International Union of Angiology (IUA) consensus paper on imaging strategies in atherosclerotic carotid artery imaging: From basic strategies to advanced approaches

Cardiovascular disease (CVD) is the leading cause of mortality and disability in developed countries. According to WHO, an estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Of these deaths, 85% were due to major adverse cardiac and cerebral events. Early detection and care for individuals at high risk could save lives, alleviate suffering, and diminish economic burden associated with these diseases. Carotid artery disease is not only a well-established risk factor for ischemic stroke, contributing to 10%–20% of strokes or transient ischemic attacks (TIAs), but it is also a surrogate marker of generalized atherosclerosis and a predictor of cardiovascular events. In addition to diligent history, physical examination, and laboratory detection of metabolic abnormalities leading to vascular changes, imaging of carotid arteries adds very important information in assessing stroke and overall cardiovascular risk. Spanning from carotid intima-media thickness (IMT) measurements in arteriopathy to plaque burden, morphology and biology in more advanced disease, imaging of carotid arteries could help not only in stroke prevention but also in ameliorating cardiovascular events in other territories (e.g. in the coronary arteries). While ultrasound is the most widely available and affordable imaging methods, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), their combination and other more sophisticated methods have introduced novel concepts in detection of carotid plaque characteristics and risk assessment of stroke and other cardiovascular events. However, in addition to robust progress in usage of these methods, all of them have limitations which should be taken into account. The main purpose of this consensus document is to discuss pros but also cons in clinical, epidemiological and research use of all these techniques

A Pharmaceutical Paradigm for Cardiovascular Composite Risk Assessment Using Novel Radiogenomics Risk Predictors in Precision Explainable Artificial Intelligence Framework: Clinical Trial Tool

Background: Cardiovascular disease (CVD) is challenging to diagnose and treat since symptoms appear late during the progression of atherosclerosis. Conventional risk factors alone are not always sufficient to properly categorize at-risk patients, and clinical risk scores are inadequate in predicting cardiac events. Integrating genomic-based biomarkers (GBBM) found in plasma/serum samples with novel non-invasive radiomics-based biomarkers (RBBM) such as plaque area, plaque burden, and maximum plaque height can improve composite CVD risk prediction in the pharmaceutical paradigm. These biomarkers consider several pathways involved in the pathophysiology of atherosclerosis disease leading to CVD. Objective: This review proposes two hypotheses: (i) The composite biomarkers are strongly correlated and can be used to detect the severity of CVD/Stroke precisely, and (ii) an explainable artificial intelligence (XAI)-based composite risk CVD/Stroke model with survival analysis using deep learning (DL) can predict in preventive, precision, and personalized (aiP 3 ) framework benefiting the pharmaceutical paradigm. Method: The PRISMA search technique resulted in 214 studies assessing composite biomarkers using radiogenomics for CVD/Stroke. The study presents a XAI model using AtheroEdge TM 4.0 to determine the risk of CVD/Stroke in the pharmaceutical framework using the radiogenomics biomarkers. Conclusions: Our observations suggest that the composite CVD risk biomarkers using radiogenomics provide a new dimension to CVD/Stroke risk assessment. The proposed review suggests a unique, unbiased, and XAI model based on AtheroEdge TM 4.0 that can predict the composite risk of CVD/Stroke using radiogenomics in the pharmaceutical paradigm

A Pharmaceutical Paradigm for Cardiovascular Composite Risk Assessment Using Novel Radiogenomics Risk Predictors in Precision Explainable Artificial Intelligence Framework: Clinical Trial Tool

Cardiovascular disease (CVD) is challenging to diagnose and treat since symptoms appear late during the progression of atherosclerosis. Conventional risk factors alone are not always sufficient to properly categorize at-risk patients, and clinical risk scores are inadequate in predicting cardiac events. Integrating genomic-based biomarkers (GBBM) found in plasma/serum samples with novel non-invasive radiomics-based biomarkers (RBBM) such as plaque area, plaque burden, and maximum plaque height can improve composite CVD risk prediction in the pharmaceutical paradigm. These biomarkers consider several pathways involved in the pathophysiology of atherosclerosis disease leading to CVD.This review proposes two hypotheses: (i) The composite biomarkers are strongly correlated and can be used to detect the severity of CVD/Stroke precisely, and (ii) an explainable artificial intelligence (XAI)-based composite risk CVD/Stroke model with survival analysis using deep learning (DL) can predict in preventive, precision, and personalized (aiP3) framework benefiting the pharmaceutical paradigm.The PRISMA search technique resulted in 214 studies assessing composite biomarkers using radiogenomics for CVD/Stroke. The study presents a XAI model using AtheroEdgeTM 4.0 to determine the risk of CVD/Stroke in the pharmaceutical framework using the radiogenomics biomarkers.Our observations suggest that the composite CVD risk biomarkers using radiogenomics provide a new dimension to CVD/Stroke risk assessment. The proposed review suggests a unique, unbiased, and XAI model based on AtheroEdgeTM 4.0 that can predict the composite risk of CVD/Stroke using radiogenomics in the pharmaceutical paradigm

Advancements and applications of Artificial Intelligence in cardiology: Current trends and future prospects

Using Artificial intelligence technologies in cardiology has witnessed rapid advancements across various domains, fostering innovation and reshaping clinical practices. The study aims to provide a comprehensive overview of these AI-driven advancements and their implications for enhancing cardiovascular healthcare. A systematic approach was adopted to conduct an extensive review of scholarly articles and peer-reviewed literature focusing on the application of AI in cardiology. Databases including PubMed/MEDLINE, ScienceDirect, IEEE Xplore, and Web of Science were systematically searched. Articles were screened following a defined selection criteria. These articles' synthesis highlighted AI's diverse applications in cardiology, including but not limited to diagnostic innovations, precision medicine, remote monitoring technologies, drug discovery, and clinical decision support systems. The review shows the significant role of AI in reshaping cardiovascular medicine by revolutionising diagnostics, treatment strategies, and patient care. The diverse applications of AI in cardiology showcased in this study reflect the transformative potential of these technologies. However, challenges such as algorithm accuracy, interoperability, and integration into clinical workflows persist. AI's continued advancements and strategic integration in cardiology promise to deliver more personalised, efficient, and effective cardiovascular care, ultimately improving patient outcomes and shaping the future of cardiology practice

Imaging Atherosclerosis.

Advances in atherosclerosis imaging technology and research have provided a range of diagnostic tools to characterize high-risk plaque in vivo; however, these important vascular imaging methods additionally promise great scientific and translational applications beyond this quest. When combined with conventional anatomic- and hemodynamic-based assessments of disease severity, cross-sectional multimodal imaging incorporating molecular probes and other novel noninvasive techniques can add detailed interrogation of plaque composition, activity, and overall disease burden. In the catheterization laboratory, intravascular imaging provides unparalleled access to the world beneath the plaque surface, allowing tissue characterization and measurement of cap thickness with micrometer spatial resolution. Atherosclerosis imaging captures key data that reveal snapshots into underlying biology, which can test our understanding of fundamental research questions and shape our approach toward patient management. Imaging can also be used to quantify response to therapeutic interventions and ultimately help predict cardiovascular risk. Although there are undeniable barriers to clinical translation, many of these hold-ups might soon be surpassed by rapidly evolving innovations to improve image acquisition, coregistration, motion correction, and reduce radiation exposure. This article provides a comprehensive review of current and experimental atherosclerosis imaging methods and their uses in research and potential for translation to the clinic.J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). M.D is supported by the British Heart Foundation (FS/14/78/31020). N.R.E. is supported by a research training fellowship from the Dunhill Medical Trust (RTF44/0114). A.J.B. is supported by the British Heart Foundation. J.H.F.R. is part-supported by the HEFCE, the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust.This is the final version of the article. It first appeared from the American Heart Association via http://dx.doi.org/10.1161/CIRCRESAHA.115.30624

Non-coding RNA-based therapeutics and biomarkers for treatment and detection of vascular disease

Cardiovascular disease (CVD), with atherosclerosis as its main underlying pathology, is the most prominent cause of death worldwide. Progression and rupture of atherosclerotic plaques lead to potential adverse pathological events such as myocardial infarction and stroke. Although largely successful, primary and secondary prevention strategies have thus far been insufficient in minimizing the vast consequences of atherosclerotic disease progression on global health. Abdominal aortic aneurysm (AAA) disease shares a similar risk profile with atherosclerosis. A consequence of undiagnosed AAAs can be their subsequent rupture, which up to 90% of patients will not survive. In both atherosclerosis and AAA, treatment and prevention are complicated by the fact that they progress silently and rarely lead to significant health impacts in their early stages. In addition, different pathological processes are known to be of importance as the diseases progress. These are also affected by patient-specific genetic and environmental risk factors. It would therefore be of benefit to find better ways of stratifying patient-specific disease risk and develop novel treatments. In the past decades, non-coding RNAs have emerged as powerful disease regulators in CVD and have been implicated as disease biomarkers in several research fields. In this thesis, we have sought to: (1) identify novel long non-coding RNAs (lncRNAs) involved in late-stage atherosclerotic disease and AAA, (2) establish techniques of their targeted delivery to affected vasculature, and (3) identify novel microRNA biomarkers of AAA with direct roles in disease development and progression. In study I, we have identified lncRNA MIAT as a novel regulator of vascular smooth muscle cell (VSMC) dynamics in carotid atherosclerotic disease, with positive effects on their survival – a beneficial trait in late-stage disease. Its effects on earlier disease stages were however detrimental through regulation of VSMC phenotypic switching into macrophage-like phenotypes and through regulation of macrophage-specific processes. In study II, we identified the lncRNA NUDT6, the natural antisense transcript of FGF2, to be up-regulated in fibrous caps of vulnerable vs stable plaques. NUDT6 was also up-regulated in AAA vs control aortic tissues. In experimental animal models of atherosclerosis and AAA, FGF2 de-repression by the way of NUDT6 inhibition had a beneficial effect on disease phenotypes and was successful in limiting the progression of these diseases. In studies II and III, we successfully used drug-eluting balloons to deliver therapeutics to the abdominal aorta of the translational mini-pig model of AAA. In addition, in study III, we observed beneficial effects of lenvatinib (VEGF-signaling inhibitor) on experimental AAA disease phenotype through positive effects on VSMC contractility and decreased diameter growth. Finally, in study IV, we identified miR-15a-5p as a novel disease biomarker of AAA. We showed miR-15a-5p to be relevant in AAA pathogenesis through its ability to modulate VSMCs into more inflammatory phenotypes, and its inhibition was able to limit experimental murine AAA diameter growth. In conclusion, our studies not only confirm that non-coding RNAs are promising targets for treatment of CVD, but also underline the translational feasibility of their use

Plaques and patients:The role of carotid imaging in the prevention of ischemic stroke

Since the first discoveries of the pathologist Rudolph Virchow, we have gained many insights in the pathophysiology of ischemic stroke and in carotid atherosclerosis as one of its main causes. Nearly two centuries later, research in this field is going on and is still highly important. Although we have made considerable advances, our knowledge ‘is still a mere island in an ocean of ignorance’. What kind of factors exactly drive initiation, growth or stabilization of carotid atherosclerosis? Could these play a role in identification of patients at high risk of stroke? Or could imaging add to this risk prediction? And, if so, what do we need in the near future to use this knowledge in clinical practice? These are all current knowledge gaps and all highly relevant with regard to the further improvement of stroke care. In this thesis I have focused on these questions, summarized in three aims:1. investigation of determinants of carotid atherosclerosis;2. description of the natural course of carotid atherosclerosis; and3. identification of plaque characteristics that predict recurrent ischemic strokes.Most of the studies in this thesis are conducted using data of the Plaque At RISK (PARISK) study, a cohort including patients with symptomatic mild-to-moderate carotid stenosis.<br/

Protheomic and adipo/cytokine biomarker analysis of unstable carotid atheroma plaque

L'arteriosclerosi és un procés patològic que provoca manifestacions clíniques de malalties vasculars. Els objectius daquesta tesi són identificar possibles biomarcadors d?aterosclerosi carotídia (AC) en mostres de secretoma dels pacients amb placa carotídia inestable i estudiar el possible paper d’algunes adipo/citoquines en l’estabilitat de les plaques ateroscleròtiques. També analitzem els nivells de diverses adipes/citocines pro i antiinflamatòries en sèrum i secretoma de placa inestable segons la presència de factors de risc cardiovascular. En el primer estudi, realitzem una anàlisi proteòmica quantitativa a les mostres de secretoma obtingudes de plaques ateroscleròtiques carotídies humanes mitjançant endarterectomia carotídia. En un segon estudi, analitzem els nivells de diverses adipes/citocines pro i antiinflamatòries en sèrum i secretoma de placa inestable mitjançant assaigs immunoabsorbents lligats a enzims. Es van detectar alguns canvis proteòmics en els secretomes de les plaques ateroscleròtiques carotídies (CAP) en comparació amb les artèries mamàries no ateroscleròtiques (AMNE). Les proteïnes augmentades als secretomes de CAP van ser la defensina 1 de neutròfils, l'apolipoproteïna E, la clusterina i la glicoproteïna alfa-2 de zinc. Pel que fa als nivells sèrics de visfatina, no hi va haver diferències entre els grups de CAP inestable i AMNE.La arteriosclerosis es un proceso patológico que provoca manifestaciones clínicas de enfermedades vasculares. Los objetivos de esta tesis son identificar posibles biomarcadores de aterosclerosis carotídea (AC) en muestras de secretoma de pacientes con placa carotídea inestable y estudiar el posible papel de algunas adipo/citoquinas en la estabilidad de las placas ateroscleróticas. También analizamos los niveles de varias adipo/citocinas pro y antiinflamatorias en suero y secretoma de placa inestable según la presencia de factores de riesgo cardiovascular. En el primer estudio, realizamos un análisis proteómico cuantitativo en las muestras de secretoma obtenidas de placas ateroscleróticas carotídeas humanas mediante endarterectomía carotídea. En un segundo estudio, analizamos los niveles de varias adipo/citocinas pro y antiinflamatorias en suero y secretoma de placa inestable mediante ensayos inmunoabsorbentes ligados a enzimas. Se detectaron algunos cambios proteómicos en los secretomas de las placas ateroscleróticas carotídeas (CAP) en comparación con las arterias mamarias no ateroscleróticas (AMNE). Las proteínas aumentadas en los secretomas de CAP fueron la defensina 1 de neutrófilos, la apolipoproteína E, la clusterina y la glicoproteína alfa-2 de zinc.Arteriosclerosis is prevalent pathological process that causes clinical manifestations of vascular diseases such as myocardial infarction, stroke or peripheral arterial occlusive disease. Objectives of this thesis are to identify potential candidate biomarkers for carotid atherosclerosis (CA) in secretome samples of patients with unstable carotid plaque and to study the possible role of some adipo/cytokines in the stability of atherosclerotic plaques. We also analysed the levels of several pro- and anti-inflammatory adipo/cytokines in serum and unstable plaque secretome according to the presence of cardiovascular risk factors. In a first study, we performed proteomic quantitative analysis in secretome samples obtained from human carotid atherosclerotic plaques by carotid endarterectomy. In a second, we analysed the levels of several pro- and anti-inflammatory adipo/cytokines in serum and unstable plaque secretome by enzyme-linked immunosorbent assays (ELISA). Some proteomic changes were detected in the secretomes of carotid atherosclerotic plaques (CAP) compared with non atherosclerotic mammary arteries. The increased proteins in CAP secretomes were neutrophil defensin 1, apolipoprotein E, clusterin and zinc-alpha-2-glycoprotein

Plaques and patients:The role of carotid imaging in the prevention of ischemic stroke

Since the first discoveries of the pathologist Rudolph Virchow, we have gained many insights in the pathophysiology of ischemic stroke and in carotid atherosclerosis as one of its main causes. Nearly two centuries later, research in this field is going on and is still highly important. Although we have made considerable advances, our knowledge ‘is still a mere island in an ocean of ignorance’. What kind of factors exactly drive initiation, growth or stabilization of carotid atherosclerosis? Could these play a role in identification of patients at high risk of stroke? Or could imaging add to this risk prediction? And, if so, what do we need in the near future to use this knowledge in clinical practice? These are all current knowledge gaps and all highly relevant with regard to the further improvement of stroke care. In this thesis I have focused on these questions, summarized in three aims:1. investigation of determinants of carotid atherosclerosis;2. description of the natural course of carotid atherosclerosis; and3. identification of plaque characteristics that predict recurrent ischemic strokes.Most of the studies in this thesis are conducted using data of the Plaque At RISK (PARISK) study, a cohort including patients with symptomatic mild-to-moderate carotid stenosis.<br/