Spontaneous baroreflex measurement in the assessment of cardiac vagal control

Abstract. Spontaneous baroreflex sensitivity (SBR) has been suggested to be a measure of tonic parasympathetic cardiac control. The decrease of SBR during vagal inhibition was proven before. In this study, we investigated the response of SBR during vagal activation by administering intravenous atropine and phenylephrine in eight and ten healthy volunteers respectively. Atropine was given at a rate of 0.5 µg/kg/min for 20 minutes and the infusion rate of phenylephrine was adjusted to increase the blood pressure 20 to 30 mmHg above baseline value. We found that SBR at first increased from 16.9 ± 9.5 to 41.5 ± 24.9 ms/mm Hg (p < 0.05) and then decreased to 8.9 ± 6.2 ms/mm Hg (p < 0.05 compared with the peak value) after the initiation of atropine infusion. SBR also increased significantly (27.2 ± 12.5 to 49.6 ± 11.3 ms/mm Hg, p < 0.01) during phenylephrine infusion. The authors propose SBR as a measure of cardiac vagal effect because SBR increases under vagal activation.     

Low-dose atropine in electroconvulsive therapy.

Anticholinergic medications such as atropine or glycopyrrolate have long been used in electroconvulsive therapy (ECT) to eliminate parasympathetically mediated dysrhythmias. However, such agents increase heart rate and myocardial workload and may increase risk of cardiac adverse events. What is needed is an intervention that is parasympatholytic without substantially increasing myocardial workload. In this study, a low dose of atropine was compared with placebo in ECT with attention to heart rate, blood pressure, cardiac rhythm, myocardial workload, and parasympathetic function. The dose of atropine that was used effectively blocked vagal tone with only a small and probably not clinically significant rise in myocardial workload for only a few minutes after the ECT seizure.     

Adrenergic and vagal baroreflex sensitivity in autonomic failure

BACKGROUND: The baroreflex is responsible for maintaining a stable blood pressure (BP) despite changes in body positions and fails in many autonomic disorders. The baroreflex regulates BP by changing the heart rate (vagal component) and total peripheral resistance (adrenergic component). Baroreflex sensitivity is widely used to quantify the vagal component of the reflex, but the adrenergic component is not quantifiable in the autonomic laboratory. OBJECTIVES: To develop and validate an index of adrenergic baroreflex sensitivity. DESIGN: We validated this index with microneurographically recorded muscle sympathetic nerve discharges generated by the Valsalva maneuver and verified it against groups of patients with graded severities of adrenergic failure. RESULTS: Adrenergic baroreflex sensitivity relates BP recovery time to the preceding decrease in BP evoked by the Valsalva maneuver. This index showed a graded and highly significant impairment in 3 groups of patients, (1) those with orthostatic hypotension (n = 26), (2) those with borderline orthostatic hypotension (n = 34), and (3) those with impaired reflex vasoconstriction without orthostatic BP change (n = 24), when compared with an age- and sex-matched control group (n = 29). Adrenergic baroreflex sensitivity better tracked the severity of adrenergic failure than the vagal component of baroreflex sensitivity and provides a much needed index to quantify total peripheral resistance changes in patients with adrenergic failure. CONCLUSIONS: The 2 indices of baroreflex sensitivity separately evaluate the vagal and adrenergic components of the baroreflex. Combined, they provide an index of composite or global baroreflex function.     

Neurosteroid modulation of arterial baroreflex function in the rostral ventrolateral medulla

Through both genomic and nongenomic actions, ovarian hormones and their metabolites have significant effects on the central nervous system to modulate a variety of regulatory systems, including the cardiovascular system. The major metabolite of progesterone, 3α-hydroxy-dihydroprogesterone, is the most potent endogenous positive modulator of GABA(A) receptors known and central nervous system levels of this progesterone metabolite fluctuate with the ovarian cycle and are elevated in pregnant animals. Pregnancy is associated with attenuated arterial baroreflex sympathoexcitation and increased tonic GABAergic inhibition of the rostral ventrolateral medulla (RVLM) likely contributes. The current experiments were performed to determine if the effects of pregnancy on arterial baroreflex control of renal sympathetic nerve activity could be mimicked by microinjection of the neuroactive progesterone metabolite into the RVLM. Compared to control values, 15 min after microinjection of 3α-hydroxy-dihydroprogesterone into the RVLM (n=10), baseline renal sympathetic nerve activity was decreased to 82% of baseline, and the range (157±10 to 131±11%) and maximum nerve activity (164±9 to 136±12%) for the arterial baroreflex curves were decreased. In contrast, microinjection of the inactive isomer, 3β-hydroxy-dihydroprogesterone into the RVLM (n=9), had no effect on baseline nerve activity or the arterial baroreflex nerve activity range or maximum. Thus, although multiple mechanisms likely contribute to pregnancy associated changes in baroreflex function, these experiments suggest that increased levels of 3α-hydroxy-dihydroprogesterone in the RVLM might contribute.     

Determination of vagal baroreflex sensitivity in normal subjects

Introduction: The Valsalva maneuver (VM) is used widely to quantify the sensitivity of the vagal baroreflex loop (vagal baroreflex sensitivity, BRS_v), but most studies have focused on the heart rate (HR) response to blood pressure (BP) decrement (BRS_v↓), even though the subsequent response to an increment in BP after the VM (BRS_v↑) is important and different. Methods: We evaluated recordings of HR and BP in 187 normal subjects during the VM and determined both BRS_v↑, as determined by relating HR to the BP increase after phase III and BRS_v↓. Results: BRS_v↑ was related inversely to age. In addition, BRS_v↓, age, and magnitude of phase IV were independent predictors of BRS_v↑ in a multivariate model, accounting for 47% of the variance of BRS_v↑. Conclusions: The results indicate that both BRS_v↑ and BRS_v↓ become blunted with increasing age and that these indices relate to each other. Muscle Nerve 50: 535–540, 2014     

Effects of inspiratory impedance on the carotid–cardiac baroreflex response in humans

Abstract. We were interested in a therapeutic device designed to increase carotid–cardiac baroreflex sensitivity (BRS) since high BRS is associated with a lower risk for development of hypotension in humans with experimentally–induced central hypovolemia. We hypothesized that spontaneous breathing through an impedance threshold device (ITD) designed to increase negative intrathoracic pressure during inspiration and elevate arterial blood pressure would acutely increase BRS in humans.We tested this hypothesis by measuring heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures, and carotid-cardiac BRS in 10 female and 10 male subjects breathing through a face mask at three separate ITD conditions: (a) 6 cm H₂O; (b) 12 cm H₂O; and (c) a control (0 cm H₂O). HR was increased (P = 0. 013) from 64 ± 3 bpm during control to 68 ± 3 bpm at 6 cm H₂O ITD and 71 ± 4 bpm at 12 cm H₂O ITD breathing conditions. During ITD breathing, BRS was not altered but responses were shifted to higher arterial pressures. However, SBP and DBP were elevated for both the 6 and 12 cm H₂O conditions compared to the 0 cm H₂O condition, but returned to control (sham) levels by 30 minutes after cessation of ITD breathing. There were no gender effects for BRS or any hemodynamic responses to breathing through the ITD. We conclude that breathing with inspiratory impedance at relatively low pressures can increase baseline arterial blood pressure, i. e., reset the operational point for SBP on the baroreflex stimulus–response relationship, in healthy subjects. This resetting of the cardiac baroreflex may represent a mechanism that allows blood pressure to increase without a reflex–mediated reduction in HR.     

Balance between sympathetic response to head-up tilt and cardiac vagal factors in healthy humans

We evaluated the association between cardio-vagal baroreflex sensitivity (BRS; assessed with modified Oxford technique) and catecholamine response to 5 min 60° head-up tilt (HUT) in 46 young healthy adults. HUT increased HR, mean arterial pressure, and NE (P < 0.05 for all). BRS was negatively correlated with NE response to HUT (r = −0.36, P < 0.05), suggesting that subjects with high vagal modulation (high BRS) require less sympathetic response (NE) to maintain normotension during orthostatic stress.     

Cold face test in the assessment of trigeminal-brainstem- vagal function in humans

Study of the reflex heart rate response in humans to apneic facial immersion (simulated diving) and its modifications showed that bradycardia caused by simple application of cold compresses to the face (cold face test) correlated well with that produced by the simulated diving reflex. Bilateral application of cold stimulus to the individual divisions of the trigeminal nerve revealed the ophthalmic division to be the most sensitive pathway for this reflex. The cold face test was standardized in 50 normal individuals and further validated in 10 patients by comparison with the simulated diving reflex, the Valsalva maneuver, and administration of atropine. Patients with diabetes mellitus, brainstem stroke, multiple sclerosis, or Shy-Drager syndrome developed less than normal bradycardia or minimal tachycardia in response to the cold facial stimulus. The cold face test is a novel, simple, safe, and economical test of the integrity of trigeminal-brainstem-vagal reflex pathways, can be utilized practically to assess vagal and brainstem dysfunctions, and has the special advantage of being applicable even in an uncooperative or comatose patient.     

Volume loading inhibits baroreflex vagal bradycardia in rats.

Volume loading tends to increase blood pressure. Resultant arterial baroreflexes, especially the heart rate component, would counteract renal compensation of volume expansion. In this study, we investigated effect of volume loading on baroreflex vagal bradycardia (BVB) induced by electrical stimulation of the aortic depressor nerves in chloralose/urethane-anesthetized, succinylcholine-immobilized, artificially ventilated rats. As a result, we confirmed that volume loading inhibits BVB. The inhibition was abolished following spinal cord transection at C2. In contrast, volume loading did not affect the bradycardia induced by electrical stimulation of peripheral cut ends of the cervical vagus. These findings suggest that the inhibition of BVB by volume loading is mediated by afferent input which is conveyed in the sympathetic nerves and ascends in the spinal cord, and produced at a central site.     

Dorsal hippocampus cholinergic and nitrergic neurotransmission modulates the cardiac baroreflex function in rats

Hippocampus is a limbic structure involved in the baroreflex and chemoreflex control that receives extensive cholinergic input from basal forebrain. Hippocampal muscarinic receptors activation by acetylcholine might evoke nitric oxide synthesis, which is an important neuromodulator of cardiovascular responses. Thus, we hypothesize that cholinergic and nitrergic neurotransmission within the DH modulates the baroreflex and chemoreflex function. We have used vasoactive drugs (phenylephrine and sodium nitroprusside), and potassium cyanide infused peripherally to induce, respectively, baroreflex or chemoreflex responses in awake animals. Bilateral injection into the DH of the acetylcholinesterase inhibitor (neostigmine) reduced baroreflex responses. Meanwhile, the non‐selective muscarinic receptor antagonist (atropine) or the M1‐selective muscarinic receptor antagonist increased baroreflex responses (pirenzepine). Furthermore, the neuronal nitric oxide synthase inhibitor (N‐propyl) or the intracellular NO scavenger (carboxy‐PTIO) increased baroreflex responses, as well as the selective inhibitor of NO‐sensitive guanylyl cyclase (ODQ), increased the baroreflex responses. Besides, bilateral administration of an ineffective dose of a neuronal nitric oxide synthase inhibitor abolished the reduction in the baroreflex responses evoked by an acetylcholinesterase inhibitor. On the other hand, we have demonstrated that hippocampal cholinergic neurotransmission did not influence the chemoreflex function. Taken together, our findings suggest that nNOS‐derived nitric oxide in the DH participates in acetylcholine‐evoked baroreflex responses.     

Suppressing cardiac vagal modulation and changing sleep patterns in rats after chronic ischemic stroke injury

Chronic autonomic function and sleep architecture changes in patients post-stroke are not well understood. Using wireless polysomnographic recordings, this study aimed to investigate the long-term effects on sleep patterns and autonomic function in free moving rats after middle cerebral artery occlusion (MCAO). The sleep pattern and heart rate variability (HRV) of Wistar-Kyoto rats (WKY) were analyzed. After 7-10days, the rats were divided into two groups: an MCAO group (n=8) and a sham surgery group (n=8). Compared with shams, MCAO rats showed decreased accumulated quiet sleep (QS) time over 24h during the 3rd week. The time percentage, duration and delta power of QS were also significantly decreased in the MCAO group during the dark period. Compared with baseline, there were significant increases in the parasympathetic-associated HRV measures in the sham group, including the total power (TP), high frequency power (HF) and lower frequency power (LF), throughout the post-operative weeks (primarily the 2nd and 3rd weeks), reflecting a developmental increase of parasympathetic modulation; the normalized LF and the LF-HF ratio were unaffected. In great contrast, however, most of the HRV measures in the MCAO group were not significantly changed. Therefore, this study showed that the long-term effects of ischemic stroke injury involve retardation of the establishment of parasympathetic enhancement and disturbance of the normal sleep-wake cycle.     

Effect of age on adrenergic and vagal baroreflex sensitivity in normal subjects

The baroreflex maintains a stable blood pressure (BP) by dynamically adjusting heart rate (vagal component) and total peripheral resistance (adrenergic component). Vagal baroreflex sensitivity (BRS-v) is widely used but no methodology existed to quantitate adrenergic baroreflex sensitivity (BRS-a) until we developed the indices of BP recovery time (PRT) and BRS-a. The aims of this study were to generate a normative database and to evaluate whether there is an age effect on the cardiovagal and adrenergic sensitivities. We evaluated recordings of heart rate (HR) and BP in 255 normal subjects during the Valsalva maneuver (VM) and determined both BRS-v and BRS-a sensitivities. PRT increased with age whereas all other parameters declined with age. The adrenergic parameters correlated well with each other but not significantly with BRS-v. The results indicate that both BRS-a and BRS-v become blunted with increasing age and that these indices behave independently of each other.     

Acute effects of aldosterone on the autonomic nervous system and the baroreflex function in healthy humans

Aldosterone has been reported to impair the baroreflex response in animal models. The present study aimed to investigate the acute effects of aldosterone on the autonomic nervous system and the baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. Nine healthy subjects were examined in a double-blind, placebo-controlled, cross-over study design, receiving either i.v. aldosterone (100 microg) or placebo on the experimental day. Heart rate variability (HRV) was measured at rest, whereas blood pressure, heart rate and MSNA (assessed by microneurography from the peroneal nerve) were monitored both at rest and during baroreflex tests. Baroreceptor stimulation and deactivation was induced by i.v. infusion of incremental doses of phenylephrine and sodium nitroprusside. HRV indices at rest were specifically changed by aldosterone with a significant increase in standard deviation of RR intervals and total power, and a trend towards increased time domain parameters indicating parasympathetic predominance in heart rate regulation. Basal MSNA, blood pressure and heart rate remained unaffected by aldosterone administration. Sodium nitroprusside decreased diastolic blood pressure and increased MSNA as well as heart rate in both the aldosterone and placebo experiments. However, the tachycardic response to arterial baroreceptor deactivation was more pronounced in the aldosterone experiments. By contrast, baroreflex control of MSNA and heart rate during phenylephrine infusion was not affected by aldosterone. Thus, our study demonstrates that, in healthy humans, aldosterone tends to increase cardiac vagal activity and enhances the heart rate response to nitroprusside whereas MSNA remains unaffected.     

Induction of chronic non-inflammatory widespread pain increases cardiac sympathetic modulation in rats

Fibromyalgia (FM) is characterized by chronic non-inflammatory widespread pain (CWP) and changes in sympathetic function. In attempt to elucidate the pathophysiological mechanisms of FM we used a well-established CWP animal model. We aimed to evaluate changes in cardiac autonomic balance and baroreflex function in response to CWP induction in rats. CWP was induced by two injections of acidic saline (pH 4.0, n=8) five days apart into the left gastrocnemius muscle. Control animals were injected twice with normal saline (pH 7.2, n=6). One day after the second injection of acidic saline or normal saline, the animals had pulse interval (PI) and systolic arterial pressure (SAP) variability, and spontaneous baroreflex sensitivity (BRS) evaluated. After induction of CWP, there was an increase of power in the low frequency (LF) band of PI spectrum (12.75 ± 1.04 nu), a decrease in the high frequency (HF) band (87.25 ± 1.04 nu) and an increase of LF/HF ratio (0.16 ± 0.01), when compared to control animals (7.83 ± 1.13 nu LF; 92.16 ± 1.13 nu HF; 0.08 ± 0.01 LF/HF). In addition, there was an increase of power in the LF band of SAP spectrum (7.93 ± 1.39 mmHg(2)) when compared to control animals (2.97 ± 0.61 mmHg(2)). BRS was lower in acidic saline injected rats (0.59 ± 0.06 ms/mmHg) when compared to control animals (0.71 ± 0.03 ms/mmHg). Our results showed that induction of CWP in rats shifts cardiac sympathovagal balance towards sympathetic predominance and decreases BRS. These data corroborate findings in humans with FM.     

Tirasemtiv amplifies skeletal muscle response to nerve activation in humans

Introduction: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. Methods: Healthy men received tirasemtiv and placebo in a randomized, double‐blind, 4‐period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force–frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. Results: Tirasemtiv increased force produced by the tibialis anterior in a dose‐, concentration‐, and frequency‐dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz ). Conclusions: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input. Muscle Nerve 50 : 925–931, 2014     

Comparison of aortic and carotid baroreflex stimulus-response characteristics in humans

In order to characterize the stimulus-response relationships of the arterial, aortic, and carotid baroreflexes in mediating cardiac chronotropic function, we measured heart rate (HR) responses elicited by acute changes in mean arterial pressure (MAP) and carotid sinus pressure (CSP) in 11 healthy individuals. Arterial (aortic + carotid) baroreflex control of HR was quantified using ramped changes in MAP induced by bolus injection of phenylephrine (PE) and sodium nitroprusside (SN). To assess aortic-cardiac responses, neck pressure (NP) and suction (NS) were applied during PE and SN administration, respectively, to counter alterations in CSP thereby isolating the aortic baroreflex. Graded levels of NP and NS were delivered to the carotid sinus using a customized neck collar device to assess the carotid-cardiac baroreflex, independent of drug infusion. The operating characteristics of each reflex were determined from the logistic function of the elicited HR response to the induced change in MAP. The arterial pressures at which the threshold was located on the stimulus-response curves determined for the arterial, aortic and carotid baroreflexes were not significantly different (72+/-4, 67+/-3, and 72+/-4 mm Hg, respectively, P > 0.05). Similarly, the MAP at which the saturation of the reflex responses were elicited did not differ among the baroreflex arcs examined (98+/-3, 99+/-2, and 102+/-3 mm Hg, respectively). These data suggest that the baroreceptor populations studied operate over the same range of arterial pressures. This finding indicates each baroreflex functions as both an important anti-hypotensive and anti-hypertensive mechanism. In addition, this investigation describes a model of aortic baroreflex function in normal healthy humans, which may prove useful in identifying the origin of baroreflex dysfunction in disease- and training-induced conditions.     

Hemispheric influence on autonomic modulation and baroreflex sensitivity

Several studies suggest hemispheric lateralization of autonomic cardiovascular control. There is controversy regarding which hemisphere dominates sympathetic or parasympathetic activity. Hemispheric influences on baroreflex sensitivity (BRS) have not yet been evaluated. To determine hemispheric autonomic control in epilepsy patients, we assessed cardiovascular and baroreflex modulation before and during hemispheric inactivation. For 15 patients with drug-refractory epilepsy, we analyzed autonomic heart rate (HR) and blood pressure (BP) modulation and BRS before and during left and right intracarotid amobarbital procedure (IAP). After Blackman-Tukey spectral analysis, we calculated the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.5 Hz) power of HR and BP as well as BRS as the LF transfer function gain between BP and HR. Right hemispheric inactivation induced a significant decrease of BP and an increase of HF power of HR and BP (p < 0.05). Left inactivation increased HR, BP, and LF power of both signals and decreased BRS by nearly 30% (p < 0.05). The results confirm previous IAP studies showing sympathetic lateralization in the right hemisphere and, moreover, demonstrate parasympathetic predominance and up-regulation of BRS in the left hemisphere. In epilepsy patients, unilateral electrical activity might derange autonomic balance between both hemispheres and contribute to cardiovascular dysregulation and sudden fatalities.     

Reduced cardiac vagal excitability in hyperthyroidism

A great deal of uncertainty persists regarding the exact nature of the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate. In the present work we investigated whether reduced vagal influence could contribute to the tachycardia in hyperthyroidism. Vagal excitability was studied in ten hyperthyroid patients. Prolongation of R-R interval in response to carotid baroreceptor stimulation by neck suction was found to be less in the hyperthyroid state compared to the control state after therapy. The extent of nocturnal bradycardia and the vagal excitatory response to the central effect of low dose atropin was significantly reduced in hyperthyroid patients compared to euthyroid controls. We concluded that in the hyperthyroid state cardiac vagal motoneurones were in a low excitability state, and speculated that the inhibition might have resulted from thyroid hormone action on CNS structures integrating autonomic function and behaviour.     

Brain systems for baroreflex suppression during stress in humans

The arterial baroreflex is a key mechanism for the homeostatic control of blood pressure (BP). In animals and humans, psychological stressors suppress the capacity of the arterial baroreflex to control short-term fluctuations in BP, reflected by reduced baroreflex sensitivity (BRS). While animal studies have characterized the brain systems that link stressor processing to BRS suppression, comparable human studies are lacking. Here, we measured beat-to-beat BP and heart rate (HR) in 97 adults who performed a multisource interference task that evoked changes in spontaneous BRS, which were quantified by a validated sequence method. The same 97 participants also performed the task during functional magnetic resonance imaging (fMRI) of brain activity. Across participants, task performance (i) increased BP and HR and (ii) reduced BRS. Analyses of fMRI data further demonstrated that a greater task-evoked reduction in BRS covaried with greater activity in brain systems important for central autonomic and cardiovascular control, particularly the cingulate cortex, insula, amygdala, and midbrain periaqueductal gray (PAG). Moreover, task performance increased the functional connectivity of a discrete area of the anterior insula with both the cingulate cortex and amygdala. In parallel, this same insula area showed increased task-evoked functional connectivity with midbrain PAG and pons. These novel findings provide human evidence for the brain systems presumptively involved in suppressing baroreflex functionality, with relevance for understanding the neurobiological mechanisms of stressor-related cardiovascular reactivity and associated risk for essential hypertension and atherosclerotic heart disease.     

Acupuncture to Danzhong but not to Zhongting increases the cardiac vagal component of heart rate variability

There is currently no convincing evidence that acupuncture has any specific effects on autonomic nervous function as assessed by heart rate variability (HRV). We examined whether the stimulation of neighboring acupunctural points, Danzhong (CV17) and Zhongting (CV16) on the anterior median line of the thorax, induced different effects on HRV. In 14 healthy males, epifascial acupunctural stimulation (single instantaneous needle stimulation on the fascial surface without producing De-Qi sensation) was performed at CV17 and CV16 on different days in a clinical study utilizing a cross-over design. We found that the stimulation of CV17, but not of CV16, decreased the heart rate (P=0.01, repeated measures ANOVA) and increased the power of the high-frequency component of the HRV, an index of cardiac vagal activity (P=0.01). The low-frequency to high-frequency ratio, an index of sympathetic activity showed no significant changes for either point. Our observations could not be explained as either nonspecific or psychological/placebo effects of needle stimulation. This study provides strong evidence for the presence of a specific acupunctural point that causes the modulation of cardiac autonomic function.