Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium

G. Chad Hughes; Brian H. Annex; Bangliang Yin; Anne M. Pippen; Pengnian Lin; Alan P. Kypson; Kevin G. Peters; James E. Lowe; Kevin P. Landolfo

doi:10.1016/S0008-6363(99)00182-0

Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium

G. Chad Hughes, Brian H. Annex, Bangliang Yin, Anne M. Pippen, Pengnian Lin, Alan P. Kypson, Kevin G. Peters, James E. Lowe, Kevin P. Landolfo

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Objective: Transmyocardial laser revascularization (TMR) is emerging as a potential treatment option for patients with end-stage CAD, and adjuvant gene therapy may be helpful in further improving the results of the procedure. However, the effects of TMR on gene transfer are unknown. Methods: Swine underwent left thoracotomy. TMR was performed to create five channels at 2-cm intervals in the anterolateral free wall of the left ventricle (LV) followed by injection of 1x10⁹ plaque-forming units (pfu) of a replication-deficient adenovirus vector carrying the reporter gene β-galactosidase (Ad.Pac β-gal). An additional five direct injections of 1x10⁹ pfu Ad.Pac β-gal were made at 2-cm intervals in the posterolateral LV of each heart. Control animals underwent TMR alone/vehicle alone (n=3) or empty virus alone/no treatment (n=3) of the anterolateral/posterolateral LV, respectively. Results: ELISA revealed significantly greater transgene expression in the direct Ad.Pac β-gal injection versus TMR plus Ad.Pac β-gal inject regions at both 3 (n=6) (273.0±58.5 vs. 133.4+28.1 pg β-gal/g protein, P=0.02) and 7 days (n=6) (180.0+59.9 vs. 56.7+18.1 pg β-gal/g protein, P=0.02) postoperatively. At 14 days postoperatively (n=2), no transgene expression was detected in either region. No transgene expression was detected in any of the control regions at 3 days postoperatively. CD-18 staining revealed significantly greater inflammation in the TMR plus Ad.Pac β-gal and TMR alone regions as compared to Ad.Pac β-gal or vehicle (P<0.001). Conclusions: Adenoviral-mediated gene transfer in conjunction with TMR is possible, although TMR appears to limit the degree of transgene expression attained as compared to direct intramyocardial injection alone, likely due to the greater immune response observed with the former. These findings may have important implications for therapeutic strategies aimed at combining TMR with gene therapy for CAD. Copyright (C) 1999 Elsevier Science B.V.

Original language	English (US)
Pages (from-to)	81-90
Number of pages	10
Journal	Cardiovascular Research
Volume	44
Issue number	1
DOIs	https://doi.org/10.1016/S0008-6363(99)00182-0
State	Published - Oct 1999
Externally published	Yes

Keywords

Cardiovascular surgery
Coronary disease
Gene expression
Gene therapy
Inflammation
Swine

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1016/S0008-6363(99)00182-0

Cite this

@article{d2357906d6134680b2438720f93e6df8,

title = "Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium",

abstract = "Objective: Transmyocardial laser revascularization (TMR) is emerging as a potential treatment option for patients with end-stage CAD, and adjuvant gene therapy may be helpful in further improving the results of the procedure. However, the effects of TMR on gene transfer are unknown. Methods: Swine underwent left thoracotomy. TMR was performed to create five channels at 2-cm intervals in the anterolateral free wall of the left ventricle (LV) followed by injection of 1x109 plaque-forming units (pfu) of a replication-deficient adenovirus vector carrying the reporter gene β-galactosidase (Ad.Pac β-gal). An additional five direct injections of 1x109 pfu Ad.Pac β-gal were made at 2-cm intervals in the posterolateral LV of each heart. Control animals underwent TMR alone/vehicle alone (n=3) or empty virus alone/no treatment (n=3) of the anterolateral/posterolateral LV, respectively. Results: ELISA revealed significantly greater transgene expression in the direct Ad.Pac β-gal injection versus TMR plus Ad.Pac β-gal inject regions at both 3 (n=6) (273.0±58.5 vs. 133.4+28.1 pg β-gal/g protein, P=0.02) and 7 days (n=6) (180.0+59.9 vs. 56.7+18.1 pg β-gal/g protein, P=0.02) postoperatively. At 14 days postoperatively (n=2), no transgene expression was detected in either region. No transgene expression was detected in any of the control regions at 3 days postoperatively. CD-18 staining revealed significantly greater inflammation in the TMR plus Ad.Pac β-gal and TMR alone regions as compared to Ad.Pac β-gal or vehicle (P<0.001). Conclusions: Adenoviral-mediated gene transfer in conjunction with TMR is possible, although TMR appears to limit the degree of transgene expression attained as compared to direct intramyocardial injection alone, likely due to the greater immune response observed with the former. These findings may have important implications for therapeutic strategies aimed at combining TMR with gene therapy for CAD. Copyright (C) 1999 Elsevier Science B.V.",

keywords = "Cardiovascular surgery, Coronary disease, Gene expression, Gene therapy, Inflammation, Swine",

author = "Hughes, {G. Chad} and Annex, {Brian H.} and Bangliang Yin and Pippen, {Anne M.} and Pengnian Lin and Kypson, {Alan P.} and Peters, {Kevin G.} and Lowe, {James E.} and Landolfo, {Kevin P.}",

note = "Funding Information: This work was supported in part through a National Research Service Award from the National Institutes of Health and the National Heart, Lung, and Blood Institute (G.C.H.) (Grant no. 1 F32 HL09969-01) as well as an unrestricted educational grant from Microheart, Inc. (Eldorado Hills, CA, USA) and Eclipse Surgical Technologies, Inc. (Sunnyvale, CA, USA). In addition, the authors gratefully acknowledge Mr. Michael Lowe for his surgical technical assistance.",

year = "1999",

month = oct,

doi = "10.1016/S0008-6363(99)00182-0",

language = "English (US)",

volume = "44",

pages = "81--90",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "1",

}

TY - JOUR

T1 - Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium

AU - Hughes, G. Chad

AU - Annex, Brian H.

AU - Yin, Bangliang

AU - Pippen, Anne M.

AU - Lin, Pengnian

AU - Kypson, Alan P.

AU - Peters, Kevin G.

AU - Lowe, James E.

AU - Landolfo, Kevin P.

N1 - Funding Information: This work was supported in part through a National Research Service Award from the National Institutes of Health and the National Heart, Lung, and Blood Institute (G.C.H.) (Grant no. 1 F32 HL09969-01) as well as an unrestricted educational grant from Microheart, Inc. (Eldorado Hills, CA, USA) and Eclipse Surgical Technologies, Inc. (Sunnyvale, CA, USA). In addition, the authors gratefully acknowledge Mr. Michael Lowe for his surgical technical assistance.

PY - 1999/10

Y1 - 1999/10

N2 - Objective: Transmyocardial laser revascularization (TMR) is emerging as a potential treatment option for patients with end-stage CAD, and adjuvant gene therapy may be helpful in further improving the results of the procedure. However, the effects of TMR on gene transfer are unknown. Methods: Swine underwent left thoracotomy. TMR was performed to create five channels at 2-cm intervals in the anterolateral free wall of the left ventricle (LV) followed by injection of 1x109 plaque-forming units (pfu) of a replication-deficient adenovirus vector carrying the reporter gene β-galactosidase (Ad.Pac β-gal). An additional five direct injections of 1x109 pfu Ad.Pac β-gal were made at 2-cm intervals in the posterolateral LV of each heart. Control animals underwent TMR alone/vehicle alone (n=3) or empty virus alone/no treatment (n=3) of the anterolateral/posterolateral LV, respectively. Results: ELISA revealed significantly greater transgene expression in the direct Ad.Pac β-gal injection versus TMR plus Ad.Pac β-gal inject regions at both 3 (n=6) (273.0±58.5 vs. 133.4+28.1 pg β-gal/g protein, P=0.02) and 7 days (n=6) (180.0+59.9 vs. 56.7+18.1 pg β-gal/g protein, P=0.02) postoperatively. At 14 days postoperatively (n=2), no transgene expression was detected in either region. No transgene expression was detected in any of the control regions at 3 days postoperatively. CD-18 staining revealed significantly greater inflammation in the TMR plus Ad.Pac β-gal and TMR alone regions as compared to Ad.Pac β-gal or vehicle (P<0.001). Conclusions: Adenoviral-mediated gene transfer in conjunction with TMR is possible, although TMR appears to limit the degree of transgene expression attained as compared to direct intramyocardial injection alone, likely due to the greater immune response observed with the former. These findings may have important implications for therapeutic strategies aimed at combining TMR with gene therapy for CAD. Copyright (C) 1999 Elsevier Science B.V.

AB - Objective: Transmyocardial laser revascularization (TMR) is emerging as a potential treatment option for patients with end-stage CAD, and adjuvant gene therapy may be helpful in further improving the results of the procedure. However, the effects of TMR on gene transfer are unknown. Methods: Swine underwent left thoracotomy. TMR was performed to create five channels at 2-cm intervals in the anterolateral free wall of the left ventricle (LV) followed by injection of 1x109 plaque-forming units (pfu) of a replication-deficient adenovirus vector carrying the reporter gene β-galactosidase (Ad.Pac β-gal). An additional five direct injections of 1x109 pfu Ad.Pac β-gal were made at 2-cm intervals in the posterolateral LV of each heart. Control animals underwent TMR alone/vehicle alone (n=3) or empty virus alone/no treatment (n=3) of the anterolateral/posterolateral LV, respectively. Results: ELISA revealed significantly greater transgene expression in the direct Ad.Pac β-gal injection versus TMR plus Ad.Pac β-gal inject regions at both 3 (n=6) (273.0±58.5 vs. 133.4+28.1 pg β-gal/g protein, P=0.02) and 7 days (n=6) (180.0+59.9 vs. 56.7+18.1 pg β-gal/g protein, P=0.02) postoperatively. At 14 days postoperatively (n=2), no transgene expression was detected in either region. No transgene expression was detected in any of the control regions at 3 days postoperatively. CD-18 staining revealed significantly greater inflammation in the TMR plus Ad.Pac β-gal and TMR alone regions as compared to Ad.Pac β-gal or vehicle (P<0.001). Conclusions: Adenoviral-mediated gene transfer in conjunction with TMR is possible, although TMR appears to limit the degree of transgene expression attained as compared to direct intramyocardial injection alone, likely due to the greater immune response observed with the former. These findings may have important implications for therapeutic strategies aimed at combining TMR with gene therapy for CAD. Copyright (C) 1999 Elsevier Science B.V.

KW - Cardiovascular surgery

KW - Coronary disease

KW - Gene expression

KW - Gene therapy

KW - Inflammation

KW - Swine

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U2 - 10.1016/S0008-6363(99)00182-0

DO - 10.1016/S0008-6363(99)00182-0

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C2 - 10615392

AN - SCOPUS:0033214604

SN - 0008-6363

VL - 44

SP - 81

EP - 90

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 1

ER -

Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium

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