Molecular imaging of myocardial infarction and remodeling

Introduction

Current treatment strategies, including early revascularization, have significantly improved patient survival after acute myocardial infarction (AMI). Despite optimal medical therapies, however, survivors are at an increased risk for post–myocardial infarction (MI) heart failure (HF). Conventional management of patients with HF post-MI include a broad range of systemic therapies designed to attenuate the risk for adverse left ventricular (LV) remodeling. This one-size-fits-all approach for treatment in HF after MI could benefit from a more personalized, targeted approach. These considerations are further fueled by emerging targets involved in myocardial repair after MI, including inflammatory/immune cells, fibroblasts, and cardiac progenitor cells. Some novel targeted therapies, however, which demonstrated promising results in early testing and a preclinical environment, failed to translate into meaningful clinical benefit, ^, and others demonstrated promising results in lowering recurrent cardiovascular events. Such striking patient-to-patient heterogeneity emphasizes the opportunity for tailoring novel targeted drugs to the individual patient’s characteristics. In this regard, the expanded use of “liquid biopsies” is helping to identify patient-specific pathophysiologic makeup by investigating components of the myocardial injury/repair process that are shed from the heart into the circulatory system. Although liquid biopsies hold the promise to overcome certain drawbacks compared with conventional tissue-based biopsies, such approaches neglect intrinsic heterogeneity or tissue-specific information or variations. Thus noninvasive molecular imaging, which identifies even modest alterations at a (sub)cellular level may meet the increasing demands associated with precision medicine by providing critical insights into the underlying pathophysiologic process that affects the development of HF after AMI. Thus, applying molecular imaging combined with specific radiotracers may open avenues for tailoring the initiation of novel drugs for myocardial repair and, ideally, allow for optimal-effective dose determination strategies after the acute event. For instance, the peptidic macrocycle C-X-C motif chemokine receptor 4 (CXCR4) antagonist POL5551 and its clinical stage analog POL6326 modulated the immune response to injury, enhanced tissue repair, and led to an improvement of mechanical function after AMI in both mice and pigs. In addition, there is evidence that another CXCR4 antagonist, AMD3100, prolongs bone marrow progenitor mobilization, improving functional recovery in a murine model of transient coronary occlusion. These encouraging preclinical results have paved the way for initiation of clinical trials investigating the effects of CXCR4 antagonists as stem cell mobilizing agents in patients after AMI. Interestingly, the novel CXCR4-targeted positron emission tomography (PET) probe, ⁶⁸ gallium (Ga)-Pentixafor, could potentially be used as a diagnostic counterpart for CXCR4-targeted therapy and may identify the patients who will be the most likely to respond to this therapy. In this regard, distinct patient heterogeneity of the Pentixafor signal has been reported in patients after AMI, ranging from intense CXCR4 upregulation in the infarct territory ( Fig. 26.1 ) to no discernible radiotracer accumulation after MI ( Fig. 26.2 ). The large heterogeneity in signal strength in the area at risk may be caused by multiple factors, including the timing of imaging after AMI, the response to concomitant medications or differences in CXCR4 activation, and the selective recruitment of tissue-specific leukocytes. Nonetheless, the observed heterogeneous uptake pattern in the infarct territory may provide a guide for the timing of initiation of small molecular inhibitors of CXCR4 during the peak of cardiac uptake.

Molecular repair mechanisms after acute myocardial infarction: Inflammation, fibrosis, and angiogenesis

Established molecular imaging-guided concepts

To date, ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG) is the only radiotracer approved by the U.S. Food and Drug Administration for the evaluation of myocardial viability in ischemic cardiomyopathy. As discussed in Chapters 19 and 20 , the underlying concept is based on the recognition that ischemic cardiomyopathy can result from myocardial scar (i.e., irreversible injury of cardiomyocytes) or hibernating myocardium (i.e., temporary loss of contraction ability within an area of viable tissue). As such, LV dysfunction may be reversible from hibernation by revascularization procedures, underpinning the importance of reliably segregating between ischemically affected but still viable tissue and scar formation. ¹⁸ F-FDG PET-assisted management in patients with coronary artery disease (CAD) serves as a gatekeeper to the catheterization laboratory and has substantially improved outcome with revascularization. Nonetheless, the current approach of considering flow-metabolism mismatch as ischemic but still viable has inherent limitations. ^, First, cardiac glucose metabolism may be altered by multiple patient-specific factors, such as dietary state, blood glucose level, cardiac workload, or sympathetic tone. Second, a considerable number of patients referred to PET centers to conduct myocardial viability assessments with ¹⁸ F-FDG are afflicted by insulin resistance from diabetes and/or HF and even after oral glucose loading, the amount of endogenous insulin may be insufficient to achieve maximal stimulation of ¹⁸ F-FDG uptake. A hyperinsulinemic euglycemic clamp may overcome this issue by switching insulin-sensitive tissues to glucose use, but the challenging and time-consuming nature of this technique limits its more widespread adoption in the clinic. Finally, variable uptake of ¹⁸ F-FDG by inflammatory cells or activated fibroblasts in the ischemically injured region may also confound the interpretation of FDG retention, especially early after AMI. This is supported by the fact that the magnitude of increased glucose utilization in the culprit territory 7 days after MI is associated with activation of lymphoid tissue in spleen and bone marrow. Consequently, there is a need for more specific approaches targeting inflammation, especially as novel and highly innovative therapies for myocardial repair, such as specific anti-inflammatory drugs or even T cell–based immunotherapies, are being developed. ^, This opens new opportunities for targeted molecular imaging approaches to evaluate the timing and efficacy of novel reparative interventions ( Fig. 26.3 ).