How does cardiovascular imaging work?

During diagnostic imaging for surgical vascular patients, early disease detection, disease phenotyping and risk stratification is crucial for adequate patient selection prior to (endo)vascular treatment and for treatment response monitoring. Conventional and novel (functional) imaging modalities can contribute to this. For example, by identifying the vascular flow within blood vessels after angioplasty or thrombectomy.

Additionally, cardiovascular molecular imaging can be used in drug development. More precisely, it allows for the evaluation of pharmacokinetics and biodistribution of a fluorescent or nuclear labelled therapeutic compound in CVD, depending on the depth of imaging. For this purpose, the understanding of imaging tools based on disease biology is key to improve further development in a research setting and towards clinical translation into routine application.

Cardiovascular molecular imaging of atherosclerotic plaque.

Molecular imaging exposes the underlying cellular and molecular processes that initiate pathophysiological changes. For example, analysis of the composition of the atherosclerotic plaque in the coronary arteries or carotid artery could be a valuable clinical tool. Namely, patients with a so-called vulnerable atherosclerotic plaque are prone to respectively an increased risk of cardiac ischemia or neurological ischemic stroke. Atherosclerotic plaque formation is mainly characterized by an increased level of biological activity at different cellular mechanisms. More specifically, the most pronounced is local inflammation with intra-plaque neovascularization and subsequent macrophage infiltration¹.

There are quantitative nuclear and optical molecular imaging technologies that evaluate these relevant biological features of vascular disease. For instance, the intensity of ¹⁸F-fluorodeoxyglucose (FDG) correlates with the degree of macrophage infiltration in the atherosclerotic plaque. This is measured with a PET/CT scan. The correlation provides insight into the inflammatory role and progression of atherosclerotic lesions over time. In other words, patients with a high FDG uptake have shown to be at the highest risk for a vascular event. Therefore, FDG-PET using molecular information identifying inflammation could be a novel powerful tool to evaluate inflammatory response.

Nevertheless, PET/CT scans use ionizing radiation and are costly. A recent preclinical study reported that over-expression of VEGF-A in carotid plaques is correlated with vulnerability ². In turn, these findings were translated towards a first-in-human clinical fluorescent imaging trial in patients with carotid stenosis. Investigators examined whether the use of the intravenously administered VEGF-A targeted imaging agent, bevacizumab-800CW, combined with optoacoustic imaging was able to identify the vulnerable plaque by targeting the intra-plaque neovascularization.

Optoacoustic imaging of atherosclerotic plaque.

Optoacoustic imaging is a non-invasive and non-radioactive imaging modality. It emits transient laser pulses in multiple wavelengths. Underlying molecules absorb these pulses, undergo thermoelastic expansion and eventually emit ultrasound wavelengths. Consecutively, these can be detected by specific highly sensitive transducers.

Using optoacoustic imaging, endogenous molecules, such as hemoglobin and deoxyhemoglobin, can be identified as a parameter for vascularization and degree of stenosis. Potentially, by combining this information with the use of a plaque-specific contrast agent, patient selection for surgery might be improved. More precisely, it could assist by distinguishing the vulnerable from the non-vulnerable plaque. Additionally, the possibility for repeatedly imaging on multiple time points has become possible. This creates opportunities for monitoring disease-progression and innovative therapeutic interventions to reduce the risk of plaque rupture in the patient. The identification of endogenous molecular markers would be ideal to allow for such an easy, non-radioactive repetitive imaging modality.

Cardiovascular imaging in clinical trials.

Cardiovascular imaging is an important factor of drug discovery trials, as both the on- and off-target effect of novel drugs need to be quantified and established. Namely, patients with carotid artery or peripheral arterial disease surgery are more accessible for evaluating fluorescent or radioactive labelled therapeutic compounds as a representative for cardiovascular disease. Thus, the pharmacokinetic and biodistribution imaging data of a nuclear/fluorescent labelled therapeutic compound can be evaluated non-invasively over time. For determining targeting specificity, the excised plaque specimen can be used for ex vivo cross-validation of the in vivo imaging data using immunohistochemistry and fluorescence microscopy. Therefore, the vulnerable or culprit plaque creates an ideal in-human drug evaluation model to screen and evaluate new therapeutics. Especially in early small-smart clinical imaging trials.

The introduction of innovative cardiovascular imaging in drug development and tracer labelling methodologies allows for a high-expert multidisciplinary environment. Physicians, chemists, engineers, pharmacists and entrepreneurs are needed to create the optimal workflow to improve the current settings of drug development and 1^st in-human evaluation. At TRACER, we connect all these state-of-the-art technologies and professional networks to create an innovative, efficient and highly successful working environment to assess cardiovascular imaging studies and develop new therapies. Contact us to learn more about cardiovascular imaging.

References.

1. Sedding, D. G. et al. Vasa vasorum angiogenesis: Key player in the initiation and progression of atherosclerosis and potential target for the treatment of cardiovascular disease. Frontiers in Immunology vol. 9 (2018).
2. Huisman, L. A. et al. Feasibility of ex vivo fluorescence imaging of angiogenesis in (non-) culprit human carotid atherosclerotic plaques using bevacizumab-800CW. Scientific Reports 11, (2021).