Elevated Sympathetic Activity Research Articles

안마의자를 활용하는 마사지가 성인 남녀의 자율신경균형도에 미치는 즉각적 영향: 전향적 관찰연구

Objectives The aim of this study was to examine the immediate impact of a massage chair intervention on homeostasis and the balance of the autonomic nervous system in individuals aged 20 to 64. Methods This study was a single-center, prospective, single-arm, investigator-initiated observational study. Non-underweight adults without significant health concerns underwent a 40-minute massage chair intervention. Measurements of heart rate variability, functional near-infrared spectroscopy, and vital signs were conducted before and after the intervention. Additionally, participants completed the Mibyeong questionnaire and a satisfaction survey. Results A 40-minute massage chair session led to a notable decrease in average heart rate and low frequency to high frequency (LF/HF) ratio, coupled with an increase in root mean square of the successive differences (RMSSD) and standard deviation of NN interval (SDNN). No adverse reactions were noted. Subjects with elevated sympathetic nerve activity exhibited a reduction in LF/HF ratio, whereas those with heightened parasympathetic activity demonstrated an increase in LF/HF ratio post-intervention. Conclusions The findings indicate that the massage chair intervention has the potential to activate the parasympathetic nervous system, promote blood pressure homeostasis and autonomic nervous system balance. However, further research over a more extended period is crucial to validate these conclusions.

Oxytocin and corticotropin-releasing hormone exaggerate nucleus tractus solitarii neuronal and synaptic activity following chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) in rodents mimics the hypoxia-induced elevation of blood pressure seen in individuals experiencing episodic breathing. The brainstem nucleus tractus solitarii (nTS) is the first site of visceral sensory afferent integration, and thus is critical for cardiorespiratory homeostasis and its adaptation during a variety of stressors. In addition, the paraventricular nucleus of the hypothalamus (PVN), in part through its nTS projections that contain oxytocin (OT) and/or corticotropin-releasing hormone (CRH), contributes to cardiorespiratory regulation. Within the nTS, these PVN-derived neuropeptides alter nTS activity and the cardiorespiratory response to hypoxia. Nevertheless, their contribution to nTS activity after CIH is not fully understood. We hypothesized that OT and CRH would increase nTS activity to a greater extent following CIH, and co-activation of OT+CRH receptors would further magnify nTS activity. Our data show that compared to their normoxic controls, 10days' CIH exaggerated nTS discharge, excitatory synaptic currents and Ca2+ influx in response to CRH, which were further enhanced by the addition of OT. CIH increased the tonic functional contribution of CRH receptors, which occurred with elevation of mRNA and protein. Together, our data demonstrate that intermittent hypoxia exaggerates the expression and function of neuropeptides on nTS activity. KEY POINTS: Episodic breathing and chronic intermittent hypoxia (CIH) are associated with autonomic dysregulation, including elevated sympathetic nervous system activity. Altered nucleus tractus solitarii (nTS) activity contributes to this response. Neurons originating in the paraventricular nucleus (PVN), including those containing oxytocin (OT) and corticotropin-releasing hormone (CRH), project to the nTS, and modulate the cardiorespiratory system. Their role in CIH is unknown. In this study, we focused on OT and CRH individually and together on nTS activity from rats exposed to either CIH or normoxia control. We show that after CIH, CRH alone and with OT increased to a greater extent overall nTS discharge, neuronal calcium influx, synaptic transmission to second-order nTS neurons, and OT and CRH receptor expression. These results provide insights into the underlying circuits and mechanisms contributing to autonomic dysfunction during periods of episodic breathing.

Influence of sex and sedentary conditions on sympathetic burst characteristics in prepubertal, postpubertal, and young adult rats.

Recent evidence indicates that sex-based differences in cardiovascular disease (CVD) begin early in life, particularly when associated with risk factors such as a sedentary lifestyle. CVD is associated with elevated sympathetic nerve activity (SNA), quantified as increased SNA burst activity in humans. Whether burst characteristics are influenced by sex or sedentary conditions at younger ages is unknown. The purpose of our study is to compare SNA bursts in active and sedentary female and male rats at ages including prepuberty and young adulthood. We hypothesized that burst characteristics and blood pressure are higher under sedentary conditions and lower in female rats compared with males. We analyzed splanchnic SNA (SpSNA) recordings from Inactin-anesthetized male and female rats at 4-, 8-, and 16-wk of age. Physically active and sedentary rats were each housed in separate, environmentally controlled chambers where physically active rats had free access to an in-cage running wheel. Sympathetic bursts were obtained by rectifying and integrating the raw SpSNA signal. Burst frequency, burst height, and burst width were calculated using the Peak Parameters extension in LabChart. Our results showed that sedentary conditions produced a greater burst width in 8- and 16-wk-old rats compared with 4-wk-old rats in both males and females (P < 0.001 for both). Burst frequency and incidence were both higher in 16-wk-old males compared with 16-wk-old females (P < 0.001 for both). Our results suggest that there are sedentary lifestyle- and sex-related mechanisms that impact sympathetic regulation of blood pressure at ages that range from prepuberty into young adulthood.NEW & NOTEWORTHY The mechanisms of decreased incidence of cardiovascular disease (CVD) in reproductive-age women compared with age-matched men are unknown. The strong association between elevated sympathetic activity and CVD led us to characterize splanchnic sympathetic bursts in female and male rats. Prepubescent males and females exhibited narrower sympathetic bursts, whereas young adult males had higher resting burst frequency compared with age-matched females. Sex-based regulation of sympathetic activity suggests a need for sex-dependent therapeutic strategies to combat CVD.

Acute combined effects of concurrent physical activities on autonomic nervous activation during cognitive tasks.

Backgrounds: The validity of heart rate variability (HRV) has been substantiated in mental workload assessments. However, cognitive tasks often coincide with physical exertion in practical mental work, but their synergic effects on HRV remains insufficiently established. The study aims were to investigate the combined effects of cognitive and physical load on autonomic nerve functions. Methods: Thirty-five healthy male subjects (aged 23.5 ± 3.3years) were eligible and enrolled in the study. The subjects engaged in n-back cognitive tasks (1-back, 2-back, and 3-back) under three distinct physical conditions, involving isotonic contraction of the left upper limb with loads of 0kg, 3kg, and 5kg. Electrocardiogram signals and cognitive task performance were recorded throughout the tasks, and post-task assessment of subjective experiences were conducted using the NASA-TLX scale. Results: The execution of n-back tasks resulted in enhanced perceptions of task-load feelings and increased reaction times among subjects, accompanied by a decline in the accuracy rate (p < 0.05). These effects were synchronously intensified by the imposition of physical load. Comparative analysis with a no-physical-load scenario revealed significant alterations in the HRV of the subjects during the cognitive task under moderate and high physical conditions. The main features were a decreased power of the high frequency component (p < 0.05) and an increased low frequency component (p < 0.05), signifying an elevation in sympathetic activity. This physiological response manifested similarly at both moderate and high physical levels. In addition, a discernible linear correlation was observed between HRV and task-load feelings, as well as task performance under the influence of physical load (p < 0.05). Conclusion: HRV can serve as a viable indicator for assessing mental workload in the context of physical activities, making it suitable for real-world mental work scenarios.

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat.

Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ± 5.8 to 119.5 ± 6.9 mmHg in the SHR and from 111.8 ± 7.0 to 84.2 ± 8.3 mmHg in the WKY and the RSNA response from 186.2 ± 7.1 to 142.7 ± 7.3% of baseline in the SHR and from 201.0 ± 11.5 to 160.2 ± 9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ± 5.0 to 126.2 ± 7.7 mmHg and the RSNA response from 189.9 ± 13.7to 168.5 ± 12.7% of baseline but had no effect in the WKY. These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.

Is polycystic ovary syndrome associated with elevated muscle sympathetic nerve activity?

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities, cardiometabolic disturbances and a heightened risk of cardiovascular disease. A small but compelling body of research demonstrates that females with PCOS present with elevated muscle sympathetic nerve activity (MSNA) at rest. Heightened MSNA is present in lean, overweight and obese females with PCOS, but limited evidence suggests that androgens may be more strongly linked to elevated MSNA in lean females with PCOS than in obese females with PCOS. Although the specific mechanisms underlying elevated MSNA in PCOS remain elusive, sympathetic activation is implicated in the progression of several cardiovascular diseases and may contribute to the cardiovascular pathophysiology of PCOS. Encouragingly, MSNA appears responsive to non-pharmacological intervention, making the sympathetic nervous system a promising therapeutic target to mitigate cardiovascular risk in PCOS. This brief review summarizes the existing evidence regarding elevated MSNA, cardiovascular risk profile and vascular function, as well as the potential for clinical intervention and future research directions in females with PCOS. NEW FINDINGS: What is the topic of this review? The presence of elevated muscle sympathetic nerve activity in females with polycystic ovary syndrome and the implications for cardiovascular health. What advance does it highlight? The sympathetic nervous system likely contributes to elevated cardiovascular disease risk in females with polycystic ovary syndrome. Moreover, it presents as a promising therapeutic target for mitigating cardiovascular disease and merits further investigation.

Assessment of Frontal Hemispherical Lateralization in Plaque Psoriasis and Atopic Dermatitis

Background: Each brain hemisphere plays a specialized role in cognitive and behavioral processes, known as hemispheric lateralization. In chronic skin diseases, such as plaque psoriasis (Pso) and atopic dermatitis (AD), the degree of lateralization between the frontal hemispheres may provide insight into specific connections between skin diseases and the psyche. This study aims to analyze the hemispherical lateralization, neurovegetative responses, and psychometric characteristics of patients with Pso and AD. Methods: The study included 46 patients with Pso, 56 patients with AD, and 29 healthy control (Ctrl) subjects. The participants underwent frontal electroencephalogram (EEG) measurement, heart rate variability (HRV) assessment, and psychological tests. Statistical analyses were performed using ANOVA, with Bonferroni correction applied for multiple comparisons. Results: This study shows a significant right-lateralized prefrontal activity in both AD patients (p &lt; 0.001) and Pso patients (p = 0.045) compared with Ctrl, with no significant difference between the AD and Pso groups (p = 0.633). AD patients with right-hemispheric dominant prefrontal activation exhibited increased inhibition and avoidance markers, while Pso patients showed elevated sympathetic nervous system activity. Conclusion: Psychophysiological and psychometric data suggest a shared prevalence of right-hemispheric dominance in both AD and Pso patient groups. However, the findings indicate distinct psychodermatological mechanisms in AD and Pso.

Sympathoinhibitory electroacupuncture (EA) interacts positively with anti-inflammatory EA alleviating blood pressure in hypertensive rats.

Elevated sympathetic activity and chronic inflammation are known contributory factors observed in hypertension. We have observed that sympathoinhibitory electroacupuncture (SI-EA) at acupoints ST36-37 alleviates sympathetic activity and hypertension. Additionally, EA at acupoints SP6-7 exerts anti-inflammatory (AI-EA) effects. However, it is not known whether simultaneous stimulation of this combination of acupoints attenuates or enhances individual effects. A 2 × 2 factorial design was used to test the hypothesis that combining SI-EA and AI-EA (cEA) leads to greater reduction of hypertension by decreasing sympathetic activity and inflammation in hypertensive rats than either set of acupoints alone. Dahl salt-sensitive hypertensive (DSSH) rats were treated with four EA regimens including cEA, SI-EA, AI-EA, and sham-EA twice weekly for five weeks. A group of normotensive (NTN) rats served as control. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were measured non-invasively by tail-cuff. Plasma norepinephrine (NE), high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) concentrations were determined with ELISA at the completion of treatments. DSSH rats on high salt diet progressively developed moderate hypertension within five weeks. DSSH rats treated with sham-EA showed continuous increase in SBP and DBP and elevations in plasma NE, hs-CRP, and IL-6 levels relative to NTN control. Both SI-EA and cEA decreased SBP and DBP, and had corresponding changes in biomarkers (NE, hs-CRP, and IL-6) compared with sham-EA. AI-EA prevented SBP and DBP elevation and decreased IL-6 and hs-CRP relative to sham-EA. Importantly in DSSH rats that received repetitive cEA treatment, SI-EA interacted positively with AI-EA leading to greater reduction of SBP, DBP, NE, hs-CRP, and IL-6 than SI-EA or AI-EA alone. These data suggest that by targeting both elevated sympathetic activity and chronic inflammation, cEA regimen results in a greater reduction of BP effects in treating hypertension compared to using individual SI-EA or AI-EA alone.

Skin sympathetic nerve activity and nocturnal blood pressure nondipping in patients with postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS. We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ± 11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring. Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group ( P = 0.016, P = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ± 0.103 vs. 0.095 ± 0.099 μV, P = 0.021, and Δmean BP 15.0 ± 5.2 vs. 4.9 ± 4.2 mmHg, P < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P = 0.013) and the differences between standing and supine NE levels ( r = 0.411, P = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ± 0.081 and 0.936 ± 0.080 μV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ± 0.087 μV, P < 0.001 for both) in the same patient. POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.

Association Between Arterial Stiffness and Measures of Autonomic Dysfunction in People With Chronic Kidney Disease.

Autonomic nervous system (ANS) dysfunction and vascular stiffness increase cardiovascular risk in people with chronic kidney disease (CKD). Chronic elevations in sympathetic activity can lead to increased arterial stiffness; however, the relationship between these variables is unknown in CKD. To explore the association between measures of autonomic function and arterial stiffness in patients with moderate-to-severe CKD. This study was a prespecified secondary analysis of a randomized controlled trial. This included the following measures: 24-hour ambulatory blood pressure (BP), carotid-femoral and carotid-radial pulse wave velocity (PWV), and postexercise heart rate recovery (HRR). We used mixed effect linear regression models with Bayesian information criteria (BIC) to assess the contribution of ANS measurements. Forty-four patients were included in the analysis. Mean carotid-femoral and carotid-radial PWV were 7.12 m/s (95% CI 6.13, 8.12) and 8.51 m/s (7.90, 9.11), respectively. Mean systolic dipping, calculated as percentage change in mean systolic readings from day to night, was 10.0% (95% CI 7.79, 12.18). Systolic dipping was independently associated with carotid-radial PWV, MD -0.09 m/s (95% CI -0.15, -0.02) and had the lowest BIC. Systolic dipping was associated with carotid-radial PWV in people with moderate-to-severe CKD; however, there was no association with carotid-femoral PWV. Systolic dipping may be a feasible surrogate of ANS function, as the association with carotid-radial PWV was consistent with the minimal clinically important difference (MCID). Future studies are needed to define the relationship between ANS function, arterial stiffness, and CV events over time in people with CKD.

PS-B10-8: BLOCKADE OF AT1 RECEPTORS RESTORE P2/P1 WITHOUT CHANGING INTRACRANIAL PRESSURE IN RENOVASCULAR HYPERTENSIVE RATS WITH 0.3 M NACL AD LIBITUM

Objective: Renovascular hypertension is characterized by activation of the renin angiotensin aldosterone system, elevated sympathetic nerve activity and sodium appetite behavior. The association of increased sodium intake and hypertension can worsen the injury to end organs. We tested the effects of AT1 receptors blockade (losartan, 10 mg/kg iv) on mean arterial pressure (MAP), intracranial pressure (ICP) and P2/P1 ratio (index of brain compliance) in 2K1C rats with 0.3 M NaCl ad libitum. Design and Methods: Male Holtzman rats (150 tp 180 g) with water and food ad libitum received a silver clip around the left renal artery to induce 2K1C or no clip (SHAM surgery) resulting 3 groups: SHAM (n = 9), 2K1C (n = 9) and 2K1C/Na (n = 7), which had an additional bottle of 0.3 M NaCl ad libitum. Six weeks after the renal surgery, MAP and ICP were recorded under urethane anesthesia (1.2 g/kg iv) and the P2/P1 was calculated offline from the waveform. Saline (0.2 ml/rat) was used as control injection before losartan. Results: In SHAM rats, ICP and P2/P1 were not changed by losartan (7.8 ± 1.1 and 0.88 ± 0.02; vs. saline: 7.9 ± 1.1 and 0.83 ± 0.01 mmHg, respectively), while MAP was decreased (104 ± 5, vs. saline: 120 ± 3 mmHg, p &lt; 0.05). In 2K1C, MAP, ICP and P2/P1 values were greater than SHAM (respectively, 196 ± 6, 14.7 ± 2.7 and 1.1 ± 0.03 mmHg, vs. SHAM; p &lt; 0.05) and all of them were decreased by losartan pre-treatment (137 ± 6, 8.6 ± 1.3 and 0.87 ± 0.05 mmHg, vs. saline, respectively). In 2K1C-Na MAP and P2/P1 were greater than in SHAM (186 ± 7 and 1.15 ± 0.06 mmHg, vs sham p &lt; 0.05) and were decreased by losartan (162 ± 8 and 0.87 ± 0.02 mmHg, vs. saline; p &lt; 0.05), although the decrease in MAP after losartan was lesser than the observed in 2K1C rats (p &lt; 0.05). In 2K1C-Na rats, ICP was not different from SHAM (10.8 ± 1.2, vs. SHAM: 7.8 ± 1.1 mmHg, p &gt; 0.05) and losartan had no effect on ICP (10.3 ± 1.7, vs. saline: 10.8 ± 1.2 mmHg, p &gt; 0.05). Conclusion: Even without a change in ICP, AT1 blockade in 2K1C-Na was effective in restoring P2/P1 ratio, suggesting a beneficial effect on brain compliance in this situation.

Could Orthostatic Stress Responses Predict Acute Mountain Sickness Susceptibility Prior to High Altitude Travel? A Pilot Study.

Bellovary, Bryanne N., Andrew D. Wells, Zachary J. Fennel, Jeremy B. Ducharme, Jonathan M. Houck, Trevor J. Mayschak, Ann L. Gibson, Scott N. Drum, and Christine M. Mermier. Could orthostatic stress responses predict acute mountain sickness susceptibility before high altitude travel? A pilot study. High Alt Med Biol. 24:19-26, 2023. Purpose: This study assessed head-up tilt (HUT) responses in relation to acute mountain sickness (AMS)-susceptibility during hypoxic exposure. Materials and Methods: Fifteen participants completed three lab visits: (1) protocol familiarization and cycle maximal oxygen consumption (VO2max) test; (2) HUT test consisting of supine rest for 20 minutes followed by 70° tilting for ≤40 minutes; and (3) 6 hours of hypobaric hypoxic exposure (4,572 m) where participants performed two 30-minute cycling bouts separated by 1 hour at a 50% VO2max workload within the first 3 hours and rested when not exercising. During HUT, systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR), and variability (blood pressure variability [BPV] and HR variability [HRV]) were measured continuously. The AMS scores were determined after 6 hours of exposure. Correlations determined relationships between HUT cardiovascular responses and AMS scores. Repeated-measures analysis of variance (ANOVA) assessed differences between those with and without AMS symptoms during HUT. Results: Higher AMS scores correlated with greater change in SBP variability (r = 0.52, p = 0.048) and blunted changes in HRV (root mean square of successive differences between normal heartbeats r = 0.81, p = 0.001, percentage of adjacent normal sinus intervals that differ by more than 50 milliseconds [pNN50] r = 0.87, p < 0.001) during HUT. A pNN50 interaction (p = 0.02) suggested elevated cardiac sympathetic activity at baseline and a blunted increase in cardiac sympathetic influence throughout HUT in those with AMS (pNN50 baseline: AMS = 26.2% ± 15.3%, no AMS = 51.0% ± 13.5%; first 3 minutes into HUT: AMS = 17.2% ± 19.1%, no AMS = 17.1% ± 10.9%; end of HUT: AMS = 6.2% ± 9.1%, no AMS 11.0% ± 10.0%). Conclusions: The results suggest autonomic responses via HUT differ in AMS-susceptible individuals. Changes in HRV and BPV during HUT may be a promising predictive measurement for AMS-susceptibility, but further research is needed for confirmation.

In this Issue

HomeCirculation ResearchVol. 131, No. 8In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published29 Sep 2022https://doi.org/10.1161/RES.0000000000000573Circulation Research. 2022;131:651is related toExtracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart FailureImpaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2is related toTranscriptional and Immune Landscape of Cardiac SarcoidosisCardiac Sarcoidosis Immune Landscape (p 654)Download figureDownload PowerPointLiu et al examine the transcriptional and cellular composition of cardiac sarcoidosis.Sarcoidosis is a rare inflammatory disease in which granulomas—small, localized sites of inflammation—afflict various parts of the body, most commonly the lungs, skin and lymph nodes. While sarcoidosis can be managed, there is no cure for the condition and, if it manifests in the heart, it can be deadly. Because little is known about the specific pathology of cardiac sarcoidosis (CS), and because it can resemble other forms of heart inflammation, Liu and colleagues set out to map the specific transcriptional and cellular landscape of CS lesions. Using a combination of spatial transcriptomics, single-nucleus RNA sequencing and immunofluorescence, the team compared tissue samples from CS patients with those from patients with other types of myocarditis. CS granulomas had a particular cellular arrangement, the team found, with HLA-DR+ macrophages immediately adjacent to and surrounding multinucleated giant cells. The giant cells expressed transmembrane glycoprotein NMB—a novel marker of these cells—while activation of mTOR genes was a feature of the surrounding macrophages. These analyses were carried out on a small number of patient samples but, if further studies validate the findings, they could form the basis of future diagnostic tests for CS, say the team.Impaired Dynamic SR Ca Buffering Causes AD-CPVT2 (p 673)Download figureDownload PowerPointWleklinski et al reveal the molecular effects of a dominant CPVT-causing mutation.Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure and other features of the fight-or-flight response. For people with catecholaminergic polymorphic ventricular tachycardia (CPVT), however, physical activity or stress can cause potentially lethal arrythmias. Mutation of calsequestrin-2 (CASQ2)—a sarcoplasmic reticulum (SR) calcium binding protein—is a major cause of CPVT and can be recessive or dominant in nature. For many recessive mutations, disease occurs due to loss of CASQ2 protein. Wleklenski and colleagues have investigated a dominant lysine-to-arginine mutation (K180R) and find, by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so too was the protein’s subcellular localization. The mutation instead interfered with CASQ2’s calcium binding, or buffering, capability within the SR. The result was that, upon catecholamine injection or exercise, the unbound calcium released prematurely from the SR triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations, say the team.EV-Mediated Heart Brain Communication in CHF (p 687)Download figureDownload PowerPointTian et al discover signals from the failing heart to the brain that may further exacerbate cardiac dysfunction.After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling and ultimately heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI—likely due to upregulation of Nrf2-targeting microRNAs. These miRNAs can also be packaged into vesicles and released from stressed heart cells, and now Tian and colleagues show that rats and humans with chronic heart failure (CHF) have an abundance of these miRNA-containing EVs in their blood. In the rats with CHF, these EVs were found to be taken up by neurons of the rostral ventrolateral medulla (RVLM) wherein the miRNAs suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system and, in the presence of the EVs, it ramped up sympathetic excitation. Because such elevated sympathetic activity can induce the fight-or-flight response—including increased heart rate and blood pressure—this would likely worsen heart failure progression. The team found, however, that inhibiting the miRNAs in the EVs prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesExtracellular Vesicles Regulate Sympatho-Excitation by Nrf2 in Heart FailureChanghai Tian, et al. Circulation Research. 2022;131:687-700Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2Matthew J. Wleklinski, et al. Circulation Research. 2022;131:673-686Transcriptional and Immune Landscape of Cardiac SarcoidosisJing Liu, et al. Circulation Research. 2022;131:654-669 September 30, 2022Vol 131, Issue 8 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000573 Originally publishedSeptember 29, 2022 PDF download Advertisement

Sensitization of Hypertension: The Impact of Earlier Life Challenges: Excellence Award for Hypertension Research 2021.

Hypertension affects over 1 billion individuals worldwide. Because the cause of hypertension is known only in a small fraction of patients, most individuals with high blood pressure are diagnosed as having essential hypertension. Elevated sympathetic nervous system activity has been identified in a large portion of hypertensive patients. However, the root cause for this sympathetic overdrive is unknown. A more complete understanding of the breadth of the functional capabilities of the sympathetic nervous system may lead to new insights into the cause of essential hypertension. By employing a unique experimental paradigm, we have recently discovered that the neural network controlling sympathetic drive is more reactive after rats are exposed to mild challenges (stressors) and that the hypertensive response can be sensitized (ie, hypertensive response sensitization [HTRS]). We have also found that the induction of HTRS involves plasticity in the neural network controlling sympathetic drive. The induction and maintenance of the latent HTRS state also require the functional integrity of the brain renin-angiotensin-aldosterone system and the presence of several central inflammatory factors. In this review, we will discuss the induction and expression of HTRS in adult animals and in the progeny of mothers with prenatal obesity/overnutrition or with maternal gestational hypertension. Also, interventions that reverse the effects of stressor-induced HTRS will be reviewed. Understanding the mechanisms underlying HTRS and identifying the beneficial effects of maternal or offspring early-life interventions that prevent or reverse the sensitized state can provide insights into therapeutic strategies for interrupting the vicious cycle of transgenerational hypertension.

Abstract 053: Increased Arterial Pressure Precedes Renal Dysfunction And Elevated Renal Sympathetic And Afferent Nerve Activity In Deoxycorticosterone-Salt Rat

Hypertension (HTN) is a primary risk factor for cardiovascular disease - the leading cause of death worldwide. HTN is multifaceted but a key factor is aberrant autonomic signaling, including renal sympathetic (RSNA) and afferent nerve activity (ARNA). ARNA is elevated in several models of HTN and renal afferent nerve ablation can mitigate the HTN. It is unknown if ARNA rises before changes in blood pressure (BP) or renal function in HTN. This study aimed to determine when renal nerve activity changes vis a vis BP and renal function in a model of salt sensitive HTN. We hypothesized increased ARNA and RSNA would coincide with a rise in BP and decline in renal function. To test this hypothesis, 24 uninephrectomized male Sprague Dawley rats (300g) received a deoxycorticosterone acetate (DOCA; 100mg, SC) implant and 0.9% NaCl drinking water. Renal function (serum creatinine; Cr) and systolic BP (SBP; tail cuff) were measured weekly. Animals were randomly allocated to acute renal nerve recording on protocol day (D) 0, 7, 14, or 21. Multiunit RSNA and ARNA were recorded serially, as ARNA was isolated after sectioning proximal side. RSNA is expressed as bursts/heartbeat, ARNA and expressed as %ARNA max (response to intrapelvic capsaicin). Data were analyzed by one-way ANOVA with Bonferroni post hoc. Data presented as mean±SEM; *p&lt;.05 vs D0. SBP (mmHg) progressively increased on D7 (*152 ± 3), D14 (*171 ± 3), and D21 (*197 ± 7) vs D0 (138 ± 3). ARNA (%) increased at D14 (*23.0 ± 4.7) and D21 (*34.2 ± 4.4) vs D0 (10.1 ± 0.8), but no changes were detected at D7 (13.4 ± 2.1). No changes in RSNA from D0 were detected. Cr (mg/dL) increased at D14 (*1.2 ± 0.1) and D21 (*1.2 ± 0.1) vs D0 (0.9 ± 0.0), indicating a decline in kidney function. These data do not support the hypothesis that ARNA and RSNA increase in parallel to increasing BP. Rather, BP appears to initially increase independent of detectable changes in RSNA, ARNA or renal dysfunction. Interestingly, renal dysfunction and elevated ARNA were detected on D14, which coincides with our previous report that renal inflammation is first detected at D14. These data do not support a causal role of ARNA in this model. Rather, ARNA may subsequently drive disease progression. Further studies on the cause of increased ARNA and inflammation interaction are underway.

Abstract P235: Relationship Between Skin Sympathetic Nerve Activity And Nocturnal Non-dipping Blood Pressure In Patients With Postural Orthostatic Tachycardia Syndrome

Background: Patients with postural orthostatic tachycardia syndrome (POTS) have a high incidence of nocturnal non-dipping of blood pressure (BP). Objective: To test the hypothesis that non-dipping of BP is associated with persistently elevated nocturnal skin sympathetic nerve activity (SKNA) in patients with POTS. Methods: We used Bittium Faros 180 ECG monitor to simultaneously record electrocardiogram (ECG) and SKNA, and SpaceLab OnTrak arterial BP monitor (ABPM) over 24-hr in 55 POTS patients (51 women, 36±10 years-old). The Faros signals were high pass filtered at 300 Hz to display the SKNA. The same original signals were bandpass filtered 0.05-150 Hz to display ECG. BP was measured every 30-min when awake (7 AM to 9 PM) and hourly at night (9 PM to 7 AM). Results: The overall successful ABPM measurement was 71±18%. Nocturnal dipping of BP was presented in 40 patients with an average dipping% of 15.5±4.8%. Nocturnal non-dipping of BP was present in 15 patients with an average dipping% of 3.9±3.7% (p&lt;0.001). Figure A shows hourly averaged SKNA. A mixed effect model was used to compare the log (SKNA) values of two groups of patients at all time points, with patient as a random effect. The non-dipping group had higher SKNA from midnight of day 1 to 4 am of day 2 (indicated by the red bars, p=0.0118, 0.0223, 0.0402, 0.0382, 0.0424). The difference between awake time and sleep time (determined by patients’ diary) average SKNA was 0.155±0.106 μV in dipping group and 0.076± 0.101 μV in the non-dipping group (p=0.017, Figure B ). Conclusion: Nocturnal non-dipping of BP is associated with non-dipping of SKNA in patients with POTS suggesting sympathetic nerve activity plays an important mechanistic role.

Sympathetic activation leads to Schlemm's canal expansion via increasing vasoactive intestinal polypeptide secretion from trabecular meshwork

We previously demonstrated vasoactive intestinal polypeptide (VIP) eyedrops reduce intraocular pressure (IOP) and stabilize cytoskeleton of the Schlemm's canal (SC) endothelium in a chronic ocular hypertension rat model. Here we determine if the trabecular meshwork (TM) releases endogenous VIP and affect SC in paracrine manner, and whether this cellular interaction via VIP is strengthened under stimulated sympathetic activity. A rat model of moderate-intensity exercise was established to stimulate sympathetic activation. IOP post exercise was measured by a rebound tonometer. Sympathetic nerve activity at the TM was immunofluorescence-stained with DβH and PGP9.5. Morphological changes of TM and SC were quantitatively measured by hematoxylin-eosin (HE) staining. Further, epinephrine was applied to mimic sympathetic excitation on primary rat TM cells, and ELISA to measure VIP levels in the medium. The cytoskeleton protective effect of VIP in the epinephrine-stimulated conditioned medium (Epi-CM) was evaluated in oxidative stressed human umbilical vein endothelial cells (HUVECs). Elevated sympathetic nerve activity was found at TM post exercise. Changes accompanying the sympathetic excitation included thinned TM, expanded SC and decreased IOP, which were consistent with epinephrine treatment. Epinephrine decreased TM cell size, enhanced VIP expression and release in the medium in vitro. Epi-CM restored linear F-actin and cell junction integrity in H2O2 treated HUVECs. Blockage of VIP receptor by PG99-465 attenuated the protective capability of Epi-CM. VIP expression was upregulated at TM and the inner wall of SC post exercise in vivo. PG99-465 significantly attenuated exercise-induced SC expansion and IOP reduction. Thus, the sympathetic activation promoted VIP release from TM cells and subsequently expanded SC via stabilizing cytoskeleton, which resulted in IOP reduction.

Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects.

Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body’s systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3β, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1β, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3β (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1β, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.

Saxagliptin Cardiotoxicity in Chronic Heart Failure: The Role of DPP4 in the Regulation of Neuropeptide Tone.

Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, the mechanism of this potential cardiotoxicity is unclear. We aimed to establish a cellular platform to investigate DPP4 inhibition and the role of its neuropeptide substrates substance P (SP) and neuropeptide Y (NPY), and to determine the expression of DDP4 and its neuropeptide substrates in the human heart. Western blot, radio-, enzyme-linked immuno-, and RNA scope assays were performed to investigate the expression of DPP4 and its substrates in human hearts. Calcein-based viability measurements and scratch assays were used to test the potential toxicity of DPP4 inhibitors. Cardiac expression of DPP4 and NPY decreased in heart failure patients. In human hearts, DPP4 mRNA is detectable mainly in cardiomyocytes and endothelium. Treatment with DPP4 inhibitors alone/in combination with neuropeptides did not affect viability but in scratch assays neuropeptides decreased, while saxagliptin co-administration increased fibroblast migration in isolated neonatal rat cardiomyocyte-fibroblast co-culture. Decreased DPP4 activity takes part in the pathophysiology of end-stage heart failure. DPP4 compensates against the elevated sympathetic activity and altered neuropeptide tone. Its inhibition decreases this adaptive mechanism, thereby exacerbating myocardial damage.

Disease Associated Microglia Is Identified As A Major Contributor To Neuroinflammation Associated To Chronic Hypoxia Induced‐Pulmonary Hypertension

IntroductionPulmonary hypertension (PH) is a progressive disease that leads to right heart failure and death. Increased sympathetic activity in PH patients is associated with a worse prognosis due to a series of well‐established downstream sequelae. However, the mechanism behind chronic elevation in sympathetic activity in PH is poorly understood. Our fundamental hypothesis is that neuroinflammation in the hypothalamic paraventricular nucleus (PVN) is essential for elevated sympathetic activity in PH. This hypothesis is supported by our published data demonstrating: 1) increased number of microglia in the PVN is observed in multiple animal models of PH; 2) Microglia inhibition attenuates sympathetic activity and PH cardiopulmonary effects. However, microglia are, a heterogeneous with respect to gene expression and function. Indicating that characterization of the specific microglia subtypes involved in PH pathophysiology would be the key to identify possible targets to improve PH therapy.Methods3‐months‐old SD rats were subjected to monocrotaline induced PH model. After 28 days, CD45+CD11b+ cells were isolated from the PVN followed by single‐cell RNA Sequencing (scRNA Seq) analysis. The disease associated microglia (DAM), which highly express Trem2, displayed the most significant phenotypic changes in PH. 3‐months‐old WT mice (n=12/group) were exposed to chronic hypoxia induced‐PH (CH‐PH) (10%O2) or Normoxia for 4 weeks in a ventilated chamber. CD45+CD11b+ cells were isolated from the PVN to evaluate TREM2 expression by flow cytometry in the same population. Then, TREM2 global knock‐out mice (TREM2‐KO) and WT (n=10/group) were exposed to CH‐PH model and pulmonary hemodynamics were evaluated using a Millar pressure catheter in a terminal procedure.ResultsWe identified 10 clusters as microglia/macrophage. Following evaluation of several cluster markers used to identify microglia subtypes, we found the cluster with the most significant differences in gene profile and biological processes by comparing control and PH samples. This cluster was identified as the disease‐associated microglia (DAM), characterized by high expression of TREM2. Data was also confirmed in chronic hypoxia induced PH (CH‐PH) model by flow cytometry. CH induced a two‐fold increase of TREM2+microglia (CD11+, CD45+, TMEM119+) expression compared to normoxia controls. Fascinatingly, TREM2 deficient mice demonstrated a significant attenuation in the pulmonary pressure, represented by its surrogate the right ventricular systolic pressure (RVSP), and remarkably, reduction in overall lung inflammation induced by hypoxia.ConclusionsWhile TREM2 contribution has been extensively studied in neurodegenerative diseases and cancer therapy, these experiments are the first to demonstrate the potential of Trem2 targeted therapy in context of PH. Moreover, we believe that data generated from these studies may lead to translational studies evaluating the potential of TREM2 as a therapeutic target for PH.