Transcatheter aortic valve replacement is now indicated across all risk categories of patients with symptomatic severe aortic stenosis and has been proposed as first line option for the majority of patients >74 years old. However, median age of patients enrolled in the transcatheter aortic valve replacement low-risk trials is 74 years and transcatheter aortic valve replacement has never been systematically investigated in young low risk patients. Although the long-term data in surgical aortic valve replacement in young patients (age <75) are well known, such data remain lacking in transcatheter aortic valve replacement. In the absence of clear guideline recommendations in patients with challenging anatomies (eg, hostile calcium, bicuspid), it is important to know the potential advantages and disadvantages of each treatment and to consider how they might integrate with each other in the lifetime management of such patients. In this review, we discuss current outstanding issues on the management of severe aortic stenosis from a lifetime management perspective, particularly in terms of initial intervention and future reinterventions.

Purpose of the Review: This review discusses the molecular mechanisms involved in the immuno-pathogenesis of atherosclerosis, the pleiotropic anti-inflammatory effects of approved cardiovascular therapies and the available evidence on immunomodulatory therapies for atherosclerotic cardiovascular disease (ACVD). We highlight the importance of clinical and translational research in identifying molecular mechanisms and discovering new therapeutic targets. Recent Findings: The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) trial was the first to demonstrate a reduction in cardiovascular (CV) risk with anti-inflammatory therapy, irrespective of serum lipid levels. Summary: ACVD is the leading cause of death worldwide. Although targeting principal risk factors significantly reduces CV risk, residual risk remains unaddressed. The immunological mechanisms underlying atherosclerosis represent attractive therapeutic targets. Several commonly used and non-primarily anti-inflammatory drugs (i.e. SGLT2i, and PCSK9i) exhibit pleiotropic properties. Otherwise, recent trials have investigated the blockade of primarily inflammatory compounds, trying to lower the residual risk via low-dose IL-2, PTPN22 and CD31 pathway modulation. In the era of precision medicine, modern approaches may explore new pharmacological targets, identify new markers of vascular inflammation, and evaluate therapeutic responses.

Personalized Medicine (PM) has shifted the traditional top-down approach to medicine based on the identification of single etiological factors to explain diseases, which was not suitable for explaining complex conditions. The concept of PM assumes several interpretations in the literature, with particular regards to Genetic and Genomic Medicine. Despite the fact that some disease-modifying genes affect disease expression and progression, many complex conditions cannot be understood through only this lens, especially when other lifestyle factors can play a crucial role (such as the environment, emotions, nutrition, etc.). Personalizing clinical phenotyping becomes a challenge when different pathophysiological mechanisms underlie the same manifestation. Brain disorders, cardiovascular and gastroenterological diseases can be paradigmatic examples. Experiences on the field of Fondazione Policlinico Gemelli in Rome (a research hospital recognized by the Italian Ministry of Health as national leader in “Personalized Medicine” and “Innovative Biomedical Technologies”) could help understanding which techniques and tools are the most performing to develop potential clinical phenotypes personalization. The connection between practical experiences and scientific literature highlights how this potential can be reached towards Systems Medicine using Artificial Intelligence tools.

Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways. We enrolled 24 CCS and 25 Non-ST Elevation Myocardial Infarction-ACS patients with IFC (n = 11) and RFC (n = 14) culprit lesions according to optical coherence tomography analysis. A real-time PCR primer array was performed on peripheral blood mononuclear cells for 17 different molecules whose expression is linked to WSS. Computational fluid dynamics simulations were performed in high-fidelity 3D-coronary artery anatomical models for three patients per group. A total of nine genes were significantly overexpressed in the unstable patients as compared to CCS patients, with no differences between IFC and RFC groups (GPX1, MMP1, MMP9, NOS3, PLA2G7, PI16, SOD1, TIMP1, and TFRC) while four displayed different levels between IFC and RFC groups (TNFα, ADAMTS13, EDN1, and LGALS8). A significantly higher WSS was observed in the RFC group (p < 0.001) compared to the two other groups. A significant correlation was observed between TNFα (p < 0.001), EDN1 (p = 0.036), and MMP9 (p = 0.005) and WSS values in the RFC group. Our data demonstrate that IFC and RFC plaques are subject to different WSS conditions and gene expressions, suggesting that WSS profiling may play an essential role in the plaque instability characterization with relevant diagnostic and therapeutic implications in the era of precision medicine.