GLP-1 in the Hypothalamic Paraventricular Nucleus Promotes Sympathetic Activation and Hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.

miR-22-3p in the rostral ventrolateral medulla promotes hypertension through inhibiting ß-arrestin-1.

It has been documented that increased sympathetic activity contributes to the development of cardiovascular diseases, such as hypertension. We previously reported that ß-arrestin-1, a multifunctional cytoskeletal protein, was downregulated in the rostral ventrolateral medulla (RVLM) of the spontaneously hypertensive rat (SHR), and its overexpression elicited an inhibitory effect on sympathetic activity in hypertension. microRNA (miR)-22-3p has been reported to be associated with the pathological progress of hypertension. The purpose of this study was to determine the role of miR-22-3p in ß-arrestin-1-mediated central cardiovascular regulation in hypertension. It was observed that miR-22-3p was upregulated in the RVLM of SHRs compared with normotensive Wistar-Kyoto (WKY) rats, and it was subsequently confirmed to target the ß-arrestin-1 gene using a dual-luciferase reporter assay. miR-22-3p was downregulated in the RVLM using adeno-associated virus with 'tough decoys', which caused a significant increase of ß-arrestin-1 expression and decrease of noradrenaline and blood pressure (BP) in SHRs. However, upregulation of miR-22-3p using lentivirus in the RVLM of WKY rats significantly increased BP. In in vitro PC12 cells, enhanced oxidative stress activity induced by angiotensin II was counteracted by pretreatment with miR-22-3p inhibitor, and this effect could be abolished by ß-arrestin-1 gene knockdown. Furthermore, microglia exhaustion significantly diminished miR-22-3p expression, and enhanced ß-arrestin-1 expression in the RVLM of SHRs. Activation of BV2 cells in vitro evoked a significant increase of miR-22-3p expression, and this BV2 cell culture medium was also able to facilitate miR-22-3p expression in PC12 cells. Collectively, our findings support a critical role for microglia-derived miR-22-3p in inhibiting ß-arrestin-1 in the RVLM, which is involved in central cardiovascular regulation in hypertension. KEY POINTS: Impairment of ß-arrestin-1 function in the rostral ventrolateral medulla (RVLM) has been reported to be associated with the development of sympathetic overactivity in hypertension. However, little is known about the potential mechanisms of ß-arrestin-1 dysfunction in hypertension. miR-22-3p is implicated in multiple biological processes, but the role of miR-22-3p in central regulation of cardiovascular activity in hypertension remains unknown. We predicted that miR-22-3p could directly bind to the ß-arrestin-1 gene (Arrb1), and this hypothesis was confirmed by using a dual-luciferase reporter assay. Inhibition of ß-arrestin-1 by miR-22-3p was further verified in both in vivo and in vitro experiments. Furthermore, our results suggested miR-22-3p as a risk factor for oxidative stress in the RVLM, thus contributing to sympatho-excitation and hypertension. Our present study provides evidence that microglia-derived miR-22-3p may underlie the pathogenesis and progression of neuronal hypertension by inhibiting ß-arrestin-1 in the RVLM.

Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. METHODS: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. RESULTS: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. CONCLUSIONS: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.

Reliability of heart rate in reflecting cardiac sympathetic overdrive in type 2 diabetes mellitus.

PURPOSE: Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree. METHODS: In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values. RESULTS: In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls. CONCLUSIONS: In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects.

Neural Correlates of Pain-Autonomic Coupling in Patients With Complex Regional Pain Syndrome Treated by Repetitive Transcranial Magnetic Stimulation of the Motor Cortex.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic pain condition involving autonomic dysregulation. In this study, we report the results of an ancillary study to a larger clinical trial investigating the treatment of CRPS by neuromodulation. This ancillary study, based on functional magnetic resonance imaging (fMRI), evaluated the neural correlates of pain in patients with CRPS in relation to the sympathetic nervous system and for its potential relief after repetitive transcranial magnetic stimulation of the motor cortex. MATERIALS AND METHODS: Eleven patients with CRPS at one limb (six women, five men, aged 52.0 ± 9.6 years) were assessed before and one month after the end of a five-month repetitive transcranial magnetic stimulation (rTMS) therapy targeting the motor cortex contralateral to the painful limb, by means of electrochemical skin conductance (ESC) measurement, daily pain intensity scores on a visual numerical scale (VNS), and fMRI with motor tasks (alternation of finger movements and rest). The fMRI scans were analyzed voxelwise using ESC and VNS pain score as regressors to derive their neural correlates. The criterion of response to rTMS therapy was defined as ≥30% reduction in VNS pain score one month after treatment compared with baseline. RESULTS: At baseline, ESC values were reduced in the affected limb vs the nonaffected limb. There was a covariance of VNS with brain activation in a small region of the primary somatosensory cortex (S1) contralateral to the painful side on fMRI investigation. After rTMS therapy on motor cortex related to the painful limb, the VNS pain scores significantly decreased by 22% on average. The criterion of response was met in six of 11 patients (55%). In these responders, at one month after treatment, ESC value increased and returned to normal in the CRPS-affected limb, and overall, the increase in ESC correlated with the decrease in VNS after motor cortex rTMS therapy. At one month after treatment, there also was a covariance of both variables (ESC and VNS) with fMRI activation of the S1 region previously mentioned. The fMRI activation of other brain regions (middle frontal gyrus and temporo-parietal junction) showed correlation with ESC values before and after treatment. Finally, we found a positive correlation at one month after treatment (not at baseline) between VNS pain score and fMRI activation in the temporo-parietal junction contralateral to painful side. CONCLUSIONS: This study first shows a functional pain-autonomic coupling in patients with CRPS, which could involve a specific S1 region. However, the modulation of sympathetic sudomotor activities expressed by ESC changes was rather correlated with functional changes in other brain regions. Finally, the pain relief observed at one month after rTMS treatment was associated with a reduced activation of the temporo-parietal junction on the side in which rTMS was performed. These findings open perspectives to define new targets or biomarkers for using rTMS to treat CRPS-associated pain. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02817880.

Reconceptualizing autonomic function testing in migraine: a systematic review and meta-analysis.

BACKGROUND: Autonomic nervous system (ANS) testing has aided in our ability to evaluate autonomic dysfunction in migraine patients. We reviewed the literature in multiple databases which investigate ANS function in migraine patients and healthy subjects. METHODS: This systematic review and meta-analysis examined the respective deep breathing, Valsalva manoeuvre, orthostatic and isometric challenge results, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses of Observational Studies in Epidemiology (MOOSE) statements. RESULTS: Seven articles met all inclusion criteria. Fixed-effects meta-analysis showed migraine patients (n = 424), collectively, had lower interictal autonomic test results compared with healthy controls (n = 268). In detail, this was true for the standardized mean difference (g) of deep breathing (g= -0.32; 95% confidence interval (CI) -0.48, -0.16), orthostatic challenge (g= -0.28; 95% CI -0.44, -0.13) and isometric challenge (g= -0.55; 95% CI -0.71, -0.39) and for the difference of means (MD) of the Valsalva ratio (MD = -0.17; 95% CI -0.23, -0.10). CONCLUSIONS: Interictal ANS dysfunction can be identified in migraine patients when compared to healthy controls. These findings indicate the importance to evaluate ANS function in migraine patients - especially, as migraine-specific prophylactic therapies (such as anti-calcitonin gene-related peptide (CGRP) antibodies) may affect the function of the ANS.

Surge of Sympathetic Activity during Hyperventilation at the End of Apnea for Patients with Obstructive Sleep Apnea.

Background and Objectives: The mechanisms connecting obstructive sleep apnea (OSA) and cardiovascular disease are multifactorial, involving intermittent hypoxia, hypercapnia, and sympathetic activation. The aim of this study was to explore the oscillations of sympathetic activity during the sleep apnea episodes throughout the entire night in patients with OSA. Materials and Methods: The participants received whole-night polysomnography (PSG), and electrocardiogram (EKG) data from the PSG were collected for heart rate variability (HRV) analysis. HRV measurements were conducted in the time and frequency domains. The root mean square of successive differences between normal heartbeats (RMSSD), which reflects parasympathetic activity, and the ratio of the absolute power of the low-frequency band (0.04-0.15 Hz) to the absolute power of the high-frequency band (0.015-0.4 Hz) (LF/HF ratio), which indicates sympathetic activity, were computed. Results: A total of 43 participants (35 men and 8 women) were included in the analysis. The mean age of the participants was 44.1 ± 11.3 years old, and the mean BMI was 28.6 ± 5.4 kg/m2. The sleep apnea episodes throughout the entire night in patients with OSA were selected randomly and occurred most frequently during the non-REM stages (39, 90.7%). The selected sleep apnea episodes typically exhibited multiple apneas, often interrupted by snoring respiration and followed by hyperventilation at the end of the episode (HE). Our findings indicate that the centers of the 5 min HRV window for the lowest and highest LF/HF ratios, at 111.8 ± 88.2 and 117.4 ± 88.6 min after sleep onset, respectively, showed a statistically significant difference (p < 0.001). Similarly, the ratios of the lowest and highest LF/HF, at 0.82 ± 0.56 and 3.53 ± 2.94, respectively, exhibited a statistically significant difference (p < 0.001). Conclusions: In the current study, the selected sleep apnea episodes throughout the entire night in patients with OSA occurred primarily during the non-REM stages. Additionally, we observed that sympathetic activity reached its peak in the window that includes hyperventilation at the end stage of apnea, potentially posing a cardiovascular risk. However, additional studies are needed to validate these results.

Rhythmic firing of neurons in the medulla of conscious freely behaving rats: rhythmic coupling with baroreceptor input.

Recent investigations emphasized the importance of neural control of cardiovascular adjustments in complex behaviors, including stress, exercise, arousal, sleep-wake states, and different tasks. Baroreceptor feedback is an essential component of this system acting on different time scales from maintaining stable levels of cardiovascular parameters on the long-term to rapid alterations according to behavior. The baroreceptor input is essentially rhythmic, reflecting periodic fluctuations in arterial blood pressure. Cardiac rhythm is a prominent feature of the autonomic control system, present on different levels, including neuron activity in central circuits. The mechanism of rhythmic entrainment of neuron firing by the baroreceptor input was studied in great detail under anesthesia, but recordings of sympathetic-related neuron firing in freely moving animals remain extremely scarce. In this study, we recorded multiple single neuron activity in the reticular formation of the medulla in freely moving rats during natural behavior. Neurons firing in synchrony with the cardiac rhythm were detected in each experiment (n = 4). In agreement with prior observations in anesthetized cats, we found that neurons in this area exhibited high neuron-to-neuron variability and temporal flexibility in their coupling to cardiac rhythm in freely moving rats, as well. This included firing in bursts at multiples of cardiac cycles, but not directly coupled to the heartbeat, supporting the concept of baroreceptor input entraining intrinsic neural oscillations rather than imposing a rhythm of solely external origin on these networks. It may also point to a mechanism of maintaining the basic characteristics of sympathetic neuron activity, i.e., burst discharge and cardiac-related rhythmicity, on the background of behavior-related adjustments in their firing rate.

Greater resting muscle sympathetic nerve activity reduces cold pressor autonomic reactivity in older women, but not older men.

Previous work demonstrates augmented muscle sympathetic nerve activity (MSNA) responses to the cold pressor test (CPT) in older women. Given its interindividual variability, however, the influence of baseline MSNA on CPT reactivity in older adults remains unknown. Sixty volunteers (60-83y; 30 women) completed testing where MSNA (microneurography), blood pressure (BP), and heart rate (HR) were recorded during baseline and a 2-min CPT (~4°C). Participant data were terciled by baseline MSNA (n=10/group); comparisons were made between the high baseline men (HM) and women (HW), and low baseline men (LM) and women (LW). By design, HM and HW, vs. LM and LW, had greater baseline MSNA burst frequency (37±5 and 38±3 vs. 9±4 and 15±5 bursts/min) and burst incidence (59±14 and 60±8 vs. 16±10 and 23±7 bursts/100hbs; both P<0.001). However, baseline BP and HR were not different between the groups (all P>0.05). During the CPT, there were no differences in the increase in BP and HR (all P>0.05). Conversely, ΔMSNA burst frequency was lower in HW vs. LW (8±9 vs. 22±12 bursts/min; P=0.012) yet was similar in HM vs. LM (17±12 vs. 19±10 bursts/min, P=0.994). Further, ΔMSNA burst incidence was lower in HW vs. LW (9±13 vs. 28±16 bursts/100hbs; P=0.020), with no differences between HM vs. LM (21±17 vs. 31±17 bursts/100hbs; P=0.455). Our findings suggest that heightened baseline activity in older women attenuates the typical CPT-mediated increase in MSNA without changing cardiovascular reactivity. While the underlying mechanisms remain unknown, altered sympathetic recruitment or neurovascular transduction may contribute to these disparate responses.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

The association between sleep duration and muscle sympathetic nerve activity.

PURPOSE: Sleep duration is associated with risk of hypertension and cardiovascular diseases. It is thought that shorter sleep increases sympathetic activity. However, most studies are based on acute experimental sleep deprivation that have produced conflicting results. Furthermore, there are limited data available on habitual sleep duration and gold-standard measures of sympathetic activation. Hence, this study aimed to assess the association between habitual sleep duration and muscle sympathetic nerve activity. METHODS: Twenty-four participants aged ≥ 18 years were included in the study. Sleep was assessed using at-home 7-day/night actigraphy (ActiGraph™ GT3X-BT) and sleep questionnaires (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale). Microelectrode recordings of muscle sympathetic nerve activity were obtained from the common peroneal nerve. Participants were categorised into shorter or longer sleep duration groups using a median split of self-report and actigraphy sleep measures. RESULTS: Compared to longer sleepers, shorter sleepers averaged 99 ± 40 min and 82 ± 40 min less sleep per night as assessed by self-report and objective measures, respectively. There were no differences in age (38 ± 18 vs 39 ± 21 years), sex (5 male, 7 female vs 6 male, 6 female), or body mass index (23 ± 3 vs 22 ± 3 kg/m2) between shorter and longer sleepers. Expressed as burst frequency, muscle sympathetic nerve activity was higher in shorter versus longer sleepers for both self-report (39.4 ± 12.9 vs 28.4 ± 8.5 bursts/min, p = 0.019) and objective (37.9 ± 12.4 vs 28.1 ± 8.8 bursts/min, p = 0.036) sleep duration. CONCLUSIONS: Shorter sleep duration assessed in a home setting was associated with higher muscle sympathetic nerve activity. Sympathetic overactivity may underlie the association between short sleep and hypertension.

Sympathetic activity is not a main cause of blood pressure reduction with exercise training in un-medicated middle-aged/older men.

BACKGROUND: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. METHODS: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55 ± 3 years; n = 13) and normotensive controls (mean age 60 ± 5 years; n = 12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated. RESULTS: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (p < 0.05), expressed as burst frequency (burst/min), overall, and to a similar extent, in both groups (17% and 27%, respectively, in hypertensive and normotensive group), whereas blood pressure was only significantly (p < 0.05) lowered (by 4 mmHg in both systolic and diastolic pressure) in the hypertensive group. Training did not (p > 0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (p < 0.05) the baroreceptor threshold with a main effect for both groups. Training adherence and intensity were similar in both groups yet absolute maximal oxygen uptake increased by 15% in the normotensive group only. CONCLUSION: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.

Intermittent Hypoxia and Diet-Induced Obesity on the Intestinal Wall Morphology in a Murine Model of Sleep Apnea.

This work analyzes the impact of two conditions, intermittent hypoxia exposure and high-fat diet in rats as models of sleep apnea. We studied the autonomic activity and histological structure of the rat jejunum and whether the overlapping of both conditions, as often observed in patients, induces more deleterious effects on the intestinal barrier. We found alterations in jejunum wall histology, predominantly in HF rats, based on increased crypt depth and submucosal thickness, as well as decreased muscularis propria thickness. These alterations were maintained with the IH and HF overlap. An increase in the number and size of goblet cells in the villi and crypts and the infiltration of eosinophils and lymphocytes in the lamina propria suggest an inflammatory status, confirmed by the increase in plasma CRP levels in all experimental groups. Regarding the CAs analysis, IH, alone or combined with HF, causes a preferential accumulation of NE in the catecholaminergic nerve fibers of the jejunum. In contrast, serotonin increases in all three experimental conditions, with the highest level in the HF group. It remains to be elucidated whether the alterations found in the present work could affect the permeability of the intestinal barrier, promoting sleep apnea-induced morbidities.

Sympathetic Nervous System and Atherosclerosis.

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, ß1, ß2, and ß3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of ß blockers and ß3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established.

The Effect of Renal Denervation on T Cells in Patients with Resistant Hypertension.

(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) Methods: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) Results: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (TEM), CD4+ effector memory residential (TEMRA) and CD8+ central memory (TCM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by -17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ TEM (r -0.421, p = 0.02) and CD8+ TCM (r -0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ TEMRA frequencies with increased cellular cytokine production. (4) Conclusions: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN.

MIBG cardiac imaging compared to ejection fraction in evaluation of cardiotoxicity: a systematic review.

BACKGROUND: Advances in diagnosis and treatment of cancer has improved survival but resulted in increased cardiotoxic effects. The decrease in left ventricular ejection fraction (EF), one of the pillars of diagnosis of cardiotoxicity, seems to be a late process in the evolution of the disease, so 123I-metaiodobenzylguanidine (MIBG) cardiac imaging has been proposed to detect early cardiac impairment. The aim of this systematic review was to evaluate the performance of MIBG cardiac scan in this scenario. METHODS AND RESULTS: A systematic search was conducted in five international databases comparing MIBG parameters with EF for evaluation of cardiotoxicity. Twelve studies were included and separated in three groups. First, studies evaluating patients with established cardiotoxicity, in which EF was reduced and MIBG parameters were abnormal. Second, studies analyzing patients during or after treatment compared to controls, with MIBG parameters significantly different between groups in most studies, even when EF remained normal. Finally, studies analyzing anthracycline (ATC) dose-related changes, with alteration in MIBG parameters occurring even when EF was preserved. CONCLUSION: Although studies had high methodological variability, cardiac sympathetic innervation imaging seems to be a promising tool for assessing early cardiotoxicity. Further studies are needed to analyze its diagnostic value in this scenario.

Association Between Insulin Resistance, Oxidative Stress, Sympathetic Activity and Coronary Microvascular Function in Patients With Early Stage Impaired Glucose Metabolism.

BACKGROUND: Although acute hyperglycemia and insulin resistance (IR) are risk factors for atherosclerosis development through oxidative stress and sympathetic activation in diabetes mellitus, the association of these factors with coronary microvascular function in the early diabetic stage remains controversial.Methods and Results: Using transthoracic echocardiography, coronary flow velocity (CFV) and its reserve (CFVR) as parameters of coronary microvascular function were measured before and 1 h after an oral glucose tolerance test (OGTT) in 40 patients (aged 59±12 years) without diagnosed diabetes mellitus or coronary artery disease. Plasma glucose, insulin and thiobarbituric acid reactive substance (TBARS; an oxidative stress marker) were measured during the OGTT. IR was evaluated as homeostasis model assessment of IR (HOMA-R). Sympathetic activity was evaluated by using plasma catecholamines after OGTT. CFVR decreased after an OGTT (P<0.0001) mainly because of an increased baseline CFV (P<0.0001). Although the change in CFVR was not associated with the change in TBARS and catecholamines, it was independently associated with HOMA-R on the multivariate regression analysis (ß=-0.40, P=0.01). Another multivariate regression analysis revealed that change in baseline CFV was independently associated with HOMA-R (ß=0.35, P=0.03). CONCLUSIONS: IR, rather than oxidative stress and sympathetic activity, was associated with an increase in baseline CFV and a decline in CFVR during acute hyperglycemia. IR might play an important role in increased myocardial oxygen demand and coronary microvascular dysfunction.

Influence of cerebral infarction on both bladder and urethral activities and changes after tramadol administration in rats.

AIMS: We investigated the changes in bladder and urethral function after cerebral infarction (CI) and the influence of tramadol on these functions. METHODS: Twenty-eight female Sprague Dawley rats were divided into normal and CI groups. In the awake condition, metabolic cage study and blood pressure were evaluated. Under urethane anesthesia, the intravenous effect of tramadol (0.01-1 mg/kg), which has both µ-opioid receptor stimulation and inhibition of norepinephrine and serotonin reuptake, on continuous cystometry, and simultaneous measurements of bladder and urethral perfusion pressure (UPP) were recorded. Infarcted lesions were examined by staining with triphenyltetrazolium chloride, a marker of mitochondrial enzyme activity. RESULTS: CI rats showed impaired sympathetic activity with Horner's syndrome and lower blood pressure. In metabolic cage study, urinary frequency during the dark phase was increased in CI rats. On bladder activity, in CI rats, the baseline pressure threshold for inducing bladder contractions was significantly lower (p < 0.01), and the intercontraction interval was prolonged after tramadol administration. On urethral activity, the baseline UPP was significantly lower in CI rats than in normal rats and it did not change after tramadol administration. Residual urine rate was significantly increased in normal rats, but not in CI rats. CI rats showed brain infarction including the cortex and hypothalamus, which is a center of the autonomic nervous system. CONCLUSIONS: CI-induced ischemic brain damage results in impairment of both bladder and urethral functions, in addition to decreased sympathetic activity. Bladder overactivity after CI can be improved by tramadol; however, urethral activity cannot be improved by it.

Renin-Angiotensin System Blockade Is Associated with Exercise Capacity, Sympathetic Activity, and Endothelial Function in Patients with Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) patients have exercise intolerance and exaggerated blood pressure reactivity during exercise that are mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. The activation of the renin-angiotensin system (RAS) increases SNS activation and reduces NO synthesis, and prior studies suggest that RAS blockade attenuates declines in physical function. We hypothesized that RAS inhibitor (RASi) use is associated with higher exercise capacity mediated by decreased SNS activity and increased NO-dependent endothelial function in CKD. METHOD: In 35 CKD patients (57 ± 7 years) and 20 controls (CONs) (53 ± 8 years), we measured exercise capacity (peak oxygen consumption [VO2peak]), muscle sympathetic nervous activity (MSNA), and flow-mediated dilation (FMD) for NO-dependent endothelial function. RESULTS: CKD patients treated with RASi (CKD + RASi, n = 25) had greater VO2peak than CKD patients not treated with RASi (CKD no RASi, n = 10), but lower VO2peak than CONs (23.3 ± 5.8 vs. 16.4 ± 2.9, p = 0.007; vs. 30.0 ± 7.7, p = 0.016 mL/min/kg, respectively). CKD + RASi had lower resting MSNA and greater FMD than CKD no RASi. Compared to CONs, CKD + RASi had similar MSNA but lower FMD. VO2peak was positively associated with FMD (r = 0.417, p = 0.038) and was predicted by the combination of FMD and RASi status (r2 = 0.344, p = 0.01) and MSNA and RASi status (r2 = 0.575, p = 0.040) in CKD patients. CONCLUSION: In summary, CKD patients with RASi have higher exercise capacity than those not on RASi. Higher exercise capacity in the RASi-treated group was associated with lower resting SNS activity and higher NO-dependent vascular endothelial function.

Elevated heart rate as sympathetic biomarker in human obesity.

BACKGROUND AND AIM: The present study was aimed at determining whether and to what extent a specific heart rate (HR) cutoff value allows to identify in obeses a more pronounced level of adrenergic overdrive. METHODS AND RESULTS: In 86 obese subjects aged 44.7 ± 0.9 (mean ± SEM) years and in 45 heathy lean controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in 3 different groups according to their resting clinic and 24-h HR values (<70, 70-79 and 80-89 beats/minute). MSNA and plasma NE values detected in the three obese groups were almost superimposable each other, no significant difference between groups being observed. A similar behavior was observed when HR values were assessed during the 24-h Holter monitoring. In the group as a whole no significant relationship was detected between MSNA, plasma NE and clinic HR, this being the case also when 24-h HR replaced clinic HR in the correlation analysis. In contrast lean controls displayed a progressive significant increase in MSNA values form the group with clinic (and 24 Holter) values below 70 beats/minute to the ones with HR values between 70 and 79 and above 80 beats/minute. CONCLUSIONS: In the obese state measurement of resting HR may allow to provide some general information on the functional status of the adrenergic cardiovascular drive. When the information required, however, are more subtle the sensitivity of the approach appears to be reduced and HR cannot be regarded as a faithful sympathetic biomarker.