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Evidence for Tissue Angiotensin-Converting Enzyme in Explanted Hearts of Ischemic Cardiomyopathy Using Targeted Radiotracer Technique

¹ Division of Nuclear Medicine, the University of Maryland Hospital and School of Medicine, Baltimore, Maryland; ² Molecular Tracer, LLC, Bethesda, Maryland; ³ School of Medicine, Universidad Panamericana, Mexico City, Mexico; ⁴ National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland; and ⁵ Division of Cardiology, Geisinger Medical Center, Danville, Pennsylvania

Correspondence: For correspondence or reprints contact: Vasken Dilsizian, MD, University of Maryland Medical Center, 22 S. Greene St., Room N2W78, Baltimore, MD 21201-1595. E-mail: vdilsizian{at}umm.edu

This study aimed to determine the magnitude and distribution of tissue angiotensin-converting enzyme (ACE), mast-cell chymase, and angiotensin II, type 1, plasma membrane receptor (AT₁R), in relation to collagen replacement in infarcted and noninfarcted left ventricular myocardial segments. A new radiotracer, ¹⁸F-fluorobenzoyl-lisinopril (FBL), was synthesized without compromising its affinity for tissue ACE. Methods: Five- to 10-µm contiguous short-axis slices of explanted hearts from 3 patients with ischemic cardiomyopathy were incubated in vitro with FBL, with and without 10^–6 M lisinopril. Tissue radioactivity was recorded as a function of position in photostimulating luminescence units (PSL). Immunohistochemistry studies were performed with mouse monoclonal antibody against ACE, anti–mast cell chymase, and polyclonal antibody against the human AT₁R. Results: There was specific binding of FBL to ACE; mean FBL binding was 6.6 ± 5.2 PSL/mm², compared with 3.4 ± 2.5 PSL/mm² in segments incubated in solution containing cold, 10^–6 M lisinopril (P < 0.0001). Mean FBL binding was 6.3 ± 4.5 PSL/mm² in infarcted, 7.6 ± 4.7 PSL/mm² in periinfarcted, and 5.0 ± 1.0 PSL/mm² in remote, noninfarcted (P < 0.02 vs. periinfarcted) segments. The autoradiographic observations concerning FBL binding were confirmed by ACE and AT₁R immunoreactivity. Distribution of mast cell chymase differed from ACE, as a higher number of mast cells was present in the remote, noninfarcted myocardium than in the periinfarcted myocardium (5.1 ± 3.2 vs. 3.2 ± 2.2 mast cells per field, P < 0.001). The number of mast cells in ischemic hearts exceeded that in normal hearts (4.2 ± 2.7 vs. 1.5 ± 1.2 mast cells per field, x200, P < 0.001). Conclusion: FBL binds specifically to ACE. The binding is nonuniform in infarcted, periinfarcted, and remote, noninfarcted segments, and there is apparently increased ACE activity in the juxtaposed areas of replacement fibrosis. On the other hand, the distribution of mast cell chymase appears nonuniform and disparate from ACE.

Key Words: angiotensin-converting enzyme • angiotensin receptor • heart failure • radionuclide imaging • remodeling • chymase

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