Outcomes of hypothalamic oxytocin neuron-driven cardioprotection after acute myocardial infarction.

Altered autonomic balance is a hallmark of numerous cardiovascular diseases, including myocardial infarction (MI). Although device-based vagal stimulation is cardioprotective during chronic disease, a non-invasive approach to selectively stimulate the cardiac parasympathetic system immediately after an infarction does not exist and is desperately needed. Cardiac vagal neurons (CVNs) in the brainstem receive powerful excitation from a population of neurons in the paraventricular nucleus (PVN) of the hypothalamus that co-release oxytocin (OXT) and glutamate to excite CVNs. We tested if chemogenetic activation of PVN-OXT neurons following MI would be cardioprotective. The PVN of neonatal rats was transfected with vectors to selectively express DREADDs within OXT neurons. At 6 weeks of age, an MI was induced and DREADDs were activated with clozapine-N-oxide. Seven days following MI, patch-clamp electrophysiology confirmed the augmented excitatory neurotransmission from PVN-OXT neurons to downstream nuclei critical for parasympathetic activity with treatment (43.7 ± 10 vs 86.9 ± 9 pA; MI vs. treatment), resulting in stark improvements in survival (85% vs. 95%; MI vs. treatment), inflammation, fibrosis assessed by trichrome blue staining, mitochondrial function assessed by Seahorse assays, and reduced incidence of arrhythmias (50% vs. 10% cumulative incidence of ventricular fibrillation; MI vs. treatment). Myocardial transcriptomic analysis provided molecular insight into potential cardioprotective mechanisms, which revealed the preservation of beneficial signaling pathways, including muscarinic receptor activation, in treated animals. These comprehensive results demonstrate that the PVN-OXT network could be a promising therapeutic target to quickly activate beneficial parasympathetic-mediated cellular pathways within the heart during the early stages of infarction.

Open thoracic surgical implantation of cardiac pacemakers in rats.

Genetic engineering and implantable bioelectronics have transformed investigations of cardiovascular physiology and disease. However, the two approaches have been difficult to combine in the same species: genetic engineering is applied primarily in rodents, and implantable devices generally require larger animal models. We recently developed several miniature cardiac bioelectronic devices suitable for mice and rats to enable the advantages of molecular tools and implantable devices to be combined. Successful implementation of these device-enabled studies requires microsurgery approaches that reliably interface bioelectronics to the beating heart with minimal disruption to native physiology. Here we describe how to perform an open thoracic surgical technique for epicardial implantation of wireless cardiac pacemakers in adult rats that has lower mortality than transvenous implantation approaches. In addition, we provide the methodology for a full biocompatibility assessment of the physiological response to the implanted device. The surgical implantation procedure takes ~40 min for operators experienced in microsurgery to complete, and six to eight surgeries can be completed in 1 d. Implanted pacemakers provide programmed electrical stimulation for over 1 month. This protocol has broad applications to harness implantable bioelectronics to enable fully conscious in vivo studies of cardiovascular physiology in transgenic rodent disease models.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

Photocurable bioresorbable adhesives as functional interfaces between flexible bioelectronic devices and soft biological tissues.

Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic-tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.

Fully implantable and bioresorbable cardiac pacemakers without leads or batteries.

Temporary cardiac pacemakers used in periods of need during surgical recovery involve percutaneous leads and externalized hardware that carry risks of infection, constrain patient mobility and may damage the heart during lead removal. Here we report a leadless, battery-free, fully implantable cardiac pacemaker for postoperative control of cardiac rate and rhythm that undergoes complete dissolution and clearance by natural biological processes after a defined operating timeframe. We show that these devices provide effective pacing of hearts of various sizes in mouse, rat, rabbit, canine and human cardiac models, with tailored geometries and operation timescales, powered by wireless energy transfer. This approach overcomes key disadvantages of traditional temporary pacing devices and may serve as the basis for the next generation of postoperative temporary pacing technology.

Outcomes of Paraesophageal Hernia Repair: Analysis of the Veterans Affairs Surgical Quality Improvement Program Database.

BACKGROUND: While there have been many outcome studies on paraesophageal hernia repair in the civilian population, there is sparse recent data on the veteran population. This study analyzes the mortality and morbidities of veterans who underwent paraesophageal hernia repair in the Veterans Affairs Surgical Quality Improvement Program database. METHODS: Veterans who underwent paraesophageal hernia repair from 2010 to 2017 were identified using Current Procedural Terminology codes. Multivariable analysis was used to compare laparoscopic and open, including abdominal and thoracic approaches, groups. The outcomes were postoperative complications and mortality. RESULTS: There were 1607 patients in the laparoscopic group and 366 in the open group, with 84.1% men and mean age of 61 years. Gender and body mass index did not influence the type of surgical approach. The mortality rates at 30 and 180 days were 0.5% and 0.7%, respectively. Postoperative complications, including reintubation (2.2%), pneumonia (2.0%), intubation > 48 h (2.0%), and sepsis (2.0%) were higher in the open group (15.9% versus 7.2%, p < 0.001). The laparoscopic group had a significantly shorter length of stay (4.3 versus 9.6 days, p < 0.001) and a lower percentage of return to surgery within 30 days (3.9% versus 8.2%, p < 0.001) than the open group. The ratio of open versus laparoscopic paraesophageal hernia repairs varied significantly by different Veterans Integrated Services Network regions. CONCLUSIONS: Veterans undergoing laparoscopic paraesophageal hernia repair experience similar outcomes as patients in the private sector. Veterans who underwent laparoscopic paraesophageal hernia repair had significantly less complications compared to an open approach even after adjusting for patient comorbidities and demographics. The difference in open versus laparoscopic practices between various regions requires further investigation.

Impact of Timing of Smoking Cessation on 30-Day Outcomes in Veterans Undergoing Lobectomy for Cancer.

The adverse effects of tobacco use on postoperative outcomes are well documented. While smoking cessation is associated with overall improvement in long-term survival for lung cancer patients, the effects of cessation shortly before lung surgery are unclear. This study compares 30-day outcomes after lobectomy between active smokers, recent quitters, and nonsmokers. Patients who underwent lobectomy for cancer at national Veterans Affairs medical centers from 2012 to 2018 were retrospectively identified in the Veterans Affairs Surgical Quality Improvement Program database. The sample was stratified into 3 groups: smokers within 2 weeks of surgery ("active smokers"), those who quit between 2 weeks and 3 months prior to surgery ("recent quitters"), and "nonsmokers." Propensity score matching was performed to compare groups. Of 5715 patients who met inclusion criteria, 2696 were nonsmokers, 774 were recent quitters, and 2245 were active smokers. After propensity matching, 572 patients comprised each group. Compared to recent quitters, active smokers had 48% higher odds of suffering a pulmonary complication (95% confidence interval [CI]: 1.03-2.14; P = 0.035) and 72% higher odds of suffering multiple complications (CI: 1.07-2.76; P = 0.026). Relative to nonsmokers, active smokers had 81% higher odds of pulmonary complications (CI: 1.34-2.65; P = 0.003). No differences were detected in outcomes comparing recent quitters to nonsmokers. Veterans undergoing lobectomy for cancer who quit 2 weeks before surgery had less pulmonary complications than active smokers. Recent quitters have similar outcomes to nonsmokers. Surgeons should therefore encourage patients to quit smoking, including just prior to lung surgery.

Complications and Management of the Thoracic Endovascular Aortic Repair.

Endovascular treatment in thoracic aortic diseases has increased in use exponentially since Dake and colleagues first described the use of a home-made transluminal endovascular graft on 13 patients with descending thoracic aortic aneurysm at Stanford University in the early 1990s. Thoracic endovascular aneurysm repair (TEVAR) was initially developed for therapy in patients deemed unfit for open surgery. Innovations in endograft engineering design and popularization of endovascular techniques have transformed TEVAR to the predominant treatment choice in elective thoracic aortic repair. The number of TEVARs performed in the United States increased by 600% from 1998 to 2007, while the total number of thoracic aortic repairs increased by 60%. As larger multicenter trials and meta-analysis studies in the 2000s demonstrate the significant decrease in perioperative morbidity and mortality of TEVAR over open repair, TEVAR became incorporated into standard guidelines. The 2010 American consensus guidelines recommend TEVAR to be "strongly considered" when feasible for patients with degenerative or traumatic aneurysms of the descending thoracic aorta exceeding 5.5 cm, saccular aneurysms, or postoperative pseudoaneurysms. Nowadays, TEVAR is the predominant treatment for degenerative and traumatic descending thoracic aortic aneurysm repair. Although TEVAR has been shown to have decreased early morbidity and mortality compared with open surgical repair, endovascular manipulation of a diseased aorta with endovascular devices continues to have significant risks. Despite continued advancement in endovascular technique and devices since the first prospective trial examined the complications associated with TEVAR, common complications, two decades later, still include stroke, spinal cord ischemia, device failure, unintentional great vessel coverage, access site complications, and renal injury. In this article, we review common TEVAR complications with some corresponding radiographic imaging and their management.

Preoperative Factors Associated with Appendiceal Tumors in Nonelective Appendectomy.

Background: The rates of incidental appendiceal neoplasms after appendectomy performed for acute appendicitis is <2%. To date, no large studies have investigated the preoperative risk factors or imaging findings associated with incidental appendiceal tumors that present as appendicitis. Our study aims to identify preoperative factors that are associated with an increased risk of appendiceal tumors in patients who present with signs and symptoms of acute appendicitis. Materials and Methods: Using the targeted appendectomy American College of Surgeons National Surgical Quality Improvement Program database, we identified patients who underwent nonelective appendectomy for acute appendicitis in 2016. Patients with final pathology consistent with a tumor were compared with those with only appendicitis. A nonmatched case/control method was used to pull a random sample from the appendicitis cohort using a 1:4 ratio (tumor: acute appendicitis) to obtain adequate power for comparison. Preoperative patient variables and imaging findings were investigated using stepwise logistic regression to identify variables associated with appendiceal tumor. Results: Following multivariate analysis, preoperative imaging read of "indeterminate" and "not consistent with appendicitis," female gender, increased age, and lower preoperative white blood cell (WBC) count were significant predictors of tumor causing symptoms of appendicitis. The odds of having tumor pathology were significantly increased in patients with preoperative imaging of "indeterminate" and "not consistent with appendicitis." The odds of having tumor pathology were 82% higher for females than for males, increased by 2% for every 1-year increase in age, and increased by 3% for every one-unit decrease in WBC count. Conclusion: While incidental appendiceal tumors can present as acute appendicitis, 3 patient variables and one imaging finding were identified that may increase suspicion for appendiceal tumors. Consideration should be given to patients with these associated risk factors for additional preoperative consultation in addition to the potential for intraoperative pathology consultation.

Long-Term Outcomes of Coronary Artery Bypass Grafting in Veterans with Ischemic Cardiomyopathy.

BACKGROUND: The Surgical Treatment for Ischemic Heart Failure (STICH) trial showed that surgical revascularization in ischemic cardiomyopathy (ICM) patients improves long-term mortality compared with medical treatment alone. This study examines how veterans with ICM undergoing revascularization fare against patients without ICM; it also examines the outcomes in the veteran population. METHODS: This is a retrospective review of a single-center database. From 2000 to 2018, 1,461 patients underwent isolated coronary artery bypass grafting (CABG). Two-hundred-one patients with an ejection fraction less than 35% were classified as the ICM cohort. The primary outcome was mortality. Secondary outcomes included postoperative complications. Subgroup analysis was performed within the ICM cohort comparing off-pump CABG (OPCAB) versus on-pump CABG (ONCAB). RESULTS: ICM patients had a higher incidence of myocardial infarction (MI), diabetes, chronic kidney disease (CKD), and preoperative intra-aortic balloon pump (IABP) use. The non-ICM cohort was more functionally independent. OPCAB was performed in 80.1% of ICM and 66.3% of non-ICM cohorts. There was no statistical difference between ICM and non-ICM cohorts in 30-day mortality (OR 1.94[0.79 - 4.75], P = .15). The ICM cohort had an increased 5-year mortality (OR 1.75[1.14 - 2.69], P = .01) and 10-year mortality (OR 1.71[1.09 - 2.67], P = .02). The ICM cohort showed improved, although not statistically significant, short-term mortality with OPCAB compared with ONCAB (3.1% versus 12.5%, OR 0.31[0.05 - 1.82], P = .20). CONCLUSION: Veterans with ICM undergoing CABG demonstrated similar short-term survival compared with non-ICM veterans. The long-term survival in the ICM cohort still is inferior to patients without ICM. There is a trend toward improved short-term survival in patients with ICM undergoing OPCAB.

Influence of Age on Cardiac Surgery Outcomes in United States Veterans.

OBJECTIVE: Heart disease is still the leading cause of death for both men and women in the United States, and the rate of cardiovascular disease in veterans is even higher than in civilians. This study examines age-related outcomes for veterans undergoing cardiac surgeries at a single institution. METHODS: We included all veterans undergoing coronary artery bypass grafting (CABG) and/or valve surgery between 1997 to 2017 at a single Veterans Affairs (VA) medical center. We stratified this cohort into 4 age groups: ≤59 years old, 60-69 years old, 70-79 years old, and ≥80 years old. Outcomes in age groups were compared using standard statistical methods with the ≤59 years old group as reference. RESULTS: A total of 2,301 patients underwent open cardiac procedures at our institution. The frequency of simultaneous CABG and valve operations increased with age. Usage of cardiopulmonary bypass versus off-pump CABG and operative time was not associated with age. Increased pulmonary and renal complications as well as rates of postoperative arrhythmias all were associated with increasing age. There was no statistically significant difference in 30-day mortality. However, multivariable analysis adjusted for covariates showed all-cause mortality significantly was increased with older age groups (aHR ≥80 years old: 2.94 [2.07-4.17], P < .01; aHR 70-79 years old: 2.15 [1.63-2.83], P < 0.01, with ≤59 years old as reference). CONCLUSIONS: Older patients may have comparable perioperative mortality as their younger counterparts. However, age still is a significant predictor of all-cause mortality, pulmonary and renal complications, and postoperative arrhythmia, and should be considered as a major factor in preoperative risk assessment.

Flexible and Transparent Metal Oxide/Metal Grid Hybrid Interfaces for Electrophysiology and Optogenetics.

Flexible and transparent microelectrodes and interconnects provide the unique capability for a wide range of emerging biological applications, including simultaneous optical and electrical interrogation of biological systems. For practical biointerfacing, it is important to further improve the optical, electrical, electrochemical, and mechanical properties of the transparent conductive materials. Here, high-performance microelectrodes and interconnects with high optical transmittance (59-81%), superior electrochemical impedance (5.4-18.4 Ω cm2), and excellent sheet resistance (5.6-14.1 Ω sq-1), using indium tin oxide (ITO) and metal grid (MG) hybrid structures are demonstrated. Notably, the hybrid structures retain the superior mechanical properties of flexible MG other than brittle ITO with no changes in sheet resistance even after 5000 bending cycles against a small radius at 5 mm. The capabilities of the ITO/MG microelectrodes and interconnects are highlighted by high-fidelity electrical recordings of transgenic mouse hearts during co-localized programmed optogenetic stimulation. In vivo histological analysis reveals that the ITO/MG structures are fully biocompatible. Those results demonstrate the great potential of ITO/MG interfaces for broad fundamental and translational physiological studies.

Wireless, battery-free, fully implantable multimodal and multisite pacemakers for applications in small animal models.

Small animals support a wide range of pathological phenotypes and genotypes as versatile, affordable models for pathogenesis of cardiovascular diseases and for exploration of strategies in electrotherapy, gene therapy, and optogenetics. Pacing tools in such contexts are currently limited to tethered embodiments that constrain animal behaviors and experimental designs. Here, we introduce a highly miniaturized wireless energy-harvesting and digital communication electronics for thin, miniaturized pacing platforms weighing 110 mg with capabilities for subdermal implantation and tolerance to over 200,000 multiaxial cycles of strain without degradation in electrical or optical performance. Multimodal and multisite pacing in ex vivo and in vivo studies over many days demonstrate chronic stability and excellent biocompatibility. Optogenetic stimulation of cardiac cycles with in-animal control and induction of heart failure through chronic pacing serve as examples of modes of operation relevant to fundamental and applied cardiovascular research and biomedical technology.

Internal jugular vein stenosis is common in patients presenting with neurogenic thoracic outlet syndrome.

Previous magnetic resonance imaging studies have shown abnormalities of the internal jugular veins in patients with thoracic outlet syndrome (TOS), but this finding has largely been ignored. We, thus, prospectively performed diagnostic brachiocephalic venograms in all patients with diagnosed neurogenic TOS from April 2008 to December 2011 (mean age, 42.6; r, 16-68; 77.8% women and 22.2% men). Stenosis of the left internal jugular vein, left subclavian vein, right internal jugular vein, and right subclavian vein were assessed, and significant stenoses of these vessels were seen in 63.49%, 65.08%, 60.32%, and 68.25% of patients, respectively. Internal jugular vein stenosis was not present in 23.81%, present unilaterally in 28.57%, and present bilaterally in 47.62% of patients. Subclavian vein stenosis was not present in 17.46%, present unilaterally in 28.57%, and present bilaterally in 53.97% of patients. Phi coefficients of correlation were 0.067 between left internal jugular vein and left subclavian vein stenoses, 0.061 between right internal jugular vein and right subclavian vein stenoses, and 0 between any internal jugular vein and any subclavian vein stenoses, indicating there is no correlation between jugular vein stenosis and subclavian vein stenosis in these patients. We conclude that right and left internal jugular vein stenosis is common in patients with neurogenic TOS symptoms. Treatment of internal jugular vein stenosis could potentially benefit these patients, and the implications of these findings warrant further study.

What is the true incidence of anomalous bovine left common carotid artery configuration?

BACKGROUND: Earlier studies have indicated that bovine left common carotid artery configuration occurs in 10.2-22% of patients and increases the complexity of navigating endovascular devices in the aortic arch. However, we anecdotally noted a higher incidence of bovine arch among angiosuite outpatients in Los Angeles, California. Thus, we retrospectively reviewed aortic arch angiograms performed in 93 unique outpatients to determine the true incidence of this anomalous configuration. METHODS: We were able to obtain complete angiographies from clinical data on 90 patients (mean age 50 years, SD 15.23 years, range 17-88 years) from May 2006 to January 2012. Angiograms were categorized as: normal arch; bovine arch with brachiocephalic trunk; bovine arch with common trunk; or indeterminate. RESULTS: The findings indicated an overall 35.16% bovine arch incidence, of which 78.13% is bovine arch with common trunk and 21.88% is bovine arch with brachiocephalic trunk. There was a higher prevalence in the women (40%, n = 60) than men (26.67%, n = 30). Caucasians had a lower incidence of bovine arch (27.78%, n = 47) compared with other ethnicities. The prevalence of bovine arch in different ethnicity and gender groups was assessed and the differences were not statistically significant. CONCLUSIONS: The incidence of bovine left common carotid artery is higher than previously reported and varies by gender and race. Advanced knowledge of the high prevalence of this anomaly could reduce the risks and increase the efficiency of navigating catheters through the tortuous vessels during endovascular procedures. The clinical implications of this report warrant further investigation.