Near-infrared spectroscopy-intravascular ultrasound to improve assessment of coronary artery disease severity in patients referred for transcatheter aortic valve implantation (The IMPACTavi registry): Design and rationale.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) was established as a standard treatment for high-operative risk patients with severe aortic stenosis (AS). Although coronary artery disease (CAD) often coexists with AS, clinical and angiographic evaluations of stenosis severity are unreliable in this specific setting. To provide precise risk stratification of coronary lesions, combined near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS) was developed to integrate morphological and molecular information on plaque composition. However, there is a lack of evidence on the association between NIRS-IVUS derived findings such as maximum 4mm lipid core burden index (maxLCBI4mm) and clinical outcomes in AS patients undergoing TAVI. This registry aims to assess feasibility and safety of NIRS-IVUS imaging in the setting of routine pre-TAVI coronary angiography to improve assessment of CAD severity. METHODS: The registry is designed as a non-randomized, prospective, observational, multicenter cohort registry. Patients referred for TAVI with angiographic evidence of CAD receive NIRS-IVUS imaging and are followed up to 24 months. Enrolled patients are classified as NIRS-IVUS positive and NIRS-IVUS negative, respectively, based on their maxLCBI4mm to compare their clinical outcomes. The primary endpoint of the registry is major adverse cardiovascular events over a 24-month follow-up period. CONCLUSIONS: Identification of patients likely or unlikely to benefit from revascularization prior to TAVI represents an important unmet clinical need. This registry is designed to investigate whether NIRS-IVUS-derived atherosclerotic plaque characteristics can identify patients and lesions at risk for future adverse cardiovascular events after TAVI, in order to refine interventional decision-making in this challenging patient population.

Are we curing one evil with another? A translational approach targeting the role of neoatherosclerosis in late stent failure.

Neoatherosclerosis is defined as foamy macrophage infiltration into the peri-strut or neointimal area after stent implantation, potentially leading to late stent failure through progressive atherosclerotic changes including calcification, fibroatheroma, thin-cap fibroatheroma, and rupture with stent thrombosis (ST) in advanced stages. Human autopsy as well as intravascular imaging studies have led to the understanding of neoatherosclerosis formation as a similar but significantly accelerated pathophysiology as compared to native atherosclerosis. This acceleration is mainly based on disrupted endothelial integrity with insufficient barrier function and augmented transmigration of lipids following vascular injury after coronary intervention and especially after implantation of drug-eluting stents. In this review, we summarize translational insights into disease pathophysiology and discuss therapeutic approaches to tackle this novel disease entity. We introduce a novel animal model of neoatherosclerosis alongside accompanying in vitro experiments, which show impaired endothelial integrity causing increased permeability for low-density lipoprotein cholesterol resulting in foam cell transformation of human monocytes. In addition, we discuss novel intravascular imaging surrogates to improve reliable diagnosis of early stage neoatherosclerosis. Finally, a therapeutic approach to prevent in-stent neoatherosclerosis with magnesium-based bioresorbable scaffolds and systemic statin treatment demonstrated the potential to improve arterial healing and re-endothelialization, leading to significantly mitigated neoatherosclerosis formation in an animal model of neoatherosclerosis.

La neoateroesclerosis se define como infiltración de macrófagos espumosos en la zona periprotésica o de la neoíntima tras una implantación de stent, lo cual posiblemente derive en un fracaso tardío del stent mediante cambios ateroescleróticos progresivos, incluidos la calcificación, fibroateromas, fibroateromas de cápsula fina (FACF) y trombosis del stent (TS). Gracias a los estudios de autopsia humana y de imagen intravascular se ha podido comprender la formación de la neoateroesclerosis de una manera fisiopatológica similar a la ateroesclerosis nativa pero significativamente acelerada. Esta aceleración se basa principalmente en la alteración de la integridad endotelial con una función de barrera insuficiente y una mayor transmigración de lípidos a consecuencia de una lesión vascular tras una intervención coronaria y, especialmente, tras la implantación de stents farmacoactivos. En este artículo ofrecemos un resumen de las perspectivas translacionales sobre la fisiopatología de la enfermedad y analizamos los enfoques terapéuticos para abordar esta nueva enfermedad. Presentamos un modelo animal de neoateroesclerosis innovador junto con experimentos in vitro complementarios, en los cuales se pone de manifiesto que la integridad endotelial dañada causa una mayor permeabilidad para el colesterol de las LDL (LDL), lo que da lugar a que los monocitos se transformen en células espumosas. Asimismo, comentamos los criterios indirectos de valoración de imagen intravascular a fin de mejorar el diagnóstico fiable de la neoateroesclerosis en fase inicial. Por último, en un enfoque terapéutico para prevenir la neoateroesclerosis del stent con andamios de magnesio biorreabsorbibles (BRS) y un tratamiento sistémico con estatinas se demostró la posibilidad de mejorar la cicatrización y la reendotelización arteriales, lo que derivó en la formación de neoateroesclerosis significativamente más lenta en un modelo animal de neoateroesclerosis.

Small Dimension-Big Impact! Nanoparticle-Enhanced Non-Invasive and Intravascular Molecular Imaging of Atherosclerosis In Vivo.

Extensive translational research has provided considerable progress regarding the understanding of atherosclerosis pathophysiology over the last decades. In contrast, implementation of molecular in vivo imaging remains highly limited. In that context, nanoparticles represent a useful tool. Their variable shape and composition assure biocompatibility and stability within the environment of intended use, while the possibility of conjugating different ligands as well as contrast dyes enable targeting of moieties of interest on a molecular level and visualization throughout various imaging modalities. These characteristics have been exploited by a number of preclinical research approaches aimed at advancing understanding of vascular atherosclerotic disease, in order to improve identification of high-risk lesions prior to oftentimes fatal thromboembolic events. Furthermore, the combination of these targeted nanoparticles with therapeutic agents offers the potential of site-targeted drug delivery with minimized systemic secondary effects. This review gives an overview of different groups of targeted nanoparticles, designed for in vivo molecular imaging of atherosclerosis as well as an outlook on potential combined diagnostic and therapeutic applications.

Assessment of DNA synthesis in Islet-1⁺ cells in the adult murine heart.

RATIONALE: Islet-1 positive (Islet-1(+)) cardiac progenitor cells give rise to the right ventricle, atria and outflow tract during murine cardiac development. In the adult heart Islet-1 expression is limited to parasympathetic neurons, few cardiomyocytes, smooth muscle cells, within the proximal aorta and pulmonary artery and sinoatrial node cells. Its role in these cells is unknown. Here we tested the hypothesis that Islet-1(+) cells retain proliferative activity and may therefore play a role in regenerating specialized regions in the heart. METHODS AND RESULTS: DNA synthesis was analyzed by the incorporation of tritiated thymidine ((3)H-thymidine) in Isl-1-nLacZ mice, a transgenic model with an insertion of a nuclear beta-galactosidase in the Islet-1 locus. Mice received daily injections of (3)H-thymidine for 5 days. DNA synthesis was visualized throughout the heart by dipping autoradiography of cryosections. Colocalization of an nLacZ-signal and silver grains would indicate DNA synthesis in Islet-1(+) cells. Whereas Islet(-) non-myocyte nuclei were regularly marked by accumulation of silver grains, colocalization with nLacZ-signals was not detected in >25,000 cells analyzed. CONCLUSIONS: Islet-1(+) cells are quiescent in the adult heart, suggesting that, under normal conditions, even pacemaking cells do not proliferate at higher rates than normal cardiac myocytes.

Incidence of systemic inflammatory response syndrome and patient outcome following transcatheter edge-to-edge mitral valve repair.

OBJECTIVES: Systemic inflammatory response syndrome (SIRS) is a common finding after cardiovascular interventions. Data on the incidence of SIRS and its impact on outcome in patients undergoing transcatheter edge-to-edge mitral valve repair (MV-TEER) for mitral regurgitation (MR) is lacking. METHODS: From January 2013 to December 2020, 373 patients with moderate or severe MR undergoing MV-TEER were included. SIRS was defined as at least two of the following criteria within 48 h after the procedure: leucocyte count > 12.0 or < 4.0 × 109/l, respiratory rate > 20 breaths per minute or PaCO2 ≤ 4.3 kPa/32 mmHg, heart rate > 90 bpm and temperature > 38.0 °C or < 36.0 °C. The primary endpoint was 3-years all-cause mortality. RESULTS: SIRS was observed in 49.6% (185/373) of patients. Patients who developed SIRS presented more frequently with NYHA III/IV at baseline [SIRS: 82.4% (149/185) vs. no SIRS: 79.0% (147/188); p = 0.029]. Patients who developed SIRS spent more days on ICU (p < 0.001) and overall length of stay was longer (p < 0.001). Relevant residual MR, defined as MR ≥ III in-hospital, was present more often in patients who developed SIRS [SIRS: 11.3% (20/177) vs. no SIRS: 3.93% (7/178), p = 0.036]. At 3 years, all-cause mortality in the entire population was 33.5% (125/373) with an increased all-cause mortality in patients with SIRS compared to patients without SIRS (HR 1.49, [CI 95% 1.04, 2.13]; p = 0.0264). In the multivariate analysis development of SIRS (HR 1.479 [CI 95% 1.016, 2.154]; p = 0.041) was identified as predictor for 3-years all-cause mortality. CONCLUSIONS: SIRS is a common finding after MV-TEER occurring in approximately half of patients. SIRS after MV-TEER was associated with a longer in-hospital stay. In addition, we observed an increased 3-years all-cause mortality in patients with SIRS.

Echocardiographic evaluation of left ventricular function using an automated analysis algorithm is feasible for beginners and experts: comparison with invasive and non-invasive methods.

AIMS: Echocardiographic measurement of left ventricular function using a user-friendly automated three-dimensional algorithm is highly attractive as it promises quick and accurate diagnosis, circumventing limitations associated with visual estimation or manual biplane measurements. We sought to assess the feasibility and correlation of such automated analysis with clinically established methods. METHODS: A total of 198 patients undergoing transthoracic echocardiography (TTE) with assessment of left ventricular parameters by automated software algorithm (Philips 3D-Heartmodel; 3D-HM) which additionally had either left ventricular angiography (LVA) or cardiac magnetic resonance (CMR) within 24 h of the TTE examination were analyzed. Left ventricular parameters (left ventricular end-diastolic volume, LVEDV, left ventricular end-systolic volume, LVESV as well as left ventricular ejection fraction, LVEF) were compared between 3D-HM, CMR and LVA. RESULTS: Correlation of left ventricular measurements was overall good to excellent and stronger for CMR (EF r = 0.824) than for LVA (EF r = 0.746). Unexperienced and expert clinicians yielded comparable good results. For CMR, highest correlation was detected in patients with BMI < 25 and excellent image quality. High agreement was seen between 3D-HM and CMR or LVA when stratifying patients according to heart failure categories. CONCLUSIONS: Echocardiographic quantification of left ventricular parameters using a software-based algorithm correlated well with established invasive and non-invasive modalities in the clinical setting, even for unexperienced clinicians. Such automated approaches are promising as they allow a reliable, more observer-independent as well as reproducible assessment of left ventricular function.

Challenges of the newer generation of resorbable magnesium scaffolds: Lessons from failure mechanisms of the past generation.

Bioresorbable scaffolds (BRS) were developed to overcome the obstacles of metallic stents, mostly related to sustained presence of metallic foreign body in the coronary vessel. Following earlier success of single-arm BRS studies, randomized controlled trials of Absorb bioresorbable vascular scaffold (Abbott Vascular, Santa Clara, CA, USA) showed poor long-term clinical outcomes, particularly in terms of scaffold thrombosis. BRS made from magnesium alloy provide a promising alternative in terms of radial force, strut thickness and, potentially lower thrombogenicity. A recent clinical study demonstrated that magnesium-based BRS seems to be promising with regards to the risk of scaffold thrombosis. In this review, our aim is to describe the issues that prevented Absorb BVS from achieving favorable outcomes, provide current status of existing BRS technologies and the challenges that newer generation BRSs need to overcome, and the results of clinical studies for commercially available magnesium-based BRS, which remain the only BRS actively studied in clinical practice.

Timing and predictors of definite stent thrombosis in comatose survivors of out-of-hospital cardiac arrest undergoing percutaneous coronary intervention and therapeutic hypothermia (ST-OHCA study).

BACKGROUND: Incidence of stent thrombosis (ST) in comatose survivors of out-of-hospital cardiac arrest (OHCA) undergoing immediate percutaneous coronary intervention (PCI) and therapeutic hypothermia (TH) varies considerably, from 2.7% to 31.2%, in retrospective studies. AIMS: We aimed to investigate occurrence, timing and predictors of definite ST. METHODS: We prospectively investigated consecutive comatose survivors of OHCA with presumed cardiac aetiology undergoing immediate PCI with drug-eluting stents (DES) and TH targeted at 32-34°C admitted between August 2016 and July 2021. Repeat coronary angiography (CAG) was performed if ST was suspected and systematically between day 8-12 in the absence of clinical signs. All deceased patients underwent autopsy and histopathological analysis.  Results: Among 362 comatose survivors of OHCA, immediate PCI with stenting was performed in 169 patients (47%). Since 18 patients did not complete follow-up, 151 patients were ultimately enrolled in ST analysis. Definite ST was confirmed in 29 patients (19.2%; 95% confidence interval [CI]: 12.9%-25.6%) either by CAG (n=18) or autopsy (n=11). ST occurred within 3 days in 62% and presented with at least one clinical sign in 79%. Survival with good neurological recovery was observed in 17% of patients with ST and in 60% of patients without ST (p<0.001). Independent predictors of ST were longer prehospital resuscitation, lower arterial pH and increased creatinine on admission. CONCLUSIONS: The incidence of definite ST in comatose survivors of OHCA undergoing immediate PCI and TH targeted at 32-34°C is substantial (19.2%) and significantly higher than in other PCI subsets despite systematic use of contemporary DES and anticoagulation/antiplatelet treatment.

The impact of extra-valvular cardiac damage on mid-term clinical outcome following transcatheter aortic valve replacement in patients with severe aortic stenosis.

Aims: To quantify extra-valvular cardiac damage associated with severe aortic valve stenosis (AS), a novel staging model was proposed. This study aimed to validate this model in patients undergoing transcatheter aortic valve replacement (TAVR) as well as to assess its prognostic impact. Methods and results: Based on echocardiographic findings, the following stages were applied: isolated AS (stage 0), left ventricular (LV) damage (stage 1), left atrial or mitral valve damage (stage 2), pulmonary hypertension or tricuspid regurgitation (stage 3), or right ventricular dysfunction (stage 4). The primary endpoint was 2-year all-cause mortality. The distribution across stages was 0.8% at stage 0, 7.5% at stage 1, 63.3% at stage 2, 18.3% at stage 3, and 10.1% at stage 4. All-cause mortality increased at all stages 1-4 (12.1%, 18.2%, 26.6%, and 28.2%; p = 0.023). In the multivariate model, the stage of cardiac damage, age, New York Heart Association (NYHA) class III/IV, peripheral artery disease, and previous pacemaker were independent predictors of the primary endpoint. Conclusions: Patients treated for severe AS show a high prevalence of extra-valvular cardiac damage. An increase in stage is associated with higher 2-year all-cause mortality. The application of this staging model may add value to current treatment algorithms.

Intravascular molecular imaging: translating pathophysiology of atherosclerosis into human disease conditions.

Progression of atherosclerotic plaque in coronary arteries is characterized by complex cellular and non-cellular molecular interactions. Within recent years, atherosclerosis has been recognized as inflammation-driven disease condition, where progressive stages are characterized by morphological changes in plaque composition but also relevant molecular processes resulting in increased plaque vulnerability. While existing intravascular imaging modalities are able to resolve key morphological features during plaque progression, they lack capability to characterize the molecular profile of advanced atherosclerotic plaque. Because hybrid imaging modalities may provide incremental information related to plaque biology, they are expected to provide synergistic effects in detecting high risk patients and lesions. The aim of this article is to review existing literature on intravascular molecular imaging approaches, and to provide clinically oriented proposals of their application. In addition, we assembled an overview of future developments in this field geared towards detection of patients at risk for cardiovascular events.

Periprocedural myocardial injury according to optical characteristics of neointima and treatment modality of in-stent restenosis.

AIMS: Aim of the present study was to investigate the impact of increasing neointimal inhomogeneity and neoatherosclerosis as well as of treatment modality of in-stent restenosis (ISR) on the occurrence of periprocedural myocardial injury (PMI). METHODS AND RESULTS: Patients with normal or stable/falling increased baseline high-sensitivity troponin T (hs-cTnT) undergoing intravascular optical coherence tomography (OCT) and subsequent percutaneous coronary intervention (PCI) of ISR by means of drug-coated balloon (DCB) or drug-eluting stent (DES) were included. Overall, 128 patients were subdivided into low (n = 64) and high (n = 64) inhomogeneity groups, based on the median of distribution of non-homogeneous quadrants. No significant between-group differences were detected in terms of hs-cTnT changes (28.0 [12.0-65.8] vs. 25.5 [9.8-65.0] ng/L; p = 0.355), or the incidence of major PMI (31.2 vs. 31.2%; p = 1.000). Similarly, no differences were observed between DCB- and DES-treated groups in terms of hs-cTn changes (27.0 [10.0-64.0] vs. 28.0 [11.0-73.0] ng/L; p = 0.795), or the incidence of major PMI (28.9 vs. 35.6%; p = 0.566). Additionally, no significant interaction was present between optical neointimal characteristics and treatment modality in terms of changes in hs-cTnT (Pint = 0.432). No significant differences in PMI occurrence were observed between low and high neoatherosclerosis subgroups. CONCLUSIONS: In patients undergoing PCI for ISR, there was no association between increasing neointimal inhomogeneity, or increasing expression of neoatherosclerotic changes and occurrence of PMI. PMI occurrence was not influenced by the treatment modality (DCB vs. DES) of ISR lesions, a finding that supports the safety of DCB treatment for ISR.

Prognostic implications of impaired longitudinal left ventricular systolic function assessed by tissue Doppler imaging prior to transcatheter aortic valve implantation for severe aortic stenosis.

Change in longitudinal left ventricular (LV) systolic function serves as an early marker of the deleterious effect of aortic stenosis (AS) and other cardiac comorbidities on cardiac function. We explored the prognostic value of tissue Doppler imaging (TDI)-derived longitudinal LV systolic function, defined by the peak systolic average of lateral and septal mitral annular velocities (average S') among symptomatic patients with severe AS undergoing transcatheter aortic valve implantation (TAVI). 297 consecutive patients with severe AS undergoing TAVI at three european centers with available average S' at preprocedural echocardiography were retrospectively included. The primary endpoint was the Kaplan Meier estimate of all-cause mortality. After a median 18 months (IQR 12-18) follow-up, 36 (12.1%) patients had died. Average S' was associated with all-cause mortality (per 1 cm/sec decrease: HR 1.29, 95%CI 1.03-1.60, p = 0.025), the cut-off of 6.5 cm/sec being the most accurate. Patients with average S' < 6.5 cm/sec (55.2%) presented characteristics of more advanced LV remodeling and functional impairment along with higher burden of cardiac comorbidities, and experienced higher all-cause mortality (17.6% vs. 7.5%, p = 0.007), also when adjusted for in-study outcome predictors (adj-HR: 2.69, 95%CI 1.22-5.93, p = 0.014). Results were consistent among patients with preserved ejection fraction, normal-flow AS, high-gradient AS and in those without LV hypertrophy. Longitudinal LV systolic function assessed by average S' is independently associated with long-term all-cause mortality among TAVI patients. An average S' below 6.5 cm/sec best defines clinically meaningful reduced longitudinal systolic function and may aid clinical risk stratification in these patients.

Histopathology-Based Deep-Learning Predicts Atherosclerotic Lesions in Intravascular Imaging.

Background: Optical coherence tomography is a powerful modality to assess atherosclerotic lesions, but detecting lesions in high-resolution OCT is challenging and requires expert knowledge. Deep-learning algorithms can be used to automatically identify atherosclerotic lesions, facilitating identification of patients at risk. We trained a deep-learning algorithm (DeepAD) with co-registered, annotated histopathology to predict atherosclerotic lesions in optical coherence tomography (OCT). Methods: Two datasets were used for training DeepAD: (i) a histopathology data set from 7 autopsy cases with 62 OCT frames and co-registered histopathology for high quality manual annotation and (ii) a clinical data set from 51 patients with 222 OCT frames in which manual annotations were based on clinical expertise only. A U-net based deep convolutional neural network (CNN) ensemble was employed as an atherosclerotic lesion prediction algorithm. Results were analyzed using intersection over union (IOU) for segmentation. Results: DeepAD showed good performance regarding the prediction of atherosclerotic lesions, with a median IOU of 0.68 ± 0.18 for segmentation of atherosclerotic lesions. Detection of calcified lesions yielded an IOU = 0.34. When training the algorithm without histopathology-based annotations, a performance drop of >0.25 IOU was observed. The practical application of DeepAD was evaluated retrospectively in a clinical cohort (n = 11 cases), showing high sensitivity as well as specificity and similar performance when compared to manual expert analysis. Conclusion: Automated detection of atherosclerotic lesions in OCT is improved using a histopathology-based deep-learning algorithm, allowing accurate detection in the clinical setting. An automated decision-support tool based on DeepAD could help in risk prediction and guide interventional treatment decisions.

Validation and application of OCT tissue attenuation index for the detection of neointimal foam cells.

Neointimal infiltration with foamy macrophages is recognized as an early and important sign of de-novo atherosclerosis after stent implantation (neoatherosclerosis). Recent histopathological studies have proven that automated quantification of signal attenuation using intravascular optical coherence tomography (OCT) imaging allows for sensitive identification of macrophages in native atherosclerotic disease. Whether this is true for neointimal foam cells in the setting of neoatherosclerosis remains unknown. Autopsy samples of stented coronary arteries (n = 13 cases) were evaluated by histology and OCT. After co-registration with histology, the attenuation rate of emitted laser light was measured in regions with and without neointimal foamy macrophages relative to its peak intensity at the blood-tissue interface. Attenuation index was subsequently determined as slope of a regression curve fitted to individual data points. Receiver operating curve (ROC) analysis was used to establish an optimal cut-off for detecting foamy macrophages in homogenous and non-homogenous neointima, respectively. Finally, the tissue attenuation index was applied to confirm or exclude the presence of neointimal foamy macrophages in symptomatic patients presenting with in-stent restenosis and undergoing intravascular OCT imaging (n = 29 cases). Tissue attenuation index derived from post-mortem samples differed significantly between histologically confirmed regions with and without neointimal foamy macrophages (- 1.23 ± 1.42 vs. - 0.52 ± 1.79, p < 0.05). ROC analysis was able to distinguish neointima with foamy macrophage infiltration from neointima without (93% sensitivity, 73% specificity, cut-off - 0.79, AUC 0.87 for homogenous neointima and 40% sensitivity, 95% specificity, cut-off - 1.93, AUC 0.69 for non-homogenous neointima). In symptomatic patients presenting with in-stent restenosis after stent implantation and undergoing intravascular imaging with OCT, neointimal foamy macrophages were detected in 34.2% of homogenous and 43.6% of non-homogenous neointimal ROI's evaluated. OCT-derived and histopathologically validated tissue attenuation index enables identification of neointimal foamy macrophages in stented coronary arteries. Such image-based post-processing software algorithm may help discern and triage subjects at increased risk for device-related events.

Thrombus NET content is associated with clinical outcome in stroke and myocardial infarction.

OBJECTIVE: To investigate whether immune cell composition and content of neutrophil extracellular traps (NETs) in relation to clinical outcome are different between acute ischemic stroke (AIS) and acute myocardial infarction (AMI), we performed histologic analysis and correlated results with clinical and procedural parameters. METHODS: We retrieved thrombi from patients with AIS (n = 71) and AMI (n = 72) during endovascular arterial recanalization and analyzed their immune cell composition and NET content by immunohistology. We then associated thrombus composition with procedural parameters and outcome in AIS and with cardiac function in patients with AMI. Furthermore, we compared AIS thrombi with AMI thrombi and differentiated Trial of Org 10172 in Acute Stroke Treatment classifications to address potential differences in thrombus pathogenesis. RESULTS: Amounts of leukocytes (p = 0.133) and neutrophils (p = 0.56) were similar between AIS and AMI thrombi. Monocytes (p = 0.0052), eosinophils (p < 0.0001), B cells (p < 0.0001), and T cells (p < 0.0001) were more abundant in stroke compared with AMI thrombi. NETs were present in 100% of patients with AIS and 20.8% of patients with AMI. Their abundance in thrombi was associated with poor outcome scores in patients with AIS and with reduced ejection fraction in patients with AMI. CONCLUSION: In our detailed histologic analysis of arterial thrombi, thrombus composition and especially abundance of leukocyte subsets differed between patients with AIS and AMI. The presence and amount of NETs were associated with patients' outcome after AIS and AMI, supporting a critical impact of NETs on thrombus stability in both conditions.

Preclinical investigation of neoatherosclerosis in magnesium-based bioresorbable scaffolds versus thick-strut drug-eluting stents.

AIMS: Neoatherosclerosis is a frequent finding after implantation of permanent metallic stents. Bioresorbable scaffolds (BRS) are considered to reduce the incidence of neoatherosclerosis owing to their dissolution and consequent vascular restoration. The aim of this study was to evaluate the formation of neoatherosclerosis between magnesium-based BRS and thick-strut metallic drug-eluting stents (DES) in a rabbit model of neoatherosclerosis and in proportion to the effect of high-dose statin medication. METHODS AND RESULTS: Fully bioresorbable magnesium scaffolds (BRS, n=45) and thick-strut permanent metallic DES of equivalent geometry and design (n=45) were implanted into the iliac arteries of New Zealand White rabbits (n=45) following endothelial balloon injury and exposure to a cholesterol diet. Endothelialisation was assessed in 12 animals after 35 days using scanning electron microscopy (SEM), showing significantly enhanced re-endothelialisation above struts in the BRS (n=13) compared to DES (n=10). Eleven (11) animals were terminated for baseline assessment after 91 days while the remaining 22 animals were randomised to receive high-dose statin treatment (3 mg/kg) or placebo. BRS-treated vessels showed a significant reduction in foam cell infiltration as a sign of early neoatherosclerosis by histology and OCT when compared to thick-strut DES-treated vessels. Statin treatment resulted in significant reduction of foam cell infiltration in BRS and DES by histology. CONCLUSIONS: Our findings suggest reduced neoatherosclerosis formation in magnesium-based BRS relative to thick-strut DES. High-dose statin treatment may be a promising measure to reduce neoatherosclerosis progression, both on its own and in synergy with site-targeted device-based treatment.

Assessment of a pro-healing stent in an animal model of early neoatherosclerosis.

BACKGROUND: Neoatherosclerosis represents an accelerated manifestation of atherosclerosis in nascent neointima after stenting, associated with adverse events. We investigated whether improved reendothelialization using RGD-coated stents results in diminished vascular permeability and reduced foam cell formation compared to standard DES in atherosclerotic rabbits. METHODS AND RESULTS: Neointimal foam cell formation was induced in rabbits (n = 7). Enhanced endothelial integrity in RGD-coated stents resulted in decreased vascular permeability relative to DES, which was further confirmed by SEM and TEM. Cell culture experiments examined the effect of everolimus on endothelial integrity. Increasing concentrations of everolimus resulted in a dose-dependent decrease of endothelial cell junctions and foam cell transformation of monocytes, confirming the relevance of endothelial integrity in preventing permeability of LDL. CONCLUSION: Incomplete endothelial integrity was confirmed as a key factor of neointimal foam cell formation following stent implantation. Pro-healing stent coatings may facilitate reendothelialization and reduce the risk of neoatherosclerosis.

Neoatherosclerosis: from basic principles to intravascular imaging.

Development of new atherosclerotic lesions within the neointima of stented vessels has been recognized as a novel disease manifestation of atherosclerosis (neoatherosclerosis), often manifesting as in-stent restenosis (ISR) or in-stent thrombosis (ST). The pathobiology of this entity is still not fully understood and definite diagnosis is challenging owing to limitations in resolution of contemporary intravascular imaging modalities and lack of consequent histopathology correlation studies. Yet, intravascular imaging has emerged as the gold standard for the diagnosis of in-stent pathologies, the most routinely used modalities being intravascular ultrasound (IVUS) and optical coherence tomography (OCT). In this review, we will give a concise summary about the basic understanding and histological findings of neoatherosclerosis. We will focus on the description of in-vivo findings using IVUS and OCT, discussing advantages and pitfalls. Furthermore, recent developments regarding innovative molecular imaging techniques for a more precise and advanced examination of neoatherosclerotic plaques will be discussed.

No effect of thymosin beta-4 on the expression of the transcription factor Islet-1 in the adult murine heart.

The transcription factor Islet-1 marks a progenitor cell population of the second heart field during cardiogenesis. In the adult heart Islet-1 expression is limited to the sinoatrial node, the ventricular outflow tract, and parasympathetic ganglia. The regenerative effect in the injured mouse ventricle of thymosin beta-4 (TB4), a 43-aminoacid peptide, was associated with increased Islet-1 immunostaining, suggesting the induction of an Islet-1-positive progenitor state by TB4. Here we aimed to reassess this effect in a genetic model. Mice from the reporter mouse line Isl1-nLacZ were primed with TB4 and subsequently underwent myocardial infarction. Islet-1 expression was assessed 2, 7, and 14 days after infarction. We detected only a single Islet-1+ cell in 8 TB4 treated and infarcted hearts which located outside of the sinoatrial node, the outflow tract or cardiac ganglia (in ~2500 sections). Two cells were identified in 5 control infarcted hearts. TB4 did not induce LacZ positivity in ventricular explants cultures of Isl1-nLacZ mice nor did it affect the density of LacZ+ cells in explant cultures of nLacZ+ regions of the heart. In summary, we found no evidence that TB4 reactivates Islet-1 expression in adult mouse ventricle.