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Molecular Imaging for Efficacy of Pharmacologic Intervention in Myocardial Remodeling

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, Jagat Narula, MD, PhD, FACC^_*,_*

^_* Division of Cardiology and Department of Pathology, University of California, Irvine School of Medicine, Irvine, California
Department of Cardiology, Biochemistry, Pathology and Pharmacology, University Hospital Maastricht, Maastricht, the Netherlands
GE Healthcare, AS, Oslo, Norway
University Henri Poincaré, Nancy, France
^¶ Division of Cardiology, University of Michigan, Ann Arbor, Michigan

^_* 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 (Email: narula{at}uci.edu).

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.

Key Words: collagen • remodeling • radionuclide imaging • angiotensin receptors • angiotensin-converting enzyme • mineralocorticoids • heart failure

Abbreviations and Acronyms   ACE-I = angiotensin-converting enzyme inhibitor   ARB = angiotensin receptor blocker   ASMA = alpha smooth muscle actin   C = captopril   CRIP = Cy5.5-RGD imaging peptide   L = losartan   LV = left ventricular   MI = myocardial infarction   RGD = Arg-Gly-Asp.   S = spironolactone   SARA = selective aldosterone receptor antagonist   sCRIP = scrambled Cy5.5-RGD imaging peptide   99mTc = technetium-99m

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