Assessment of myocardial infarction and postinfarction scar remodeling with an elastin-specific magnetic resonance agent.

BACKGROUND: To prospectively evaluate an elastin-specific MR contrast agent (ESMA) for in vivo targeting of elastic fibers in myocardial infarction (MI) and postinfarction scar remodeling. METHODS AND RESULTS: MI was induced in C57BL/6J mice (n=40) by permanent ligation of the left anterior descending coronary artery. MRI was performed at 7 and 21 days after MI. The merits of gadolinium-based ESMA (Gd-ESMA) were compared with gadopentetic acid (Gd-DTPA) for infarct size determination, contrast-to-noise ratio (CNR), and enhancement kinetics. Specific binding in vivo was evaluated by blocking the molecular target using nonparamagnetic lanthanum-ESMA. In vivo imaging results were confirmed by postmortem triphenyltetrazolium chloride staining, elastica van Gieson staining, and Western blotting. Delayed enhancement MRI revealed prolonged enhancement of Gd-ESMA in the postischemic scar compared with Gd-DTPA. Infarct size measurements showed good agreement between Gd-ESMA and Gd-DTPA and were confirmed by ex vivo triphenyltetrazolium chloride staining. Preinjection of the blocking lanthanum-ESMA resulted in significantly lower CNR of Gd-ESMA at the infarct site (P=0.0019). Although no significant differences in CNR were observed between delayed enhancement imaging and Gd-DTPA between days 7 and 21 (1.8± versus 3.8; P=ns), Gd-ESMA showed markedly higher CNR on day 21 after MI (14.1 versus 4.9; P=0.0032), which correlated with increased synthesis of tropoelastin detected by Western blot analysis and histology. Higher CNR values for Gd-ESMA further correlated with improved ejection fraction of the mice on day 21 after MI. CONCLUSIONS: Gd-ESMA enables targeting of elastin within the infarct scar in a mouse model of MI. The imaging properties of Gd-ESMA allow quantification of intrascar elastin content in vivo and thereby provide potential for noninvasive characterization of postinfarction scar remodeling.

Cardioprotective C-kit⁺ bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

Cardiomyocyte loss via apoptosis plays a crucial role in ventricular remodeling following myocardial infarction (MI). Cell-based therapy approaches using bone marrow derived c-kit⁺ pluripotent cells may attenuate apoptosis following ischemic injury. We therefore thought to examine the early course of apoptosis following myocardial infarction - in-vivo - and non-invasively determine the effect of c-kit⁺ bone marrow cells on post-MI remodeling. We studied apoptosis in wild-type Kit(+/+) , c-kit mutant Kit(W)/Kit(W-v) and Kit(W)/Kit(W-v) mice after cell therapy with bone-marrow derived c-kit⁺ cells after ischemia-reperfusion injury. Mice were followed by hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) at 6h, 24h and 7 days after ischemia-reperfusion injury using an Annexin V-based fluorescent nanosensor targeting phosphatidylserine. Kit(W)/Kit(W-v) mice showed increased and prolonged apoptosis compared to control Kit(+/+) mice while c-kit cell therapy was able to attenuate the altered apoptosis rates. Increased apoptosis was accompanied by severe decline in heart function, determined by cardiac Magnetic Resonance Imaging, and cell therapy was able to rescue the animals from deleterious heart failure. Post-mortem cryoslicing and immunohistochemistry localized the fluorescence signal of the Annexin V sensor within the infarcted myocardium. Flow cytometry of digested infarct specimens identified apoptotic cardiomyocytes as the major source for the in-vivo Annexin V signal. In-vivo molecular imaging using hybrid FMT-XCT reveals increased cardiomyocyte apoptosis in Kit(W)/Kit(W-v) mice and shows that c-kit⁺ cardioprotective cells are able to attenuate post-MI apoptosis and rescue mice from progressive heart failure.

Evaluation of phase-sensitive versus magnitude reconstructed inversion recovery imaging for the assessment of myocardial infarction in mice with a clinical magnetic resonance scanner.

PURPOSE: To evaluate phase-sensitive inversion-recovery (PSIR) imaging at 1.5 T in a mouse model of permanent coronary artery ligation as a potentially rapid and robust alternative for the accurate assessment of myocardial infarction (MI) by cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: PSIR late gadolinium enhancement (LGE) imaging was compared to conventional 2D segmented inversion-recovery imaging for the assessment of murine MI. RESULTS: PSIR images provided comparable contrast and kinetics of intravenously injected gadopentetate dimeglumine (Gd-DTPA). At the mid-ventricular level there was good agreement between conventional IR and PSIR for infarct size assessment. After intravenous injection a limited time window of ∼6 minutes is available for delayed enhancement imaging in mice. Whole-heart infarct imaging with 1 mm thick slices was only possible in this restricted time frame when the PSIR method is applied, avoiding the need for repetitively adapting the correct inversion time. Infarct size determined by PSIR MRI demonstrated good agreement with postmortem histology. Infarct size determined by PSIR LGE MRI inversely correlates with left-ventricular function on day 7 after MI. CONCLUSION: The PSIR technique provides stable and consistent contrast between hyperenhanced and remote myocardium independent of the selected inversion time (TI) and proved to be a robust, fast, and accurate tool for the assessment of MI in mice.