Computational modelling of cardiovascular pathophysiology to risk stratify commercial spaceflight.

For more than 60 years, humans have travelled into space. Until now, the majority of astronauts have been professional, government agency astronauts selected, in part, for their superlative physical fitness and the absence of disease. Commercial spaceflight is now becoming accessible to members of the public, many of whom would previously have been excluded owing to unsatisfactory fitness or the presence of cardiorespiratory diseases.

Extended-volume image-derived models of coronary microcirculation.

Objective: Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets.

Methods: We acquired coronary microvasculature images throughout an entire short-axis slice of a 3-month-old Wistar-Kyoto rat heart.

A predictive patient-specific computational model of coronary artery bypass grafts for potential use by cardiac surgeons to guide selection of graft configurations.

Cardiac surgeons face a significant degree of uncertainty when deciding upon coronary artery bypass graft configurations for patients with coronary artery disease. This leads to significant variation in preferred configuration between different surgeons for a particular patient. Additionally, for the majority of cases, there is no consensus regarding the optimal grafting strategy.

Venous thrombosis risk during and after medical and surgical hospitalizations: The medical inpatient thrombosis and hemostasis (MITH) study.

Background: Thirty to seventy percent of all venous thromboembolism (VTE) events are associated with hospitalization. The absolute and relative risks during and after hospitalization are poorly characterized.

Objectives: Quantify the absolute rate and relative risk of VTE during and up to 3 months after medical and surgical hospitalizations.

Effects of Thyroid Function on Hemostasis, Coagulation, and Fibrinolysis: A Mendelian Randomization Study.

Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on hemostasis, coagulation, and fibrinolysis are unknown. In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism ( = 134,641), normal-range thyrotropin (TSH;  = 54,288) and free thyroxine (fT4) ( = 49,269), hyperthyroidism ( = 51,823), and thyroid peroxidase antibody positivity ( = 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor [VWF], factor VIII [FVIII], prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator [TPA], plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium ( = 2583-120,246).

It's clearly the heart! Optical transparency, cardiac tissue imaging, and computer modelling.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity.

Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model.

Background: MBL-producing strains of Enterobacteriaceae are a major public health concern. We sought to define optimal combination regimens of ceftazidime/avibactam with aztreonam in a hollow-fibre infection model (HFIM) of MBL-producing strains of Escherichia coli and Klebsiella pneumoniae.

Methods: E.

Reconstruction of coronary circulation networks: A review of methods.

Building anatomically accurate models of the coronary vascular system enables potentially deeper understandings of coronary circulation. To achieve this, (a) images at different levels of vascular network-arteries, arterioles, capillaries, venules, and veins-need to be obtained through suitable imaging modalities; and (b) from images, morphological and topological information needs to be extracted using image processing techniques. While there are several modalities that enable the imaging of large vessels, microcirculation imaging-capturing vessels having diameter lesser than 100 μm-has to date been typically confined to small regions of the heart.

Decreasing Compensatory Ability of Concentric Ventricular Hypertrophy in Aortic-Banded Rat Hearts.

The cardiac system compensates for variations in physiological and pathophysiological conditions through a dynamic remodeling at the organ, tissue, and intracellular levels in order to maintain function. However, on longer time scales following the onset of ventricular pressure overload, such remodeling may begin to inhibit physiological function and ultimately lead to heart failure. This progression from compensatory to decompensatory behavior is poorly understood, in particular owing to the absence of a unified perspective of the concomitantly remodeling subsystems.

Compensatory and decompensatory alterations in cardiomyocyte Ca dynamics in hearts with diastolic dysfunction following aortic banding.

Key Points: At the cellular level cardiac hypertrophy causes remodelling, leading to changes in ionic channel, pump and exchanger densities and kinetics. Previous studies have focused on quantifying changes in channels, pumps and exchangers without quantitatively linking these changes with emergent cellular scale functionality. Two biophysical cardiac cell models were created, parameterized and validated and are able to simulate electrophysiology and calcium dynamics in myocytes from control sham operated rats and aortic-banded rats exhibiting diastolic dysfunction.

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes.

Experimental data from human cardiac myocytes at body temperature is crucial for a quantitative understanding of clinically relevant cardiac function and development of whole-organ computational models. However, such experimental data is currently very limited. Specifically, important measurements to characterize changes in tension development in human cardiomyocytes that occur with perturbations in cell length are not available.

Accurate and Standardized Coronary Wave Intensity Analysis.

Objective: Coronary wave intensity analysis (cWIA) has increasingly been applied in the clinical research setting to distinguish between the proximal and distal mechanical influences on coronary blood flow. Recently, a cWIA-derived clinical index demonstrated prognostic value in predicting functional recovery postmyocardial infarction. Nevertheless, the known operator dependence of the cWIA metrics currently hampers its routine application in clinical practice.

Beyond Bernoulli: Improving the Accuracy and Precision of Noninvasive Estimation of Peak Pressure Drops.

Background: Transvalvular peak pressure drops are routinely assessed noninvasively by echocardiography using the Bernoulli principle. However, the Bernoulli principle relies on several approximations that may not be appropriate, including that the majority of the pressure drop is because of the spatial acceleration of the blood flow, and the ejection jet is a single streamline (single peak velocity value).

Methods And Results: We assessed the accuracy of the Bernoulli principle to estimate the peak pressure drop at the aortic valve using 3-dimensional cardiovascular magnetic resonance flow data in 32 subjects.

Analysis of lead placement optimization metrics in cardiac resynchronization therapy with computational modelling.

Aims: The efficacy of cardiac resynchronization therapy (CRT) is known to vary considerably with pacing location, however the most effective set of metrics by which to select the optimal pacing site is not yet well understood. Computational modelling offers a powerful methodology to comprehensively test the effect of pacing location in silico and investigate how to best optimize therapy using clinically available metrics for the individual patient.

Methods And Results: Personalized computational models of cardiac electromechanics were used to perform an in silico left ventricle (LV) pacing site optimization study as part of biventricular CRT in three patient cases.

Non-invasive Model-Based Assessment of Passive Left-Ventricular Myocardial Stiffness in Healthy Subjects and in Patients with Non-ischemic Dilated Cardiomyopathy.

Patient-specific modelling has emerged as a tool for studying heart function, demonstrating the potential to provide non-invasive estimates of tissue passive stiffness. However, reliable use of model-derived stiffness requires sufficient model accuracy and unique estimation of model parameters. In this paper we present personalised models of cardiac mechanics, focusing on improving model accuracy, while ensuring unique parametrisation.

Impact of coronary bifurcation morphology on wave propagation.

The branching pattern of the coronary vasculature is a key determinant of its function and plays a crucial role in shaping the pressure and velocity wave forms measured for clinical diagnosis. However, although multiple scaling laws have been proposed to characterize the branching pattern, the implications they have on wave propagation remain unassessed to date. To bridge this gap, we have developed a new theoretical framework by combining the mathematical formulation of scaling laws with the wave propagation theory in the pulsatile flow regime.

In silico coronary wave intensity analysis: application of an integrated one-dimensional and poromechanical model of cardiac perfusion.

Coronary wave intensity analysis (cWIA) is a diagnostic technique based on invasive measurement of coronary pressure and velocity waveforms. The theory of WIA allows the forward- and backward-propagating coronary waves to be separated and attributed to their origin and timing, thus serving as a sensitive and specific cardiac functional indicator. In recent years, an increasing number of clinical studies have begun to establish associations between changes in specific waves and various diseases of myocardium and perfusion.

Investigating a Novel Activation-Repolarisation Time Metric to Predict Localised Vulnerability to Reentry Using Computational Modelling.

Exit sites associated with scar-related reentrant arrhythmias represent important targets for catheter ablation therapy. However, their accurate location in a safe and robust manner remains a significant clinical challenge. We recently proposed a novel quantitative metric (termed the Reentry Vulnerability Index, RVI) to determine the difference between activation and repolarisation intervals measured from pairs of spatial locations during premature stimulation to accurately locate the critical site of reentry formation.

The calcium-frequency response in the rat ventricular myocyte: an experimental and modelling study.

Key Points: In the majority of species, including humans, increased heart rate increases cardiac contractility. This change is known as the force-frequency response (FFR). The majority of mammals have a positive force-frequency relationship (FFR).

Verification of cardiac mechanics software: benchmark problems and solutions for testing active and passive material behaviour.

Models of cardiac mechanics are increasingly used to investigate cardiac physiology. These models are characterized by a high level of complexity, including the particular anisotropic material properties of biological tissue and the actively contracting material. A large number of independent simulation codes have been developed, but a consistent way of verifying the accuracy and replicability of simulations is lacking.