Early detection of doxorubicin-induced cardiotoxicity using the matrix metalloproteinase (MMP) targeted radiotracer, 99mTc-RP805.

Objectives Doxorubicin (DOX) induces cardiotoxicity in 3-26% of patients. A reliable non-invasive imaging approach for the detection of early cardiotoxicity during doxorubicin chemotherapy that precedes the development of irreversible cardiac injury is currently not available. Clinical imaging approaches (e.g., using echocardiography, SPECT, MR, etc.) typically detect late-stage cardiotoxicity, which manifests as gross and often irreversible cardiac dysfunction. Recent experimental evidence has uncovered a link between early cardiotoxicity and myocardial activation of matrix metalloproteinases (MMPs)—enzymes that degrade both extracellular matrix (ECM) and non-ECM substrates. The radiolabeled tracer, ^99mTc-RP805, binds to the active catalytic site of MMPs. Our objective was to determine whether evaluation of myocardial MMP activation with ^99mTc-RP805 provides a sensitive indicator of early chemotherapy-induced cardiotoxicity in a rat model.

Methods Male Wistar rats were injected intraperitoneally with 25 mg/kg of DOX HCL (n=5) or an equivalent volume of 0.9% NaCl (n=7, controls (CTL)). On day 5 post treatment, global diastolic and systolic function were assessed with echocardiography. In addition, left ventricular (LV) MMP activity was assessed with tissue well counting 4 hours following intravenous injection of ^99mTc-RP805 (~5 mCi). MMP activity is expressed as percent injected dose per gram of myocardial tissue (% Inj. Dose/g).

Results DOX treatment reduced body weight (CTL: 371.9 ± 6.3 g; DOX: 291.8 ± 5.7 g, P<0.0001), LV mass (CTL: 748.7 ± 22.5 mg; DOX: 570.2 ± 45.8 mg, P=0.002), heart weight/body weight ratio (-11%, P<0.05) and LV diastolic volume (CTL: 333.2 ± 21.0 μL; DOX: 240.6 ± 41.7 μL, P<0.05) compared to controls. LV ejection fraction and global radial and longitudinal myocardial strain were not changed by DOX treatment, however significantly reduced cardiac output (CTL: 91.4 ± 5.0 mL/min; DOX: 55.7 ± 5.2 mL/min, P<0.001) and stroke volume (CTL: 242.7 ± 13.0 μL; DOX: 177.7 ± 24.5 μL, P<0.05). DOX treatment also impaired diastolic function, as represented by decreases in mitral inflow E-wave velocity (CTL: 889.7 ± 101.2 mm/s; DOX 623.6 ±42.3 mm/s, P<0.05), and lateral mitral annulus (MV LW) E’ (CTL: -49.2 ± 6.6 mm/s; DOX: -27.7 ± 3.7 mm/s, P<0.05) and MV LW A’ (CTL: -51.7 ± 9.1 mm/s; DOX -33.4 ± 9.4 mm/s, P<0.05) tissue velocities. These functional changes were accompanied by an increase in LV MMP activity in DOX treated compared to CTL rats (Figure 1 A). Interestingly, LV MMP activity was negatively correlated with cardiac output (Figure 1B).

Conclusions Increases in myocardial MMP activity precede clinically used echocardiographic indices for early detection of cardiotoxicity, including ejection fraction and global myocardial strain. Therefore, ^99mTc-RP805 may serve as a promising approach for early detection of DOX-induced cardiotoxicity when combined with SPECT/CT imaging.

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