Cardiovascular diseases (CVDs) are a group of conditions associated with heart and blood vessels and are considered the leading cause of death globally. Coronary heart disease, atherosclerosis, myocardial infarction represents the CVDs. Since CVDs are associated with a series of pathophysiological conditions with an alarming mortality and morbidity rate, early diagnosis and appropriate therapeutic approaches are critical for saving patients’ lives. Conventionally, diagnostic tools are employed to detect disease conditions, whereas therapeutic drug candidates are administered to mitigate diseases. However, the advent of nanotechnological platforms has revolutionized the current understanding of pathophysiology and therapeutic measures. The concept of combinatorial therapy using both diagnosis and therapeutics through a single platform is known as theranostics. Nano-based theranostics are widely used in cancer detection and treatment, as evident from pre-clinical and clinical studies. Nanotheranostics have gained considerable attention for the efficient management of CVDs. The differential physicochemical properties of engineered nanoparticles have been exploited for early diagnosis and therapy of atherosclerosis, myocardial infarction and aneurysms. Herein, we provided the information on the evolution of nano-based theranostics to detect and treat CVDs such as atherosclerosis, myocardial infarction, and angiogenesis. The review also aims to provide novel avenues on how nanotherapeutics’ trending concept could transform our conventional diagnostic and therapeutic tools in the near future. Since the discovery of antibiotics, a significant development in the biomedical and healthcare sectors’ technological interventions has revolutionized the current understanding of disease diagnosis and therapy. In the last few decades, the global healthcare network’s advancement has also provided a platform to protect and maintain human beings’ health profiles . HoweverCVDs include a collection of several health conditions, including atherosclerosis, cardiomyopathy, arrhythmia, myocardial infarction, coronary artery disease, aneurysm and hypertension. Since CVDs infer the assemblage of several diseased conditions and disorders, the occurrence of CVDs become a severe global trend. The emergence of CVDs poses serious health complications resulting in severe implications on any given country’s economy. As per the data available, approximately 17.7 million people died across the globe in 2015 due to the complications associated with CVDs. In this context, it is estimated that by 2030, the mortality due to CVDs could rise to 22 million. In this context, the advancement in the technological perspectives could provide an array of therapeutic alternatives to minimize the nuisances of chronic diseases and disorders associated with CVDs. However, the co-occurrence of CVDs and chronic infectious ailments poses a severe challenge to the current therapeutic strategies. Immunotherapy, chemotherapy, and other conventional approaches are considered as the frontline warriors to fight against CVDs. The concept of host-directed therapies also gained considerable attention in the last few years for their ability to fight against NCDs, particularly CVDs . In thisFor the management of any chronic diseases and/or disorders, the foremost important thing is the early diagnosis of disease progression and based upon the diagnostic information, implementing the proper therapeutic measures. In this regard, approximately two decades ago, a combinatorial modality involving both diagnosis and therapeutics came into the limelight. The integrated concept of ‘theranostic’ was derived from therapy and diagnostics. The term “theranostics,” coined by John Funkhouser in 2002, refers to an assemblage of diagnostic tools and appropriate therapeutic measures under a single platform ,7. The tThe advent of theranostics has provided a selective platform for transforming conventional therapeutic medicines to personalized and particular treatments, suggesting a more holistic strategy to counteract health consequences of chronic health disease’ . The conNanotechnology in biomedicine and healthcare settings has resulted in the paradigm shift in understanding the disease prognosis and efficient therapeutic strategies to overcome chronic health consequences. The nano-based platforms provided a multifaceted platform for rapid and early diagnosis of disease progression. Furthermore, they exhibited therapeutic applications, including spatial targeting of therapeutic drug moieties and tracking of therapeutic response from the cellular system using different therapeutic modules such as gene therapy, chemotherapy, photodynamic therapy and photothermal therapy with differential specificity in terms of therapeutic efficacy ,17,18 F. The emeThe engineered nanomaterials of differential classes such as magnetic nanoparticles, carbon-based nanomaterials, silica-based nanomaterials, metal-based nanoparticles, and polymeric nanoparticles exhibited bimodal applications in terms of both diagnostics and therapeutic perspectives. In particular, the light-emitting and light-responsive nanomaterials, such as metal-based nanoparticles with high plasmon resonance (HPR), semiconductor quantum dots (QDs), organic and polymeric nanomaterials, gained considerable attention as cost-effective and efficient theranostic agents . The uniThe highly defined and unique physicochemical properties of nanomaterials are being exploited as prolific contrasting agents, which proves to be instrumental in the early detection and diagnosis of disease prognosis. Hence, nanomaterials are considered effective bioimaging modalities. Nanomaterials are being used as effective contrasting agents for various conventional diagnostic tools such as optical imaging, ultrasonography, magnetic resonance imaging (MRI), positron emission tomography (PET), photoacoustic tomography and computed tomography (CT). Thus, the role of nanomaterials as bioimaging tools has guided the scientific community towards bioimaging-guided therapeutics against NCDs .The ease of synthesis, unique physicochemical characteristics, and bimodal applications associated with the nanomaterials provided a unique platform for detecting and redefining the therapeutic measures for various chronic healthcare conditions, including neurodegenerative diseases Alzheimer’s disease and Parkinson’s disease . The nanAmong the notable non-communicable diseases in recent decades, CVDs emerged as the most life-threatening disease condition along with cancer in both developed and developing countries. CVDs are pathophysiological conditions of the cardiovascular system, including the blockage of blood vessels, irregular rhythmic function of heart muscles (arrhythmias), myocardial infractions, dilated cardiomyopathy, etc. CVDs are estimated to contribute to the highest percentage of mortalities by the year 2025 among the NCDs. As per the records received in the year 2017, CVDs are responsible for 17.7 million deaths worldwide, which accounts for approximately 1/3rd of the total global deaths suggesting the severity of CVDs . When thThe conventional therapeutic strategy for vascular diseases includes administering small drug molecules through oral, parenteral, intravenous, and intra-arterial routes. However, systemic side effects, rapid drug clearance, drug instability, and non-targeted localization limits the applications of drug molecules. Apart from administering drug molecules, invasive procedures such as angioplasty, atherectomy, stenting, bypass grafting are commonly employed to treat vascular diseases. However, the lack of bioimaging modalities limits their usefulness. In this context, alternative, non-invasive, target-oriented, and bioimaging assisted modalities could be considered to manage vascular diseases .Since the advent of nanotechnological concepts and their intervention into biological issues, a long-range of spatially designed nanomaterials are being considered for widespread applications in various fields. The emergence of nanobiotechnology has specifically revolutionized the biomedical sectors and characteristically improve the current understanding of various pathophysiological conditions and their guided therapeutic measures. A number of factors such as high surface plasmon resonance (SPR), high surface to volume ratio, tunability, biocompatibility, optical and magnetic properties are responsible for their influence in disease diagnosis and as localized therapeutics . Inorganvβ3 integrin is also considered a unique biomarker as it is associated with the process of angiogenesis and transiently expressed when the endothelial layer remains physiologically intact. Hence, the therapeutic measures centered around targeting these important physiological markers when spatially designed nanomaterials are being considered as theranostic materials [Atherosclerosis refers to the pathophysiological conditions where the medium and large arteries are significantly affected due to spatial deposition of various materials such as lipoproteins (particularly cholesterol), immune cells (circulating monocytes), proinflammatory factors , degraded extracellular matrix components and necrotic products. Atherosclerosis is considered to be the primary cause of chronic CVDs, including coronary heart disease, cerebrovascular disease, and peripheral arterial disease ,39,40. Aaterials . Lookingaterials . Additioaterials .The concept of nano-based platforms represents the basis for multifaceted applications such as diagnosis of pathophysiological conditions of any particular disease and critically modulating the therapeutic measures from a single platform. The nano-based theranostics are regularly used in cancer diagnosis and therapies. The promising theranostic aspects of nano-based cancer therapy platforms gained considerable interest in the last few years for targeted image-guided treatment of other chronic diseases, including CVDs. Spatially designed nano-systems are considered the highly decorated arsenal to treat atherosclerosis  Figure . As per Similarly, polymeric nanoparticles and HDL mimicking nanoparticles have also gained the center of attraction for determining the bioimaging and therapeutic modalities in managing atherosclerosis . In the vβ3 integrin and thus served as multimodal nanocomplexes for diagnosis and therapy [Angiogenesis is a standard process during atherosclerosis growth and progression. Hence, anti-angiogenic factors and drug moieties are being considered therapeutic modules for atherosclerosis treatment. For more specificity, the anti-angiogenic drug, perfluorocarbon, was designed into the phospholipid bilayer-based nano-emulsions targeting the α therapy . In addi therapy . Since tThe characteristic physicochemical properties such as high SPR, absorption capability, optical properties, biocompatibility and ability to bind to targeting agents provide the functional attributes of gold nanoparticles (AuNPs) as bioimaging and therapeutic modules. The high SPR effect of AuNPs is being deployed for photothermal therapy (PTT), where AuNPs promote macrophage depletion by transducing the light energy into heat in atherosclerotic conditions. Inorganic nanoparticles are being actively employed for PTT utilizing spatial wavelength of near-infrared laser light, leading to intracellular hyperthermia. The use of gold nanorods and silica-gold hybrid nanoparticles was reported to work in tandem with PTT and induce a series of physiological events, including the macrophages apoptosis and reduced risk of cardiovascular mortality by decreasing the total atheroma volume, respectively . AuNPs aSimilarly, mesoporous silica-coated conversion nanoparticles are being exploited as a platform for photosensitizers to trigger NIR-mediated PDT. Under NIR irradiation’s influence, a significant decrease in the intracellular lipids and an increased influx of cholesterol efflux were observed, suggesting an antagonistic effect on atherosclerosis ,60. In tm-hydroxyphenyl) chlorin (THPC) for macrophage targeted atherosclerosis therapeutics under the influence of near-infrared light. Based upon the promising results, it could be suggested that nanocarriers-based PDT may provide an added advantage to deep tissue imaging and therapy [Paramagnetic nanoparticles are highly effective in the diagnosis and treatment of atherosclerosis. Anti-angiogenic factors could be encapsulated into the magnetically active nanomaterials for effective clearance of atherosclerotic plaques associated with angiogenesis. The optical properties also facilitate the bioimaging module, which further enables therapeutic measures under consideration . Other i therapy ,63.Based upon the characteristic physicochemical properties such as biocompatibility, stability, high drug payload, sustained-release efficacy, localized drug targeting, and relatively low toxicity, the lipid-based nanoparticles, including liposomes, are being actively exploited for diagnosis and therapies of atherosclerosis. Since the liposomal carrier could incorporate both hydrophilic and hydrophobic drug molecules, encapsulation of drug moieties and antibiotics of different specificity are encapsulated into the liposomal carrier for diagnosis and/or therapy for atherosclerosis ,64. WhenUnderstanding the pathophysiology of atherosclerosis, it was observed that CC chemokine receptor 2 (CCR2) tends to be highly expressed on inflammatory cells and in the atherosclerotic plaques. Hence, targeting the transcriptomic profiling of CCR2 could pave the way for effective therapeutics in atherosclerosis management. In this context, self-assembled specific peptide-based nanoparticles were spatially designed to target CCR2. Since CCR2 is associated with atherosclerosis progression, the high affinity towards CCR2 could provide the platform for both diagnosis and therapeutics of atherosclerosis. The spatially designed peptide-based nanoparticles inhibited the expression of CCR2 by mediating a cascade of events such as ameliorating the monocyte migration and modulating the inflammatory response of IL-1β . It is eIn recent times, considerable interest is being laid upon using naturally derived molecules, mostly from plant sources, for therapeutic applications. Plant-based natural products are also observed for the synthesis of biogenic nanoparticles. Besides, plant-based compounds are also spatially incorporated into specific nanocarriers as effective therapeutics. In this context, plant-based compounds loaded into nanocarriers also gained considerable attention for the treatment of vascular diseases, including CVDs, as it is evident that inorganic nanoparticles are being actively used as contrast agents and therapeutic drug delivery. Recently, curcumin, a bioactive compound, was incorporated into titanium oxide nanoparticles and conjugated with the MCP-1 antibody. The resulting nanoplatforms exhibited promising attributes as contrast agents for MRI and could be utilized for the early diagnosis of atherosclerosis .The pathophysiological condition of ‘aneurysm’ is inferred to the enlargement/ bulging/ distention of the artery due to the weakening of the arterial wall and proved to be associated with fatal complications when ruptured at a later stage of development. As per the recent trends and reports from the Centers for Disease Control and Prevention (CDC), an aortic aneurysm causes the death of approximately 25,000 people every year in the United States. The excessive deposition of fats and cholesterol, high blood pressure, obesity, smoking, age, and family history of heart diseases are the common risk factors associated with aneurysms. Based upon the localization of arterial distention, the aneurysm is categorized into the aortic aneurysm (linked to the main aorta carrying blood from left ventricles of the heart through the chest and abdomen), cerebral aneurysm/intracranial aneurysm (arteries supplying blood to the brain) and peripheral aneurysm . The aneurysm associated with the heart is further categorized into a more pronounced abdominal aortic aneurysm (AAA) and lesser-known thoracic aortic aneurysm (TAA). Both aortic and cerebral aneurysms were highly fatal and could lead to lethal conditions due to stroke. Among the different types of aneurysms, AAA gained considerable attention as it is the primary cause of the high mortality rate and morbidity in older adults. When ruptured, the fatality of AAAs could be observed from several pathophysiological events such as neovascularization, increased reactive oxygen species (ROS) generation, apoptosis of vascular smooth muscles, and degradation of aortic lamellae and infiltration of inflammatory cells . The aboAs per the therapeutic procedures, mechanical and invasive intervention proved to be effective in treating aneurysms. The invasive procedures involve either open surgery to fit a synthetic or stent-graft or the endovascular repair using stent-graft surgery. For open-type AAA repair, the abdomen is incised to expose the aorta, followed by applying a graft into the aneurysm site. Meanwhile, in the endovascular method, an endovascular graft is inserted through the incision using a catheter followed by the graft’s repositioning to seal the aneurysm. Open surgery is generally associated with perioperative mortality and morbidity. On the other hand, the endovascular repair mechanism is generally contributing 60–70% success rate as this mechanism is also associated with several complications such as the requirement of reintervention due to reperfusion (bleeding around the graft), blockage of the stent, nerve damage, kidney failure and erectile dysfunction [Based upon the severity of aneurysms and limitations associated with the conventional invasive procedures, highly sufficient and alternative non-invasive approaches for diagnosis and therapeutics are the need of the hour. As the multifaceted nanoplatforms exhibit promising physicochemical properties, they are being considered effective theranostic agents. The exploitation of nano-based platforms improved the early diagnosis due to the spatial optical and magnetic properties. It provided a basis for encapsulating drug moieties of interest for targeted delivery to manage aneurysms . It is kTargeting the regulation of matrix metalloprotease and delaying the growth and progression of AAAs are viable methodologies for therapeutics. Though doxycycline (tetracycline-based antibiotic) is clinically reported for slowing the AAAs progression, relative systemic side effects and promoting the inhibition of elastin matrix deposition limit its widespread therapeutic application ,73. In tThe localized delivery of doxycycline from PLGA based nanomaterials improved the elastogenesis and strongly inhibited the matrix metalloprotease activity . The chaFor therapeutic intervention in targeting the AAAs, it is equally important to diagnose the growth and pathophysiological changes. Conventional anatomical imaging techniques such as Computed tomography (CT), magnetic resonance imaging (MRI), nuclear imaging and optical imaging are widely used for diagnosis. Similarly, coronary artery aneurysms, coronary angiography, intravascular ultrasound, CT angiography, echocardiography and coronary MR angiography are regularly used for diagnosis . The limFor early diagnosis and treatment of aortic aneurysms, lipid-based nanomaterials are considered to be highly effective. These nanomaterials can encapsulate both hydrophilic and hydrophobic drug molecules with a high drug payload. In addition, ease of surface functionalization, controlled release profile, biocompatibility, and localized drug targeting are the most important lipid-based nanoparticles’ attributes. Paramagnetic/fluorescent micellar nanomaterials functionalized with collagen-binding protein (CAN-35) exhibited promising aspects as diagnostic tools to visualize fibrotic response in the aortic wall associated with aneurysms . RecentlMyocardial infarction refers to the obstruction of coronary arteries resulting in prolonged ischemia and loss of cardiomyocytes, vascular cells and interstitial cells . Myocard2) motifs were engineered. The novel nanocomposites exhibited a multi-fold increase in the relaxation of myocardial infarction. The nanocomposites were spatially designed to accumulate in the heart’s ischemic tissue, from where they were uptake by macrophages. Once the nanocomposites were uptake, Mn2+ was released and used as a biomarker for high precision bioimaging [In the quest for novel non-invasive techniques for early diagnosis and treatment of myocardial infarctions, the conventional bioimaging modalities were developed in combination with precise nanomaterials. Nanomaterials’ physicochemical and optical properties are considered as prolific contrasting agents for bioimaging modalities with improved resolution. In this regard, pH-sensitive albumin nanocomposites in conjugation with manganese dioxide -N-(ethylisoluminol)-functionalized gold nanoparticles (ABEI-AuNPs) and citrate-capped AuNPs were developed for sensitive detection of human cardiac troponin I, an important biomarker for diagnosis of acute myocardial infarction [Myoglobin is a crucial cardiac biomarker for early detection and diagnosis of myocardial infarction as it released into the bloodstream once there is an incidence of cardiac muscle injury. Hence, monitoring the myoglobin level could facilitate the early detection and appropriate therapeutic measures for myocardial infarction. In this context, Mn-doped zinc oxide nanoparticles (Mn-ZnO NPs) were spatially designed to detect early signs of acute myocardial infarction by monitoring myoglobin content. As evidenced from results, the engineered nanomaterials observed to detect the electrochemical changes in the level of myoglobin and could be considered as ultrasensitive biosensors . For efffarction ,92.3+) is being actively employed as contrasting agents for CMR. As contrasting agents’ role critically influences the detection and monitoring of different pathophysiological conditions, it is essential to the quest for novel nano-based polar agents. In this regard, Gd-based paramagnetic quantum dots in conjugation with specific tripeptide were developed as contrasting agents for detecting and imaging myocardial neovasculature. Though Gadolinium is observed to be safe as a contrasting agent, in few cases, Gd-based contrasting agents’ regular use leads to severe nephrogenic systemic fibrosis. In this context, physiocochemical properties of various nanomaterials physiochemical properties could be considered as alternative and effective contrasting agents for diagnosis purposes. For instance, SPIONs were reported for their ability to detect the difference between normal and infarcted myocardium due to contrasting differential measures [For the detection and monitoring of pathophysiological conditions associated with myocardial tissues, cardiac magnetic resonance imaging (CMR) was developed. Paramagnetic gadolinium  and B-cell lymphoma 2 . In an eFDA-approved PLGA-based polymeric nanoparticles are also employed for the treatment of myocardial infarction. For instance, insulin-like growth factor (IGF-1) complexed with PLGA nanoparticles exhibited increased retention of IGF-1 as it is important in regulating myocardial function, growth of cardiomyocytes and cardiomyocytes survival. When IGF-1 was exogenously supplied, when complexed with PLGA nanoparticles, increased cardioprotection incidence, prevention of cardiomyocyte apoptosis, reduction in infarct size, and improved left ventricular incidence ejection fraction (LVEF) were observed ,101. The2+ following the reperfusion injury leading to cell death and cardiac hypertrophy. In this regard, spatially designed multifunctional poly(glycidyl methacrylate) (PGMA) nanoparticles loaded with specific peptide  of L-type Ca2+ channel) and potent antioxidant molecules (curcumin/resveratrol) for combinatorial therapy. The simultaneous delivery of the specific peptide and antioxidant moieties allowed the reduction in the elevated level of ROS and Ca2+ and thus was observed to be involved in minimizing the pathophysiological events associated with ischemic injuries [Cardiac ischemia-induced myocardial infarction is generally associated with elevated ROS and intracellular Cainjuries .One of the most exciting aspects of therapies associated with CVDs is the restoration of blood supply, as there are several instances of blood occlusion during the progression of CVDs. The repair of blood vessels is achieved through many inter-related physiological mechanisms such as angiogenesis, vasculogenesis and arteriogenesis. Angiogenesis refers to the restoration of blood vessels by augmenting the host angiogenic response. The process of angiogenesis is a highly regulated mechanism involving the interplay between pro-angiogenic and anti-angiogenic factors. The process of angiogenesis involves a sequential cascade of events, including activation , progression , migration, differentiation and maturation .Therapeutic angiogenesis forms the basis for revascularizing the ischemic tissues by promoting specific growth factors and progenitor cells . Gene thThe advent of nano-based delivery systems has revolutionized the healthcare sectors and showed promising aspects in the management of CVDs. Localized targeting, controlled release, and increased circulation time are essential for therapeutic efficacy. In this regard, the factors responsible for angiogenesis also required suitable nano-based delivery systems for promoting angiogenesis. An important factor for angiogenesis is microRNA-126 (miR-126), which plays a crucial role by blocking the expression of sprouty-related EVH1 domain-containing protein 1 (SPRED1). Since SPRED1 is known to inhibit the angiogenic factor, VEGF; blocking the SPRED1 is essential for maintaining the angiogenesis. For effective control of SPRED1, miR-126 loaded PLGA nanoparticles were designed. The nanoparticles allowed the localized and sustained release of miR-126 to inhibit SPRED1 and thus promoted angiogenesis . Based oGraphene oxide and reduced graphene oxide specifically induced angiogenesis by modulating the physiological level of ROS, reactive nitrogen species (RNS) and activation of endothelial nitric oxide synthase. PEGylated graphene oxide also promotes angiogenesis with reduced cytotoxic effects ,121. EarSeveral therapeutic drug molecules were developed in the biotechnological and pharmaceutical sectors, with differential functional attributes. For example, few drug moieties can be used as a biomarker for diagnosis purposes, whereas other drug molecules exhibited therapeutic efficacy. Though an array of drug molecules is being employed to manage CVDs, they only temporarily delayed the progress of pathophysiological conditions. Besides, the therapeutic use of these drug molecules also leads to systemic side effects. In this context, nano-based platforms proved to be a dual-responsive system where they could be utilized both as diagnostic and therapeutic tools from a single platform. The localized drug delivery and prolonged therapeutic effect due to increased circulation time also characteristically established the utility of nano-based media . The nanBased upon the differential physicochemical properties, optical characteristics and magnetic behavior, engineered nanomaterials exhibited widespread functional attributes. No doubt, various nanomaterials as theranostics are used for different purposes; their specificity and efficacy are based upon the target specificity. Nanomaterials were designed and engineered for multiple applications with differential advantages and disadvantages. One of the most important limitations of the use of engineered nanomaterials as next-generation nanotheranostic agents is the use of these nanoplatforms is limited to laboratory setup and in the preliminary stage of clinical settings. Hence, it is important to decipher the sustainability and prospective toxicity profile of the engineered nanomaterials before being considered for clinical applications . Though Considerable progress has been made in the last few decades on developing theranostic nanoparticles with differential formulation for multifunctional biomaterials for various biomedical applications and is being patented. This progress could be instrumental in the future for efficient management of CVDs and other diseases ,129,130.Since the engineered nanomaterials with suitable therapeutic drug moieties exhibited certain advantages as well as few limitations, however, the ease of synthesis, surface modification, and functionalization provided new avenues to re-engineer the theranostic nanomaterials of particular interest to improve diagnosis and therapy efficacy. Though the engineered theranostic nanoparticles possess few differential limitations, the advent of nanotheranostics has opened a new door for a new scope and scintillating avenues for developing novel platforms to improve healthcare settings and minimize the nuisances of different pathophysiological conditions. As discussed earlier, the intervention of nanotheranostics has revolutionized our knowledge to tackle the problems associated with CVDs by complementing the available diagnostic and therapeutic tools. The increased incidence of nanotheranostics in biomedical sectors emerged as prolific non-invasive techniques, thereby augmenting the limitations associated with traditional invasive procedures to treat CVDs. No doubt, nanotheranostics constitute widespread applications for disease diagnosis and therapies, but it is also important to regulate these engineered theranostic nanoparticles’ rational use. One more interesting aspect in utilizing theranostic nanoparticles is the imbalance between the number of different theranostic agents reported for their widespread biomedical applications and the number of engineered theranostic nanoparticles that cross the clinical barriers and are employed for human use. In this context, regulatory bodies should evaluate and formulate regulatory guidelines to transform theranostic nanoparticles’ laboratory settings to clinical settings followed by human consumption and/or use.Technology intervention and improved healthcare settings have provided a cue to diagnose and develop one or other therapeutic measures for CVDs. In the development of novel therapeutics, the emergence of theranostic nanoparticles allows dual-responsive modalities to diagnose the pathophysiological conditions and provides therapeutic modalities through a single platform. The impact of nanotheranostics in cancer biology has provided a new dimension to design and develop novel nanotheranostics to manage other diseases and disorders. Though the intervention of nanotheranostics in the management of CVDs is a new venture in the healthcare settings, the impact observed has revolutionized our understanding of the pathophysiology of CVDs and interpreted appropriate therapeutic measures. The spatially designed theranostic nanoparticles exhibited promising influence in augmenting atherosclerosis progression, ischemic heart disease, myocardial infarction, and aneurysms. Besides, the theranostic nanoparticles also tend to promote angiogenesis, which is essential for maintaining the cardiovascular apparatus’s health. In the last few years, the incidence of theranostic nanoparticles employed for the management of CVDs was increased exponentially in laboratory settings. It is essential to transform theranostic nanoparticles’ efficacy into clinical health settings before being considered for human use.


There is evidence that genetic polymorphisms and environmentally induced epigenetic changes play an important role in modifying disease risk. The commensal microbiota has the ability to affect the cellular environment throughout the body without requiring direct contact; for example, through the generation of a pro-inflammatory state. In this review, we discuss evidence that dysbiosis in intestinal, pharyngeal, oral, and ocular microbiome can lead to epigenetic reprogramming and inflammation making the host more susceptible to ocular disease such as autoimmune uveitis, age-related macular degeneration, and open angle glaucoma. Several mechanisms of action have been proposed to explain how changes to commensal microbiota contribute to these diseases. This is an evolving field that has potentially significant implications in the management of these conditions especially from a public health perspective. Many chronic non-infectious diseases like Alzheimer’s disease (AD), age-related macular degeneration (AMD), autoimmune uveitis (AU), and open angle glaucoma, have multifactorial etiologies that frequently include the interaction of environmental risk factors and genetic predisposition. Despite decades of linkage and family studies, only a limited number of polymorphisms or mutations have been identified which have a causative role in these conditions . Even thIn an effort to understand how the genetic background affects disease susceptibility and possibly determine environmental factors that contribute to such susceptibility, attention has been focused in recent years on the role of the human microbiome. The human microbiome project was established by the National Institutes of Health in order to identify the microbial composition in different body regions  , 69, 95.Under physiologic conditions, commensal homeostasis is maintained via cross-regulation between the host and the resident microbiota , 61, 113Commensal bacteria help maintain a symbiotic relationship often with host cells via epigenetic modifications of host genes. For example, the intestinal microbiome can directly impact the intestinal epithelial cells (IECs), which line the large intestine lumen, through epigenetic changes in toll-like receptors  in order to prevent the triggering of an excessive inflammatory reaction . IECs seIn recent years, the pathogenesis of diabetes mellitus, inflammatory bowel syndrome (IBS), atherosclerosis, obesity, liver disease, and cancer have been associated with a disbalance of commensal microbiota homeostasis , 113. ThDysbiosis can induce or exacerbate disease via toxic effects from direct invasion/infection or via epigenetic changes to host cells. At the cellular level, commensal microbiome-induced epigenetic changes commonly occur via either histone acetylation/deacetylation or DNA methylation .Histone acetylation usually promotes active gene transcription while deacetylation represses gene expression. Bacteria can regulate histone acetyl modifications via production of short chain fatty acids (SCFAs) , which are transported into the cell via monocarboxylate transporters. There they are metabolized and can function as substrates for acetylases or as inhibitors of histone deacetylases (HDAC) . AcetateSCFAs and other bacterial metabolic products  can also cause DNA methylation. For example, SCFAs have been reported to correct aberrant expressions of adiponectin and resistin in high-fat diet-induced obesity by promoter methylation .Epigenetic changes caused by bacterial metabolites may occur at sites remote from the site that the bacteria are actually present. For example, folate produced by Bifidobacterium species in the gut can enter the circulation and serve as a co-factor of DNA methyltransferases in many tissues around the body. Epigenetic changes, however, can also be caused by the microbiome indirectly through modulation of the immune or neural systems. SCFAs affect dendritic cells and macrophages for example, inducing IL-10 and retinoic acid which are known to have inhibitory actions on histone deacetylase activity  while thSimilarly, commensal bacteria can cause secondary epigenetic changes by affecting neural activity. It is known that the gastrointestinal microbiota can influence cognitive function and behavior by direct reprogramming of the hypothalamus pituitary adrenal (HPA) axis . Such chThe eye is an immune privileged organ with little direct contact (except on its surface) with bacteria, fungi or viruses.The eye is part of the CNS and thus understanding the underlying relationships and mechanisms in this organ can provide insights into the role of microbiome in other CNS pathologies.The current review focuses on the eye for two reasons:We summarize evidence that links a number of important ocular pathologies with the microbiome, discuss possible mechanisms, and articulate some of the topics that need further exploration.Anatomically, the eye Fig.  is comprAs with the rest of CNS, the eye is immune privileged. The blood-retinal barrier (BRB) restricts free access of immune cells, microorganisms, and some molecules into the retina and is composed of the non-fenestrated capillaries of retinal circulation and the tight junctions between retinal pigment epithelial cells . SimilarThe presence of lymphatics in the eye is controversial. Until recently, it was believed that there is no lymphatic outflow from the eye. However, recent research using lymphatic endothelium markers, combined with intracameral tracer injections, led to the discovery of lymphatic vessels in the corneal limbus and the ciliary body and choroid of the human eye . The funPseudomonas, Corynebacterium, Acinetobacter, Staphylococci, Streptococcus, Streptophyta, Methylobacterium, Bradyrhizobium, Propionibacterium, Brevundimonas, Aquabacterium, and Sphyngomonas) comprise 96% of the ocular microbiome ). species . EAU mic species . Raising species . Further species , 80). Thial load . While aial load . The useial load ; Phoebe ial load , 80). AnIn the R161H spontaneous uveitis mouse model, mice express a transgenic T cell receptor targeting IRBP (J ). This tAlthough, it is difficult to discern the original trigger for uveitis, based on the data presented, it appears that disease progression may be linked to intestinal permeability and intestinal microbiome dysbiosis  through At a molecular level, recent studies have suggested that disease development in the EAU model is mediated through epigenetic changes. Tbx21 and Rorc are master transcription factors for differentiation of helper and regulatory T cells; therefore, dynamic changes in their expression would lead to alterations in the levels of these immune cells , 60. HypDespite the studies cited above, our current understanding of the disease process remains incomplete. For example, it is unclear how primed T cells in the gut cause inflammation in the eye, which is normally immunologically privileged . In addiAge-related macular degeneration (AMD) is a progressive degenerative disorder leading to the loss of central vision as the disease preferentially affects the macular region of the retina that subserves central vision. Approximately 30–50 million individuals are affected with AMD globally with an estimated prevalence of 300 million by 2040 . AMD is The disease is categorized into dry or wet (neovascular) forms Fig. . Dry AMDIn wet AMD, there is choroidal neovascularization which can cause subretinal and/or intra-retinal fluid accumulation, hemorrhage, and lipid exudates all leading to RPE detachment and RPE and photoreceptor cell death , 107. ThThe proliferation of aberrant vessels in wet AMD has been linked to an enhanced immune and vascular  response . The patComplement polymorphisms have been genetically linked to AMD , 114. A megaterium) were discovered in some drusen of patients with AMD [In individuals not possessing high-risk complement polymorphic variants, it is hypothesized that AMD pathogenesis involves complement overactivation in response to stimuli at the retina and choriocapillaris. Potential triggers for the complement pathway include microbial colonizers. Bacteria  are capable of enhancing the immune response to drusen deposition at Bruch’s membrane [A link between pharyngeal microbiome dysbiosis and AMD development has also been reported . Pathogemembrane . AlthougRuminococcus torques, and Eubacterium ventriosum species, while controls have an enrichment in Bacteroides eggerthii species [Streptococcus and Gemella species along with reduced levels of Prevotella and Leptotrichia species, when compared to controls. These microbiome changes became more evident with increasing disease severity. There is speculation that intestinal microbial populations could potentially serve as a trigger for drusen formation or progression [Known environmental risk factors associated with the development of AMD include aging, smoking, dietary intake, hypertension, and atherosclerosis. Diet is one of the modifiable risk factors for AMD. For example, following current dietary recommendations from the Age-Related Eye Disease Studies (AREDS and AREDS2) can reduce disease progression from dry to wet AMD for some patient groups . As diet species . It is i species . It was gression .Gut microbiome dysbiosis is often linked to chronic inflammation and enhanced intestinal permeability, thus allowing bacterial products and pathogen-associated molecular patterns (PAMPS) to enter the circulation and interact with downstream pattern recognition receptors (PRRs), such as Toll-like receptors (TLR), to activate the innate immune response. Ocular cells, such as microglia, macrophages, and RPE cells, express PRRs and can thus become induced to an inflammatory state .Alterations to the intestinal microbiome have also been shown to cause exacerbations of choroidal neovascularization in animal models. Experiments in mice were used to test the association between diet, obesity, microbiome alterations, and choroidal neovascularization. Mice fed either a regular diet or high-fat diet underwent laser-induced choroidal neovascularization as a model of AMD. Compared to regular diet fed controls, high-fat diet mice had a significant increase in weight associated with a 60% increase in the development of choroidal neovascularization . An inveThus far, the microbiome has been linked to retinal changes at the tissue level that are potentially related to AMD pathogenesis. Research on a connection between the microbiome and intracellular modifications in AMD is currently lacking. Epigenetic events associated with AMD include post-translational modifications in the form of DNA methylation and histone acetylation in the retina , 37, 87.Glaucoma is a group of diseases characterized by progressive irreversible optic neuropathy, with retinal ganglion cell (RGC) axon and subsequent cell body degeneration, that results initially in peripheral visual field loss and can eventually lead to blindness . More thMYOC, CYP1BI, FOXC1, PITX2, PAX6, and OPTN genes have been associated with early onset glaucoma and appear to be causative although they have variable penetrance [Other risk factors that contribute to OAG development include age, systemic diseases such as hypertension or hypotension, hyperlipidemia, diabetes, obstructive sleep apnea, thyroid disease, and genetic mutations . Mnetrance , 21.Helicobacter pylori infections was detected in glaucoma patients when compared to non-glaucomatous controls [H. pylori causes the release of various inflammatory factors, such as cytokines, ureases, and the neutrophil-activating protein VacA [H. pylori eradication improves IOP control in addition to improved visual performance [A potential link between glaucomatous optic neuropathy and microorganisms has become a recent topic of investigation. A higher rate of gastric controls , 57. HP controls . Severalein VacA . These, ein VacA , 58, 82.Streptococci) and worse oral health (fewer teeth) in patients with glaucoma compared to controls [Other investigations into a possible relationship between microbiota and glaucoma detected a higher quantity of oral bacterial organisms  was administered in the hind foot pad in two separate glaucoma mouse models: the microbead induced-IOP elevation model and the spontaneous DBA/2J model . This pa+ T cell infiltration following their activation by commensal microflora [+ T cells into the retina. These T cells, which target bacterial heat shock proteins (HSP’s), cross react with human HSP’s leading to the development of optic nerve neurodegeneration that can persist despite IOP normalization  autoantibodies such as HSP-27 antibody level and decreased antibody reactivity of α-enolase (a member of heat shock protein family) in glaucomatous human and animal tissues . Furthercroflora . Experimation (H ).At the molecular level, a number of epigenetic changes have been identified in association with glaucomatous optic nerve damage. These include abnormal histone acetylation/deacetylation in retinal ganglion cells (RGCs) that may be related to RGCs damage in glaucoma. For instance, histone deacetylase 2 and 3 expression were found to be significantly upregulated and histone H4 acetylase was found to be downregulated in RGCs . This abThus, broadly speaking, inflammation caused by microbial dysbiosis can potentially lead to microglial activation within the retina and optic nerve via the following pathways: (1) direct (live) bacterial dissemination to the optic nerve and/or retina, (2) bacterial product dissemination to the optic nerve and/or retina, (3) effects secondary to changes in the vascular system, and (4) effects secondary to changes in the systemic immune system.where to look: Understanding which microbiome is important to individual pathologies. Data from association studies provide some initial clues, but often dysbiosis in a specific microbiome is associated with changes at other microbiome sites.Knowing when to look: Understanding the temporal relationship between changes in a specific microbiome and development or exacerbation of disease. Cross-sectional studies are not ideal for detecting such temporal relationships. Many of the diseases in question develop over a period of months to years. The development of biomarkers that will measure long-term or past changes in the microbiome are sorely needed.Knowing what to look for: Understanding whether specific bacteria/viruses/fungi are linked to pathology or whether a mere shift in the normal populations is more important. Association studies can provide clues for hypothesis generation but these need to be tested in well-controlled prospective studies.Knowing The role of the microbiome in modulating human disease is slowly beginning to emerge. However, a number of critical barriers exist that hinder our ability to prove its role. These include:Furthermore, disease heterogeneity, as well as, local and temporal variations of the microbiome often caused by environmental conditions  compound the difficulty in establishing causal relationships.Once an unequivocal relationship is established, understanding the mechanisms involved would become more straightforward although this task is by no means trivial. Use of animal models may be flawed because of different physiology. At the same time, in vitro studies often lack the complexity necessary to evaluate the interaction of multiple organ systems on the generation of pathology.Finally, even when a causative link between the microbiome and an eye disease is confirmed, it will still take much work to develop rational interventions. Our knowledge of how to specifically affect microbial populations is limited at this time. Tools at our disposal (such as antibiotics or probiotics) are rather crude and often have significant side-effects. Improving our understanding of the interactions between individual members of the microbiome, and between them and the host will be critical in devising strategies to mitigate microbiome effects on disease development or progression. It is encouraging that research is rapidly expanding in all of the above areas but there is still a lot to be learned.


Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities. Absence seizures are sudden, relatively brief lapses of consciousness associated with lack of voluntary movements and distinctive electrographic spike-wave discharges (SWD) at 2.5–4 Hz  Panayio highlighHere, we discuss novel insights on absence seizure initiation, ictogenesis, comorbidity and therapy that have originated both from non-invasive human studies and invasive investigations in animal models. Points of controversy and crucial gaps in knowledge will be highlighted raising questions that should contribute to improve current clinical practice and to focus future clinical and experimental research. The emphasis will mainly be on absence seizure of childhood absence epilepsy (CAE)  and on animal models with an absence seizure-only phenotype, as in these children and model systems the epileptogenesis and ictogenesis of absence seizures are not compromised or modulated by the concomitant presence of other types of seizures. Nevertheless, many of the findings, key issues and conclusions raised and discussed in this review do apply to absence seizures that are present in other epilepsies  functional MRI studies have been critical in identifying key regions involved in human absence seizures . NotablyWhereas the above functional MRI studies investigated changes in BOLD amplitude, a recent study has analysed the phase-synchrony of BOLD signals in people with generalized SWD, including a small CAE cohort . Then, fThe existence of altered resting state functional connectivity that may underlie some of the inter-ictal behavioural impairments is supported by the correlation between decreased medial frontal cortex activation during a cognitive task and impaired task performance in CAE    selectively in layer 6 pyramidal neurons  are crucial for SWD generalization. Many studies in young and adult cohorts with absence seizures indicate the critical involvement of the thalamus in the expression of these seizures , may be 2+ channels (T-channels) at each paroxysmal cycle of a SWD form the rhythmogenic network mechanism of absence seizures  neurons through their bursts of action potentials mediated by T-type Caseizures   are not essential for spontaneous absence seizures in GAERS rats whereas those of the CIN  and NRT (i.e Cav3.2 and Cav3.3) are  are .v3.2 subtype of T-channels reported in some children with absence seizures (v3.2 (C456S) mutant channels in the barrel cortex of normal mice does elicit absence seizures   McCaffe  ethosuximide-sensitive absence seizures  in these two absence seizure models   tIn summary, solid experimental and clinical evidence strongly suggest that, in contrast to the classical view that absence seizures are driven by increased excitation and/or decreased inhibition in all brain regions involved in the paroxysmal activity, the ictogenic thalamic mechanism of absence seizure is uniquely shaped by the enhanced GABAergic inhibition of thalamocortical neurons that derives both from intra-thalamic (NRT), and extra-thalamic (SNr) sources. Whether other sources of thalamic GABAergic inhibition  (≥10 years) outcomes (i.e. seizure- and medication-free) in children initially treated with ethosuximide  than with valproic acid   in contrast to prevailing views ‘appropriately chosen and used antiepileptic drugs’ (the ILAE criterion for drug-resistant epilepsy)  smaller grey matter volume of brain regions involved in attention  . HoweverPsychiatric comorbid conditions, in particular attention deficits, may precede the first absence seizure and the epilepsy diagnosis . WhereasAbsence seizure models do show psychiatric comorbidities, providing additional validity to these models and a means for future mechanistic studies into these conditions. Subtle alterations in attention, that may be task-specific, have been reported in GAERS (Chronic (19 weeks) and acute administration of ethosuximide mitigate the anxiety-like phenotype in GAERS a, it worHowever, the interpretation of many of these studies on comorbidity in absence seizure models is compromised by several issues. First, the majority of these investigations did not record the EEG during the behavioural tests, making it impossible to ascertain how the observed changes in behaviour are linked to ictal and interictal periods. Second, in studies using inbred absence seizure models, a comparison with normal animals as well as inbred non-epileptic control strains would be essential to control for potential effects of long-term inbreeding of the non-epileptic strain , persist even after seizures are pharmacologically controlled  and are v1.1, Nav1.6 and HCN1 in WAG/Rij rats  demand urgent action on novel treatments. Naturally, the best therapy for any epilepsy is one that would block epileptogenesis, i.e. has a disease-modifying effect. As far as current anti-absence drugs are concerned, some limited evidence in children suggests that early, effective treatment with ethosuximide has positive long-term (≥10 years) outcomes, i.e. seizure- and medication-free , an oral form of cannabidiol, a phytocannabinoid devoid of psychotropic actions . This is2+ channels of cortical and NRT neurons are key to absence seizure expression  neurons from CIN neuronal ensembles in non-anaesthetized animal models coupled with a systematic investigation of subthreshold oscillations and passive and active membrane properties of the various neuronal populations in CIN slices. Some patchy experimental evidence does exist but was obtained in cortical areas other than the CIN or under anaesthetic conditions  than nonseizures  and theiThe mechanism underlying the termination of absence seizures has not been directly investigated. Changes in Granger causality values among the activity of cortical and subcortical regions  and SWD of absence seizure  whereas rization  coupled Finally, the slowing of the rhythmic activity in both excitatory and inhibitory neurons towards the end of partial  seizures has been suggested to involve a progressive increase in synchrony among participating neurons and to play a role in seizure termination . As a slCACNA1H polymorphism (P640L) is more commonly expressed in children non-responding to ethosuximide monotherapy  a more negative treatment outcome, independently of the initial treatment , occurs for absence seizure without face/limb motor automatisms (A major future research task relates to the inability of current therapies to effectively control absence seizure comorbidities since we have no indication as to whether absence seizures and comorbidities share initial common genetic and mechanistic pathways that once fully developed become independent from each other (The large incidence of neuropsychiatric comorbidities and the marked increase in attention deficits observed with valproic acid treatment in CAE (


Neurodegenerative diseases are characterized by irreversible cell damage, loss of neuronal cells and limited regeneration potential of the adult nervous system. Pluripotent stem cells are capable of differentiating into the multitude of cell types that compose the central and peripheral nervous systems and so have become the major focus of cell replacement therapies for the treatment of neurological disorders. Human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC)-derived cells have both been extensively studied as cell therapies in a wide range of neurodegenerative disease models in rodents and non-human primates, including Parkinson’s disease, stroke, epilepsy, spinal cord injury, Alzheimer’s disease, multiple sclerosis and pain. In this review, we discuss the latest progress made with stem cell therapies targeting these pathologies. We also evaluate the challenges in clinical application of human pluripotent stem cell (hPSC)-based therapies including risk of oncogenesis and tumor formation, immune rejection and difficulty in regeneration of the heterogeneous cell types composing the central nervous system.  Stem cell biology is indisputably a fast-moving field of research and over the past few years human pluripotent stem cells (hPSC)-based therapies have progressed into early clinical trials, with several patients now receiving hPSC-derived cells. Transplantations of retinal pigmented epithelium (RPE) derived from human embryonic stem cells (hESC) ,2,3 and Over the past few decades, stem cell therapies have advanced further towards the clinic to treat damaged tissues and various degenerative diseases, especially those affecting the nervous system. Neurodegenerative diseases are frequently characterized by the irreversible functional impairment and/or loss of cells and limited regeneration of the adult nervous system. Cell replacement, therefore, represents a critical strategy for the effective treatment of neurodegenerative diseases. HPSC can be differentiated into many kinds of neuronal cells, from neural progenitors to specialized mature neurons, astrocytes or oligodendrocytes. All have great potential in treating neuropathies such as PD, multiple sclerosis (MS) or spinal cord injury (SCI). Recently, two studies have reported oncogenic mutations in hiPSC  and hESCParkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons (DANs) within the substantia nigra, subsequently causing bradykinesia, tremor and other debilitating symptoms such as cognitive decline. Therapies that increase dopamine (DA) level in the brain, including the DA precursor L-DOPA (levodopa), and deep brain stimulation are currently the gold standard treatment for PD . AdminisWhilst human fetal material has long been explored for Parkinson’s disease, human embryos are not a viable source of material for cell therapy. Various human stem cell derivatives, the most common being neural stem cells (NSCs) or neural progenitor cells (NPCs) and DANs, have already shown an improvement in symptoms following cell transplantation in rodent and primate PD models , Table 1A pioneering study used a co-culture system of telomerase-immortalized human fetal midbrain astrocytes with hESC to achieve high-efficiency dopaminergic neurogenesis in hESC. This highly enriched DANs population provided significant functional benefit when transplanted into the striatum of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD . While tProlonged maturation of hESC-DANs in vitro prior to transplantation was showed to reduce the risk of tumor formation without affecting their function and efficacy in a primate model of PD . More efAutologous human induced pluripotent stem cells (hiPSCs) cells potentially represent a more tolerable cell transplantation option than hESC and have attracted significant interest ,20,21,23In addition to rodent models, non-human primate (NHP) models of PD have been used to test hiPSC-based therapy. Following bilateral transplantation of hiPSC-derived NPCs into the putamen of MPTP -treated cynomolgus monkey, cells survived for six months and differentiated into DANs. A single parkinsonian monkey was transplanted and behaviorally assessed for skilled reaching. Results showed a slight functional improvement . A subseTogether, these studies build on evidence that an hPSC-based therapy has considerable potential for reversing motor defects of PD patients. The replacement of DANs from the substantia nigra by hPSC-DANs restores the deficit of dopamine release, subsequently stimulating the medium spiny neurons of the striatum and alleviating PD disabilities that include bradykinesia, resting tremor and muscle rigidity. Cell replacement therapy also could reduce the side effects of medication such as dyskinesia (uncontrolled involuntary movements) resulting from the long-term use of Levodopa. A major limitation of such treatment however is its sole focus on motor symptoms, which comprise only part of PD pathology. It remains unclear whether any of these treatments will have an impact on the non-motor symptoms of PD including mood disorders, such as depression, and cognitive decline.Despite stroke being a significant cause of disability in adults , outsideDue to the heterogeneity of cells lost in stroke, several different cell types have been used for transplantation therapies . It remaLong-term self-renewing neuro-epithelial-like stem (lt-NES) cells are multipotent progenitors that can give rise to glia and neurons and are most similar to the early neuroepithelium of the developing embryo. Lt-NES cells can be derived from human iPSC or ESC . In contAs an alternative strategy, hiPSC-derived NPCs have been transplanted into stroke-damaged rodents and shown to be equally as effective in promoting functional recovery. Neuro-progenitor cells differ from IT-NES by their more limited capacity to proliferate, although they retain multipotency. This characteristic may help to mitigate the problem of graft overgrowth observed with It-NES and a number of studies have claimed significant success with this strategy in both mice and rats. NPCs  transplanted into the striatum of ischemic mice survive, migrate and are associated with an improvement of modified neurological severity score (mNSS) for up to six weeks post-transplantation. The functional recovery observed in the transplanted group could be explained by neural circuit reconstitution . SimilarTo date, only one study involving the use of hiPSC has been carried out in a non-rodent stroke model. HiPSC-NSCs were transplanted into the brain parenchyma surrounding MRI-identified lesions of an ischemic pig stroke model and were shown to survive long-term, differentiate to neurons and oligodendrocytes and improve tissue recovery in the damaged brain. Metabolic effects were recorded post-transplantation, such as reduced changes in white matter integrity, enhanced cerebral blood perfusion and recovery of brain metabolism in the damaged tissue. HiPSC-NSC post-stroke transplantation also lead to neuronal protection and reduced microglial activation. However, no confirmation of functional recovery was assessed in this study .A limitation of the field is that only short-term studies have been carried out to date. Longer-term functional follow-ups are necessary to provide evidence of therapeutic efficacy. Stroke is also a difficult disease to model as the pathology depends on the brain regions affected. From these studies it remains unclear whether functional recovery could be attained in all brain regions and the extent to which the degree of neuropathology alters the results. Epilepsy is a common neurological disorder which manifests by an excessive, rhythmic  and abnormal brain activity causing spontaneous recurrent seizures, unusual behavior or sensations and loss of consciousness. Dysfunction of GABAergic inhibitory interneurons plays a major role in the pathological hyper-excitability underlying epilepsy, owing to their responsibility for dampening neuronal activity and promoting network inhibition. Inflammation also has a significant role in epilepsy. However, there is an active debate as to whether inflammation is the cause or consequence of epilepsy ,60. AlthHESCs can be differentiated into medial ganglionic eminence (MGE) cells, precursors of GABAergic interneurons (GINs). Significant cognitive improvement was observed after transplantation of hESC-MGE progenitors into the hippocampus of a pilocarpine-induced temporal lobe epilepsy (TLE) mouse model. Grafted hESC-MGE progenitor cells differentiated into active GABAergic neurons with mature firing patterns, showing their integration into the host hippocampal circuitry and suggesting a synaptic mode of action ,35. AlteIn one of the studies, transplanted cells were also functionally effective at reducing seizure activity for up to four months post-transplantation, which was directly attributed to transplant-derived inhibitory currents passed onto endogenous hippocampal neurons . HoweverLearning and memory are complex cognitive processes involving hippocampal function that are severely affected by aging and some neurodegenerative disorders such as Alzheimer’s disease (AD). AD is the most common age-related form of dementia and is clinically characterized by a progressive loss of cholinergic neurons and synapses, deposition of neurotoxic proteins such as extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) . While AOver the last decade, numerous preclinical stem cell therapies have been attempted to replace lost neurons or support existing neurons in animal models of AD. NSCs derived from mouse adult brain or ESC were transplanted into AD rodent models and resulted in generation of cholinergic neurons, increased synaptic strength and enhancement of memory performance ,66,67. IYAC128 HD mice [Accumulating evidence suggests that stem cells transplantation influences the pathological features of AD through multiple modes of action. Similar to stroke, the therapeutic potential can be partly attributed to a paracrine effect of neurotrophic factors (in this case BDNF and GDNF) that ameliorate various cellular functions in animal models of AD, including neural integrity, endogenous neurogenesis, microglial activity, angiogenesis, mitochondrial function, autophagy and apoptosis ,70 toget HD mice ,72. Tran HD mice , the mosNeprilysin-2 (NEP2), a secretable protease with Aβ-degrading activity. HiPSC-ML/NEP2 were injected into the hippocampus of the 5XFAD transgenic AD mice [While most NPC/NSC and BFCN transplantations were successful at improving cognitive dysfunction in AD animal models, they failed to reduce the level of Aβ plaques in the AD brain. Following a different strategy, hiPSC-derived macrophage-like (ML) cells were generated and engineered to express  AD mice ,73. AlthMultiple Sclerosis (MS) is a chronic demyelinating disease that affects the CNS. Current therapies are primarily directed against the immune system to treat the inflammatory component of the disorder. However, the real challenge is to develop re-myelinating and neuro-protective therapies. To establish a potential source of myelinogenic oligodendrocytes for the treatment of MS, several protocols were developed to generate oligodendrocyte precursors cells (OPCs) from hiPSC ,74,75. HSpinal cord injury (SCI) often results in catastrophic neurological deficits which dramatically diminish the quality of life of affected individuals. Surgery  and rehabilitation are the only interventions commonly used to improve functional recovery after SCI. The corticosteroid methylprednisolone is the only pharmacotherapy currently approved and has been used to reduce inflammation in the spinal cord (SC) acutely after injury. However, it has limited efficacy and serious side-effects, such as gastrointestinal hemorrhage and respiratory bacterial infection, and this medication is no longer routinely provided . DespiteCentral to the pathology of SCI is a major insult to the nervous system. A trauma of the spinal cord can cause acute damage to ascending and descending tracts and lead to axotomy (severing of axons). Immediately after primary injury, a robust neuro-inflammatory response occurs and triggers the secondary injury mechanisms in the chronic phases of SCI, leading to cell death and further tissue degeneration . Around the site of the injury, the formation of a cyst and a growth inhibitory scar  will prevent tissue regeneration . For theHuman iPSC-derived neurospheres were transplanted into a mouse model of contusive SCI at the T10 level . The celNotch activation induced by injury in the SC has been shown to orient transplanted hiPSC-NPCs towards astrocyte lineage and reduce their therapeutic efficiency [HiPSC-NPCs have also been transplanted into an immuno-competent mouse model of SCI but showed very limited survival, no reduction of the size of the lesion and no functional recovery . In contficiency . RemarkaHiPSC-NSCs have also been trialed as cell therapy in a marmoset model of SCI. Injury was induced at the C5 level of the spinal cord and behavioral analyses were performed for up to 12 weeks afterwards. Functional recovery was observed in motor parameters such as open field, bar grip and cage climbing tests. However, although transplanted cells were found to differentiate into all three lineages , approximately one quarter of the cells remained immature. Despite this limitation, no tumorigenicity was observed in the limited time frame of the study . Longer Because re-myelination of axons is an essential component of the recovery, others have evaluated the therapeutic potential of OPCs, derived from hESC or hiPSC, for the restoration of neuronal pathways after moderate contusive SCI in rats. In both cases, most cells differentiated to mature oligodendrocytes expressing Myelin Basic Protein (MBP) and integrated in the host spinal cord. Transplanted 2 h after injury, hESC-OPCs lead to an improvement of somatosensory evoked potential (SSEPs) recorded at the cortex showing functional improvement of sensory pathways . TransplLastly, some investigations have focused on other pathological aspects of SCI, which include neurogenic bladder disorders and neuropathic pain. A shared hallmark of both conditions is the loss of GABAergic inhibitory tone in the injured spinal cord ,82. HESCDespite all preclinical studies performed in rodents to establish an hPSC-based approach for spinal regenerative medicine, clinical trials using hPSC to target SCI have not been fully conducted. The Food and Drug Administration (FDA) approved the first clinical trial in the US for the use of hESC-derived oligodendrocytes to treat SCI. Geron Corporation started the trial on 4 patients in 2010 but it was later closed for business reasons. Asterias Biotherapeutics re-initiated a Phase 1/2a Dose Escalation Study with 25 patients in 2015 but, to date, no results have been reported . Chronic neuropathic pain can be classified as a neurodegenerative disease ,84 that Neuropathic pain is currently treated with non-specific management strategies such as anti-epileptics, antidepressants and, in some cases, opioids. However, these treatments are known to have poor efficiency, produce undesirable side effects and/or long term addiction ,89. CellThe challenges in the clinical application of hPSC transplantation for the treatment of neurodegenerative diseases or conditions fall broadly into two categories: issues with hPSC transplantation generally (including hPSC generation and differentiation), and those specific to the regeneration of the central nervous system .Pluripotent stem cells have the unlimited capability to self-renew and differentiate into virtually all cell types of the body. These attributes make them an attractive candidate for cell replacement therapies and hPSC hold much hope for regenerative medicine. However, when transplanted in vivo undifferentiated hPSC form teratomas and the risk of tumor formation has largely restricted the clinical application of hPSC. c-MYC has been identified as the major oncogenic effector of Wnt/β-catenin signaling in hESC tumorigenicity [OCT4 is involved in the development of multiple cancers, such as ovarian [OCT4 expression correlates with worse cancer outcome in most tumors [OCT4 is not the only important pluripotency factor. It forms a complex with other TFs such as SOX2 and NANOG to regulate the expression of different genes and maintain ESCs in an undifferentiated state. NANOG also plays a role in the self-renewal of CD24+ cancer stem cells in hepatocellular carcinomas [SOX2 has been shown to be expressed in at least 25 different types of cancer and to drive cancer cell survival [KLF-4 (Krüppel-like factor 4), has been reported to promote DNA repair checkpoint uncoupling and cellular proliferation in breast cancer by p53 suppression [KLF4 also acts as an oncogene in Glioblastoma by supporting glioblastoma stem cells survival and promoting their proliferation [p53 [Rb (retinoblastoma tumor suppressor protein) inactivation regulating their cell cycle [p53 mutations by both hiPSCs and hESCs in prolonged culture, similar to the ones observed in human cancer [Pluripotent stem cells share a number of characteristics with cancer cells. Both fundamentally possess an indefinite capacity to proliferate, the ability to bypass DNA repair checkpoints ,93 and egenicity . Many of ovarian ,103, cer ovarian , colorec ovarian ,106, liv ovarian , and ora ovarian . Generalt tumors , while it tumors . OCT4 isrcinomas  and has rcinomas ,113. SOXsurvival . Anotherpression . KLF4 alferation . Pluripoferation , loss ofion [p53 ,119 and ll cycle . Furtherll cycle . An impoAfter hPSC differentiation, residual undifferentiated or partially differentiated cells may remain and induce tumor formation when implanted into animal models. In the case of neurodegenerative diseases, the risk is not only the development of teratomas from undifferentiated hiPSC/hESC but also undifferentiated neural tumors, whether primitive neuroectodermal tumors or gliomas, from partially differentiated neuronal cells. Persistent proliferation and tumorigenic masses were observed after transplantation of hPSC neuronal derivatives in rodent models of PD ,21, epilIn an effort to overcome this issue, several strategies have been explored for the development of safer stem cell therapies. Prolonged maturation of hPSC-DANs in vitro prior to implantation has been shown to reduce graft overgrowth and tumor formation in primate model of PD brain . HoweverSuicide genes have also been employed for the elimination of undifferentiated and potentially tumorigenic cells. Herpes simplex virus thymidine kinase (HSV-TK) is the most commonly used suicide gene in hESC/hiPSC and has proven efficient in eliminating tumor formation after transplantation ,129,130.All these approaches provide a safeguard for clinical use of hPSC-cell therapies. However, because most of hPSC transplantation studies are performed in immune-deficient animals or in presence of immune-suppressive drugs, the real risk of tumor formation in immune-competent hosts is mostly unknown. Recently, using multiple models of humanized mice it has been suggested that autologous hPSC-derived therapies are unlikely to form teratomas in the presence of natural killer (NK) cells . Despite their obvious advantage, using hiPSC in regenerative medicine implies additional risks. Genome-wide studies have unveiled numbers of large and point mutations in hiPSC, leading to serious doubts regarding their safety and potential clinical applications ,139. It Reprogramming adult somatic cells to a state of pluripotency requires their exposure to multiple reprograming factors  which are critical for both the acquisition and maintenance of induced pluripotency but can promote oncogenic transformation as previously discussed. The process of reprogramming itself also induces genomic alterations. Single nucleotide variations (SNVs) sometimes occur in the coding region of a gene, resulting in the expression of a mutated protein that can lose or gain function and become potentially harmful. Copy-number variations (CNVs), involving the duplication or deletion of a large portion of DNA, can also be generated by reprogramming, causing potentially dangerous mutations in different genes . FurtherTo acquire pluripotency, a somatic cell needs to be reprogrammed from a differentiated state into a permissive state similar to the early embryo. During this process of reprogramming, the genome may permanently be altered through aberrant imprinting, activation of endogenous retroviruses , and incIPSC derived by reprogramming show DNA methylation signatures similar to their somatic tissue of origin, which promote their differentiation into lineages related to the donor cell and restrict their participation to other cell fates ,153,154.A crucial step toward successful clinical application of hPSC is to overcome the immune response that may be evoked by their transplantation. Since their groundbreaking discovery by Shinya Yamanaka in 2006, iPSC have revolutionized regenerative medicine. In addition to avoiding the ethical concerns linked to the destruction of human embryos, the main advantage of hiPSC over hESC is that they can be derived directly from the patients themselves and be used for autologous cell replacement therapy. Unlike an allogenic graft using hESC, autologous transplantation with hiPSC would, in theory, elicit negligible immune response, eliminating the risk of graft rejection.IPSC immunogenicity was not initially questioned as it seemed obvious that the reprogrammed iPSC carried the same markers of immunogenicity that they expressed in their original somatic state. Zhao et al., 2011 were the first to investigate the matter by testing the immunological reactions triggered by auto-graft of undifferentiated mouse and human iPSC in syngenic or humanized mice respectively ,161. AltHowever, many studies have since counterbalanced this initial observation. Immunogenicity of endothelial, hepatocyte and neuronal cells derived from ESC and iPSC was tested by assessing cytotoxic T lymphocyte response in vitro and in vivo after transplantation in syngeneic mice. No immune response to syngeneic iPSC was observed . SimilarSeveral mechanisms such as epigenetic and genetic instability in hiPSC could explain immune responses in transplant recipients even when differentiated cells are transplanted. A host immune response (T-cell infiltration) to hiPSC appears to be dependent on the antigenic profile of the transplant. Misexpression of immunogenic antigens, Zg16 and Hormad1, was found in hiPSC-derived SMCs, but not in hiPSC-derived RPEs, and potentially explains the disparity in immunogenicity of these two hiPSC derivatives after transplantation in humanized mice . First, Many practical concerns arise with autologous transplantation. Autologous hiPSC-cell therapies are labour-intensive and a highly time-consuming process. The time pressure often associated with treating conditions such as severe SCI or stroke is incompatible with the time required to perform personalized stem cell work . Early neuronal transplantation following SCI is indeed very beneficial as it can potentially avoid secondary injury and enhances recovery ,49. The In contrast to hiPSC, an allogenic graft using hESC would incontestably require some form of pharmacological immunosuppression to avoid rejection by the recipient’s immune system. Long term immunosuppression comes with risks of infections and cancer and may lead to serious complications such as cardiovascular diseases . The higDRB1 haplotypes, 10, 75, and 140 HLA-homozygous iPSC lines would match approximately 50%, 80%, and 90% of the Korean/Japanese population, respectively [In organ transplantation, matching HLA-A, -B, and -DR, improves the graft survival rates  and coulectively ,171. Thiectively . Allele-ectively . MHC matectively . This idectively . Similarectively .Beta-2Microglobulin (B2M) gene eliminates surface expression of all HLA class Ia and b molecules and prevent the cells from being recognized as allogeneic by CD8+ T cells. However, B2M KO hPSC become vulnerable to NK cell-mediated rejection through missing-self response. Forced expression of minimally polymorphic HLA-E is one way to confer resistance to NK cells when HLA I is removed [+ T cell-mediated cytotoxicity without losing the HLA class Ib  protective function against NK cells mediated lysis [PDL1 and CD47 also confers an additional advantage by protecting cells from T cell rejection and preventing macrophage engulfment respectively [, unlocking their full potential for regenerative medicine.As an alternative, a number of groups have set out to generate universal stem cells capable of evading any patient’s immune system. These approaches consist of manipulating genes that encode for HLA I and II proteins ,178,179. removed . Individed lysis ,179. Oveectively ,179. EngIn humans, or in mammals in general, the adult CNS has a limited regenerative capacity and is unable to fully restore its function after injury. Consequently, CNS trauma generally results in severe and persistent functional deficits which drastically reduce quality of life. This regeneration failure is mainly due to the very limited number of neural stem cells that the CNS retains into adulthood, which prevents the replacement of lost neurons, and to its low capacity to repair damaged neurons. Human brains, in particular, are controversially reported to have limited or no adult de novo neurogenesis ,182,183.The non-permissive nature of the CNS environment for axonal regeneration is largely attributable to non-neuronal components of the CNS , in partLesions in the CNS cause changes in the microenvironment directly surrounding the site of the injury. Myelin, a lipid-rich substance normally insulating the axons, becomes severely damaged and leaves the axons exposed and vulnerable to myelin-derived inhibitory molecules such as Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). Nogo-A is considered to be the major inhibitor of axonal regeneration and is thought to launch a signaling cascade which induces cytoskeletal changes and destabilization in the growth cones . Its expAnother critical component of the limited regenerative potential of the adult CNS is neuro-inflammation. In addition to severed axons, trauma to the spinal cord causes blood-spinal cord barrier disruption, which in turn causes localized neuronal death. This induces further oxidative stress and glutamate release causing excitotoxic death of neighboring neurons and glia. Shortly after the injury, resident microglia become reactivated, initiating a robust immune response by secreting various cytokines, and peripheral macrophages are recruited to the lesion site. This inflammatory response may have additional deleterious effect on neuronal regeneration and prevent functional recovery. Depletion of peripheral macrophages  and admiBecause of the importance of the immune component in CNS regeneration, caution is necessary in translating preclinical models of neurodegenerative diseases to human. As discussed previously, functional recovery following transplantation of various hES/hiPS cell-derived neural cell types has been well reported in rodents with SCI, PD, stroke or MS. However, in most cases, transplantations were tested in immune-deficient animals and cannot translate directly to human patients. Interestingly, unlike successful studies performed in immuno-deficient mice, the transplantation of hiPSC-NPCs in immuno-competent SCI mice treated with tacrolimus (an immunosuppressive drug) led to very disappointing results. Behavioral assessment showed failure to improve functional recovery and overall poor long-term survival . WhetherThe glial scar is one of the most established barriers of CNS regeneration. The glial scar has been largely studied in the context of SCI, but also occurs after traumatic brain injury or ischemic stroke and in neurodegenerative diseases such as AD, or in demyelinating and inflammatory pathologies such as MS.As discussed previously, damage to the spinal cord is followed by an acute inflammatory response. Resident microglia are activated, and peripheral immune cells (including macrophages and lymphocytes) enter the lesion site. This inflammatory reaction eventually becomes chronic and at this point, astrocytes proliferate, hypertrophy and overlap to contain the damage and isolate the lesion from the spared tissue, forming a regeneration-inhibiting glial scar. The repressive nature of the glial scar has been largely attributed to a high concentration of ECM (extra-cellular matrix) and inhibitory proteins, including myelin-associated chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes . CPSGs hConversely, a beneficial role of the glial scar has also been described. By preventing resident astrocytes from proliferating after SCI , recovery from spinal cord lesions was reduced. The injured area in the spinal cord expanded, more axons were severed and an increased neuronal death was observed in mice unable to generate glial scars. This study also demonstrated that astrocytes of the glial scar are a major source of neurotrophic factors  required for the survival of neurons adjacent to the lesion after SCI . FurtherOver the past decades, neurodegenerative diseases and nervous system injury have been a major focus of regenerative medicine, with many studies dedicated to developing efficient and clinically relevant hPSC replacement therapies for the treatment of a variety of neurological disorders. However, the clinical feasibility of these therapies requires further assessment. A deeper understanding of differentiation pathways and mechanisms will permit the development of defined cell populations that can be used as more potent therapeutics. Moreover, the increased risk of cancer caused by the use of hiPSCs raised serious reservations regarding the development of autologous cell therapies. Future directions will concentrate on banking clinically safe and universally compatible hPSC to overcome the challenge of immune rejection. Nonetheless, hPSC therapies provide genuine hope for a wide range of currently devastating degenerative diseases, and will eventually change the way we see aging and the associated tissue degeneration by redefining the impossible.


Risk scores are widely used in patients with acute coronary syndrome (ACS) prior to treatment decision-making at different points in time. At initial hospital presentation, risk scores are used to assess the risk for developing major adverse cardiac events (MACE) and can guide clinicians in either discharging the patients at low risk or swiftly admitting and treating the patients at high risk for MACE. During hospital admission, risk assessment is performed to estimate mortality, residual ischemic and bleeding risk to guide further in-hospital management  and post-discharge management . In the months and years following ACS, long term risk can also be assessed to evaluate current treatment strategies . As multiple risk scores have been developed over the last decades, this review summarizes the most relevant risk scores used in ACS patients. Acute coronary syndrome (ACS), including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI), is one of the most frequent reasons for cardiac hospital admission . For eveSince the widely used Framingham risk score was published as a prediction model for incident cardiovascular disease, numerous risk prediction models used in cardiovascular medicine have been developed over the last few decades . Risk moAt different moments in the timeline of ACS, risk scores can be used for risk stratification. At initial presentation, risk scores are used in patients with acute chest pain and possible ACS to, first, identify patients at low risk for major adverse cardiac events (MACE) and second, as a decision rule to swiftly discharge these patients without additional invasive testing. At admission, risk scores are used to estimate the in-hospital or short-term risk of mortality and/or bleeding and to guide further in-hospital management . Individual risk of mortality, myocardial infarction (MI) or bleeding may be re-evaluated before hospital discharge to determine the outpatient treatment strategy. In the months or years following ACS, risk scores are available to calculate ischemic-bleeding trade-off risk for optimal antithrombotic management or to estimate long term risk for future cardiovascular events. Using this ACS timeline, the most relevant risk scores used for patients with ACS will be discussed in this review using general performance metrics, model discrimination and calibration, and if available, results of both internal and external validation studies. An overview of all risk scores and pathways with their components are found in the The initial differentiation between non-ST-segment elevation ACS (NSTE-ACS), i.e., UA and NSTEMI, and other (benign) causes of chest pain is not always clear. Therefore, most practices perform adequate risk assessment based on objective parameters, clinical judgement and risk scores. The risk scores most commonly used for patients with suspected NSTE-ACS are found in The history, electrocardiogram, age, risk factors, troponin (HEART)-score is a simple five-item risk score consisting of variables that were chosen based on clinical experience (“common sense”) and medical literature ,8. The HOther risk scores or decision rules, such as the Emergency Department Assessment of Chest pain Score (EDACS) ,14 or thIn both American and European guidelines, it is advised to use risk scores for the prognosis assessment for early risk stratification, i.e., ischemic and bleeding risk assessment at the start of hospital admission  2,5]. B,5. B2,5]Developed by the TIMI study group in the early 2000s, two separate risk scores were made from two different cohorts, the TIMI risk score for UA/NSTEMI predicted the risk of a combined end point of death, MI or urgent revascularization within two weeks after presentation and the TIMI risk score for STEMI predicted the 30 day mortality risk  29,30].,30.29,30From The Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients (PARIS) registry , a prospAs the majority of ACS patients receive PCI or coronary artery bypass grafting, the residual ischemic risk in these patients is largely influenced by the complexity of the procedure . ReassesSimilar to ischemic risk assessment, evaluation of bleeding risk should also be evaluated at initial hospital admission as recommended by the guidelines . As the p = 0.04), while no significant differences were found in those with low or intermediate bleeding risk  . While mPatients with ACS have shown to be at higher risk for mortality, subsequent ischemic and bleeding events than patients with stable coronary artery disease (CAD). As risk is not static, it may be wise to consider reassessing the risks in the months or years following ACS. A risk score designed specifically to assess long term risk is the Dual AntiPlatelet Therapy (DAPT)-score  52]. Th. Th52]. Long-term risk scores for primary cardiovascular disease prevention, such as Systematic Coronary Risk Evaluation (SCORE), are widely used and recommended by prevention guidelines ,57. In t2DS2VASc risk score) [Risk scores used for patients with ACS are widely used and often available on online calculators. The most optimal risk score should be easily accessible, simple to interpret, adequately assess the risk of the outcome interested and provide treatment advice based on individually calculated risk. Its use should complement clinical judgement and contribute to primary or secondary prevention. It is implausible that one utopic risk model will become available for every risk and every situation, as it is also impractical to have separate risk scores for all risks and outcomes. The large heterogeneity  in study cohorts in which risk scores or models are evaluated will in most cases explain why discrimination and calibration measures often perform less well in external validation studies. Nevertheless, even risk scores with moderate or limited discriminative values are recommended by international guidelines and used worldwide in clinical practice  .If a risk score is used in clinical practice, it is important to know its specific limitations. For example, the PRECISE-DAPT and DAPT scores were developed from large PCI cohorts in patients treated with DAPT, but those with a long-term indication for OAC were excluded in these cohorts. These scores are also not validated in conservatively treated ACS patients, which make up for 10–30% of all NSTE-ACS patients . Though A short overview of risk scores recommended by the current guidelines for ACS patients are summarized in Alternatives to traditional risk scores have been proposed. The Academic Research Consortium (ARC) have published a consensus-based definition on high bleeding risk (ARC-HBR) criteria . Rather Another impressive alternative is the use of machine learning to create and validate models based on large datasets or even electronic hospital records. In over 11,000 patients with suspected MI, machine learning was applied to create a model with the variables age, sex, paired cardiac troponin I concentrations (including time and rate of change), which could stratify patients into low, moderate or intermediate risk for MI . ExcelleRisk scores can be of value in prognosis assessment and decision-making management in patients with ACS. Physicians should meticulously choose the optimal risk score per situation and at different points in time along the ACS pathway ,52.