Transcatheter aortic valve replacement 23 years after heart transplant for aortic insufficiency.

BACKGROUND: Clinicians continue to expand the availability of transcatheter aortic valve replacement (TAVR) for patients who historically would have been ineligible for surgical aortic valve replacement. Historically, reoperative aortic valve surgery after transplant was immensely complicated and high risk due to the repeat sternotomy approach, and the immunosuppression in transplant patients. As heart transplant patients continue to live longer, patients are beginning to develop novo aortic pathology of the transplanted organ. In these patients, TAVR may be a valuable rescue therapy for those with de-novo aortic valve disease. CASE PRESENTATION: Here, we present a single case of a 70-year-old man with a history of heart transplant 23 years prior complicated by severe sternal infection and subsequent removal of his sternum. Additionally, this patient had a recent history of kidney transplant due to renal cell carcinoma necessitating nephrectomy. He subsequently developed progressive symptomatic aortic insufficiency and underwent a successful TAVR to treat his new aortic disease. CONCLUSIONS: To our knowledge, this represents only the second case report of TAVR for severe aortic insufficiency and one of the first reports of TAVR in a multiple organ recipient. TAVR may represent an important rescue therapy for post-transplant valve pathologies instead of high-risk reoperative surgical aortic valve replacement.

The effect of tracheostomy on extracorporeal membrane oxygenation outcomes.

INTRODUCTION: The optimal timing for pursuing tracheostomy in patients with prolonged mechanical ventilation with either veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is a discussion of risk versus benefit. Depending on the etiology, cardiothoracic surgical patients carry some of the highest risk for respiratory failure postprocedure. Given that patients with end-stage cardiopulmonary status may be fraught with substantial comorbidities, it is critically important to manage the risk-benefit profile of performing a tracheostomy procedure on a patient requiring ECMO support. These cohorts have risk factors that may depend on each patient's inflammatory state, lung de-recruitment peri-procedure and postprocedure and bleeding requiring transfusions to name a few. We provide a descriptive analysis of ECMO patients on both VA and VV configurations who survived to hospital discharge receiving tracheostomy either during or after their ECMO course. METHODS: A retrospective single-institutional study collected all consecutive patients age 18 and above who received any form of ECMO between 2016 and 2020. Five hundred forty-five patients were screened based on having received ECMO. Patients with mixed EMCO modality were excluded due to heterogeneity of disease process. A total of 521 patients received either VV or VA ECMO. A total of 54 patients received tracheostomy and had sufficiently clean data for analysis. Tracheostomy patients were compared based on survival to discharge, tracheostomy surgical complications, ECMO duration, ECMO configuration, inotrope and vasopressor use, transfusion rates, total ventilator days, total days on intravenous sedation, and history of cardiotomy or heart transplant were assessed. Baseline characteristics of race, age, gender, and body mass index (BMI) were also collected. RESULTS: A total of 54 patients received tracheostomy. Twenty-nine of those patients received tracheostomy during the course of their ECMO, of whom 13 were on VV ECMO, 16 on VA ECMO. Another 25 patients underwent tracheostomy after successful ECMO explant; 8 of those were VV ECMO with the remaining 17 were on VA ECMO before explantation, with mean delay to tracheostomy, 10 and 19 days after explant between both modalities, respectively. A statistically significantly greater proportion of VV ECMO patients received a tracheostomy at any point versus VA ECMO patients (25.93% vs. 8.35%, p ≤ .0001). No statistically significant difference was noted in timing of tracheostomy when stratified by EMCO modality (VA 51.51% after explant vs. VV 38.10% after explant, p = .33). There was a greater frequency of minor tracheostomy complications in patients who were on ECMO at the time of their tracheostomy (p = .014) than in those who received their tracheostomy after being explanted. However, these minor complications did not contribute to a change in survival to hospital discharge (p = .58). Similarly, the small number of major complications (n = 13) did not impair survival to hospital discharge (p = .84). Finally, mean duration of ECMO was longer in those who received tracheostomy during ECMO versus after ECMO. (488.45 vs. 259.72 h, p < .01). CONCLUSIONS: Tracheostomy is known to increase patient mobility, clinical participation, and overall decrease in sedation use. Pursuing tracheostomy during ECMO is feasible, does not result in major bleeding, and is associated with only minor complications that overall do not decrease survival. While there is an increased duration of ECMO support in the tracheostomy cohort, this may be due to existing patient conditions, and may not be causal. Research is needed to further determine the external patient factors and specific timing to optimize both VV and VA ECMO courses. CLINICAL IMPLICATIONS: We hope that our analysis will pave the initial pathway for an evidence-based guideline on optimal timing of tracheostomy in ECMO patients, whether initiated during or after ECMO and taking into consideration ECMO configuration, its expected duration, and patient comorbidities.

Targeted Delivery of Doxorubicin Liposomes for Her-2+ Breast Cancer Treatment.

The adverse side effects and toxicity caused by the non-targeted delivery of doxorubicin has emphasized the demand of emerging a targeted delivery system. The goal of this study is to enhance the delivery of doxorubicin by formulating an aptamer-labeled liposomal nanoparticle delivery system that will carry and deliver doxorubicin specifically into Her-2+ breast cancer cells. Twelve liposomal batches were prepared using different saturated (HSPC and DPPC) and unsaturated (POPC and DOPC) lipids by thin film hydration. The liposomes were characterized for their particle size, zeta potential, and drug encapsulation efficiency. The particles were also assessed for in vitro toxicity and DOX delivery into the breast cancer cells. The formulations, F1 through F12, had a small particle size of less than 200 nm and a high entrapment efficiency of about 88 ± 5%. The best formulation, F5, had a particle size of 101 ± 14nm, zeta potential of + 5.63 ± 0.46 mV, and entrapment efficiency of ≈ 93%. The cytotoxicity studies show that the DOX-loaded liposomal formulations are more effective in killing cancer cells than the free DOX in both MCF-7 and SKBR-3 cells. The uptake studies show a significant increase in the uptake of the aptamer-labeled liposomes (i.e., F5) by more than 60% into Her-2+ MCF-7 and SKBR-3 breast cancer cells compare to non-aptamer-labeled nanoparticles. F5 also shows ≈ 1.79-fold increase in uptake of DOX in the Her-2+ cells compared to the Her-2- cells. This preliminary study indicates that aptamer-labeled F5 nanoparticles among several batches showed the highest uptake as well as the targeted delivery of doxorubicin into Her-2+ breast cancer cells. Thus, aptamer targeted approach results in substantial reduction in the dose of DOX and improves the therapeutic benefits by promoting the target specificity.

Aptamer-functionalized Hybrid Nanoparticles to Enhance the Delivery of Doxorubicin into Breast Cancer Cells by Silencing P-glycoprotein.

OBJECTIVE: The MDR of metastatic breast cancer cells is accompanied by the overexpression of P-gp transporter. This study has been focused to determine whether silencing the expression of P-gp by aptamer-labeled siRNA nanoparticles could enhance the delivery of doxorubicin into breast cancer cells in culture. METHODOLOGY: The nanoparticle F-31 was prepared using DOTAP, cholesterol, and PLGA, and then incorporating Mal-PEG to facilitate aptamer-binding. The nanoparticles were surface-functionalized with aptamer A6, which targets Her-2 receptors overexpressed on the surface of breast cancer cells. RESULTS: This study has shown that the uptake of Dox by Dox-resistant 4T1-R is significantly less than Dox-sensitive 4T1-S which is partly attributed to the higher expression of drug-efflux pump P-gp on the surface of the resistant cells. The targeted knockdown of P-gp has been enhanced when the particles carrying P-gp siRNA was labeled with aptamer. Concurrently, the uptake of Dox into the Dox-resistant 4T1-R breast cancer cells has increased significantly when the P-gp was silenced by P-gp siRNA-encapsulated aptamer-labeled nanoparticles. CONCLUSIONS: This preliminary study concludes that downregulating P-gp expression by targeted delivery of P-gp siRNA using aptamer-labeled lipid-based hybrid nanoparticles could effectively increase the intracellular trafficking of doxorubicin in Dox-resistant mouse breast cancer cells.