Impaired Baroreflex Control Research Articles

Augmented resting beat-to-beat blood pressure variability in patients with chronic kidney disease.

Our aim was to test the hypothesis that patients with chronic kidney disease (CKD) would exhibit augmented resting beat-to-beat blood pressure variability (BPV) that is associated with poor clinical outcomes independent of mean blood pressure (BP). In addition, since the arterial baroreflex plays a critical role in beat-to-beat BP regulation, we further hypothesized that an impaired baroreflex control would be associated with an augmented resting beat-to-beat BPV. In 25 sedentary patients with CKD stages III-IV (62 ± 9years) and 20 controls (57 ± 10years), resting beat-to-beat BP (finger photoplethysmography) and heart rate (electrocardiography) were continuously measured for 10min. We calculated the standard deviation (SD), average real variability (ARV) and other indices of BPV. The sequence technique was used to estimate spontaneous cardiac baroreflex sensitivity. Compared with controls (CON), the CKD group had significantly increased resting BPV. The ARV (2.2 ± 0.6 versus 1.6 ± 0.5mmHg, P < 0.001; 1.6 ± 0.7 versus 1.3 ± 0.3mmHg, P = 0.039; 1.4 ± 0.5 versus 1.0 ± 0.2mmHg, P < 0.001) of systolic, diastolic and mean BP, respectively, was increased in CKD versus controls. Other traditional measures of variability showed similar results. The cardiac baroreflex sensitivity was lower in CKD compared with controls (CKD: 8.4 ± 4.5ms/mmHg versus CON: 14.0 ± 8.2ms/mmHg, P = 0.008). In addition, cardiac baroreflex sensitivity was negatively associated with BPV [systolic blood pressure (SBP) ARV; r = -0.44, P = 0.003]. In summary, our data demonstrate that patients with CKD have augmented beat-to-beat BPV and lower cardiac baroreflex sensitivity. BPV and cardiac baroreflex sensitivity were negatively correlated in this cohort. These findings may further our understanding about cardiovascular dysregulation observed in patients with CKD.

Temporal and Region‐Specific Tau Protein Hyper‐Phosphorylation in the Brain Coincides with the Development of Impaired Baroreflex Control of Arterial Pressure and Spatial Learning in Male Obese Zucker Rats

Obesity and other traits of metabolic syndrome (MetS) are recognized risk factors for the development of neurodegenerative diseases such as Alzheimer’s Disease (AD) and related dementias. Emerging evidence indicates pathophysiologies common to MetS and AD, such as obesity, hypertension, insulin resistance, and impaired glycemic control, occur with development of tauopathies and cognitive decline. Male obese Zucker rats (OZRs), a hyperphagic genetic model of MetS, develop these deleterious traits with predictable ages of onset and time courses. Juvenile OZRs display prominently elevated triglycerides and insulin compared to age‐matched lean Zucker rats (LZRs). By 12‐14 weeks of age although fasting glucose is still comparable in OZRs and LZRs, with access to food the OZRs exhibit chronic, marked hyperglycemia. At this age male OZRs also become hypertensive with impaired short‐term control of arterial pressure by baroreflexes, which are improved by treatments that normalize blood glucose. We hypothesized that young adult male OZRs would develop age‐dependent expression of markers of neurodegeneration in medulla and hippocampus coincident with deficits in functions related to these brain regions. Cohorts of age‐matched male OZRs and LZRs underwent cognitive testing using the Morris water maze (MWM). At 18‐19 weeks, the escape latencies and path lengths were comparable in male OZRs and LZRs (n=12/group). In contrast, at 28 weeks of age, OZRs (n=16) exhibited a greater than 2‐fold higher escape latency and significantly longer path lengths (p&lt;0.05) in the acquisition and retention phases of the MWM compared to age‐matched LZRs (n=15), suggesting the emergence of impaired spatial learning ability in the OZRs. The 18‐19‐week‐old male OZRs exhibited tau hyper‐phosphorylation (S396 and S199,and S202) in the medulla, but the expressions of these markers in the hippocampus were comparable in OZRs and LZRs (n=6/group) at this age. In contrast, 27‐28‐week‐old OZRs (n=6) exhibited tau hyperphosphorylation at S396in hippocampus as well as medulla compared to LZRs (n=6). Our data suggest that changes in tau phosphorylation in male OZRs occur in a temporal and spatial manner coincident with changes in brain function in these regions. In male OZRs, earlier manifestation in the medulla occurred with impaired short‐term regulation of arterial pressure by the medulla. Later manifestation of tau hyperphosphorylation in hippocampus coincided with deficits in spatial learning. Understanding mechanisms by which these histological, physiological, and behavioral changes occur in male OZRs may provide important insights into connections between the development of MetS and AD‐related dementias in humans to yield improved early‐stage interventions.

Prolonged unloading of the cardiovascular system during bedrest and spaceflight weakens neural coupling between blood pressure and heart rate

Impaired baroreflex control following bedrest and spaceflight severely affects rate of recovery and return to ambulatory tasks. Post-bedrest/spaceflight orthostatic intolerance remains a major concern for bedrest confined older patients and for astronauts on long-duration missions. Here, we investigated how baroreflex changes following cardiovascular unloading were associated with autonomic neural coupling between blood pressure and heart rate in returning astronauts and in healthy participants who had undergone prolonged bedrest. Cardiovascular data collected from 27 shuttle astronauts (8–16 days) were compared with 19 head-down tilt bedrest (HDBR, 60 days) volunteers. In each group, beat-by-beat systolic blood pressure (SBP) and heart period (R-to-R intervals, RR) were collected simultaneously during a supine-to-stand test (5–10 min) conducted around 10 days before launch or HDBR and within 120 min of landing or exiting HDBR. Indices characterizing interaction time (fraction time active), response gain (gain), and control directionality (causality) between SBP and RR (SBP→RR: neural reflex, and RR→SBP: mechanical coupling) during standing were derived from the beat-by-beat data. Following spaceflight, cardiac baroreflex fraction time active was reduced along with neural reflex causality, with much larger reductions seen with HDBR. No change in mechanical causality pre-post flight or HDBR was observed; however, comparison of male and female astronauts indicated that neural and mechanical causality were both lower in females. Altogether, these findings suggest that changes in blood pressure regulation after bedrest and spaceflight are primarily reflex/neurally mediated and provides a target for therapeutic approaches to cardiovascular deconditioning.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.

Autonomic biomarkers of shock in idiopathic systemic capillary leak syndrome.

ObjectiveThe term Idiopathic Systemic Capillary Leak Syndrome (ISCLS) refers to an uncommon condition of severe distributive shock, resulting from an abrupt shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesise that the autonomic nervous system (ANS) fails in regulating the response to hypovolemia in acute ISCLS and that ANS variables characterise the progression to the recovery.DesignProspective cohort study of patients admitted to ICU for severe ISCLS flares.SettingSingle, referral center in Italy for ISCLS.PatientsAnalysis of cardiovascular signals recorded during seven severe ISCLS attacks and one prodromal period in five patients.InterventionsANS was studied non-invasively by means of heart rate variability (HRV) and blood pressure variability analysis, as an estimation of vagal and sympathetic modulation directed to the heart and vessels. Heart rate and systolic arterial pressure (SAP) variability were also used to assess baroreflex sensitivity. ANS variables were measured during the subsequent phases which characterise ISCLS flares, namely the acute phase, the post-acute phase, and the recovery phase.Measurements and main resultsHRV was severely depressed during the acute phase accounting for the loss of ANS modulation during massive capillary extravasation. This phase was characterised by shock and impaired baroreflex control, which allowed SAP to oscillate driven by respiratory activity. Impending shock and transition from shock to a post-acute phase were marked by change of baroreflex spectral variables. The baroreflex control was fully restored during recovery.ConclusionsANS modulation and baroreflex control are severely impaired during the acute haemodynamic instability which characterises ISCLS crises and their progressive restoration may be a clue of improvement. ANS indices during ISCLS flares might serve as useful biomarkers, able to timely announce the transition from one phase to the subsequent one, thus helping to adapt therapy accordingly.

Increased muscle sympathetic nerve activity and impaired baroreflex control in isolated REM-sleep behavior disorder

ObjectiveChanges in baroreflex sensitivity have been reported in patients with idiopathic Parkinson’s disease (PD). We sought to investigate the hypothesis that patients with isolated rapid eye movement (REM)-sleep behavior disorder (iRBD), known to be a prodromal stage for PD, will show abnormalities in baroreflex control. MethodsTen iRBD patients were compared to 10 sex- and age-matched healthy controls. Their cardiovascular parameters and muscle sympathetic nerve activity (MSNA) were evaluated at rest and during baroreflex stimulation. ResultsMSNA at rest was higher in iRBD patients (burst frequency [BF]: 44 ± 3 bursts/min; burst incidence [BI]: 60 ± 8 bursts/100 heartbeats) as compared to the controls (BF: 29 ± 3 bursts/min, p < 0.001; BI: 43 ± 9 bursts/100 heartbeats, p < 0.001). During baroreflex stimulation, iRBD patients showed increased absolute values of MSNA (BF: F = 62.728; p < 0.001; BI: F = 16.277; p < 0.001) as compared to the controls. The iRBD patients had decreased diastolic blood pressure at baseline and during lower body negative pressure, but the level of significance was not met. ConclusionOur study shows increased MSNA and impaired baroreflex control in iRBD patients. We propose that the inhibitory effect of locus coeruleus on baroreflex function might be impaired, leading to the disinhibition of sympathetic outflow. SignificanceThese findings might reflect the destruction of brain areas due to the ascending P-α-synuclein deposits in iRBD patients.

Reduced resting beat‐to‐beat blood pressure variability in multiple sclerosis

Multiple Sclerosis (MS) is an autoimmune disease associated with central nervous system demyelination known to impair healthy autonomic function. We have previously demonstrated individuals with MS exhibit lower resting muscle sympathetic nerve activity and impaired carotid baroreflex control of arterial blood pressure compared to controls. Recently, increased resting beat-to-beat blood pressure variability (BPV) has been shown to be a strong predictor of cardiovascular risk in other clinical populations. Taken together, the aim of the current investigation was to test the hypothesis that resting beat-to-beat BPV is increased in individuals with MS compared to matched healthy controls. In 7 patients with relapsing-remitting MS (5 females/2 males, EDSS <4) and 7 sex-, age-, and weight-matched healthy controls, beat-to-beat blood pressure (Finometer) was recorded during 10 minutes of quiet supine rest. Individuals with MS had similar resting mean blood pressure (BP) compared to healthy controls (P= 0.736), however the BP standard deviation (SD) and coefficient of variation (CV) was less in MS (BP SD; MS: 3.2 ± 0.2 vs. CON: 4.0 ± 0.2, P=0.022 and BP CV; MS: 3.8 ± 0.3 vs. CON: 4.7 ± 0.2, P=0.025). Similarly, mean resting systolic blood pressure (SBP) was not different between MS and healthy controls (P=0.207) but the SBP standard deviation and coefficient of variation was less in MS (SBP SD; MS: 4.7 ± 0.4 vs. CON: 6.6 ± 0.5, P=0.013 and SBP CV; MS: 4.3 ± 0.4 vs. CON: 5.8 ± 0.4, P=0.033). In contrast, there was no difference in the DBP standard deviation or coefficient of variation between the two groups (P= 0.321 and P=0.295; respectively). In summary, contrary to our original hypothesis, individuals with MS exhibited reduced resting beat-to-beat BPV compared to healthy controls. These preliminary findings may be related to altered autonomic function in this clinical population.

Androgen Effects on Baroreflex Sensitivity in Women with AE‐PCOS

Polycystic ovary syndrome (PCOS) is a reproductive endocrinopathy affecting approximately 10% of reproductive age women. Hyperandrogenism in women may be associated with increased sympathetic activity and impaired blood pressure (BP) regulation. Women with the Androgen-Excess PCOS (AE-PCOS) phenotype can have severe clinical metabolic and cardiovascular comorbidities, including elevated BP. We tested the hypothesis that androgen exposure in AE-PCOS increases BP and impairs BP regulation, as indexed by sympathetic baroreflex sensitivity (BRS). We measured BRS in 5 women with AE-PCOS (mean±SD, age=25±5 y; BMI=40±2 kg/m2) at Baseline (BSL), after 4 days of reproductive hormone suppression with a gonadotropin-releasing hormone (GnRH) antagonist (ANT, 250 μg/day) and 4 days of GnRH ant+testosterone (T, 5 mg/day). Before participating, subjects were screened to demonstrate insulin resistance using an oral glucose tolerance test (AUC=25949±11038 IU for insulin, AUC=23385±2561 mg/dl for glucose). Muscle sympathetic nerve activity (MSNA), expressed in bursts/100 heartbeat (Hb), and diastolic BP (DBP) were measured during the Modified Oxford technique, and sympathetic BR gain (MSNA/DBP) served as an index of sympathetic BRS. We also assessed integrated BR gain with forearm vascular resistance changes as a function of lower body negative pressure (LBNP). Reproductive hormone suppression decreased resting mean arterial pressure compared to BSL (114±10 mm Hg) under both ANT (107±2 mm Hg) and T conditions (106±9 mm Hg, P=0.04). Sympathetic BR gain during ANT was greater compared to BSL (-0.922±0.506 vs. -0.800±0.542 bursts/100 Hb/mm Hg, respectively), and gain was unaffected when androgens were reintroduced (T=-0.819±0.276 bursts/100 Hb, P=0.29). Integrated BRS during LBNP was unaffected by hormone treatment (BSL=0.911±0.653; ANT=0.794±0.967; T= 1.002±0.367 units/mm Hg). In obese, insulin resistant women with AE-PCOS, suppressing testosterone and estrogen (E2) improved arterial BR control of MSNA, while testosterone administration did not restore BR control. Thus, our initial hypothesis that T impairs baroreflex control of MSNA is not supported by these data but suggests that the continued suppression of E2 during ANT and ANT+T may play a more important role. The potential impact of E2 could be a promising clinical intervention and will be directly tested in our future studies.

Inappropriate sinus tachycardia: a review.

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of >100 beats per minute and an average 24-hour heart rate >90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoantibody, beta-adrenergic receptor supersensitivity, muscarinic receptor autoantibody, or hyposensitivity, impaired baroreflex control, depressed efferent parasympathetic/vagal function, nociceptive stimulation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine, beta-adrenergic blockers, calcium channel blockers, psychiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinus node, thoracoscopic epicardial ablation of the sinus node, sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophysiological basis of IST and its management options.

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

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

The protective role of SOD1 overexpression in central mediation of bradycardia following chronic intermittent hypoxia in mice.

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications. Similar to OSA, chronic intermittent hypoxia (CIH) (a model for OSA) leads to oxidative stress and impairs baroreflex control of the heart rate (HR) in rodents. The baroreflex arc includes the aortic depressor nerve (ADN), vagal efferent, and central neurons. In this study, we used mice as a model to examine the effects of CIH on baroreflex sensitivity, aortic baroreceptor afferents, and central and vagal efferent components of the baroreflex circuitry. Furthermore, we tested whether human Cu/Zn Superoxide Dismutase (SOD1) overexpression in transgenic mice offers protection against CIH-induced deficit of the baroreflex arc. Wild-type C57BL/6J and SOD1 mice were exposed to room air (RA) or CIH and were then anesthetized, ventilated, and catheterized for measurement of mean arterial pressure (MAP) and HR. Compared with wild-type RA control, CIH impaired baroreflex sensitivity but increased maximum baroreceptor gain and bradycardic response to vagal efferent stimulation. Additionally, CIH reduced the bradycardic response to ADN stimulation, indicating a diminished central regulation of bradycardia. Interestingly, SOD1 overexpression prevented CIH-induced attenuation of HR responses to ADN stimulation and preserved HR responses to vagal efferent stimulation in transgenic mice. We suggest that CIH decreased central mediation of the baroreflex and SOD1 overexpression may prevent the CIH-induced central deficit.

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.

The probiotic Lactobacillus fermentum 296 attenuates cardiometabolic disorders in high fat diet-treated rats

Background and aimHigh-fat (HF) diet consumption has been associated with gut dysbiosis and increased risk of dyslipidemia, type 2 diabetes mellitus and hypertension. Probiotic administration has been suggested as a safe therapeutic strategy for the treatment of cardiometabolic disorders. This study was designed to assess the effects of probiotic Lactobacillus (L.) fermentum 296, a fruit-derived bacteria strain, against cardiometabolic disorders induced by HF diet. Methods and resultsMale Wistar rats were divided into control diet (CTL); HF diet; and HF diet treated with Lactobacillus fermentum 296 (HF + Lf 296). The L. fermentum 296 strain at 1 × 109 colony forming units (CFU)/ml were daily administered by oral gavage for 4 weeks. The results showed that rats fed with HF diet displayed insulin resistance, reduced Lactobacillus spp. counts in feces, serum lipids, and oxidative profile. Rats fed on HF diet also demonstrated augmented blood pressure associated with sympathetic hyperactivity and impaired baroreflex control. The administration of L. fermentum 296 for 4 weeks recovered fecal Lactobacillus sp. counts and alleviated hyperlipidemia, sympathetic hyperactivity, and reduced systolic blood pressure in HF rats without affecting baroreflex sensibility. ConclusionOur results suggest the ability of L. fermentum 296 improve biochemical and cardiovascular parameters altered in cardiometabolic disorders.

Impaired Baroreflex Function during Rest and Graded Orthostasis in Women with PTSD

Post‐traumatic stress disorder (PTSD) is more prevalent in women and associated with significantly higher risk of hypertension and cardiovascular disease. The underlying mechanisms are unclear, but impaired baroreflex function and vasomotor sympathetic neural control may be involved. We hypothesized that women with PTSD would have an impaired baroreflex control of muscle sympathetic nerve activity (MSNA). MSNA and hemodynamics were measured supine and during 30º and 60º head‐up tilt (HUT) in 14 women with PTSD and 14 healthy women (Controls). Sympathetic baroreflex sensitivity(BRS) was quantified using the slope of the linear correlation between MSNA and diastolic pressure during spontaneous breathing. Age and body mass index were not different between groups. Supine resting MSNA was greater in women with PTSD (PTSD vs. Controls: 27±3 vs. 14±3 bursts/min; P=0.002, mean±SEM). Sympathetic BRS was impaired in women with PTSD compared to controls in the supine position (PTSD vs. Controls: −43±7 vs. −64±9 units 100beats−1 mmHg−1, P=0.02). It remained lower in women with PTSD during 30º and 60º HUT (posturexgroup interaction P=0.1, time P=0.003, group P=0.03). MSNA response to the graded HUT was not different between groups but the efficacy of MSNA for vasoconstriction was greater in women with PTSD (HUT 30: 1.8±0.5 vs.0.9±0.4 %TPR/%totalMSNA; P=0.01, HUT60: 1.2±0.4 vs. 0.7±0.3; P=0.04). Our findings demonstrate that women with PTSD have decreased sympathetic BRS and it may contribute to augmented sympathetic activity. The higher efficacy of MSNA for vasoconstriction in PTSD suggests greater sympathetic vascular transduction and/or other nonadrenergic mechanisms responsible for vasoconstriction. These results may explain, in part, the underlying mechanisms for the greater risk of developing hypertension and cardiovascular disease in women with PTSD.Support or Funding InformationSupported by the Harry S. Moss Heart TrustThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vascular and autonomic changes in adult cancer patients receiving anticancer chemotherapy.

Chemotherapy is associated with acute and long-term cardiotoxicity. To date, risk assessment has primarily focused on the heart; however, recent findings suggest that vascular and autonomic function may also be compromised. Whether this occurs during chemotherapy treatment remains unknown. Therefore, the present study evaluated carotid artery stiffness, cardiovagal baroreflex sensitivity (cBRS), and heart rate variability (HRV) in cancer patients currently being treated with adjuvant chemotherapy. Eleven current cancer patients receiving adjuvant chemotherapy and 11 matched (1:1) controls were studied. Carotid artery stiffness was assessed via two-dimensional ultrasonography. cBRS was assessed from the spontaneous changes in beat-to-beat time series of R-R interval and systolic blood pressure via the cross-correlation technique. HRV was assessed using the standard deviation of R-R intervals (SDNN) and low (LF) and high (HF) power frequencies. Carotid artery β-stiffness was significantly higher in the cancer patients compared with control participants (8.0 ± 0.8 vs. 6.3 ± 0.6 U, respectively; P = 0.02). cBRS was lower in the cancer patients compared with controls (4.3 ± 0.7 vs. 10.7 ± 1.9 ms/mmHg, respectively; P = 0.01), and all indices of HRV were lower in the cancer patients (SDNN, P = 0.02; LF, P = 0.01; HF, P = 0.02). There was no significant correlation between β-stiffness and cBRS ( P = 0.4). However, LF power was significantly correlated with cBRS (r = 0.66, P < 0.001). Compared with matched healthy controls, cancer patients undergoing chemotherapy demonstrated a significantly higher arterial stiffness and lower cBRS. The previously reported adverse effects of chemotherapy on the heart appear to also influence other aspects of cardiovascular health. NEW & NOTEWORTHY Patients treated with anticancer chemotherapy exhibit an impaired baroreflex control of arterial blood pressure and increased arterial stiffness. These findings hold significant value, in particular as part of a risk-stratification strategy in current cancer patients receiving chemotherapy. This is the first investigation, to our knowledge, to demonstrate an attenuated spontaneous baroreflex control of arterial blood pressure in cancer patients currently undergoing chemotherapy.

Central Angiotensin-II Increases Blood Pressure and Sympathetic Outflow via Rho Kinase Activation in Conscious Rabbits.

Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipump: AngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.

Impaired carotid baroreflex control of arterial blood pressure in multiple sclerosis.

Multiple sclerosis (MS), a progressive neurological disease, can lead to impairments in the autonomic control of cardiovascular function. We tested the hypothesis that individuals with relapsing-remitting MS (n = 10; 7 females, 3 males; 13 ± 4 yr from diagnosis) exhibit impaired carotid baroreflex control of blood pressure and heart rate compared with sex, age, and body weight-matched healthy individuals (CON: n = 10; 7 females, 3 males). At rest, 5-s trials of neck pressure (NP; +40 Torr) and neck suction (NS; -60 Torr) were applied to simulate carotid hypotension and hypertension, respectively, while mean arterial pressure (MAP; finger photoplethysmography), heart rate (HR), cardiac output (CO; Modelflow), and total vascular conductance (TVC) were continuously measured. In response to NP, there was a blunted increase in peak MAP responses (MS: 5 ± 2 mmHg) in individuals with MS compared with healthy controls (CON: 9 ± 3 mmHg; P = 0.005), whereas peak HR responses were not different between groups. At the peak MAP response to NP, individuals with MS demonstrated an attenuated decrease in TVC (MS, -10 ± 4% baseline vs. CON, -15 ± 4% baseline, P = 0.012), whereas changes in CO were similar between groups. Following NS, all cardiovascular responses (i.e., nadir MAP and HR and percent changes in CO and TVC) were not different between MS and CON groups. These data suggest that individuals with MS have impaired carotid baroreflex control of blood pressure via a blunted vascular conductance response resulting in a diminished ability to increase MAP in response to a hypotensive challenge.

Autonomic Findings in Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy (TC) often occurs after emotional or physical stress. Norepinephrine levels are unusually high in the acute phase, suggesting a hyperadrenergic mechanism. Comparatively little is known about parasympathetic function in patients with TC. We sought to characterize autonomic function at rest and in response to physical and emotional stimuli in 10 women with a confirmed history of TC and 10 age-matched healthy women. Sympathetic and parasympathetic activity was assessed at rest and during baroreflex stimulation (Valsalva maneuver and tilt testing), cognitive stimulation (Stroop test), and emotional stimulation (event recall, patients). Ambulatory blood pressure monitoring and measurement of brachial artery flow-mediated vasodilation were also performed. TC women (tested an average of 37 months after the event) had excessive pressor responses to cognitive stress (Stroop test: p <0.001 vs baseline and p = 0.03 vs controls) and emotional arousal (recall of TC event: p = 0.03 vs baseline). Pressor responses to hemodynamic stimuli were also amplified (Valsalva overshoot: p <0.05) and prolonged (duration: p <0.01) in the TC women compared with controls. Plasma catecholamine levels did not differ between TC women and controls. Indexes of parasympathetic (vagal) modulation of heart rate induced by respiration and cardiovagal baroreflex gain were significantly decreased in the TC women versus controls. In conclusion, even long after the initial episode, women with previous episode of TC have excessive sympathetic responsiveness and reduced parasympathetic modulation of heart rate. Impaired baroreflex control may therefore play a role in TC.

Abnormal central control underlies impaired baroreflex control of heart rate and sympathetic nerve activity in female Lewis polycystic kidney rats.

Why baroreflex dysfunction occurs in females with chronic kidney disease is unknown. We therefore aimed to examine whether temporal changes in baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) occur in female Lewis polycystic kidney (LPK) rats and whether this is associated with any changes in afferent, central or efferent processing of the reflex pathway. Using urethane-anaesthetized juvenile and adult LPK and Lewis control rats (n = 40), baroreflex-mediated changes in HR, RSNA and aortic depressor nerve activity (ADNA) were examined. Reflex changes to aortic depressor and vagal efferent nerve stimulation were also determined. In the juvenile LPK rats, except for a slight reduction in the gain of the normalized HR and RSNA baroreflex function curves, no difference in baroreflex control of HR, RSNA or ADNA was observed. Responses to aortic depressor and vagal efferent nerve stimulation were also comparable. In the adult hypertensive LPK rats, the range of both HR (35 ± 8 vs. 78 ± 9 bpm, P ≤ 0.05 LPK vs. Lewis) and RSNA (60 ± 7 vs. 80 ± 3%, P ≤ 0.05 LPK vs. Lewis) was also reduced. This was not associated with any change in the ADNA baroreflex function curves or reflex HR responses to vagal efferent nerve stimulation, but was associated with a reduction in the reflex bradycardic (-21 ± 4 vs. -34 ± 8 bpm, P < 0.01 LPK vs. Lewis) and sympathoinhibitory (-30 ± 8 vs. -54 ± 12%, P < 0.001 LPK vs. Lewis) responses to aortic depressor nerve stimulation. In female LPK rats, baroreflex dysfunction results from impaired central processing of the reflex.

Long-term changes in blood pressure control in elementary school-aged children with sleep-disordered breathing

ObjectiveIn adults sleep-disordered breathing (SDB) has been associated with impaired baroreflex control of blood pressure (BP), which has been linked to increased cardiovascular morbidity. In children, the long-term effects of SDB on baroreflex sensitivity (BRS) and BP variability (BPV) are unknown. MethodsChildren previously diagnosed with SDB (n=40) and 20 nonsnoring controls aged 11–16y underwent overnight polysomnography with continuous BP measurement, four years after the original diagnosis. At follow-up, SDB was categorized as resolved (absence of snoring and obstructive apnea hypopnea index (OAHI)⩽1) or unresolved (continued to snore or had an OAHI>1). BRS and BPV were calculated using cross-spectral analysis and power spectral analysis, respectively. ResultsOnly children with resolved obstructive sleep apnea (OSA) at follow-up demonstrated an increase in BRS from 9.7±3(msmmHg−1) at baseline to 11.8±4(msmmHg−1) at follow-up (P=.03). However, children with all severities of both resolved and unresolved SDB showed a significant decrease in BPV from baseline to follow-up (a decrease in total power BPV (P<.05) and a shift in BPV spectra away from respiratory-related frequencies (increased low-frequency/high-frequency [LF/HF] ratio, P<.01). The change in OAHI was the sole determinant of change in BRS, HF power, and LF/HF ratio. ConclusionsImprovement in SDB was associated with improved BP control, regardless if SDB was treated or spontaneously resolved four years after initial diagnosis. Our findings highlight the importance of monitoring children to ensure improvement of SDB and reduce the risk for cardiovascular morbidity in the future.