Research Article
No access
Published Online: 1 October 2016

Intramyocardial Gene Therapy Directed to Hibernating Heart Muscle Using a Combination of Electromechanical Mapping and Positron Emission Tomography

Publication: Human Gene Therapy
Volume 27, Issue Number 10

Abstract

Cardiac gene transfer for the treatment of ischemic diseases has suffered from low gene transfer efficiency and inability to target treatment genes to the ischemic myocardium. A combined method has been developed based on electromechanical mapping and radiowater PET imaging to target gene therapy to viable but ischemic and hibernating areas of the myocardium. Electromechanical NOGA mapping produces three-dimensional images of myocardium with both an electric activity map and a myocardial contractility map. These have been converted to 17-segment 2D bull's-eye maps, which were superimposed onto PET radiowater perfusion imaging maps of the myocardium. This technique was applied in a Phase I/IIa clinical trial to target gene therapy for refractory angina patients. It was found that by combining electromechanical map with PET imaging, targeting of gene therapy to hibernating ischemic myocardium can be significantly improved. Here, the methods for the identification of viable, ischemic, and hibernating myocardium for gene transfer are described, and examples of treated refractory angina patients who have benefited from the improved gene transfer method to the ischemic myocardium are presented.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Williams B, Menon M, Satran D, et al. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter Cardiovasc Interv 2010,75:886–891.
2.
Rutanen J, Rissanen TT, Markkanen JE, et al. Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation 2004;109:1029–1035.
3.
Byzova TV, Goldman CK, Jankau J, et al. Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood 2002;99:4434–4442.
4.
Rissanen TT, Markkanen JE, Gruchala M, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 2003,92:1098–1106.
5.
Kastrup J, Jørgensen E, Rück A, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol 2005;45:982–988.
6.
Stewart DJ, Kutryk MJ, Fitchett D, et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther 2009;17:1109–1115.
7.
Berman DS, Kang X, Slomka PJ, et al. Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease. J Nucl Cardiol 2007;14:521–528.
8.
Danad I, Uusitalo V, Kero T, et al. Quantitative assessment of myocardial perfusion in the detection of significant coronary artery disease: cutoff values and diagnostic accuracy of quantitative 15O H2O PET imaging. J Am Coll Cardiol 2014;64:1464–1475.
9.
Pavo N, Jakab A, Emmert MY, et al. Comparison of NOGA endocardial mapping and cardiac magnetic resonance imaging for determining infarct size and infarct transmurality for intramyocardial injection therapy using experimental data. PLoS One 2014;9:e113245.
10.
Kuopio University Hospital. Endocardial Vascular Endothelial Growth Factor D (VEGF-D) Gene Therapy for the Treatment of Severe Coronary Heart Disease (KAT301). In Clinicaltrials.gov. Available from https://clinicaltrials.gov/ct2/show/NCT01002430 (accessed on September 10, 2016).
11.
Saraste A, Ukkonen H, Varis A, et al. Effect of spinal cord stimulation on myocardial perfusion reserve in patients with refractory angina pectoris. Eur Heart J Cardiovasc Imaging 2015;16:449–455.
12.
Westphal M, Ylä-Herttuala S, Martin J, et al. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol 2013;14:823–833.
13.
Jauhiainen S, Häkkinen SK, Toivanen PI, et al. Vascular endothelial growth factor (VEGF)-D stimulates VEGF-A, stanniocalcin-1, and neuropilin-2 and has potent angiogenic effects. Arterioscler Thromb Vasc Biol 2011;31:1617–1624.
14.
Nieminen T, Toivanen PI, Rintanen N, et al. The impact of the receptor binding profiles of the vascular endothelial growth factors on their angiogenic features. Biochim Biophys Acta 2014;1840:454–463.
15.
European Commission. Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use; April 2006. Enterprise and industry directorate-general (Consumer goods, Pharmaceuticals); Brussels, ENTR/CT3, Revision 2.

Information & Authors

Information

Published In

cover image Human Gene Therapy
Human Gene Therapy
Volume 27Issue Number 10October 2016
Pages: 830 - 834
PubMed: 27553362

History

Published in print: October 2016
Published online: 1 October 2016
Published ahead of production: 23 August 2016
Accepted: 23 August 2016
Received: 23 August 2016

Permissions

Request permissions for this article.

Authors

Affiliations

Iiro Hassinen
Heart Center, Kuopio University Hospital, Kuopio, Finland
Antti Kivelä
Heart Center, Kuopio University Hospital, Kuopio, Finland
Antti Hedman
Heart Center, Kuopio University Hospital, Kuopio, Finland
Antti Saraste
Turku PET Centre, Turku University Hospital, Turku, Finland
Juhani Knuuti
Turku PET Centre, Turku University Hospital, Turku, Finland
Juha Hartikainen
Heart Center, Kuopio University Hospital, Kuopio, Finland
Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Seppo Ylä-Herttuala*
Heart Center, Kuopio University Hospital, Kuopio, Finland
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Science Service Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

Notes

*
Correspondence: Prof. Seppo Ylä-Herttuala, FESC, University of Eastern Finland, Kuopio, Finland. E-mail: [email protected]

Author Disclosure

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top