Percutaneous transvenous cellular cardiomyoplasty
A novel nonsurgical approach for myocardial cell transplantation
Craig A. Thompson, MD* ||,*,
Boris A. Nasseri, MD ,
Joshua Makower, MD¶,
Stuart Houser, MD ,
Michael McGarry, MSc,
Theodore Lamson, PhD,
Irina Pomerantseva, MD, PhD*,
John Y. Chang, MS ME¶,
Herman K. Gold, MD, FACC*,
Joseph P. Vacanti, MD and
Stephen N. Oesterle, MD, FACC*
* Cardiovascular Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Tissue Engineering Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Pathology Department, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
|| Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
¶ TransVascular, Inc., Menlo Park, California, USA
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Figure 1 The coronary venous system. Coronary veins parallel the major epicardial coronary arteries, but are free of obstructive disease, and thus can provide a platform for myocardial access. The anterior, septal, and lateral walls are drained by branching vessels from the anterior interventricular coronary vein (AIV) (which parallels the left anterior descending artery), which drains into the great cardiac vein (GCV) (paralleling the left circumflex artery) and through the coronary sinus (CS) into the right atrium. (A) Anterior and (B) posterior views. AIV = anterior interventricular coronary vein; CS = coronary sinus; GCV = great cardiac vein. Courtesy of Transvascular, Inc.
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Figure 2 Transcoronary venous myocardial access can be achieved by intravascular, ultrasound-guided, transvenous needle puncture into targeted areas of the myocardium (infarct area depicted in gray), providing a stable and accurate platform for direct myocardial therapeutic agent delivery. AIV = anterior interventricular coronary vein. Courtesy of Transvascular, Inc.
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Figure 3 TransAccess composite catheter (A) incorporates phased-array intravascular ultrasound (IVUS) to accurately guide transvenous myocardial puncture with a sheathed, extendable nitinol needle (black arrow). Once the myocardium is accessed, (B) the IntraLume microinfusion catheter (white arrow) can be advanced to remote areas of myocardium for targeted therapeutic agent delivery. AIV = anterior interventricular coronary vein; IVUS = intravascular ultrasound; LAD = left anterior descending coronary artery; OM = obtuse marginal artery; PDA = posterior descending artery; PDV = posterior descending vein, or middle cardiac vein; PLV = posterolateral vein. Courtesy of Transvascular, Inc.
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Figure 4 Trans(coronary) venous cell delivery. (A) The coronary sinus (CS) is engaged, and a J-tipped hydrophilic guide wire is placed into the anterior interventricular coronary vein (AIV). (B) The CS and SS guiding catheters are placed using conventional over-the-wire wire technique. (C) The hydrophilic wire is exchanged for a 0.014-inch guidewire, and the TransAccess catheter is advanced into position. (D,E) IVUS provides anatomic orientation for transvenous, myocardial puncture into the anterior (D) and septal (E) (IVUS pointer marker delineated by yellow arrows) walls from the AIV with (F) an extendable nitinol needle (arrows). The IntraLume microinfusion catheter is advanced to targeted areas for cell delivery (G, arrows delineate contrast-enhanced cell injections). This method allows contiguous "beads" of cell substrate to be placed. AIV = anterior interventricular coronary vein; CS = coronary sinus; GW = guide wire; IVUS = intravascular ultrasound; LAD = left anterior descending coronary artery; SS = subselective; TA = TransAccess catheter.
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Figure 5 Cardiac magnetic resonance imaging of microlume infusion catheter and injection site (gadolinium contrast enhancement in black) performed in ex vivo pig heart.
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Figure 6 Gross examination of the myocardium demonstrated rows of cell–biogel substrate, identified macroscopically with black tissue dye.
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Figure 7 A bone marrow cell subpopulation was transduced with green fluorescence protein (GFP) using vesiculostomatitis virus, expanded in culture, and resuspended in a collgen biogel (A, in vitro imaging, 200x magnification), and demonstrated in vivo at 14 days (B, FITC conjugation, 200x magnification), and 28 days (C, direct green fluorescence, 400x magnification) in myocardial tissue demarcated by marker dye.
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Figure 8 Immunohistologic confirmatory analysis demonstrated evidence of transplanted, autologous, "donor" bone marrow cells at 0 (A–D), 14 E–H), and 28 (I–L) days in targeted myocardial tissue demarcated by tissue dye. Primary antibody versus green fluorescence protein (GFP), and secondary antibody conjugated to HRP, DAB chromagen (A, E, I, red arrows) were used to determine cell presence. Negative controls (B, F, J) had nonspecific immunoglobulins used as primary antibody. Hematoxylin–eosin (H&E) stains (C, G, K) show preserved myocardial architecture, and minimal fibrosis is seen on trichrome staining (D, H, L). The animal that received collagen biogel alone did not react nonspecifically to similar antibody staining (M) and had similar preservation of myocardial architecture by H&E (N). Note the collagen biogel fragments (E, closed black arrows) and interstitial biogel deposition (O, blue coloration, trichrome stain). The black (M, N, O) are tissue dye remnants. Positive control for the immunostain was assured using myocardial tissue from a transgenic mouse, positive for GFP (C–D, E–H, K–P, 200x magnification; A–B, I–J, 400x magnification).
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Figure 9 Longitudinal section in targeted myocardial tissue demarcated by tissue dye of (A) unstained, (B) direct green fluorescence, and (C) immunostain versus green fluorescence protein (GFP) (phycoerythrin secondary antibody, red immunofluorescence) demonstrating GFP+ cell structures morphologically at 28 days (400x magnification).
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