Pathophysiology and potential clinical applications for testing of peripheral chemosensitivity in heart failure.

Enhanced peripheral chemosensitivity (PChS) is a common finding in congestive heart failure (CHF). Although initially it may be regarded as a compensatory mechanism to maintain adequate oxygenation and tissue perfusion, importantly it also contributes to disease progression. The magnitude of PChS is related to the severity of CHF but does not depend on its etiology. Numerous methodologies have been developed to assess PChS reliably; however, only two methods based on acute hypoxia have proven to be clinically and prognostically useful. The pathophysiology behind increased PChS is complex and involves disturbances in regional blood flow, gaseous neurotransmission, redox processes, and angiotensin signaling. Augmented PChS is believed to translate into sympathetic overactivity, decreased barosensitivity, reduced exercise tolerance, more arrhythmic events, and poor outcomes. In this review, we present current knowledge regarding the pathophysiology of peripheral chemoreflex, available methods for assessment, and clinical significance of increased PChS.

Continuous positive airway pressure increases heart rate variability in heart failure patients with obstructive sleep apnoea.

Patients with heart failure or OSA (obstructive sleep apnoea) have reduced HF-HRV (high-frequency heart rate variability), indicating reduced cardiac vagal modulation, a marker of poor prognosis. CPAP (continuous positive airway pressure) abolishes OSA in patients with heart failure, but effects on daytime HF-HRV have not been determined. We hypothesized that, in patients with heart failure, treatment of coexisting OSA by CPAP would increase morning HF-HRV. In 19 patients with heart failure (left ventricular ejection fraction <45%) and OSA (>/=20 apnoeas and hypopnoeas/h of sleep), HF-HRV was quantified before and 1 month after randomization to a control or CPAP-treated group. In the control group (n=7), there were no changes in HF-HRV over the 1 month study during wakefulness in the morning. In the CPAP-treated group (n=12) HF-HRV increased significantly during wakefulness in the morning [from 2.43+/-0.55 to 2.82+/-0.50 log(ms(2)/Hz); P=0.002] due to an increase in transfer function between changes in lung volume and changes in HF-HRV (92.37+/-96.03 to 219.07+/-177.14 ms/l; P=0.01). In conclusion, treatment of coexisting OSA by nocturnal CPAP in patients with heart failure increases HF-HRV during morning wakefulness, indicating improved vagal modulation of heart rate. This may contribute to improved prognosis.

The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis.

OBJECTIVE: The purpose of this study is to ascertain the effects of spatially variable ACh distributions on arrhythmogenesis in a morphologically realistic computer model of canine atria. BACKGROUND: Vagal stimulation releases acetylcholine (ACh), which causes a dose-dependent reduction in action potential duration (APD) in the atria. Due to the nonuniform distribution of nerve endings, APD dispersion may result, which has been shown to play a role in the breakup of activity. METHODS: Reentry was initiated in a computationally efficient, morphologically realistic computer model of the atria. Discrete regions corresponding to ACh release sites, referred to as islands, were assigned shortened APDs in an ACh-dependent fashion. Island APD was varied as well as the basal APD. The window of vulnerability for ectopic beat-induction of sustained reentry was determined for both left atrial(LA) and right atrial (RA) stimulation. The resulting reentries were categorized based on type and location. RESULTS: 1) Atrial geometry severely restricts the formation of reentrant circuits. 2) Wave fractionation only occurred for large differences between island and basal APD. 3) Small ACh concentration differences produced stable figure-of-8 reentrant patterns. 4) Large islands displayed more wave breakup but could sometimes anchor reentries. CONCLUSIONS: Large APD gradients produced by ACh heterogeneity can lead to a breakdown of organized activity.

Chemoreceptor tumors diagnosed at the Western College of Veterinary Medicine 1967-1979.

Twenty-nine chemoreceptor tumors submitted to the Western College of Veterinary Medicine, Saskatoon, Saskatchewan between 1967 and 1979 were compared with those previously reported. The prevalence was low, with 28 cases occurring in dogs while only one was diagnosed in a cat. Old male dogs and the Boxer, Boston bull terrier and Collie breeds were affected most commonly. The prevalence in Collies (five of 28 dogs) was unexpected but may have been coincidental in this size of sample. The chemoreceptor tumor was often of clinical significance because in two-thirds of the cases it was either the presenting complaint or considered at necropsy to have caused illness or death.

[Glomus vagale tumor--diagnosis and treatment]. / Glomus vagale--diagnostyka i leczenie.

Paraganglioma, being tumors arising from the paraganglion cells of the parasympathetic system, were first reported in man in 1935. Within, the head and neck glomus vagale tumors account for less than 5% of all paragangliomas, with approximately 10% being multicentric. Although histologically these tumors have been shown to contain neurosecretory granules, they are rarely functional. Vagal chemodectomas are histologically benign, but are one of the most difficult tumors of the skull base to manage. Authors present a case of 56 years old woman with glomus vagale tumor treated in ENT Dept. in Poznan.

[Vasovagal syncope in 15-year-old girl]. / Zespól wazowagalny jako przyczyna omdlen u 15-letniej dziewczynki.

The authors present a case of a 15-year-old girl with syncope and bradycardia, in whom vasovagal syncope was recognized. The diagnosis was confirmed by positive tilt test. Because of the dominant vasodepressor reaction, Effortil was started to prevent further syncope, with good results.

Autonomic control of the cardiovascular system in the cat during hypoxemia.

This study aimed to determine the roles played by the autonomic interoreceptors, the carotid bodies (cbs) and the aortic bodies (abs) in anesthetized, paralyzed, artificially ventilated cats' response to systemic hypoxemia. Four 15min challenges stimulated each of 15 animals: (1) hypoxic hypoxia (10%O2 in N2; HH) in the intact (int) cat where both abs and cbs sent neural traffic to the nucleus tractus solitarius (NTS); (2) carbon monoxide hypoxia (30%O2 in N2 with the addition of CO; COH) in the intact cat where only the abs sent neural traffic to the NTS; (3) HH in the cat after transection of both aortic depressor nerves, resecting the aortic bodies (HHabr), where only the cbs sent neural traffic to the NTS; (4) COH to the abr cat where neither abs nor cbs sent neural traffic to the NTS. Cardiac output (C.O.), contractility (dP/dt(MAX)), systolic/diastolic pressures, aortic blood pressure, total peripheral resistance, pulmonary arterial pressure, and pulmonary vascular resistance (PVR) were measured. When both cbs and abs were active the maximum increases were observed except for PVR which decreased. Some variables showed the cbs to have a greater effect than the abs. The abs proved to be important during some challenges for maintaining blood pressure. The data support the critically important role for the chemoreceptor-sympathetic nervous system connection during hypoxemia for maintaining viable homeostasis, with some differences between the cbs and the abs.

Gastric electrical stimulation significantly increases canine lower esophageal sphincter pressure.

This study determined the effect of low-frequency and high-frequency gastric electrical stimulation (GES) on canine lower esophageal sphincter (LES) pressure and also evaluated the effect of such stimulation on neurohumoral factors that modulate LES pressure. Eight dogs were fitted with stimulation wires along the greater curvature of the stomach. A sleeve device measured LES pressure before, during, and after GES, and regulatory peptides were measured during fasting and after a meal. A consistent and significant rise in LES pressure was observed during GES, and it was sustained after GES was discontinued. Plasma concentration and area under the curve of pancreatic polypeptide, motilin, gastrin and neurotensin were not affected by GES. We conclude that acute low- and high-frequency GES significantly increases LES pressure. This effect may not be modulated by efferent vagal activity or release of regulatory peptides.

Influence of arterial hypoxia on cardiac and coronary dynamics in the conscious sinoaortic-denervated dog.

Arterial hypoxia was produced in 10 conscious, chronically instrumented, tracheostomized dogs by allowing them to breathe 7.5% O2 in N2 for 10 min. Hypoxia (Pao2 = 28 +/- 0.7 (SE) Torr) caused significant increases in coronary blood flow (+196%), left ventricular dP/dt max (+60%), aortic blood flow (+48%), heart rate (+50%), and left ventricular systolic (+12%) and aortic (+10%) pressures. Left ventricular end-diastolic pressure and stroke volume were unchanged, while systemic (-30%) and coronary diastolic (-66%) vascular resistances declined significantly. When equivalent levels of arterial hypoxia were produced in four of these dogs after chronic sinoaortic denervation, the coronary, cardiac, and systemic hemodynamic responses were not significantly different, with the exception that the small arterial pressure response was abolished. Thus the peripheral chemoreflexes are not essential for the normal coronary vasodilator and cardiac adjustments to occur during hypoxia in the conscious dog. The data support the hypothesis that a large part of the cardiac adjustments to hypoxia is initiated outside the sinoaortic reflexogenic zones, probably within the central nervous system.

Comparison of aortic and carotid chemoreceptor responses to hypercapnia and hypoxia.

A quantitative comparison of the responses between aortic and carotid chemoreceptors to steady-state levels of arterial CO2 and O2 partial pressure was made in 35 cats anesthetized, paralyzed, and artificially ventilated. The measurements on the two receptors were made simultaneously in 6 cats and separately in 29 cats. The response of aortic chemoreceptors to a CO2 stimulus was a fraction of that of carotid chemoreceptors, and the response to hypoxia was relatively blunted. The differences between the two chemoreceptors are quantitative rather than qualitative. Since a low arterial CO2 partial pressure stimulus is known to attenuate the hypoxic response of carotid chemoreceptors, it is suggested that the low CO2 response of aortic body chemoreceptors is responsible for their blunted hypoxic response.

Role of the carotid bodies in ventilatory acclimation to chronic hypoxia by the awake cat.

Steady-state breathing patterns during air and hypoxia (PIO2 = 84 Torr) were measured in awake cats in the following conditions: (1) during 7 months of exposure to air following carotid body resection (CBR; N = 6); (2) during 7 months of hypobaric hypoxia (PIO2 = 84 Torr; N = 5) following CBR; (3) during 5 months of exposure to hypobaric hypoxia (N = 4) while intact and then following CBR. Also, in groups (1) and (2) the aortic nerves were sectioned (ANX) at the end of the acclimation periods. The results show that the awake cat hypoventilates if the carotid bodies have been removed, and hypoxic sensitivity is reduced during long-term exposures to either hypoxia or normoxia. ANX caused a slight increase in respiratory frequency, indicating a minor role for the aortic bodies. CBR after acclimation to hypoxia resulted in decreased tidal volume but no change in respiratory frequency. The slight ventilatory acclimation to hypoxia in CBR cats was solely due to increased respiratory frequency. The phenomenon of 'hypoxic tachypnea' was modulated by acclimation, indicating that the effect of hypoxic acclimation upon respiratory frequency is due to central mechanisms.

Anemia as a stimulus to aortic and carotid chemoreceptors in the cat.

In cats anesthetized with alpha-chloralose, the activities of aortic and carotid chemoreceptor nerves were measured during a control period and during anemia where the hematocrit was lowered in steps by dextran-for-blood exchange. With anemia there was a sustained nonlinear increase in firing of aortic chemoreceptors. There was a greater firing of aortic chemoreceptors for a given lowering of hematocrit from an initial low blood hematocrit than for a similar decrease in hematocrit from an initial high blood hematocrit. Tonic carotid chemoreceptor firing was independent of blood hematocrit and was only transiently increased at the time of dextran-for-blood exchange. The lack of effect of anemia on carotid chemoreceptor activity appeared to be due to sympathetic nerve activity. Section of the sympathetic nerves to the carotid chemoreceptors resulted in an increase in carotid chemoreceptor afferent activity during anemia in a manner similar to the increase in aortic chemoreceptor activity.

Relative responses of aortic body and carotid body chemoreceptors to hypotension.

Responses to acute arterial blood pressure changes of a single or a few chemoreceptor afferents from the aortic body and carotid body at constant arterial blood gases and pH were measured in 16 adult cats. During normocapnic normoxia and moderate hypoxia (arterial oxygen tension of 60 Torr) an induced hypotension of 80 Torr increased strikingly the discharge rate of all aortic chemoreceptors but not of most carotid chemoreceptors; hypotension down to the level of 50 Torr stimulated most carotid chemoreceptors only slightly. Hyperoxia eliminated the stimulatory effect of this degree of hypotension on carotid chemoreceptors; it did not affect aortic chemoreceptors to the same extent. Hypoxia augmented the effect on aortic chemoreceptors more than the effect on carotid chemoreceptors. Thus the effect of hypotension was dependent on arterial oxygen tension. The greater effect of hypotension on aortic body chemoreceptor activity indicates a greater normal circulatory constraint for the aortic body. Accordingly, aortic chemoreceptors are more suited to monitor circulatory changes in O2 flow, and carotid chemoreceptors are more suited to monitor arterial gas pressure changes due to respiration.

Responses of aortic chemoreceptors before and after pneumothorax in the cat.

That the response of aortic chemoreceptors to hypercapnia is considerably smaller than that of carotid chemoreceptors is well accepted, but the mechanism for the difference is not known. It has been suggested that surgical exposure of the carotid body may contribute to the difference. Accordingly, the response of aortic body chemoreceptors to CO2 would be expected to resemble quantitatively that of carotid chemoreceptors after exposure of the aortic bodies by pneumothorax. The effect of opening the chest on aortic and carotid chemoreceptor responses to several levels of arterial CO2 and O2 tension and arterial blood pressure were studied in anesthetized cats. The activity of aortic chemoreceptors increased in spite of a decreased stimulus level in the thoracic cavity after pneumothorax. The activity remained higher than the control at all levels of arterial CO2 and O2 tension and arterial blood pressure. However, the slopes of CO2 response curves, which were initially small, did not change after pneumothorax. Thus a change in the normal environment of the aortic bodies by experimental manipulation did not cause the aortic chemoreceptor responses to resemble those of carotid chemoreceptors.

Inhibition of aortic chemoreceptor responses by metabolic alkalosis in the cat.

The responses of the same aortic chemoreceptor afferents to steady-state isocapnic hypoxia and to hypercapnia on hyperoxia, before and after the induction of metabolic alkalosis, were investigated in 12 anesthetized cats. Metabolic alkalosis was achieved by intravenous administration of sodium bicarbonate in the average dose of 7 mmol . kg-1. On the average, arterial pH (pHa) increased from 7.383 to 7.650 at an arterial CO2 partial pressure (PaCO2) of 30 Torr. The increase in pHa resulted in a decrease in chemoreceptor activity, the effect being greater at a lower arterial O2 partial pressure. Increases in PaCO2 during hyperoxia resulted in an increased activity of the chemoreceptors both before and after NaHCO3 injection. The stimulatory effect of hypercapnia, however, was attenuated by metabolic alkalosis. At a constant PaCO2, decreases in arterial [H+] by the NaHCO3 administration caused an approximately linear decrease in the chemoreceptor activity. At a constant arterial [H+], higher PaCO2 was associated with a slightly greater activity of the chemoreceptors. These results indicate that the major effect of CO2 is mediated by [H+], but there appears to be another mechanism, albeit small, for the effect of CO2.

Ventilatory control in peripheral chemoreceptor-denervated ponies during chronic hypoxemia.

The present study was designed to provide further insight into the role of the carotid and aortic chemoreceptors in ventilatory (VE) acclimatization during sojourn at altitude. Measurements were made: 1) on 10 ponies near sea level (SL, 740 Torr) under normal conditions, 2) on 6 of these at SL following chemoreceptor denervation (CD), and 3) subsequently on all 10 during 4 days of hypobaric hypoxia (PaO2 = 40-47 Torr). CD resulteo in hypoventilation at SL (deltaPaCO2 = d8 Torr, P less than 0.05), and it prevented hyperventilation normally observed with injection of NaCN and acute exposure to hypoxia (less than 1 h). In contrast, hyperventilation was evident in normal ponies during acute hypoxia (deltaPaCO2 = -6.7 Torr). Ventilation increased in both groups between the 2nd and 8th h of hypoxia (deltaPaCO2 from 1 h = -4 Torr, P less than 0.05). This change, a common characteristic of acclimatization, persisted throughout 4 days of hypoxia in the normal ponies. However, in the CD ponies this change was evident consistently only through the 12th h and after the 44 h hyperventilation was no longer evident. We conclude that the peripheral chemoreceptors are essential in ponies for normal VE acclimatization to this degree of hypoxemia. Two additional findings in CD ponies suggest the presence of a CNS inhibitory influence on the VE control center during chronic hypoxemia. First, acute hyperoxygenation on the 4th day of hypoxemia induced hyperventilation (deltaPaCO2 = -5 Torr, P less than 0.05). Second, again on the 4th day and during hyperoxygenation, VE responsiveness to CO2 and doxapram HCl was greater than at sea level.

Cardiovascular responses to hypoxia in the spontaneously breathing cat: reflexes originating from carotid and aortic bodies.

The heart rate (fH) and systemic arterial pressure (Pa) responses to transient anoxemic and cytotoxic hypoxia were studied in 18 pentobarbitone-anesthetized, spontaneously breathing cats, by applying N2 tests and i.v. injections of NaCN. Hyperventilation was accompanied by short-latency increases in Pa and fH; they persisted after bilateral vagotomy, sparing the aortic nerves. Acute section of carotid or aortic nerves in different sequences reduced both fH and Pa responses, the contribution of both pairs of nerves being similar. The recording of carotid chemosensory discharges showed transient stimulus-dependent increases in their frequency, to which the ensuing fH and Pa rises were correlated. After sectioning the four buffer nerves, hypoxia provoked long-lasting hypotension and bradycardia. Tachycardia was also observed in response to hypoxia in 4 out of 6 chloralose-anesthetized spontaneously breathing cats, the other two presenting bradycardia. The direction of these cyanide-induced changes in fH was not modified by bilateral vagotomy. It is concluded that tachycardia and hypertension in response to hypoxia are not vagally-mediated consequences of hyperventilation.

Adrenergic mechanisms in oxygen chemoreception in the cat aortic body.

Sixteen cats were studied to test the hypothesis that oxygen chemoreception in the cat aortic body is dependent on the beta-adrenergic mechanism. The chemoreceptor activity was measured from a few aortic chemoreceptor afferents in each cat, anesthetized with alpha-chloralose (60 mg X kg-1). Three types of experiments were conducted. Aortic chemoreceptor responses to steady-state hypoxia (PaO2 range, 100-30 Torr) were measured (a) before and during intravenous infusion of the beta-receptor agonist, isoproterenol (0.5 micrograms X kg-1) in nine spontaneously breathing cats, and (b) before and after intravenous injection of the beta-receptor antagonist, propranolol (1 mg X kg-1) in seven cats which were paralyzed and artificially ventilated. In the third category (c) the stimulatory effect of hypotension on aortic chemoreceptor activity was measured in six of the seven cats in group (b) before and after propranolol injection. Isoproterenol infusion only moderately stimulated aortic chemoreceptor activity. This stimulation was blocked by propranolol. However, propranolol did not attenuate aortic chemoreceptor responses to hypoxia or to hypotension. We conclude that the beta-receptor adrenergic mechanism does not mediate oxygen chemoreception in the cat aortic body.