Abeel A. Mangi

Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts

Transplantation of adult bone marrow–derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 × 106 cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80–90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Enhanced Inhibition of Neointimal Hyperplasia by Genetically Engineered Endothelial Progenitor Cells

Background—Circulating endothelial progenitor cells (EPCs) have been reported previously. In this study, we examined the hypothesis that overexpression of vasculoprotective gene endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in EPCs enhances their ability to inhibit neointimal hyperplasia. Methods and Results—EPCs were isolated from rabbit peripheral blood, expanded in culture, and transduced with pseudotyped retroviral vectors expressing human eNOS (eNOS-EPCs), HO-1 (HO-1-EPCs), or green fluorescent protein (GFP-EPCs). Transduction efficiency of EPCs ex vivo was >90%. Four groups of rabbits (n=5 to 6 per group) were subjected to balloon angioplasty of the common carotid artery. Immediately after injury, ≈5×106 autologous eNOS-EPCs or HO-1-EPCs were transplanted into the injured vessel. Control animals received an equivalent number of GFP-EPCs or Ringer’s saline. Two weeks after transplantation, eNOS and HO-1 transgene transcripts and proteins were detected in the transduced rabbit vessels. Endothelialization was enhanced in the EPC-transplanted vessels independently of gene transfer. Neointimal thickening was significantly reduced in the GFP-EPC–treated vessels relative to the saline control. Neointima size was further reduced in vessels treated with eNOS-EPCs. Surprisingly, no additional reduction was seen in vessels treated with HO-1-EPCs relative to GFP-EPCs. Thrombosis occurred in ≈50% of the saline-treated vessels but was virtually absent in all EPC-transplanted vessels. Conclusions—We conclude that transplantation of autologous EPCs overexpressing eNOS in injured vessels enhances the vasculoprotective properties of the reconstituted endothelium, leading to inhibition of neointimal hyperplasia. This cell-based gene therapy strategy may be useful in treatment of vascular disease.

Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy

Cell-based therapies for the prevention and treatment of cardiac dysfunction offer the potential to significantly modulate cardiac function and improve outcomes in patients with cardiovascular disease. To date several clinical studies have suggested the potential efficacy of several different stem cell types; however, the benefits seen in clinical trials have been inconsistent and modest. In parallel, preclinical studies have identified key events in the process of cell-based myocardial repair, including stem cell homing, engraftment, survival, paracrine factor release, and differentiation that need to be optimized to maximize cardiac repair and function. The inconsistent and modest benefits seen in clinical trials combined with the preclinical identification of mediators responsible for key events in cell-based cardiac repair offers the potential for cell-based therapy to advance to cell-based gene therapy in an attempt to optimize these key events in the hope of maximizing clinical benefit. Below we discuss potential key events in cardiac repair and the mediators of these events that could be of potential interest for genetic enhancement of stem cell-based cardiac repair.

Gastrointestinal Complications in Patients Undergoing Heart Operation: An Analysis of 8709 Consecutive Cardiac Surgical Patients

Introduction:Gastrointestinal (GI) complications following heart operation may be life-threatening. Systematic analysis of risk factors to allow early identification of patients at risk for GI complication may lead to the development of strategies to mitigate this complication as well as to optimize management after its occurrence. Methods:Of 8709 consecutive patients undergoing heart operation during 7 years (1997–2003), 46 (0.53%) developed GI complications requiring surgical consultation. Preoperative, intraoperative, and postoperative predictors of complication and death were identified and compared with a control group. Results:Significant (P < 0.05) preoperative predictors of complication were prior cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), type II heparin-induced thrombocytopenia, atrial fibrillation, prior myocardial infarction, renal insufficiency, hypertension, and need for intra-aortic balloon counter-pulsation. The most frequent serious GI complication was mesenteric ischemia, which developed in 31 (67%) patients. Twenty-two (71%) of these patients were explored, and 14 (64%) died within 2 days of heart operation. Of the 9 patients with mesenteric ischemia who were not explored, 7 (78%) died within 3 days of heart operation. Other complications included diverticulitis (5), pancreatitis (4), peptic ulcer disease (4), and cholecystitis (2). The mortality rate in this group of other diagnoses was lower (40%), and death occurred later (32 days) after heart operation (P = 0.03 compared with mesenteric ischemia). Predictors of death from GI complication included New York Heart Association (NYHA) class III and IV heart failure, smoking, chronic obstructive pulmonary disease, history of syncope, aspartate aminotransferase (AST) >600U/L, direct bilirubin >2.4mg/dL, pH < 7.30, and the need for >2 pressors. Conclusions:The most common catastrophic GI complication after cardiac surgery is mesenteric ischemia, which is frequently fatal. This complication may be a result of atheroembolization, heparin-induced thrombocytopenia, or hypoperfusion. Techniques to reduce the occurrence of and/or preemptively diagnosis postcardiotomy mesenteric ischemia are necessary to decrease its associated mortality.

Adjuvant radiation therapy for stage II thymoma.

BACKGROUND Thymoma is difficult to study because of its indolent natural history. The criteria for administration of adjuvant radiation therapy remain controversial, and it is unclear whether patients with Masaoka stage II thymoma benefit from adjuvant radiation. The goal of this report was to determine whether or not this group benefits from radiation therapy in terms of disease-specific survival and tumor recurrence. METHODS Case records of the Massachusetts General Hospital were retrospectively reviewed from 1972 to 1999. One hundred fifty-five patients underwent resection for thymoma, of which, 49 had stage II disease. The world literature was reviewed using a Medline search (1966 to 2001), and a secondary review of referenced works was performed. RESULTS Fourteen stage II patients underwent radiation therapy. Thirty-five did not receive radiation therapy. Baseline prognostic factors between radiated and nonradiated groups were similar. All patients underwent complete resection. The addition of adjuvant radiotherapy did not significantly alter local or distant recurrence rates in stage II thymoma. Disease-specific survival at 10 years in stage II patients was 100% with radiotherapy and without radiotherapy (p = 0.87). There was one recurrence in the nonradiated group at 180 months, which was outside the usual radiation portal. CONCLUSIONS Most stage II patients do not require adjuvant radiation therapy and can be observed after complete resection.

Bridge to lung transplantation using short-term ambulatory extracorporeal membrane oxygenation

Severe respiratory failure refractory to mechanical ventilation can occur in patients awaiting lung transplantation (LTx). Use of extracorporeal membrane oxygen (ECMO) to bridge these patients to LTx is associated with considerable morbidity and mortality. Most techniques rely on femoral cannulation, thereby immobilizing patients. This in turn can lead to rapid deconditioning and predisposes patients to nosocomial pneumonia, deep venous thrombosis, and muscle wasting. This case highlights the use of upper-extremity ECMO, which was established without intubation in a critically ill transplant candidate, allowed ambulation, and ultimately served as a successful bridge to LTx.

Comparative Survival and Cost Effectiveness of Advanced Therapies for End-stage Heart Failure

Background—Treatment options for end-stage heart failure include inotrope-dependent medical therapy, orthotopic heart transplantation (OHT), left ventricular assist device (LVAD) as destination therapy or bridge to transplant. Methods and Results—We developed a state-transition model to simulate 4 treatment options and associated morbidity and mortality. Transition probabilities, costs, and utilities were estimated from published sources. Calculated outcomes included survival, quality-adjusted life-years, and incremental cost-effectiveness. Sensitivity analyses were performed on model parameters to test robustness. Average life expectancy for OHT-eligible patients is estimated at 1.1 years, with 39% surviving to 1 year. OHT with a median wait time of 5.6 months is estimated to increase life expectancy to 8.5 years, and costs <

Benign broncho-esophageal fistula in the adult

100 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Bridge to transplant-LVAD followed by OHT further is estimated to increase life expectancy to 12.3 years, for

Trends in left ventricular assist device use and outcomes among Medicare beneficiaries, 2004-2011.

226 000/quality-adjusted life-year gained versus OHT. Among OHT-ineligible patients, mean life expectancy with inotrope-dependent medical therapy is estimated at 9.4 months, with 26% surviving to 1 year. Patients who instead received destination therapy-LVAD are estimated to live 4.4 years on average from extrapolation of recent constant hazard rates beyond the first year. This strategy costs