Multimodality imaging results of TAP versus novel modified TAP stenting in coronary bifurcation: From bench testing to first-in-man investigation.

OBJECTIVES: We investigated the results of T and small protrusion (TAP) versus a novel modification of TAP (mTAP) stenting by multimodality imaging in bench testing and in patients with coronary bifurcation lesions (CBL). BACKGROUND: TAP stenting is a suboptimal technique for bailout side branch (SB) stenting. METHODS: In a bench model, optical coherence tomography (OCT), microscopic examinations (ME), and computational fluid dynamics (CFD) were performed after TAP and mTAP stenting. In 20 patients with CBL, 80 intravascular ultrasound (IVUS) examinations were performed during mTAP stenting in which the SB stent was pulled-back to indent the inflated main vessel (MV) balloon and deployed while deflating it. For TAP stenting, the tip of the SB stent was positioned in the MV and deployed. RESULTS: In bench testing, OCT showed neocarina length (NL) was shorter and minimum stent area (MSA) was larger after mTAP versus TAP stenting (2.84 ± 0.70 vs. 4.80 ± 020 mm; 6.75 ± 1.50 vs. 4.5 ± 2.2 mm2 ; respectively; p < 0.05). By ME, NL was shorter and shear rate trended lower after mTAP versus TAP stenting. In patients, IVUS showed MSA was larger after versus before mTAP stenting (6.32 ± 0.58 vs. 5.21 ± 0.56 mm2 ; p < 0.01); NL was 1.43 ± 0.22 mm with SB ostium coverage. The Seattle Angina questionnaire (SAQ) score was higher at 6 months versus baseline (85 ± 4.0 vs. 48 ± 6.0, respectively; p < 0.001). CONCLUSIONS: This multimodality imaging study showed, for the first time, mTAP stenting resulted in larger stent area and shorter neocarina than TAP stenting in bench testing. In patients with CBL, mTAP stenting led to larger stent area, short neocarina with complete SB ostium coverage, and improved the SAQ score at follow-up.

Morphological characteristics of lesions with thin cap fibroatheroma-a substudy from the COMBINE (OCT-FFR) trial.

AIMS: To study if any qualitative or quantitative optical coherence tomography (OCT) variables in combination with thin cap fibroatheroma (TCFA) patients could improve the identification of lesions at risk for future major adverse cardiac events (MACEs). METHODS AND RESULTS: From the combined optical coherence tomography morphologic and fractional flow reserve hemodynamic assessment of non- culprit lesions to better predict adverse event outcomes in diabetes mellitus patients: COMBINE (OCT-FFR) trial database (NCT02989740), we performed a detailed assessment OCT qualitative and quantitative variables in TCFA carrying diabetes mellitus (DM) patients with vs. without MACE during follow-up. MACEs were defined as a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, and hospitalization for unstable angina. From the 390 fractional flow reserve (FFR)-negative DM patients, 98 (25.2%) had ≥1 OCT-detected TCFA, of which 13 (13.3%) had MACE and 85 (86.7%) were event-free (non-MACE). The baseline characteristics were similar between both groups; however, a smaller minimal lumen area (MLA) and lower mean FFR value were observed in MACE group (1.80 vs. 2.50 mm2, P = 0.01, and 0.85 vs. 0.89, P = 0.02, respectively). Prevalence of healed plaque (HP) was higher in the MACE group (53.85 vs. 21.18%, P = 0.01). TCFA were predominantly located proximal to the MLA. TCFA area was smaller in the MACE group, while no difference was observed regarding the lesion area. CONCLUSION: Within TCFA carrying patients, a smaller MLA, lower FFR values, and TCFA location adjacent to a HP were associated with future MACE. Carpet-like measured lesion area surface was similar, while the TCFA area was smaller in the MACE arm, and predominantly located proximal to the MLA.

Stent malapposition generates stent thrombosis: Insights from a thrombosis model.

BACKGROUND: Currently, there exists differing conclusions on the role of acute stent malapposition and its role in stent thrombosis (ST). The European Association of Percutaneous Cardiovascular Interventions (EAPCI) consensus recommends that acute malapposition <0.4 mm with longitudinal extension <1 mm need not be corrected since there is no clear correlation of malapposition with adverse clinical outcomes. However, malapposition was identified as the main mechanism of ST in the Bern and PESTO registries, and one of the three leading mechanism in the PRESTIGE study. METHODS: In this study, a validated perfused benchtop thrombosis model was deployed to evaluate the role of both stent under-expansion (UE) and acute stent malapposition (MA) on thrombus formation in vitro in a controlled reproducible environment. RESULTS: The results showed that UE alone did not result in acute thrombus formation, but UE together with MA did. The data suggested that a MA distance of 0.25 mm led to significant thrombus formation; and a positive correlation exists between the longitudinal extension of the MA and the thrombus volume formed. CONCLUSION: Experiments in this in vitro model demonstrated that platelets and a thrombosis cascade were activated and developed around large segments of malapposed stent. This was significantly more thrombus formation than in the under-expanded stent region.

Progress in drug-delivery systems in cardiovascular applications: stents, balloons and nanoencapsulation.

Drug-delivery systems in cardiovascular applications regularly include the use of drug-eluting stents and drug-coated balloons to ensure sufficient drug transfer and efficacy in the treatment of cardiovascular diseases. In addition to the delivery of antiproliferative drugs, the use of growth factors, genetic materials, hormones and signaling molecules has led to the development of different nanoencapsulation techniques for targeted drug delivery. The review will cover drug delivery and coating mechanisms in current drug-eluting stents and drug-coated balloons, novel innovations in drug-eluting stent technologies and drug encapsulation in nanocarriers for delivery in vascular diseases. Newer technologies and advances in nanoencapsulation techniques, such as the use of liposomes, nanogels and layer-by-layer coating to deliver therapeutics in the cardiovascular space, will be highlighted.

Nanoparticles-reinforced poly-l-lactic acid composite materials as bioresorbable scaffold candidates for coronary stents: Insights from mechanical and finite element analysis.

Current generation of bioresorbable coronary scaffolds (BRS) posed thrombogenicity and deployment issues owing to its thick struts and overall profile. To this end, we hypothesize that the use of nanocomposite materials is able to provide improved material properties and sufficient radial strength for the intended application even at reduced strut thickness. The nanocomposite formulations of tantalum dioxide (Ta2O5), L-lactide functionalized (LA)-Ta2O5, hydroxyapatite (HA) and LA-HA with poly-l-lactic acid (PLLA) were evaluated in this study. Results showed that tensile modulus and strength were enhanced with non-functionalized nanofillers up until 15 wt% loading, whereas ductility was compromised. On the other hand, functionalized nanofillers/PLLA exhibited improved nanofiller dispersion which resulted higher tensile modulus, strength, and ductility. Selected nanocomposite formulations were evaluated using finite element analysis (FEA) of a stent with varying strut thickness (80, 100 and 150 µm). FEA data has shown that nanocomposite BRS with thinner struts (80-100 µm) made with 15 wt% LA-Ta2O5/PLLA and 10 wt% LA-HA/PLLA have increased radial strength, stiffness and reduced recoil compared to PLLA BRS at 150 µm. The reduced strut thickness can potentially mitigate issues such as scaffold thrombosis and promote re-endothelialisation of the vessel.

T and Small Protrusion (TAP) vs Double-Kissing Crush Technique: Insights From In Vitro Models.

BACKGROUND: Percutaneous coronary interventions on complex bifurcation lesions may require implantation of two stents to appropriately treat diffuse side-branch (SB) disease. Comparisons among different bifurcation stenting techniques are continuously attempted by various study designs (bench tests, computer simulations, clinical studies). Among different techniques, double kissing crush (DKC) represents the last evolution for "crushing" while T and small Protrusion (TAP) represents the evolution of "T stenting". Both techniques are actually gaining popularity, but head-to-head comparisons are lacking. METHODS AND RESULTS: Two last generation drug-eluting stents (Synergy™, Boston Scientific, MA, USA and Ultimaster™,Terumo Corp., Japan) were implanted in left main bifurcation bench models using TAP (n = 6 sets) and DKC (n = 6 sets) techniques. A peristaltic pump with fresh porcine blood was used to perfuse the blood through the silicone model at a flow rate of 200 ml/min for 4 min. Optical coherence tomography (OCT) was used to assess stent struts geometry and thrombus formation. SB cross sectional area as well as SB obstruction did not significantly differ between the two techniques. Numerical (but not statistically significant) differences were found in terms of malapposed struts (fewer with TAP) and floating struts (fewer with DKC). Thrombus formation after blood perfusion was similar between TAP and DKC technique (1.53 ± 1.12 vs. 1.20 ± 1.01 mm2, p = 0.6). CONCLUSION: The result of the present in-vitro study shows the absence of significant difference between TAP and DKC in terms of stent struts apposition and acute thrombus formation potential. Despite the completely different technical steps required, both techniques have similar performance according to such articulated pre-clinical evaluation. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: Due to its limited complexity, T and Protrusion (TAP) technique is considered the to-go technique for bifurcation lesions with good long-term results. Recently, double kissing crush (DKC) technique has been gaining popularity and demonstrated promising results in randomized clinical trials. WHAT DOES THIS STUDY ADD?: This in-vitro bench test study provides a unique detailed OCT comparison and local hemodynamic environment analysis of the two techniques. HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE?: New insights of acute thrombogenicity and computational flow model simulation may guide percutaneous therapeutic strategies of bifurcation lesions.

Drug-coated balloons: Technical and clinical progress.

The advancement of drug-coated balloons (DCB) presents an alternative nonstent method in the percutaneous treatment of atherosclerotic lesions. While the current generation of drug-eluting stents (DES) are the device of choice, especially in coronary artery disease (CAD), DCB has potential applications in the treatment of de novo lesions, in-stent restenosis (ISR), bifurcations, and in peripheral artery disease (PAD). In terms of coronary clinical experience, DCB is used most in ISR scenarios and more data are collected to support the use of DCB in de novo lesions compared to best-in-class DES. The use of DCB in bifurcation side branch treatment has demonstrated safety, and with good angiographic and clinical outcomes, but more data from randomized trials will be required to assess its clinical value. For PAD, the clinical outcomes of DCB with and without debulking devices in diseased femoropopliteal arteries and treatment of below-the-knee (BTK) vessels with DCB are discussed. Current data demonstrated conflicting long-term safety outcomes in the use of paclitaxel devices in the femoral and/or popliteal arteries, while the role of DCB in BTK disease remains uncertain due to a lack of randomized controlled trial data. In summary, this review provides an overall view of current DCB technologies and progress, followed by an update on DCB clinical data in the treatment of CAD and PAD.

Bioresorbable Polymeric Scaffold in Cardiovascular Applications.

Advances in material science and innovative medical technologies have allowed the development of less invasive interventional procedures for deploying implant devices, including scaffolds for cardiac tissue engineering. Biodegradable materials (e.g., resorbable polymers) are employed in devices that are only needed for a transient period. In the case of coronary stents, the device is only required for 6-8 months before positive remodelling takes place. Hence, biodegradable polymeric stents have been considered to promote this positive remodelling and eliminate the issue of permanent caging of the vessel. In tissue engineering, the role of the scaffold is to support favourable cell-scaffold interaction to stimulate formation of functional tissue. The ideal outcome is for the cells to produce their own extracellular matrix over time and eventually replace the implanted scaffold or tissue engineered construct. Synthetic biodegradable polymers are the favoured candidates as scaffolds, because their degradation rates can be manipulated over a broad time scale, and they may be functionalised easily. This review presents an overview of coronary heart disease, the limitations of current interventions and how biomaterials can be used to potentially circumvent these shortcomings in bioresorbable stents, vascular grafts and cardiac patches. The material specifications, type of polymers used, current progress and future challenges for each application will be discussed in this manuscript.

Double-kissing culotte technique for coronary bifurcation stenting.

AIMS: The aim of this study was to assess whether the culotte technique could be improved by an additional kissing dilation prior to main branch (MB) stenting. METHODS AND RESULTS: Double-kissing (DK) culotte was compared to the culotte and DK-crush techniques in a bench model (n=24). Results were evaluated for stent apposition, luminal opening and flow dynamics. The total procedure duration of DK-culotte was 18.3±3.4 minutes, significantly lower than for DK-crush (24.3±5.7 min; p=0.015), but similar to culotte (21.6±5.9 min, p=0.104). In DK-culotte the overall rate of moderate (200-500 µm) and significant (>500 µm) malapposition was 2.1±1.9% and 0.4±0.2%, similar as compared to culotte (3.7±3.8%, p=0.459 and 1.0±1.0%, p=0.517, respectively), and lower as compared to DK-crush (8.1±2.5%, p<0.001 and 3.7±5.3%, p=0.002, respectively). The lower malapposition rate of DK-culotte as compared to DK-crush was due to less moderate and significant malapposition in the proximal MB (0.0±0.0% vs 14.0±7.6%, p<0.001 and 0.0±0.0% vs 4.2±9.1%, p=0.026, respectively). Micro-computed tomography did not show a difference in luminal opening at the proximal MB, distal MB or SB. There was no difference either in the maximum shear rate or in areas of high shear or recirculation. CONCLUSIONS: Bench test data suggest that the DK approach facilitates the culotte technique. The clinical validity and relevance remain to be confirmed in a larger in vivo population.

Adventitial injection delivery of nano-encapsulated sirolimus (Nanolimus) to injury-induced porcine femoral vessels to reduce luminal restenosis.

Endovascular therapy in peripheral intervention has grown exponentially in the past decade, but the issue of high restenosis rates in lower extremity arteries still persist. While drug-coated balloons (DCB) have been the device of choice, recent controversary regarding the long-term safety of paclitaxel have raised concern over current DCBs. In our study, we proposed that the direct injection of a sirolimus nanoliposomal formulation (Nanolimus) using a infusion catheter can attenuate inflammation response in injured vessels. In vitro characterization showed retention of the nanoliposomes size and detectable drug amount up to 336 days in storage. For in vivo study, four female, mixed breed swines were subjected to balloon injury of the femoral arteries before treatment with either injection of saline (n = 4) or Nanolimus (n = 12) using the Bullfrog catheter. Pharmacokinetic analysis demonstrated sustained sirolimus release in the arteries and undetectable systemic drug level at 28 days. Arteries treated with Nanolimus showed significant reduction in neointima area (0.2 ± 0.3 mm2 vs 2.0 ± 1.2 mm2, p < 0.01) and luminal stenosis (14.2 ± 7.2% vs. 67.7 ± 24.8%, p < 0.01) compared to controls. In summary, adventitial delivery of sirolimus using an infusion catheter is a feasible and safe method to reduce vascular restenosis.

Efficacy and Reproducibility of Attenuation-Compensated Optical Coherence Tomography for Assessing External Elastic Membrane Border and Plaque Composition in Native and Stented Segments　- An In Vivo and Histology-Based Study.

BACKGROUND: Attenuation-compensated (AC) technique was recently introduced to improve the plaque characterization of optical coherence tomography (OCT). Histological validation demonstrated promising results but the efficacy and reproducibility of this technique for assessing in-vivo tissue composition remains unclear.Methods and Results:OCT images portraying native (n=200) and stented (n=200) segments and 31 histological cross-sections were analyzed. AC-OCT appeared superior to conventional (C)-OCT in detecting the external elastic lamina (EEM) borders (76% vs. 65.5%); AC-OCT enabled larger EEM arc detection compared with C-OCT (174.2±58.7° vs. 137.5±57.9°; P<0.001). There was poor agreement between the 2 techniques for detection of lipid in native and lipid and calcific tissue in stented segments (κ range: 0.164-0.466) but the agreement of C-OCT and AC-OCT was high for calcific tissue in native segments (κ=0.825). Intra and interobserver agreement of the 2 analysts was moderate to excellent with C-OCT (κ range: 0.681-0.979) and AC-OCT (κ range: 0.733-0.892) for all tissue types in both native and stented segments. Ex-vivoanalysis demonstrated that C-OCT was superior to AC-OCT (κ=0.545 vs. κ=0.296) for the detection of the lipid component in native segments. CONCLUSIONS: The AC technique allows better delineation of the EEM but it remains inferior for lipid pool detection and neointima characterization. Combined AC- and C-OCT imaging may provide additional value for complete assessment of plaque and neointima characteristics.

Local Hemodynamic Forces After Stenting: Implications on Restenosis and Thrombosis.

Local hemodynamic forces are well-known to modulate atherosclerotic evolution, which remains one of the largest cause of death worldwide. Percutaneous coronary interventions with stent implantation restores blood flow to the downstream myocardium and is only limited by stent failure caused by restenosis, stent thrombosis, or neoatherosclerosis. Cumulative evidence has shown that local hemodynamic forces affect restenosis and the platelet activation process, modulating the pathophysiological mechanisms that lead to stent failure. This article first covers the pathophysiological mechanisms through which wall shear stress regulates arterial disease formation/neointima proliferation and the role of shear rate on stent thrombosis. Subsequently, the article reviews the current evidence on (1) the implications of stent design on the local hemodynamic forces, and (2) how stent/scaffold expansion can influence local flow, thereby affecting the risk of adverse events.

Serial 5-Year Evaluation of Side Branches Jailed by Bioresorbable Vascular Scaffolds Using 3-Dimensional Optical Coherence Tomography: Insights From the ABSORB Cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions).

BACKGROUND: The long-term fate of Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, CA) struts jailing side branch ostia has not been clarified. We therefore evaluate serially (post-procedure and at 6 months, 1, 2, 3, and 5 years) the appearance and fate of jailed Absorb bioresorbable vascular scaffold struts. METHODS AND RESULTS: We performed 3-dimensional optical coherence tomographic analysis of the ABSORB Cohort B trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) up to 5 years using a novel, validated cut-plane analysis method. We included 29 patients with a total of 85 side branch ostia. From the 12 ostia which could be assessed in true serial fashion, 7 showed a pattern of initial decrease in the ostial area free from struts, followed by an increase in strut-free ostial area toward the end of the 5 years of follow-up. In a repeated-measures analysis with time as fixed variable and ostial area free from struts as dependent variable, we showed a numeric decrease in the estimated ostial area free from struts from 0.75 mm2 (baseline) to 0.68 mm2 (first follow-up visit at 6 months or 1 year) and 0.63 mm2 (second follow-up visit at 2 or 3 years). However, from the second visit to the 5-year follow-up visit, there was a statistically significant increase from 0.63 to 0.89 mm2 (P=0.001). Struts overlying an ostium divided the ostium into compartments, and the number of these compartments decreased over time. CONCLUSIONS: This study showed that in most cases, the side branch ostial area free from struts initially decreased. However, with full scaffold bioresorption, the ostial area free from scaffold increased between 2 to 3 years and 5 years in the vast majority of patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856856.

Stent malapposition and the risk of stent thrombosis: mechanistic insights from an in vitro model.

AIMS: The aim of this report was to examine the effect of underexpansion on stent thrombogenicity with an in vitro perfusion model. METHODS AND RESULTS: Drug-eluting stent (DES) samples were partially underdeployed in silicone tubes and perfused with porcine blood containing 10% anticoagulant citrate dextrose solution for four minutes at a flow rate of 200 ml/min. Thrombus formation was evaluated and compared between the well-apposed and malapposed sections. The malapposed sections showed significantly more thrombus formation compared to the well-apposed sections (13.9 vs. 0.41 mm2, p<0.001). CONCLUSIONS: Stent malapposition has a very direct impact on thrombus formation. Optimised stent implantation is required to minimise malapposition in DES and BVS to reduce thrombus formation.

Bioresorbable vascular scaffold radial expansion and conformation compared to a metallic platform: insights from in vitro expansion in a coronary artery lesion model.

AIMS: This study aimed to compare the acute expansion behaviour of a polymer-based bioresorbable scaffold and a second-generation metallic DES platform in a realistic coronary artery lesion model. Experimental mechanical data with conventional methods have so far shown little difference between metallic stents and currently available polymer-based bioresorbable scaffolds (BRS). Nevertheless, differences in acute results have been observed in clinical studies comparing BRS directly with metallic DES platforms. METHODS AND RESULTS: We examined the expansion behaviour of the bioresorbable vascular scaffold (3.0×18 mm Absorb BVS; Abbott Vascular, Santa Clara, CA, USA) and a metallic DES (3.0×18 mm XIENCE Prime; Abbott Vascular) after expansion at 37°C using identical coronary artery stenosis models (in total 12 experiments were performed). Device expansion was compared during balloon inflation and after deflation using microscopy to allow assessment of plaque recoil. Minimal lumen diameter (MLD) and minimal lumen area (MLA) and stent eccentricity were quantified from optical coherence tomography (OCT) imaging at nominal diameter and after post-dilation at 18 atm. The MLA in the models with BVS deployed was 4.92±0.17 mm² while in the metallic DES it was 5.40±0.13 mm2 (p=0.02) at nominal pressure (NP), and 5.41±0.20 and 6.07±0.25 mm2 (p=0.02), respectively, after expansion at 18 atm. Stent eccentricity index at the MLA was 0.71±0.02 in BVS compared to 0.81±0.02 in the metal stent at NP (p=0.004), and 0.73±0.03 compared to 0.75±0.02 at 18 atm (p=0.39). CONCLUSIONS: Results obtained in this in vitro lesion model were comparable to the results in randomised clinical trials comparing BVS and XIENCE stents in vivo. Such models may be useful in future BRS developments to predict their acute response in vivo in eccentric lesions.

Early coverage of drug-eluting stents analysed by optical coherence tomography: evidence of the impact of stent apposition and strut characteristics on the neointimal healing process.

AIMS: Previous studies have associated issues such as incomplete stent apposition with delayed healing and adverse events (stent thrombosis). The aim of this study was to evaluate the impact of strut apposition and stent type on the progression of stent strut coverage. METHODS AND RESULTS: We evaluated in vivo in porcine models the follow-up response and coverage characteristics of well-apposed and malapposed segments of drug-eluting stents (DES) (CYPHER, PROMUS Element and Orsiro) and the Absorb bioresorbable vascular scaffold (BVS) by optical coherence tomography (OCT) sequentially, at baseline, and at one week and four weeks of follow-up. Supporting results were provided by histological analysis performed at four-week follow-up and computer simulation describing the shear characteristics around apposed and non-apposed struts. A total of 325 cross-sections containing 3,166 struts were analysed. The extent of malapposition decreased over time as a result of neointimal healing (from 7.1% at baseline to 0% at four weeks; p=0.03). At one week, 13.6% of struts in well-apposed segments were still uncovered versus 19.2% of struts in malapposed cross-sections and 77.8% of NASB struts (p<0.01). At four-week follow-up, 3.1% of struts were uncovered in well-apposed cross-sections vs. 1.6% in malapposed cross-sections and 35.7% of NASB struts (p<0.01). A comparison of the apposed segments revealed that the thin-strut Orsiro had only 1.3% of uncovered struts at one week while PROMUS Element, CYPHER and BVS had 6.6%, 48.4% and 16.2% of struts still uncovered, respectively. CONCLUSIONS: This study shows that early coverage is influenced by stent apposition as well as platform strut characteristics (stent type). At four weeks, NASB struts remained a focus of delayed endothelialisation.