Objectives: To highlight current evidence pertaining to the measurement methods and prevalence of high on-treatment platelet reactivity (HTPR) in patients with PAD, as well as to evaluate the... Show moreObjectives: To highlight current evidence pertaining to the measurement methods and prevalence of high on-treatment platelet reactivity (HTPR) in patients with PAD, as well as to evaluate the relationship between HTPR and recurrent adverse cardiovascular and limb events in PAD patients.Methods: A systematic review of English-language literature on HTPR in patients with PAD. An electronic literature search of PubMed and Medline was performed in May 2021.Results: A total of 29 studies with a total number of 11,201 patients with PAD were identified. HTPR during clopidogrel treatment ranges from 9.8 to 77%, and during aspirin treatment ranges from 4.1 to 50% of PAD patients. HTPR was associated with adverse clinical outcomes. The need for limb revascularisation was higher in patients with HTPR during clopidogrel use. Similarly, HTPR during aspirin use in the PAD population was predictive of adverse cardiovascular events (HR 3.73; 95% CI, 1.43–9.81; p = .007). A wide range of techniques were applied to measure platelet resistance, without consensus on cut-off values. Furthermore, differing patient populations, a variety of antiplatelet regimens, and differingclinical endpoints highlight the high degree of heterogeneity in the studies included in this review.Conclusion: No consensus on technique or cut-off values for HTPR testing has been reached. Patients with HTPR are potentially at a greater risk of adverse limb-related and cardiovascular events than patients sensitive to antiplatelet therapy illustrating the need for clinical implementation of HTPR testing. Future research must aim for consistent methodology. Adaptation of antiplatelet therapy based on HTPR results requires further exploration. Show less
Background: In diagnosing peripheral arterial disease (PAD), medial arterial calcification (MAC) hampers arterial compression and could lead to unreliable ankle brachial index (ABI), toe brachial... Show moreBackground: In diagnosing peripheral arterial disease (PAD), medial arterial calcification (MAC) hampers arterial compression and could lead to unreliable ankle brachial index (ABI), toe brachial index (TBI) and toe pressure (TP). Doppler ultrasonography (DUS) derived maximal systolic acceleration (ACCmax) might be more accurate to diagnose PAD. In an in vitro study, a strong correlation between ACCmax and the severity of stenotic disease was determined. The aim of this study was to investigate the ACCmax in correlation with conventional non-invasive diagnostics in an in vivo setting. Methods: In twelve healthy individuals, an arterial stenosis was mimicked by compression on the common femoral artery by an ultrasounds probe, creating a local stenosis of 50%, 70% and 90%. The ABI, TBI, TP and several DUS parameters (including ACCmax) were assessed at the ankle during these different degrees of stenosis. All DUS parameters were measured separately by two observers to determine the interobserver variability. Results: Overall the ABI, TBI, TP, ACCmax, ACCsys and PSV decreased significantly when the degree of stenosis increased. The ACCmax showed the highest correlation with the degree of stenosis (r -.884), compared to ABI (r -.726), TBI (r -.716) and TP (r -.758). Furthermore, the interobserver variability of ACCmax was excellent, with an intraclass correlation coefficient (ICC) of .97. Conclusion: ACCmax is an accurate non-invasive DUS parameter to diagnose and assess the severity of a mimicked arterial stenosis in healthy individuals. Further prospective assessment of the clinical value of ACCmax and its potential benefits in patients with PAD is needed. Show less
Inhibition of the 14q32 microRNAs, miR-329-3p and miR-495-3p, improves post-ischemic neovascularization. Cold-inducible RNA-binding protein (CIRBP) facilitates maturation of these microRNAs. We... Show moreInhibition of the 14q32 microRNAs, miR-329-3p and miR-495-3p, improves post-ischemic neovascularization. Cold-inducible RNA-binding protein (CIRBP) facilitates maturation of these microRNAs. We hypothesized that CIRBP deficiency improves post-ischemic angiogenesis via downregulation of 14q32 microRNA expression. We investigated these regulatory mechanisms both in vitro and in vivo. We induced hindlimb ischemia in Cirp(-/-) and C57Bl/6-J mice, monitored blood flow recovery with laser Doppler perfusion imaging, and assessed neovascularization via immunohistochemistry. Post-ischemic angiogenesis was enhanced in Cirp(-/-) mice by 34.3% with no effects on arteriogenesis. In vivo at day 7, miR-329-3p and miR-495-3p expression were downregulated in Cirp(-/-) mice by 40.6% and 36.2%. In HUVECs, CIRBP expression was upregulated under hypothermia, while miR-329-3p and miR-495-3p expression remained unaffected. siRNA-mediated CIRBP knockdown led to the downregulation of CIRBP-splice-variant-1 (CIRBP-SV1), CIRBP antisense long noncoding RNA (lncRNA-CIRBP-AS1), and miR-495-3p with no effects on the expression of CIRBP-SV2-4 or miR-329-3p. siRNA-mediated CIRBP knockdown improved HUVEC migration and tube formation. SiRNA-mediated lncRNA-CIRBP-AS1 knockdown had similar long-term effects. After short incubation times, however, only CIRBP knockdown affected angiogenesis, indicating that the effects of lncRNA-CIRBP-AS1 knockdown were secondary to CIRBP-SV1 downregulation. CIRBP is a negative regulator of angiogenesis in vitro and in vivo and acts, at least in part, through the regulation of miR-329-3p and miR-495-3p. Show less
Background:Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay... Show moreBackground:Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization.Methods:We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities.Results:Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004.Conclusions:Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations. Show less
The aim of this study was to validate a Dutch translation of the Cardiff wound impact schedule (CWIS), a disease-specific instrument to measure the health-related quality of life (HRQoL) in... Show moreThe aim of this study was to validate a Dutch translation of the Cardiff wound impact schedule (CWIS), a disease-specific instrument to measure the health-related quality of life (HRQoL) in patients with chronic leg ulcers. To achieve this, the original instrument was translated. A total of 83 patients with chronic lower leg ulcers were included and completed the translated instrument and SF36 at baseline after assessment of their wound severity. Follow-up was performed 1 week after inclusion. The psychometric properties of the instrument were assessed. Construct validity was positively evaluated by an expert panel. Face validity was positively evaluated in a cognitive debriefing of a pilot group. Discriminant validity was assessed by correlating 1-year amputation risk according to the Wound, Ischaemia, foot Infection classification system with the instrument scores. Significant correlation could not be proven. Criterion validity was assessed by correlating domain scores of the instrument with domain scores of the gold standard: SF36. Moderate to high correlation was calculated for most domains of the instrument. Test-retest reliability and internal consistency were evaluated as acceptable. In conclusion, the Dutch translation of the CWIS is a valid and reliable disease-specific instrument to assess the HRQoL in patients with chronic lower leg ulcers. Show less
