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J Thorac Cardiovasc Surg 2006;132:170-173
© 2006 The American Association for Thoracic Surgery
Brief Communication |
a Center for Cardiovascular Repair, University of Minnesota, Minneapolis, Minn
b Division of Cardiology, University of Minnesota, Minneapolis, Minn
c Department of Radiology, University of Minnesota, Minneapolis, Minn
Received for publication November 19, 2005; revisions received February 1, 2006; accepted for publication February 21, 2006. * Address for reprints: Doris A. Taylor, PhD, Center for Cardiovascular Repair, University of Minnesota, 312 Church St SE, BSBE 7, Minneapolis, MN 55455. (Email: dataylor{at}umn.edu).
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Cardiac cell transplantation offers new opportunities as a potent therapeutic tool to improve left ventricular (LV) function and reverse postinfarction remodeling in ischemic heart disease. Skeletal myoblasts (SKMBs) engraft within infarcted myocardium, form myotubes, induce angiogenesis, and improve both diastolic and systolic LV function.
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Bone marrow–derived mononuclear cells (BM-MNCs) likewise engraft, increase angiogenesis, and improve myocardial perfusion.
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Both cell types have moved to clinical testing, and preclinical studies suggest that they could have synergistic functional benefits that argue for combined transplantation.
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Intramyocardial injections are currently performed either percutaneously through an endoventricular or transvenous approach or surgically through a thoracotomy or sternotomy. We recently reported a video-assisted thoracoscopic technique to reduce invasiveness and perioperative risk of surgical cell delivery that was tested in uninjured swine hearts.
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In the setting of heart failure (HF), mechanical manipulation of the left ventricle both by means of stabilization and cell injection must be minimized to prevent hemodynamic compromise, arrhythmia, and ventricular perforation. Robotically assisted cardiac surgery combines the advantages of minimal invasiveness and thoracoscopic access but adds a 3-dimensional view and 7 degrees of freedom that requires less cardiac manipulation than with the 2-dimensional view and limited freedom of motion of video-assisted thoracoscopic surgery.
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We therefore propose a robot-assisted, beating-heart cell transplantation technique for use in severe HF to increase safety, optimize targeting, and reduce procedural time.
Procedure Description
Eleven injured swine in which HF was previously induced by means of coronary occlusion and coronary embolism (left anterior descending coronary artery, n = 9; circumflex artery, n = 2) underwent robot-assisted cell (n = 7) or vehicle (n = 4) injection by using the daVinci robotic system (Intuitive Surgical, Sunnyvale, Calif). During right single-lung ventilation and antiarrhythmic prophylaxis (amiodarone, 3 mg/kg; lidocaine, 1 mg/kg), we inserted the camera port, 2 instrument ports, and an auxiliary port (Figure 1,
A). After removal of the pericardial fat pad, we incised the pericardium along the sternal border, dissected pericardial adhesions, and created a triangular pericardial flap. We inserted the prefilled injection needle (27-gauge needle attached to 12-inch tubing; Saf-T E-Z Set, BD, Sandy, Utah) through the auxiliary port and injected a 7-mL cell suspension containing a combination of 2.9 x 108 ± 5.9 x 107 autologous SKMBs and 1.1 x 108 ± 6.8 x 106 autologous BM-MNCs (Figure 1, B) at 6 to 10 sites. SKMBs were iron oxide labeled, as previously described.
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Viability at the time of injection was greater than 85%, and CD56 expression was greater than 80%. BM-MNCs were acutely isolated from bone marrow aspirate through Ficoll density gradient centrifugation. Injections were performed tangentially to minimize perforation risk and injectate backflow, covering a target area of 15 to 20 cm2. After cell delivery, the pericardial flap was readapted, all instrument ports were removed, and the left lung was expanded under visual control. We inserted a chest tube through the inferior instrument port, closed the port sites in 3 layers, and flushed the left thoracic cavity with 0.9% saline (200 mL). After removal of the chest tube, animals were extubated and recovered according to postoperative standards. Baseline magnetic resonance imaging (MRI) was performed 5 weeks after myocardial injury. Follow-up MRI was repeated at 4 and 7 weeks after cell/vehicle transplantation.
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Cell transplantation was completed successfully in 6 of 7 cases. Intractable ventricular fibrillation occurred in one animal during cell injection. No conversion to open chest surgery was necessary, and no other procedure-related complications occurred. Over the course of the study, single-lung ventilation time was reduced to a minimum of 23 minutes, and total anesthesia time was reduced to a minimum of 44 minutes. Cells were successfully transplanted into the apical, anterior, and lateral target regions of the left ventricle, including into thinned sections of the scar (target region wall thickness, 3-14 mm), without ventricular perforation. Postoperative MRI studies confirmed retention of iron oxide–labeled cells in the apex (Figure 2, A) and lateral wall (Figure 2, B) up to 7 weeks after injection. Prussian blue staining of tissue sections showed engraftment of iron oxide–labeled myotubes in treated areas (Figure 2, C). Immunofluorescent staining for slow skeletal myosin confirmed the skeletal muscle phenotype (Figure 2, D). Functional data are shown in Table 1.
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Within the past few years, robot-assisted surgery has revolutionized minimally invasive cardiac surgery, allowing complex procedures to be performed on the beating heart. Its major advantages are increased degrees of freedom, 3-dimensional vision, and magnification of the operating field. Furthermore, it combines minimally invasive access with improved targeting and a decreased risk of hemodynamic compromise and ventricular perforation, making it amenable to patients with severely impaired LV function and remodeling who are not necessarily amenable to endoscopic procedures. In the present study the robot-assisted technique allowed controlled cell delivery to the anterior, apical, and lateral regions of the left ventricle, with minimal requirement for stabilization and mechanical manipulation. In contrast to current catheter-based transventricular approaches, safe treatment of target segments with a wall thickness of less than 5 mm was achievable. Although efficacy was a secondary end point of the present study, the improved LV function after cell delivery reinforces the feasibility of this procedure. A more thorough investigation, including larger experimental groups, will be necessary to clarify whether the herein proposed combination of autologous SKMBs and BM-MNCs is superior to the isolated transplantation of each cell type. If this is the case, as suggested by other preclinical studies,
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our proposed protocol would offer a streamlined option to provide patients with HF a combination of autologous SKMBs and BM-MNCs in one minimally invasive procedure.
In summary, this new method might provide a feasible option for patients who are currently not eligible for surgical cell transplantation. It combines the benefits of a surgical approach with the reduction of perioperative risk associated with a minimally invasive procedure. Further investigation is required to clarify whether the efficacy of robotic cell transplantation equals direct surgical and catheter-based injection.
Acknowledgments
We thank experimental surgical services and research animal resources at the University of Minnesota for diligent and expert assistance in animal anesthesia and perioperative care.
Footnotes
This work was supported in part by National Heart, Lung, and Blood Institute/National Institutes of Health awards to Dr Taylor (R-01 HL-63346, HL-63703).
References
This article has been cited by other articles:
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  J. L. Herrmann, A. M. Abarbanell, B. R. Weil, Y. Wang, M. Wang, J. Tan, and D. R. Meldrum Cell-based therapy for ischemic heart disease: a clinical update. Ann. Thorac. Surg., November 1, 2009; 88(5): 1714 - 1722. [Abstract] [Full Text] [PDF]
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 T. Ota, N. A. Patronik, D. Schwartzman, C. N. Riviere, and M. A. Zenati Minimally Invasive Epicardial Injections Using a Novel Semiautonomous Robotic Device Circulation, September 30, 2008; 118(14_suppl_1): S115 - S120. [Abstract] [Full Text] [PDF]
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