Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins.

BACKGROUND: The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. METHODS: We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. RESULTS: In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of ß2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. CONCLUSIONS: Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.

Venous and autonomic function in formerly pre-eclamptic women and controls matched for body mass index.

OBJECTIVE: Prepregnancy reduced plasma volume (PV) increases the risk of subsequent pre-eclamptic pregnancy. Reduced PV is thought to reflect venous reserve capacity, especially when venous vasculature is constricted and sympathetic tone is elevated. As obesity might affect these variables, and is associated with pre-eclampsia, increased body weight may underlie these observations. The aim of this study was to determine whether the relationship between reduced venous reserve and pre-eclampsia is independent of body mass index (BMI). METHODS: This was an observational case-control study in which venous reserve capacity in 30 formerly pre-eclamptic, but currently non-pregnant, women divided equally into three groups based on BMI (BMI 19.5-24.9, 25.0-29.9 or ≥ 30.0 kg/m2 ), was compared with that in 30 healthy parous, non-pregnant controls. Cases and controls were matched for BMI, age and parity. Venous reserve capacity was quantified by assessing PV and venous compliance (VeC). The autonomic nervous system regulating venous capacitance was evaluated using heart rate (HR) variability analysis, with the women in a resting supine position and during positive head-up tilt (HUT). RESULTS: Compared with controls, formerly pre-eclamptic women had, when in a resting supine position, lower PV (1339 ± 79 vs 1547 ± 139 mL/m2 (P < 0.0001)), lower VeC (0.04 ± 0.02 vs 0.07 ± 0.02 mL/dL/mmHg (P < 0.0001)), higher sympathetic tone (1.9 ± 1.1 vs 1.2 ± 0.7 (P = 0.002)) and lower baroreceptor sensitivity (BRS; 8.7 ± 3.8 vs 19.0 ± 1.7 ms/mmHg (P < 0.0001)). During HUT, women with a history of pre-eclampsia had less modulatory capacity over VeC and BRS, while HR and sympathetic tone remained consistently higher. CONCLUSIONS: Women with a history of pre-eclampsia had reduced venous reserve capacity compared with that in BMI-matched controls. This is reflected by lower PV and VeC, with the autonomic balance being shifted towards sympathetic dominance and lower BRS. This suggests that underlying reduced venous reserve, but not BMI, relates to pre-eclampsia. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Reappraisal of systemic venous chemoreceptors: might they explain the matching of breathing to metabolic rate in humans?

NEW FINDINGS: What is the topic of this review? One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s. What advances does it highlight? New evidence shows that their apparent dismissal needs reappraisal. The paper on which this depends has more than one interpretation, and another paper obtained the opposite result. Previous search ignored all locations between skeletal muscle and the right heart. Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans. One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. First, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate during exercise. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous PO2 and PCO2 values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence.

Peripheral venous distension elicits a blood pressure raising reflex in young and middle-aged adults.

Distension of peripheral veins in humans elicits a pressor and sympathoexcitatory response that is mediated through group III/IV skeletal muscle afferents. There is some evidence that autonomic reflexes mediated by these sensory fibers are blunted with increasing age, yet to date the venous distension reflex has only been studied in young adults. Therefore, we tested the hypothesis that the venous distension reflex would be attenuated in middle-aged compared with young adults. Nineteen young (14 men/5 women, 25 ± 1 yr) and 13 middle-aged (9 men/4 women, 50 ± 2 yr) healthy normotensive participants underwent venous distension via saline infusion through a retrograde intravenous catheter in an antecubital vein during limb occlusion. Beat-by-beat blood pressure, muscle sympathetic nerve activity (MSNA), and model flow-derived cardiac output (Q), and total peripheral resistance (TPR) were recorded throughout the trial. Mean arterial pressure (MAP) increased during the venous distension in both young (baseline 83 ± 2, peak 94 ± 3 mmHg; P < 0.05) and middle-aged adults (baseline 88 ± 2, peak 103 ± 3 mmHg; P < 0.05). MSNA also increased in both groups [young: baseline 886 ± 143, peak 1,961 ± 242 arbitrary units (AU)/min; middle-aged: baseline 1,164 ± 225, peak 2,515 ± 404 AU/min; both P < 0.05]. TPR (P < 0.001), but not Q (P = 0.76), increased during the trial. However, the observed increases in blood pressure, MSNA, and TPR were similar between young and middle-aged adults. Additionally, no correlation was found between age and the response to venous distension (all P > 0.05). These findings suggest that peripheral venous distension elicits a pressor and sympathetic response in middle-aged adults similar to the response observed in young adults.

Limb suction evoked during arterial occlusion causes systemic sympathetic activity in humans.

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP). We hypothesized that the application of suction to the human limbs would activate this venous distension reflex and raise sympathetic outflow. We placed airtight pressure tanks and applied 100 mmHg negative pressure to an arterially occluded limb (occlusion and suction, O&S) to induce tissue deformation without fluid translocation. BP, heart rate (HR), and MSNA were assessed in 19 healthy subjects during 2 min of arm or leg O&S. Occlusion without suction served as a control. During a separate visit, saline (5% forearm volume) was infused into veins of the arterially occluded arm (n = 13). The O&S increased limb circumference, MSNA burst rate (arm: Δ6.7 ± 0.7; leg: Δ6.8 ± 0.7 bursts/min), and total activity (arm: Δ199 ± 14; leg: Δ172 ± 22 units/min) and BP (arm: Δ4.3 ± 0.3; leg: Δ9.4 ± 1.4 mmHg) from the baseline. The MSNA and BP responses during arm O&S correlated with those during leg O&S. Occlusion alone had no effect on MSNA and BP. MSNA (r = 0.607) responses during arm O&S correlated with those evoked by the saline infusion into the arm. These correlations suggest that sympathetic activation during limb O&S is likely, at least partially, to be evoked via the venous distension reflex. These data suggest that suction of an occluded limb evokes sympathetic activation and that the limb venous distension reflex exists in arms and legs of normal humans.

Suitability of the pericardiophrenic veins for phrenic nerve stimulation: an anatomic study.

OBJECTIVE: The objective of this study was to assess the potential of the pericardiophrenic veins (PPVs) as conduits for transvenous stimulation of the phrenic nerves. Modulating respiration with transvenous phrenic nerve stimulation via the PPVs might reduce or eliminate the adverse effects of central sleep apnea in heart failure. METHODS: Forty-eight fixed cadavers were dissected to study the anatomic characteristics of the PPVs and related neurovascular structures. RESULTS: The right PPV, found in only 1 of 35 cadavers, was <0.5 mm diameter. The left PPV, located in all 48 cadavers, drained into the left brachiocephalic vein (BCV) directly or into the BCV via the superior intercostal vein (SICV). Mean ± SD SICV trunk diameter was 4 ± 2 mm. Mean ± SD left PPV diameter was 2 ± 1 mm. The length between the point of separation of the left PPV from the phrenic nerve to its junction with the BCV or SICV trunk ranged from 6 to 40 mm. The angle of approach, defined as the angle formed by the intersection of the longitudinal axis of the BCV and the longitudinal axis of the PPV or SICV trunk, and which represents the angle that would need to be navigated when inserting a stimulation lead into the PPV using a peripheral cannulation approach, was 99 ± 28 degrees. Valves were identified in 54% of left PPVs. CONCLUSIONS: Because of its extremely small size, the right PPV appears unsuitable for transvenous phrenic nerve stimulation. In contrast, the left PPV may be accessible via the left BCV using standard transvenous catheterization techniques; however, the small caliber of the left PPV and the frequent presence of valves within it might pose challenges in navigating the vessel to achieve transvenous phrenic nerve stimulation.

[The efficacy of hand desimpatization after sympatectomy by complex regional pain syndrome].

64 patients operated on the reason of complex regional hand pain syndrome were examined with the use of laser spectral Doppler flowmetry and thermography. 33 patients had thoracoscopic Th3 ganglion clipation; 16 patients had brachial artery and vein perivascular sympathectomy; 15 patients periarterial sympathectomy on the level of brachial artery. Desympathisation (microcirculatory hemodynamic improvement and trophotropic microcirculation regulatory changes) was mostly apparent after thoracoscopic clipation and perivascular desympatisation in comparison with isolated periarterial sympatectomy.

[Retrospective monocentric comparative evaluation by sifting of vein grafts versus nerve grafts in palmar digital nerves defects. Report of 32 cases]. / Evaluation rétrospective monocentrique comparative par tamisage des greffes veineuses et des greffes nerveuses dans les pertes de substance des nerfs collatéraux digitaux palmaires. A propos de 32 cas.

AIM: Palmar digital nerves defects can be treated by conventional nerve grafts or by means of a conduit, such as a vein. We compared a vein graft technique to a nerve graft technique in a retrospective monocentric study. MATERIAL AND METHOD: A surgeon who was not involved in the treatment reviewed blind 15 nerve grafts and 17 vein grafts. The evaluation concerned sensitivity, pain, donor site morbidity, social integration and autoassessment of the benefits by the patient. Data were compacted by a sifting method eliminating bad results. The classical functional scores (British Medical Research Council, Möberg, Chanson, Alnot, Dumontier) were also used. RESULTS: The evaluation was carried out at least 11 months after treatment. Defect was never greater than 30 mm. After sifting, vein grafts appeared less efficient than nerve grafts (41% good results against 73%), except in emergencies (86% good results). CONCLUSION: For defect loss of no more than 30 mm in emergencies, the authors propose to use vein grafting. In other situations, the surgeon must take into account the patient's profile and the hemi-pulp concerned, dominant or non-dominant, before opting for a nerve or a vein graft.

Peripheral venous pressure waveform.

PURPOSE OF REVIEW: The focus of intraoperative monitoring is moving away from invasive monitoring. This has been attributed to procedure time, cost, and the known risks, which include carotid artery puncture, arrhythmia, pneumothorax, and infection. Until recently, the venous system's contribution to the circulatory system has been incorrectly identified as being insignificant. This article summarizes the unique characteristics of the peripheral venous system. RECENT FINDINGS: Numerous studies done in the last few years have paid attention to peripheral venous pressure and more specifically its pressure waveform. The popularity of, and further focus on, the field of photoplethysmography has described a strong venous component. Analysis of venous waveforms has indicated that, like arterial waveforms, they too exhibit respiratory variations and change in response to physiologic challenges. SUMMARY: The veins play a critical role in cardiovascular homeostasis; they do more than conduct blood to the heart. Considering the ease of measurement from a peripheral intravenous catheter, further study should be conducted to investigate the usefulness and limitations of such a minimally invasive and inexpensive monitoring device.

[Pain and other symptoms of chronic venous diseases: pathophysiology and therapeutic principles].

The literature review presented herein analyses the mechanism of the development of pain and othersubjective signs and symptoms in chronic venous diseases. Also discussed are numerous findings suggesting a pivotal role played by the leukocytic-endothelial inflammatory reaction as the main stimulator of the nociceptors of the venous wall and paravasal tissue, resulting information of the pain syndrome. This is followed by substantiating the necessity of early initiation of comprehensive conservative therapy making it possible to block the molecular and cellular mechanisms damaging the venous wall and microcirculatory bed in patients presenting with various stages of venous chronic diseases.

Secondary nerve reconstruction using vein conduit grafts for neglected digital nerve injuries.

Digital nerve defects can result from neglected nerve injuries. The standard method of reconstruction is nerve grafting, but donor-site morbidity encourages searching for alternative graft materials, including vein conduit grafts. From 1995-2005, three patients with neglected digital nerve injuries received vein conduit grafting for digital nerve reconstruction in our hospital. The interval between the injury and the reconstructive procedure ranged from 17 days to 2 years, and the length of the defects ranged from 0.8 to 2.5 cm. All the vein grafts were harvested from the distal forearm. Patient 1 had a moving and a static two-point discrimination (M2PD and S2PD) of 3 and 4 mm, respectively, at a 12-year follow-up. Patient 2 had an M2PD of 5 mm and S2PD of 6 mm at an 11-year follow-up, and the patient 3 had both an M2PD and S2PD of 4 mm at a near 3-year follow-up. They all achieved useful sensory function (S3 and S3+) by modified Highet and Sander criteria. Although previous studies showed secondary repair using vein grafts yielded worse sensory recovery than that of primary repair, in our cases, secondary digital nerve reconstruction with vein conduit grafts gives excellent results at the long-term sensory evaluation, two of them with more than 10 years' follow-up. To the best of our knowledge, this might be the longest follow-up after secondary digital nerve reconstruction using a vein conduit graft. It bears the advantages of readily accessible, no donor-site morbidity, and compatible in size with digital nerves.

Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs.

The pathogenesis of hyperadrenergic orthostatic hypotension was studied in eight patients. Correction of the abnormal orthostatic changes by an inflated pressure suit (MAST) confirmed previous evidence of excessive gravitational pooling of blood in the leg veins. Intravenous L-norepinephrine infusion raised diastolic blood pressure in the same relationship to the infusion-induced increments in plasma norepinephrine concentrations as in normal subjects, indicating normal arteriolar responses. Contractile responses of the veins to infused L-norepinephrine were measured with a linear variable differential transformer (LVDT). The venous responses of hand veins in the patients fell within the 95% confidence limits of the responses of normal hand veins, as did the responses of foot veins in the seven normal subjects. However, foot veins of the patients with hyperadrenergic orthostatic hypotension, and both hand and foot veins of patients with "diffuse" autonomic failure, were supersensitive to norepinephrine, as reflected by a steeper slope of the regression of log (norepinephrine infusion rate) on percentage reduction in venous distensibility, and a significantly lower ED50 (i.e., norepinephrine infusion rate that induced 50% reduction in venous distensibility). The findings suggest anatomical or functional postganglionic denervation of lower limb veins causing excessive gravitational blood pooling with consequent orthostatic hypotension in these patients.

Autonomic nerves in pulmonary veins.

Rapid repetitive activities arising from pulmonary veins may initiate atrial fibrillation. The basis of these rapid repetitive activities remains unclear, but recent evidence suggests that the autonomic nervous system plays an important role in their formation. Pulmonary veins and the adjoining left atrium are highly innervated structures. This review summarizes recent developments in the understanding of the anatomy of autonomic nerves in and around pulmonary veins and their implications for atrial fibrillation.

Autonomic control of the venous system in health and disease: effects of drugs.

The venous system contains approximately 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an alpha1- or alpha2-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An alpha1- or alpha2-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several alpha-adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.

Pial vascular behavior during bilateral and contralateral cervical sympathetic stimulation.

The present study in cats investigates the effect of cervical sympathetic stimulation on changes of diameter of pial arteries and veins, CBF, and intracranial pressure (ICP) using the cranial window and hydrogen clearance techniques. During 20 min of bilateral stimulation, pial arteries maximally constricted by 12%, veins by 13-15%. While the constriction of the large arteries remained stable during the whole 20-min period of bilateral stimulation, small arteries escaped after some 2 min. A similar though weaker trend was noted for the veins. CBF was reduced at 2 min by 31%, and was not different from resting at 18 min. Contralateral stimulation for 20 min induced early constriction only in small arteries, while all other vessels remained more or less unreactive. This phenomenon is explained by interhemispheric arterial collaterals that bring sympathetic fibers mainly to small arteries contralaterally. ICP was lowered initially by 47 +/- 12% during bilateral and by 23 +/- 5% during contralateral stimulation. ICP escaped after 2 and 5 min during bilateral and contralateral stimulation, respectively, and even started to rise after some 10 min. From these data, it is concluded that the sympathoadrenergic system exerts a short-lasting protective effect upon cerebral vascular volume. Small arteries escape from constriction as a consequence of primarily myogenic counteraction of pial and intraparenchymal vessels, and probably additional metabolic dilatation of intraparenchymal vessels.

Innervation of the cerebral veins as compared with the cerebral arteries: a histochemical and electron microscopic study.

The distribution of nerve fibers in the cerebral veins was studied by catecholamine fluorescence simultaneously with acetylcholinesterase (AChE) histochemistry. A comparison of nerve fibers in the cerebral arteries was made. The ultrastructure of terminal boutons in the veins fixed with potassium permanganate was also studied. In the adventitia of the cerebral artery, green fluorescent aminergic fibers and brownish AChE-reactive (probably cholinergic) fibers were observed. In contrast, the cerebral venous system showed no AChE-positive fibers. Catecholamine fluorescent varicose fibers were detected in the dural sinus, the internal cerebral vein, and the superficial vein of Labbé. The highest density of aminergic fibers was found in the dural sinus and the second highest in the internal cerebral vein. Most of the terminal boutons in the adventitia of the cerebral veins were found adjacent to a muscle-like cell and showed only cored vesicles under electron microscopy. Results of our study suggest that the cerebral venous system has a neurogenic innervation, mainly from aminergic fibers, which is different from the neurogenic supply to the cerebral arterial system.

Vascular participation in deep cold pain.

As the magnitude of cold pain probably depends on blood flow and thus on internal limb temperature, the activated nociceptors should be close to or within the walls of veins. This hypothesis was tested by injecting small quantities (20 ml) of cold saline into an empty vein of the hand in 16 subjects. Saline temperatures below 26 degrees C elicited pure cold sensations whereas temperatures below 20 degrees C evoked both cold and pain sensations. Pain was mainly described as deep and it tended to radiate along the veins. With saline of 5 degrees C the pain tolerance level of several subjects was reached. Pain always appeared after cold and it disappeared before or together with cold. The results can be explained on the basis of two types of vascular receptors: a sensitive specific cold receptor and a nociceptor with a threshold around 20 degrees C.

The role of pain from veins for the formation of perivenous edema in humans.

To test the hypothesis that nociception from veins plays a role in the formation of perivenous edema, we looked at edema along hand veins of humans during painful noxious stimulation in the presence and absence of nerve conduction block. Pain from vascularly isolated hand vein segments was evoked by perfusion with hyperosmolar saline and rated with the help of an electronically controlled visual analogue scale. Perivenous edema measured as changes in skin altitude was continuously recorded by means of infrared reflection. To alternately block the innervation of skin and vein segment we used a perivenous block (vein but not skin numbed), a distal ulnar nerve block (skin but not vein numbed), and a proximal ulnar nerve block (both vein and skin numbed). Without nerve block, hyperosmolar saline always evoked both pain and a continuous increase in perivenous edema to a maximum of 2.0-3.2 mm after 30 min. On painless control perfusions with isoosmolar saline, edema increased slightly (0.2-0.8 mm) to a plateau which was maintained until the end of perfusion. When the vein was denervated by perivenous or proximal ulnar nerve block, hyperosmolar saline evoked a slight increase in edema which resembled that of control perfusions in both extent and time course. On distal ulnar nerve block, which numbed the skin but not the vein, both pain and substantial edema were evoked. These observations show that nociception from veins is a prerequisite for perivenous edema to occur.

Involvement of the NO/cyclic GMP pathway in bradykinin-evoked pain from veins in humans.

Cyclic GMP is probably a second messenger in vascular nociceptors that are excited by nitric oxide (NO), because NO is known to activate the guanylate cyclase. If so, inhibition of this enzyme should render nociceptors insensitive to algesics that act via NO. To test this hypothesis, the effect of the specific guanylate cyclase inhibitor methylene blue was studied on bradykinin-evoked, i.e. NO-mediated pain and, for control, on mechanically-evoked pain, which is probably not mediated by NO. In eight subjects, pain was evoked from isolated hand vein segments by either injection of bradykinin (1 x 10(-6) M) or noxious balloon distention. Pretreatment of the vein segments with methylene blue inhibited bradykinin-evoked pain in a concentration-dependent manner and abolished pain at a concentration of 1 x 10(-3) M. Methylene blue had no effect on mechanically evoked pain. Tachyphylaxis to intravenously applied bradykinin was not observed. These results are consistent with the hypothesis that cyclic GMP plays a role in the transduction of NO-mediated noxious stimuli in vascular nociceptors in humans.