Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients.

BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.

Preoperative Vitamin K Reduces Blood Transfusions at Time of Left Ventricular Assist Device Implant.

BACKGROUND: Congestive heart failure patients have hepatic congestion and abnormal coagulation profiles, increasing perioperative bleeding at time of ventricular assist device implantation. This study examined the impact of the preoperative administration of vitamin K on perioperative blood transfusion requirements. METHODS: Retrospectively, 190 patients met inclusion criteria. Patients received no vitamin K (n = 62) or two 10-mg doses of intravenous vitamin K (n = 128) in the 24 hours before assist device implantation. Primary end points included transfusion requirements and reexploration rates for bleeding. Secondary outcomes were pump thrombosis and in-hospital mortality. RESULTS: Baseline characteristics were similar between the 2 groups, with slight differences (not statistically significant) noted in the Interagency Registry for Mechanically Assisted Circulatory Support profile and total bilirubin levels. The only significant difference noted was the year of implantation (P < .001). Blood product usage was significantly lower in the vitamin K group compared to the no vitamin K group (P < .001). Higher rates of reexploration for bleeding (29.7% vs 13.6%, P = .023) and death at hospital discharge (16.2% vs 2.8%, P = .004) were noted for the no vitamin K group compared with the vitamin K group. After adjusting for age, sex, race, body mass index, Interagency Registry for Mechanically Assisted Circulatory Support profile, total bilirubin, surgeon, and year of operation, reexploration rates and death did not achieve statistical significance. No statistically significant difference was observed in stroke and pump thrombosis rates between the 2 groups. CONCLUSIONS: Preoperative vitamin K administration may help reduce blood product use without any increased risk for strokes or pump thrombosis.

Right Heart Failure in Different Left Ventricular Assist Devices: Single-Center Experience.

Background: Right heart failure (RHF) following left ventricular assist device (LVAD) implantation increases morbidity and mortality for those who develop this complication. The purpose of this study was to assess the differences in incidence of RHF and outcomes between 2 types of continuous-flow LVADs at a single center. Methods: From January 2012 through June 2016, 184 patients were implanted with a continuous-flow LVAD (161 patients with the HeartMate II and 23 patients with the HeartWare device) either as a bridge to transplant or as destination therapy. Preoperative demographics, medical history, laboratory values, hemodynamics, and device type were analyzed to determine the variables associated with RHF and mortality. Results: Preoperative variables between the 2 groups were homogeneous. Most patients were Interagency Registry for Mechanically Assisted Circulatory Support profile 1 or 2 (92%) and New York Heart Association class IV (81%). More patients in the HeartMate II group had the indication of destination therapy (54% vs 30%), while more patients in the HeartWare group were implanted as bridge to transplant (70% vs 46%). RHF occurred in 57% of HeartWare patients compared to 16% of patients who received the HeartMate II (P=0.0001). After propensity score analysis, patients receiving the HeartWare device had increased odds for RHF (P=0.0013) and renal failure requiring dialysis (P=0.0135). The HeartMate II patient survival rate exceeded the HeartWare patient survival rate at 1 year (82.1% vs 67.2%) and at 2 years (74.6% vs 61.7%), but this difference did not achieve statistical significance (log-rank P=0.087). Conclusion: These results indicate that device type may affect RHF incidence and mortality. Studies at other centers are needed to replicate these findings.

Distal landing zone optimization before endovascular repair of aortic dissection.

BACKGROUND: The general goals of endovascular management in chronic distal thoracic aortic dissection are optimizing the true lumen, maintaining branch patency, and promoting false lumen (FL) thrombosis. Distal seal can be challenging in chronic distal thoracic aortic dissection due to the well-established secondary fenestrations and fibrotic septum. We describe our approach of distal landing zone optimization (DLZO) to enable full-diameter contact of the distal endoprosthesis. MATERIALS AND METHODS: Our experience includes 19 procedures in 16 patients (12 male, age 68 ± 8 years) between May 2014 and November 2017. A history of previous ascending repair for type A dissection was present in 8 patients. Treatment indication was enlarging aneurysm in all subjects, and 4 patients had associated chronic visceral or distal ischemia. Point septal fenestrations were expanded by serial balloon dilation and/or wire-pull approaches. Balloon molding was used to ensure complete endograft apposition and FL collapse. RESULTS: One death occurred due to aortic perforation during wire-pull fenestration in a patient with heavily calcified and angulated aorta. The remaining procedures were accomplished safely and successfully. Balloon fenestration was used in 16 procedures, alone or in combination with a limited wire pull component. Adjunct procedures for distal seal included surgeon-modified fenestrated stent graft (3), iliac branch device (3), parallel superior mesenteric artery stent-graft (1), renal artery or superior mesenteric artery stent-graft (4), iliac stent (3), and plug obliteration of FL (5). Reintervention was required in 3 patients due to delayed loss of seal after the initial procedure (3, 8, and 12 months). Two were managed by repeat DLZO and distal extension. The third had distal extension via a surgeon-modified fenestrated stent-graft component. Follow-up imaging was available in 14 patients (16.0 ± 12.5 months, range: 1-33), with stable or regressed sac diameter with complete or near-complete thrombosis of the FL in all patients. CONCLUSIONS: DLZO enabled creation of a distal seal zone in all patients. Residual retrograde filling of the FL is a marker of procedure failure, especially when seal segment length or feasible endoprosthesis oversizing are marginal. Insufficient landing segment can be circumvented with the use of a fenestrated or branched device to accomplish seal in the visceral aorta or iliac bifurcation. Adjunct FL ablation is also a valuable technique to promote FL thrombosis.

Cardiac resynchronization therapy and outcomes in patients with left ventricular assist devices: a systematic review and meta-analysis.

The impact of cardiac resynchronization therapy (CRT) on clinical outcome in patients with a continuous-flow left ventricular assist device (LVAD) is currently not well understood. We conducted a systematic literature review and meta-analysis with an intention to summarize all published clinical evidence. We searched MEDLINE and EMBASE databases through March 2018 for studies that compared the outcomes in patients with LVAD and CRT. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effects model, inverse variance method. The between-study heterogeneity was assessed using the Q statistic and I2. A total of seven studies that included 1157 (575 CRT; 582 non-CRT) patients were identified. Our meta-analysis did not demonstrate a significant difference in the risk of mortality (pooled OR = 1.21, 95% CI 0.90-1.63, P = 0.21), ventricular arrhythmia incidence (pooled OR = 1.36, 95% CI 0.99-1.86, P = 0.06), hospitalization (pooled OR = 1.36, 95% CI 0.59-3.14, P = 0.48), or implantable cardioverter defibrillator therapies (pooled OR = 1.08, 95% CI 0.51-2.30, P = 0.84) among the CRT group compared with the non-CRT group. There was high heterogeneity with an I2 of 75% for ICD therapies. Among LVAD patients, CRT combined did not significantly affect mortality, re-hospitalization, ventricular arrhythmia incidence, and ICD therapies.

Left Ventricular Assist Device Inflow Cannula Position May Contribute to the Development of HeartMate II Left Ventricular Assist Device Pump Thrombosis.

BACKGROUND: Pump thrombosis (PT) is a dreaded complication after left ventricular assist device (LVAD) implantation. Problems with inflow cannula (IC) position may precipitate thrombus development. We sought to determine if IC position contributes to the development of PT. METHODS: We conducted a retrospective review of 76 HeartMate II LVAD implants. The angle of the IC (AIC) to the horizontal plane was measured on chest x-rays. Patients who developed PT (PT group) were compared to the remaining patients (control group). RESULTS: The mean age at implantation was 56 ± 14 years, and 82% of the patients were male. Ten patients (13%) developed PT. Six (60%) required device exchange, and 4 (40%) were managed with anticoagulation and/or thrombolysis. The median AIC for all patients at implantation was 59° (range, 38°-98°; 25th-75th interquartile range, 50°-75°). In the PT group, the median AIC was larger at the time of PT diagnosis compared to implantation (70° vs 60°, P = 0.005). In the control group, the median AIC was also larger at follow-up compared to implantation (61° vs 58°, P < 0.001) although to a lesser degree than in the PT group. No difference was seen in the median AIC between the PT group and the control group at implantation (60° vs 58°, respectively; P = 0.668) or at follow-up (70° vs 61°, respectively; P = 0.309). However, the median AIC at follow-up in the PT group was significantly larger than the median AIC at implantation in the control group (70° vs 58°, respectively; P = 0.014). CONCLUSION: The HeartMate II LVAD IC position contributes to the development of PT. Regular monitoring of cannula position may help identify patients at risk for this problem.

Clinical experience with temporary right ventricular mechanical circulatory support.

OBJECTIVES: This study sought to determine if indication for support affects the outcomes after temporary right ventricular mechanical circulatory support after postcardiotomy cardiogenic shock, cardiac transplant, or left ventricular assist device placement. METHODS: A retrospective review was performed on 80 patients receiving a right ventricular assist device. Data were collected from a prospectively maintained database. Kaplan-Meier survival analysis was performed to compare survival between groups. Multivariate regression analysis was performed to identify risk factors for failure to wean from support. RESULTS: The indication for support was postcardiotomy cardiogenic shock in 13 patients (16%), cardiac transplant in 25 patients (31%), and left ventricular assist device in 42 patients (53%). Median support time was 6 days. Device was successfully weaned in 6 postcardiotomy cardiogenic shock cases (46%), 21 cardiac transplant cases (84%), and 35 left ventricular assist device cases (83%). Survival was worse for patients with postcardiotomy cardiogenic shock compared with patients with a left ventricular assist device. Survival up to 3 months was better for patients who received immediate (n = 43) versus delayed (n = 37) support (79% vs 46%, P = .003). Weaning and survival remained static across implant era. Risk factor analysis identified postcardiotomy cardiogenic shock indication (odds ratio, 0.161; P = .007; confidence interval, 0.043-0.600) as an independent negative predictor of weaning from mechanical support. CONCLUSIONS: Temporary right ventricular mechanical support remains an effective treatment strategy after left ventricular assist device placement with immediate support resulting in superior short-term survival. Caution should be applied in postcardiotomy cardiogenic shock when weaning and survival are poor. Overall survival outcomes have remained relatively static over time.

Extracorporeal Support During Bilateral Sequential Lung Transplantation in Patients With Pulmonary Hypertension: Risk Factors and Outcomes.

OBJECTIVE: To identify preoperative predictors of extracorporeal support in patients with pulmonary hypertension (PH) undergoing bilateral sequential lung transplantation (LTx), and to examine outcomes associated with the use of extracorporeal support. DESIGN: Retrospective, observational study. SETTING: Single organ transplantation and tertiary care university medical center. PARTICIPANTS: Adults with PH (preoperative mean pulmonary artery pressure (mPAP)≥25 mmHg) who underwent primary bilateral sequential LTx during 2007 to 2013. MEASUREMENTS AND MAIN RESULTS: Of 262 patients with PH undergoing LTx, extracorporeal support was initiated intraoperatively in 149 (57%). Preoperative severe right ventricle (RV) dysfunction and moderate or severe tricuspid regurgitation (TR) were associated with extracorporeal support. In the remaining 208 patients without those factors, increasing preoperative oxygen requirement (odds ratio [OR] 1.30 per 1 L/min, 95% confidence intervals [CI] 1.11-1.52, p = 0.001), presence of RV dilation (OR 2.77, 95% CI 1.28-6.02, p = 0.010), and mPAP (OR 1.33 per 5-mmHg increase in mPAP, 95% CI 1.04-1.70, p = 0.021) were associated independently with extracorporeal support in the multivariable model. Analysis of 49 propensity-matched pairs showed longer intensive care unit (5 v 14 days, p = 0.006) and hospital stays (27 v 39 days, p = 0.016) and increased need for tracheostomy (16% v 41%, p = 0.017) in patients exposed to extracorporeal support but no differences in 30-day mortality, stroke, myocardial infarction, or dialysis. CONCLUSIONS: Severity of RV dysfunction, TR, RV dilatation, increasing oxygen requirement, and increasing mPAP showed significant associations with the need for extracorporeal support during LTX in patients with PH. Extracorporeal support was associated with increased length of stay and tracheostomy but not with mortality or other complications. © 2016 Elsevier Inc. All rights reserved.

Using the Minimally Invasive Impella 5.0 via the Right Subclavian Artery Cutdown for Acute on Chronic Decompensated Heart Failure as a Bridge to Decision.

BACKGROUND: Outcomes of traditional mechanical support paradigms (extracorporeal membrane oxygenation, intraaortic balloon pump [IABP], and permanent left ventricular assist device [LVAD]) in acute decompensated heart failure have generally been suboptimal. Novel approaches, such as minimally invasive LVAD therapy (Impella 5.0 device), promise less invasive but equivalent hemodynamic support. However, it is yet unknown whether the outcomes with such devices support widespread acceptance of this new technology. We recently started utilizing the right subclavian artery (RSA) for Impella 5.0 implantation and report our early experience and outcomes with this novel approach. METHODS: A single-center retrospective review was performed of 24 patients with acute on chronic decompensated heart failure who received the Impella 5.0 via the RSA from June 2011 to May 2014. The device was implanted via a cutdown through an 8-mm vascular graft sewn to the RSA. The device was positioned with fluoroscopy and transesophageal echocardiography. RESULTS: The mean age of the patients was 51.29 years, and 75% were male. At implantation, all patients were mechanically ventilated on at least 2 inotropes with persistent cardiogenic shock, and 17 (70.8%) were on IABP support. Postimplantation, 21 (87.5%) tolerated extubation, and all 17 of the patients with IABPs tolerated discontinuation of IABP support. The reduction in the Model for End-Stage Liver Disease score preimplantation vs postimplantation was statistically significant (21.17 vs 14.88, P=0.0014), suggesting improvement in end organ function. A significant decrease was also seen in creatinine levels before and after implantation (2.17 mg/dL vs 1.50 mg/dL, P=0.0043). The endpoint of support included recovery in 6 patients (25.0%), permanent LVAD in 9 (37.5%), and heart transplantation in 2 (8.3%). Death occurred in 7 patients (29.2%) as a result of multisystem organ failure, infection, or patient withdrawal of care. CONCLUSION: Minimally invasive LVAD therapy using the Impella 5.0 via the RSA cutdown is an attractive option in acute on chronic decompensated heart failure. Improvement in end organ function allows for transition to recovery or to advanced surgical therapies such as permanent LVAD and heart transplantation. Significant advantages to this approach include improved left ventricular unloading, lower anticoagulation need, and the potential for ambulation and physical therapy.