Baroreceptor Reflex Sensitivity Research Articles

Adipocyte-Specific Disruption of the BBSome Causes Metabolic and Autonomic Dysfunction.

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of 8 conserved Bardet-Biedl Syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high fat & high sucrose diet (HFHSD). However, constitutive BBSome defiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific constitutive disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis, sympathetic traffic. The BBSome also contribute to baroreflex sensitivity under HFHSD, but not normal chow.

Cardiovascular Protective Effect of Garcinia dulcis Flower Acetone Extract in 2-Kidney-1-Clip Hypertensive Rats.

Morelloflavone and camboginol are bioactive compounds purified from Garcinia dulcis (GD), which has anti-inflammatory and antihypertensive properties. The objective of this study was to examine the cardiovascular protective effect of GD flower acetone extract in 2-kidney-1-clip (2K1C) hypertensive rats. Male Wistar rats underwent 2K1C or sham operation (SO) and were housed for 4 weeks. Each group of rats, then, was further divided into 2 subgroups receiving oral administration of either 50 mg/kg BW GD extract or corn oil (vehicle) daily for 4 weeks. Noninvasive blood pressure (BP) and body weight were measured weekly throughout the study. Subsequently, the invasive measurement of arterial BP and the heart rate were determined in all anesthetized rats. The baroreceptor reflex sensitivity (BRS) was investigated by injection of either phenylephrine or sodium nitroprusside for bradycardia or tachycardia response, respectively. Histological examination of the heart and thoracic aorta was also performed in order to investigate the general morphology and the tumor necrosis factor alpha (TNF-α) expression. We found that the GD flower extract significantly diminished the BP and restored the impaired BRS. Moreover, it also decreased the TNF-α expression in the cardiac muscle and thoracic aorta of 2K1C when compared to the SO group. Taken together, our data showed that GD flower extract exhibits the cardiovascular protective effect in the 2K1C hypertensive rats.

Effects of vasodilators on beat-to-beat and every fifteen minutes blood pressure variability induced by noradrenaline infusion in rats

Increased blood pressure variability (BPV) was shown to be associated with cardiovascular morbidities and/or mortalities. There are various types of BPV depending on time intervals of BP measurements, ranging from beat-to-beat to visit-to-visit or year-to-year. We previously found that continuous infusion of noradrenaline (NA) for 14 days increased short-term BPV every 15 min in rats. The aims of this study were to examine (1) whether NA infusion increases very short-term beat-to-beat BPV, (2) the effects of azelnidipine and hydralazine on NA-induced BPV, and (3) whether baroreceptor reflex sensitivity (BRS) is affected by NA or NA plus those vasodilators. Nine-week-old Wistar rats infused subcutaneously with 30 μg/h NA were orally treated with or without 9.7 mg/day azelnidipine or 5.9 mg/day hydralazine over 14 days. BP levels were continuously monitored via abdominal aortic catheter with a telemetry system in an unrestrained condition. Standard deviations (SDs) were used to evaluate beat-to-beat BPV and BPV every 15 min which was obtained by averaging BP levels for 10-s segment at each time point. BRS was determined by a sequence analysis. Continuous NA infusion over 14 days increased average BP, beat-to-beat BPV, and BPV every 15 min, lowering BRS. Comparing the two vasodilators, hydralazine reduced BP elevation by NA; meanwhile, azelnidipine alleviated BPV augmentation, preserving BRS, despite a smaller BP reduction. Thus, NA infusion increased both very short- and short-term BPV concomitantly with impaired BRS, while azelnidipine had an inhibitory effect, possibly independent of BP-lowering, on those types of BPV and impairment of BRS.

Baroreceptor Reflex Sensitivity in Patients with Atrial Fibrillation

Purpose: Persistent atrial fibrillation decreases baroreflex sensitivity (BRS), which is considered an indicator of cardiac autonomy. Furthermore, atrial fibrillation ablation has also been found to reduce the BRS. The baseline BRS of patients with paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PeAF) was compared and the BRS-modifying effect of ablation was investigated. Methods: The BRS was measured before and after the procedure and the presence or absence of atrial fibrillation recurrence was assessed. Results: Pre-operative BRS was significantly lower in patients with PeAF compared with those with PAF. The BRS was significantly reduced postoperatively in all patients, with a particularly large reduction in PAF patients. The BRS decreased to a lesser extent with ablation in patients with recurrent PAF. Conclusions: Baseline BRS was lower in patients with PeAF. Atrial fibrillation ablation reduced BRS in both PAF and PeAF patients but had a stronger reduction effect in PAF patients.

Abstract P330: Two Rodent Models Of Augmented 24-hour Blood Pressure Variability Showing Similar Pathophysiological Features: Rats Infused With Norepinephrine Or Angiotensin II

Background: Augmented fluctuation of blood pressure (BP), so-called BP variability (BPV), was shown to be associated with cardiovascular diseases independently of BP levels. Recently we reported that 24-h BP variability is augmented in rats continuously infused with norepinephrine (NE) or angiotensin II (Ang II), assuming these animals as models of augmented BPV seen in ambulatory BP monitoring (ABPM) of humans. This study was aimed to clarify the underlying mechanisms for augmented BPV and the effects of azelnidipine, a calcium channel blocker, in rats infused with Ang II or NE. Methods and Materials: Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 μg/h NE or 5.2 μg/h Ang II with or without oral administration with 30 mg/kg/day azelnidipine (Azl) for 14 days (n=8 to 9 per group). BPV was evaluated before and after 14 days of the infusions, using standard deviations (SDs) of systolic and diastolic BP (SBP and DBP) recorded every 15 min under an unrestrained condition by a radiotelemetry system. Baroreceptor reflex sensitivity (BRS) was quantified with a sequence analysis, while sections of the aortic arch, where baroreceptors are thought to be located, were microscopically evaluated by computerized measurement. Results: Both SBP and DBP rose following infusion of NE or Ang II, while these increases were attenuated by Azl (P<0.01). SDs of SBP at the light (L) and dark (D) cycles were increased by NE (L, +94%; D, +117%, P<0.01) and Ang II (L, +94%; D +95%, P<0.01), with similar changes in SDs of DBP. These increases in SDs were attenuated following treatment with Azl almost to the control level (P<0.01). Augmented BPVs in both the NE and Ang II groups were accompanied by reductions in BRS (P<0.05) and by thickened medial area of the aortic arch (P<.0.01), while Azl alleviated impairment of BRS and aortic medial thickening (P<0.05). When analyzed for all groups by a simple regression, augmented BPV correlated with impairment of BRS (r=-0.54, P<0.01), which was associated with aortic medial area (r=-0.56, P<0.01). Conclusion: Rats infused chronically with NE or Ang II are models of increased 24-h BPV, both of which similarly showed impaired BRS and thickening medial layer of the aortic arch in association with augmented BPV.

Abstract 038: Adipocyte-specific BBSome Deficiency Impacts The Sympathetic Nervous System And Baroreceptor Reflex Sensitivity

The BBSome, a protein complex of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as an important regulator of metabolic, cardiovascular, and autonomic functions. Patients with Bbs gene mutations display severe obesity, type II diabetes and hypertension. Previous studies demonstrated that neuronal BBSome contributes to metabolic homeostasis and blood pressure regulation, however the importance of adipocyte BBSome in controlling glucose homeostasis and blood pressure remains poorly understood. To address this, we generated mice lacking the BBSome specifically in adipocytes through selective deletion of the Bbs1 gene (Adipo Cre /Bbs1 fl/fl ) by crossing the adiponectin Cre (Adipo Cre ) male mice crossing with female Bbs1 floxed (Bbs1 fl/fl ) mice. Adipocyte-specific Cre recombinase was validated by further crossing the Adipo Cre mice with td-Tomato reporter mice. Bbs1 gene deletion in adipocytes was confirmed by measuring Bbs1 gene expression in adipose tissue using qRT-PCR. To induce obesity, mice were fed a high fat high sucrose diet (HFHSD) for 16 weeks starting at 4 weeks of age. Interestingly, the weight gain evoked by HFHSD was comparable between male and female Adipo Cre /Bbs1 fl/fl mice and littermate controls. Similarly, Adipo Cre /Bbs1 fl/fl mice displayed unaltered blood glucose as indicated by glucose and insulin tolerance tests. Using radiotelemetry, we found no significant difference in systolic, diastolic, and mean arterial pressure and heart rate between control and Adipo Cre /Bbs1 fl/fl mice fed HFHSD. Surprisingly, a significant increase in renal sympathetic nerve activity was observed in Adipo Cre /Bbs1 fl/fl mice (Control: 101.1 ± 16.23 spikes/sec, Adipo Cre /Bbs1 fl/fl : 133.2 ± 32.15 spikes/sec, p < 0.05). Next, we measured baroreceptor reflex sensitivity by analyzing the responses to sodium nitroprusside (SNP) and phenylephrine (PE). The slope analysis showed that Adipo Cre /Bbs1 fl/fl mice were less sensitive to SNP (Control: -2.56 ± 0.82, Adipo Cre /Bbs1 fl/fl : -1.746± 0.29, p < 0.05), demonstrating altered baroreflex. Taken together, our data implicate the adipocyte BBSome is a regulator of sympathetic nervous activation and baroreflex sensitivity.

The Impact of Burst Motor Cortex Stimulation on Cardiovascular Autonomic Modulation in Chronic Pain: A Feasibility Study for a New Approach to Objectively Monitor Therapeutic Effects.

Chronic refractory pain of various origin occurs in 30-45% of pain patients, and a considerable proportion remains resistant to pharmacological and behavioral therapies, requiring adjunctive neurostimulation therapies. Chronic pain is known to stimulate sympathetic outflow, yet the impact of burst motor cortex stimulation (burstMCS) on objectifiable autonomic cardiovascular parameters in chronic pain remains largely unknown. In three patients with chronic pain (2 facial pain/1 post-stroke pain), we compared pain intensity using a visual analog scale (VAS 1-10) and parameters of autonomic cardiovascular modulation at supine rest, during parasympathetic challenge with six cycles per minute of metronomic deep breathing, and during sympathetic challenge (active standing) at baseline and after 4months of burstMCS compared to age-/gender-matched healthy controls. While two out of three patients were responsive after 4months of adjunctive burstMCS (defined as pain reduction of > 30%), no differences were found in any of the three patients regarding the R-R intervals of adjacent QRS complexes (RRI, 642 vs. 676ms) and blood pressure (BP, 139/88 vs. 141/90mmHg). Under resting conditions, parameters of parasympathetic tone [normalized units of high-frequency oscillations of RRI (RRI-HFnu power) 0.24 vs. 0.38, root-mean-square differences of successive RRI (RRI-RMSSD) 7.7 vs. 14.7ms], total autonomic cardiac modulation [RRI total power 129.3 vs. 406.2ms2, standard deviation of RRI (RRI-SD) 11.6 vs. 18.5ms, coefficient of variation of RRI (RRI-CV) 1.9 vs. 3.7%], and baroreceptor reflex sensitivity (BRS, 1.9 vs. 2.3ms/mmHg) increased, and parameters of sympathetic tone [normalized units of low-frequency oscillations of RRI (RRI-LFnu power) 0.76 vs. 0.62] and sympatho-vagal balance [ratio of RR-LF to RRI-HF power (RRI-LF/HF ratio) 3.4 vs. 1.9] decreased after 4months of burstMCS. Low-frequency oscillations of systolic blood pressure (SBP-LF power), a parameter of sympathetic cardiovascular modulation, increased slightly (17.6 vs. 20.4mmHg2). During parasympathetic stimulation, the expiratory-inspiratory ratio (E/I ratio) increased slightly, while upon sympathetic stimulation, the ratio between the shortest RRI around the 15th heartbeat and the longest RRI around the 30th heartbeat after standing up (RRI 30/15 ratio) remained unchanged. Four months of adjunctive burstMCS was associated with an increase in parameters reflecting both total and parasympathetic autonomic modulation and baroreceptor reflex sensitivity. In contrast, sympathetic tone declined in our three patients, suggesting stimulation-associated improvement not only in subjectively perceived VAS pain scores, but also in objectifiable parameters of autonomic cardiovascular modulation.

PS-B03-1: MECHANISM FOR INCREASED BLOOD PRESSURE VARIABILITY AND EFFECT OF AZELNIDIPINE IN RATS INFUSED WITH NORADRENALIN

Objective: Augmented blood pressure variability (BPV) has been shown to be associated with cardiovascular diseases. There are various types of BPV depending on time periods for which BP levels are evaluated, while there are reportedly factors, such as aging and stiffened large arteries, which are related to any type of BPV. However, the mechanistic relationships between these factors and augmented variability remain to be specified. Recently, we found that 24-h BPV was augmented following continuous infusion of noradrenalin (NA) over 14 days in rats, assuming this animal as a model of augmented BPV of 24-h ambulatory BP monitoring (ABPM) of humans. The aim of the present study was to explore the mechanism underlying NA-induced BPV and the pharmacological action of the calcium channel blocker (CCB) azelnidipine, focusing on alterations in baroreceptor reflex sensitivity (BRS) and morphological findings of the aortic arch, where baroreceptors are thought to be located. Methods: Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 ug/h NA with or without oral administration with 30 mg/kg/day azelnidipine for 14 days. BPV was evaluated by a coefficient of variation (CV) of BP recorded every 15 min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. To estimate BRS, data obtained from continuous BP monitoring were analyzed by a sequence technique with the software HemoLab. Sections of the aortic arch were stained with hematoxylin-eosin, and cross-sectional areas were determined by computerized measurement. Results: CVs of systolic and diastolic BP during 24-h period almost doubled at day 7 and 14 following continuous infusion of NA. Increased 24-h variabilities were accompanied by impaired BRS (P < 0.01) and thickened aortic media (P < 0.01) at day 14 of the infusion. Meanwhile, azelnidipine administration mostly (P < 0.01) suppressed NA-induced BPV, and significantly (P < 0.01) alleviated impairment of BRS and aortic medial thickening. When analyzed for all groups by a simple regression, CV of systolic BP at day 14 significantly correlated with reduction in BRS (r = 0.45, P < 0.01), which was associated with aortic medial area (r = 0.57, P < 0.01). Conclusions: The present findings suggest a possible mechanism underlying NA-induced BPV: aortic arch stiffened by medial thickening may be partly involved in impaired BRS, resulting in augmented BPV. Meanwhile, azelnidipine alleviated BPV, preserving BRS probably via inhibition of NA-induced aortic medial thickening in rats.

Analysis of Mechanisms for Increased Blood Pressure Variability in Rats Continuously Infused with Angiotensin II.

We reported that rats infused with angiotensin II (Ang II) are not only a model of hypertension but also of augmented 24 h blood pressure variability (BPV). In this study, we examined the mechanisms for Ang II-induced BPV, focusing on BP, heart rate (HR), baroreceptor reflex sensitivity (BRS), and medial area of the aortic arch. Nine-week-old male Wistar rats were infused with subcutaneous 5.2 μg/kg/h Ang II with or without oral administration with 30 mg/kg/day azelnidipine for 14 days. BP and HR were recorded every 15 min under an unrestrained condition by a radiotelemetry system, while BPV was evaluated by standard deviation of BP. BRS was quantified by a sequence analysis, and medial thickness of the aortic arch was measured by microscopic examination. BPV increased at days 7 and 14 following continuous infusion of Ang II. Before the infusion, a positive correlation was found between BP and HR, but it became negative at day 7 and then weakened or disappeared at day 14. BRS was slightly impaired at day 7 and significantly lowered at day 14, a phenomenon accompanied by thickened medial area of the aortic arch in Ang II-infused rats. Those Ang II-induced alterations were all significantly attenuated by azelnidipine. The present findings suggest sequential changes in the mechanisms behind augmented BPV in rats continuously infused with Ang II over 14 days.

The contribution of autonomic mechanisms to pain in temporomandibular disorders: A narrative review.

Temporomandibular disorders (TMD) are diagnosed based on symptom presentation and, like other functional pain disorders, often lack definitive pathology. There is a strong association between elevated stress levels and the severity of TMD-related pain, which suggests that alterations in autonomic tone may contribute to this pain condition. This narrative review examines the association between altered autonomic function and pain in TMD. Relevant articles were identified by searching PubMed and through the reference list of those studies. TMD sufferers report an increased incidence of orthostatic hypotension. As in other chronic musculoskeletal pain conditions, TMD is associated with increased sympathetic tone, diminished baroreceptor reflex sensitivity and decreased parasympathetic tone. It remains to be determined whether ongoing pain drives these autonomic changes and/or is exacerbated by them. To examine whether increased sympathetic tone contributes to TMD-related pain through β2 adrenergic receptor activation, clinical trials with the beta blocker propranolol have been undertaken. Although evidence from small studies suggested propranolol reduced TMD-related pain, a larger clinical trial did not find a significant effect of propranolol treatment. This is consistent with human experimental pain studies that were unable to demonstrate an effect of β2 adrenergic receptor activation or inhibition on masticatory muscle pain. In preclinical models of temporomandibular joint arthritis, β2 adrenergic receptor activation appears to contribute to inflammation and nociception, whereas in masticatory muscle, α1 adrenergic receptor activation has been found to induce mechanical sensitisation. Some agents used to treat TMD, such as botulinum neurotoxin A, antidepressants and α2 adrenergic receptor agonists, may interact with the autonomic nervous system as part of their analgesic mechanism. Even if dysautonomia turns out to be a consequence rather than a causative factor of painful TMD, the study of its role has opened up a greater understanding of the pathogenesis of this condition.

Mechanisms for blood pressure reduction following isometric exercise training: a systematic review and meta-analysis.

Isometric exercise training (IET) is established as an effective antihypertensive intervention. Despite this, the physiological mechanisms driving blood pressure (BP) reductions following IET are not well understood. Therefore, we aimed to perform the first meta-analysis of the mechanistic changes measured following IET. PubMed, Cochrane library and SPORTDiscus were systematically searched for randomized controlled trials published between January 2000 and December 2021 reporting the effects of IET on resting BP and at least one secondary mechanistic parameter following a short-term intervention (2-12 weeks). Eighteen studies with a pooled sample size of 628 participants were included in the final analysis. IET produced significant reductions in resting systolic and diastolic BP of 9.35 mmHg (95% confidence interval [CI] = -7.80 to -10.89, P < 0.001) and 4.30 mmHg (CI = -3.01 to -5.60, P < 0.001), respectively. Mechanistically, IET produced a statistically significant reduction in resting heart rate (mean difference [MD]: -1.55 bpm, CI = -0.14 to -2.96, P = 0.031) and a significant increase in stroke volume (MD: 6.35 ml, CI = 0.35 to 12.60, P = 0.038), with no significant change in cardiac output. Conversely, total peripheral resistance (TPR) significantly decreased following IET (MD: -100.38 dyne s -1 cm 5 , CI = -14.16 to -186.61, P = 0.023), with significant improvements in the low frequency to high frequency heart rate variability ratio (MD: -0.41, CI = -0.09 to -0.73, P = 0.013) and baroreceptor reflex sensitivity (MD: 7.43 ms/mmHg, P < 0.001). This work demonstrates that a reduction in TPR, potentially mediated through enhanced autonomic vasomotor control, is primarily responsible for BP reductions following IET. Furthermore, this novel analysis suggests wall squat interventions to be the most effective IET mode, with clinically relevant differences in BP reductions compared to handgrip and leg extension IET; although future direct comparative research is required.

Premedication of Oral Clonidine 2mcg/kg and 4mcg/kg for Analgesic and Pressure Response During First Twenty-four Hours After Upper Abdominal Surgery: A Comparative Study

Traditionally postoperative period analgesia was maintained by opoids and which frequently increasethe hospital stay time and cost by delayed bowel movement and others side effects. on the other handupper abdominal surgery is very much painful, usually Opiods are used as good analgesic, but havesome adverse effect and addiction effect; anaesthesiologists want to reduce its requirements. In upperabdominal surgery adequate analgesia, stable haemodynamic, early bowel movement, free from nauseaand vomiting is wanted, as a part of multimodal analgesic approach, premedication by clonidine is veryimportant for it analgesic, angiolytic and sedative properties. Alpha two (α–2) adrenoreceptor agonist,Clonidine exerts central sympatholytic effect for 8 to 10 hours as its half life is 9-12 h. So thatpremedication with oral clonidine causes reduction of anxiety, reduction of perioperative analgesicdrugs and also reduction of anaesthetic doses. In addition, clonidine increases cardiac baroreceptorreflex sensitivity to increase in systolic blood pressure, and thus stabilizes blood pressure. Clonidine israpidly and almost completely absorbed after oral administration with a time to maximum plasmaconcentration of between 1.5 and 2 hr and elimination half-life of 8 to 12 hr. But clonidine producesanalgesia in a dose dependent manner, achieving complete pain relief for up to 5 hours without sensoryor motor block at large doses (oral 7000 to 900 mcg) however large doss were associated withdisadvantage including hypotension, bradycardia and transient sedation. It also reported thatclonidine 150mcg intravenous (I/V) produce a similar analgesic effect to morphine 5mg in patient afterorthopedic surgery. Because of its dose, route, and surgical variation it is very much important tospecify the dose for upper abdominal surgery.The primary aim of this study to compare the effects of clonidine premedication at different doses (2 &amp;4mcg/kg) on postoperative analgesia and hemodynamic status in upper abdominal surgery with largeincision area. (like- hepatobiliary surgery, gastrectomy, esophagectomy, hepatictomy, and whipplesoperations). JBSA 2022; 35 (2) : 17-21

A Feasibility Study Exploring Measures of Autonomic Function in Patients With Failed Back Surgery Syndrome Undergoing Spinal Cord Stimulation

ObjectivesFailed back surgery syndrome (FBSS) is associated with impaired autonomic tone, characterized by sympathetic prevalence and vagal withdrawal. Although spinal cord stimulation (SCS) alleviates pain in FBSS, there is limited research investigating how SCS affects measures of autonomic function. This was a prospective, open-label, feasibility study exploring measures of autonomic function in patients with FBSS receiving SCS therapy. Materials and MethodsA total of 14 patients with FBSS were recruited for baseline measurements and underwent a trial of 10-kHz SCS. There were three failed trials, resulting in the remaining 11 participants receiving a fully implanted 10-kHz SCS system. One participant requested an explant, resulting in ten participants completing both baseline and follow-up (three to six months after SCS implant) measurements. Autonomic function was assessed using time- and frequency-domain heart rate variability (HRV), baroreceptor reflex sensitivity (BRS), and muscle sympathetic nerve activity (MSNA) using microneurography. Because this was a feasibility study, most of the analysis was descriptive. However, paired t-tests and Wilcoxon signed-rank tests tested for differences between baseline and follow-up. ResultsIn the whole (N = 14) and final (N = 10) samples, there was between-participant variation in baseline and follow-up measures. This, combined with a small sample, likely contributed to finding no statistically significant differences in any of the measures between baseline and follow-up. However, plotting baseline and follow-up scores for individual participants revealed that those who showed increases in MSNA frequency, square root of the mean of the squared differences between adjacent RR intervals (RMSSD), percentage of the number of RR intervals >50 ms (pRR50), total power, and up BRS between baseline and follow-up had distinct clustering of baseline values compared with those who showed decreases in these measures. ConclusionsFindings from this feasibility study will aid with informing hypotheses for future research. A key aspect that should be considered in future research concerns exploring the role of baseline measures of autonomic function in influencing change in autonomic function with SCS therapy.

Impaired Spontaneous Baroreceptor Reflex Sensitivity in Patients With COPD Compared to Healthy Controls: The Role of Lung Hyperinflation.

Background and Objectives: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for cardiovascular disease. This study aimed to investigate the relationship between pulmonary hyperinflation and baroreceptor reflex sensitivity (BRS), a surrogate for cardiovascular risk.Methods: 33 patients with COPD, free from clinical cardiovascular disease, and 12 healthy controls were studied. Participants underwent pulmonary function and non-invasive hemodynamic measurements. BRS was evaluated using the sequence method during resting conditions and mental arithmetic stress testing.Results: Patients with COPD had evidence of airflow obstruction [forced expiratory volume in 1 s predicted (FEV1%) 26.5 (23.3–29.1) vs. 91.5 (82.8–100.8); P < 0.001; geometric means (GM) with 95% confidence interval (CI)] and lung hyperinflation [residual volume/total lung capacity (RV/TLC) 67.7 (64.3–71.3) vs. 41.0 (38.8–44.3); P < 0.001; GM with 95% CI] compared to controls. Spontaneous mean BRS (BRSmean) was significantly lower in COPD, both during rest [5.6 (4.2–6.9) vs. 12.0 (9.1–17.6); P = 0.003; GM with 95% CI] and stress testing [4.4 (3.7–5.3) vs. 9.6 (7.7–12.2); P < 0.001; GM with 95% CI]. Stroke volume (SV) was significantly lower in the patient group [−21.0 ml (−29.4 to −12.6); P < 0.001; difference of the means with 95% CI]. RV/TLC was found to be a predictor of BRS and SV (P < 0.05 for both), independent of resting heart rate.Conclusion: We herewith provide evidence of impaired BRS in patients with COPD. Hyperinflation may influence BRS through alteration of mechanosensitive vagal nerve activity.

Left ventricular mechanical, cardiac autonomic and metabolic responses to a single session of high intensity interval training.

High-intensity interval training (HIIT) produces significant health benefits. However, the acute physiological responses to HIIT are poorly understood. Therefore, we aimed to measure the acute cardiac autonomic, haemodynamic, metabolic and left ventricular mechanical responses to a single HIIT session. Fifty young, healthy participants completed a single HIIT session, comprising of three 30-s maximal exercise intervals on a cycle ergometer, interspersed with 2-min active recovery. Cardiac autonomics, haemodynamics and metabolic variables were measured pre-, during and post-HIIT. Conventional and speckle tracking echocardiography was used to record standard and tissue Doppler measures of left ventricular (LV) structure, function and mechanics pre- and post-HIIT. Following a single HIIT session, there was significant post-exercise systolic hypotension (126 ± 13 to 111 ± 10mmHg, p < 0.05), parallel to a significant reduction in total peripheral resistance (1640 ± 365 to 639 ± 177dyne⋅s⋅cm5, p < 0.001) and significant increases in baroreceptor reflex sensitivity and baroreceptor effectiveness index (9.2 ± 11 to 24.8 ± 16.7ms⋅mmHg-1 and 41.8 ± 28 to 68.8 ± 16.2, respectively) during recovery compared to baseline. There was also a significant increase in the low- to high-frequency heart rate variability ratio in recovery (0.7 ± 0.48 to 1.7 ± 1, p < 0.001) and significant improvements in left ventricular global longitudinal strain (- 18.3 ± 1.2% to - 29.2 ± 2.3%, p < 0.001), and myocardial twist mechanics (1.27 ± 0.72 to 1.98 ± 0.72°·cm-1, p = 0.028) post-HIIT compared to baseline. A single HIIT session is associated with acute improvements in autonomic modulation, haemodynamic cardiovascular control and left ventricular function, structure and mechanics. The acute responses to HIIT provide crucial mechanistic information, which may have significant acute and chronic clinical implications.

Activation of the cholinergic antiinflammatory reflex by occipitoatlantal decompression and transcutaneous auricular vagus nerve stimulation.

The parasympathetic-mediated inflammatory reflex inhibits excessive proinflammatory cytokine production. Noninvasive techniques, including occipitoatlantal decompression (OA-D) and transcutaneous auricular vagus nerve stimulation (taVNS), have been demonstrated to increase parasympathetic tone. To test the hypothesis that OA-D and taVNS increase parasympathetic nervous system activity and inhibit proinflammatory cytokine mobilization and/or production. Healthy adult participants were randomized to receive OA-D (5min of OA-D followed by 10min of rest; n=8), taVNS (15min; n=9), or no intervention (15min, time control; n=10) on three consecutive days. Before and after these interventions, saliva samples were collected for determination of the cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α). Arterial blood pressure and the electrocardiogram were recorded for a 30-min baseline, throughout the intervention, and during a 30-min recovery period to derive heart rate and blood pressure variability markers as indices of vagal and sympathetic control. OA-D and taVNS increased root mean square of successive RR interval differences (RMSSD) and high frequency heart rate variability, which are established markers for parasympathetic modulation of cardiac function. In all three groups, the experimental protocol was associated with a significant increase in salivary cytokine concentrations. However, the increase in IL-1β was significantly less in the taVNS group (+66±13pg/mL; p<0.05) than in the time control group (+142±24pg/mL). A similar trend was observed in the taVNS group for TNF-α (+1.7±0.3pg/mL vs. 4.1±1.3pg/mL; p<0.10). In the OA-D group baseline IL-6, IL-8, and TNF-α levels on the third study day were significantly lower than on the first study day (IL-6: 2.3±0.4 vs. 3.2±0.6pg/mL, p<0.05; IL-8: 190±61 vs. 483±125pg/mL, p <0.05; TNF-α: 1.2±0.3 vs. 2.3±0.4pg/mL, p<0.05). OA-D decreased mean blood pressure from the first (100±8mmHg) to the second (92±6mmHg; p<0.05) and third (93±8mmHg; p<0.05) study days and reduced low frequency spectral power of systolic blood pressure variability (19±3mmHg2 after OA-D vs. 28±5mmHg2 before OA-D; p<0.05), a marker of sympathetic modulation of vascular tone. OA-D also increased baroreceptor-heart rate reflex sensitivity from the first (13.7±3.0ms/mmHg) to the second (18.4±4.3ms/mmHg; p<0.05) and third (16.9±4.2ms/mmHg; p<0.05) study days. Both OA-D and taVNS elicited antiinflammatory responses that were associated with increases in heart rate variability-derived markers for parasympathetic function. These findings suggest that OA-D and taVNS activate the parasympathetic antiinflammatory reflex. Furthermore, an antihypertensive effect was observed with OA-D that may be mediated by reduced sympathetic modulation of vascular tone and/or increased baroreceptor reflex sensitivity.

Pregnancy related inappropriate sinus tachycardia: a distinct arrhythmia?

Abstract Background The syndrome of inappropriate sinus tachycardia (IST) is well recognized and affects ∼1% of the population. We believe IST in pregnancy is a relatively frequent yet under-recognized phenomenon that may represent a distinct arrhythmia. To date, there are only three case reports in the literature. Purpose To further understand the natural history of IST in pregnancy, and to explore maternal outcomes. Methods A retrospective, observational cohort analysis. Results 19 pregnant women presented to our institute with a definitive diagnosis of IST (as defined by task force criteria) between January 2016 and January 2017. Symptom onset was 4–36 weeks gestation (mean 20 weeks). Of those in their second or subsequent pregnancy (n=8), 50% described symptoms compatible with IST in previous pregnancies. 42% attended the emergency department on ≥1 occasion with symptoms of IST. 32% required hospital admission. 26% required pharmacological therapy (beta-blockers in all). There were no maternal deaths, instances of heart failure or acute coronary syndrome, no thromboembolic or haemorrhagic complications during pregnancy. Rates of Caesarean section were similar to the background rate of our unit; however, rates of induction were notably elevated (58% vs 25%), with 55% of these women being induced purely for symptoms of IST. Following delivery, symptoms resolved within one week for 17 of the women in the cohort, 1 had symptoms resolve after 4 month and 1 had persistent symptoms as she became pregnant again. Conclusion IST in pregnancy likely represents a distinct arrhythmia; the majority of individuals here had symptoms only during pregnancy, which resolved rapidly postpartum. Additionally, half of the women in a second or subsequent pregnancy had suffered IST symptoms during previous pregnancies, with no symptoms in between pregnancies. It is biologically plausible and may represent an exaggerated cardio-autonomic response to the physiological changes of pregnancy such as increased sympathetic tone and change in baroreceptor reflex sensitivity. Recognition of the condition is important given it is associated with significant morbidity, the distressing nature of symptoms leading to high rates of hospitalization and induction of labour. Funding Acknowledgement Type of funding source: None

Assessment of baroreceptor reflex sensitivity in young obese Saudi males at rest and in response to physiological challenges.

Autonomic imbalance in overweight/obese persons could lead to an increased risk of cardiovascular complications including hypertension and arrhythmias. Baroreceptor reflex sensitivity is a sensitive indicator to detect an altered sympathovagal balance in overweight/obese individuals. This study investigated the effects of overweight/obesity on baroreceptor sensitivity in young Saudi males at rest and in response to physiological challenges.Subjects and methodsIn this cross‐sectional study, spontaneous baroreceptor sensitivity at rest and in response to deep breathing, isometric hand grip exercise and moderate intensity isotonic exercise were recorded in 20 normal weight and 20 overweight/obese subjects. Finger arterial blood pressure signal, recorded through Finometer, was used to calculate baroreceptor sensitivity through cross‐correlation method. The baroreceptor sensitivity data were log transformed before application of parametric tests.ResultsThe spontaneous baroreceptor sensitivity was similar in both groups at baseline, but exhibited a significant increase during deep breathing only in normal weight (p < .001). Immediately after the isotonic exercise the baroreceptor sensitivity was significantly lower than baseline in both normal weight and overweight/obese and remained significantly lower in overweight/obese individuals compared to normal weight (p < .05) throughout the recovery period. There was a significant rise in baroreceptor sensitivity after isometric exercise in overweight/obese group only (p = .001). Pearson's correlation showed a significant negative correlation of baroreceptor sensitivity with body mass index during deep breathing (r = −.472, p = .004) and in post‐isotonic exercise recovery period (r = −.414, p = .013).ConclusionA significantly reduced baroreceptor sensitivity response to deep breathing, reduced baroreceptor sensitivity recovery after isotonic exercise, and an exaggerated shoot up after isometric exercise in overweight/obese suggests an altered sympathovagal balance. Baroreceptor sensitivity measurements in response to physiological challenges, deep breathing, and isotonic exercise, may be more sensitive investigations for detection of early attenuation of cardiac autonomic function. This would enable timely intervention thereby delaying complications and improving the quality of life.

Continuous cardiac autonomic and haemodynamic responses to isometric exercise in females.

Hypertension is associated with impaired haemodynamic control mechanisms and autonomic dysfunction. Isometric exercise (IE) interventions have been shown to improve autonomic modulation and reduce blood pressure (BP) predominantly in male participants. The physiological responses to IE are unexplored in female populations; therefore, this study investigated the continous cardiac autonomic and haemodynamic response to a single bout of IE in a large female population. Forty physically inactive females performed a single, individually prescribed isometric wall squat training session. Total power spectral density of heart rate variability (HRV) and associated low-frequency (LF) and high-frequency (HF) power spectral components were recorded in absolute (ms2) and normalised units (nu) pre, during and post an IE session. Heart rate (HR) was recorded via electrocardiography and baroreceptor reflex sensitivity (BRS) via the sequence method. Continuous blood pressure was recorded via the vascular unloading technique and stroke volume via impedance cardiography. Total peripheral resistance (TPR) was calculated according to Ohm's law. During IE, there were significant reductions in HRV (p < 0.001) and BRS (p < 0.001), and significant increases in heart rate (p < 0.001), systolic, mean and diastolic BP (p < 0.001 for all). In recovery following the IE session, cardiac autonomic parameters returned to baseline (p = 0.974); however, total peripheral vascular resistance significantly reduced below baseline (p < 0.001). This peripheral vascular response was associated with significant reductions in systolic (-17.3 ± 16.5mmHg, p < 0.001), mean (-18.8 ± 17.4mmHg, p < 0.001) and diastolic BP (-17.3 ± 16.2mmHg, p < 0.001), below baseline. A single IE session is associated with improved haemodynamic cardiovascular responses in females. Cardiac autonomic responses return to baseline values, which suggests that alternative mechanisms are responsible for the post-exercise haemodynamic improvements in females. Future mechanistic research is required to investigate the acute and chronic effects of IE in female populations with different resting BP profiles.

A Chemogenetic Tool that Enables Functional Neural Circuit Analysis

Chemogenetics enables manipulation of neuronal activity in experimental animals. While providing information about the transduced neuron expressing a ligand-activated molecule, chemogenetics does not provide understanding about the antecedent circuit that drives that neuron's activity. For current approaches, this is not feasible, because the activating molecules are not genetically encoded. The insect allatostatin/allatostatin receptor system, a highly specific, powerful inhibitory chemogenetic approach, has this advantage, because the ligand, being a peptide, is genetically encoded. We developed viral vector-based systems to express biologically active allatostatin in neurons invivo and allatostatin receptors in subpopulations of postsynaptic neurons. We demonstrate that activity-dependent release of allatostatin induces inhibition of allatostatin receptor-expressing neurons. We validate the approach in the vagal viscerosensory system where inhibitory, rather than the usual excitatory, viscerosensory input leads to sustained decreases in baroreceptor reflex sensitivity and bodyweight.