Circulation 2010年9月14日Vol. 122, No. 11增刊1 （摘要，全文免费）

http://circ.ahajournals.org/content/vol122/11_suppl_1

--------------------------------------------------------------------------------
Abstract 1 of 34 (Circulation. 2010;122:S193-S200.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Arrhythmia Surgery

Alteration of Parasympathetic/Sympathetic Ratio in the Infarcted Myocardium After Schwann Cell Transplantation Modified Electrophysiological Function of Heart
A Novel Antiarrhythmic Therapy
Hao Zhang, MD, PhD*; Xin Yuan, MD, PhD*; Pei-feng Jin, MD; Jian-feng Hou, MD, PhD; Wei Wang, MD, PhD; Ying-jie Wei, PhD; Shengshou Hu, MD, FACC
From the Department of Surgery (H.Z., X.Y., J.-f.H., W.W., S.H.), Research Center for Cardiac Regenerative Medicine of the Ministry of Health, Cardiovascular Institute, and Fu Wai Hospital (H.Z., X.Y., J.-f.H., Y.-j.W., S.H.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Surgery, 1st Affiliated Hospital, Wenzhou Medical College, Wenzhou, China (P.-f.J.).

Correspondence to Sheng-Shou Hu, MD, Chief of the Department of Cardiac Surgery, President of the Cardiovascular Institute and Fu Wai Heart Hospital, Prof at Peking Union Medical College, 167 Beilishilu, Beijing 100037, China. E-mail shengshouhu@yahoo.com

Background—Neural remodeling after myocardial infarction (MI) may cause fatal ventricular arrhythmia. Schwann cells (SCs), which are important for neurogenesis, are dramatically reduced after MI. We investigated the feasibility of modifying nervous system regeneration after MI and the efficacy by which it may prevent ventricular arrhythmia following SC transplantation.

Methods and Results—Immediately after creation of MI, syngenic Lewis rats were randomized into cell transplantation (n=80) and control groups (n=72). SCs were isolated from sciatic nerves, and 5x106 cells were intramyocardially injected into the infarct region. Expression levels of myocardial nerve growth factor, vascular endothelial growth factor, growth-associated protein 43, connexin 43, and laminin in the SC group were significantly higher than control at 7 and 14 days after cell transplantation. Immunohistochemical staining illustrated increases in sympathetic and parasympathetic nerves in both groups. However, SC transplantation significantly increased the parasympathetic/sympathetic ratio at 14 days after cell injection. Dynamic electrocardiography and programmed electric stimulation were also performed. The SCs significantly decreased the low-/high-frequency ratio and arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia at 2 weeks after cell injection. However, SCs did not restore heart function.

Conclusion—Transplanted SCs in the infarcted myocardium secrete multiple biological molecules, which alter the ratio of parasympathetic/sympathetic nerve density to normalize irritable myocardium. SC transplantation might be a novel cell-based antiarrhythmic therapy following MI.

Key Words: myocardial infarction • ventricular arrhythmia • cell transplantation • neural remodeling

[Full Text of Zhang et al.] [Reprint (PDF) Version of Zhang et al.]

--------------------------------------------------------------------------------
Abstract 2 of 34 (Circulation. 2010;122:S85-S91.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cardiac Transplantation and Surgery for Heart Failure

Post–Heart Transplant Survival Is Inferior at Low-Volume Centers Across All Risk Strata
Mark J. Russo, MD, MS; Alexander Iribarne, MD, MS; Rachel Easterwood, BA; Ali N. Ibrahimiye, MD; Ryan Davies, MD; Kimberly N. Hong, MHSA; Deborah D. Ascheim, MD; Annetine C. Gelijns, PhD; Yoshifumi Naka, MD, PhD
From the Division of Cardiothoracic Surgery (M.J.R., A.I., R.E., A.N.I., R.D., Y.N.), Department of Surgery, College of Physicians and Surgeons, Columbia University; and International Center for Health Outcomes and Innovation Research (InCHOIR) (M.J.R., A.I., K.N.H., D.D.A., A.C.G.), Department of Health Policy and Evidence, Mount Sinai School of Medicine, New York.

Correspondence to Mark J. Russo, MD, MS, Section of Cardiac and Thoracic Surgery, The University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 5040, Chicago, Il 60637. E-mail mr2143@columbia.edu; mr2143@gmail.com

Background—Previous studies have demonstrated a relationship between increasing center volume and cardiac transplant outcomes. The purpose of this study was to confirm a relationship between post–heart transplant outcomes and center experience and to determine whether this relationship persists among low- and high-risk heart transplant recipient–donor pairs.

Methods and Results—The United Network for Organ Sharing (UNOS) provided deidentified patient-level data. Analysis included 8029 heart transplant recipients aged 18 years and transplanted between January 1, 2001 and December 31, 2006 with follow-up available through February 3, 2009. The primary outcome was observed 1-year posttransplant graft survival. Multivariable logistic regression was used to calculate expected 1-year survival for recipients. Threshold analysis identified 3 discrete risk groups of transplant recipients: high-risk, moderate-risk, and low-risk. Three discrete risk strata for center volume: low (<10.5 recipients/yr), intermediate (10.5 to 47 recipients/yr), and high (>47 recipients/yr) were also identified. 2 test was used to compare 1-year survival at low- and intermediate- with high-volume centers. In multivariable logistic regression analysis, annual center volume was significantly associated with posttransplant graft survival at 1 year (odds ratio [OR]=0.995, 0.992 to 0.999; P=0.010) and primary graft failure (OR=0.985, 0.972 to 0.997; P=0.015), but not stroke (OR=0.996, 0.990 to 1.003; P=0.295), infection (OR=1.001, 0.998 to 1.003; P=0.613), or dialysis (OR=1.001, 0.997 to 1.005; P=0.522). Log-rank test demonstrated significant difference in survival between volume groups with respect to high-risk (P=0.0032) and low-risk (P=0.00415), but not moderate-risk (P=0.128) patients.

Conclusions—A direct relationship existed between increasing center volume and improved graft survival. Across all recipient–donor pair risk strata, posttransplant graft survival at 1 year was significantly lower at low-volume centers. The volume–outcomes relationship was strongest in the highest-risk recipient–donor category.

Key Words: outcomes • heart transplantation • hospital volume • survival

[Full Text of Russo et al.] [Reprint (PDF) Version of Russo et al.]

--------------------------------------------------------------------------------
Abstract 3 of 34 (Circulation. 2010;122:S92-S99.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cardiac Transplantation and Surgery for Heart Failure

Visceral Arterial Compromise During Intra-Aortic Balloon Counterpulsation Therapy
Ardawan Julian Rastan, MD, PhD; Eugen Tillmann, MD; Sreekumar Subramanian, MD; Lukas Lehmkuhl, MD; Anne Kathrin Funkat, PhD; Sergej Leontyev, MD; Torsten Doenst, MD, PhD; Thomas Walther, MD, PhD; Matthias Gutberlet, MD, PhD; Friedrich Wilhelm Mohr, MD, PhD
From the Department of Cardiac Surgery (A.J.R., E.T., S.S., A.K.F., S.L., T.D., T.W., F.W.M.) and the Department of Radiology (L.L., M.G.), Heart Center, University of Leipzig, Germany.

Correspondence to Ardawan Julian Rastan, MD, University of Leipzig, Department of Cardiac Surgery, Heart Center Leipzig, Struempellstr 39, 04289 Leipzig, Germany. E-mail rastan@rz.uni-leipzig.de

Background—Intraaortic balloon pump (IABP) therapy is a widely used method of circulatory support. Based on frequent findings of balloon malposition with visceral arterial compromise on computerized tomographic (CT) imaging studies, we conducted a systematic review of cardiac surgical IABP patients with available CT scans to determine reasons, incidence, and clinical relevance of malposition.

Methods and Results—From January 2007 to March 2009, a total of 621 of 7756 cardiac surgical patients (8.0%) received perioperative IABP support, of whom 63 (10.1%) received a thoracoabdominal CT scan during IABP support. Proximal and distal balloon positions were analyzed. The anatomic distance from the left subclavian artery to celiac trunk and aortic transverse diameter were measured in all patients and compared with implanted balloon dimensions. Mean age was 67.1±11.9 years; 33.3% were female, and height was 169±9 cm. Based on radiography, proximal balloon position was correct in 96.8% but only appropriate in 38.1% based on CT. In 61 of 63 patients, compromise of at least 1 visceral artery was found: celiac trunk, 96.8%; superior mesenteric artery, 87.3%; and renal arteries, 66.7%. Left subclavian artery to celiac trunk distance was 241±23 mm, and balloon length was 248±17 mm and corresponded to an anatomic to balloon length mismatch in 68.2%. Spinal deformations were found in 42.9%. Laparotomy for mesenteric ischemia was required in 23.8%. Hospital mortality rate was 60.3%.

Conclusions—IABP malposition was commonly identified by CT. Reasons included incorrect proximal balloon position as well as an anatomic-to-balloon length mismatch. Thus, shorter than recommended balloon sizes and better positioning strategies had to be considered.

Key Words: IABP • renal artery • visceral artery • visceral ischemia • balloon size

[Full Text of Rastan et al.] [Reprint (PDF) Version of Rastan et al.]

--------------------------------------------------------------------------------
Abstract 4 of 34 (Circulation. 2010;122:S100-S106.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cell Transplantation and Tissue Regeneration

Development of a Completely Autologous Valved Conduit With the Sinus of Valsalva Using In-Body Tissue Architecture Technology
A Pilot Study in Pulmonary Valve Replacement in a Beagle Model
Masashi Yamanami, MD; Yuki Yahata, BS; Masami Uechi, DVM, PhD; Megumi Fujiwara, DVM; Hatsue Ishibashi-Ueda, MD, PhD; Keiichi Kanda, MD, PhD; Taiji Watanabe, MD; Tsutomu Tajikawa, PhD; Kenkichi Ohba, PhD; Hitoshi Yaku, MD, PhD; Yasuhide Nakayama, PhD
From Department of Cardiovascular Surgery (M.Y., K.K., T.W., H.Y.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Medical Engineering and Materials (M.Y., Y.Y., T.W., Y.N.), National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan; Department of Mechanical and Systems Engineering (Y.Y., T.T., K.O.), Kansai University, Osaka, Japan; Department of Veterinary Medicine (M.U., M.F.), College of Bioresource Sciences, Nihon University, Kanagawa, Japan; Department of Phathology (H.I.-U.), National Cerebral and Cardiovascular Center Hospital, Osaka, Japan.

Correspondence to Dr Yasuhide Nakayama, Division of Medical Engineering and Materials, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail nakayama@ri.ncvc.go.jp; and Dr Keiichi Kanda, Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: kei@koto.kpu-m.ac.jp.

Background—We developed autologous prosthetic implants by simple and safe in-body tissue architecture technology. We present the first report on the development of autologous valved conduit with the sinus of Valsalva (BIOVALVE) by using this unique technology and its subsequent implantation in the pulmonary valves in a beagle model.

Methods and Results—A mold of BIOVALVE organization was assembled using 2 types of specially designed silicone rods with a small aperture in a trileaflet shape between them. The concave rods had 3 projections that resembled the protrusions of the sinus of Valsalva. The molds were placed in the dorsal subcutaneous spaces of beagle dogs for 4 weeks. The molds were covered with autologous connective tissues. BIOVALVEs with 3 leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds. These valves had adequate burst strength, similar to that of native valves. Tight valvular coaptation and sufficient open orifice area were observed in vitro. These BIOVALVEs were implanted to the main pulmonary arteries as allogenic conduit valves (n=3). Postoperative echocardiography demonstrated smooth movement of the leaflets with trivial regurgitation. Histological examination of specimens obtained at 84 days showed that the surface of the leaflet was covered by endothelial cells and neointima, including an elastin fiber network, and was formed at the anastomosis sides on the luminal surface of the conduit.

Conclusion—We developed the first completely autologous BIOVALVE and successfully implanted these BIOVALVEs in a beagle model in a pilot study.

Key Words: prosthesis • regenerative medicine • tissue • Valsalva • valves

[Full Text of Yamanami et al.] [Reprint (PDF) Version of Yamanami et al.]

--------------------------------------------------------------------------------
Abstract 5 of 34 (Circulation. 2010;122:S107-S117.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cell Transplantation and Tissue Regeneration

Stromal Cell-Derived Factor-1 Activation of Tissue-Engineered Endothelial Progenitor Cell Matrix Enhances Ventricular Function After Myocardial Infarction by Inducing Neovasculogenesis
John R. Frederick, MD; J. Raymond Fitzpatrick, III, MD; Ryan C. McCormick, BS; David A. Harris, BS; Ah-Young Kim, MS; Jeffrey R. Muenzer, BS; Nicole Marotta, BS; Maximilian J. Smith, BS; Jeffrey E. Cohen, MD; William Hiesinger, MD; Pavan Atluri, MD; Y. Joseph Woo, MD
From the Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.

Correspondence to Y. Joseph Woo, MD, 3400 Spruce St, 6 Silverstein, Philadelphia, PA 19104. E-mail wooy@uphs.upenn.edu

Background—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-1 (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.

Methods and Results—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.

Conclusions—Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.

Key Words: angiogenesis • vasculogenesis • endothelial progenitor cells • extracellular matrix • ischemic heart disease

[Full Text of Frederick et al.] [Reprint (PDF) Version of Frederick et al.]

--------------------------------------------------------------------------------
Abstract 6 of 34 (Circulation. 2010;122:S118-S123.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cell Transplantation and Tissue Regeneration

Composite Cell Sheets
A Further Step Toward Safe and Effective Myocardial Regeneration by Cardiac Progenitors Derived From Embryonic Stem Cells
Alain Bel, MD; Valérie Planat-Bernard, PhD, MD; Atsuhiro Saito, PhD; Lionel Bonnevie, MD; Valérie Bellamy, MSc; Laurent Sabbah, MD; Linda Bellabas; Benjamin Brinon, MSc; Valérie Vanneaux, MD, PhD; Pascal Pradeau, DVet; Séverine Peyrard, MSc; Jérôme Larghero, MD, PhD; Julia Pouly, MD; Patrice Binder, MD; Sylvie Garcia, PhD; Tatsuya Shimizu, PhD; Yoshiki Sawa, MD; Teruo Okano, PhD; Patrick Bruneval, MD; Michel Desnos, MD, PhD; Albert A. Hagège, MD, PhD; Louis Casteilla, PhD; Michel Pucéat, PhD; Philippe Menasché, MD, PhD
From the Assistance Publique-Hôpitaux de Paris (A.B., J.P., P.M.), Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery; University Paris Descartes; INSERM U633, Laboratory of Biosurgical Research, Paris, France; University of Toulouse (V.P.-B., L.C.), UPS, CNRS, UMR 5241 Métabolisme, Plasticité et Mitochondrie, Toulouse, France; Medical Center for Translational Research (A.S., Y.S.), Osaka University Hospital, Osaka, Japan; Hôpital d’Instruction des Armées Bégin (L.B.), Vincennes, France; INSERM U633 (V.B., L.B., B.B.), Laboratory of Biosurgical Research, Paris, France; Assistance Publique-Hôpitaux de Paris (L.S., M.D., A.A.H.), Hôpital Européen Georges Pompidou, Department of Cardiology; University Paris Descartes; INSERM U633, Laboratory of Biosurgical Research, Paris, France; Assistance Publique-Hôpitaux de Paris (V.V., J.L.), Hôpital Saint-Louis, Unit of Cell Therapy; University Paris Diderot; INSERM UMRS940, Paris, France; Institut de Médecine Aérospatiale du Service de Santé des Armées (P.P., P.B.), Brétigny-sur-Orge, France; Assistance Publique-Hôpitaux de Paris (S.P.), Hôpital Européen Georges Pompidou, Epidemiology and Clinical Research Unit; INSERM CIE4, Paris, France; Unité de Biologie des Populations Lymphocytaires (S.G.), URA CNRS 1961, Institut Pasteur, Paris, France; Institute of Advanced Biomedical Engineering and Science (T.S., T.O.), Tokyo Women’s Medical University, Tokyo, Japan; Assistance Publique-Hôpitaux de Paris (P.B.), Hôpital Européen Georges Pompidou, Department of Pathology; University Paris Descartes; INSERM U970; and INSERM Avenir programme (M.P.), Stem Cell and Cardiogenesis, INSERM U633; University Paris Descartes; Evry, France.

Correspondence to Philippe Menasché, MD, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France. E-mail philippe.menasche@egp.aphp.fr

Background—The safety and efficacy of myocardial regeneration using embryonic stem cells are limited by the risk of teratoma and the high rate of cell death.

Methods and Results—To address these issues, we developed a composite construct made of a sheet of adipose tissue–derived stroma cells and embryonic stem cell–derived cardiac progenitors. Ten Rhesus monkeys underwent a transient coronary artery occlusion followed, 2 weeks later, by the open-chest delivery of the composite cell sheet over the infarcted area or a sham operation. The sheet was made of adipose tissue–derived stroma cells grown from a biopsy of autologous adipose tissue and cultured onto temperature-responsive dishes. Allogeneic Rhesus embryonic stem cells were committed to a cardiac lineage and immunomagnetically sorted to yield SSEA-1+ cardiac progenitors, which were then deposited onto the cell sheet. Cyclosporine was given for 2 months until the animals were euthanized. Preimplantation studies showed that the SSEA-1+ progenitors expressed cardiac markers and had lost pluripotency. After 2 months, there was no teratoma in any of the 5 cell-treated monkeys. Analysis of >1500 histological sections showed that the SSEA-1+ cardiac progenitors had differentiated into cardiomyocytes, as evidenced by immunofluorescence and real-time polymerase chain reaction. There were also a robust engraftment of autologous adipose tissue–derived stroma cells and increased angiogenesis compared with the sham animals.

Conclusions—These data collected in a clinically relevant nonhuman primate model show that developmentally restricted SSEA-1+ cardiac progenitors appear to be safe and highlight the benefit of the epicardial delivery of a construct harboring cells with a cardiomyogenic differentiation potential and cells providing them the necessary trophic support.

Key Words: heart failure • myocardial infarction • transplantation • cells • stem cells

[Full Text of Bel et al.] [Reprint (PDF) Version of Bel et al.]

--------------------------------------------------------------------------------
Abstract 7 of 34 (Circulation. 2010;122:S124-S131.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cell Transplantation and Tissue Regeneration

MicroRNA-210 as a Novel Therapy for Treatment of Ischemic Heart Disease
Shijun Hu, PhD; Mei Huang, PhD; Zongjin Li, PhD; Fangjun Jia, PhD; Zhumur Ghosh, PhD; Maarten A. Lijkwan, MD; Pasquale Fasanaro, PhD; Ning Sun, PhD; Xi Wang, MD, PhD; Fabio Martelli, PhD; Robert C. Robbins, MD; Joseph C. Wu, MD, PhD
From the Department of Medicine (S.H., M.H., Z.L., F.J., Z.G., N.S., J.C.W.), Division of Cardiology, the Department of Radiology (S.H., M.H., Z.L., F.J., Z.G., N.S., J.C.W.), Molecular Imaging Program, and the Department of Cardiothoracic Surgery (M.A.L., X.W., R.C.R.), Stanford University School of Medicine, Stanford, Calif; IRCCS-Policlinico San Donato (P.F.), Milan, Italy; and Istituto Dermopatico dell’Immacolata-IRCCS (F.M.), Rome, Italy.

Correspondence to Joseph C. Wu, MD, PhD, Stanford University School of Medicine, Grant Building S140, Stanford, CA 94305-5111. E-mail joewu@stanford.edu

Background—MicroRNAs are involved in various critical functions, including the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. We hypothesize that microRNA-210 can rescue cardiac function after myocardial infarction by upregulation of angiogenesis and inhibition of cellular apoptosis in the heart.

Methods and Results—Using microRNA microarrays, we first showed that microRNA-210 was highly expressed in live mouse HL-1 cardiomyocytes compared with apoptotic cells after 48 hours of hypoxia exposure. We confirmed by polymerase chain reaction that microRNA-210 was robustly induced in these cells. Gain-of-function and loss-of-function approaches were used to investigate microRNA-210 therapeutic potential in vitro. After transduction, microRNA-210 can upregulate several angiogenic factors, inhibit caspase activity, and prevent cell apoptosis compared with control. Afterward, adult FVB mice underwent intramyocardial injections with minicircle vector carrying microRNA-210 precursor, minicircle carrying microRNA-scramble, or sham surgery. At 8 weeks, echocardiography showed a significant improvement of left ventricular fractional shortening in the minicircle vector carrying microRNA-210 precursor group compared with the minicircle carrying microRNA-scramble control. Histological analysis confirmed decreased cellular apoptosis and increased neovascularization. Finally, 2 potential targets of microRNA-210, Efna3 and Ptp1b, involved in angiogenesis and apoptosis were confirmed through additional experimental validation.

Conclusion—MicroRNA-210 can improve angiogenesis, inhibit apoptosis, and improve cardiac function in a murine model of myocardial infarction. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.

Key Words: gene therapy • ischemic heart disease • microRNA • minicircle vector

[Full Text of Hu et al.] [Reprint (PDF) Version of Hu et al.]

--------------------------------------------------------------------------------
Abstract 8 of 34 (Circulation. 2010;122:S132-S141.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Cell Transplantation and Tissue Regeneration

Intramyocardial Peptide Nanofiber Injection Improves Postinfarction Ventricular Remodeling and Efficacy of Bone Marrow Cell Therapy in Pigs
Yi-Dong Lin, MS; Ming-Long Yeh, PhD; Yu-Jen Yang, MD, PhD; Da-Ching Tsai, MS; Ting-Yu Chu, BA; Ya-Yun Shih, MS; Min-Yao Chang, MS; Yen-Wen Liu, MD; Alan C.L. Tang, MS; Tsai-Yun Chen, MD; Chwan-Yau Luo, MD, MS; Kung-Chao Chang, MD, PhD; Jyh-Hong Chen, MD, PhD; Hua-Lin Wu, PhD; Tin-Kan Hung, PhD; Patrick C.H. Hsieh, MD, PhD
From the Institute of Biomedical Engineering (Y.D.L., M.L.Y., M.Y.C., P.C.H.H.), Institute of Clinical Medicine & Research Center of Clinical Medicine (Y.D.L., D.C.T., T.Y.C., Y.Y.S., M.Y.C., Y.W.L., A.C.L.T., P.C.H.H.), Department of Surgery (Y.J.Y., C.Y.L., P.C.H.H.), Department of Medicine (Y.W.L., T.Y.C., J.H.C.), Department of Pathology (K.C.C.), and Department of Biochemistry and Molecular Biology (H.L.W.), National Cheng Kung University & Hospital, Tainan, Taiwan; the Institute of Biomedical Sciences (P.C.H.H.), Academia Sinica, Taipei, Taiwan; and the Department of Bioengineering (T.K.H.), University of Pittsburgh, Pittsburgh, Pa.

Correspondence to Patrick C.H. Hsieh, MD, PhD, Institute of Clinical Medicine & Research Center of Clinical Medicine, National Cheng Kung University & Hospital, 35 Xiao-Dong Road, Room 7063, Tainan 70428, Taiwan. E-mail phsieh@mail.ncku.edu.tw

Background—Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model.

Methods and Results—A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1x108 isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and –dP/dt (1214.5±91.9 and –1109.7±91.2 mm Hg/s in MI+NS, 1693.7±84.7 and –1809.6±264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3±4.5 cells/mm2 in MI+MNCs and 229.4±41.4 cells/mm2 in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area.

Conclusions—We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future.

Key Words: biomaterials • bone marrow mononuclear cells • cardiac tissue engineering • myocardial infarction

[Full Text of Lin et al.] [Reprint (PDF) Version of Lin et al.]

--------------------------------------------------------------------------------
Abstract 9 of 34 (Circulation. 2010;122:S142-S149.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia
Michael P. Robich, MD; Robert M. Osipov, MD; Reza Nezafat, PhD; Jun Feng, MD, PhD; Richard T. Clements, PhD; Cesario Bianchi, MD, PhD; Munir Boodhwani, MD, MMSc; Michael A. Coady, MD; Roger J. Laham, MD; Frank W. Sellke, MD
From the Department of Surgery (M.P.R., F.W.S.), Division of Cardiothoracic Surgery, Warren Alpert School of Medicine, Brown University, Providence, RI; the Department of Surgery (M.P.R., R.M.O., F.W.S.), Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Department of Medicine (R.N., R.J.L.), Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Department of Surgery (J.F., R.T.C., C.B., M.A.C.), Division of Cardiothoracic Surgery, Rhode Island Hospital, Providence, RI; and the Division of Cardiac Surgery (M.B.), University of Ottawa Heart Institute, Ottawa, Canada.

Correspondence to Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, 593 Eddy St, APC 424, Providence, RI 02903. E-mail fsellke@lifespan.org

Background—Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia.

Methods and Results—Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (P<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (P=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (P=0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine (P=0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment (P=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine (P=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF (P=0.002), peNOS (ser1177) (P=0.04), NFkB (P=0.004), and pAkt (thr308) (P=0.001).

Conclusions—Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway.

Key Words: coronary disease • hypercholesterolemia • ischemia • perfusion • angiogenesis

[Full Text of Robich et al.] [Reprint (PDF) Version of Robich et al.]

--------------------------------------------------------------------------------
Abstract 10 of 34 (Circulation. 2010;122:S150-S155.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Effects of Cardiopulmonary Bypass on Endothelin-1–Induced Contraction and Signaling in Human Skeletal Muscle Microcirculation
Jun Feng, MD, PhD; Louis M. Chu, MD; Michael P. Robich, MD; Richard T. Clements, PhD; Kamal R. Khabbaz, MD; Robert Hagberg, MD; Yuhong Liu, MD; Robert M. Osipov, MD; Frank W. Sellke, MD
From the Division of Cardiothoracic Surgery (J.F., L.M.C., M.P.R., R.T.C., Y.L., F.W.S.), Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI; and the Division of Cardiothoracic Surgery (K.R.K., R.H., R.M.O.), Department of Surgery, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass.

Correspondence to Frank W. Sellke, MD, Division of Cardiothoracic Surgery, 593 Eddy St, APC 424, Providence, RI 02903. E-mail fsellke@lifespan.org

Background—We investigated the effects of cardiopulmonary bypass (CPB) on the contractile response of human peripheral microvasculature to endothelin-1 (ET-1), examined the role of specific ET receptors and protein kinase C-alpha (PKC-), and analyzed ET-1–related gene/protein expression in this response.

Methods and Results—Human skeletal muscle arterioles (90 to 180 µm in diameter) were dissected from tissue harvested before and after CPB from 30 patients undergoing cardiac surgery. In vitro contractile response to ET-1 was assessed by videomicroscopy, with and without an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) antagonist, or a PKC- inhibitor. The post-CPB contractile response of peripheral arterioles to ET-1 was significantly decreased compared with pre-CPB response. The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 but unchanged in the presence of the ET-B receptor antagonist BQ788. Pretreatment with the PKC- inhibitor safingol reversed ET-1–induced response from contraction to relaxation. The total protein levels of ET-A and ET-B receptors were not altered after CPB. Microarray analysis showed no significant changes in the gene expression of ET receptors, ET-1–related proteins, and protein kinases after CPB.

Conclusions—CPB decreases myogenic contractile function of human peripheral arterioles in response to ET-1. The contractile response to ET-1 is through activation of ET-A receptors and PKC-. CPB has no effects on ET-1–related gene/protein expression. These results provide novel mechanisms of ET-1–induced contraction in the setting of vasomotor dysfunction after cardiac surgery.

Key Words: cardiopulmonary bypass • endothelin • genes • microcirculation • vasoconstriction

[Full Text of Feng et al.] [Reprint (PDF) Version of Feng et al.]

--------------------------------------------------------------------------------
Abstract 11 of 34 (Circulation. 2010;122:S156-S161.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Epidermal Growth Factor-Like Domain 7 Suppresses Intercellular Adhesion Molecule 1 Expression in Response to Hypoxia/Reoxygenation Injury in Human Coronary Artery Endothelial Cells
Mitesh V. Badiwala, MD; Laura C. Tumiati, BSc; Jemy M. Joseph, BSc; Rohit Sheshgiri, MSc; Heather J. Ross, MD, MHSc; Diego H. Delgado, MD, MSc; Vivek Rao, MD, PhD
From the Divisions of Cardiovascular Surgery (M.V.B., L.C.T., J.M.J., R.S., V.R.) and Cardiology (H.J.R., D.H.D.), Peter Munk Cardiac Centre, Toronto General Hospital-University Health Network, Toronto, Ontario, Canada.

Correspondence to Vivek Rao, MD, PhD, Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, 4N-464, 200 Elizabeth St, Toronto, Ontario M5G 2**, Canada. E-mail vivek.rao@uhn.on.ca

Background—Epidermal growth factor-like domain 7 (Egfl7) is a chemoattractant for endothelial cells, and its expression is restricted to endothelial cells. Hypoxia/reoxygenation (H/R) induced endothelial injury that occurs during transplantation contributes to the subsequent development of allograft vasculopathy. We investigated the effect of Egfl7 on endothelial cell intercellular adhesion molecule 1 expression in response to H/R injury.

Methods and Results—Human coronary artery endothelial cells were submitted to hypoxia (0.1% O2) followed by normoxia (21% O2) in the presence or absence of Egfl7 (100 ng/mL). Hypoxia alone increased the expression of Egfl7x140±8% of control at 3 hours (n=6; P<0.05) and 385±50% of control at 6 hours (n=6; P<0.001). Incubation with Egfl7 during the reoxygenation period prevented intercellular adhesion molecule 1 upregulation (mean fluorescence intensity: 5.37±0.92 versus 3.81±0.21; P<0.05; n=4 per group). Nuclear factor-B nuclear localization on H/R injury was blocked by Egfl7 administration (cytosolic/nuclear ratio of 0.93±0.01 versus 1.44±0.24; P<0.05; n=4 per group). Inhibitor of nuclear factor-B protein level was significantly reduced on H/R injury (26±4.6% of control expression; P<0.05; n=4 per group); however, concurrent incubation with Egfl7 attenuated this reduction (46±6.2% of control expression; P<0.05 when compared with H/R injury alone; n=4 per group).

Conclusions—Our study reveals the novel observation that hypoxia upregulates human coronary artery endothelial cells expression of Egfl7 and that Egfl7 inhibits expression of intercellular adhesion molecule 1 subsequent to H/R injury. Mechanistically, Egfl7 prevented nuclear factor-B nuclear localization and augmented inhibitor of nuclear factor-B protein levels, suggesting that it inhibits nuclear factor-B activation, a key step in the inflammatory activation of endothelial cells. Egfl7 may be protective against H/R injury incurred during transplantation and may modulate the events that lead to the development of graft vasculopathy.

Key Words: ischemia • reperfusion • endothelium • cell adhesion molecules

[Full Text of Badiwala et al.] [Reprint (PDF) Version of Badiwala et al.]

--------------------------------------------------------------------------------
Abstract 12 of 34 (Circulation. 2010;122:S162-S169.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Effect of Thrombin Fragment (TP508) on Myocardial Ischemia Reperfusion Injury in a Model of Type 1 Diabetes Mellitus
Louis M. Chu, MD; Robert M. Osipov, MD; Michael P. Robich, MD; Jun Feng, MD, PhD; Michael R. Sheller, PhD; Frank W. Sellke, MD, FAHA, FACS
From the Department of Surgery (L.M.C., R.M.O., M.P.R., J.F., F.W.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; Division of Cardiothoracic Surgery (F.W.S.), Alpert Medical School of Brown University, Providence, RI; Capstone Therapeutics (M.R.S.), Tempe, Ariz.

Correspondence to Frank W. Sellke, Alpert Medical School of Brown University, 2 Dudley St, Providence, RI 02905. E-mail fsellke@lifespan.org

Background—We investigated the efficacy of novel thrombin fragment TP508 on ischemia-reperfusion injury using a porcine model of type 1 diabetes mellitus.

Methods and Results—Alloxan-induced diabetic male Yucatan swine underwent 60 minutes of mid-left anterior descending coronary artery occlusion, followed by 120 minutes of reperfusion. Fifty minutes into ischemia, animals received either placebo (DM; n=8) or TP508 as a bolus of 1 mg/kg followed by infusion at 2.5 mg/kg per hour (DMT; n=8). Hemodynamic parameters and myocardial function were monitored. Monastryl blue/triphenyl tetrazolium chloride staining was used to assess sizes of the areas at risk and infarction. Coronary microvascular reactivity was measured and expression of cell survival and proapoptotic proteins quantified. Preoperative serum glucose values were similar between groups (309±57 mg/dL in DM versus 318±67 mg/dL in DMT; P=0.92). Infarct size was smaller in the TP508-treated group (5.3±1.9% in DMT versus 19.4±5.6% in DM; P=0.03). There was no statistically significant difference in global or regional left ventricular function between groups. Endothelium-dependent microvessel relaxation was moderately improved in the DMT group (P=0.09), whereas endothelium-independent relaxation was similar between groups. The expression of cell survival proteins Akt, phospho-p38, and mammalian target of rapamycin was higher in the areas at risk of DMT animals compared with DM animals (P<0.05), and expressions of proapoptotic glycogen synthase kinase 3β and caspase 3 were lower in the DMT group (P<0.05).

Conclusions—This study demonstrates that, in type 1 diabetic swine, TP508 reduces infarct size after ischemia-reperfusion. Thus, TP508 may offer a novel approach in cardioprotection from ischemia-reperfusion injury in diabetic patients.

Key Words: ischemia • reperfusion • diabetes mellitus • pharmacology

[Full Text of Chu et al.] [Reprint (PDF) Version of Chu et al.]

--------------------------------------------------------------------------------
Abstract 13 of 34 (Circulation. 2010;122:S170-S178.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Sustained Inhibition of Protein Kinase C Inhibits Vascular Restenosis After Balloon Injury and Stenting
Tobias Deuse, MD; Tomoyoshi Koyanagi, MD; Reinhold G. Erben, MD; Xiaoqin Hua, MD; Joachim Velden, MD; Fumiaki Ikeno, MD; Hermann Reichenspurner, MD; Robert C. Robbins, MD; Daria Mochly-Rosen, MD; Sonja Schrepfer, MD, PhD
From the Departments of Cardiothoracic Surgery (T.D., R.C.B., S.S.); Cardiovascular Medicine (F.I.), Stanford University School of Medicine, Stanford, CA; Department of Cardiovascular Surgery, Transplant and Stem Cell Immunobiology Lab (T.D., X.H., H.R., S.S.); Cardiovascular Research Center (T.D., X.H., H.R., S.S.); Department of Pathology (J.V.), University Hospital Hamburg, Hamburg, Germany; Department of Chemical and Systems Biology, Stanford University, Stanford, CA (T.K., D.M.-R.); University of Veterinary Medicine Vienna, Vienna, Austria (R.G.E.).

Correspondence to Sonja Schrepfer, MD, PhD, Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Dr, Cardiovascular Research Building 5407, Stanford, CA 94305. E-mail schrepfer@stanford.edu

Background— Protein kinase C (PKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of PKC in the development of restenosis.

Methods and Results—Rat models of aortic balloon injury with or without subsequent stenting were used. Rats were treated with the selective PKC activator receptor for activated protein kinase C (RACK), the selective PKC inhibitor V1–2, or saline. Both down-stream cascades of the platelet-derived growth factor receptor via extracellular signal-regulated kinase and Akt, respectively, were evaluated in vivo and in VSMC cultures. Intimal hyperplasia with luminal obliteration developed in saline-treated balloon-injured rat aortas (20.3±8.0%), and RACK significantly promoted neointima development (32.4±4.9%, P=0.033), whereas V1–2 significantly inhibited luminal narrowing (9.2±4.3%, P=0.039). PKC inhibition led to significantly reduced VSMC extracellular signal-regulated kinase phosphorylation in vivo, whereas Akt phosphorylation was not markedly affected. Neointimal proliferation in vivo and platelet-derived growth factor-induced VSMC proliferation/migration in vitro were significantly inhibited by V1–2. The inhibition of the platelet-derived growth factor pathway was mediated by inhibiting down-stream extracellular signal-regulated kinase and Akt phosphorylation. In vitro, V1–2 showed inhibitory properties on endothelial cell proliferation, but that did not prevent reendothelialization in vivo. V1–2 showed proapoptotic effects on VSMC in vitro. After stent implantation, luminal restenosis (quantified by optical coherence tomography imaging) was significantly reduced with V1–2 (8.0±2.0%) compared with saline (20.2±9.8%, P=0.028).

Conclusions—PKC seems to be centrally involved in the development of neointimal hyperplasia. We suggest that PKC inhibition may be mediated via inhibition of extracellular signal-regulated kinase and Akt activation. PKC modulation may become a new therapeutic target against vascular restenosis.

Key Words: protein kinase C • vascular restenosis • platelet-derived growth factor pathway

[Full Text of Deuse et al.] [Reprint (PDF) Version of Deuse et al.]

--------------------------------------------------------------------------------
Abstract 14 of 34 (Circulation. 2010;122:S179-S184.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Profound Cardioprotection With Chloramphenicol Succinate in the Swine Model of Myocardial Ischemia-Reperfusion Injury
Javier A. Sala-Mercado, MD, PhD; Joseph Wider, BS; Vishnu Vardhan Reddy Undyala, MS; Salik Jahania, MD; Wonsuk Yoo, PhD; Robert M. Mentzer, Jr, MD; Roberta A. Gottlieb, MD; Karin Przyklenk, PhD
From the Cardiovascular Research Institute (J.A.S.-M., J.W., V.V.R.U,. S.J., R.M.M. Jr, K.P.) and Departments of Physiology (J.A.S.-M., R.M.M. Jr, K.P.), Surgery (S.J., R.M.M. Jr), and Translational Research and Clinical Epidemiology (W.Y.), Wayne State University School of Medicine, Detroit, MI; Radical Therapeutix, Inc, San Diego, CA (R.A.G.).

Correspondence to: Karin Przyklenk, PhD, Director, Cardiovascular Research Institute, Wayne State University School of Medicine, Elliman Bldg, Room 1107, 421 E Canfield, Detroit, MI 48201. E-mail. E-mail kprzykle@med.wayne.edu

Background—Emerging evidence suggests that "adaptive" induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction.

Methods and Results—Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with "delayed" treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins.

Conclusion—Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.

Key Words: myocardial infarction • ischemia • reperfusion • autophagy

[Full Text of Sala-Mercado et al.] [Reprint (PDF) Version of Sala-Mercado et al.]

--------------------------------------------------------------------------------
Abstract 15 of 34 (Circulation. 2010;122:S185-S192.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Myocardial Protection, Perioperative Management, and Vascular Biology

Adropin Is a Novel Regulator of Endothelial Function
Fina Lovren, PhD; Yi Pan, MD; Adrian Quan, MPhil; Krishna K. Singh, PhD; Praphulla C. Shukla, PhD; Milan Gupta, MD; Mohammed Al-Omran, MD, MSc; Hwee Teoh, PhD; Subodh Verma, MD, PhD
From the Divisions of Cardiac Surgery (F.L., Y.P., A.Q., K.K.S., P.C.S., M.G., H.T., S.V.); Cardiometabolic Risk Initiative (M.G., H.T., S.V.); Keenan Research Centre in the Li Ka Shing Knowledge Institute (F.L., Y.P., A.Q., K.K.S., P.C.S., M.G., M.A.-O., H.T., S.V.), St. Michael’s Hospital, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada (S.V.); Division of Vascular Surgery, College of Medicine and King Khalid University Hospital (M.A.-O.), King Saud University-Li Ka Shing Collaborative Research Program (M.A.-O., S.V.), Riyadh, Kingdom of Saudi Arabia; Department of Medicine, McMaster University, Hamilton, Ontario, Canada (M.G.); Division of Cardiology, William Osler Health Centre, Brampton, Ontario, Canada (M.G.); Canadian Cardiovascular Research Network, Brampton, ON, Canada (M.G., H.T., S.V.).

Correspondence to Subodh Verma, MD, PhD, FRCSC, FAHA, Division of Cardiac Surgery, Suite 8-003F, Bond Wing, St. Michael’s Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. E-mail subodh.verma@sympatico.ca; or Hwee Teoh, PhD, Division of Cardiac Surgery, Room 8-012, Queen Wing, St. Michael’s Hospital, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. E-mail teohh@smh.ca.

Background—Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium.

Methods and Results—In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin. Adropin was expressed in human umbilical vein and coronary artery endothelial cells (ECs). Adropin-treated endothelial cells exhibited greater proliferation, migration and capillary-like tube formation and less permeability and tumor necrosis factor-–induced apoptosis. In keeping with a vascular protective effect, adropin stimulated Akt Ser473 and endothelial nitric oxide (NO) synthase Ser1177 phosphorylation. The former was abrogated in the presence of the phosphatidylinositol 3-kinase inhibitor LY294002, whereas the latter was attenuated by LY294002 and by mitogen-activated protein kinase kinase 1 inhibition with PD98059. Together, these findings suggest that adropin regulates NO bioavailability and events via the phosphatidylinositol 3-kinase-Akt and extracellular signal regulated kinase 1/2 signaling pathways. Adropin markedly upregulated vascular endothelial growth factor receptor-2 (VEGFR2) transcript and protein levels, and in VEGFR2-silenced endothelial cells, adropin failed to induce phosphorylation of endothelial NO synthase, Akt, and extracellular signal regulated kinase 1/2, supporting VEGFR2 as an upstream target of adropin-mediated endothelial NO synthase activation. Last, adropin improved murine limb perfusion and elevated capillary density following induction of hindlimb ischemia.

Conclusions—We report a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3-kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. Adropin represents a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile.

Key Words: adropin • angiogenesis • endothelium • nitric oxide

[Full Text of Lovren et al.] [Reprint (PDF) Version of Lovren et al.]

--------------------------------------------------------------------------------
Abstract 16 of 34 (Circulation. 2010;122:S74-S80.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Surgery for Aortic Disease

Impact of New Development of Ulcer-Like Projection on Clinical Outcomes in Patients With Type B Aortic Dissection With Closed and Thrombosed False Lumen
Takeshi Kitai, MD; Shuichiro Kaji, MD; Atsushi Yamamuro, MD; Tomoko Tani, MD; Makoto Kino***a, MD; Natsuhiko Ehara, MD; Atsushi Kobori, MD; Toru Kita, MD; Yutaka Furukawa, MD
From the Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Correspondence to Shuichiro Kaji, MD, Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, Japan, 4–6 Minatojima-nakamachi Chuo-ku, Kobe, 650-0046, Japan. E-mail skaji@kcgh.gr.jp

Background—The purpose of this study was to investigate the clinical importance of newly developed ulcer-like projection (ULP) in patients with type B aortic dissection with closed and thrombosed false lumen (AD with CTFL), which is better known as aortic intramural hematoma.

Methods and Results—A total of 170 patients with acute type B AD with CTFL were admitted to our institution from 1986 to 2008 and treated initially with medical therapy. There were 31 late deaths, including 9 cases of aortic rupture. The actuarial survival rates of all patients were 99%, 89%, 83% at 1, 5, and 10 years, respectively. A total of 62 (36%) patients showed new ULP development within 30 days from the onset. Patients who had ULP showed significantly poorer survival rates than patients who did not have ULP (P=0.037). Development of ULP was also associated with a significant increase in adverse aorta-related events (P<0.001). In addition, patients with ULP in the proximal descending thoracic aorta (PD) showed significantly higher aorta-related event rates than patients without ULP in the PD (P<0.001). Initial aortic diameter (hazard ratio, 3.55; P<0.001) and development of ULP in PD (hazard ratio, 3.79; P=0.003) were the strongest predictors of adverse aorta-related events.

Conclusions—Initial aortic diameter and development of ULP in the PD are both strong predictors of adverse aorta-related events in patients with type B AD with CTFL. Patients with newly developed ULP should be more carefully followed up with close surveillance imaging than those without ULP.

Key Words: aorta • follow-up studies • mortality • prognosis • and survival

[Full Text of Kitai et al.] [Reprint (PDF) Version of Kitai et al.]

--------------------------------------------------------------------------------
Abstract 17 of 34 (Circulation. 2010;122:S81-S84.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Surgery for Aortic Disease

Late Outcomes of Reintervention on the Descending Aorta After Repair of Aortic Coarctation
Morgan L. Brown, MD; Harold M. Burkhart, MD; Heidi M. Connolly, MD; Joseph A. Dearani, MD; Donald J. Hagler, MD; Hartzell V. Schaff, MD
From the Department of Anesthesiology and Pain Medicine (M.L.B.), University of Alberta, Edmonton, Alberta, Canada; and the Divisions of Cardiovascular Surgery (H.M.B., J.A.D., H.V.S.), Cardiovascular Medicine (H.M.C.), and Pediatric Cardiology (D.J.H.), Mayo Clinic, Rochester, Minn.

Correspondence to Harold M. Burkhart, MD, Mayo Clinic 200 1st Street SW Rochester, MN USA. E-mail burkhart.harold@mayo.edu

Background—After repair of aortic coarctation, patients may develop restenosis, aneurysms, and pseudoaneurysms at the site of prior repair. We assessed the outcomes of late reintervention on the descending aorta after aortic coarctation repair.

Methods and Results—From March 1954 to July 2008, 130 patients had operations or endovascular procedures on the descending aorta after previous coarctation repair. We excluded patients who had complex left-sided cardiac lesions or interrupted aortic arch. Mean age at reintervention was 32±24 years and 28% were female. The interval between coarctation repair and reintervention was 17±13 years. Seventy-four percent of patients had hypertension. Reasons for reintervention were restenosis (n=122 [94%]), aneurysm (n=4 [3%]), and pseudoaneurysm (n=4 [3%]). Ninety-five patients (73%) underwent operative procedures including an extra-anatomic conduit (n=41), patch repair (n=32), interposition graft (n=14), end–end anastomosis (n=6), and subclavian flap (n=2). Thirty-five patients underwent endovascular treatment (balloon dilatation, n=22 or stenting, n=13). There was no early mortality. In the surgical group, 5 patients required early reoperation for bleeding and 5 patients had early vocal cord paralysis. One patient in the endovascular group had aortic rupture at the time of intervention requiring urgent operation. Survival was 97% at 10 years. At 5 years, freedom from a second repeat procedure on the descending aorta was 96% in the surgical group and 72% in the endovascular group (P<0.001). Five years after reintervention, fewer patients required treatment for hypertension (57% versus 74%, P<0.001) and a median of 1 antihypertensive medication was prescribed compared with a median of 2 medications preintervention.

Conclusions—Operative and endovascular management of recoarctation can be performed safely with good late outcomes.

Key Words: aorta • coarctation • hypertension • stents • surgery

[Full Text of Brown et al.] [Reprint (PDF) Version of Brown et al.]

--------------------------------------------------------------------------------
Abstract 18 of 34 (Circulation. 2010;122:S201-S208.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Surgery for Congenital Heart Disease

Randomized Trial of Pulmonary Valve Replacement With and Without Right Ventricular Remodeling Surgery
Tal Geva, MD; Kimberlee Gauvreau, ScD; Andrew J. Powell, MD; Frank Cecchin, MD; Jonathan Rhodes, MD; Judith Geva, MSW; Pedro del Nido, MD
From the Department of Cardiology, Children’s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, MA (T.G., K.G., A.J.P., F.C., J.R., J.G.); Department of Cardiac Surgery, Children’s Hospital Boston and Department of Surgery, Harvard Medical School, Boston, MA (P.d.N.).

Correspondence to Tal Geva, MD, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail tal.geva@cardio.chboston.org

Background—Although pulmonary valve replacement (PVR) is effective in reducing right ventricular (RV) volume overload in patients with chronic pulmonary regurgitation, persistent RV dysfunction and subsequent adverse clinical outcomes have been reported. This trial was conducted to investigate whether the addition of surgical RV remodeling with exclusion of scar tissue to PVR would result in improved RV function and laboratory and clinical parameters, as compared with PVR alone.

Methods and Results—Between February 2004 and October 2008, 64 patients who underwent RV outflow tract procedures in early childhood had more than or equal to moderate pulmonary regurgitation, and fulfilled defined criteria for PVR were randomly assigned to undergo either PVR alone (n=34) or PVR with surgical RV remodeling (n=30). No significant difference was observed in the primary outcome (change in RV ejection fraction, –2±7% in the PVR alone group and –1±7% in the PVR with RV remodeling group; P=0.38) or in any of the secondary outcomes at 6-month postoperative follow-up. Multivariable analysis of the entire cohort identified preoperative RV end-systolic volume index <90 mL/m2 and QRS duration <140 ms to be associated with optimal postoperative outcome (normal RV size and function), and RV ejection fraction <45% and QRS duration 160 ms to be associated with suboptimal postoperative outcome (RV dilatation and dysfunction).

Conclusion—The addition of surgical remodeling of the RV to PVR in patients with chronic pulmonary regurgitation did not result in a measurable early benefit. Referral to PVR based on QRS duration, RV end-systolic volume, or RV ejection fraction may be beneficial.

Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00112320.

Key Words: tetralogy of Fallot • heart defect, congenital • remodeling • surgery • MRI

[Full Text of Geva et al.] [Reprint (PDF) Version of Geva et al.]

--------------------------------------------------------------------------------
Abstract 19 of 34 (Circulation. 2010;122:S209-S215.)
© 2010 American Heart Association, Inc.

--------------------------------------------------------------------------------

Surgery for Congenital Heart Disease

Echocardiographic Definition and Surgical Decision-Making in Unbalanced Atrioventricular Septal Defect
A Congenital Heart Surgeons’ Society Multiinstitutional Study
Anusha Jegatheeswaran, MD; Christian Pizarro, MD; Christopher A. Caldarone, MD; Meryl S. Cohen, MD; Jeanne M. Baffa, MD; David B. Gremmels, MD; Luc Mertens, MD, PhD; Victor O. Morell, MD; William G. Williams, MD; Eugene H. Blackstone, MD; Brian W. McCrindle, MD, MPH; David M. Overman, MD
From the Labatt Family Heart Centre (A.J., C.A.C., L.M., W.G.W., B.W.M.), Hospital for Sick Children, Toronto, Ontario, Canada; Nemours Cardiac Center (C.P., J.M.B.), Alfred I. duPont Hospital for Children, Wilmington, Del; Children’s Hospital of Philadelphia (M.S.C.), Pa; Children’s Heart Clinic (D.B.G., D.M.O.), Children’s Hospitals and Clinics of Minnesota, Minneapolis; Children’s Hospital of Pittsburgh (V.O.M.), Pa; and Cleveland Clinic Foundation (E.H.B.), Ohio.

Correspondence to Anusha Jegatheeswaran, MD, CHSS Data Center, The Hospital for Sick Children, 555 University Ave, Room 4431, Toronto, ON M5G 1X8, Canada. E-mail anusha.jegatheeswaran@utoronto.ca

Background—Although identification of unbalanced atrioventricular septal defect (AVSD) is obvious when extreme, exact criteria to define the limits of unbalanced are not available. We sought to validate an atrioventricular valve index (AVVI) (left atrioventricular valve area/total atrioventricular valve area, centimeters squared) as a discriminator of balanced and unbalanced forms of complete AVSD and to characterize the association of AVVI with surgical strategies and outcomes.

Methods and Results—Diagnostic echocardiograms and hospital records of 356 infants with complete AVSD at 4 Congenital Heart Surgeons’ Society (CHSS) institutions (2000–2006) were reviewed and AVVI measured (n=315). Patients were classified as unbalanced if AVVI0.4 (right dominant) or 0.6 (left dominant). Surgical strategy and outcomes were examined across the range of AVVI. Competing risks analysis until the time of commitment to a surgical strategy examined 4 end states: biventricular repair (BVR), univentricular repair (UVR), pulmonary artery banding (PAB), and death before surgery. A prediction nomogram for surgical strategy based on AVVI was developed.

The majority of patients had balanced AVSD (0.4<AVVI<0.6) and underwent BVR. Patients with AVVI<0.19 uniformly underwent UVR. Heterogeneous repair strategies were found when 0.19AVVI0.39 (UVR and BVR), with a disproportionate number of deaths in this range. AVVI0.6 (left dominant) was less common. The proportion of subjects predicted for the end states at 12 months after diagnosis are: BVR, 86%; UVR, 7%; PAB, 1%; death without surgery, 1%; alive without surgery, 5%.

Conclusions—AVVI effectively characterizes the transition between balanced and unbalanced AVSD with important correlation to anatomic substrate and selected surgical strategy.

Key Words: diagnosis • heart defects, congenital • heart septal defects • echocardiography • atrioventricular septal defect