COVID-19 and thrombosis: The role of hemodynamics.

Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, a leading cause for adverse outcomes in patients afflicted by the more serious manifestation of the disease. These thromboembolic complications expressed as sepsis-induced coagulopathy, disseminated intravascular coagulation, venous and arterial thromboembolism, pulmonary embolism, microthrombosis, and thrombotic microangiopathy have been observed to affect different organs such as the lungs, heart, kidneys, and brain. Endothelial injury and dysfunction have been identified as the critical pathway towards thrombogenesis, and contributions of other mechanisms such as hypercoagulability, cytokine storm, neutrophils have been studied. However, the contribution of hemodynamic pathways towards thrombosis in severe COVID-19 cases has not been investigated. From the classical theory of Virchow's triad to the contemporary studies on the effect of shear enhanced platelet activation, it is well established that hemodynamics plays a role in the initiation and growth of thrombosis. This article reviews recent studies on COVID-19 related thrombotic events and offers hypotheses on how hemodynamics may be responsible for some of the adverse outcomes observed in severe COVID-19 cases. While thrombogenesis through endothelial injury and the effects of hypercoagulability on thrombosis are briefly addressed, the crux of the discussion is focused on hemodynamic factors such as stasis, turbulent flow, and non-physiological shear stress and their effects on thrombosis. In addition, hemodynamics-dependent venous, arterial, and microvascular thrombosis in COVID-19 cases is discussed. We also propose further investigation of diagnostic and therapeutic options that address the hemodynamics aspects of COVID-19 thrombus formation to assess their potential in patient care.

Comparative Study of Human and Murine Aortic Biomechanics and Hemodynamics in Vascular Aging.

Introduction: Aging has many effects on the cardiovascular system, including changes in structure (aortic composition, and thus stiffening) and function (increased proximal blood pressure, and thus cardiac afterload). Mouse models are often used to gain insight into vascular aging and mechanisms of disease as they allow invasive assessments that are impractical in humans. Translation of results from murine models to humans can be limited, however, due to species-specific anatomical, biomechanical, and hemodynamic differences. In this study, we built fluid-solid-interaction (FSI) models of the aorta, informed by biomechanical and imaging data, to compare wall mechanics and hemodynamics in humans and mice at two equivalent ages: young and older adults. Methods: For the humans, 3-D computational models were created using wall property data from the literature as well as patient-specific magnetic resonance imaging (MRI) and non-invasive hemodynamic data; for the mice, comparable models were created using population-based properties and hemodynamics as well as subject-specific anatomies. Global aortic hemodynamics and wall stiffness were compared between humans and mice across age groups. Results: For young adult subjects, we found differences between species in pulse pressure amplification, compliance and resistance distribution, and aortic stiffness gradient. We also found differences in response to aging between species. Generally, the human spatial gradients of stiffness and pulse pressure across the aorta diminished with age, while they increased for the mice. Conclusion: These results highlight key differences in vascular aging between human and mice, and it is important to acknowledge these when using mouse models for cardiovascular research.

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls.

BACKGROUND: Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. OBJECTIVES: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. METHODS: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. RESULTS: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. CONCLUSIONS: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.

CRIMSON: An open-source software framework for cardiovascular integrated modelling and simulation.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization.

Evaluation of 4D flow MRI-based non-invasive pressure assessment in aortic coarctations.

Severity of aortic coarctation (CoA) is currently assessed by estimating trans-coarctation pressure drops through cardiac catheterization or echocardiography. In principle, more detailed information could be obtained non-invasively based on space- and time-resolved magnetic resonance imaging (4D flow) data. Yet the limitations of this imaging technique require testing the accuracy of 4D flow-derived hemodynamic quantities against other methodologies. With the objective of assessing the feasibility and accuracy of this non-invasive method to support the clinical diagnosis of CoA, we developed an algorithm (4DF-FEPPE) to obtain relative pressure distributions from 4D flow data by solving the Poisson pressure equation. 4DF-FEPPE was tested against results from a patient-specific fluid-structure interaction (FSI) simulation, whose patient-specific boundary conditions were prescribed based on 4D flow data. Since numerical simulations provide noise-free pressure fields on fine spatial and temporal scales, our analysis allowed to assess the uncertainties related to 4D flow noise and limited resolution. 4DF-FEPPE and FSI results were compared on a series of cross-sections along the aorta. Bland-Altman analysis revealed very good agreement between the two methodologies in terms of instantaneous data at peak systole, end-diastole and time-averaged values: biases (means of differences) were +0.4 mmHg, -1.1 mmHg and +0.6 mmHg, respectively. Limits of agreement (2 SD) were ±0.978 mmHg, ±1.06 mmHg and ±1.97 mmHg, respectively. Peak-to-peak and maximum trans-coarctation pressure drops obtained with 4DF-FEPPE differed from FSI results by 0.75 mmHg and -1.34 mmHg respectively. The present study considers important validation aspects of non-invasive pressure difference estimation based on 4D flow MRI, showing the potential of this technology to be more broadly applied to the clinical practice.

Sex-dependent differences in central artery haemodynamics in normal and fibulin-5 deficient mice: implications for ageing.

Mouse models provide unique opportunities to study vascular disease, but they demand increased experimental and computational resolution. We describe a workflow for combining in vivo and in vitro biomechanical data to build mouse-specific computational models of the central vasculature including regional variations in biaxial wall stiffness, thickness and perivascular support. These fluid-solid interaction models are informed by micro-computed tomography imaging and in vivo ultrasound and pressure measurements, and include mouse-specific inflow and outflow boundary conditions. Hence, the model can capture three-dimensional unsteady flows and pulse wave characteristics. The utility of this experimental-computational approach is illustrated by comparing central artery biomechanics in adult wild-type and fibulin-5 deficient mice, a model of early vascular ageing. Findings are also examined as a function of sex. Computational results compare well with measurements and data available in the literature and suggest that pulse wave velocity, a spatially integrated measure of arterial stiffness, does not reflect well the presence of regional differences in stiffening, particularly those manifested in male versus female mice. Modelling results are also useful for comparing quantities that are difficult to measure or infer experimentally, including local pulse pressures at the renal arteries and characteristics of the peripheral vascular bed that may differ with disease.

Management of closed sternal incision after bilateral internal thoracic artery grafting with a single-use negative pressure system.

Single-use, closed incision management (CIM) systems offer a practical means of delivering negative pressure wound therapy to patients. This prospective study evaluates the Prevena™ Therapy system in a cohort of coronary patients at high risk of deep sternal wound infection (DSWI). Fifty-three consecutive patients undergoing bilateral internal thoracic artery (BITA) grafting were preoperatively elected for CIM with the Prevena™ Therapy system, which was applied immediately after surgery. The actual rate of DSWI in these patients was compared with the expected risk of DSWI according to two scoring systems specifically created to predict either DSWI after BITA grafting (Gatti score) or major infections after cardiac surgery (Fowler score). The actual rate of DSWI was lower than the expected risk of DSWI by the Gatti score (3.8 vs. 5.8%, p = 0.047) but higher than by the Fowler score (2.3%, p = 0.069). However, while the Gatti score showed very good calibration (χ2 = 4.8, p = 0.69) and discriminatory power (area under the receiver-operating characteristic curve 0.838), the Fowler score showed discrete calibration (χ2 = 10.5, p = 0.23) and low discriminatory power (area under the receiver-operating characteristic curve 0.608). Single-use CIM systems appear to be useful to reduce the risk of DSWI after BITA grafting. More studies have to be performed to make stronger this finding.

Sutureless versus Transfemoral Transcatheter Aortic Valve Implant: A Propensity Score Matching Study.

BACKGROUND AND AIM OF THE STUDY: Transcatheter aortic valve implantation (TAVI), especially via the transfemoral (TF) route, is increasingly performed in patients considered in the 'gray zone' between TAVI and surgery. However, the best treatment option in this patient population remains to be established. METHODS: Since 2010, a total of 923 patients underwent either TAVI (n = 538) or sutureless aortic valve replacement (AVR) (n = 385) at the authors' institutions. Among these patients, 79 treated with TF-TAVI were compared with 79 propensity score-matched patients who had undergone elective isolated AVR with the sutureless Perceval bioprosthesis. RESULTS: In-hospital mortality did not differ significantly between patients who underwent sutureless AVR or TF-TAVI (none versus three; 3.8%; p = 0.123). Similarly, postoperative complications were comparable between groups. Atrioventricular block requiring postoperative pacemaker implantation occurred in seven patients (9.2%) of the sutureless group and in eight patients (11.1%) of the TF-TAVI group (p = 0.455). The use of blood products varied between groups in terms of red blood cell transfusions (1.7 ± 2 versus 0.3 ± 0.9 units for the sutureless group versus TF-TAVI group; p <0.001). Paravalvular leakage at discharge was present in three patients (3.8%) in the sutureless group and in 26 patients (32.9%) in the TF-TAVI group (p <0.001). The mean follow up was longer for sutureless AVR (36 ± 21 versus 27 ± 20 months; p = 0.003). Survival rates were 97.5% and 84.8% in the sutureless and TF-TAVI groups, respectively (p = 0.001). CONCLUSIONS: Both, TF-TAVI and sutureless AVR are well-standardized, safe and effective procedures. TF-TAVI seems to be a valuable alternative to surgical AVR for frail patients, reducing the need for perioperative blood transfusion. In contrast, in patients with a favorable long-term survival outcome, minimally invasive AVR remains the procedure of choice as it is associated with better long-term results.

Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling.

Although considered by many as the gold standard clinical measure of arterial stiffness, carotid-to-femoral pulse wave velocity (cf-PWV) averages material and geometric properties over a large portion of the central arterial tree. Given that such properties may evolve differentially as a function of region in cases of hypertension and aging, among other conditions, there is a need to evaluate the potential utility of cf-PWV as an early diagnostic of progressive vascular stiffening. In this paper, we introduce a data-driven fluid-solid-interaction computational model of the human aorta to simulate effects of aging-related changes in regional wall properties (e.g., biaxial material stiffness and wall thickness) and conduit geometry (e.g., vessel caliber, length, and tortuosity) on several metrics of arterial stiffness, including distensibility, augmented pulse pressure, and cyclic changes in stored elastic energy. Using the best available biomechanical data, our results for PWV compare well to findings reported for large population studies while rendering a higher resolution description of evolving local and global metrics of aortic stiffening. Our results reveal similar spatio-temporal trends between stiffness and its surrogate metrics, except PWV, thus indicating a complex dependency of the latter on geometry. Lastly, our analysis highlights the importance of the tethering exerted by external tissues, which was iteratively estimated until hemodynamic simulations recovered typical values of tissue properties, pulse pressure, and PWV for each age group.

An Experimental-Computational Study of Catheter Induced Alterations in Pulse Wave Velocity in Anesthetized Mice.

Computational methods for solving problems of fluid dynamics and fluid-solid-interactions have advanced to the point that they enable reliable estimates of many hemodynamic quantities, including those important for studying vascular mechanobiology or designing medical devices. In this paper, we use a customized version of the open source code SimVascular to develop a computational model of central artery hemodynamics in anesthetized mice that is informed with experimental data on regional geometries, blood flows and pressures, and biaxial wall properties. After validating a baseline model against available data, we then use the model to investigate the effects of commercially available catheters on the very parameters that they are designed to measure, namely, murine blood pressure and (pressure) pulse wave velocity (PWV). We found that a combination of two small profile catheters designed to measure pressure simultaneously in the ascending aorta and femoral artery increased the PWV due to an overall increase in pressure within the arterial system. Conversely, a larger profile dual-sensor pressure catheter inserted through a carotid artery into the descending thoracic aorta decreased the PWV due to an overall decrease in pressure. In both cases, similar reductions in cardiac output were observed due to increased peripheral vascular resistance. As might be expected, therefore, invasive transducers can alter the very quantities that are designed to measure, yet advanced computational models offer a unique method to evaluate or augment such measurements.