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Objective: This study aimed to evaluate the use of a double injured atherosclerotic iliac rabbit model for myointimal hyperplasia evaluation. Secondarily, this animal model was use for pre clincial evaluation of a new anti-in stent restenosis simvastatin electrospun covered stent. Methods: Twenty four New Zealand White (NZW) rabbits were included in this study. In order to enhance and accelerate atherogenesis, atherogenic diet (0.3% cholesterol and 4.9% coconut oil) and mechanical endothelial injury of iliac artery were used. Twelve rabbits (24 iliac arteries) were used to evaluate the benefit of intimal balloon injury compared to the diet alone on myointimal hyperplasia. On day 7, rabbits beneficiated balloon iliac injury on the left side only. Eight weeks they were scarified and iliac arteries were harvested to histologic examination and comparaison. Twelve rabbits were included in the second evaluation to compare anti instent restenosis effect of a new drug eluting chrome-cobalt stent (DES) coated with polycyclodextrin-chitosan-simvastatin polymer after electrospinning technique. Balloon injury were performed on both iliacs on day 7, then stenting of BMS on right iliac and DES on left iliac and animals were sacrified 4 weeks later after angiography for histologic examination. Results: Balloon iliac injuries (BI) revealed a significant higher Schwartz injury score (0.599±0.368 control vs 1.150±0.306 BI, p=0.013), percentage of stenosis (25.7±19.1 control vs 49.9±21.9 BI, p=0.012) and ratio collagen (0.252 ± 0.017 control vs 0.365 ± 0.011 BI, p=0.0001) than atherosclerotic diet only. Five rabbits died before the end of the protocol. After appaired comparison of BMS and DES, results were significantly better for BMS and pre-euthanasia angiography revealed that 3/7 DES were thrombosed versus 0/7 for BMS. Conclusions : Association of atherogenic diet and balloon injuries allow to obtain important neointimal hyperplasia and wall remodeling in rabbit iliac arteries that confirm its interest as in stent restenosis model for new DES.; Introduction La resténose intra-stent (RIS) reste le talon d'Achille des techniques de revascularisation endovasculaire. La supériorité des stents actifs pour l’artériopathie oblitérante des membres inférieurs n'a pas été clairement démontrée et les modèles animaux restent peu fiables pour évaluer l'efficacité des nouveaux dispositifs. L’objectif est de définir sur un modèle lagomorphe, un protocole expérimental adapté à l’étude de la RIS et l’appliquer à l’évaluation in vivo de stents recouverts d’une membrane électrofilée contenant de la simvastatine. Matériel et méthode Des stents en chrome cobalt ont été recouverts d’une membrane électrofilée composée de chitosan (106000 g/mol, 2.97 % w/v), polymère de cyclodextrine (64650 g/mol, 3.3% w/v), polyethylène oxide (PEO, 900000 g/mol, 0.33% w/v) et simvastatine (33 wt-%). Les études de libération in vivo ont été conduites dans un milieu de PBS/SDS 0,7 wt-% (pH 7,4, 37°C). Des lapins mâles adultes blancs néo zélandais ont été soumis à un régime enrichi en cholestérol (0,3 %) et huile de noix de coco (4,9 %) pendant 7 semaines suivi d’une alimentation normale. Une lésion au ballon était réalisée au niveau des axes iliaques et le stenting iliaque était réalisé par voie fémorale. Trois protocole ont été conduits : 1) évaluation les lésions histomorphologiques induites par le régime hypercholestérolémique et la lésion artérielle au ballon, 2) comparaison stents nu versus stents enduits d’éverolimus et 3) stents nus versus stents recouverts d’une membrane électrofilée contenant de la simvastatine dits stents fonctionnalisés. Résultats La quantité totale de SV chargée sur la membrane après 30 min d’électrofilage était de 4,01 μg/mm² de membrane (± 0,44 μg/mm²). Trente lapins ont été inclus dans ce travail. Le pourcentage de sténose et le pourcentage de remodelage étaient significativement plus important dans le groupe lésion au ballon par rapport au groupe « contrôle » , respectivement 49,9% ± 21,9% vs 25,7% ± 19,1% (p=0,012), 33,9% ± 18,7% vs 17,8% ± 13,4 (p< 0,001). Il n’a pas été mis en évidence de différence significative entre stents nus et stents enduits d’éverolimus. L’aire de la lumière artérielle était significativement plus faible dans le groupe stent fonctionnalisé (p=0,002). L’aire de la néointima, le pourcentage de sténose et de remodelage et le score de lésion artérielle étaient significativement plus importants dans le groupe stents fonctionnalisés (p=0,05). Conclusion Le modèle animal à 2 lésions artérielles tel que nous le proposons a été optimisé pour être reproductible et pertinent dans le cadre de la maladie athérosclérotique et de la RIS. Les résultats in vivo des stents fonctionnalisés nous indiquent de modifier la nature du polymère et de pousser les investigations sur l’action « locale » de la SV, son seuil toxique et intervalles thérapeutiques qui ne sont, à ce jour, pas déterminées.

Introduction: In-stent restenosis (ISR) is induced by an uncontrolled smooth muscular cells (SMC) proliferation after bare metal stent (BMS) implantation. It is associated with recurrence of symptoms and additional health costs. Drug-eluting stents have demonstrated efficiency on ISR but induce a high risk of late acute thrombosis due to a delayed struts reendothelialization. Polydopamine (PDA), a biocompatible polymer inspired from mussels byssus, has been reported to promote endothelial cells (EC) and inhibit SMC proliferation in-vitro, thus suggesting a potential pro-healing effect on the vascular wall. Furthermore, polydopamine expresses amine, catechol and quinone functions on its surface and can be used as an anchor for another therapeutic agent. This study aimed at 1) evaluating the impact of a PDA-coated stent on in-stent restenosis (ISR), 2) designing a vascular stent with a potential additional pro-healing drug, hemin, immobilized via the PDA layer.Methods: In the first part of this study, PDA coatings were obtained by dip coating of cobalt-chromium disks or stents in a dopamine solution. Disk samples were used to evaluate biocompatibility and hemocompatibility. The pro-healing potential was investigated in-vitro by seeding human EC and SMC on the different samples. In-vivo experimentations were conducted to assess the pro-healing effect in a rat model. ISR was evaluated in optic microscopy with quantification of the neointima/media (n/m) ratio after eosin/hematoxillin coloration. Quality of the struts reendothelialization was assessed with transmission electron microscopy (TEM). Molecular pathways involved in a potential pro-healing effect were investigated with western blot analyses.In the second part of this work, PDA-coated surfaces were modified with polyethylenimine (PEI) to enhance the expression of amine functions. This modified coating was characterized and cytocompatibility was assessed in-vitro. This modified surface was used to immobilized hemin, a therapeutic agent, on the sample surfaces. Functionalized surfaces were characterized, and presence of the therapeutic agent was assessed and quantified. The potential healing effect of the hemin-stent was evaluated in-vitro and in-vivo.Results: PDA surfaces demonstrated a pro-healing effect in-vitro compared to bare chromium-cobalt. PDA stents demonstrated a significant reduction in ISR compared to bare metal stents (ratio n/m = 0.48 (+/- 0.26) versus 0.83 (+/- 0.42), p

Introduction: In-stent restenosis (ISR) is induced by an uncontrolled smooth muscular cells (SMC) proliferation after bare metal stent (BMS) implantation. It is associated with recurrence of symptoms and additional health costs. Drug-eluting stents have demonstrated efficiency on ISR but induce a high risk of late acute thrombosis due to a delayed struts reendothelialization. Polydopamine (PDA), a biocompatible polymer inspired from mussels byssus, has been reported to promote endothelial cells (EC) and inhibit SMC proliferation in-vitro, thus suggesting a potential pro-healing effect on the vascular wall. Furthermore, polydopamine expresses amine, catechol and quinone functions on its surface and can be used as an anchor for another therapeutic agent. This study aimed at 1) evaluating the impact of a PDA-coated stent on in-stent restenosis (ISR), 2) designing a vascular stent with a potential additional pro-healing drug, hemin, immobilized via the PDA layer.Methods: In the first part of this study, PDA coatings were obtained by dip coating of cobalt-chromium disks or stents in a dopamine solution. Disk samples were used to evaluate biocompatibility and hemocompatibility. The pro-healing potential was investigated in-vitro by seeding human EC and SMC on the different samples. In-vivo experimentations were conducted to assess the pro-healing effect in a rat model. ISR was evaluated in optic microscopy with quantification of the neointima/media (n/m) ratio after eosin/hematoxillin coloration. Quality of the struts reendothelialization was assessed with transmission electron microscopy (TEM). Molecular pathways involved in a potential pro-healing effect were investigated with western blot analyses.In the second part of this work, PDA-coated surfaces were modified with polyethylenimine (PEI) to enhance the expression of amine functions. This modified coating was characterized and cytocompatibility was assessed in-vitro. This modified surface was used to immobilized hemin, a therapeutic agent, on the sample surfaces. Functionalized surfaces were characterized, and presence of the therapeutic agent was assessed and quantified. The potential healing effect of the hemin-stent was evaluated in-vitro and in-vivo.Results: PDA surfaces demonstrated a pro-healing effect in-vitro compared to bare chromium-cobalt. PDA stents demonstrated a significant reduction in ISR compared to bare metal stents (ratio n/m = 0.48 (+/- 0.26) versus 0.83 (+/- 0.42), p, Introduction : La resténose intra-stent (RIS) est induite par une prolifération incontrôlée des cellules musculaires lisses (CML) après l'implantation d'une stent métallique nu (BMS). Elle est associée à la récurrence des symptômes et à des coûts de santé supplémentaires. Les stents à élution médicamenteuse, dits « actifs », ont démontré leur efficacité sur la RIS, mais induisent un risque élevé de thrombose aiguë tardive due à une réendothélialisation tardive des mailles. La polydopamine (PDA), un polymère biocompatible inspiré du mucus secrété par les moules, promouvrait la prolifération de cellules endothéliales (CE) et inhiberait la prolifération des CMV in-vitro, ce qui suggère un effet pro-cicatrisant potentiel sur la paroi vasculaire. De plus, la polydopamine exprime des fonctions amines, catéchols et quinones à sa surface et peut être utilisée comme ancrage pour un autre agent thérapeutique. Le but de ce travail était 1) d'évaluer l'impact d'un stent enduit de PDA sur la RIS, 2) de concevoir un stent vasculaire à base de PDA délivrant une autre substance pro-cicatrisante, l'hémine.Méthodes : Dans la première partie de cette étude, les revêtements PDA étaient obtenus par immersion de disques de cobalt-chrome ou de stents dans une solution de dopamine. La biocompatibilité et l'hémocompatibilité étaient vérifiées in vitro. Le potentiel pro-cicatrisant était étudié in vitro par culture d'EC et de CML d'origine humaine sur les différents échantillons. L'effet pro-cicatrisant était étudié in-vivo après implantation de stents en position aortique chez le rat. La RIS était évaluée en microscopie optique par quantification du rapport néointima/media (n/m) après coloration éosine/hématoxilline. La qualité de la réendothélialisation des mailles était évaluée par microscopie électronique à transmission (MET). Les voies moléculaires potentiellement impliquées dans un effet pro-cicatrisant étaient étudiées par analyses Western Blot.Dans la deuxième partie de ce travail, les surfaces revêtues de PDA étaient modifiées avec de la polyéthylèneimine (PEI) pour améliorer l'expression des fonctions amines. Ce revêtement modifié était caractérisé et sa cytocompatibilité évaluée in vitro. Cette surface modifiée était ensuite utilisée pour immobiliser l'hémine. Les surfaces fonctionnalisées étaient caractérisées et la quantité d'hémine greffée déterminée. L'effet pro-cicatrisant potentiel du stent à l'hémine était évalué in vitro et in vivo.Résultats : Les surfaces de PDA démontraient un effet pro-cicatrisant in-vitro par rapport au chrome-cobalt nu. Les stents PDA montraient une réduction significative de la RIS par rapport aux stents nu (rapport n/m = 0,48 (+/- 0,26) contre 0,83 (+/- 0,42), p

The disturbance of the flow in the vicinity of the arterial wall equipped with a stent plays a key role in the onset and development of complications related to cardiovascular diseases (stenosis, restenosis, thrombosis...). The topology of the flow field in the intra-stent zone is very complex. Indeed, in the vicinity of the stent, recirculation zones form upstream and downstream of the stent strut where wall shear stress is very low. In vivo and in vitro studies have demonstrated the role of the in-stent flow features on cardiovascular diseases.The correct estimation of the wall shear stress, the understanding of the behavior of the in-stent flow and its role in the transfer of the drug are expected to help optimize treatments (stent geometry, drug composition...). The numerical approach (CFD) is a useful and versatile way to study these phenomena. However, the accuracy and the relevance of the results depend on the choice of the flow model, the boundary conditions and the stent and artery geometry.Firstly we study in this work the impact of the hemodynamic model on the in-stent flow characteristics. Three numerical models describing the coronary flow are used. These models are: the steady model "MP", the simplified pulsatile model "MPS" and the complete pulsatile model "MPC" based on Womersley's analysis. We show the importance of the pulsatility of the flow but at the expense of a high increase in the computing time. Secondly we study experimentally the in-stent flow using measurement technique "PIV". This experimental study confirms the previous numerical results. Finally we examine numerically the effects of the flow pulsatility on the mass fluxes released by the faces of a drug eluting stent. This numerical study highlights the importance of the coupling between the recirculation zones and the mass transfer into the arterial wall., La perturbation des écoulements au voisinage de la paroi artérielle équipée d'un stent joue un rôle prépondérant dans l'apparition et le développement des complications liées aux maladies cardiovasculaires (sténose, resténose, thrombose...). La topologie de l'écoulement dans ces régions est très complexe. En effet, au voisinage du stent, des zones de recirculation se forment en amont et aval de chaque branche et les contraintes pariétales y sont très faibles. Des études in vivo et in vitro ont mis en évidence le rôle de ces caractéristiques de l'écoulement intra-stent sur les maladies cardiovasculaires. Pour cela, la bonne estimation des contraintes pariétales et la compréhension du comportement de l'écoulement intra-stent et son rôle dans le transfert du principe actif devraient permettre d'optimiser les traitements (design de la prothèse, principe actif...). L'approche numérique est une voie très utile pour étudier ces phénomènes. Cependant, la bonne précision du calcul dépend du choix du modèle d'écoulement, des conditions aux limites, de la géométrie du stent et de l'artère pour réaliser une simulation pertinente.Nous étudions ici dans un premier temps l'effet du choix du modèle hémodynamique sur les caractéristiques de l'écoulement intra-stent. Trois modèles numériques décrivant l'écoulement coronaire ont été utilisés. Ces modèles sont : un modèle stationnaire "MP", le modèle pulsé simplifié "MPS" et le modèle pulsé complet "MPC" basé sur l'analyse de Womersley. Nous avons ainsi montré l'importance de la prise en compte de l'instationnarité de l'écoulement mais au dépens d'un temps de calcul très accru. Dans un second temps, nous étudions expérimentalement l'écoulement intra-stent en utilisant la technique de mesure "PIV". Cette étude expérimentale a permis de confirmer les résultats numériques précédents. Au final, nous examinons numériquement l'effet de la pulsatilitié de l'écoulement sur les flux massiques libérés par les faces d'une branche de stent actif. Cette étude numérique a mis en exergue l'importance du couplage entre les recirculations et le transfert de masse vers la paroi artérielle.

SummaryBackgroundDrug-eluting stents (DES) are more effective than bare-metal stents (BMS) in small coronary vessel disease. Whether this is true in elderly patients, it is unclear, as frailty and a high rate of comorbidities could increase the rate of DES-related complications.AimsTo assess procedural and long-term clinical outcomes of elderly patients with small vessel disease treated with DES or BMS.MethodsConsecutive elderly patients (≥ 75 years old) treated with stenting of native small coronary arteries (reference vessel diameter and implanted stent

Summary Aim To assess the feasibility and safety of a hybrid myocardial revascularization strategy combining “exclusive arterial” conventional coronary artery bypass grafting (CABG) followed by early drug-eluting stent (DES) implantation in multivessel coronary artery disease (CAD). Methods Eighteen consecutive patients with multivessel CAD were enrolled prospectively. Within 48 hours of CABG using left internal mammary artery (IMA) to left anterior descending (LAD) coronary artery with or without right IMA to non-LAD vessel in an open chest approach, DESs were implanted systematically in an additional vessel after a clopidogrel 300-mg preloading dose. This group was compared with 18 matched patients who underwent standard CABG alone using left IMA to LAD and at least one additional graft. Results Baseline clinical characteristics were similar in both groups. There were 46 grafts in the CABG group and 28 in the hybrid group. In the hybrid group, 27.8% of patients were treated off-pump versus none in the CABG group; a median of 2 (interquartile range: 1–2) stents was implanted per patient. The hybrid procedure was associated with shorter durations of cardiopulmonary bypass (77 [67–100] min versus 97 [90–105] min, P = 0.049). Major bleeding rates were higher in the CABG group, but the difference was not statistically significant (44.4% versus 11.1%, P = 0.06). Re-intervention for bleeding was not needed in either group. One (5.6%) myocardial infarction occurred in hospital in each group following CABG. At 1 year, the cumulative rates of major adverse cardiac events (death, myocardial infarction, target vessel revascularization) were similar (11.2% in hybrid group versus 5.6% in CABG group, P = 0.99). One death occurred in the CABG group and one target vessel revascularization in the hybrid group. Conclusion A hybrid revascularization strategy, combining conventional CABG with exclusive arterial conduits followed by early DES implantation, is feasible. One-year event rates compare favourably to those with traditional CABG alone.

International audience; BACKGROUND: Very late thrombosis of drug eluting stents is a rare complication that might be triggered by resistance to platelet antiaggregants (PAAs). AIM: Following an initial case where clinical data strongly suggested resistance to PAAs, we carried out a prospective systematic analysis of platelet aggregation in four subsequent cases of late thrombosis. METHODS: Resistance to aspirin was investigated with the PFA-100 test employing a collagen-epinephrine cartridge (Platelet Function Analyzer; Dade Behring). Resistance to clopidogrel was determined by flow cytometry of intraplatelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. RESULTS: All four cases showed resistance to either aspirin or clopidogrel, and two cases showed dual resistance to both of these PAAs. CONCLUSION: Analysis of platelet function in a patient with late stent thrombosis is useful and may allow adaptation of subsequent patient management. The value of monitoring platelet function after implantation of a drug eluting stent should be evaluated in prospective studies.

Summary Background After coronary stenting with drug eluting stents, long-term clinical outcome of unprotected left main coronary artery disease is unknown, even large scale registries or randomised trials with coronary artery bypass graft are ongoing. Aims To report clinical and angiographic results of paclitaxel-eluting stent implantation for left main coronary artery stenosis (a series of 101 consecutive patients). Methods This report is a prospective study performed to evaluate the immediate and mid-term clinical and angiographic outcomes of patients undergoing paclitaxel-eluting stent (PES) implantation for unprotected left main coronary artery (LMCA) stenosis. From January 2004 to December 2005, 101 consecutive patients were stented with paclitaxel-eluting stents (the provisional T stenting technique followed by Kissing balloon for distal left main vessel disease). Results Mean age was 68.9 ± 11.07 years. 73.3% of patients were male. Acute coronary syndrome was present in 65% of patients, of whom 22.8% had ST elevation. Distal left main trunk lesions were present in 87.1% of cases. Three-vessel disease represented 7% of cases. Angiographic success was obtained in 97.03% of patients with an acute gain of 2.18 ± 0.53 mm. GPIIbIIIa inhibitors were used in only 8.9% of cases. Hospital stay was 7.6 ± 3.7 days. In-hospital complications were present in 7.9%, with a hospital mortality rate of 2%. At six month follow-up, the rate of target lesion revascularization (TLR) was 3%, and the rate for major adverse cardiac events (MACE) was 8.9%. Angiographic control was performed in 88.1% and a late loss of 0.1 mm (0.04–0.2 mm) was noted. Re-stenosis occurred in 4 patients (4.5% of cases). 4 patients (4%) died, including 2 from cardiac causes. Conclusion Paclitaxel-eluting stent implantation for unprotected left main coronary disease appears to be safe with high procedural success rate and a low re-stenosis rate at six month-follow-up.

Summary Background The ideal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) is under debate. Lesion length is a well-recognized predictor of PCI complexity and long-term outcome. Aim To evaluate the determinants and impact on outcome of long-term DAPT in a retrospective cohort of patients treated for a long coronary lesion. Methods Patients ( n = 460) who underwent PCI for a long lesion (> 30 mm) were divided into two groups according to antiplatelet regimen at 1 year: patients who stopped DAPT before 1 year (single antiplatelet therapy group; n = 168) and patients who continued DAPT for longer than 1 year ( n = 292). Results Mean lesion length was 35.7 ± 7.1 mm. The proportion of patients who continued DAPT after 1 year was 63.5%. The main determinants of long-term DAPT were initial presentation as myocardial infarction and implantation of a drug-eluting stent. Median follow-up was 37.4 (23–51) months after the 1-year period following the index PCI. Long-term DAPT was highly associated with a lower risk of all-cause and cardiovascular mortality by multivariable analysis and after adjustment for other predictors: hazard ratios 0.11 (95% confidence interval 0.03–0.32) and 0.15 (95% confidence interval 0.04–0.62), respectively. No increase in major bleeding was noted. Conclusion In a contemporary practice, nearly two-thirds of patients who undergo PCI for a long lesion are treated with DAPT for several years. Our results suggest that long-term DAPT is beneficial in this subset of patients identified as being at high risk.

Summary Background It is unknown whether the efficacy and safety of drug-eluting stents (DES) apply in patients with chronic renal failure (CRF). Aims To compare DES with bare metal stents (BMS) for percutaneous coronary intervention (PCI) in CRF patients. Patients and methods Consecutive patients treated by PCI were allocated to four groups according to type of stent used (DES versus BMS) and creatinine clearance (CrCl). CRF was defined as CrCl less than 60 mL/minute. Cardiovascular death, major adverse cardiac events (MACE, defined as cardiovascular death, myocardial infarction, stroke and target lesion revascularization [TLR]), TLR and definite stent thrombosis (ST) were recorded at 1 year. Results We note that 1376 consecutive patients underwent PCI with stent within 18 months: 534 (39%) and 492 (36%) patients without CRF and 224 (16%) and 126 (9%) patients with CRF were treated with BMS and DES, respectively. In the entire cohort, patients treated with DES had a higher restenosis risk profile. BMS were predominantly (87%) used for ST-segment elevation myocardial infarction. At 1 year, 6.2% had cardiovascular death, 15.8% MACE, 7.3% TLR and 1.5% ST. Cardiovascular death and MACE occurred less frequently in DES groups. The TLR rate was not significantly different in the CRF groups (BMS 9.8% vs DES 7.1%; P = 0.44). No excess of ST was observed in the DES groups and use of DES was independently associated with absence of MACE and TLR. Conclusions In patients with CRF, DES appear to be at least as effective as BMS — despite a higher restenosis risk profile — with no excess of ST at 1 year.

Summary Background The zotarolimus-eluting stent (ZES) is a new drug-eluting stent that delivers zotarolimus, a synthetic analogue of sirolimus, through a biocompatible phosphorylcholine polymer coating. ZES has shown promising results compared with bare-metal stents, but its safety and efficacy against sirolimus-eluting (SES) and paclitaxel-eluting (PES) stents is yet to be established. Aims We aimed to summarize current evidence from randomized trials comparing ZES with SES and PES. Methods We searched the Medline, Embase and CENTRAL databases for randomized studies comparing ZES with SES and PES for percutaneous coronary intervention. Relevant clinical and angiographic outcomes were extracted and combined using random and fixed-effect models for heterogeneous and homogenous outcomes, respectively. Results Seven randomized trials met the inclusion criteria: ZES group, n = 3787; SES group, n = 2606; PES group, n = 1966. Compared with SES, ZES was associated with significantly higher odds of clinically driven target vessel revascularization (odds ratio [OR] 2.36, 95% confidence interval [CI] 1.78–3.14) and target lesion revascularization (OR 2.46, 95% CI 1.36–4.46). Compared with SES, ZES had higher in-stent restenosis (OR 6.13, 95% CI 3.96–9.50), late lumen loss ‘in-stent’ (mean difference [MD] 0.39 mm, 95% CI 0.34–0.44) and late lumen loss ‘in-segment’ (MD 0.18 mm, 95% CI 0.15–0.21). ZES was associated with higher in-stent late lumen loss than PES (MD 0.18 mm, 95% CI 0.07–0.28). There were no differences in mortality, reinfarction or stent thrombosis with ZES compared with SES and PES. Conclusion ZES is not superior to PES and is inferior to SES in terms of angiographic outcomes and clinically driven revascularization.