Ischemic Heart disease (IHD) is not anymore synonymous with obstructive (Obs) flow-limiting coronary artery disease (CAD), especially in women that are more commonly affected by non-obstructive (non-Obs) disease (i.e.,
In preliminary studies we developed an interpretable machine learning-based model that discriminates non-Obs and Obs CAD through features that capture i) the reduction of physiological functional reserve of individuals (i.e. frailty); ii) the inflammatory burden; and iii) the complexity that gender encompasses (identity, role, relations and institutionalized gender). We found that while Obs CAD associates with increased frailty index, older age and a cytokine signature characterized by IL-1ß, IL-12p70 and IL-33, non-Obs CAD is more likely to associate with a feminine gender score and with a cytokine signature characterized by IL-18, IL-8, IL-23. Thus, we hypothesize that different thrombo-inflammatory mechanisms underlie different types of CAD.
To test this hypothesis, we here propose 3 tasks to be pursued by a coordinated effort of 3 research units. The Unit lead by L. Stefanini will compare platelet reactivity in Obs and non-Obs CAD patients (task 1). The Unit lead by S. Piconese will characterize by multi-color flow cytometry the immunological profile of these patients and the crosstalk between platelets and immune cells in collaboration with Unit Stefanini (task 2). The Unit lead by V. De Cicco will use data obtained in tasks 1-2 to compute a simplified model of platelet activation to predict how inflammatory cytokines affect platelet function (task 3). In summary, the proposed project will employ state-of-the-art flow cytometry and mathematical techniques to dissect the mechanisms underlying non-Obs and Obs CAD. We anticipate that these studies will facilitate the tailoring of safer patient-specific therapies.
The proposed project is novel at various levels.
It aims to understand the molecular mechanisms of non-obstructive IHD an emerging clinical issue that has been recognised only recently.
It will tackle this important medical issue by employing a combination of "wet" and "dry" research techniques. State-of-the-art multicolor flow cytometry will be used to maximize the acquired data while minimizing the volume of blood needed for the experiments. Mathematical modelling will be used to study how signaling pathways evoked by different cytokines are integrated with the classical signaling pathways that we know control platelet activation.
Furthermore, the knowledge advancements ensured by this project will enable the implementation of precision medicine.
An increasing number of patients with evidence of ischemia but non-Obs CAD at coronary angiography are being recognised. Although these patients were previously thought to be at low risk for major adverse cardiovascular events (MACE) and were provided only reassurance, newer data document that these patients are a heterogeneous population with an elevated MACE risk. Thus, there is an urgent need to address several important knowledge gaps to improve the diagnosis and the management of these patients.
The work laid out in this proposal will advance the diagnosis and management of IHD in 3 ways:
First we will further optimize an interpretable ML-based prediction tool that we have developed to discriminate non-obstructive and obstructive CAD through features that capture i) the reduction of physiological functional reserve of individuals (i.e., frailty); ii) the inflammatory burden of IHD; and iii) the complexity that gender encompasses (identity, role, relations and institutionalized gender). By adding to the model biological information pertaining the platelet functional status we may achieve a higher prediction accuracy/precision. This model is an easily accessible tool that will enable us to classify patients into discrete disease endotypes with non-invasive procedures, improve diagnosis and facilitate the tailoring of a personalized therapy.
Secondly, the ML-model will enable us to establish how these biological, clinical and psycho-socio-cultural features relate to the different CAD types and to each other. For instance, we will explore how gender or frailty interact with biological factors to affect coronary health. In our model, the feminine gender score, is a feature strongly associated with non-obstructive CAD and with a cytokine signature that promotes plaque stability but increased neutrophil recruitment, likely because women have an enhanced immune reactivity. On the other hand, age and frailty associate to Obs-CAD because aging and comorbidities promote plaque growth and plaque instability.
Last but not least, we anticipate that understanding the mechanistic interplay between platelets and inflammation will aid in the identification of new and potentially safer therapeutic strategies. Since antiplatelet therapy not only reduces the thrombo-ischemic risk but also decreases ongoing platelet-driven systemic inflammation, prolonged intensified antiplatelet therapy may also lower the risk of non-obstructive ischemic heart disease. However, targeting molecules implicated in the overall platelet activation, such as P2Y12, may protect from IHD at the cost of enhanced bleeding complications. Each of the molecular determinants of platelet-leukocyte cross-talk is a potential target for novel pharmacological agents. Thus, a more detailed understanding of the interplay between platelets and the immune system in the context of IHD may help identify new targets that would interfere with platelet-driven inflammation while preserving hemostasis.
Moreover, our observations so far support the idea that targeting inflammation to reduce the risk of CVD could be a more successful strategy if we would target specific thrombo-inflammatory pathways in specific subset of patients. The moderate success of the CANTOS trial that tested the efficacy of the IL-1ß inhibitor, canakinumab, could be due to the fact that IL-1ß is particularly high in Obs IHD but not in non-OBs IHD. Based on our hypothesis, non-Obs IHD would be prevented more effectively with drugs targeting IL-23/IL-17, developed to treat psoriasis, or by novel strategies aimed at preventing platelet-neutrophil binding or NETs release.
The subjects that would benefit the most from this precision medicine approach would be women. In our study we show that females with CAD have a greater inflammatory burden than males, confirming the generally accepted notion that female mount stronger immune responses than men and suggesting that this predisposition might put them at higher risk of CAD with inflammatory pathogenesis.