David A Bull

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Courses

Scholarly Contributions

Chapters

• Bull, D. A. (2004). Clinical Properties and Healing Characteristics of e-PTFE Vascular Grafts and Their Effect on Long-Term Patency. In Tissue Engineering and Novel Delivery Systems. New York, New York: Marcel Dekker, Inc.
• Bull, D. A. (2003). The Healing Characteristics, Durability and Long-Term Complications of Vascular Prostheses. In Complications in Vascular Surgery IV. New York, New York: Marcel Dekker, Inc.
• Bull, D. A. (2001). Gene Therapy for Cardiovascular Disease. In Pharmaceutical Perspectives on Nuclei-Acid Based Therapeutics. Gordon and Breach Publishing.
• Bull, D. A. (1996). Heart Surgery. In Academic American Encyclopedia. Danbury, Conn: Grolier Publishing, Inc.
• Bull, D. A. (1993). Noninfectious Complications in Vascular Surgery. In Vascular Surgery - A Comprehensive Review. W.B. Saunders Co.
• Bull, D. A. (1991). Growth Factors and the Arterial Wall: Implications for Vessel Repair, Atherosclerosis and Intimal Hyperplasia. In Perspectives in Vascular Surgery(pp 87-103). In Goldstone J (Ed.) 4: St Louis: Quality Medical Publishing, Inc.
• Bull, D. A. (1991). The Healing Characteristics, Durability and Long-Term Complications of Vascular Prostheses. In Complications in Vascular Surgery III. St Louis: Quality Medical Publishing, Inc.

Journals/Publications

• Bull, D. A., Lick, S. D., Hsu, C., & Kazui, T. (2020). Short term risk of bilateral internal mammary artery grafting in diabetic patients. Seminars in Thoracic and Cardiovascular Surgery.
• Martin, D. R., Unger, E. C., Bull, D. A., Zhao, M., Desai, A. A., Chen, Q., Furenlid, L. R., Won, Y., Wan, L., Gupta, A., Barber, C., & Liu, Z. (2019). Imaging Assessment of Cardioprotection Mediated by a Dodecafluoropentane Oxygen-Carrier Administered During Myocardial Infarction. Nuclear Medicine and Biology, 70, 67-77. doi:10.1016/j.nucmedbio.2019.01.004
• Bacon, B., Silverton, N., Katz, M., Heath, E., Bull, D. A., Harig, J., & Tonna, J. E. (2018). Local Anesthetic Systemic Toxicity Induced Cardiac Arrest After Topicalization for Transesophageal Echocardiography and Subsequent Treatment With Extracorporeal Cardiopulmonary Resuscitation. Journal of cardiothoracic and vascular anesthesia.
• Kim, S. S., Kim, S. S., Bull, D. A., Bull, D. A., Garland, L. L., Garland, L. L., Khalpey, Z. I., Khalpey, Z. I., Stea, B., Stea, B., Yi, S. K., Yi, S. K., Hsu, C., & Hsu, C. (2018). Is there a role for cancer directed surgery in early stage sarcomatoid or biphasic mesothelioma. Ann Thorac Surg. doi:10.1016/j.athoracsur.2018.07.081
• Kim, S., Bull, D. A., Garland, L., Khalpey, Z., Stea, B., Yi, S., & Hsu, C. C. (2018). Is There a Role for Cancer Directed Surgery in Early Stage Sarcomatoid or Biphasic Mesothelioma?. The Annals of thoracic surgery.
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  Benefits of surgery for early stage non-epithelioid MPM have not been clearly elucidated. This study investigated whether cancer-directed surgery affects overall survival compared to non-surgical therapies for T1-T2N0M0 sarcomatoid or biphasic malignant pleural mesothelioma (MPM) patients.
• Brigham, E. P., Matsui, E. C., Appel, L. J., Bull, D. A., Curtin-Brosnan, J., Zhai, S., White, K., Charleston, J. B., Hansel, N. N., Diette, G. B., & McCormack, M. C. (2017). A pilot feeding study for adults with asthma: The healthy eating better breathing trial. PloS one, 12(7), e0180068.
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  Evidence from observational studies and to a lesser extent clinical trials suggest that a healthy diet may improve symptoms and lung function in patients with asthma. We conducted a pilot study to determine the feasibility of conducting a larger scale dietary trial and to provide preliminary evidence on the impact of a healthy diet on asthma outcomes.
• Bull, D. A. (2017). Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium. Physiol Rep, 5, 20.
• Bull, D. A. (2017). Cell surface-engineering to embed targeting ligands or tracking agents on the cell membrane. Biochem Biophys Res Commun, Jan 22;482(4), 1042-1047.
• Bull, D. A. (2017). Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax. Case Rep Oncol, July 14; 10(2), 660-665.
• Bull, D. A. (2017). Secondary surgical-site infection after coronary artery bypass grafting: A multi-institutional prospective cohort study. Journal Thoracic Cardiovascular Surgery, 10, 078.
• Bull, D. A., & Tandar, a. (2017). Bioprosthetic Aortic Paravalvular Leak: Is Valve-in-Valve Another Solution. J Invasive Cardiol, Jan;29(1), E1-E7.
• Bull, D. A., Brigham, E. P., Matsui, E. C., Appel, L. J., Curtin-Brosnan, J., Zhai, S., White, K., Charleston, J. B., Hansel, N. N., Diette, G. B., & McCormack, M. C. (2017). A pilot feeding study for adults with asthma: the healthy eating better breathing trial. PLoS One, Jul 13; 12(7).
• Bull, D. A., Fante, R. G., Hunter, G. C., VanDalen, J., Lee, D., Bernhard, V. M., & McIntyre, K. E. (2017). Correlation of ophthalmic findings with carotid artery stenosis. The Journal of cardiovascular surgery, 33(4), 401-6.
  More info

  Patients presenting with symptoms suggestive of amaurosis fugax, or with findings of Hollenhorst plaques on fundoscopy are frequently referred for duplex evaluation to detect possible carotid artery disease. To better determine the reliability of monocular visual loss and the presence of Hollenhorst plaques for predicting the presence or significance of carotid artery stenosis, we prospectively studied 66 patients with these ocular signs and symptoms. After evaluation, the patients were categorized as follows: 34 of 66 (52%) patients had amaurosis fugax, 23 (35%) had asymptomatic Hollenhorst plaques, 7 (11%) had retinal artery occlusion, and 2 (3%) had venous stasis retinopathy. All patients were evaluated ophthalmologically, with carotid duplex scanning and spectral analysis. A stenosis of greater than 60% was regarded as significant. The presence of risk factors including hypertension, diabetes, a history of CVA or TIA's, tobacco use and hyperlipidemia was recorded. There were no statistically significant differences (p greater than 0.05) in the incidence of atherosclerotic risk factors between the four groups. Patients with amaurosis fugax were more likely to have a significant carotid artery stenosis than those with asymptomatic Hollenhorst plaques or retinal artery occlusion (53% vs 9% vs 0% respectively) (p less than 0.006). We conclude that routine carotid duplex scanning is indicated in all patients with amaurosis fugax in view of the frequent association with significant carotid stenosis (53%). However, the presence of Hollenhorst plaques in the absence of visual symptoms appears not to have a significant association with carotid disease and may not necessarily require routine screening unless other risk factors for carotid stenosis are present.(ABSTRACT TRUNCATED AT 250 WORDS)
• Bull, D. A., Silverton, N. A., & Morrissey, C. K. (2017). Excessive Surgical Adhesive Mimicking Aortic Root Abscess: A Case Report. AA Case Rep, July 15;9(2), 57-59.
• Bull, D. A., Stahl, R. D., McMahan, D. L., Jones, K. W., Hawkins, J. A., Renlund, D. G., Taylor, D. O., & Karwande, S. V. (2017). The high risk heart donor: potential pitfalls. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 14(3), 424-8.
  More info

  The use of potentially infected donor hearts has been advocated to extend the supply of available hearts for transplantation.
• Johnson, E. D., Downs-Kelly, E., Bull, D. A., & Gulbahce, H. E. (2017). Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax. Case reports in oncology, 10(2), 660-665.
  More info

  Primary pleuropulmonary synovial sarcomas are quite rare, representing 0.1-0.5% of all pulmonary malignancies. We report an entirely cystic monophasic synovial sarcoma in a 25-year-old male who presented with recurrent pneumothorax and no evidence of a mass lesion on imaging. The purpose of this case report is to increase awareness of neoplasms clinically presenting as a pneumothorax with no imagining evidence of a mass-forming lesion and emphasize the significance of fluorescent in situ hybridization testing in nontypical synovial sarcoma cases.
• Kim, S. H., Jeong, J. H., Kim, T. I., Kim, S. W., & Bull, D. A. (2017). VEGF siRNA delivery system using arginine-grafted bioreducible poly(disulfide amine). Molecular pharmaceutics, 6(3), 718-26.
  More info

  Small interfering RNAs (siRNAs) are able to silence their target genes when they are successfully delivered intact into the cytoplasm. Delivery systems that enhance siRNA localization to the cytoplasm can facilitate gene silencing by siRNA therapeutics. We describe an arginine-conjugated poly(cystaminebisacrylamide-diaminohexane) (poly(CBA-DAH-R)), a bioreducible cationic polymer, as an siRNA carrier for therapeutic gene silencing for cancer. After intracellular uptake of the siRNA/poly(CBA-DAH-R) polyplexes, the reductive environment of the cytoplasm cleaves the disulfide linkages in the polymeric backbone, resulting in decomplexing of the siRNA/poly(CBA-DAH-R) polyplexes and release of siRNA molecules throughout the cytoplasm. The siRNA/poly(CBA-DAH-R) polyplexes, which demonstrate increased membrane permeability with arginine modification, have a similar level of cellular uptake as siRNA/bPEI polyplexes. The VEGF siRNA/poly(CBA-DAH-R) polyplexes, however, inhibit VEGF expression to a greater degree than VEGF siRNA/bPEI in various human cancer cell lines. The improved RNAi activity demonstrated by the VEGF siRNA/poly(CBA-DAH-R) polyplexes is due to enhanced intracellular delivery and effective localization to the cytoplasm of the VEGF siRNAs. These results demonstrate that the VEGF siRNA/poly(CBA-DAH-R) polyplex delivery system may useful for siRNA-based approaches for cancer therapy.
• Kumpati, G. S., Bull, D. A., & Patel, A. N. (2017). Trans-Carotid Placement of Balloon Expandable Covered Stent for Unplanned Left Carotid Coverage during Endovascular Repair of Distal Arch Aneurysm. Innovations (Philadelphia, Pa.), 10(3), 209-11.
  More info

  We present a technique for endovascular management of unplanned coverage of the left common carotid artery during endovascular repair of a distal aortic arch aneurysm. A balloon expandable covered stent was placed into the proximal left common carotid artery by neck incision.
• Kumpati, G. S., Tandar, A., Patel, A., Badger, R. S., & Bull, D. A. (2017). Impella 5.0 support in severe peripheral vascular disease via iliac artery approach. Innovations (Philadelphia, Pa.), 7(5), 379-81.
  More info

  Impella has been reported to provide hemodynamic support in cardiogenic shock patients, acute myocardial infarction, and high-risk percutaneous coronary intervention. We are reporting the case of using iliac artery cut down for Impella 5.0 in a high-risk percutaneous coronary intervention for a patient with severe ischemic cardiomyopathy who was not a surgical candidate.
• LeWinter, M. M., Taatjes, D., Ashikaga, T., Palmer, B., Bishop, N., VanBuren, P., Bell, S., Donaldson, C., Meyer, M., Margulies, K. B., Redfield, M., Bull, D. A., & Zile, M. (2017). Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium. Physiological reports, 5(20).
  More info

  Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients (71 M, 27 F) with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction-relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/μm(2) were 14.7% higher in mitochondria than the rest of the cytoplasm (P 
• Lim, K. S., Lee, D. Y., Valencia, G. M., Won, Y. W., & Bull, D. A. (2017). Cell surface-engineering to embed targeting ligands or tracking agents on the cell membrane. Biochemical and biophysical research communications, 482(4), 1042-1047.
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  The key challenge to improve the efficacy of cell therapy is how to efficiently modify cells with a specific molecule or compound that can guide the cells to the target tissue. To address this, we have developed a cell surface engineering technology to non-invasively modify the cell surface. This technology can embed a wide variety of bioactive molecules on any cell surface and allow for the targeting of a wide range of tissues in a variety of disease states. Using our cell surface engineering technology, mesenchymal stem cells (MSC)s were modified with: 1) a homing peptide or a recombinant protein to facilitate the migration of the cells toward a specific molecular target; or 2) magnetic resonance imaging (MRI) contrast agents to allow for in vivo tracking of the cells. The incorporation of a homing peptide or a targeting ligand on MSCs facilitated the migration of the cells toward their molecular target. MRI contrast agents were successfully embedded on the cell surfaces without adverse effects to the cells and the contrast agent-labeled cells were detectable by MRI. Our technology is a promising method of cell surface engineering that is applicable to a broad range of cell therapies.
• Neumayer, L. A., Bull, D. A., Hunter, G. C., McIntyre, K. E., Yoshino, M. T., Aguirre, M. L., & Bernhard, V. M. (2017). Atherosclerotic aneurysms of the axillary artery. A report of two cases and a review of the literature. The Journal of cardiovascular surgery, 33(2), 172-7.
  More info

  Atherosclerotic axillary artery aneurysms are rare. We report two cases of this entity and review the literature with respect to clinical presentation, diagnosis, operative management, and long-term outcome of these lesions.
• Parent, F. N., Piotrowski, J. J., Bernhard, V. M., Pond, G. D., Pabst, T. S., Bull, D. A., Hunter, G. C., & McIntyre, K. E. (2017). Outcome of intraarterial urokinase for acute vascular occlusion. The Journal of cardiovascular surgery, 32(5), 680-9.
  More info

  Intraarterial urokinase (IAUK) was administered to 33 patients on 40 occasions for the treatment of acute extremity ischemia and long-term patency was assessed. Lysis was successful in 39 of the 40 cases (95%). Occlusive thrombus was cleared in 12 of 13 patients with native artery occlusion (7 complete, 5 partial), 8 of 9 with autologous vein grafts (5 complete, 3 partial), and in all 18 patients with synthetic grafts (17 complete, 1 partial). The primary cumulative patency following successful IAUK was 100% for native arteries and 47% for synthetic grafts at 12 months, and 23% for autologous grafts at 9 months. The difference in rethrombosis rate between autologous vein (67%) and native artery (0%) was significant (p = 0.02) as was the difference between infrainguinal prosthetic grafts (63%) and native artery (p = 0.025). IAUK is most effective for the treatment of native artery occlusion, but is significantly less effective for thrombosed infrainguinal autologous vein or synthetic grafts due to the likelihood of reocclusion, despite the high immediate success rate. For autologous vein grafts, lysis is frequently incomplete and patency rapidly deteriorates regardless of adjunctive therapy to relieve the underlying obstruction.
• Silverton, N. A., Bull, D. A., & Morrissey, C. K. (2017). Excessive Surgical Adhesive Mimicking Aortic Root Abscess: A Case Report. A & A case reports, 9(2), 57-59.
  More info

  Aortic root abscess is a complication of aortic valve endocarditis that is associated with a high morbidity and mortality. The diagnosis usually is made with transesophageal echocardiography, which is highly sensitive and specific for the disease. We present a case of suspected aortic root abscess 1 week after mechanical aortic valve replacement for native valve endocarditis. The diagnosis was made by the use of transesophageal echocardiography but surgical inspection revealed that the paravalvular fluid collection was excessive surgical adhesive. We discuss the clinical significance and differential diagnosis of aortic root abscess in the setting of infective endocarditis.
• Silverton, N. A., Bull, D. A., & Morrissey, C. K. (2017). Excessive Surgical Adhesive: A Case Report of Aortic Root Abscess Doppelgänger. A & A case reports.
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  Aortic root abscess is a complication of aortic valve endocarditis that is associated with a high morbidity and mortality. The diagnosis usually is made with transesophageal echocardiography, which is highly sensitive and specific for the disease. We present a case of suspected aortic root abscess 1 week after mechanical aortic valve replacement for native valve endocarditis. The diagnosis was made by the use of transesophageal echocardiography but surgical inspection revealed that the paravalvular fluid collection was excessive surgical adhesive. We discuss the clinical significance and differential diagnosis of aortic root abscess in the setting of infective endocarditis.
• Tandar, A., Bull, D. A., & Welt, F. G. (2017). Bioprosthetic Aortic Paravalvular Leak: Is Valve-in-Valve Another Solution?. The Journal of invasive cardiology, 29(1), E1-E7.
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  Paravalvular leak (PVL) following aortic valve implantation is a rare complication but may cause potentially serious consequences. It occurs in 2%-10% of surgical aortic valve replacements and 7%-17% of surgical mitral valve replacements. Transcatheter valve replacement data show that significant PVL occurs in 6%-8% of cases. The management of significant PVL has traditionally involved repeat surgical repair. However, many of these patients are considered too high risk to undergo a repeat surgical procedure; hence, a percutaneous transcatheter approach has often been utilized to treat these patients. Vascular plugs have been used to close PVLs, with variable results; the procedure is complex and technically demanding. Transcatheter aortic valve replacement, using a valve-in-valve approach, may provide an alternative approach for bioprosthetic PVL in the aortic position.
• Cirulis, M. M., Emerson, L. L., Bull, D. A., Hatton, N., Nativi-Nicolai, J., Hildebrandt, G. C., & Ryan, J. J. (2016). Pulmonary arterial hypertension in primary amyloidosis. Pulmonary circulation, 6(2), 244-8.
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  Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.
• Patel, A. N., Selzman, C. H., Kumpati, G. S., McKellar, S. H., & Bull, D. A. (2016). Evaluation of autologous platelet rich plasma for cardiac surgery: outcome analysis of 2000 patients. Journal of cardiothoracic surgery, 11(1), 62.
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  Deep and superficial sternal wound infections (DSWI & SWI) following cardiac surgery increase morbidity, mortality and cost. Autologous platelet rich plasma (PRP) derived from the patient's own blood has been used in other surgical settings to promote successful wound healing. The goal of this study was to analyze the addition of PRP using a rapid point of care bedside system to standard wound care in all patients undergoing sternotomy for cardiac surgical procedures.
• Bull, D. A., Fante, R. G., Hunter, G. C., VanDalen, J., Lee, D., Bernhard, V. M., & McIntyre, K. E. (2015). Correlation of ophthalmic findings with carotid artery stenosis. The Journal of cardiovascular surgery, 33(4), 401-6.
  More info

  Patients presenting with symptoms suggestive of amaurosis fugax, or with findings of Hollenhorst plaques on fundoscopy are frequently referred for duplex evaluation to detect possible carotid artery disease. To better determine the reliability of monocular visual loss and the presence of Hollenhorst plaques for predicting the presence or significance of carotid artery stenosis, we prospectively studied 66 patients with these ocular signs and symptoms. After evaluation, the patients were categorized as follows: 34 of 66 (52%) patients had amaurosis fugax, 23 (35%) had asymptomatic Hollenhorst plaques, 7 (11%) had retinal artery occlusion, and 2 (3%) had venous stasis retinopathy. All patients were evaluated ophthalmologically, with carotid duplex scanning and spectral analysis. A stenosis of greater than 60% was regarded as significant. The presence of risk factors including hypertension, diabetes, a history of CVA or TIA's, tobacco use and hyperlipidemia was recorded. There were no statistically significant differences (p greater than 0.05) in the incidence of atherosclerotic risk factors between the four groups. Patients with amaurosis fugax were more likely to have a significant carotid artery stenosis than those with asymptomatic Hollenhorst plaques or retinal artery occlusion (53% vs 9% vs 0% respectively) (p less than 0.006). We conclude that routine carotid duplex scanning is indicated in all patients with amaurosis fugax in view of the frequent association with significant carotid stenosis (53%). However, the presence of Hollenhorst plaques in the absence of visual symptoms appears not to have a significant association with carotid disease and may not necessarily require routine screening unless other risk factors for carotid stenosis are present.(ABSTRACT TRUNCATED AT 250 WORDS)
• Bull, D. A., Stahl, R. D., McMahan, D. L., Jones, K. W., Hawkins, J. A., Renlund, D. G., Taylor, D. O., & Karwande, S. V. (2015). The high risk heart donor: potential pitfalls. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 14(3), 424-8.
  More info

  The use of potentially infected donor hearts has been advocated to extend the supply of available hearts for transplantation.
• David Gomez, A., Bull, D. A., & Hsu, E. W. (2015). Finite-Element Extrapolation of Myocardial Structure Alterations Across the Cardiac Cycle in Rats. Journal of biomechanical engineering, 137(10), 101010.
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  Myocardial microstructures are responsible for key aspects of cardiac mechanical function. Natural myocardial deformation across the cardiac cycle induces measurable structural alteration, which varies across disease states. Diffusion tensor magnetic resonance imaging (DT-MRI) has become the tool of choice for myocardial structural analysis. Yet, obtaining the comprehensive structural information of the whole organ, in 3D and time, for subject-specific examination is fundamentally limited by scan time. Therefore, subject-specific finite-element (FE) analysis of a group of rat hearts was implemented for extrapolating a set of initial DT-MRI to the rest of the cardiac cycle. The effect of material symmetry (isotropy, transverse isotropy, and orthotropy), structural input, and warping approach was observed by comparing simulated predictions against in vivo MRI displacement measurements and DT-MRI of an isolated heart preparation at relaxed, inflated, and contracture states. Overall, the results indicate that, while ventricular volume and circumferential strain are largely independent of the simulation strategy, structural alteration predictions are generally improved with the sophistication of the material model, which also enhances torsion and radial strain predictions. Moreover, whereas subject-specific transversely isotropic models produced the most accurate descriptions of fiber structural alterations, the orthotropic models best captured changes in sheet structure. These findings underscore the need for subject-specific input data, including structure, to extrapolate DT-MRI measurements across the cardiac cycle.
• Holt-Casper, D., Theisen, J. M., Moreno, A. P., Warren, M., Silva, F., Grainger, D. W., Bull, D. A., & Patel, A. N. (2015). Novel xeno-free human heart matrix-derived three-dimensional scaffolds. Journal of translational medicine, 13, 194.
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  Myocardial infarction (MI) results in damaged heart tissue which can progress to severely reduce cardiac function, leading to death. Recent studies have injected dissociated, suspended cardiac cells into coronary arteries to restore function with limited results attributed to poor cell retention and cell death. Extracellular matrix (ECM) injected into damaged cardiac tissue sites show some promising effects. However, combined use of human cardiac ECM and cardiac cells may produce superior benefits to restore cardiac function.
• Johnson, E. D., Downs-Kelly, E., Bull, D. A., & Gulbahce, H. E. (2015). Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax. Case reports in oncology, 10(2), 660-665.
  More info

  Primary pleuropulmonary synovial sarcomas are quite rare, representing 0.1-0.5% of all pulmonary malignancies. We report an entirely cystic monophasic synovial sarcoma in a 25-year-old male who presented with recurrent pneumothorax and no evidence of a mass lesion on imaging. The purpose of this case report is to increase awareness of neoplasms clinically presenting as a pneumothorax with no imagining evidence of a mass-forming lesion and emphasize the significance of fluorescent in situ hybridization testing in nontypical synovial sarcoma cases.
• Kim, S. H., Jeong, J. H., Kim, T. I., Kim, S. W., & Bull, D. A. (2015). VEGF siRNA delivery system using arginine-grafted bioreducible poly(disulfide amine). Molecular pharmaceutics, 6(3), 718-26.
  More info

  Small interfering RNAs (siRNAs) are able to silence their target genes when they are successfully delivered intact into the cytoplasm. Delivery systems that enhance siRNA localization to the cytoplasm can facilitate gene silencing by siRNA therapeutics. We describe an arginine-conjugated poly(cystaminebisacrylamide-diaminohexane) (poly(CBA-DAH-R)), a bioreducible cationic polymer, as an siRNA carrier for therapeutic gene silencing for cancer. After intracellular uptake of the siRNA/poly(CBA-DAH-R) polyplexes, the reductive environment of the cytoplasm cleaves the disulfide linkages in the polymeric backbone, resulting in decomplexing of the siRNA/poly(CBA-DAH-R) polyplexes and release of siRNA molecules throughout the cytoplasm. The siRNA/poly(CBA-DAH-R) polyplexes, which demonstrate increased membrane permeability with arginine modification, have a similar level of cellular uptake as siRNA/bPEI polyplexes. The VEGF siRNA/poly(CBA-DAH-R) polyplexes, however, inhibit VEGF expression to a greater degree than VEGF siRNA/bPEI in various human cancer cell lines. The improved RNAi activity demonstrated by the VEGF siRNA/poly(CBA-DAH-R) polyplexes is due to enhanced intracellular delivery and effective localization to the cytoplasm of the VEGF siRNAs. These results demonstrate that the VEGF siRNA/poly(CBA-DAH-R) polyplex delivery system may useful for siRNA-based approaches for cancer therapy.
• Kumpati, G. S., Bull, D. A., & Patel, A. N. (2015). Trans-Carotid Placement of Balloon Expandable Covered Stent for Unplanned Left Carotid Coverage during Endovascular Repair of Distal Arch Aneurysm. Innovations (Philadelphia, Pa.), 10(3), 209-11.
  More info

  We present a technique for endovascular management of unplanned coverage of the left common carotid artery during endovascular repair of a distal aortic arch aneurysm. A balloon expandable covered stent was placed into the proximal left common carotid artery by neck incision.
• Kumpati, G. S., Tandar, A., Patel, A., Badger, R. S., & Bull, D. A. (2015). Impella 5.0 support in severe peripheral vascular disease via iliac artery approach. Innovations (Philadelphia, Pa.), 7(5), 379-81.
  More info

  Impella has been reported to provide hemodynamic support in cardiogenic shock patients, acute myocardial infarction, and high-risk percutaneous coronary intervention. We are reporting the case of using iliac artery cut down for Impella 5.0 in a high-risk percutaneous coronary intervention for a patient with severe ischemic cardiomyopathy who was not a surgical candidate.
• Neumayer, L. A., Bull, D. A., Hunter, G. C., McIntyre, K. E., Yoshino, M. T., Aguirre, M. L., & Bernhard, V. M. (2015). Atherosclerotic aneurysms of the axillary artery. A report of two cases and a review of the literature. The Journal of cardiovascular surgery, 33(2), 172-7.
  More info

  Atherosclerotic axillary artery aneurysms are rare. We report two cases of this entity and review the literature with respect to clinical presentation, diagnosis, operative management, and long-term outcome of these lesions.
• Parent, F. N., Piotrowski, J. J., Bernhard, V. M., Pond, G. D., Pabst, T. S., Bull, D. A., Hunter, G. C., & McIntyre, K. E. (2015). Outcome of intraarterial urokinase for acute vascular occlusion. The Journal of cardiovascular surgery, 32(5), 680-9.
  More info

  Intraarterial urokinase (IAUK) was administered to 33 patients on 40 occasions for the treatment of acute extremity ischemia and long-term patency was assessed. Lysis was successful in 39 of the 40 cases (95%). Occlusive thrombus was cleared in 12 of 13 patients with native artery occlusion (7 complete, 5 partial), 8 of 9 with autologous vein grafts (5 complete, 3 partial), and in all 18 patients with synthetic grafts (17 complete, 1 partial). The primary cumulative patency following successful IAUK was 100% for native arteries and 47% for synthetic grafts at 12 months, and 23% for autologous grafts at 9 months. The difference in rethrombosis rate between autologous vein (67%) and native artery (0%) was significant (p = 0.02) as was the difference between infrainguinal prosthetic grafts (63%) and native artery (p = 0.025). IAUK is most effective for the treatment of native artery occlusion, but is significantly less effective for thrombosed infrainguinal autologous vein or synthetic grafts due to the likelihood of reocclusion, despite the high immediate success rate. For autologous vein grafts, lysis is frequently incomplete and patency rapidly deteriorates regardless of adjunctive therapy to relieve the underlying obstruction.
• Ryan, J. J., Suksaranjit, P., Hatton, N., Bull, D. A., & Wilson, B. D. (2015). Eisenmenger syndrome with unrepaired patent ductus arteriosus. Circulation, 131(16), e409-11.
• Wooderchak-Donahue, W., VanSant-Webb, C., Tvrdik, T., Plant, P., Lewis, T., Stocks, J., Raney, J. A., Meyers, L., Berg, A., Rope, A. F., Yetman, A. T., Bleyl, S. B., Mesley, R., Bull, D. A., Collins, R. T., Ojeda, M. M., Roberts, A., Lacro, R., Woerner, A., , Stoler, J., et al. (2015). Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. American journal of medical genetics. Part A, 167A(8), 1747-57.
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  Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.
• Zile, M. R., Baicu, C. F., Ikonomidis, J. S., Stroud, R. E., Nietert, P. J., Bradshaw, A. D., Slater, R., Palmer, B. M., Van Buren, P., Meyer, M., Redfield, M. M., Bull, D. A., Granzier, H. L., & LeWinter, M. M. (2015). Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation, 131(14), 1247-59.
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  The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin.
• Henry, T. D., Traverse, J. H., Hammon, B. L., East, C. A., Bruckner, B., Remmers, A. E., Recker, D., Bull, D. A., & Patel, A. N. (2014). Safety and efficacy of ixmyelocel-T: an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy. Circulation research, 115(8), 730-7.
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  Ixmyelocel-T is associated with a wide range of biological activities relevant to tissue repair and regeneration.
• Kumpati, G. S., Gray, R., Patel, A., & Bull, D. A. (2014). Endovascular repair of acute ascending aortic disruption via the right axillary artery. The Annals of thoracic surgery, 97(2), 700-3.
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  Endovascular repair of emergent syndromes involving the ascending aorta is uncommon. We describe an acute disruption of the ascending aorta during stenting of the pulmonary artery, resulting in an acute aortopulmonary artery defect and severe pulmonary edema. The disruption was treated successfully using an endovascular approach, with rapid resolution of the patient's pulmonary edema.
• Kumpati, G. S., Patel, A. N., & Bull, D. A. (2014). Thrombosis of a descending thoracic aortic endovascular stent graft in a patient with factor V Leiden: case report. Journal of cardiothoracic surgery, 9, 47.
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  We present a case of a 14 year old Caucasian male who underwent initially successful endovascular repair of a traumatic injury to the descending thoracic aorta. The patient had undiagnosed Factor V Leiden at the time of the endovascular repair. He later presented with thrombosis of the endovascular stent graft, necessitating open removal of the stent graft and replacement of the involved aorta with a Dacron graft.
• Silva, F. J., Holt, D. J., Vargas, V., Yockman, J., Boudina, S., Atkinson, D., Grainger, D. W., Revelo, M. P., Sherman, W., Bull, D. A., & Patel, A. N. (2014). Metabolically active human brown adipose tissue derived stem cells. Stem cells (Dayton, Ohio), 32(2), 572-81.
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  Brown adipose tissue (BAT) plays a key role in the evolutionarily conserved mechanisms underlying energy homeostasis in mammals. It is characterized by fat vacuoles 5-10 µm in diameter and expression of uncoupling protein one, central to the regulation of thermogenesis. In the human newborn, BAT depots are typically grouped around the vasculature and solid organs. These depots maintain body temperature during cold exposure by warming the blood before its distribution to the periphery. They also ensure an optimal temperature for biochemical reactions within solid organs. BAT had been thought to involute throughout childhood and adolescence. Recent studies, however, have confirmed the presence of active BAT in adult humans with depots residing in cervical, supraclavicular, mediastinal, paravertebral, and suprarenal regions. While human pluripotent stem cells have been differentiated into functional brown adipocytes in vitro and brown adipocyte progenitor cells have been identified in murine skeletal muscle and white adipose tissue, multipotent metabolically active BAT-derived stem cells from a single depot have not been identified in adult humans to date. Here, we demonstrate a clonogenic population of metabolically active BAT stem cells residing in adult humans that can: (a) be expanded in vitro; (b) exhibit multilineage differentiation potential; and (c) functionally differentiate into metabolically active brown adipocytes. Our study defines a new target stem cell population that can be activated to restore energy homeostasis in vivo for the treatment of obesity and related metabolic disorders.
• Won, Y. W., Bull, D. A., & Kim, S. W. (2014). Functional polymers of gene delivery for treatment of myocardial infarct. Journal of controlled release : official journal of the Controlled Release Society, 195, 110-9.
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  Ischemic heart disease is rapidly growing as the common cause of death in the world. It is a disease that occurs as a result of coronary artery stenosis and is caused by the lack of oxygen within cardiac muscles due to an imbalance between oxygen supply and demand. The conventional medical therapy is focused on the use of drug eluting stents, coronary-artery bypass graft surgery and anti-thrombosis. Gene therapy provides great opportunities for treatment of cardiovascular disease. In order for gene therapy to be successful, the development of proper gene delivery systems and hypoxia-regulated gene expression vectors is the most important factors. Several non-viral gene transfer methods have been developed to overcome the safety problems of viral transduction. Some of which include plasmids that regulate gene expression that is controlled by environment specific promoters in the transcriptional or the translational level. This review explores polymeric gene carriers that target the myocardium and hypoxia-inducible vectors, which regulate gene expression in response to hypoxia, and their application in animal myocardial infarction models.
• Won, Y. W., Patel, A. N., & Bull, D. A. (2014). Cell surface engineering to enhance mesenchymal stem cell migration toward an SDF-1 gradient. Biomaterials, 35(21), 5627-35.
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  Mesenchymal stem cell (MSC) therapy for the treatment of myocardial infarction (MI) has shown considerable promise in clinical trials. A billion MSCs need to be administered for therapeutic efficacy, however, because only ∼1% of the cells reach the ischemic myocardium after systemic infusion. This is due to the loss of the homing signal on the surface of the MSCs during their expansion in culture. Stromal-derived factor-1 (SDF-1) is up-regulated immediately after infarction and is released into the peripheral blood. This SDF-1 reaches the bone marrow and recruits CXC chemokine receptor 4 (CXCR4)-positive stem cells. The CXCR4/SDF-1 axis plays an important role in MSC homing to the ischemic myocardium. Since SDF-1 is highly expressed for only 48 h after infarction, the current approaches requiring long-term culture of MSCs to induce CXCR4 expression are not clinically useful. To provide a clinically viable means to improve the homing of MSCs, we have developed a surface modification method to incorporate recombinant CXCR4 protein on the membrane of MSCs within 10 min. Using this method, we have confirmed the improved migration of MSCs toward an SDF-1 gradient.
• Bull, D. A., Fann, J. I., & , A. C. (2013). Historical perspectives of The American Association for Thoracic Surgery: Frank Gerbode (1907-1984). The Journal of thoracic and cardiovascular surgery, 146(6), 1317-20.
• Chen, H. H., Anstrom, K. J., Givertz, M. M., Stevenson, L. W., Semigran, M. J., Goldsmith, S. R., Bart, B. A., Bull, D. A., Stehlik, J., LeWinter, M. M., Konstam, M. A., Huggins, G. S., Rouleau, J. L., O'Meara, E., Tang, W. H., Starling, R. C., Butler, J., Deswal, A., Felker, G. M., , O'Connor, C. M., et al. (2013). Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA, 310(23), 2533-43.
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  Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested.
• Patel, A. N., Vargas, V., Revello, P., & Bull, D. A. (2013). Mesenchymal stem cell population isolated from the subepithelial layer of umbilical cord tissue. Cell transplantation, 22(3), 513-9.
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  The therapeutic use of stem cells to treat diseases and injuries is a promising tool in regenerative medicine. The umbilical cord provides a rich source of stem cells; we have previously reported a population of stem cells isolated from Wharton's jelly. In this report, we aimed to isolate a novel cell population that was different than those found in Wharton's jelly. We isolated stem cells from the subepithelial layer of the umbilical cord; the cells could be expanded for greater than 90 population doubling and had mesenchymal stem cell characteristics, expressing CD9, SSEA4, CD44, CD90, CD166, CD73, and CD146 but were negative for STRO-1. The cells can be directionally differentiated and undergo osteo-, chondro-, adipo-, and cardiogenesis. In addition, we have identified for the first time that mesenchymal stem cells isolated from umbilical cord can produce microvesicles, termed exosomes. This is the first report describing a stem cell population isolated from the subepithelial layer of the umbilical cord. Given the growth capacity, multilineage potential, and most importantly the low levels of HLA-ABC, we propose that this novel cell isolated from the subepithelial layer of umbilical cord is an ideal candidate for allogeneic cell-based therapy.
• Patel, A. N., Yockman, J., Vargas, V., & Bull, D. A. (2013). Putative population of adipose-derived stem cells isolated from mediastinal tissue during cardiac surgery. Cell transplantation, 22(3), 507-11.
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  Mesenchymal stem cells have been isolated from various adult human tissues and are valuable for not only therapeutic applications but for the study of tissue homeostasis and disease progression. Subcutaneous adipose depots have been shown to contain large amounts of stem cells. There is little information that has been reported to date describing the isolation and characterization of mesenchymal stem cells from visceral adipose tissue. In this study, we describe a mesenchymal stem cell population isolated from mediastinal adipose depots. The cells express CD44, CD105, CD166, and CD90 and are negative for hematopoietic markers CD34, CD45, and HLA-DR. In addition, the cells have a multilineage potential, with the ability to differentiate into adipogenic, osteogenic, and chondrogenic cell types. The biological function of visceral adipose tissue remains largely unknown and uncharacterized. However, the proximity of adipose tissue to the heart suggests a potential role in the pathogenesis of cardiovascular disease in obesity. In addition, with the ability of fat to regulate metabolic activity in humans, this novel stem cell source may be useful to further study the mechanisms involved in metabolic disorders.
• Redfield, M. M., Chen, H. H., Borlaug, B. A., Semigran, M. J., Lee, K. L., Lewis, G., LeWinter, M. M., Rouleau, J. L., Bull, D. A., Mann, D. L., Deswal, A., Stevenson, L. W., Givertz, M. M., Ofili, E. O., O'Connor, C. M., Felker, G. M., Goldsmith, S. R., Bart, B. A., McNulty, S. E., , Ibarra, J. C., et al. (2013). Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA, 309(12), 1268-77.
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  Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF).
• Spadaccio, C., Rainer, A., De Marco, F., Lusini, M., Gallo, P., Sedati, P., Muda, A. O., De Porcellinis, S., Gregorj, C., Avvisati, G., Trombetta, M., Chello, M., Covino, E., Bull, D. A., Patel, A. N., & Genovese, J. A. (2013). In situ electrostimulation drives a regenerative shift in the zone of infarcted myocardium. Cell transplantation, 22(3), 493-503.
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  Electrostimulation represents a well-known trophic factor for different tissues. In vitro electrostimulation of non-stem and stem cells induces myogenic predifferentiation and may be a powerful tool to generate cells with the capacity to respond to local areas of injury. We evaluated the effects of in vivo electrostimulation on infarcted myocardium using a miniaturized multiparameter implantable stimulator in rats. Parameters of electrostimulation were organized to avoid a direct driving or pacing of native heart rhythm. Electrical stimuli were delivered for 14 days across the scar site. In situ electrostimulation used as a cell-free, cytokine-free stimulation system, improved myocardial function, and increased angiogenesis through endothelial progenitor cell migration and production of vascular endothelial growth factor (VEGF). In situ electrostimulation represents a novel means to stimulate repair of the heart and other organs, as well as to precondition tissues for treatment with cell-based therapies.
• Won, Y. W., Lee, M., Kim, H. A., Bull, D. A., & Kim, S. W. (2013). Hypoxia-inducible plasmid expressing both miSHP-1 and HO-1 for the treatment of ischemic disease. Journal of controlled release : official journal of the Controlled Release Society, 165(1), 22-8.
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  Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Unfortunately, current pharmacological treatments for ischemic heart disease do not reliably prevent the remodeling of the left ventricle and the progression to heart failure. Gene therapy offers a novel means to directly treat the pathophysiology underlying the long-term complications of ischemic heart disease. To date, gene therapies directed at single molecular targets have not been successful in the treatment of ischemic heart disease. In this study, we describe a gene therapy combination for inhibiting cardiomyocyte apoptosis under hypoxic conditions. This gene therapy combination utilizes a hypoxia-inducible plasmid expressing both heme oxygenase-1 (HO-1) and the Src homology domain-2 containing tyrosine phosphatase-1 microRNA (miSHP-1): pEpo-SV-miSHP-HO-1. This novel gene therapy construct demonstrated an enhanced expression of HO-1, production of miSHP-1, down-regulation of SHP-1, and inhibition of cardiomyocyte apoptosis under hypoxic compared to normoxic conditions. These results suggest that pEpo-SV-miSHP-HO-1 may be a promising gene therapy combination construct for the clinical treatment of ischemic disease.
• Won, Y. W., Lee, M., Kim, H. A., Nam, K., Bull, D. A., & Kim, S. W. (2013). Synergistically combined gene delivery for enhanced VEGF secretion and antiapoptosis. Molecular pharmaceutics, 10(10), 3676-83.
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  With current pharmacological treatments, preventing the remodeling of the left ventricle and the progression to heart failure is a difficult task. Gene therapy is considered to provide a direct treatment to the long-term complications of ischemic heart diseases. Although current gene therapies that use single molecular targets seem potentially possible, they have not achieved success in the treatment of ischemic diseases. With an efficient polymeric gene carrier, PAM-ABP, we designed a synergistically combined gene-delivery strategy to enhance vascular endothelial growth factor (VEGF) secretion and to prolong its antiapoptotic effects. A hypoxia-inducible plasmid expressing both hypoxia-inducible heme oxygenase-1 (HO-1) and the Src homology domain-2 containing tyrosine phosphatase-1 microRNA (miSHP-1) as well as a hypoxia-responsive VEGF plasmid were combined in this study. The positive feedback circuit between HO-1 and VEGF and the negative regulatory role of SHP-1 in angiogenesis enhance VEGF secretion synergistically. The synergy in VEGF secretion as a consequence of the gene combination and prolonged HO-1 activity was confirmed in hypoxic cardiomyocytes and cardiomyocyte apoptosis under hypoxia and was decreased synergistically. These results suggest that the synergistic combination of VEGF, HO-1, and miSHP-1 may be promising for the clinical treatment of ischemic diseases.
• Won, Y. W., McGinn, A. N., Lee, M., Bull, D. A., & Kim, S. W. (2013). Targeted gene delivery to ischemic myocardium by homing peptide-guided polymeric carrier. Molecular pharmaceutics, 10(1), 378-85.
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  Myocardial ischemia needs an alternative treatment such as gene therapy for the direct protection of cardiomyocytes against necrosis or apoptosis and to prevent the development of myocardial fibrosis and cardiac dysfunction. Despite the utility of gene therapy, its therapeutic use is limited due to inadequate transfection in cardiomyocytes and difficulty in directing to ischemic myocardium. Here, we present a polymeric gene carrier that is capable of targeting ischemic myocardium, resulting in high localization within the ischemic zone of the left ventricle (LV) of an ischemia/reperfusion (I/R) rat model upon systemic administration. Cystamine bisacrylamide-diamino hexane (CD) polymer was modified with the ischemic myocardium-targeted peptide (IMTP) and D-9-arginine (9R) for dual effects of the homing to ischemic myocardium and enhanced transfection efficiency with minimized polymer use. Conjugation of IMTP and 9R to CD led to an increase in transfection under hypoxia and significantly reduced the amount of polymer required for high transfection. Finally, we confirmed targeting of IMTP-CD-9R/DNA polyplex to ischemic myocardium and enhanced gene expression in LV of the I/R rat after tail vein injection. This study provides a clue that gene therapy for the treatment of myocardial ischemia can be achieved by using homing peptide-guided gene delivery systems.
• Won, Y. W., McGinn, A. N., Lee, M., Nam, K., Bull, D. A., & Kim, S. W. (2013). Post-translational regulation of a hypoxia-responsive VEGF plasmid for the treatment of myocardial ischemia. Biomaterials, 34(26), 6229-38.
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  Vascular endothelial growth factor (VEGF) gene therapy to promote therapeutic angiogenesis has been advanced as an alternative treatment for myocardial ischemia. The unregulated expression of VEGF and the use of viral vectors, however, have slowed the clinical development of angiogenic gene therapy. The development of clinically beneficial angiogenic gene therapy requires a disease-specific gene expression system and an efficient non-viral gene carrier. To address these requirements, we developed a new post-translationally regulated hypoxia-responsible VEGF plasmid, pβ-SP-ODD-VEGF, and a dendrimer-type bio-reducible polymer, PAM-ABP. The efficacy of VEGF gene therapy with the PAM-ABP/pβ-SP-ODD-VEGF was evaluated and compared to the RTP-VEGF plasmid, a previously constructed hypoxia-inducible plasmid, in an ischemia/reperfusion (I/R) rat model. Cine magnetic resonance imaging was used to analyze the ischemia/reperfusion rats treated with either the PAM-ABP/pβ-SP-ODD-VEGF or the PAM-ABP/RTP-VEGF. The PAM-ABP/pβ-SP-ODD-VEGF treatment more effectively protected cardiomyocytes against apoptosis, preserved left ventricular (LV) function, and prevented LV remodeling compared to the PAM-ABP/RTP-VEGF-treated rats. These results suggest that the pβ-SP-ODD-VEGF with PAM-ABP may be efficacious in the treatment of acute ischemic heart disease.
• Bart, B. A., Goldsmith, S. R., Lee, K. L., Givertz, M. M., O'Connor, C. M., Bull, D. A., Redfield, M. M., Deswal, A., Rouleau, J. L., LeWinter, M. M., Ofili, E. O., Stevenson, L. W., Semigran, M. J., Felker, G. M., Chen, H. H., Hernandez, A. F., Anstrom, K. J., McNulty, S. E., Velazquez, E. J., , Ibarra, J. C., et al. (2012). Ultrafiltration in decompensated heart failure with cardiorenal syndrome. The New England journal of medicine, 367(24), 2296-304.
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  Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function.
• Bart, B. A., Goldsmith, S. R., Lee, K. L., Redfield, M. M., Felker, G. M., O'Connor, C. M., Chen, H. H., Rouleau, J. L., Givertz, M. M., Semigran, M. J., Mann, D., Deswal, A., Bull, D. A., Lewinter, M. M., & Braunwald, E. (2012). Cardiorenal rescue study in acute decompensated heart failure: rationale and design of CARRESS-HF, for the Heart Failure Clinical Research Network. Journal of cardiac failure, 18(3), 176-82.
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  Worsening renal function is common among patients hospitalized for acute decompensated heart failure (ADHF). When this occurs, subsequent management decisions often pit the desire for effective decongestion against concerns about further worsening renal function. There are no evidence-based treatments or guidelines to assist in these difficult management decisions. Ultrafiltration is a potentially attractive alternative to loop diuretics for the management of fluid overload in patients with ADHF and worsening renal function.
• Gupta, A., Braunwald, E., McNulty, S., Felker, G. M., Gilbert, E. M., Alharethi, R., Lee, K. L., Anstrom, K. J., Redfield, M. M., Goldsmith, S. R., O'Connor, C. M., Bull, D. A., Stehlik, J., & Litwin, S. E. (2012). Obesity and the response to intensified diuretic treatment in decompensated heart failure: a DOSE trial substudy. Journal of cardiac failure, 18(11), 837-44.
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  Obesity could attenuate diuretic effectiveness in treatment of acute decompensated heart failure (HF).
• Hu, N., Sabey, K. H., Curtis, H. R., Hoang, N., Dowdle, S. B., Garzarelli, A. A., Buswell, H. R., Dibella, E., Yockman, J. W., & Bull, D. A. (2012). Magnetic resonance imaging (MRI) assessment of ventricular remodeling after myocardial infarction in rabbits. Comparative medicine, 62(2), 116-23.
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  To understand the structure-function relationship in the postinfarcted myocardium in rabbits, we induced cardiac ischemia by ligating the left circumflex coronary artery. Sham controls underwent thoracotomy only. At 7 and 30 d after ligation, cardiac MRI was conducted by using pulse-oxymetry-gated cine acquisition to provide complete phases of the heartbeat. The rabbits were anesthetized under 1.5% isoflurane ventilation, and ultrafast techniques made breath-hold 3D coverage in different cardiac axes feasible. Viability imaging was performed after intravenous injection of 0.15 mmol/kg gadolinium to assess the extent of infarction. Data (n ≥ 6) are presented as mean ± SEM and analyzed by ANOVA and ANCOVA. In postligation rabbits, end-systolic (mean ± SEM, 2.3 ± 0.3 mL) and end-diastolic (4.2 ± 0.4 mL) volumes were increased compared with preligation values (end-systolic, 1.1 ± 0.1 mL; end-diastolic, 2.98 ± 0.2 mL). Ejection fraction was influenced adversely by the presence of scar tissue at both 7 and 30 d after ligation and apparently nonlinear with the heart rate. Cardiac force was increased in the basal region in both end-systole and end-diastole in postligation hearts but progressively decreased toward the apex. Late gadolinium enhancement delineated 15.2 ± 5.8% myocardial infarction at 7 d after ligation and 14.5 ± 5.8% at 30 d, with limited wall motion and wall thinness. Compensatory wall thickening was present in the basal region when compared with that in preligation hearts. MRI offers detailed spatial resolution and tissue characterization after myocardial infarction.
• Nam, H. Y., Kim, J., Kim, S. W., & Bull, D. A. (2012). Cell targeting peptide conjugation to siRNA polyplexes for effective gene silencing in cardiomyocytes. Molecular pharmaceutics, 9(5), 1302-9.
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  To deliver siRNA specifically to cardiomyocytes with a high transfection efficiency, primary cardiomyocyte-targeting (PCM) and/or cell-penetrating (Tat) peptides were incorporated into the siRNA. With the addition of plasmid DNA, these peptide-conjugated siRNAs were able to form compact and stable nanosized polyplex particles with bioreducible poly(CBA-DAH). The peptide-modified siRNA polyplexes enhanced the cellular uptake and the gene-silencing capacity of the siRNA in cardiomyocytes without significant immunogenicity or cytotoxicity. These findings demonstrate that the cell-targeting peptide and/or cell-penetrating peptide conjugation of siRNA may be a potentially important strategy for cell-specific gene therapy in gene-mediated disease states.
• Nam, H. Y., Lee, Y., Lee, M., Shin, S. K., Kim, T. I., Kim, S. W., & Bull, D. A. (2012). Erythropoietin gene delivery using an arginine-grafted bioreducible polymer system. Journal of controlled release : official journal of the Controlled Release Society, 157(3), 437-44.
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  Erythropoietin (EPO) plays a key regulatory role in the formation of new red blood cells (RBCs). Erythropoietin may also have a role as a therapeutic agent to counteract ischemic injury in neural, cardiac and endothelial cells. One of the limitations preventing the therapeutic application of EPO is its short half-life. The goal of this study was to develop a gene delivery system for the prolonged and controlled release of EPO. The arginine grafted bioreducible polymer (ABP) and its PEGylated version, ABP-PEG10, were utilized to study the expression efficiency and therapeutic effectiveness of this erythropoietin gene delivery system in vitro. Poly(ethylene glycol) (PEG) modification of the ABP was employed to inhibit the particle aggregation resulting from the interactions between cationic polyplexes and the negatively charged proteins typically present in serum. Both the ABP and the ABP-PEG10 carriers demonstrated efficient transfection and long-term production of EPO in a variety of cell types. The expressed EPO protein stimulated hematopoietic progenitor cells to form significant numbers of cell colonies in vitro. These data confirm that this EPO gene delivery system using a bioreducible polymeric carrier, either ABP or ABP-PEG 10, merits further testing as a potential therapeutic modality for a variety of clinically important disease states.
• Nam, H. Y., Nam, K., Lee, M., Kim, S. W., & Bull, D. A. (2012). Dendrimer type bio-reducible polymer for efficient gene delivery. Journal of controlled release : official journal of the Controlled Release Society, 160(3), 592-600.
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  Arginine-grafted bio-reducible poly(disulfide amine) (ABP) was incorporated into the poly(amido amine) (PAMAM) dendrimer, creating a high molecular weight bio-reducible polymer, PAM-ABP, to overcome the limitations of the low molecular weight ABP. The newly synthesized PAM-ABP was studied to determine its efficacy as a gene delivery carrier. The PAM-ABP demonstrated superior condensing ability for plasmid DNA through the formation of compact nanosized polyplexes. These compact polyplexes enhanced cellular uptake and were less susceptible to reducing agents, resulting in greater transfection efficiency compared to ABP alone. Based on these results, this newly developed PAM-ABP polyplex is a promising delivery system for clinical gene therapy.
• Won, Y. W., Lee, M., Kim, H. A., Bull, D. A., & Kim, S. W. (2012). Post-translational regulated and hypoxia-responsible VEGF plasmid for efficient secretion. Journal of controlled release : official journal of the Controlled Release Society, 160(3), 525-31.
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  Gene therapy using angiogenic genes has emerged as a potentially viable alternative treatment strategy for myocardial ischemia. Non-specific expression of angiogenic genes, however, may result in side effects, including the growth of occult tumors. Regulation of gene expression may help to avoid the occurrence of these side effects. In this study, a plasmid expressing vascular endothelial growth factor (VEGF) was constructed with an oxygen dependent degradation (ODD) domain and a secretion signal peptide (SP) in order to stabilize the VEGF protein and facilitate the secretion of VEGF protein, specifically under hypoxic conditions. We found that this plasmid, pβ-SP-ODD-VEGF, expresses the SP-ODD-VEGF protein at increased levels under hypoxic conditions compared to normoxic conditions. Since the size of the ODD domain is almost the same as that of VEGF, the ODD-VEGF fusion protein may have lower secretion efficiency. To address this issue, a furin recognition site was located between the ODD domain and the VEGF site to facilitate elimination of the SP-ODD domain from the fusion protein before its secretion. This optimizes the likelihood that the VEGF secreted from the target cells will be wild-type VEGF. Treatment with a furin inhibitor reduced the secretion efficiency of the VEGF, indicating that furin digestion increases the secretion of VEGF. The secreted wild-type VEGF facilitated the growth of endothelial cells more efficiently under hypoxic conditions than normoxic conditions. These results suggest that this plasmid, pβ-SP-ODD-VEGF, warrants further study as a more efficient form of hypoxia-inducible gene therapy for the treatment of myocardial ischemia.
• Wozniak, C. J., Baird, B. C., Stehlik, J., Drakos, S. G., Bull, D. A., Patel, A. N., & Selzman, C. H. (2012). Improved survival in heart transplant patients living at high altitude. The Journal of thoracic and cardiovascular surgery, 143(3), 735-741.e1.
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  Higher altitudes are associated with chronic hypoxia and elevated pulmonary vascular resistance, both potentially detrimental to patients requiring heart transplantation. The purpose of the present study was to determine whether altitude negatively affects survival among patients undergoing heart transplantation.
• Felker, G. M., Lee, K. L., Bull, D. A., Redfield, M. M., Stevenson, L. W., Goldsmith, S. R., LeWinter, M. M., Deswal, A., Rouleau, J. L., Ofili, E. O., Anstrom, K. J., Hernandez, A. F., McNulty, S. E., Velazquez, E. J., Kfoury, A. G., Chen, H. H., Givertz, M. M., Semigran, M. J., Bart, B. A., , Mascette, A. M., et al. (2011). Diuretic strategies in patients with acute decompensated heart failure. The New England journal of medicine, 364(9), 797-805.
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  Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.
• Healy, A. H., Mason, N. O., Hammond, M. E., Reid, B. B., Clayson, S. E., Drakos, S. G., Kfoury, A. G., Patel, A. N., Bull, D. A., Budge, D., Alharethi, R. A., Bader, F. M., Gilbert, E. M., Stehlik, J., & Selzman, C. H. (2011). Allograft rejection in patients supported with continuous-flow left ventricular assist devices. The Annals of thoracic surgery, 92(5), 1601-7; discussion 1607.
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  Both pulsatile-flow and continuous-flow left ventricular assist devices (LVADs) successfully provide patients a bridge to transplantation. Some data suggest that continuous-flow pumps increase the risk of allograft rejection, contributing to posttransplantation morbidity and mortality. We sought to analyze the relationship between LVAD flow characteristics and subsequent allograft rejection in bridge to transplant (BTT) patients.
• McGinn, A. N., Nam, H. Y., Ou, M., Hu, N., Straub, C. M., Yockman, J. W., Bull, D. A., & Kim, S. W. (2011). Bioreducible polymer-transfected skeletal myoblasts for VEGF delivery to acutely ischemic myocardium. Biomaterials, 32(3), 942-9.
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  Implantation of skeletal myoblasts to the heart has been investigated as a means to regenerate and protect the myocardium from damage after myocardial infarction. While several animal studies utilizing skeletal myoblasts have reported positive findings, results from clinical studies have been mixed. In this study we utilize a newly developed bioreducible polymer system to transfect skeletal myoblasts with a plasmid encoding vascular endothelial growth factor (VEGF) prior to implantation into acutely ischemic myocardium. VEGF has been demonstrated to promote revascularization of the myocardium following myocardial infarction. We report that implanting VEGF expressing skeletal myoblasts into acutely ischemic myocardium produces superior results compared to implantation of untransfected skeletal myoblasts. Skeletal myoblasts expressing secreted VEGF were able to restore cardiac function to non-diseased levels as measured by ejection fraction, to limit remodeling of the heart chamber as measured by end systolic and diastolic volumes, and to prevent myocardial wall thinning. Additionally, arteriole and capillary formation, retention of viable cardiomyocytes, and prevention of apoptosis was significantly improved by VEGF expressing skeletal myoblasts compared to untransfected myoblasts. This work demonstrates the feasibility of using bioreducible cationic polymers to create engineered skeletal myoblasts to treat acutely ischemic myocardium.
• Nam, H. Y., Kim, J., Kim, S., Yockman, J. W., Kim, S. W., & Bull, D. A. (2011). Cell penetrating peptide conjugated bioreducible polymer for siRNA delivery. Biomaterials, 32(22), 5213-22.
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  The primary cardiomyocyte-specific peptide (PCM) and the cell-penetrating peptide (CPP), HIV-Tat (49-57), were incorporated into the polymer, cystamine bisacrylamide-diaminohexane (CBA-DAH), to increase the delivery of RNAi to target cells, specifically cardiomyocytes. Interestingly, the impact of PCM and Tat conjugation on cellular uptake and transfection efficiency was greater in H9C2 rat cardiomyocytes than in NIH 3T3 cells. We examined the potential for siRNA targeting SHP-1 or Fas to inhibit the apoptosis of cardiomyocytes under hypoxic conditions using PCM and Tat-modified poly(CBA-DAH), (PCM-CD-Tat). To evaluate for efficacy in inhibiting apoptosis, either Fas siRNA/polymer or SHP-1 siRNA/polymer were transfected into cardiomyocytes treated under hypoxic and serum-deprived conditions. After incubation under hypoxic conditions, treatment with either the SHP-1 siRNA complex or the Fas siRNA complex resulted in an increase in cell viability and a reduction in LDH-cytotoxicity. The cells transfected with either of the siRNA polyplexes had a lower incidence of apoptosis as demonstrated by Annexin V-FITC/PI staining. Both the SHP-1 siRNA/PCM-CD-Tat complex and the Fas siRNA/PCM-CD-Tat complex warrant further investigation as therapeutic agents to inhibit the apoptosis of cardiomyocytes.
• Bull, D. A., Reid, B. B., Selzman, C. H., Mesley, R., Drakos, S., Clayson, S., Stoddard, G., Gilbert, E., Stehlik, J., Bader, F., Kfoury, A., Budge, D., Eckels, D. D., Fuller, A., Renlund, D., & Patel, A. N. (2010). The impact of bridge-to-transplant ventricular assist device support on survival after cardiac transplantation. The Journal of thoracic and cardiovascular surgery, 140(1), 169-73.
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  To determine the impact of bridge-to-transplant ventricular assist device support on survival after cardiac transplantation.
• Hu, N., Straub, C. M., Garzarelli, A. A., Sabey, K. H., Yockman, J. W., & Bull, D. A. (2010). Ligation of the left circumflex coronary artery with subsequent MRI and histopathology in rabbits. Journal of the American Association for Laboratory Animal Science : JAALAS, 49(6), 838-44.
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  Provided is the surgical procedure for ligating the left circumflex coronary artery to simulate heart ischemia by using a rabbit model. Heart rate monitored by electrocardiogram was increased at 5 min after ligation (mean ± SEM, 205 ± 13 bpm) when compared with that before ligation (170 ± 12 bpm), but returned to baseline at 25 min after ligation (183 ± 11 bpm). A marked elevation in the ST segment and reduction of the QRS wave of the electrocardiogram indicated the evolving myocardial infarct. The ejection fraction derived from MRI was decreased by 20% in the infarcted heart. The extent of necrosis and fibrosis in the myocardium due to ischemia led to decreased compliance and efficiency of the left ventricle. Masson trichrome staining showed blue-stained fibrils with the appearance of loose, threadlike scar tissue dispersed transmurally in the left ventricle and extending toward the apex. This study demonstrates the feasibility of MRI analysis of myocardial infarction in a rabbit model. The myocardial architecture, including the geometry of the myofibers which determines the contractile function of the heart, is clearly demonstrated by using cardiac MRI. Understanding the 3-dimensional arrangement of the myocardial microstructure and how remodeling of the infarcted myocardium affects cardiac function in an animal model has important implications for the study of heart disease in humans.
• Kim, S. H., Ou, M., Bull, D. A., & Kim, S. W. (2010). Reductive degradation behavior of bioreducible poly(disulfide amine) for enhancing SiRNA efficiency. Macromolecular bioscience, 10(8), 898-905.
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  Bioreducible cationic polymer poly(CBA-DAH) containing repeated disulfide linkages on the polymer backbone was synthesized through Michael-type polyadditions of CBA to DAH monomers. Poly(CBA-DAH) could spontaneously form nanoscale polyelectrolyte complexes through electrostatic interactions with siRNA in an aqueous phase. These nanoparticles were rapidly degraded under the reductive cytoplasmic environment with subsequently releasing the siRNA cargo into the cytoplasm where RNAi takes place, as a result of the breakdown of disulfide bonds in the polymers. The reductive degradation behavior of the poly(CBA-DAH)/siRNA polyplexes is more likely to increase RNAi activity with enhancing the cytoplasmic localization of siRNA molecules. Poly(CBA-DAH) may have great potential as a gene carrier especially for therapeutic applications of siRNAs owing to the reductive degradation characteristics.
• Kotter, J. R., Drakos, S. G., Horne, B. D., Hammond, E. H., Stehlik, J., Bull, D. A., Reid, B. B., Gilbert, E. M., Everitt, M., Alharethi, R., Budge, D., Verma, D. R., Li, D. Y., Li, Y., & Kfoury, A. G. (2010). Effect of blood product transfusion-induced tolerance on incidence of cardiac allograft rejection. Transplantation proceedings, 42(7), 2687-92.
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  Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial.
• Nam, H. Y., McGinn, A., Kim, P. H., Kim, S. W., & Bull, D. A. (2010). Primary cardiomyocyte-targeted bioreducible polymer for efficient gene delivery to the myocardium. Biomaterials, 31(31), 8081-7.
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  A cardiomyocyte-targeted Fas siRNA delivery system was developed using primary cardiomyocyte (PCM) specific peptide-modified polymers with high transfection efficiency and low cytotoxicity. Primary cardiomyocyte (PCM) specific peptide, selected by phage display, was conjugated to bioreducible poly(cystamine bisacrylamide-diaminohexane, CBA-DAH) (PCD). The specificity of the PCM-modified polymer to cardiomyocytes was confirmed by competition study with free PCM ligand and by delivery to non-cardiomyocyte NIH 3T3 fibroblasts. The cellular binding and uptake of the PCM-polymer/pDNA polyplex was inhibited by addition of free PCM peptide. The impact of PCM conjugation on cellular uptake and transfection efficiency was greater in H9C2 rat cardiomyocytes than in NIH 3T3 cells. Fas siRNA/PCM-polymer polyplexes exhibited significant Fas gene silencing in rat cardiomyocytes under hypoxic conditions, leading to inhibition of cardiomyocyte apoptosis. These findings demonstrate the utility of the addition of a primary cardiomyocyte (PCM) specific peptide modification to a bioreducible polymer for targeted delivery of Fas siRNA to inhibit cardiomyocyte apoptosis.
• Nativi, J. N., Kfoury, A. G., Myrick, C., Peters, M., Renlund, D., Gilbert, E. M., Bader, F., Singhal, A. K., Everitt, M., Fisher, P., Bull, D. A., Selzman, C., & Stehlik, J. (2010). Effects of the 2006 U.S. thoracic organ allocation change: analysis of local impact on organ procurement and heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 29(3), 235-9.
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  The United Network for Organ Sharing (UNOS) implemented a thoracic organ allocation policy change (APC) in July 2006 that aimed to reduce death on the waiting list by expanding regional organ sharing. As such, organs would be allocated to the sickest recipients with highest listing status across the region. Our aim was to determine the impact of the new policy on the procurement and transplant process within our program.
• Ou, M., Kim, T. I., Yockman, J. W., Borden, B. A., Bull, D. A., & Kim, S. W. (2010). Polymer transfected primary myoblasts mediated efficient gene expression and angiogenic proliferation. Journal of controlled release : official journal of the Controlled Release Society, 142(1), 61-9.
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  This study was designed to assess the in vitro gene expression efficiency and therapeutic effectiveness of polymer mediated transfection of primary myoblasts. Autologous primary myoblast transplantation may improve the function of infarcted myocardium via myogenesis. In addition, primary myoblasts can carry exogenous angiogenic genes that encode angiogenic factors to promote therapeutic angiogenesis. Viral vectors have limited clinical application due to the induction of inflammatory reactions, tumorigenic mutations and genome integration. To overcome these problems, two new biodegradable poly(disulfide amine)s, poly(cystaminebisacryamide-diaminohexane) [poly(CBA-DAH)] and poly(cystaminebisacryamide-diaminohexane-arginine) [poly(CBA-DAH-R)], were synthesized as polymer carriers for gene delivery. In this study, primary myoblasts were isolated and purified from rat skeletal muscles. Based on an optimized polymer mediated transfection procedure using a luciferase assay and confocal microscopy, these two poly(disulfide amine)s induced up to 16-fold higher luciferase expression and much higher green fluorescence protein expression than branched poy(ethylenimine) (bPEI, 25kDa) in primary myoblasts. By flow cytometry, poly(CBA-DAH) and poly(CBA-DAH-R) promote rates of cellular uptake of florescence-labeled polymer/pDNA complexes of 97% and 99%, respectively, which are rates higher than that of bPEI 25kDa (87%). Both poly(disulfide amine)s were much less cytotoxic than bPEI 25kDa. The in vitro time-course and co-culture experiments verified that polymer engineered primary myoblasts have the ability to stimulate endothelial proliferation. These data confirmed that poly(disulfide amine)s are the safe and feasible polymeric gene carriers to transfect VEGF(165) into primary myoblasts. Polymer engineered primary myoblasts have potential for therapeutic application in the treatment of ischemic heart diseases.
• Connors, R. C., Doty, J. R., Bull, D. A., May, H. T., Fullerton, D. A., & Robbins, R. C. (2009). Effect of work-hour restriction on operative experience in cardiothoracic surgical residency training. The Journal of thoracic and cardiovascular surgery, 137(3), 710-3.
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  Resident work-hour regulations were instituted to improve patient care during resident training. Although initial data have not shown the intended benefit of limiting resident work hours, concern has developed as to whether resident operative experience has significantly decreased since instituting the work-hour restrictions.
• Ou, M., Xu, R., Kim, S. H., Bull, D. A., & Kim, S. W. (2009). A family of bioreducible poly(disulfide amine)s for gene delivery. Biomaterials, 30(29), 5804-14.
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  A family of bioreducible poly(disulfide amine)s, which differ in the length of polymethylene spacer [-(CH(2))(n)-] in the main chain and the side chain, has been synthesized. These bioreducible poly(disulfide amine)s exhibit local environment specific degradability and are associated with lower cytotoxicity than branched poly(ethylenimine) (bPEI, 25 kDa). These cationic polymers also show higher buffering capacity and protonation degree than bPEI, facilitating the endosomal escape of carried genetic materials. The transfection efficiency of these agents is oligomethylene length dependent. Poly(cystaminebisacrylamide-spermine) [poly(CBA-SP)], poly(cystaminebisacrylamide-bis(3-aminopropyl)-1,3-propanediamine) [poly(CBA-APPD)], and poly(cyxtaminebisacrylamide-bis(3-aminopropyl)-ethylenediamine) [ploy(CBA-APED)] with longer propylene [-(CH(2))(3)-] side spacer, demonstrate higher transfection efficacy than the counterpart poly(cystaminebisacrylamide-bis(2-aminoethyl)-1,3-propanediamine) [poly(CBA-AEPD)] and poly(cystaminebisacrylamide-triethylenetetramine) [poly(CBA-TETA)], which have shorter ethylene [-(CH(2))(2)-] side spacer. The poly(CBA-SP), poly(CBA-APPD), poly(CBA-APED) with the main chain spacer of -(CH(2))(4)-, -(CH(2))(3)-, -(CH(2))(2)- demonstrate similar transfection efficiency, indicating the length of polymer main chain spacer has less influence on transfection efficiency. However, with the same short ethylene [-(CH(2))(2)-] side spacer, poly(CBA-AEPD), with the longer main chain oligomethylene units [-(CH(2))(3)-], showed relatively higher transfection efficiency than poly(CBA-TETA), having shorter main chain oligomethylene units [-(CH(2))(2)-]. Of these polymeric carriers, poly(CBA-SP) demonstrated the highest transfection in the C2C12 cell line, while poly(CBA-APED) showed the highest transfection in the HeLa cell line. All of these agents showed greater transfection activity than commercialized bPEI 25 kDa. The poly(disulfide amine)s are promising safe and efficient non-viral vectors for gene delivery.
• Stehlik, J., Islam, N., Hurst, D., Kfoury, A. G., Movsesian, M. A., Fuller, A., Delgado, J. C., Hammond, M. E., Gilbert, E. M., Renlund, D. G., Bader, F., Fisher, P. W., Bull, D. A., Singhal, A. K., & Eckels, D. D. (2009). Utility of virtual crossmatch in sensitized patients awaiting heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 28(11), 1129-34.
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  Organ transplant candidates with serum antibodies directed against human leukocyte antigens (HLA) face longer waiting times and higher mortality while awaiting transplantation. This study examined the accuracy of virtual crossmatch, in which recipient HLA-specific antibodies, identified by solid-phase assays, are compared to the prospective donor HLA-type in heart transplantation.
• Yockman, J. W., Choi, D., Whitten, M. G., Chang, C. W., Kastenmeier, A., Erickson, H., Albanil, A., Lee, M., Kim, S. W., & Bull, D. A. (2009). Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct. Gene therapy, 16(1), 127-35.
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  The development of clinically beneficial myocardial gene therapy has been slowed by reliance on the use of viral carriers and non-physiologic, constitutive gene expression. To specifically address these issues, we have developed a non-viral gene carrier, water-soluble lipopolymer (WSLP), and an ischemia-inducible plasmid construct expressing vascular endothelial growth factor (VEGF), pRTP801-VEGF, to treat myocardial ischemia and infarction. Rabbits underwent ligation of the circumflex artery followed by injection of (a) an ischemia-inducible VEGF gene construct in a WSLP carrier; (b) a constitutively expressed, or unregulated, SV-VEGF gene construct in a WSLP carrier; (c) WSLP carrier alone; or (d) no injection therapy. Following 4 weeks treatment, ligation alone resulted in infarction of 48+/-7% of the left ventricle. With injection of WSLP carrier alone, 49+/-6% of the left ventricle was infarcted (P=NS). The constitutively expressed gene construct, SV-VEGF, reduced the infarct size to 32+/-7% of the left ventricle (P=0.007). The ischemia-inducible gene construct, RTP801-VEGF, further reduced the infarct size to 13+/-4% of the left ventricle (P
• Yockman, J. W., Kim, S. W., & Bull, D. A. (2009). Women and heart disease--physiologic regulation of gene delivery and expression: bioreducible polymers and ischemia-inducible gene therapies for the treatment of ischemic heart disease. Advanced drug delivery reviews, 61(10), 863-70.
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  Ischemic heart disease (IHD) is the leading cause of death in the United States today. This year over 750,000 women will have a new or recurrent myocardial infarction. Currently, the mainstay of therapy for IHD is revascularization. Increasing evidence, however, suggests that revascularization alone is insufficient for the longer-term management of many patients with IHD. To address these issues, innovative therapies that extend beyond revascularization to protection of the myocyte and preservation of ventricular function are required. The emergence of gene therapy and proteomics offers the potential for innovative prophylactic and treatment strategies for IHD. The goal of our research is to develop therapeutic gene constructs for the treatment of myocardial ischemia that are clinically safe and effective. Toward this end, we describe the development of physiologic regulation of gene delivery and expression using bioreducible polymers and ischemia-inducible gene therapies for the potential treatment of ischemic heart disease in women.
• Kim, S. H., Jeong, J. H., Ou, M., Yockman, J. W., Kim, S. W., & Bull, D. A. (2008). Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis. Biomaterials, 29(33), 4439-46.
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  A cardiomyocyte-targeted Fas siRNA delivery system was developed using prostaglandin E(2) (PGE(2))-modified siRNA polyplexes formed by a reducible poly(amido amine) to inhibit cardiomyocyte apoptosis. PGE(2), which was used as a specific ligand for cardiomyocyte targeting, was conjugated to the terminal-end of the sense siRNA (PGE(2)-siRNA). The reducible cationic copolymer, synthesized via Michael-type polyaddition of 1,6-diaminohexane and cystamine bis-acrylamide (poly(DAH/CBA)), tightly condensed the PGE(2)-siRNA conjugate to form nanosize polyplexes having a diameter of 100-150 nm. The PGE(2)-siRNA/poly(DAH/CBA) polyplexes decomplexed to release PGE(2)-siRNA in a cytosolic reducing environment due to the degradation of the reducible poly(DAH/CBA). The cellular uptake of the PGE(2)-siRNA/poly(DAH/CBA) polyplex was increased in rat cardiomyocytes (H9C2 cells) due to PGE(2) receptor-mediated endocytosis. When H9C2 cells were transfected with siRNA against Fas, a key regulator of ischemia-induced apoptosis, the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex delivery system led to a significant increase in Fas gene silencing, resulting in inhibition of cardiomyocyte apoptosis. The PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex did not induce interferon-alpha in peripheral blood mononuclear cells. These results suggest that the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex formulation may be clinically applicable as a cardiomyocyte-targeted Fas siRNA delivery system to inhibit apoptosis in cardiovascular disease.
• Ou, M., Wang, X. L., Xu, R., Chang, C. W., Bull, D. A., & Kim, S. W. (2008). Novel biodegradable poly(disulfide amine)s for gene delivery with high efficiency and low cytotoxicity. Bioconjugate chemistry, 19(3), 626-33.
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  Novel biodegradable poly(disulfide amine)s with defined structure, high transfection efficiency, and low cytotoxicity were designed and synthesized as nonviral gene delivery carriers. Michael addition between N, N'-cystaminebisacrylamide (CBA) and three N-Boc protected diamines ( N-Boc-1,2-diaminoethane, N-Boc-1,4-diaminobutane, and N-Boc-1,6-diaminohexane) followed by N-Boc deprotection under acidic condition resulted in final cationic polymers with disulfide bonds, tertiary amine groups in main chains, and pendant primary amine groups in side chains. Polymer structures were confirmed by 1H NMR, and their molecular weights were in the range 3.3-4.7 kDa with narrow polydispersity (1.12-1.17) as determined by size exclusion chromatography (SEC). Acid-base titration assay showed that the poly(disulfide amine)s possessed superior buffering capacity to branched PEI 25 kDa in the pH range 7.4-5.1, which may facilitate the escape of DNA from the endosomal compartment. Gel retardation assay demonstrated that significant polyplex dissociation was observed in the presence of 5.0 mM DTT within 1 h, suggesting rapid DNA release in the reduction condition such as cytoplasm due to the cleavage of disulfide bonds. Genetic transfections mediated by these poly(disulfide amine)s were side-chain spacer length dependent. The poly(disulfide amine) with a hexaethylene spacer, poly(CBA-DAH), had comparable transfection efficiency to bPEI 25 kDa in the tested cell lines, i.e., 293T cells, Hela cells, and NIH3T3 cells. This same poly(disulfide amine) mediated 7-fold higher luciferase expression than bPEI 25 kDa in C2C12 cells (mouse myoblast cell line), a cell line difficult to transfect with many cationic polymers. Furthermore, MTT assay indicated that all three poly(disulfide amine)s/pDNA polyplexes were significantly less toxic than bPEI/pDNA complexes.
• Yockman, J. W., Kastenmeier, A., Erickson, H. M., Brumbach, J. G., Whitten, M. G., Albanil, A., Li, D. Y., Kim, S. W., & Bull, D. A. (2008). Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction. Journal of controlled release : official journal of the Controlled Release Society, 132(3), 260-6.
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  The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [P. Poirier, et al., Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss, Arterioscler Thromb Vasc Biol. 26(5), (2006) 968-976.; K. Obunai, S. Jani, G.D. Dangas, Cardiovascular morbidity and mortality of the metabolic syndrome, Med.Clin. North Am., 91(6), (2007) 1169-1184]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [C.F. McTiernan, et al., Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts, Gene Ther, 14(23), (2007) 1613-1622]. However, this high transduction does not necessarily translate into improved efficacy [X. Hao, et al., Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model, Cardiovasc Res., 73(3), (2007) 481-487]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regard to secondary end-points of reduced symptomatology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [P.B. Shah, D.W. Losordo, Non-viral vectors for gene therapy: clinical trials in cardiovascular disease, Adv Genet, 54, (2005) 339-361]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes. Currently, polymeric non-viral gene delivery to cardiac myocardium remains underrepresented. In the past decade several advances in non-viral vector development has demonstrated increased transfection efficiency [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Of these polymers, those that employ lipid modifications to improve transfection or target cardiovascular tissues have proven themselves to be extremely beneficial. Water-soluble lipopolymer (WSLP) consists of a low molecular weight branched PEI (1800) and cholesterol. The cholesterol moiety adds extra condensation by forming stable micellular complexes and was later employed for myocardial gene therapy to exploit the high expression of lipoprotein lipase found within cardiac tissue. Use of WSLP to deliver hypoxia-responsive driven expression of hVEGF to ischemic rabbit myocardium has proven to provide for even better expression in cardiovascular cells than Terplex and has demonstrated a significant reduction in infarct size (13+/-4%, p
• Christensen, L. V., Chang, C. W., Yockman, J. W., Conners, R., Jackson, H., Zhong, Z., Feijen, J., Bull, D. A., & Kim, S. W. (2007). Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery. Journal of controlled release : official journal of the Controlled Release Society, 118(2), 254-61.
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  Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted ratio of 12:1 (polymer/DNA) mediates 16 fold higher expression of luciferase compared to an optimized bPEI control. FACS analysis revealed up to 57+/-2% GFP positive H9C2s. The efficiency of plasmid delivery to H9C2 using SS-PAED was found to depend upon glutathione (GSH) levels inside the cell. SS-PAED mediated delivery of RTP-VEGF plasmid produced significantly higher levels of VEGF expression (up to 76 fold) under hypoxic conditions compared to normoxic conditions in both H9C2 and rat aortic smooth muscle cells (A7R5). Using SS-PAED, delivery of RTP-VEGF was investigated in a rabbit myocardial infarct model using 100 mug RTP-VEGF. Results showed up to 4 fold increase in VEGF protein expression in the region of the infarct compared to injections of SS-PAED/RTP-Luc. In conclusion, SS-PAED mediated therapeutic delivery improves the efficacy of ischemia-inducible VEGF gene therapy both in vitro and in vivo and therefore, has potential for the promotion of neo-vascular formation and improvement of tissue function in ischemic myocardium.
• Connors, R. C., Muir, J. J., Liu, Y., Reiss, G. R., Kouretas, P. C., Whitten, M. G., Sorenson, T. K., Prestwich, G. D., & Bull, D. A. (2007). Postoperative pericardial adhesion prevention using Carbylan-SX in a rabbit model. The Journal of surgical research, 140(2), 237-42.
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  The presence of dense adhesions within the pericardial space complicates reoperative cardiac surgery. Prior attempts to reduce adhesion formation after primary cardiac surgery using medications or biomaterials have had variable success. Carbylan-SX (Carbylan Biosurgery Inc., Palo Alto, CA) is a hyaluronan-based biomaterial, which has been shown to be effective at reducing adhesions in a nonthoracic rat model. This study evaluates whether Carbylan-SX can effectively reduce postoperative adhesions within the pericardial cavity.
• Connors, R. C., Reuben, B. C., Neumayer, L. A., & Bull, D. A. (2007). Comparing outcomes after transthoracic and transhiatal esophagectomy: a 5-year prospective cohort of 17,395 patients. Journal of the American College of Surgeons, 205(6), 735-40.
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  Debate continues over whether transhiatal esophagectomy (THE) offers decreased morbidity and mortality compared with transthoracic esophagectomy (TTE). To definitively answer this question, we used the Nationwide Inpatient Sample database to compare morbidity and mortality after THE and TTE.
• Drakos, S. G., Kfoury, A. G., Gilbert, E. M., Long, J. W., Stringham, J. C., Hammond, E. H., Jones, K. W., Bull, D. A., Hagan, M. E., Folsom, J. W., Horne, B. D., & Renlund, D. G. (2007). Multivariate predictors of heart transplantation outcomes in the era of chronic mechanical circulatory support. The Annals of thoracic surgery, 83(1), 62-7.
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  Determining which pretransplantation (TX) characteristics predict the development of chronic renal dysfunction (CRD) or death after heart TX would enable more accurate risk assessment at the time of candidate evaluation.
• Kfoury, A. G., Hammond, M. E., Snow, G. L., Stehlik, J., Reid, B. B., Long, J. W., Gilbert, E. M., Bader, F. M., Bull, D. A., & Renlund, D. G. (2007). Early screening for antibody-mediated rejection in heart transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 26(12), 1264-9.
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  The International Society for Heart and Lung Transplantation (ISHLT) recently established a diagnostic scheme for antibody-mediated rejection (AMR). Currently, however, confirmatory immunohistochemistry studies are recommended only if AMR is clinically or histologically suspected. In this study, we examine whether a pattern of repetitive AMR occurred early enough after transplantation to warrant prospective immunohistochemistry screening in all recently transplanted recipients.
• Lee, M., Choi, D., Choi, M. J., Jeong, J. H., Kim, W. J., Oh, S., Kim, Y. H., Bull, D. A., & Kim, S. W. (2006). Hypoxia-inducible gene expression system using the erythropoietin enhancer and 3'-untranslated region for the VEGF gene therapy. Journal of controlled release : official journal of the Controlled Release Society, 115(1), 113-9.
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  Gene therapy with the vascular endothelial growth factor (VEGF) gene is a potential treatment for many disorders or injuries with ischemia. However, unregulated expression of VEGF may induce pathological angiogenesis, promoting tumor growth, diabetic proliferative retinopathy and rupture of atherosclerotic plaque. Therefore, the effective regulation of the gene expression is one of the requirements for the VEGF gene therapy. In this research, we evaluated the hypoxia-inducible gene expression system with the erythropoietin (Epo) enhancer and the Epo 3'-untranslated region (UTR). The luciferase plasmids were constructed with the Epo enhancer (pEpo-SV-Luc), the Epo 3'-UTR (pSV-Luc-EpoUTR) or both (pEpo-SV-Luc-EpoUTR). The polyethylenimine/plasmid complexes were transfected to 293 or A7R5 cells and the cells were incubated under normoxia or hypoxia. The results showed that the Epo enhancer or Epo 3'-UTR increased the target gene expression under hypoxia. pEpo-SV-Luc-EpoUTR showed the highest luciferase expression. The VEGF expression plasmid with the Epo enhancer and 3'-UTR was also constructed. The VEGF expression by pEpo-SV-VEGF-EpoUTR showed the highest specificity of the gene expression in the hypoxic cells. The results suggest that the VEGF plasmid with the Epo enhancer and the Epo 3'-UTR may be useful for gene therapy for ischemic diseases.
• Sturrock, A., Cahill, B., Norman, K., Huecksteadt, T. P., Hill, K., Sanders, K., Karwande, S. V., Stringham, J. C., Bull, D. A., Gleich, M., Kennedy, T. P., & Hoidal, J. R. (2006). Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology, 290(4), L661-L673.
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  Transforming growth factor-beta1 (TGF-beta1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remains unsettled. We studied the consequences of TGF-beta1 stimulation on freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF-beta1 initially promoted differentiation, with upregulated expression of smooth muscle contractile proteins. TGF-beta1 also induced expression of Nox4, the only NAD(P)H oxidase membrane homolog found in HPASMC, through a signaling pathway involving Smad 2/3 but not mitogen-activated protein (MAP) kinases. TGF-beta1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase flavoprotein inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF-beta1, Nox4 was present in freshly cultured cells but progressively lost with each passage in culture, paralleling a decrease in ROS production by HPASMC over time. At a later time point (72 h), TGF-beta1 promoted HPASMC proliferation in a manner partially inhibited by Nox4 small interfering RNA and dominant negative Smad 2/3, indicating that TGF-beta1 stimulates HPASMC growth in part by a redox-dependent mechanism mediated through induction of Nox4. HPASMC activation of the MAP kinases ERK1/2 was reduced by the NAD(P)H oxidase inhibitors DPI and 4-(2-aminoethyl)benzenesulfonyl fluoride, suggesting that TGF-beta1 may facilitate proliferation by upregulating Nox4 and ROS production, with transient oxidative inactivation of phosphatases and augmentation of growth signaling cascades. These findings suggest that Nox4 is the relevant Nox homolog in HPASMC. This is the first observation that TGF-beta1 regulates Nox4, with important implications for mechanisms of pulmonary vascular remodeling.
• Lee, M., Bikram, M., Oh, S., Bull, D. A., & Kim, S. W. (2004). Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease. Pharmaceutical research, 21(5), 736-41.
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  Gene therapy using vascular endothelial growth factor (VEGF) is a new potential treatment of ischemic disease. To be safe and effective, VEGF expression should be enhanced locally in ischemic tissue. In this study, we identified the cis-regulatory element for the hypoxia induction of the RTP801 promoter. In addition, pRTP801-VEGF was evaluated as a therapeutic plasmid in vitro.
• Bailey, S. H., Bull, D. A., Harpole, D. H., Rentz, J. J., Neumayer, L. A., Pappas, T. N., Daley, J., Henderson, W. G., Krasnicka, B., & Khuri, S. F. (2003). Outcomes after esophagectomy: a ten-year prospective cohort. The Annals of thoracic surgery, 75(1), 217-22; discussion 222.
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  The Department of Veterans Affairs National Surgical Quality Improvement Program is a unique resource to prospectively analyze surgical outcomes from a cross-section of surgical services nationally. We used this database to assess risk factors for morbidity and mortality after esophagectomy in Veterans Affairs Medical Centers from 1991 to 2001.
• Bull, D. A., & Maurer, J. (2003). Aprotinin and preservation of myocardial function after ischemia-reperfusion injury. The Annals of thoracic surgery, 75(2), S735-9.
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  Ischemia-reperfusion injury, a complex process involving the generation and release of inflammatory cytokines, accumulation and infiltration of neutrophils and macrophages, release of oxygen free radicals, activation of proteases, and generation of nitric oxide (NO), may result in myocardial dysfunction and possible injury to other major organs. Aprotinin, a nonspecific serine protease inhibitor used to reduce the blood loss and transfusion requirements accompanying cardiac surgery, has dose-dependent effects on coagulation, fibrinolytic, and inflammatory variables. Data indicate that aprotinin may provide protection from ischemia-reperfusion injury. In myocardial tissue models of ischemia and reperfusion, aprotinin has been shown to reduce uptake of tumor necrosis factor-alpha (TNF-alpha), generation of NO, and accumulation of leukocytes. Improved myocardial function has been observed with aprotinin treatment in animal models of ischemia-reperfusion injury. In humans, data indicate that integrin expression associated with leukocyte transmigration as well as markers of myocardial damage are reduced in patients receiving aprotinin. Further, data suggest that patients who receive aprotinin may have a reduced need for inotropic support and a decreased incidence of postoperative atrial fibrillation. In all, review of this topic indicates that aprotinin may reduce aspects of ischemia-reperfusion injury and prospective clinical studies are needed to evaluate the impact of aprotinin on associated patient outcomes.
• Bull, D. A., Bailey, S. H., Rentz, J. J., Zebrack, J. S., Lee, M., Litwin, S. E., & Kim, S. W. (2003). Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction. Journal of controlled release : official journal of the Controlled Release Society, 93(2), 175-81.
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  We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model.
• Lee, M., Rentz, J., Bikram, M., Han, S., Bull, D. A., & Kim, S. W. (2003). Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer. Gene therapy, 10(18), 1535-42.
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  Therapeutic angiogenesis with gene encoding vascular endothelial growth factor (VEGF) is a new potential treatment in cardiovascular disease. However, unregulated VEGF-mediated angiogenesis has the potential to promote tumor growth, accelerate diabetic proliferative retinopathy, and promote rupture of atherosclerotic plaque. To be safe and effective, gene therapy with VEGF must be regulated. To limit the risk of pathological angiogenesis, we developed a hypoxia-inducible VEGF gene therapy system using the erythropoietin (Epo) enhancer and water-soluble lipopolymer (WSLP). pEpo-SV-VEGF or pSV-VEGF-Epo was constructed by insertion of the Epo enhancer upstream of the Simian Virus 40 (SV40) promoter or downstream of the poly(A) signal of pSV-VEGF. In vitro transfection showed that pEpo-SV-VEGF, not pSV-VEGF-Epo, induced the VEGF expression in hypoxic cells. In addition, the VEGF protein, which was produced from the Epo-SV-VEGF-transfected and hypoxia-incubated cells, was able to enhance the proliferation of the endothelial cells. Injection of the pEpo-SV-VEGF/WSLP complex showed that the expression of VEGF was induced in ischemic myocardium, compared to normal myo-cardium. Therefore, with the localized induction of VEGF and the low cytotoxicity of WSLP, the pEpo-SV-VEGF/WSLP system may be helpful to eventually treat ischemic heart disease.
• Lee, M., Rentz, J., Han, S. O., Bull, D. A., & Kim, S. W. (2003). Water-soluble lipopolymer as an efficient carrier for gene delivery to myocardium. Gene therapy, 10(7), 585-93.
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  Water-soluble lipopolymer (WSLP), which consisted of polyethylenimine (PEI, 1800 Da) and cholesterol, was characterized as a gene carrier to smooth muscle cells and myocardium. Acid-base titration showed that WSLP had a proton-buffering effect. The size of WSLP/plasmid DNA (pDNA) complex was around 70 nm. WSLP/pDNA complex was transfected to A7R5 cells, a smooth muscle cell line. WSLP showed the highest transfection at a 40/1 N/P ratio. WSLP has higher transfection efficiency than PEI (1800 and 25 000 Da), SuperFect, and lipofectamine. In addition, WSLP has less cytotoxicity than PEI (25 000 Da), SuperFect, and lipofectamine. Since WSLP has cholesterol moiety, it may utilize cellular cholesterol uptake pathway, in which low-density lipoprotein (LDL) is involved. An inhibition study with free cholesterol or low-density lipoprotein (LDL) showed that transfection was inhibited by cholesterol or LDL, suggesting that WSLP/pDNA complex is transfected to the cells through the cholesterol uptake pathway. To evaluate the transfection efficiency to myocardium, WSLP/pDNA complex was injected into the rabbit myocardium. WSLP showed higher transfection than PEI and naked pDNA. WSLP expressed the transgene for more than 2 weeks. In conclusion, WSLP is an efficient carrier for local gene transfection to myocardium, and useful in in vivo gene therapy.
• Affleck, D. G., Bull, D. A., Bailey, S. H., Albanil, A., Connors, R., Stringham, J. C., & Karwande, S. V. (2002). PDGF(BB) increases myocardial production of VEGF: shift in VEGF mRNA splice variants after direct injection of bFGF, PDGF(BB), and PDGF(AB). The Journal of surgical research, 107(2), 203-9.
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  Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis. We hypothesized that a combination of recombinant angiogenic proteins might induce myocardial VEGF production and cause a shift in the mRNA signal produced.
• Affleck, D. G., Bull, D. A., Albanil, A., Shao, Y., Brady, J., Karwande, S. V., Eichwald, E. J., & Shelby, J. (2001). Interleukin-18 production following murine cardiac transplantation: correlation with histologic rejection and the induction of INF-gamma. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 21(1), 1-9.
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  Interleukin-18 (IL-18) and IL-12 have been shown to play an important role in the induction of interferon-gamma (IFN-gamma). IFN-gamma induces the proliferation of T cells and natural killer (NK) cells and augments the Th1 immune cascade. The role of IL-18 and IL-12 in the induction of IFN-gamma following allogeneic heart transplantation has not been described. We sought to characterize the IL-12 and IL-18 response to murine allogeneic heart transplantation, particularly with respect to IFN-gamma production and histologic transplant rejection. Forty-eight heterotopic heart transplants were performed in two groups of mice: syngeneic C3H/HeN to C3H/HeN mice and allogeneic BALB/C to C3H/HeN mice. Transplants were followed out to 2, 6, 10, and 14 days. Six transplants were performed in each group. Serum and splenic samples were used to evaluate the cytokine response by ELISA. Explanted heart tissue was processed for evidence of histologic rejection, and RT-PCR was performed to evaluate the IL-12, IL-18, and IFN-gamma signal qualitatively. Analysis of variance (ANOVA), Fisher's projected least significant difference (PLSD) was used for statistical analysis. Transplant rejection occurred in the allogeneic group histologically by day 6 and clinically by day 10. Serum IFN-gamma levels rose significantly by day 6 in the allogeneic group and then continued to rise in the splenocyte cultures. Serum IL-18 also rose significantly in the allogeneic group at day 6 compared with syngeneic group. RT-PCR revealed that the allogeneic tissue contained an increased signal for IL-12, IL-18, and IFN-gamma beginning at day 6 and peaking at day 10 after transplant. Beginning 6 days after transplantation, IL-12 and IL-18 appear to play a significant role in the induction of IFN-gamma in allogeneic heart transplants.
• Affleck, D. G., Yu, L., Bull, D. A., Bailey, S. H., & Kim, S. W. (2001). Augmentation of myocardial transfection using TerplexDNA: a novel gene delivery system. Gene therapy, 8(5), 349-53.
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  Gene therapy is a potential new strategy for the treatment of cardiovascular disease. The most efficacious method of gene delivery remains a key hurdle to effective gene therapy. We present the application of a novel, nonviral gene delivery system (TerplexDNA) to augment myocardial transfection. The hearts of New Zealand white rabbits were injected with reporter genes, luciferase cDNA or beta-galactosidase cDNA, either as naked plasmid DNA or plasmid DNA complexed with stearyl-poly(L-lysine)-low density lipoprotein (TerplexDNA). Three day left heart myocardial cell lysates produced 44571 +/- 8730 RLU (RLU = total light units/mg protein) for the TerplexDNA luciferase rabbits versus 1638 +/- 567 RLU for the naked luciferase rabbits (P = 0.002). Thirty days after injection, myocardial lysates produced 677 +/- 52 RLU for the TerplexDNA luciferase hearts versus 18 +/- 3 RLU for the naked luciferase hearts (P = 0.002). Histologic analysis of the hearts transfected with beta-galactosidase showed that TerplexDNA increased the area and depth of transfection compared with the naked plasmid DNA alone. The hearts of Sprague-Dawley rats were injected in a similar fashion and analyzed at 1, 3, 5, 10, 15, 25 and 30 days after injection. The naked luciferase injected hearts showed transient elevation of luciferase activity to day 5 but fell back to baseline levels after that time-point. The TerplexDNA luciferase injected hearts had significantly elevated luciferase activity to 30 days. The Terplex gene delivery system significantly augments myocardial transfection compared with a naked plasmid DNA system alone. The advantage in transfection efficiency appears to be related to the unique properties of the TerplexDNA carrier molecule. The TerplexDNA delivery system represents a novel means to augment transfection of the myocardium.
• Bull, D. A., Neumayer, L. A., Stringham, J. C., Meldrum, P., Affleck, D. G., & Karwande, S. V. (2001). Coronary artery bypass grafting with cardiopulmonary bypass versus off-pump cardiopulmonary bypass grafting: does eliminating the pump reduce morbidity and cost?. The Annals of thoracic surgery, 71(1), 170-3; discussion 173-5.
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  Cardiopulmonary bypass (CPB) may contribute to the complications and cost of coronary artery bypass grafting (CABG). Off-pump CABG (OPCAB) allows coronary revascularization without CPB. We hypothesized that OPCAB provides satisfactory graft patency while reducing complications and cost compared with CABG with CPB.
• Bull, D. A., Stringham, J. C., Karwande, S. V., & Neumayer, L. A. (2001). Effect of a resident self-study and presentation program on performance on the thoracic surgery in-training examination. American journal of surgery, 181(2), 142-4.
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  In this study we examine whether conversion from a didactic lecture format to a resident self-study and presentation program can improve performance on the Thoracic Surgery In-Training Examination (TSITE).
• Affleck, D. G., Karwande, S. V., Bull, D. A., Haller, J. R., Stringham, J. C., & Davis, R. K. (2000). Functional outcome and survival after pharyngolaryngoesophagectomy for cancer. American journal of surgery, 180(6), 546-50.
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  Surgical resection of the larynx, hypopharynx and cervical esophagus, or pharyngolaryngoesophagectomy (PLE), with pharyngogastric anastomosis (PGA) offers a means of controlling local and regional carcinoma of the upper aerodigestive tract (UADT). We reviewed our experience with PLE for carcinoma of the UADT to evaluate functional outcome and survival.
• Bull, D. A., Connors, R. C., Albanil, A., Reid, B. B., Neumayer, L. A., Nelson, R., Stringham, J. C., & Karwande, S. V. (2000). Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor. The Journal of thoracic and cardiovascular surgery, 119(2), 242-50.
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  Inflammatory cytokines, particularly tumor necrosis factor, contribute to myocardial dysfunction after ischemia-reperfusion injury. Aprotinin may improve outcomes in cardiac surgery through suppression of inflammatory mediators. We hypothesized that aprotinin may exert its beneficial effects through suppression of tumor necrosis factor alpha.
• Bull, D. A., Connors, R. C., Reid, B. B., Albanil, A., Stringham, J. C., & Karwande, S. V. (2000). Improved biochemical preservation of lung slices during cold storage. The Journal of surgical research, 90(2), 144-8.
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  Development of lung preservation solutions typically requires whole-organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that lung slices could be used to assess preservation of biochemical function during cold storage.
• Bull, D. A., Reid, B. B., Connors, R. C., Albanil, A., Stringham, J. C., & Karwande, S. V. (2000). Improved biochemical preservation of heart slices during cold storage. International journal of surgical investigation, 2(2), 117-23.
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  Development of myocardial preservation solutions requires the use of whole organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that myocardial slices could be used to assess preservation of biochemical function during cold storage.
• Shapiro, S. B., Morris, S. E., Bull, D. A., & Barton, R. G. (2000). Hypoxemia from an atrial septal defect 7 days after blunt thoracic trauma. Journal of cardiothoracic and vascular anesthesia, 14(1), 56-8.
• Stringham, J. C., Bull, D. A., & Karwande, S. V. (2000). Patch closure of the aortic anulus in a recipient of a ventricular assist device. The Journal of thoracic and cardiovascular surgery, 119(6), 1293-4.
• Stringham, J. C., Bull, D. A., Fuller, T. C., Kfoury, A. G., Taylor, D. O., Renlund, D. G., & Karwande, S. V. (1999). Avoidance of cellular blood product transfusions in LVAD recipients does not prevent HLA allosensitization. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 18(2), 160-5.
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  Transfusion of cellular blood products during left ventricular assist device (LVAD) implantation has been associated with HLA allosensitization, resulting in the need for a negative prospective cross-match and prolonged transplant waiting times. In order to prevent this risk, we developed a protocol to avoid transfusion of cellular blood products.
• Swenson, J. D., & Bull, D. A. (1999). Intraoperative diagnosis and treatment of pleural effusion based on transesophageal echocardiographic findings. Anesthesia and analgesia, 89(2), 309-10.
• Swenson, J. D., & Bull, D. A. (1997). Postoperative ulnar neuropathy associated with prolonged ischemia in the upper extremity during coronary artery bypass surgery. Anesthesia and analgesia, 85(6), 1275-7.
• Bull, D. A., Karwande, S. V., Hawkins, J. A., Neumayer, L. A., Taylor, D. O., Jones, K. W., Renlund, D. G., Putnam, C. W., & Putnam, C. W. (1996). Long-term results of cardiac transplantation in patients older than sixty years. UTAH Cardiac Transplant Program. The Journal of thoracic and cardiovascular surgery, 111(2), 423-7; discussion 427-8.
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  Advanced age has traditionally been a contraindication to cardiac transplantation. We have, however, offered cardiac transplantation to patients older than 60 years with end-stage heart failure if they were otherwise acceptable candidates. From 1985 to 1994, 527 patients underwent cardiac transplantation. Among these patients, 101 were older than 60 years at transplantation. The mean follow-up of this group is 6 years. Patients older than 60 years had significantly fewer rejection episodes per patient than those who were younger than 60 years at transplantation (1.9 +/- 1.3 vs 2.6 +/- 1.8, p = 0.009). No difference in the number of infectious complications per patient was detected between the two groups. Both short-term and long-term survival after transplantation were significantly lower for patients who were older than 60 years at transplantation than for younger patients (p < 0.05). The 6-year actuarial survival after transplantation for patients older than 60 years was 54% compared with 72% for patients younger than 60 years at transplantation (p < 0.05). Patients older than 60 years at transplantation were more likely to die of infectious complications or malignant disease after transplantation (p < 0.05). We believe caution is warranted in offering cardiac transplantation to patients older than 60 years. This group of patients should be carefully observed for the development of potentially life-threatening infectious complications or new malignant tumors after transplantation.
• Hunter, G. C., Smyth, S. H., Aguirre, M. L., Baxter, B. T., Bull, D. A., King, D. D., Wang, Y. P., Hall, K. A., & Putnam, C. W. (1996). Incidence and histologic characteristics of blebs in patients with abdominal aortic aneurysms. Journal of vascular surgery, 24(1), 93-101.
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  Aortic blebs-focal outpouchings within aortic aneurysms-may contribute to their eventual rupture. In this study we determine the incidence of aortic blebs and describe their microscopic features.
• Sprung, R. F., Cataldo, R. M., Gregory, M. C., Marks, M. L., Bull, D. A., & Litwin, S. E. (1996). Ruptured sinus of Valsalva aneurysm in a patient with autosomal dominant polycystic kidney disease. The Western journal of medicine, 165(6), 379-82.
• Bull, D. A., Hunter, G. C., Holubec, H., Aguirre, M. L., Rappaport, W. D., & Putnam, C. W. (1995). Cellular origin and rate of endothelial cell coverage of PTFE grafts. The Journal of surgical research, 58(1), 58-68.
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  To determine the origin, cell type present, and rate of endothelial cell coverage of PTFE grafts, 5-cm segments of 4-mm-diameter, 60-microns PTFE grafts were implanted end-to-end bilaterally in the carotid arteries of greyhound dogs. An external jugular vein wrap was applied to the outer surface of one of the PTFE grafts; the contralateral PTFE graft, which was unwrapped, served as its control. Two dogs each were sacrificed at 3, 5, 7, 14, 21, 28, and 35 days postimplantation. Anastomotic endothelial ingrowth was analyzed using scanning electron microscopy. Microvessel ingrowth was documented in longitudinal H&E sections. Cell identity was established by immunohistochemistry with factor VIII antibody, Ulex europaes, leukocyte common antigen, and antibodies to alpha-actin, desmin, vimentin, and basic fibroblast growth factor. All grafts were patent at the time of harvest. Endothelial cell migration from the native artery adjacent to the anastomosis commenced at 7 days, extended to 5 mm beyond the proximal and distal anastomoses by 14 days and to 1.0 cm by 35 days. Endothelialization of the mid-portion of the wrapped grafts occurred via microvessel ingrowth, a process which began at 7 days. Microvessels reached the luminal surface by 28 days and an endothelial cell monolayer was established by 35 days. Wrapping the external surface of the graft with vein increased the rate of graft healing. Basic fibroblast growth factor was detectable by immunohistochemistry at the vein wrap-graft interface in the first 14 days.
• Erdoes, L. S., Hunter, G. C., Venerus, B. J., Hall, K. A., Bull, D. A., Berman, S. S., Pallos, L. L., & Copeland, J. C. (1995). Prospective evaluation of peripheral vascular disease in heart transplant recipients. Journal of vascular surgery, 22(4), 434-40; discussion 440-2.
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  Retrospective reviews suggest that the progression of peripheral vascular disease (PVD) may be accelerated in heart transplant recipients. This study was undertaken to determine the incidence and to identify those risk factors that may be associated with the development or progression of PVD in these patients.
• Bull, D. A., Neumayer, L. A., Venerus, B. J., Putnam, C. W., Rosado, L., Lund, P., McIntyre, K. E., Bernhard, V. M., Copeland, J. G., & Sethi, G. K. (1994). The effects of improved hemodynamics on aortic dimensions in patients undergoing heart transplantation. Journal of vascular surgery, 20(4), 539-44; discussion 544-5.
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  Retrospective studies have demonstrated an accelerated growth rate of abdominal aortic aneurysms in heart transplant patients. This prospective study was undertaken to define the relationship between cardiac hemodynamics and posttransplant aortic dilation.
• Bull, D. A., Hunter, G. C., Crabtree, T. G., Bernhard, V. M., & Putnam, C. W. (1993). Hepatic ischemia, caused by celiac axis compression, complicating pancreaticoduodenectomy. Annals of surgery, 217(3), 244-7.
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  In the course of pancreaticoduodenectomy, profound hepatic ischemia developed in two patients (one with ampullary carcinoma, the other with chronic pancreatitis). This article addresses the diagnosis and correction of the celiac axis compression responsible in this complication.
• Bull, D. A., Neumayer, L. A., Hunter, G. C., Keksz, J., Sethi, G. K., McIntyre, K. E., & Bernhard, V. M. (1993). Risk factors for stroke in patients undergoing coronary artery bypass grafting. Cardiovascular surgery (London, England), 1(2), 182-5.
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  Stroke is a significant cause of morbidity and mortality following coronary artery bypass grafting (CABG). Over a 30-month period, 245 consecutive patients undergoing elective CABG were prospectively examined to determine which risk factors might predispose to stroke following surgery. The risk factors evaluated included hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, smoking, atrial fibrillation, a history of cerebrovascular accident or transient ischemic attack, carotid artery stenosis > 60% documented by duplex scanning, severe atherosclerosis of the ascending aorta, and the presence of ventricular thrombus. Postoperative stroke occurred in five of the 245 patients (2%), four evident immediately on awakening and one on day 7 after surgery. The probable causes of the immediate strokes were atheroembolism in three patients and severe ipsilateral carotid stenosis in one. Hypertensive hemorrhage was responsible for the one case of delayed stroke. In this study, carotid artery stenosis did not presage stroke following CABG, but ventricular thrombus was highly predictive of stroke after surgery.
• Bull, D. A., Seftor, E. A., Hendrix, M. J., Larson, D. F., Hunter, G. C., & Putnam, C. W. (1993). Putative vascular endothelial cell chemotactic factors: comparison in a standardized migration assay. The Journal of surgical research, 55(5), 473-9.
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  While a number of chemoattractants of vascular endothelial cells have now been identified in vitro, differences in methodology preclude comparisons of substances evaluated in different assays. Here, we report a standardized chemotactic assay in which the migration of calf pulmonary artery endothelial cells in a 48-well microchemotaxis chamber was determined. Nonstimulated (control) migration was remarkably constant (mean +/- SD, 96 +/- 14) from plate to plate, thus allowing the indexing of relative migration of stimulated cells to that of nonstimulated cells in the control wells of that plate. Based on the relative migrations observed in response to each of the substances evaluated, those proving to be stimulatory of migration were placed in rank order by potency. The growth factors epidermal growth factor, transforming growth factor-alpha, and basic fibroblast growth factor (followed by pentosan polysulfate, plasmin, fibronectin, fibrinogen, granulocyte-macrophage colony stimulating factor heparin, adenosine, and MgSO4) were the most potent. Only the platelet factors platelet-derived growth factor-BB and platelet activating factor proved inhibitory of migration. Combining fibrinogen with other chemoattractants produced either stimulation or inhibition in comparison to the migration observed with fibrinogen alone, suggesting that more than one signal transduction mechanism was, in all likelihood, invoked by the various agents. This assay will allow the rapid screening and rank ordering of additional putative chemoattractants, will facilitate the study of the biochemical mechanisms involved in endothelial cell migration, and will permit the evaluation of pharmacologic agents capable of modulating stimulated or unstimulated migration.
• Sciolaro, C., Hunter, G. C., McIntyre, K. E., Bull, D. A., Parent, F. N., & Bernhard, V. M. (1993). Thrombectomy and isolated limb perfusion with urokinase in the treatment of phlegmasia cerulea dolens. Cardiovascular surgery (London, England), 1(1), 56-60.
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  Phlegmasia cerulea dolens is a rare form of deep vein thrombosis. A patient with recurrent episodes of such thrombosis caused by protein C deficiency who developed phlegmasia cerulea dolens is reported. Limb perfusion with urokinase successfully restored venous outflow after unsuccessful attempts at thrombectomy.
• Bull, D. A., Hunter, G. C., Copeland, J. G., Bernhard, V. M., Rosado, L. J., McIntyre, K. E., Sethi, G. K., & Putnam, C. W. (1992). Peripheral vascular disease in heart transplant recipients. Journal of vascular surgery, 16(4), 546-53; discussion 553-4.
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  The improved longevity of heart transplant recipients demands heightened awareness of the long-term complications of the procedure. Between 1979 and 1990, 232 patients received 241 heart transplants at our institution. Accelerated coronary atherosclerosis occurred in 45 (19%) of the 232 patients, typically appearing within 2 years of transplantation, whereas peripheral vascular disease (PVD) appeared in 23 (10%) of the 232 patients, usually within 3 years of transplantation. In the patients with PVD, 13 had occlusive disease, nine had aneurysms, and one patient suffered a vertebral artery dissection. Accelerated coronary atherosclerosis afflicted 12 (52%) of the 23 patients affected by PVD (p < 0.05) and preceded the development of PVD in all 12. Logistic regression analysis revealed risk factors predictive of the development of PVD after transplantation to be a pretransplant history of ischemic cardiomyopathy and posttransplant hypertension and hypertriglyceridemia (p < 0.05), with the presence of more than one risk factor increasing the probability of development of PVD. Those patients thus identified as at risk should be closely monitored for the development of PVD. Aggressive medical management of hypertension and hyperlipidemia in this subpopulation may forestall or prevent the development of peripheral vascular disease after heart transplantation.
• Bull, D. A., Neumayer, L. A., Hunter, G. C., Sethi, G. K., McIntyre, K. E., Bernhard, V. M., & Putnam, C. W. (1992). Improved sterile technique diminishes the incidence of positive line cultures in cardiovascular patients. The Journal of surgical research, 52(2), 106-10.
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  In order to determine the incidence of positive line cultures, especially as affected by differing protocols for line insertion, cultures were obtained from lines in residence for up to 4 days from cardiac patients (who received Cefuroxime) and vascular patients (who received Cefazolin) as prophylaxis perioperatively. Positive cultures were obtained from 95 (19%) of 496 lines in cardiac patients and 83 (31%) of 261 lines in vascular patients. There was a linear relationship between duration of line residence and the incidence of positive line cultures, increasing from 14% on Day 1 to 33% on Day 4. The use of full sterile technique at the time of insertion halved the incidence of subsequent positive line cultures. Four of the 403 (1%) patients each had a single episode of postoperative line sepsis. Another four patients developed wound infections with the same organisms as cultured from their lines. One patient has had a vascular graft infection with the same organism cultured as was isolated from a Swan-Ganz line 1 year previously. These data suggest that monitoring lines should be inserted using full sterile technique and removed as soon as the patient is hemodynamically stable.
• Hall, K. A., Wong, R. W., Hunter, G. C., Camazine, B. M., Rappaport, W. A., Smyth, S. H., Bull, D. A., McIntyre, K. E., Bernhard, V. M., & Misiorowski, R. L. (1992). Contrast-induced nephrotoxicity: the effects of vasodilator therapy. The Journal of surgical research, 53(4), 317-20.
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  The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with peripheral vascular disease has generated concern about the incidence and avoidance of contrast-induced nephrotoxicity (CIN). In this prospective study, we sought to identify those patients at greater risk of developing CIN and to evaluate the efficacy of vasodilator therapy with dopamine in limiting this complication. Baseline serum creatinine (Cr) concentrations were obtained on admission and daily for up to 72 hr after angiography in 222 patients undergoing 232 angiographic procedures. The preangiographic treatment was varied at 2-month intervals for 1 year. All patients received an intravenous infusion of 5% dextrose and 0.45% normal saline at a rate of 75 to 125 ml/hr. During the first interval patients received 12.5 g of 25% mannitol immediately prior to their contrast load, in addition to intravenous fluids. During the next 2-month period the patients were given renal dose dopamine intravenously (3 micrograms/kg/min) commencing the evening before angiography and continued to the next morning. During the latter half of the study the treatment regimens were modified so that the use of mannitol was restricted to patients with diabetes mellitus and dopamine to patients with serum creatinine concentrations of > or = 2 mg/dl. Postangiographic elevation in Cr occurred in 2, 10.4, and 62% of studies in patients with baseline creatinine levels of < or = 1.2 mg/dl, 1.3 to 1.9 mg/dl, and > or = 2.0 mg/dl, respectively. None of the patients receiving dopamine experienced an elevation in creatinine. There was no statistical correlation between age, diabetes, or medication with calcium channel blockers and CIN.(ABSTRACT TRUNCATED AT 250 WORDS)
• Holubec, H., Hunter, G. C., Putnam, C. W., Bull, D. A., Rappaport, W. D., & Chvapil, M. (1992). Effect of surgical manipulation of polytetrafluoroethylene grafts on microstructural properties and healing characteristics. American journal of surgery, 164(5), 512-6.
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  The effects on graft healing of alterations in the microstructure of polytetrafluoroethylene (PTFE) grafts induced by surgical instruments have not been fully elucidated. This study evaluates changes in the structural and physical properties of PTFE grafts resulting from the intentional application of commonly used surgical instruments and the influence of these changes on cellular ingrowth. The extent of cellular ingrowth into intact (10, 30, and 60 microns unreinforced and 30 microns reinforced [R]) and structurally compromised PTFE grafts (30 reinforced and 60 microns nonreinforced) implanted subcutaneously in Sprague-Dawley (n = 14) rats was evaluated at 7 and 21 days. The thrombogenicity of 10-, 30-, 60-, and 80-microns intact graft segments was determined gravimetrically after suspension in the internal jugular vein of dogs for 90 minutes. Cellular ingrowth consisting of fibroblasts, macrophages, and microvessels was directly related to porosity and was most extensive in 60-microns uncompromised graft segments, being 7-, 17-, and 20-fold greater than was observed in 60- and 30R-microns compromised grafts and undamaged 10-microns grafts, respectively. There was a direct relationship between porosity and thrombogenicity of intact graft segments suspended in the jugular vein. The amount of thrombus adherent to 80-microns graft segments was eightfold greater compared with 10-microns grafts. Manipulation of PTFE with surgical instruments significantly impairs healing and may be a possible etiologic factor in the poor long-term performance of these grafts.
• Valente, J. F., Bull, D. A., Fennerty, B. P., & Rappaport, W. D. (1991). Gallstone pancreatitis. Choosing and timing treatment. Postgraduate medicine, 89(2), 123-4, 126-8, 130.
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  Patients with gallstone pancreatitis are often seen initially by primary care physicians. Prompt diagnosis and timely intervention are crucial in reducing morbidity and mortality. Initial management should include supportive medical care and surgical consultation. The timing of surgery is then dictated by serum enzyme levels and liver function test results as well as by the patient's condition. The role of endoscopic intervention is currently evolving. Whether surgery or endoscopic sphincterotomy is preferable as primary therapy for gallstone pancreatitis remains unresolved. However, sphincterotomy with stone extraction is a viable option in selected cases, especially in patients who have severe gallstone pancreatitis.
• Neumayer, L. A., Bull, D. A., Mohr, J. D., & Putnam, C. W. (1990). The acutely affected abdomen in paraplegic spinal cord injury patients. Annals of surgery, 212(5), 561-6.
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  The records of 145 paraplegic or quadriplegic patients were reviewed to identify those factors useful in the correct diagnosis of the acute abdomen in this population. Twenty-one patients had 22 episodes of acute or subacute abdominal problems. Presenting complaints, physical findings, and laboratory results were useful in various ways. However appropriate radiographic studies led to the correct diagnosis in 77% of patients. Although paraplegic and quadriplegic patients are predisposed to a distinct constellation of medical problems, including urinary tract infection and calculi, they also may present with other abdominal conditions that cause significant morbidity and mortality if not promptly recognized.

Proceedings Publications

• Bull, D. A., Skokan, M. D., & Elstad, M. R. (2000, Spring). Percutaneous Cardiopulmonary Bypass For Bronchoscopic Therapy of Severe Nonmalignant Tracheal Stenosis. In Proceedings of the American College of Chest Physicians.
• Bull, D. A., Stringham, J. C., Karwande, S. V., & Neumayer, L. A. (2000, Spring). Effect of a Resident Self-Study and Presentation Program on Performance on the Thoracic Surgery In Training Examination. In Proceedings of the Association for Surgical Education.
• Bull, D. A., Stringham, J. C., Neumayer, L. A., & Karwande, S. V. (2000, Spring). CABG with Cardiopulmonary bypass versus OPCAB: Does Eliminating the pump Reduce Morbidity and Cost?. In Proceedings of the 36th Annual Meeting of the Society of Thoracic Surgeons.
• Bull, D. A., Swenson, J., & Stringham, J. C. (2000, Fall). Subjective Assessment of Ventricular Preload Using TEE during Separation from Cardiopulmonary Bypass. In Proceedings of the Annual Meeting of the International Anesthesia Research Society.
• Bull, D. A., Conners, R. C., Albanil, A., Stringham, J. C., & Karwande, S. V. (1999, Spring). Aprotinin Preserves Myocardial Biochemical Function During Cold Storage Through Suppression of TNF. In Proceedings of the 25th Annual Meeting of the Western Thoracic Surgical Association.
• Bull, D. A., Connors, R. C., Reid, B. A., Albanil, A., Stringham, J. C., & Karwande, S. V. (1999, Fall). Improved Biochemical Preservation of Lung Slices During Cold Storage. In Preceedings of the Association for Academic Surgery.
• Bull, D. A., Reid, B. A., Stringham, J. C., & Karwande, S. V. (1999, Spring). A Rapid Technique to Assess Preservation of Myocardial Biochemical Function During Cold Storage. In Proceedings of the 23rd Scientific Symposium of the Association of VA Surgeons.
• Bull, D. A., Stringham, J. C., Kfoury, A. G., Taylor, D. O., Renlund, D. G., & Karwande, S. V. (1998, Spring). Avoidance of Cellular Blood Product Transfusions in LVAD Recipients Does Not Prevent HLA Allosensitization. In Proceedings of the 18th Annual Meeting and Scientific Session of the International Society for Heart and Lung Transplantation.
• Bull, D. A., Karwande, S. V., Hawkins, J. A., Neumayer, L. A., Taylor, D. O., Jones, K. W., Renlund, D. G., & Putnam, C. W. (1995, Fall). Long-term Results of Cardiac Transplantation in Patients Older than 60 years. In Proceedings of the Western Thoracic Surgical Association.
• Bull, D. A., Neumayer, L. A., & Hunter, G. C. (1994, Spring). The Effects of Improved Hemodynamics on Aortic Dimensions in Cardiac Transplant Patients. In Proceedings of the Western Vascular Society.
• Bull, D. A., Stahl, R. D., & Karwande, S. V. (1994, Spring). The High Risk Cardiac Donor: Potential Pitfalls. In Proceedings of the International Society for Heart and Lung Transplantation.
• Bull, D. A., Hunter, G. C., Copeland, J. G., Bernhard, V. M., Rosado-Lopez, L., Sethi, G. K., & McIntyre, K. E. (1992, Spring). Risk Factors for Peripheral Vascular Disease in Heart Transplant Patients. In Proceedings of the Western Vascular Society.
• Bull, D. A., Fante, R., Van Dalen, J. T., Hunter, G. C., McIntyre, K. E., & Bernhard, V. M. (1991, Spring). Correlation of Eye Findings with Carotid Artery Stenosis. In Proceedings of the XX World Congress of the International Society for Cardiovascular Surgery.
• Bull, D. A., Neumayer, L. A., Hunter, G. C., McIntyre, K. E., Keksz, J. A., & Bernhard, V. M. (1991, Spring). Risk Factors for Stroke Following Coronary Artery Bypass Grafting. In Proceedings of the XX World Congress of the International Society for Cardiovascular Surgery.
• Bull, D. A., Neumayer, L., Hunter, G. C., Sethi, G. K., McIntyre, K. E., & Bernhard, V. M. (1991, Spring). The Influence of Sterile Technique on the Incidence of Positive Line Cultures in Cardiovascular Patients. In Proceedings of the Association of VA Surgeons.
• Bull, D. A., Pedersen, D., Rappaport, W., Hunter, G. C., & Halldorsson, A. (1991, Fall). The Natural History of Diaphragmatic Injuries in the Rabbit Model. In Proceedings of the ACS Committee on Trauma.
• Bull, D. A., Hunter, G. C., & Copeland, J. G. (1990, Fall). The Progression of Atherosclerotic Lesions in Heart Transplant Patients. In Proceedings of the Western Vascular Society.
• Bull, D. A., Neumayer, L., Hunter, G. C., Putnam, C. W., McIntyre, K. E., & Bernhard, V. M. (1990, Spring). The Effect of Insertion Technique on the Incidence of Intravascular Line Cultures. In Proceedings of the First International Conference on the Prevention of Infection.
• Bull, D. A., Parent, F. N., Piotrowski, J. J., Bernhard, V. M., Pond, G. D., Pabst, T. S., Hunter, G. C., & McIntyre, K. E. (1989, Fall). Outcome of Intraarterial Urokinase for Acute Vascular Occlusion. In Proceedings of the Western Vascular Society.

Presentations

• Hsu, C., Malo, J., Mosier, J. M., Natt, B., Hypes, C., Lick, S. D., & Bull, D. A. (2019, May/). Duration and Outcomes of Veno-Venous Extracorporeal Membrane Oxygenation Support in Acute Respiratory Distress Syndrome: Results from ELSO database. American association for thoracic surgery 99th annual meeting. Toronto: American association for thoracic surgery.
• Kazui, T., Lick, S. D., Hsu, C., & Bull, D. A. (2019, January). Does use of bilateral mammary arteries increase short-term risk in diabetic patients? Results from The Society of Thoracic Surgeons Adult Cardiac Surgery Database. 55th STS annual meeting. San Diego: STS.
• Bull, D. A., Adluru, G., Chen, L., Kim, S., Hu, N., Sabey, K., Kholmovski, E., Marrouche, N., & DiBella, E. (2011, Spring). Late Gadolinium Enhancement Imaging Using Stack of Stars and Compressed Sensing. 2011 SCMR/EuroCMR Joint Scientific Sessions. Nice, France.
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  meeting presentation - not published abstract and not published posterInternational
• Bull, D. A. (2004, Spring). Genetics and the Response to Cardiopulmonary Bypass. Innovative Strategies to Improve Open Heart Surgery Outcomes. San Antonio, TX.
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  meeting presentation - not published abstract and not published postersNational2004
• Bull, D. A. (2003, Fall). Overview of Ishcemia-reperfusion injury. Innovative Strategies to Improve Open Heart Surgery Outcomes. Chicago, Illinois.
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  meeting presentation - not published abstracts and not published postersNational2003
• Bull, D. A. (2003, Spring). The role of TNF in the response to ischemia-reperfusion and cardio-pulmonary bypass. Innovative Strategies to Improve Open Heart Surgery Outcomes. San Francisco, CA.
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  meeting presentation - not published abstract and not published posterNational2003
• Bull, D. A. (2002, Spring). Ani-inflammatory Agents and Cardiopulmonary Bypass. presented at the 3rd International Symposium for Myocardial Protection from Surgical Ischemic-Reperfusion Injury. Asheville, Norch Carolina.
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  meeting presentation -- not published abstract and not published posterInternational
• Bull, D. A. (2001, Fall). OPCAB: An Evolving Experience. Innovative Strategies to Improve Open Heart Surgery Outcomes. San Francisco, CA.
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  meeting presentation - not published abstract and not published postersNational 2001
• Bull, D. A. (2000, Fall). Esophageal Cancer: The operative approach. The University of Utah School of Medicine & The Huntsman Cancer Institute's Second Annual Gastrointestional Conference. Park City, Utah: University of Utah.
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  meeting presentation - not published abstracts & not published postersLocal/Regional2000

Poster Presentations

• Bull, D. A., Lick, S. D., Hypes, C., Natt, B., Mosier, J. M., Malo, J., Hsu, C., & Kazui, T. (2020, April). Interfacility transfer via a mobile intensive care unit following a double lumen catheter cannulation at the referring facility for veno-venous extracorporeal membrane oxygenation. THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION 2020 Scientific Program. Montreal, Canada: THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION.
• Kazui, T., Hsu, C., Lick, S. D., & Bull, D. A. (2019, October). Venovenous extracorporeal membrane oxygenation and risk factors for adverse outcomes in acute respiratory distress syndrome: Results from the extracorporeal life support organization database. 2nd Annual Scientific Meeting of the Japanese Association for Thoracic Surgery. Kyoto, Japan: Japanese Association for Thoracic Surgery.

Reviews

• Bull, D. A. (2003. Aprotinin and preservation of myocardial function after ischemia-reperfusion injury [Review](pp S735-9).
• Bull, D. A. (1998. Core Curriculum Review (Video).
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  book reviewCore Curriculum Review (Video)
• Bull, D. A. (1993. The Fibroblast Growth Factor Family.
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  book reviewCurr Surg, 50, 675video/Film/CD/Web/Podcast
• Bull, D. A. (1992. Atherosclerotic aneurysms of the axillary artery. A report of two cases and a review of the literature [Review](pp 172-7).
• Bull, D. A. (1991. Gallstone pancreatitis. Choosing and timing treatment [Review](pp 123-4, 126-8, 130).

Others

• Bull, D. A., Donaldson, C., Palmer, B., Zile, M., Takamaru, S., Meyer, M., VanBuren, P., Spinale, F., Maughan, D., Redfield, M., & LeWinter, M. (2011, June). Passive Myocardial tension in patients with hypertension, type 2 diabetes and coronary artery disease [Abstract].
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  06-01-2011
• Bull, D. A., Hu, N., Sabey, K., & Hwang, J. (2011, Fall). Netrin-1 enhances coronary revascularization in the conotruncalbanded chick embryo [Abstract].
• Bull, D. A., Hu, N., Sabey, K., Garzarelli, G., Buswell, H., & Dibella, E. (2011, Fall). Magnetic resonance imaging assessment in ventricular remodelinb after myocardial infarction in the rabbit [Abstract]. Experimental Biology.
• Bull, D. A., Sabey, K. H., Hu, N., & Hawkins, J. A. (2010, July). Coronary Artery Remodeling in the Conotruncal Banded Click Embryo [Abstract]. University of Utah Undergraduate Research Abstracts.
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  University of Utah Undergraduate Research Abstracts 07-01-2010
• Bull, D. A., Affleck, D. G., Bailey, S. H., Albanil, A., Connors, R., Stringham, J. C., & Karwande, S. V. (2001, Spring). PDGFBB Increases Myocardial Production of VEGF: Shift in VEGF mRNA Splice Variants After Direct Injection of BFGF, PDGFBB and PDGFAB [Abstract]. J Surg Res.
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  Presented at the 35th Annual Meeting of the Association for Academic Surgery [Abstract]J Surg Res, 100, 251
• Bull, D. A., Bailey, S. H., Zebrack, J. S., Litwin, S. E., Affleck, D. G., Yu, L., & Kim, S. W. (2001, Spring). Terplex DAN Mediated VEGF-165 gene and Protein Therapy Augments Recovery of Left Ventricular Function Following Acute Ischemia. Circulation, 104(17), 11-149.
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  presented at the American Heart Association Scientific Sessions [Abstract]
• Bull, D. A., Doty, J. R., Flores, J. H., & Doty, D. B. (2001, Spring). Valve Repair and Replacement For Valvular Heart Disease Secondary To Phentermine-Fenfluramin Use. Circulation, 104(17), II-685.
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  Presented at the American Heart Association Scientific Session [Abstract]
• Bull, D. A., Yazaki, Y., Kfourty, A. G., Dabbas, B., Hammond, E. H., Moore, S. V., Long, J. W., Stringham, J. C., & Taylor, D. O. (2001, Spring). Risk Fasctor for Persistent or Recurrent Steroid-Resistant Cardiac Allograft Rejection: Is Pre-Transplant Diagnosis of Idiopathic Dilated Cardiomyopathy A Risk Factor Associated With Poor Outcome?. Circulation, 104(17), II-365.
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  Presented at the American Heart Association Scientific Sessions [Abstract]published abstract
• Bull, D. A., Karwande, S. V., Meldrum, P. A., Lonardo, N. W., & Stringham, J. C. (2000, Spring). Oral Amiodarone for Atrial Fibrillation Prophylaxis: Does It Work? [Abstract]. Chest.
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  published abstractChest, 118(4), 212-213 S
• Bull, D. A., McKellar, S., Marks, J., Roberts, L., Fuller, T., Stringham, J., & Long, J. (1998, Fall). Impact of HLA-Alloimmunization in Mechanical Bridge-to-Transplantation [Abstract]. ASAIO.
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  published abstractASAIO, 44(2), 36
• Bull, D. A., Stringham, J. C., Kfoury, A. G., Taylor, D. O., Renlund, D. G., & Karwande, S. V. (1998, Spring). Avoidance of Cellular Blood Product Transfusions in LVAD Recipients Does Not Prevent HLA Allosensitization [Abstract]. J Heart Lung Transplant.
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  published abstractJ Heart Lung Transplant, 17, 72
• Bull, D. A., Trehan, S., McKellar, S., Marks, J. D., Stringham, J. C., Taylor, D. O., Renlund, D. G., Fuller, T. C., & Long, J. W. (1998, Fall). One Year Outcome after Cardiac Transplantation is not Compromised by Elevated Pretransplant Panel Reactive Antibody Levels in Patients with Ventricular Assist Devices [Abstract]. JACC.
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  published abstractJACC, 31(2), 290A