Uncovering Contributors to Hypertension through Experimental and Computational Simulation (CHECS)

Lead Research Organisation: King's College London
Department Name: Imaging & Biomedical Engineering

Abstract

High blood pressure, or hypertension, is one of the most important causes of global morbidity and mortality in the developed world [1]. It has been shown that hypertensive people have a high risk of stroke, heart attack, heart failure and renal failure. The Health Survey for England in 2006 demonstrated that the prevalence of hypertension in the UK increased from 17% in the age group 40-49 years to 77% in those aged 70-79 years [2].

Hypertensive patients are usually identified by a threshold diagnosis of their systolic or diastolic pressures exceeding 140 or 90 mmHg respectively. However this diagnosis tends to misdiagnose the individuals in the large population in and around the threshold making the selection for appropriate therapy difficult. For example one important determinant of hypertension is the flexibility of the aorta (the first artery leading from the heart), which becomes stiffer with age and arteriosclerosis. However, such "stiffness" is only one among other geometrical and mechanical factors that influence the pressure pulse and thus hypertension. Therefore, non-invasive measurement of pulse pressure waveforms has been of interest for more than 100 years, and includes tonometry, Ultrasound and Magnetic Resonance Imaging (MRI). Although the non-invasive measurement of waveforms has become fast, the current analysis of the measured waveform data is relatively simplistic. In particular, the analysis of certain waveform features are performed in isolation and are impeded by a lack of understanding of the relative contributions from arterial stiffness/geometry, wave reflection and ventricular/arterial interaction to hypertensive pressure. Over the last two decades, computational modelling has been established as a new discipline to study the interaction of different parameters in the cardiovascular system. These models can help to separate the various contributions to the pressure waveform and elucidate complex interaction of parameters affecting hypertension. More recently, imaging data of the patient's anatomy and physiology has been introduced in numerical simulations to produce patient-specific models. Although, different models have been developed to investigate the influence of geometrical and mechanical factors, a model validation remains challenging since it would require large studies in animals and patients.

This proposal aims at the identification of high-risk individuals by determining the mechanical factors which cause their pressure to be pathological. This approach would allow a better selection of appropriate treatments for the individual patient. For this, we propose the construction of a comprehensive experimental arterial model with which to determine and quantify main contributors to hypertensive pressure as well as to validate our existing computational arterial simulation frameworks (1D and 3D). Translation of these technologies towards the clinic will be facilitated with the construction of full-scale silicone arterial model, which will experimentally simulate haemodynamics of a hypertensive patient dataset. This will be followed by a clinical validation of a computational analysis tools in volunteers and a small patient cohort.

References:
[1] MacMahon, S., et al.: Blood-pressure-related disease is a global healthy priority. Lancet, 2006. 371: p. 1480-1482.
[2] NHS, Health survey for england 2006 latest trends. 2008: Leeds.

Planned Impact

We propose a collaborative project between different disciplines to improve the clinical management of hypertension by understanding its main haemodynamic contributors. For this, we will develop novel experimental and numerical models of the aorta using medical measurements (e.g. imaging and pressure). The proposed project has a strong focus on clinical translation of biomedical engineering techniques by exploiting our existing academic and clinical network. Furthermore, we will investigate different pathways to impact of research results for different beneficiaries:

1. Hypertensive patients are usually identified by a threshold diagnosis, based normally on their systolic or diastolic pressures exceeding 140 or 90 mmHg respectively. Advice for these thresholds are based on large population studies such as the HOT study [1] rather than individual assessments. However such a pressure threshold diagnosis creates a substantial grey area of subjects within and around these values, and does not identify the individual causes of hypertension making the selection of an appropriate therapy difficult. This proposal aims to identify high-risk individuals and the determining mechanical factors, which cause their pressure to be pathological allowing better selection of appropriate treatments for the individual patient.

2. Socio-Economic. Despite progress in recent years in the prevention, detection, and treatment of high blood pressure, hypertension remains an important public health challenge. Hypertension affects approximately 1 billion people worldwide and contributes to approximately 50% of all cardiovascular deaths, (estimated 8 million deaths/year worldwide). The American Heart Association estimated the direct and indirect costs of high blood pressure in 2010 as $76.6 billion [2]. In the UK, the clinical management of hypertension is one of the most common interventions in primary care, accounting for approximately £1 billion in drug costs alone in 2006 [NICE clinicl guideline 127- Hypertension]. Our project aims to develop tools to identify those patients who would benefit from drug treatments.

3. NHS. Our project aims at assessment through data integration of different clinical measurements using a computational model. The NHS would greatly benefit from a more a patient specific approach to reduce the number of hospital visits and to increase the overall success of treatments.

4. Industry. The demonstration of clinical feasibility of data integration with computational modelling tool has a high potential for commercialization. In addition, the application of the experimental model could be of great interest for device companies to develop and test new devices. The well-defined haemodynamic environment could be also of high benefit for medical diagnostic companies to test the accuracy and reproducibility of haemodynamic waveform measurements.

5. Academia. The UK has a leading international position in clinical research and medical imaging. Over the last decade tremendous achievements in computational modelling were made to describe haemodynamics with an integrative biophysical theory. Our project avoids the extensive use of animal models to study the different contributors and thus follows the NC3R-guidelines. Furthermore, our proposed experimental model can replace partly expensive, and ethically involved animal models in haemodynamic research. Our project will further strengthen and expand the position of UK academia both in biomedical engineering and medicine.

References:
[1] Hansson, L., et al.: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the hypertension optimal treatment (hot) randomised trial. The Lancet, 1998. 351(9118): p. 1755-1762.
[2] Lloyd-Jones, D., et al.: Heart disease and stroke statistics-2010 update. Circulation, 2010. 121(7): p. e46-e215.

Publications

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Alastruey J (2014) Novel wave intensity analysis of arterial pulse wave propagation accounting for peripheral reflections. in International journal for numerical methods in biomedical engineering

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Boileau E (2015) A benchmark study of numerical schemes for one-dimensional arterial blood flow modelling. in International journal for numerical methods in biomedical engineering

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De Vecchi A (2014) Catheter-induced errors in pressure measurements in vessels: an in-vitro and numerical study. in IEEE transactions on bio-medical engineering

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Epstein S (2015) Reducing the number of parameters in 1D arterial blood flow modeling: less is more for patient-specific simulations. in American journal of physiology. Heart and circulatory physiology

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Flores J (2016) A Novel Analytical Approach to Pulsatile Blood Flow in the Arterial Network. in Annals of biomedical engineering

 
Description The aim of the project was to improve diagnosis and treatment of patients with hypertension by identifying the underlying biomechanical contributors, using advanced imaging and novel biophysical modelling techniques. We designed and built a 1:1 scale cardiovascular simulator rig for validation of different biophysical models and assessment of the main contributors to the healthy/hypertensive pressure waveform through incremental parameter adjustments (WP1). Furthermore, we produced a computational analysis tool to accurately simulate and analyse blood flow and pressure pulse waveforms in the aorta and other large systemic arteries under normal physiological conditions and with hypertension (WP2). We tested our new computational framework by comparison against analytical, in vitro and in vivo data.

Using our computational and in vitro tools of blood flow modelling in combination with our novel pulse wave analysis tools, we uncovered physical contributors to hypertension: theoretically using computational simulations; in vitro using the cardiovascular simulator rig produced during the project; and in vivo in hypertensive patients and controls. We also developed and tested algorithms to infer properties relevant for the study of hypertension that cannot be directly measured in the clinic; e.g. aortic stiffness and non-invasive aortic blood pressure.
An important outcome of this project was the creation of a population of thousands of virtual (computed) subjects, each with distinctive pulse waveforms. For each subject, blood pressure, blood flow and luminal area waveforms are available at multiple arterial locations, together with anatomical and structural properties (e.g. vessel geometry, vessel wall stiffness), which can be calculated from the parameters of the simulation. The population enables testing and development of pulse wave analysis tools for the assessment of cardiovascular function. It provides a cost-effective initial step to identify those tools that are more likely to be found clinically relevant when carrying out more expensive and time-consuming testing and development using clinical data. Our virtual approach has been proven to be very useful to develop indices of aortic stiffness/compliance and algorithms for the non-invasive estimation of central blood pressure - which are both very important to assess hypertensive patients - and to uncover the main physical contributors to hypertension. We made available the complete population to the research community (http://haemod.uk/virtual-database). Although the project focused on the important application of hypertension, we also used the cardiovascular simulator rig to study other clinically relevant problems, including aortic coarctation and aortic dissection problems. Furthermore, the in vitro model was used for training and teaching of BEng and clinical students through lab projects.
Exploitation Route The cardiovascular simulator rig of the aorta and larger branches could be adapted to simulate blood flow in other parts of the circulation; e.g. in the pulmonary and coronary arteries. The in vitro model could be used to validate different biophysical models, different imaging and data analysis techniques, to evaluate the design and testing of existing and new interventional devices (e.g. catheters, stents), and for training and teaching of students. The in vitro model of the systemic circulation has been used for a BEng student lab-project (part of the Fluids module lead by the PI at King's College London).
Sectors Education,Healthcare

URL http://haemod.uk/virtual-database
 
Description Industrial funding
Amount £13,298 (GBP)
Organisation Polar Electro Oy 
Start 07/2017 
End 11/2017
 
Description Interdisciplinary PhD Studentship Non-invasive Assessment Of Left Ventricular Pressure, Myocardial Wall Stress And Work
Amount £120,976 (GBP)
Funding ID RE/08/003 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description PhD Studentship Endothelial function assessment by pulse wave analysis
Amount £71,212 (GBP)
Organisation King's College London 
Department King's College London, Graduate School
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 09/2021
 
Description PhD Studentship Non-invasive proximal blood pressure estimation by combining MR imaging with one-dimensional flow modelling
Amount £92,000 (GBP)
Funding ID 1834677 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2019
 
Description Project Grant How accurate are our clinical measures of aortic stiffness? A combined in vitro, in silico and in vivo study
Amount £200,904 (GBP)
Funding ID PG/15/104/31913 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 01/2020
 
Description Project Grant Partitioning the determinants of pulse pressure into those due to ventricular ejection and characteristics of the arterial tree
Amount £275,269 (GBP)
Funding ID PG/17/50/32903 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description TSB Grant Atherosclerosis stratification using advanced imaging and computer-based models
Amount £309,709 (GBP)
Funding ID EP/L505304/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 01/2014 
End 12/2017
 
Title Database of Thousands of Virtual Subjects 
Description Many indices and algorithms have been proposed to infer the physiological state of the cardiovascular system by analysing pulse waveforms. Developing and testing them using in vivo waveforms is a complex task: clinical measurements are expensive to acquire, are subject to experimental errors, and are seldom available at multiple locations for the same subject. We provide a novel methodology to perform this task in silico. Using Nektar1D, we have created a database of over 3,325 virtual subjects, each with distinctive arterial pulse waveforms available at multiple arterial locations. For each subject, blood pressure, blood flow and luminal area waveforms are available at multiple arterial locations, together with the parameters of the simulation (e.g. vessel geometries, cardiac output, pulse wave velocities). In our initial study (Am J Phys, 2015), we used the database to assess the accuracy of clinical indices of aortic pulse wave velocity (PWV). 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact The database has been used by several overseas researchers to develop and test their own pulse wave analysis algorithms. 
URL http://haemod.uk/virtual-database
 
Title Nektar1D 
Description Nektar1D is our in-house code for solving the nonlinear, one-dimensional (1D) equations of blood flow in a given network of compliant vessels subject to boundary and initial conditions. All the files needed to compile Nektar1D, together with examples of 1D model simulations used in our articles, can be requested by email addressed to jordi.alastruey-arimon@kcl.ac.uk. A reference manual for Nektar1D describing how to compile the code, create and run simulations, and interpret the results is available online (http://haemod.uk/nektar). 
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact Several external researchers to my lab have used Nektar1D for their peer-reviewed publications. 
URL http://haemod.uk/nektar
 
Description Atherosclerosis stratification using advanced imaging and computer-based models 
Organisation Philips Healthcare
Country Netherlands 
Sector Private 
PI Contribution The project team developed a tool for vascular function assessment (4D flow) and a tool for vascular vulnerability analysis (plaque). Both tools process images obtained from multi-parametric magnetic resonance imaging (MRI). Together these are going to form the "vascular research suite" of Philips IntelliSpace Discovery. 4D flow assessment has been sold to first customers in 2017. I contributed mainly to the development of the 4D flow tool with my group's numerical tools of blood flow modelling and analysis. The project was funded by a Technology Strategy Board CR&D Grant (EP/L505304/1) (£309,709) of which I was Co-I. Philips contributed with a further £162,981.
Collaborator Contribution Philips provided code and expertise for the analysis of MRI data.
Impact The following publications resulted from this partnership: [1] Florkowa M, Mariscal Harana J, van Engelen A, Schneider T, Rafiq I, de Bliek H, Alastruey J, Botnar R. An integrated software application for non-invasive assessment of local aortic haemodynamic parameters. Procedia Computer Science 90, 2-8, 2016; [2] van Engelen A, Vieira MS, Rafiq I, Cecelja M, Schneider T, de Bliek H, Figueroa CA, Hussain T, Botnar R, Alastruey J. Aortic length measurements for pulse wave velocity calculation: manual 2D vs automated 3D centreline extraction. Journal of Cardiovascular Magnetic Resonance 19:32 (13 pages), 2017 (DOI: 10.1186/s12968-017-0341-y; PubMed ID: 28270208); [3] van Engelen A, Mariscal-Harana J, Schneider T, Florkow M, Charlton P, Ruijsink B, de Bliek H, Valverde I, Charakida M, Pushparajah K, Botnar R, Alastruey J. Validation of non-invasive MRI-based assessment of central blood pressure in a population of repaired coarctation patients. Circulation 136:A15764, 2017. In addition, as part of this collaboration, we started developing a computational framework to assess blood pressure in the systemic circulation from MRI and tonometry data. This is the PhD project of my student Jorge Mariscal-Harana, who is funded by the EPSRC CDT in Medical Imaging.
Start Year 2014
 
Description With Chowienczyk - Blood flow and pharmacological interventions 
Organisation King's College London
Department Cardiovascular Division
Country United Kingdom 
Sector Academic/University 
PI Contribution The aim of this investigation is to study physical mechanisms underlying the shape of the blood pressure waveform using in vivo human data under normal conditions and during pharmacological interventions that change the physical properties of the cardiovascular system. I am contributing with the analysis of the in vivo data using pulse wave analysis and numerical tools based on the one-dimensional formulation of pulse wave propagation in compliant vessels. Professor Chowienczyk and I have jointly supervised 2 PhD students (Sally Epstein and Samuel Vennin) working on this project. Both have completed their PhD. We are currently supervising two RAs.
Collaborator Contribution Chowienczyk is contributing with his clinical pharmacological expertise and by providing in vivo data measured in humans in normal conditions and under the effect of several pharmacological drugs.
Impact Sally Epstein was funded by the Wellcome Trust Medical Engineering Centre at KCL. Samuel Vennin was funded by the BHF Centre of Medical Excellence at King's College London. The two RAs are currently being funded by the BHF. This is a multi-disciplinary collaboration involving clinical and engineering disciplines.
Start Year 2011
 
Description With Figueroa and Xiao - Systematic comparison between 1-D and 3-D haemodynamics in compliant arterial models 
Organisation King's College London
Department Department of Biomedical Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution The aim of this collaboration was to compare arterial hemodynamics computed using a one-dimensional (1-D) and a three-dimensional (3-D) formulation. In the former, blood pressure and flow are allowed to change only along the axial direction of arteries, and in the latter the full 3-D problem is solved in deformable vessels. I contributed with (i) producing the 1-D results in several benchmark models of the aorta and its main branches and (ii) calculating the parameters of the boundary conditions of both the 1-D and 3-D models to achieve a specific target pulse pressure and diastolic pressure at a specific location in the vessel. This is the first time that such a comparison was carried out to assess the accuracy of the 1-D formulation with such level of detail. Comparisons were done in several idealised arterial geometries - ranging for a straight model of the carotid artery to a full model of the aorta and its larger branches - and in an anatomically correct model of the upper thoracic aorta with model parameters obtained from MRI and applanation tonometry data measured in a single volunteer. Our work is clinically relevant, since 1-D modelling is the basis of wave intensity analysis and the reservoir-wave separation, which have been used in many clinical studies.
Collaborator Contribution Figueroa and Xiao contributed with the 3-D simulations.
Impact We published two manuscripts: [1] Alastruey J, Xiao N, Fok H, Schaeffter T, Figueroa CA. On the impact of modelling assumptions in multi-scale, subject-specific models of aortic haemodynamics. Journal of the Royal Society Interface 13(119):1-17, 2016 (DOI: 10.1098/rsif.2016.0073; PubMed ID: 27307511); [2] Xiao N, Alastruey J, Figueroa CA. A systematic comparison between 1-D and 3-D hemodynamics in compliant arterial models. International Journal for Numerical Methods in Biomedical Engineering, 30(2) 204-231, 2014. Nan Xiao presented preliminary results of our collaboration at the ECCOMAS 2012 Congress in Vienna last September.
Start Year 2011
 
Description With Pushparajah and Chabiniok - Developing physiological biomarkers in the Fontan circulation 
Organisation Evelina London Children's Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution The aim of the study is to understand the haemodynamics in symptomatic patients with Fontan circulation during rest and exercise conditions, and to investigate the changes in haemodynamics under the effects of a pulmonary vasodilator. My team is contributing with the computational side of the project and the analysis of the clinical data provided by the clinical partners.
Collaborator Contribution Pushparajah is contributing with his clinical expertise and providing in vivo haemodynamic data measured in Fontan patients during rest and exercise conditions.
Impact This is a multi-disciplinary collaboration involving clinical and engineering disciplines.
Start Year 2018