A new arteriovenous fistula model to study the development of neointimal hyperplasia.

This study describes an alternative arteriovenous fistula (AVF) model in the rat in which the animals develop significant neointimal hyperplasia (NIH) not only at the distal anastomotic site, but also throughout the fistula body. This aortocaval fistula was established by anastomosing the distal end of the renal vein to the abdominal aorta after unilateral nephrectomy. The increased hemodynamic stress resulting from exposing the renal vein to the arterial circulation induced venous NIH as early as 7 days after surgery. This experimental AVF was characterized by the early lack of endothelium, the accumulation of proliferating vascular smooth muscle cells and the neovascularization of the fistula adventitia. In summary, we have described an informative animal model to study the pathobiology of NIH in native AVF.

Outcome and Cost Comparisons Between Surgical and Transcatheter Aortic Valve Replacements.

OBJECTIVE: Surgical aortic valve replacement (SAVR) has been the standard of care for severe aortic stenosis. In 2019, annual transcatheter aortic valve replacement (TAVR) implantations surpassed SAVR. We compared in-hospital costs and outcomes between these two procedures. METHODS: A single-center retrospective review was performed of patients who underwent isolated SAVR or TAVR from October 2013 to December 2019. Baseline patient characteristics, operating room (OR) time, intensive care unit (ICU) length of stay (LOS), total LOS, cumulative cost, and complication rates were collected. Propensity matching was performed to identify differences in costs and outcomes between comparable groups. RESULTS: There were 515 patients who met inclusion criteria. TAVR was performed in 402 patients, while SAVR was performed in 113. Propensity matching resulted in 82 matched pairs. The SAVR cohort more frequently spent >1 day in the ICU, had longer total hospital LOS, longer OR time, and higher hospitalization cost. However, TAVR was associated with higher mean OR cost and higher valve cost. The cumulative index admission costs were not significantly different between groups. TAVR patients had less postoperative atrial fibrillation but more frequent pacemaker placement. One-year mortality was similar between SAVR (2.4%) and TAVR (3.8%), but 3-year (5.8% vs 19.2%) and 5-year (5.8% vs 37.2%) mortality favored SAVR. CONCLUSIONS: In propensity-matched groups, TAVR was associated with shorter ICU and hospital LOS and OR times but increased permanent pacemaker rates. In addition, while 1-year survival was similar between groups, SAVR had significantly improved 3-year and 5-year survival.

Monitored Anesthesia Care Versus General Anesthesia for Transcatheter Aortic Valve Replacement.

OBJECTIVE: Monitored anesthesia care (MAC) has been increasingly used in lieu of general anesthesia (GA) for transcatheter aortic valve replacement (TAVR). We sought to compare outcomes and in-hospital costs between MAC and GA for TAVR at a Veterans Affairs Medical Center. METHODS: A single-center retrospective review was performed of 349 patients who underwent transfemoral TAVR (MAC, n = 244 vs GA, n = 105) from January 2014 to December 2019. Baseline patient characteristics, operating room (OR) time, intensive care unit (ICU) length of stay (LOS), and cost, total LOS, hospital cost, total cost, and complication rates were collected. Propensity matching was performed and resulted in 83 matched pairs. RESULTS: In the unmatched TAVR cohort, MAC TAVR was associated with reduced OR time (146 vs 198 min, P < 0.001), ICU LOS (1.4 vs 1.8 days, P < 0.001), total hospital LOS (3.4 vs 5.4 days, P < 0.001), and lower index total cost ($81,300 vs $85,400, P = 0.010). After propensity matching, MAC TAVR patients had reduced OR time (146 vs 196 min, P < 0.05), ICU LOS (1.2 vs 1.7 days, P = 0.006), total LOS (3.5 vs 5.1 days, P = 0.001), and 180-day mortality (2.4% vs 12%, P < 0.03). There was no difference in total hospitalization cost or total cost. CONCLUSIONS: In propensity-matched groups, TAVR utilizing MAC is associated with improved OR time efficiency, decreased LOS, and a reduction in 180-day mortality but no significant difference in cost.

Origin of neointimal cells in arteriovenous fistulae: bone marrow, artery, or the vein itself?

To elucidate the source of neointimal cells, experimental fistulas were created in Lewis wild-type (WT) and transgenic rats that constitutively expressed the green fluorescent protein (GFP) in all tissues. Arteriovenous fistula (AVFs) were created by anastomosing the left renal vein to the abdominal aorta. The contribution of bone marrow (BM)-derived cells to the AVF neointima was examined in lethally irradiated WT rats that had been rescued with GFP BM cells. Neointimal cells in these chimeric rats were mostly GFP negative indicating the non-BM origin of those cells. Then, the contribution of arterial cells to the AVF neointima was assessed in a fistula made with a GFP aorta that had been implanted orthotopically into a WT rat. Most of the neointimal cells were also GFP negative demonstrating that AVF neointimal cells are not derived from the feeding artery. Finally to study local resident cells contribution to the formation of neointimal lesions, a composite fistula was created by interposing a GFP vein between the renal vein and the aorta in a WT recipient rat. GFP neointimal cells were only found in the transplanted vein. This study suggests that neointimal cells originate from the local resident cells in the venous limb of the fistula.

Coronary Artery Bypass: Review of Surgical Techniques and Impact on Long-Term Revascularization Outcomes.

Coronary revascularization for multivessel disease remains a common and costly source of hospitalizations in the United States. Surgical techniques influence outcomes for coronary bypass and also affect the need for percutaneous coronary intervention in the future. As more radial access has been used for coronary angiography, consideration for use of the radial artery as a surgical conduit remains unclear. Saphenous vein grafts are commonly used for coronary bypass, however long-term patency remains suboptimal, and is also associated with a higher risk of adverse events with percutaneous coronary intervention. Thus, understanding the interplay between coronary bypass techniques and percutaneous coronary intervention has become increasingly important.

Relationship between Invasive and Echocardiographic Transvalvular Gradients after Transcatheter Aortic Valve Replacement.

INTRODUCTION: Lower transcatheter aortic valve replacement (TAVR) pressure gradients have been reported after implantation of self-expanding valves compared with balloon-expandable valves; however, there is a paucity of data on the relationship between invasively measured transvalvular pressure gradients and Doppler-derived measurements. METHODS: From September 2013 to September 2018, patients with native aortic valve stenosis who had both intraoperative invasive and postoperative echocardiography transvalvular pressure gradients were included for analysis. We used parametric and nonparametric statistics to compare aortic gradients within and between groups. RESULTS: Of 171 patients, 152 (88.9%) patients had TAVR with a balloon-expandable valve and 19 (11.1%) with a self-expanding valve. Among all patients, the invasive aortic gradient was 7.8 ± 3.2 mmHg and the Doppler-derived aortic gradient was 11.0 ± 4.5 mmHg (p < 0.001). Among those who received a balloon-expandable valve, the invasive aortic gradient was 7.5 ± 3 mmHg and the Doppler aortic gradient was 11.4 ± 4.5 mmHg (p < 0.001). In contrast, among patients who received a self-expanding valve, the invasive aortic gradient was 10.3 ± 3.4 mmHg and the Doppler aortic gradient was 8.5 ± 4.6 mmHg (p = 0.18). CONCLUSIONS: Balloon-expandable valves were associated with lower invasive measurements versus post-TAVR Doppler gradients, while results were inconclusive regarding self-expanding valves.

Proteasome peptidase activities parallel histomorphological and functional consequences of ischemia-reperfusion injury in the lung.

Several lines of evidence suggest that the proteasome contributes to ischemia-reperfusion injury (I-RI) of organs. Although I-RI contributes to multiple disease processes in the lung, the regulation of proteasome activities during pulmonary I-RI is unknown. Thus, the authors performed a pilot study to define time-related changes of lung proteasome peptidase activities and to evaluate if possible alterations correspond to morphological and functional consequences of I-RI using a rat model. Animals underwent 120 minutes of unilateral lung ischemia. Ischemic and contralateral lungs were harvested at multiple time points for up to 168 hours of reperfusion (I-R30 min-168 h). Chymotryptic-like (CT-L) and tryptic-like (T-L) proteasome peptidase activities were measured in lung extracts. An early I-R-associated inactivation of proteasome activities paralleled impairment of oxygenation, edema formation, and degree of histopathology, and resolved with restoration of function within 24 to 72 hours. Although functional and histomorphological baseline conditions were still not fully achieved at I-R168h, proteasome activities increased continuously 1.4-fold (CT-L) and 5.7-fold (T-L) until I-R168h. Apparent K(M) values for the CT-L/T-L substrates were not influenced by I-R. This pilot study establishes an initial link between proteasome activities and physiological relevant consequences of lung I-RI, and further points towards a possible role of the proteasome during the postischemic tissue repair process.

Ubiquitin enhances the Th2 cytokine response and attenuates ischemia-reperfusion injury in the lung.

OBJECTIVE: To determine whether ubiquitin treatment modulates the lung cytokine response and attenuates lung ischemia-reperfusion injury. DESIGN AND SETTING: Randomized and blinded treatment of unilateral lung ischemia-reperfusion injury in a research laboratory. SUBJECTS: Twenty anesthetized and mechanically ventilated Brown Norway rats. INTERVENTIONS: Unilateral clamping of the left lung for 90 mins followed by 60 mins of reperfusion. Intravenous administration of 1.5 mg/kg of ubiquitin (n = 10) or albumin (n = 10) 5 mins before reperfusion. MEASUREMENTS AND MAIN RESULTS: Blood pressure was measured by the tail-cuff method. Oxygenation via the ischemic lung was assessed by PaO2 measurements after right lung exclusion. Wet-to-dry weight ratios of the ischemic lungs were determined gravimetrically. Tissue homogenates (n = 5/group) were prepared from ischemic lungs at the end of reperfusion and assayed for malondialdehyde in combination with 4-hydroxyalkenals to assess lipid peroxidation, and for a panel of 22 cytokines/chemokines using a multiplex assay. Ubiquitin serum levels were determined by enzyme-linked immunosorbent assay.All animals were hemodynamically stable during the experimental procedure. Ubiquitin serum levels (mean +/- SD) were 650 +/- 40 ng/mL in controls and 1206 +/- 181 ng/mL in the ubiquitin treatment group at the end of the experiment. PaO2 after right lung exclusion was 45 (32-72) mm Hg with albumin and 61 (range, 36-132) mm Hg with ubiquitin (p = .0185). Wet-to-dry weight ratios of the injured lungs were 8.7 (range, 5.5-19.1) and 7.8 (range, 5.7-8.3) in the albumin and ubiquitin groups, respectively (p = .035). Malondialdehyde/4-hydroxyalkenals concentrations (mean +/- SD, nmol/mg protein) were 2.5 +/- 0.4 with ubiquitin and 3.0 +/- 0.3 with albumin (p > .05). Concentrations of the interleukins 4, 10, and 13 were significantly increased in lung homogenates after ubiquitin treatment (p < .05). CONCLUSION: Ubiquitin treatment enhances the Th2 cytokine response in postischemic lungs during reperfusion, reduces lung edema formation, and improves pulmonary function during lung ischemia-reperfusion injury. This study further defines ubiquitin's anti-inflammatory properties, and suggests that it could be used therapeutically to improve function of postischemic lungs.

Late Paravalvular Aortic Regurgitation: Migration of the Valve or Late Recoil?

A 79-year-old man underwent trans-catheter aortic valve replacement for symptomatic severe aortic stenosis with a 26-mm Edwards SAPIEN XT valve. Immediately after valve deployment there was moderate amount of paravalvular leak. Post-dilation was performed with an additional 2 cc of volume, and the paravalvular leak was reduced to trace. Nine months later, trans-thoracic echocardiography revealed moderate to severe paravalvular leak and possible aortic migration of the valve. The patient was brought back for the treatment of the paravalvular leak which was suspected to be due to valve migration. However, fluoroscopy and trans-esophageal echocardiography showed good valve position. Measurement of late valve recoil in the Coplanar view using cine-angiographic analysis software showed that the lower third of the valve had the greatest late recoil (-1.74 mm, 6.55%), which presumably accounted for the progression of the paravalvular leak. Valve-in-valve trans-catheter aortic valve replacement was performed with a 26-mm SAPIEN 3 valve and the paravalvular leak was reduced to trace. This case displays late recoil as a likely mechanism for development of paravalvular leak after SAPIEN XT valve implantation. Our case illustrates that late recoil needs to be systematically evaluated in future studies, especially when trans-catheter aortic valve replacement is being expanded to lower risk and younger patients for whom the longevity and long-term performance of these valves is of critical importance.

Comparison of Different Invasive Hemodynamic Measurements as a Prediction Tool for Mortality after Transcatheter Aortic Valve Replacement in Men: A Retrospective Observational Study.

INTRODUCTION: Hemodynamic measurements can assess for paravalvular aortic regurgitation after transcatheter aortic valve replacement (TAVR). This study compared the utility of different invasive hemodynamic measures in providing prognostic information. METHODS: This retrospective observational study of TAVR patients at a Veterans Hospital assessed aortic regurgitation index, diastolic delta, pulse pressure, and heart rate adjusted diastolic delta obtained at valve implantation. The primary outcome was total mortality. RESULTS: Overall, 151 patients underwent TAVR. Immediately after implantation, mean aortic regurgitation index was 31 ± 8.6, mean diastolic delta was 38 ± 9.8 mmHg, mean pulse pressure was 67 ± 18 mmHg, and mean heart rate adjusted diastolic delta was 47 ± 14.3 mmHg/beats per minute. Two percent of patients had ≥ moderate paravalvular aortic regurgitation by postoperative transthoracic echocardiography. Total mortality was 15.2% at a mean follow-up of 12.7 ± 9.2 months. Aortic regurgitation index <25 vs. ≥25, diastolic delta <19 vs. ≥19 mmHg, and pulse pressure >60 vs. ≤60 mmHg were not associated with total mortality. However, total mortality was 50% for heart rate adjusted diastolic delta <25 mmHg/beats per minute vs. 12.6% for heart rate adjusted diastolic delta ≥25 mmHg/beats per minute (p = 0.017). In a multivariate Cox regression analysis, heart rate adjusted diastolic delta <25 mmHg/beats per minute vs. heart rate adjusted diastolic delta ≥25 mmHg/beats per minute was associated with total mortality (hazard ratio 9.4, 95% confidence interval 2.0-44, p = 0.004). CONCLUSIONS: Among a cohort of TAVR patients, the only invasive hemodynamic test independently associated with total mortality was heart rate adjusted diastolic delta.

Breast and lung metastasis from pancreatic neuroendocrine carcinoma.

Pancreatic neuroendocrine tumors (PNETs) are an uncommon malignancy, accounting for a small percentage of all pancreatic malignancies. Due to their insidious course, most PNETs present with metastatic disease. Although reports in the literature describe PNET metastasis to the liver, lung and brain, to date there are no reports of stage IV disease involving the breast. Moreover, the lack of consensus regarding classification and treatment of this entity leaves practitioners without standards of practice or a firm base from which to formulate prognosis. In this report, the case of a previously healthy 51-year-old woman with stage IV PNET is examined. After combined neoadjuvant therapy with 5-fluorouracil, carboplatin, etoposide and radiation, surgical resection revealed metastatic PNET to the breast and lung, with no microscopic evidence of residual disease within the pancreas. An extensive analysis of the presentation, diagnosis, imaging modalities, treatment options, and prognosis is included in the discussion. As demonstrated by our review, there is a need for further studies to delineate inconclusive evidence with respect to subtype classification, treatment and prognosis of PNETs.

Interleukin-10 delivery via mesenchymal stem cells: a novel gene therapy approach to prevent lung ischemia-reperfusion injury.

Ischemia-reperfusion (IR) injury is an important cause of primary graft failure in lung transplantation. In this study, viral interleukin-10 (vIL-10)-engineered mesenchymal stem cells (MSCs) were tested for their ability to prevent lung IR injury. Bone marrow-derived MSCs were transduced with rvIL-10-retrovirus. After 120 min of warm left lung ischemia, rats received approximately 15 x 10(6) vIL-10-engineered MSCs (MSC-vIL-10), empty vector-engineered MSCs (MSC-vec), or saline intravenously. Mean blood oxygenation (PaO(2)/FiO(2) ratio, mmHg) was measured at 4 hr, 24 hr, 72 hr, and 7 days. As early as 4 hr post-IR injury with MSC-vIL-10 treatment, blood oxygenation was significantly (p < 0.05) improved (319 +/- 94; n = 7) compared with untreated (saline) controls (63 +/- 19; n = 6). At 24 hr post-IR injury, in the MSC-vIL-10-treated group there was a further increase in blood oxygenation (353 +/- 105; n = 10) compared with the MSC-vec group (138 +/- 86; n = 9) and saline group (87 +/- 39; n = 10). By 72 hr, oxygenation reached normal (475 +/- 55; n = 9) in the MSC-vIL-10-treated group but not in the saline-treated and MSC-vec-treated groups. At 4 hr after IR injury, lungs with MSC-vIL10 treatment had a lower (p < 0.05) injury score (0.9 +/- 0.4) compared with lungs of the untreated (saline) group (2.5 +/- 1.4) or MSC-vec-treated group (2 +/- 0.4). Lung microvascular permeability and wet-to-dry weight ratios were markedly lower in the MSC-vIL10 group compared with untreated (saline) controls. ISOL (in situ oligonucleotide ligation for DNA fragmentation detection) and caspase-3 staining demonstrated significantly (p < 0.05) fewer apoptotic cells in MSC-vIL10-treated lungs. Animals that received MSC-vIL10 therapy had fewer (p < 0.05) CD4(+) and CD8(+) T cells in bronchoalveolar lavage fluid compared with untreated control animals. A therapeutic strategy using vIL-10-engineered MSCs to prevent IR injury in lung transplantation seems promising.