Current and Future Applications of Computational Fluid Dynamics in Coronary Artery Disease.

Hemodynamics interacts with the cellular components of human vessels, influencing function and healthy status. Locally acting hemodynamic forces have been associated-by a steadily increasing amount of scientific evidence-with nucleation and evolution of atherosclerotic plaques in several vascular regions, resulting in the formulation of the 'hemodynamic risk hypothesis' of the atherogenesis. At the level of coronary arteries, however, the complexity of both anatomy and physiology made the study of this vascular region particularly difficult for researchers. Developments in computational fluid dynamics (CFD) have recently allowed an accurate modelling of the intracoronary hemodynamics, thus offering physicians a unique tool for the investigation of this crucial human system by means of advanced mathematical simulations. The present review of CFD applications in coronary artery disease was set to concisely offer the medical reader the theoretical foundations of quantitative intravascular hemodynamics-reasoned schematically in the text in its basic (i.e., pressure and velocity) and derived quantities (e.g., fractional flow reserve, wall shear stress and helicity)-along with its current implications in clinical research. Moreover, attention was paid in classifying computational modelling derived from invasive and non-invasive imaging modalities with unbiased remarks on the advantages and limitations of each procedure. Finally, an extensive description-aided by explanatory figures and cross references to recent clinical findings-was presented on the role of near-wall hemodynamics, in terms of shear stress, and of intravascular flow complexity, in terms of helical flow.

Coronary Artery Stenting Affects Wall Shear Stress Topological Skeleton.

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.

Pathophysiology of the ascending aorta: Impact of dilation and valve phenotype on large-scale blood flow coherence detected by 4D flow MRI.

BACKGROUND AND OBJECTIVE: The evidence on the role of hemodynamics in aorta pathophysiology has yet to be robustly translated into clinical applications, to improve risk stratification of aortic diseases. Motivated by the need to enrich the current understanding of the pathophysiology of the ascending aorta (AAo), this study evaluates in vivo how large-scale aortic flow coherence is affected by AAo dilation and aortic valve phenotype. METHODS: A complex networks-based approach is applied to 4D flow MRI data to quantify subject-specific AAo flow coherence in terms of correlation between axial velocity waveforms and the aortic flow rate waveform along the cardiac cycle. The anatomical length of persistence of such correlation is quantified using the recently proposed network metric average weighted curvilinear distance (AWCD). The analysis considers 107 subjects selected to allow an ample stratification in terms of aortic valve morphology, absence/presence of AAo dilation and of aortic valve stenosis. RESULTS: The analysis highlights that the presence of AAo dilation as well as of bicuspid aortic valve phenotype breaks the physiological AAo flow coherence, quantified in terms of AWCD. Of notice, it emerges that cycle-average blood flow rate and relative AAo dilation are main determinants of AWCD, playing opposite roles in promoting and hampering the persistence of large-scale flow coherence in AAo, respectively. CONCLUSIONS: The findings of this study can contribute to broaden the current mechanistic link between large-scale blood flow coherence and aortic pathophysiology, with the prospect of enriching the existing tools for the in vivo non-invasive hemodynamic risk assessment for aortic diseases onset and progression.

Blood Flow Energy Identifies Coronary Lesions Culprit of Future Myocardial Infarction.

The present study establishes a link between blood flow energy transformations in coronary atherosclerotic lesions and clinical outcomes. The predictive capacity for future myocardial infarction (MI) was compared with that of established quantitative coronary angiography (QCA)-derived predictors. Angiography-based computational fluid dynamics (CFD) simulations were performed on 80 human coronary lesions culprit of MI within 5 years and 108 non-culprit lesions for future MI. Blood flow energy transformations were assessed in the converging flow segment of the lesion as ratios of kinetic and rotational energy values (KER and RER, respectively) at the QCA-identified minimum lumen area and proximal lesion sections. The anatomical and functional lesion severity were evaluated with QCA to derive percentage area stenosis (%AS), vessel fractional flow reserve (vFFR), and translesional vFFR (ΔvFFR). Wall shear stress profiles were investigated in terms of topological shear variation index (TSVI). KER and RER predicted MI at 5 years (AUC = 0.73, 95% CI 0.65-0.80, and AUC = 0.76, 95% CI 0.70-0.83, respectively; p < 0.0001 for both). The predictive capacity for future MI of KER and RER was significantly stronger than vFFR (p = 0.0391 and p = 0.0045, respectively). RER predictive capacity was significantly stronger than %AS and ΔvFFR (p = 0.0041 and p = 0.0059, respectively). The predictive capacity for future MI of KER and RER did not differ significantly from TSVI. Blood flow kinetic and rotational energy transformations were significant predictors for MI at 5 years (p < 0.0001). The findings of this study support the hypothesis of a biomechanical contribution to the process of plaque destabilization/rupture leading to MI.

Association Between Automated 3D Measurement of Coronary Luminal Narrowing and Risk of Future Myocardial Infarction.

This study focuses on identifying anatomical markers with predictive capacity for long-term myocardial infarction (MI) in focal coronary artery disease (CAD). Eighty future culprit lesions (FCL) and 108 non-culprit lesions (NCL) from 80 patients underwent 3D quantitative coronary angiography. The minimum lumen area (MLA), minimum lumen ratio (MLR), and vessel fractional flow reserve (vFFR) were evaluated. MLR was defined as the ratio between MLA and the cross-sectional area at the proximal lesion edge, with lower values indicating more abrupt luminal narrowing. Significant differences were observed between FCL and NCL in MLR (0.41 vs. 0.53, p < 0.001). MLR correlated inversely with translesional vFFR (r = - 0.26, p = 0.0004) and was the strongest predictor of MI at 5 years (AUC = 0.75). Lesions with MLR < 0.40 had a fourfold increased MI incidence at 5 years. MLR is a robust predictor of future adverse coronary events.

Modelling blood flow in coronary arteries: Newtonian or shear-thinning non-Newtonian rheology?

BACKGROUND: The combination of medical imaging and computational hemodynamics is a promising technology to diagnose/prognose coronary artery disease (CAD). However, the clinical translation of in silico hemodynamic models is still hampered by assumptions/idealizations that must be introduced in model-based strategies and that necessarily imply uncertainty. This study aims to provide a definite answer to the open question of how to properly model blood rheological properties in computational fluid dynamics (CFD) simulations of coronary hemodynamics. METHODS: The geometry of the right coronary artery (RCA) of 144 hemodynamically stable patients with different stenosis degree were reconstructed from angiography. On them, unsteady-state CFD simulations were carried out. On each reconstructed RCA two different simulation strategies were applied to account for blood rheological properties, implementing (i) a Newtonian (N) and (ii) a shear-thinning non-Newtonian (non-N) rheological model. Their impact was evaluated in terms of wall shear stress (WSS magnitude, multidirectionality, topological skeleton) and helical flow (strength, topology) profiles. Additionally, luminal surface areas (SAs) exposed to shear disturbances were identified and the co-localization of paired N and non-N SAs was quantified in terms of similarity index (SI). RESULTS: The comparison between paired N vs. shear-thinning non-N simulations revealed remarkably similar profiles of WSS-based and helicity-based quantities, independent of the adopted blood rheology model and of the degree of stenosis of the vessel. Statistically, for each paired N and non-N hemodynamic quantity emerged negligible bias from Bland-Altman plots, and strong positive linear correlation (r > 0.94 for almost all the WSS-based quantities, r > 0.99 for helicity-based quantities). Moreover, a remarkable co-localization of N vs. non-N luminal SAs exposed to disturbed shear clearly emerged (SI distribution 0.95 [0.93, 0.97]). Helical flow topology resulted to be unaffected by blood rheological properties. CONCLUSIONS: This study, performed on 288 angio-based CFD simulations on 144 RCA models presenting with different degrees of stenosis, suggests that the assumptions on blood rheology have negligible impact both on WSS and helical flow profiles associated with CAD, thus definitively answering to the question "is Newtonian assumption for blood rheology adequate in coronary hemodynamics simulations?".

Is spontaneous coronary artery dissection (SCAD) related to local anatomy and hemodynamics? An exploratory study.

AIMS: Spontaneous coronary artery dissection (SCAD) is an increasingly diagnosed cause of myocardial infarction with unclear pathophysiology. The aim of the study was to test if vascular segments site of SCAD present distinctive local anatomy and hemodynamic profiles. METHODS: Coronary arteries with spontaneously healed SCAD (confirmed by follow-up angiography) underwent three-dimensional reconstruction, morphometric analysis with definition of vessel local curvature and torsion, and computational fluid dynamics (CFD) simulations with derivation of time-averaged wall shear stress (TAWSS) and topological shear variation index (TSVI). The (reconstructed) healed proximal SCAD segment was visually inspected for co-localization with curvature, torsion, and CFD-derived quantities hot spots. RESULTS: Thirteen vessels with healed SCAD underwent the morpho-functional analysis. Median time between baseline and follow-up coronary angiograms was 57 (interquartile range [IQR] 45-95) days. In seven cases (53.8%), SCAD was classified as type 2b and occurred in the left anterior descending artery or near a bifurcation. In all cases (100%), at least one hot spot co-localized within the healed proximal SCAD segment, in 9 cases (69.2%) ≥ 3 hot spots were identified. Healed SCAD in proximity of a coronary bifurcation presented lower TAWSS peak values (6.65 [IQR 6.20-13.20] vs. 3.81 [2.53-5.17] Pa, p = 0.008) and hosted less frequently TSVI hot spots (100% vs. 57.1%, p = 0.034). CONCLUSION: Vascular segments of healed SCAD were characterized by high curvature/torsion and WSS profiles reflecting increased local flow disturbances. Hence, a pathophysiological role of the interaction between vessel anatomy and shear forces in SCAD is hypothesized.

Coronary artery plaque rupture and erosion: Role of wall shear stress profiling and biological patterns in acute coronary syndromes.

AIMS: Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways. METHODS AND RESULTS: We enrolled 24 CCS and 25 Non-ST Elevation Myocardial Infarction-ACS patients with IFC (n = 11) and RFC (n = 14) culprit lesions according to optical coherence tomography analysis. A real-time PCR primer array was performed on peripheral blood mononuclear cells for 17 different molecules whose expression is linked to WSS. Computational fluid dynamics simulations were performed in high-fidelity 3D-coronary artery anatomical models for three patients per group. A total of nine genes were significantly overexpressed in the unstable patients as compared to CCS patients, with no differences between IFC and RFC groups (GPX1, MMP1, MMP9, NOS3, PLA2G7, PI16, SOD1, TIMP1, and TFRC) while four displayed different levels between IFC and RFC groups (TNFα, ADAMTS13, EDN1, and LGALS8). A significantly higher WSS was observed in the RFC group (p < 0.001) compared to the two other groups. A significant correlation was observed between TNFα (p < 0.001), EDN1 (p = 0.036), and MMP9 (p = 0.005) and WSS values in the RFC group. CONCLUSIONS: Our data demonstrate that IFC and RFC plaques are subject to different WSS conditions and gene expressions, suggesting that WSS profiling may play an essential role in the plaque instability characterization with relevant diagnostic and therapeutic implications in the era of precision medicine.

Modelling coronary flows: impact of differently measured inflow boundary conditions on vessel-specific computational hemodynamic profiles.

BACKGROUND AND OBJECTIVES: The translation of hemodynamic quantities based on wall shear stress (WSS) or intravascular helical flow into clinical biomarkers of coronary atherosclerotic disease is still hampered by the assumptions/idealizations required by the computational fluid dynamics (CFD) simulations of the coronary hemodynamics. In the resulting budget of uncertainty, inflow boundary conditions (BCs) play a primary role. Accordingly, in this study we investigated the impact of the approach adopted for in vivo coronary artery blood flow rate assessment on personalized CFD simulations where blood flow rate is used as inflow BC. METHODS: CFD simulations were carried out on coronary angiograms by applying personalized inflow BCs derived from four different techniques assessing in vivo surrogates of flow rate: continuous thermodilution, intravascular Doppler, frame count-based 3D contrast velocity, and diameter-based scaling law. The impact of inflow BCs on coronary hemodynamics was evaluated in terms of WSS- and helicity-based quantities. RESULTS: As main findings, we report that: (i) coronary flow rate values may differ based on the applied flow derivation technique, as continuous thermodilution provided higher flow rate values than intravascular Doppler and diameter-based scaling law (p = 0.0014 and p = 0.0023, respectively); (ii) such intrasubject differences in flow rate values lead to different surface-averaged values of WSS magnitude and helical blood flow intensity (p<0.0020); (iii) luminal surface areas exposed to low WSS and helical flow topological features showed robustness to the flow rate values. CONCLUSIONS: Although the absence of a clinically applicable gold standard approach prevents a general recommendation for one coronary blood flow rate derivation technique, our findings indicate that the inflow BC may impact computational hemodynamic results, suggesting that a standardization would be desirable to provide comparable results among personalized CFD simulations of the coronary hemodynamics.

Mismatch between morphological and functional assessment of the length of coronary artery disease.

BACKGROUND: Morphological evaluation of coronary lesion length is a paramount step during invasive assessment of coronary artery disease. Likewise, the extent of epicardial pressure losses can be measured using longitudinal vessel interrogation with fractional flow reserve (FFR) pullbacks. We aimed to quantify the mismatch in lesion length between morphological (based on quantitative coronary angiography, QCA, and optical coherence tomography, OCT) and functional evaluations. METHODS: This is a prospective and multicenter study of patients evaluated by QCA, OCT and motorized fractional flow reserve pullbacks (mFFR). The difference in lesion length between the functional and anatomical evaluations was referred to as FAM. RESULTS: 117 patients (131 vessels) were included. Median lesion length derived from angiography was 16.05 mm [11.40-22.05], from OCT was 28.00 mm [16.63-38.00] and from mFFR 67.12 mm [25.38-91.37]. There was no correlation between QCA and mFFR lesion length (r = 0.124, 95% CI -0.168-0.396, p = 0.390). OCT lesion length did correlate with mFFR (r = 0.469, 95% CI 0.156-0.696, p = 0.004). FAM was strongly associated with the improvement in vessel conductance with percutaneous coronary intervention (PCI), higher mismatch was associated with lower post-PCI FFR. CONCLUSIONS: Lesion length assessment differs between morphological and functional evaluations. The morphological-functional mismatch in lesion length is frequent, and influences the results of PCI in terms of post-PCI FFR. Integration of the extent of pressure losses provides clinically relevant information that may be useful for clinical decision-making concerning revascularization strategy.

Hemodialysis arterio-venous graft design reducing the hemodynamic risk of vascular access dysfunction.

Although arterio-venous grafts (AVGs) represent the second choice as permanent vascular access for hemodialysis, this solution is still affected by a relevant failure rate due to graft thrombosis, and development of neointimal hyperplasia (IH) at the distal vein. As a key role in these processes has been attributed to the abnormal hemodynamics establishing in the distal vein, the optimization of AVGs design aimed at minimizing flow disturbances would reduce AVG hemodynamic-related risks. In this study we used computational fluid dynamics to investigate the impact of alternative AVG designs on the reduction of IH and thrombosis risk at the distal venous anastomosis. The performance of the newly designed AVGs was compared to that of commercially available devices. In detail, a total of eight AVG models in closed-loop configuration were constructed: two models resemble the commercially available straight conventional and helical-shaped AVGs; six models are characterized by the insertion of a flow divider (FD), straight or helical shaped, differently positioned inside the graft. Unfavorable hemodynamic conditions were analyzed by assessing the exposure to disturbed shear at the distal vein. Bulk flow was investigated in terms of helical blood flow features, potential thrombosis risk, and pressure drop over the graft. Findings from this study clearly show that using a helically-shaped FD located at the venous side of the graft could induce beneficial helical flow patterns that, minimizing flow disturbances, reduce the IH-related risk of failure at the distal vein, with a clinically irrelevant increase in thrombosis risk and pressure drop over the graft.

Does the inflow velocity profile influence physiologically relevant flow patterns in computational hemodynamic models of left anterior descending coronary artery?

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.

In-stent graft helical flow intensity reduces the risk of migration after endovascular aortic repair.

During the last years endovascular aneurysm repair (EVAR) became the elective treatment for abdominal aortic aneurysms (AAAs) thanks to lower mortality and morbidity rates than open surgery. In face of these advantages, stent-graft performances are still clinically suboptimal. In particular, post-surgical complications derive from device migration as a consequence of the hemodynamic forces acting on the endograft. In this regard, while the importance of hemodynamic surface forces is well recognized, the role of the in-stent flow is still unclear. Here we hypothesize that in-stent helical blood flow patterns might influence the distribution of the displacement forces (DFs) acting on the stent-graft and, ultimately, the risk of stent migration. To test this hypothesis, the hemodynamics of 20 post-EVAR models of patients treated with two different commercial endografts was analyzed using computational hemodynamics. The main findings of the study indicate that: (1) helical flow intensity decreases the risk of endograft migration, as given by an inverse correlation between helicity intensity (h2) and time-averaged displacement forces (TADFs) (p < 0.05); (2) unbalanced counter-rotating helical structures in the legs of the device contribute, in particular along the systole, to significantly suppress TADFs (p < 0.01); (3) as expected, helical flow intensity is positively correlated with pressure drop and resistance to flow (p < 0.001). The findings of this study suggest that a design strategy promoting in-stent helical flow structures could contribute to minimize the risk of migration of implanted EVAR devices.