Baroreflex Control Of Heart Rate Research Articles

Arterial baroreflex control of heart rate in young and older adults and in patients with heart failure with preserved ejection fraction

Background: The arterial baroreflex (ABR) plays an important role in evoking appropriate cardiovascular adjustments in response to perturbations such as exercise. The ABR control of heart rate (HR) becomes attenuated with advancing age and in a variety of patient populations, but limited information is available in patients with heart failure with preserved ejection fraction (HFpEF). The present study tested the hypothesis that the ABR control of HR is attenuated to a greater extent in patients with HFpEF compared to older and young controls. Methods: Six patients with HFpEF (71±6 years; 35.3±6.6 kg/m2), 4 older controls (68±4 years; 25.1±3.4 kg/m2), and 7 young controls (27±4 years; 26.6±3.9 kg/m2) underwent sequential bolus infusions of sodium nitroprusside (50-100 μg) and phenylephrine (150 μg) (modified Oxford technique) to provoke acute hypotension (“BP falls”) and hypertension (“BP rises”), respectively. Cardiac baroreflex gain was quantified as the weighted linear regression slope between the R-R interval and systolic blood pressure (BP). Results: Compared to young controls (10.7±3.4 ms/mmHg), overall cardiac baroreflex gain was reduced in older controls (3.4±1.6 ms/mmHg) and patients with HFpEF (2.1±1.8 ms/mmHg) (p<0.05), with no difference between the older controls and patients with HFpEF (p=0.718). During BP falls, cardiac baroreflex gain was not different between groups (p=0.06), but was qualitatively lower in patients with HFpEF (0.6±1.5 ms/mmHg) compared to young (5.3±5.5 ms/mmHg) and older controls (5.2±1.9 ms/mmHg). During BP rises, cardiac baroreflex gain was not different between older controls (2.6±0.8 ms/mmHg) and patients with HFpEF (2.3±2.0 ms/mmHg) (p>0.05); however, responses in patients with HFpEF were attenuated compared to young controls 10.7±5.8 ms/mmHg) (p<0.05). Conclusion: These findings suggest an age-related attenuation in the overall ARB control of HR that does not appear to be further exacerbated in patients with HFpEF. However, patients with HFpEF may exhibit a selective attenuation in ABR-mediated tachycardia in response to acute reductions in BP that may pose an increased risk of hypotension and frank syncope. This work was funded in part by the U.S. Department of Veterans Affairs (RX001311, to D.W.W.; IK2RX003670, to K.B.). 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.

Arterial Baroreflex Control of Heart Rate in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) patients have greater blood pressure reactivity to acute cardiovascular stressors and a higher prevalence of hypertension; however, limited information is available regarding the potential role of impaired baroreflex control in non-dialysis CKD patients. The baroreflex plays a homeostatic role in beat-to-beat blood pressure (BP) regulation and impaired cardiac baroreflex sensitivity (cBRS) has been associated with increased blood pressure reactivity and cardiovascular events. However, previous studies in CKD have shown mixed results or have been confounded with co-morbid conditions such as hypertension. Therefore, the aim of the present study was to test the hypothesis that baroreflex control of heart rate (HR) is attenuated in patients with CKD compared to hypertensive controls. Additionally, we tested whether cardiovascular risk factors such as age, arterial stiffness, and BMI are associated with cBRS in patients with CKD. In 15 stage III-IV CKD patients [7 male/8 female, age: 60±10 yr, 14 Black/1 White, systolic/diastolic BP: 145.1±20/71.9 ± 10 mmHg, 100% hypertensive, BMI: 31±5 kg/m2] and 5 matched controls [5 male/0 female, age: 56 ± 4 yr, 5 Black/0 White, systolic/diastolic BP: 130.6± 24/69.0 ±15 mmHg, 100% hypertensive, BMI: 34±4 kg/m2], continuous beat-to-beat BP (finger photoplethysmography) and HR (electrocardiography) were recorded while resting supine for 5-minutes. We utilized the sequence technique in which the slopes of the systolic BP and RR interval relationships were calculated and averaged for a measure of cBRS. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) using tonometry. Systolic beat-to-beat BP (CKD 145.1±20 vs. CT 130.6± 24 mmHg, P = 0.184) and HR (CKD 64.2 ± 7 vs. CT 67.5 ± 6 beats/min, P = 0.352) were similar between groups. Likewise, no differences in spontaneous cBRSall (CKD 10.495 ± 5 vs. CT 8.800 ± 3 ms/mmHg, P = 0.487), cBRSup (CKD 9.138 ± 5 vs. CT 9.776 ± 3 ms/mmHg, P = 0.778) and cBRSdown (CKD 11.238 ± 6 vs. CT 8.218 ± 3 ms/mmHg, P = 0.267) were observed. No significant correlations were observed between cBRS with age, BMI, PWV, or eGFR. In summary, contrary to our hypothesis, our preliminary data suggest that CKD does not worsen cBRS compared to age- and co-morbidity-matched controls, but greater sample size is needed to support our results. Funded by American Physiological Society, NIH R01HL135183, NIH R61 AT10457, and VA Merit I01CX001065. 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.

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.

Hemorrhage Hypotension Influences on Plasma Glucose Concentration: A New Approach for Evaluating Baroreflex Effects on Metabolic Adjustments

The present study shows that hyperglycemic response to hemorrhage is an easy method for evaluating metabolic adjustments in normal rats and in other models that show autonomic and metabolic imbalances. In this regard, the baroreflex control of hyperglycemic response induced by hemorrhage hypotension was evaluated by removing blood through the jugular catheter (1.2 mL/100g b.w./ 2 min). Blood samples (0.2mL) were collected immediately before hemorrhage and at 5, 10, 20 and 30 minutes after hemorrhage [1, 2]. In addition, the baroreflex control of heart rate was assessed by pharmacological test, using intravenous doses of phenylephrine hydrochloride (PE, 10 μg/mL) and sodium nitroprusside (SNP, 10 μg/mL) in random order. Heart rate and blood pressure were measured through the insertion of a polyethylene catheter inserted into the abdominal aorta through the left femoral artery. The derived variables of baroreflex control to heart rate and hemorrhage hyperglycemia response were measured according to the following equation: Y = A1/{1+ exp[A2(X - A3)]} + A4. The evaluation of a new approach for studying the baroreflex effects on metabolic adjustments was done with animals fed with a hypercaloric diet. Hypercaloric diet induced an upward shift in the baroreflex curve to heart rate (p<0.05) and an increased heart rate reflex due to the change in MAP during the operating range (p<0.05). It also shifted the baroreflex curve to a higher level of hyperglycemic response to hemorrhage (p<0.05), as well as, increased maximal gain (p<0.05) and augmented hyperglycemic response to hemorrhage hypotension during the operating range (p<0.05). Therefore, we propose that the baroreflex control of hyperglycemic response should be a useful tool for evaluating metabolic dysfunction related to hemorrhage in models of animals that show autonomic imbalance, such as malnutrition, hypertension, diabetes and obesity.

181-OR: Sympathetic Activity in Patients with Type 2 Diabetes Mellitus Treated with Empagliflozin or Hydrochlorothiazide

Changes in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose transporter (SGLT2) inhibition on cardiovascular outcomes. We hypothesized that SGLT inhibition with empagliflozin lowers sympathetic activity compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from non-specific responses to increased natriuresis. In this double-blind, randomized study patients with type 2 diabetes mellitus on metformin monotherapy received either 25 mg/day empagliflozin (n=20) or 25 mg/day HCT (n=21) for 6 weeks. Muscle sympathetic nerve activity (MSNA) , blood pressure, cardiovascular, and metabolic biomarkers were assessed at baseline and end of treatment. Empagliflozin significantly increased urinary glucose excretion (difference in change from baseline 47.4 mmol/l vs. HCT) , reduced fasting plasma glucose (-1.91 mmol/l) , HbA1c (-0.58%) , and body weight (-1.23 kg, all p<0.05) . Office systolic blood pressure decreased with both treatments. MSNA (burst frequency -1.95 [95% confidence interval -8.67; 4.78] bursts/min) , baroreflex heart rate control (0.84 [-1.18; 2.87] ms/mmHg) and plasma catecholamines did not change significantly with either treatment. MSNA increased with higher body weight loss with both treatments, but more pronounced and significant only with HCT (p=0.0015) . In conclusion, neither empagliflozin nor HCT treatment led to clinically relevant changes in sympathetic activity. Given the important role of the sympathetic nervous system in the progression of cardiovascular disease, mechanisms attenuating sympathetic activity in the face of increased sodium excretion deserve further attention. Disclosure K.Heusser: None. J.Tank: None. A.Fischer: None. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.Jordan: Consultant; Novo Nordisk, Other Relationship; Eternygen, Research Support; Boehringer Ingelheim International GmbH.

Pleural pressure during sleep in Marfan syndrome: details about the CPAP effect.

Pleural pressure during sleep in Marfan syndrome: details about the CPAP effect.

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.

Role of linkage between cerebral activity and baroreflex control of heart rate via central vasopressin V1a receptors in food-deprived mice.

We previously reported that cerebral activation at the onset of voluntary locomotion suppressed baroreflex control of heart rate (HR) and increased arterial pressure via vasopressin V1a receptors in the brain. Here, we examined whether these responses were associated with food seeking, a motivated behavior, using free-moving wild type (WT, n = 10), V1a receptor knockout (KO, n = 9), and wild-type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n = 10). For three consecutive days, mice were fed ad libitum (Fed), food deprived (FD), and refed (RF) under a dark/light cycle (1900/0700). Food was removed on day 2 and restored on day 3 at 1800. Throughout the protocol, cerebral activity was determined from the power density ratio of θ- to δ-wave band (θ/δ) by electroencephalogram every 4 s. Baroreflex was evaluated by the cross-correlation function [R(t)] between changes in HR and arterial pressure every 4 s. The cerebro-baroreflex linkage was then evaluated by the cross-correlation function between θ/δ and R(t). Behavior was recorded with CCD camera. We found that cerebro-baroreflex linkage, enhanced in WT at night after FD (P = 0.006), returned to Fed level after RF (P = 0.68). Similarly, food-seeking behavior increased after FD to a level twofold higher than during Fed (P < 0.001) and returned to Fed level after RF (P = 0.54). However, none of these changes occurred in KO or BLK (P > 0.11). Thus, the suppression of baroreflex control of HR linked with cerebral activation via central V1a receptors might play an important role at the onset of motivated behaviors, such as food seeking induced by FD.NEW & NOTEWORTHY Motivated behaviors, characterized by goal-directed and persistent movements, are indispensable for living. However, how cerebro-cardiovascular adjustment occurs during such behaviors remains unknown. By focusing on food-seeking behavior in a food-deprived condition using free-moving mice, we found that this condition enhanced the linkage between cerebral activation and suppression of baroreflex control of heart rate through central vasopressin V1a receptors, making it easier to start motivated behaviors by enhancing pressor response.

Maybe angiotensin II is getting on our nerves, and the role of exercise.

Maybe angiotensin II is getting on our nerves, and the role of exercise.

Blunted Cardiac Response to Head-up Tilt Occurs in Sickle Cell Disease but Not Healthy Controls

Introduction: Sickle cell disease (SCD) is characterized by microvascular occlusion from sickled red blood cells that can develop into full-blown vaso-occlusive crisis. We hypothesize that abnormal autonomic function plays a role in promoting microvascular occlusion in SCD. Head-up tilt (HUT) evokes a strong sympathetic response to the transient drop in blood pressure resulting from blood pooling in the lower extremities. Baroreflex regulation leads to heart rate (HR) increase and peripheral vasoconstriction. In this study, we subjected control and SCD subjects to the HUT test to assess their autonomic response.Objective: To evaluate the autonomic response and determine the relative contributions of the cardiac and peripheral vascular responses to HUT in SCD compared to control subjects.Experimental Protocols: 22 SCD and 17 control (healthy and sickle cell trait) subjects were recruited at Children's Hospital Los Angeles. Each subject laid supine on the tilt table for 5 minutes prior to being tilted up to 70° for 7 minutes, and subsequently returned to supine. Electrocardiogram, respiration, continuous blood pressure and photoplethysmograph (PPG) were measured continuously throughout the protocol. PPG amplitude was taken to represent peripheral blood flow (PBF) since reductions in PPG amplitude reflect vasoconstriction.Analysis: Mean systolic blood pressure (SBP), HR and PBF were calculated over 2 minutes under baseline and HUT conditions. In HUT, we analyzed the physiological responses following 3 minutes of stabilization. Heart rate variability indices: high frequency power (HFP) and low-to-high ratio (LHR), reflecting parasympathetic activity and sympatho-vagal balance respectively, were also computed. Percent change from baseline of all parameters were computed to assess the tilt response after adjusting for their baseline values.Results: There was not a significant change in SBP from baseline to HUT across all subjects. To maintain blood pressure, the response to HUT was categorized into 3 groups: 1) those who had increased HR (>15%) AND decreased PBF (>20%) from baseline, 2) those who only had increased HR, and 3) those who only had decreased PBF (Fig.1). While Group 1 and 2 responses were found in both controls and SCD, Group 3 responses consisted only of SCD subjects (Table 1). Although mean HR at baseline was not different from the other two groups, we found that HFP of Group 3 was lower compared to Group 1 (p = 0.0007) and Group 2 (p = 0.0396), while Group 3 LHR was higher than Group 1 (p = 0.0020).Discussion & Conclusions: HUT is standard and well-recognized assessment of the autonomic response to transient drop in blood pressure. While most subjects maintained their SBP by increasing both HR and peripheral resistance, a subset of SCD subjects responded to HUT via only peripheral vasoconstriction. Moreover, these SCD subjects had significantly lower parasympathetic HR modulation at baseline as reflected by lower HFP and higher LHR, an index of sympatho-vagal balance. The findings suggest that baroreflex control of heart rate during HUT in this subset of SCD subjects was blunted due to low vagal and high cardiac sympathetic tone, whereas baroreflex control of peripheral vascular resistance remained relatively intact. These data provide further evidence that there is significant autonomic dysfunction in some patients with SCD. This hypersensitivity to vasoconstriction would decrease microvascular flow and would likely lead to vaso-occlusion. We speculate that this subset of SCD subjects may also be the most vulnerable to reduced PBF and thus VOC during orthostatic stress. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Assessment of Heart Rate Baroreflex Control during Veloergometric Exercises with Different Intensities

Assessment of Heart Rate Baroreflex Control during Veloergometric Exercises with Different Intensities

Central Ang II (Angiotensin II)-Mediated Sympathoexcitation: Role for HIF-1α (Hypoxia-Inducible Factor-1α) Facilitated Glutamatergic Tone in the Paraventricular Nucleus of the Hypothalamus.

Central infusion of Ang II (angiotensin II) has been associated with increased sympathetic outflow resulting in neurogenic hypertension. In the present study, we appraised whether the chronic increase in central Ang II activates the paraventricular nucleus of the hypothalamus (PVN) resulting in elevated sympathetic tone and altered baro- and chemoreflexes. Further, we evaluated the contribution of HIF-1α (hypoxia-inducible factor-1α), a transcription factor involved in enhancing the expression of N-methyl-D-aspartate receptors and thus glutamatergic-mediated sympathetic tone from the PVN. Ang II infusion (20 ng/minute, intracerebroventricular, 14 days) increased mean arterial pressure (126±9 versus 84±4 mm Hg), cardiac sympathetic tone (96±7 versus 75±6 bpm), and decreased cardiac parasympathetic tone (16±2 versus 36±3 versus bpm) compared with saline-infused controls in conscious rats. The Ang II-infused group also showed an impaired baroreflex control of heart rate (-1.50±0.1 versus -2.50±0.3 bpm/mm Hg), potentiation of the chemoreflex pressor response (53±7 versus 30±7 mm Hg) and increased number of FosB-labeled cells (53±3 versus 19±4) in the PVN. Concomitant with the activation of the PVN, there was an increased expression of HIF-1α and N-Methyl-D-Aspartate-type1 receptors in the PVN. Further, Ang II-infusion showed increased renal sympathetic nerve activity (20.5±2.3% versus 6.4±1.9% of Max) and 3-fold enhanced renal sympathetic nerve activity responses to microinjection of N-methyl-D-aspartate (200 pmol) into the PVN of anesthetized rats. Further, silencing of HIF-1α in NG108 cells abrogated the expression of N-methyl-D-aspartate-N-methyl-D-aspartate-type1 induced by Ang II. Taken together, our studies suggest a novel Ang II-HIF-1α-N-methyl-D-aspartate receptor-mediated activation of preautonomic neurons in the PVN, resulting in increased sympathetic outflow and alterations in baro- and chemoreflexes.

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.

Blood pressure profile, sympathetic nervous system activity, and subclinical target organ damage in patients with polycythemia vera.

Polycythemia vera (PV) is a rare myeloproliferative disease associated with an increased prevalence of hypertension and increased risk of cardiovascular complications. However, the precise mechanisms leading to the elevation of blood pressure (BP) and secondary target organ damage remain poorly understood. The study aimed to evaluate BP profile, assess the activity of the sympathetic nervous system and the renin‑angiotensin system, and provide a comprehensive assessment of subclinical target organ damage in patients with PV. Twenty consecutive patients with newly diagnosed PV and 20 control subjects were included. The following were assessed: BP, levels of catecholamines, urinary and plasma O‑methylated catecholamine metabolites, concentrations of aldosterone and renin. We also assessed microneurography sympathetic nervous system activity (MSNA) and baroreflex control of heart rate as well as subclinical target organ damage. At similar levels of BP, BP variability was decreased in the PV group (mean [SD] 24‑hour systolic BP, 9 [3] vs 12 [3] mm Hg; P = 0.003). Patients with PV had lower norepinephrine excretion (mean [SD], 16.54 [6.32] vs 25.46 [12.88] μg/d; P = 0.03) as well as decreased MSNA as assessed by microneurography compared with controls (mean [SD] MSNA, 30.7 [8.7] bursts/min vs 38.7 [5.4] bursts/min; P = 0.007 and MSNA 51.8 [11] bursts/100 beats vs 61.1 [11.3] bursts/100 heart beats; P = 0.04). Baroreflex control of HR was unaltered in the PV group. Increased hemoglobin levels and red blood cell count correlated with decreased retinal capillary flow in patients with PV. Patients with PV, characterized by high hemoglobin concentrations and hematocrit levels had lower sympathetic nervous activity and decreased BP variability as compared with controls. There was no relationship between hemoglobin plasma concentration, hematocrit level, and target organ damage.

Blood Pressure Maintained in Response to a Hypotensive Stimulus During Mild Acute Inflammation

IntroductionSevere acute inflammation such as sepsis disrupts autonomic nervous system function and jeopardizes blood pressure regulation. Severe experimental inflammation (endotoxin) blunts the vascular baroreflex to increase muscle sympathetic nerve activity in response to reductions in blood pressure and abolishes baroreflex control of heart rate. Whether mild acute inflammation alters the ability to maintain blood pressure and peripherally vasoconstrict during a hypotensive challenge is unknown.PurposeDetermine whether mild acute inflammation alters the ability to maintain blood pressure and peripherally vasoconstrict during lower body negative pressure (LBNP).MethodsThirteen young, healthy adults (26 ± 4.5 yrs; male n=5; 21.3 ± 2.0 kg/m2) completed assessments before (baseline) and 24h after the induction of acute inflammation via typhoid vaccination. Measures were completed after 10 min rest (rest) and after 2 minutes of equilibration to −20 mmHg of LBNP. Measures included brachial blood flow via ultrasonography and brachial blood pressure and heart rate via an automatic blood pressure cuff. Conductance was calculated as blood flow/mean arterial pressure (MAP). ELISAs were performed on serum blood samples from baseline and 24h to assess inflammatory markers C‐reactive protein (CRP) and interleukin‐6 (IL‐6).ResultsAcute inflammation was evident at 24h by increases in IL‐6 (0.98 ± 0.55 to 1.78 ± 0.68 pg/mL, p&lt;0.01) and CRP (0.42 ± 0.98 to 1.30 ± 1.44 mg/L, p=0.02). Acute inflammation did not alter the blood flow, conductance, diameter, or MAP response to LBNP (see table , p for interactions &gt;0.05). Blood flow, conductance, and velocity were lower during LBNP compared to rest (p&lt;0.01) whereas brachial diameter and MAP were maintained (p&gt;0.05). Heart rate was elevated at 24h and increased during LBNP at baseline (p&lt;0.01) but did not change during LBNP at 24h (interaction p&lt;0.01).ConclusionThe ability of young adults to respond to a hypotensive challenge and maintain blood pressure was preserved during mild acute inflammation, however, the heart rate response was altered. Our data may suggest that mild acute inflammation alters baroreflex control of the heart rate response to a hypotensive challenge. Hemodynamic response to LBNP at baseline and during acute inflammation. Baseline 24H p‐value Rest LBNP Rest LBNP Visit LBNP Interaction Brachial blood flow, mL/min 47.0 ± 14.4 40.8 ± 11.8 45.4 ± 14.2 42.0 ± 16 0.94 0.04 0.56 Conductance, mL/min/mmHg 52.2 ± 15.5 44.7 ± 11.9 49.8 ± 14.3 46.5 ± 16.6 0.93 0.03 0.46 Brachial diameter, mm 3.81 ± 0.85 3.83 ± 0.87 3.89 ± 0.84 3.81 ± 0.81 0.46 0.62 0.12 Mean velocity, cm/s 7.5 ± 3.3 6.4 ± 2.9 6.8 ± 3 6.4 ± 2.6 0.35 0.04 0.44 MAP, mmHg 90 ± 9 91 ± 8 91 ± 6 90 ± 7 0.81 0.87 0.23 Heart rate, bpm 52 ± 11 57 ± 11 56 ± 12 57 ± 12 0.08 &lt;0.01 &lt;0.01 Data mean ± standard deviation. MAP, mean arterial pressure.

Chapter 3 - Adaptations in autonomic nervous system regulation in normal and hypertensive pregnancy

There is an increase in basal sympathetic nerve activity (SNA) during normal pregnancy; this counteracts profound primary vasodilation. However, pregnancy also impairs baroreflex control of heart rate and SNA, contributing to increased mortality secondary to peripartum hemorrhage. Pregnancy-induced hypertensive disorders evoke even greater elevations in SNA, which likely contribute to the hypertension. Information concerning mechanisms is limited. In normal pregnancy, increased angiotensin II acts centrally to support elevated SNA. Hypothalamic sites, including the subfornical organ, paraventricular nucleus, and arcuate nucleus, are likely (but unproven) targets. Moreover, no definitive mechanisms for exaggerated sympathoexcitation in hypertensive pregnancy have been identified. In addition, normal pregnancy increases gamma aminobutyric acid inhibition of the rostral ventrolateral medulla (RVLM), a key brainstem site that transmits excitatory inputs to spinal sympathetic preganglionic neurons. Accumulated evidence supports a major role for locally increased production and actions of the neurosteroid allopregnanolone as one mechanism. A consequence is suppression of baroreflex function, but increased basal SNA indicates that excitatory influences predominate in the RVLM. However, many questions remain regarding other sites and factors that support increased SNA during normal pregnancy and, more importantly, the mechanisms underlying excessive sympathoexcitation in life-threatening hypertensive pregnancy disorders such as preeclampsia.

Dynamical interaction between heart rate and blood pressure of end-stage renal disease patients evaluated by cross recurrence plot diagonal analysis.

The assessment of spontaneous variability of blood pressure and heart rate is based on specific physiological hypotheses about dynamic features, for example, the baroreflex modulation of heart rate over time in daily life. Usually, arterial baroreflex control of heart rate is explored without delays between blood pressure and heart rate data points, within a narrow range of values, excluding the analysis of saturation regions or low-threshold changes. In this work, we examine the dynamic interactions between systolic blood pressure (SBP) and interbeat interval (IBI), in 15-min length time series and for the first time using the analysis of diagonals derived from a cross-recurrence plots in healthy persons and end-stage renal disease (ESRD) patients. We found that ESRD patients have stronger intermittent dynamical interactions between IBI and SBP, but they lose most of the dynamical interactions. Although healthy subjects exhibit a continuously changing order of precedence between IBI and SBP at different lags, ESRD patients preserve this changing order of precedence only for lags >0 beats.NEW & NOTEWORTHY This study is the first to compare the time-variant pattern of systolic blood pressure (SBP) and interbeat interval (IBI) coupling between ESRD patients and healthy volunteers through the analysis of diagonal in cross-recurrence plots, and in the face of an orthostatic challenge. Our results demonstrated alternant interactions on the order of precedence (IBI → SBP or SBP→ IBI) at different time delays. This pattern is different in resting position and during active standing for the two groups studied, and interestingly, some association patterns are lost in ESRD patients. These patterns of alternant interactions on the order of precedence could be related to autonomic neural activities and cardiovascular synchronization at different scales both in time and space. This could reflect physiological adaptive flexibility of cardiovascular regulation. Losing some association patterns in ESRD may be the result of chronic adjustments of many physiological mechanisms (including chronic sympathetic hyperactivity), which could increase cardiovascular vulnerability to hemodynamic challenges.

Impaired Baroreflex Function in an Ovine Model of Chronic Heart Failure Induced by Multiple Coronary Microembolizations.

Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF. HF was induced by infusion of microspheres (45 micron; 1.3 ml) into the proximal left coronary artery or left descending coronary arteries, with three sequential embolizations over 3 weeks. Twelve to 14 weeks after the final embolization, and when ejection fraction had decreased below 45%, animals were instrumented to record blood pressure and heart rate. Baroreflex control of heart rate was investigated in conscious animals. Additionally, pressure-volume loops were constructed under anesthesia. Embolization-induced HF was associated with a decrease in mean arterial pressure (67 ± 2 vs. 85 ± 4 mmHg, p < 0.05), an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05), and a significant increase in left ventricular end-diastolic pressure (11.4 ± 2 vs. 6.2 ± 1 mmHg, p < 0.01). Under conscious conditions, there was a significant decrease in the gain (−8.2 ± 2 vs. −4.1 ± 1 beats/min/mmHg, p < 0.05) as well as the lower plateau of the baroreflex in HF compared to control animals. HF was also associated with significantly increased respiratory rate (107 ± 4 vs. 87 ± 4 breaths/min, p < 0.01) and incidence of apneas (520 ± 24 vs. 191 ± 8 apnea periods >4 s, p < 0.05), compared to control sheep. The microembolization model of heart failure is associated with an increase in left ventricular end-diastolic pressure, impaired cardiac function, and altered baroreflex control of the heart. These findings suggest this chronic model of HF is appropriate to use for investigating interventions aimed at improving neural control in HF.

Melatonin attenuates renal sympathetic overactivity and reactive oxygen species in the brain in neurogenic hypertension.

Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.

The Baroreflex Control of Heart Rate is Impaired in Patients with Peripheral Arterial Disease

Prior reports suggest that exercise pressor reflex is heightened in peripheral arterial disease (PAD). It is unclear if PAD alters the baroreflex. We hypothesized that the sensitivity of baroreflex (BRS) control of heart rate (HR) in PAD patients would be lower than that in healthy control subjects. We studied 12 PAD patients (8 M, 4 F, 66 ± 2 yrs), and 10 healthy control subjects (7 M, 3 F, 65 ± 2 yrs). The ankle‐brachial pressure index in the most affected leg in the patients was 0.64 ± 0.03. ECG and beat‐by‐beat blood pressure (BP, Finometer) were recorded for 10 min under resting condition. Thereafter, the subjects performed rhythmic plantar flexion with incremental loading (2–12 kg, +1 kg/min) until the subject reached fatigue or exercised for a maximum of 14 min. The PAD patients performed the exercise with the most affected leg. The cardiac BRS was estimated with the sequence technique. The HR variability (HRV) indices were also calculated. Under resting conditions, cardiac BRS in PAD patents was significantly lower than that in the control subjects (5.5 ± 0.7 vs. 12.0 ± 2.3 ms/mmHg, P=0.008). The resting time domain HRV in PAD patents was also lower than in healthy subjects. Plantar flexion exercise induced BP response was greater at end exercise in PAD patients than that in healthy control subjects. Interestingly, plantar flexion exercise tended to decrease cardiac BRS in healthy subjects, whereas it tended to increase cardiac BRS in PAD patients. The plantar flexion exercise decreased the time domain HRV index (last 5 min) in the both groups. We speculate that the decreased cardiac BRS as well as the attenuated vagal tone (i.e. lower HRV) indicate that autonomic function is impaired in PAD. Further studies are needed to examine if exercise training in PAD alters the baroreflex function.Support or Funding InformationSupported by National Institutes of Health Grants P01 HL134609 (Sinoway), UL1 TR002014 (Sinoway), and Pennsylvania Department of Health Tobacco CURE Funds SAP#4100079742 (Cui).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.