of TNF-α that contributes to augmented sympathetic nerve activity in heart failure (HF) and hypertension (HTN). Our previous study indicated that TACE is upregulated in the subfornical organ (SFO) and hypothalamic paraventricular nucleus (PVN), two key cardiovascular and autonomic brain centers, in rats with ischemia-induced HF, and is associated with TNF-α –induced sympathetic excitation in that setting. However, the mechanisms regulating TACE activity in the brain remain a mystery. The present study sought to determine whether angiotensin II (ANG II) or interleukin-1β (IL-1β), which increase in SFO and PVN in HF, upregulate TACE expression. Urethane anesthetized male SD rats underwent a 4- hour intracerebroventricular (ICV) infusion of artificial cerebrospinal fluid (aCSF), ANG II (100 ng/hr) or IL-1β (50 ng/hr). Some rats were euthanized to collect SFO and PVN tissues to measure TACE mRNA and protein; others were transcardially perfused with 4% paraformaldehyde to immunostain for TACE in SFO and PVN. ICV infusion of ANG II (n=6) or IL-1β (n=6) significantly (*p&lt;0.05) increased TACE mRNA level (fold change) in SFO (2.54 ± 0.24* and 2.36 ± 0.21*, respectively) and PVN (2.39* ± 0.25 and 2.23 ± 0.20*, respectively) compared with ICV aCSF infusion. Western blot analysis also revealed a significant increase in the TACE protein (normalized to β-actin) in ANG II or IL-1β infused rats in SFO (0.31±0.06* and 0.26±0.05* respectively) and PVN (0.27 ± 0.04*, 0.24 ± 0.03*, respectively) compared with ICV aCSF-infused rats (SFO: 0.12±0.05; PVN: 0.09±0.04). Confocal images exhibited that TACE-like immunoreactivity was markedly higher in all four subdivisions of PVN and in SFO in rats treated with ICV ANG II or IL-1β, compared with aCSF-infused rats. These data indicate that ANG II and IL-1β upregulate TACE expression in SFO and PVN, suggesting that activation of the renin-angiotensin system and augmented inflammation may upregulate TACE expression in the SFO and PVN in HF and HTN. TACE-mediated ectodomain shedding in SFO and PVN may contribute to ANG II- and cytokine-driven sympathoexcitation in HF and HTN.

Olmesartan combined with renal denervation reduces blood pressure in association with sympatho-inhibitory and aldosterone-reducing effects in hypertensive mice with chronic kidney disease

ABSTRACTBackground: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD.Methods and Results: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH.Conclusion: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.

Different Strategies to Treat Paroxysmal AF in Patients with Moderate CKD and Severe OSA: a sub group Analysis

Accentuated sympathetic nerve activity is a strong danger feature for cardiovascular major episodes, such as cerebral and myocardial ischemia/infarction. Peripheric sympathetic nerve activity is emphasized in the hypertensive state, congestive cardiac failure, OSA, heaviness, diabetes, and chronic kidney disease (CKD) subjects. Leastwise a half of individuals with hypertension present augmented sympathetic nerve activity. Our group believes that RSD can reduce AF recurrence in patients with CKD and OSA by modulation of the sympathetic hyperactivity present in these diseases. The goal of this prospective study was to compare the impact of different treatments including CPAP, PVI, RSD, and some combination of them in controlled hypertensive patients with paroxysmal AF, moderate CKD, and severe OSA. Our data suggest that the patients underwent RSD associated to CPAP treatment or PVI, or both of them presented an improvement in the renal function, a decrease in AHI and a lower chance to present AF recurrence than the ones that did not suffer this intervention. Although encouraging, our data are preliminary and need long-term validation in a large population.

Abstract P390: Combining Olmesartan and Renal Denervation Elicits Strong Blood Pressure Reduction in Association With Sympatho-inhibitory and Aldosterone-reducing Effects in Hypertensive Mice With Chronic Kidney Disease

Background: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) are involved in the pathogenesis of hypertension (HT) accompanied with chronic kidney disease (CKD). The oxidative stress in the hypothalamus in the brain increases SNA in HT. The renal denervation (RDN) or angiotensin receptor blocker (olmesartan; OLM) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combining RDN and OLM reduces SNA through oxidative stress in the hypothalamus and RAAS in hypertensive mice with CKD. Methods and Results: In 5/6-nephrectomized ICR-mice (Nx, n=19) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased (147±3 vs. 107±3mmHg, p&lt;0.001), accompanied by increased SNA (urinary norepinephrine (uNE): 504±21 vs. 243±25μg/24hrs, p&lt;0.001) and albuminuria (547±80 vs. 108±15mg/g creatinine, p&lt;0.01) compared with those in control-mice (n=9). Nx-mice were orally-administered OLM (10mg/kg/day), vehicle, or performed RDN under OLM-administration, and divided into Nx-OLM (n=5), Nx-VEH (n=9), and Nx-OLM/RDN (n=5), respectively. In Nx-OLM and -OLM/RDN at 8-weeks after therapy, SBP were significantly decreased (124±3 and 116±3 vs. 144±2mmHg, n=5-9, p&lt;0.05) accompanied with inhibition of both uNE (379±69 and 347±61 vs. 568±24μg/day, n=5-9, p&lt;0.05) and oxidative stress in the hypothalamus (thiobarbituric acid-reactive substances: 0.952±0.06 and 1.012±0.041 vs. 1.222±0.047nmol/mg protein, n=5-9, p&lt;0.05) compared with those in Nx-VEH, without worsening creatinine clearance. In Nx-OLM and -OLM/RDN, the albuminuria was also suppressed compared with that in Nx-VEH (476±56 and 499±82 vs. 1059±165mg/g creatinine, n=5-9, p&lt;0.05). In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration level was significantly decreased compared with that in Nx-VEH (441±35 vs. 675±33pg/ml, n=5-9, p&lt;0.05). Conclusion: These findings suggest that the OLM/RDN combination therapy have a strong antihypertensive effect associated with inhibiting SNA through reducing oxidative stress in the brain and the plasma aldosterone in hypertensive mice with CKD.

Single-Unit Muscle Sympathetic Nerve Activity Reflects Sleep Apnea Severity, Especially in Severe Obstructive Sleep Apnea Patients.

Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity, as assessed by multi-unit muscle sympathetic nerve activity (MSNA). However, it is still unclear whether single-unit MSNA is a better reflection of sleep apnea severity according to the apnea-hypopnea index (AHI). One hundred and two OSAS patients underwent full polysomnography and single- and multi-unit MSNA measurements. Univariate and multivariate regression analysis were performed to determine which parameters correlated with OSAS severity, which was defined by the AHI. Single- and multi-unit MSNA were significantly and positively correlated with AHI severity. The AHI was also significantly correlated with multi-unit MSNA burst frequency (r = 0.437, p < 0.0001) and single-unit MSNA spike frequency (r = 0.632, p < 0.0001). Multivariable analysis revealed that SF was correlated most significantly with AHI (T = 7.27, p < 0.0001). The distributions of multiple single-unit spikes per one cardiac interval did not differ between patients with an AHI of <30 and those with and AHI of 30–55 events/h; however, the pattern of each multiple spike firing were significantly higher in patients with an AHI of >55. These results suggest that sympathetic nerve activity is associated with sleep apnea severity. In addition, single-unit MSNA is a more accurate reflection of sleep apnea severity with alternation of the firing pattern, especially in patients with very severe OSAS.

ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction.

Brain MAPK signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether decreasing ERK1/2 (also known as p44/42 MAPK) signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympathoexcitatory mediators in the PVN and augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or sham operation, small interfering (si)RNAs targeting ERK1/2 or a nontargeting control siRNA was microinjected bilaterally into the PVN. Experiments were conducted 5-7 days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot analysis confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fos-related antigen-like-immunoreactive neurons), lower plasma norepinephrine levels, and improved peripheral manifestations of HF compared with HF rats treated with control siRNAs. These results demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction and may be a novel target for therapeutic intervention.

Abstract 17981: Decreased Oscillatory Pattern of Sympathetic Nerve Activity is Associated With Arterial Baroreflex Dysfunction in Chronic Heart Failure Patients

Background: Sympathetic activation and arterial baroreflex (ABR) dysfunction typify chronic heart failure (CHF). In addition, decreased oscillatory pattern of muscle sympathetic nerve activity (MSNA, LF MSNA /HF MSNA ) seems to contribute to sympathetic exacerbation in patients with CHF. Unknown is whether the LF MSNA /HF MSNA is associated with ABR dysfunction in CHF patients. To answer this question, we investigated the association between gain, latency and coupling of ABR function and LF MSNA /HF MSNA in CHF patients. Methods and Results: Forty-three CHF patients, Functional Class II to III, NYHA, ejection fraction ≤40% were allocated into two groups according to the level of LF MSNA /HF MSNA index: 1) Higher LF MSNA /HF MSNA (n=21, 52±2 years) and 2) Lower LF MSNA /HF MSNA (n=22, 54±1 years). Blood pressure (BP, oscillometric beat-to-beat basis) and MSNA (microneurography technique) were recorded during 10 min at rest. Spectral and cross-spectral analyses of BP and MSNA variabilities were conducted to assess the LF MSNA /HF MSNA and the gain, latency and coupling between BP and MSNA of ABR function. Etiology, ejection fraction, gain and latency of ABR function were similar between groups. However, the patients with lower LF MSNA /HF MSNA had increased MSNA bursts frequency (53±2vs. 39±3 bursts/min, P&lt;0.01) and total activity (180±15 vs. 126±17 a.u, P=0.03) compared to the patients with higher LF MSNA /HF MSNA . In contrast, the patients with lower LF MSNA /HF MSNA had reduced coupling of ABR function (69±3 vs. 80±2 %, P&lt;0.01). Further analysis showed a significant association between the coupling of ABR function and LF MSNA /HF MSNA (R=0.36, P=0.02). Conclusions: There is an inverse association between the LF MSNA /HF MSNA index and sympathetic nerve activity. In addition, there is a direct association between the LF MSNA /HF MSNA index and the coupling of ABR, which suggests that the ABR dysfunction explains, at least in part, the augmented sympathetic nerve activity in CHF patients.