Hydrogen sulfide release via the ACE inhibitor Zofenopril prevents intimal hyperplasia in human vein segments and in a mouse model of carotid artery stenosis
Diane MacabreyC DeslarzesAlban LongchampMartine LambeletC. Keith OzakiJean-Marc CorpatauxFlorent AllagnatSébastien Deglise
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The current strategies to reduce intimal hyperplasia (IH) principally rely on local drug delivery, in endovascular approach. The oral angiotensin converting enzyme inhibitor (ACEi) Zofenopril has additional effects compared to other non-sulfyhydrated ACEi to prevent intimal hyperplasia and restenosis. Given the number of patients treated with ACEi worldwide, these findings call for further prospective clinical trials to test the benefits of sulfhydrated ACEi over classic ACEi for the prevention of restenosis in hypertensive patients. Abstract Objectives Hypertension is a major risk factor for intimal hyperplasia (IH) and restenosis following vascular and endovascular interventions. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl-containing angiotensin-converting enzyme inhibitor Zofenopril is a source of H2S. Here, we hypothesized that Zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitor (ACEi), in reducing intimal hyperplasia in the context of hypertension. Materials Spontaneously hypertensive male Cx40 deleted mice (Cx40-/-) or WT littermates were randomly treated with Enalapril 20 mg (Mepha Pharma) or Zofenopril 30 mg (Mylan SA). Discarded human vein segments and primary human smooth muscle cells (SMC) were treated with the active compound Enalaprilat or Zofenoprilat. Methods IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for 7 days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro. Results Compared to control animals (intima/media thickness=2.3±0.33), Enalapril reduced IH in Cx40-/- hypertensive mice by 30% (1.7±0.35; p=0.037), while Zofenopril abrogated IH (0.4±0.16; p<.0015 vs. Ctrl and p>0.99 vs. sham-operated Cx40-/-mice). In WT normotensive mice, enalapril had no effect (0.9665±0.2 in control vs 1.140±0.27; p>.99), while Zofenopril also abrogated IH (0.1623±0.07, p<.008 vs. Ctrl and p>0.99 vs. sham-operated WT mice). Zofenoprilat, but not Enalaprilat, also prevented intimal hyperplasia in human veins segments ex vivo. The effect of Zofenopril on carotid and SMC correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the MAPK and mTOR pathways in SMC and human vein segments. Conclusion Zofenopril provides extra beneficial effects compared to non-sulfhydryl ACEi to reduce SMC proliferation and restenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.Keywords:
Intimal hyperplasia
Carotid artery stenosis is identified more and more common in clinical, and gradually become one of the causes of death and disablement. With the continuous development of medical technology, and medical device and apparatus equipment, surgical therapy and endovascular therapy have become one of the major principal methods in treatment of carotid artery stenosis. This article briefly discusses the current several processes and techniques of the surgical and endovascular treatment of carotid stenosis disease, and carries on the evaluation.
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Carotid stenosis/SU; Review
Medical treatment
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Objective To evaluate the accuracy of carotid artery stenosis by three-Dimensional ultrasound reconstruction. Methods Studies 8 carotid stenosis models made of plastic film by three-dimension reconstruction. Results Our findings indicated that not only the morphology of carotid stenosis models could be truly displayed by three-dimensional reconstruction, but also their stenosis rate could be precisely measured(r0.99,P0.001). Conclusion The design of our self-made three-dimensional ultrasound reconstruction is reasonable and the measurement is accurate.
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Carotid artery stenosis is a disabling disease in all age groups.Elderly people are more prone to recurrent strokes due to advancing age and multiple co--morbidities.Treatment options for symptomatic carotid stenosis in the very elderly are the same as in younger patients although with a higher operative risk.We describe a successful case of carotid artery stenting in a nonagenarian with symptomatic carotid artery stenosis, a subgroup for whom treatment options are rarely discussed in guidelines. Key Words Carotid artery stenosis; nonagenarian; carotid artery stenting Implications for Practice1. Carotid artery stenting is an accepted treatment modality for atherosclerotic carotid artery stenosis.2. Carotid artery stenosis is an important cause of stroke in elderly and outcomes after stroke are highly influenced by advancing age.3. Very elderly symptomatic patients should be investigated and considered for intervention after careful individual patient and lesion assessment.
Carotid stenting
Carotid artery disease
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We report our experience of carotid artery stenting (CAS) for the endovascular treatment of significant carotid stenosis over 16 years.Data of all consecutive patients who came for a significant carotid artery stenosis from January 1st 1999 to August 31st 2015 were retrospectively collected and analyzed. Primary outcomes were the occurrence of death and major cerebrovascular events (MCE) both at 30-day and at long-term.In our experience CAS was a safe and effective technique, with acceptable mortality and neurological complication rates, both at 30 days and in the long term.Carotid stenting, Carotid stenosis, Long-term follow-up.Da più di 50 anni l’endoarteriectomia carotidea (CEA) è stata considerata il trattamento standard per le stenosi carotidee gravi asintomatiche e sintomatiche. Lo stenting carotideo (CAS) è progressivamente emerso negli ultimi 15 anni come alternativa alla chirurgia, specialmente nei pazienti ad alto rischio. Da allora, molti studi clinici randomizzati sono stati pubblicati per valutare la superiorità di un metodo rispetto all’altro, tuttavia i risultati dei trials hanno generato più dubbi che certezze nell’interpretazione dei loro risultati, gravati come sono da diverse limitazioni: la principale riguarda la ridotta competenza endovascolare richiesta per gli operatori che hanno eseguito lo stenting carotideo e partecipato ai trials. Inoltre questi trials sono stati eseguiti circa 10 anni fa, con materiali e farmaci differenti rispetto a quelli usati attualmente. Attualmente i registri su larga scala e le casistiche che riportano risultati a lungo termine sono maggiormente rappresentativi di una esperienza reale, che riflette ciò che accade di routine nella pratica clinica. Nella nostra Unità Operativa di Chirurgia Vascolare, il CAS è stato offerto dal 1999 come alternativa alla CEA per il trattamento delle stenosi carotidee sintomatiche e asintomatiche nei pazienti a rischio moderato-alto. Scopo del nostro lavoro è di riportare la nostra esperienza retrospettiva, con alcuni consigli e suggerimenti che derivano da ciò che abbiamo imparato in più di 16 anni. Abbiamo pertanto raccolto e analizzato retrospettivamente i dati di tutti i pazienti consecutivi che sono venuti per una stenosi carotidea significativa dal 1 ° gennaio 1999 al 31 agosto 2015. I risultati basilari sono stati la mortalità e la morbilità cerebrovascolare maggiore (MCE) sia a 30 giorni che a lungo termine. Lo studio è stato condotto su 1017 pazienti (677 maschi, 66.6%, età media 74 anni, IQR 69-79 anni) trattati sia per stenosi carotidea sintomatica (n=392, 38.5%) che asintomatica. Il successo tecnico è stato raggiunto nel 99% delle procedure. A 30 giorni abbiamo osservato 3 decessi (0.3%) e 12 MCE (1.2%, 7 dei quali minor stroke e 5 stroke maggiori). A 5 e 10 anni, la sopravvivenza è stata rispettivamente dell’86.3%±1.5% e del 73.5%±2.3%, significativamente influenzata dall’età (P=.04), dalla sintomatologia neurologica preoperatoria (P=.04) e da una durata della procedura maggiore di 60 minuti (P =.0017). La libertà da ictus è stata del 97.1%±0.8% a 5 anni e del 91.2%±1.9% a 10 anni rispettivamente per i pazienti asintomatici, e del 95.7%±1.9% a 5 anni e dell’81.7%±5% a 10 anni rispettivamente per i pazienti sintomatici (P=.008). Il verificarsi di MCE è stato significativamente influenzato dalla sintomatologia neurologica preoperatoria (P=.01) e da una durata della procedura maggiore di 60 minuti (P <.001). Nella nostra esperienza il CAS è risultato sicuro ed efficace, con tassi di mortalità e di complicanze neurologiche accettabili, sia a 30 giorni che a lungo termine.
Carotid stenting
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In Brief Carotid artery stenosis causes one-half of the 700,000 strokes that occur each year in the United States. And it's responsible for 80% of the up to 500,000 transient ischemic attacks that affect patients annually. Wondering what you can do to root out carotid artery stenosis and keep your patients stroke-free? In this article, we'll give you the low-down on carotid artery stenosis: why it occurs, what it looks like, how to detect it, and how to treat it. Carotid artery stenosis is a major risk factor for ischemic stroke. In this article, well give you the lowdown on carotid artery stenosis: why it occurs, what it looks like, how to detect it, and how to treat it.
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In Brief Carotid artery stenosis is a major risk factor for ischemic stroke. In this article, well give you the lowdown on carotid artery stenosis: why it occurs, what it looks like, how to detect it, and how to treat it.
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Carotid artery stenosis is one of the major causes of ischemic strokes.1 To prevent or reduce the occurrences of ischemic strokes, carotid endarterectomies (CEAs) were performed on 48 patients with carotid artery stenosis from November 2000 to June 2003. Results from this study were analyzed and presented here.
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Objective To evaluate the value of high resolution MRI in detecting carotid atherosclerosis.Methods Philips Achieve 1.5T MR and SENSE Flex Medium Coil were used to perform high resolution carotid arteries MRI in 20 patients.Carotid arteries were scanned with four sequences (including DIR-T1WI,TSE-T2WI,TSE-PDWI and 3D-TOF) to detect carotid atherosclerosis,evaluate the level of stenosis and characterize the morphology of individual plaques.Results 20 patients with many stenosis sites of carotid arteries were demonstrated by MRI, including 6 with moderate stenosis,severe stenosis 2 and complete obliteration 1.20 patients with 9 consecutive plaques and 40 local plaques were demonstrated(62 changes of carotid atherosclerotic plaque according to sites of plaques),including 19 in the common carotid artery,carotid artery bifurcation 19,internal carotid artery 23,and external carotid artery 1.MRI classification included typeⅢ 15,type Ⅳ-Ⅴ 43,type Ⅵ 2 and type Ⅷ2.Conclusion High resolution MRI is a powerful imaging tool in evaluating carotid arterial stenosis and demonstrating the tissue components of atherosclerotic plaques.It is helpful for early diagnosis and treatment planning of angiocardiopathy and cerebrovascular disease.
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