Bio

Clinical Focus


  • Aortic Diseases
  • Thoracic Surgery
  • Cardiothoracic Surgery

Academic Appointments


Honors & Awards


  • Donald Morton Research Award, Department of Surgery - UCLA School of Medicine (2003)
  • Ronald K. Tompkins Golden Apple Teaching Award, UCLA School of Medicine (2003)
  • Golden Scalpel Award for Teaching Excellence, Division of General Surgery - UCLA School of Medicine (2003)
  • Caves Scientific Award, International Society for Heart and Lung Transplantation - Osaka, Japan (2000)
  • Cum Laude Graduate, Boston University School of Medicine (1995)
  • Alpha Omega Alpha, Boston University School of Medicine (1994)

Professional Education


  • Board Certification: Thoracic Surgery, American Board of Thoracic Surgery (2007)
  • Fellowship:Stanford University Medical Center (2006) CA
  • Board Certification: General Surgery, American Board of Surgery (2004)
  • Residency:UCLA School of Medicine (2003) CA
  • Medical Education:Boston University Medical Center (1995) MA
  • PhD, University of California, Los Angeles, Microbiology and Immunology (2001)
  • MD, Boston University School of Medicine, Medicine - Cum Laude (1995)
  • BS, University of California, Los Angeles, Kinesiology (1990)

Research & Scholarship

Current Research and Scholarly Interests


Molecular and genetic mechanisms of aortic aneurysm/dissection development. Molecular mechanisms of aneurysm formation in Marfan Syndrome. Clinical research interests include thoracic aortic diseases (aneurysms, dissections).

Clinical Trials


  • To Evaluate the Safety and Efficacy for GORE TAG Thoracic Endoprosthesis in the Treatment of Thoracic Aortic Disease Not Recruiting

    Study Type: Interventional Study Design: Treatment, Open Label, Uncontrolled, Single Group Assignment, Safety and Efficacy study Official Title: A Clinical Study of the TAG Thoracic Endoprosthesis in the Treatment of Thoracic Aortic Diseases for Non-Surgical Candidates under the Physician Sponsored IDE. PURPOSE OF RESEARCH: You are invited to participate in a research study for treatment of aneurysms of the descending thoracic aorta. The investigational device, called the TAG Thoracic Endoprosthesis (device) has been designed to simplify treatment of aneurysms of the descending thoracic aorta. The other pathologies treated can include pseudoaneurysms, acute and chronic dissections, penetrating ulcers, mycotic aneurysms, ruptures, fistulae, and transections.The device is made from a graft (an artificial vessel) which is surrounded on the outside by a metal mesh-like form. The device is in the shape of a tube. The device reinforces the weakened part of the aorta from the inside. Blood flows through the device to the arteries that go to your abdomen and legs. The device is folded tightly onto a catheter (a flexible, hollow tube) that is put into the aorta through an artery in your leg. Unless there is a problem, you would not need to have your chest opened.

    Stanford is currently not accepting patients for this trial. For more information, please contact Archana Verma, (650) 736 - 0959.

    View full details

Teaching

2013-14 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • miR-29b Participates in Early Aneurysm Development in Marfan Syndrome CIRCULATION RESEARCH Merk, D. R., Chin, J. T., Dake, B. A., Maegdefessel, L., Miller, M. O., Kimura, N., Tsao, P. S., Iosef, C., Berry, G. J., Mohr, F. W., Spin, J. M., Alvira, C. M., Robbins, R. C., Fischbein, M. P. 2012; 110 (2): 312-?

    Abstract

    Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-? (TGF-?) signaling. Although TGF-? blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-? causes aneurysms remain ill-defined.We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor ?B, a repressor of miR-29b, and a factor suppressed by TGF-?, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor ?B inhibitor increased miR-29b levels, whereas TGF-? blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

    View details for DOI 10.1161/CIRCRESAHA.111.253740

    View details for Web of Science ID 000299432600015

    View details for PubMedID 22116819

  • Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion Sheikh, A. Y., Hill, C. C., Goodnough, L. T., Leung, L. L., Fischbein, M. P. 2014; 54 (2): 300-305

    Abstract

    BACKGROUND: Glanzmann thrombasthenia (GT) is an autosomal recessive disorder in which the platelet (PLT) glycoprotein IIb/IIIa complex is either deficient or dysfunctional. In its most severe form, GT may result in spontaneous bleeding, although most cases are first detected in the setting of an invasive procedure. CASE REPORT: A 59-year-old male with Type I GT and a history of transfusion reactions to PLT infusions developed severe aortic stenosis secondary to bicuspid valve disease. He successfully underwent open aortic valve replacement with cardiopulmonary bypass without perioperative bleeding complications. RESULTS: A multidisciplinary team (anesthesia, hematology, cardiac surgery, and transfusion medicine) was established to optimize perioperative hematologic management. Bleeding risk was assessed given the patient's prior history and a dosing timeline for administration of blood products and recombinant clotting factors was established. Successful management was achieved during the operation by prophylactic administration of HLA-matched PLTs and Factor VIIa. Prophylactic PLT administration was continued through the immediate postoperative period and no bleeding complications occurred. Thromboelastograms (TEGs) were used in conjunction with traditional hematologic laboratory analysis to optimize clinical management. CONCLUSION: Patients with GT requiring cardiac surgical procedures are at high risk for perioperative bleeding complications. This case report illustrates the importance of multidisciplinary planning, TEG analysis, and the judicious use of recombinant factors to minimize operative bleeding risk.

    View details for DOI 10.1111/trf.12275

    View details for PubMedID 23710629

  • A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. journal of experimental medicine Khatri, P., Roedder, S., Kimura, N., De Vusser, K., Morgan, A. A., Gong, Y., Fischbein, M. P., Robbins, R. C., Naesens, M., Butte, A. J., Sarwal, M. M. 2013; 210 (11): 2205-2221

    Abstract

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

    View details for DOI 10.1084/jem.20122709

    View details for PubMedID 24127489

  • Tirone David valve-sparing aortic root replacement and cusp repair for bicuspid aortic valve disease JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kari, F. A., Liang, D. H., Kvitting, J. E., Stephens, E. H., Mitchell, R. S., Fischbein, M. P., Miller, D. C. 2013; 145 (3): S35-?

    Abstract

    The durability of valve-sparing aortic root replacement with or without cusp repair in patients with bicuspid aortic valve (BAV) disease is questioned. We analyzed the results of 75 patients with a BAV undergoing Tirone David reimplantation valve-sparing aortic root replacement.Average age was 45 ± 10 years; 80% were male; 31% had 2+ or greater aortic regurgitation (AR); annular diameter averaged 28 ± 3 mm; 32% had a Sievers' type 0 BAV, and 66% underwent concomitant cusp repair (usually cusp free margin shortening) to correct prolapse. Early (6 ± 3 days) and late (2.9 ± 1.7, 1-10 years) postoperative echocardiographic results were compared (cumulative echocardiographic follow-up, 190 patient-years; median late interval, 2 years [interquartile range, 0.68, 4.2]). Seven patients remained at risk beyond 6 years. Clinical outcome and valve function were analyzed using log-rank calculations.Actuarial survival was 99% ± 2%; freedom from reoperation was 90% ± 5%, infection 98% ± 2%, and stroke 100% at 6 years. After initial improvement in degree of AR (P < .001), minor subclinical progression of AR was observed (P > .5); however, freedom from AR of more than 2+ was 100%. Cusp free margin shortening was not associated with valve deterioration, but commissural suspensory polytetrafluoroethylene neochord creation (n = 4) portended a higher probability of recurrent AR (P = .025).After David procedure and cusp repair in patients with a BAV, midterm clinical and valve function outcomes were favorable out to 6 years. More follow-up is required to determine long-term valve durability and the hazard of other clinically important late adverse events, including eventual reoperation, to beyond 10 years.

    View details for DOI 10.1016/j.jtcvs.2012.11.043

    View details for Web of Science ID 000314884000009

    View details for PubMedID 23260433

  • David valve-sparing aortic root replacement: Equivalent mid-term outcome for different valve types with or without connective tissue disorder JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kvitting, J. E., Kari, F. A., Fischbein, M. P., Liang, D. H., Beraud, A., Stephens, E. H., Mitchell, R. S., Miller, D. C. 2013; 145 (1): 117-?

    Abstract

    Although implicitly accepted by many that the durability of valve-sparing aortic root replacement in patients with bicuspid aortic valve disease and connective tissue disorders will be inferior, this hypothesis has not been rigorously investigated.From 1993 to 2009, 233 patients (27% bicuspid aortic valve, 40% Marfan syndrome) underwent Tirone David valve-sparing aortic root replacement. Follow-up averaged 4.7 ± 3.3 years (1102 patient-years). Freedom from adverse outcomes was determined using log-rank calculations.Survival at 5 and 10 years was 98.7% ± 0.7% and 93.5% ± 5.1%, respectively. Freedom from reoperation (all causes) on the aortic root was 92.2% ± 3.6% at 10 years; 3 reoperations were aortic valve replacement owing to structural valve deterioration. Freedom from structural valve deterioration at 10 years was 96.1% ± 2.1%. No significant differences were found in survival (P = .805, P = .793, respectively), reoperation (P = .179, P = .973, respectively), structural valve deterioration (P = .639, P = .982, respectively), or any other functional or clinical endpoints when patients were stratified by valve type (tricuspid aortic valve vs bicuspid aortic valve) or associated connective tissue disorder. At the latest echocardiographic follow-up (95% complete), 202 patients (94.8%) had none or trace aortic regurgitation, 10 (4.7%) mild, 0 had moderate to severe, and 1 (0.5%) had severe aortic regurgitation. Freedom from greater than 2+ aortic regurgitation at 10 years was 95.3% ± 2.5%. Six patients sustained acute type B aortic dissection (freedom at 10 years, 90.4% ± 5.0%).Tirone David reimplantation valve-sparing aortic root replacement in carefully selected young patients was associated with excellent clinical and echocardiographic outcome in patients with either a tricuspid aortic valve or bicuspid aortic valve. No demonstrable adverse influence was found for Marfan syndrome or connective tissue disorder on durability, clinical outcome, or echocardiographic results.

    View details for DOI 10.1016/j.jtcvs.2012.09.013

    View details for Web of Science ID 000312386300027

    View details for PubMedID 23083792

  • Bicuspid aortic valve configuration and aortopathy pattern might represent different pathophysiologic substrates JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Kari, F. A., Fazel, S. S., Mitchell, R. S., Fischbein, M. P., Miller, D. C. 2012; 144 (2): 516-517

    View details for DOI 10.1016/j.jtcvs.2012.05.035

    View details for Web of Science ID 000306482400046

    View details for PubMedID 22698560

  • Potential Role of gamma delta T Cell-Derived IL-17 in Acute Cardiac Allograft Rejection ANNALS OF THORACIC SURGERY Kimura, N., Nakae, S., Itoh, S., Merk, D. R., Wang, X., Gong, Y., Okamura, H., Chang, P. A., Adachi, H., Robbins, R. C., Fischbein, M. P. 2012; 94 (2): 542-548

    Abstract

    Although ?? T cells are known to participate in the development of acute cardiac allograft rejection, the role of ?? T cells remains poorly understood. We hypothesized that ?? T cells contribute to acute allograft rejection thru interleukin (IL)-17 production.Donor hearts from FVB mice (H-2q) were heterotopically transplanted into C57BL/6-wild type (WT) and ?? T cell-deficient (TCR?-/-) recipient mice (H-2b). Overall graft survival was monitored. Graft infiltrating cell profile, including ?? T cell subtype, cytokine expression, and myeloperoxidase activity were measured by flow cytometry, TaqMan (Applied Biosystems, Carlsbad, CA) polymerase chain reaction, and myeloperoxidase assay, respectively, on postoperative days 3 and 6.Graft survival was prolonged in TCR?-/- recipients compared with WT controls. Graft infiltrating cells, including CD45+, CD4+, CD8+, and Gr1+ cells were significantly decreased in TCR?-/- recipients compared with WT. Donor hearts transplanted into TCR?-/- recipients had reduced IL-17 and IL-6 messenger RNA expression. Corroborating the gene expression, intracellular cytokine staining showed decreased IL-17 producing cells in TCR?-/- recipients. Finally, V?1+ and V?4+ T cells did not produce IL-17, although both represent 20% to 30% total graft infiltrating ?? T cells.The ?? T cells promote acute cardiac allograft rejection, presumably by producing IL-17. The ?? T cell depletion may prove beneficial in prolonging allograft survival by suppressing IL-17 production.

    View details for DOI 10.1016/j.athoracsur.2012.03.049

    View details for Web of Science ID 000306700100040

    View details for PubMedID 22560321

  • Two-Year Outcomes after Transcatheter or Surgical Aortic-Valve Replacement NEW ENGLAND JOURNAL OF MEDICINE Kodali, S. K., Williams, M. R., Smith, C. R., Svensson, L. G., Webb, J. G., Makkar, R. R., Fontana, G. P., Dewey, T. M., Thourani, V. H., Pichard, A. D., Fischbein, M., Szeto, W. Y., Lim, S., Greason, K. L., Teirstein, P. S., Malaisrie, S. C., Douglas, P. S., Hahn, R. T., Whisenant, B., Zajarias, A., Wang, D., Akin, J. J., Anderson, W. N., Leon, M. B. 2012; 366 (18): 1686-1695

    Abstract

    The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits.At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation.The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001).A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).

    View details for Web of Science ID 000303434300008

    View details for PubMedID 22443479

  • Molecular Imaging of Bone Marrow Mononuclear Cell Survival and Homing in Murine Peripheral Artery Disease JACC-CARDIOVASCULAR IMAGING van der Bogt, K. E., Hellingman, A. A., Lijkwan, M. A., Bos, E., de Vries, M. R., van Rappard, J. R., Fischbein, M. P., Quax, P. H., Robbins, R. C., Hamming, J. F., Wu, J. C. 2012; 5 (1): 46-55

    Abstract

    This study aims to provide insight into cellular kinetics using molecular imaging after different transplantation methods of bone marrow-derived mononuclear cells (MNCs) in a mouse model of peripheral artery disease (PAD).MNC therapy is a promising treatment for PAD. Although clinical translation has already been established, there is a lack of knowledge about cell behavior after transplantation and about the mechanism whereby MNC therapy might ameliorate complaints of PAD.MNCs were isolated from F6 transgenic mice (FVB background) that express firefly luciferase (Fluc) and green fluorescence protein (GFP). Male FVB and C57Bl6 mice (n = 50) underwent femoral artery ligation and were randomized into 4 groups receiving the following: 1) single intramuscular (IM) injection of 2 × 10(6) MNCs; 2) 4 weekly IM injections of 5 × 10(5) MNCs; 3) 2 × 10(6) MNCs intravenously; and 4) phosphate-buffered saline as control. Cells were characterized by flow cytometry and in vitro bioluminescence imaging (BLI). Cell survival, proliferation, and migration were monitored by in vivo BLI, which was validated by ex vivo BLI, post-mortem immunohistochemistry, and flow cytometry. Paw perfusion and neovascularization was measured with laser Doppler perfusion imaging (LDPI) and histology, respectively.In vivo BLI revealed near-complete donor cell death 4 weeks after IM transplantation. After intravenous transplantation, BLI revealed that cells migrated to the injured area in the limb, as well as to the liver, spleen, and bone marrow. Ex vivo BLI showed presence of MNCs in the scar tissue and adductor muscle. However, no significant effects on neovascularization were observed, as monitored by LDPI and histology.This is one of the first studies to assess kinetics of transplanted MNCs in PAD using in vivo molecular imaging. MNC survival is short-lived, MNCs do not preferentially home to injured areas, and MNCs do not significantly stimulate perfusion in this particular model.

    View details for DOI 10.1016/j.jcmg.2011.07.011

    View details for Web of Science ID 000299392300007

    View details for PubMedID 22239892

  • In Vivo Functional and Transcriptional Profiling of Bone Marrow Stem Cells After Transplantation Into Ischemic Myocardium ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Sheikh, A. Y., Huber, B. C., Narsinh, K. H., Spin, J. M., van der Bogt, K., de Almeida, P. E., Ransohoff, K. J., Kraft, D. L., Fajardo, G., Ardigo, D., Ransohoff, J., Bernstein, D., Fischbein, M. P., Robbins, R. C., Wu, J. C. 2012; 32 (1): 92-102

    Abstract

    Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model.We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis.Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.

    View details for DOI 10.1161/ATVBAHA.111.238618

    View details for Web of Science ID 000298288700014

    View details for PubMedID 22034515

  • Interleukin-16 deficiency suppresses the development of chronic rejection in murine cardiac transplantation model JOURNAL OF HEART AND LUNG TRANSPLANTATION Kimura, N., Itoh, S., Nakae, S., Axtell, R. C., Velotta, J. B., Bos, E. J., Merk, D. R., Gong, Y., Okamura, H., Nagamine, C. M., Adachi, H., Kornfeld, H., Robbins, R. C., Fischbein, M. P. 2011; 30 (12): 1409-1417

    Abstract

    IL-16 promotes the recruitment of various cells expressing CD4, a receptor for IL-16. The precise role of IL-16 in transplant rejection remains unknown; therefore, the present study investigated the contribution of IL-16 to the development of chronic rejection in heart transplants.C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into (1) IL-16-deficient (IL-16(-/-)) C57BL/6J or (b) wild type (WT) control recipients (MHC class II mismatch). Grafts were harvested at 52 days, parenchymal rejection was assessed by the ISHLT grading system, and CAV was examined morphometrically. Graft infiltrating cells were detected 10 and 52 days after transplantation. Intragraft cytokine and chemokine profiles were assessed. To confirm the role of IL-16 in CAV development, C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into C57BL/6J WT recipients treated with (1) anti-IL-16-neutralization monoclonal antibody or (b) control immunoglobulin G. Grafts were harvested at 52 days, and CAV was quantified morphometrically. Graft-infiltrating cells were examined histologically.Parenchymal rejection and CAV was significantly attenuated in donor hearts transplanted into IL-16(-/-) recipient mice compared with WT controls. Donor hearts transplanted into IL-16(-/-) recipients had a significant reduction in coronary artery luminal occlusion, intima-to-media ratio, and percentage of diseased vessels. CAV was associated with decreased donor organ inflammation, as well as donor organ cytokine (IL-1? and IL-6) and chemokine (MCP-1 and KC) protein expression. Intimal proliferation and inflammatory cell infiltration were significantly reduced in hearts transplanted into recipients treated with an IL-16-neutralization antibody.IL-16-deficiency reduced graft inflammatory cell recruitment, and allograft inflammatory cytokine and chemokine production. Therefore, IL-16 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

    View details for DOI 10.1016/j.healun.2011.08.017

    View details for Web of Science ID 000297385400016

    View details for PubMedID 22055099

  • A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection. Yale journal of biology and medicine Chin, J. T., Troke, J. J., Kimura, N., Itoh, S., Wang, X., Palmer, O. P., Robbins, R. C., Fischbein, M. P. 2011; 84 (4): 423-432

    Abstract

    The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.

    View details for PubMedID 22180679

  • Prevention of transplant coronary artery disease by prenylation inhibitors JOURNAL OF HEART AND LUNG TRANSPLANTATION Stein, W., Schrepfer, S., Itoh, S., Kimura, N., Velotta, J., Palmer, O., Bartos, J., Wang, X., Robbins, R. C., Fischbein, M. P. 2011; 30 (7): 761-769

    Abstract

    In this study we systematically dissect the prenylation pathway to better define the mechanism behind statin inhibition in chronic allograft rejection in heart transplants, or transplant coronary artery disease (TCAD).Utilizing a murine heterotopic heart transplant model, animals received daily treatments of either statin or selective isoprenoid blockade inhibitors to block the four major downstream branches of the mevalonate pathway. TCAD was assessed by morphometric analysis at Day 52. Graft-infiltrating cells, cytokine production, smooth muscle cell proliferation and migration and endothelial cell MHC II expression were detected on Day 7.Atorvastatin and two prenylation inhibitors, NE-10790 and manumycin A, significantly reduced TCAD lesions compared with untreated animals. Perillyl alcohol treatment resulted in a trend toward decreased luminal narrowing. Finally, zaragozic acid (cholesterol blockade only) did not alter TCAD severity. Statins and prenylation inhibitors reduced inflammatory cell allograft recruitment, but did not always correlate with TCAD reduction. Cytokine production was decreased in recipient spleens in all treatment groups. Both in vitro and in vivo IFN-?-stimulated MHC II expression was decreased in a dose-dependent manner in the atorvastatin, perillyl alcohol and NE-10790 groups. In vitro smooth muscle cell proliferation was decreased in all treatment groups. Finally, in vitro smooth muscle cell migration was decreased in the atorvastatin, NE-10790 and manumycin A groups only.FPT and GGPT-2 (inhibition) are the key enzymes in the HGM-CoA reductase pathway and most influential in TCAD prevention. TCAD reduction is most closely related to smooth muscle cell migration, but not its anti-inflammatory properties.

    View details for DOI 10.1016/j.healun.2011.01.720

    View details for Web of Science ID 000291898800004

    View details for PubMedID 21458297

  • alpha B-Crystallin Improves Murine Cardiac Function and Attenuates Apoptosis in Human Endothelial Cells Exposed to Ischemia-Reperfusion ANNALS OF THORACIC SURGERY Velotta, J. B., Kimura, N., Chang, S. H., Chung, J., Itoh, S., Rothbard, J., Yang, P. C., Steinman, L., Robbins, R. C., Fischbein, M. P. 2011; 91 (6): 1907-1913

    Abstract

    This study investigates the protective effect of exogenous ?B-crystallin (CryAB) on myocardial function after ischemia-reperfusion injury.Mice underwent temporary left anterior descending artery occlusion for 30 minutes. Either CryAB (50 ?g) or phosphate-buffered saline (100 ?L [n=6, each group]) were injected in the intramyocardial medial and lateral perinfarct zone 15 minutes before reperfusion. Intraperitoneal injections were administered every other day. Left ventricular ejection fraction was evaluated on postoperative day 40 with magnetic resonance imaging. To investigate the effect of CryAB on apoptosis after hypoxia/reoxygenation in vitro, murine atrial cardiomyocytes (HL-1 cells) or human microvascular endothelial cells (HMEC-1) were incubated with either 50 ?g CryAB (500 ?g /10 mL) or phosphate-buffered saline in a hypoxia chamber for 6, 12, and 24 hours, followed by 30 minutes of reoxygenation at room air. Apoptosis was then assessed by western blot (Bcl-2, free bax, cleaved caspases-3, 9, PARP) and enzyme-linked immunosorbent assay analyses (cytoplasmic histone-associated DNA fragments and caspase-3 activity).On postoperative day 40, CryAB-treated mice had a 1.8-fold increase in left ventricular ejection fraction versus control mice (27%±6% versus 15%±4% SD, p<0.005). In vitro, (1) the HL-1 cells showed no significant difference in apoptotic protein expression, cytoplasmic histone-associated DNA fragments, or caspase-3 activity; (2) the HMEC-1 cells had increased but not significant apoptotic protein expression with, however, a significant decrease in cytoplasmic histone-associated DNA fragments (1.5-fold, p<0.01) and caspase-3 activity (2.7-fold, p<0.005).Exogenous CryAB administration significantly improves cardiac function after ischemia-reperfusion injury, in vivo. The protective anti-apoptotic affects of CryAB may target the endothelial cell.

    View details for DOI 10.1016/j.athoracsur.2011.02.072

    View details for Web of Science ID 000291019400043

    View details for PubMedID 21619989

  • "Peninsula- Style" Transverse Aortic Arch Replacement in Patients With Bicuspid Aortic Valve ANNALS OF THORACIC SURGERY Itoh, A., Fischbein, M., Arata, K., Miller, D. C. 2010; 90 (4): 1369-1371

    Abstract

    Although the optimal surgical treatment of the dilated aortic arch is controversial in patients with a bicuspid aortic valve, such exists in more than 70% of bicuspid aortic valve patients. Aortic wall histologic abnormalities are present from the aortic root to the distal arch regardless of aortic size. We describe a simple "peninsula-style" technique of transverse arch replacement used in conjunction with valve-sparing aortic root replacement for patients with a bicuspid aortic valve. This provides resection of the entire dilated thoracic aorta, preserving the arch branches in continuity with the proximal descending aorta.

    View details for DOI 10.1016/j.athoracsur.2009.11.029

    View details for Web of Science ID 000282145000067

    View details for PubMedID 20868855

  • The role of recipient mast cells in acute and chronic cardiac allograft rejection in C57BL/6-KitW-sh/W-sh mice JOURNAL OF HEART AND LUNG TRANSPLANTATION Itoh, S., Nakae, S., Velotta, J. B., Kosuge, H., Connolly, A., Tsai, M., Adachi, H., Galli, S. J., Robbins, R. C., Fischbein, M. P. 2010; 29 (4): 401-409

    Abstract

    Mast cells are hypothesized to promote rejection and adverse remodeling in cardiac allografts. In contrast, it has been reported that mast cells may enhance cardiac allograft survival in rats. We used C57BL/6-Kit(W-sh/W-sh) mast cell-deficient and corresponding wild-type mice to investigate possible contributions of recipient mast cells to acute or chronic cardiac allograft rejection.FVB (H-2(q); acute rejection), or C-H-2(bm12)KhEg (H-2(bm12); chronic rejection) donor hearts were heterotopically transplanted into C57BL/6-Kit(W-sh/W-sh) (H-2(b)) or C57BL/6-Kit(+/+) (H-2(b)) mice. The degree of acute rejection was assessed at 5 days and chronic rejection, at 52 days.In the acute rejection model, donor heart vascular cell adhesion molecule-1 (VCAM-1) expression was significantly lower in C57BL/6-Kit(W-sh/W-sh) than in wild-type recipients; however, acute rejection scores, graft survival, inflammatory cells, or cytokine expression did not differ significantly. In the chronic rejection model, the number of mast cells/mm(2) of allograft tissue was significantly increased 52 days after transplantation in allografts transplanted into C57BL/6-Kit(+/+) but not C57BL/6-Kit(W-sh/W-sh) mice; however, no substantial differences were noted in graft coronary artery disease, graft inflammatory cells, or levels of graft tissue expression of cytokines or adhesion molecules.Cardiac allografts undergoing chronic rejection in wild-type C57BL/6-Kit(+/+) mice exhibit increased numbers of mast cells, but acute or chronic cardiac allograft rejection can develop in C57BL/6-Kit(W-sh/W-sh) mice even though these recipients virtually lack mast cells. These findings indicate that recipient mast cells are not required for acute or chronic cardiac allograft rejection in the models examined.

    View details for DOI 10.1016/j.healun.2009.08.019

    View details for Web of Science ID 000276915100003

    View details for PubMedID 19818646

  • IL-17 Contributes to the Development of Chronic Rejection in a Murine Heart Transplant Model JOURNAL OF CLINICAL IMMUNOLOGY Itoh, S., Nakae, S., Axtell, R. C., Velotta, J. B., Kimura, N., Kajiwara, N., Iwakura, Y., Saito, H., Adachi, H., Steinman, L., Robbins, R. C., Fischbein, M. P. 2010; 30 (2): 235-240

    Abstract

    Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection.Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (gammadelta) T cells appear to be the predominant source of IL-17 production.Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

    View details for DOI 10.1007/s10875-009-9366-9

    View details for Web of Science ID 000275798900007

    View details for PubMedID 20130970

  • Long-Term Durability of Open Thoracic and Thoracoabdominal Aneurysm Repair SEMINARS IN VASCULAR SURGERY Fischbein, M. P., Miller, D. C. 2009; 22 (2): 74-80

    Abstract

    Results of open surgical repair of descending and thoracoabdominal aortic aneurysms have improved dramatically over the years. Nevertheless, while adjunctive protective strategies, such as spinal cord drainage and distal aortic perfusion, have improved outcomes, clinical challenges remain. In the current era, thoracic aortic surgeons must possess both open and endovascular stent-graft capabilities to offer these complex patients the most optimal and individualized treatment approach. Herein we summarize the contemporary outcomes of open surgical repair of patients with either descending thoracic or thoracoabdominal aortic aneurysms, focusing on the risk of complications and means for preventing their occurrence.

    View details for DOI 10.1053/j.semvascsurg.2009.04.001

    View details for Web of Science ID 000268036200004

    View details for PubMedID 19573745

  • Comparison of different adult stem cell types for treatment of myocardial ischemia CIRCULATION van der Bogt, K. E., Sheikh, A. Y., Schrepfer, S., Hoyt, G., Cao, F., Ransohoff, K. J., Swijnenburg, R., Pearl, J., Lee, A., Fischbein, M., Contag, C. H., Robbins, R. C., Wu, J. C. 2008; 118 (14): S121-U166

    Abstract

    A comparative analysis of the efficacy of different cell candidates for the treatment of heart disease remains to be described. This study is designed to evaluate the therapeutic efficacy of 4 cell types in a murine model of myocardial infarction.Bone marrow mononuclear cells (MN), mesenchymal stem cells (MSC), skeletal myoblasts (SkMb), and fibroblasts (Fibro) expressing firefly luciferase (Fluc) and green fluorescence protein (GFP) were characterized by flow cytometry, bioluminescence imaging (BLI), and luminometry. Female FVB mice (n=70) underwent LAD ligation and intramyocardially received one cell type (5x10(5)) or PBS. Cell survival was measured by BLI and by TaqMan PCR. Cardiac function was assessed by echocardiography and invasive hemodynamic measurements. Fluc expression correlated with cell number in all groups (r(2)>0.93). In vivo BLI revealed acute donor cell death of MSC, SkMb, and Fibro within 3 weeks after transplantation. By contrast, cardiac signals were still present after 6 weeks in the MN group, as confirmed by TaqMan PCR (P<0.01). Echocardiography showed significant preservation of fractional shortening in the MN group compared to controls (P<0.05). Measurements of left ventricular end-systolic/diastolic volumes revealed that the least amount of ventricular dilatation occurred in the MN group (P<0.05). Histology confirmed the presence of MN, although there was no evidence of transdifferentiation by donor MN into cardiomyocytes.This is the first study to show that compared to MSC, SkMB, and Fibro, MN exhibit a more favorable survival pattern, which translates into a more robust preservation of cardiac function.

    View details for DOI 10.1161/CIRCULATIONAHA.107.759480

    View details for Web of Science ID 000259648600018

    View details for PubMedID 18824743

  • Effect of inhaled tacrolimus on cellular and humoral rejection to prevent posttransplant obliterative airway disease AMERICAN JOURNAL OF TRANSPLANTATION Schrepfer, S., Deuse, T., Reichenspurner, H., Hoffmann, J., Haddad, M., Fink, J., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. 2007; 7 (7): 1733-1742

    Abstract

    This study aimed to investigate the pharmacokinetics after tacrolimus aerosol inhalation and to assess its efficacy to suppress acute and chronic airway allograft rejection. Orthotopic tracheal transplantations were performed and tacrolimus (4 mg/kg) was administered orally (PO) or via aerosol (AER). Tracheal tissue level AUCs(0-12) were similar in both treatment groups, but blood AUCs(0-12) were approximately 5.5-fold lower with AER (p < 0.001). Interestingly, only PO animals showed elevated BUN, cholesterol and triglycerides on POD 60 (p < 0.05). Histology of grafts harvested after 6 and 60 days revealed that both treatment groups were similarly effective in suppressing graft mononuclear infiltration (p < 0.001). Cellular immune activation (assessed by IFN-gamma- and IL-4-ELISPOTS), however, was far more effectively suppressed by tacrolimus PO (p < 0.001). In both treatment groups, the vigorous alloreactive IgM-antibody surge was effectively inhibited (p < 0.001). Due to the insufficient systemic cellular immunosuppression, discontinuation of tacrolimus AER resulted in a far stronger (3.5-fold) graft infiltration on POD 8 compared to PO (p < 0.001). Tacrolimus aerosol reduces systemic side effects and effectively protects the airway graft from early cellular rejection and chronic obliterative airway disease.

    View details for DOI 10.1111/j.1600-6143.2007.01858.x

    View details for Web of Science ID 000247109900009

    View details for PubMedID 17532751

  • Techniques for experimental heterotopic and orthotopic tracheal transplantations - When to use which model? TRANSPLANT IMMUNOLOGY Deuse, T., Schrepfer, S., Reichenspurner, H., Hoyt, G., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. 2007; 17 (4): 255-261

    Abstract

    Different animal models have been developed to study the pathogenesis and treatment of obliterative airway disease (OAD). Here we describe the techniques of heterotopic and orthotopic tracheal transplantations in the rat, comparing the kinetics of systemic host immune response and of histopathologic OAD development.Heterotopic and orthotopic tracheal transplantations were performed in both allogeneic (Brown Norway-to-Lewis) and syngeneic (Lewis-to-Lewis) models. Grafts were harvested after 7, 30, and 60 days post-transplant for histologic evaluation and analysis of host cellular and humoral response.Syngeneic tracheal grafts did not develop luminal obliteration and were morphologically indistinguishable from native tracheas. In heterotopic allografts, airway epithelium was rapidly destroyed and OAD progressed with complete luminal occlusion by 30 days. Orthotopic allografts showed enhanced early infiltration (1298+/-45 vs. 674+/-75 cells/high power field, p<0.001) with concomitant greater day 7 luminal narrowing (45+/-6% vs. 14+/-3%, p<0.001). In this model, donor-type BN epithelium (62+/-17%, 21+/-19%, and 1+/-1% on days 7, 30, and 60) was gradually replaced by recipient-type epithelial cells (2+/-4%, 70+/-22%, and 98+/-2%). OAD developed with circular orientation of cells and connective tissue fibers to 45+/-6% obliteration by day 60. Cellular host response, as determined by IFN-gamma-ELISPOT assay (548+/-132 vs. 402+/-197 spots, p=0.046) and anti-donor alloreactive IgM antibody production (2827+/-148 vs. 1565+/-393 mean channel fluorescence, p<0.001) were significantly stronger in rats bearing orthotopic vs. heterotopic allografts.The orthotopic tracheal transplantation model may be more representative of OAD found in human lung transplant recipients and we therefore encourage the wider use of this model.

    View details for DOI 10.1016/j.trim.2007.01.009

    View details for Web of Science ID 000247093000005

    View details for PubMedID 17493528

  • Stem cell transplantation: The lung barrier TRANSPLANTATION PROCEEDINGS Schrepfer, S., Deuse, T., Reichenspurner, H., Fischbein, M. P., Robbins, R. C., Pelletier, M. P. 2007; 39 (2): 573-576

    Abstract

    Mesenchymal stem cells (MSCs) show differentiation capacity along mesenchymal lineages and have the potential to aid tissue regeneration. MSC transplantation strategies are therefore currently being assessed following injury to various organs. However, potential MSC migration to these organs after intravenous (IV) MSC injection continues to be impeded by cell trapping within the lung.Mouse MSCs were isolated, purified, transfected with firefly luciferase, and labeled with CSFE. Their size was assessed in vitro. To estimate the diameter of mouse pulmonary capillaries, fluorescence-labeled microspheres of different sizes were injected with or without sodium nitroprusside (SN) pretreatment. The lungs were harvested after 30 seconds and mean numbers of trapped microspheres per high-power field (HPF) were calculated. After IV injection of MSC suspensions (with or without SN), their dynamic distribution was monitored by in vivo luciferine imaging as well as by histopathology.The diameter of suspended MSCs in vitro was 15 to 19 microm. Whereas nearly no 4-microm microspheres could be detected in lung sections, the numbers of trapped 10- and 15-microm microspheres could be significantly decreased by prior SN injection from 19.3 +/- 11.1 to 6.0 +/- 1.6 cells/HPF (P = .004) and from 34.9 +/- 11.9 to 25.6 +/- 8.1 cells/HPF (P = .028), respectively. Within seconds after MSC IV injection, the vast majority of cells was found in the lungs. However, cell trapping in the pulmonary microvasculature was significantly reduced by pre-treatment with SN.We demonstrate that cell trapping in lungs can be reduced with IV SN pretreatment, increasing MSC passage through the lung capillaries, and potentially facilitating cell access to injured organs.

    View details for DOI 10.1016/j.transproceed.2006.12.019

    View details for Web of Science ID 000245344200067

    View details for PubMedID 17362785

  • Is the malononitrilamide FK778 better for the prevention of acute or chronic rejection? TRANSPLANTATION PROCEEDINGS Deuse, T., Schrepfer, S., Pelletier, M. P., Fischbein, M. P., Robbins, R. C., Reichenspurner, H. 2007; 39 (2): 569-572

    Abstract

    The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents.Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses.In untreated recipients, cardiac allograft survival was 6.2 +/- 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 +/- 2.8, 18.5 +/- 2.7, 25.0 +/- 2.5, 20.7 +/- 3.8, 14.5 +/- 2.2, and 23.2 +/- 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% +/- 16.4%, 44.2% +/- 33.6%, 12.3% +/- 3.3%, 61.7% +/- 18.6%, 18.3% +/- 11.3%, 55.0% +/- 30.9%, and 8.5% +/- 3.5% (P < .05). All 4 high-dose groups showed similar efficacy.When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.

    View details for DOI 10.1016/j.transproceed.2006.12.020

    View details for Web of Science ID 000245344200066

    View details for PubMedID 17362784

Conference Proceedings


  • Interleukin-17 Accelerates Allograft Rejection by Suppressing Regulatory T Cell Expansion Itoh, S., Kimura, N., Axtell, R. C., Velotta, J. B., Gong, Y., Wang, X., Kajiwara, N., Nambu, A., Shimura, E., Adachi, H., Iwakura, Y., Saito, H., Okumura, K., Sudo, K., Steinman, L., Robbins, R. C., Nakae, S., Fischbein, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2011: S187-S196

    Abstract

    Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice.Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls.During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

    View details for DOI 10.1161/CIRCULATIONAHA.110.014852

    View details for Web of Science ID 000294782800025

    View details for PubMedID 21911812

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