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(Circulation. 2000;102:965.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Left Ventricular Electromechanical Mapping to Assess Efficacy of phVEGF165 Gene Transfer for Therapeutic Angiogenesis in Chronic Myocardial Ischemia
Presented as an entry in the finals for the Samuel A. Levine Young Investigator Award at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-24. Abstract 122).
From the Divisions of Cardiology and Vascular Medicine (P.R.V., D.W.L., M.M., D.D.E., J.M.I.), Cardiovascular Research (C.E.M.), and Cardiothoracic Surgery (J.F.S.), St. Elizabeth’s Medical Center and Tufts University School of Medicine, Boston, Mass.
Correspondence to Douglas Losordo, MD, or Jeffrey M. Isner, MD, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.com
Background—NOGA left ventricular (LV) electromechanical mapping (EMM) can be used to distinguish among infarcted, ischemic, and normal myocardium. We investigated the use of percutaneous LV EMM to assess the efficacy of myocardial gene transfer (GTx) of naked plasmid DNA encoding for vascular endothelial growth factor (phVEGF165), administered during surgery by direct myocardial injection in patients with chronic myocardial ischemia.
Methods and Results—A total of 13 consecutive patients (8 men,
mean age 60.1±2.3 years) with chronic stable angina due to
angiographically documented coronary artery disease, all of
whom had failed conventional therapy (drugs, PTCA, and/or CABG), were
treated with direct myocardial injection of phVEGF165 via a
minithoracotomy. Foci of ischemic myocardium were
identified on LV EMM by preserved viability associated with an
impairment in linear local shortening. Myocardial viability, defined by
mean unipolar and bipolar voltage recordings 
5 and 2 mV,
respectively, did not change significantly after GTx. Analysis
of linear local shortening in areas of myocardial ischemia,
however, disclosed significant improvement after (15.26±0.98%) versus
before (9.94±1.53%, P=0.004) phVEGF165
GTx. The area of ischemic myocardium was
consequently reduced from 6.45±1.37 cm2 before GTx to
0.95±0.41 cm2 after GTx (P=0.001). These
findings corresponded to improved perfusion scores calculated from
single-photon emission CT–sestamibi myocardial perfusion scans
recorded at rest (7.4±2.1 before GTx versus 4.5±1.4 after GTx,
P=0.009) and after pharmacological stress (12.8±2.7
before GTx versus 8.5±1.7 after GTx, P=0.047).
Conclusions—The results of EMM constitute objective evidence that phVEGF165 GTx augments perfusion of ischemic myocardium. These findings, together with reduction in the size of the defects documented at rest by serial single-photon emission CT–sestamibi imaging, suggest that phVEGF165 GTx may successfully rescue foci of hibernating myocardium.
Key Words: mapping • coronary disease • angiogenesis • ischemia
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|
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|
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|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 M. Schwaiger Future perspectives and conclusions Eur. Heart J. Suppl., September 1, 2001; 3(suppl_F): F19 - F21. [Abstract] [PDF]
|
|
|
|
 |
|
 J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects Circ. Res., August 31, 2001; 89(5): 389 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
C. Lenfant Cardiovascular Research : A Look Into Tomorrow Circ. Res., February 16, 2001; 88(3): 253 - 255. [Full Text] [PDF]
|
|
|
|
 |
|
 H.K. Hammond and M.D. McKirnan Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials Cardiovasc Res, February 16, 2001; 49(3): 561 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 H. Su, R. Lu, and Y. W. Kan Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart PNAS, November 22, 2000; (2000) 250488097. [Abstract] [Full Text]
|
|
|
|
|
|
R. Morishita Adventure of Gene Therapy Into the Brain: A New Era for Cardiovascular Gene Therapy Circ. Res., October 27, 2000; 87(9): 719 - 721. [Full Text] [PDF]
|
|
|
|
|
|
C. Patterson and M. S. Runge Therapeutic Myocardial Angiogenesis Via Vascular Endothelial Growth Factor Gene Therapy : Moving on Down the Road Circulation, August 29, 2000; 102(9): 940 - 942. [Full Text] [PDF]
|
|
|
|
|
|
H. Su, R. Lu, and Y. W. Kan Adeno-associated viral vector-mediated vascular endothelial growth factor gene transfer induces neovascular formation in ischemic heart PNAS, December 5, 2000; 97(25): 13801 - 13806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
|
|
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