The efficacy of pulmonary rehabilitation training program for patients after lung transplantation.

Background: Pulmonary rehabilitation is recognized widely as one of the most effective measures to promote postoperative recovery of lung transplant recipients (LTRs), and it has positive effects on both short- and long-term quality of life (QoL) and survival outcomes. However, no standardized pulmonary rehabilitation training programs exist specifically for LTRs. The pulmonary rehabilitation programs widely used in clinical practice focus mainly on exercise or respiratory training, to some extent neglecting other therapeutic methods that could promote patient health, such as nutrition support, pain control, spiritual comfort, and so on. This study aimed to develop a postoperative pulmonary rehabilitation training program for LTRs and evaluate its effectiveness. Methods: Using convenience sampling, all patients who underwent lung transplantation (LTx) at Shanghai Pulmonary Hospital from January 2021 to December 2022 were screened for inclusion and exclusion criteria, and a total of 68 patients were finally included in this study. A non-synchronous quasi-experimental design was used, with patients who underwent LTx in 2021 as the control group and patients who underwent LTx in 2022 as the experimental group. The control group received routine treatment, health education, and rehabilitation guidance when patients determined the date of surgery. In addition to this, the experimental group received pulmonary rehabilitation training. The incidence of postoperative pulmonary complications (pulmonary infections), duration of chest tube drainage, intensive care unit (ICU) length of stay, postoperative pain scores, postoperative QoL, pulmonary function, oxygenation index, and the distance in the 6-minute walking test (6MWD) were compared between the two groups. Results: The length of ICU stay and duration of chest tube drainage in the experimental group were lower than those in the control group, and the results of oxygenation index, 6MWD, and St. George's Respiratory Questionnaire (reflecting the QoL) were better than those of the control group (P<0.05). There was no significant difference in the pain of the two groups 1 week after surgery and 3 months after surgery, and the pain score of the experimental group was lower than that of the control group at 1 month after surgery (P<0.05). There was no significant difference in the incidence of complications between the two groups (P>0.05). Conclusions: The postoperative pulmonary rehabilitation training program for LTRs is safe and effective. It can shorten both the duration of chest tube drainage and ICU stay, it can also improve patients' exercise capacity and pulmonary function while also promote safety outcomes of LTRs, and improve QoL scores.

Patient-specific severity of von Willebrand factor degradation identifies patients with a left ventricular assist device at high risk for bleeding.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) cause an acquired von Willebrand factor (VWF) deficiency and bleeding. Models to risk-stratify for bleeding are urgently needed. We developed a model of continuous-flow LVAD bleeding risk from patient-specific severity of VWF degradation. METHODS: In a prospective, longitudinal cohort study, paired blood samples were obtained from patients (n = 67) with a continuous-flow LVAD before and during support. After 640 ± 395 days, patients were categorized as all-cause bleeders, gastrointestinal (GI) bleeders, or nonbleeders. VWF multimers and VWF clotting function were evaluated to determine bleeding risk. RESULTS: Of 67 patients, 34 (51%) experienced bleeding, 26 (39%) experienced GI bleeding, and 33 (49%) did not bleed. In all patients, LVAD support significantly reduced high-molecular-weight VWF multimers (P < .001). Bleeders exhibited greater loss of high-molecular-weight VWF multimers (mean ± standard deviation, -10 ± 5% vs -7 ± 4%, P = .008) and reduced VWF clotting function versus nonbleeders (median [interquartile range], -12% [-31% to 4%] vs 0% [-9 to 26%], P = .01). A combined metric of VWF multimers and VWF function generated the All-Cause Bleeding Risk Score, which stratified bleeders versus nonbleeders (86 ± 56% vs 41 ± 48%, P < .001) with a positive predictive value of 86% (95% confidence interval, 66%-95%) and diagnostic odds ratio of 11 (95% confidence interval, 2.9-44). A separate GI Bleeding Risk Score stratified GI bleeders versus nonbleeders (202 ± 114 vs 120 ± 86, P = .003) with a positive predictive value of 88% (64%-97%) and diagnostic odds ratio of 18 (3.1-140). CONCLUSIONS: The severity of loss of VWF multimers and VWF clotting function generated Bleeding Risk Scores with high predictive value for LVAD-associated bleeding. This model may guide personalized antithrombotic therapy and patient surveillance.

FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfß1 signaling pathway.

Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfß1 signaling pathway. Tgfß1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfß1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfß1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfß1 signaling cascade also underlay adipose browning induced by ß3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfß1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfß1 signaling.

A Novel Organ-Specific Approach to Selectively Target Sensory Afferents Innervating the Aortic Arch.

The brain maintains cardiovascular homeostasis, in part, via the arterial baroreflex which senses changes in blood pressure (BP) at the level of the aortic arch. Sensory afferents innervating the aortic arch employ baroreceptors to convert stretch exerted on the arterial wall into action potentials carried by the vagus nerve to second order neurons residing within the nucleus of the solitary tract (NTS). Although the baroreflex was described more than 80 years ago, the specific molecular, structural, and functional phenotype of the baroreceptors remain uncharacterized. This is due to the lack of tools that provide the genetic and target organ specificity that is required to selectively characterize baroreceptor afferents. Here, we use a novel approach to selectively target baroreceptors. Male mice on a C57BL/6J background were anesthetized with isoflurane, intubated, and artificially ventilated. Following sternotomy, the aortic arch was exposed, and a retrograde adeno-associated virus was applied to the aortic arch to direct the expression of channelrhoropsin-2 (ChR2) and/or tdTomato (tdTom) to sensory afferents presumably functioning as baroreceptors. Consistent with the structural characteristics of arterial baroreceptors, robust tdTom expression was observed in nerve endings surrounding the aortic arch, within the fibers of the aortic depressor and vagus nerves, cell bodies of the nodose ganglia (NDG), and neural projections to the caudal NTS (cNTS). Additionally, the tdTom labeled cell bodies within the NDG also expressed mRNAs coding for the mechanically gated ion channels, PIEZO-1 and PIEZO-2. In vitro electrophysiology revealed that pulses of blue light evoked excitatory post-synaptic currents in a subset of neurons within the cNTS, suggesting a functional connection between the labeled aortic arch sensory afferents and second order neurons. Finally, the in vivo optogenetic stimulation of the cell bodies of the baroreceptor expressing afferents in the NDG produced robust depressor responses. Together, these results establish a novel approach for selectively targeting sensory neurons innervating the aortic arch. This approach may be used to investigate arterial baroreceptors structurally and functionally, and to assess their role in the etiology or reversal of cardiovascular disease.

Neurosurgical Patients' Experiences and Surgical Outcomes Among Single Tertiary Hospitals in Ethiopia and the United States.

Background In 2020, we published findings on reported outcomes of anterior cervical decompression and fusion surgery among neurosurgeons in Africa and North America. We found more similarities in outcomes than expected, however, differences still existed. Most notable was the length of stay of patients postoperatively in Africa compared to North America. We sought to examine the neurosurgical practices more closely at a single hospital in Ethiopia and compare it to our own institution, the University of Missouri in Columbia (UMC). Methods Two authors spent one week at Aabet Hospital (AH) in Ethiopia. Throughout the week, one author rotated in the clinic and OR gathering the information. Data collection for patients at UMC was collected through retrospective chart review over one week. Results A total of eight elective surgeries and four emergency procedures occurred at AH and 18 clinic patients were included in the study. The intraoperative data was collected during the elective procedures at AH. At UMC there were 99 clinic patients, and 29 elective surgeries and one emergency procedure were performed. Procedures at both institutions included cranial, spinal, vascular, and implantable/other cases. Distance travelled by patients to UMC was an average of 57 miles compared to 85 miles at AH. The median pre-op and post-op stays at AH were 2.5 and 6 days compared to 0.2 and 2.1 at UMC, respectively. Blood loss was greater at AH with a median blood loss of 175 mL. Median blood loss at UMC was 50 mL. Conclusion We found notable differences among neurosurgical practice and patient demographics at AH compared to UMC. This information will serve as the cornerstone for gathering more information about neurosurgical practice in Ethiopia where electronic medical records are unavailable.

Iliocostalis Muscle Rotational Flap: A Novel Flap for Esophagopleural Fistula Repair.

Intrathoracic fistulas present major challenges to reconstructive surgeons. Reconstruction with muscle flaps have been shown to improve patient outcomes; however, there are patients for whom one or more of the commonly used muscle flaps is not available for several reasons. We describe the use of an iliocostalis muscle rotational flap for the repair of a caudally located esophagopleural fistula in the setting of definitive chemoradiotherapy for treatment of nonsmall-cell lung cancer and reirradiation with photons for local recurrence 5 years later. Our repair remained intact through the nearly 12-month follow-up period during which the patient tolerated a regular diet. This report demonstrates that the iliocostalis lumborum muscle is a viable option for repair of intrathoracic fistulas that are located in the distal esophagus, even in the setting of previous thoracotomy and radiation, and should be part of the reconstructive surgeon's armamentarium in the management of intrathoracic fistulas.

Limited Left Thoracoscopic Sympathectomy Effectively Silences Refractory Electrical Storm.

BACKGROUND: An electrical storm (ES) is a life-threatening condition that affects up to 20% of patients with implantable cardioverter defibrillators. In this small retrospective study, we report our results with left video-assisted thoracoscopic sympathectomy/ganglionectomy (VATSG) to treat refractory ES in low-ejection fraction patients who were not candidates for catheter ablation. METHODS: We identified 12 patients who presented with ES and underwent a total of 14 video-assisted thoracoscopic sympathectomy/ganglionectomy, including 3 patients on venoarterial extracorporeal membrane oxygenation. We reviewed demographic data, survival to discharge, number of cardioversions (before and after VATSG), need for readmissions, and need for right-sided procedures. RESULTS: In the 30 days before a left VATSG, mean number of shocks was 22.67 for all patients. For the patients who survived to discharge, the mean was 3.55 since surgery and the median was zero shocks after a median follow-up of 358 days. Six patients did not experience further cardioversions since the last VATSG and 5 were not readmitted for ventricular tachycardia. Two patients had staged bilateral procedures owing to recurrences; of those, 1 did not require further cardioversions. CONCLUSIONS: Limited left VATSG is an appropriate and effective initial treatment for ES patients who are not candidates for catheter ablation, including those on venoarterial extracorporeal membrane oxygenation for hemodynamic support.

Peripheral cannulation for extracorporeal membrane oxygenation yields superior neurologic outcomes in adult patients who experienced cardiac arrest following cardiac surgery.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest has improved mortality in post-cardiac surgery patients; however, loss of neurologic function remains one of the main and devastating complications. We reviewed our experience with ECPR and investigated the effect of cannulation strategy on neurologic outcome in adult patients who experienced cardiac arrest following cardiac surgery that was managed with ECPR. METHODS: Patients were categorized by central versus percutaneous peripheral VA-extracorporeal membrane oxygenation (ECMO) cannulation strategy. We reviewed patient records and evaluated in-hospital mortality, cause of death, and neurologic status 72 hours after cannulation. RESULTS: From January 2010 to September 2019, 44 patients underwent post-cardiac surgery ECPR for cardiac arrest. Twenty-six patients received central cannulation; 18 patients received peripheral cannulation. Mean post-operative day of the cardiac arrest was 3 and 9 days (p = 0.006), and mean time between initiation of CPR and ECMO was 40 ± 24 and 28 ± 22 minutes for central and peripheral cannulation, respectively. After 72 hours of VA-ECMO support, 30% of centrally cannulated patients versus 72% of peripherally cannulated patients attained cerebral performance status 1-2 (p = 0.01). Anoxic brain injury was the cause of death in 26.9% of centrally cannulated and 11.1% of peripherally cannulated patients. Survival to discharge was 31% and 39% for central and peripheral cannulation, respectively. CONCLUSIONS: Peripheral VA-ECMO allows for continuous CPR and systemic perfusion while obtaining vascular access. Compared to central cannulation, a peripheral cannulation strategy is associated with improved neurologic outcomes and decreased likelihood of anoxic brain death.

Central and peripheral GLP-1 systems independently suppress eating.

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice.

Blood pressure is controlled by endocrine, autonomic, and behavioral responses that maintain blood volume and perfusion pressure at levels optimal for survival. Although it is clear that central angiotensin type 1a receptors (AT1aR; encoded by the Agtr1a gene) influence these processes, the neuronal circuits mediating these effects are incompletely understood. The present studies characterize the structure and function of AT1aR neurons in the lamina terminalis (containing the median preoptic nucleus and organum vasculosum of the lamina terminalis), thereby evaluating their roles in blood pressure control. Using male Agtr1a-Cre mice, neuroanatomical studies reveal that AT1aR neurons in the area are largely glutamatergic and send projections to the paraventricular nucleus of the hypothalamus (PVN) that appear to synapse onto vasopressin-synthesizing neurons. To evaluate the functionality of these lamina terminalis AT1aR neurons, we virally delivered light-sensitive opsins and then optogenetically excited or inhibited the neurons while evaluating cardiovascular parameters or fluid intake. Optogenetic excitation robustly elevated blood pressure, water intake, and sodium intake, while optogenetic inhibition produced the opposite effects. Intriguingly, optogenetic excitation of these AT1aR neurons of the lamina terminalis also resulted in Fos induction in vasopressin neurons within the PVN and supraoptic nucleus. Further, within the PVN, selective optogenetic stimulation of afferents that arise from these lamina terminalis AT1aR neurons induced glutamate release onto magnocellular neurons and was sufficient to increase blood pressure. These cardiovascular effects were attenuated by systemic pretreatment with a vasopressin-1a-receptor antagonist. Collectively, these data indicate that excitation of lamina terminalis AT1aR neurons induces neuroendocrine and behavioral responses that increase blood pressure.SIGNIFICANCE STATEMENT Hypertension is a widespread health problem and risk factor for cardiovascular disease. Although treatments exist, a substantial percentage of patients suffer from "drug-resistant" hypertension, a condition associated with increased activation of brain angiotensin receptors, enhanced sympathetic nervous system activity, and elevated vasopressin levels. The present study highlights a role for angiotensin Type 1a receptor expressing neurons located within the lamina terminalis in regulating endocrine and behavioral responses that are involved in maintaining cardiovascular homeostasis. More specifically, data presented here reveal functional excitatory connections between angiotensin-sensitive neurons in the lamina terminals and vasopressin neurons in the paraventricular nucleus of the hypothalamus, and further indicate that activation of this circuit raises blood pressure. These neurons may be a promising target for antihypertensive therapeutics.

Implantation of Left Ventricular Assist Device After Descending Aortic Stent Graft for Mural Thrombus.

In patients with intraluminal thrombus, commonly applied temporary circulatory support modalities are contraindicated secondary to concern regarding distal or proximal (specifically veno-arterial extracorporeal membrane oxygenation) embolization of the thrombus. Therefore, in patients with cardiogenic shock and synchronous intraluminal descending aortic thrombus, support options are quite limited. We report a case of a 66-year-old man in cardiogenic shock, due to an ischemic cardiomyopathy, who also had intramural thrombus with an intraluminal component in the descending thoracic aorta. An endovascular stent graft was inserted inside the aorta over the location of the mural thrombus. This allowed for the placement of an intra-aortic balloon pump (IABP) for pre-operative optimization. After 3 days, a left ventricular assist device (LVAD) was implanted via left anterolateral thoracotomy with hemi-sternotomy, and the IABP was removed. Post-operatively, he had a relatively uncomplicated course without signs of embolic phenomena and ultimately was discharged home. Surveillance computed tomography imaging at 6 months showed no endovascular leak or migration of the stent. This case demonstrates the feasibility of aortic stent graft placement to allow safe insertion of an IABP in the setting of aortic mural thrombus.  Furthermore, it demonstrates the safety and feasibility of LVAD implantation after recent aortic stent graft placement.

An anti-CRF antibody suppresses the HPA axis and reverses stress-induced phenotypes.

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction contributes to numerous human diseases and disorders. We developed a high-affinity monoclonal antibody, CTRND05, targeting corticotropin-releasing factor (CRF). In mice, CTRND05 blocks stress-induced corticosterone increases, counteracts effects of chronic variable stress, and induces other phenotypes consistent with suppression of the HPA axis. CTRND05 induces skeletal muscle hypertrophy and increases lean body mass, effects not previously reported with small-molecule HPA-targeting pharmacologic agents. Multiorgan transcriptomics demonstrates broad HPA axis target engagement through altering levels of known HPA-responsive transcripts such as Fkbp5 and Myostatin and reveals novel HPA-responsive pathways such as the Apelin-Apelin receptor system. These studies demonstrate the therapeutic potential of CTRND05 as a suppressor of the HPA axis and serve as an exemplar of a potentially broader approach to target neuropeptides with immunotherapies, as both pharmacologic tools and novel therapeutics.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain.

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.

Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain.

Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (MΦs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs. Furthermore, AT2R activation in MΦs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MΦs) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MΦ-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.

Fate of remnant sinuses of Valsalva in patients with bicuspid and trileaflet valves undergoing aortic valve, ascending aorta, and aortic arch replacement.

OBJECTIVE: In patients presenting with aortic valvulopathy with concomitant ascending aortic aneurysm, surgical management of the sinus of Valsalva segment remains undefined, especially for moderately dilated aortic roots. In patients with this pathology undergoing aortic valve replacement with supracoronary ascending aorta replacement, we assessed the fate of the remnant preserved sinus of Valsalva segment stratified by aortic valve morphology and pathology. METHODS: From 2002 to 2015, 428 patients underwent elective aortic valve replacement with supracoronary ascending aorta replacement. Patients were stratified on the basis of valvular morphology (bicuspid aortic valve [n = 254] and tricuspid aortic valve [n = 174]), valvular pathology (bicuspid aortic valve with aortic stenosis [n = 178], bicuspid aortic valve with aortic insufficiency [n = 76], tricuspid aortic valve with aortic stenosis [n = 61], tricuspid aortic valve with aortic insufficiency [n = 113]), and preoperative sinus of Valsalva dimensions (<40, 40-45, >45 mm). RESULTS: Kaplan-Meier analysis revealed no significant difference in freedom from reoperation in tricuspid aortic valve versus bicuspid aortic valve (P = .576). Multivariable Cox regression model performed with sinus of Valsalva dimensions at baseline and follow-up as time-varying covariates did not adversely affect survival. A repeated-measure, mixed-effects model constructed to assess longitudinal sinus of Valsalva trends revealed that the retained sinus of Valsalva dimensions remain stable over long-term follow-up (discharge to ≥10 years), irrespective of valvular morphology/pathology (bicuspid aortic valve with aortic insufficiency, tricuspid aortic valve with aortic insufficiency, tricuspid aortic valve with aortic stenosis) and preoperative sinus of Valsalva groups (<40, 40-45, >45 mm). CONCLUSIONS: In patients with nonaneurysmal sinuses of Valsalva undergoing aortic valve replacement with supracoronary ascending aorta replacement, the sinus segment can be preserved irrespective of the type of valvular pathology (aortic stenosis vs aortic insufficiency) or valvular morphology (bicuspid aortic valve vs tricuspid aortic valve). Aortic valve replacement with supracoronary ascending aorta replacement may have a stabilizing effect on the sinus segment over long-term follow-up in patients with tricuspid aortic valves or bicuspid aortic valves.

Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets.

The mesolimbic dopamine (DA) circuitry determines which behaviors are positively reinforcing and therefore should be encoded in the memory to become a part of the behavioral repertoire. Natural reinforcers, like food and sex, activate this pathway, thereby increasing the likelihood of further consummatory, social, and sexual behaviors. Oxytocin (OT) has been implicated in mediating natural reward and OT-synthesizing neurons project to the ventral tegmental area (VTA) and nucleus accumbens (NAc); however, direct neuroanatomical evidence of OT regulation of DA neurons within the VTA is sparse. To phenotype OT-receptor (OTR) expressing neurons originating within the VTA, we delivered Cre-inducible adeno-associated virus that drives the expression of fluorescent marker into the VTA of male mice that had Cre-recombinase driven by OTR gene expression. OTR-expressing VTA neurons project to NAc, prefrontal cortex, the extended amygdala, and other forebrain regions but less than 10% of these OTR-expressing neurons were identified as DA neurons (defined by tyrosine hydroxylase colocalization). Instead, almost 50% of OTR-expressing cells in the VTA were glutamate (GLU) neurons, as indicated by expression of mRNA for the vesicular GLU transporter (vGluT). About one-third of OTR-expressing VTA neurons did not colocalize with either DA or GLU phenotypic markers. Thus, OTR expression by VTA neurons implicates that OT regulation of reward circuitry is more complex than a direct action on DA neurotransmission. J. Comp. Neurol. 525:1094-1108, 2017. © 2016 Wiley Periodicals, Inc.

Outcomes of extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest in adult cardiac surgery patients.

BACKGROUND: The role of extracorporeal cardiopulmonary resuscitation (ECPR) in adult cardiac surgery patients with refractory cardiac arrest is uncertain. We hypothesized that ECPR would be associated with better than expected outcomes in this group of patients. METHODS: We conducted a single-center retrospective cohort study of adult cardiac surgery patients who underwent ECPR for refractory cardiac arrest during a 6-year period (2010 to 2015). In-hospital mortality, survival at last follow-up, and cerebral performance category (CPC) were examined as outcomes, and potential risk factors for mortality were explored. RESULTS: Twenty-three patients underwent ECPR when spontaneous circulation did not return with conventional resuscitation. Thirty-day mortality was 65.2%, and in-hospital mortality was 69.6%. Six of the 23 patients (26.1%) were discharged with a favorable neurologic outcome, defined as CPC 1 or 2. Most patients who died had multiple organ dysfunction syndrome (43.8%), and a smaller number had severe brain injury (25.0%). Kaplan-Meier survival analysis suggested age as a critical factor affecting survival (P = .04, log-rank test). CONCLUSIONS: ECPR may have a role in younger adult cardiac surgery patients who experience refractory cardiac arrest. Future studies are needed to identify patients who will benefit most from ECPR.

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors.

Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ∼62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the BLA.

Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction post-myocardial ischemia.

High-mobility group box 1 (HMGB1) triggers and amplifies inflammation cascade following ischemic injury, and its elevated levels are associated with adverse clinical outcomes in patients with myocardial infarction (MI). Angiotensin-converting enzyme 2 (ACE2), a key member of vasoprotective axis of the renin-angiotensin system (RAS), regulates cardiovascular functions and exerts beneficial effects in cardiovascular disease. However, the association between HMGB1 and ACE2 has not been studied. We hypothesized that overexpression of ACE2 provides cardioprotective effects against MI via inhibiting HMGB1 and inflammation. ACE2 knock-in (KI) mice and littermate wild-type (WT) controls were subjected to either sham or coronary artery ligation surgery to induce MI. Heart function was assessed 4 weeks after surgery using echocardiography and Millar catheterization. Tissues were collected for histology and analysis of the expression of HMGB1, RAS components, and inflammatory cytokines. ACE2 in the heart of the ACE2 KI mice was 58-fold higher than WT controls. ACE2-MI mice exhibited a remarkable preservation of cardiac function and reduction of infarct size in comparison to WT-MI mice. Notably, ACE2 overexpression significantly reduced the MI-induced increase in apoptosis, macrophage infiltration, and HMGB1 and proinflammatory cytokine expression (TNF-α and IL-6). Moreover, in an in vitro study, ACE2 activation prevented the hypoxia-induced cell death and upregulation of HMGB1 in adult cardiomyocytes. This protective effect is correlated with downregulation of HMGB1 and downstream proinflammatory cascades, which could be useful for the development of novel treatment for ischemic heart disease.

Acute hypernatremia exerts an inhibitory oxytocinergic tone that is associated with anxiolytic mood in male rats.

Anxiety disorders are the most common psychiatric illnesses and are associated with heightened stress responsiveness. The neuropeptide oxytocin (OT) has garnered significant attention for its potential as a treatment for anxiety disorders; however, the mechanism mediating its effects on stress responses and anxiety is not well understood. Here we used acute hypernatremia, a stimulus that elevates brain levels of OT, to discern the central oxytocinergic pathways mediating stress responsiveness and anxiety-like behavior. Rats were rendered hypernatremic by acute administration of 2.0 M NaCl and had increased plasma sodium concentration, plasma osmolality, and Fos induction in OT-containing neurons relative to 0.15 M NaCl-treated controls. Acute hypernatremia decreased restraint-induced elevations in corticosterone and created an inhibitory oxytocinergic tone on parvocellular neurosecretory neurons within the paraventricular nucleus of the hypothalamus. In contrast, evaluation of Fos immunohistochemistry determined that acute hypernatremia followed by restraint increased neuronal activation in brain regions receiving OT afferents that are also implicated in the expression of anxiety-like behavior. To determine whether these effects were predictive of altered anxiety-like behavior, rats were subjected to acute hypernatremia and then tested in the elevated plus maze. Relative to controls given 0.15 M NaCl, rats given 2.0 M NaCl spent more time in the open arms of the elevated plus maze, suggesting that acute hypernatremia is anxiolytic. Collectively the results suggest that acute elevations in plasma sodium concentration increase central levels of OT, which decreases anxiety by altering neuronal activity in hypothalamic and limbic nuclei.