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Summary Background The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. Methods Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). Findings The PRAISE score showed an AUC of 0·82 (95% CI 0·78–0·85) in the internal validation cohort and 0·92 (0·90–0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70–0·78) in the internal validation cohort and 0·81 (0·76–0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66–0·75) in the internal validation cohort and 0·86 (0·82–0·89) in the external validation cohort for 1-year major bleeding. Interpretation A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. Funding None.

Patient-specific computational fluid dynamics is a powerful tool for investigating the hemodynamic risk in coronary arteries. Proper setting of flow boundary conditions in computational hemodynamic models of coronary arteries is one of the sources of uncertainty weakening the findings of in silico experiments, in consequence of the challenging task of obtaining in vivo 3D flow measurements within the clinical framework. Accordingly, in this study we evaluated the influence of assumptions on inflow velocity profile shape on coronary artery hemodynamics. To do that, (1) ten left anterior descending coronary artery (LAD) geometries were reconstructed from clinical angiography, and (2) eleven velocity profiles with realistic 3D features such as eccentricity and differently shaped (single- and double-vortex) secondary flows were generated analytically and imposed as inflow boundary conditions. Wall shear stress and helicity-based descriptors obtained prescribing the commonly used parabolic velocity profile were compared with those obtained with the other velocity profiles. Our findings indicated that the imposition of idealized velocity profiles as inflow boundary condition is acceptable as long the results of the proximal vessel segment are not considered, in LAD coronary arteries. As a pragmatic rule of thumb, a conservative estimation of the length of influence of the shape of the inflow velocity profile on LAD local hemodynamics can be given by the theoretical entrance length for cylindrical conduits in laminar flow conditions.

Despite the important advancements in the stent technology for the treatment of diseased coronary arteries, major complications still affect the postoperative long-term outcome. The stent-induced flow disturbances, and especially the altered wall shear stress (WSS) profile at the strut level, play an important role in the pathophysiological mechanisms leading to stent thrombosis (ST) and in-stent restenosis (ISR). In this context, the analysis of the WSS topological skeleton is gaining more and more interest by extending the current understanding of the association between local hemodynamics and vascular diseases. This study aims to analyze the impact that a deployed coronary stent has on the WSS topological skeleton. Computational fluid dynamics (CFD) simulations were performed in three stented human coronary artery geometries reconstructed from clinical images. The selected cases presented stents with different designs (i.e., two contemporary drug-eluting stents and one bioresorbable scaffold) and included regions with stent malapposition or overlapping. A recently proposed Eulerian-based approach was applied to analyze the WSS topological skeleton features. The results highlighted that the presence of single or multiple stents within a coronary artery markedly impacts the WSS topological skeleton. In particular, repetitive patterns of WSS divergence were observed at the luminal surface, highlighting a WSS contraction action exerted proximal to the stent struts and a WSS expansion action distal to the stent struts. This WSS action pattern was independent from the stent design. In conclusion, these findings could contribute to a deeper understanding of the hemodynamics-driven processes underlying ST and ISR.

Background: Conversion of cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiac stromal cells under the control of YAP (yes-associated protein) transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ (transcriptional coactivator with PDZ-binding motif) complex with their cognate transcription factors TEADs (TEA domain transcription factors), under high-strain and profibrotic stimulation. Methods: We employed high content imaging, 2-dimensional/3-dimensional culture, atomic force microscopy mapping, and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiac stromal cells. We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. Results: Our experiments suggested that pharmacologically targeting the YAP-dependent pathway overrides the profibrotic activation of cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of profibrotic signaling mediated by TGF-β1 (transforming growth factor beta-1). In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. Conclusions: Our study indicates that preventing molecular translation of mechanical cues in cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.

BACKGROUND The risk of recurrent ischemia and bleeding after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) may vary during the first year of follow-up according to clinical presentation, and medical and interventional strategies. METHODS BleeMACS and RENAMI are 2 multicenter registries enrolling patients with ACS treated with PCI and clopidogrel, prasugrel, or ticagrelor. The average daily ischemic and bleeding risks (ADIR and ADBR) in the first year after PCI were the primary end points. The difference between ADBR and ADIR was calculated to estimate the potential excess of bleeding/ischemic events in a given period or specific subgroup. RESULTS A total of 19,826 patients were included. Overall, in the first year after PCI, the ADBR was 0.008085%, whereas ADIR was 0.008017% (P = .886). In the first 2 weeks ADIR was higher than ADBR (P = .013), especially in patients with ST-segment elevation myocardial infarction or incomplete revascularization. ADIR continued to be, albeit non-significantly, greater than ADBR up to the third month, whereas ADBR became higher, although not significantly, afterward. Patients with incomplete revascularization had an excess in ischemic risk (P = .003), whereas non-ST-segment elevation ACS patients and those on ticagrelor had an excess of bleeding (P = .012 and P = .022, respectively). CONCLUSIONS In unselected ACS patients, ADIR and ADBR occurred at similar rates within 1 year after PCI. ADIR was greater than ADBR in the first 2 weeks, especially in ST-segment elevation myocardial infarction patients and those with incomplete revascularization. In the first year, ADIR was higher than ADBR in patients with incomplete revascularization, whereas ADBR was higher in non-ST-segment elevation ACS patients and in those discharged on ticagrelor.

The aggregation of amyloid-beta peptides is associated with the pathogenesis of Alzheimer’s disease. The hydrophobic core of the amyloid beta sequence contains a GxxxG repeated motif, called glycine zipper, which involves crucial residues for assuring stability and promoting the process of fibril formation. Mutations in this motif lead to a completely different oligomerization pathway and rate of fibril formation. In this work, we have tested G33L and G37L residue substitutions by molecular dynamics simulations. We found that both protein mutations may lead to remarkable changes in the fibril conformational stability. Results suggest the disruption of the glycine zipper as a possible strategy to reduce the aggregation propensity of amyloid beta peptides. On the basis of our data, further investigations may consider this key region as a binding site to design/discover novel effective inhibitors. Communicated by Ramaswamy H. Sarma

Three-dimensional dynamic suspension is becoming an effective cell culture method for a wide range of bioprocesses, with an increasing number of bioreactors proposed for this purpose. The complex hydrodynamics establishing within these devices affects bioprocess outcomes and efficiency, and usually expensive in vitro trial-and-error experiments are needed to properly set the working parameters. Here we propose a methodology to define a priori the hydrodynamic working parameters of a dynamic suspension bioreactor, selected as a test case because of the complex hydrodynamics characterizing its operating condition. A combination of computational and analytical approaches was applied to generate operational guideline graphs for defining a priori specific working parameters. In detail, 43 simulations were performed under pulsed flow regime to characterize advective transport within the device depending on different operative conditions, i.e., culture medium flow rate and its duty cycle, cultured particle diameter, and initial particle suspension volume. The operational guideline graphs were then used to set specific hydrodynamic working parameters for an in vitro proof-of-principle test, where human induced pluripotent stem cell (hiPSC) aggregates were cultured for 24 h within the bioreactor. The in vitro findings showed that, under the selected pulsed flow regime, sedimentation was avoided, hiPSC aggregate circularity and viability were preserved, and culture heterogeneity was reduced, thus confirming the appropriateness of the a priori method. This methodology has the potential to be adaptable to other dynamic suspension devices to support experimental studies by providing in silico-based a priori knowledge, useful to limit costs and to optimize culture bioprocesses.

Introduction and objectives There is little evidence on rates of stent thrombosis (ST) in patients receiving dual antiplatelet therapy (DAPT) with ticagrelor or prasugrel . The aim of this study was to analyze the incidence and predictors of ST after an acute coronary syndrome among patients receiving DAPT with ticagrelor vs prasugrel. Methods We used data from the RENAMI registry (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), analyzing a total of 4123 acute coronary syndrome patients discharged with DAPT with ticagrelor or prasugrel in 11 centers in 6 European countries. The endpoint was definite ST within the first year. A competitive risk analysis was carried out using a Fine and Gray regression model, with death being the competitive event. Results A total of 2604 patients received DAPT with ticagrelor and 1519 with prasugrel; ST occurred in 41 patients (1.10%), with a similar cumulative incidence between ticagrelor (1.21%) and prasugrel (0.90%). The independent predictors of ST were age (sHR, 1.03; 95% C I, 1.01-1.06), ST segment elevation (sHR, 2.24; 95%CI, 1.22-4.14), previous myocardial infarction (sHR, 2.56; 95%CI, 1.19-5.49), and serum creatinine (sHR, 1.29; 95%CI, 1.08-1.54). Conclusions Stent thrombosis is infrequent in patients receiving DAPT with ticagrelor or prasugrel. The variables associated with an increased risk of ST were advanced age, ST segment elevation, previous myocardial infarction, and serum creatinine.

Resumen Introduccion y objetivos Hay muy poca evidencia sobre las tasas de trombosis del stent (TS) en pacientes que reciben tratamiento antiagregante plaquetario doble (TAPD) con ticagrelor o prasugrel. El objetivo de este estudio es analizar la incidencia y predictores de la TS tras un sindrome coronario agudo en pacientes que reciben TAPD con ticagrelor frente a prasugrel. Metodos Se utilizaron datos del registro RENAMI (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), y se analizo en total a 4.123 pacientes con sindrome coronario agudo dados de alta con TAPD con ticagrelor o prasugrel en 11 centros de 6 paises europeos. Se considero como evento la TS confirmada en el primer ano. Se realizo un analisis de riesgos competitivos mediante un modelo de regresion de Fine y Gray, siendo la muerte el evento competitivo. Resultados Recibieron TAPD con ticagrelor 2.604 pacientes y con prasugrel, 1.519; 41 pacientes (1,10%) presentaron TS, con incidencias acumuladas similares entre ticagrelor (1,21%) y prasugrel (0,90%). Los predictores independientes de la TS fueron: la edad (sHR = 1,03; IC95%, 1,01-1,06), la elevacion del segmento ST (sHR = 2,24; IC95%, 1,22-4,14), el antecedente de infarto de miocardio (sHR = 2,56; IC95%, 1,19-5,49) y la creatinina serica (sHR = 1,29; IC95%, 1,08-1,54). Conclusiones La TS es infrecuente en pacientes que reciben TAPD con ticagrelor y prasugrel. La edad avanzada, la elevacion del segmento ST, el antecedente de infarto y la creatinina serica son las variables que se asocian con mayor riesgo de TS.

Micromechanical characterization by nanoindentation of PDMS substrates for cardiac mechanobiology studies.

A low-cost particle image velocimetry set-up that allows to investigate the fluid dynamics inside realistic coronary artery phantoms has been implemented. The proposed smart test bench for experimental characterization of arterial hemodynamics also in the presence of implanted devices represents a low-cost equipment that can be easily implemented in non-expert laboratories for research as well as educational applications.

Endovascular aneurysm repair (EVAR), despite its advantages over abdominal aortic aneurysm (AAA) open surgery, still presents risks of failure linked to Endograft (EG) migration. We here explore the link between intravascular blood flow features and Displacement Forces (DFs) acting on the EG. DFs are inversely associated with the amount of helical flow within the EG.

BACKGROUND AND AIMS Wall shear stress (WSS) has been associated with atherogenesis and plaque progression. The present study assessed the value of WSS analysis derived from conventional coronary angiography to detect lesions culprit for future myocardial infarction (MI). METHODS AND RESULTS Three-dimensional quantitative coronary angiography (3DQCA), was used to calculate WSS and pressure drop in 80 patients. WSS descriptors were compared between 80 lesions culprit of future MI and 108 non-culprit lesions (controls). Endothelium-blood flow interaction was assessed by computational fluid dynamics (10.8 ± 1.41 min per vessel). Median time between baseline angiography and MI was 25.9 (21.9-29.8) months. Mean patient age was 70.3 ± 12.7. Clinical presentation was STEMI in 35% and NSTEMI in 65%. Culprit lesions showed higher percent area stenosis (%AS), translesional vFFR difference (ΔvFFR), time-averaged WSS (TAWSS) and topological shear variation index (TSVI) compared to non-culprit lesions (p

Coronary atherosclerosis is a leading cause of illness and death in Western World and its mechanisms are still non completely understood. Several animal models have been used to 1) study coronary atherosclerosis natural history and 2) propose predictive tools for this disease, that is asymptomatic for a long time, aiming for a direct translation of their findings to human coronary arteries. Among them, swine models are largely used due to the observed anatomical and pathophysiological similarities to humans. However, a direct comparison between swine and human models in terms of coronary hemodynamics, known to influence atherosclerotic onset/development, is still lacking. In this context, we performed a detailed comparative analysis between swine- and human-specific computational hemodynamic models of coronary arteries. The analysis involved several near-wall and intravascular flow descriptors, previously emerged as markers of coronary atherosclerosis initiation/progression, as well as anatomical features. To do that, non-culprit coronary arteries (18 right–RCA, 18 left anterior descending–LAD, 13 left circumflex–LCX coronary artery) from patients presenting with acute coronary syndrome were imaged by intravascular ultrasound and coronary computed tomography angiography. Similarly, the three main coronary arteries of ten adult mini-pigs were also imaged (10 RCA, 10 LAD, 10 LCX). The geometries of the imaged coronary arteries were reconstructed (49 human, 30 swine), and computational fluid dynamic simulations were performed by imposing individualized boundary conditions. Overall, no relevant differences in 1) wall shear stress-based quantities, 2) intravascular hemodynamics (in terms of helical flow features), and 3) anatomical features emerged between human- and swine-specific models. The findings of this study strongly support the use of swine-specific computational models to study and characterize the hemodynamic features linked to coronary atherosclerosis, sustaining the reliability of their translation to human vascular disease.

Background The use of potent P2Y12 inhibitors (ticagrelor & prasugrel) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary interventions (PCI) is a class I recommendation. We performed a sex-specific analysis comparing the difference in efficacy and safety outcomes between ticagrelor and prasugrel in a real-world ACS population. Methods Data from the multicenter REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) for 4424 ACS patients who underwent PCI and were treated with ticagrelor or prasugrel between 2012 to 2016 were analyzed. Mean follow-up was 17±9 months. Results After propensity score matching, there was no significant difference in the occurrence of primary endpoint of net adverse cardiac events between ticagrelor and prasugrel in men (HR: 0.94; 95% CI: 0.69-1.29; P=0.71), or women (HR: 1.17; 95% CI: 0.63-2.20; P=0.62; P interaction [sex] = 0.40). Similarly, no differences were found in the occurrence of any of the secondary endpoints (MACE, all cause death, re-infarction, stent thrombosis, BARC major bleeding and BARC any bleeding) between the two P2Y12 groups between men and women. Conclusions In this real-world ACS population, no relative difference in efficacy or safety outcomes were found between ticagrelor and prasugrel between sexes.

Inspired by Nature, where storing information is an intrinsic ability of natural systems, here we investigate the capability of interacting systems to transport/store the information generated/exchanged in the interaction process in the form of energy or matter, preserving it over time. In detail, here we test the possibility to consider a fluid as a carrier of information, speculating about how to use such information. The aim of this work is to propose that information theory can be used to enlighten physical observations, even in those cases where the equations describing the phenomenon under investigation are intractable, are affected by a budget of uncertainty that makes their solution not affordable or may not even be known. In this exploratory work, an information theory-based approach is applied to microfluidic data. In detail, the classical study of the fluid flow in a microchannel with obstacles of different geometry is faced by integrating fluid mechanics theory with Shannon’s theory of information, interpreted in terms of thermodynamics. Technically, computational fluid dynamics simulations at Reynolds’ numbers (Re) equal to 1 and 50 were carried out in fluidic channels presenting obstacles with rectangular and semicircular shape, and on the simulated flow fields, the Shannon’s information theory was applied evaluating the fluid dynamics information entropy content. It emerged that the Shannon Entropy (SE) evaluated at the outflow section of the flow channel depends upon the geometric features (i.e., position, shape, aspect ratio) of the obstacles. This suggests an interpretation of the fluid dynamics establishing in a flow channel presenting obstacles in terms of information theory, that can be used to identify a posteriori the geometric features of the obstacles the fluid interacts with. The proposed approach can be applied to flow data at the boundaries of fluid domains of interest to extract information on the process occurring inside a system, without making any appeal to the governing equations of the phenomenon under observation or intrusive measurements.

Background Carotid endarterectomy (CEA) remains the first-line treatment option of symptomatic and asymptomatic carotid stenosis, while stenting (CAS) is reserved for selected patients at high surgical risk. Here, we compare the vascular remodeling process in CEA- and CAS-treated patients with respect to morphological and hemodynamic features, because of their possible engagement in carotid atherosclerosis. Methods Twelve (12) patients were included, half with patched CEA and half with CAS. Pre- and post-operative 3D image-based models of the carotid bifurcation were anatomically characterized in terms of flare, tortuosity, and curvature. Individual computational fluid dynamics simulations allowed to quantify the postoperative hemodynamic milieu in terms of (1) wall shear stress and (2) helical flow. Results Carotid flare increased in all cases, but a more marked increase emerged after CEA compared to CAS. Tortuosity and curvature increased after CEA but decreased after CAS. CEA patients presented with significantly higher postoperative tortuosity than CAS patients. CEA was associated with a worse (non-statistically significant) score in all flow disturbance indicators vs. CAS. Conclusion The increased flare and tortuosity of the carotid bifurcation after CEA vs. CAS is a marked difference in the vascular remodeling process between the two modalities. CAS seems to induce a less pro-restenosis hemodynamic environment compared to CEA. The emerged differences stimulate further analysis on a larger cohort with long-term outcomes, to shed light on the clinical impact of the observations.

The degeneration of the arterial wall at the basis of the ascending thoracic aortic aneurysm (ATAA) is a complex multifactorial process, which may lead to clinical complications and, ultimately, death. Individual genetic, biological or hemodynamic factors are inadequate to explain the heterogeneity of ATAA development/progression mechanisms, thus stimulating the analysis of their complex interplay. Here the disruption of the hemodynamic environment in the ATAA is investigated integrating patient-specific computational hemodynamics, CT-based in vivo estimation of local aortic stiffness and advanced fluid mechanics methods of analysis. The final aims are (1) deciphering the ATAA spatiotemporal hemodynamic complexity and its link to near-wall topological features, and (2) identifying the existing links between arterial wall degeneration and hemodynamic insult. Technically, two methodologies are applied to computational hemodynamics data, the wall shear stress (WSS) topological skeleton analysis, and the Complex Networks theory. The same analysis was extended to the healthy aorta. As main findings of the study, we report that: (1) different spatiotemporal heterogeneity characterizes the ATAA and healthy hemodynamics, that markedly reflect on their WSS topological skeleton features; (2) a link (stronger than canonical WSS-based descriptors) emerges between the variation of contraction/expansion action exerted by WSS on the endothelium along the cardiac cycle, and ATAA wall stiffness. The findings of the study suggest the use of advanced methods for a deeper understanding of the hemodynamics disruption in ATAA, and candidate WSS topological skeleton features as promising indicators of local wall degeneration.

Resumen Introduccion y objetivos La puntuacion PARIS permite una estratificacion combinada de los riesgos isquemico y hemorragico de los pacientes con cardiopatia isquemica tratados con stent coronario y tratamiento antiagregante plaquetario doble (TAPD). Se desconoce su utilidad en pacientes con sindrome coronario agudo (SCA) tratados con ticagrelor o prasugrel. Se investiga este aspecto en un registro internacional. Metodos Estudio retrospectivo multicentrico con participacion voluntaria de 11 centros de 6 paises europeos. Se estudio a 4.310 pacientes con SCA dados de alta en TAPD con ticagrelor o prasugrel. Se definio evento isquemico como trombosis de stent o infarto de miocardio espontaneo, y evento hemorragico segun BARC (Bleeding Academic Research Consortium) tipo 3 o 5. Se calculo la discriminacion y la calibracion para ambas vertientes de la puntuacion PARIS (PARISisquemico y PARIShemorragico). El beneficio neto isquemico-hemorragico se obtuvo mediante la diferencia entre las probabilidades predichas de eventos isquemicos y hemorragicos. Resultados Durante 17,2 ± 8,3 meses, hubo 80 eventos isquemicos (el 1,9% anual) y 66 eventos hemorragicos (el 1,6% anual). PARISisquemico y PARIShemorragico se asociaron con el riesgo de eventos isquemicos (sHR = 1,27; IC95%, 1,16-1,39) y hemorragicos (sHR = 1,14; IC95%, 1,01-1,30) respectivamente. La discriminacion de eventos isquemicos fue discreta (indice C = 0,64) y la de eventos hemorragicos, pobre (indice C = 0,56), con buena calibracion para ambos. El beneficio neto isquemico-hemorragico resulto negativo (mas eventos hemorragicos) en pacientes con alto riesgo hemorragico y positivo (mas eventos isquemicos) en pacientes con alto riesgo isquemico. Conclusiones En pacientes con SCA tratados con TAPD con ticagrelor o prasugrel, la escala PARIS ayuda a establecer un equilibrio apropiado del riesgo isquemico-hemorragico.

This study explored the potential of hemodynamic disturbances and geometric features to predict long-term carotid restenosis after carotid endarterectomy (CEA). Thirteen CEA for carotid diameter stenosis > 70% were performed with patch graft (PG) angioplasty in nine cases, and primary closure (PC) in four cases. MRI acquisitions within one month after CEA were used for hemodynamic and geometric characterization. Personalized computational hemodynamic simulations quantified the exposure to low and oscillatory wall shear stress (WSS). Geometry was characterized in terms of flare (the expansion at the bulb) and tortuosity. At 60 months after CEA, Doppler ultrasound (DUS) was applied for restenosis detection and intima-media thickness determination. Larger flares were associated to larger exposure to low WSS (Pearson R2 values up to 0.38, P 50% at 60 months. Linear regressions revealed associations of DUS observations of thickening with flare variables (up to R2 = 0.84, P

Arterial hemodynamics is markedly characterized by the presence of helical flow patterns. Previous observations suggest that arterial helical blood flow is of physiological significance, and that its quantitative analysis holds promise for clinical applications. In particular, it has been reported that distinguishable helical flow patterns are potentially atheroprotective in the carotid bifurcation as they suppress flow disturbances. In this context, there is a knowledge gap about the physiological significance of helical flow in coronary arteries, a prominent site of atherosclerotic plaque formation. This study aimed at the quantitative assessment of helical blood flow in coronary arteries, and to investigate its possible associations with vascular geometry and with atherogenic wall shear stress (WSS) phenotypes in a representative sample of 30 swine coronary arteries. This study demonstrates that in coronary arteries: (1) the hemodynamics is characterized by counter-rotating bi-helical flow structures; (2) unfavorable conditions of WSS are strongly and inversely associated with helicity intensity (r = − 0.91; p

Introduction: Injectable scaffolds are emerging as a promising strategy in the field of myocardial tissue engineering. Among injectable scaffolds, microparticles have been poorly investigated. The goal of this study was the development of novel gelatin/gellan microparticles that could be used as an injectable scaffold to repair the infarcted myocardium. In particular, the effect of particle size on cardiac progenitor cell response was investigated. Methods: Particles were produced by a water-in-oil emulsion method. Phosphatidylcholine was used as a surfactant. Particles with different diameter ranges (125–300 µm and 350–450 µm) were fabricated using two different surfactant concentrations. Morphological, physicochemical, and functional characterizations were carried out. Cardiac progenitor cell adhesion and growth on microparticles were tested both in static and dynamic suspension culture conditions. Results: Morphological analysis of the produced particles showed a spherical shape and porous surface. The hydrophilicity of particle matrix and the presence of intermolecular interactions between gellan and gelatin were pointed out by the physicochemical characterization. A weight loss of 75 ± 5 % after 90 days of hydrolytic degradation was observed. Injectability through a narrow needle (26 G) and persistence of the microparticles at the injection site were preliminarily verified by ex vivo test. In vitro cell culture tests showed a preservation of rat cardiac progenitor biologic properties and indicated a preferential cell adherence to microparticles with a smaller size. Conclusion: Overall, the obtained results indicate that the produced gelatin/gellan microparticles could be potentially employed as injectable scaffolds for myocardial regeneration.

The efficacy of a pharmaceutical treatment is often countered by the inadequate membrane permeability, that prevents drugs from reaching their specific intracellular targets. Cell penetrating peptides (CPPs) are able to route across cells' membrane various types of cargo, including drugs and nanoparticles. However, CPPs internalization mechanisms are not yet fully understood and depend on a wide variety of aspects. In this contest, the entry of a CPP into the lipid bilayer might induce molecular conformational changes, including marked variations on membrane's mechanical properties. Understanding how the CPP does influence the mechanical properties of cells membrane is crucial to design, engineer and improve new and existing penetrating peptides. Here, all atom Molecular Dynamics (MD) simulations were used to investigate the interaction between different types of CPPs embedded in a lipid bilayer of dioleoyl phosphatidylcholine (DOPC). In a greater detail, we systematically highlighted how CPP properties are responsible for modulating the membrane bending modulus. Our findings highlighted the CPP hydropathy strongly correlated with penetration of water molecules in the lipid bilayer, thus supporting the hypothesis that the amount of water each CPP can route inside the membrane is modulated by the hydrophobic and hydrophilic character of the peptide. Water penetration promoted by CPPs leads to a local decrease of the lipid order, which emerges macroscopically as a reduction of the membrane bending modulus.

Personalized computational hemodynamics (CH) is a promising tool to clarify/predict the link between low density lipoproteins (LDL) transport in aorta, disturbed shear and atherogenesis. However, CH uses simplifying assumptions that represent sources of uncertainty. In particular, modelling blood-side to wall LDL transfer is challenged by the cumbersomeness of protocols needed to obtain reliable LDL concentration profile estimations. This paucity of data is limiting the establishment of rigorous CH protocols able to balance the trade-offs among the variety of in vivo data to be acquired, and the accuracy required by biological/clinical applications. In this study, we analyze the impact of LDL concentration initialization (initial conditions, ICs) and inflow boundary conditions (BCs) on CH models of LDL blood-to-wall transfer in aorta. Technically, in an image-based model of human aorta, two different inflow BCs are generated imposing subject-specific inflow 3D PC-MRI measured or idealized (flat) velocity profiles. For each simulated BC, four different ICs for LDL concentration are applied, imposing as IC the LDL distribution resulting from steady-state simulations with average conditions, or constant LDL concentration values. Based on CH results, we conclude that: (1) the imposition of realistic 3D velocity profiles as inflow BC reduces the uncertainty affecting the representation of LDL transfer; (2) different LDL concentration ICs lead to markedly different patterns of LDL transfer. Given that it is not possible to verify in vivo the proper LDL concentration initialization to be applied, we suggest to carefully set and unambiguously declare the imposed BCs and LDL concentration IC when modelling LDL transfer in aorta, in order to obtain reproducible and ultimately comparable results among different laboratories.

The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self-association mechanisms and fibril formation of full-length ATX1.

Microspheres can be regarded as a suitable platform for the development of ad hoc drug delivery systems, since the targeted release of a therapeutic agent can effectively contribute to support and improve a pharmacological protocol. However, several crucial factors related to the selection of materials, drugs and fabrication techniques should be critically analyzed in order to enhance the expected performance. Dealing with highly compatible materials, e.g. naturally-derived polymers and "green" reagents, can be a valid approach. For this aim, gelatin, chitosan and blend microspheres were produced by emulsion technique simply using distilled water and olive oil. Necessarily, due to the intrinsic instability of the selected materials in aqueous environment, microspheres were cross-linked with genipin, an extremely low cytotoxic agent, at three different concentration (i.e., 0.1, 0.5, 1% w/v). Collected microspheres were then loaded with methylene blue (MB), as drug model. Morphological analysis revealed homogeneous microspheres characterized by an average diameter comprised in the range 42-54μm. In vitro MB temporal delivery was assessed until complete release, which occurred in about 3days for gelatin and 30days for chitosan microspheres. Nanoindentation analysis was performed to evaluate how polymers and genipin influenced the mechanical properties of microspheres. Finally, the effect of released MB was investigated by means of chicken embryo chorioallantoic membrane assay, highlighting anti-angiogenic properties for gelatin differently from chitosan and blend microspheres.

Physical stimuli are crucial for the structural and functional maturation of tissues both in vivo and in vitro. In tissue engineering applications, bioreactors have become fundamental and effective tools for providing biomimetic culture conditions that recapitulate the native physical stimuli. In addition, bioreactors play a key role in assuring strict control, automation, and standardization in the production process of cell-based products for future clinical application. In this study, a compact, easy-to-use, tunable stretch bioreactor is proposed. Based on customizable and low-cost technological solutions, the bioreactor was designed for providing tunable mechanical stretch for biomimetic dynamic culture of different engineered tissues. In-house validation tests demonstrated the accuracy and repeatability of the imposed mechanical stimulation. Proof of concepts biological tests performed on engineered cardiac constructs, based on decellularized human skin scaffolds seeded with human cardiac progenitor cells, confirmed the bioreactor Good Laboratory Practice compliance and ease of use, and the effectiveness of the delivered cyclic stretch stimulation on the cardiac construct maturation.

Elucidating structural features of protein aggregation at molecular level may provide novel opportunities for overarching therapeutic approaches such as blocking common aggregation-induced cellular toxicity pathways. In this context molecular modelling stimulates further research on amyloid aggregation modulators and modelling platforms can be used to test the efficiency of potential aggregation inhibitors aimed at destabilizing/reducing the stability of the amyloidogenic proteins

Aims The aim of the present study was to establish the safety and efficacy profile of prasugrel and ticagrelor in real-life acute coronary syndrome (ACS) patients with renal dysfunction. Methods and results All consecutive patients from RENAMI (REgistry of New Antiplatelets in patients with Myocardial Infarction) and BLEEMACS (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome) registries were stratified according to estimated glomerular filtration rate (eGFR) lower or greater than 60 mL/min/1.73 m2. Death and myocardial infarction (MI) were the primary efficacy endpoints. Major bleedings (MBs), defined as Bleeding Academic Research Consortium bleeding types 3 to 5, constituted the safety endpoint. A total of 19 255 patients were enrolled. Mean age was 63 ± 12; 14 892 (77.3%) were males. A total of 2490 (12.9%) patients had chronic kidney disease (CKD), defined as eGFR Conclusion In ACS patients with CKD, prasugrel and ticagrelor are associated with lower risk of death and recurrent MI without increasing the risk of MB.

International audience; Introduction: In new generation drug eluting stents (DESs) era, the impact of stent geometry on freedom from recurrent events has been poorly explored. Impact of struts thickness and the number of crowns and connectors on clinical outcomes were evaluated in the present study.Methods: Randomized controlled trials comparing last generation DESs were selected. The primary endpoint was the rate of target lesion revascularization (TLR), while secondary was definite stent thrombosis (ST).Results: Fifty-three studies with 52,006 patients were included. A struts thickness ≤81 nm was associated with a lower incidence of TLR (2.9%: 2.4-3.4 vs. 3.6%: 3.0-4.3) and ST (0.8%: 0.6-1.1 vs. 1.3%: 0.9-1.8). A mean number of connectors >2.5 was also associated with a lower incidence of TLR (3.2%: 2.8-3.6 vs. 3.5%: 2.9-4.2) and ST (1.0%:0.8-1.3 vs. 1.3%: 0.9-1.7 vs. for ST). On the other hand, stents with average number of crowns

Introduction The benefits of short versus long-term dual antiplatelet therapy (DAPT) based on the third generation P2Y12 antagonists prasugrel or ticagrelor, in patients with acute coronary syndromes treated with percutaneous coronary intervention remain to be clearly defined due to current evidences limited to patients treated with clopidogrel. Methods All acute coronary syndrome patients from the REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) undergoing percutaneous coronary intervention and treated with aspirin, prasugrel or ticagrelor were stratified according to DAPT duration, that is, shorter than 12 months (D1 group), 12 months (D2 group) and longer than 12 months (D3 group). The three groups were compared before and after propensity score matching. Net adverse clinical events (NACEs), defined as a combination of major adverse cardiac events (MACEs) and major bleedings (including therefore all cause death, myocardial infarction and Bleeding Academic Research Consortium (BARC) 3–5 bleeding), were the primary end points, MACEs (a composite of all cause death and myocardial infarction) the secondary one. Single components of NACEs were co-secondary end points, along with BARC 2–5 bleeding, cardiovascular death and stent thrombosis. Results A total of 4424 patients from the RENAMI registry with available data on DAPT duration were included in the model. After propensity score matching, 628 patients from each group were selected. After 20 months of follow up, DAPT for 12 months and DAPT for longer than 12 months significantly reduced the risk of NACE (D1 11.6% vs. D2 6.7% vs. D3 7.2%, p = 0.003) and MACE (10% vs. 6.2% vs. 2.4%, p Conclusion In unselected real world acute coronary syndrome patients treated with percutaneous coronary intervention, DAPT with prasugrel or ticagrelor prolonged beyond 12 months markedly reduces fatal and non-fatal ischaemic events, offsetting the increased risk deriving from the higher bleeding risk. On the contrary, patients >75 years old and female ones showed a less favourable risk–benefit ratio for longer DAPT due to excess of bleedings.

The ICE Cubes Facility is a capable experiment platform on board the Columbus Module of the International Space Station that offers flexibility to host many different experiments. The ICE Cubes Facility is suited for any scientific research and technological demonstrator that requires the study of the effects of microgravity and radiation exposure in a pressurised volume. The ICE Cube Service is also open to different schooling levels (primary, secondary, universities) and to different STEAM curricula and offers University students (Master and PhD) the opportunity to design, develop, test and operate a real experiment for the ISS under the supervision of experts from the ICE Cube Service.The Artery In Microgravity (AIM) project is a 2U ICE Cubes experiment cube and the first experiment to be selected for the Orbit Your Thesis! programme of ESA Academy. The cube is expected to be launched on SpaceX-20 in early 2020. The project is being developed by an international group of students from ISAE-Supaero and Politecnico di Torino. The experiment will investigate coronary heart disease, the most common form of cardiovascular disease and the cause of approximately 9 million deaths every year. In view of the very long duration missions to come, such diseases may also affect healthy astronauts in space. The AIM cube is a test-bench for investigating haemodynamics in microgravity and will study the effects of microgravity on blood flow in the coronary artery with and without an implanted coronary stent and the impact of augmented radiation levels on metallic ion release from coronary stents.The experimental setup consists of a closed hydraulic loop containing two models of a coronary artery in series. An electric pump and reservoir will control the flow of a blood-mimicking fluid through the system. One model of the coronary artery will contain a coronary stent. The pressure of the fluid will be studied along its path using a series of pressure sensors and a camera will visualise the flow. Ground tests will be conducted concurrently in order to perform a comparison between the on-ground behaviour and the behaviour in microgravity.The paper will showcase the design and development of the AIM experiment cube, the results of testing and the educational applications of theICE Cubes Facility. The full data and results will be available after the completion of the mission which is expected to be between March and June 2020.

The use of injectable scaffolds to repair the infarcted heart is receiving great interest. Thermosensitive polymers, in situ polymerization, in situ cross-linking, and self-assembling peptides are the most investigated approaches to obtain injectability.Aim of the present work was the preparation and characterization of a novel bioactive scaffold, in form of injectable microspheres, for cardiac repair. Gellan/gelatin microspheres were prepared by a water-in-oil emulsion and loaded by adsorption with Insulin-like growth factor 1 to promote tissue regeneration. Obtained microspheres underwent morphological, physicochemical and biological characterization, including cell culture tests in static and dynamic conditions and in vivo tests. Morphological analysis of the microspheres showed a spherical shape, a microporous surface and an average diameter of 66 ± 17µm (under dry conditions) and 123 ± 24 µm (under wet conditions). Chemical Imaging analysis pointed out a homogeneous distribution of gellan, gelatin and Insulin-like growth factor-1 within the microsphere matrix. In vitro cell culture tests showed that the microspheres promoted rat cardiac progenitor cells adhesion, and cluster formation. After dynamic suspension culture within an impeller-free bioreactor, cells still adhered to microspheres, spreading their cytoplasm over microsphere surface. Intramyocardial administration of microspheres in a cryoinjury rat model attenuated chamber dilatation, myocardial damage and fibrosis and improved cell homing.Overall, the findings of this study confirm that the produced microspheres display morphological, physicochemical, functional and biological properties potentially adequate for future applications as injectable scaffold for cardiac tissue engineering.

Incidence and predictors of adverse events after dual antiplatelet therapy (DAPT) cessation in patients treated with thin stents (

Background The PRECISE-DAPT and PARIS risk scores (RSs) were recently developed to help clinicians at individualizing the optimal dual antiplatelet therapy duration (DAPT) after percutaneous coronary intervention (PCI). Nevertheless, external validation of these RSs it has not yet been performed in ACS (acute coronary syndrome) patients treated with prasugrel or ticagrelor in a real- world scenario. Methods 4424 ACS patients who underwent PCI and survived to hospital discharge, from January 2012 to December 2016 at 12 European centers, were included. PRECISE-DAPT and PARIS bleeding RS, as well as PARIS ischemic RS, were computed, and their performance at predicting major bleeding (MB; BARC type 3 or 5) and ischemic events (MI and stent thrombosis) during follow up was compared. Results After a median follow-up of 14 (interquartile range 12–20.9) months, 83 (1.88%) patients developed MB and 133 (3.0%) suffered an ischemic episode. PRECISE-DAPT performed better than PARIS bleeding RS (c-statistic = 0.653 vs. 0.593; p = .01 for comparison) in predicting MB. The RSs performance for MB prediction remained consistent in STEMI patients (c-statistic = 0.632 vs 0.575) or in those treated with prasugrel (c-statistic = 0.623 vs 0.586). PARIS ischemic RS exhibited superior discrimination in predicting ischemic complications compared to PRECISE-DAPT (c-statistic = 0.604 vs 0.568 p = .05 for comparison). Conclusion Our data provide support to the use of PRECISE-DAPT in MB risk stratification for patients receiving DAPT in form of aspirin and prasugrel or ticagrelor whereas the PARIS ischemic RS has potential to complement the risk prediction with respect to ischemic events.

Wall Shear Stress (WSS) topological skeleton, composed by fixed points and the manifolds linking them, reflects the presence of blood flow features associated to adverse vascular response. However, the influence of WSS topological skeleton on vascular pathophysiology is still underexplored. This study aimed to identify direct associations between the WSS topological skeleton and markers of vascular disease from real-world clinical longitudinal data of long-term restenosis after carotid endarterectomy (CEA). Personalized computational hemodynamic simulations were performed on a cohort of 13 carotid models pre-CEA and at 1 month after CEA. At 60 months after CEA, intima-media thickness (IMT) was measured to detect long-term restenosis. The analysis of the WSS topological skeleton was carried out by applying a Eulerian method based on the WSS vector field divergence. To provide objective thresholds for WSS topological skeleton quantitative analysis, a computational hemodynamic dataset of 46 ostensibly healthy carotid bifurcation models was considered. CEA interventions did not completely restore physiological WSS topological skeleton features. Significant associations emerged between IMT at 60 months follow-up and the exposure to (1) high temporal variation of WSS contraction/expansion (R2 = 0.51, p R2 = 0.53, p

Atherosclerosis at the early stage in coronary arteries has been associated with low cycle-average wall shear stress magnitude. However, parallel to the identification of an established active role for low wall shear stress in the onset/progression of the atherosclerotic disease, a weak association between lesions localization and low/oscillatory wall shear stress has been observed. In the attempt to fully identify the wall shear stress phenotype triggering early atherosclerosis in coronary arteries, this exploratory study aims at enriching the characterization of wall shear stress emerging features combining correlation-based analysis and complex networks theory with computational hemodynamics. The final goal is the characterization of the spatiotemporal and topological heterogeneity of wall shear stress waveforms along the cardiac cycle. In detail, here time-histories of wall shear stress magnitude and wall shear stress projection along the main flow direction and orthogonal to it (a measure of wall shear stress multidirectionality) are analyzed in a representative dataset of 10 left anterior descending pig coronary artery computational hemodynamics models. Among the main findings, we report that the proposed analysis quantitatively demonstrates that the model-specific inlet flow-rate shapes wall shear stress time-histories. Moreover, it emerges that a combined effect of low wall shear stress magnitude and of the shape of the wall shear stress–based descriptors time-histories could trigger atherosclerosis at its earliest stage. The findings of this work suggest for new experiments to provide a clearer determination of the wall shear stress phenotype which is at the basis of the so-called arterial hemodynamic risk hypothesis in coronary arteries.

Introduction: Real-life data comparing clopidogrel, prasugrel, and ticagrelor for unselected patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) are lacking, as are data for the temporal distribution of ischemic and bleeding risks. Methods: A total of 19,825 patients were enrolled from the RENAMI and BleeMACS registries. Both were multicenter, retrospective, observational registries including the data and outcomes of consecutive patients with ACS who underwent primary PCI and were discharged with dual antiplatelet therapy (DAPT). We evaluated the long-term outcome stratified by the different antiplatelet agents. Results: A total of 14,105 patients (71.2%) were treated with clopidogrel, 2364 patients (11.9%) with prasugrel and 3356 patients (16.9%) with ticagrelor. After propensity score matching, at 1 year, prasugrel reduced the incidence of net adverse clinical events (NACE; a composite endpoint of all-cause death, myocardial infarction [MI] and Bleeding Academic Research Consortium [BARC] 3–5 bleeding) (4.2% vs.7.6%, p = 0.002) and of major adverse cardiovascular events (MACE; a composite endpoint of death and MI) compared with clopidogrel (2.6% vs. 5.2%, p = 0.007). Ticagrelor decreased rates of MACE compared with clopidogrel (2.7% vs. 6.2%, p < 0.001), but not of NACE (6.6% vs. 8.7%, p = 0.07). Ticagrelor presented similar performance in terms of MACE compared with prasugrel (2.8% vs. 2.4%, p = 0.56), with a trend towards a reduction in MI (0.2% vs. 0.4%, p = 0.56), but with higher risk of BARC 3–5 bleedings (3.8% vs. 1.7%, p = 0.04). In the daily risk analysis, clopidogrel presented a binomial distribution with a peak of ischemic risk at 3 months, which decreased towards bleedings; prasugrel had a constant equivalence between opposite risks; and ticagrelor constantly reduced recurrent MIs despite higher risk of BARC 3–5 events. Conclusion: In real life, ticagrelor is more effective in reducing ischemic events during the first year after ACS, despite an increased risk of major bleedings, while prasugrel assures a better balance between ischemic and bleeding recurrent events.

Decellularized extracellular matrix is one of the most promising biological scaffold supporting in vitro tissue growth and in vivo tissue regeneration in both preclinical research and clinical practice. In case of thick tissues or even organs, conventional static decellularization methods based on chemical or enzymatic treatments are not effective in removing the native cellular material without affecting the extracellular matrix. To overcome this limitation, dynamic decellularization methods, mostly based on perfusion and agitation, have been proposed. In this study, we developed a low-cost scalable 3D-printed sample-holder for agitation-based decellularization purposes, designed for treating multiple specimens simultaneously and for improving efficiency, homogeneity and reproducibility of the decellularization treatment with respect to conventional agitation-based approaches. In detail, the proposed sample-holder is able to house up to four specimens and, immersed in the decellularizing solution within a beaker placed on a magnetic stirrer, to expose them to convective flow, enhancing the solution transport through the specimens while protecting them. Computational fluid dynamics analyses were performed to investigate the fluid phenomena establishing within the beaker and to support the sample-holder design. Exploratory biological tests performed on human skin specimens demonstrated that the sample-holder reduces process duration and increases treatment homogeneity and reproducibility.

Noninvasive continuous positive airway pressure (NIV-CPAP) is effective in patients with hypoxemic respiratory failure. Building evidence during the COVID-19 emergency reported that around 50% of patients in Italy treated with NIV-CPAP avoided the need for invasive mechanical ventilation. Standard NIV-CPAP systems operate at high gas flow rates responsible for noise generation and inadequate humidification. Furthermore, open-configuration systems require a high concentration of oxygen to deliver the desired FiO2 . Concerns outlined the risk for aerosolization in the ambient air and the possible pressure drop in hospital supply pipes. A new NIV-CPAP system is proposed that includes automatic control of patient respiratory parameters. The system operates as a closed-loop breathing circuit that can be assembled, combining a sleep apnea machine with existing commercially available components. Analytical simulation of a breathing patient and simulation with a healthy volunteer at different FiO2 were performed. Inspired and expired oxygen fraction and inspired and expired carbon dioxide pressure were recorded at different CPAP levels with different oxygen delivery. Among the main findings, we report (a) a significant (up to 30-fold) reduction in oxygen feeding compared to standard open high flow NIV-CPAP systems, to assure the same FiO2 levels, and (b) a negligible production of the noise generated in ventilatory systems, and consequent minimization of patients' discomfort. The proposed NIV-CPAP circuit, reshaped in closed-loop configuration with the blower outside of the circuit, has the advantages of minimizing aerosol generation, environmental contamination, oxygen consumption, and noise to the patient. The system is easily adaptable and can be implemented using standard CPAP components.

International audience; Objectives: To evaluate the independent clinical impact of stent structural features in a large cohort of patients undergoing unprotected left main (ULM) or coronary bifurcation percutaneous coronary intervention (PCI) with a range of very thin strut stents.Background: Clinical impact of structural features of contemporary stents remains to be defined.Methods: All consecutive patients enrolled in the veRy thin stents for patients with left mAIn or bifurcatioN in real life (RAIN) registry were included. The following stent structural features were studied: antiproliferative drugs (everolimus vs. sirolimus vs. zotarolimus), strut material (platinum-chromium vs. cobalt-chromium), polymer (bioresorbable vs. durable), number of crowns (

Ultrasound-based technologies are widely adopted in the clinical practice. Recently, the ultrasound stable cavitation has been proposed as a strategy to destabilize amyloid aggregates in Alzheimer disease. However, the molecular mechanisms driving ultrasound-induced amyloid destabilization are not fully clarified yet. Here, molecular dynamics is applied to investigate in silico the conformational dynamics induced by ultrasound stable cavitation on S-shaped Aβ1-42 amyloid fibrils, which has been highlighted as a more stable architecture with respect to U-shaped Aβ1-42. The findings of the study suggested that ultrasound exposure could affect S-shaped aggregates folding dynamics and kinetics, with a marked dependence on the fibril polymorphism. More in detail, here we suggest that the molecular mechanisms of amyloid destabilization could be driven by residues not involved in defined secondary structures, with unstructured amyloid regions acting as source of instability for the overall fibril by opening a nanofracture able to propagate into the protein, until the complete unfolding of the molecular assembly takes place.