William Hiesinger, MD

All Publications

• Injectable Bioengineered Hydrogel Therapy in the Treatment of Ischemic Cardiomyopathy. Current treatment options in cardiovascular medicine MacArthur, J. W., Steele, A. N., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. J. 2017; 19 (4): 30-?

  Abstract

  Over the past two decades, the field of cardiovascular medicine has seen the rapid development of multiple different modalities for the treatment of ischemic myocardial disease. Most research efforts have focused on strategies aimed at coronary revascularization, with significant technological advances made in percutaneous coronary interventions as well as coronary artery bypass graft surgery. However, recent research efforts have shifted towards ways to address the downstream effects of myocardial infarction on both cellular and molecular levels. To this end, the broad application of injectable hydrogel therapy after myocardial infarction has stimulated tremendous interest. In this article, we will review what hydrogels are, how they can be bioengineered in unique ways to optimize therapeutic potential, and how they can be used as part of a treatment strategy after myocardial infarction.

  View details for DOI 10.1007/s11936-017-0530-x

  View details for PubMedID 28337717

• Operative technique and pitfalls in donor heart procurement. Asian cardiovascular & thoracic annals Shudo, Y., Hiesinger, W., Oyer, P. E., Woo, Y. J. 2017; 25 (1): 80-82

  Abstract

  We describe a simple and reproducible donor heart procurement technique in sequential steps. A detailed understanding of procurement and organ preservation techniques should be an essential part of a heart transplant training program.

  View details for DOI 10.1177/0218492316678716

  View details for PubMedID 28074702

• An innovative biologic system for photon-powered myocardium in the ischemic heart. Science advances Cohen, J. E., Goldstone, A. B., Paulsen, M. J., Shudo, Y., Steele, A. N., Edwards, B. B., Patel, J. B., MacArthur, J. W., Hopkins, M. S., Burnett, C. E., Jaatinen, K. J., Thakore, A. D., Farry, J. M., Truong, V. N., Bourdillon, A. T., Stapleton, L. M., Eskandari, A., Fairman, A. S., Hiesinger, W., Esipova, T. V., Patrick, W. L., Ji, K., Shizuru, J. A., Woo, Y. J. 2017; 3 (6): e1603078

  Abstract

  Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

  View details for DOI 10.1126/sciadv.1603078

  View details for PubMedID 28630913

  View details for PubMedCentralID PMC5470824

• Biochemically engineered stromal cell-derived factor 1-alpha analog increases perfusion in the ischemic hind limb. Journal of vascular surgery Edwards, B. B., Fairman, A. S., Cohen, J. E., Macarthur, J. W., Goldstone, A. B., Woo, J. B., Hiesinger, W., Woo, Y. J. 2016; 64 (4): 1093-1099

  Abstract

  Despite promising therapeutic innovation over the last decade, peripheral arterial disease remains a prevalent morbidity, as many patients are still challenged with peripheral ischemia. We hypothesized that delivery of engineered stromal cell-derived factor 1-alpha (ESA) in an ischemic hind limb will yield significant improvement in perfusion.Male rats underwent right femoral artery ligation, and animals were randomized to receive a 100 μL injection of saline (n = 9) or 6 μg/kg dosage of equal volume of ESA (n = 12) into the ipsilateral quadriceps muscle. Both groups of animals were also given an intraperitoneal injection of 40 μg/kg of granulocyte macrophage colony-stimulating factor (GMCSF). Perfusion was quantified using a laser Doppler imaging device preoperatively, and on postoperative days 0, 7, and 14. Immunohistochemistry was performed to quantify angiogenesis on day 14, and an mRNA profile was evaluated for angiogenic and inflammatory markers.Compared with the saline/GMCSF group at day 14, the ESA/GMCSF-injected animals had greater reperfusion ratios (Saline/GMCSF, 0.600 ± 0.140 vs ESA/GMCSF, 0.900 ± 0.181; group effect P = .006; time effect P < .0001; group×time effect P < .0001), elevated capillary density (10×; Saline/GMCSF, 6.40 ± 2.01 vs ESA/GMCSF, 18.55 ± 5.30; P < .01), and increased mRNA levels of vascular endothelial growth factor-A (Saline/GMCSF [n = 6], 0.298 ± 0.205 vs ESA/GMCSF [n = 8], 0.456 ± 0.139; P = .03).Delivery of ESA significantly improves perfusion in a rat model of peripheral arterial disease via improved neovasculogenesis, a finding which may prove beneficial in the treatment strategy for this debilitating disease.

  View details for DOI 10.1016/j.jvs.2015.06.140

  View details for PubMedID 26372192

• Cell transplantation in heart failure: where do we stand in 2016? EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY MacArthur, J. W., Goldstone, A. B., Cohen, J. E., Hiesinger, W., Woo, Y. 2016; 50 (3): 396–99

  View details for DOI 10.1093/ejcts/ezw230

  View details for Web of Science ID 000386056400002

  View details for PubMedID 27587719

  View details for PubMedCentralID PMC5853589

• Hybrid coronary revascularization: Ready for prime time, but who should star? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2016; 151 (4): 1090–91

  View details for DOI 10.1016/j.jtcvs.2015.12.015

  View details for Web of Science ID 000372436900056

  View details for PubMedID 26809426

• Building a better bridge: Remodeling, recovery, and a better understanding of the biologic foundation of mechanical circulatory support JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Atluri, P. 2015; 150 (5): 1342–43

  View details for DOI 10.1016/j.jtcvs.2015.09.042

  View details for Web of Science ID 000365038900062

  View details for PubMedID 26546204

• A Tissue-Engineered Chondrocyte Cell Sheet Induces Extracellular Matrix Modification to Enhance Ventricular Biomechanics and Attenuate Myocardial Stiffness in Ischemic Cardiomyopathy TISSUE ENGINEERING PART A Shudo, Y., Cohen, J. E., MacArthur, J. W., Goldstone, A. B., Otsuru, S., Trubelja, A., Patel, J., Edwards, B. B., Hung, G., Fairman, A. S., Brusalis, C., Hiesinger, W., Atluri, P., Hiraoka, A., Miyagawa, S., Sawa, Y., Woo, Y. J. 2015; 21 (19-20): 2515-2525

  Abstract

  There exists a substantial body of work describing cardiac support devices to mechanically support the left ventricle (LV); however, these devices lack biological effects. To remedy this, we implemented a cell sheet engineering approach utilizing chondrocytes, which in their natural environment produce a relatively elastic extracellular matrix (ECM) for a cushioning effect. Therefore, we hypothesized that a chondrocyte cell sheet applied to infarcted and borderzone myocardium will biologically enhance the ventricular ECM and increase elasticity to augment cardiac function in a model of ischemic cardiomyopathy (ICM). Primary articular cartilage chondrocytes of Wistar rats were isolated and cultured on temperature-responsive culture dishes to generate cell sheets. A rodent ICM model was created by ligating the left anterior descending coronary artery. Rats were divided into two groups: cell sheet transplantation (1.0 × 10(7) cells/dish) and no treatment. The cell sheet was placed onto the surface of the heart covering the infarct and borderzone areas. At 4 weeks following treatment, the decreased fibrotic extension and increased elastic microfiber networks in the infarct and borderzone areas correlated with this technology's potential to stimulate ECM formation. The enhanced ventricular elasticity was further confirmed by the axial stretch test, which revealed that the cell sheet tended to attenuate tensile modulus, a parameter of stiffness. This translated to increased wall thickness in the infarct area, decreased LV volume, wall stress, mass, and improvement of LV function. Thus, the chondrocyte cell sheet strengthens the ventricular biomechanical properties by inducing the formation of elastic microfiber networks in ICM, resulting in attenuated myocardial stiffness and improved myocardial function.

  View details for DOI 10.1089/ten.tea.2014.0155

  View details for Web of Science ID 000362546100006

  View details for PubMedID 26154752

  View details for PubMedCentralID PMC4605354

• A "Repair-All" Strategy for Degenerative Mitral Valve Disease Safely Minimizes Unnecessary Replacement ANNALS OF THORACIC SURGERY Goldstone, A. B., Cohen, J. E., Howard, J. L., Edwards, B. B., Acker, A. L., Hiesinger, W., MacArthur, J. W., Atluri, P., Woo, Y. J. 2015; 99 (6): 1983-1991

  View details for DOI 10.1016/j.athoracsur.2014.12.076

  View details for Web of Science ID 000357521600028

  View details for PubMedID 25865766

• Ventricular assist device implantation in the elderly. Annals of cardiothoracic surgery Hiesinger, W., Boyd, J. H., Woo, Y. J. 2014; 3 (6): 570-572

  Abstract

  Dramatic advances in ventricular assist device (VAD) design and patient management have made mechanical circulatory support an attractive therapeutic option for the growing pool of elderly heart failure patients.A literature review of all relevant studies was performed. No time or language restrictions were imposed, and references of the selected studies were checked for additional relevant citations.In concordance with the universal trend in mechanical circulatory support, continuous flow devices appear to have particular benefits in the elderly. In addition, the literature suggests that early intervention before the development of cardiogenic shock, important in all patients, is particularly paramount in older patients.The ongoing refinement of patient selection, surgical technique, and post-operative care will continue to improve surgical outcomes, and absolute age may become a less pivotal criterion for mechanical circulatory support. However, clear guidelines for the use of mechanical circulatory support in the elderly remain undefined.

  View details for DOI 10.3978/j.issn.2225-319X.2014.09.07

  View details for PubMedID 25512896

• Bioengineered Stromal Cell- Derived Factor-1 alpha Analogue Delivered as an Angiogenic Therapy Significantly Restores Viscoelastic Material Properties of Infarcted Cardiac Muscle JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Trubelja, A., MacArthur, J. W., Sarver, J. J., Cohen, J. E., Hung, G., Shudo, Y., Fairman, A. S., Patel, J., Edwards, B. B., Damrauer, S. M., Hiesinger, W., Atluri, P., Woo, Y. J. 2014; 136 (8)

  Abstract

  Ischemic heart disease is a major health problem worldwide, and current therapies fail to address microrevascularization. Previously, our group demonstrated that the sustained release of novel engineered stromal cell-derived factor 1-a analogue (ESA) limits infarct spreading, collagen deposition, improves cardiac function by promoting angiogenesis in the region surrounding the infarct, and restores the tensile properties of infarcted myocardium. In this study, using a well-established rat model of ischemic cardiomyopathy, we describe a novel and innovative method for analyzing the viscoelastic properties of infarcted myocardium. Our results demonstrate that, compared with a saline control group, animals treated with ESA have significantly improved myocardial relaxation rates, while reducing the transition strain, leading to restoration of left ventricular mechanics.

  View details for DOI 10.1115/1.4027731

  View details for Web of Science ID 000338507000012

• A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circulation. Heart failure Cohen, J. E., Purcell, B. P., Macarthur, J. W., Mu, A., Shudo, Y., Patel, J. B., Brusalis, C. M., Trubelja, A., Fairman, A. S., Edwards, B. B., Davis, M. S., Hung, G., Hiesinger, W., Atluri, P., Margulies, K. B., Burdick, J. A., Woo, Y. J. 2014; 7 (4): 619-626

  Abstract

  Neuregulin-1β (NRG) is a member of the epidermal growth factor family possessing a critical role in cardiomyocyte development and proliferation. Systemic administration of NRG demonstrated efficacy in cardiomyopathy animal models, leading to clinical trials using daily NRG infusions. This approach is hindered by requiring daily infusions and off-target exposure. Therefore, this study aimed to encapsulate NRG in a hydrogel to be directly delivered to the myocardium, accomplishing sustained localized NRG delivery.NRG was encapsulated in hydrogel, and release over 14 days was confirmed by ELISA in vitro. Sprague-Dawley rats were used for cardiomyocyte isolation. Cells were stimulated by PBS, NRG, hydrogel, or NRG-hydrogel (NRG-HG) and evaluated for proliferation. Cardiomyocytes demonstrated EdU (5-ethynyl-2'-deoxyuridine) and phosphorylated histone H3 positivity in the NRG-HG group only. For in vivo studies, 2-month-old mice (n=60) underwent left anterior descending coronary artery ligation and were randomized to the 4 treatment groups mentioned. Only NRG-HG-treated mice demonstrated phosphorylated histone H3 and Ki67 positivity along with decreased caspase-3 activity compared with all controls. NRG was detected in myocardium 6 days after injection without evidence of off-target exposure in NRG-HG animals. At 2 weeks, the NRG-HG group exhibited enhanced left ventricular ejection fraction, decreased left ventricular area, and augmented borderzone thickness.Targeted and sustained delivery of NRG directly to the myocardial borderzone augments cardiomyocyte mitotic activity, decreases apoptosis, and greatly enhances left ventricular function in a model of ischemic cardiomyopathy. This novel approach to NRG administration avoids off-target exposure and represents a clinically translatable strategy in myocardial regenerative therapeutics.

  View details for DOI 10.1161/CIRCHEARTFAILURE.113.001273

  View details for PubMedID 24902740

• Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1a analog in a translational ovine myocardial infarction model. Circulation research Macarthur, J. W., Cohen, J. E., McGarvey, J. R., Shudo, Y., Patel, J. B., Trubelja, A., Fairman, A. S., Edwards, B. B., Hung, G., Hiesinger, W., Goldstone, A. B., Atluri, P., Wilensky, R. L., Pilla, J. J., Gorman, J. H., Gorman, R. C., Woo, Y. J. 2014; 114 (4): 650-659

  Abstract

  After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

  View details for DOI 10.1161/CIRCRESAHA.114.302884

  View details for PubMedID 24366171

  View details for PubMedCentralID PMC4137973

• Therapeutic potential of Rb phosphorylation in atherosclerosis CELL CYCLE Hiesinger, W., Cohen, J. E., Atluri, P. 2014; 13 (3): 352

  View details for DOI 10.4161/cc.27551

  View details for Web of Science ID 000332833400010

  View details for PubMedID 24346501

  View details for PubMedCentralID PMC3956530

• Sustained release of engineered stromal cell-derived factor 1-a from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation Macarthur, J. W., Purcell, B. P., Shudo, Y., Cohen, J. E., Fairman, A., Trubelja, A., Patel, J., Hsiao, P., Yang, E., Lloyd, K., Hiesinger, W., Atluri, P., Burdick, J. A., Woo, Y. J. 2013; 128 (11): S79-86

  Abstract

  Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction.Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls.We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

  View details for DOI 10.1161/CIRCULATIONAHA.112.000343

  View details for PubMedID 24030424

• Predicting Right Ventricular Failure in the Modern, Continuous Flow Left Ventricular Assist Device Era 59th Annual Meeting of the Southern-Thoracic-Surgical-Association (STSA) Atluri, P., Goldstone, A. B., Fairman, A. S., MacArthur, J. W., Shudo, Y., Cohen, J. E., Acker, A. L., Hiesinger, W., Howard, J. L., Acker, M. A., Woo, Y. J. ELSEVIER SCIENCE INC. 2013: 857–64

  Abstract

  In the era of destination continuous flow left ventricular assist devices (LVAD), the decision of whether a patient will tolerate isolated LVAD support or will need biventricular support (BIVAD) can be challenging. Incorrect decision making with delayed right ventricular (RV) assist device implantation results in increased morbidity and mortality. Continuous flow LVADs have been shown to decrease pulmonary hypertension and improve RV function. We undertook this study to determine predictors in the continuous flow LVAD era that identify patients who are candidates for isolated LVAD therapy as opposed to biventricular support.We reviewed demographic, hemodynamic, laboratory, and echocardiographic variables for 218 patients who underwent VAD implant from 2003 through 2011 (LVAD=167, BIVAD=51), during the era of continuous flow LVADs.Fifty preoperative risk factors were compared between patients who were successfully managed with an LVAD and those who required a BIVAD. Seventeen variables demonstrated statistical significance by univariate analysis. Multivariable logistic regression analysis identified central venous pressure>15 mmHg (OR 2.0, "C"), severe RV dysfunction (OR 3.7, "R"), preoperative intubation (OR 4.3, "I"), severe tricuspid regurgitation (OR 4.1, "T"), heart rate>100 (OR 2.0, Tachycardia-"T")-CRITT as the major criteria predictive of the need for biventricular support. Utilizing these data, a highly sensitive and easy to use risk score for determining RV failure was generated that outperformed other established risk stratification tools.We present a preoperative risk calculator to determine suitability of a patient for isolated LVAD support in the current continuous flow ventricular assist device era.

  View details for DOI 10.1016/j.athoracsur.2013.03.099

  View details for Web of Science ID 000323940200026

  View details for PubMedID 23791165

• Rapid onset of fulminant myocarditis portends a favourable prognosis and the ability to bridge mechanical circulatory support to recovery EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Atluri, P., Ullery, B. W., MacArthur, J. W., Goldstone, A. B., Fairman, A. S., Hiesinger, W., Acker, M. A., Woo, Y. J. 2013; 43 (2): 379-382

  Abstract

  Fulminant myocarditis with cardiogenic shock is fatal without mechanical circulatory support. Once haemodynamic stability has been established with a ventricular assist device (VAD), the decision to wait for myocardial recovery as opposed to listing for an orthotopic heart transplant (OHT) can be difficult. We have undertaken this study to establish the criteria for determining the need for heart transplantation following VAD implant for fulminant myocarditis.A total of 442 VADs were implanted between 1993 and 2011. Twenty-four VADs were implanted for fulminant myocarditis with refractory cardiogenic shock. We retrospectively analysed the variables and the pathology for this cohort. Patients who had a full recovery of myocardial function and subsequent VAD explant (Explant) were compared with those bridged to OHT. There was one acute death.There was no difference in the past medical history between the groups. Explant patients had a more acute onset of heart failure with a median of 7 days between the onset of symptoms and VAD implant, when compared with 22 days for OHT (P = 0.01). A rapid recovery in myocardial function was seen in the Explant group, with recovery of myocardial function (ejection fraction = 53 ± 24%) in 14 ± 7 days. Myocardial function was sustained for 5 years following the VAD explant. The female gender favoured myocardial recovery and VAD explantability. Two patients had giant cell myocarditis, neither of whom had a recovery of function, and they were bridged to heart transplant with a VAD.Fulminant myocarditis is a fatal condition without mechanical support. The rapid onset of symptoms is associated with a complete recovery of myocardial function and VAD explant. The absence of rapid recovery of myocardial function should prompt listing for a heart transplant.

  View details for DOI 10.1093/ejcts/ezs242

  View details for Web of Science ID 000313829300031

  View details for PubMedID 22564805

• Mathematically engineered stromal cell-derived factor-1 alpha stem cell cytokine analog enhances mechanical properties of infarcted myocardium JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY MacArthur, J. W., Trubelja, A., Shudo, Y., Hsiao, P., Fairman, A. S., Yang, E., Hiesinger, W., Sarver, J. J., Atluri, P., Woo, Y. J. 2013; 145 (1): 278-284

  Abstract

  The biomechanical response to a myocardial infarction consists of ventricular remodeling that leads to dilatation, loss of contractile function, abnormal stress patterns, and ultimately heart failure. We hypothesized that intramyocardial injection of our previously designed pro-angiogenic chemokine, an engineered stromal cell-derived factor-1α analog (ESA), improves mechanical properties of the heart after infarction.Male rats (n = 54) underwent either sham surgery (n = 17) with no coronary artery ligation or ligation of the left anterior descending artery (n = 37). The rats in the myocardial infarction group were then randomized to receive either saline (0.1 mL, n = 18) or ESA (6 μg/kg, n = 19) injected into the myocardium at 4 predetermined spots around the border zone. Echocardiograms were performed preoperatively and before the terminal surgery. After 4 weeks, the hearts were explanted and longitudinally sectioned. Uniaxial tensile testing was completed using an Instron 5543 Microtester. Optical strain was evaluated using custom image acquisition software, Digi-Velpo, and analyzed in MATLAB.Compared with the saline control group at 4 weeks, the ESA-injected hearts had a greater ejection fraction (71.8% ± 9.0% vs 55.3% ± 12.6%, P = .0004), smaller end-diastolic left ventricular internal dimension (0.686 ± 0.110 cm vs 0.763 ± 0.160 cm, P = .04), greater cardiac output (36 ± 11.6 mL/min vs 26.9 ± 7.3 mL/min, P = .05), and a lower tensile modulus (251 ± 56 kPa vs 301 ± 81 kPa, P = .04). The tensile modulus for the sham group was 195 ± 56 kPa, indicating ESA injection results in a less stiff ventricle.Direct injection of ESA alters the biomechanical response to myocardial infarction, improving the mechanical properties in the postinfarct heart.

  View details for DOI 10.1016/j.jtcvs.2012.09.080

  View details for Web of Science ID 000312386300047

  View details for PubMedID 23244259

• Re-Engineered Stromal Cell-Derived Factor-1 alpha and the Future of Translatable Angiogenic Polypeptide Design TRENDS IN CARDIOVASCULAR MEDICINE Hiesinger, W., Goldstone, A. B., Woo, Y. J. 2012; 22 (6): 139-144

  Abstract

  Smaller engineered analogs of angiogenic cytokines may provide translational advantages, including enhanced stability and function, ease of synthesis, lower cost, and, most important, the potential for modulated delivery via engineered biomaterials. In order to create such a peptide, computational molecular modeling and design was employed to engineer a minimized, highly efficient polypeptide analog of the stromal cell-derived factor-1α (SDF) molecule. After removal of the large, central β-sheet region, a designed diproline linker connected the native N-terminus (responsible for receptor activation and binding) and C-terminus (responsible for extracellular stabilization). This yielded energetic and conformational advantages resulting in a small, low-molecular-weight engineered SDF polypeptide analog (ESA) that was shown to have angiogenic activity comparable to or better than that of recombinant human SDF both in vitro and in a murine model of ischemic heart failure.

  View details for Web of Science ID 000311065900001

  View details for PubMedID 22902182

• Myocardial tissue elastic properties determined by atomic force microscopy after stromal cell-derived factor 1 alpha angiogenic therapy for acute myocardial infarction in a murine model 37th Annual Meeting of the Western-Thoracic-Surgical-Association Hiesinger, W., Brukman, M. J., McCormick, R. C., Fitzpatrick, J. R., Frederick, J. R., Yang, E. C., Muenzer, J. R., Marotta, N. A., Berry, M. F., Atluri, P., Woo, Y. J. MOSBY-ELSEVIER. 2012: 962–66

  Abstract

  Ventricular remodeling after myocardial infarction begins with massive extracellular matrix deposition and resultant fibrosis. This loss of functional tissue and stiffening of myocardial elastic and contractile elements starts the vicious cycle of mechanical inefficiency, adverse remodeling, and eventual heart failure. We hypothesized that stromal cell-derived factor 1α (SDF-1α) therapy to microrevascularize ischemic myocardium would rescue salvageable peri-infarct tissue and subsequently improve myocardial elasticity.Immediately after left anterior descending coronary artery ligation, mice were randomly assigned to receive peri-infarct injection of either saline solution or SDF-1α. After 6 weeks, animals were killed and samples were taken from the peri-infarct border zone and the infarct scar, as well as from the left ventricle of noninfarcted control mice. Determination of tissues' elastic moduli was carried out by mechanical testing in an atomic force microscope.SDF-1α-treated peri-infarct tissue most closely approximated the elasticity of normal ventricle and was significantly more elastic than saline-treated peri-infarct myocardium (109 ± 22.9 kPa vs 295 ± 42.3 kPa; P < .0001). Myocardial scar, the strength of which depends on matrix deposition from vasculature at the peri-infarct edge, was stiffer in SDF-1α-treated animals than in controls (804 ± 102.2 kPa vs 144 ± 27.5 kPa; P < .0001).Direct quantification of myocardial elastic properties demonstrates the ability of SDF-1α to re-engineer evolving myocardial infarct and peri-infarct tissues. By increasing elasticity of the ischemic and dysfunctional peri-infarct border zone and bolstering the weak, aneurysm-prone scar, SDF-1α therapy may confer a mechanical advantage to resist adverse remodeling after infarction.

  View details for DOI 10.1016/j.jtcvs.2011.12.028

  View details for Web of Science ID 000301609200036

  View details for PubMedID 22264415

• Oxygen-dependent quenching of phosphorescence used to characterize improved myocardial oxygenation resulting from vasculogenic cytokine therapy JOURNAL OF APPLIED PHYSIOLOGY Hiesinger, W., Vinogradov, S. A., Atluri, P., Fitzpatrick, J. R., Frederick, J. R., Levit, R. D., McCormick, R. C., Muenzer, J. R., Yang, E. C., Marotta, N. A., MacArthur, J. W., Wilson, D. F., Woo, Y. J. 2011; 110 (5): 1460-1465

  Abstract

  This study evaluates a therapy for infarct modulation and acute myocardial rescue and utilizes a novel technique to measure local myocardial oxygenation in vivo. Bone marrow-derived endothelial progenitor cells (EPCs) were targeted to the heart with peri-infarct intramyocardial injection of the potent EPC chemokine stromal cell-derived factor 1α (SDF). Myocardial oxygen pressure was assessed using a noninvasive, real-time optical technique for measuring oxygen pressures within microvasculature based on the oxygen-dependent quenching of the phosphorescence of Oxyphor G3. Myocardial infarction was induced in male Wistar rats (n = 15) through left anterior descending coronary artery ligation. At the time of infarction, animals were randomized into two groups: saline control (n = 8) and treatment with SDF (n = 7). After 48 h, the animals underwent repeat thoracotomy and 20 μl of the phosphor Oxyphor G3 was injected into three areas (peri-infarct myocardium, myocardial scar, and remote left hindlimb muscle). Measurements of the oxygen distribution within the tissue were then made in vivo by applying the end of a light guide to the beating heart. Compared with controls, animals in the SDF group exhibited a significantly decreased percentage of hypoxic (defined as oxygen pressure ≤ 15.0 Torr) peri-infarct myocardium (9.7 ± 6.7% vs. 21.8 ± 11.9%, P = 0.017). The peak oxygen pressures in the peri-infarct region of the animals in the SDF group were significantly higher than the saline controls (39.5 ± 36.7 vs. 9.2 ± 8.6 Torr, P = 0.02). This strategy for targeting EPCs to vulnerable peri-infarct myocardium via the potent chemokine SDF-1α significantly decreased the degree of hypoxia in peri-infarct myocardium as measured in vivo by phosphorescence quenching. This effect could potentially mitigate the vicious cycle of myocyte death, myocardial fibrosis, progressive ventricular dilatation, and eventual heart failure seen after acute myocardial infarction.

  View details for DOI 10.1152/japplphysiol.01138.2010

  View details for Web of Science ID 000290472400043

  View details for PubMedID 21292844

  View details for PubMedCentralID PMC3098666

• Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-alpha (SDF) Generates a Supra-Efficient Angiogenic Polypeptide Analog Hiesinger, W., Perez-Aguilar, J., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Muenzer, J. R., Levit, R. D., Yuan, L., MacArthur, J. W., Saven, J. G., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231600703

• Acute Myocardial Rescue with Endogenous Endothelial Progenitor Cell Therapy HEART LUNG AND CIRCULATION Atluri, P., Panlilio, C. M., Liao, G. P., Hiesinger, W., Harris, D. A., McCormick, R. C., Cohen, J. E., Jin, T., Feng, W., Levit, R. D., Dong, N., Woo, Y. J. 2010; 19 (11): 644-654

  Abstract

  Post-myocardial infarction heart failure is a major health concern with limited therapy. Molecular revascularisation utilising granulocyte-macrophage colony stimulating factor (GMCSF) mediated endothelial progenitor cell (EPC) upregulation and stromal cell derived factor-1α (SDF) mediated myocardial EPC chemokinesis, may prevent myocardial loss and adverse remodelling. Vasculogenesis, viability, and haemodynamic improvements following therapy were investigated.Lewis rats (n=91) underwent LAD ligation and received either intramyocardial SDF and subcutaneous GMCSF or saline injections at the time of infarction. Molecular and haemodynamic assessments were performed at pre-determined time points following ligation.SDF/GMCSF therapy upregulated EPC density as shown by flow cytometry (0.12±0.02% vs. 0.06±0.01% circulating lymphocytes, p=0.005), 48hours following infarction. A marked increase in perfusion was evident eight weeks after therapy, utilising confocal angiography (5.02±1.7×10(-2)μm(3)blood/μm(3)myocardial tissue vs. 2.03±0.710(-2)μm(3)blood/μm(3)myocardial tissue, p=0.00004). Planimetric analysis demonstrated preservation of wall thickness (0.98±0.09mm vs. 0.67±0.06mm, p=0.003) and ventricular diameter (7.81±0.99mm vs. 9.41±1.1mm, p=0.03). Improved haemodynamic function was evidenced by echocardiography and PV analysis (ejection fraction: 56.4±18.1% vs. 25.3±15.6%, p=0.001; pre-load adjusted maximal power: 6.6±2.6mW/μl(2) vs. 2.7±1.4mW/μl(2), p=0.01).Neovasculogenic therapy with GMCSF-mediated EPC upregulation and SDF-mediated EPC chemokinesis maybe an effective therapy for infarct modulation and preservation of myocardial function following acute myocardial infarction.

  View details for DOI 10.1016/j.hlc.2010.06.1056

  View details for Web of Science ID 000283908600002

  View details for PubMedID 20719564

  View details for PubMedCentralID PMC3235678

• Spliced stromal cell-derived factor-1 alpha analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hiesinger, W., Frederick, J. R., Atluri, P., McCormick, R. C., Marotta, N., Muenzer, J. R., Woo, Y. J. 2010; 140 (5): 1174-1180

  Abstract

  Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI.EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis.EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats.A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α.

  View details for DOI 10.1016/j.jtcvs.2010.08.012

  View details for Web of Science ID 000283057600043

  View details for PubMedID 20951261

• Stromal Cell-Derived Factor-1 alpha Activation of Tissue-Engineered Endothelial Progenitor Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis 82nd National Conference and Exhibitions and Annual Scientific Session of the American-Heart-Association Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Harris, D. A., Kim, A., Muenzer, J. R., Marotta, N., Smith, M. J., Cohen, J. E., Hiesinger, W., Atluri, P., Woo, Y. J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S107–S117

  Abstract

  Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction.Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure-volume conductance, and Doppler flow.Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.

  View details for DOI 10.1161/C1RCULATIONAHA.109.930404

  View details for Web of Science ID 000282294800017

  View details for PubMedID 20837901

• Rapid Onset of Fulminant Myocarditis Portends a Favorable Prognosis and Ability To Bridge Mechanical Support to Recovery Atluri, P., Ullery, B. W., Howard, J. L., Hiesinger, W., Filzpatrick, J., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: S51

  View details for DOI 10.1016/j.cardfail.2010.06.176

  View details for Web of Science ID 000281501800162

• Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared with delayed conversion of a left ventricular assist device to a biventricular assist device JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Fitzpatrick, J. R., Frederick, J. R., Hiesinger, W., Hsu, V. M., McCormick, R. C., Kozin, E. D., Laporte, C. M., O'Hara, M. L., Howell, E., Dougherty, D., Cohen, J. E., Southerland, K. W., Howard, J. L., Paulson, C., Acker, M. A., Morris, R. J., Woo, Y. J. 2009; 137 (4): 971-977

  Abstract

  It is generally accepted that patients who require biventricular assist device support have poorer outcomes than those requiring isolated left ventricular assist device support. However, it is unknown how the timing of biventricular assist device insertion affects outcomes. We hypothesized that planned biventricular assist device insertion improves survival compared with delayed conversion of left ventricular assist device support to biventricular assist device support.We reviewed and compared outcomes of 266 patients undergoing left ventricular assist device or biventricular assist device placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided patients receiving biventricular assist devices into planned biventricular assist device (P-BiVAD) and delayed biventricular assist device (D-BiVAD) groups based on the timing of right ventricular assist device insertion. We defined the D-BiVAD group as any failure of isolated left ventricular assist device support.Of 266 patients who received left ventricular assist devices, 99 (37%) required biventricular assist device support. We compared preoperative characteristics, successful bridging to transplantation, survival to hospital discharge, and Kaplan-Meier 1-year survival between the P-BiVAD (n = 71) and D-BiVAD (n = 28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. Left ventricular assist device (n = 167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD group outcomes. Furthermore, patients in the P-BiVAD group had superior survival to discharge than patients in the D-BiVAD group (51% vs 29%, P < .05). One-year and long-term Kaplan-Meier survival distribution confirmed this finding. There was also a trend toward improved bridging to transplantation in the P-BiVAD (n = 55) versus D-BiVAD (n = 22) groups (65% vs 45%, P = .10).When patients at high risk for failure of isolated left ventricular assist device support are identified, proceeding directly to biventricular assist device implantation is advised because early institution of biventricular support results in dramatic improvement in survival.

  View details for DOI 10.1016/j.jtcvs.2008.09.021

  View details for Web of Science ID 000264562000028

  View details for PubMedID 19327526

  View details for PubMedCentralID PMC3232461

• Off-pump, minimally invasive and robotic coronary revascularization yield improved outcomes over traditional on-pump CABG INTERNATIONAL JOURNAL OF MEDICAL ROBOTICS AND COMPUTER ASSISTED SURGERY Atluri, P., Kozin, E. D., Hiesinger, W., Woo, Y. J. 2009; 5 (1): 1-12

  Abstract

  Coronary artery disease is a global health concern, with increasing morbidity and mortality. Surgical coronary artery bypass grafting has been performed on cardiopulmonary bypass for nearly four decades, with excellent long-term durability. Beating-heart coronary surgery has been increasing in frequency in an attempt to decrease cardiopulmonary bypass-related morbidity. Furthermore, with increasing expertise and technology, minimally invasive and robotic techniques have been developed to enhance post-operative recovery, patient satisfaction and cosmesis. Several clinical trials have demonstrated decreased morbidity and more rapid recovery following off-pump, minimally invasive and robotic procedures when compared to on-pump coronary artery bypass grafts (CABGs). An equivalent extent of revascularization and medium-term anastomotic patency has been demonstrated among all approaches. Furthermore, for a large number of patients who do not have anatomy amenable to traditional coronary revascularization, adjunctive molecular therapies may provide alternative myocardial micro-revascularization.

  View details for DOI 10.1002/rcs.230

  View details for Web of Science ID 000263998300001

  View details for PubMedID 19117020

• Cardiac retransplantation is an efficacious therapy for primary cardiac allograft failure JOURNAL OF CARDIOTHORACIC SURGERY Atluri, P., Hiesinger, W., Gorman, R. C., Pochettino, A., Jessup, M., Acker, M. A., Morris, R. J., Woo, Y. J. 2008; 3

  Abstract

  Although orthotopic heart transplantation has been an effective treatment for end-stage heart failure, the incidence of allograft failure has increased, necessitating treatment options. Cardiac retransplantation remains the only viable long-term solution for end-stage cardiac allograft failure. Given the limited number of available donor hearts, the long term results of this treatment option need to be evaluated.709 heart transplants were performed over a 20 year period at our institution. Repeat cardiac transplantation was performed in 15 patients (2.1%). A retrospective analysis was performed to determine the efficacy of cardiac retransplantation. Variables investigated included: 1 yr and 5 yr survival, length of hospitalization, post-operative complications, allograft failure, recipient and donor demographics, renal function, allograft ischemic time, UNOS listing status, blood group, allograft rejection, and hemodynamic function.Etiology of primary graft failure included transplant arteriopathy (n = 10), acute rejection (n = 3), hyperacute rejection (n = 1), and a post-transplant diagnosis of metastatic melanoma in the donor (n = 1). Mean age at retransplantation was 45.5 +/- 9.7 years. 1 and 5 year survival for retransplantation were 86.6% and 71.4% respectively, as compared to 90.9% and 79.1% for primary transplantation. Mean ejection fraction was 67.3 +/- 12.2% at a mean follow-up of 32.6 +/- 18.5 mos post-retransplant; follow-up biopsy demonstrated either ISHLT grade 1A or 0 rejection (77.5 +/- 95.7 mos post-transplant).Cardiac retransplantation is an efficacious treatment strategy for cardiac allograft failure.

  View details for DOI 10.1186/1749-8090-3-26

  View details for Web of Science ID 000262855000001

  View details for PubMedID 18462494

  View details for PubMedCentralID PMC2432055

• Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression CELLULAR & MOLECULAR BIOLOGY LETTERS Atluri, P., Morine, K. J., Liao, G. P., Panlilio, C. M., Berry, M. F., Hsu, V. M., Hiesinger, W., Cohen, J. E., Woo, Y. J. 2007; 12 (1): 127-138

  Abstract

  Apelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy.Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750+/-133500 vs. 901600+/-143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0+/-4.6 vs. 1.0+/-1.2 ng/ml, n=5, p=0.006) and western blot (1579400+/-477733 vs. 943000+/-157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.

  View details for DOI 10.2478/s11658-006-0058-7

  View details for Web of Science ID 000244632300011

  View details for PubMedID 17119870