title: Nonphysiologic blood flow triggers endothelial and arterial remodeling in vivo: implications for novel left ventricular assist devices with a peripheral anastomosis.
abstract: OBJECTIVE
  Less invasive circulatory support devices have been developed that require anastomosis to a peripheral artery. The Symphony Heart Assist System (Abiomed, Inc, Danvers, Mass) is a volume-displacement pump sewn to the subclavian artery to provide partial circulatory support. The surgical configuration produces nonphysiologic blood pressure and bidirectional flow in the subclavian artery. Our objective was to identify effects of altered hemodynamics on arterial structure and function.
  
  
  METHODS
  In calves (n = 23; 80-100 kg), the Symphony pump was sewn end-to-side to the carotid artery. Acutely, carotid blood pressure and flow were recorded to evaluate hemodynamic changes. After medium-term support (1-4 weeks), carotid artery was studied. Histologic and molecular assays evaluated architectural changes. Quantitative real-time polymerase chain reaction evaluated gene expression of matrix metalloproteinase (MMP)-2, MMP-9, and connective tissue growth factor. In vitro carotid arterial-ring studies evaluated physiologic responses.
  
  
  RESULTS
  During Symphony support, carotid arterial pressure was 200/15 mm Hg. Antegrade flow increased significantly (P < .05) from 1.40 ± 0.32 to 4.29 ± 0.33 L/min. Flow during native cardiac diastole reversed completely from 0.25 ± 0.05 to -4.15 ± 0.38 L/min in carotid artery proximal to the anastomosis. After medium-term support, the carotid artery was significantly dilated with significantly thinner tunica media and thicker tunica adventitia than in control carotid arteries. MMP-9 gene expression decreased significantly, connective tissue growth factor gene expression increased significantly, and collagen, elastin, and total extracellular matrix increased significantly. Endothelial cells were significantly hypertrophied and produced significantly more von Willebrand factor. Endothelial apoptosis increased significantly. Platelet-endothelial interactions decreased significantly. Endothelial-independent contraction decreased significantly, whereas endothelial-dependent relaxation increased modestly.
  
  
  CONCLUSIONS
  Assisted circulation with a left ventricular assist device triggered arterial remodeling that allowed a peripheral artery to accommodate the altered hemodynamics of a novel partial-support pump. Further delineation of remodeling pathways may be of significance for the emerging field of partial circulatory support.
authors: Division of Cardiovascular Surgery, University of Pennsylvania, Philadelphia, Pa; MD/PhD Program, University of Louisville School of Medicine, Louisville, Ky. Electronic address: carlo.bartoli@uphs.upenn.edu.
authors: Carlo R
authors: CR
authors: Bartoli
authors: SCR Inc, Louisville, Ky.
authors: Paul A
authors: PA
authors: Spence
authors: Abiomed, Inc, Danvers, Mass.
authors: Thorsten
authors: T
authors: Siess
authors: Abiomed, Inc, Danvers, Mass.
authors: Daniel H
authors: DH
authors: Raess
authors: Department of Bioengineering, University of Louisville, Louisville, Ky.
authors: Steven C
authors: SC
authors: Koenig
authors: Dowling Consulting, PSC, Louisville, Ky.
authors: Robert D
authors: RD
authors: Dowling
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D017209:Apoptosis; D062186:Arterial Pressure; D001783:Blood Flow Velocity; D006348:Cardiac Surgical Procedures / Q000295:instrumentation*; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D002417:Cattle; D055513:Connective Tissue Growth Factor / Q000235:genetics; D004108:Dilatation, Pathologic; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D005786:Gene Expression Regulation; D006353:Heart-Assist Devices; D006439:Hemodynamics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D011474:Prosthesis Design; D019919:Prosthesis Implantation / Q000295:instrumentation*; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D013997:Time Factors; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D012333:RNA, Messenger; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9