Author + information
- Received June 9, 2008
- Revision received October 31, 2008
- Accepted November 6, 2008
- Published online February 1, 2009.
- Susanne W.M. van den Borne, MD⁎,†,
- Satoshi Isobe, MD, PhD⁎,
- H. Reinier Zandbergen, MD†,
- Peng Li, MD, PhD⁎,
- Artiom Petrov, PhD⁎,
- Nathan D. Wong, PhD, FACC⁎,
- Shinichiro Fujimoto, MD, PhD⁎,
- Ai Fujimoto, MD, PhD⁎,
- Dagfinn Lovhaug, PhD‡,
- Jos F.M. Smits, PhD†,
- Mat J.A.P. Daemen, MD, PhD†,
- W. Matthijs Blankesteijn, PhD†,
- Chris Reutelingsperger, PhD†,
- Faiez Zannad, MD, PhD, FACC§,
- Navneet Narula, MD⁎,
- Mani A. Vannan, MD, FACC⁎,
- Bertram Pitt, MD, FACC¶,
- Leonard Hofstra, MD, PhD† and
- Jagat Narula, MD, PhD, FACC⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Jagat Narula, Division of Cardiology, University of California, Irvine School of Medicine, UCI Main Campus, Medical-Science Building I, Room C 112, Irvine, California 92697
Objectives Using molecular imaging techniques, we examined interstitial alterations during postmyocardial infarction (MI) remodeling and assessed the efficacy of antiangiotensin and antimineralocorticoid intervention, alone and in combination.
Background The antagonists of the renin-angiotensin-aldosterone axis restrict myocardial fibrosis and cardiac remodeling after MI and contribute to improved survival. Radionuclide imaging with technetium-99m–labeled Cy5.5 RGD imaging peptide (CRIP) targets myofibroblasts and indirectly allows monitoring of the extent of collagen deposition post-MI.
Methods CRIP was intravenously administered for gamma imaging after 4 weeks of MI in 63 Swiss-Webster mice and in 6 unmanipulated mice. Of 63 animals, 50 were treated with captopril (C), losartan (L), spironolactone (S) alone, or in combination (CL, SC, SL, and SCL), 8 mice received no treatment. Echocardiography was performed for assessment of cardiac remodeling. Hearts were characterized histopathologically for the presence of myofibroblasts and thick and thin collagen fiber deposition.
Results Acute MI size was similar in all groups. The quantitative CRIP percent injected dose per gram uptake was greatest in the infarct area of untreated control mice (2.30 ± 0.14%) and decreased significantly in animals treated with 1 agent (C, L, or S; 1.71 ± 0.35%; p = 0.0002). The addition of 2 (CL, SC, or SL 1.31 ± 0.40%; p < 0.0001) or 3 agents (SCL; 1.16 ± 0.26%; p < 0.0001) demonstrated further reduction in tracer uptake. The decrease in echocardiographic left ventricular function, strain and rotation parameters, as well as histologically verified deposition of thin collagen fibers, was significantly reduced in treatment groups and correlated with CRIP uptake.
Conclusions Radiolabeled CRIP allows for the evaluation of the efficacy of neurohumoral antagonists after MI and reconfirms superiority of combination therapy. If proven clinically, molecular imaging of the myocardial healing process may help plan an optimal treatment for patients susceptible to heart failure.
- radionuclide imaging
- angiotensin receptors
- angiotensin-converting enzyme
- heart failure
Dr. van den Borne was partially supported by a grant from the Netherlands Heart Foundation (2006R013). Dr. Lovhaug is an employee of GE Healthcare, involved in tracer preparation for the imaging studies. Dr. Pitt is a consultant to Pfizer, Merck, Takeda, Astra Zeneca, Synvista, Novartis, and Nile therapeutics but has no conflicts directly with the project. H. William Strauss, MD, acted as Guest Editor for this paper.
- Received June 9, 2008.
- Revision received October 31, 2008.
- Accepted November 6, 2008.
- American College of Cardiology Foundation