Preklinische multiparametrische MRI van het hart: geïntegreerde beoordeling van weefselbeschadiging, ontsteking en post-ischemische hartremodellering

Cardiovascular disease remains one of the leading causes of morbidity and mortality worldwide, and myocardial infarction (MI) is a major driver of this burden. Although treatments that rapidly reopen blocked coronary arteries have transformed emergency care, final myocardial damage can still be amplified when blood flow is suddenly restored, a process known as ischemia-reperfusion injury (IRI). These early ischemic and reperfusion-related events can initiate longer-term cardiac remodeling, i.e., progressive structural, functional, and biological changes of the left ventricle. While this remodeling initially serves as an adaptive mechanism to maintain cardiac output and stabilize the injured wall, it frequently becomes maladaptive over time, driving adverse alterations that may ultimately cumulate to heart failure. The microvascular and inflammatory mechanisms that shape myocardial salvage evolve within minutes to hours after coronary occlusion and reopening, a time window that is difficult to interrogate directly and systematically in patients. Small-animal IRI models therefore provide a practical way to impose ischemia and reperfusion on a defined timeline and to test time-sensitive cardioprotective strategies under controlled conditions, while enabling serial, non-invasive readouts that can be linked to later outcomes. In this context, magnetic resonance imaging (MRI) is particularly well suited because it offers multiparametric assessment of cardiac structure, function, and tissue status and can be repeated longitudinally in the same animals. This PhD project aimed to strengthen preclinical multiparametric cardiac MRI for the anatomical, functional, and molecular assessment of remodeling after IRI. The strategy combined model development with biologically targeted imaging to enable MRI at the earliest stages of injury while supporting longitudinal follow-up. By moving beyond classic functional assessment and later-stage tissue endpoints, this work aimed to capture early microvascular and endothelial inflammatory signals that may influence the spatial pattern and severity of subsequent injury and remodeling. A first objective was to develop and establish a new mouse ischemia-reperfusion injury model that enables cardiac MRI acquisition during coronary occlusion and during the first moments after reperfusion. This approach targets a critical window that is largely missed in conventional workflows: the occlusion-reperfusion transition, when injury mechanisms accelerate and when many time-sensitive cardioprotective strategies are expected to exert their strongest effects. After a brief surgical intervention to prepare for the coronary occlusion, the animal's chest is closed before ischemia is induced, in contrast to the gold standard IRI model in which the chest remains open during the ischemic period. This less invasive IRI design therefore allows MRI readouts during a less surgically disruptive ischemic phase and provides a more time-controlled framework for evaluating acute interventions. A second objective was to exploit this in-scanner model to perform manganese-enhanced MRI (MEMRI) at the moment of ischemia and during the earliest phase of reperfusion. Such early microvascular and tissue-level changes influence which myocardial regions remain salvageable and which progress to irreversible damage, yet these transitions are difficult to capture non-invasively with conventional imaging protocols. Integrating MEMRI with the proposed IRI model therefore adds a mechanistically informative dimension of tissue characterization within a time frame that is rarely accessible in mice. As a calcium analog actively taken up by functional cardiomyocytes, manganese serves as an intracellular viability probe, generating contrast that directly reflects cellular integrity and calcium channel activity. This approach also enables evaluation of whether early manganese uptake can provide sensitive markers of rapid treatment effects and early indicators of downstream injury progression and remodeling, helping to sharpen the timing and selection of candidate cardioprotective strategies before longer-term endpoints are reached. Alternative timing strategies could shift the biological emphasis toward viability or calcium-handling-related responses during reperfusion, a relevant target because early calcium dysregulation is closely linked to cardiomyocyte survival and functional recovery. A third objective was to evaluate endothelial activation as an in vivo molecular marker of inflammation after IRI using vascular cell adhesion molecule-1 (VCAM-1) targeted microparticles of iron oxide (MPIO). Endothelial activation is an early gateway to post-ischemic inflammation that shapes immune cell recruitment and microvascular dysfunction and may influence where injury expands or stabilizes, yet this process was until now rarely mapped directly in vivo in mouse IRI studies. We therefore implemented VCAM-1-targeted MPIO in a gold-standard murine IRI model to assess the broader potential of endothelial molecular MRI in this setting. By mapping early spatial patterns of VCAM-1 signal and relating them to subsequent myocardial injury, this work tested whether an endothelial readout can add a mechanistic layer that complements conventional structural, functional, and tissue-based MRI readouts. The resulting framework positions endothelial activation as a candidate early imaging marker that could help interpret, and potentially anticipate, the later distribution and severity of post-ischemic injury and remodeling. In summary, this thesis presents a coherent preclinical framework that expands cardiac MRI into the most time-sensitive phase of IRI while adding molecular specificity to early inflammatory assessment. By creating an in-scanner IRI model, demonstrating its utility for early MEMRI, and evaluating VCAM-1-targeted MPIO in a gold-standard setting, the work broadens the non-invasive toolbox for studying myocardial injury and the pathways that drive later remodeling. This combined workflow supports more precise longitudinal studies and provides a stronger foundation for preclinical testing of cardioprotective strategies designed to limit early damage and improve longer-term outcomes.