No approved-drug candidate for carotid artery disease is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
RCSB Protein Data Bank · entry 6GIU · 1.39 Å · ligand [1-(4-oxidanylphenoxy)-1-phosphono-ethyl]phosphonic acid (L69). Experimental structure, not a prediction.
In a rat model of carotid artery injury, local inhibition of hypoxia-inducible factor-1 (HIF-1) using a dominant-negative adenoviral construct prevented post-injury vascular remodelling. In human carotid artery vascular smooth muscle cells, growth factors such as platelet-derived growth factor activated the Akt pathway, which increased HIF-1 activation and glycolysis. Hexokinase 2 expression and mitochondrial activity rose during HIF-1 activation, leading to hyperpolarised mitochondrial membrane potential and suppression of apoptosis; HIF-1 inhibition blocked these effects and also reduced cell proliferation. No human trial of HIF-1 inhibition for carotid disease has been reported.
A retrospective analysis of 246 Asian patients who underwent carotid artery stenting reported a procedural success rate of 98.3% and a mean follow-up of 49.2 months. Within 30 days, 4.3% of procedures had peri-procedural complications. During follow-up, 9.7% of patients developed restenosis and 15.0% had an ischaemic stroke. Independent predictors of restenosis included prior head and neck radiotherapy (hazard ratio 9.9), smaller stent diameter, and predilatation. Predictors of recurrent ipsilateral ischaemic stroke were hypercholesterolaemia (hazard ratio 0.25, suggesting a protective association), prior radiotherapy (hazard ratio 6.2), and restenosis (hazard ratio 3.6).
A systematic review of 44 studies examined the link between infection and carotid plaque disease. Three of six studies on plaque destabilisation reported a significant association between infection and symptoms. For individual pathogens, positive associations with carotid plaque characteristics (intima-media thickness >1 mm or symptoms) were found in three studies for hepatitis C virus, two for cytomegalovirus, and one each for enterovirus, Epstein-Barr virus, hepatitis B virus, and HIV. Among bacteria, positive associations were reported in four studies on dental pathogens (e.g. Porphyromonas gingivalis), five on Helicobacter pylori strains, and one on Borrelia burgdorferi. No interventional trial testing antibiotics or antivirals for carotid plaque disease is described in the reviewed literature.
The randomised NASCET and ECST trials from the 1990s showed that carotid endarterectomy reduced stroke risk in symptomatic patients with 50–69% stenosis (number needed to treat 22) and 70–99% stenosis (number needed to treat 6) at five years. The more recent ACST-1 trial, randomising over 3100 patients with asymptomatic carotid stenosis, found a 5.4% absolute risk reduction at five years with endarterectomy plus best medical therapy versus best medical therapy alone. The authors of the 2022 commentary argue that modern medical therapy has not yet been shown to provide greater benefit than surgery for symptomatic patients, and that the natural stroke risk in asymptomatic patients on best medical therapy is now below 1% per year. What remains missing are adequately powered randomised trials comparing contemporary best medical therapy alone against revascularisation in well-stratified patient groups, particularly for asymptomatic stenosis, and any clinical trial of HIF-1 inhibitors or anti-infective agents in carotid artery disease.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cardiovascular Research · 2010 · 93 citations · open access
HIF-1 inhibition decreases systemic vascular remodelling diseases by promoting apoptosis through a hexokinase 2-dependent mechanism
AbstractAIMS: Vascular remodelling diseases are characterized by the presence of proliferative and apoptosis-resistant vascular smooth muscle cells (VSMC). There is evidence that pro-proliferative and anti-apoptotic states are characterized by metabolic remodelling (a glycolytic phenotype with hyperpolarized mitochondria) involving Akt pathway activation by circulating growth factors. Hypoxia-inducible factor-1 (HIF-1) is involved in different vascular diseases. Since this transcription factor is implicated in metabolic responses, we hypothesized that HIF-1 activity could be involved in vascular remodelling in response to arterial injury. METHODS AND RESULTS: Our findings indicate that growth factors, such as platelet-derived growth factor (PDGF), activate the Akt pathway (measured by immunoblot) in human carotid artery VSMC. Activation of this pathway increased HIF-1 activation (measured by immunoblot), leading to increased glycolysis in VSMC. Expression and mitochondrial activity of hexokinase 2 (HXK2), a primary initiator of glycolysis, are increased during HIF-1 activation. The mitochondrial activity of HXK2 in VSMC led to the hyperpolarization of mitochondrial membrane potential (measured by tetramethylrhodamine methyl-ester perchlorate) and the suppression of apoptosis (measured by TUNEL assay and 3 activity), effects that are blocked by HIF-1 inhibition. Additionally, HIF-1 inhibition also decreased VSMC proliferation (proliferating cell nuclear antigen and Ki-67 assays). In vivo, we demonstrate that localized HIF-1 inhibition, using a dominant-negative HIF-1α adenoviral construct, prevented carotid artery post-injury remodelling in rats. CONCLUSION: We propose that HIF-1 is centrally involved in carotid artery remodelling in response to arterial injury and that localized inhibition of HIF-1 may be a novel therapeutic strategy to prevent carotid stenosis.
https://doi.org/10.1093/cvr/cvq152Journal of Endovascular Therapy · 2014 · 36 citations
Long-term Results of Drug-Eluting Balloon Angioplasty for Treatment of Refractory Recurrent Carotid In-Stent Restenosis
AbstractPURPOSE: To evaluate the potential role, safety, and efficacy of paclitaxel-eluting balloon angioplasty for treatment of recurrent carotid in-stent restenosis (ISR). METHODS: Among 856 consecutive patients who underwent carotid artery stenting from May 2002 to January 2008, 41 patients had a significant ISR (>80% stenosis). Of these, 9 patients (7 women; mean age 78.1±5.6 years) had recurrent ISR despite multiple endovascular treatments (3.4±0.9 interventions) within a short period of time (2-5 months). These patients were treated with drug-eluting balloon (DEB) angioplasty for neointimal hyperplasia. Imaging (ultrasound or computed tomographic angiography) was performed at 1, 3, and 6 months and yearly thereafter. RESULTS: Technical success was obtained in 100% of cases, with angiographic stenosis decreasing from 87%±4% to 6%±4% post treatment. Peak systolic velocity decreased significantly from 4.7±1.5 m/s to 0.6.±0.3 m/s after the procedure. Over a mean follow-up of 36.6±2.7 months, ultrasound imaging indicated recurrent ISR in only 3 patients at 18, 25, and 32 months after DEB angioplasty, respectively. The target vessel revascularization rate was 33.3% at 36 months. No neurological or myocardial events were recorded during follow-up. One patient died at 3 months. CONCLUSION: DEB may have a potential role improving outcomes of those patients treated for early recurrent carotid ISR.
https://doi.org/10.1583/14-4715mr.1PubMed · 2016 · 19 citations
Prognostic Factors for Neurologic Outcome in Patients with Carotid Artery Stenting.
AbstractBACKGROUND: Carotid artery stenting (CAS) is a valid treatment for patients with carotid artery stenosis. The long-term outcome and prognostic factors in Asian population after CAS are not clear. This study aimed to identify the prognostic factors among Asian patients who have undergone CAS. METHODS: We retrospectively analyzed 246 patients with CAS. Annual carotid duplex ultrasound was used to identify restenosis. Peri-procedural complications, restenosis, neurologic outcomes, and mortality were recorded. Cox regression analyses were used to identify prognostic factors. RESULTS: The mean follow-up time was 49.2 months. Procedural success was achieved in 237 patients (98.3%), and protection devices were used in 208 patients (84.5%). Within 30 days of CAS, 13 (4.3% per procedure) peri-procedural complications occurred. During the follow-up period, 24 (9.7%) patients developed restenosis, and 37 (15.0%) developed ischemic strokes. In a multiple logistic regression analysis, head and neck radiotherapy [hazard ratio (HR) = 9.9, 95% confidence interval (CI), 3.38-29.1, p < .001], stent diameter (HR = 0.72, 95% CI, 0.58-0.89, p = .003), and predilatation (HR = 3.08 95% CI, 1.21-7.81, p = .018) were independent predictors for restenosis. In Cox regression analysis, hypercholesterolemia (HR = 0.25, 95% CI, 0.07-0.94, p = .04), head and neck radiotherapy (HR = 6.2, 95% CI, 1.8-21.3, p = .004), and restenosis (HR = 3.6, 95% CI, 1.1-11.18, p = .04) were predictors for recurrent ipsilateral ischemic stroke. CONCLUSIONS: CAS provides reliable long-term results in Asian patients with carotid stenosis. Restenosis is associated with an increased rate of recurrent stroke and should be monitored carefully following CAS. KEY WORDS: Carotid artery disease • Prognosis • Cerebrovascular disease.
https://doi.org/10.6515/acs20150119hCurrent Vascular Pharmacology · 2010 · 16 citations
The Role of Infection in Carotid Plaque Pathogenesis and Stability: The Clinical Evidence
AbstractIntroduction: Chlamydia pneumoniae was the first pathogen linked with carotid atherosclerotic changes and plaque rupture. Currently, other common pathogens are also under investigation as potential contributors. Methods: A systematic review of PubMed and Scopus databases was performed. Studies evaluating the infectious burden between symptomatic and asymptomatic patients with carotid plaque disease (CPD) were included. Furthermore, trials referring to common infectious agents (other than C. pneumoniae) incriminated for contribution in CPD were analyzed separately. Results: Forty four studies were identified; 6 investigated the connection of infection with the plaque destabilization, 3 of which reported a significant association between infection and symptoms. Studies retrieved for the investigation of agents other than C. pneumoniae were: 18 about viruses, 16 about other bacteria and 4 examining both. Significant association or high detection rates of agents’ genome or specific antibodies with CPD characteristics (intima media thickness values > 1mm or symptoms) were found in a number of studies: 3 for HCV, 2 for CMV and 1 for enterovirus, EBV, HBV, and HIV. Moreover 4 studies about dental pathogens (i.e. Porpyromonas gingivalis), 5 about H. Pylori strains and 1 about Borrelia burgdorferi were identified supporting a positive association. Conclusion: There is considerable evidence supporting the contribution of other commonly encountered pathogens in the pathogenesis and rupture of the carotid plaque. Research in this direction should not be abandoned and further studies are necessary to elucidate the exact role of common infections in the pathogenesis and development of CPD and how this can be translated into novel pharmacological approaches for prevention and treatment. Keywords: Carotid plaque, infection, antibiotics, antivirals, Chlamydia pneumoniae, carotid atherosclerotic changes, carotid plaque disease, HCV, CMV, enterovirus, EBV, HBV, HIV, Porpyromonas gingivalis, H. Pylori, Borrelia burgdorferi, Atherosclerosis, anti-chlamydial agents, coronary artery dis-ease, Helicobacter pylori, herpes simplex virus, cytomegalovirus, carotid endarterectomy, polymerase chain reaction, tumor necrosis factor, atherosclerotic plaques, hepatitis C, hepatitis B, intima media thickness, antiretroviral therapy, periodontitis, Por-phyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Mycobacterium Tuberculosis, Diphtheroid, Staphylococcus Species, CD8 positive cytotoxic T cells, CD4 positive T cells, azithromycin, clarythromycin, roxyth-romycin
https://doi.org/10.2174/157016110793563889Interactive Cardiovascular and Thoracic Surgery · 2015 · 12 citations · open access
Surgical treatment for pseudo-occlusion of the internal carotid artery
AbstractOBJECTIVES: Carotid artery pseudo-occlusion is a rare condition and its natural history and clinicopathological characteristics are not well defined. We reported our 7-year experience in the surgical treatment of carotid artery pseudo-occlusion to determine the real benefit of the surgical option. METHODS: From January 2006 to December 2013, 1414 patients were treated for high-grade stenosis of the internal carotid artery, 33 (2.3%) presented with a carotid pseudo-occlusion (26 males and 7 females, mean age: 70 ± 10). Nineteen patients were symptomatic, and 14 asymptomatic. Carotid artery pseudo-occlusion was identified by duplex scan (segmental occlusion at the origin of internal carotid artery with very thin distal flow) and the diagnostic confirmation was obtained by angio-computed-tomography (CT) scan. The operation was performed under general anaesthesia and constant Electroencephalography (EEG) monitoring. The follow-up was performed by duplex scan at discharge, 30 days, 6 months and yearly. RESULTS: Politetrafluoroetilene (PTFE) patch endarterectomy, eversion endarterectomy and carotid bypass were performed in 20 (61%), 10 (30%) and 3 patients (9%), respectively. No mortality or stroke was observed in postoperative period. Four patients presented with an asymptomatic postoperative thrombosis of the internal carotid artery. No restenosis was observed. CONCLUSIONS: Surgical treatment for carotid artery pseudo-occlusion is safe and effective.
https://doi.org/10.1093/icvts/ivv016Revista de Neurología · 2005 · 3 citations
Tratamiento endovascular de la enfermedad carotídea. Situación actual, aspectos técnicos y capacitación profesional
AbstractAIMS: The aim of this study was to carry out a review of the state of the art in the endovascular treatment of carotid disease, taking into account the findings currently available, its indications, the technical aspects linked to the intervention as well as those related to the occupational training of the specialists involved in performing the technique. DEVELOPMENT: Surgical treatment of carotid artery disease can be of benefit to symptomatic patients with stenoses above 70% and to subgroups of patients with symptomatic stenoses between 50-69%. The benefit of carotid endarterectomy in asymptomatic patients is the object of a great deal of controversy that is concerned with the reduction in risk that is obtained and also the large number of patients to be treated in order to prevent the occurrence of ischaemic events. The endovascular treatment of carotid disease comes to the fore, then, as an alternative to surgical treatment. At the present time, a number of randomised multicentre studies are being conducted that will allow the two techniques to be compared in homogeneous groups of patients. Preliminary data nevertheless seem to suggest that this technique offers a number of benefits, especially in groups of subjects with a high surgical risk, and thus they could allow the indications for revascularisation to be extended. We analyse the technical and medical aspects linked to this procedure, the findings from studies carried out to date, its indications and the occupational training of the specialists involved in performing the technique. CONCLUSIONS: The endovascular treatment of carotid disease constitutes an alternative to surgical treatment in specifically selected patients. The potential increase in its indications is conditioned by the results from the multicentre studies currently being carried out.
https://doi.org/10.33588/rn.4112.2004336British journal of surgery · 2022 · 2 citations · open access
Modern medical therapy does not provide greater benefit than surgery for patients with symptomatic carotid disease
AbstractThe discussion about the safety and efficacy of carotid endarterectomy (CEA) in stroke prevention continues to rage. Best medical therapy (BMT) leads to plaque stabilization, and thereby significantly reduces the incidence of stroke and transient ischaemic attack (TIA). Patient selection for revascularization accordingly becomes more and more important. It is important to consider the factors that place patients at higher risk of stroke. All this is certainly true for asymptomatic stenosis, where plaque stability is high and the natural stroke risk decreases to below 1 per cent per year with BMT1. However, it is hardly reasonable to suggest that BMT alone is sufficient to prevent embolization to the brain once an atherosclerotic plaque has ruptured. The NASCET (North American Symptomatic Carotid Endarterectomy Trial) and ECST (European Carotid Surgery Trial) demonstrated the effectiveness of CEA in stroke prevention among symptomatic patients in the 1990s. The absolute risk reduction reached between 4.6 and 15.9 per cent at 5 years, depending on the degree of carotid stenosis. Accordingly, the numbers needed to treat (NNTs) were 22 for 50–69 per cent stenoses and impressively low for high-grade stenoses (70–99 per cent) (NNT 6)2. Critics argue that NASCET and ECST data are too old and do not reflect contemporary clinical practice. However, the more recently conducted ACST-1 (Asymptomatic Carotid Surgery Trial)3 randomized more than 3100 patients with asymptomatic internal carotid artery (ICA) stenosis to CEA plus BMT or BMT alone, and still confirmed the benefit of CEA in this group of patients (5.4 per cent absolute risk reduction at 5 years).
https://doi.org/10.1093/bjs/znac219British journal of surgery · 2022 · 0 citations
Modern medical therapy provides greater benefit than surgery for patients with symptomatic carotid disease
AbstractCarotid endarterectomy (CEA) is usually offered to patients presenting with transient ischaemic attack (TIA) or minor stroke, where the cause has been identified as a stenosis in the internal carotid artery of 50 per cent or more. This practice is based on randomized trial evidence demonstrating that CEA results in a 50 per cent relative risk reduction of stroke or death in comparison to medical therapy1,2. Recruitment to the trials that inform this practice took place between 1981 and 1991. Medical therapy has changed considerably since then, with dual antiplatelet regimens, widespread use of high-dose statins, multimodal, target-directed blood pressure algorithms, and a stronger focus on smoking cessation and other lifestyle interventions. Medical therapy alone may now be an attractive alternative option to CEA for patients as it avoids the risks of surgery and is attractive to healthcare systems through saved costs. There is no contemporaneous direct clinical trial evidence for or against the motion that modern medical therapy provides greater benefit than surgery for patients with symptomatic carotid disease. The trials that informed the current practice of offering CEA are no longer relevant to current clinical care pathways. Aspirin was the main antiplatelet agent used in ECST (European Carotid Surgery Trial) and NASCET (North American Carotid Endarterectomy Trial). The CHANCE3 and POINT4 trials have demonstrate the superiority of dual antiplatelet regimens for the prevention of recurrent events in the acute phase. The benefits of clopidogrel monotherapy over aspirin for long-term management have long been established5. The trials that clinicians still use to inform their practice are therefore no longer applicable to modern clinical management. There is accumulating evidence that modern medical therapy may now be of equivalent or even greater benefit than CEA for patients with symptomatic carotid disease. Dual antiplatelet therapy alone has been shown to reduce cerebral embolization in patients with symptomatic carotid artery disease. In the CARESS study6 of dual antiplatelet therapy (current treatment) versus aspirin monotherapy (main treatment during CEA trials), the rate of recurrent stroke/TIA was halved in the dual antiplatelet group (9.8 versus 21.4 per cent). A mechanistic study7 of the effect of dual antiplatelet therapy on cerebral microembolization in patients waiting for carotid surgery demonstrated a 75 per cent reduction in microemboli in those treated with dual-antiplatelet therapy compared with aspirin monotherapy. In the 30 years since NASCET and ECST were undertaken, increasing antithrombotic use and better BP control in patients presenting with TIA and/or stroke has reduced the risk of recurrent stroke and other vascular events8, and new aggressive lipid-lowering strategies have been shown to reduce cardiovascular events compared with those in use at the time of these trials9. Overall, multimodal therapy, including antiplatelet therapy, statins, and BP management, now reduces the stroke risk after TIA by up to 80 per cent10. There is also clinical evidence that modern medical therapy now prevents most recurrent events in the very high-risk period immediately after an index event. Using individual-patient data from trials of both CEA and carotid artery stenting (CAS), Fisch et al.11 demonstrated that, in patients with symptomatic carotid stenosis awaiting CEA or CAS, the 120-day stroke risk observed in early trials (1981–1996) was 5.00 per cent, but that had fallen to 1.97 per cent in later trials (2000–2008). A similar Danish study12 demonstrated a recurrent stroke risk of only 1 per cent at 2 weeks (high-risk period) with contemporaneous best medical therapy. Observational studies have suggested that a medical therapy-first approach might be justified. In the first UK wave of the COVID-19 pandemic in 2020, the international COVER study13 was established to determine the impact of service restriction on patients with vascular disease. Of the 123 patients referred for CEA in the COVER study, 34 (27.6 per cent) did not have surgery because operating theatres were not available or there were risks related to the admission. Managed medically, none of these 34 patients had had a stroke by 6 months’ follow-up (1 was lost to follow-up, 1 died from cancer)13. This small single study provides the only contemporaneous data set reporting the potential safety of medical therapy in patients with symptomatic carotid stenosis who would usually have been offered surgery. Of course, the counterargument to abandoning CEA in favour of medical therapy is that the risks associated with CEA have also reduced over time, with surgeons pointing to data such as the 30-day risk of operative mortality or stroke in NASCET being 5.8 per cent, in comparison to current procedural stroke risks in the region of 2.6 per cent, such as that observed in the UK National Vascular Registry (NVR)14. This of course ignores the other procedural risks associated with CEA, such as those reported in the NVR: bleeding (1.9 per cent), cranial nerve injury (1.7 per cent), and myocardial infarction (1.3 per cent)14. Focusing treatment decisions on stroke risk alone ignores the other harms associated with surgery. Furthermore, registry data such as the NVR are based on surgeons reporting their own outcomes and the true incidence of stroke may be different from that reported. The missing component in the arguments for or against this motion is the patient voice. The above focuses on measurable clinical benefits and harms of treatment. Patient preferences for treatment are currently unknown. Without contemporaneous evidence to inform patients, their carers, and the public about treatments, it is difficult to properly counsel patients regarding the risks and benefits of medical treatment or surgery. At present it is difficult to state that modern medical therapy provides greater benefit than surgery for patients with symptomatic carotid disease. It is equally difficult to state that surgery provides greater benefit than modern medical therapy for these patients, however, because there is no clinical trial evidence to support either viewpoint. The well documented risks of surgery suggest it is entirely possible that the risks of surgery now outweigh the risks of medical therapy alone. How will this argument be resolved? The impact of observational studies in this field is limited and therefore new trials of medical therapy versus CEA are required to inform future clinical practice. Although recruiting patients into such trials may be uncomfortable for some, without such data it is not possible for surgeons to know that they are not causing more harm than good by continuing to offer CEA to patients with acutely symptomatic carotid artery stenosis. The authors have no funding to declare. This article has been adapted from text written for a National Institute for Health and Care Research grant submission. The grant writing team comprised A. Davies, H. Markus, J. Minhas, D. Epstein, A. Saratzis, S. Peerbux, E. Mukaetova-Ladinska, J. Norrie, A. Thapar, K. Ray, and M. Bown. Disclosure.The authors declare no conflict of interest.
https://doi.org/10.1093/bjs/znac220Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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