Molecular imaging for efficacy of pharmacologic intervention in myocardial remodeling.
OBJECTIVE
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.
Division of Cardiology and Department of Pathology, University of California Irvine School of Medicine, Irvine, CA 92697, USA.
Susanne W M
SW
van den Borne
Satoshi
S
Isobe
H Reinier
HR
Zandbergen
Peng
P
Li
Artiom
A
Petrov
Nathan D
ND
Wong
Shinichiro
S
Fujimoto
Ai
A
Fujimoto
Dagfinn
D
Lovhaug
Jos F M
JF
Smits
Mat J A P
MJ
Daemen
W Matthijs
WM
Blankesteijn
Chris
C
Reutelingsperger
Faiez
F
Zannad
Navneet
N
Narula
Mani A
MA
Vannan
Bertram
B
Pitt
Leonard
L
Hofstra
Jagat
J
Narula
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D002232:Carbocyanines; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004452:Echocardiography; D024022:Fibrillar Collagens / Q000378:metabolism; D005347:Fibroblasts / Q000000981:diagnostic imaging / Q000187:drug effects; D005355:Fibrosis; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides; D011237:Predictive Value of Tests; D013148:Spironolactone / Q000494:pharmacology; D013667:Technetium; D015899:Tomography, Emission-Computed, Single-Photon; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D002317:Cardiovascular Agents; D024022:Fibrillar Collagens; D000451:Mineralocorticoid Receptor Antagonists; D009842:Oligopeptides; D013148:Spironolactone; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid; D002216:Captopril; D019808:Losartan