Comparison of arterial storage conditions for delayed arterial ring testing.

Objective: Arterial ring testing is the gold standard for measuring arterial function. Increased arterial tone through arterial contraction and impaired endothelial relaxation (endothelial dysfunction) are key metrics of impaired arterial health in peripheral arterial disease (PAD). To allow for comparative testing of arteries during standard laboratory hours, storage buffers and conditions have been used to extend the functional life of arteries. Various storage conditions have been compared, but there has not been a robust comparison or validation in human arteries. The objective of this work is to optimize storage of arterial segments for endothelial cell (EC) testing in a murine model and to test EC function in human PAD arteries. We hypothesized that certain storage conditions would be superior to others. Methods: Healthy murine aortas were harvested from 10- to 14-week-old C57/Bl6J male and female mice and compared under different storage protocols (24 hours) to immediate arterial testing. The storage conditions tested were: Opti-MEM (37°C or 4°C), Krebs-HEPES with 1.8 mmol/L or 2.5 mmol/L calcium (4°C), or Wisconsin (WI) solution at 4°C. Vascular function was evaluated by isometric force testing. Endothelium-dependent and -independent relaxation were measured after precontraction with addition of methacholine or sodium nitroprusside, respectively. Arterial contraction was stimulated with potassium chloride or phenylephrine. Analysis of variance was used to determine significance compared with immediate testing with P < .05. Under institutional review board approval, 28 PAD arteries were collected at amputation and underwent vascular function testing as described. Disturbed flow conditions were determined by indirect (upstream occlusion) flow to the harvested tibial arteries. Stable flow arteries had in-line flow. Arterial calcification was quantified manually as present or not present. Results: We found that 4°C WI and 37°C Opti-MEM best preserved endothelium-dependent relaxation and performed similarly to immediately testing aortas (termed fresh for freshly tested) (P > .95). Other storage conditions were inferior to freshly tested aortas (P < .05). Vascular smooth muscle function was tested by endothelial-independent relaxation and contractility. All storage conditions preserved endothelial-independent relaxation and contractility similar to freshly tested arteries. However, 4°C WI and 37°C Opti-MEM storage conditions most closely approximated the maximum force of contraction of freshly tested arteries in response to potassium chloride (P > .39). For human arterial testing, 28 tibial arteries were tested for relaxation and contraction with 16 arteries with peripheral artery occlusive disease (PAD with disturbed flow) and 12 without peripheral artery occlusive disease (PAD with stable flow), of which 14 were calcified and 14 were noncalcified. Endothelial-dependent relaxation data was measurable in 9 arteries and arterial contraction data was measurable in 14 arteries. When comparing flow conditions, arteries exposed to disturbed flow (n = 4) had significantly less relaxation (2% vs 59%; P = .03) compared with stable flow conditions (n = 5). In contrast, presence the (n = 6) or absence of calcification (n = 3) did not impact arterial relaxation. Arterial contraction was not different between groups in either comparison by flow (n = 9 disturbed; n = 5 stable) or calcification (n = 6 present; n = 8 absent). Conclusions: In healthy murine aortas, arterial storage for 24 hours in 4°C WI or 37°C Opti-MEM both preserved endothelium-dependent relaxation and maximum force of contraction. In human PAD arteries stored in 4° WI, flow conditions before arterial harvest, but not arterial calcification, led to differences in arterial relaxation in human PAD arteries. Arterial contractility was more robust (11/28 arteries) compared with arterial relaxation (7/28 arteries), but was not significantly different under flow or calcification parameters. This work defines ideal storage conditions for arterial ring testing and identifies that EC dysfunction from disturbed flow may persist in delayed ex vivo arterial testing.

Myoglobinemia, Peripheral Arterial Disease, and Patient Mortality.

BACKGROUND: Peripheral arterial disease (PAD) causes leg muscle damage due to inadequate perfusion and increases cardiovascular events and mortality 2- to 3-fold. It is unclear if PAD is a biomarker for high-risk cardiovascular disease or if skeletal muscle injury harms arterial health. The objective of this work is to test if serum myoglobin levels (myoglobinemia) are a marker of PAD, and if so, whether myoglobin impairs vascular health. STUDY DESIGN: Patient blood samples were collected from PAD and control (no PAD) patients and interrogated for myoglobin concentrations and nitric oxide bioavailability. Patient mortality over time was captured from the medical record. Myoglobin activity was tested on endothelial cells and arterial function. RESULTS: Myoglobin is a biomarker for symptomatic PAD and was inversely related to nitric oxide bioavailability; 200 ng/mL myoglobin in vitro increased endothelial cell permeability in vitro and decreased nitrate bioavailability. Ex vivo, 100 ng/mL myoglobin increased vascular tone in naive murine aortas approximately 1.5 times, impairing absolute vessel relaxation. In vivo, we demonstrated that myoglobinemia caused impaired flow-mediated dilation in a porcine model. Patients presenting with myoglobin levels of 100 ng/mL or greater had significantly more deaths than those with myoglobin levels of less than 100 ng/mL. CONCLUSIONS: Using a combination of patient data, in vitro, ex vivo, and in vivo testing, we found that myoglobin is a biomarker for symptomatic PAD and a potent regulator of arterial health that can increase vascular tone, increase vascular permeability, and cause endothelial dysfunction, all of which may contribute to the vulnerability of PAD patients to cardiovascular events and death.

Phase of Care Mortality Analysis According to Individual Patient Risk Profile.

BACKGROUND: Phase of care mortality analysis (POCMA) is a quality improvement tool categorizing triggers for mortality into phases of patient care. However, the relationship between a patient's risk profile and the triggers for mortality is incompletely understood. METHODS: POCMA was implemented for cases with available Society of Thoracic Surgeons (STS) risk models. Risk-adjusted rates were obtained from the STS database. Mortality triggers were categorized by the phase of occurrence (preoperative, intraoperative, intensive care unit [ICU], postoperative floor, and discharge). Patients were then stratified by STS risk score: low risk (<4%), intermediate (4% to 8%), and high risk (>8%). RESULTS: A total of 3,919 isolated coronary artery bypass grafting (CABG), 901 isolated valve, and 321 CABG plus single-valve procedures were performed from 2012 to 2018, with 4.6% crude mortality and a median STS risk score of 5.8%. POCMA was performed on 67 patient mortalities, with triggers occurring in the following phases of care: 49.3% preoperative, 13.4% intraoperative, 23.9% ICU, 3.0% postoperative floor, and 10.4% discharge phase. Mortality distribution was bimodal, occurring mostly in low-risk (37.3%) and high-risk (38.8%) patients. For low-risk patients, the trigger for mortality most frequently occurred during the postoperative ICU phase, while for high-risk patients, the trigger for mortality most frequently occurred during the preoperative phase. CONCLUSIONS: Mortality had a bimodal distribution with respect to patient risk profile. Phase-of-care triggers for mortality differed according to patient risk profile: low-risk triggers during the postoperative ICU phase versus high-risk triggers typically during the preoperative phase. Specific focus on phases according to the patient's risk profile represents an opportunity to improve quality and outcomes.

Review of minimal access versus transcatheter aortic valve replacement for patients with severe aortic stenosis.

Transcatheter aortic valve replacement (TAVR) and minimally invasive aortic valve replacement (miniAVR) have become alternatives to surgical aortic valve replacement via median sternotomy (SAVR) to treat severe aortic stenosis (AS). Despite increased interest and utilization, few studies have directly compared TAVR and miniAVR. A review of the current literature shows TAVR to be an indispensable tool for inoperable, high-risk, and perhaps intermediate-risk patients with severe AS. However, it is associated with a number of deleterious perioperative outcomes, such as valvular regurgitation and vascular complications. MiniAVR is associated with decreased intensive care unit (ICU) and hospital length of stay, a lower incidence of blood transfusions, decreased ventilation time, and improved cosmetic results. MiniAVR maintains potential advantages over SAVR, including the implantation of a durable prosthesis and low rates of perioperative myocardial infarction and paravalvular leak. It is associated with longer aortic cross clamp and cardiopulmonary bypass (CPB) times; however, the use of sutureless valve implants can circumvent this. Studies comparing TAVR and miniAVR demonstrate decreased postoperative mortality, valvular regurgitation, and incidence of stroke in the miniAVR cohorts. Few studies currently exist comparing TAVR and miniAVR, as it is hard to compare the typically low-risk miniAVR versus high-risk TAVR patient populations. It is clear that both strategies will be cornerstones in the modern AVR era, but the situations in which to apply each strategy have not yet been clearly delineated. This highlights the need for surgeons to adopt these minimally invasive techniques. We believe there is a compelling role for miniAVR in low- and intermediate-risk patients, but due to the paucity of data, neither TAVR nor miniAVR should be discounted before a randomized, risk-stratified trial is performed. More studies are needed to compare TAVR and miniAVR in low- and intermediate-risk patients.

Minimally Invasive Versus Transcatheter and Surgical Aortic Valve Replacement: A Propensity Matched Study.

BACKGROUND: An increasing number of options exist for the treatment of severe symptomatic aortic stenosis. The study aim was to compare short-term outcomes in patients undergoing surgical aortic valve replacement (SAVR), minimally invasive aortic valve replacement (MIAVR), and transcatheter aortic valve replacement (TAVR). METHODS: A multi-institutional retrospective review of 2,571 patients undergoing SAVR (n = 842), MIAVR via right anterior thoracotomy (n = 699) and TAVR (n = 1,030) between 2011 and 2014 was conducted. TAVR patients were further stratified as either transfemoral (TF) or transapical (TA). Propensity matching was performed between MIAVR and SAVR (384 pairs), MIAVR and TA-TAVR (115 pairs), and MIAVR and TF-TAVR (247 pairs). RESULTS: Total numbers of AVR increased between 2011 and 2014. When stratified by procedure type, MIAVR and TF-TAVR accounted for most of the growth, while TA-TAVR and SAVR each experienced a decreased volume. Propensity matched comparisons of SAVR, TF-TAVR, and TA-TAVR versus MIAVR revealed no difference in 30-day mortality. TF-TAVR versus MIAVR revealed that MIAVR had a decreased rate of stroke (0.4% versus 3.6%, p = 0.02) and increased atrial fibrillation (AF; 19.4% versus 4%, p <0.01). When compared to SAVR, MIAVR had a lower incidence of AF (19% versus 32.6%, p <0.01). MIAVR exhibited decreased ventilation time (27.2 versus 134 h, p = 0.03) and intensive care unit time (63.7 versus 92.7 h, p = 0.02) compared to TA-TAVR. CONCLUSIONS: During recent years, MIAVR and TFTAVR have experienced significant growth in volume with near-comparable short-term outcomes, while SAVR and TA-TAVR volumes have declined. These results underscore the importance of surgeons adopting MIAVR and TF-TAVR techniques in order to offer patients optimal outcomes.

Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

BACKGROUND: Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. METHODS: Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). RESULTS: Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. LIMITATIONS: This study was not performed on an animal model of TRD. CONCLUSION: MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation.

Clinical trends in surgical, minimally invasive and transcatheter aortic valve replacement†.

OBJECTIVES: Transcatheter aortic valve replacement (TAVR) and minimally invasive aortic valve replacement (MIAVR) have emerged as alternatives to surgical aortic valve replacement (SAVR) via traditional sternotomy. However, their effect on clinical practice remains unclear. The study's objective is to describe clinical trends between TAVR, MIAVR and SAVR in patients with severe aortic stenosis (AS). METHODS: This retrospective observational study analyzed trends in isolated severe aortic valve replacement (AVR) among three high volume TAVR, MIAVR and SAVR centres in the United States. The cohort included 2571 patients from 2011 through 2014 undergoing SAVR ( n = 842), MIAVR ( n = 699) and TAVR ( n = 1030) further stratified into transapical (TA-TAVR) and trans-femoral (TF-TAVR). RESULTS: Total AVR volume increased +107% with increases in TF-TAVR (+595%) and MIAVR (+57%). However, SAVR (-15%) and TA-TAVR (-49%) decreased from 2013 to 2014. In the final year, risk stratification by age ≥ 80, redo AVR, patients receiving dialysis and STS score >8% revealed increases in TF-TAVR and MIAVR, while SAVR decreased for all groups. CONCLUSIONS: TF-TAVR and MIAVR increased while SAVR and TA-TAVR trended down in the latter periods, which underscore a paradigm shift in the treatment of severe AS and the importance of surgeon adoption of TF-TAVR and MIAVR techniques. As the demand for minimally invasive modalities increases, further studies comparing MIAVR versus TF-TAVR in low and intermediate risk patients are warranted.