Molecular Imaging for Efficacy of Pharmacologic Intervention in Myocardial Remodeling

Molecular Imaging to Demonstrate Efficacy of Pharmacological Intervention in Myocardial Remodeling

Susanne W. M. van den Borne, Satoshi Isobe, H. Reinier Zandbergen, Peng Li, Artiom Petrov, Nathan D. Wong, Shinichiro Fujimoto, Ai Fujimoto, Dagfinn Lovhaug, Jos F. M. Smits, Mat J. A. P. Daemen, W. Matthijs Blankesteijn, Chris Reutelingsperger, Faiez Zannad, Navneet Narula, Mani A. Vannan, Bertram Pitt, Leonard Hofstra, Jagat Narula

Employing technetium-99m-labeled Cy5.5 RGD imaging peptide (^99mTc-CRIP) for molecular imaging, the authors examined interstitial alterations during post-myocardial infarction (MI) remodeling and assessed the efficacy of antiangiotensin and antimineralocorticoid intervention, alone and in combination. ^99mTc-CRIP uptake decreased significantly in animals that were treated with 1 neurohumoral antagonist; 2 or 3 agents demonstrated further reduction in the tracer uptake. The extent of uptake correlated with echocardiographic parameters of ventricular remodeling and histologically-verified deposition of thin collagen fibers. Radiolabeled ^99mTc-CRIP allows evaluation of the efficacy of neurohumoral antagonists post-MI by monitoring interstitial alterations and collagen deposition and confirms the superiority of combination therapy.

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