Shift In Sympathovagal Balance Research Articles

Rosuvastatin, but not atorvastatin, enhances the antihypertensive effect of cilostazol in an acute model of hypertension

PurposeHypertensive emergency, a sudden and severe increase in blood pressure, necessitates immediate intervention to avoid end-organ damage. Cilostazol, a selective phosphodiesterase-III inhibitor, has vasodilator effect. Here, we investigated the effect of two commonly used statins, atorvastatin or rosuvastatin, on cilostazol antihypertensive activity in acute model of hypertension.MethodsHypertensive emergency was induced via angiotensin II intravenous infusion (120 ng.kg−1.min−1). Rats were subjected to real-time arterial hemodynamics and electrocardiogram recording while investigated drugs were injected slowly at cumulative doses 0.5, 1, and 2 mg.kg−1, individually or in combination, followed by baroreflex sensitivity (BRS) analysis and serum electrolytes (Na+ and K+) and vasomodulators (norepinephrine (NE), and nitric oxide (NO)) assessment.ResultsCilostazol reduced systolic blood pressure (SBP), while co-injection with rosuvastatin augmented cilostazol SBP-reduction up to 30 mmHg. Compared to atorvastatin, rosuvastatin boosted the cilostazol-associated reduction in peripheral resistance, as evidenced by further decrease in diastolic, pulse, and dicrotic-notch pressures. Rosuvastatin co-injection prevented cilostazol-induced changes of ejection and non-ejection durations. Additionally, rosuvastatin coadministration produced better restoration of BRS, with an observed augmented increase in BRS indexes from spectral analysis. Greater reduction in sympathetic/parasympathetic ratio and serum NE upon rosuvastatin coadministration indicates further shift in sympathovagal balance towards parasympathetic dominance. Additionally, rosuvastatin coinjection caused a greater decrease in serum sodium, while more increase in NO indicating augmented reduction of extracellular volume and endothelial dysfunction.ConclusionRosuvastatin boosted cilostazol’s antihypertensive actions through effects on peripheral resistance, BRS, sympathovagal balance, endothelial dysfunction, and electrolytes balance, while atorvastatin did not demonstrate a comparable impact.

Alterations in short-term blood pressure variability related to disease severity and autonomic symptoms in myasthenia gravis patients

ObjectivesWe aimed to evaluate beat-to-beat blood pressure variability (BPV) during head-up tilt test (HUTT) in patients with mild and moderate myasthenia gravis (MG) compared to healthy controls (HCs), and its association with the severity of autonomic symptoms.MethodsA total of 50 MG patients and 30 HCs were evaluated. Patients were stratified into 2 groups regarding Myasthenia Gravis Foundation of America (MGFA) classification: mild (I,II MGFA), moderate form (III MGFA). Autonomic symptoms were assessed by COMPASS-31 questionnaire. Cardiovascular parameters, indices of very short-term systolic (SBPV), and diastolic blood pressure (BP) variability (DBPV) were assessed at rest, and during HUTT.ResultsModerate MG patients were characterized by an overall shift of sympathovagal balance toward sympathetic predominance, either at rest and during HUTT, as well as lower values of high frequency (HFnu) of DBPV during HUTT, compared to HCs and mild MG. Similarly, moderate MG showed higher resting low frequency (LFnu) of DBPV (p=0.035), higher COMPASS-31 score (p=0.031), and orthostatic intolerance sub-score (p=0.019) than mild MG patients. Compared to HCs, mild MG patients showed lower Δmean BP (p=0.029), Δdiastolic BP (p=0.016). Autonomic symptoms were associated with lower BP values, at rest and during HUTT, and lower LF BPV parameters during HUTT.ConclusionMG patients present significant alterations in BPV, both at rest and in response to orthostatic stress, which are related to autonomic symptoms and disease severity. This study confirms the importance of monitoring BPV when evaluating cardiovascular autonomic function and its evolution over the course of MG disease.

Impacts of frailty on heart rate variability in aging mice: Roles of the autonomic nervous system and sinoatrial node.

Heart rate variability (HRV) is determined by intrinsic sinoatrial node (SAN) activity and the autonomic nervous system (ANS). HRV is reduced in aging; however, aging is heterogeneous. Frailty, which can be measured using a frailty index (FI), can quantify health status in aging separately from chronological age. The purpose of this study was to investigate the impacts of age and frailty on HRV in mice. Frailty was measured in aging mice between 10 and 130 weeks of age. HRV was assessed using time domain, frequency domain, and Poincaré plot analyses in anesthetized mice at baseline and after ANS blockade, as well as in isolated atrial preparations. HRV was reduced in aged mice (90-130 weeks and 50-80 weeks old) compared to younger mice (10-30 weeks old); however, there was substantial variability within age groups. In contrast, HRV was strongly correlated with FI score regardless of chronological age. ANS blockade resulted in reductions in heart rate that were largest in 90- to 130-week-old mice and were correlated with FI score. HRV after ANS blockade or in isolated atrial preparations was increased in aged mice but again showed high variability among age groups. HRV was correlated with FI score after ANS blockade and in isolated atrial preparations. HRV is reduced in aging mice in association with a shift in sympathovagal balance and increased intrinsic SAN beating variability; however, HRV is highly variable within age groups. HRV was strongly correlated with frailty, which was able to detect differences in HRV separately from chronological age.

Sympathetic predominance before tourniquet deflation is associated with a reduction in arterial blood pressure after tourniquet deflation during total knee arthroplasty.

High dependency of arterial blood pressure (ABP) on enhanced sympathetic activity, which maintains vascular tone, leads to hypotension after hemodynamic insults that blunt the sympathetic activity. Therefore, we hypothesized that sympathovagal balance before tourniquet deflation (TD) determines the extent of a reduction in ABP after TD during total knee arthroplasty (TKA). Fifty-four hypertensive female patients undergoing TKA under spinal anesthesia were analyzed. The sympathovagal balance [low-to-high frequency ratio of heart rate variability (LF/HF)] before TD was defined as (LF/HF during 5 min before TD-preanesthetic LF/HF)/preanesthetic LF/HF (%). An increase in its value represents a shift in sympathovagal balance toward sympathetic predominance. The percent change in the mean ABP (MAP) after TD was defined as (minimum MAP during 10 min after TD-averaged MAP during 5 min before TD)/averaged MAP during 5 min before TD (%). Simple linear regression was performed to assess the correlation between the sympathovagal balance before TD and change in MAP after TD. The correlation was also assessed by multiple linear regression controlling for age, duration of tourniquet inflation, and spinal anesthesia-induced hypotension. Thirty-two minutes (on average) after tourniquet inflation, the MAP was decreased by 12.1 (-3.0 to 47.9) % [mean (range)] upon TD (P<0.001). The sympathovagal balance before TD was negatively proportional to the change in MAP after TD in both simple and multiple linear regression models (R2=0.323 and 0.340, P<0.001). A shift in sympathovagal balance toward sympathetic predominance before TD is associated with a decrease in ABP after TD.

Cardiac Autonomic Dysfunction in Myasthenia Gravis and Relapsing-Remitting Multiple Sclerosis-A Pilot Study.

This study assessed cardiac autonomic response to head-up tilt test (HUTT) in 23 myasthenia gravis (MG) and 23 relapsing-remitting multiple sclerosis (RRMS) patients compared to 30 healthy controls (HC). Task Force® Monitor was used to evaluate cardiac inotropy parameters, baroreflex sensitivity (BRS), heart rate (HRV), and blood pressure variability (BPV) during HUTT. MG patients were characterized by reduced BRS (p < 0.05), post-HUTT decrease in high-frequency component (p < 0.05) and increase in sympathovagal ratio of HRV (p < 0.05) when compared to controls indicating parasympathetic deficiency with a shift of sympathovagal balance toward sympathetic predominance. Compared to HC, MG patients also showed lower cardiac inotropy parameters, specifically, left ventricular work index (LVWI) during supine rest (p < 0.05) as well as LVWI and cardiac index values in response to orthostatic stress (p < 0.01 and p < 0.05, respectively). Compared to controls, RRMS patients were characterized by lower HRV delta power spectral density (p < 0.05) and delta low-frequency HRV (p < 0.05) in response to HUTT suggesting combined sympathetic and parasympathetic dysfunction. There were no differences in cardiac autonomic parameters between MG and MS patients (p > 0.05). Our study highlights the possibility of cardiac and autonomic dysfunction in patients with MG and RRMS which should be considered in the pharmacological and rehabilitation approach to managing these conditions.

Effectiveness of mantra meditation as a neurophysiological phenomenon for stress management in undergraduate medical students

Background: Meditation has widely been used to combat stress and its effects, yet the universality of its effectiveness and duration remains unclear. Aim and Objectives: This study aimed to evaluate differences in its effectiveness among individuals with different baseline stress levels and recommend duration of practice to produce constructive outcomes. Materials and Methods: A total of 30 undergraduate medical students (15 males and 15 females) with a mean age of 21 (±0.95) years volunteered for the study. Preliminarily, using the perceived stress scale (PSS), they were categorized into high (0), moderate (25), and low (5) stress groups; following which they were pre-tested for heart rate (HR), HR variability, and galvanic skin resistance (GSR), subject to a computer game stressor. Students were then instructed to undertake meditation sessions and were tested for the same parameters at intervals of 3 and 6 weeks from the pre-test. Results: Moderate stress individuals showed a significant (P ≤ 0.05) increase in high frequency band, GSR, RMSSD (square root of the mean of the sum of the squares of the differences between adjacent RR intervals) and the percentage of RR 50 counts; accompanied with a significant decrease in PSS score, low frequency to high frequency ratio and HR; with parameters becoming significant within 3 weeks of practice, and no further significant changes in the 3–6 weeks period. None of the parameters were significant for the low stress group, although similar trends were observed. Conclusion: The study indicated the usefulness of a 3-week meditation program for individuals with moderate or high stress, and recommendation to include a meditation program into the undergraduate medical curriculum. Positive effects were attributed to a shift of sympathovagal balance to parasympathetic dominance.

Effects of nasal high flow on sympathovagal balance, sleep, and sleep-related breathing in patients with precapillary pulmonary hypertension

BackgroundIn precapillary pulmonary hypertension (PH), nasal high flow therapy (NHF) may favorably alter sympathovagal balance (SVB) and sleep-related breathing through washout of anatomical dead space and alleviation of obstructive sleep apnea (OSA) due to generation of positive airway pressure.ObjectivesTo investigate the effects of NHF on SVB, sleep, and OSA in patients with PH, and compare them with those of positive airway pressure therapy (PAP).MethodsTwelve patients with PH (Nice class I or IV) and confirmed OSA underwent full polysomnography, and noninvasive monitoring of SVB parameters (spectral analysis of heart rate, diastolic blood pressure variability). Study nights were randomly split into four 2-h segments with no treatment, PAP, NHF 20 L/min, or NHF 50 L/min. In-depth SVB analysis was conducted on 10-min epochs during daytime and stable N2 sleep at nighttime.ResultsAt daytime and compared with no treatment, NHF20 and NHF50 were associated with a flow-dependent increase in peripheral oxygen saturation but a shift in SVB towards increased sympathetic drive. At nighttime, NHF20 was associated with increased parasympathetic drive and improvements in sleep efficiency, but did not alter OSA severity. NHF50 was poorly tolerated. PAP therapy improved OSA but had heterogenous effects on SVB and neutral effects on sleep outcomes. Hemodynamic effects were neutral for all interventions.ConclusionsIn sleeping PH patients with OSA NHF20 but not NHF50 leads to decreased sympathetic drive likely due to washout of anatomical dead space. NHF was not effective in lowering the apnea-hypopnoea index and NHF50 was poorly tolerated.

Two weeks of remote ischaemic preconditioning alters sympathovagal balance in healthy humans.

What is the central question of this study? Delayed cardiovascular responses occur following a single bout of remote ischaemic preconditioning (RIPC). Is heart rate variability (HRV), a surrogate marker of cardiac vagal control, able to detect a delayed effect after a single bout of RIPC? Do repeated bouts of RIPC further alter HRV? What is the main finding and its importance? Indices of HRV indicated a shift in sympathovagal balance toward greater parasympathetic activity following 2weeks of RIPC but not after a single bout of RIPC. Thus, repeated bouts of RIPC were necessary to elicit changes in autonomic function. Remote ischaemic preconditioning (RIPC), induced by brief periods of ischaemia followed by reperfusion, protects against ischaemia-reperfusion injury and improves microvascular function. However, the effect of RIPC on autonomic function remains unclear. We hypothesized that RIPC, administered as a single bout or repeated over a 2-week period, will increase markers of cardiac vagal control measured by heart rate variability (HRV). Thirty-two young adults performed a single bout (n=13), repeated bouts (n=11), or served as a time control (n=8). RIPC sessions consisted of four repetitions of 5min unilateral brachial artery occlusion interspersed by 5min of reperfusion. For the single bout protocol, resting lead II electrocardiogram (ECG) was collected before and 24, 48, 72 and 168h post-RIPC. The repeated bout protocol consisted of three 4-day periods of RIPC training, each interspersed by a 1-day break. Similar to time controls, ECG was collected before and 24h after the last RIPC bout. HRV was analysed by power spectral density and symbolic dynamics using 350-beat ECG segments. After a single bout of RIPC, no changes in HRV were observed at any time point (P>0.05). After 2weeks of repeated RIPC, the percentage of zero-variation fragments (baseline=13.1±1.9%, post-RIPC=6.9±1.5%, P<0.05) and the LF/HF ratio decreased (baseline=1.1±0.2, post-RIPC=0.7±0.1, P<0.01), whereas the percentage of two-variation fragments increased (baseline=42.9±3.6%, post-RIPC=52.5±3.0%, P<0.01). These data indicate that repeated RIPC is necessary to elicit changes in sympathovagal balance, specifically resulting in increased vagal and decreased sympathetic activity.

Vagus Nerve Stimulation Attenuates Multiple Organ Dysfunction in Resuscitated Porcine Progressive Sepsis.

To investigate the potential benefits of vagus nerve stimulation in a clinically-relevant large animal model of progressive sepsis. Prospective, controlled, randomized trial. University animal research laboratory. Twenty-five domestic pigs were divided into three groups: 1) sepsis group (eight pigs), 2) sepsis + vagus nerve stimulation group (nine pigs), and 3) control sham group (eight pigs). Sepsis was induced by cultivated autologous feces inoculation in anesthetized, mechanically ventilated, and surgically instrumented pigs and followed for 24 hours. Electrical stimulation of the cervical vagus nerve was initiated 6 hours after the induction of peritonitis and maintained throughout the experiment. Measurements of hemodynamics, electrocardiography, biochemistry, blood gases, cytokines, and blood cells were collected at baseline (just before peritonitis induction) and at the end of the in vivo experiment (24 hr after peritonitis induction). Subsequent in vitro analyses addressed cardiac contractility and calcium handling in isolated tissues and myocytes and analyzed mitochondrial function by ultrasensitive oxygraphy. Vagus nerve stimulation partially or completely prevented the development of hyperlactatemia, hyperdynamic circulation, cellular myocardial depression, shift in sympathovagal balance toward sympathetic dominance, and cardiac mitochondrial dysfunction, and reduced the number of activated monocytes. Sequential Organ Failure Assessment scores and vasopressor requirements significantly decreased after vagus nerve stimulation. In a clinically-relevant large animal model of progressive sepsis, vagus nerve stimulation was associated with a number of beneficial effects that resulted in significantly attenuated multiple organ dysfunction and reduced vasopressor and fluid resuscitation requirements. This suggests that vagus nerve stimulation might provide a significant therapeutic potential that warrants further thorough investigation.

Shift in Sympathovagal Balance Toward Parasympathetic Predominance Is Associated With Attenuation of Portal Hyperperfusion in Cirrhotic Recipients Undergoing Living Donor Liver Transplant

BackgroundThe autonomic innervation to a liver graft remains lost up to 1 year after liver transplant. Therefore, we investigated the effects of recipients' autonomic nervous activity on the extent of portal hyperperfusion of a partial liver graft in the absence of the autonomic innervation. MethodsA total of 31 cirrhotic recipients undergoing right lobe living donor liver transplant were analyzed. Following a 10-minute absence of surgical stimulation after hepatic artery and bile duct reconstruction, the electrocardiogram and blood pressure waveforms were recorded for 5 minutes. Low-frequency (LF) and high-frequency (HF) powers and their ratio (LF/HF) were calculated using fast Fourier transform from the electrocardiogram waveform. A decrease in LF/HF represents a shift in sympathovagal balance toward parasympathetic predominance. Then, portal venous (PVF) and hepatic arterial (HAF) blood flows were measured in mL/min per 100 g of liver weight using spectral Doppler ultrasonography. A decrease in their ratio (PVF/HAF) represents attenuation of portal hyperperfusion. ResultsThe medians of the PVF and HAF were 349 and 27 mL/min/100 g liver weight with interquartile ranges of 272 to 617 mL/min/100 g liver weight and 22 to 41 mL/min/100 g liver weight, respectively, yielding a median of the PVF/HAF of 13.7 (interquartile range, 8.5–21.3). The median of LF/HF was 0.67 (interquartile range, 0.16–1.45). With a reduction in LF/HF, PVF/HAF decreased according to an S-curve regression model between them (PVF/HAF=e2.743+−0.031LF/HF,adjustedR2=0.129,P=0.027). ConclusionA shift in sympathovagal balance toward parasympathetic predominance is associated with attenuation of portal hyperperfusion in a partial liver graft.

Gastric cooling and menthol cause an increase in cardiac parasympathetic efferent activity in healthy adult human volunteers

What is the central question of this study? How do gastric stretch and gastric cooling stimuli affect cardiac autonomic control? What is the main finding and its importance? Gastric stretch causes an increase in cardiac sympathetic activity. Stretch combined with cold stimulation result in an elimination of the sympathetic response to stretch and an increase in cardiac parasympathetic activity, in turn resulting in a reduction in heart rate. Gastric cold stimulation causes a shift in sympathovagal balance towards parasympathetic dominance. The cold-induced bradycardia has the potential to decrease cardiac workload, which might be significant in individuals with cardiovascular pathologies. Gastric distension increases blood pressure and heart rate in young, healthy humans, but little is known about the effect of gastric stretch combined with cooling. We used a randomized crossover study to assess the cardiovascular responses to drinking 300ml of ispaghula husk solution at either 6 or 37°C in nine healthy humans (age 24.08±9.36years) to establish the effect of gastric stretch with and without cooling. The effect of consuming peppermint oil capsules to activate cold thermoreceptors was also investigated. The ECG, respiratory movements and continuous blood pressure were recorded during a 5min baseline period, followed by a 115min post-drink period, during which 5min epochs of data were recorded. Cardiac autonomic activity was assessed using time and frequency domain analyses of respiratory sinus arrhythmia to quantify parasympathetic autonomic activity, and corrected QT (QTc) interval analysis to quantify sympathetic autonomic activity. Gastric stretch only caused a significant reduction in QTc interval lasting up to 15min, with a concomitant but non-significant increase in heart rate, indicating an increased sympathetic cardiac tone. The additional effect of gastric cold stimulation was significantly to reduce heart rate for up to 15min, elevate indicators of cardiac parasympathetic tone and eliminate the reduction in QTc interval seen with gastric stretch only. Stimulation of gastric cold thermoreceptors with menthol also caused a significant reduction in heart rate and concomitant increase in the root mean square of successive differences. These findings indicate that gastric cold stimulation causes a shift in the sympathovagal balance of cardiac control towards a more parasympathetic dominant pattern.

Correction: Developmental milestones of the autonomic nervous system revealed via longitudinal monitoring of fetal heart rate variability.

[This corrects the article DOI: 10.1371/journal.pone.0200799.].

Developmental milestones of the autonomic nervous system revealed via longitudinal monitoring of fetal heart rate variability.

BackgroundFetal heart rate variability (fHRV) of normal-to-normal (NN) beat intervals provides high-temporal resolution access to assess the functioning of the autonomic nervous system (ANS).AimTo determine critical periods of fetal autonomic maturation. The developmental pace is hypothesized to change with gestational age (GA).Study designProspective longitudinal observational study.Subjects60 healthy singleton fetuses were followed up by fetal magnetocardiographic heart rate monitoring 4–11 times (median 6) during the second half of gestation.Outcome measureFHRV parameters, accounting for differential aspects of the ANS, were studied applying linear mixed models over four predefined pregnancy segments of interest (SoI: <27; 27+0–31+0; 31+1–35+0; >35+1 weeks GA). Periods of fetal active sleep and quiescence were accounted for separately.ResultsSkewness of the NN interval distribution VLF/LF band power ratio and complexity describe a saturation function throughout the period of interest. A decreasing LF/HF ratio and an increase in pNN5 indicate a concurrent shift in sympathovagal balance. Fluctuation amplitude and parameters of short-term variability (RMSSD, HF band) mark a second acceleration towards term. In contrast, fetal quiescence is characterized by sequential, but low-margin transformations; ascending overall variability followed by an increase of complexity and superseded by fluctuation amplitude.ConclusionsAn increase in sympathetic activation, connected with by a higher ability of parasympathetic modulation and baseline stabilization, is reached during the transition from the late 2nd into the early 3rd trimester. Pattern characteristics indicating fetal well-being saturate at 35 weeks GA. Pronounced fetal breathing efforts near-term mirror in fHRV as respiratory sinus arrhythmia.

Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms.

In the present study, we provide evidence for divergent physiological responses to moderate compared to severe hypoxia, addressing an important knowledge gap related to severity, duration and after-effects of hypoxia encountered in cardiopulmonary situations. The physiological responses to moderate and severe hypoxia were not proportional, linear or concurrent with the time-of-day. Hypoxia elicited severity-dependent physiological responses that either persisted or fluctuated throughout normoxic recovery. The physiological basis for these distinct cardiovascular responses implicates a shift in the sympathovagal set point and probably not molecular changes at the artery resulting from hypoxic stress. Hypoxia is both a consequence and cause of many acute and chronic diseases. Severe hypoxia causes hypertension with cardiovascular sequelae; however, the rare studies using moderate severities of hypoxia indicate that it can be beneficial, suggesting that hypoxia may not always be detrimental. Comparisons between studies are difficult because of the varied classifications of hypoxic severities, methods of delivery and use of anaesthetics. Thus, to investigate the long-term effects of moderate hypoxia on cardiovascular health, radiotelemetry was used to obtain in vivo physiological measurements in unanaesthetized mice during 24h of either moderate or severe hypoxia, followed by 72h of normoxic recovery. Systolic blood pressure was decreased during recovery following moderate hypoxia but increased following severe hypoxia. Moderate and severe hypoxia increased haeme oxygenase-1 expression during recovery, suggesting parity in hypoxic stress at the level of the artery. Severe but not moderate hypoxia increased the low/high frequency ratio of heart rate variability 72h post-hypoxia, indicating a shift in sympathovagal balance. Moderate hypoxia dampened the amplitude of circadian rhythm, whereas severe disrupted rhythm during the entire insult, with perturbations persisting throughout normoxic recovery. Thus, hypoxic severity differentially regulates circadian blood pressure.

Cardiac Autonomic Changes After Thoracic Sympathectomy: A Prospective, Randomized Study

We evaluated whether cardiac autonomic changes could be associated with different extent of sympathetic nerve resection in the management of essential palmar hyperhidrosis. Sixty patients with essential palmar hyperhidrosis were randomly allocated to undergo excision of T3 ganglia (sympathicectomy group; n= 30) or to interruption of sympathetic chain at the T2 to T3 level with ganglion sparing (sympathicotomy group; n= 30). Time and frequency domains were measured with a 24-Holter monitor during daytime, nighttime, and 24-hour periods at different interval points (7 days before operation; 24 hours; and 1, 3, and 6 months later), and the differences were statistically compared. Clinical outcomes were also evaluated. Twenty-eight of 30 patients of the sympathectomy and 29 of 30 patients of the sympathicotomy group completed the study. In both groups, we observed a significant increase (p < 0.05) of vagal activity measurements as root mean square of the successive differences of heart period; proportion of adjacent normal R-R intervals >50 ms; high frequency; and a significant decrease (p < 0.05) of adrenergic activity variables as heart rate, low frequency, and the ratio between low frequency and high frequency during daytime, nighttime, and 24-hour periods. These changes were significantly more evident (p < 0.05) in the sympathectomy group than in the sympathicotomy group. Clinical outcomes were similar between the two groups. Endoscopic thoracic sympathectomy caused a shift of sympathovagal balance toward parasympathetic tone that seems to be associated with the extent of denervation. This trial was registered at clinicaltrials.gov as NCT02733497.

Distinctive cardiac autonomic dysfunction following stress exposure in both sexes in an animal model of PTSD

It is unclear whether the poor autonomic flexibility or dysregulation observed in patients with posttraumatic stress disorder (PTSD) represents a pre-trauma vulnerability factor or results from exposure to trauma. We used an animal model of PTSD to assess the association between the behavioral response to predator scent stress (PSS) and the cardiac autonomic modulation in male and female rats.The rats were surgically implanted with radiotelemetry devices to measure their electrocardiograms and locomotor activity (LMA). Following baseline telemetric monitoring, the animals were exposed to PSS or sham-PSS. Continuous telemetric monitoring (24h/day sampling) was performed over the course of 7days. The electrocardiographic recordings were analyzed using the time- and frequency-domain indexes of heart rate variability (HRV). The behavioral response patterns were assessed using the elevated plus maze and acoustic startle response paradigms for the retrospective classification of individuals according to the PTSD-related cut-off behavioral criteria.During resting conditions, the male rats had significantly higher heart rates (HR) and lower HRV parameters than the female rats during both the active and inactive phases of the daily cycle. Immediately after PSS exposure, both the female and male rats demonstrated a robust increase in HR and a marked drop in HRV parameters, with a shift of sympathovagal balance towards sympathetic predominance. In both sexes, autonomic system habituation and recovery were selectively inhibited in the rats whose behavior was extremely disrupted after exposure to PSS. However, in the female rats, exposure to the PSS produced fewer EBR rats, with a more rapid recovery curve than that of the male rats. PSS did not induce changes to the circadian rhythm of the LMA.According to our results, PTSD can be conceptualized as a disorder that is related to failure-of-recovery mechanisms that impede the restitution of physiological homeostasis.

Impaired Autonomic Regulation in Posttraumatic Stress Disorder

Post‐traumatic stress disorder (PTSD) is associated with a significantly increased risk of cardiovascular disease (CVD) and accumulating clinical evidence suggests that autonomic dysregulation due to sympathetic overactivity and/or parasympathetic insufficiency may contribute to progression of CVD in PTSD. Therefore, utilizing a translational approach, we sought to examine autonomic function in both a clinical PTSD population as well as in an animal model of PTSD. In experimental studies, mice were instrumented with radiotelemetry probes to evaluate autonomic indices following Pavlovian fear conditioning. Fear conditioning involves the pairing of a conditioned stimulus (e.g. tone) paired with an aversive uconditioned stimulus (e.g. foot shock) that evokes a conditioned response (e.g. freezing). Twenty‐four hours following fear conditioning, spectral analysis of heart rate was performed and the low‐to high‐frequency ratio (LF:HF) was used as an index of sympathovagal balance. Fear conditioned animals displayed a significant increase in the LF:HF ratio relative to baseline (1.21 ± 0.46; p&lt;0.05) indicating a shift in sympathovagal balance. Two weeks following fear conditioning, we assessed the contribution of sympathetic activity to the maintenance of blood pressure using the ganglionic blocker chlorisondamine (12ug/g i.p.). In response to sympathetic nervous system blockade, fear conditioned animals had a greater fall in blood pressure compared to control (Δ Systolic −71.7± 1.9 vs −39.8 ± 5.8 mmHg; p&lt;0.05). Collectively, these results suggest impairments in autonomic control in an animal model of PTSD prior to the onset of CVD. Finally, these findings will be compared to an ongoing clinical study using a population of combat‐related PTSD (n=13) versus age‐matched controls without PTSD (n=9). Continuous elecrocardiography, beat‐to‐beat arterial blood pressure (BP) measurements, and 24‐hour ambulatory BP measurements have been collected at rest, during, and following mental stress. In an effort to translate our pre‐clinical results, these data will be analyzed for spectral analysis of heart rate variability, BP variability, and 24‐hour ambulatory BP patterns.Support or Funding InformationNIH R00 HL107675‐03 American Heart Association ‐ 15CSA24340001

Analysis of cardiorespiratory phase coupling and cardiovascular autonomic responses during food ingestion

The present study analyzed whether the phase coherency (λ) of respiratory sinus arrhythmia (RSA) is altered by food ingestion in healthy young subjects. After 5min of resting control, 13 healthy volunteers were asked to eat a solid meal with access to water at their own pace, followed by 5min of the postprandial state. The R-R interval (RRI), beat-to-beat blood pressure (BP), and respiratory activity were recorded using electrocardiography, a Finapres device, and inductance plethysmography, respectively. The stroke volume was calculated by the pulse-contour method from continuous BP measurement, and the cardiac output (CO) was obtained by multiplying the stroke volume by the heart rate. From the oscillatory signals of RSA and respiration, λ was computed; additionally, frequency domain indexes of the heart rate variability (HRV) were calculated using a short-time Fourier transform. A steady-state 3-min resting period (R), food ingestion period (FOOD), and the first 2-min and the last 3-min of the post prandial period were analyzed separately. We also compared the responses to gum chewing (GUM) and water intake (WATER) using the same protocol on separate days. A shortening of RRI and increases in BP and CO were observed in FOOD compared to R, suggesting a shift of sympathovagal balance toward sympathetic activation. Similar responses but smaller magnitudes were observed in the GUM condition, whereas only transient shortening of RRI was observed in the WATER condition. The HRV indexes did not show any significant changes in response to GUM and WATER but sympathovagal balance was shifted in favor of sympathetic dominance in FOOD. λ decreased during all of the conditions. There was a significant negative correlation between λ and the indirect measure of sympathovagal balance. These results suggest that ingestion of food induces enhanced cardiac sympathetic activity and that a phase coherence of RSA could provide a sensitive measure for evaluating the cardiac autonomic profile.

Heart Rate Variability in Porcine Progressive Peritonitis-Induced Sepsis.

Accumulating evidence suggests that heart rate variability (HRV) alterations could serve as an indicator of sepsis progression and outcome, however, the relationships of HRV and major pathophysiological processes of sepsis remain unclear. Therefore, in this experimental study HRV was investigated in a clinically relevant long-term porcine model of severe sepsis/septic shock. HRV was analyzed by several methods and the parameters were correlated with pathophysiological processes of sepsis. In 16 anesthetized, mechanically ventilated, and instrumented domestic pigs of either gender, sepsis was induced by fecal peritonitis. Experimental subjects were screened up to the refractory shock development or death. ECG was continuously recorded throughout the experiment, afterwards RR intervals were detected and HRV parameters computed automatically using custom made measurement and analysis MATLAB routines. In all septic animals, progressive hyperdynamic septic shock developed. The statistical measures of HRV, geometrical measures of HRV and Poincaré plot analysis revealed a pronounced reduction of HRV that developed quickly upon the onset of sepsis and was maintained throughout the experiment. The frequency domain analysis demonstrated a decrease in the high frequency component and increase in the low frequency component together with an increase of the low/high frequency component ratio. The reduction of HRV parameters preceded sepsis-associated hemodynamic changes including heart rate increase or shock progression. In a clinically relevant porcine model of peritonitis-induced progressive septic shock, reduction of HRV parameters heralded sepsis development. HRV reduction was associated with a pronounced parasympathetic inhibition and a shift of sympathovagal balance. Early reduction of HRV may serve as a non-invasive and sensitive marker of systemic inflammatory syndrome, thereby widening the therapeutic window for early interventions.

Pyridostigmine enhances atrial tachyarrhythmias in aging spontaneously hypertensive rats.

This study examined whether chronic administration of pyridostigmine, a reversible cholinesterase inhibitor, would exacerbate episodes of spontaneous atrial tachyarrhythmia (AT) in conscious, aging, spontaneously hypertensive rats (SHRs). Telemetric recordings of electrocardiogram (ECG, n = 5) and ECG/arterial pressure (n = 3) were performed in male 49-week old SHRs. After a 1-week period of continuous recording under baseline conditions, rats were implanted with osmotic minipumps that delivered pyridostigmine (15 mg/kg/day subcutaneously) for either 1 (n = 8) or 3 (n = 5) weeks. In the latter case, sympathovagal balance was assessed during the last infusion week by measuring heart rate (HR) changes in response to administration of cardiac autonomic blockers. An additional 1-week recording was performed after explantation of minipumps. Significant (P = 0.02) reductions in HR with no consistent changes in arterial pressure were observed. Frequency and duration of AT episodes were increased by pyridostigmine (0.01 ≤ P ≤ 0.07). This increase was sustained across the 3-week treatment period and reversible after cessation of treatment. Autonomic blockade revealed that intrinsic HR was above (P = 0.04) resting HR, pointing to a shift of sympathovagal balance towards vagal predominance. However, the respiratory-related component of HR variability (high-frequency power of RR interval) was lowered (P = 0.01) by pyridostigmine treatment, indicating reduced vagal modulation of HR. The results are consistent with a pathogenic role of the parasympathetic nervous system in the aging SHR model, and raise the possibility that sustained vagal activation may facilitate atrial arrhythmias.