Impaired Baroreflex Sensitivity Research Articles

Sympathoexcitation and impaired arterial baroreflex sensitivity are linked to vascular inflammation in individuals with elevated resting blood pressure.

Elevated Resting Blood Pressure (ERBP) in the prehypertensive range is associated with increased risk of hypertension and cardiovascular disease, the mechanisms of which remain unclear. Prior studies have suggested that ERBP may be associated with overactivation and dysregulation of the sympathetic nervous system (SNS). We hypothesized that compared to normotensives (≤120/80 mmHg), ERBP (120/80–139/89 mmHg) has higher SNS activity, impaired arterial baroreflex sensitivity (BRS), and increased vascular inflammation. Twenty‐nine participants were studied: 16 otherwise healthy individuals with ERBP (blood pressure (BP) 130 ± 2/85 ± 2 mmHg) and 13 matched normotensive controls (mean BP 114 ± 2/73 ± 2 mmHg). We measured muscle sympathetic nerve activity (MSNA), beat‐to‐beat BP, and continuous electrocardiogram at rest and during arterial BRS testing via the modified Oxford technique. Blood was analyzed for the following biomarkers of vascular inflammation: lipoprotein‐associated phospholipase A2 (Lp‐PLA2), E‐selectin, and intercellular adhesion molecule 1 (ICAM‐1). Resting MSNA burst frequency (22 ± 2 vs. 16 ± 2 bursts/min, P = 0.036) and burst incidence (36 ± 3 vs. 25 ± 3 bursts/100 heart beats, P = 0.025) were higher in ERBP compared to controls. Cardiovagal BRS was blunted in ERBP compared to controls (13 ± 2 vs. 20 ± 3 msec/mmHg, P = 0.032), while there was no difference in sympathetic BRS between groups. Lp‐PLA2 (169 ± 8 vs. 142 ± 9 nmol/min/mL, P = 0.020) and E‐selectin (6.89 ± 0.6 vs. 4.45 ± 0.51 ng/mL, P = 0.004) were higher in ERBP versus controls. E‐selectin (r = 0.501, P = 0.011) and ICAM‐1 (r = 0.481, P = 0.015) were positively correlated with MSNA, while E‐selectin was negatively correlated with cardiovagal BRS (r = −0.427, P = 0.030). These findings demonstrate that individuals with ERBP have SNS overactivity and impaired arterial BRS that are linked to biomarkers of vascular inflammation.

Long‐Term Effects of Device‐Guided Slow Breathing on Autonomic Control of Blood Pressure at Rest and During Stress in Post‐Traumatic Stress Disorder

Post‐traumatic stress disorder (PTSD) is characterized by augmented sympathetic nervous system (SNS) reactivity, impaired baroreflex sensitivity (BRS), and an increased risk for developing hypertension and cardiovascular disease. We recently showed that device‐guided slow breathing (DGB) using the RESPeRATE device acutely lowers blood pressure (BP) and muscle sympathetic activity (MSNA) and improves sympathetic BRS in PTSD. The aim of this study was to determine if long‐term daily DGB leads to sustained improvements in resting MSNA, BP, sympathetic BRS, and neurocirculatory reactivity during mental stress in combat veterans with PTSD. 19 post 9/11 veterans with PTSD (age, 36±2 years) were enrolled and randomized to either 8 weeks of DGB (n=9) versus an identical Sham device (n=10) for 15 minutes daily. Using biofeedback and musical tones, DGB guided respiratory rate (RR) to a subphysiologic rate of 5–6 breaths/min, while Sham guided RR to a normal rate of 12–14 breaths/min. BP, heart rate (HR), RR and MSNA were measured at rest and during 3 minutes of mental arithmetic (MA). Sympathetic and cardiovagal BRS were assessed with pharmacologic manipulation of BP using the modified Oxford technique. All physiologic measures were obtained before, and after 8 weeks of breathing intervention. Age, BMI, BP and HR were similar between the groups, while baseline MSNA at rest was greater in the DGB group pre‐intervention (p=0.048). Contrary to our hypothesis, there was no difference in the change in resting systolic BP (visit*group, p=0.097), diastolic BP (visit*group, p=0.571), HR (visit*group, p=0.323) and RR (visit*group, p=0.304) after 8 weeks of DGB versus Sham. There was a trend towards a difference in change in resting MSNA between the groups (visit*group, p=0.081). However, contrary to our hypothesis, there was no change in resting MSNA from pre to post 8 weeks of DGB (19±4 vs 20±2 burst/min, p>0.05), while there was an increase in resting MSNA after 8 weeks of Sham (9±2 vs 19±3 burst/min, p<0.001). There was no difference in change in cardiovagal BRS between the groups (visit*group, p= 0.139). Meanwhile, sympathetic BRS (visit*group, p=0.031) was not altered by 8 weeks of DGB (−1.47±0.5 vs 1.13±0.4, p=0.401), but improved with 8 weeks of Sham (−0.63±0.3 vs 1.45±0.4, p=0.032). During stress, neural and hemodynamic responses to MA (time*visit*group, p >0.05 for BP, HR and MSNA) were not different between the treatment groups. In summary, although our previous data showed that DGB acutely improves SNS activity and regulation in PTSD, we observed no sustained improvements in resting MSNA, BRS, hemodynamics, or neurocirculatory reactivity during mental stress with long‐term DGB in PTSD.Support or Funding InformationSupported by NIH HL‐098744, NIH DK‐00756, VA Merit I01CX001065, AHA 15CSA24340001This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Baroreceptor Sensitivity Predicts Functional Outcome and Complications after Acute Ischemic Stroke.

Autonomic dysfunctions including impaired baroreflex sensitivity (BRS) can develop after acute ischemic stroke (AIS) and may predispose patients to subsequent cardiovascular adverse events and serve as potential indicators of long-term mortality. This study aimed to determine the potential short-term prognostic significance of BRS after AIS. All patients admitted to Kaohsiung Veterans General Hospital within 72 h after onset of first-ever AIS between April 2008 and December 2012 were enrolled. Autonomic evaluation with continuous 10-minute monitoring of beat-to-beat hemodynamic and intracranial parameters was performed within 1 week after stroke by using the Task Force Monitor and transcranial Doppler. The 176 enrolled AIS patients were divided into high-BRS and low-BRS groups. All but two enrolled patients (who died within 3 months after stroke) attended scheduled follow-ups. The high-BRS group had significantly lower National Institutes of Health Stroke Scale (NIHSS) scores at 1 and 2 weeks after stroke and at discharge; lower modified Rankin scale (mRS) scores 1, 3, 6, and 12 months after stroke; and lower rates of complications and stroke recurrence compared to the low-BRS group. This study provides novel evidence of the utility of BRS to independently predict outcomes after AIS. Furthermore, modifying BRS may hold potential in future applications as a novel therapeutic strategy for acute stroke.

Klotho deficiency aggravates sepsis-related multiple organ dysfunction.

Sepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti-senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho-haploinsufficient mice and their wild-type littermates (CLP- Kl/+ and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP- Kl/+ mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-κB activation. It is noteworthy that CLP- Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprusside, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction, Klotho might play a protective role in sepsis, especially in elderly individuals in whom Klotho expression is naturally reduced.

Elevated resting blood pressure augments autonomic imbalance in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is characterized by increased sympathetic nervous system (SNS) activity, blunted parasympathetic nervous system (PNS) activity, and impaired baroreflex sensitivity (BRS), which contribute to accelerated cardiovascular disease. Patients with PTSD also have chronic stress-related elevations in resting blood pressure (BP), often in the prehypertensive range; yet, it is unclear if elevated resting blood pressure (ERBP) augments these autonomic derangements in PTSD. We hypothesized that compared with normotensive PTSD (N-PTSD), those with ERBP (E-PTSD) have further increased SNS, decreased PNS activity, and impaired BRS at rest and exaggerated SNS reactivity, PNS withdrawal, and pressor responses during stress. In 16 E-PTSD and 17 matched N-PTSD, we measured continuous BP, ECG, muscle sympathetic nerve activity (MSNA), and heart rate variability (HRV) markers reflecting cardiac PNS activity [standard deviation of R-R intervals (SDNN), root mean square of differences in successive R-R intervals (RMSSD), and high frequency power (HF)] during 5 min of rest and 3 min of mental arithmetic. Resting MSNA ( P = 0.943), sympathetic BRS ( P = 0.189), and cardiovagal BRS ( P = 0.332) were similar between groups. However, baseline SDNN (56 ± 6 vs. 78 ± 8 ms, P = 0.019), RMSSD (39 ± 6 vs. 63 ± 9 ms, P = 0.018), and HF (378 ± 103 vs. 693 ± 92 ms2, P = 0.015) were lower in E-PTSD versus N-PTSD. During mental stress, the systolic blood pressure response ( P = 0.011) was augmented in E-PTSD. Although MSNA reactivity was not different ( P > 0.05), the E-PTSD group had an exaggerated reduction in HRV during mental stress ( P < 0.05). PTSD with ERBP have attenuated resting cardiac PNS activity, coupled with exaggerated BP reactivity and PNS withdrawal during stress.

Abstract P331: Transition From Pre-Diabetes To Diabetes Is Associated With Worsening Of Cardiac Autonomic Neuropathy: Reversal By Anti-Diabetic Drugs

Cardiac autonomic neuropathy (CAN) occurs early in the course of diabetes leading to significant cardiovascular mortality and morbidity. Manifested as impaired heart rate variability (HRV) and baroreflex sensitivity (BRS), CAN represents an independent risk predictor of cardiac mortality. CAN development is linked to hyperglycemia; however, current understanding extends cardiovascular risk to pre-diabetic patients with slight glycemic changes. Here, we assessed the incidence and manifestation of CAN in a rat model of metabolic challenge prior to and after the development of diabetes. Rats were fed a hypercaloric (HC) diet (4.035 KCal/g vs. 3 KCal/g for control rats) composed of: weight (calories) 18.06 % fat (38.68%), 15.8% protein (15.66%), and 46.13% carbohydrates (45.73%). Stable fasting hyperglycemia developed by 16 weeks of feeding. The pre-diabetic stage was associated with signs of perivascular and epicardiac adipose inflammation (4- and 40- fold increase in IL-1β and TGF-β and 2-fold increase in NK-κB expression; and macrophage infiltration) and increased brainstem oxidative stress accompanied with impairment of HRV (total power decrease from 3098 ± 233 to 89 ± 88μs 2 ) and the parasympathetic arm of the baroreflex (slope decrease from -1.02 ± 0.12 to -0.34 ± 0.04). These abnormalities were reversed upon treatment with non-hypoglycemic doses of either metformin or pioglitazone or upon lowering the rat caloric intake. On the other hand, after progression to diabetes, the autonomic deficit progressed to the sympathetic arm of the baroreflex (Slope reduction from -0.35 ± 0.02 to -0.09 ± 0.03). The same hypoglycemic doses of metformin and pioglitazone failed to reverse the impaired HRV and BRS. Whereas, reduction of hyperglycemia to control levels by insulin was only capable of reversing the sympathetic impairment (BRS slope of -0.28 ± 0.04). Our present results outline a framework for sequential involvement of different detrimental mechanisms in the course of metabolic disease leading to differential impact on cardiac autonomic control. Furthermore, our findings emphasize the value of early intervention with antidiabetic drugs with potential protective pleiotropic effects.

Expression of α7 Nicotinic ACh Receptors in Blood Mononuclear Cells: Correlation with Impaired Baroreflex Sensitivity in Patients with Heart Failure

Autonomic imbalance, including depleted parasympathetic drive, is a fundamental pathophysiological feature of heart failure (HF). In clinical studies, parasympathetic withdrawal is assessed using arterial baroreflex sensitivity (BRS). Parasympathetic activity can also be tracked based on the assessment of molecular elements of cholinergic signaling in target cells. Hence, we investigated whether BRS is associated with the mRNA expression of nicotinic cholinergic receptors (α7nAChR) in peripheral blood mononuclear cells (PBMCs) in subjects with and without HF. We examined 39 patients with stable systolic HF (35 men, 4 women, age 56 ± 13 years, left ventricular ejection fraction, LVEF, 30 ± 9%) and 17 healthy subjects (6 men, 11 women, age 60 ± 11 years, LVEF 64 ± 9%). BRS was assessed using a phenylephrine test. Relative transcript levels of α7nAChRs in PBMCs were analyzed using a real-time PCR. Patients with HF, as compared to healthy subjects, demonstrated much higher expression of α7nAChR mRNA in PBMCs (4.4 ± 2.2 vs. 1.4 ± 2.2 AU; P 0.2). In a combined sampling including subjects with and without HF, BRS negatively correlated with the content of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) (r = –0.43, P < 0.05). In such sampling, α7nAChR expression in PBMCs also negatively correlated with LVEF (r = –0.39, P < 0.05) and was positively associated with plasma NT-proBNP (r = 0.38, P < 0.01), but without associations with other clinical and laboratory measures. Expression of α7nAChRs in PMBCs is inversely correlated with BRS (r = –0.50, P < 0.01). Thus, autonomic imbalance confirmed by physiological tests is accompanied by increased expression of α7 nicotinic receptors on circulating immune cells.

Vascular Dysfunction in Exfoliation Syndrome.

Both exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) are associated with systemic vascular diseases and abnormalities. Although no uniform relationship between XFS/XFG and clinical systemic vascular diseases has been established across various populations, vascular dysfunction with or without clinically significant consequences has been repeatedly detected with both epidemiological and pathophysiological methods. Elevated plasma homocysteine, reduced cutaneous capillary flow reactions, damaged conduit artery dysfunction, impaired baroreflex sensitivity, parasympathetic cardiovascular neuropathy, and pathologic heart rate variability indices have all been shown in XFS and XFG. These pathophysiological alterations exceed the normal age-dependent decline and are considered strongly related to systemic elastosis and increased oxidative stress, but are not direct consequences of the presence of the risk alleles of the lysyl oxydase-like 1 gene. The mechanisms of the development of the clinically significant consequences (eg, increased frequency of myocardial dysfunction, stroke, aorta aneurism, and white matter lesions) are only partially understood. The current knowledge on vascular dysfunction in XFS/XFG is summarized in this article.

Impaired Baroreflex Sensitivity in Patients with Recent-Onset Type 2 Diabetes

Impaired baroreflex sensitivity (BRS) is a sign of diabetic cardiovascular autonomic neuropathy (CAN) which often remains undiscovered during the early course of diabetes. We aimed to determine whether BRS alterations can be detected in patients with recent-onset type 1 and type 2 diabetes. Continuous plethysmographic arterial pressure and R-R intervals were recorded using the Finometer (Finapres Medical Systems) from the left middle finger in 586 participants from the baseline German Diabetes Study (GDS) cohort with type 1 or type 2 diabetes and a known diabetes duration ≤1 year (T1D/T2D [mean±SD]: n=208/378; age: 34.7±11.1/51.6±10.3 years; male: 60/74%; BMI: 24.7±4.2/31.7±6.3 kg/m²; diabetes duration: 6.3±3.3/5.9±3.5 months; HbA1c: 6.5±1.1/6.5±0.9%) and corresponding controls (CON1/CON2: n=74/208; age: 36.4±10.1/49.4±14.8 years; male: 64/64%; BMI: 26.5±4.9/26.6±4.9 kg/m²; HbA1c: 5.2±0.3/5.3±0.3%). BRS parameters included the alpha index of spectral power (BRSα), transfer function cross spectrum (xBRS), and sequence analyses (BRSseq). After adjustment for sex, age, BMI, and smoking, all three BRS measures were reduced in T2D vs. CON2 (BRSα: 10.1±8.6 vs. 15.4±10.2 ms/mmHg; xBRS: 7.84±6.94 vs. 10.4±8.2 ms/mmHg; BRSseq: 9.85±9.07 vs. 13.3±9.6 ms/mmHg) (P≤0.01), while no such differences were observed in T1D vs. CON1. Multiple regression analyses revealed, that systolic blood pressure (SBP) was the strongest determinant of lower BRS in T2D (xBRS/BRSseq/BRSα: β=-0.32/-0.23/-0.22) followed by age (xBRS: β=-0.18) and lower HDL cholesterol (BRSseq: β=-0.23), while in T1D it was age (xBRS/BRSseq/BRSα: β=-0.37/-0.36/-0.34), SBP (xBRS/BRSα: β=-0.26), and BMI (BRSseq: β=-0.24) (all P≤0.01). In conclusion, reduced baroreflex sensitivity indicates early CAN in recent-onset type 2 diabetes in relation to modifiable risk factors such as higher systolic blood pressure and lower HDL cholesterol. Disclosure G.J. Bönhof: None. A. Strom: None. K. Bódis: None. K. Müssig: None. J. Szendroedi: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. D. Ziegler: None.

Aldosterone infusion into the 4th ventricle produces sodium appetite with baroreflex attenuation independent of renal or blood pressure changes

Aldosterone infusion into the 4th ventricle (4th V), upstream the nucleus of the solitary tract (NTS), produces strong 0.3 M NaCl intake. In the present study, we investigated whether aldosterone infusion into the 4th V activates HSD2 neurons, changes renal excretion, or alters blood pressure and cardiovascular reflexes. Chronic infusion of aldosterone (100 ng/h) into the 4th V increased daily 0.3 M NaCl intake (up to 44 ± 10, vs. vehicle: 5.6 ± 3.4 ml/24 h) and also c-Fos expression in HSD2 neurons in the NTS and in non-HSD2 neurons in the NTS. Natriuresis, diuresis and positive sodium balance were present in rats that ingested 0.3 M NaCl, however, renal excretion was not modified by 4th V aldosterone in rats that had no access to NaCl. 4th V aldosterone also reduced baroreflex sensitivity (−2.8 ± 0.5, vs. vehicle: −5.1 ± 0.9 bpm/mmHg) in animals that had sodium available, without changing blood pressure. The results suggest that sodium intake induced by aldosterone infused into the 4th V is associated with activation of NTS neurons, among them the HSD2 neurons. Aldosterone infused into the 4th V in association with sodium intake also impairs baroreflex sensitivity, without changing arterial pressure.

Baroreflex Impairment Precedes Cardiometabolic Dysfunction in an Experimental Model of Metabolic Syndrome: Role of Inflammation and Oxidative Stress

This study analyzes whether autonomic dysfunction precedes cardiometabolic alterations in spontaneously hypertensive rats (SHR) with fructose overload. Animals were randomly distributed into three groups: control, hypertensive and hypertensive with fructose overload. Fructose overload (100 g/L) was initiated at 30 days old, and the animals (n = 6/group/time) were evaluated after 7, 15, 30 and 60 days of fructose consumption. Fructose consumption reduced baroreflex sensitivity by day 7, and still induced a progressive reduction in baroreflex sensitivity over the time. Fructose consumption also increased TNFα and IL-6 levels in the adipose tissue and IL-1β levels in the spleen at days 15 and 30. Fructose consumption also reduced plasmatic nitrites (day 15 and 30) and superoxide dismutase activity (day 15 and 60), but increased hydrogen peroxide (day 30 and 60), lipid peroxidation and protein oxidation (day 60). Fructose consumption increased arterial pressure at day 30 (8%) and 60 (11%). Fructose consumption also induced a late insulin resistance at day 60, but did not affect glucose levels. In conclusion, the results show that baroreflex sensitivity impairment precedes inflammatory and oxidative stress disorders, probably by inducing hemodynamic and metabolic dysfunctions observed in metabolic syndrome.

A Newly Isolated Carboxymethyl-Glucan (CM-G) Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats.

This study was designed to investigate the effects of a newly synthesized carboxymethyl-glucan (CM-G) on blood pressure (BP), baroreflex sensitivity (BRS) and sympathetic vascular modulation in renovascular hypertensive rats. Male Wistar rats were divided into four groups: Sham (n = 10); 2K1C (subjected to renal artery clipping to induce renovascular hypertension, n = 10); Sham + CM-G (treated with CM-G, n = 7) and 2K1C + CM-G (treated with CM-G, n = 7). The daily treatment with CM-G (40 mg/kg) was performed for 2 weeks. Blood pressure, heart rate (HR), systolic BP variability, baroreflex sensitivity (BRS) and sympathetic vascular tone were evaluated. After six weeks of renal artery clipping, 2K1C rats exhibited arterial hypertension (171 ± 11 vs. 118 ± 4 mmHg, p < 0.05), impaired BRS (-1.30 ± 0.10 vs. -2.59 ± 0.17 bpm.mmHg-1, p < 0.05) and enhanced sympathetic activity as shown by the hexamethonium test (-60 ± 5 vs. -33 ± 2 ΔmmHg, p < 0.05) when compared to sham rats. Oral administration of CM-G in renovascular hypertensive rats reduced hypertension (126 ± 4 vs. 171 ± 11 mmHg, p < 0.05) and improved the BRS (-2.03 ± 0.16 vs. -1.30 ± 0.10 bpm.mmHg-1, p < 0.05) in 2K1C rats when compared to placebo. Those effects seem to be caused by a reduction in sympathetic activity. The present study revealed for the first time that CM-G treatment reduces arterial hypertension and restores arterial baroreflex sensitivity via a reduction in the sympathetic tone in conscious renovascular hypertensive rats.

Acute effects of device-guided slow breathing on sympathetic nerve activity and baroreflex sensitivity in posttraumatic stress disorder.

Patients with posttraumatic stress disorder (PTSD) have elevated sympathetic nervous system reactivity and impaired sympathetic and cardiovagal baroreflex sensitivity (BRS). Device-guided slow breathing (DGB) has been shown to lower blood pressure (BP) and sympathetic activity in other patient populations. We hypothesized that DGB acutely lowers BP, heart rate (HR), and improves BRS in PTSD. In 23 prehypertensive veterans with PTSD, we measured continuous BP, ECG, and muscle sympathetic nerve activity (MSNA) at rest and during 15 min of DGB at 5 breaths/min ( n = 13) or identical sham device breathing at normal rates of 14 breaths/min (sham; n = 10). Sympathetic and cardiovagal BRS was quantified using pharmacological manipulation of BP via the modified Oxford technique at baseline and during the last 5 min of DGB or sham. There was a significant reduction in systolic BP (by -9 ± 2 mmHg, P < 0.001), diastolic BP (by -3 ± 1 mmHg, P = 0.019), mean arterial pressure (by -4 ± 1 mmHg, P = 0.002), and MSNA burst frequency (by -7.8 ± 2.1 bursts/min, P = 0.004) with DGB but no significant change in HR ( P > 0.05). Within the sham group, there was no significant change in diastolic BP, mean arterial pressure, HR, or MSNA burst frequency, but there was a small but significant decrease in systolic BP ( P = 0.034) and MSNA burst incidence ( P = 0.033). Sympathetic BRS increased significantly in the DGB group (-1.08 ± 0.25 to -2.29 ± 0.24 bursts·100 heart beats-1·mmHg-1, P = 0.014) but decreased in the sham group (-1.58 ± 0.34 to -0.82 ± 0.28 bursts·100 heart beats-1·mmHg-1, P = 0.025) (time × device, P = 0.001). There was no significant difference in the change in cardiovagal BRS between the groups (time × device, P = 0.496). DGB acutely lowers BP and MSNA and improves sympathetic but not cardiovagal BRS in prehypertensive veterans with PTSD. NEW & NOTEWORTHY Posttraumatic stress disorder is characterized by augmented sympathetic reactivity, impaired baroreflex sensitivity, and an increased risk for developing hypertension and cardiovascular disease. This is the first study to examine the potential beneficial effects of device-guided slow breathing on hemodynamics, sympathetic activity, and arterial baroreflex sensitivity in prehypertensive veterans with posttraumatic stress disorder.

Tonic peripheral chemoreflex activation contributes to cardiac autonomic modulation at rest and impairs cardiac baroreflex sensitivity during orthostatic challenge in patients with pulmonary arterial hypertension

Patients with pulmonary arterial hypertension (PAH) often experience orthostatic hypotension, and this may be mediated, to some extent, by impaired baroreflex sensitivity (BRS). The impairment in BRS is possibly caused by multiple factors. Of note, however, accumulating evidence has supported that tonic peripheral chemoreflex activation plays a key role for autonomic impairment in diseases like systemic hypertension and heart failure, due to, in part, alterations that are also commonly found in PAH (e.g., inflammation and oxidative stress). Thus we sought to test two hypotheses: 1) patients with PAH present impaired BRS during an orthostatic challenge; 2) the peripheral chemoreflex is sensitized in patients with PAH and contributes to cardiac autonomic modulation and BRS at rest and BRS during an orthostatic challenge. Twenty non‐hypoxemic patients with PAH and 10 healthy controls (CON) were assessed. Peripheral chemosensitivity was measured via the ventilatory response to transient inhalation of pure nitrogen. Beat‐by‐beat heart rate (ECG) and arterial pressure (finger photoplethismography) were measured at seated rest and during a repeated sit‐to‐stand maneuver (six consecutive repetitions of 10‐s sit and 10‐s stand), while participants randomly inhaled 100% of O2 to inhibit the peripheral chemoreflex tonic activity (i.e., hyperoxia), and 21% of O2 as control (i.e., normoxia). Isocapnia was maintained via a rebreathing system. Cardiac autonomic modulation was quantified via heart rate variability (HRV) indexes, which were calculated in time and frequency domains. The CBRS was calculated at rest via sequence and alpha index methods, and during a sit‐to‐stand maneuver via sequence method. The PAH group showed significantly higher peripheral chemosensitivity (PAH: 0.32 ± 0.04 vs CON: 0.18 ± 0.02 L/%SpO2, P &lt; 0.05) and significantly lower CBRS during the sit‐to‐stand maneuver, compared to the CON group. Peripheral chemoreflex inhibition via hyperoxia similarly increased HRV and CBRS in both groups at rest. In addition, hyperoxia significantly increased BRS during the sit‐to‐stand maneuver only in the PAH group, and then, the BRS was normalized (i.e., attained the CON group level). In summary, this study provides novel evidence that patients with PAH present low CBRS during an orthostatic challenge. Furthermore, data supports that the peripheral chemoreflex is sensitized and tonically contributes to cardiac autonomic modulation in patients with PAH at rest, and most notably, to impaired cBRS during an orthostatic challenge.Support or Funding InformationThe study was supported by São Paulo Research Foundation, FAPESP (2015/221982; 2017/077713)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sympathetic Baroreflex Sensitivity During Mental Stress in Humans With Chronic Anxiety

Elevated muscle sympathetic nerve activity (MSNA) is associated with the pathogenesis of hypertension and cardiac arrhythmias, and may be related to greater cardiovascular disease (CVD) risk among individuals with chronic anxiety. Augmented sympathetic responsiveness in chronic anxiety may potentially be attributed to alteration in sympathetic baroreflex control. We hypothesized that MSNA and its responsiveness to stress would be augmented in chronic anxiety, and that augmented MSNA responsiveness would be related to impaired sympathetic baroreflex sensitivity. Sympathetic baroreflex sensitivity was assessed by relating spontaneous changes in multi‐unit MSNA to beat‐to‐beat changes in diastolic blood pressure (DBP) using a weighted linear regression at rest (10 min) and during mental stress (MS, 4‐min mental arithmetic) in 18 individuals with moderate/high chronic anxiety (ANX, 6 men/12 women; 32±2 yrs; 27±2 kg/m2) who were nonsmokers and free of CVD, and in 18 healthy controls with low/no anxiety (CON, 8 men/10 women; 39±3 yrs; 30±1 kg/m2). Resting MSNA was not elevated among ANX compared to CON (MSNA burst incidence: ANX 29 ± 5 vs. CON 40 ± 4 bursts/100hb; Avg. relative MSNA burst amplitude: ANX 48 ± 1 vs. CON 47 ± 1 AU). Avg. relative MSNA burst amplitude in response to MS was significantly augmented among ANX compared to CON (ANX: 61 ± 2 vs. CON: 54 ± 2 AU, P=0.02), while % change in MSNA burst incidence was not significantly different between ANX and CON (ANX: 4 ± 7 vs. CON: 6 ± 7 bursts/100hb, P=0.86). Increases in avg. relative MSNA burst amplitude during MS were significantly correlated with trait anxiety score among all participants after adjusting for age, sex, and BMI (R=0.48, P=0.01). The slope between MSNA burst incidence and DBP was not different between ANX and CON at rest (ANX: −2.8 ± 0.6 vs. CON: −3.5 ± 0.5 bursts/100hb/mmHg−1, P=0.35), and was significantly reduced during MS (P=0.03) with no difference between ANX and CON (ANX: −2.2 ± 0.4 vs. CON: −2.3 ± 0.5 bursts/100hb/mmHg−1, P=0.42). The slope between total MSNA and diastolic BP was similar between ANX and CON at rest (ANX: −1.5 ± 0.3 vs. CON: −1.9 ± 0.3 AU/beat/mmHg−1, P=0.3) and unchanged (P=0.49) during MS (ANX: −1.5 ± 0.3 vs. CON: −1.5 vs. 0.3 AU/beat/mmHg−1, P=0.99). These preliminary findings demonstrate that individuals with chronic anxiety exhibit augmented increases in MSNA burst amplitude but not burst incidence to mental stress, and this alteration in the MSNA response to mental stress in chronic anxiety is not a result of impairment in sympathetic baroreflex sensitivity.Support or Funding InformationAHA 17POST33440101, T32 HL07121 NHLBI (P01HL014388), U54 TR001356 and AHA (13DG143400012)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired baroreflex sensitivity and increased systolic blood pressure variability in chronic post-ischemic stroke

OBJECTIVES:Acute post-stroke patients present cardiovascular autonomic dysfunction, which manifests as lower heart rate variability and impaired baroreflex sensitivity. However, few studies performed to date have evaluated cardiovascular autonomic function in chronic post-stroke patients. The aim of this study was to evaluate cardiovascular autonomic modulation in chronic post-ischemic stroke patients.METHODS:The seventeen enrolled subjects were divided into a stroke group (SG, n=10, 5±1 years after stroke) and a control group (CG, n=7). Non-invasive curves for blood pressure were continuously recorded (Finometer®) for 15 minutes while the subject was in a supine position. Heart rate variability and blood pressure variability were analyzed in the time and frequency domains.RESULTS:No differences were observed in systolic and diastolic pressure and heart rate between post-stroke patients and healthy individuals. The SG group had lower indexes for heart rate variability in the time domain (standard deviation of normal to normal R-R intervals, SDNN; variance of normal to normal R-R intervals, VarNN; and root mean square differences of successive R-R intervals, RMSSD) and a lower high-frequency band for heart rate variability than was observed in the CG. Systolic blood pressure variability and the low-frequency band for systolic pressure were higher in post-stroke patients, while the alpha index was lower in the SG than in the CG.CONCLUSION:After ischemic stroke, affected patients present chronically reduced heart rate variability, impaired cardiac vagal modulation, increased systolic blood pressure variability and higher sympathetic vascular modulation along with impaired baroreflex sensitivity, which can increase the risk of cardiovascular events, despite adequate blood pressure control.

Fructose intake impairs baroreflex sensitivity in the early stage of fructose-induced hypertension through central nervous system regulation in rats

Fructose intake impairs baroreflex sensitivity in the early stage of fructose-induced hypertension through central nervous system regulation in rats

Impaired baroreflex sensitivity, carotid stiffness, and exaggerated exercise blood pressure: a community-based analysis from the Paris Prospective Study III.

People with exaggerated exercise blood pressure (BP) have adverse cardiovascular outcomes. Mechanisms are unknown but could be explained through impaired neural baroreflex sensitivity (BRS) and/or large artery stiffness. This study aimed to determine the associations of carotid BRS and carotid stiffness with exaggerated exercise BP. Blood pressure was recorded at rest and following an exercise step-test among 8976 adults aged 50 to 75 years from the Paris Prospective Study III. Resting carotid BRS (low frequency gain, from carotid distension rate, and heart rate) and stiffness were measured by high-precision echotracking. A systolic BP threshold of ≥ 150mmHg defined exaggerated exercise BP and ≥140/90mmHg defined resting hypertension (±antihypertensive treatment). Participants with exaggerated exercise BP had significantly lower BRS [median (Q1; Q3) 0.10 (0.06; 0.16) vs. 0.12 (0.08; 0.19) (ms2/mm) 2×108; P < 0.001] but higher stiffness [mean ± standard deviation (SD); 7.34 ± 1.37 vs. 6.76 ± 1.25 m/s; P < 0.001) compared to those with non-exaggerated exercise BP. However, only lower BRS (per 1SD decrement) was associated with exaggerated exercise BP among people without hypertension at rest {specifically among those with optimal BP; odds ratio (OR) 1.16 [95% confidence intervals (95% CI) 1.01; 1.33], P = 0.04 and high-normal BP; OR, 1.19 (95% CI 1.07; 1.32), P = 0.001} after adjustment for age, sex, body mass index, smoking, alcohol, total cholesterol, high-density lipoprotein cholesterol, resting heart rate, and antihypertensive medications. Impaired BRS, but not carotid stiffness, is independently associated with exaggerated exercise BP even among those with well controlled resting BP. This indicates a potential pathway from depressed neural baroreflex function to abnormal exercise BP and clinical outcomes.

General Anesthesia Imposes Negative Effects on Heart Rate and Blood Pressure Regulation in Patients With a History of Head and Neck Radiation Therapy.

Head and neck radiation therapy (HNRT) impairs baroreflex sensitivity, and it may potentiate the effects of anesthetics on heart rate (HR) and blood pressure (BP) regulation. Currently, the impacts of HNRT on HR and BP under anesthesia remain unclear. In this study, 472 patients with primary oral cavity or oropharyngeal cancer at all stages were examined. Half of the patients underwent HNRT plus surgery. The other half underwent surgery only and was matched with the treatment patients according to age, sex, and body mass index at a 1:1 ratio. The HRs and BPs in the 2 groups during anesthetic induction, skin incision, and emergence were compared retrospectively. A multivariable model of repeated measures with unstructured covariance structure was used to examine the associations of HNRT with intraoperative HRs and BPs after adjusting for baseline HR and BP, time, use of β-blockers, history of chemotherapy, and American Society of Anesthesiologists physical status score. BPs and HRs were collected every 5 minutes. The baseline HR and BP measurements were not included in the outcome vector and were only used as adjustment for baselines. Compared with corresponding baseline values in controls, the baseline HR was significantly higher (P = .0012) and the baseline systolic BP was lower (P < .0001) in the treatment group. The baseline diastolic BP levels did not differ significantly (P = .6411). Fewer patients receiving HNRT than controls took β-blockers daily (17% vs 28%; P = .0041). Comparing the corresponding values in control and treatment groups, multivariable analysis revealed significant associations of HNRT with decreases in HR during anesthesia induction (-2.21 [95% confidence interval {CI}, -4.42 to -0.01]; P = .0492) and skin incision (-2.66 [95% CI, -5.16 to -0.16]; P = .0373) and of HNRT with decreases in systolic BP during anesthesia induction (-6.88 [95% CI, -10.99 to -2.78]; P = .0011) and skin incision (-15.87 [95% CI, -20.45 to -11.29]; P < .001). However, we observed a significant association of HNRT with decrease in diastolic BP only during skin incision (-6.50 [95% CI, -9.47 to -3.53]; P < .0001). The significant finding in the study was that general anesthesia imposed a negative chronotropic effect on HR in the group given HNRT. Therefore, one should be watchful for bradycardia in these patients; particularly those with low BPs. Their hemodynamics may rapidly progress into an unstable status when bradycardia and hypotension develop altogether.

Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms.

Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension.