Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region.

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Impact of presenting stroke severity and thrombolysis on outcomes following urgent carotid interventions.

BACKGROUND: Carotid interventions are increasingly performed in select patients following acute stroke. We aimed to determine the effects of presenting stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and use of systemic thrombolysis (tissue plasminogen activator [tPA]) on discharge neurological outcomes (modified Rankin scale [mRS]) after urgent carotid endarterectomy (uCEA) and urgent carotid artery stenting (uCAS). METHODS: Patients undergoing uCEA/uCAS at a tertiary Comprehensive Stroke Center (January 2015 to May 2022) were divided into two cohorts: (1) no thrombolysis (uCEA/uCAS only) and (2) use of thrombolysis before the carotid intervention (tPA + uCEA/uCAS). Outcomes were discharge mRS and 30-day complications. Regression models were used to determine an association between tPA use and presenting stroke severity (NIHSS) and discharge neurological outcomes (mRS). RESULTS: Two hundred thirty-eight patients underwent uCEA/uCAS (uCEA/uCAS only, n = 186; tPA + uCEA/uCAS, n = 52) over 7 years. In the thrombolysis cohort compared with the uCEA/uCAS only cohort, the mean presenting stroke severity was higher (NIHSS = 7.6 vs 3.8; P = .001), and more patients presented with moderate to severe strokes (57.7% vs 30.2% with NIHSS >4). The 30-day stroke, death, and myocardial infarction rates in the uCEA/uCAS only vs tPA + uCEA/uCAS were 8.1% vs 11.5% (P = .416), 0% vs 9.6% (P < .001), and 0.5% vs 1.9% (P = .39), respectively. The 30-day stroke/hemorrhagic conversion and myocardial infarction rates did not differ with tPA use; however, the difference in deaths was significantly higher in the tPA + uCEA/uCAS cohort (P < .001). There was no difference in neurological functional outcome with or without thrombolysis use (mean mRS, 2.1 vs 1.7; P = .061). For both minor strokes (NIHSS ≤4 vs NIHSS >4: relative risk, 1.58 vs 1.58, tPA vs no tPA, respectively, P = .997) and moderate strokes (NIHSS ≤10 vs NIHSS >10: relative risk, 1.94 vs 2.08, tPA vs no tPA, respectively; P = .891), the likelihood of discharge functional independence (mRS score of ≤2) was not influenced by tPA. CONCLUSIONS: Patients with a higher presenting stroke severity (NIHSS) had worse neurological functional outcomes (mRS). Patients presenting with minor and moderate strokes were more likely to have discharge neurological functional independence (mRS of ≤2), regardless of whether they received tPA or not. Overall, presenting NIHSS is predictive of discharge neurological functional autonomy and is not influenced by the use of thrombolysis.

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

OBJECTIVES: "Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. METHODS: In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance. RESULTS: From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78). CONCLUSION: "Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

A pro-inflammatory and fibrous cap thinning transcriptome profile accompanies carotid plaque rupture leading to stroke.

Atherosclerotic plaque rupture is the etiology of ischemic stroke and myocardial infarction. The molecular mechanisms responsible for rupture remain unclear, in part, due to the lack of data from plaques at the time of rupture. Ribosome-depleted total RNA was sequenced from carotid plaques obtained from patients undergoing carotid endarterectomy with high-grade stenosis and either (1) a carotid-related ischemic cerebrovascular event within the previous 5 days ('recently ruptured,' n = 6) or (2) an absence of a cerebrovascular event ('asymptomatic,' n = 5). Principal component analysis confirmed plaque rupture was responsible for the greatest percentage of the variability between samples (23.2%), and recently ruptured plaques were enriched for transcripts associated with inflammation and extracellular matrix degradation. Hierarchical clustering achieved differentiation of the asymptomatic from the recently ruptured plaques. This analysis also found co-expression of transcripts for immunoglobulins and B lymphocyte function, matrix metalloproteinases, and interferon response genes. Examination of the differentially expressed genes supported the importance of inflammation and inhibition of proliferation and migration coupled with an increase in apoptosis. Thus, the transcriptome of recently ruptured plaques is enriched with transcripts associated with inflammation and fibrous cap thinning and support further examination of the role of B lymphocytes and interferons in atherosclerotic plaque rupture.

Neurologic outcomes of carotid and other emergent interventions for ischemic stroke over 6 years with dataset enhanced by machine learning.

BACKGROUND: The current mainstays of ischemic stroke treatment include the use of thrombolysis (tissue plasminogen activator [tPA]), urgent carotid endarterectomy (uCEA) or urgent carotid artery stenting (uCAS), and mechanical endovascular reperfusion/thrombectomy (MER). Scarce data describe the presenting stroke severity and neurologic outcomes for these acute ischemic stroke interventions, alone or in combination. The authors hypothesize that patients undergoing carotid interventions experience better functional neurologic outcomes than other stroke interventions. METHODS: A comprehensive stroke center dataset was combined with data for stroke-related procedures, comorbidities, complications, and physician documentation collected from electronic medical record data. A total of 10,975 patient encounter records from January 1, 2015, through July 31, 2021, were retrieved. The presenting stroke severity was determined by vascular/stroke neurologists using the National Institutes of Health Stroke Scale (NIHSS). Functional neurologic outcomes were reported using the modified Rankin scale (mRS) score, which quantifies the degree of neurologic disability. Because mRS values were only available for 3627 encounters in the original dataset, the authors developed a machine learning algorithm to analyze physician documentation and assign an mRS value. After the exclusion and machine learning analysis, a total of 5170 patient encounters were included for statistical analysis. Statistical analyses included the χ2 test, one-way analysis of variance and logistic regression on 30-day complications, stroke severity, and neurologic outcomes. RESULTS: Patients were divided into five cohorts: (1) uCEA or uCAS (n = 189), (2) tPA alone (n = 1053), (3) MER alone (n = 418), (4) tPA + MER (n = 199), and (5) no intervention (n = 3311). Patients undergoing uCEA/uCAS were significantly more likely to be male, smokers, and have a history of peripheral arterial disease compared with other stroke cohorts. The length of stay was shortest for patients who only received tPA or no intervention (6 days), followed by uCEA/uCAS (7.2 days), MER (10.2 days), and tPA + MER (8.8 days) cohorts (P < .001). The 30-day mortality was highest in the MER cohort (12.2%) and lowest in the uCEA/uCAS cohort (2.6%). The uCEA/uCAS cohort compared with other cohorts had the lowest presenting stroke severity (NIHSS 4.9 vs NIHSS 6.9-16.0), and best neurologic outcomes (mRS 1.7 vs mRS 1.8-2.6). CONCLUSIONS: After an ischemic stroke, patients undergoing urgent carotid interventions had the lowest presenting stroke severity (NIHSS) and highest rate of independent neurologic outcomes (mRS) compared with other stroke interventions. Incoming stroke severity correlates with functional neurologic outcomes, and patients who present with an NIHSS of 10 or less who undergo uCEA/uCAS have a high likelihood of independent neurologic functional outcome (mRS of ≤2).

Financial viability of endovascular aortic repair in the modern era.

BACKGROUND: In the current era of cost containment, the financial impact of high-cost procedures such as endovascular aneurysm repair (EVAR) remains an area of intensive interest. Previous reports suggested slim to negative operating margins with EVAR, prompting widespread initiatives to reduce cost and to improve reimbursement. In 2015, the Centers for Medicare and Medicaid Services (CMS) announced the reclassification of EVAR to more specific diagnosis-related group (DRG) coding and predicted an overall increase in hospital reimbursement. The potential impact of this change has not been described. METHODS: Patients undergoing elective EVAR at a single institution between January 2014 and December 2018 were identified retrospectively, then stratified by date. Group 1 patients underwent EVAR before DRG change in 2015 and were classified with DRG 237/238, major cardiovascular procedure. Group 2 patients underwent EVAR after the change and were classified as DRG 268/269, aortic/heart assist procedures. The total direct cost included implant cost, operating room (OR) labor, room and board, and other supply costs. Net revenue reflected real payer mix values without extrapolation based on standard Medicare rates. Hospital profit was defined as the contribution to indirect (CTI), subtracting total direct cost from net revenue. RESULTS: A total of 188 encounters were included, 67 (36%) in group 1 and 121 (64%) in group 2. Medicare patients composed 84% of group 1 and 81% of group 2. CTI (profit) increased by $4447 (+123%) from $3615 in group 1 to $8062 in group 2. Net revenue per encounter increased by $2054 (+7.1%). In group 1, the higher reimbursement DRG code 237 was applied in 5 of 67 (7.5%) patients, whereas DRG code 268 was assigned in 19 of 121 (15.1%) patients in group 2. Total direct cost per encounter decreased by $2012 (-7.9%). This decrease in cost was driven by a reduction in implant cost, from a mean $16,914 per encounter in group 1 to a mean $15,655 in group 2 (-$1259 or -7.4% per encounter) and by a decrease in OR labor cost, $2838 in group 1 to $2361 in group 2 (-$477 or -17.0% per encounter). CONCLUSIONS: A significant improvement in hospital CTI was observed for elective EVAR during the course of the study. The increased DRG reimbursement after the Centers for Medicare and Medicaid Services coding changes in 2015 was a major driver of this salutary change. Notably, efforts to reduce implant and OR cost as well as to improve coding and documentation accuracy over time had an equally important impact on financial return.

Rapid progression of carotid stenosis was rare in a large integrated healthcare system during an eight-year period.

OBJECTIVE: Few studies have evaluated the rapid progression of carotid stenosis on a large scale. We created a custom software algorithm to analyze an electronic medical record database to examine the natural progression of carotid stenosis, identify a subset of patients with rapid progression, and evaluate the specific patient risk factors associated with this rapid progression. METHODS: Patients in a large integrated healthcare system who had undergone two or more carotid ultrasound scans from August 2010 to August 2018 were identified. We did not distinguish between those with an established carotid stenosis diagnosis and those with a screening ultrasound scan. We used our novel algorithm to extract data from their carotid ultrasound reports. The degrees of carotid stenosis were categorized as follows: level 1, 0% to 39%; level 2, 40% to 59%; level 3, 60% to 79%; level 4, 80% to 99%; and level 5, complete occlusion. The primary endpoint was rapid vs slow progression of carotid stenosis, with rapid progression defined as an increase of two or more levels within any 18-month period of the study, regardless of the date of the initial ultrasound scan. The association of the demographic and clinical characteristics with rapid progression was assessed by univariable and multivariable logistic regression. RESULTS: From a cohort of 4.4 million patients, we identified 4982 patients with two or more carotid ultrasound scans and a median follow-up period of 13.1 months (range, 0.1-93.7 months). Of the 4982 patients, 879 (17.6%) had shown progression of carotid stenosis. Only 116 patients (2.3%) had had progression to level 4 (80%-99% stenosis) from any starting level during a median of 11.5 months. A total of 180 patients (3.6%) were identified as experiencing rapid progression during a median follow-up of 9.9 months. The final multivariable analysis showed that younger age (P < .01), white race (P = .02), lower body mass index (P = .01), a diagnosis of peripheral arterial disease (P = .03), and a diagnosis of transient ischemic attack (P < .01) were associated with rapid progression. CONCLUSIONS: Using a novel algorithm to extract data from >4 million patient records, we found that rapid progression of carotid stenosis appears to be rare. Although 17.6% of patients showed any degree of progression, only 3.6% had experienced rapid progression. Among those with any disease progression, 20.5% had experienced rapid progression. Although the overall incidence of rapid progression was low, patients with any progression might warrant close follow-up, especially if they have the associated risk factors for rapid progression. The custom software algorithm might be a powerful tool for creating and evaluating large datasets.

A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis.

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

Patients with moderate to severe strokes (NIHSS score >10) undergoing urgent carotid interventions within 48 hours have worse functional outcomes.

OBJECTIVE: Increasing evidence suggests that urgent carotid intervention after a nondisabling stroke is safe. However, the functional outcome of such patients has not been quantified for various degrees of stroke. We aimed to determine whether increased presenting stroke severity and timing to intervention are associated with poor functional outcomes in patients undergoing urgent carotid endarterectomy (CEA) or carotid artery stenting (CAS) after an acute transient ischemic attack or stroke. METHODS: We reviewed all urgent carotid interventions from January 2013 through April 2017 at a single tertiary referral center. Preoperative variables analyzed included admission stroke severity, calculated by National Institutes of Health Stroke Scale (NIHSS). The primary end point was the patient's neurologic functional independence at discharge, quantified by the modified Rankin scale (mRS) score (≤2, functionally independent; ≥3, dependent). Primary complications were defined as new or worsened stroke, intracranial hemorrhage, and death. RESULTS: A total of 120 urgent carotid interventions (CEA, n = 96; CAS, n = 22; 1 CEA with middle cerebral artery aspiration thrombectomy and 1 carotid embolectomy) were performed. Bivariate analysis demonstrated a correlation between admission NIHSS score and mRS score when patients were divided into groups with an admission NIHSS score ≤10 and >10 (P = .0029). Patients presenting with larger strokes (NIHSS score >10) were 3.4 times more likely (95% confidence interval [CI], 1.2-9.6; P = .024) to have functional dependence (mRS score ≥3) at discharge than patients presenting with minor to moderate strokes (NIHSS score ≤10). Patients undergoing CEA or CAS before 48 hours were also associated with a worse discharge mRS score compared with those undergoing carotid interventions after 48 hours (odds ratio, 3.5; 95% CI, 1.4-8.7; P = .007). Even when emergent carotid interventions were excluded from the subgroup of patients undergoing CEA or CAS within 48 hours, discharge mRS correlated with time to procedure (days 1- 2 compared with >2 days). The odds of having discharge functional dependence (mRS score ≥3) were 3.4 times more likely for patients with the procedure performed at 1 to 2 days compared with >2 days (95% CI, 1.3-9.1; P = .014). CONCLUSIONS: Urgent carotid intervention performed in patients with moderate or severe strokes (NIHSS score >10) and before 48 hours is associated with functional dependence (mRS score ≥3) on hospital discharge. By demonstrating a clear correlation between admission NIHSS score and interval time to procedure with independent neurologic functional outcomes, these data aid in clinical decision-making for this high-risk subpopulation of patients who present with acute symptomatic carotid lesions.

Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease.

BACKGROUND: Efficient biomarkers for early prediction and diagnosis of an acutely symptomatic carotid plaque rupture event are currently lacking, impairing the ability to diagnose and treat patients with an acute plaque rupture events in a timely fashion. Resolvins are endogenous inflammation-resolving lipid mediators that are induced by inflammatory insults. We hypothesized that resolvin and other lipid profiles in sera likely mark the process towards plaque rupture. METHODS: Circulating lipids associated with plaque rupture events were quantitatively profiled via targeted mediator-lipidomics using ultraperformance liquid chromatography tandem mass spectrometry in patients with acutely symptomatic and asymptomatic carotid disease. RESULTS: Resolvin D1 (RvD1, 82 ± 11pM vs. 152 ± 17pM, p = 0.001) and docosahexaenoic acid (DHA) (0.052 ± 0.007µM versus 0.076 ± 0.008µM, p = 0.025) levels are decreased in the sera of patients presenting with an acutely symptomatic carotid plaque rupture event (n = 21) compared to patients with asymptomatic (n = 24) high-grade carotid stenosis. Circulating arachidonic acid (AA) levels, however, were higher (0.429 ± 0.046µM versus 0.257 ± 0.035µM, p < 0.01) in acutely symptomatic compared to asymptomatic carotid patients. ROC curve analysis demonstrates that the serum ratio AA:RvD1 (AUC 0.84, sensitivity 0.71, specificity 0.92) and AA:DHA (AUC 0.86, sensitivity 0.90, specificity 0.71) are biomarkers for the risk of atherosclerotic plaque rupture. CONCLUSIONS: A circulating pro-inflammatory lipid profile, characterized by high AA:RvD1 and AA:DHA, is associated with acutely symptomatic carotid disease and stroke.

Carotid Plaque Rupture Is Accompanied by an Increase in the Ratio of Serum circR-284 to miR-221 Levels.

BACKGROUND: Atherosclerotic plaque rupture is accompanied by an acute decrease in the carotid plaque expression of micro-RNAs (miRs)-221 and miR-222. Circular RNA (circR)-284 is a potential inhibitor of miR-221/miR-222 activity. We aimed to determine whether changes in the serum levels of these noncoding RNAs are observed in patients with asymptomatic high-grade carotid disease versus patients with acutely symptomatic carotid disease and recent ischemic stroke. Additionally, we tested the use of functionally related noncoding RNA pairs to enhance the discriminatory power of noncoding RNAs as circulating biomarkers. METHODS AND RESULTS: Serum levels of miR-221, miR-222, miR-145, and circR-284 were measured in 24 asymptomatic (asymptomatic) and 17 acutely symptomatic patients ([urgent] ischemic cerebrovascular event within the previous 5 days) undergoing carotid endarterectomy. miR-221 was significantly lower, whereas circR-284 was elevated in the serum of the urgent compared with the asymptomatic group. The ratio of serum circR-284:miR-221 was significantly elevated in the urgent group (P=0.0002) and exhibited favorable characteristics as a biomarker indicative of carotid plaque rupture and stroke. A validation study in 112 patients (47 asymptomatic, 41 urgent, and 24 patients with a cerebrovascular event between 5 and 180 days of the carotid endarterectomy [symptomatic]) confirmed elevation of serum circR-284:miR-221 uniquely in the urgent group (P<0.001) and favorable sensitivity and specificity for detecting plaque rupture and stroke. CONCLUSIONS: Serum circR-284:miR-221 has potential as a diagnostic biomarker of carotid plaque rupture and stroke. Moreover, we demonstrate the use of functionally related pairs of circulating noncoding RNAs as biomarkers in cardiovascular disease.

Complications after endovascular treatment of hepatic artery stenosis after liver transplantation.

BACKGROUND: Hepatic artery stenosis (HAS) after liver transplantation can progress to hepatic artery thrombosis (HAT) and a subsequent 30% to 50% risk of graft loss. Although endovascular treatment of severe HAS after liver transplantation has emerged as the dominant method of treatment, the potential risks of these interventions are poorly described. METHODS: A retrospective review of all endovascular interventions for HAS after liver transplantation between August 2009 and March 2016 was performed at a single institution, which has the largest volume of liver transplants in the United States. Severe HAS was identified by routine surveillance duplex ultrasound imaging (peak systolic velocity >400 cm/s, resistive index <0.5, and presence of tardus parvus waveforms). RESULTS: In 1129 liver transplant recipients during the study period, 106 angiograms were performed in 79 patients (6.9%) for severe de novo or recurrent HAS. Interventions were performed in 99 of 106 cases (93.4%) with percutaneous transluminal angioplasty alone (34 of 99) or with stent placement (65 of 99). Immediate technical success was 91%. Major complications occurred in eight of 106 cases (7.5%), consisting of target vessel dissection (5 of 8) and rupture (3 of 8). Successful endovascular treatment was possible in six of the eight patients (75%). Ruptures were treated with the use of a covered coronary balloon-expandable stent graft or balloon tamponade. Dissections were treated with placement of bare-metal or drug-eluting stents. No open surgical intervention was required to manage any of these complications. With a median of follow-up of 22 months, four of eight patients (50%) with a major complication progressed to HAT compared with one of 71 patients (1.4%) undergoing a hepatic intervention without a major complication (P < .001). One patient required retransplantation. Severe vessel tortuosity was present in 75% (6 of 8) of interventions with a major complication compared with 34.6% (34 of 98) in those without (P = .05). In the complication cohort, 37.5% (3 of 8) of the patients had received a second liver transplant before intervention compared with 12.6% (9 of 71) of the patients in the noncomplication cohort (P = .097). CONCLUSIONS: Although endovascular treatment of HAS is safe and effective in most patients, target vessel injury is possible. Severe tortuosity of the hepatic artery and prior retransplantation were associated with a twofold to threefold increased risk of a major complication. Acute vessel injury can be managed successfully using endovascular techniques, but these patients have a significant risk of subsequent HAT and need close surveillance.

Heparin-Bonded Polytetrafluorethylene Does Not Improve Hemodialysis Arteriovenous Graft Function.

BACKGROUND: Heparin-bonded polytetrafluorethylene (hep PTFE), when compared with standard PTFE, has been shown to have a modest improvement in distal extremity bypass grafts. The data supporting its usage for dialysis access are less clear. We compared the patency rates, number of interventions, and complications between hep PTFE grafts and nonheparin-bonded PTFE (nonhep PTFE) grafts placed for dialysis access. METHODS: A retrospective review of all dialysis access procedures between January 2013 and March 2014 entered into a prospectively maintained vascular surgery database was performed. Our primary end point was functional graft patency. Secondary end points were primary, primary assisted, and secondary patency, as well as time to graft abandonment, and number of procedures required to maintain or restore graft patency. The number of interventions required to maintain graft patency and graft-related complications were also reviewed. Kaplan-Meier curves were used to compare the 2 groups. RESULTS: Between January 2013 and March 2014, 301-dialysis access procedures were performed, which included 70 arteriovenous grafts (AVGs) comprised 32 hep PTFE (32, 6-mm straight grafts) and 38 nonhep PTFE (35, 4-7-mm taper and 3, 6-mm straight). Mean follow-up was 7.35 ± 5.15 months. At 1 year, Kaplan-Meier survival curves showed that functional patency between hep PTFE and nonhep PTFE AVG were 60% and 75%, respectively (P = 0.37). Primary and secondary patencies were not significantly different between groups; however, primary-assisted patency was significantly improved at 1 year (hep PTFE versus nonhep PTFE: 50% vs. 80%; P = 0.02). The number of hep PTFE grafts undergoing percutaneous thrombectomy was significantly higher than the nonhep PTFE grafts (11 vs. 2; P = 0.009). The incidence and time to graft abandonment were not statistically different. The same was true for the number of complications between the 2 groups. Multivariate analysis showed nonhep PTFE AVG to be advantageous for primary and primary-assisted patency. CONCLUSIONS: We did not demonstrate a benefit to the routine use of hep PTFE for AVG creation especially given the higher cost of these grafts. Functional patency rates were not improved, and the rates of reintervention and thrombectomy were higher with hep PTFE AVGs.

Acute Loss of miR-221 and miR-222 in the Atherosclerotic Plaque Shoulder Accompanies Plaque Rupture.

BACKGROUND AND PURPOSE: Atherosclerotic plaque vulnerability is accompanied by changes in the molecular and cellular function in the plaque shoulder, including a decrease in vascular smooth muscle cell proliferation. We aimed to determine whether the expression of 3 miRNAs that regulate vascular smooth muscle cell proliferation (miR-145, miR-221, and miR-222) is altered with plaque rupture, suggesting a role in regulating plaque stability. METHODS: miRNAs were measured in the plaque shoulder of carotid plaques obtained from patients undergoing carotid endarterectomy (CEA) for 3 distinct clinical scenarios: (1) patients without previous neurological events but high-grade carotid stenosis (asymptomatic), (2) patients with an acute neurological event within 5 days of the CEA (urgent), and (3) patients undergoing CEA>5 days after a neurological event (symptomatic). RESULTS: Mean time from plaque rupture event to CEA was 2.4 days in the urgent group. The urgent group exhibited a significant decrease in miR-221 and miR-222 expression in the plaque shoulder, whereas no significant differences were seen in miR-145 across the 3 groups. Regression analysis demonstrated a significant correlation between time from the neurological event to CEA and increasing miR-221 and miR-222, but not miR-145. mRNA encoding p27Kip1, a target of miR-221 and miR-222 that inhibits vascular smooth muscle cell proliferation, was increased in the urgent group. CONCLUSIONS: Atherosclerotic plaque rupture is accompanied by a loss of miR-221 and miR-222 and an increase in p27Kip1 mRNA expression in the plaque shoulder, suggesting an association between these miRNAs and atherosclerotic plaque stability.

Urgent carotid intervention is safe after thrombolysis for minor to moderate acute ischemic stroke.

OBJECTIVE: Carotid intervention shortly after an acute neurologic ischemic event is being performed more frequently in stroke centers to reduce the risk of recurrent stroke. Thrombolysis with recombinant tissue plasminogen activator (tPA) is offered to select patients with ischemic stroke symptoms who present within 4.5 hours. However, there is a paucity of data as to whether tPA followed by urgent carotid endarterectomy (CEA) or carotid artery stenting (CAS) has an increased risk of complications, particularly intracerebral hemorrhage (ICH). We sought to determine the periprocedural complications of urgently performed CEA or CAS following tPA. METHODS: From January 2009 to January 2015, 762 patients underwent carotid interventions (CEA, n = 440; CAS, n = 322) at a tertiary referral center and 165 patients (21.6%) underwent an urgent CEA or CAS during the index hospitalization for an acute transient ischemic attack or stroke. We compared the effect of intravenous tPA on 30-day complications, including ICH. The χ(2) and Fisher exact tests were used to determine significance between groups. RESULTS: During the 6-year period, 165 patients underwent urgent carotid interventions (CEA, n = 135; CAS, n = 30) for acute neurologic symptoms. Of these, 19% (31 patients [CEA, n = 25; CAS, n = 6]) had tPA for an acute stroke; the remaining (134 patients [CEA, n = 110; CAS, n = 24]) fell outside of the tPA time window. Most strokes were minor or moderate with a mean National Institutes of Health Stroke Scale (NIHSS) score of 6.6 (range, 0-19). The mean time to intervention for both groups was 2.4 days (0-15 days). The 30-day stroke, death, and myocardial infarction rates were 9.7% (3 of 31) for the tPA group compared with 4.5% (6 of 134) for the no-tPA group (P = .37). Including bleeding complications in these 30-day outcomes, there was no difference between the tPA (3 of 31) and the no-tPA cohorts (8 of 134; P = .43). In the tPA group, there were one ICH, one neck hematoma/death, and an additional death; in the no-tPA group, there were one ICH, two neck hematomas, one stroke, two myocardial infarctions, one ICH/death, and one additional death. No significant increased rates of bleeding were noted within the tPA group (2 of 31) compared with the no-tPA group (4 of 134; P = .32). Moreover, in the tPA cohort, more than half of the patients (17 of 31) underwent revascularization within 72 hours (CEA = 13; CAS = 4) with outcomes similar to those who underwent revascularization after 72 hours. CONCLUSIONS: Thrombolysis followed by urgent CEA or CAS is not associated with an increased risk of complications in select patients who present with acute neurologic symptoms. Selection of patients is important; there was no ICH and only one death in each group for patients with minor to moderate ischemic stroke (NIHSS score <10).

Primary stent placement for hepatic artery stenosis after liver transplantation.

OBJECTIVE: Significant hepatic artery stenosis (HAS) after orthotopic liver transplantation (OLT) can lead to thrombosis, with subsequent liver failure in 30% of patients. Although operative intervention or retransplantation has been the traditional solution, endovascular therapy has emerged as a less invasive treatment strategy. Prior smaller studies have been conflicting in the relative efficacy of percutaneous transluminal angioplasty (PTA) vs primary stent placement for HAS. METHODS: This was a single-center retrospective review of all endovascular interventions for HAS after OLT during a 54-month period (August 2009-December 2013). Patients with ultrasound imaging with evidence of severe HAS (peak systolic velocity >400-450 cm/s, resistive index <0.5) underwent endovascular treatment with primary stent placement or PTA. Outcomes calculated were technical success, primary and primary assisted patency rates, reinterventions, and complications. RESULTS: Sixty-two interventions for HAS were performed in 42 patients with a mean follow-up of 19.1 ± 15.2 months. During the study period, 654 OLTs were performed. Of 61 patients diagnosed with HAS, 42 underwent an endovascular intervention. The rate of endovascularly treated HAS was 6.4% (42 of 654). Primary technical success was achieved in 95% (59 of 62) of the interventions. Initial treatment was with PTA alone in 17 or primary stent in 25. Primary patency rates after initial stent placement were 87%, 76.5%, 78%, and 78% at 1, 6, 12, and 24 months, respectively, compared with initial PTA rates of 64.7%, 53.3%, 40%, and 0% (P = .19). There were 20 reinterventions in 14 patients (eight stents, six PTAs). The time to the initial reintervention was 51 days in patients with PTA alone vs 105.8 days for those with an initial stent (P = .16). Overall primary assisted patency was 93% at 24 months. Major complications were one arterial rupture and two hepatic artery dissections. The long-term risk of hepatic artery thrombosis in the entire patient cohort was 3.2%. CONCLUSIONS: HAS after OLT can be treated endovascularly with high technical success and excellent primary assisted patency. This series represents the largest reported cohort of endovascular interventions for HAS to date. Initial use of a stent showed a strong trend toward decreasing the need for reintervention. Avoidance of hepatic artery thrombosis is possible in >95% of patients with endovascular treatment and close follow-up.

Transradial approach for percutaneous intervention of malfunctioning arteriovenous accesses.

OBJECTIVE: Interventions on arteriovenous (AV) access are typically performed with a direct puncture into the fistula. An alternative is the transradial approach (TRA), which offers the advantage of visualizing both the arterial and venous limbs as well as any juxta-anastomotic stenosis, all through one access. METHODS: From September 2010 to 2013, 511 fistulograms were performed on 322 patients, 55 of which were TRA procedures in 40 patients (50% male; mean age, 60.4 ± 16.5 years). Of these, 37 of 40 accesses (92.5%) were AV fistulas, and 54 of 55 interventions (98%) were performed for stenotic lesion(s). There were 37 initial interventions, 13 secondary inventions, and five diagnostic fistulograms through the TRA. Stenotic lesions were juxta-anastomotic in 28, venous in 11, or both in 11. Mean follow-up was 14.3 months in 37 of 40 patients. Outcomes included technical and clinical success, complications, functional patency, and flow rate changes. RESULTS: All TRA punctures were successful, with no radial artery thromboses or hand ischemia. Technical success was 88% (44 of 50). Functional patency rates were 88.5% (23 of 26), 84.2% (16 of 19), and 83% (10 of 12) at 1, 6, and 12 months, respectively. The complication rate was 1.8% (one of 55), consisting of AV fistula rupture after angioplasty. The average flow rate in the 20 juxta-anastomotic stenosis increased from 637 mL/min to 1094 mL/min (P = .01) after the procedure. CONCLUSIONS: The TRA is a practical option with functional patency rates that are comparable to traditional approaches when intervening on a malfunctioning dialysis access in the appropriately selected patient. No hand ischemia was noted. This approach may be particularly attractive for treatment of juxta-anastomotic stenoses in a variety of AV accesses and offers unique practical advantages for the maintenance of AV accesses.

Descending thoracic aortic aneurysm: case presentation and review.

Descending thoracic aortic aneurysms, similar to other aneurysms, are often incidentally diagnosed in patients with unrelated complaints. Management of these aneurysms is largely dependent on their size and anatomy. Most individuals with asymptomatic descending thoracic aortic aneurysms may be safely managed with cardiovascular risk factor modification until the aneurysm size reaches 6 cm. A subset of individuals, such as those whose descending thoracic aortic aneurysm measures > 6 cm or in cases of rapid growth, should be offered repair, increasingly performed via an endovascular approach. The higher risk of aneurysm rupture in women poses a unique consideration, although to date no gender-specific consensus screening guideline exists for aneurysmal disease of the thoracic aorta.

Hospital reimbursement for carotid stenting and endarterectomy.

PURPOSE: To investigate the cost-effectiveness of carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) in terms of hospital reimbursement. METHODS: A retrospective analysis was conducted of hospital reimbursement for patients undergoing CEA and CAS from 1 January 2008 through 30 September 2010 at a single tertiary referral institution. Hospital cost and reimbursement were assessed using patient-specific data gathered by the institution's cost accounting system. Professional fees were excluded. RESULTS: Hospital reimbursement data were extracted for a total of 301 cases (169 CEA and 132 CAS). Mean hospital reimbursement was 16% higher for CAS ($12,000±$7372) vs. CEA ($10,160±$6840, p=0.02). However, because of the significantly higher cost of materials necessary to perform CAS, the net revenue for the hospital was 29% greater in patients undergoing CEA ($3487) vs. CAS ($2603). The differences in hospital reimbursement and net revenue were consistent in asymptomatic (n=183), symptomatic (n=123), and urgent (n=36) subgroups. When focusing on cases by diagnosis-related group (DRG) codes vs. current procedural terminology (CPT) codes, the data shifted. Several patients were coded as an outpatient procedure (DRG 0): 28 (21%) of the 132 CAS patients and 7 (4%) of the 169 CEA patients, reducing their mean reimbursement to $4046 and $2513, respectively. If these patients were excluded, the mean hospital reimbursement differential widened between and CEA ($10,515) and CAS ($13,825). CONCLUSION: Hospital reimbursement for CAS is significantly higher than that for CEA. While both procedures created net positive income for the hospital, CEA was associated with a 29% higher net revenue due to the 40% cost premium of CAS when looking at all carotid procedures. However, proper DRG coding of CAS cases would have likely resulted in similar net revenue. Asymptomatic patients had the lowest cost and highest net revenue of all the subgroups. Per capita, significantly more healthcare resources were expended with CAS when compared to CEA. Given the lack of improved clinical outcome in most cases, CAS cannot be considered cost-effective for most patients.