Low-frequency Blood Pressure Variability Research Articles

Noninvasive Biomarkers for Cardiovascular Dysfunction Programmed in Male Offspring of Adverse Pregnancy.

[Figure: see text].

Longitudinal Assessment of Autonomic Function during the Acute Phase of Spinal Cord Injury: Use of Low-Frequency Blood Pressure Variability as a Quantitative Measure of Autonomic Function

High-level spinal cord injury (SCI) can disrupt cardiovascular autonomic function. However, the evolution of cardiovascular autonomic function in the acute phase following injury is unknown. We evaluated the timing, severity, progression, and implications of cardiovascular autonomic injury following acute SCI. We tested 63 individuals with acute traumatic SCI (aged 48 ± 2 years) at five time-points: <2 weeks, and 1, 3, 6-12, and >12 months post-injury. Supine beat-to-beat systolic arterial pressure (SAP) and R-R interval (RRI) were recorded and low-frequency variability (LF SAP and LF RRI) determined. Cross-spectral analyses were used to determine baroreflex function (low frequency) and cardiorespiratory interactions (high frequency). Known electrocardiographic (ECG) markers for arrhythmia and self-reported symptoms of cardiovascular dysfunction were determined. Comparisons were made with historical data from individuals with chronic SCI and able-bodied controls. Most individuals had high-level (74%) motor/sensory incomplete (63%) lesions. All participants had decreased LF SAP at <2 weeks (2.22 ± 0.65 mm Hg2). Autonomic injury was defined as high-level SCI with LF SAP <2 mm Hg2. Two distinct groups emerged by 1 month: autonomically complete SCI with sustained low LF SAP (0.76 ± 0.17 mm Hg2) and autonomically incomplete SCI with increased LF SAP (5.46 ± 1.0 mm Hg2, p < 0.05). Autonomically complete injuries did not recover over time. Cardiovascular symptoms were prevalent and worsened with time, especially in those with autonomically complete lesions, and chronic SCI. Baroreflex function and cardiorespiratory interactions were impaired after SCI. Risk of arrhythmia increased immediately after SCI, and remained elevated throughout the acute phase. Acute SCI is associated with severe cardiovascular dysfunction. LF SAP provides a simple, non-invasive, translatable, quantitative assessment of autonomic function, and is most informative 1 month after injury.

Anti‐inflammatory Effect of Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation and Osteopathic Manipulative Treatment

BackgroundThe anti‐inflammatory reflex inhibits excessive pro‐inflammatory cytokine production through the parasympathetic nervous system. It has been demonstrated that non‐invasive transcutaneous auricular vagus nerve stimulation (taVNS) increases various heart rate variability (HRV)‐derived parameters that are associated with parasympathetic modulation of cardiac function. Likewise, osteopathic occipito‐atlantal decompression (OA‐D) has been demonstrated to increase HRV, consistent with increased vagal tone. However, it is not known if these interventions also inhibit inflammation. Thus, the hypothesis of this study was that noninvasive taVNS and osteopathic OA‐D decrease synthesis and/or release of pro‐inflammatory cytokines through an increase in parasympathetic nervous system activity.MethodsAdult healthy participants received OA‐D (5 min, n=7), taVNS (15 min, n=8), or no intervention (15 min, control group, n=8) on three consecutive days. Before and after these interventions, noninvasive arterial blood pressure (Finapres Finometer Pro) and the ECG were recorded continuously for 30 min. Before and after each daily experiment, saliva samples were collected for determination of salivary interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNF‐α) by ELISA.ResultsOnly in the OA‐D group, mean blood pressure decreased from the first (100±8 mmHg) to the third (93±8 mmHg, P&lt;0.05) study day. Low frequency blood pressure variability, a marker of sympathetic modulation of vascular tone, declined only in response to OA‐D (− 8.6±3.5 mmHg2, P&lt;0.05 vs. +3.8±2.9 mmHg2 in taVNS and +1.0±2.9 mmHg2 in control). RMSSD, a time domain HRV parameter that reflects parasympathetic modulation of cardiac function, increased only in response to taVNS (+5.0±1.6 ms, P&lt;0.05 vs. +2.4±4.8 ms in OA‐D and +3.1±3.8 ms in control). In control subjects the 2‐hour experimental procedure increased salivary IL‐1β (+288±84 pg/mL, P&lt;0.05) and TNF‐α (+2.5±0.3 pg/mL, P&lt;0.05). As illustrated in Fig. 1, noninvasive taVNS blunted both, the IL‐1β (+54±18 pg/mL, P&lt;0.05 vs. control) and TNF‐α (+1.5±0.3 pg/mL, P&lt;0.05 vs. control) responses, while OA‐D reduced only the IL‐1β response (+104±43 pg/mL, P&lt;0.05 vs. control).Summary/ConclusionOA‐D reduces arterial blood pressure, possibly through inhibition of sympathetic modulation of vascular function. The experimental protocol was associated with a pro‐inflammatory response as indicated by the marked increase in salivary IL‐1β and TNF‐α in the control group. This pro‐inflammatory response was inhibited by OA‐D and taVNS, although this anti‐inflammatory effect was more pronounced by taVNS that blunted both, the IL‐1β and TNF‐α responses, while OA‐D only reduced the IL‐1β response. The increase in RMSSD associated with taVNS suggests that taVNS inhibits inflammation through the parasympathetic anti‐inflammatory reflex.Support or Funding InformationSupported by the American Osteopathic Association (Grant #19137759) and generous funding by the Research Office at Burrell College of Osteopathic Medicine.Differences (⊗) in the salivary concentrations of the pro‐inflammatory cytokines interleukin‐1β (IL‐1β, left) and tumor necrosis factor‐α (TNF‐α, right) before and after the experimental protocol. The cytokine concentrations from days 1 to 3 were averaged. CTR: control group; OMT: osteopathic occipito‐atlantal decompression (OA‐D) group; taVNS: transcutaneous auricular vagus nerve stimulation group; *: P&lt;0.05 vs control.Figure 1

Portal vein innervation underlying the pressor effect of water ingestion with and without cold stress.

Water-induced pressor response appears mediated through the activation of transient receptor potential channel TRPV4 on hepatic portal circulation in animals. We sought to elucidate the mechanism of portal vein signaling in this response. Forty-five rats were divided into four groups: control rats without water ingestion (WI), control rats with WI, portal vein denervation rats with WI (PVDWI), and TRPV4 antagonist-treated rats with WI (anti-TRPV4WI). Cardiovascular responses were monitored throughout the experiments. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at baseline (PreCS) before cold stress trial (CS), WI elicited robust pressor and tachycardia responses accompanied by spectral power changes, in particular, increases of low-frequency BPV (LFBPV) and very-LFBPV (VLFBPV), but decrease of very-low-frequency HRV. PVDWI, likewise, elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, high-frequency HRV, LFBPV, low-frequency HRV, and VLFBPV. When compared with WI at PreCS, WI at CS elicited pressor and tachycardia responses accompanied by increases of high-frequency BPV, LFBPV, and VLFBPV, whereas in WI, the CS-evoked pressor response and the accompanied LFBPV and VLFBPV increases were all tended augmented by PVDWI. When compared with WI and PVDWI at both PreCS and CS, however, anti-TRPV4WI attenuated their pressor responses and attenuated their increased LFBPV, VLFBPV, and very-low-frequency HRV. The results indicate that the portal vein innervation is critical for a buffering mechanism in splanchnic sympathetic activation and water-induced pressor response.

Role of vasopressin V1 antagonist in the action of vasopressin on the cooling-evoked hemodynamic perturbations of rats

We aimed to investigate the role of arginine vasopressin (AVP) acting via the AVPV1 receptor in the autonomic cardiovascular responses to cold stress (CS). The study was conducted on adult male Sprague-Dawley rats with telemetry transmitters implanted to monitor heart rate (HR) and systolic blood pressure (SBP) throughout the experiment course. Rats were divided into four groups and were given, respectively, saline (control group), AVPV1 antagonist (V1880) alone, and V1880 following the removal of sympathetic outflows using hexamethonium (HEX+V1880) or guanethidine (GUA + V1880). Rats were subjected to the CS stimuli (rapid immersion of the rat's limbs into 4 °C water). Hemodynamic responses were recorded at baseline (PreCS), during CS, and after CS. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at PreCS, inhibition of AVPV1 increases SBP and HR as well as very-low-frequency BPV and low-frequency BPV, which is attenuated by hexamethonium (effect on SBP only) and guanethidine (effect on both SBP and HR). HEX+V1880 results in increased high-frequency BPV and attenuated very-low-frequency HRV, while GUA + V1880 results in increased high-frequency HRV and attenuated very-low-frequency HRV. During CS, we observed that SBP and HR, as well as very-low-frequency BPV and low-frequency BPV, were similar in the control group and the group with AVPV1 inhibition, while AVPV1 inhibition results in attenuated high-frequency BPV. Furthermore, we observed that changes produced by AVPV1 inhibition alone were affected differently by HEX+V1880 and GUA + V1880, particularly in low-frequency HRV and very-low-frequency HRV. The results support that AVPV1 mediates autonomic cardiovascular responses at both baseline and CS stimuli conditions are associated with central mechanism engagement.

Nrf2 Dysfunction in the RVLM is Associated with Obesity‐Induced Sympathoexcitation

Sympathetic overactivity contributes to the pathogenesis of obesity‐induced hypertension. The rostral ventrolateral medulla (RVLM) is an important brainstem region that regulates sympathetic nerve activity (SNA) to peripheral tissues. Oxidative stress and neuroinflammation in the RVLM are believed to be important contributors for augmented SNA in obesity, however, the molecular mechanisms that initiate and sustain the pro‐inflammatory milieu in the RVLM during obesity are not clear. Nuclear factor erythroid 2‐related factor (Nrf2) is a master transcriptional factor that regulates the expression of anti‐oxidant and anti‐inflammatory genes. We hypothesized that obesity impairs Nrf2 signaling to increase oxidative stress in the RVLM leading to increases in SNA and hypertension. To test this, 2 months‐old male C57BL/6J mice were fed a high‐fat diet (HFD; 60% fat) or normal chow diet (10% fat for 16 weeks and were instrumented with radiotelemeters in the last 2 weeks for measuring blood pressure and SNA. Heart rate variability and depressor response to ganglionic blockade were used to assess SNA. At the end of 16 weeks, animals were sacrificed, brainstem was isolated and sectioned. Superoxide levels were assessed in the frozen sections by dihydroethidium staining (DHE). RVLM was microdissected for gene expression analysis. Data were analyzed by students t‐test and p&lt;0.05 was considered statistically significant. HFD feeding resulted in a mild but significant increase in mean arterial pressure (103.7 ± 0.9 vs 108.6 ± 0.73 mmHg, normal chow diet vs HFD; P&lt;0.05; n=4) and systolic blood pressure (121.2 ± 1.2 vs 129 ± 0.67 mmHg, p&lt;0.05; n=4) compared to normal chow‐fed animals. Ganglionic blockade using hexamethonium showed greater depressor response (−0.21 ± 2.9 vs 13.13 ± 1.3 mmHg, normal chow diet vs HFD; p&lt;0.05; n=4) to HFD feeding. Furthermore, low‐frequency blood pressure variability and the ratio of low‐frequency to high‐frequency heart rate variability in HFD mice were significantly higher than in the control mice suggesting HFD upregulated SNA. In addition, obesity‐induced sympathoexcitation was associated with increased superoxide levels (DHE staining) and decreased mRNA levels of Nrf2 (1.05 ± 0.16 vs 0.48 ± 0.06 fold, normal diet vs HFD; p&lt;0.05) and its target genes (e.g. NQO1 1.08 ± 0.22 vs 0.51 ± 0.08 fold, p&lt;0.05 and SOD2 1.03 ± 0.13 vs 0.48 ± 0.05 fold; p&lt;0.05) in the RVLM of HFD mice. Collectively, our results show for the first time, evidence for obesity‐associated Nrf2 dysfunction in the RVLM. Future studies will investigate the mechanistic role of Nrf2 signaling in the RVLM in obesity‐induced sympathoexcitation.Support or Funding InformationRAC fund, CVHS, Oklahoma State UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Moderate Physical Training Ameliorates Cardiovascular Dysfunction Induced by High Fat Diet After Cessation of Training in Adult Rats

We aimed to test whether moderate physical training can induce long-lasting protection against cardiovascular risk factors induced by high fat diet (HFD) intake, even after cessation of training. 90-days-old Wistar rats were submitted to a sedentary lifestyle or moderate physical training, three times a week, for 30 days. Following this, at 120 days-of age, sedentary and trained rats received a hypercaloric diet (HFD) or a commercial diet normal fat diet (NFD) for 30 days. Body weight (BW) and food intake were evaluated weekly. At 150 days-of age, hemodynamic measures (systolic, diastolic, mean blood pressure, pulse pressure, pulse interval and heart rate) were made via an indwelling femoral artery catheter. Beat-to-beat data were analyzed to calculate power spectra of systolic blood pressure (SBP) and pulse interval. After euthanasia, mesenteric fat pads were removed and weighted and total blood was stored for later analysis of lipid profile. Consumption of a HFD increased blood pressure (BP), pulse pressure, low frequency BP variability, BW gain, fat pad stores and induced dyslipidemia. Interestingly, prior physical training was able to partially protect against this rise in BP and body fat stores. Prior physical training did not totally protect against the effects of HFD consumption but previously trained animals did demonstrate resistance to the development of cardiometabolic alterations, which illustrate that the benefits of physical training may be partially maintained even after 30 days of detraining period.

Differences in Autonomic Recovery Following Maximal Resistance Exercise in Young and Older Adults

Aging is associated with negative changes in autonomic function and an increased risk of cardiovascular disease. The risk of a sudden cardiovascular event is elevated during and immediately following vigorous exercise, potentially due to increased sympathetic dominance. Because resistance exercise provides a large hypertensive stimulus and young adults show reduced cardiac vagal control during recovery, further exploration of the effects of an acute bout of resistance exercise on autonomic function and recovery in older adults is required.PurposeTo evaluate the effects of high‐intensity lower body resistance exercise on autonomic modulation in young (YA) and older adults (OA).MethodsThirty‐five YA (17 female, 26±5 years, BMI: 23.8±3.2 kg/m2) and 25 OA (14 female, 60±6 years, BMI: 29.9±5.4 kg/m2) completed 3 sets of 10 repetitions of maximal isokinetic knee flexion/extension on a force dynamometer in a semi‐recumbent position. Throughout the protocol, participants were instrumented with a 3‐lead ECG and finger‐photoplethysmography for continuous heart rate and blood pressure recordings. Time and spectral components of heart rate (HRV) and blood pressure variability (BPV), non‐invasive indices of autonomic function, were analyzed using five‐minute segments at baseline and 5‐minutes post‐resistance exercise.ResultsAt baseline, OA had higher systolic and mean blood pressure, as well as lower root mean square of successive differences (RMSSD), low‐frequency (LF) RRI, high‐frequency (HF) RRI, and baroreceptor sensitivity (BRS) (p&lt;0.05). At 5‐minutes post‐exercise, LF/HF ratio and LF systolic blood pressure increased (p&lt;0.05). RMSSD, HF RRI, and BRS, were greater at baseline for YA and all variables decreased at 5‐min, while older adults did not change over time (interactions, p&lt;0.05).ConclusionsThese results suggest YA exhibited parasympathetic withdrawal 5‐minutes post‐exercise, whereas OA either did not exhibit parasympathetic withdrawal or had already recovered at 5 min post exercise, but this cannot be distinguished from our data. Both groups appear to have elevated sympathetic modulation at 5‐min, as indicated by RRI, LF/HF and LF BPV. Further investigation of the response during exercise is required. However, there are clear differences in autonomic recovery following maximal resistance exercise in OA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Low-frequency blood pressure oscillations and inotrope treatment failure in premature infants.

The underlying mechanism as to why some hypotensive preterm infants do not respond to inotropic medications remains unclear. For these infants, we hypothesize that impaired vasomotor function is a significant factor and is manifested through a decrease in low-frequency blood pressure variability across regulatory components of vascular tone. Infants born ≤28 wk estimated gestational age underwent prospective recording of mean arterial blood pressure for 72 h after birth. After error correction, root-mean-square spectral power was calculated for each valid 10-min data frame across each of four frequency bands (B1, 0.005-0.0095 Hz; B2, 0.0095-0.02 Hz; B3, 0.02-0.06 Hz; and B4, 0.06-0.16) corresponding to different components of vasomotion control. Forty infants (twenty-nine normotensive control and eleven inotrope-exposed) were included with a mean ± SD estimated gestational age of 25.2 ± 1.6 wk and birth weight 790 ± 211 g. 9.7/11.8 Million (82%) data points were error-free and used for analysis. Spectral power across all frequency bands increased with time, although the magnitude was 20% less in the inotrope-exposed infants. A statistically significant increase in spectral power in response to inotrope initiation was noted across all frequency bands. Infants with robust blood pressure response to inotropes had a greater increase compared with those who had limited or no blood pressure response. In this study, hypotensive infants who require inotropes have decreased low-frequency variability at baseline compared with normotensive infants, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.NEW & NOTEWORTHY In this study, we examine patterns of low-frequency oscillations in blood pressure variability across regulatory components of vascular tone in normotensive and hypotensive infants exposed to inotropic medications. We found that hypotensive infants who require inotropes have decreased low-frequency variability at baseline, which increases after inotrope initiation. Low-frequency spectral power does not change for those with inotrope treatment failure, suggesting dysfunctional regulation of vascular tone as a potential mechanism of treatment failure.

Hypertension Does Not Alter the Increase in Cardiac Baroreflex Sensitivity Caused by Moderate Cold Exposure.

Exposure to cold increases blood pressure and may contribute to higher wintertime cardiovascular morbidity and mortality in hypertensive people, but the mechanisms are not well-established. While hypertension does not alter responses of vagally-mediated heart rate variability to cold, it is not known how hypertension modifies baroreflex sensitivity (BRS) and blood pressure variability during cold exposure. Our study assessed this among untreated hypertensive men during short-term exposure comparable to habitual winter time circumstances in subarctic areas. We conducted a population-based recruitment of 24 untreated hypertensive and 17 men without hypertension (age 55–65 years) who underwent a whole-body cold exposure (−10°C, wind 3 m/s, winter clothes, 15 min, standing). Electrocardiogram and continuous blood pressure were measured to compute spectral powers of systolic blood pressure and heart rate variability at low (0.04–0.15 Hz) and high frequency (0.15–0.4 Hz) and spontaneous BRS at low frequency (LF). Comparable increases in BRS were detected in hypertensive men, from 2.6 (2.0, 4.2) to 3.8 (2.5, 5.1) ms/mmHg [median (interquartile range)], and in control group, from 4.3 (2.7, 5.0) to 4.4 (3.1, 7.1) ms/mmHg. Instead, larger increase (p < 0.05) in LF blood pressure variability was observed in control group; response as median (interquartile range): 8 (2, 14) mmHg2, compared with hypertensive group [0 (−13, 20) mmHg2]. Untreated hypertension does not disturb cardiovascular protective mechanisms during moderate cold exposure commonly occurring in everyday life. Blunted response of the estimate of peripheral sympathetic modulation may indicate higher tonic sympathetic activity and decreased sympathetic responsiveness to cold in hypertension.

The Effect of Hostility Reduction on Autonomic Control of the Heart and Vasculature: A Randomized Controlled Trial.

Hostility is associated with coronary artery disease. One candidate mechanism may be autonomic nervous system (ANS) dysregulation. In this study, we report the effect of cognitive behavioral treatment on ANS regulation. Participants were 158 healthy young adults, high in hostility measured by the Cook-Medley Hostility and Spielberger Trait Anger scales. Participants were also interviewed using the Interpersonal Hostility Assessment Technique. They were randomized to a 12-week cognitive behavioral treatment program for reducing hostility or a wait-list control group. The outcome measures were preejection period, low-frequency blood pressure variability, and high-frequency heart rate variability measured at rest and in response to and recovery from cognitive and orthostatic challenge. Linear-mixed models were used to examine group by session and group by session by period interactions while controlling for sex and age. Contrasts of differential group and session effects were used to examine reactivity and recovery from challenge. After Bonferroni correction, two-way and three-way interactions failed to achieve significance for preejection period, low-frequency blood pressure variability, or high-frequency heart rate variability (p > .002), indicating that hostility reduction treatment failed to influence ANS indices. Reduction in anger and hostility failed to alter ANS activity at rest or in response to or recovery from challenge. These findings raise questions about whether autonomic dysregulation represents a pathophysiological link between hostility and heart disease.

Autonomic Responses to Orthostasis after Acetylcholinesterase Inhibition in Tetraplegia

PURPOSE: We have demonstrated that acetylcholinesterase inhibition (AcHi: pyridostigmine bromide: PB) improves orthostatic blood pressure (BP) responses to head-up tilt (HUT) compared to no drug (ND) in some individuals with tetraplegia and theorize that difference between subjects with an orthostatic BP response to PB (responders [R]) and those without a BP response (non-responders [nR]) may relate to the autonomic completeness of injury. Although we cannot directly asses the degree of autonomic cardiovascular impairment, we determined differences in the autonomic response to HUT using heart rate (HR) variability (HFV) and BP variability (BPV) after administration of PB (60 mg) compared to ND in subjects with tetraplegia. METHODS: Mixed factor ANOVA was used to determine main and interaction effects for high frequency HRV (HF: vagal) and low frequency BPV (LFsbp: sympathetic) responses to HUT (0°, 15°, 25°, 35°) following PB and ND administration in the R and nR. Beat-to-beat HR and BP were assessed using a 3-lead ECG and finger photoplethysmography, respectively; data were collected at 500 Hz for 5-minutes at each angle of HUT. RESULTS: Eleven individuals with SCI participated; however, one subject was unable to tolerate the HUT maneuver during ND therefore, results are presented in 10 subjects (age: 38±10 years; duration of injury: 13±10 years; level: C4-6; AIS: A, B, C). Five individuals were R and 5 were nR (+6.9±5.5 vs. -7.1±8.1 mmHg, respectively; p=0.012); demographics did not differ between the groups. Supine HR was lower in R compared to nR (48±3 vs. 57±8 bpm, respectively; p=0.049); supine BP did not differ. Although supine HF did not differ, supine LFsbp was increased in R compared to the nR (4.11±0.12 vs.3.82±0.24 ln, respectively; p=0.041). The group (R, nR) by condition (PB, ND) by HUT interaction effect was significant for HF (3.639; p=0.044), but not for LFsbp. CONCLUSION: These data suggest that tetraplegic individuals with increased resting sympathetic nervous system activity (LFsbp) respond to AcHi with an increased BP and vagal response to HUT, indicative of improved orthostatic baroreceptor function.

Sympathetic activation is associated with increased IL-6, but not CRP in the absence of obesity: lessons from postural tachycardia syndrome and obesity.

Sympathetic activation is thought to contribute to the inflammatory process associated with obesity, which is characterized by elevated circulating C-reactive protein (hsCRP) and interleukin-6 (IL-6). To evaluate whether sympathetic activation is associated with inflammation in the absence of obesity, we studied patients with postural tachycardia syndrome (POTS), a condition characterized by increased sympathetic tone in otherwise healthy individuals. Compared with 23 lean controls, 43 lean female POTS had greater vascular sympathetic modulation (low-frequency blood pressure variability, LFSBP, 3.2 ± 0.4 vs. 5.5 ± 0.6 mmHg(2), respectively, P = 0.006), lower cardiac parasympathetic modulation (high-frequency heart rate variability, 1,414 ± 398 vs. 369 ± 66 ms(2), P = 0.001), and increased serum IL-6 (2.33 ± 0.49 vs. 4.15 ± 0.54 pg/ml, P = 0.011), but this was not associated with increases in hsCRP, which was low in both groups (0.69 ± 0.15 vs. 0.82 ± 0.16 mg/l, P = 0.736). To explore the contribution of adiposity to inflammation, we then compared 13 obese female POTS patients and 17 obese female controls to matched lean counterparts (13 POTS and 11 controls). Compared with lean controls, obese controls had increased LFSBP (3.3 ± 0.5 vs. 7.0 ± 1.1 mmHg(2); P = 0.016), IL-6 (2.15 ± 0.58 vs. 3.92 ± 0.43 pg/ml; P = 0.030) and hsCRP (0.69 ± 0.20 vs. 3.47 ± 0.72 mg/l; P = 0.001). Obese and lean POTS had similarly high IL-6 but only obese POTS had increased hsCRP (5.76 ± 1.99 mg/l vs. 0.65 ± 0.26; P < 0.001). In conclusion, sympathetic activation in POTS is associated with increased IL-6 even in the absence of obesity. The coupling between IL-6 and CRP, however, requires increased adiposity, likely through release of IL-6 by visceral fat.

Long-Term Exposure to Concentrated Ambient PM 2.5 Increases Mouse Blood Pressure through Abnormal Activation of the Sympathetic Nervous System: A Role for Hypothalamic Inflammation

Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown.Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation.Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system.Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation.Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation.Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151

Effects of aerobic conditioning on cardiovascular sympathetic response to and recovery from challenge

Exercise has widely documented cardioprotective effects, but the mechanisms behind these effects are still poorly understood. Here, we test the hypothesis that aerobic training lowers cardiovascular sympathetic responses to and speeds recovery from challenge. We conducted a randomized, controlled trial contrasting aerobic versus strength training on indices of cardiac (pre-ejection period, PEP) and vascular (low-frequency blood pressure variability, LF-BPV) sympathetic responses to and recovery from psychological and orthostatic challenge in 149 young, healthy, sedentary adults. Aerobic and strength training did not alter PEP or LF-BPV reactivity to or recovery from challenge. These findings, from a large randomized, controlled trial using an intent-to-treat design, show that moderate aerobic exercise training has no effect on PEP and LF-BPV reactivity to or recovery from psychological or orthostatic challenge. In healthy young adults, the cardioprotective effects of exercise training are unlikely to be mediated by changes in sympathetic activity.

Aerobic Exercise and Strength Training Effects on Cardiovascular Sympathetic Function in Healthy Adults

Exercise has widely documented cardioprotective effects, but the mechanisms underlying these effects are not entirely known. Previously, we demonstrated that aerobic but not strength training lowered resting heart rate and increased cardiac vagal regulation, changes that were reversed by sedentary deconditioning. Here, we focus on the sympathetic nervous system and test whether aerobic training lowers levels of cardiovascular sympathetic activity in rest and that deconditioning would reverse this effect. We conducted a randomized controlled trial contrasting the effects of aerobic (A) versus strength (S) training on indices of cardiac (preejection period, or PEP) and vascular (low-frequency blood pressure variability, or LF BPV) sympathetic regulation in 149 young, healthy, and sedentary adults. Participants were studied before and after conditioning, as well as after 4 weeks of sedentary deconditioning. As previously reported, aerobic capacity increased in response to conditioning and decreased after deconditioning in the aerobic, but not the strength, training group. Contrary to prediction, there was no differential effect of training on either PEP (A: mean [SD] -0.83 [7.8] milliseconds versus S: 1.47 [6.69] milliseconds) or LF BPV (A: mean [SD] -0.09 [0.93] ln mm Hg(2) versus S: 0.06 [0.79] ln mm Hg(2)) (both p values > .05). These findings, from a large randomized controlled trial using an intent-to-treat design, show that moderate aerobic exercise training has no effect on resting state cardiovascular indices of PEP and LF BPV. These results indicate that in healthy, young adults, the cardioprotective effects of exercise training are unlikely to be mediated by changes in resting sympathetic activity. Clinicaltrials.gov identifier: NCT00358137.

Chronic fluoxetine reduces autonomic control of cardiac rhythms in rats with congestive heart failure

Up to 40% of patients with heart failure develop depression, and depression is an independent risk factor for cardiovascular mortality in this patient population. Consequently, increasing numbers of patients with heart failure are treated with antidepressants. Selective serotonin reuptake inhibitors are typically the antidepressant of choice since this drug class has limited cardiovascular toxicity. However, little is known about the effects of selective serotonin reuptake inhibitors on autonomic cardiac regulation in congestive heart failure (CHF). Here, indexes of cardiac autonomic control were evaluated before and during chronic fluoxetine (FLX) treatment (20 mg·kg(-1)·day(-1), 5 wk) in rats that developed CHF after coronary artery ligation. FLX reduced the low-frequency (LF) component of heart rate variability (HRV; P < 0.01) as well as the sympathetic contribution to LF HRV (P < 0.01) in both CHF and sham-operated rats. Both FLX and CHF reduced high-frequency HRV (P < 0.01). Spontaneous baroreflex gain was decreased in CHF rats 8 wk after ligation (P < 0.01). Cross-spectral coherence between the interbeat interval and mean arterial pressure was reduced in the LF domain 3 wk after ligation in CHF rats (P < 0.01) and was further reduced after chronic FLX treatment (P < 0.01). Plasma catecholamines and LF blood pressure variability were not affected by FLX. Chronotropic responses to both efferent vagal nerve stimulation and isoproterenol administration were reduced in CHF rats and by FLX (P < 0.01), whereas inotropic responses to isoproterenol were reduced only in CHF rats (P < 0.01). These data indicate that chronic FLX reduces the responsiveness to autonomic output controlling cardiac rhythm and may further compromise autonomic regulation of cardiac function in CHF.

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.

Spectral Analyses of Cardiovascular Control in Rodents with Spinal Cord Injury

The severity of injury to cardiovascular autonomic pathways following clinical spinal cord injury (SCI) can be evaluated with spectral analyses. Whether this technique provides a translatable assessment of cardiovascular autonomic function in rodent SCI is unknown. Beat-to-beat blood pressure and pulse interval were measured in male rats 1 month after complete T3 or T10 SCI, and in uninjured control animals. Univariate autoregressive spectral analyses were performed and the power of the low frequency (LF), high frequency (HF), and very low frequency (VLF) peaks identified. Frequency domain variables were correlated with the severity of orthostatic hypotension (OH) and the severity of hypertension during autonomic dysreflexia (AD). Total heart rate variability (HRV) and blood pressure variability (BPV) were reduced in animals with T3, but not T10, SCI. VLF and LF HRV were reduced and HF HRV was increased in animals with T3 SCI compared to controls; there were no changes in animals with T10 SCI. BPV in the VLF and LF range was reduced in animals with T3 SCI, but not T10 SCI. In all animals with SCI, severity of OH was positively correlated with LF BPV, and negatively correlated with HF BPV. Severity of AD was positively correlated with HF BPV and HF HRV, and negatively correlated with VLF HRV. Spectral analyses can detect alterations in cardiovascular autonomic function in animals with SCI at rest. These parameters underscore the distinct cardiovascular ramifications of high- versus low-thoracic SCI, and correlate with the severity of AD and OH, clinically-relevant measures of abnormal blood pressure control.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling.Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis.A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats.Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.