Surgically induced aortic coarctation in a neonatal porcine model allows for longitudinal assessment of cardiovascular changes.

Noncritical aortic coarctation (COA) typically presents beyond early childhood with hypertension. Correction of COA does not ensure a return to normal cardiovascular health, but the mechanisms are poorly understood. Therefore, we developed a porcine COA model to study the secondary cardiovascular changes. Eight male neonatal piglets (4 sham, 4 COA) underwent left posterolateral thoracotomy with descending aorta (DAO) mobilization. COA was created via a 1-cm longitudinal DAO incision with suture closure, plication, and placement and an 8-mm external band. All animals had cardiac catheterization at 6 (11-13 kg), 12 (26-31 kg), and 20 (67-70 kg) wk of age. Aortic luminal diameters were similar along the thoracic aorta, except for the COA region [6.4 mm COA vs. 17.3 mm sham at 20 wk (P < 0.001)]. Collateral flow could be seen as early as 6 wk. COA peak systolic pressure gradient was 20 mmHg at 6 wk and persisted through 20 wk increasing to 40 mmHg with dobutamine. Pulse pressures distal to the COA were diminished at 12 and 20 wk. This model addresses many limitations of prior COA models including neonatal creation at an expected anatomic position with intimal injury and vessel sizes similar to humans.NEW & NOTEWORTHY A neonatal model of aortic coarctation was developed in a porcine model using a readily reproducible method of aortic plication and external wrap placement. This model addresses the limitations of existing models including neonatal stenosis creation, appropriate anatomic location of the stenosis, and intimal injury creation and mimics human somatic growth. Pigs met American Heart Association (AHA) criteria for consideration of intervention, and the stenoses were graded as moderate to severe.

Elastin Insufficiency Confers Proximal and Distal Pulmonary Vasculopathy in Mice, Partially Remedied by the KATP Channel Opener Minoxidil: Considerations and Cautions for the Treatment of People With Williams-Beuren Syndrome.

Background: Williams Beuren syndrome (WBS) is a recurrent microdeletion disorder that removes one copy of elastin (ELN), resulting in large artery vasculopathy. Early stenosis of the pulmonary vascular tree is common, but few data are available on longer-term implications of the condition. Methods: Computed tomography (CT) angiogram (n = 11) and echocardiogram (n = 20) were performed in children with WBS aged 3.4-17.8 years. Controls (n = 11, aged 4.4-16.8 years) also underwent echocardiogram. Eln +/- mice were analyzed by invasive catheter, echocardiogram, micro-CT (µCT), histology, and pressure myography. We subsequently tested whether minoxidil resulted in improved pulmonary vascular endpoints. Results: WBS participants with a history of main or branch pulmonary artery (PA) stenosis requiring intervention continued to exhibit increased right ventricular systolic pressure (RVSP, echocardiogram) relative to their peers without intervention (p < 0.01), with no clear difference in PA size. Untreated Eln +/- mice also show elevated RVSP by invasive catheterization (p < 0.0001), increased normalized right heart mass (p < 0.01) and reduced caliber branch PAs by pressure myography (p < 0.0001). Eln +/- main PA medias are thickened histologically relative to Eln +/+ (p < 0.0001). Most Eln +/- phenotypes are shared by both sexes, but PA medial thickness is substantially greater in Eln +/- males (p < 0.001). Eln +/- mice showed more acute proximal branching angles (p < 0.0001) and longer vascular segment lengths (p < 0.0001) (µCT), with genotype differences emerging by P7. Diminished PA acceleration time (p < 0.001) and systolic notching (p < 0.0001) were also observed in Eln +/- echocardiography. Vascular casting plus µCT revealed longer generation-specific PA arcade length (p < 0.0001), with increased PA branching detectable by P90 (p < 0.0001). Post-weaning minoxidil decreased RVSP (p < 0.01) and normalized PA caliber (p < 0.0001) but not early-onset proximal branching angle or segment length, nor later-developing peripheral branch number. Conclusions: Vascular deficiencies beyond arterial caliber persist in individuals with WBS who have undergone PA stenosis intervention. Evaluation of Eln +/- mice reveals complex vascular changes that affect the proximal and distal vasculatures. Minoxidil, given post-weaning, decreases RVSP and improves lumen diameter, but does not alter other earlier-onset vascular patterns. Our data suggest additional therapies including minoxidil could be a useful adjunct to surgical therapy, and future trials should be considered.

Airflow Obstruction in Adults with Williams Syndrome and Mice with Elastin Insufficiency.

Williams−Beuren syndrome (WS) results from the deletion of 25−27 coding genes, including elastin (ELN), on human chromosome 7q11.23. Elastin provides recoil to tissues; emphysema and chronic obstructive pulmonary disease have been linked to its destruction. Consequently, we hypothesized that elastin insufficiency would predispose to obstructive features. Twenty-two adults with WS (aged 18−55) and controls underwent pulmonary function testing, 6 min walk, and chest computed tomography (CT). Lung and airspace dimensions were assessed in Eln+/− and control mice via microCT and histology. The forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) were lower in adults with WS (p < 0.0001 and p < 0.05, respectively). The FEV1/FVC ratio was more frequently below the lower limit of normal in cases (p < 0.01). The ratio of residual volume to total lung capacity (RV/TLC, percent predicted) was higher in cases (p < 0.01), suggesting air trapping. People with WS showed reduced exercise capacity (p < 0.0001). In Eln+/− mice, ex vivo lung volumes were increased (p < 0.0001), with larger airspaces (p < 0.001). Together these data show that elastin insufficiency impacts lung physiology in the form of increased air trapping and obstruction, suggesting a role for lung function monitoring in adults with WS.

Optimal management of upper extremity deep vein thrombosis: Is venous thoracic outlet syndrome underrecognized?

BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) accounts for ~10% of all cases of DVT. In the most widely referenced general review of DVT, the American Academy of Chest Physicians essentially recommended that UEDVT be treated identically to that of lower extremity DVT, with anticoagulation the default therapy. However, the medical literature has not differentiated well between DVT in the arm vs DVT in the leg and has not emphasized the effects of the costoclavicular junction and the lack of the effect of gravity to the point at which UEDVT due to extrinsic bony compression at the costoclavicular junction is classified as "primary." METHODS: We performed a comprehensive literature review, beginning with both Medline and Google Scholar searches, in addition to collected references. Next, we manually reviewed the relevant citations within the initial reports studied. Both surgical and medical journals were explored. RESULTS: It has been proposed that "effort thrombosis" should be classified as a secondary cause of UEDVT, limiting the definition of "primary" to that which is truly idiopathic. Other causes of secondary UEDVT include catheter- and pacemaker-related thrombosis (the most common cause but often asymptomatic), thrombosis related to malignancy and hypercoagulable conditions, and the rare case of thrombosis due to compression of the vein by a focal malignancy or other space-occupying lesion. In true primary UEDVT and those secondary cases in which no mechanical cause is present or can be corrected, anticoagulation remains the treatment of choice, usually for 3 months or the duration of a needed catheter. However, evidence has suggested that many cases of effort thrombosis are likely missed by a too-narrow adherence to this protocol. CONCLUSIONS: Because proper treatment of effort thrombosis would decrease the long-term symptomatic status rate from 50% to almost 0% and because these are healthy patients with a long lifespan, we believe that a more aggressive attitude toward thrombolysis should be followed for any patient with a reasonable degree of suspicion for venous thoracic outlet syndrome.

Elevated Cardiopulmonary Complications after Revascularization in Patients with Severe Mental Health Disorders.

Introduction: Mental health disorders (MHD) are prevalent within surgical patient populations and can be associated with poorer postoperative outcomes, particularly in those with more severe MHD (schizophrenia and bipolar disorder). However, these associations have not been examined in vascular surgery patients. This study investigated patients undergoing lower extremity revascularization, hypothesizing that those with severe MHD would experience worse health and postoperative outcomes. Methods: A retrospective chart review of patients from 2010-2015 with peripheral arterial disease (PAD) requiring revascularization was conducted, with subsequent narrowing to those with concurrent MHD diagnoses, including severe MHD (sMHD) defined as bipolar disorder or schizophrenia and non-severe MHD (nsMHD), defined as anxiety or depression. The primary endpoints were 30-day mortality; Major Adverse Limb Events (MALE) including amputation at the above or below knee level; and Major Adverse Cardiac Events (MACE) including myocardial infarction (MI), congestive heart failure (CHF) exacerbation, and arrhythmia. Secondary endpoints were readmission within 30 days, pulmonary complications, and wound infection. Statistical analyses included Fisher Exact Test and Student's T-test. Results: Eighteen patients with MHD (sMHD, n=10; nsMHD, n=8) were identified and stratified. Twenty-four limbs were revascularized (sMHD, n=13; nsMHD, n=11). Overall incidence of 30-day mortality, MALE, and MACE were 4.2%, 33.3%, and 50.0%, respectively. Readmission rate, pneumonia, and wound infection occurred in 41.7%, 20.8%, and 16.7% of the population. Stratifying by MHD severity, no significant differences were observed for medical comorbidities, MALE, intervention type (open vs. endovascular), or treatment indication (claudication vs. critical limb ischemia). Patients with sMHD had significantly higher rates of MACE compared to patients with nsMHD (30.8% vs. 18.2%, p<.05). Pneumonia was also more prevalent in this group (38.5% vs. 0.0%, p<.05). Conclusion: While patients with concurrent diagnoses of MHD and PAD presented with similar comorbidities, comparable disease severity, and were equally treated by open versus endovascular techniques, those with severe MHD suffered significantly elevated rates of cardiopulmonary complications, specifically MACE and pneumonia. Further investigation is warranted to identify opportunities to optimize post-operative care for these complex patients.

Vascular Casting of Adult and Early Postnatal Mouse Lungs for Micro-CT Imaging.

Blood vessels form intricate networks in 3-dimensional space. Consequently, it is difficult to visually appreciate how vascular networks interact and behave by observing the surface of a tissue. This method provides a means to visualize the complex 3-dimensional vascular architecture of the lung. To accomplish this, a catheter is inserted into the pulmonary artery and the vasculature is simultaneously flushed of blood and chemically dilated to limit resistance. Lungs are then inflated through the trachea at a standard pressure and the polymer compound is infused into the vascular bed at a standard flow rate. Once the entire arterial network is filled and allowed to cure, the lung vasculature may be visualized directly or imaged on a micro-CT (µCT) scanner. When performed successfully, one can appreciate the pulmonary arterial network in mice ranging from early postnatal ages to adults. Additionally, while demonstrated in the pulmonary arterial bed, this method can be applied to any vascular bed with optimized catheter placement and endpoints.

Racial and Gender Disparity in Achieving Optimal Medical Therapy for Inpatients with Peripheral Artery Disease.

Best medical therapy for peripheral artery disease (PAD) includes statin and anti-platelet agents, a combination shown to decrease rates of major cardiovascular events. Despite these findings, many patients remain undertreated and the objective of this project was to investigate the rate of initiating anti-platelet and statin therapy for inpatients newly diagnosed with PAD with a focus on disparities by race and sex. A retrospective chart review of inpatients with newly diagnosed PAD was performed between January 1, 2016 to December 31, 2016 at a single institution. Demographics and comorbid conditions were collected. Primary outcomes included antiplatelet and statin prescription at discharge. The 44 patients included in this study were predominantly male (59% vs. 41%) and African American (61% vs. 39%). Between admission and discharge, prescriptions rose from 70% to 82% for statin and 82% to 91% for anti-platelet agents. Vascular specialists were more successful than non-vascular specialists at initiating medical therapy, with statin prescriptions increasing 22% and anti-platelet prescriptions climbing 23% for those admitted to a vascular specialist. Interestingly, when the ABI was reported in the normal range, rates of statin initiation were particularly compromised at only 40%. For the total patient sample, those discharged without a statin were more commonly African American (63%) and the majority were female (67%). All patients discharged without an antiplatelet were African American and 50% were females. Despite national guidelines, patients with PAD continue to be discharged without optimal medical therapy. This study suggests that obstacles to initiation may include race, sex, admitting service, or presence of a normal ABI. Further investigation is warranted to determine effective avenues for provider education and system-wide initiatives.

A Switch and Wave of Neuronal Activity in the Cerebral Cortex During the First Second of Conscious Perception.

Conscious perception occurs within less than 1 s. To study events on this time scale we used direct electrical recordings from the human cerebral cortex during a conscious visual perception task. Faces were presented at individually titrated visual threshold for 9 subjects while measuring broadband 40-115 Hz gamma power in a total of 1621 intracranial electrodes widely distributed in both hemispheres. Surface maps and k-means clustering analysis showed initial activation of visual cortex for both perceived and non-perceived stimuli. However, only stimuli reported as perceived then elicited a forward-sweeping wave of activity throughout the cerebral cortex accompanied by large-scale network switching. Specifically, a monophasic wave of broadband gamma activation moves through bilateral association cortex at a rate of approximately 150 mm/s and eventually reenters visual cortex for perceived but not for non-perceived stimuli. Meanwhile, the default mode network and the initial visual cortex and higher association cortex networks are switched off for the duration of conscious stimulus processing. Based on these findings, we propose a new "switch-and-wave" model for the processing of consciously perceived stimuli. These findings are important for understanding normal conscious perception and may also shed light on its vulnerability to disruption by brain disorders.

Human bedside evaluation versus automatic responsiveness testing in epilepsy (ARTiE).

Evaluation of behavioral impairment during epileptic seizures is critical for medical decision making, including accurate diagnosis, recommendations for driving, and presurgical evaluation. We investigated the quality of behavioral testing during inpatient video-electroencephalography (EEG) monitoring at an established epilepsy center, and introduce a technical innovation that may improve clinical care. We retrospectively reviewed video-EEG data from 152 seizures in 33 adult or pediatric patients admitted for video-EEG monitoring. Behavioral testing with questions or commands was performed in only 50% of seizures ictally, 73% of seizures postictally, and 80% with either ictal or postictal testing combined. Furthermore, the questions or commands were highly inconsistent and were performed by nonmedical personnel in about one fourth of cases. In an effort to improve this situation we developed and here introduce Automatic Responsiveness Testing in Epilepsy (ARTiE), a series of video-recorded behavioral tasks automatically triggered to play in the patient's room by computerized seizure detection. In initial technical testing using prerecorded or live video-EEG data we found that ARTiE is initiated reliably by automatic seizure detection. With additional clinical testing we hope that ARTiE will succeed in providing comprehensive and reliable behavioral evaluation during seizures for people with epilepsy to greatly improve their clinical care.