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.

Sympathetic activation by chemical stimulation of white adipose tissues in rats.

Injection of leptin into white adipose tissue (WAT) increases sympathetic outflow. The present study was designed to determine the effects of capsaicin and other chemicals in WAT on the sympathetic outflow and blood pressure and the roles of WAT afferents and hypothalamic paraventricular nucleus (PVN) in the adipose afferent reflex (AAR). The AAR was induced by injection of capsaicin, bradykinin, adenosine, adenosine triphosphate (ATP), or leptin into inguinal WAT (iWAT) or retroperitoneal WAT (rWAT) in anesthetized rats. The iWAT injection of capsaicin increased the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) but not the heart rate. Bradykinin, adenosine, or leptin but not ATP in the iWAT caused similar effects to capsaicin on the RSNA and MAP. Intravenous, intramuscular, or intradermal injection of capsaicin had no significant effects on the RSNA and MAP. The effects of capsaicin in rWAT were similar to that in iWAT on the RSNA and MAP. Furthermore, injection of capsaicin into the iWAT increased the WAT afferent nerve activities, WAT efferent nerve activity, and brown adipose tissue efferent nerve activity. The iWAT denervation or chemical lesion of the PVN neurons with kainic acid abolished the AAR induced by the iWAT injection of capsaicin. These results indicate that the stimulation of iWAT afferents with capsaicin, bradykinin, adenosine, or leptin reflexly increases the RSNA and blood pressure. The iWAT afferents and the PVN are involved in the AAR induced by capsaicin in the iWAT.

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.

The use of autogenous veins for microsurgical repair of the sural nerve after nerve biopsy.

OBJECTIVES: This study evaluates the results of an alternative technique developed to minimize the risk of complications associated with sural nerve biopsy for histopathological analysis. METHODS: Twelve subjects underwent sural nerve biopsy and the defect created in the nerve was bridged by a 50-mm-length segment of the saphenous vein; the control group enrolled 23 patients in whom the entire length of the nerve was harvested to be used as autograft for reconstruction of nerves in the upper limb. Sensory reinnervation was quantified by use of the monofilament test and the static 2-point discrimination test, after a follow-up period of 18 months. RESULTS: The mean time for recovery of protective sensation was 8.7 months in patients submitted to nerve repair, and 10.3 months in the control group (P > .05). The monofilament test and static 2-point discrimination testing demonstrated a mean value of 3.22 and 8 mm (S3), respectively, in the group who underwent sural nerve repair; and 4.17 and 13 mm (S2), respectively, for the control group (P <.05). CONCLUSION: The use of vein as conduits for the repair of the sural nerve did not shorten the time for sensory recovery at the autonomous zone of the nerve; however, the quality of the reinnervation was considered better than the control group. This study suggests that empty veins could be used as conduits to bridge gaps with a length up to 50 mm in cases of injuries of the sural nerve and, possibly, for injuries of other pure sensory nerves as well.

[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.

Quantifying perivascular sympathetic innervation: regional differences in male C57BL/6 mice at 3 and 20 months.

Perivascular sympathetic innervation density (PSID) is a key determinant of vasomotor responses to sympathetic nerve activity. However, total axonal length (for en passant neurotransmission) per vessel surface area has not been well defined, particularly while preserving 3-dimensional vascular structure. We developed a novel method for quantifying PSID using 3-dimensional anatomical reconstruction and compare a variety of blood vessels in Young (3 months) and Old (20 months) male C57BL/6 mice. Individual vessels were dissected and immunolabeled for tyrosine hydroxylase. The total length of fluorescent axons in defined vessel surface areas was quantified by mapping Z-stack images (magnification=760x). For Young mice, innervation densities (mum axon length/mum(2) vessel surface area) in mesenteric (0.075+/-0.002) and femoral (0.080+/-0.003) arteries were greater (P<0.05) than mesenteric veins (0.052+/-0.002) and gracilis muscle feed arteries (0.040+/-0.002). Carotid arteries and gracilis muscle veins were not immunoreactive nor were there significant differences in PSID between Young and Old animals. We demonstrate a novel approach to quantify sympathetic innervation of the vasculature while preserving its 3-dimensional structure and document regional variation in PSID that persists with aging in mice. This analytical approach may be used for quantifying PSID in other tissues that have superficial vessels which can be studied in situ or from which embedded vessels can be excised. With appropriate visualization of neuronal projections, it may also be applied to tissues that have other sources of superficial innervation.

[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.

Venous response to orthostatic stress.

Head-up tilt (HUT) induces a reduction in preload, which is thought to be restored through sympathetic venoconstriction, reducing unstressed volume (V(u)) and venous compliance (VeC). In this study, we assessed venous inflow and outflow responses and their reproducibility and determined the relation with autonomic function during HUT. Eight healthy non-pregnant women were subjected to 20 degrees head-down tilt to 60 degrees HUT at 20 degrees intervals. At each rotational step, we randomly assessed forearm pressure-volume (P-V) curves (venous occlusion plethysmography) during inflow (VeC(IN)) and outflow [venous emptying rate (VER(OUT))]. VeC(IN) was defined as the ratio of the slope of the volume-time curve and pressure-time curve, with direct intravenous pressure measurement. VER(OUT) was determined using the derivate of a quadratic regression model using cuff pressure. We defined V(u) as the y-intercept of the P-V curve. We calculated, for both methods, the coefficients of reproducibility (CR) and variation (CV). Vascular sympathetic activity was determined by spectral analysis. VeC(IN) decreased at each rotational step compared with the supine position (P<0.05), whereas VER(OUT) increased. CR of VeC(IN) was higher in the supine position than VER(OUT) but lower during HUT. CV varied between 19% and 25% (VeC(IN)) and between 12% and 21% (VER(OUT)). HUT decreased V(u). The change in VeC(IN) and VER(OUT) correlated with the change in vascular sympathetic activity (r= -0.36, P<0.01, and r=0.48, P<0.01). This is the first study in which a reproducible reduction in VeC(IN) and V(u) and a rise in VER(OUT) during HUT are documented. The alterations in venous characteristics relate to changes in vascular sympathetic activity.

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.

Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation.

The purpose of the present study was to determine whether thoracic veins may act as ectopic pacemakers and whether nodelike cells and rich sympathetic innervation are present at the ectopic sites. We used a 1,792-electrode mapping system with 1-mm resolution to map ectopic atrial arrhythmias in eight normal dogs during in vivo right and left stellate ganglia (SG) stimulation before and after sinus node crushing. SG stimulation triggered significant elevations of transcardiac norepinephrine levels, sinus tachycardia in all dogs, and atrial tachycardia in two of eight dogs. Sinus node crushing resulted in a slow junctional rhythm (51 +/- 6 beats/min). Subsequent SG stimulation induced 20 episodes of ectopic beats in seven dogs and seven episodes of pulmonary vein tachycardia in three dogs (cycle length 273 +/- 35 ms, duration 16 +/- 4 s). The ectopic beats arose from the pulmonary vein (n = 11), right atrium (n = 5), left atrium (n = 2), and the vein of Marshall (n = 2). There was no difference in arrhythmogenic effects of left vs. right SG stimulation (13/29 vs. 16/29 episodes, P = nonsignificant). There was a greater density of periodic acid Schiff-positive cells (P < 0.05) and sympathetic nerves (P < 0.05) at the ectopic sites compared with other nonectopic atrial sites. We conclude that, in the absence of a sinus node, thoracic veins may function as subsidiary pacemakers under heightened sympathetic tone, becoming the dominant sites of initiation of focal atrial arrhythmias that arise from sites with abundant sympathetic nerves and periodic acid Schiff-positive cells.