The 'Digital Twin' to enable the vision of precision cardiology.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.

Patient-specific modeling of left ventricular electromechanics as a driver for haemodynamic analysis.

AIMS: Models of blood flow in the left ventricle (LV) and aorta are an important tool for analysing the interplay between LV deformation and flow patterns. Typically, image-based kinematic models describing endocardial motion are used as an input to blood flow simulations. While such models are suitable for analysing the hemodynamic status quo, they are limited in predicting the response to interventions that alter afterload conditions. Mechano-fluidic models using biophysically detailed electromechanical (EM) models have the potential to overcome this limitation, but are more costly to build and compute. We report our recent advancements in developing an automated workflow for the creation of such CFD ready kinematic models to serve as drivers of blood flow simulations. METHODS AND RESULTS: EM models of the LV and aortic root were created for four pediatric patients treated for either aortic coarctation or aortic valve disease. Using MRI, ECG and invasive pressure recordings, anatomy as well as electrophysiological, mechanical and circulatory model components were personalized. RESULTS: The implemented modeling pipeline was highly automated and allowed model construction and execution of simulations of a patient's heartbeat within 1 day. All models reproduced clinical data with acceptable accuracy. CONCLUSION: Using the developed modeling workflow, the use of EM LV models as driver of fluid flow simulations is becoming feasible. While EM models are costly to construct, they constitute an important and nontrivial step towards fully coupled electro-mechano-fluidic (EMF) models and show promise as a tool for predicting the response to interventions which affect afterload conditions.

Differentiating Left Ventricular Remodeling in Aortic Stenosis From Systemic Hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy occurs in both aortic stenosis (AS) and systemic hypertension (HTN) in response to wall stress. However, differentiation of hypertrophy due to these 2 etiologies is lacking. The aim was to study the 3-dimensional geometric remodeling pattern in severe AS pre- and postsurgical aortic valve replacement and to compare with HTN and healthy controls. METHODS: Ninety-one subjects (36 severe AS, 19 HTN, and 36 healthy controls) underwent cine cardiac magnetic resonance. Cardiac magnetic resonance was repeated 8 months post-aortic valve replacement (n=18). Principal component analysis was performed on the 3-dimensional meshes reconstructed from 109 cardiac magnetic resonance scans of 91 subjects at end-diastole. Principal component analysis modes were compared across experimental groups together with conventional metrics of shape, strain, and scar. RESULTS: A unique AS signature was identified by wall thickness linked to a LV left-right axis shift and a decrease in short-axis eccentricity. HTN was uniquely linked to increased septal thickness. Combining these 3 features had good discriminative ability between AS and HTN (area under the curve, 0.792). The LV left-right axis shift was not reversible post-aortic valve replacement, did not associate with strain, age, or sex, and was predictive of postoperative LV mass regression (R2=0.339, P=0.014). CONCLUSIONS: Unique remodeling signatures might differentiate the etiology of LV hypertrophy. Preliminary findings suggest that LV axis shift is characteristic in AS, is not reversible post-aortic valve replacement, predicts mass regression, and may be interpreted to be an adaptive mechanism.

Phenotyping heart failure by echocardiography: imaging of ventricular function and haemodynamics at rest and exercise.

Traditionally, congestive heart failure (HF) was phenotyped by echocardiography or other imaging techniques according to left ventricular (LV) ejection fraction (LVEF). The more recent echocardiographic modality speckle tracking strain is complementary to LVEF, as it is more sensitive to diagnose mild systolic dysfunction. Furthermore, when LV systolic dysfunction is associated with a small, hypertrophic ventricle, EF is often normal or supernormal, whereas LV global longitudinal strain can reveal reduced contractility. In addition, segmental strain patterns may be used to identify specific cardiomyopathies, which in some cases can be treated with patient-specific medicine. In HF with preserved EF (HFpEF), a diagnostic hallmark is elevated LV filling pressure, which can be diagnosed with good accuracy by applying a set of echocardiographic parameters. Patients with HFpEF often have normal filling pressure at rest, and a non-invasive or invasive diastolic stress test may be used to identify abnormal elevation of filling pressure during exercise. The novel parameter LV work index, which incorporates afterload, is a promising tool for quantification of LV contractile function and efficiency. Another novel modality is shear wave imaging for diagnosing stiff ventricles, but clinical utility remains to be determined. In conclusion, echocardiographic imaging of cardiac function should include LV strain as a supplementary method to LVEF. Echocardiographic parameters can identify elevated LV filling pressure with good accuracy and may be applied in the diagnostic workup of patients suspected of HFpEF.

Nanostructures for Solar Energy Harvesting.

Renewable energy sources are becoming more and more essential to energy production as societies evolve toward a fossil-fuel-free world. Solar energy is one of the most abundant sources of green energy. Nanoantennas can be used to improve and enhance the absorption of light into a photovoltaic cell in order to generate more current. In this study, different nanoantenna structures are analysed in tandem with a silicon solar cell in an effort to improve its output. The nanoantennas studied are metallic aperture nanoantennas made up of either silver, aluminium, gold or copper. The three geometries compared are rectangular, circular and triangular. The maximum field enhancement obtained is for an aluminium rectangular nanoantenna of 50 nm thickness. Despite this, the geometry with more improvements compared with a basic silicon cell was the circle geometry with a 100 nm radius.

Distribution of myocardial work in arterial hypertension: insights from non-invasive left ventricular pressure-strain relations.

A index of non-invasive myocardial work (MWI) can account for pressure during the assessment of cardiac function, potentially separating the influence of loading conditions from the influence of the underlying tissue remodelling. The aim is to assess LV function accounted for loading and explore hypertensive MWI distribution by comparing healthy individuals to hypertensive patients without and with localized basal septal hypertrophy (BSH). An echocardiogram was performed in 170 hypertensive patients and 20 healthy individuals. BSH was defined by a basal-to-mid septal wall thickness ratio ≥ 1.4. LV speckle-tracking was performed, and the MWI calculated globally and regionally for the apical, mid and basal regions. An apex-to-base gradient, seen in regional strain values, was preserved in the distribution of myocardial work, with the apical region compensating for the impairment of the basal segments. This functional redistribution was further pronounced in patients with localized BSH. In these patients, segmental MWI analysis revealed underlying impairment of regional work unrelated to acute loading conditions. Non-invasive MWI analysis offers the possibility to compare LV function regardless of blood pressure at the time of observation. Changes in MWI distribution can be seen in hypertension unrelated to the load-dependency of strain. Accentuated functional changes affirm the role of BSH as an echocardiographic marker in hypertension.

Non-invasive estimation of relative pressure in turbulent flow using virtual work-energy.

Vascular pressure differences are established risk markers for a number of cardiovascular diseases. Relative pressures are, however, often driven by turbulence-induced flow fluctuations, where conventional non-invasive methods may yield inaccurate results. Recently, we proposed a novel method for non-turbulent flows, νWERP, utilizing the concept of virtual work-energy to accurately probe relative pressure through complex branching vasculature. Here, we present an extension of this approach for turbulent flows: νWERP-t. We present a theoretical method derivation based on flow covariance, quantifying the impact of flow fluctuations on relative pressure. νWERP-t is tested on a set of in-vitro stenotic flow phantoms with data acquired by 4D flow MRI with six-directional flow encoding, as well as on a patient-specific in-silico model of an acute aortic dissection. Over all tests νWERP-t shows improved accuracy over alternative energy-based approaches, with excellent recovery of estimated relative pressures. In particular, the use of a guaranteed divergence-free virtual field improves accuracy in cases where turbulent flows skew the apparent divergence of the acquired field. With the original νWERP allowing for assessment of relative pressure into previously inaccessible vasculatures, the extended νWERP-t further enlarges the method's clinical scope, underlining its potential as a novel tool for assessing relative pressure in-vivo.

Assessment of wall stresses and mechanical heart power in the left ventricle: Finite element modeling versus Laplace analysis.

INTRODUCTION: Stenotic aortic valve disease (AS) causes pressure overload of the left ventricle (LV) that may trigger adverse remodeling and precipitate progression towards heart failure (HF). As myocardial energetics can be impaired during AS, LV wall stresses and biomechanical power provide a complementary view of LV performance that may aide in better assessing the state of disease. OBJECTIVES: Using a high-resolution electro-mechanical (EM) in silico model of the LV as a reference, we evaluated clinically feasible Laplace-based methods for assessing global LV wall stresses and biomechanical power. METHODS: We used N = 4 in silico finite element (FE) EM models of LV and aorta of patients suffering from AS. All models were personalized with clinical data under pretreatment conditions. Left ventricle wall stresses and biomechanical power were computed accurately from FE kinematic data and compared with Laplace-based estimation methods, which were applied to the same FE model data. RESULTS AND CONCLUSION: Laplace estimates of LV wall stress are able to provide a rough approximation of global mean stress in the circumferential-longitudinal plane of the LV. However, according to FE results, spatial heterogeneity of stresses in the LV wall is significant, leading to major discrepancies between local stresses and global mean stress. Assessment of mechanical power with Laplace methods is feasible, but these are inferior in accuracy compared with FE models. The accurate assessment of stress and power density distribution in the LV wall is only feasible based on patient-specific FE modeling.

Operational stability of high initial activity protease catalysts in organic solvents.

The first studies on the operational stability of cross-linked enzyme crystals (CLECs) in organic media are described. Although these catalysts display high initial specific activity, they inactivate rapidly, losing more than 50% of the initial activity within the first 4 h under continuous flow. Furthermore, the inactivation is not reversible when returned to an aqueous medium. The same rapid inactivation occurs with adsorbed protease preparations that show similar high initial specific activity (propanol-rinsed enzyme preparations (PREPs) of subtilisin and alpha-chymotrypsin).