Baroreflex Effectiveness Index Research Articles

Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes.

There is a considerable overlap between the clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in a general group of patients with PCC and in a group of patients with ME/CFS whose disease was not related to COVID-19. We hypothesize that the similarity in the chronic symptoms of patients with PCC and ME/CFS extends to objective autonomic nervous system abnormalities. Synchronous recordings of an electrocardiogram and continuous dynamics of blood pressure in the digital artery using the Penaz method were obtained using the spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting the PCC definition and 32 healthy controls. Heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) were assessed at rest and in tests with fixed respiratory rates. Indicators of baroreflex regulation (baroreflex effectiveness index and baroreflex sensitivity) were additionally determined at rest. The total power and power of low-frequency and high-frequency of RR interval variability at rest as well as baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to healthy controls. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing, the HRV parameters returned to normal in PCC but not in ME/CFS patients. The correlation analysis revealed a close relationship of HRV, BPV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in the ME/CFS and PCC patients. A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependent dysautonomia was identified in the ME/CFS and PCC patients. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationships between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction.

P038 Characterising Pulse Wave Amplitude Drops in Patients with Acute Coronary Syndrome

Abstract Pulse wave amplitude derived from photoplethysmography signals is a surrogate measure of autonomic function and vascular response. Recent studies have demonstrated low pulse wave amplitude drop(PWAD) index to be associated with increased cardiovascular risk in obstructive sleep apnoea(OSA). The nature of PWAD in patients with cardiovascular disease remains unknown. We aimed to characterize PWAD in patients with acute coronary syndrome(ACS) diagnosed with OSA in terms of cardiovascular measures. We studied 70 patients with ACS (age:58[52,63]years, BMI:27[24,30]kg/m2). A level 2 polysomnogram was conducted to confirm OSA diagnosis within 6 months after discharge. Cardiovascular measures of heart rate variability(HRV), baroreflex sensitivity, pulse wave velocity (PWV) and endothelial function(FMD) were measured. PWAD was analysed using a validated algorithm. PWAD with an amplitude reduction of >30% from baseline and a duration >4 heartbeats were identified. PWAD frequency, duration, amplitude, area under the curve(AUC), descending and ascending slopes were calculated. There was no relationship between PWAD frequency and AHI (r=0.057, p=0.642). PWAD amplitude (rs= 0.308, p=0.031) and duration (rs= -0.319, p= 0.025) correlated with baroreflex effectiveness index. After controlling for age, gender and BMI, baroreflex effectiveness index was associated with PWAD duration (β±SE: -0.009±0.003, p=0.009). Aortic augmentation index correlated with PWAD duration (rs= 0.3565, p=0.0041). HRV parameters, FMD and PWV did not correlate with PWAD parameters (data not shown). These preliminary findings suggest PWAD duration and amplitude are not associated with OSA severity in patients with ACS. However PWAD may be appropriate markers of vascular and autonomic nervous system response in patients with cardiovascular disease.

Orthostatic Stress and Baroreflex Sensitivity: A Window into Autonomic Dysfunction in Lone Paroxysmal Atrial Fibrillation.

The abnormal neural control of atria has been considered one of the mechanisms of paroxysmal atrial fibrillation (PAF) pathogenesis. The baroreceptor reflex has an important role in cardiovascular regulation and may serve as an index of autonomic function. This study aimed to analyze the baroreceptor reflex's role in heart rate regulation during upright tilt (HUT) in patients with lone PAF. The study included 68 patients with lone PAF and 34 healthy individuals who underwent baroreflex assessment. Parameters such as baroreflex sensitivity (BRS), number of systolic blood pressure (BP) ramps, and the baroreflex effectiveness index (BEI) were evaluated. The study found that PAF patients had comparable resting BPs and heart rates (HRs) to healthy individuals. However, unlike healthy individuals, PAF patients showed a sustained increase in BP with an upright posture followed by the delayed activation of the baroreceptor function with a blunted HR response and lower BEI values. This indicates a pronounced baroreflex impairment in PAF patients, even at rest. Our data suggest that together with BRS, BEI could be used as a marker of autonomic dysfunction in PAF patients, making it important to further investigate its relationship with AF recurrence after ablation and its involvement in cardiovascular autonomic remodeling.

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

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

Ontogenetic scaling of the baroreflex function in the green iguana (Iguana iguana).

Large body mass (Mb) in vertebrates is associated with longer pulse intervals between heartbeats (PI) and thicker arterial walls. Longer PI increases the time for diastolic pressure decay, possibly resulting in loss of cardiac energy as "oscillatory power," whereas thicker arterial walls may affect the transmission of impulses and sensing of pressure fluctuations thus impairing baroreflex function. We aimed to investigate the effect of growth on the relative cardiac energy loss and baroreflex function. We predicted that 1) the relative use of cardiac energy should be preserved with increased time constant for pressure decay (τ = vascular resistance × compliance) and 2) if arterial circumferential distensibility does not change, baroreflex function should be unaltered with Mb. To test these hypotheses, we used green iguanas (Iguana iguana) weighing from 0.03 to 1.34 kg (43-fold increment in Mb). PI (P = 0.037) and τ (P = 0.035) increased with Mb, whereas the oscillatory power fraction (P = 0.245) was unrelated to it. Thus, the concomitant alterations of τ and PI allowed the conservation of cardiac energy in larger lizards. Larger animals had thicker arterial walls (P = 0.0007) and greater relative collagen content (P = 0.022). Area compliance scaled positively to Mb (P = 0.045), though circumferential distensibility (P = 0.155) and elastic modulus (P = 0.762) were unaltered. In addition, baroreflex sensitivity, measured by both the pharmacological (P = 0.152) and sequence methods (P = 0.088), and the baroreflex effectiveness index (P = 0.306) were also unrelated to Mb. Therefore, changes in arterial morphology did not affect circumferential distensibility and presumably sensing of pressure fluctuation, and the cardiovagal baroreflex is preserved across different Mb.

Acute cardiac autonomic and haemodynamic responses to leg and arm isometric exercise.

Acute cardiovascular responses following a single session of isometric exercise (IE) have been shown to predict chronic adaptations in blood pressure (BP) regulation. It was hypothesised that exercises which recruit more muscle mass induce greater reductions in BP compared to exercises using smaller muscle mass. To test this hypothesis, the current study aimed to compare the acute haemodynamic and autonomic responses to a single session of isometric wall squat (IWS) and isometric handgrip (IHG) training. Twenty-six sedentary participants performed a single IWS and IHG session in a randomised cross-over design, with training composed of 4 × 2-min contractions, with 2-min rest, at 95 HRpeak and 30% MVC respectively. Haemodynamic and cardiac autonomic variables were recorded pre, during, immediately post, and 1-h post-exercise, with the change from baseline for each variable used for comparative analysis. During IWS exercise, there was a significantly greater increase in systolic BP (P < 0.001), diastolic BP (P < 0.001), mean BP (P < 0.001), heart rate (P < 0.001), and cardiac output (P < 0.001), and a contrasting decrease in baroreflex effectiveness index (BEI) and cardiac baroreceptor sensitivity (cBRS). In the 10-min recovery period following IWS exercise, there was a significantly greater reduction in systolic BP (P = 0.005), diastolic BP (P = 0.006), mean BP (P = 0.003), total peripheral resistance (TPR) (P < 0.001), BEI (P = 0.003), and power spectral density (PSD-RRI) (P < 0.001). There were no differences in any variables between conditions 1-h post exercise. Isometric wall squat exercise involving larger muscle mass is associated with a significantly greater post-exercise hypotensive response during a 10-min recovery window compared to smaller muscle mass IHG exercise. The significantly greater reduction in TPR may be an important mechanism for the differences in BP response.

Impact of angiotensin-converting enzyme inhibition on hemodynamic and autonomic profile of elastase-2 knockout mice.

Elastase-2 (ELA-2) is an angiotensin II-generating enzyme that participates in the cardiovascular system. ELA-2 is involved in hemodynamic and autonomic control and is upregulated in myocardial infarction and hypertension. The inhibition of angiotensin-converting enzyme (ACE) increased ELA-2 expression in the carotid arteries and heart of spontaneously hypertensive rats. In this study, we sought to investigate the role of ACE inhibition in hemodynamic and autonomic balance in elastase-2 knockout (ELA-2 KO) mice. Male ELA-2 KO and C57BL/6 mice were treated with the ACE inhibitor enalapril or saline for 10 days. After treatment, mice underwent surgery for cannulation of the femoral artery and arterial pressure recordings were made five days later in awake animals. The variability of systolic blood pressure (SBP) and pulse interval (PI) was evaluated in the time and frequency domain. Spontaneous baroreflex was assessed by the sequencing method. ACE inhibition caused a significant decrease in mean arterial pressure (117±2.2 vs 100±2.8 mmHg) and an increase in heart rate (570±32 vs 655±15 bpm) in ELA-2 KO mice. Despite a tendency towards reduction in the overall heart rate variability (standard deviation of successive values: 7.6±1.1 vs 4.7±0.6 ms, P=0.08), no changes were found in the root of the mean sum of squares or in the power of the high-frequency band. ACE inhibition did not change the spontaneous baroreflex indices (gain and baroreflex effectiveness index) in ELA-2 KO mice. Altogether, this data suggested that ACE played a role in the maintenance of hemodynamic function in ELA-2 KO mice.

Early Left Ventricular Diastolic Dysfunction, Reduced Baroreflex Sensitivity, and Cardiac Autonomic Imbalance in Anabolic-Androgenic Steroid Users.

The effects of androgen anabolic steroids (AAS) use on athletes’ cardiac autonomic activity in terms of baroreflex sensitivity (BRS), and heart rate variability (HRV) have not yet been adequately studied. Furthermore, there is no information to describe the possible relationship between the structural and functional cardiac remodeling and the cardiac autonomic nervous system changes caused by AAS abuse. Thus, we aimed to study the effects of long-term AAS abuse on cardiac autonomic efficacy and cardiac adaptations in strength-trained athletes. In total, 80 strength-trained athletes (weightlifters and bodybuilders) participated in the study. Notably, 40 of them using AAS according to their state formed group A, 40 nonuser strength-trained athletes comprised group B, and 40 healthy nonathletes (group C) were used as controls. All subjects underwent a head-up tilt test using the 30 min protocol to evaluate the baroreflex sensitivity and short HRV modulation. Furthermore, all athletes undertook standard echocardiography, a cardiac tissue Doppler imaging (TDI) study, and a maximal spiroergometric test on a treadmill to estimate their maximum oxygen consumption (VO2max). The tilt test results showed that group A presented a significantly lower BRS and baroreflex effectiveness index than group B by 13.8% and 10.7%, respectively (p < 0.05). Regarding short-term HRV analysis, a significant increase was observed in sympathetic activity in AAS users. Moreover, athletes of group A showed increased left ventricular (LV) mass index (LVMI) by 8.9% (p < 0.05), compared to group B. However, no difference was found in LV ejection fraction between the groups. TDI measurements indicated that AAS users had decreased septal and lateral peak E’ by 38.0% (p < 0.05) and 32.1% (p < 0.05), respectively, and increased E/E’ by 32.0% (p < 0.05), compared to group B. This LV diastolic function alteration was correlated with the year of AAS abuse. A significant correlation was established between BRS depression and LV diastolic impairment in AAS users. Cardiopulmonary test results showed that AAS users had significantly higher time to exhaustion by 11.0 % (p < 0.05) and VO2max by 15.1% (p < 0.05), compared to controls. A significant correlation was found between VO2max and LVMI in AAS users. The results of the present study indicated that long-term AAS use in strength-trained athletes led to altered cardiovascular autonomic modulations, which were associated with indices of early LV diastolic dysfunction.

The AT-1 Angiotensin Receptor is Involved in the Autonomic and Neuroendocrine Responses to Acute Restraint Stress in Male Rats.

The renin-angiotensin system (RAS) is involved in cardiovascular and hydroelectrolytic control, being associated with the development of hypertension. The restraint stress (RS) model is an aversive situation, which promotes a sustained increase in blood pressure and heart rate, and stimulation of the hypothalamic-pituitary-adrenal axis. Stress leads to an increase of angiotensin-II contents both in the circulation and the central nervous system (CNS), as well as an increased expression of AT-1 receptors in CNS structures related to stress. Stressful stimuli are associated with the modulation of autonomic nervous system, as well as baroreflex; changes in this adjustment mechanism are related to cardiovascular diseases. We hypothesized that RAS is involved in the modulation of autonomic, neuroendocrine, and functional RS-caused alterations. The intravenous (i.v) pretreatment of rats with lisinopril, an angiotensin-converting-enzyme inhibitor, reduced the RS-evoked pressor response. The doses of 0.1 and 0.3mg/kg also reduced the RS-evoked tachycardia, while in the dose of 1mg/kg of lisinopril potentiated the tachycardic one. Additionally, i.v. pretreatment with losartan, a selective AT-1 receptor antagonist, reduced the pressor and the tachycardic responses caused by RS. Pretreatment with lisinopril 0.3mg/kg increased the power of the low frequency (LF) band of the systolic BP spectrum after the treatment without affecting this parameter during RS. The pretreatment with losartan 1mg/kg increased the power of the high frequency (HF) band and reduced the LF (n.u.) and the LF/HF ratio of the pulse interval spectrum in the first hour of RS. Concerning baroreflex sensitiveness (SBR), pretreatments with losartan or lisinopril did not affect the gain of the baroreflex sequences. However, the pretreatment with losartan reduced the baroreflex effectiveness index of the total sequences in the third hour of the RS. These results indicate that Ang-II, via the AT-1 receptor, plays a facilitating influence on the cardiovascular response caused by RS; facilitates sympathetic activation and reduces parasympathetic activity related to RS; facilitates the baroreflex activation during RS and favors corticosterone release under this stress model. The impairment of Ang-II synthesis, as well as the blockade of AT-1 receptors, may constitute an important pharmacological strategy to treat cardiovascular consequences caused by stress.

CRF1 and CRF2 receptors in the lateral hypothalamus differently modulate the baroreflex function in unanesthetized rats

The lateral hypothalamus (LH) is a diencephalic structure that has been considered part of the central circuitry regulating the baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this hypothalamic area are poorly understood. Therefore, in the present study we investigated the role of corticotropin-releasing factor (CRF) neurotransmission within the LH acting via local CRF1 and CRF2 receptors in cardiac baroreflex responses in unanesthetized rats. For this, the baroreflex activity was assessed using two approaches: i) the pharmacological approach via intravenous infusion of vasoactive agents, and ii) the sequence analysis technique that evaluates reflex responses during spontaneous arterial pressure variations. The sequence analysis technique indicated that LH treatment with the selective CRF1 receptor antagonist CP376395 decreased the baroreflex effectiveness index, whereas the selective CRF2 receptor antagonist antisauvagine-30 increased the reflex shortening of pulse interval during spontaneous arterial pressure decreases. However, the pharmacological approach did not indicate effect of the bilateral microinjection of either CP376395 or antisauvagine-30 into the LH in the tachycardia evoked by blood pressure decrease or the reflex bradycardia caused by blood pressure increase. Overall, these findings indicate that CRF neurotransmission within the LH controls baroreflex function during a narrow range of physiological arterial pressure variations. Besides, results provide evidence that CRF1 and CRF2 receptors in the LH oppositely modulate the spontaneous baroreflex activity through different mechanisms.

Cardiac baroreflex function and vascular reactivity recovery after aerobic exercise in patients with early cirrhosis.

To investigate the effects of aerobic exercise on the cardiac baroreflex function and vascular reactivity in patients with cirrhosis. Thirteen patients with cirrhosis were submitted to exercise and control intervention. At baseline and at 30 and 60 min following intervention, we evaluated cardiac baroreflex sensitivity (cBRS) and the baroreflex effectiveness index (BEI) using sequence technique. Vascular reactivity was assessed inducing reactive hyperemia before and 60 min after intervention. At baseline, there was no difference (P interaction = 0.848) between exercise (from 3.0 ± 0.34 to 14.60 ± 1.06 ml/100ml/min) and control sessions (from 2.38 ± 0.10 to 13.73 ± 1.05 ml/100ml/min) regarding the increase in forearm blood flow during reactive hyperemia. However, this response was higher postexercise (from 3.38 ± 0.31 to 16.58 ± 1.58 ml/100ml/min) than postcontrol intervention (from 2.04 ± 0.23 to 11.98 ± 1.16 ml/100ml/min, P interaction < 0.001). BEI increased at 30- and 60-min postexercise (from 32 ± 7 to 42 ± 7 and 46 ± 7%), but not after control intervention (from 33 ± 6 to 31 ± 5 and 33 ± 7%, P interaction = 0.014). In contrast, cBRS decreased at 30-min postexercise (from 10.3 ± 1.9 to 8.2 ± 1.4 and 10.3 ± 2.1 ms/mmHg) and increased postcontrol intervention (from 7.9 ± 0.9 to 10.5 ± 1.5 and 10.3 ± 1.3 ms/mmHg, P interaction = 0.012). The results suggest that a single bout of aerobic exercise improved cardiac baroreflex function and increased vascular reactivity in patients with early-stage cirrhosis.

Baroreflex function and postprandial hypotension in older adults.

Postprandial hypotension (PPH) is a common but poorly understood etiology for fainting in older adults. One potential mechanism is age-related baroreflex dysfunction. We examined baroreflex function in older adults with PPH and without PPH (noPPH) during a standardized meal test. 57 adults (age ≥ 65; 24 PPH, 33 noPPH, mean age 77.9 ± 0.9years, 54% female) were recruited and had meal tests performed. The baroreflex effectiveness index (BEI, %) and baroreflex sensitivity (BRS, ms/mm Hg) were calculated using the sequence method. Baseline BEI (22 ± 2 versus 23 ± 2 percent, t = - 0.411, p = 0.682) and BRS (14.1 ± 2.4 versus 13.8 ± 2.5ms/mm of Hg, t = - 0.084, p = 0.933) were similar in PPH and noPPH subjects. During the meal test PPH subjects showed significantly lower BEI as compared to noPPH subjects (time × PPH, F = 2.791, p = 0.042), while there was no difference in the postprandial change in BRS (time, F = 0.618, p = 0.605). Patients with PPH demonstrated an acute postprandial decrease in baroreflex effectiveness during meal testing as compared with normal subjects, suggesting a potential contributing mechanism for this condition.

Can Slow Deep Breathing Reduce Pain? An Experimental Study Exploring Mechanisms

Slow deep breathing (SDB) is commonly employed in the management of pain, but the underlying mechanisms remain equivocal. This study sought to investigate effects of instructed breathing patterns on experimental heat pain and to explore possible mechanisms of action. In a within-subject experimental design, healthy volunteers (n = 48) performed 4 breathing patterns: 1) unpaced breathing, 2) paced breathing (PB) at the participant's spontaneous breathing frequency, 3) SDB at 6 breaths per minute with a high inspiration/expiration ratio (SDB-H), and 4) SDB at 6 breaths per minute with a low inspiration/expiration ratio (SDB-L). During presentation of each breathing pattern, participants received painful heat stimuli of 3 different temperatures and rated each stimulus on pain intensity. Respiration, heart rate, and blood pressure were recorded. Compared to unpaced breathing, participants reported less intense pain during each of the 3 instructed breathing patterns. Among the instructed breathing patterns, pain did not differ between PB and SDB-H, and SDB-L attenuated pain more than the PB and SDB-H patterns. The latter effect was paralleled by greater blood pressure variability and baroreflex effectiveness index during SDB-L. Cardiovascular changes did not mediate the observed effects of breathing patterns on pain. PerspectivesSDB is more efficacious to attenuate pain when breathing is paced at a slow rhythm with an expiration that is long relative to inspiration, but the underlying mechanisms remain to be elucidated.

Stroke Outcome Prediction by Blood Pressure Variability, Heart Rate Variability, and Baroreflex Sensitivity.

Background and Purpose- Poststroke autonomic dysfunction portended an unfavorable prognosis. We investigated whether blood pressure variability (BPV), heart rate variability, and baroreflex sensitivity might predict stroke functional outcome. Methods- We calculated BPV, heart rate variability, baroreflex slope, and baroreflex effectiveness index from a 5-minute beat-to-beat blood pressure and heart rate monitoring within 7 days from the stroke onset. We compared the parameters between patients with a good outcome (modified Rankin Scale score, 0-2) and those with a poor outcome. Results- Among 142 patients (mean age, 63.9±10.2 years; 88.0% men), functional outcome was good in 112 (78.9%) and poor in 30 (21.1%). There were significant differences in admission National Institutes of Health Stroke Scale, prior stroke, high-frequency systolic BPV, low/high-frequency ratio of BPV, baroreflex sensitivity-up, and baroreflex sensitivity-total between the 2 groups (all P<0.05). In multivariate analysis, National Institutes of Health Stroke Scale (OR, 1.672 [95% CI, 1.316-2.125]; P<0.001), low/high-frequency ratio of systolic BPV (OR, 0.493 [95% CI, 0.250-0.973]; P=0.041), and baroreflex effectiveness index-down (OR, 0.958 [95% CI, 0.924-0.992]; P=0.017) independently predicted a poor functional outcome. Conclusions- A decreased low/high-frequency ratio of systolic BPV and impaired baroreflex sensitivity predicted an unfavorable stroke outcome, in addition to the established prognostic factor such as the National Institutes of Health Stroke Scale.

Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction

BackgroundDecreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS).MethodsSystemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25–0.8 Hz) and high-frequency (HF; 0.8–2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump.ResultsThe suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline.ConclusionThese results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

68 Autonomic Impairment and its Manifestations in Patients with Delirium

Abstract Background Delirium is common among unwell older adults. Despite this the pathophysiology remains poorly understood. We hypothesised that autonomic dysfunction may be associated with the development of delirium. Methods 35 participants completed a case-control study. Delirium was assessed using DSM-IV and DRS-R98. Autonomic function was assessed with Head-Up Tilt testing (HUT), baroreflex sensitivity (BRS) testing using Baroreflex Effectiveness Index (BEI), 24-hour blood pressure variability (BPV), nocturnal blood pressure dipping status and 24-hour heart rate variability (HRV). A subgroup analysis of those without pre-existing cognitive impairment (CI) was completed. Results During tilting the delirium group (DG) had a median decrease of 1mmHg (IQR 38.5) in systolic blood pressure (SBP) compared to a median decrease of 17.5mmHg (IQR 20.75) in the control group (CG) (p=0.04). Increased delirium severity correlated with a reduction in the decrease in SBP (rs= -0.42, p=0.03). In those without CI, BRS testing during HUT showed that increases in blood pressure were not followed by an appropriate reduction in heart rate with a mean BEI of 36.87% (SD 22.26) in the DG and 56.03% (SD 23.04) in the CG (p=0.05). Nocturnal dipping differed during subgroup analysis. 58.3% (7) of DG were reverse dippers, 33.3% (4) were non-dippers and 8.3% (1) had a normal dipping pattern. In CG 57.1% (4) were non-dippers, 14.3% (1) had a normal dipping pattern and 28.6% (2) were extreme dippers (p=0.01). BPV was measured by average real variability (ARV). In those without CI mean ARV was 13.81 (SD 5.98) in the CG and 9.69 (SD 2.75) in the DG (p=0.05). No difference was detected in HRV. Conclusion We identified differences in autonomic function between the DG and CG. This is the first study to look at several components of autonomic function in delirium and thus can provide insights into physiological abnormalities present during, or contributing to delirium.

AT2 and MAS (but not AT1) angiotensinergic receptors in the medial amygdaloid nucleus modulate the baroreflex activity in rats.

The medial amygdaloid nucleus (MeA) is a limbic structure that has been demonstrated to be part of the central circuitry regulating baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this forebrain structure is poorly understood. Thus, in the present study, we investigated the specific role of AT1, AT2, and MAS angiotensinergic receptors within the MeA in baroreflex responses in unanesthetized rats. For this, the baroreflex function was assessed using both the pharmacological approach via intravenous infusion of vasoactive agents and the sequence analysis technique. Using the pharmacological approach, we observed that bilateral microinjection of the selective AT2 receptor antagonist PD123319 into the MeA increased the tachycardia evoked by blood pressure decrease, but without affecting the reflex bradycardia caused by blood pressure increase. Besides, bilateral microinjection of the selective MAS receptor antagonist A-779 decreased both tachycardic and bradycardic responses of the baroreflex. The sequence analysis technique indicated that PD123319 into the MeA increased baroreflex effectiveness index while A-779 had an opposite effect. Treatment of the MeA with the selective AT1 receptor antagonist losartan did not affect baroreflex function assessed by either the pharmacological approach or sequence analysis technique. Overall, these findings provide evidence that MAS receptor within the MeA plays a facilitatory role in baroreflex function, whereas local AT2 receptor inhibits cardiac baroreflex responses. Results also indicate that AT1 receptor within the MeA is not involved in the control of baroreflex function.

Baroreflex circulation regulation during tilt test in young males with a history of vasovagal syncopes

Background. Vasovagal syncopes (VVS) are relatively often recorded in the population of young people. Objective. To establish the changes in the baroreflex function during the tilt test in healthy young males with the history of VVS. Design and methods. A total of 102 people aged 18–30 years were examined and divided into 4 groups, taking into account the specific features of fainting history and response to the tilt test. Subjects of the group 1 (n = 14) had a history of VVS and a positive response to the tilt test (syncope). Subjects of the group 2 (n = 14) had a history of VVS and a pattern of postural tachycardia without fainting verified during the tilt test. Subjects of the group 3 (n = 42) had a history of VVS and a negative response to the tilt test. Subjects of the group 4 (n = 32) did not have a history of VVS and showed a negative response to the tilt test. During the tilt test, we studied the dynamics of the baroreflex functional parameters (the number of baroreflex reactions (NBR), the baroreflex effectiveness index (BEI), the baroreflex sensitivity (BRS)). Results. In the individuals of each group, in the initial horizontal phase, values of NBR, BEI, BRS were within normal range and did not show significant intergroup differences (p &gt; 0,05). The passive orthostasis was associated with the increase in NBR (in each group beside control group), a decrease in BEI and BRS. The increase in NBR in the vertical phase of the tilt test (relative to the initial horizontal phase) was 87 %, 6 %, 16 % in the groups 1, 2, 3 and 4, respectively. The tilt-induced decrease in NBR comprised 8 % in the group 4. The decrease in the BEI in the vertical phase of the tilt test (relative to the initial horizontal phase) consisted: 22 %, 19 %, 12 %, 10 % in subjects of the 1, 2, 3, 4 groups, respectively. During the passive orthostasis we observed a decrease in BRS: by 65 %, 69 %, 64 %, 57 % in individuals of the groups 1, 2, 3 and 4, respectively. Returning from a vertical to a horizontal position in all groups led to a pronounced decrease in NBR and an increase in the BEI to values lower than in baseline horizontal tilt test phase; to an excessive increase in the BRS exceeding the pre-test values in each study group. Conclusions. In prolonged passive orthostasis, healthy young males, regardless of the fainting history, demonstrate a decrease in the baroreflex regulation. Among those with the history of VVS, tilt-positive subjects are characterized by a more pronounced orthostasis-induced drop in the baroreflex sensitivity and the baroreflex effectiveness index and a slow recovery of the baroreflex regulatory function compared to the tilt-negative subjects and to those who demonstrated postural tachycardia pattern without syncope.

Evaluation of the sequence method as a tool to assess spontaneous baroreflex in reptiles.

The sequence method is an alternative to the traditional pharmacological approach (i.e., the Oxford technique) used to calculate baroreflex gain (G) in mammals. Although the sequence method assesses baroreflex by measuring spontaneous events of blood pressure regulation, the pharmacological method relies on the injection of vasoactive drugs that impact the baroreflex mechanism itself. The sequence method might be relevant for dynamic measurement of baroreflex modulation but it was never validated for vertebrates with low heart rate. Hence, we tested the sequence method in three species of reptiles and compared the results with those provided by the classic pharmacological method. G was similar between both methods and values correlated when parameters for the sequence method were set at delay 0 or 1 (i.e., the baroreflex system responds immediately to blood pressure changes or after 1 heartbeat). Calculation of the baroreflex effectiveness index was adequate at a minimum of 300 cycles and a delay of 1 for the three species. Therefore, the sequence method has been validated to investigate baroreflex regulation in reptiles, enabling studies during dynamic alterations in homeostasis.

552-P: Baroreflex Function and Postprandial Hypotension in Older Adults With and Without Type 2 Diabetes

Background: Type 2 diabetes (T2DM) is a common etiology of postprandial hypotension (PPH), possibly as a result of autonomic neuropathy resulting in baroreflex dysfunction. We examined baroreflex function in older adults with PPH (with and without T2DM) during a standardized meal test. Methods: 57 adults with PPH (age &amp;gt;= 65; 30 without T2DM, 27 with T2DM) were recruited sequentially from a geriatric medicine clinic (mean age 77.9±0.9 years, 54% female) and had meal tests performed. A Finometer (Finapres Medical Systems) was used to monitor blood pressure. The baroreflex effectiveness index (BEI, percent) was calculated using the sequence method. Results: Baseline BEI showed no association with the average PPH response (p=0.521), the maximal PPH response (p=0.282), or the number of hypotensive episodes (p=0.859). As shown in Figure 1, baseline BEI was lower in subjects with T2DM than in those without T2DM (p&amp;lt;0.001), but this impairment in baroreflex function was not observed postprandially. There was no significant difference in the average PPH response between those with and without T2DM (p=0.358). Conclusions: Although older subjects with PPH secondary to T2DM have lower baseline baroreflex function than older subjects with PPH without T2DM, this baroreflex impairment was not associated with the size of the PPH response. This suggests that PPH in the T2DM is not due to impairments in the arterial baroreflex. Disclosure K.M. Madden: None. B. Feldman: None. G.S. Meneilly: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. Funding Allan M. McGavin Foundation; Canadian Diabetes Association