Emily A. Downs

A novel chronic advanced stage abdominal aortic aneurysm murine model

Objective: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Methods: Wild‐type 8‐week‐old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3‐aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 &mgr;L of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 &mgr;L of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Results: Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long‐term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro‐matrix metalloproteinase 9, interleukin‐1&bgr;, interleukin‐6, chemokine [C‐C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3‐positive T cells in the BAPN+elastase group were elevated on days 28 and 100. Conclusions: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced‐stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development. Clinical Relevance: A chronic abdominal aortic aneurysm (AAA) animal model is described which possesses more characteristics of human AAA compared with other AAA models. Because this model demonstrates all stages of aneurysm formation, it is a useful tool for investigational aneurysm studies, especially for end‐stage AAA with thrombus formation and spontaneous rupture. The model can also be performed in genetically modified strains to explore the sophisticated mechanisms of aneurysm formation.

B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm

Objective—B-cell depletion therapy is widely used for treatment of cancers and autoimmune diseases. B cells are abundant in abdominal aortic aneurysms (AAA); however, it is unknown whether B-cell depletion therapy affects AAA growth. Using experimental models of murine AAA, we aim to examine the effect of B-cell depletion on AAA formation. Approach and Results—Wild-type or apolipoprotein E–knockout mice were treated with mouse monoclonal anti-CD20 or control antibodies and subjected to an elastase perfusion or angiotensin II infusion model to induce AAA, respectively. Anti-CD20 antibody treatment significantly depleted B1 and B2 cells, and strikingly suppressed AAA growth in both models. B-cell depletion resulted in lower circulating IgM levels, but did not affect the levels of IgG or cytokine/chemokine levels. Although the total number of leukocyte remained unchanged in elastase-perfused aortas after anti-CD20 antibody treatment, the number of B-cell subtypes was significantly lower. Interestingly, plasmacytoid dendritic cells expressing the immunomodulatory enzyme indole 2,3-dioxygenase were detected in the aortas of B-cell–depleted mice. In accordance with an increase in indole 2,3-dioxygenase+ plasmacytoid dendritic cells, the number of regulatory T cells was higher, whereas the expression of proinflammatory genes was lower in aortas of B-cell–depleted mice. In a coculture model, the presence of B cells significantly lowered the number of indole 2,3-dioxygenase+ plasmacytoid dendritic cells without affecting total plasmacytoid dendritic cell number. Conclusions—The present results demonstrate that B-cell depletion protects mice from experimental AAA formation and promotes emergence of an immunosuppressive environment in aorta.

Current state of transcatheter mitral valve repair with the MitraClip

BACKGROUND Many patients affected with mitral valve regurgitation suffer from multiple comorbidities. The MitraClip device provides a safe means of transcatheter valve repair in patients with suitable mitral valve anatomy who are at prohibitive risk for surgery. We describe our early procedural outcomes and present a summary of the current state of MitraClip technology in the United States. METHODS We performed a retrospective chart review of initial high-risk or inoperable patients who underwent MitraClip placement at our institution after completion of the EVEREST II study. We examined the primary outcome of 30-day mortality, and secondary outcomes included extent of reduction of mitral regurgitation (MR), New York Heart Association (NYHA) functional class improvement, length of stay, and major complications. RESULTS A total of 115 high-risk patients (mean Society of Thoracic Surgeons predicted risk of mortality 9.4%±6.1%) underwent the MitraClip procedure at our institution between March 2009 and April 2014. Co-morbidities including coronary artery disease (67.8%), pulmonary disease (39.1%) and previous cardiac surgery (44.3%) were common. The device was placed successfully in all patients with a 30-day mortality of 2.6%. All patients demonstrated 3+ or 4+ MR on preoperative imaging, and 80.7% of patients had trace or 1+ MR at hospital discharge. NYHA class improved substantially, with 79% of patients exhibiting class III or IV symptoms pre-procedure and 81% reporting class I or II symptoms at one month follow-up. CONCLUSIONS The MitraClip procedure provides a safe alternative to surgical or medical management for high-risk patients with MR and suitable valve anatomy. A comprehensive heart team approach is essential, with surgeons providing critical assessment of patient suitability for surgery versus percutaneous therapy as well as performance of the valve procedure.

Enteral Access is not Required for Esophageal Cancer Patients Undergoing Neoadjuvant Therapy

BACKGROUND The nutritional status of esophageal cancer patients during neoadjuvant therapy remains a challenging problem. The objective of this study was to determine whether routine enteral feeding tube placement improved nutritional status and perioperative outcomes for patients undergoing neoadjuvant therapy for esophageal cancer. METHODS The Society of Thoracic Surgeons database was used to identify patients who underwent neoadjuvant therapy and esophagectomy at our institution between 2010 and 2014. Nutritional status before and after neoadjuvant therapy was determined through standardized nutrition consultations. Predictors of change in nutrition and adverse events were evaluated with multivariable and univariate logistic regressions. RESULTS Two hundred thirty-four esophagectomy patients were identified, and 127 (54%) received neoadjuvant therapy. Of those receiving neoadjuvant therapy, 80% (102/127) presented with dysphagia, and 48% (61/127) received enteral feeding access (EA). Multivariable regression revealed that high initial albumin level, high initial body mass index, and presence of EA were associated with nutritional stability during neoadjuvant therapy. However, 27.9% (17/61) of patients who received EA did not use their access at all or did not use it consistently during the course of preoperative treatment. The preoperative grades of malnutrition and esophagectomy outcomes were similar between groups (EA vs no EA). CONCLUSIONS EA is associated with improved nutritional status for patients undergoing neoadjuvant therapy for esophageal cancer. However, adverse events and suboptimal use are common. Esophagectomy outcomes were similar for patients with and without EA. These results support judicious patient selection for EA, expedited neoadjuvant therapy, and close collaboration with nutritionists.

Pre-Procedural 6-Min Walk Test as a Mortality Predictor in Patients Undergoing Transcatheter Mitral Valve Repair

The simple, functional 6-min walk test (6MWT) can predict exercise capacity and is widely used to assess treatment outcomes [(1)][1]. Transcatheter mitral valve repair (TMVR) (MitraClip, Abbott Vascular, Menlo Park, California) has become widely adopted for clinical use in high-risk or prohibitive-

Good at One or Good at All? Variability of Coronary and Valve Operation Outcomes Within Centers

BACKGROUND The technical expertise required for treatment of coronary and structural heart valve disease differs. Correlation between center-specific mortality rates after coronary artery bypass grafting (CABG) and valve operations has not been demonstrated. This study tested the hypothesis that risk-adjusted outcomes between coronary and valve procedures do not correlate within centers. METHODS Records of patients undergoing isolated CABG, isolated aortic valve replacement (AVR), or isolated mitral valve replacement (MVR) procedures from 2008 to 2015 in a multi-institutional Society of Thoracic Surgeons (STS) database were used to generate observed-to-expected (O/E) ratios for morbidity and death. Ratios were based on the STS predicted risks of morbidity and death and were calculated by procedure for each institution. Linear regression models evaluated the relationship between institutional performance in CABG and valve operations. RESULTS A total of 22,258 records from 18 institutions were analyzed: 17,026 CABG, 3,238 isolated AVR, and 1,994 MVR procedures. With respect to deaths, the correlation coefficients were weak; for AVR and CABG, it was 0.22 and was 0.26 for MVR and CABG. With respect to morbidity, a strong relationship was seen between the morbidity O/E ratios, with coefficients of 1.03 for AVR and 0.97 for MVR, suggesting a nearly 1:1 relationship between morbidities observed in an institutions CABG and valve operations. CONCLUSIONS Sites that perform CABG with low mortality rates may not have similarly low mortality rates with valve operations. Most striking, however, is the nearly identical O/E ratio for morbidity for CABG and valve operations at each center. These findings suggest postoperative care as a major determinant for morbidity after cardiac operation.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an uncommon condition with grave consequences. It is a clinicopathological diagnosis which can often be complex. However, delayed diagnosis and inadequate or inappropriate treatment can lead to life- and limb-threatening outcomes. This chapter will describe the syndrome of HIT (and HITT—heparin-induced thrombocytopenia with thrombosis) as it is now known, including its history, pathophysiology, diagnostic process with the current testing paradigm, and updated treatment options for HIT.

Invited Commentary on Grimm et al. MELD-XI Score Predicts Early Mortality in Patients After Heart Transplantation. Ann Thorac Surg 2015;100:1737–43

Grimm and colleagues [1] have presented a simple tool, the MELD-XI, based on creatinine and bilirubin alone, that correlates strongly with mortality after orthotopic heart transplantation. The original MELD score, which is based on these factors in addition to the International Normalized Ratio (INR), has been used in several settings to predict patient outcomes and to risk stratify those with hepatic dysfunction, regardless of the cause of liver disease [2]. Indeed, our group was the first to demonstrate that MELD correlates with outcomes following high-risk cardiac surgical procedures (tricuspid valve operation) even in patients without primary liver disease [3]. As with many patients undergoing transplantation, preoperative anticoagulant therapy is common, making the conventional MELD score artificially inaccurate. Thus, the MELD-XI introduces a highly useful alternative to assess risk in patients undergoing preoperative anticoagulant therapy. This well-written study highlights the importance of creatinine and bilirubin and prompts several key issues. 1) Baseline creatinine is well known to correlate with outcomes in cardiac operations; however, this can fluctuate greatly in patients awaiting heart transplantation depending on their medications, fluid status, and right ventricular (RV) function. This brings up the greatest limitation of this study: the timing of the calculated MELD-XI score in the United Network for Organ Sharing database is unknown. In addition, acute renal dysfunction likely has improved the prospect for recovery and overall outcome in comparison with long-standing preexisting renal disease. 2) Bilirubin can be elevated for several reasons, including primary liver disease, hepatic congestion from RV dysfunction, and hemolysis, particularly in patients with a left ventricular assist device. Inasmuch as not all of these factors are likely to have the same impact on mortality, the cause of the elevated bilirubin should be considered. Unfortunately, the cause of elevated bilirubin is unknown, and one might hypothesize that patients with primary liver diseases would have worse long-term

Anatomic Considerations for Tricuspid Valve Interventions

The anatomy of the tricuspid valve produces several specific concerns when considering transcatheter repair or replacement strategies. The annular geometry, leaflet anatomy, and important neighboring cardiac structures must each be carefully addressed when planning tricuspid valve interventions. The variety of pathologies affecting the tricuspid valve, from organic causes to functional regurgitation, provides another layer of complexity in approaching repair or replacement. Most importantly, surgical treatment of the tricuspid valve is associated with high mortality, and development of catheter-based interventions may provide a desirable alternative to open surgical approaches.

Edge-to-Edge Repair with MitraClip for Functional Mitral Regurgitation

Functional mitral regurgitation (FMR) presents a challenge in surgical therapy, with continuing debates as to the benefits of repair versus replacement. Similarly, the appropriate application of MitraClip for FMR remains under evaluation. Several studies have documented that many high-risk patients with FMR do benefit from MitraClip placement with durable reduction in MR and symptomatic relief. Data from European registries and results of the ongoing COAPT trial in US patients may better inform which FMR patients are most likely to benefit from MitraClip placement.