Application of Hybrid Matrix Metalloproteinase-Targeted and Dynamic ²⁰¹ Tl Single-Photon Emission Computed Tomography/Computed Tomography Imaging for Evaluation of Early Post-Myocardial Infarction Remodeling

Abstract

Background: The induction of matrix metalloproteinases (MMPs) and reduction in tissue inhibitors of MMPs (TIMPs) plays a role in ischemia/reperfusion (I/R) injury post-myocardial infarction (MI) and subsequent left ventricular remodeling. We developed a hybrid dual isotope single-photon emission computed tomography/computed tomography approach for noninvasive evaluation of regional myocardial MMP activation with 99m Tc-RP805 and dynamic 201 Tl for determination of myocardial blood flow, to quantify the effects of intracoronary delivery of recombinant TIMP-3 (rTIMP-3) on I/R injury. Methods: Studies were performed in control pigs (n=5) and pigs following 90-minute balloon occlusion–induced ischemia/reperfusion (I/R) of left anterior descending artery (n=9). Before reperfusion, pigs with I/R were randomly assigned to intracoronary infusion of rTIMP-3 (1.0 mg/kg; n=5) or saline (n=4). Three days post-I/R, dual isotope imaging was performed with 99m Tc-RP805 and 201 Tl along with contrast cineCT to assess left ventricular function. Results: The ischemic to nonischemic ratio of 99m Tc-RP805 was significantly increased following I/R in saline group (4.03±1.40), and this ratio was significantly reduced with rTIMP-3 treatment (2.22±0.57; P =0.03). This reduction in MMP activity in the MI-rTIMP-3 treatment group was associated with an improvement in relative MI region myocardial blood flow compared with the MI-saline group and improved myocardial strain in the MI region. Conclusions: We have established a novel hybrid single-photon emission computed tomography/computed tomography imaging approach for the quantitative assessment of regional MMP activation, myocardial blood flow, and cardiac function post-I/R that can be used to evaluate therapeutic interventions such as intracoronary delivery of rTIMP-3 for reduction of I/R injury in the early phases of post-MI remodeling.

Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology

“…Further, a marked but transient rise in MMP activity in the early post-MI phase was found to be responsible for the adverse remodeling and increased rate of LV rupture in Timp3 −/− mice, since early treatment with a broad-spectrum MMP inhibitor ameliorated the adverse LV remodeling and rupture (Kandalam et al, 2010). On the other hand, targeted overexpression of TIMP3 or delivery of recombinant TIMP3 protein into the myocardium also improved the infarcted myocardium and heart function through suppression of the MMP activity and inflammation, and promoting angiogenesis (Eckhouse et al, 2014;Purcell et al, 2014Purcell et al, , 2018Barlow et al, 2017;Takawale et al, 2017;Chintalgattu et al, 2018;Thorn et al, 2019).…”

“…In a model of cardiac ischemia/reperfusion (I/R) injury in pigs, intracoronary infusion of full-length human TIMP3 protein reduced infarct size and LV end-diastolic volume, and increased ejection fraction at 28 days post-I/R (Barlow et al, 2017;Thorn et al, 2019). Clearly, intracoronary delivery will require a larger amount of rTIMP3 compared to local myocardium injection in order to acquire the cardiac protective effect, while intracoronary infusion could result in off-target effects of TIMP3.…”

Potential novel imaging targets of inflammation in cardiac sarcoidosis

“…The study further showed that tracer-guided targeted delivery of TIMP can favorably influence ischemia/reperfusion injury. 101 Pre-clinical Data 99m Tc-RP805 is a proprietary agent currently owned MicroVide, L.L.C. 100 To this date, only animal models have studied the effects of post-infarction remodeling, 100,101 anthracycline-induced cardiotoxicity, 102 and most recently aortic valve calcification.…”

Modulation of Cardiac Fibrosis in and Beyond Cells

“…Therefore, MMP-independent functions of TIMP3 are involved in its anti-fibrotic functions in the heart. A noninvasive imaging approach with single-photon emission computed tomography (SPECT)/CT is also explored in a pig I/R model to monitor the activation of MMPs, myocardial blood flow and strain ( Thorn et al, 2019 ). It facilitates the targeted and timely application of TIMP3 in I/R or MI models and observation of therapeutic effects.…”