Spontaneous Baroreflex Sensitivity Research Articles

Oral Administration of Amiloride Does Not Affect Spontaneous Cardiac Baroreflex Sensitivity in Humans

Pre-clinical models suggested that administration of Amiloride at the carotid sinus antagonizes the acid-sensing ion channels (ASICS), an essential component of the mechanoelectrical transducer in the arterial baroreceptors, reducing cardiac baroreflex sensitivity and perturbing the homeostatic beat-to-beat blood pressure (BP) regulation. However, it is still undetermined whether these findings could be translated into humans. Therefore, we determined whether oral administration of Amiloride reduces the spontaneous cardiac baroreflex (cBRS) sensitivity and perturbs BP regulation in humans. Heart rate (HR; electrocardiography) and beat-to-beat BP (finger photoplethysmography) were continuously measured in 5 healthy men (32 ± 6 yrs) during at least 5 min in two different conditions: (1) Control (CTL) and (2) 3 h after of oral administration of Amiloride (AMD – 5 mg + 50 mg of hydrochlorothiazide), a non-selective antagonist of ASICs. Spontaneous cardiac BRS was determined for all sequences (three or more consecutive beats with corresponding increases or decreases in systolic BP and R-R interval) combined (cBRSall) and separately for up (cBRSup – increases in BP and R-R interval) and down (cBRSdown – decreases in BP and R-R interval) sequences. HR (AMD 65 ± 7 vs. CLT 63 ± 12 beats/min, P = 0.543), mean (AMD 88 ± 9 vs. CLT 88 ± 7 mmHg, P = 0.687), and systolic BP (AMD 126 ± 14 vs. 128 ± 11 mmHg, P = 0.717) were similar in both conditions. Likewise, spontaneous cBRSall (AMD 20 ± 9 vs. CTL 22 ± 6 ms/mmHg, P = 0.543), cBRSup (AMD 19 ± 10 vs. CTL 22 ± 6 ms/mmHg, P = 0.495,) and cBRSdown (AMD 21 ± 9 vs. CTL 21 ± 8 ms/mmHg, P = 0.937) were preserved after AMD administration. In summary, our preliminary results demonstrated that the non-selective antagonism of ASICS via oral administration of AMD did not affect spontaneous cardiac baroreflex sensitivity and BP regulation in humans. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Decentering and baroreflex sensitivity in adults with elevated blood pressure

Previous studies have linked the ability to decenter, a non-judgmental view of emotions, with lower arterial stiffness and better nocturnal blood pressure dipping in adults. It is unknown however if autonomic regulation of blood pressure is linked to decentering. Therefore, the purpose of this study was to determine if decentering ability is related to cardiovagal or sympathetic baroreflex sensitivity. Thirty-three adults (age 25±6 years; BMI 25±3 kg/m2) with resting blood pressure ≥120/80 mmHg volunteered for this study. All participants had a BMI <30 kg/m2, and had no history of smoking, diabetes, or prescriptions for blood pressure or cardiac function. Participants completed an 11-item experiences questionnaire to evaluate decentering, and then were equipped for a supine autonomic evaluation. The autonomic evaluation included continuous recording of heart rate via 3-lead ECG, muscle sympathetic nerve activity (MSNA) via microneurography, and beat-to-beat blood pressure via finger photoplethysmography. Cardiovagal baroreflex sensitivity (n=33) included estimation of vagal activation by evaluating up-up relationships between systolic arterial pressure (SAP) and R-R intervals of the ECG. Vagal withdrawal was also estimated via the down-down relationships between SAP and R-R intervals. Spontaneous sympathetic baroreflex sensitivity (n=26) was evaluated by evaluating the relationship between changes in diastolic arterial pressure (DAP) in 3 mmHg bins vs. changes in MSNA burst incidence (i.e., bursts / 100 heart beats). Results from 2-tailed Pearson correlation analyses revealed that there was not a relationship between decentering and vagal activation (r=-0.07; p=0.71) or between decentering and vagal withdrawal (r=-0.28; p=0.12). Likewise, there was no relationship between decentering and sympathetic baroreflex sensitivity (r=0.10; p=0.64). Our findings suggest that there is not a clear link between decentering and autonomic regulation of blood pressure as estimated through both cardiovagal and baroreflex sensitivity. NIH (1R15HL140596-01); Nils K. Nelson Endowment Fund This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Spontaneous Cardiac Baroreflex Sensitivity in Young, Healthy Black and White Adults: Influence of Race and Sex

Background: Black (BL) individuals living in the United States are more likely to develop hypertension and cardiovascular disease compared to their White (WH) counterparts. However, studies investigating racial differences in blood pressure regulation and baroreflex sensitivity (BRS) are limited and have reported equivocal results. Furthermore, despite BL females also having a high prevalence of hypertension and cardiovascular disease, sex differences are often not considered. Additionally, baroreflex effectiveness index (BEI) is a newer measure used to estimate baroreflex function, yet studies have not examined the influence of sex or race on BEI. Therefore, the purpose of this project was to investigate the effects of both race and sex on cardiac BRS and BEI. We hypothesized that BL individuals would have lower cardiac BRS and BEI than WH individuals. Methods: We studied 88 young healthy adults, 28 BL males (21 ± 3 years; mean ± SD), 17 WH males (24 ± 4 years), 15 BL females (21 ± 3 years), and 28 WH females (23 ± 4 years). Heart rate (ECG) and beat-to-beat arterial blood pressure (finger photoplethysmography) were continuously recorded during a five-minute resting baseline. Cardiac BRS was measured using the Sequence Method, by identifying the gain of the relationship between systolic blood pressure and RRI from sequence(s) of three or more consecutive heartbeats in which systolic blood pressure and RRI change in the same direction. BEI was quantified by baroreflex-driven ramps relative to all systolic blood pressure ramps. Results: Cardiac BRS was significantly higher in BL individuals (31 ± 15 ms/mmHg) compared to WH individuals (25 ± 11 ms/mmHg; main effect of race, p = 0.02). Interestingly, post hoc comparisons revealed that this was only true within the males (p = 0.03), but not females (p = 0.63). However, there was no difference in cardiac BRS between males and females (main effect of sex, p = 0.35) and no interaction between sex and race (p = 0.27). There were also no effects of race (p = 0.65) or sex (p = 0.15) on BEI. Conclusion: These preliminary data suggest that, in contrast to our hypothesis, young BL individuals have higher cardiac BRS compared to WH individuals; an effect that is only present in males. In contrast, BEI was not influenced by race or sex. Collectively, our findings do not suggest that lower cardiac BRS plays a major role in the higher prevalence of cardiovascular disease in BL individuals. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Evaluation of hemorrhagic shock and traumatic brain injury effects on hemodynamics and metabolomics

Traumatic brain injury (TBI) is often accompanied by hemorrhage. However, treatment of hemorrhagic shock (HS) after TBI is challenging because the treatment strategies for TBI and HS often conflict. Little is known about the complex pathophysiological differences between these two traumas when happening individually or combined. The aim of the present study was to evaluate effects of HS and TBI individually and combined on hemodynamics, baroreflex and brain metabolomics. Male Wistar rats were instrumented with catheters and subjected to TBI through a pneumatic controlled cortical impact. HS was induced by blood withdrawal to achieve a blood pressure (BP) between 35-40mmHg, and this hypotensive state was maintained for 90 min. Animals were separated into 4 groups (n=5): Sham (underwent surgery, but no TBI or HS was done), HS (animals were placed in the stereotaxic, but no TBI), TBI (TBI was performed and timeline was followed as described, but no HS was done), and TBI+HS. Rats were sacrificed 90 min after HS and tissues were harvested. BP, heart rate (HR), and indices of spontaneous baroreflex sensitivity were evaluated at baseline, 10 min after TBI, and at 10 and 90 min after HS. The brain was harvested and a metabolomic analysis for tricarboxylic acid (TCA) cycle, amino acids and lipids was performed in the impacted area. BP decreased in the TBI group compared to Sham and, as expected, it severely decreased in HS and TBI+HS groups, once they were kept at lower pressure levels for 90 min. Heart Rate (HR) was lower in the HS group compared to Sham and TBI groups. It was observed that HS decreases the BP alteration events’ number during a fixed 10 min period compared to Sham and TBI groups, however the association of TBI with HS normalized this parameter. This suggests that HS is decreasing BP variability in the HS group, while the association of HS with TBI did not show the same response. Baroreflex sensitivity was higher in both HS and HS+TBI compared to both Sham and TBI groups. TCA cycle and amino acids metabolites increased in all the groups with trauma compared to Sham, however the increase in the HS and TBI+HS was around 2.5X-fold, while for the TBI group it was around 1.5X-fold. Moreover, the lipids metabolites decreased for all the groups submitted to trauma, with the highest effects observed for the groups submitted to HS and TBI+HS. These results suggest that HS has a higher effect on metabolites abnormalities compared to TBI alone. Our results suggest that HS has a higher contribution for hemodynamics and metabolism abnormalities when compared to TBI alone. It is interesting that the association of TBI with HS does not seem to change parameters such HR and BP variability. However, further investigations are necessary to better understand the impact of the lack of alteration of these hemodynamics parameters, since this trauma combination is complex and the adequate treatment for these situations remains unclear. This study was supported by National Institutes of Health grants R01HL162120, R01HL159862 and the Department of Defense under grants W81XWH1810059. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

An Innovative Toolkit to Investigate the Complex Mechanisms of Cardiac Arrhythmias

ARTICLES DISCUSSED: Tomsits, P., Schuttler, D., Kaab, S., Clauss, S., Voigt, N. Isolation of high quality murine atrial and ventricular myocytes for simultaneous measurements of Ca2+ transients and L-Type calcium current. Journal of Visualized Experiments. (165), 10.3791/61964 (2020). Seibertz, F., Reynolds, M., Voigt, N. Single-Cell optical action potential measurement in human induced pluripotent stem cell-derived cardiomyocytes. Journal of Visualized Experiments. (166), 10.3791/61890 (2020). Xia, R. et al. Isolation and culture of resident cardiac macrophages from the murine sinoatrial and atrioventricular node. Journal of Visualized Experiments. (171), 10.3791/62236 (2021). Xia, R. et al. Whole-Mount immunofluorescence staining, confocal imaging and 3D reconstruction of the sinoatrial and atrioventricular node in the mouse. Journal of Visualized Experiments. (166), 10.3791/62058 (2020). Kumar, P., Si, M., Paulhus, K., Glasscock, E. Microelectrode array recording of sinoatrial node firing rate to identify intrinsic cardiac pacemaking defects in mice. Journal of Visualized Experiments. (173), 10.3791/62735 (2021). Scherschel, K. et al. Location, dissection, and analysis of the murine stellate ganglion. Journal of Visualized Experiments. (166), 10.3791/62026 (2020). Shimura, D., Hunter, J., Katsumata, M., Shaw, R. M. Removal of an internal translational start site from mRNA while retaining expression of the full-length protein. Journal of Visualized Experiments. (181), 10.3791/63405 (2022). Rotzer, R. D. et al. Implantation of combined telemetric ECG and blood pressure transmitters to determine spontaneous baroreflex sensitivity in conscious mice. Journal of Visualized Experiments. (168), 10.3791/62101 (2021). Tomsits, P. et al. Analyzing long-term electrocardiography recordings to detect arrhythmias in mice. Journal of Visualized Experiments. (171), 10.3791/62386 (2021). Grab, M. et al. Development and evaluation of 3D-printed cardiovascular phantoms for interventional planning and training. Journal of Visualized Experiments. (167), 10.3791/62063 (2021).

Association between preoperative autonomic nervous system function and post-induction hypotension in elderly patients: a protocol for a cohort study

IntroductionPost-induction hypotension (PIH), which is prevalent among elderly patients, is associated with adverse perioperative outcomes. As a critical part of blood pressure regulation, baroreflex control is believed to be closely...

Cardiovagal baroreflex sensitivity, blood pressure and blood pressure variability - the Maastricht study.

Low baroreflex sensitivity (BRS) has been hypothesized to underlie high blood pressure (BP) and greater BP variability on the longer term, but evidence is scarce. In addition, these associations may differ by sex and (pre)diabetes. Therefore, we investigated whether cardiovagal BRS is associated with short- to mid-term mean BP and BP variability, and differs according to sex and (pre)diabetes. Cross-sectional data from the population-based Maastricht study (age 60 ± 8 years, 52% men), where office ( n = 2846), 24-h ( n = 2404) and 7-day BP measurements ( n = 2006) were performed. Spontaneous BRS was assessed by cross-correlating systolic BP and instantaneous heart rate. We used linear regression with adjustments for age, sex, BP or BP variability, and cardiovascular risk factors. With regard to BP, 1-SD (standard deviation) lower BRS (-5.75 ms/mmHg) was associated with higher office, 24-h and 7-day systolic BP (2.22 mmHg [95% confidence interval [CI]: 1.59; 2.80], 0.95 mmHg [0.54; 1.36], and 1.48 mmHg [0.99; 1.97], respectively) and diastolic BP (1.31 mmHg [0.97; 1.66], 0.57 mmHg [0.30; 0.84], and 0.86 mmHg [0.54; 1.17], respectively). Per 1-SD lower BRS, these associations were stronger in women (0.5-1.5 mmHg higher compared to men), and weaker in those with type 2 diabetes (1-1.5 mmHg lower compared to normal glucose metabolism). With regard to BP variability, BRS was not consistently associated with lower BP variability. Lower cardiovagal BRS is associated with higher mean BP from the short- to mid-term range, and not consistently with BP variability. The associations with mean BP are stronger in women and weaker in those with type 2 diabetes.

Posture-related changes in sympathetic baroreflex sensitivity during normal pregnancy.

Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6-11weeks) and late (32-36weeks) pregnancy and 6-10weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (-3.8 ± 0.4bursts/100heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (-5.9 ± 0.4bursts/100heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6bursts/100heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6bursts/100heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

Alterations in Baroreflex Sensitivity and Blood Pressure Variability Following Sport-Related Concussion.

Current methods to diagnose concussions are subjective and difficult to confirm. A variety of physiological biomarkers have been reported, but with conflicting results. This study assessed heart rate variability (HRV), spontaneous baroreflex sensitivity (BRS), and systolic blood pressure variability (BPV) in concussed athletes. The assessment consisted of a 5-min seated rest followed by a 5-min (0.1 Hz) controlled breathing protocol. Thirty participants completed baseline assessments. The protocol was repeated during the post-injury acute phase (days one to five). Total (p = 0.02) and low-frequency (p = 0.009) BPV spectral power were significantly decreased during the acute phase of concussion. BRS down-sequence (p = 0.036) and up-sequence (p = 0.05) were significantly increased in the acute phase of concussion, with a trend towards an increased BRS pooled (p = 0.06). Significant decreases in HRV were also found. Acute concussion resulted in altered BRS and BPV dynamics compared to baseline. These findings highlight objective physiological parameters that could aid concussion diagnosis and return-to-play protocols.

Sympathovagal imbalance in early ischemic stroke is linked to impaired cerebral autoregulation and increased infarct volumes.

Autonomic dysfunction is associated with worse outcome of ischemic stroke patients by mechanisms that are not fully understood. There is evidence of autonomic influence in cerebrovascular control but this has not been studied in acute stroke. Therefore, we examined the relationship between heart rate variability (HRV) and baroreflex sensitivity (BRS) in dynamic cerebral autoregulation in the early hours post ischemia, and its impact in clinical and radiological outcome. We prospectively enrolled 26 patients with acute ischemic stroke in middle cerebral artery. Arterial blood pressure (Finometer), cerebral blood flow velocity (transcranial Doppler), and electrocardiogram were recorded within 6h. HRV was assessed by the standard side deviations of normal inter-beat intervals, spectral analysis and non-linear entropy indexes. Spontaneous BRS was assessed by spectral and sequence methods. Dynamic cerebral autoregulation was assessed by transfer function analysis (coherence, phase and gain). Infarct volume was calculated from computed tomography at 24h. Clinical outcome was assessed by the modified Rankin scale. Increased BRS and HRV high frequencies power, both reflecting increased vagal modulation, were correlated with higher gain values of cerebral autoregulation (p<0.05). The higher vagal modulation was also associated with later large infarct volumes (p<0.05) but not with clinical outcome. Increased vagal modulation in early hours of acute ischemic stroke, may interfere with cerebrovascular control and is associated with larger infarcts. Understanding the mechanisms that govern this complex interplay can be useful as novel therapeutic targets to improvement of outcome.

Baroreflex sensitivity during rest and pressor challenges in obstructive sleep apnea patients with and without CPAP

IntroductionObstructive sleep apnea (OSA) increases sympathetic vasoconstrictor drive and reduces baroreflex sensitivity (BRS), the degree to which blood pressure changes modify cardiac output. Whether nighttime continuous positive airway pressure (CPAP) corrects BRS in the awake state in OSA remains unclear. We assessed spontaneous BRS using non-invasive continuous BP and ECG recordings at rest and during handgrip and Valsalva challenges, maneuvers that increase vasoconstrictor drive with progressively higher BP, in untreated OSA (unOSA), CPAP-treated OSA (cpOSA) and healthy (CON) participants. MethodsIn a cross-sectional study of 104 participants, 34 unOSA (age mean±std, 50.6±14.1years; Respiratory Event Index [REI] 21.0±15.3 events/hour; 22male), 31 cpOSA (49.6±14.5years; REI 23.0±14.2 events/hour; 22male; self-report 4+hours/night,5+days/week,6months), and 39 CON (42.2±15.0years; 17male), we calculated BRS at rest and during handgrip and Valsalva. Additionally, we correlated BP variability (BPV) with BRS during these protocols. ResultsBRS in unOSA, cpOSA and CON was, respectively (mean±sdv in ms/mmHg), at rest: 14.8±11.8, 15.8±17.0, 16.1±11.3; during handgrip 13.3±7.6, 12.7±8.4, 16.4±8.7; and during Valsalva 12.7±8.0, 11.5±6.6, 15.1±8.9. BRS was lower in cpOSA than CON for handgrip (p=0.04) and Valsalva (p=0.03). BRS was negatively correlated with BPV in unOSA during Valsalva and handgrip for cpOSA, both R=−0.4 (p=0.02). BRS was negatively correlated with OSA severity (levels: none, mild, moderate, severe) at R=−0.2 (p=0.04,n=104). ConclusionsAs expected, BRS was lower and BPV higher in OSA during the pressor challenges, and disease severity negatively correlated with BRS. In this cross-sectional study, both CPAP-treated (self-reported) and untreated OSA showed reduced BRS, leaving open whether within-person CPAP improves BRS.

Reliability of measuring resting spontaneous cardiac baroreflex sensitivity using short sampling durations in healthy humans: Impact of central blood volume mobilization

IntroductionCalculation of spontaneous cardiac baroreflex sensitivity (cBRS) is used commonly to quantify arterial baroreflex buffering of beat‐to‐beat changes in blood pressure (BP). Studies report large interindividual variability in resting cBRS, which may be exacerbated by the supine posture and the use of shorter sampling duration (1‐3 min). However, this has yet to be reported in humans. Therefore, the purpose of the present study was to examine the impact of sampling duration on the intratest reliability of resting cBRS in healthy subjects. To accomplish this, we sought to compare resting cBRS derived from a standard 10‐min epoch (control) with values sampled over 7, 5, 3, and 1 min epoch durations. In addition, we examined the impact of central blood volume (CBV) mobilization on intratest reliability of resting cBRS.MethodsIn 30 healthy subjects (28 men; 22±3yrs) beat‐to‐beat measurements of BP and heart rate were recorded for 10‐min during both sitting and supine position. The cBRS was derived by sequence technique. Randomly selected epochs of 1‐min, 3‐min, 5‐min and 7‐min were then compared to the 10‐min control. To calculate the relative and absolute reliability we analyzed the technical error of the measurement (TEM), the intraclass correlation coefficients (ICC), Bland‐Altman analysis and coefficient of variations (CV). To test the impact of CBV mobilization on resting cBRS, ten subjects were also randomized to a non‐hypotensive lower body negative pressure (LBNP) trial at ‐20mmHg.ResultscBRS was lower in the sitting position than in the supine position (P&lt;0.01). All cBRS values were similar between each sampling duration compared to the 10‐min control (P&gt;0.12). The ICC obtained for cBRS ranged from very good to excellent in the supine position, whereas in the sitting position values demonstrated excellent between‐sampling duration reliability. The absolute and relative TEM increased with a shorter sampling duration (Table 1). In the LBNP trial, no significant differences in cBRS were observed within sampling durations in the LBNP trial (P=0.27). No significant differences in cBRS were observed between supine LBNP, sitting and supine positions (P=0.17). During LBNP trial, TEM increased with shorter sampling durations [10 vs. 7‐min: 0.7 ms/mmHg (4%), 10 vs. 5‐min: 1.4 ms/mmHg (8%), 10 vs. 3‐min: 1.9 ms/mmHg (11%), 10 vs. 1‐min: 3.1 ms/mmHg (17%), which was similar to the sitting position when compared to the supine posture.ConclusionOur findings show that 1) reliability decreased progressively using the 3‐ and 1‐min sampling durations; 2) the sitting position provides more reliable measures than all epoch durations measured in the supine position and; 3) the increases in the limits of agreement with shorter durations were attenuated by supine LBNP, suggesting that a cardiopulmonary baroreflex mechanism may play a role in the level of variability in resting cBRS.

Spontaneous Cardiovagal Baroreflex Sensitivity in Females with Multiple Sclerosis

Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system that is known to disrupt autonomic function. Females with MS are at an increased risk of cardiovascular disease partly due to altered autonomic regulation of arterial blood pressure. Longitudinal data suggest that low spontaneous cardiovagal baroreflex sensitivity is a predictor of cardiovascular disease. Therefore, the purpose of this investigation is to test the hypothesis that spontaneous cardiovagal baroreflex sensitivity (cBRS) is less in females with MS compared to healthy controls. Electrocardiogram (ECG) and beat‐to‐beat blood pressure (Finometer) were continuously recorded during 10 minutes of quiet supine rest in 3 females with relapsing‐remitting MS (Expanded Disability Scale Score &lt; 6.0) and 3 sex‐, age‐, height‐, weight‐ and race‐ matched healthy controls. Spontaneous cBRS was determined using the sequence method (CardioSeries v2.7). Spontaneous cBRS gain is calculated as the average slope of the relationship between R‐R interval and systolic blood pressure from individual sequences of 3 or more consecutive cardiac cycles where both variables are increasing (up‐up sequences) or decreasing (down‐down sequences). Females with MS had similar resting mean arterial pressures (P=0.55), systolic blood pressures (P=0.53) and heart rates (P=0.18) compared to healthy controls. Overall spontaneous cBRS gain was greater in females with MS compared to healthy controls (27.1 ± 6.3 ms/mmHg vs. 18.8 ± 1.1 ms/mmHg respectively; P=0.04). Spontaneous cBRS gain from up‐up sequences was also greater in females with MS compared to healthy controls (27.6 ± 5.1 ms/mmHg vs. 17.1 ± 2.1 ms/mmHg respectively; P=0.01). Spontaneous cBRS gain from down‐down sequences trended to be greater in females with MS compared to healthy controls but was not statistically significant (27.2 ± 7.8 ms/mmHg vs. 20.1 ± 2.4 ms/mmHg respectively; P=0.10). Counter to our hypothesis, these preliminary findings in a small sample suggest that females with MS have increased spontaneous cBRS compared to healthy controls. If this relationship continues with additional data collection, it may indicate that females with MS have enhanced cardiac responses to regulate arterial blood pressure.

High‐Fat Diet and Environmentally Relevant Secondhand Smoke Co‐exposure and Cardiovascular Regulation in Mice

BACKGROUNDOver the past few decades, cardiovascular disease incidence significantly decreased by 27%. Paradoxically, the number of deaths from cardiovascular diseases increased by 42% over the same period, owing to population growth and longevity. Consequently, cardiovascular diseases remain the leading cause of global death. Cardiovascular diseases are complex, multifactorial diseases that cannot be ascribed to a single factor. High‐fat diet (HFD) and secondhand smoke (SHS) are two preventable risk factors for the development of cardiovascular diseases. Studies have shown that SHS exposure is associated with poor dietary habits, suggesting the importance of potential confounding diet effects on health effects of SHS exposure. We previously showed that, in mice, environmentally relevant SHS exposure resulted in 10% decrease in baroreflex sensitivity (BRS) and 13% decrease in measures of heart rate variability (HRV). Here, we sought to characterize how HFD interplay with SHS in inducing cardiovascular dysfunction.METHODSMale C57BL/6J mice (11 wk) implanted with BP/ECG telemetry devices were fed with either normal diet (ND, 13.6 kcal% fat) or HFD (60 kcal% fat) and exposed to either filtered air (FA) or SHS (3 mg/m3, 6 hr/d, 5 d/wk) for 11 weeks. 36‐hr continuous BP/ECG recordings were performed. Data were divided into three 12‐hour periods: the first dark cycle (dark 1) immediately after the last day of exposure, and the following light and dark (dark 2) cycles. Spontaneous baroreflex sensitivity (BRS) was determined with the sequence method. Standard time domain heart rate variability (HRV) parameters were obtained from normal‐to‐normal R‐R intervals.RESULTSHFD‐fed mice had significantly greater weight gain than ND‐fed group (+15.3 g and +2.8 g over 11 weeks, HFD and ND, respectively). SHS exposure had no effect on body weight. Compared to ND mice, HFD mice had significantly higher BP (~6.5 mmHg), HR (~98 bpm), and lower BRS (~15% decrease) in the light cycle. Furthermore, HFD significantly reduced overall and short‐term HRV (36% and 47% reduction for SDNN and rMSSD, respectively, p &lt; 0.05) across all three light cycles. The reduction in HRV is unlikely due to a higher HR in HFD mice because normalizing the HRV measures to baseline R‐R intervals did not change the results. SHS exposure did not pose additional effects on these HFD‐induced changes. While HFD alone did not affect BP variability, co‐exposure of SHS and HFD significantly increased BP variability during the first dark cycle (16.8%, 15.6%, and 17.3% higher than HFD+FA group, for systolic, diastolic, and mean BP variability, respectively, p &lt; 0.05), suggesting a co‐exposure‐induced BP dysregulation.CONCLUSIONSThis study emphasizes the importance of accounting for differences in diet when studying the cardiovascular effects of SHS.

Increased Muscle Sympathetic Nerve Activity with Acute Hyperinsulinemia: Role of Insulin‐stimulated Peripheral Vasodilation and the Response of the Arterial Baroreflex

ObjectiveHyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP).MethodsIn 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m2) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s).ResultsInsulin infusion increased MSNA (p=0.05) and decreased TPR (p&lt;0.05), with no effects on arterial baroreflex sensitivity or BP (p&gt;0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p&gt;0.05). Similar to insulin, SNP increased MSNA (p&lt;0.01) and decreased TPR (p&lt;0.05), with no effect on baroreflex sensitivity (p&gt;0.05).ConclusionsPresent findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

Different Relationship Between Glycemic Status and Autonomic Function in Patients with Type 2 Diabetes Mellitus and in Healthy Controls

Autonomic neuropathy is a common complication in diabetes mellitus (DM). Decreased vagal nerve activity and augmented sympathetic nerve activity have been reported in patients with DM. However, the relationship between autonomic function and glycemic status in DM and in individuals without DM remains unclear. We hypothesized that indices of sympathetic and vagal nerve activity are related to glycemic status. Eleven patients who were clinically diagnosed with type‐2 DM (HbA1c, 6.8 ± 0.3%; age, 54 ± 3 yrs), and 20 healthy non‐DM individuals (including 10 pre‐DM; HbA1c &lt; 6.5%; range 5.1‐6.1%; age, 59 ± 2 yrs) were studied (19 male, 12 female). Five DM patients had hypertension. Patients with DM and hypertensives were treated with standard medications. Beat‐by‐beat blood pressure (BP), heart rate (HR) and muscle sympathetic nerve activity (MSNA) were recorded under resting conditions. HR variability (HRV) was calculated and spontaneous cardiovagal baroreflex sensitivity (CBRS) was evaluated with the sequence method. CBRS in DM was lower than in non‐DM subjects (P &lt; 0.05). MSNA in DM was also lower than in non‐DM subjects (P &lt; 0.05). In linear regression analyses with data from all subjects, CBRS was negatively correlated with fasting blood glucose (FBG) (R = ‐0.47), insulin (R = ‐0.42), and homeostasis model assessment of insulin resistance (HOMA‐IR) (R = ‐0.43) (P &lt; 0.05 for all). MSNA was negatively correlated with HbA1c and HOMA‐IR (R = ‐0.41, ‐0.42, respectively; both, P &lt; 0.05). The high frequency (HF) component of HRV (i.e., an index of vagal tone) was negatively correlated with insulin (R = ‐0.46) and HOMA‐IR (R = ‐0.42) in all subjects (P &lt; 0.05 for both). In non‐DM subjects, CBRS was negatively correlated with FBG (R = ‐0.53, P &lt;0.05). HF was negatively correlated with FBG (R = ‐0.51), insulin (R = ‐0.66), and HOMA‐IR (R = ‐0.66) (P &lt; 0.05 for all), but MSNA was not correlated with glycemic/insulin status in non‐DM subjects. Whereas in DM patients, MSNA tended to be negatively correlated with HOMA‐IR (R = ‐0.77, P = 0.07). In the present study, both MSNA and vagal activity (CBRS and HF) were decreased in relation to the glycemic/insulin status. Vagal nerve activity was associated with the glycemic/insulin status even in non‐DM subjects (i.e., healthy and pre‐DM). Based on these results, we speculate that both vagal and sympathetic nerves were injured by DM progression, and that vagal neuropathy preceded the sympathetic neuropathy. Our results differ from prior reports that showed that MSNA in DM was higher than in non‐DM. However, in our study subjects, the severity of DM was mild, and except for hypertension in 5 subjects, none had manifestations of diabetic end‐organ damage. Differences in the duration and severity of DM as well as the effects of the treatments could contribute to the differences in the results. Further studies on the autonomic function during the DM progression are warranted.

Potentiation of GABAergic synaptic transmission by diazepam acutely increases resting beat-to-beat blood pressure variability in young adults.

Resting beat-to-beat blood pressure variability is a powerful predictor of cardiovascular events and end-organ damage. However, its underlying mechanisms remain unknown. Herein, we tested the hypothesis that a potentiation of GABAergic synaptic transmission by diazepam would acutely increase resting beat-to-beat blood pressure variability. In 40 (17 females) young, normotensive subjects, resting beat-to-beat blood pressure (finger photoplethysmography) was continuously measured for 5-10 min, 60 min after the oral administration of either diazepam (10 mg) or placebo. The experiments were conducted in a randomized, double-blinded, and placebo-controlled design. Stroke volume was estimated from the blood pressure waveform (ModelFlow) permitting the calculation of cardiac output and total peripheral resistance. Direct recordings of muscle sympathetic nerve activity (MSNA, microneurography) were obtained in a subset of subjects (n = 13), and spontaneous cardiac and sympathetic baroreflex sensitivity were calculated. Compared with placebo, diazepam significantly increased the standard deviation of systolic blood pressure (4.7 ± 1.4 vs. 5.7 ± 1.5 mmHg, P = 0.001), diastolic blood pressure (3.8 ± 1.2 vs. 4.5 ± 1.2 mmHg, P = 0.007), and mean blood pressure (3.8 ± 1.1 vs. 4.5 ± 1.1 mmHg, P = 0.002), as well as cardiac output (469 ± 149 vs. 626 ± 259 mL/min, P < 0.001) and total peripheral resistance (1.0 ± 0.3 vs. 1.4 ± 0.6 mmHg/L/min, P < 0.001). Similar results were found using different indices of variability. Furthermore, diazepam reduced MSNA (placebo: 22 ± 6 vs. diazepam: 18 ± 8 bursts/min, P = 0.025) without affecting the arterial baroreflex control of heart rate (placebo: 18.6 ± 6.7 vs. diazepam: 18.8 ± 7.0 ms/mmHg, P = 0.87) and MSNA (placebo: -3.6 ± 1.2 vs. diazepam: -3.4 ± 1.5 bursts/100 Hb/mmHg, P = 0.55). Importantly, these findings were not impacted by biological sex. We conclude that GABAA receptors modulate resting beat-to-beat blood pressure variability in young adults.

Combined effects of angiotensin receptor blocker use and physical training in hypertensive men

ABSTRACT Purpose Pharmacological (angiotensin II receptor type 1 receptor blocker use) and non-pharmacological treatment (physical aerobic exercise) are important strategies to reduces blood pressure and control arterial hypertension; however, only few clinical studies have evaluated their combined effects on autonomic cardiovascular control. Therefore, we investigated the effect of a combination intervention that involved losartan administration and physical aerobic training on autonomic cardiovascular control. Methods Thirty-two men (aged 40 to 60 years) were assigned into two groups: normotensive group, without any pharmacological treatment (NG, N = 16), or hypertensive group, with losartan administration (HG, N = 16). They underwent a physical aerobic training for 16 weeks, thrice a week. Hemodynamic parameters, heart rate variability (HRV), blood pressure variability, and spontaneous baroreflex sensitivity (BRS) were measured before and after training. Results Before training, both the groups showed similar values of hemodynamic parameters. However, the HG showed decreased BRS and HRV, characterized by reduction in sympathetic (p = .02) and vagal (p < .001) modulation. After training, the NG exhibited decreased heart rate (HR) at rest (p < .001), whereas the HG showed decreased HR at rest (p < .001) and blood pressure (BP) (p = .001). The HG showed decreased sympathetic modulation (p = .02) and increased BRS (p < .001) and vagal modulation (p < .001), but HRV (p < .001) and BRS gain (p < .001) remained significantly lower when compared to the NG. Conclusions Physical aerobic training was essential to improve the BRS and HRV cardiac autonomic modulation in the HG. However, it was not sufficient to normalize the analyzed autonomic parameters.