Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure.

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 6-7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722-1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Severe impaired blood pressure control caused by baroreflex failure as a late sequela of neck irradiation.

: A 64-year-old man, whose medical history was significant only for locally advanced squamocellular carcinoma of the right palatine tonsil treated with extended neck radiotherapy 9 years before, was evaluated for traumatic cerebral haemorrhage secondary to syncope after a postural change. The selective angiographic study of cerebral vessels was negative. No heart arrhythmias were recorded at ECG monitoring. The 24-h ABPM revealed sudden pressor and depressor episodes during day-time and a reverse dipper pattern during night-time. Noninvasive autonomic nervous system function testing showed supine hypertension and orthostatic hypotension caused by afferent baroreflex failure. According to literature, even if only few cases are described, neck irradiation can be assumed to be the major cause of baroreflex failure. No treatment is currently approved. The patient was treated with a selective beta-blocker (bisoprolol) administered at bedtime. Repeated ABPM after 1 month of therapy showed absence of sudden pressor and depressor episodes and no dipper pattern during night-time.

Acute effect of photobiomodulation using light-emitting diodes (LEDs) on baroreflex sensitivity during and after constant loading exercise in patients with type 2 diabetes mellitus.

To evaluate the photobiomodulation (PBM) effect on the cardiovascular autonomic control, analyzed by baroreflex sensitivity (sequence method), during constant load exercise and recovery in diabetic men, we evaluated 11 men with type 2 diabetes (DM2) (40-64 years). The constant workload exercise protocol (TECC) was performed on two different days, 14 days apart from each other, to guarantee PBM washout period. After PBM by light-emitting diode (LED) irradiation (150 J or 300 J or placebo), 10 min of rest (REST) was performed. After this period, the volunteer was positioned on a cycloergometer to start the test (1-min rest, 3-min free-load heating, 6-min constant workload-EXERCISE, 6-min free-load cool-down, 1-min rest) followed by a sitting period of 10 min (RECOVERY). The constant workload corresponded to 80%VO2GET (gas exchange threshold) identified by a previous cardiopulmonary exercise test (CPET). PBM was applied in continuous mode, contact technique, bilaterally, on both femoral quadriceps and gastrocnemius muscle groups. The electrocardiogram R-R intervals (BioAmp FE132) and the peripheral pulse pressure signals (Finometer PRO) were collected continuously throughout the protocol. Stable sequences of 256 points were chosen at REST, EXERCISE, and RECOVERY. The baroreflex sensitivity (BRS) was computed in time domain according to the sequence method (αseq). The comparison between therapies (150 J/300 J/placebo) and condition (REST, EXERCISE, and RECOVERY) was performed using the ANOVA two-way repeated measures test. There was no interaction between therapy and conditions during the TECC. There was only the condition effect (p < 0.001), showing that the behavior of αseq was similar regardless of the therapy. Photobiomodulation with 150 J or 300 J applied previously to a moderate-intensity TECC in DM2 was not able to promote cardiovascular autonomic control changes leading to an improvement in BRS.

Cardiovascular sequel of neck irradiation in head and neck cancer patients.

PURPOSE: The baroreflex is an important afferent mechanism controlling autonomic functions. As afferent nerves course through the neck, they are susceptible to damage by neck irradiation in head and neck cancer patients. With increased survival of head and neck cancer patients because of improved therapy, the cardiovascular morbidity and mortality in them have become apparent and this is of clinical concern. There are few case reports of baroreflex failure as a chronic sequel to neck irradiation. OBJECTIVES: The present study evaluated the changes in cardio-autonomic tone and postural cardiovascular reflex in neck-irradiated patients. METHODS: Head and neck cancer patients who had received neck irradiation (n = 15) and healthy controls (n = 15) were evaluated for heart rate variability with time domain analysis of 5 min ECG recording. Postural cardiovascular reflexes were studied with changes in blood pressure and heart rate in the lying to standing test. RESULTS: Our results suggest that there is a reduction in overall time domain measures of heart rate variability and weakened postural reflexes in neck-irradiated patients. CONCLUSION: Decreased heart rate variability in neck-irradiated patients reflects an independent risk of cardiovascular morbidity. The early detection of cardiovascular impairment in such patients may help healthcare professionals in providing better care. Furthermore, the dose delivered to the carotid sinus should be monitored and restricted.

Static magnetic field reduces blood pressure short-term variability and enhances baro-receptor reflex sensitivity in spontaneously hypertensive rats.

PURPOSE: It has been shown that chronic exposure of young spontaneously hypertensive rats (SHR) to static magnetic field (SMF) delays the development of overt hypertension. Therefore the aim of the present work was to investigate the effects of SMF on autonomic cardiovascular control in adult spontaneously hypertensive rats. MATERIALS AND METHODS: Experiments were performed in freely moving spontaneously hypertensive rats equipped with femoral arterial catheter for blood pressure recording. Spontaneously hypertensive rats were exposed for 30 days to upward-oriented SMF (n = 17) or downward-oriented SMF (n = 17) of 16 mT intensity. A control group of spontaneously hypertensive rats (n = 17) was not exposed to SMF. Neurogenic cardiovascular control was evaluated by spectral analysis of arterial blood pressure and heart rate short-term variability and baro-receptor reflex sensitivity using the sequence method. RESULTS: Exposure of spontaneously hypertensive rats to both upward- and downward-oriented SMF significantly reduced arterial blood pressure and enhanced baro-receptor reflex sensitivity. Downward-oriented SMF reduced heart rate, too. SMF of either orientation reduced systolic blood pressure variability in very low frequency domain while downward-oriented SMF also reduced low-frequency and increased high frequency domains. CONCLUSION: It follows that prolonged exposure to SMF is beneficial for neurogenic cardiovascular control in hypertension.

Dialysate temperature adjustment as an effective treatment for baroreflex failure syndrome in hemodialysis patient.

BACKGROUND: Baroreflex failure syndrome is a rare disorder which causes labile blood pressure, headache, flushing, diaphoresis and emotional lability. It is caused by history of trauma or radiotherapy in the cervical legion, bilateral carotid-body tumor or resection of glossopharyngeal nerve. We experienced a case of hemodialysis patient who had difficulty in controlling blood pressure during dialysis because of his baroreflex failure syndrome and successfully controlled his blood pressure by adjusting dialysate temperature. CASE PRESENTATION: We report a case of a 68-year-old CKD5 patient who had difficulty in hemodialysis treatment because of severe fluctuations in blood pressure with hypertensive attacks and hypotensive episodes which caused him a severe discomfort. His dialysis treatment was started in 2010 and since that time baroreflex failure syndrome has been suspected because of his clinical manifestations and history of radiotherapy in the cervical region for his lingual cancer in 1994. Baroreflex failure syndrome is diagnosed by symptoms and cold stressor test. We performed a cold stressor test on an experimental baroreflex failure syndrome mouse and induced a significant elevation of blood pressure. From this experimental finding of model mouse, we changed the patients dialysate temperature between 34-38° according to his change in blood pressure though 80-240 mmHg. From this attempt, his blood pressure was successfully controlled between 100-180 mmHg and he was able to continue hemodialysis without any discomfort. CONCLUSION: In our case, environmental stimulation such as temperature change modified the patients fluctuating blood pressure. Change of dialysate temperature could be an option for controlling the unstable blood pressure due to baroreflex failure syndrome.

Baroreflex activation therapy in patients with pre-existing implantable cardioverter-defibrillator: compatible, complementary therapies.

AIMS: The Neo™ System (CVRx) is an implantable device, CE certified for the treatment of resistant hypertension and investigationally used to treat systolic heart failure by electrical stimulation of the carotid baroreceptors. It is unknown whether interaction might exist between the Neo System and implantable cardioverter-defibrillators (ICDs). METHODS AND RESULTS: Compatibility of the Neo device was tested in seven consecutive patients with pre-existing ICDs. Intra- and post-operative testing was completed with ICD and Neo settings programmed to provoke interaction. Intracardiac electrograms were printed to determine interaction with the ICD. Interaction testing during implantation and follow-up showed that there was no device-device interaction. No interaction was observed at maximum atrial and ventricular sensitivity settings and maximum Neo output settings. CONCLUSION: Combined therapy with the Neo device and at least in this study reported that transvenous ICD systems can be performed safely.

Depressor effect of closed-loop chip system in spontaneously hypertensive rats.

We previously reported that a closed-loop chip system was designed to decrease arterial pressure in normal rabbits and rats. In the present study, the depressor effects of the chip system were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The arterial pressure was recorded, sampled, operated and processed in the chip system. The chip system instantaneously controlled arterial pressure by stimulating the left aortic depressor nerve according to the feedback signals of arterial pressure. The closed-loop chip system effectively decreased mean arterial pressure (MAP) and heart rate (HR) in both SHR and WKY rats. It decreased the duration and the maximal MAP level of the pressor response evoked by either intravenous injection of phenylephrine or cutaneous nociceptive stimulation in SHR, but had no significant effect on the magnitude of the increase in MAP. Furthermore, the chip system significantly increased the baroreflex gain in SHR, but not in normal WKY rats. These results suggest that the closed-loop chip system effectively decreases the arterial pressure and increases baroreflex gain in SHR. The chip system does not abolish the arterial pressure responses to accidental pressor events, but decreases the duration and the maximal MAP level of the pressor responses.

[Effect of radiotherapy on heart rate stability in cancer patients].

Heart rate variability at rest and in active orthostatic test (AOT), before and after radiotherapy (STD 3Gy; TTD 30Gy), was studied in 4 left-breast cancer patients and 8 cases of esophageal (middle third) cancer. AOT involved by decreased baroreflective activity (7) and parasympathetic reactivity. Sympathoadrenal fraction was relatively prominent in 6 patients against the background of average declined heart rate (3). Prior to radiotherapy, average heart rate was low in all patients, and continued to fall in 10 patients after treatment. While tumor process inhibited functional status and systemic reactions of adaptation, they were still further depressed by radiotherapy resulting eventually in failure of such response.

Endomorphin-2 in the medial NTS attenuates the responses to baroreflex activation.

We have previously reported that microinjections of endomorphin-2 (E-2; an endogenous mu-receptor agonist) into the medial subnucleus of the NTS (mNTS) elicit depressor and bradycardic responses via activation of ionotropic glutamate receptors located on secondary mNTS-neurons. Based on this report, it was hypothesized that activation of secondary mNTS neurons by E-2 may result in an exaggeration of baroreflex responses. In order to test this hypothesis, baroreflex responses were studied in adult, urethane-anesthetized, artificially ventilated, male Wistar rats before and after the microinjections of E-2 into the mNTS. Baroreceptors were stimulated by applying pressure increments (80-100 mm Hg) in the carotid sinus and by electrical stimulation (stimulus intensity: 0.5 V, frequencies 5, 10, and 25 pulses/s, pulse duration: 1 ms) of the aortic nerve for 30-s periods. Baroreceptor stimulation elicited depressor and bradycardic responses. Microinjections (100 nl) of E-2 (0.4 mmol/l) into the mNTS attenuated the baroreflex responses. Microinjections of naloxone (an opioid receptor antagonist) into the mNTS (0.5 mmol/l) did not alter baroreflex responses. Based on these results, it was concluded that activation of mu-opioid receptors in the mNTS attenuates baroreflex responses. Possible mechanisms for excitatory effects of E-2 in the mNTS resulting in depressor and bradycardic responses, on one hand, and inhibitory effects resulting in attenuation of baroreflex responses, on the other, are discussed.

Electrical activation of the human vestibulo-sympathetic reflex.

Muscle sympathetic nerve activity (MSNA) is modulated on a beat-to-beat basis by the baroreflex. Vestibular input from the otolith organs also modulates MSNA, but characteristics of the vestibulo-sympathetic reflex (VSR) are largely unknown. The purpose of this study was to elicit the VSR with electrical stimulation to estimate its latency in generating MSNA. The vestibular nerves of seven subjects were stimulated across the mastoids with short trains of high frequency, constant current pulses. Pulse trains were delivered every fourth heartbeat at delays of 300-700 ms after the R wave of the electrocardiogram. Vestibular nerve stimulation given 500 ms after the R wave significantly increased baroreflex-driven MSNA, as well as the diastolic blood pressure threshold at which bursts of MSNA occurred. These changes were specific to beats in which vestibular stimulation was applied. Electrical stimulation across the shoulders provided a control condition. When trans-shoulder trials were subtracted from trials with vestibular nerve stimulation, eliminating the background baroreflex-driven sympathetic activity, there was a sharp increase in MSNA beginning 660 ms after the vestibular nerve stimulus and lasting for about 60 ms. The increase in the MSNA produced by vestibular nerve stimulation, and the associated increase in the diastolic blood pressure threshold at which the baroreflex-driven bursts occurred, provide evidence for the presence of a short-latency VSR in humans that is likely to be important for the maintenance of blood pressure during rapid changes in head and body position with respect to gravity.

Target site of inhibition of baroreflex vagal bradycardia by nasal stimulation.

We have previously reported that stimulation of nasal mucosa inhibits baroreflex vagal bradycardia (BVB) and this inhibition was mediated exclusively by the trigeminal nerve, and occurred principally at pontomedullary level. In this study, to identify the target site of the inhibition, several types of experiments were conducted in chloralose-urethane-anesthetized, beta-adrenergic receptor-blocked rats. Afferent discharges in the ethmoidal nerve (EN5) were increased in response to nasal stimulation by smoke, and electrical stimulation of the EN5 suppressed BVB induced by electrical stimulation of the aortic depressor nerve (ADN). Electrical stimulation of the EN5 inhibited vagal bradycardia evoked by either electrical or chemical stimulation of the nucleus tractus solitarius (NTS), while it rather facilitated bradycardia by stimulation of the nucleus ambiguus (NA) region. Microstimulation of the NTS induced antidromic compound spike potential along the ADN but this was not affected by stimulation of the EN5. ADN-evoked field potentials and unitary responses of neurons in the NTS were suppressed by stimulation of the EN5. These results suggested that barosensitive neurons in the NTS are the major target sites of inhibition of BVB by nasal stimulation in rats.

Geomagnetic field effect on cardiovascular regulation.

The goal of the present research was try to explain the physiological mechanism for the influence of the geomagnetic field (GMF) disturbance, reflected by the indices of the geomagnetic activity (K, K(p), A(k), and A(p) indices), on cardiovascular regulation. One hundred forty three experimental runs (one daily) comprising 50 min hemodynamic monitoring sequences were carried out in rabbits sedated by pentobarbital infusion (5 mg/kg/h). We examined the arterial baroreflex effects on the short term blood pressure and heart rate (HR) variabilities reflected by the standard deviation (SD) of the average values of the mean femoral arterial blood pressure (MAP) and the HR. Baroreflex sensitivity (BRS) was estimated from blood pressure/HR response to intravenous (i.v.) bolus injections of vasoconstrictor (phenylephrine) and vasodilator (nitroprusside) drugs. We found a significant negative correlation of increasing GMF disturbance (K(p)) with BRS (P = 0.008), HR SD (P =0.022), and MAP SD (P = 0.002) signifying the involvement of the arterial baroreflex mechanism. The abrupt change in geomagnetic disturbance from low (K = 0) to high (K = 4-5) values was associated with a significant increase in MAP (83 +/- 5 vs. 99 +/- 5 mm Hg, P = 0.045) and myocardial oxygen consumption, measured by MAP and HR product (24100 +/- 1800 vs. 31000 +/- 2500 mm Hg. bpm, P = 0.034), comprising an additional cardiovascular risk. Most likely, GMF affects brainstem and higher neural cardiovascular regulatory centers modulating blood pressure and HR variabilities associated with the arterial baroreflex.

Verapamil protective effect on natural and artificial magnetic field cardiovascular impact.

Previously we found an opposite effect of artificial static magnetic field (SMF) and natural geomagnetic field (GMF) on arterial baroreceptors. A 0.35 T SMF increased baroreflex sensitivity (BRS), whereas GMF disturbance decreased BRS. Here, we investigated interrelated impacts on arterial baroreceptors of 0.35 T SMF, generated by Nd(2)-Fe(14)-B alloy magnets, GMF, and verapamil, a Ca(2+) channel blocking agent. We measured BRS in rabbits before and after local SMF exposure of sinocarotid baroreceptors or after simultaneous SMF and verapamil application, in conjunction with geomagnetic disturbance during actual experimental run (determined by K-index) and geomagnetic disturbance over the preceding 24 h of each experiment (A(k)-index). BRS was estimated from peak responses of mean arterial pressure (MAP) and heart rate, expressed as percentages of the resting values preceding each pair of pressure (phenylephrine) and depressor drug (nitroprusside) injections. Prior to verapamil and/or SMF application we found a significant positive correlation of K-index with MAP (t = 2.39, P =.021, n = 44), but negative with BRS (t = -4.60, P =.0003, n = 44), and found a negative correlation of A(k)-index with BRS (t = -2.7, P = 0.01, n = 44). SMF induced an increase in BRS (0.79 +/- 0.1 vs. 1.15 +/- 0.1 bpm%/mmHg%, initial value vs. SMF exposure, P <.0002, n = 26). Verapamil infusion blocked the SMF and GMF effect on BRS, indicating Ca(2+) channels as a possible site of both fields' impact. SMF and GMF probably affect baroreceptor sensory transduction, modulating baroreceptor membranes' Ca(2+) channel permeability.

Arterial baroreflex and peripheral chemoreflex function after radiotherapy for laryngeal or pharyngeal cancer.

PURPOSE: Denervation of the carotid sinus causes baroreflex and chemoreflex failure, resulting in labile hypertension and loss of hypoxic responsiveness. We investigated whether radiation therapy for laryngeal or pharyngeal cancer affects baroreflex and chemoreflex function. METHODS AND MATERIALS: Twelve patients were studied after radiation therapy for locally advanced laryngeal or pharyngeal cancer (11 male, 1 female, age: 56.0 +/- 7.9 years), 3.3 years (median; range 1.0-4.7) after radiotherapy and 15 healthy controls (11 male, 4 female, 53.4 +/- 9.2 years). We measured baroreflex sensitivity (phenylephrine), blood pressure level and variability (24-h Spacelabs and 5-h Portapres recordings), responses to cardiovascular reflex tests, and the ventilatory responses to normocapnic and hypercapnic hypoxia. RESULTS: Baroreflex sensitivity was lower in patients (9.7 +/- 7.8 ms/mm Hg) than in controls (17.5 +/- 10.3 ms/mm Hg, p = 0.011). Mean office blood pressure was significantly higher in patients (141.5 +/- 27.8/89.2 +/- 10.6 mm Hg, 63.3 +/- 12.3 bpm) than in controls (117.3 +/- 10.1/75.1 +/- 6.8 mm Hg, 61.8 +/- 10.8 bpm). Blood pressure variability was not different between groups, nor were the responses to reflex tests. The normo/hypercapnic ventilatory response to hypoxia was similar in patients (0.21 +/- 0.10/1.37 +/- 0.60 L/min/%) and controls (0.22 +/- 0.16/1.19 +/- 0.78 L/min/%). CONCLUSIONS: Radiation therapy for laryngeal or pharyngeal carcinoma does not affect chemoreflex function, but results in an attenuated baroreflex sensitivity. Clinically relevant blood pressure lability is absent however.

[Labile hypertension due to iatrogenic denervation of the carotid sinus]. / Labiele hypertensie door iatrogene denervatie van de sinus caroticus.

Two patients, a man and a woman aged 36 and 40 years, respectively, were found to have disturbed blood pressure regulation after medical intervention in the jugular area. The man had undergone radiation therapy of the neck due to regional lymph node involvement of a nasopharyngeal carcinoma. Six years later he developed episodic complaints of headache accompanied by labile hypo- and hypertension. Mental and physical stimuli resulted in excessive sympathetic activation. In the woman, a carotid body tumour was resected bilaterally. There was an immediate onset of hypertension after surgery. In both patients, the clinical syndrome was attributed to afferent baroreflex failure due to carotid sinus denervation.

Baroreflex failure following radiation therapy for nasopharyngeal carcinoma.

The authors present a 51-year-old man with right-sided nasopharyngeal carcinoma who was treated for regional lymph node involvement by bilateral radiation therapy of the neck. Six years later he presented with episodic complaints of headache, flushing, and palpitations accompanied by elevations of blood pressure. Examination of arterial baroreflex function indicated selective afferent carotid sinus denervation. Cross spectral analysis of spontaneous heart rate and blood pressure variability showed decreased arterial baroreflex sensitivity (6.5 ms/mm Hg). Twenty-four hour measurements of blood pressure and heart rate variability showed labile hypertension during normal daytime activities. Baroreflex failure in this patient probably represents a late complication of bilateral radiation therapy of the neck.

Assessment of baroreflex control from beat-to-beat blood pressure and heart rate changes: a validation study.

In this study, we tested the validity of a new method designed to estimate baroreflex control of heart rate from spontaneous changes in systolic pressure and pulse interval. This method was compared with a conventional method of assessing baroreflex control through measuring reflex adjustments in pulse interval associated with pharmacological manipulations of blood pressure. The estimates of baroreflex control derived from the two methods were significantly correlated; however, only the estimate derived using pharmacological changes in pressure detected significant impairment of baroreflex control in patients with damage to baroafferents produced by radiation for oropharyngeal cancer. Analysis of spontaneous changes in pressure and pulse interval therefore provide a meaningful estimate of baroreflex control of heart rate that is, however, less sensitive than estimates obtained using pharmacological manipulations in pressure.