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Invited Commentary |

Searching for New Meaning in PREVENT IV?  A Project of Ex-Vivo Vein Graft Engineering via Transfection IV Substudy

David D. Yuh, MD1
[+] Author Affiliations
1Section of Cardiac Surgery, Yale University School of Medicine, New Haven, Connecticut
JAMA Surg. 2014;149(8):805-806. doi:10.1001/jamasurg.2014.106.
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The mechanisms behind saphenous vein graft failure (VGF) in patients undergoing coronary artery bypass grafting have remained elusive. Sophisticated approaches toward modifying the biology of vein graft endothelium exemplified by the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial1 have repeatedly met with disappointing results. Nevertheless, Harskamp and colleagues2 have identified reduced VGF rates in veins preserved with buffered saline compared with both placebo preservatives (ie, normal saline and blood) used in PREVENT IV. The reduction in VGF rates in the buffered saline group is perhaps made even more significant with the greater use of endoscopic vein harvesting in that group, given that well-designed studies have suggested higher VGF rates in veins harvested with this technique, irrespective of the use of cardiopulmonary bypass.3,4 Furthermore, the reduced quality of vein grafts and target coronary arteries in this group should also have exerted a substantial negative effect on vein graft patency rates.

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Why Blood-Based Preservation Could Lead to Vein Graft Failure
Posted on June 26, 2014
Hemant S. Thatte, MSc, PhD
Harvard Medical School and VA Boston Healthcare System
Conflict of Interest: None Declared
An important point has been raised by Dr. Yuh in his invited commentary on the manuscript published by Harskamp et al.(1) as to why the use of blood based preservation of vascular conduits does not afford similar reduction in vein graft failure (VGF) rates as buffered saline. It is generally assumed that autologous blood would be an ideal medium for the preservation of vascular conduits during surgery. Apart from cytokine storm and activation of WBC, blood chemistry plays an important 'protective' or 'lack thereof' role in preservation of conduits during surgery. Crucially due to decrease in pCO2 ex vivo, there is a rapid loss of CO2 from the blood leading to substantial increase in pH, values reaching as high as pH 8.0 within minutes (2), unless the blood is buffered adequately. Such increase in pH is because of loss of CO2 mediated formation of carbonic acid in well-established chemistry of acid-base balance that helps maintain the pH of the blood at physiological levels (3). Alkaline pH (and/or acidic pH) temporally affects the endothelial and smooth muscle function due to loss of ionic balance as well as pH dependent enzyme activity amongst others, leading to attenuated function, injury and loss in cellular homeostasis that can result in early graft failure (4, 5). This phenomenon could have contributed to reported observation of increased VGF rate when blood-based preservation was used1.To address such issues we had developed GALA, a physiological surgical conduit preservation solution (6). Using state-of-the-art multiphoton imaging technology, we demonstrated that preservation of human saphenous vein conduits in saline and/or autologous blood during CABG surgery leads to rapid attenuation of calcium mobilization and nitric oxide generation via suppression of eNOS function6. Additionally, over 90% of endothelial cells were shown to develop significant injury during storage because of acidic pH of saline and alkaline pH of blood. Cellular injury and loss in ability to generate agonist-induced vasodilators in response to change in physiological parameters (6, 7) can lead to collapse of vasomotor function resulting in adverse outcomes. The shortcomings of saline and autologous blood were addressed in GALA, which provides total electrolyte balance, substrates for energy, eNOS function and nitric oxide generation, and protection against reperfusion and apoptosis injury. GALA preserves structural and functional viability of saphenous veins, radial arteries (and IMA) during extended storage (5-8). GALA has been used in our hospital and other US hospitals since 2001 for CABG and peripheral vascular surgery. Preliminary results have been very encouraging, our observations we believe, strongly supported by the recent publication in JAMA Surgery (1); however, whether GALA truly improves long-term patient outcomes by decreasing VGF rates is currently under retrospective and prospective evaluation. REFERENCES1. Harskamp RE, Alexander JH, Schulte PJ, et al. Vein graft preservation solutions, patency, and outcomes after coronary artery bypass graft surgery [published online June 18, 2014]. JAMA Surg. doi: 10.1001/jamasurg.2014.87. Invited Commentary; DD Yuh, MD.2. Kirschbaum B. Loss of carbon dioxide from serum samples exposed to air. Effect on blood gas parameters and strong ions. Clin Chim Acta. 2003; 334:241-244.3. Davenport HW. The ABC of Acid-Base Chemistry: The Elements of Physiological Blood-Gas Chemistry for Medical Students and Physicians (Sixth ed. ed.). Chicago: The University of Chicago Press. 1974.4. Biswas KS, Thatte HS, Najjar SF et al. Multi-photon Microscopy in the Evaluation of Human Saphenous Vein. J Surg Res 2001; 95:37-43.5. Thatte HS, Khuri SF. The Coronary Artery Bypass Conduit: Intraoperative Endothelial Injury and its Implication on Graft Patency. Ann Thorac Surg 2001; 72:S2245-S2252.6. Thatte HS, Biswas KS, Najjar SF et al. Multi-photon microscopic evaluation of saphenous vein endothelium and its preservation with a new solution, GALA. Ann Thorac Surg. 2003; 75:1145-1152.7. Su EN, Yu, DY, Alder VA, Cringle SJ. Effects of extracellular pH on agonist-induced vascular tone of the cat opthalmociliary artery. Invest Opthalmol Vis Sci. 1994; 35:998-1007.8. Thatte HS, Haime M, Crittenden MD. Extended preservation of arterial conduits in GALA: Multiphoton Microscopic Evaluation. [Abstract] Frontiers in CardioVascular Biology Conference, July 4, 2014; Barcelona, Spain.
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