Pulse Interval Variability Research Articles

Examining the Light Heart Mobile Device App for Assessing Human Pulse Interval and Heart Rate Variability: Validation Study.

Pulse interval is a biomarker of psychological and physiological health. Pulse interval can now be assessed using mobile phone apps, which expands researchers' ability to assess pulse interval in the real world. Prior to implementation, measurement accuracy should be established. This investigation evaluated the validity of the Light Heart mobile app to measure pulse interval and pulse rate variability in healthy young adults. Validity was assessed by comparing the pulse interval and SD of normal pulse intervals obtained by Light Heart to the gold standard, electrocardiogram (ECG), in 14 young healthy individuals (mean age 24, SD 5 years; n=9, 64% female) in a seated posture. Mean pulse interval (Light Heart: 859, SD 113 ms; ECG: 857, SD 112 ms) demonstrated a strong positive linear correlation (r=0.99; P<.001) and strong agreement (intraclass correlation coefficient=1.00, 95% CI 0.99-1.00) between techniques. The Bland-Altman plot demonstrated good agreement for the mean pulse interval measured with Light Heart and ECG with evidence of fixed bias (-1.56, SD 1.86; 95% CI -5.2 to 2.1 ms), suggesting that Light Heart overestimates pulse interval by a small margin. When Bland-Altman plots were constructed for each participant's beat-by-beat pulse interval data, all participants demonstrated strong agreement between Light Heart and ECG with no evidence of fixed bias between measures. Heart rate variability, assessed by SD of normal pulse intervals, demonstrated strong agreement between techniques (Light Heart: mean 73, SD 23 ms; ECG: mean 73, SD 22 ms; r=0.99; P<.001; intraclass correlation coefficient=0.99, 95% CI 0.97-1.00). This study provides evidence to suggest that the Light Heart mobile app provides valid measures of pulse interval and heart rate variability in healthy young adults.

Protein Restriction in the Peri-Pubertal Period Induces Autonomic Dysfunction and Cardiac and Vascular Structural Changes in Adult Rats.

Perturbations to nutrition during critical periods are associated with changes in embryonic, fetal or postnatal developmental patterns that may render the offspring more likely to develop cardiovascular disease in later life. The aim of this study was to evaluate whether autonomic nervous system imbalance underpins in the long-term hypertension induced by dietary protein restriction during peri-pubertal period. Male Wistar rats were assigned to groups fed with a low protein (4% protein, LP) or control diet (20.5% protein; NP) during peri-puberty, from post-natal day (PN) 30 until PN60, and then all were returned to a normal protein diet until evaluation of cardiovascular and autonomic function at PN120. LP rats showed long-term increased mean arterial pressure (p = 0.002) and sympathetic arousal; increased power of the low frequency (LF) band of the arterial pressure spectral (p = 0.080) compared with NP animals. The depressor response to the ganglion blocker hexamethonium was increased in LP compared with control animals (p = 0.006). Pulse interval variability showed an increase in the LF band and LF/HF ratio (p = 0.062 and p = 0.048) in LP animals. The cardiac response to atenolol and/or methylatropine and the baroreflex sensitivity were similar between groups. LP animals showed ventricular hypertrophy (p = 0.044) and increased interstitial fibrosis (p = 0.028) compared with controls. Reduced protein carbonyls (PC) (p = 0.030) and catalase activity (p = 0.001) were observed in hearts from LP animals compared with control. In the brainstem, the levels of PC (p = 0.002) and the activity of superoxide dismutase and catalase (p = 0.044 and p = 0.012) were reduced in LP animals, while the levels of GSH and total glutathione were higher (p = 0.039 and p = 0.038) compared with NP animals. Protein restriction during peri-pubertal period leads to hypertension later in life accompanied by sustained sympathetic arousal, which may be associated with a disorganization of brain and cardiac redox state and structural cardiac alteration.

Abstract 32: Exercise Training Corrects Blood-brain Barrier Dysfunction Within Preautonomic Areas Of Spontaneously Hypertensive Rats By Normalizing The Augmented Transcytosis

Introduction: Besides intense neuro-hormonal activation, hypertension is accompanied by blood-brain barrier (BBB) dysfunction within preautonomic areas and marked autonomic imbalance. We showed previously that exercise training (T) corrected both increased BBB leakage and autonomic dysfunction. There is no information on the mechanism(s) conditioning the normalization of BBB function Hypothesis: We hypothesized that T could modify the transcytosis and/or the paracellular transport across the capillary endothelium Methods: SHR and Wistar rats allocated to T (55% maximal capacity) or sedentary (S) protocols were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (fluorescent Rhodamine-70kDa+FITC-10kDa dyes given ia ). To analyze hypertension- and T-induced BBB changes, paraventricular hypothalamic nuclei (PVN) was harvested and processed for immunofluorescence and transmission electron microscopy Results: SHR-S vs Wistar-S exhibited augmented SAP and reduced pulse interval (PI) variability, decreased spontaneous baroreflex sensitivity (BrS), increased both PVN BBB leakage (11.4±0.6 vs 3.48 %area) and transcytosis (8.1±1.2 vs 4.8±0.8 vesicles/capillary) but no change in tight junctions’expression (TJ, number/capillary). SHR-T showed a near normal autonomic control, resting bradycardia and a partial AP reduction (-9%) accompanied by normalization of both BBB leakage (3.6±1.5 %area) and transcytosis (3.8±0.7 vesicles/capillary), and increased TJs’ extension (60% occupancy of capillary borders) without changing its expression. Hypertension- and T-induced transcytosis changes were confirmed by caveolin-1 immunofluorescence (SHR-S=139±11, Wistar-S=86±8, SHR-T=81±6 arbitrary units). There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=1.77x -3.46, r 2 =0.722, P&lt;0.001) and BBB leakage x SAP variability (Y=2.30x +16.6, r 2 =0.246, P&lt;0.001) Conclusions: PVN BBB dysfunction in hypertension is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates SHR’s autonomic control by normalizing transcytosis, with an additional TJs structure improvement

Wrist Band Photoplethysmography Autocorrelation Analysis Enables Detection of Atrial Fibrillation Without Pulse Detection.

Atrial fibrillation is often asymptomatic and intermittent making its detection challenging. A photoplethysmography (PPG) provides a promising option for atrial fibrillation detection. However, the shapes of pulse waves vary in atrial fibrillation decreasing pulse and atrial fibrillation detection accuracy. This study evaluated ten robust photoplethysmography features for detection of atrial fibrillation. The study was a national multi-center clinical study in Finland and the data were combined from two broader research projects (NCT03721601, URL: https://clinicaltrials.gov/ct2/show/NCT03721601 and NCT03753139, URL: https://clinicaltrials.gov/ct2/show/NCT03753139). A photoplethysmography signal was recorded with a wrist band. Five pulse interval variability, four amplitude features and a novel autocorrelation-based morphology feature were calculated and evaluated independently as predictors of atrial fibrillation. A multivariate predictor model including only the most significant features was established. The models were 10-fold cross-validated. 359 patients were included in the study (atrial fibrillation n = 169, sinus rhythm n = 190). The autocorrelation univariate predictor model detected atrial fibrillation with the highest area under receiver operating characteristic curve (AUC) value of 0.982 (sensitivity 95.1%, specificity 93.7%). Autocorrelation was also the most significant individual feature (p < 0.00001) in the multivariate predictor model, detecting atrial fibrillation with AUC of 0.993 (sensitivity 96.4%, specificity 96.3%). Our results demonstrated that the autocorrelation independently detects atrial fibrillation reliably without the need of pulse detection. Combining pulse wave morphology-based features such as autocorrelation with information from pulse-interval variability it is possible to detect atrial fibrillation with high accuracy with a commercial wrist band. Photoplethysmography wrist bands accompanied with atrial fibrillation detection algorithms utilizing autocorrelation could provide a computationally very effective and reliable wearable monitoring method in screening of atrial fibrillation.

Quantitative detection of sleep apnea with wearable watch device.

The spread of wearable watch devices with photoplethysmography (PPG) sensors has made it possible to use continuous pulse wave data during daily life. We examined if PPG pulse wave data can be used to detect sleep apnea, a common but underdiagnosed health problem associated with impaired quality of life and increased cardiovascular risk. In 41 patients undergoing diagnostic polysomnography (PSG) for sleep apnea, PPG was recorded simultaneously with a wearable watch device. The pulse interval data were analyzed by an automated algorithm called auto-correlated wave detection with adaptive threshold (ACAT) which was developed for electrocardiogram (ECG) to detect the cyclic variation of heart rate (CVHR), a characteristic heart rate pattern accompanying sleep apnea episodes. The median (IQR) apnea-hypopnea index (AHI) was 17.2 (4.4-28.4) and 22 (54%) subjects had AHI ≥15. The hourly frequency of CVHR (Fcv) detected by the ACAT algorithm closely correlated with AHI (r = 0.81), while none of the time-domain, frequency-domain, or non-linear indices of pulse interval variability showed significant correlation. The Fcv was greater in subjects with AHI ≥15 (19.6 ± 12.3 /h) than in those with AHI <15 (6.4 ± 4.6 /h), and was able to discriminate them with 82% sensitivity, 89% specificity, and 85% accuracy. The classification performance was comparable to that obtained when the ACAT algorithm was applied to ECG R-R intervals during the PSG. The analysis of wearable watch PPG by the ACAT algorithm could be used for the quantitative screening of sleep apnea.

Cardiac sympathetic drive is increased in cafeteria diet-fed rats independent of impairment in peripheral baroreflex and chemoreflex functions

Background and aimsConsumption of a high caloric diet induces autonomic imbalance, which can lead to cardiovascular disease. Impaired arterial baroreflex control is suggested to play an important role in cardiovascular autonomic imbalance, often seen in obesity. We previously demonstrated that cafeteria diets increase the sympathetic drive to white and brown adipose tissue. Methods and resultsAfter feeding a cafeteria diet to rats for 26 days, we evaluated: (i)heart rate (HR) and arterial pressure (AP); (ii)baroreflex and chemoreflex function; and (iii) autonomic modulation of the heart and vessels, measured through pulse interval (PI) and systolic arterial pressure (SAP) variability analyses and following administration of autonomic blockers. The cafeteria diet increased body fat mass and serum insulin, leptin, triacylglycerol and cholesterol levels. Baseline HR (15%) was also increased, accompanied by increased power in the low frequency band (60%) and in the low frequency/high frequency ratio (104%) in the PI spectra. Nonlinear analysis revealed an increased occurrence of 0V (39%) and decreased occurrence of 2UV (18%) patterns. Following administration of autonomic blockers, we observed an increase in cardiac sympathetic tone (425%) in cafeteria diet-fed rats. The cafeteria diet had no effect on AP, SAP variability, baroreflex and chemoreflex control. ConclusionOur findings suggest that consumption of a cafeteria diet increases sympathetic drive to the heart but not to the blood vessels, independent of impairment in baroreflex and chemoreflex functions. Other mechanisms may be involved in the increased cardiac sympathetic drive, and compensatory vascular mechanisms may prevent the development of hypertension in this model of obesity.

Early activation of ubiquitin-proteasome system at the diaphragm tissue occurs independently of left ventricular dysfunction in SHR rats.

Hypertensive status induces modifications in the respiratory profile. Previous studies have indicated that hypertensive rats show increased respiratory-sympathetic coupling compared to normotensive rats. However, these effects and especially the mechanisms underlying such effects are not well known. Thus, we evaluated the influence of high blood pressure and autonomic dysfunction on a ventilatory pattern associated with lung injury and on the ubiquitin-proteasome system of the diaphragm muscle. Autonomic cardiovascular modulation (systolic BP variance and low-frequency band and pulse interval variance) and arterial blood gases patterns (pH, pO2, HCO3, SpO2), can be changed by hypertension, as well exacerbated chemoreflex pressor response. We observed that the diaphragm muscle of SHR showed increase in type I cross-sectional fiber (16%) and reduction in type II cross-sectional fiber area (41%), increased activity of the ubiquitin-proteasome system and lipid peroxidation, with no differences between groups in the analysis of ubiquitinated proteins and misfolded proteins. Our results showed that hypertension induced functional compensatory/adverse alterations associated with diaphragm fiber type changes and protein degradation as well as changed autonomic control of circulation. In conclusion, we believe there is an adaptation in ventilatory pattern in regarding to prevent the development of fatigue and muscle weakness and improve ventilatory endurance. Impact statement It was well known that hypertension can be driven by increased sympathetic activity and has been documented as a central link between autonomic dysfunction and alterations in the respiratory pattern. Our study demonstrated the impact of hypertension in ventilatory mechanics and their relationship with diaphragm muscle protein degradation. These findings may assist us in future alternative treatments to prevent diaphragm fatigue and weakness in hypertensive patients.

Cardiac autonomic regulation in patients undergoing pulmonary vein isolation for atrial fibrillation.

Ablation procedures for the treatment of atrial fibrillation lead to changes in autonomic heart control; however, there are insufficient data on the possible association of these changes with atrial fibrillation recurrence. The study aim was to assess the effects of pulmonary vein isolation (PVI) on cardiac autonomic modulation and atrial fibrillation recurrence. We screened 52 patients with atrial fibrillation referred for PVI, of whom 20 patients met inclusion and exclusion criteria, and were enrolled in the study and followed over 6 months. Beat-to-beat blood pressure monitoring was performed 1-2 days before PVI, 1 and 6 months after PVI. We estimated pulse interval variability and spontaneous baroreflex sensitivity (BRS) both in the time and frequency domains, and performed the Valsalva manoeuvre assessing the Valsalva ratio. During 6 months after PVI, atrial fibrillation recurrence was observed in six patients. One month after PVI, pulse interval variability and BRS (sequence method) significantly decreased in all patients, returning to preintervention values by 6 months. Patients without atrial fibrillation recurrence at 1 month showed a transient reduction in pulse interval variability (frequency domain) and in BRS (both methods) in contrast to those with atrial fibrillation recurrence. A significant decrease in the Valsalva ratio observed at 1 month was maintained at 6 months after PVI in both groups. Successful PVI may lead to transient autonomic alterations reflected by a reduction in pulse interval variability and BRS, with more prolonged changes in the Valsalva ratio. The efficacy of PVI in preventing atrial fibrillation recurrence seems to be related to transient parasympathetic atrial denervation.

The Effect of Different Antihypertensive Classes on the Complexity of Heart Rate and Blood Pressure Variability

Hypertension is associated with several physiological dysfunctions, including changes in the neurohumoral control of heart and vessels. Different classes of antihypertensive drugs may have distinct effects on the autonomic system and body homeostasis, but their individual effects on the complexity of cardiovascular regulation are still not established. We investigated the effect of five different classes of antihypertensive on the complexity of pulse interval (PI) and arterial pressure (AP) variability in an experimental model of renal hypertension (2 kidney 1 clip, 2K1C) in the rat. Hypertensive rats were treated (by gavage) during 15 days with: water (N=12), ramipril (2 mg/kg/day; N=7), losartan (10 mg/kg/day; N=8), atenolol (90 mg/kg/day; N=9), amlodipine (10 mg/kg/day; N=7) or hydrochlorothiazide (20 mg/kg/day; N=8). A normotensive (sham‐operated) control group (N=10) received water for the same period. After the treatment, rats had their raw AP recorded and beat‐by‐beat series of systolic AP and PI were created. The complexity of AP and PI was assessed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA). For PI series, hypertensive rats treated with water showed decreased MSE and increased DFA in the middle range of scales. For AP series, hypertensive rats untreated or treated with amlodipine have lower MSE at short and middle time scales. Hypertensive rats treated with amlodipine also showed altered DFA in comparison to the other groups. All antihypertensive drugs were efficient to restore AP to normal levels. Moreover, 2K1C untreated (water) rats presented the lowest cardiovascular complexity and all antihypertensive drugs, except for amlodipine, were capable to restore the cardiovascular complexity to normal levels. Therefore, amlodipine seems to have a deleterious effect on the cardiovascular integrative control, probably due to the increased sympathetic activity induced by amlodipine.Support or Funding InformationThis study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) ‐ Finance Code 001, São Paulo Research Foundation (FAPESP, Proc. 2013/20549‐7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Proc. 402076/2016‐8).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cholinergic Stimulation by Pyridostigmine Bromide Before Myocardial Infarction Prevent Cardiac and Autonomic Dysfunction

Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In this sense, some studies are investigating pharmacological therapies using acetylcholinesterase inhibitors, such as pyridostigmine bromide (PYR), aiming to increase parasympathetic tone after MI. Here we hypothesized that the use of PYR before the MI might bring an additional positive effect to the autonomic function, and consequently, in the inflammatory response and cardiac function. The present study aimed to evaluate left ventricular function, baroreflex sensitivity, autonomic modulation, and inflammatory profile in PYR-treated rats previously to MI. Methods: Male Wistar rats (250–300 g) were treated for 60 days with PYR. After treatment, they were submitted to the MI. After the MI, the autonomic and ventricular function were evaluated, as well as the systemic, left ventricle, and adipose tissue inflammatory profile. Results: PYR, performed before MI, prevented HR increase, systolic function impairment, baroreflex sensitivity drop, as well as pulse interval variance, RMSSD, blood pressure and parasympathetic modulation reduction in treated rats compared to untreated rats. Also, this positive functional changes may have been a result of the reduced inflammatory parameters in the left ventricle (IFN-γ, IL-6, and IL-1β), as well as increased IL-10 expression and IL-10/TNF-α ratio in treated animals before MI. Conclusion: Prior treatment with PYR prevents impairment of the autonomic nervous system after MI, which may be associated with the attenuated expression of inflammatory factors and heart dysfunction.

Assessment of Baroreflex Sensitivity Using Time-Frequency Analysis during Postural Change and Hypercapnia.

Baroreflex is a mechanism of short-term neural control responsible for maintaining stable levels of arterial blood pressure (ABP) in an ABP-heart rate negative feedback loop. Its function is assessed by baroreflex sensitivity (BRS)—a parameter which quantifies the relationship between changes in ABP and corresponding changes in heart rate (HR). The effect of postural change as well as the effect of changes in blood O2 and CO2 have been the focus of multiple previous studies on BRS. However, little is known about the influence of the combination of these two factors on dynamic baroreflex response. Furthermore, classical methods used for BRS assessment are based on the assumption of stationarity that may lead to unreliable results in the case of mostly nonstationary cardiovascular signals. Therefore, we aimed to investigate BRS during repeated transitions between squatting and standing in normal end-tidal CO2 (EtCO2) conditions (normocapnia) and conditions of progressively increasing EtCO2 with a decreasing level of O2 (hypercapnia with hypoxia) using joint time and frequency domain (TF) approach to BRS estimation that overcomes the limitation of classical methods. Noninvasive continuous measurements of ABP and EtCO2 were conducted in a group of 40 healthy young volunteers. The time course of BRS was estimated from TF representations of pulse interval variability and systolic pressure variability, their coherence, and phase spectra. The relationship between time-variant BRS and indices of ABP and HR was analyzed during postural change in normocapnia and hypercapnia with hypoxia. In normocapnia, observed trends in all measures were in accordance with previous studies, supporting the validity of presented TF method. Similar but slightly attenuated response to postural change was observed in hypercapnia with hypoxia. Our results show the merits of the nonstationary methods as a tool to study the cardiovascular system during short-term hemodynamic changes.

Hypertension induces additional cardiometabolic impairments and attenuates aerobic exercise training adaptations in fructose-fed ovariectomized rats.

We tested whether hypertension favors the development of additional cardiometabolic changes in fructose-fed ovariectomized rats and how it affects aerobic exercise training (ET) effects. All rats received fructose in drinking water (10%) beginning at weaning, were ovariectomized at 10 weeks of age and divided into the normotensive sedentary (NFOS) and trained (NFOT) and hypertensive sedentary (HFOS) and trained (HFOT) groups. ET was performed on a treadmill. Arterial pressure (AP) was directly recorded; heart rate and AP variabilities were analyzed. Lipoperoxidation (LPO) and antioxidant enzyme levels were measured in the left ventricle. In addition to increased AP levels, when compared with the NFOS group, the hypertensive groups had resting tachycardia, a reduction of 29% in the pulse interval variance (VAR-PI), 19% in RMSSD (root mean square of successive differences, a cardiac parasympathetic index) and 53% in the α-index (spontaneous baroreflex), while the systolic AP variance (VAR-SAP) and its low-frequency band (LF-SAP) were sharply increased. ET did not alter AP levels. Even in the presence of hypertension, ET induced resting bradycardia, decreases of 33% in VAR-SAP and 49% in LF-SAP, and an increase of more than 60% in VAR-PI and the α-index. However, some of these parameters were still impaired relative to those of normotensive rats. LPO was reduced and catalase was increased in both trained groups, with no difference between the normotensive and hypertensive groups. Negative correlations were obtained between LPO and RMSSD (r=-0.60, P<0.05) and α-index (r=-0.63, P<0.05). In conclusion, hypertension augmented the dysfunctions in fructose-fed ovariectomized rats and attenuated metabolic aerobic ET benefits. These changes may be related to cardiovascular autonomic and oxidative stress alterations.

Accuracy of pulse interval timing in ambulatory blood pressure measurement.

Blood pressure (BP) monitors rely on pulse detection. Some blood pressure monitors use pulse timings to analyse pulse interval variability for arrhythmia screening, but this assumes that the pulse interval timings detected from BP cuffs are accurate compared with RR intervals derived from ECG. In this study we compared the accuracy of pulse intervals detected using an ambulatory blood pressure monitor (ABPM) with single lead ECG. Twenty participants wore an ABPM for three hours and a data logger which synchronously measured cuff pressure and ECG. RR intervals were compared with corresponding intervals derived from the cuff pressure tracings using three different pulse landmarks. Linear mixed effects models were used to assess differences between ECG and cuff pressure timings and to investigate the effect of potential covariates. In addition, the maximum number of successive oscillometric beats detectable in a measurement was assessed. From 243 BP measurements, the landmark at the foot of the oscillometric pulse was found to be associated with fewest covariates and had a random error of 9.5 ms. 99% of the cuff pressure recordings had more than 10 successive detectable oscillometric beats. RR intervals can be accurately estimated using an ABPM.

Acetylcholinesterase Inhibition Attenuates the Development of Hypertension and Inflammation in Spontaneously Hypertensive Rats.

It is hypothesized that chronic increase of availability of acetylcholine, resulting from the effect of antiacetylcholinesterases, may prevent autonomic imbalance and reduce inflammation yielding benefic effects for cardiovascular disorders in hypertension. The effect of long-term administration of antiacetylcholinesterase agents with central and/or peripheral action, i.e., donepezil and pyridostigmine, were investigated on arterial pressure (AP), sympathovagal balance, plasma cytokine levels, and cardiac remodeling in spontaneously hypertensive rats (SHR). Chronic treatment with donepezil or pyridostigmine started before the onset of hypertension. AP was measured by plethysmography every 4 weeks. At the end of 16 weeks of treatment, methylatropine was used to evaluate the cardiac vagal tone; AP and pulse interval (PI) variability were also evaluated followed by plasma and heart collection for analysis. Pyridostigmine, which does not cross the blood-brain barrier, increased cardiac vagal tone, and reduced cardiomyocyte diameter and collagen density, but did not affect the AP and plasma cytokine levels. Donepezil, which crosses the blood-brain barrier, attenuated the development of hypertension, increased cardiac vagal tone, and improved AP and PI variability. Likewise, donepezil reduced the plasma levels of tumor necrosis factor-α, interleukin 6, and interferon γ, besides reducing cardiomyocyte diameter and collagen density. Donepezil attenuated the development of hypertension in SHR probably involving antiinflammatory effects, indicating that acetylcholinesterase inhibition yields benefic effects for antihypertensive therapy.

Toll-like receptor 9 plays a key role in the autonomic cardiac and baroreflex control of arterial pressure.

The crosstalk between the immune and the autonomic nervous system may impact the cardiovascular function. Toll-like receptors are components of the innate immune system and play developmental and physiological roles. Toll-like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases, such as hypertension and heart failure. Since such diseases are commonly accompanied by autonomic imbalance and lower baroreflex sensitivity, we hypothesized that TLR9 modulates cardiac autonomic and baroreflex control of arterial pressure (AP). Toll-like receptor 9 knockout (TLR9 KO) and wild-type (WT) mice were implanted with catheters into carotid artery and jugular vein and allowed to recover for 3 days. After basal recording of AP, mice received methyl-atropine or propranolol. AP and pulse interval (PI) variability were evaluated in the time and frequency domain (spectral analysis), as well as by multiscale entropy. Spontaneous baroreflex was studied by sequence technique. Behavioral and cardiovascular responses to fear-conditioning stress were also evaluated. AP was similar between groups, but TLR9 KO mice exhibited lower basal heart rate (HR). AP variability was not different, but PI variability was increased in TLR9 KO mice. The total entropy was higher in TLR9 KO mice. Moreover, baroreflex function was found higher in TLR9 KO mice. Atropine-induced tachycardia was increased in TLR9 KO mice, whereas the propranolol-induced bradycardia was similar to WT mice. TLR9 KO mice exhibit increased behavioral and decreased tachycardia responses to fear-conditioning stress. In conclusion, our findings suggest that TLR9 may negatively modulate cardiac vagal tone and baroreflex in mice.

Abstract 273: Aerobic, Resistance And Combined Exercise Training Across The Lifespan Are Effective In Improving Heart Rate And Blood Pressure Variability In Obese Mice

The aim of this study was to compare the effects of aerobic, resistance and combined exercise training on autonomic parameters in youth obese mice. Female mice (4 weeks) were randomized into: wild type sedentary (WS, n=11), ob/ob sedentary (OS, n=11), ob/ob aerobic trained (OA, n=8) (treadmill,5days/w, 60min/d, during 8 wks), ob/ob resistance trained (OR, n=8) (ladder climb, 5 days/w, during 8 wks) and ob/ob combined trained (OC, n=8) (alternate days of aerobic and resistance exercise) groups. Blood pressure (BP) signals were directly recorded using a data acquisition system. OS group presented higher blood glucose levels (169±8mg/dL) than WS animals (121±6mg/dL). In addition ob/ob trained groups (OA, OR and OC) groups had reduced blood glucose (OA:133±3, OR:155±9 and OC:143±11mg/dL) in comparison with OS group. Systolic, diastolic and mean BP and heart rate were similar among groups. The ob/ob mice showed an decrease in pulse interval variance and RMSSD compared with WS group. The three types of training were effective in increasing these parameters in trained mice compared with ob/ob sedentary mice. The BP variability was similar among groups; however, the low frequency band of BP was higher in the sedentary groups (WS:10±1 and OS:10±1mmHg 2 ) compared to OA (5±1mmHg 2 ) and OR (5±1mmHg 2 ) groups. . The spontaneous baroreflex sensitivity was lower in ob/ob groups compared to WS (3±0.3 ms/mmHg). Furthermore, the OS group showed decrease in this parameter (0.6±0.3 ms/mmHg) compared to OA (1.7±0.2ms/mmHg) and OR groups (2±0.6ms/mmHg). The OA, OR and OC groups were similar in relation to low frequency band of BP and baroreflex sensitivity. Thus, our results suggest that physical training across the lifespan, either aerobic and/or resistance exercise, can be effective in attenuating the autonomic dysfunctions associated with obesity in mice.

Spontaneous hypertension induced pulmonar and diaphragm disorders in rats (856.11)

Hypertension induces modifications of standard rhythm breathing. However, the interaction of these effects with the cardiopulmonary and diaphragm morphological changes is not well known. We evaluated the influence of high blood pressure (BP) on cardiovascular modulation, chemoreflex sensitivity, right ventricle (RV) function, arterial blood gases and pulmonary morphometric parameters in rats. We also evaluated the diaphragm muscle profile in response to possible ventilator alterations. Hypertension adversely changed arterial blood gases patterns (pH, pO2, HCO3, SpO2) and the autonomic cardiovascular modulation (systolic BP variance, low frequency band and pulse interval variance), as well exacerbated chemoreflex pressor response and increased RV end diastolic pressure. We observed that SHRs present higher lung to body weight index, arterial lumen to wall ratio (lung arteries), and collagen deposition compared to aged matched Wistar rats. The SHR diaphragm muscle showed increase in type I cross‐sectional fiber (CSA) (16%) and reduction in type II CSA area (41%), increased activity of the ubiquitin proteasome system and lipid peroxidation, with no differences between groups in the analysis of ubiquitinated proteins and misfolded proteins. In conclusion, hypertension induced cardiopulmonary morphometric and functional compensatory/adverse alterations associated with diaphragm fiber type changes and protein degradation. These data suggest a possible adaptation in ventilatory pattern as an attempt to improve ventilatory endurance and prevent the development of fatigue and muscle weakness.

Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats

Hyperhomocysteinemia (HHcy) is associated with cardiovascular disease, atherosclerosis and reactive oxygen species generation. Thus, our aim was to investigate whether there was an association between HHcy, blood pressure, autonomic control and liver oxidative stress. Male Wistar rats were divided into 2 groups and treated for 8weeks: one group (control, CO) received tap water, while the other group (methionine, ME) was given a 100mg/kg of methionine in water by gavage. Two catheters were implanted into the femoral artery and vein to record arterial pressure (AP) and heart rate (HR) and drug administration. Signals were recorded by a data acquisition system. Baroreflex sensitivity was evaluated by HR responses to AP changes induced by vasoactive drugs. HR variability and AP variability were performed by spectral analysis in time and frequency domains to evaluate the contribution of the sympathetic and parasympathetic modulation. Lipid peroxidation and antioxidant enzyme activities were evaluated by measuring superoxide dismutase, catalase and glutathione peroxidase in liver homogenates. The ME group presented a significant increase in systolic arterial pressure (118±9 vs 135±6mmHg), diastolic arterial pressure (81±6 vs. 92±4) and mean arterial pressure (95±7 vs. 106±6). In addition, pulse interval variability presented a significant decrease (41%), while the low frequency component of AP was significantly increased (delta P=6.24mmHg(2)) in the ME group. We also found a positive association between lipid peroxidation and cardiac sympathetic modulation, sympathetic and vagal modulation ratio and systolic pressure variability. Collectively, these findings showed that HHcy induced dysfunction of cardiovascular autonomic system and liver oxidative stress.

Abstract 382: Increasing Parasympathetic Function Improves the Autonomic Balance and Attenuates the Inflammatory Process During the Development of Hypertension in Spontaneously Hypertensive Rats

Autonomic dysfunction and inflammation contribute to the pathophysiology of hypertension. Therefore, an increase in parasympathetic function may have benefic effects during the development of arterial hypertension. We investigated the chronic effect (16 weeks) of the acetylcholinesterase inhibitor donepezil on arterial pressure (AP), heart rate (HR), vagal tone, AP and pulse interval (PI) variability, plasma noradrenaline and pro-inflammatory plasma cytokines in spontaneously hypertensive rats (SHR). DON administration (minipumps, 2 mg/kg/day, n=8) started with SHR aging 5 weeks. Control SHR (n=7) were implanted with empty minipumps. At the end of 16 weeks, femoral AP was recorded in conscious state and methyl atropine provided the evaluation of the vagal tone. Plasma cytokines were analyzed by ELISA. DON promoted: decrease in systolic AP (178±8 vs 202±5 mmHg in control) and HR (304±9 vs 354±13 bpm in control); increase in vagal tone (105±11 vs 64±5 bpm in control); no change of plasma noradrenaline (8.7±0.6 vs 9.1±1.1ng/mL in control); reduction of AP variance (39±7 vs 63±5 mmHg 2 in control), power of the low frequency band (LF) of the systolic AP spectrum (4±1 vs 12±3 mmHg 2 in control) and LF/HF ratio of PI spectrum (0.2±0.03 vs 0.5±0.005 in control). DON reduced the pro-inflammatory cytokines (pg/mL): TNF-α (22±9 vs 54±5 in control), IFN-γ (11±5 vs 27±5 in control) and IL-6 (22±4 vs 38±5 in control). In conclusion, the increase in parasympathetic function by means of the chronic blockade of acetylcholinesterase with DON improved the cardiovascular autonomic balance and attenuated the inflammatory process during the development of hypertension in SHR.

Abstract 268: Toll-like Receptor 9 (TLR9) Plays a Key Role in the Autonomic Cardiac and Baroreflex Control of Arterial Pressure

Introduction: The crosstalk between the immune and nervous system can impact cardiovascular regulation. Toll-like receptor 9 (TLR9) is expressed in immune cells, peripheral nerves and vascular smooth muscle cells. TLR9 is involved in hypertension and cholinergic stimulation suppresses immune responses mediated by TLR9. Based on that, we hypothesized that TLR9 plays a role in cardiac autonomic and baroreflex control of arterial pressure (AP). Methods and Results: TLR9 knockout (KO) and WT mice were anesthetized with isoflurane, implanted with catheters into left carotid artery and right jugular vein and allowed to recovery for 3 days. After basal recording of AP, mice received cardiac autonomic receptor blockers methyl atropine or propranolol. AP and pulse interval (PI) variability were evaluated using the symbolic analysis (non-linear method). Spontaneous baroreflex was evaluated by sequence technique. Mean AP was slightly higher in TLR9 KO (TLR9 KO: 126±2.8 vs WT: 115±4.4 mmHg). In the symbolic analysis the 0V pattern was lower (TLR9 KO: 20±5.4 vs WT: 35±5.0 %) and 2LV pattern was higher in the TLR9 KO (TLR9 KO: 6±1.6 vs WT: 2±0.5 %), an indication of sympathetic and parasympathetic activity, respectively. AP/PI sequences were similar between groups. However, the gain of AP/PI sequences was increased in TLR9 KO (TLR9 KO: 5±1.4 vs WT: 2±0.4 ms/mmHg). Atropine-induced tachycardia was increased in TLR9 KO (TLR9 KO: 23±8.0 vs WT: 2±0.7 ms), whereas propranolol-induced bradycardia was decreased (28±11.0 vs WT: 56±7.6 ms). Conclusions: Our findings demonstrate that TLR9 negatively modulates cardiac vagal tone, and consequently the baroreflex control of AP.