Background The prognostic utility of the ankle-brachial index (ABI) may be hampered in persons with diabetes due to peripheral arterial stiffening in the ankles. Stiffening of toe arteries occurs ...infrequently in diabetes. We aimed to determine the nature of the relationship of the toe-brachial index (TBI) and ABI with cardiovascular disease (CVD) mortality and to determine whether the associations are modified in individuals with diabetes. Methods Individuals with clinically suspected atherosclerotic peripheral arterial disease who underwent ABI and TBI measurements in a vascular laboratory were monitored longitudinally for CVD mortality. Results Among 469 participants (89% men), the mean age was 68 ± 9 years, and 36% had diabetes. The mean ABI was 0.83 ± 0.28 and the mean TBI was 0.60 ± 0.24. During median 7.0 years of follow-up, there were 158 CVD deaths. The association of the ABI categories with CVD deaths differed in diabetic vs nondiabetic participants ( P = .002 for interaction). In contrast, the association of the TBI categories with CVD deaths was similar, irrespective of diabetes status ( P = .17 for interaction). Among diabetic patients, a U-shaped relationship was observed between ABI categories and CVD death: those with low (<0.90) and high (>1.30) ABIs were both at higher risk than those with normal ABIs (range, 0.90-1.30). In nondiabetic patients, association of ABI categories with CVD death was linear, such that those with an ABI >1.30 were at the lowest risk, whereas those with an ABI <0.90 were at higher risk. In contrast, the association of TBI categories with CVD death was linear irrespective of diabetes status. High TBI categories consistently predicted low risk, whereas risk was higher with progressively lower TBI categories. Conclusions Among diabetic individuals with clinically suspected peripheral arterial disease, those with low and high ABIs are both at higher risk of CVD death. In contrast, a linear relationship was observed between TBI categories and CVD death irrespective of diabetes status. These findings suggest that stiffened ankle arteries may limit the predictive value of the ABI in individuals with diabetes, a limitation that may be overcome by measurement of the TBI.
Abstract Background and aims We aimed at investigating the role of 14q32 microRNAs in intimal hyperplasia and accelerated atherosclerosis; two major contributors to restenosis. Restenosis occurs ...regularly in patients treated for coronary artery disease and peripheral arterial disease. We have previously shown that inhibition of 14q32 microRNAs leads to increased post-ischemic neovascularization, and microRNA miR-494 also decreased atherosclerosis, while increasing plaque stability. We hypothesized that 14q32 microRNA inhibition has beneficial effects on intimal hyperplasia, as well as accelerated atherosclerosis. Methods Non-constrictive cuffs were placed around both femoral arteries of C57BL/6J mice to induce intimal hyperplasia. Accelerated atherosclerotic plaque formation was induced in hypercholesterolemic ApoE−/− mice by placing semi-constrictive collars around both carotid arteries. 14q32 microRNAs miR-329, miR-494 and miR-495 were inhibited in vivo using Gene Silencing Oligonucleotides (GSOs). Results GSO-495 administration led to a 32% reduction of intimal hyperplasia. Moreover, the number of macrophages in the arterial wall of mice treated with GSO-495 was reduced by 55%. Inhibition of miR-329 and miR-494 had less profound effects on intimal hyperplasia. GSO-495 administration also decreased atherosclerotic plaque formation by 52% and plaques of GSO-495 treated animals showed a more stable phenotype. Finally, cholesterol levels were also decreased in GSO-495 treated animals, via reduction of the VLDL-fraction. Conclusions GSO-495 administration decreased our primary outcomes, namely intimal hyperplasia, and accelerated atherosclerosis. GSO-495 administration also favourably affected multiple secondary outcomes, including macrophage influx, plaque stability and total plasma cholesterol levels. We conclude that 14q32 microRNA miR-495 is a promising target for prevention of restenosis.
Critical limb ischemia (CLI) is the most serious complication of peripheral artery disease (PAD).
The purpose of this study was to characterize pathology of PAD in below- and above-knee amputation ...specimens in patients presenting with CLI.
Peripheral arteries from 95 patients (121 amputation specimens) were examined; 75 patients had presented with CLI, and the remaining 20 had amputations performed for other reasons. The pathological characteristics were separately recorded for femoral and popliteal arteries (FEM-POP), and infrapopliteal arteries (INFRA-POP).
A total of 299 arteries were examined. In the 239 arteries from CLI patients, atherosclerotic plaques were more frequent in FEM-POP (23 of 34, 67.6%) compared with INFRA-POP (79 of 205, 38.5%) arteries. Of these 239 arteries, 165 (69%) showed ≥70% stenosis, which was due to significant pathological intimal thickening, fibroatheroma, fibrocalcific lesions, or restenosis in 45 of 165 (27.3%), or was due to luminal thrombi with (39 of 165, 23.6%) or without (81 of 165, 49.1%) significant atherosclerotic lesions. Presence of chronic luminal thrombi was more frequently observed in arteries with insignificant atherosclerosis (OR: 16.7; p = 0.0002), more so in INFRA-POP compared with FEM-POP (OR: 2.14; p = 0.0041) arteries. Acute thrombotic occlusion was less frequently encountered in INFRA-POP than FEM-POP arteries (OR: 0.27; p = 0.0067). Medial calcification was present in 170 of 239 (71.1%) large arteries.
Thrombotic luminal occlusion associated with insignificant atherosclerosis is commonly observed in CLI and suggests the possibility of atherothromboembolic disease. The pathological characteristics of arteries in CLI suggest possible mechanisms of progression of PAD to CLI, especially in INFRA-POP arteries, and may support the preventive role of antithrombotic agents.
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Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and ...cardiovascular risk.
Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events.
Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events.
Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use.
We evaluated whether altered reporting of ischemic symptoms occurs in diabetic patients with peripheral arterial disease (PAD) and stable claudication. Patients (n = 152) with claudication were ...enrolled (120 males; mean age: 71.0 ± 8.6 years): 74 with diabetes (DM-PAD) and 78 without (DMfree-PAD). The degree of muscle oxygenation at symptom onset and maximal speed (Smax) during an incremental treadmill test was recorded at the gastrocnemius by near-infrared spectroscopy (NIRS) and quantified by area under the curve of oxygenated hemoglobin (AUC-Hbo2) and area under the curve of differential hemoglobin (AUC-dHb). The DM-PAD and DMfree-PAD showed similar exercise capacities inversely correlated with the degree of muscle oxygenation but significantly lower values of AUC-Hbo2 and AUC-dHb for DM-PAD at symptom onset and Smax (−356 vs −122 and −1200 vs −359, P < .0001). During a NIRS-assisted test, the report of claudication in the presence of diabetes was delayed, occurring at a lower degree of oxygenation than in patients with PAD only, with potential implications for testing, functional staging, and balance disorders.
The Global Limb Anatomic Staging System (GLASS) is a new method of quantifying the anatomic severity of infrainguinal disease in patients with chronic limb-threatening ischemia. However, because ...GLASS has undergone limited validation, its value as an aid to shared decision-making regarding the choice of revascularization strategy remains incompletely defined. Here we report the relationship between GLASS and outcomes in a contemporary series comprising all 309 patients who underwent an attempt at femoropopliteal and/or infrapopiteal endovascular therapy for chronic limb-threatening ischemia in our unit between 2009 and 2014.
Baseline patient characteristics and outcome data including immediate technical success (ITS), amputation-free survival (AFS), overall survival, limb salvage, freedom from reintervention (FF-R), and freedom from major adverse limb events (FF-MALE) were obtained from hospital databases. GLASS grades and stage were obtained from pre-endovascular therapy angiographic imaging. Outcome data were censored on May 31, 2017.
Baseline patient characteristics were similar across different GLASS femoropopliteal and IP grades and overall limb stages. Worsening GLASS stage was associated with a significant reduction in ITS (97.5% vs 91.5% vs 84.0%; P = .029). At 72 months FF-R (hazard ratio, 2.00; 95% confidence interval, 1.11-3.57; P = .020) and FF-MALE (hazard ratio, 1.76, 95% confidence interval, 1.10-2.81; P = .019) were significant worse in GLASS stage 3 than in stage 2 limbs.
In our study, there were significant differences in ITS, FF-R and FF-MALE between limbs with GLASS stage 2 and 3 disease. However, further GLASS refinement seems likely to be required if its usefulness in everyday clinical practice as an aid to shared decision-making regarding the choice of revascularization strategy is to be maximized.
Athero-thrombosis of the arteries supplying the brain and lower limb are the main causes of stroke and limb loss. New therapies are needed to improve the outcomes of athero-thrombosis. Recent ...evidence suggests a role for epigenetic changes in the development and progression of ischaemic injury due to atherosclerotic occlusion of peripheral arteries. DNA hypermethylation have been associated with cardiovascular diseases. Histone post-translational modifications have also been implicated in atherosclerosis. Oxidized low-density lipoprotein regulated pro-inflammatory gene expression within endothelial cells is controlled by phosphorylation/acetylation of histone H3 and acetylation of histone H4 for example. There are a number of challenges in translating the growing evidence implicating epigenetics in atherosclerosis to improved therapies for patients. These include the small therapeutic window in conditions such as acute stroke and critical limb ischaemia, since interventions introduced in such patients need to act rapidly and be safe in elderly patients with many co-morbidities. Pre-clinical animal experiments have also reported conflicting effects of some novel epigenetic drugs, which suggest that further in-depth studies are required to better understand their efficacy in resolving ischaemic injury. Effective ways of dealing with these challenges are needed before epigenetic approaches to therapy can be introduced into practice.
We investigated the role played by ATP-sensitive purinergic 2 (P2) receptors in evoking the pressor response to treadmill exercise in male and female rats with and without femoral arteries that were ...ligated for ∼72 h to induce simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2 receptor antagonist, 10 mg iv) would reduce the pressor response to 4 min of treadmill exercise (15 m·min
, 1° incline) and steady-state exercise plasma norepinephrine (NE) values in male and female rats, and that the magnitude of effect of PPADS would be greater in rats with simulated PAD ("ligated") than in sham-operated rats. In males, PPADS significantly reduced the difference between steady-state exercise and baseline mean arterial pressure (ΔMAP) response to treadmill exercise in sham (
= 8; pre-PPADS: 12 ± 2, post-PPADS: 1 ± 5 mmHg;
= 0.037) and ligated (
= 4; pre-PPADS: 20 ± 2, post-PPADS: 11 ± 3 mmHg;
= 0.028) rats with a similar magnitude of effect observed between groups (
= 0.720). In females, PPADS had no effect on the ΔMAP response to treadmill exercise in sham (
= 6; pre-PPADS: 9 ± 2, post-PPADS: 7 ± 2 mmHg;
= 0.448) or ligated (
= 6; pre-PPADS: 15 ± 2, post-PPADS: 16 ± 3 mmHg;
= 0.684) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced plasma NE in male (
= 0.016) and female (
= 0.027) rats. The data indicate that P2 receptors contribute to the sympathetic response to exercise in both male and female rats but that the sympathoexcitatory role for P2 receptors translates into an obligatory role in the blood pressure response to exercise in male but not in female rats.
Here, we demonstrate that purinergic 2 (P2) receptors contribute significantly to the blood pressure response to treadmill exercise in male rats both with and without simulated PAD induced by femoral artery ligation. We found no role for P2 receptors in the blood pressure response to treadmill exercise in female rats, thus revealing clear sex differences in P2 receptor-mediated blood pressure control during exercise.
Peripheral Arterial Disease in Women: The Gender Effect Patel, Toralben; Baydoun, Hassan; Patel, Nimesh K. ...
Cardiovascular revascularization medicine,
March 2020, 2020-03-00, 20200301, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Peripheral arterial disease (PAD) is a common atherosclerotic disease approximately affecting 8.5 million Americans above age 40 and is associated with significant functional impairment, morbidity ...and mortality from both cardiovascular and non-cardiovascular causes. PAD has increasing prevalence in females contrary to previous findings. Compared to men, women with PAD are more asymptomatic or have atypical symptoms. Women with PAD have increased quality of life impairment, increased risk of depression and increased cardiovascular mortality. The intent of this review is to provide an update on gender differences in PAD that can help in timely diagnosis and appropriate management through intensive cardiovascular risk factor modification, exercise program and guideline directed therapy to improve cardiovascular outcomes.
•Peripheral arterial disease (PAD) is a significant healthcare burden affecting 8–10 million Americans.•PAD confers equal morbidity and mortality as well as economic costs to coronary artery disease and stroke.•Significant gender differences exist in epidemiology, clinical assessment, treatment and outcomes for PAD patients.•Women suffer from functional impairment, morbidity and mortality from PAD at higher rates as compared to men.•Timely diagnosis, treatment and cardiovascular risk modification in women will reduce significant morbidity and mortality from cardiovascular as well as non-cardiovascular causes.
Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1β ...(IL-1β) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1β signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle–brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990
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