Future research with advanced imaging technology and biomarkers

The identification of cardiovascular (CV) diseases before their clinical manifestation is supposed to be a very useful tool to better stratify and manage the CV risk. In the case of acute ischaemic events, early biomarkers have been demonstrated to reduce both mortality and morbidity. With this clinically relevant aim, in the last decades, several research groups focused on validating selective and specific easy-to-measure biomarkers of CV diseases. Several inflammatory molecules have been screened as potential innocent biomarkers or therapeutic targets against CV diseases.1,2 Although preliminary results in animal studies, many candidates identified in animal studies failed to become useful tools in human CV diseases. Among the more promising pathways recently targeted, some encouraging results have been recently demonstrated both in human and mouse models for the inflammation molecules IL-6/IL1.1 On the other hand, some concerns on the real safety (i.e. increased rate of infections and prolonged immune depression) of selective anti-inflammatory treatments against atherosclerosis have not been clarified yet. Considering such limitations, current research focused on promising ‘imaging biomarkers’ that might have the advantage to be intrinsically related to the atherosclerotic lesion. We believe that this shift from the ‘blood vulnerability’ to the ‘plaque vulnerability’ might be interpreted as a natural translation of research from the association to monitoring the lesion. In 2015, Libby and Pasterkamp very elegantly published the requiem for the vulnerable plaque, due to the fact that many acute coronary events are not related to the classical ‘plaque rupture’, but to plaque erosion.3 Critical advances in this field were made by the new technology of intracoronary imaging that are critical for the diagnosis making of different types of acute myocardial infarction. Interestingly the combination approach of soluble biomarkers with advanced imaging technology has been also investigated with some promising novelties. The advent of dynamic in vivo CV imaging with positron emission tomography (PET), cardiac magnetic resonance imaging (CMR), and/or computed tomography (CT) of the function and/or structure of the CV system in conjunction with plasma biomarkers, affords the unique means to investigate complex tissue response that opens new avenues to provide unique mechanistic insight into the pathophysiology of the CV system. For example, dynamic imaging of radiotracer probes in the arterial circulation and myocardium with PET affords the non-invasive assessment of myocardial blood flow and thus myocardial flow reserve in vivo. In this respect, classical CV risk factors such as arterial hypertension, smoking, diabetes mellitus, or hypercholesterolaemia commonly lead to increases in vascular oxidative stress due to stimulation of superoxide-producing endothelial enzymes, such as NAD(P)H oxidase, xanthine oxidase, or uncoupled nitric oxide synthase, leading to a reduction in the bioavailability of endothelium-derived and atheroprotective nitric oxide. Marked reductions in endothelial-derived nitric oxide are deemed to represent a common final pathway underlying endothelium-dependent coronary circulatory dysfunction, commonly seen as a functional precursor of coronary artery disease. The combination of imaging derived ‘in vivo’ structural and/or functional markers of the CV system combined with various biomarkers may provide unique mechanistic insights affecting for example coronary circulatory dysfunction due to classical, novel, and yet unknown CV risk factors (Figure 1).4,5 For example, Quercioli et al.6 could demonstrate that increases in endocannabinoid plasma levels, such as anandamide and 2-arachidonoylglycerol, are associated with coronary circulatory dysfunction, as determined with rest and pharmacologic-stress 13N-ammonia PET, in obesity. As coronary circulatory dysfunction is commonly deemed as a functional precursor for CAD and an independent predictor for worse CV outcomes, such observations may suggest indeed that increases in endocannabinoids plasma levels as a novel endogenous CV risk factor in obesity, that contrasted previous experimental investigations in this field. Albeit that increases in endocannabinoid plasma levels were independently predictive of coronary circulatory dysfunction suggesting direct adverse effects of endocannabinoids on the coronary arterial wall, someone could still argue that such in vivo observations may suggest associations between functional imaging parameters and biomarkers but not necessarily cause-effect relationships. While experimental studies are of utmost importance to examine the direct cause-effect of biomarkers and substrate targets, in vivo CV imaging with, e.g. PET and/or CMR, may unravel important associations between potential novel CV risk factors and the coronary arterial wall (Figure 1). Thus, in vivo CV imaging may also provide unique information to guide experimental research successfully to investigate more thoroughly intriguing associations between biomarkers and CV substrates. In vivo CV imaging also affords important insights into the complex nature of mechanisms underlying functional and/or structural alterations of the CV system. For example, investigating anandamide, leptin, and inflammatory plasma biomarkers and coronary circulatory dysfunction unravelled obesity and morbid obesity as different disease entities.7 In this respect, it could be shown that, apart from well-known obesity-related adverse effects of low HDL cholesterol, insulin resistance, and inflammation, increases in endocannabinoids plasma levels play a critical role in conferring alterations in endothelium-mediated coronary function in obese individuals. Interestingly and contrary to general opinions, metabolically triggered chronic microinflammation and marked increases in leptin plasma levels in morbid obesity may be associated with maintained flow-mediated and thus endothelium-dependent coronary endothelial function.8,9 Thus, it appears that other factors such as anti-inflammatory interleukin 10 in an inflammatory metabolic-vascular environment and/or adipositas-derived marked increases in leptin and/or leptin-related factors may weigh in to maintain arterial function in morbid obesity. Biomarkers and cardiovascular imaging. (A) 13N-ammonia positron emission tomography (PET) perfusion assessment with static images; (B) PET-determined myocardial blood flow in millimeter/gram/minute to assess myocardial flow reserve (MFR) and thereby coronary microvascular dysfunction; (C) plasma biomarkers; and (D) In-vivo mechanistic insights or tissue response. Taken together, in vivo CV imaging with PET and/or CMR in conjunction with a variety of biomarkers may denote important associations between CV risk and morphological and/or functional tissue substrate that may complement or even contrast experimental studies that investigate direct cause-effect relationships. This field of in vivo CV imaging in conjunction with plasma biomarkers may open a new era by providing important mechanistic information on tissue responses connecting experimental research to clinical outcome studies. None. Nothing to declare.