期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 10, 期 18, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.121.022139
关键词
cardiomyopathy; collagen peptides; heart fibrosis; molecular imaging; molecular probes; preclinical imaging
资金
- National Health and Medical Research Council of Australia (NHMRC) [GNT1120129]
- Government of Australia Training Research Program Scholarship
- Monash University, Faculty of Medicine, Nursing and Health Sciences Postgraduate Excellence Award
- NHMRC of Australia [GNT1154270]
- NHMRC [GNT1120129, GNT1140465]
This study demonstrated the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis in both animal models and human hearts. Two collagen-targeted peptides were evaluated for their ability to detect collagen accumulation in the heart, showing promising results for noninvasive diagnosis and treatment of heart disease.
Background Cardiac fibrosis is the excessive deposition of extracellular matrix in the heart, triggered by a cardiac insult, aging, genetics, or environmental factors. Molecular imaging of the cardiac extracellular matrix with targeted probes could improve diagnosis and treatment of heart disease. However, although this technology has been used to demonstrate focal scarring arising from myocardial infarction, its capacity to demonstrate extracellular matrix expansion and diffuse cardiac fibrosis has not been assessed. Methods and Results Here, we report the use of collagen-targeted peptides labeled with near-infrared fluorophores for the detection of diffuse cardiac fibrosis in the beta 2-AR (beta-2-adrenergic receptor) overexpressing mouse model and in ischemic human hearts. Two approaches were evaluated, the first based on a T peptide that binds matrix metalloproteinase-2-proteolyzed collagen IV, and the second on the cyclic peptide EP-3533, which targets collagen I. The systemic and cardiac uptakes of both peptides (intravenously administered) were quantified ex vivo by near-infrared imaging of whole organs, tissue sections, and heart lysates. The peptide accumulation profiles corresponded to an immunohistochemically-validated increase in collagen types I and IV in hearts of transgenic mice versus littermate controls. The T peptide could encouragingly demonstrate both the intermediate (7 months old) and severe (11 months old) cardiomyopathic phenotypes. Co-immunostainings of fluorescent peptides and collagens, as well as reduced collagen binding of a control peptide, confirmed the collagen specificity of the tracers. Qualitative analysis of heart samples from patients with ischemic cardiomyopathy compared with nondiseased donors supported the collagen-enhancement capabilities of these peptides also in the clinical settings. Conclusions Together, these observations demonstrate the feasibility and translation potential of molecular imaging with collagen-binding peptides for noninvasive imaging of diffuse cardiac fibrosis.
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