In this long-term follow-up of a randomized trial comparing endarterectomy with stenting for carotid-artery stenosis, the risks of periprocedural stroke, myocardial infarction, or death and ...subsequent ipsilateral stroke did not differ between groups over a 10-year period.
We previously reported the outcomes up to 4 years in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
1
No significant difference was shown between patients assigned to stenting and those assigned to endarterectomy with respect to the composite primary end point of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. At baseline, the mean age of the patients was 69 years, and at that age the average life expectancy is 15 years for men and 17 years for women.
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As such, long-term treatment differences should be central to treatment decisions. We now report whether the outcomes after stenting . . .
In this randomized comparison of stenting and endarterectomy as treatment for carotid-artery stenosis, there was no significant difference in the rate of the composite primary end point of stroke, ...myocardial infarction, or death (7.2% and 6.8%, respectively; P=0.51). Stroke was more common with carotid-artery stenting than carotid endarterectomy; myocardial infarction was more common with carotid endarterectomy. The 4-year rate of stroke or death was 6.4% for carotid-artery stenting and 4.7% for carotid endarterectomy (P=0.03).
In this randomized comparison of stenting and endarterectomy as treatment for carotid-artery stenosis, there was no significant difference in the rate of the composite primary end point of stroke, myocardial infarction, or death (7.2% and 6.8%, respectively).
Carotid-artery atherosclerosis is an important cause of ischemic stroke.
1
Carotid endarterectomy has been established as effective treatment for both symptomatic patients and asymptomatic patients.
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–
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Carotid-artery stenting is another option for treatment. The results of randomized trials comparing carotid-artery stenting and carotid endarterectomy for use in symptomatic patients are conflicting.
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7
The primary aim of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) was to compare the outcomes of carotid-artery stenting with those of carotid endarterectomy among patients with symptomatic or asymptomatic extracranial carotid stenosis.
Methods
Study Design
CREST is a randomized, controlled trial with blinded end-point adjudication. Ethics review . . .
The Society for Vascular Surgery (SVS) appointed a committee of experts to formulate evidence-based clinical guidelines for the management of carotid stenosis. In formulating clinical practice ...recommendations, the committee used systematic reviews to summarize the best available evidence and the GRADE scheme to grade the strength of recommendations (GRADE 1 for strong recommendations; GRADE 2 for weak recommendations) and rate the quality of evidence (high, moderate, low, and very low quality). In symptomatic and asymptomatic patients with low-grade carotid stenosis (<50% in symptomatic and <60% in asymptomatic patients), we recommend optimal medical therapy rather than revascularization (GRADE 1 recommendation, high quality evidence). In symptomatic patients with moderate to severe carotid stenosis (more than 50%), we recommend carotid endarterectomy plus optimal medical therapy (GRADE 1 recommendation, high quality evidence). In symptomatic patients with moderate to severe carotid stenosis (≥50%) and high perioperative risk, we suggest carotid artery stenting as a potential alternative to carotid endarterectomy (GRADE 2 recommendation, low quality evidence). In asymptomatic patients with moderate to severe carotid stenosis (≥60%), we recommend carotid endarterectomy plus medical management as long as the perioperative risk is low (GRADE 1 recommendation, high quality evidence). We recommend against carotid artery stenting for asymptomatic patients with moderate to severe (≥60%) carotid artery stenosis (GRADE 1 recommendation, low quality evidence). A possible exception includes patients with ≥80% carotid artery stenosis and high anatomic risk for carotid endarterectomy.
Objectives Ultrasound velocity criteria for the diagnosis of in-stent restenosis in patients undergoing carotid artery stenting (CAS) are not well established. In the present study, we test whether ...ultrasound velocity measurements correlate with increasing degrees of in-stent restenosis in patients undergoing CAS and develop customized velocity criteria to identify residual stenosis ≥20%, in-stent restenosis ≥50%, and high-grade in-stent restenosis ≥80%. Methods Carotid angiograms performed at the completion of CAS were compared with duplex ultrasound (DUS) imaging performed immediately after the procedure. Patients were followed up with annual DUS imaging and underwent both ultrasound scans and computed tomography angiography (CTA) at their most recent follow-up visit. Patients with suspected high-grade in-stent restenosis on DUS imaging underwent diagnostic carotid angiograms. DUS findings were therefore available for comparison with luminal stenosis measured by carotid angiograms or CTA in all these patients. The DUS protocol included peak-systolic (PSV) and end-diastolic velocity (EDV) measurements in the native common carotid artery (CCA), proximal stent, mid stent, distal stent, and distal internal carotid artery (ICA). Results Of 255 CAS procedures that were reviewed, 39 had contralateral ICA stenosis and were excluded from the study. During a mean follow-up of 4.6 years (range, 1 to 10 years), 23 patients died and 64 were lost. Available for analysis were 189 pairs of ultrasound and procedural carotid angiogram measurements; 99 pairs of ultrasound and CTA measurements during routine follow-up; and 29 pairs of ultrasound and carotid angiograms measurements during follow-up for suspected high-grade in-stent restenosis ≥80% (n = 310 pairs of observations, ultrasound vs carotid angiograms/CTA). The accuracy of CTA vs carotid angiograms was confirmed ( r2 = 0.88) in a subset of 19 patients. Post-CAS PSV ( r2 = .85) and ICA/CCA ratios ( r2 = 0.76) correlated most with the degree of stenosis. Receiver operating characteristic analysis demonstrated the following optimal threshold criteria: residual stenosis ≥20% (PSV ≥150 cm/s and ICA/CCA ratio ≥2.15), in-stent restenosis ≥50% (PSV ≥220 cm/s and ICA/CCA ratio ≥2.7), and in-stent restenosis ≥80% (PSV 340 cm/s and ICA/CCA ratio ≥4.15). Conclusions Progressively increasing PSV and ICA/CCA ratios correlate with evolving restenosis within the stented carotid artery. Ultrasound velocity criteria developed for native arteries overestimate the degree of in-stent restenosis encountered. These changes persist during long-term follow-up and across all grades of in-stent restenosis after CAS. The proposed new velocity criteria accurately define residual stenosis ≥20%, in-stent restenosis ≥50%, and high-grade in-stent restenosis ≥80% in the stented carotid artery.
Lower-extremity peripheral arterial disease (PAD) is associated with decreased functional status, diminished quality of life, amputation, myocardial infarction, stroke, and death. Nevertheless, ...public knowledge of PAD as a morbid and mortal disease has not been previously assessed.
We performed a cross-sectional, population-based telephone survey of a nationally representative sample of 2501 adults > or = 50 years of age, with oversampling of blacks and Hispanics. The survey instrument measured the demographic, risk factor, and cardiovascular disease characteristics of the study population; prevalent leg symptoms; PAD awareness relative to atherosclerosis risk factors and other cardiovascular and noncardiovascular diseases; perceived causes of PAD; and perceived systemic and limb consequences of PAD. Respondents were 67.2+/-12.6 years of age with a high prevalence of risk factors but only a modest burden of known coronary or cerebrovascular disease. Twenty-six percent of respondents expressed familiarity with PAD, a rate significantly lower than that for any other cardiovascular disease or atherosclerosis risk factor. Within the "PAD-aware" cohort, knowledge was poor. Half of these individuals were not aware that diabetes and smoking increase the risk for PAD; 1 in 4 knew that PAD is associated with increased risk of heart attack and stroke; and only 14% were aware that PAD could lead to amputation. All knowledge domains were lower in individuals with lower income and education levels.
The public is poorly informed about PAD, with major knowledge gaps regarding the definition of PAD, risk factors that lead to PAD, and associated limb symptoms and amputation risk. The public is not aware that PAD imposes a high short-term risk of heart attack, stroke, and death. For the national cardiovascular disease burden to be reduced, public PAD knowledge could be improved by national PAD public education programs designed to reduce critical knowledge gaps.
A heightened risk of stroke and death among octogenarians undergoing carotid artery stenting (CAS) has been reported. The multicenter Carotid Revascularization Endarterectomy vs. Stent Trial (CREST) ...supported by the National Institute of Neurological Disorders, National Institutes of Health, compares the efficacy of carotid endarterectomy (CEA) and CAS in an ongoing clinical trial. This effort also includes a “lead-in” phase of symptomatic (>50% stenosis) and asymptomatic (>70% stenosis) patients. The protocol calls for patients to receive aspirin and clopidogrel before and 30-days after CAS and to be examined by a study neurologist preprocedure, at 24-hours, and at 30-day. The occurrence of stroke and death was reviewed by an independent clinical events committee.
The association of age and periprocedural stroke and death was examined in 749 lead-in patients undergoing CAS (30.7% symptomatic, 69.3% asymptomatic). Patients were separated into four age categories: less than 60, 60 to 69, 70 to 79, and 80 years or older, and the proportion of patients with stroke and death during the 30-day periprocedural period was calculated for each category.
An increasing proportion of patients suffered stroke and death with increasing age (
P = .0006); 2 (1.7%) of 120 patients under age 60, 3 (1.3%) of 229 aged 60 to 69, 16 (5.3%) of 301 aged 70 to 79, and 12 (12.1%) of 99 patients aged 80 years and older. These increasingly high complication rates at older ages were not mediated by adjustment for symptomatic status, use of antiembolic devices, gender, percentage of carotid stenosis, or the presence of distal arterial tortuosity.
Interim results from the lead-in phase of CREST show that the periprocedural risk of stroke and death after CAS increases with age in the course of a credentialing registry. This effect is not mediated by potential confounding factors. Randomized trial data are needed to compare the CAS versus CEA periprocedural risk of stroke and death by age. Pending results from randomized studies, care should be taken when CAS is performed in older patient populations.
The use of stable isotopes of carbon (
δ
13
C) and nitrogen (
δ
15
N) from feces and breath offers potential as non-destructive tools to assess diets and nutrition. How stable isotope values derived ...from breath and feces compare with those from commonly used tissues, such as blood fractions and liver, remains uncertain, including understanding the metabolic routing of dietary nutrients. Here, we measured
δ
13
C and
δ
15
N from feces and
δ
13
C of breath from captive Red-necked Stints (
Calidris ruficollis
) and 26 species of wild-caught migratory shorebirds (
n
= 259 individuals) and compared them against isotopic values from blood and feathers. For captive birds fed either cereal- or fish-based diets, differences in
δ
13
C between feces and lipid-free diet were small, − 0.2 ± 0.5‰ and 0.1 ± 0.3‰, respectively, and differences in
δ
15
N, − 0.7 ± 0.5‰ and − 0.5 ± 0.5‰, respectively. Hence,
δ
13
C and
δ
15
N values from feces can serve as proxies for ingested proteinaceous tissues and non-soluble carbohydrates because isotopic discrimination can be considered negligible. Stable isotope values in plasma and feces were strongly correlated in wild-caught shorebirds, indicating feces can be used to infer assimilated macronutrients. Breath
δ
13
C was 1.6 ± 0.8‰ to 5.6 ± 1.2‰ lower than bulk food sources, and breath C derived from lipids was estimated at 47.5% (cereal) to 96.1% (fish), likely underlining the importance of dietary lipids for metabolism. The findings validate the use of stable isotope values of feces and breath in isotopic assays to better understand the dietary needs of shorebirds.
In the Carotid Revascularization Endarterectomy versus Stent Trial (CREST), carotid artery atherosclerotic lesion length and nature of the lesions were important factors that predicted the observed ...difference in stroke rates between carotid endarterectomy and carotid artery stenting (CAS). Additional patient-related factors influencing CAS outcomes in CREST included age and symptomatic status. The importance of the operator's proficiency and its influence on periprocedural complications have not been well defined. We evaluated data from CREST to determine the impact of use of multiple stents, which we speculate may be related to technical proficiency.
CREST includes CAS performed for symptomatic ≥50% carotid stenosis and asymptomatic ≥70% stenosis. Both symptomatic and asymptomatic patients were enrolled in the trial and in the lead-in registry. Data from patients enrolled in the CREST registry and randomized trial from 2000 to 2008 were reviewed for patient- and lesion-related characteristics along with number of stents deployed. The occurrence of 30-day stroke and demographic and clinical features were recorded. Odds ratios for 30-day stroke associated with the use of multiple stents were calculated in univariate analysis and on multivariable analysis after adjustment for demographics (age, sex, symptomatic status), lesion characteristics (length, ulceration, eccentric, percentage stenosis), and risk factors (diabetes, hypertension, dyslipidemia, and smoking).
The registry (n = 1531) and trial (n = 1121) enrolled 2652 patients undergoing CAS. The mean age was 69 years; 36% were women, and 38% were symptomatic. The mean diameter stenosis was 78%, and the mean lesion length was 18 mm (±standard deviation, 8 mm). Risk factors included hypertension (85%), diabetes (32%), dyslipidemia (84%), and smoking (23%). All patients received Acculink stents (Abbott Vascular, Abbott Park, Ill) that were 20, 30, or 40 mm in length (straight or tapered) and Accunet (Abbot Vascular) embolic protection when possible. Most patients received one stent (n = 2545), whereas 98 patients received two stents and 9 patients received three stents (P < .001) to treat the lesion. Patients receiving more than one stent were older (P = .01) but did not differ in other demographic or risk factors. Strokes occurred in 118 (4.5%) of all CAS procedures, in 102 (4%) with the use of one stent, and in 16 (15%) with the use of two or three stents. After adjustment for demographics, lesion characteristics, and risk factors, the use of more than one stent resulted in 2.90 odds (95% confidence interval, 1.49-5.64) for a stroke.
Although we know that lesion characteristics (length, ulceration) play an important role in CAS outcomes, in this early experience with carotid stenting, a significant and independent relationship existed between the number of stents used and procedural risk of CAS. We postulate that this was an indicator of the operator's inexperience with the procedure.
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1 Program in Vascular Biology, Department of Pharmacology and Physiology, and 2 Division of Vascular Surgery, Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey ...Medical School, Newark, New Jersey
Submitted 25 October 2004
; accepted in final form 1 June 2005
Diabetes mellitus is a major risk factor for the development of vascular complications. We hypothesized that hyperglycemia decreases endothelial cell (EC) proliferation and survival via phosphatidylinositol 3-kinase (PI3k) and Akt signaling pathways. We cultured human umbilical vein ECs (HUVEC) in 5, 20, or 40 mM D -glucose. Cells grown in 5, 20, and 40 mM mannitol served as a control for osmotic effects. We measured EC proliferation for up to 15 days. We assessed apoptosis by annexin V and propidium iodide staining and flow cytometry, analyzed cell lysates obtained on culture day 8 for total and phosphorylated PI3k and Akt by Western blot analysis, and measured Akt kinase activity using a GSK fusion protein. HUVEC proliferation was also tested in the presence of pharmacological inhibitors of PI3k-Akt (wortmannin and LY294002 ) and after transfection with a constitutively active Akt mutant. ECs in media containing 5 mM D -glucose (control) exhibited log-phase growth on days 710 . D -Glucose at 20 and 40 mM significantly decreased proliferation versus control ( P < 0.05 for both), whereas mannitol did not impair EC proliferation. Apoptosis increased significantly in HUVEC exposed to 40 mM D -glucose. D -Glucose at 40 mM significantly decreased tyrosine-phosphorylated PI3k, threonine 308-phosphorylated-Akt, and Akt activity relative to control 5 mM D -glucose. Pharmacological inhibition of PI3k-Akt resulted in a dose-dependent decrease in EC proliferation. Transfection with a constitutively active Akt mutant protected ECs by enhancing proliferation when grown in 20 and 40 mM D -glucose. We conclude that D -glucose regulates Akt signaling through threonine phosphorylation of Akt and that hyperglycemia-impaired PI3k-Akt signaling may promote EC proliferative dysfunction in diabetes.
endothelial cell proliferation; diabetes mellitus; phosphatidylinositol 3-kinase; protein kinase B; Akt; endothelial cell apoptosis
Address for reprint requests and other correspondence: B. K. Lal, Dept. of Surgery, UMDNJNew Jersey Medical School, 185 S. Orange Ave., MSB H570, PO Box 1709, Newark, NJ 071011709 (e-mail: lalbk{at}umdnj.edu )
Nitric oxide (NO) is an important regulator of blood flow, but its role in permeability is still challenged. We tested in vivo the hypotheses that: (a) endothelial nitric oxide synthase (eNOS) is not ...essential for regulation of baseline permeability;
(b) eNOS is essential for hyperpermeability responses in inflammation; and (c) molecular inhibition of eNOS with caveolin-1
scaffolding domain (AP-Cav) reduces eNOS-regulated hyperpermeability. We used eNOS-deficient (eNOSâ/â) mice and their wild-type
control as experimental animals, platelet-activating factor (PAF) at 10 â7
m as the test pro-inflammatory agent, and integrated optical intensity (IOI) as an index of microvascular permeability. PAF
increased permeability in wild-type cremaster muscle from a baseline of 2.4 ± 2.2 to a peak net value of 84.4 ± 2.7 units,
while the corresponding values in cremaster muscle of eNOSâ/â mice were 1.0 ± 0.3 and 15.6 ± 7.7 units ( P < 0.05). Similarly, PAF increased IOI in the mesentery of wild-type mice but much less in the mesentery of eNOSâ/â mice.
PAF increased IOI to comparable values in the mesenteries of wild-type mice and those lacking the gene for inducible NOS (iNOS).
Administration of AP-Cav blocked the microvascular hyperpermeability responses to 10 â7
m PAF. We conclude that: (1) baseline permeability does not depend on eNOS; (2) eNOS and NO are integral elements of the signalling
pathway for the hyperpermeability response to PAF; (3) iNOS does not affect either baseline permeability or hyperpermeability
responses to PAF; and (4) caveolin-1 inhibits eNOS regulation of microvascular permeability in vivo . Our results establish eNOS as an important regulator of microvascular permeability in inflammation.
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