Towards patient-specific modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps

Background: Ventricular Assist Devices (VADs) insertion is an established treatment for patients with end-stage heart failure waiting for a heart transplant or in need for long-term circulatory support (destination therapy). Rotary blood pumps (RBP) are the most popular devices in view of their size and performance. Pre-operative planning strategy for the insertion of a left ventricular assist device (LVAD) requires a timely discussion at a Multi-Disciplinary Team Meeting (MDT). Clinical-decision making is based according to the needs of the patient and must be processed without delays. Nevertheless, thrombus formation remains a feared complication which affects outcome. VADs operate in a flow regime which is difficult to simulate: the transitional region at the boundary of laminar and turbulent flow (low Reynolds number). Different methods have been used but the best approach remains debatable. Computational Fluid Dynamics (CFD) is an attractive and invaluable tool for the study of the interactions between VADs and the cardiovascular system. The aim of this thesis is three-fold: a) to investigate the use of pressure-volume analysis in a clinical setting through the review of six heart failure patients previously discussed at a MDT meeting with a view to predict or guide further management; b) to review the theory behind modelling approaches to VADs and their interactions with the cardiovascular system for better understanding of their clinical use. Then, an overview of computational fluid dynamics (CFD) is considered as a prelude to its application to the analysis of VADs performance. Additionally, the development of a simplified model of centrifugal pump will be used in initial simulations as preliminary analysis; c) to examine an example of a proof-of-concept pilot patient-specific model of an axial flow pump (HeartMate II) as pre-operative planning strategy in a patient-specific model with a view to identify potential critical areas that may affect pump function and outcome in a clinical setting. Material and Methods: 3D reconstruction from CT-scan images of patients who underwent the insertion of rotary blood pumps, namely HeartWare HVAD and HeartMate II. Ansys Fluent has been used for CFD analysis based on the fundamental governing equations of motion. Blood has been modelled as incompressible, Newtonian fluid with density = 1060 and viscosity = 0.0035 kg/m-s. The laminar and SST models have been used for comparison purposes. The rotational motion of the impeller has been implemented using the moving reference frame (MRF) approach. The sliding mesh method has also been used to account for unsteady interaction between stationary and moving part. The no-slip condition has been applied to all walls, which were assumed to be rigid. Boundary conditions consisting of velocity inlet and pressure outlet of the pump based on different settings and constant rotational speed for the impeller. Pressure-velocity coupling has been based on the coupled scheme. Spatial discretisation consisted of the “least square cell based” gradient for velocity and “PRESTO” or second order for pressure. Second order upwind has been set for the momentum, turbulent kinetic energy and specific dissipation rate. First order implicit has been set for transient formulation. The pseudo transient algorithm (steady state), the high order relaxation term and the warped-face gradient correction have been used to add an unsteady term to the solution equations with the aim to improve stability and enhance convergence. Specific settings have been considered for comparison purposes. Results: Pressure-volume simulation analysis in six advanced heart failure patients showed that an integrated model of the cardiovascular system based on lumped-parameter representation, modified time-varying elastance and pressure-volume analysis of ventricular function seems a feasible and suitable approach yielding a sufficiently accurate quantitative analysis in real time, therefore applicable within the time-constraints of a clinical setting. Lumped-parameter models consist of simultaneous ordinary differential equations complemented by an algebraic balance equation and are suitable for examination of global distribution of pressure, flow and volume over a range of physiological conditions with inclusion of the interaction between modelled components. Higher level lumped-parameter modelling is needed to address the interaction between the circulation and other systems based on a compromise between complexity and ability to set the required parameters to personalise an integrated lumped-parameter model for a patient-specific approach. CARDIOSIM© fulfils these requirements and does address the systems interaction with its modular approach and assembly of models with varying degree of complexity although 0-D and 1-D coupling may be required for the evaluation of long-term VAD support. The challenge remains the ability to predict outcome over a longer period of time. The preliminary CFD simulations with the HeartWare HVAD centrifugal pump demonstrated that it is possible to obtain an accurate analysis in a timely manner to complement the clinical review process. The simulations with the pilot patient-specific model of the HeartMate II axial flow pump revealed that a complex 3D reconstruction is feasible in a timely manner and can be used to generate sufficiently accurate results to be used in the context of a MDT meeting for the purposes of clinical decision-making. Overall, these three studies demonstrate that the time frame of the simulations was within hours which may fit the time constraints of the clinical environment in the context of a MDT meeting. More specifically, it was shown that the laminar model may be used for an initial evaluation of the flow development within the pump. Nonetheless, the k- model offers higher accuracy if the timeline of the clinical setting allows for a longer simulation. Conclusion: This thesis aimed at the understanding of the use of computational modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps. The novelty lays in the use of both pressure-volume simulation analysis and 3D flow dynamics studies in VADs with a view to treatment optimisation and outcome prediction within the time constraints of a clinical setting in the context of a MDT meeting. The clinical significance and the contribution to the field is a more targeted approach for different groups of patients and a more quantitative evaluation in the clinical decision process based on a pro-active co-operation between clinicians and scientists reducing the potential for “guess work”. The results of this thesis are a proof-of-concept as a prelude to a potential future implementation of patient-specific modelling within a clinical setting on a daily basis demonstrating a clear clinical significance and contribution to the field. The proposed approach does not consider modelling and simulation as a substitute for clinical experience but an additional tool to guide therapeutic intervention and complement the clinical decision process in which the clinician remains the ultimate decision-maker. Such an approach may well add a different dimension to the problem of heart failure with potential for high return in terms of patient’s outcome and long-term surveillance. The same principles would be applicable to other cardiovascular problems in line with the current concept of “Team Approach” such as the Heart Team, the Structural Heart Team or the Aortic Team. The present work has taken this concept closer to clinical delivery and has highlighted its potential but further work remains to be done in refining the technique.Background: Ventricular Assist Devices (VADs) insertion is an established treatment for patients with end-stage heart failure waiting for a heart transplant or in need for long-term circulatory support (destination therapy). Rotary blood pumps (RBP) are the most popular devices in view of their size and performance. Pre-operative planning strategy for the insertion of a left ventricular assist device (LVAD) requires a timely discussion at a Multi-Disciplinary Team Meeting (MDT). Clinical-decision making is based according to the needs of the patient and must be processed without delays. Nevertheless, thrombus formation remains a feared complication which affects outcome. VADs operate in a flow regime which is difficult to simulate: the transitional region at the boundary of laminar and turbulent flow (low Reynolds number). Different methods have been used but the best approach remains debatable. Computational Fluid Dynamics (CFD) is an attractive and invaluable tool for the study of the interactions between VADs and the cardiovascular system. The aim of this thesis is three-fold: a) to investigate the use of pressure-volume analysis in a clinical setting through the review of six heart failure patients previously discussed at a MDT meeting with a view to predict or guide further management; b) to review the theory behind modelling approaches to VADs and their interactions with the cardiovascular system for better understanding of their clinical use. Then, an overview of computational fluid dynamics (CFD) is considered as a prelude to its application to the analysis of VADs performance. Additionally, the development of a simplified model of centrifugal pump will be used in initial simulations as preliminary analysis; c) to examine an example of a proof-of-concept pilot patient-specific model of an axial flow pump (HeartMate II) as pre-operative planning strategy in a patient-specific model with a view to identify potential critical areas that may affect pump function and outcome in a clinical setting. Material and Methods: 3D reconstruction from CT-scan images of patients who underwent the insertion of rotary blood pumps, namely HeartWare HVAD and HeartMate II. Ansys Fluent has been used for CFD analysis based on the fundamental governing equations of motion. Blood has been modelled as incompressible, Newtonian fluid with density = 1060 and viscosity = 0.0035 kg/m-s. The laminar and SST models have been used for comparison purposes. The rotational motion of the impeller has been implemented using the moving reference frame (MRF) approach. The sliding mesh method has also been used to account for unsteady interaction between stationary and moving part. The no-slip condition has been applied to all walls, which were assumed to be rigid. Boundary conditions consisting of velocity inlet and pressure outlet of the pump based on different settings and constant rotational speed for the impeller. Pressure-velocity coupling has been based on the coupled scheme. Spatial discretisation consisted of the “least square cell based” gradient for velocity and “PRESTO” or second order for pressure. Second order upwind has been set for the momentum, turbulent kinetic energy and specific dissipation rate. First order implicit has been set for transient formulation. The pseudo transient algorithm (steady state), the high order relaxation term and the warped-face gradient correction have been used to add an unsteady term to the solution equations with the aim to improve stability and enhance convergence. Specific settings have been considered for comparison purposes. Results: Pressure-volume simulation analysis in six advanced heart failure patients showed that an integrated model of the cardiovascular system based on lumped-parameter representation, modified time-varying elastance and pressure-volume analysis of ventricular function seems a feasible and suitable approach yielding a sufficiently accurate quantitative analysis in real time, therefore applicable within the time-constraints of a clinical setting. Lumped-parameter models consist of simultaneous ordinary differential equations complemented by an algebraic balance equation and are suitable for examination of global distribution of pressure, flow and volume over a range of physiological conditions with inclusion of the interaction between modelled components. Higher level lumped-parameter modelling is needed to address the interaction between the circulation and other systems based on a compromise between complexity and ability to set the required parameters to personalise an integrated lumped-parameter model for a patient-specific approach. CARDIOSIM© fulfils these requirements and does address the systems interaction with its modular approach and assembly of models with varying degree of complexity although 0-D and 1-D coupling may be required for the evaluation of long-term VAD support. The challenge remains the ability to predict outcome over a longer period of time. The preliminary CFD simulations with the HeartWare HVAD centrifugal pump demonstrated that it is possible to obtain an accurate analysis in a timely manner to complement the clinical review process. The simulations with the pilot patient-specific model of the HeartMate II axial flow pump revealed that a complex 3D reconstruction is feasible in a timely manner and can be used to generate sufficiently accurate results to be used in the context of a MDT meeting for the purposes of clinical decision-making. Overall, these three studies demonstrate that the time frame of the simulations was within hours which may fit the time constraints of the clinical environment in the context of a MDT meeting. More specifically, it was shown that the laminar model may be used for an initial evaluation of the flow development within the pump. Nonetheless, the k- model offers higher accuracy if the timeline of the clinical setting allows for a longer simulation. Conclusion: This thesis aimed at the understanding of the use of computational modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps. The novelty lays in the use of both pressure-volume simulation analysis and 3D flow dynamics studies in VADs with a view to treatment optimisation and outcome prediction within the time constraints of a clinical setting in the context of a MDT meeting. The clinical significance and the contribution to the field is a more targeted approach for different groups of patients and a more quantitative evaluation in the clinical decision process based on a pro-active co-operation between clinicians and scientists reducing the potential for “guess work”. The results of this thesis are a proof-of-concept as a prelude to a potential future implementation of patient-specific modelling within a clinical setting on a daily basis demonstrating a clear clinical significance and contribution to the field. The proposed approach does not consider modelling and simulation as a substitute for clinical experience but an additional tool to guide therapeutic intervention and complement the clinical decision process in which the clinician remains the ultimate decision-maker. Such an approach may well add a different dimension to the problem of heart failure with potential for high return in terms of patient’s outcome and long-term surveillance. The same principles would be applicable to other cardiovascular problems in line with the current concept of “Team Approach” such as the Heart Team, the Structural Heart Team or the Aortic Team. The present work has taken this concept closer to clinical delivery and has highlighted its potential but further work remains to be done in refining the technique

Development and applications of in-vitro and in-silico models of the cardiovascular system to study the effects of mechanical circulatory support.

Cardiovascular diseases (CVDs) are the leading cause of mortality globally. With ongoing interest in CVDs treatment, preclinical models for drug/therapeutic development that allow for fast iterative research are needed. Owing to the inherent complexity of the cardiovascular system, current in-vitro models of the cardiovascular system fail to replicate many of the physiological aspects of the cardiovascular system. In this dissertation, the main concern is with heart failure (HF). In advanced HF, patients may receive Left Ventricular Assist Devices (LVADs) as a bridge to transplant or destination therapy. However, LVADs have many limitations, including inability to adapt to varying tissue demand conditions, risk of ventricular suction, and diminished arterial pulsatility. To address these issues, this dissertation aims to use and develop computer, cellular, and tissue models of the cardiovascular system. 1) Use an in-silico model of the cardiovascular system to develop a novel control algorithm for LVADs. The control system was rigorously tested and showed adequate perfusion during rest and exercise, protect against ventricular suction under reduced heart preload, and augment arterial pulsatility through pulse modulation without requiring sensor implantation or model-based estimations. 2) While pulsatility augmentation was feasible through the developed control algorithm, the pulse waveform that could normalize the vascular phenotype is unknown. To address this, an endothelial cell-smooth muscle cell microfluidic coculture model was developed to recreate the physiological mechanical stimulants in the vascular wall. The results demonstrated different effects of pulsatile shear stress and stretch on endothelial cells and may indicate that a pulse pressure of at least 30 mmHg is needed to maintain normal endothelial morphology. 3) In order to study the effects of mechanical unloading on the native ventricle, a novel cardiac tissue culture model (CTCM) was developed. CTCM provided physiological electromechanical and humoral stimulation with 25% preload stretch and thyroid and glucocorticoid treatment maintained the cardiac phenotype for 12 days. The device was thoroughly characterized and tested. Results demonstrated improved viability, energy utilization, fibrotic remodeling, and structural integrity compared to available culture systems. The system was also used to reproduce ventricular volume-overload and the results demonstrated hypertrophic and fibrotic remodeling, typical of volume-overload pathology

Suction Detection And Feedback Control For The Rotary Left Ventricular Assist Device

The Left Ventricular Assist Device (LVAD) is a rotary mechanical pump that is implanted in patients with congestive heart failure to help the left ventricle in pumping blood in the circulatory system. The rotary type pumps are controlled by varying the pump motor current to adjust the amount of blood flowing through the LVAD. One important challenge in using such a device is the desire to provide the patient with as close to a normal lifestyle as possible until a donor heart becomes available. The development of an appropriate feedback controller that is capable of automatically adjusting the pump current is therefore a crucial step in meeting this challenge. In addition to being able to adapt to changes in the patient\u27s daily activities, the controller must be able to prevent the occurrence of excessive pumping of blood from the left ventricle (a phenomenon known as ventricular suction) that may cause collapse of the left ventricle and damage to the heart muscle and tissues. In this dissertation, we present a new suction detection system that can precisely classify pump flow patterns, based on a Lagrangian Support Vector Machine (LSVM) model that combines six suction indices extracted from the pump flow signal to make a decision about whether the pump is not in suction, approaching suction, or in suction. The proposed method has been tested using in vivo experimental data based on two different LVAD pumps. The results show that the system can produce superior performance in terms of classification accuracy, stability, learning speed, iv and good robustness compared to three other existing suction detection methods and the original SVM-based algorithm. The ability of the proposed algorithm to detect suction provides a reliable platform for the development of a feedback control system to control the current of the pump (input variable) while at the same time ensuring that suction is avoided. Based on the proposed suction detector, a new control system for the rotary LVAD was developed to automatically regulate the pump current of the device to avoid ventricular suction. The control system consists of an LSVM suction detector and a feedback controller. The LSVM suction detector is activated first so as to correctly classify the pump status as No Suction (NS) or Suction (S). When the detection is “No Suction”, the feedback controller is activated so as to automatically adjust the pump current in order that the blood flow requirements of the patient’s body at different physiological states are met according to the patient’s activity level. When the detection is “Suction”, the pump current is immediately decreased in order to drive the pump back to a normal No Suction operating condition. The performance of the control system was tested in simulations over a wide range of physiological conditions

Preload-based Starling-like control of rotary blood pumps: an in-vitro evaluation

Due to a shortage of donor hearts, rotary left ventricular assist devices (LVADs) are used to provide mechanical circulatory support. To address the preload insensitivity of the constant speed controller (CSC) used in conventional LVADs, we developed a preload-based Starling-like controller (SLC). The SLC emulates the Starling law of the heart to maintain mean pump flow ([Formula: see text]) with respect to mean left ventricular end diastolic pressure (PLVEDm) as the feedback signal. The SLC and CSC were compared using a mock circulation loop to assess their capacity to increase cardiac output during mild exercise while avoiding ventricular suction (marked by a negative PLVEDm) and maintaining circulatory stability during blood loss and severe reductions in left ventricular contractility (LVC). The root mean squared hemodynamic deviation (RMSHD) metric was used to assess the clinical acceptability of each controller based on pre-defined hemodynamic limits. We also compared the in-silico results from our previously published paper with our in-vitro outcomes. In the exercise simulation, the SLC increased [Formula: see text] by 37%, compared to only 17% with the CSC. During blood loss, the SLC maintained a better safety margin against left ventricular suction with PLVEDm of 2.7 mmHg compared to -0.1 mmHg for CSC. A transition to reduced LVC resulted in decreased mean arterial pressure (MAP) and [Formula: see text] with CSC, whilst the SLC maintained MAP and [Formula: see text]. The results were associated with a much lower RMSHD value with SLC (70.3%) compared to CSC (225.5%), demonstrating improved capacity of the SLC to compensate for the varying cardiac demand during profound circulatory changes. In-vitro and in-silico results demonstrated similar trends to the simulated changes in patient state however the magnitude of hemodynamic changes were different, thus justifying the progression to in-vitro evaluation.Mahdi Mansouri, Shaun D. Gregory, Robert F. Salamonsen, Nigel H. Lovell, Michael C. Stevens, Jo P. Pauls, Rini Akmeliawati, Einly Li

Doctor of Philosophy

dissertationHeart disease is the leading cause of death in the United States. Mechanical circulatory support by ventricular assist devices (VADs) is a means by which deteriorating heart function can be supplemented, and is a leading therapy for latestage heart failure patients. The devices are commonly connected to the apex of the left ventricle (LV) to move oxygenated blood to the body via the aorta. Recent developments have made continuous-flow pumps commonplace in the clinical environment when compared to their pulsatile-flow predecessors. Typically, continuous-flow VADs are designed with axial- or centrifugal- (radial) configurations. The pressures and flow rates vary dramatically in the native heart as blood is moved from the LV to the aorta. This dissertation presents pressure-flow characteristics for both axial- and centrifugal-flow VADs within a wide range of pressure differential values under uniform conditions, by means of a novel, open-loop flow system. Current techniques employ a closed-loop system to determine pump performance. A closed-loop system does not allow pressure differentials less than or equal to zero to be achieved. The native heart experiences pressure gradients near zero across the aortic valve during systole, which is essentially where the VAD is placed. Thus, an open-loop flow system with independently adjustable preload and afterload pressures is required to reach physiologically-relevant pressure differential regions that approximate the pressure gradient across the aortic valve during systole. Additional modifications made to the open-loop flow system generate pulsatile flow type conditions, which mimic those of the native LV. With this type of in vitro test system, not only can general hydrodynamic performance and hydraulic efficiency of VADs be measured, but also off-design operational performance under dynamic flow conditions can be characterized. This research explores hydrodynamic performance characteristics of axial- and centrifugal-flow VADs to determine design advantages that each have. Device characteristics include pressure-flow performance curves, pressure sensitivity, pulsatility index, and pulsatility ratio. Performance curves and other relevant attributes are investigated at previously unreported pressure-flow regions. Performance is evaluated theoretically, computationally, and experimentally under both steady-state, continuous-flow and pulsatile-flow circumstances

Design and development of a pulsatile axial flow blood pump as a left ventricular assist device

This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University LondonEach year all over the world, Millions of patients from infants to adults are diagnosed with heart failure. A limited number of donor hearts available for these patients results in a tremendous demand of mechanical circulatory support (MCS) system, either in the form of total artificial heart (TAH) or a ventricular assist device (VAD). Physiologically MCS are expected to provide heart; a time to rest and potential recovery by unloading the ventricle, while maintaining the adequate peripheral as well as coronary circulation. Existing ventricular assist devices (VAD) have employed either displacement type pulsatile flow pumping systems or continuous flow type centrifugal/rotodynamic pumps systems. Displacement type devices produce a pulsatile outflow, which has significant benefits on vital organ function and end organ recovery. Continuous flow devices are small and can be placed within body using minimal invasive procedures, in addition they reduces infection as well as mechanical failure related complications. Despite availability of success stories for both types of pumping systems, the selection of the either of them is an ongoing debate. This thesis aims to merge the advantages of displacement pumps (pulsatile flow) and axial-flow pumps (continuous flow) into a novel left vertical assist device (LVAD), by designing a novel minimal invasive, miniature axial-flow pump producing pulsating outflow for the patients having early heart failure and myocardial infarction as a Bridge-To-Recovery (BTR) or Bridge-To-Decision (BTD) device. The design of VAD, the experimental setup and dedicated control system were developed for the in vitro evaluation of pulsatile flow. Computational fluid dynamics (CFD) had been employed for the detail investigation of pulsatile flow. In addition, CFD was also applied to optimize the pulse generation for low haemolysis levels. Outcome of the study produces comprehensive understanding for the generation of pulsatile flow using an axial flow pump. Further, it provides the means of generating a controlled pulse that can regulate flow rate for varying heart rate within low haemolysis levels

Model Predictive Control of Blood Pressure and Urine Production Rate for a Physiological Patient Model

The research proposes the design of a model predictive control (MPC) for automatic drug dosing to regulate high blood pressure and urine production rate in an elderly patient. Combining hydrochlorothiazide and oxybutynin is commonly used for regulation of blood pressure in elderly patients. The patient’s model tries to captures the responses to the drugs as the blood pressure and urine production rates attains their various set-points. Hence, this research aims at improving the control scheme which ensured that these two physiological variables are regulated. Simulation was done in MATLAB/Simulink environment with the use of MPC Toolbox, and the controlled variables were constrained to operate at 80mmHg for blood pressure and between 24-49 ml/kg/hr for urine production rate respectively while the manipulated variables remained unconstrained. From the simulation results, the MPC controller achieved good set-point tracking and disturbance rejection, which is an indication of a healthy level of regulation within acceptable tolerances

Treatment-Specific Approaches for Analysis and Control of Left Ventricular Assist Devices

A Left Ventricular Assist Device (LVAD) is a mechanical pump that helps patients with heart failure conditions. This rotary pump works in parallel to the ailing heart and provides an alternative path for blood flow from the weak left ventricle to the aorta. The LVAD is controlled by the power supplied to the pump motor. An increase in the pump motor power increases the pump speed and the pump flow. The LVAD is typically controlled at a fixed setting of pump power. This basically means that the controller does not react to any change in the activity level of the patient. An important engineering challenge is to develop an LVAD feedback controller that can automatically adjusts its pump motor power so that the resulting pump flow matches the physiological demand of the patient. To this end, the development of a mathematical model that can be used to accurately simulate the interaction between the cardiovascular system of the patient and the LVAD is essential for the controller design. The use of such a dynamic model helps engineers and physicians in testing their theories, assessing the effectiveness of prescribed treatments, and understanding in depth the characteristics of this coupled bio-mechanical system. The first contribution of this dissertation is the development of a pump power-based model for the cardiovascular-LVAD system. Previously, the mathematical models in the literature assume availability of the pump speed as an independent control variable. In reality, however, the device is controlled by pump motor power which, in turn, produces the rotational pump speed. The nonlinear relationship between the supplied power and the speed is derived, and interesting observations about the pump speed signal are documented. The second contribution is the development of a feedback controller for patients using an LVAD as either a destination therapy or a bridge to transplant device. The main objective of designing this controller is to provide a physiological demand of the patient equivalent of that of a healthy individual. Since the device is implanted for a long period of time, this objective is chosen to allow the patient to live a life as close to normal as possible. The third contribution is an analysis of the aortic valve dynamics under the support of an LVAD. The aortic valve may experiences a permanent closure when the LVAD pump power is increased too much. The permanent closure of the aortic valve can be very harmful to the patients using the device as a bridge to recovery treatments. The analysis illustrates the various changes in the hemodynamic variables of the patient as a result of aortic valve closing. The results establish the relationship between the activity level and the heart failure severity with respect to the duration of the aortic valve opening