Recent Submissions

  • Platelet biomarkers in patients with atherosclerotic extracranial carotid artery stenosis: a systematic review

    Naylor, Ross (2022-03)
    Objective: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. Data sources: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Review methods: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. Results: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. Conclusion: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.
  • The impact of anemia on one-year amputation-free survival in patients undergoing revascularization for chronic limb-threatening ischemia: a retrospective cohort study

    Theuma, Francesca; Nickinson, Andrew; Cullen, Sarah; Patel, Bhavisha; Dubkova, Svetlana; Davies, Robert; Sayers, Rob (2022)
    Background: Anemia is potentially associated with increased morbidity and mortality following vascular surgery procedures. This study investigated whether peri-procedural anemia is associated with reduced 1-year amputation-free survival (AFS) in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI). Methodology: A retrospective analysis of patients diagnosed with CLTI between February 2018-February 2019, who subsequently underwent revascularization, was conducted. Hemoglobin concentration measured at index assessment was recorded and stratified by WHO criteria. Subsequent peri-procedural red blood cell transfusions (RBC) were also recorded. The primary outcome was 1-year AFS. Kaplan Meier survival analysis and Cox's proportional hazard modelling were conducted to assess the effect of anemia and peri-procedure transfusion on outcomes. Results: 283 patients were analyzed, of which 148 (52.3%) were anemic. 53 patients (18.7%) underwent RBC transfusion. Patients with anemia had a significantly lower 1-year AFS (64.2% vs. 78.5%, P = 0.009). A significant difference in 1-year AFS was also observed based upon anemia severity (P = 0.008) and for patients who received RBC transfusion (45.3% vs 77.0%, P < 0.001). On multivariable analysis, moderately severe anemia was independently associated with increased risk of major amputation/death (aHR 1.90, 95% CI 1.06-3.38, P = 0.030). After adjusting for severity of baseline anemia, peri-procedural RBC transfusion was associated with a significant increase in the combined risk of major amputation/death (aHR 3.15, 95% CI 1.91-5.20, P < 0.001). Conclusion: Moderately severe peri-procedural anemia and subsequent RBC transfusion are independently associated with reduced 1-year AFS in patients undergoing revascularization for CLTI. Future work should focus on investigating alternative measures to managing anemia in this cohort.
  • Platelet biomarkers in patients with atherosclerotic extracranial carotid artery stenosis: a systematic review

    Naylor, Ross (2022)
    Objective: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. Data sources: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Review methods: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. Results: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. Conclusion: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.
  • Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

    Bown, Matthew; Samani, Nilesh (2022)
    Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
  • Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

    Bown, Matthew (2022)
    Background: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases. Methods: We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically 'favourable adiposity' (FA) and 'unfavourable adiposity' (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases. Results: MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism. Conclusions: Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy. Funding: Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.
  • The relationship between obesity and amputation-free survival in patients undergoing lower-limb revascularisation for chronic limb-threatening ischaemia: a retrospective cohort study

    Sabbagh, Cezar; Nickinson, Andrew; Cullen, Sarah; Patel, Bhavisha; Dubkova, Svetlana; Davies, Robert; Sayers, Rob (2022)
    Background: The obesity paradox is a well-documented phenomenon in cardiovascular disease, however it remains poorly understood. We aimed to investigate the relationship between body mass (as measured by body mass index [BMI]) and 1-year amputation-free survival (AFS) for patients undergoing lower limb revascularisation for chronic limb-threatening ischaemia (CLTI). Methods: A retrospective analysis was undertaken of all consecutive patients undergoing lower limb revascularisation for CLTI at the Leicester Vascular Institute between February 2018-19. Baseline demographics and outcomes were collected using electronic records. BMI was stratified using the World Health Organization criteria. One-year AFS (composite of major amputation/death) was the primary outcome. Kaplan-Meier survival analysis and adjusted Cox's proportional hazard models were used to compare groups to patients of normal mass. Results: One-hundred and ninety patients were included. Overall, no difference was identified in 1-year AFS across all groups (pooled P = 0.335). Compared to patients with normal BMI (n = 66), obese patients (n = 43) had a significantly lower adjusted combined risk of amputation/death (aHR 0.39, 95% CI 0.16-0.92, P = 0.032), however no significant differences were observed for overweight (aHR 0.89, 95% CI 0.47-1.70, P = 0.741), morbidly obese (aHR 1.15, 95% CI 0.41-3.20, P = 0.797) and underweight individuals (aHR 1.86, 95% CI 0.56-6.20, P = 0.314). Conclusions: In the context of CLTI, obesity is potentially associated with favourable amputation-free survival at 1 year, compared to normal body mass. The results of this study support the notion of an obesity paradox existing within CLTI and question whether current guidance on weight management requires a more patient-specific approach.
  • Feasibility of arterial spin labeling in evaluating high- and low-flow peripheral vascular malformations: a case series

    Ramachandran, Sanjeev; Delf, Jonathan; Adair, William; Rayt, Harjeet; Bown, Matthew; Kandiyil, Neghal (2021)
    We present a case series highlighting a novel use of arterial spin labeling (ASL), a MRI perfusion technique, to evaluate both high- and low-flow peripheral vascular malformations (PVMs) across a range of anatomical locations. While the role of ASL in assessing intracranial vascular malformations is more established, there is limited evidence for PVMs. Our results provide preliminary evidence for the feasibility of ASL in imaging PVMs and its potential ability to distinguish between high- and low-flow PVMs. In addition, we demonstrate its ability to identify focal high blood flow, which may indicate the nidus in arteriovenous malformations. Together, these findings have important implications for patient management. We also outline the potential benefits and limitations of ASL in the imaging of PVMs, and provide justification for further validation of its diagnostic performance.
  • Consultation rates in people with type 2 diabetes with and without vascular complications: a retrospective analysis of 141,328 adults in England

    Davies, Melanie; Seidu, Samuel; Webb, David; Zaccardi, Francesco
    OBJECTIVE: To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. METHODS: Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. RESULTS: 696,255 (mean 4.9 years [95% CI, 2.02-7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47-18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. CONCLUSIONS: Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.
  • Associations of clinical frailty with severity of limb threat and outcomes in chronic limb-threatening ischaemia

    Houghton, John; Nickinson, Andrew; Helm, Jessica; Dimitrova, Jivka; Dubkova, Svetlana; Rayt, Harjeet; Davies, Robert; Sayers, Rob (2021)
    Objective: Investigate the relationship of frailty and severity of chronic limb-threatening ischaemia (CLTI), and their comparative associations with one-year outcomes, in patients presenting to a vascular limb salvage (VaLS) clinic. Methods: This retrospective cohort study utilised data collected from a prospectively maintained VaLS clinic database. Patients aged ≥50 presenting to the VaLS clinic with CLTI between February 2018 and April 2019 were included. Frailty was measured using the Clinical Frailty Scale (CFS) and limb threat severity by the Wound, Ischaemia, and foot Infection (WIfI) score. Excessive polypharmacy was defined as ≥10 medications. Anticholinergic burden (ACB) score and Charlson comorbidity index (CCI) were calculated for all patients. The primary outcome measure was a composite endpoint of death or amputation at one-year. Associations with outcome were assessed using Cox regression and reported as hazards ratios (HR) with 95% confidence intervals (CI). Results: A total of 198 patients were included, with CFS scores available for 190 patients. 98 patients (52%) were frail (CFS ≥5). 127 patients (67%) initially underwent endovascular revascularisation. Excessive polypharmacy was common (55 patients; 28%). Frailty was associated with increased WIfI stage (P = 0.025) as well as age, female sex, CCI score, number of medications, excessive polypharmacy but not ACB score. Frail patients were more frequently managed non-operatively (P = 0.017). Frailty (HR 1.91; 95% CI 1.09, 3.34; P = 0.024) and WIfI stage 4 (HR 3.29; 95%CI 1.23, 8.80; P = 0.018) were associated with death or amputation on univariable analysis. WIfI stage 4 (HR 2.80; 95%CI 1.04, 7.57; P = 0.042) and CCI score (HR 1.21; 95%CI 1.03, 1.41; P = 0.015), but not frailty (HR 1.25; 95%CI 0.67, 2.33; P = 0.474), were independently associated with death or amputation on multivariable analysis. Conclusions: Frailty is highly prevalent among CLTI patients and related to severity of limb threat. The CFS may be a useful adjunct to patient risk assessment in CLTI.
  • Ultrasound shear wave elastography imaging of common carotid arteries in patients with Spontaneous Coronary Artery Dissection (SCAD)

    Marsh, Anna-Marie; Samani, Nilesh; McCann, Gerry; Adlam, David; Chung, Emma; Ramnarine, Kumar (2022)
    Background: Shear wave elastography (SWE) is emerging as a valuable clinical tool for a variety of conditions. The aim of this pilot study was to assess the potential of SWE imaging of the common carotid arteries (CCA) in patients with spontaneous coronary artery dissection (SCAD), a rare but potentially life-threatening condition, hypothesized to be linked to changes in vessel wall elasticity. Methods: Ultrasound shear wave elastography (SWE) estimates of artery wall elasticity were obtained from the left and right CCAs of 89 confirmed SCAD patients and 38 non-dissection controls. SWE images obtained over multiple cardiac cycles were analysed by a blinded observer to estimate elasticity in the form of a Young's Modulus (YM) value, across regions of interest (ROI) located within the anterior and posterior CCA walls. Results: YM estimates ranged from 17 to 133 kPa in SCAD patients compared to 34 to 87 kPa in non-dissection controls. The mean YM of 55 [standard deviation (SD): 21] kPa in SCAD patients was not significantly different to the mean of 57 [SD: 12] kPa in controls, p = 0.32. The difference between groups was 2 kPa [95% Confidence Interval - 11, 4]. Conclusions: SWE imaging of CCAs in SCAD patients is feasible although the clinical benefit is limited by relatively high variability of YM values which may have contributed to our finding of no significant difference between SCAD patients and non-dissection controls.
  • Frailty factors and outcomes in vascular surgery patients: a systematic review and meta-analysis

    Houghton, John; Nickinson, Andrew; Nduwayo, Sarah; Pepper, Coral; Rayt, Harjeet; Haunton, Victoria; Sayers, Rob
    Objective: To describe and critique tools used to assess frailty in vascular surgery patients, and investigate its associations with patient factors and outcomes. Background: Increasing evidence shows negative impacts of frailty on outcomes in surgical patients, but little investigation of its associations with patient factors has been undertaken. Methods: Systematic review and meta-analysis of studies reporting frailty in vascular surgery patients (PROSPERO registration: CRD42018116253) searching Medline, Embase, CINAHL, PsycINFO, and Scopus. Quality of studies was assessed using Newcastle-Ottawa scores (NOS) and quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria. Associations of frailty with patient factors were investigated by difference in means (MD) or expressed as risk ratios (RRs), and associations with outcomes expressed as odds ratios (ORs) or hazard ratios (HRs). Data were pooled using random-effects models. Results: Fifty-three studies were included in the review and only 8 (15%) were both good quality (NOS ≥ 7) and used a well-validated frailty measure. Eighteen studies (62,976 patients) provided data for the meta-analysis. Frailty was associated with increased age [MD 4.05 years; 95% confidence interval (CI) 3.35, 4.75], female sex (RR 1.32; 95% CI 1.14, 1.54), and lower body mass index (MD -1.81; 95% CI -2.94, -0.68). Frailty was associated with 30-day mortality [adjusted OR (AOR) 2.77; 95% CI 2.01-3.81), postoperative complications (AOR 2.16; 95% CI 1.55, 3.02), and long-term mortality (HR 1.85; 95% CI 1.31, 2.62). Sarcopenia was not associated with any outcomes. Conclusion: Frailty, but not sarcopenia, is associated with worse outcomes in vascular surgery patients. Well-validated frailty assessment tools should be preferred clinically, and in future research.
  • A Systematic Review of Procedural Outcomes in Patients With Proximal Common Carotid or Innominate Artery Disease With or Without Tandem Ipsilateral Internal Carotid Artery Disease

    Robertson, Vaux; Saratzis, Athanasios; Divall, Pip; Naylor, Ross (2020-12)
    Objective: To establish 30 day and mid term outcomes in patients treated for significant stenoses affecting the proximal common carotid artery (CCA) or innominate artery (IA) with/without tandem disease of the ipsilateral internal carotid artery (ICA). Methods: Systematic review of early and mid term outcomes in 1 969 patients from 77 studies (1960-2017) who underwent: (i) hybrid open retrograde angioplasty/stenting of the IA/proximal CCA plus carotid endarterectomy (CEA) in patients with tandem disease of the ipsilateral proximal ICA (n = 700); (ii) isolated open surgery to the IA or proximal CCA (no CEA) (n = 686); or (iii) an isolated endovascular approach to IA or proximal CCA stenoses (no CEA) (n = 583). Results: In the hybrid group with tandem disease (66% involving proximal CCA), the 30 day death/stroke was 3.3%, with a late ipsilateral stroke rate of 3.3% at a median six years follow up. Late re-stenosis was 10.5% for proximal CCA/IA and 4.1% for the ICA. In the isolated open surgery group (78% involving the IA), the 30 day death/stroke was 7%, with a late ipsilateral stroke rate of 1% at a median 12 years follow up. Late re-stenosis within aortic bypasses was 2.6%. In the isolated endovascular group (52% IA, 47% proximal CCA), the majority of procedures were done percutaneously (84%), with a 30 day death/stroke rate of 1.5%. Late ipsilateral stroke was 1% at a median four years follow up, with a re-stenosis rate of 9%. Conclusion: Procedural risks were higher following isolated open surgical interventions involving the proximal CCA/IA, compared with proximal lesions treated by isolated angioplasty/stenting, or in tandem with CEA. This higher morbidity/mortality may, however, reflect a greater proportion of innominate (vs. proximal CCA) lesions in open surgical series, changes in patient selection, time dependent evolution of medical interventions, and publication bias. The available data were limited and related to very different patient groups and management strategies spanning 57 years. Caution is raised, particularly for open surgery IA and CCA surgery, and for any procedures in asymptomatic patients. In symptomatic patients, the data cautiously support an "endovascular first" strategy for isolated proximal CCA/IA lesions and a hybrid approach for tandem proximal CCA/IA and ICA stenoses.