Blood flow velocity for transcatheter aortic valve implantation microsurgery

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POLITECNICO DI MILANO

School of Industrial and Information Engineering

Master’s Degree Course in Biomedical Engineering

Master’s Degree Thesis in Biomedical Engineering

Supervisor: Prof.ssa Signorini Maria Gabriella

A.A. 2015-2016

Author: Martena Giovanni Luca - Matricola: 800900

Blood Flow Velocity for

Transcatheter Aortic

Valve Implantation

Microsurgery

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Index

Abstract ... 4

Long Abstract ... 5

1. Introduction ... 15

Anatomy: the heart ... 15

Anatomy: the aorta ... 17

Disease: AVS and valve calcification... 19

Transcatheter Aortic Valve Implantation (T.A.V.I.) ... 20

Introduction References ... 23

2. Objectives ... 28

Specific Objectives ... 28

CASCADE Objectives ... 33

Project Workframe: the CASCADE Project ... 34

Objectives References ... 37

3. Materials and Methods ... 38

Hardware: Medyria Flowsensing System ... 38

Hardware: NDI Aurora Tracking System ... 42

Hardware: Medyria Peristaltic Pump... 43

Hardware: Materialise Aorta Mockups ... 44

Software: General Architecture ... 45

Software: Flowsensing Component Architecture ... 48

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Experimental Setup ... 54

Appendix: Libraries and Code explained ... 57

4. Results... 63

The Blood Flow and Objectives ... 63

Implementation Results ... 65

Internal Validation ... 72

External Validation ... 75

Results References ... 78

5. Conclusions ... 79

Primary Conclusions ... 79

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Abstract – page 4

Abstract

In this work, a new tool has been developed to help surgeons perform the Transcatheter Aortic Valve Implantation (T.A.V.I.) procedure, especially during the cannulation phase. The system has been developed within the framework of the C.A.S.C.A.D.E. project (Cognitive Authonomous Catheters in Dynamic Environments, http://www.cascade-fp7.eu/) in the laboratories of Medyria AG in Winterthur (Switzerland), partially in the PMS department of the Katolieke Universiteit of Leuven (Belgium) and King’s College of London (U.K.), and consists of a standard T.A.V.I. catheter with a blood flow velocity and EM position tracking sensors. In addition to the interface unit between the catheter and the computer, the system features a dedicated section in the software (property of CASCADE Consortium) designed to yield the information about the blood flow and the position of the catheter with respect to the aortic valve. To do this, two different visualizers have been developed and implemented into the software itself: a Flow VS Time and a Flow Colormap. After the catheter prototype and the software were ready, the whole system has been tested, calibrated, and given evaluation both internal and external from a CASCADE advisory board of surgeons who have been asked to try the catheter-software compound out and express an opinion on its overall usefulness. While the answers have been good for the Flow VS Time visualizer, the Flow Colormap has been judged too complicated for clinical use, even if its potential has been arising a certain amount of interest between the surgeons. Overall, the system has been evaluated as a potentially useful tool despite some limitations.

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Long Abstract – page 5

Long Abstract

The heart is a muscular organ found in humans and other animals, which pumps blood through the blood vessels of the circulatory system [1]. In humans, other mammals and birds the heart is divided into four chambers: upper left and right atria; and lower left and right ventricles. Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. The heart is enclosed in a protective sac, the pericardium, which also contains a small amount of fluid. Its wall is made up of three layers: epicardium, myocardium, and endocardium [7].

Pumping blood through both systemic and pulmonary circulatory systems, the heart is a very important and vital organ whose malfunctions and diseases can considerably lower life quality and expectancy for an individual, if not leading to death. Cardio Vascular Diseases (CVD) are the most common cause of death globally as of 2008, accounting for 30% of deaths [9][10]. Of these more than three quarters follow coronary artery disease and stroke [9]. Risk factors include: smoking, being overweight, little exercise, high cholesterol, high blood pressure, and poorly controlled diabetes, among others [11]. Diagnosis of CVD is often done by listening to the heart-sounds with a stethoscope, ECG or by ultrasound [3].

It is useful, for this work’s purposes, to consider only one of the pathologies (and complications) that a patient’s heart can show: Aortic Stenosis (AS) or Aortic Valve Stenosis (AVS) and aortic valve calcification. The Aortic Stenosis is the narrowing of the exit of the left ventricle, such that cardiovascular problems result. This may occur at the aortic valve as well as above and below this level, and it is a condition that tends to get worse over time. Causes include being born with a bicuspid aortic valve and rheumatic fever; a normal valve, however, may also harden spontaneously over time. For what it is concerned with AS, its severity can be measured in 𝑐𝑚2of aortic valve opening, and can be

classified, ranging from “Mild” (> 1.5 𝑐𝑚2_{) through Moderate (1 – 1.5 𝑐𝑚}2_{), Severe (< 1}

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The Transcatheter Aortic Valve Implantation (T.A.V.I.) or Replacement (T.A.V.R.) is a recently developed medical procedure whose primary aim is to replace a dysfunctional aortic valve with a bio-compatible prosthetic system that literally pushes away the pathologic leaflets and takes over their job of preventing blood from reflowing into the left ventricle, all carried out throughout the use of advanced mini-invasive surgery techniques. It is a procedure performed by using a catheter to deliver a system called Transcatheter Heart Valve, which is an artificial valve designed for the purpose of being inserted into the human heart and take over both the place and the functions of the old diseased one. The THV consists of a metal stent that holds the device in its intended position, and valve leaflets, usually made out of bovine pericardium, to correctly direct the blood flow from the heart to the peripheral vessels and prevent reflowing.

In the current state of the art of this procedure, there mainly are two ways to gain access to the patient’s heart with the catheter: transfemoral and transapical. In both of those approaches, as the heart is not opened to expose the aortic valve, fluoroscopy (X-rays) and transesophageal echocardiography (ultrasound) are used to visualize the heart and the catheter and to guide the whole process, from insertion of the catheter through correct placement of the THV. This can take up to 45 minutes, but since the surgeon has to cannulate the guide-wire of the catheter into the small opening of the valve, higher time windows can easily be required.

This procedure is a quite recent breakthrough in cardiovascular surgery, and studies on the mortality and complications insurgence after this type of surgery are still being conducted. One year after T.A.V.I., the rate of deaths from any cause was of 30.7% and the rate of composite end point of death from any cause or repeat hospitalization was 42.5%. Those can be considered very good results compared with respective standard therapy percentages, that are 50.7% and 71.6%. On the other side though, T.A.V.I. patients have shown higher incidence of major strokes (5.0% vs. 1.1%) and major vascular complications (16.2% vs. 1.1%).

It is then clear that even if T.A.V.I. is a real game changer in the cardiovascular surgical panorama, and its safety has been qualified as acceptable to be regularly used in the clinical procedure practice, there is still large room for improvements in this regard and research is still ongoing.

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The aim of this work is to add a completely new instrument to the equipment for the T.A.V.I. procedure. This instrument will be composed as it follows: a miniaturized sensor system, including a hot wire anemometer, will be mounted on the tip of a standard non-sensorized catheter commonly used in clinical T.A.V.I. procedures; said catheter will also mount an electro-magnetic tracking sensor, so that its position can be tracked in real time and therefore used to localize the blood flow measurements incoming from the anemometer. The merged information coming through the flow and electro-magnetic tracking sensors will have to be delivered in a user-friendly manner so that the surgeon can work freely with the catheter while looking at a screen showing said information.

The core of this information, alongside with the ultimate aim of the merging and representation, will be to underline the difference between the blood flow magnitude at the center of a vessel with respect to its borders, in front of the aortic valve: according to Bernoulli’s Law (which is applicable to blood, even if it is a non-Newtonian fluid but can be considered as one on first approximation), this magnitude will reach its maximum in front of the opening and progressively decrease, until eventually becoming null, when the sensor is on the side.

The approximation of measuring only one component of the blood flow velocity is acceptable because the objective of this work only requires to distinguish between a “high” and a “low” flow and doesn’t need exact blood flow values. This is also an advantage with regard to the fact that different patients may show substantial differences in blood flow velocity values, and those could be very hard to refer to a standard.

The modality with which these objectives will be pursued is the following: at the beginning, all efforts will be put in building the test catheters and integrating the blood flow measurement system (already developed by Medyria) with the CASCADE platform software. The blood flow will have to be correctly and reliably transferred from Medyria’s system onto the machine and the software via USB connection, then filtered and made available in real time to both the other parts of the software itself and the surgeon for consultation. The blood flow information will have to be delivered in two different forms. The first form is a 2D graph displaying the Flow VS Time, that is supposed to give the surgeon a simple visual feedback on the position of the catheter in real time. Since the

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blood flow is higher near the opening of the aortic valve (tightened by the AVS), a few minutes scanning will identify a “maximum” and “minimum” values for the flow values in that patient: therefore, when the flow in the graph is close to its maximum value, the catheter will be in front of the valve opening and the surgeon will proceed with the cannulation of the guide-wire. Other than the visualization of this type of information, the graph will also need to have a line drawn at the maximum value measured during the scanning of the environment.

The second modality of delivering the flow information is a 3D colormap of the flow. The catheter will need to be equipped with both a flow sensor and a tracking system, so that the software will be able to draw a plane representing the aortic cross-section and update it in real time by combining the flow and position informations. This instrument will be usable by the surgeon to scan the environment in the represented cross-section and draw a map of the flow distribution across it. This knowledge will be useful to the surgeon that will now have a visual feedback on where the catheter’s tip is, and be able to cannulate in a faster and safer way, due both to reduced probability of hitting the soft tissue of the valve with the tip and causing detachment of calcium plaques responsible for the risk of suffering strokes in T.A.V.I. patients, and reduced use of contrast mediums and X-radiations (introduced by the use of fluoroscopy).

Once the whole implementation will be finished, the second part of the work will start with the assembling of appropriate experimental setups to test the resulting system in order to evaluate its performances, correct flaws and improve the overall user experience, as the whole catheter-software complex is intended to be used in a highly stressful environment, as a general anesthesia delivered surgery often is even for the most experienced surgeon. This will also allow running two different kinds of planned validations: an internal and an external one.

The internal validation will consist of prolonged tests in which the author itself will try to maneuver the catheter inside a phantom vessel filled with water, scan the environment and obtain useful images and insights on how well the system will perform in the actual clinical conditions.

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The external validation will be conducted from actual surgeons who perform T.A.V.I. in their everyday working life. Another experimental setup with a phantom vessel filled with water will be built and the surgeons will try the system as it is meant to be used, by looking at the graphs while maneuvering the catheter. After that, they will be asked for an opinion of the overall experience and on the usability of the whole complex during real surgeries. All of those objectives have been carried out within the C.A.S.C.A.D.E. European research project, and using the C.A.S.C.A.D.E. Software Platform, for the majority of the time at the Medyria AG headquarters and laboratories, in Winterthur (Switzerland), and in minor measure at the PMA Division of Mechanical Engineering in the Katholieke Universiteit of Leuven (Belgium), at the Zürcher Hochschule für Angewandte Wissenschaften (ZHAW) in Winterthur, and at the King’s College in London. A brief description of all the materials that have been used follows.

The entire Medyria’s patented system, the main physical component constituting the final result of this work, is made of two different sub-components: a standard vascular catheter commonly used for T.A.V.I. procedures and mounted with Medyria’s patented sensor system, duly isolating the blood from the small currents via epoxy glue, and the board, specifically designed by Medyria R&D section to condition the sensors and correctly read the incoming information. As for the tracking system, a NDI Aurora Tracking Systema (from now on: Aurora) has been used, other than for its excellent technical specifications, for the fact that its functions had already been implemented in the Software Platform and would be thus easier to exploit. Other useful pieces of equipment that have been employed mostly in the experimental set-ups to test the system, are the Medyria’s Peristaltic Pump, which is a prototype capable of mimicking the non-continuous pumping capabilities of the human heart, and Materialise (another component of the C.A.S.C.A.D.E. research group, dealing in 3D printed parts) rigid and deformable, anatomically shaped, aortic arch mockups.

On the software side, the need for a modular, scalable and reliable platform was well addressed by the C.A.S.C.A.D.E. self-written software (whose first lines date back to 2013, with the launch of the research project itself). This software is based on the ROS (Robot Operating System) technology, and as such is made up by a lot of different “components”, or “nodes”, that can be activated separately or all at once depending on the need, and each

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component/node is referring to a different piece of technology that the platform integrates. For the purposes of this work, for instance, the “Aurora Tracking node” (named CathEMTchain in the software) was frequently held active to allow the exchange of information between the software and the Aurora tracking system, and the “Flowsensing node” was substantially modified manually in order to successfully integrate Medyria’s technology with the software.

As earlier stated, the entire line of work has been divided into three different phases. For the first phase, the one regarding hardware prototyping, two standard vascular catheters have been used. The first step was to glue the sensor on a polyhimmide bendable plaque, since the sensor itself is only a few microns thin and can be easily broken down. This was done with a bi-component conductive glue and a microscope, then the polyhimmide plaque-sensor complex had to be put in the oven at 150°C for one hour in order for the glue to cure. The resulting sensor was then cut and glued to the catheter, alongside with a tracking sensor (already coming with a wire from factory), with a bi-component epoxy glue, and put in the oven at 80°C for three hours to cure. After electrically isolating the sensors with another layer of epoxy glue around them, five copper wires were soldered to each pin of the flow sensor: ground1, ground2, flowsensor1, flowsensor2, temperature. The six wires were then rolled around all the length of the catheter and fixed to it with a layer of heat shrinking plastic tube. Soldering the connector to the free end of the wires was the final step in the production chain of the prototype catheters.

The second phase of the work was primarily aimed at developing a piece of code that could integrate the prototyped catheters in the CASCADE platform, with the use of three new classes that interact together to provide the functionalities of the flowsensing node (addressing to the problem of the base-level communication between the hardware and the software). The flowsensing node’s template was previously implemented by ZHAW and needed to be coded according to the given tasks.

In the third phase, the gathered flow information was merged with the Aurora positioning information and visually synthesized to the user with two different types of graphs: the Flow VS Time and the Flow Colormap visualizers. The Flow VS Time was planned to be a very simple and fast visualizer, able to give to the surgeon a quick overview of the environment in which the catheter is immersed. A 2D graph, with the software-filtered

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flow signal on the y-axis, over the time on the x-axis, able to present the evolution of such signal. A surgeon performing T.A.V.I. can be interested in this approach because the blood flow reaches its peak right in front of the calcified valve: this means that whenever the flow signal reaches its maximum, the surgeon can deduct the catheter is in place and the cannulation phase can now be started. To cope with the high rate of inter-subject variability of blood flow, that can also depend on a wide array of external and internal factors, two useful features have been implemented. The first one is a graphic visualization of the flow maximum value over time, and a button to reset it to 0. This way the user is provided with a visual reference to understand, after a couple of minutes of environment scanning, what is the maximum blood flow under present conditions. The second feature is the possibility to set the displayed blood flow range on the y-axis, via two text boxes, one for the minimum and one for the maximum values displayed.

The second type of visualizer implemented, is the Flow Colormap. This displaying option is somewhat more complicated, but was expected to give more accurate results even if it requires a longer environmental scanning of the proximity of the valve. The Flow Colormap is designed to display a cross-section of the aorta, chosen by the user. When the catheter tip is in that cross-section, the flow data is acquired and then displayed (with a color corresponding to a predefined color scale) in real-time, in the proper location of the Colormap, reflecting the actual position of the catheter tip in the aorta. The objective of this approach is, after four to five minutes of scanning, to obtain a fully painted Colormap in which higher flow values are condensed in a center, which is the center of the valve. Then, since the actual catheter position is also displayed on the Colormap, the surgeon can easily move it in place and start the cannulation phase in all safety. Unlike the Flow VS Time graph, it is not possible to display incoming data from more than one sensor at a time (Medyria’s Flowsensing System comes with two independent flow sensors), and thus the choice of implementing a sensor-selector. Additionally, considerations made for the first visualizer about blood flow high variability still apply, and a similar displayed range-selector, alongside with a reset button for restarting the scanning are to be implemented to address that particular need.

The results of this implementation have been living up to the expectations. During internal validation, in which several trials were made to test the entire system (catheter, mockup,

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pump, software) has been detected a significant difference in the flow signal of the Flow VS Time visualizer between when the catheter tip was near the center of the valve, when it was near the side wall, and when it was moving from the side of the wall towards the center again.

This apart from living up well with the expectations, is also an important improvement comparing to the present clinical practice for T.A.V.I. surgeries, in which the surgeon has only got his own manual sensitivity to find the center of the calcified valve: the distinction between center, side and approaching is very clear once the maximum value has been identified and seems to be a very immediate solution that can provide the surgeon with a useful and reliable instrument that dramatically augments his perception of the environment he is operating within.

For what it is concerned with the Flow Colormap, internal validation has shown that a brief 4 minutes scan of the environment could help immensely when it comes to crossing the valve: once a satisfying image has been painted, the surgeon should be able to cross safely by positioning the black square (representing the catheter tip) in correspondence of the red part of the image, and then push the catheter inside the valve.

However, this approach has shown some limitations. During the experiments it has become clear that the Flow VS Time approach is more immediate and easy to understand and use by a standard user, even if the Flow Colormap approach is more good-looking and also rather intuitive, other than being more polished in a technological way of speaking. The real limitations though, the one that bears more weight from a clinical and practical point of view, is that the image is showing the flow mapped in a parallelepiped of a certain thickness, that could also be some millimeters far away from the real position of the valve. This could make the image itself less reliable compared to the first considerations on the matter, but more importantly, to the Flow VS Time approach. There is some dependence on the plane used for the displaying, and therefore also on how the points used for building the plane have been probed: risks due to touching the valve and releasing calcium pieces into the heart may be reduced, but still exists and cannot be considered completely eliminated.

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As for the external validation, during one of the several CASCADE Integration Meetings, the partners of the project decided to invite an advisory board constituted by 5 cardiac surgeons to evaluate separately all the components and give their opinion on how to use and improve the original work that was being developed. The system had never been used before, and thus the opinion of the advisory board has been an invaluable tool for refining and further developing certain aspects of this original research.

The feedback received for the Flow VS Time approach has been very good: all the surgeons agreed upon the great help this implementation could give in the stressful environment with high psychological pressure that every surgery, especially heart-related surgeries, can bring. In this case, the external validation coincides with the internal one whilst having an actually much greater value: it is not unusual for new technologies to be entirely developed by teams of experts, but later found to be too complicated to use for a typical not-technically-trained user or too expensive for a hospital to justify its use.

When the surgeons were asked to give an opinion about the Flow Colormap, their answers have been mixed, and some useful considerations arose.

After some discussions, this second and more technologically evolved approach has still been evaluated a good work and very useful as well, though too complicated for clinical use. Even if all surgeons seemed content of being updated on the development of this new technology, asserting that could display a very overwelming potential in the near future, they were not willing to modify their habits and ways to operate to adapt to it. This makes the second validation completely corresponding the the first internal one.

For what it is concerned with the limitations of this work, the first and most important one lies probably in the whole system being widely tested and evaluated, like it usually happens with this kind of devices, only in conditions that are quite far from its actual application. Since it is very difficult for a newly designed device to be approved for in vivo tests though, it could be advisable (if not required) to at least recalibrate and test the system with the same setup containing blood instead of water, or use the deformable mockup to evaluate the influence of the tissue deformation due to the blood pumping in all tests. At the present time there are still a few settings in the program that could require the surgeon to stop the procedure and interact with the computer to adjust them. For instance,

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the range of shown blood flow velocity in the visualizers has now got general adjustable borders; but since the physiologic range for the flow velocity of the patient is not known a-priori, it should be adjusted during the procedure. Automatic adjustment based on the last few velocity values could be a partial solution, but still an issue if the catheter remains still for some seconds.

Another limitation is posed by the side branches that have to be passed before starting the cannulation procedure. When a side branch is passed, depending on where the sensor is facing, there could be spikes in the flow signals giving false informations on the catheter’s position. Extending the EM tracking sensing usage to the positioning in the entire procedure (and not only during cannulation phase), improving side branch avoidance, would surely make the operation a lot faster.

Lastly, there is a physical limitation that necessarily has to be taken into account. Due to geometric reasons, a short displacement exists between the sensor itself and the catheter’s axis. Therefore the measured signal is not precisely referred to the catheter’s tip, but more to one of its sides; more importantly though, this error can dramatically increase depending on whether the catheter is subject to rotational movements around its axis or not during its maneuvering.

This can lead to two types of errors: the first, which has already been introduced, is related to the concrete possibility that incoming blood flow signals are not referring to the actual tip of the catheter, but more to its side: this could both slightly mislead evaluations upon the relative position between the catheter tip and the center of the valve, and yield lower flow signals if the sensorized-side of the catheter is not directly facing the valve. The second type of error is caused by rotational movements of the catheter around its axis; this can reasonably happen during a scanning, and if does, the measured signal could be higher than its actual value due to an increase of the relative velocity between the catheter and the blood flowing. Those effects can be true for the EM sensor as well, but could be at least partially avoided by defining an internal “construction protocol” with exact spots for gluing the sensors. This way the errors are expected to be less randomly dispersed, more controllable, and easier to be taken into account.

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1. Introduction – page 15

1. Introduction

This initial chapter serves as an introduction to all the topics that will be addressed to during the whole thesis work. A first section describes the anatomy of the heart, the aorta and the aortic valve, to focus thereafter on a specific pathology of this complex, the aortic stenosis, and move onto the description of the newly introduced Transcatheter Aortic Valve Implantation (T.A.V.I.) procedure and some of its entailed problematics and research cues.

Anatomy: the heart

The heart is a muscular organ (whose structure and most important vessels are shown in Fig. 1) in humans and other animals, which pumps blood through the blood vessels of the circulatory system [1]. Blood provides the body with oxygen and nutrients, and also assists in the removal of metabolic wastes [2]. The heart is located in the middle compartment of the mediastinum in the chest [3].

In humans, other mammals and birds the heart is divided into four chambers, shown in Fig. 1: upper left and right atria; and lower left and right ventricles. Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. Fish in contrast have two chambers, an atrium and a ventricle, while reptiles have three chambers. In a healthy heart blood flows one way through the heart due to heart valves, which prevent backflow [3]. The heart is enclosed in a protective sac, the pericardium, which also contains a small amount of fluid. The wall of the heart is made up of three layers: epicardium, myocardium, and endocardium [7].

The heart pumps blood through both systemic and pulmonary circulatory systems. Blood low in oxygen from the systemic circulation enters the right atrium from the superior and inferior vena cavae and passes to the right ventricle. It is then pumped into the pulmonary

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circulation, through the lungs where it receives oxygen and gives off carbon dioxide [2]. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the aorta to the systemic circulation−where the oxygen is used and metabolized to carbon dioxide. In addition the blood carries nutrients from the liver and gastrointestinal tract to various organs of the body, while transporting waste to the liver and kidneys. In the healthy organism each heartbeat causes the right ventricle to pump the same amount of blood into the respiratory organ as the left ventricle pumps to the body. Veins transport blood to the heart and carry deoxygenated blood - except for the pulmonary and portal veins. Arteries transport blood away from the heart, and apart from the pulmonary artery hold oxygenated blood. Their increased distance from the heart cause veins to have lower pressures than arteries [3]. The heart contracts at a resting rate close to 72 beats per minute [2]. Exercise temporarily increases the rate, but lowers resting heart rate in the long term, and is good for heart health [8].

The heart is situated in the middle of the mediastinum behind the breastbone in the chest, at the level of thoracic vertebrae T5-T8. The largest part of the heart is usually slightly offset to the left (though occasionally it may be offset to the right) and is felt to be on the left because the left heart is stronger, since it pumps to all body parts. The left lung in turn is smaller than the right lung because it has to accommodate the heart. It is supplied by the coronary circulation and is enclosed in a double-membraned sac–the pericardium. This attaches to the mediastinum, providing anchorage for the heart [13]. The back surface of the heart lies near to the vertebral column, and the front surface sits deep to the sternum and costal cartilages [7]. Two of the great veins – the venae cavae, and the great arteries, the aorta and pulmonary artery, are attached to the upper part of the heart, called the base, which is located at the level of the third costal cartilage [7]. The aorta, amongst these, poses the highest interest for the present work.

Cardio Vascular Diseases (CVD) are the most common cause of death globally as of 2008, accounting for 30% of deaths [9][10]. Of these more than three quarters follow coronary artery disease and stroke [9]. Risk factors include: smoking, being overweight, little exercise, high cholesterol, high blood pressure, and poorly controlled diabetes, among others [11]. Diagnosis of CVD is often done by listening to the heart-sounds with a stethoscope, ECG or by ultrasound [3].

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Fig. 1: Representation of the human heart, showing an overview of its anatomy, including incoming and departing blood vessels.. Licensed under CC BY-SA 3.0

Anatomy: the aorta

The aorta is the main artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes oxygenated blood to all parts of the body through the systemic circulation [1]. In anatomical sources, the aorta is usually divided into sections [2][3].

One way of classifying a part of the aorta is by anatomical compartment, where the thoracic aorta (or thoracic portion of the aorta) runs from the heart to the diaphragm. The aorta then continues downward as the abdominal aorta (or abdominal portion of the aorta) diaphragm to the aortic bifurcation. Another system divides the aorta with respect to its course and the direction of blood flow. In this system, the aorta starts as the ascending aorta then travels superiorly from the heart and then makes a hairpin turn known as the aortic arch. Following the aortic arch, the aorta then travels inferiorly as the descending aorta. The descending aorta has two parts. The aorta begins to descend in the thoracic cavity, and consequently is known as the thoracic aorta. After the aorta passes through the diaphragm, it is known as the abdominal aorta. The aorta ends by dividing into two major blood vessels, the common iliac arteries and a smaller midline vessel, the median sacral artery [4].

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The thoracic portion of the aorta starts with the aortic valve, whose position in the heart’s anatomy is shown in Fig. 2 and is at the connection between the left ventricule and the aorta itself. The aortic valve is one of the two semilunar valves of the heart, and normally has three cusps (left, right and posterior cusps) or leaflets, although in 1-2% of the population it is found to congenitally have only two leaflets [1].

During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle rises above the pressure in the aorta, the aortic valve opens, allowing blood to exit the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle rapidly drops. When the pressure in the left ventricle decreases, the aortic pressure forces the aortic valve to close. This means that alongside with all the other heart valves, shown in Fig. 2, the aortic one is of great importance for the heart to carry out its blood-pumping role, and any reduction in its functionality poses a serious threat to an individual’s life throughout the insurgence of strokes and cardiac failure.

Fig. 2: An overview of the four heart valves: Tricuspid, Bicuspid, Pulmonary and Aortic valves. From "2011 Heart Valves" by OpenStax College - Anatomy & Physiology, Connexions Web site. Licensed

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Disease: AVS and valve calcification

Aortic stenosis (AS), or Aortic Valve Stenosis (AVS), is the narrowing of the exit of the left ventricle, such that cardiovascular problems result. This may occur at the aortic valve as well as above and below this level, and it is a condition that tends to get worse over time. Symptoms often come on gradually with a decreased ability to exercise often occurring first. If heart failure, loss of consciousness, or heart related chest pain occurs due to AS the outcomes are worse. Loss of consciousness typically occurs with standing or exercise. Signs of heart failure include shortness of breath especially with lying down, at night, and with exercise as well as swelling of the legs. Thickening of the valve without narrowing is known as aortic sclerosis [1].

Causes include being born with a bicuspid aortic valve and rheumatic fever. A bicuspid aortic valve affects about one to two percent of the population while rheumatic heart disease mostly occurring in the developing world. A normal valve, however, may also harden over the decades. Risk factors are similar to those of coronary artery disease and include smoking, high blood pressure, high cholesterol, diabetes, and male sex. The aortic valve usually has three leaflets and is located between the left ventricle of the heart and the aorta. AS typically results in a heart murmur, and its severity can be divided into mild, moderate, severe, and very severe based on ultrasound of the heart findings [1].

Normal aortic valve is a structure consisting of several layers: valvular endothelial cells at blood-contacting surface, valvular interstitial cells, and valvular extracellular matrix including collagen, elastin, and amorphous extracellular matrix with glycosaminoglycans. Valvular interstitial cells play a crucial role in valve function. They synthesize extracellular matrix and regulate matrix enzymes, which mediate remodeling of collagen and other matrix components. Degenerative aortic valve disease (recognized as the primary cause for AVS [3]) is characterized by aortic valve leaflet thickening and calcification with normal function at the beginning. It is called aortic valve sclerosis. Progression of degenerative process is characterized by formation of calcium nodules, including the formation of actual bone and new blood vessels. In end-stage disease, large nodular calcific masses are observed in aortic leaflets. Risk factors and mediators leading to calcific AS are similar for atherosclerosis (older age, male sex, hypercholesterolemia, hypertension, smoking, and diabetes) [4].

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The following table (Tab. 1) shows the classifications of aortic stenosis, ranging from mild to very severe:

Severity of Aortic Stenosis [12]

Degree Aortic Valve opening area [𝒄𝒎𝟐]

Mild > 1.5

Moderate 1.0 – 1.5

Severe < 1.0

Very Severe < 0.6

Tab. 1: Suggested classification of Aortic Stenosis Severity, according to a study of Ricardo Zalaquett, Cristóbal Camplá, et al. (2005). The severity of an aortic stenosis can range from mild to very severe,

and their relative suggested aortic valve opening area is provided.

Calcification is the accumulation of calcium salts in a body tissue. It normally occurs in the formation of bone, but calcium can be deposited abnormally in soft tissue, causing it to harden. At the aortic valve level calcification is abnormal and usually caused by mechanical stress, leading to valvular endothelial dysfunction, followed by deposition of low-density lipoprotein A and consequent inflammatory response with T-lymphocytes and macrophages, which in turn activate valvular interstitial cells resulting in their osteoblastic transformation [5-11].

Transcatheter Aortic Valve Implantation (T.A.V.I.)

The Transcatheter Aortic Valve Implantation (T.A.V.I.) or Replacement (T.A.V.R.) is a recently developed medical procedure whose primary aim is to replace a dysfunctional aortic valve with a bio-compatible prosthetic system that literally pushes away the pathologic leaflets and takes over their job of preventing blood from reflowing into the left ventricle, all carried out throughout the use of advanced mini-invasive surgery techniques. Its development has been encouraged to mitigate the mortality and morbidity associated with high-risk traditional aortic valve replacement, however with only partial success, as for now some risks remain and the T.A.V.I. procedure is exclusively reserved for high risk

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patients, whose severe medical conditions do not allow them to undergo classic open heart surgery [1].

T.A.V.I. is a procedure performed by using a system called Transcatheter Heart Valve (THV), an artificial heart valve designed to be inserted into the human heart so that it holds open and replaces the diseased aortic valve. It consists of a metal stent (made of steel or cobalt-chromium) which secures the device in its intended position inside the patient’s own valve, and valve leaflets (usually made of bovine pericardium) to direct the flow of blood out of the heart. There currently are two different ways in which a THV can be delivered, and their difference regards the way in which the access to the aortic valve is gained: transfemoral or transapical. Whether the patient is selected to undergo the transfemoral or the transapical surgery, the procedure is performed under general anesthesia. As the heart is not opened to expose the aortic valve, fluoroscopy (X-rays) and transesophageal echocardiography (ultrasound) are used to visualize the heart and the catheter, and to guide the insertion of the catheter itself. The duration of this type of surgery is normally between 30 and 45 minutes, but since the surgeon has to cannulate the guide-wire of the catheter into the small opening of the valve, higher time windows can easily be required.

The transfemoral device is designed to be implanted through the blood vessel (femoral artery) in the patient’s leg. Due to the size of the catheter (hollow tube) being placed in the artery for this approach, an evaluation of the angiograms and/or CT scans is required to ensure the patient’s blood vessels are big enough for the entire device (balloon catheter and THV). Prior to implantation, the THV is “crimped” (carefully compressed to a size that fits inside the femoral artery) using a specifically designed crimping device. The crimped THV is mounted onto a balloon delivery catheter, a special device which is used to carry the THV up to the heart and directly into the aortic valve opening. The prosthetic system is then expanded using a balloon to fit inside the old stenotic aortic valve, holding it open permanently. Once the THV is in position and the delivery system is removed from the femoral artery, the artery is closed using a special suture device designed for this purpose. After the procedure, the patient is transferred to the Coronary Care Unit (CCU).

The transapical approach is used for patients whose arteries are too small or too diseased for the transfemoral T.A.V.I.. The delivery system for this approach is designed for THV implantation through the tip (apex) of the patient’s heart, which is reached through a small

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incision made between the ribs just below the left nipple. The crimped THV and delivery system is inserted through the apex of the heart directly into the stenotic aortic valve. The prosthetic valve is then expanded using a balloon to fit across the stenotic aortic valve, holding it open permanently. After the procedure the patients is transferred to the Cardiothoracic Intensive Care Unit (CTICU).

Other than transfemoral and transapical approaches, T.A.V.I. procedure has also been delivered via other accesses such as subclavian (beneath the collar bone) or direct aortic (through a minimally invasive surgical incision into the aorta). These are not common though, and will therefore not be described in this context.

Although being a quite recent breakthrough in cardiovascular surgery (first T.A.V.I. human trial has been performed in 2002), studies on the mortality and complications insurgence after this type of surgery is being widely studied and monitored with encouraging results. At 1 year, the rate of death from any cause was 30.7% with T.A.V.I., as compared with 50.7% with standard therapy (hazard ratio with T.A.V.I., 0.55; 95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end point of death from any cause or repeat hospitalization was 42.5% with T.A.V.I. as compared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59; P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart Association class III or IV) was lower among patients who had undergone T.A.V.I. than among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days, T.A.V.I., as compared with standard therapy, was associated with a higher incidence of major strokes (5.0% vs. 1.1%, P = 0.06) and major vascular complications (16.2% vs. 1.1%, P<0.001). In the year after T.A.V.I., there was no deterioration in the functioning of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an echocardiogram [1].

But as for the post-surgery risk monitoring, also potential complication that can occur during the procedure need a deep review. As said before, it is a 30 minute long procedure that needs constant X-ray monitoring, and a massive use of C-dye for pre-operative investigation is required. It has also been demonstrated that the cannulating process itself poses serious life-threatening risks. The surface of the stenotic aortic valve in a patient with calcific degenerative disease may be layered with atheroma, calcific deposits, or secondary thrombus [2]. Anecdotal or retrospective accounts exist of calcific or platelet

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emboli to the brain and kidneys following cardiac catheterization [3]. A prospective study conducted in 2003 [4] showed a 3% incidence of clinical stroke and a 22% incidence of new defects on magnetic resonance imaging after retrograde left ventricular catheterization for aortic stenosis. By contrast, there were no strokes or defects on magnetic resonance imaging in patients who only had coronary angiography. Other potential complications of cardiac catheterization include pulmonary edema, cardiogenic shock and death, cardiac arrhythmia, and ventricular perforation. The risk of a potentially fatal complication is about 7% - double that of coronary angiography alone [4-5].

It is then clear that even if T.A.V.I. is a real game changer in the cardiovascular surgical panorama, and its safety has been qualified as acceptable to be regularly used in the clinical procedure practice, there is still large room for improvements in this regard and research is still ongoing.

Introduction References

Heart

[1]: Taber, Clarence Wilbur; Venes, Donald (2009). Taber's cyclopedic medical dictionary. F a Davis Co. pp. 1018–23. ISBN 0-8036-1559-0.

[2]: Hall, John (2011). Guyton and Hall textbook of medical physiology (12th ed. ed.). Philadelphia, Pa.: Saunders/Elsevier. p. 157. ISBN 978-1-4160-4574-8.

[3]: Keith L. Moore; Arthur F. Dalley; Anne M. R. Agur. "1".Clinically Oriented Anatomy. Wolters Kluwel Health/Lippincott Williams & Wilkins. pp. 127–173. ISBN 978-1-60547-652-0.

[7]: Betts, J. Gordon (2013). Anatomy & physiology. pp. 787–846. ISBN 1938168135. [8]: Hall, John (2011). "84". Guyton and Hall textbook of medical physiology (12th ed. ed.). Philadelphia, Pa.: Saunders/Elsevier. pp. 1039–1041. ISBN 978-1-4160-4574-8. [9]: "Cardiovascular diseases (CVDs) Fact sheet N 317 March 2013". WHO. World Health Organization.

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[10]: Longo, Dan; Fauci, Anthony; Kasper, Dennis; Hauser, Stephen; Jameson, J.; Loscalzo, Joseph (August 11, 2011).Harrison's Principles of Internal Medicine (18 ed.). McGraw-Hill Professional. p. 1811. ISBN 9780071748896.

[11]: Graham, I; Atar, D; Borch-Johnsen, K; Boysen, G; Burell, G; Cifkova, R; Dallongeville, J; De Backer, G; Ebrahim, S; Gjelsvik, B; Herrmann-Lingen, C; Hoes, A; Humphries, S; Knapton, M; Perk, J; Priori, SG; Pyorala, K; Reiner, Z; Ruilope, L; Sans-Menendez, S; Scholte op Reimer, W; Weissberg, P; Wood, D; Yarnell, J; Zamorano, JL; Walma, E; Fitzgerald, T; Cooney, MT; Dudina, A; European Society of Cardiology (ESC) Committee for Practice Guidelines, (CPG) (Oct 2007). "European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts).". European heart journal 28 (19): 2375–414. doi:10.1093/eurheartj/ehm316. PMID 17726041.

[13]: Dorland's (2012). Dorland's Illustrated Medical Dictionary (32nd ed.). Elsevier. p. 1461. ISBN 978-1-4160-6257-8.

Aorta

[1]: Maton, Anthea; Jean Hopkins; Charles William McLaughlin; Susan Johnson; Maryanna Quon Warner; David LaHart; Jill D. Wright (1995). Human Biology Health. Englewood Cliffs, New Jersey: Prentice Hall. ISBN 0-13-981176-1.

[2]: Tortora, Gerard J: "Principles of Human W. & Karen A. Koos: Human Anatomy, second edition, page 479. Wm. C. Brown Publishing, 1994. (ISBN 0-697-12252-2).

[3]: De Graaff, Van: "Human Anatomy, fifth edition", pages 548-549. WCB McGraw-Hill, 1998. (ISBN 0-697-28413-1).

[4]: Putz, R.; Pabst, R., eds. (2006). Atlas van de menselijke anatomie (Translated from German (Atlas der Anatomie des Menschen)) (in Dutch) (3rd ed.). Bohn Stafleu van Loghum. ISBN 90-313-4712-4.

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1. Introduction – page 25 Aortic Valve [1]: http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/AboutCongenitalH eartDefects/Aortic-Valve-Stenosis-AVS_UCM_307020_Article.jsp Aortic Stenosis

[1]: Czarny, MJ; Resar, JR (2014). "Diagnosis and management of valvular aortic stenosis.". Clinical Medicine Insights. Cardiology 8 (Suppl 1): 15–24. doi:10.4137/CMC.S15716. PMID 25368539.

[2]: Martin B. Leon, M.D., Craig R. Smith, M.D., Michael Mack, M.D., D. Craig Miller, M.D., Jeffrey W. Moses, M.D., Lars G. Svensson, M.D., Ph.D., E. Murat Tuzcu, M.D., John G. Webb, M.D., Gregory P. Fontana, M.D., Raj R. Makkar, M.D., David L. Brown, M.D., Peter C. Block, M.D., Robert A. Guyton, M.D., Augusto D. Pichard, M.D., Joseph E. Bavaria, M.D., Howard C. Herrmann, M.D., Pamela S. Douglas, M.D., John L. Petersen, M.D., Jodi J. Akin, M.S., William N. Anderson, Ph.D., Duolao Wang, Ph.D., and Stuart Pocock, Ph.D., “Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery”, The New England Journal of Medicine, 21 October 2010

[3] : Bernard Iunga, Gabriel Baronb, Eric G, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease Eur Heart J. 2003; 24: 1231-1243.

[4]: Rajamannan NM, Evans FJ, Aikawa E, et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the national heart and lung and blood institute aortic stenosis working group executive summary: calcific aortic valve disease - 2011 update. Circulation. 2011; 124: 1783-1791.

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[5]: Kaden JJ, Dempfle CE, Grobholz R, et al. Interleukin-1 beta promotes matrix metalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003; 170: 205-211.

[6]: Helske S, Kupari M, Lindstedt KA, Kovanen PT. Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol. 2007; 18: 483-491.

[7]: Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009; 29: 162-168.

[8]: Akat K, Borggrefe M, Kaden JJ. Aortic valve calcification: basic science to clinical practice. Heart. 2009; 95: 616-623.

[9]: Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res. 2011; 108: 1392-1412.

[10]: Kaden JJ, Kiliç R, Sarikoç A, et al. Tumor necrosis factor alpha promotes an osteoblast-like phenotype in human aortic valve myofibroblasts: a potential regulatory mechanism of valvular calcification. Int J Mol Med. 2005; 16: 869-872.

[11]: Winchester R, Wiesendanger M, O’Brien W, et al. Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. J Immunol. 2011; 187: 1006-1014.

[12]: Ricardo Zalaquett, Cristóbal Camplá, et al. (2005). "Cirugía reparadora de la válvula aórtica bicúspide insuficiente". Rev Méd Chile, 133(3): pp. 279-86. ISSN 0034-9887

T.A.V.I.

[1]: Martin B. Leon, M.D., Craig R. Smith, M.D., Michael Mack, M.D., D. Craig Miller, M.D., Jeffrey W. Moses, M.D., Lars G. Svensson, M.D., Ph.D., E. Murat Tuzcu, M.D., John G. Webb, M.D., Gregory P. Fontana, M.D., Raj R. Makkar, M.D., David L. Brown, M.D., Peter C. Block, M.D., Robert A. Guyton, M.D., Augusto D. Pichard, M.D., Joseph E. Bavaria, M.D., Howard C. Herrmann, M.D., Pamela S. Douglas, M.D., John L. Petersen, M.D., Jodi J. Akin, M.S., William N. Anderson, Ph.D., Duolao Wang, Ph.D., and Stuart Pocock, Ph.D., “Transcatheter Aortic-Valve Implantation for Aortic Stenosis in

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Patients Who Cannot Undergo Surgery”, The New England Journal of Medicine, 21 October 2010.

[2]: Otto CM, Kuusisto J, Reichanbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis: Histological and histochemical studies. Circulation 1994;90:844-853.

[3]: Bartsch B, Haase KK, Voelker W, et al. Risk of invasive diagnosis with retrograde catheterization of the left ventricle in patients with acquired aortic stenosis. Z Kardiol 1999;88:255-260.

[4]: Omran H, Schmidt H, Hackenbroch M, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: A prospective, randomised study. Lancet 2003;361:1241-1246.

[5]: Folland ED, Oprian C, Giacomini J, et al. Complications of cardiac catheterization and angiography in patients with valvular heart disease: VA cooperative study on valvular heart disease. Cathet Cardiovasc Diagn 1989;17:15-21.

[6]: Roger VL, Tajik AJ, Reeder GS, et al. Effect of Doppler echocardiography on utilization of hemodynamic cardiac catheterization in the preoperative evaluation of aortic stenosis. Mayo Clin Proc 1996;71:141-149.

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2. Objectives – page 28

2. Objectives

This chapter is divided into three subsections: Specific Objectives, CASCADE Objectives and Project Workframe. The Specific Objectives section will offer a full formal presentation of the objectives specific of this work, highlighting its original contribution, alongside with a quick insight on the physics behind the working principle of the developed system.

The need of contextualizing the working environment is addressed to in the next two subsections, CASCADE Objectives and Project Workframe, with reference to the European Commission funded CASCADE Project and its long-term objectives, the formation of the CASCADE Consortium and how this research program is inserted in the state of the art panorama of minimally invasive surgical catheterization.

Specific Objectives

The aim this work intends to achieve is to add a completely new instrument to the equipment for the T.A.V.I. procedure. The tasks required to reach this objective have been carried out almost entirely at Medyria’s R&D department in Winterthur (Switzerland), and in minor measure at PMA Division of Mechanical Engineering in the Katholieke Universiteit of Leuven (Belgium), at the Zürcher Hochschule für Angewandte Wissenschaften (ZHAW) in Winterthur, and at the King’s College in London.

The system that this work intends to build, integrate and test is composed as it follows: a miniaturized sensor system, including a hot wire anemometer, will be mounted on the tip of a standard non-sensorized catheter commonly used in clinical T.A.V.I. procedures. The catheter will also mount an electro-magnetic tracking sensor, so that its position can be tracked in real time and used to localize the blood flow measurements.

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Hot wire anemometers use a very fine wire (on the order of several micrometers) electrically heated up to some temperature above the ambient. A fluid flowing past the wire has a cooling effect on the wire. As the electrical resistance of most metals is dependent upon the temperature of the metal (tungstenis a popular choice for hot-wires), a relationship can be obtained between the resistance of the wire and the flow speed.

Hot-wire anemometers, while extremely delicate, feature extremely high frequency-response and fine spatial resolution compared to other measurement methods, and as such are almost universally employed for the detailed study of turbulent flows, or any flow in which rapid velocity fluctuations are of interest.

An electrical current 𝐼 flows in a platinum wire of resistance 𝑅 and dissipates for Joule effect a power 𝑃 = 𝐼2𝑅 (“self-heating”). Once immersed in a fluid, the wire cools down by convection and its resistance decreases. The heat flow from wire to fluid is proportional to the thermal exchange area A, to the difference of temperature between wire (w) and fluid (f) and to convection coefficient h (in turn depending on wire dimensions) and depends on density, viscosity, specific heat and thermal conductivity of the fluid. The wire, heated by the flowing electrical current, is in thermal equilibrium with the surrounding environment and the input electrical power is equal to the power lost by thermal convection (1):

𝐼2_𝑅

𝑤 = ℎ ∙ 𝐴𝑤 (𝑇𝑤− 𝑇𝑓)

Electrical resistance of the wire (2): 𝑅𝑤 = 𝑅𝑟𝑒𝑓 [1 + 𝛼 (𝑇𝑤− 𝑇𝑟𝑒𝑓)]

Thermal transfer coefficient ℎ is function of fluid velocity 𝑣_𝑓 accordingly to the King’s Law (3):

ℎ = 𝑎 + 𝑏 ∙ 𝑣_𝑓𝑐

From relationships (1), (2) and (3) it follows:

𝑎 + 𝑏 ∙ 𝑣_𝑓𝑐 = 𝐼

2_𝑅

𝑟𝑒𝑓 [1 + 𝛼 (𝑇𝑤− 𝑇𝑟𝑒𝑓)]

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2. Objectives – page 30 → 𝑣_𝑓 = { [𝐼2𝑅𝑟𝑒𝑓 [1 + 𝛼 (𝑇𝑤 − 𝑇𝑟𝑒𝑓)] 𝐴_𝑤(𝑇_𝑤− 𝑇_𝑓) − 𝑎] 𝑏 } 1 𝑐

Therefore, a sensor of this type can be used to measure the blood flow velocity. In physics, fluid dynamics is a sub-discipline of fluid mechanics that deals with fluid flow, therefore studying the behavior of fluids (liquids and gases) when put in motion. Fluid dynamics offers a systematic structure (which underlies these practical disciplines) that embraces empirical and semi-empirical laws derived from flow measurement and used to solve practical problems. The solution to a fluid dynamics problem typically involves calculating as functions of space and time various properties of the fluid, such as temperature, pressure, density, and flow velocity, the one property which is the object of interest of this thesis work.

The flow velocity is often expressed in cm/s. This value is inversely related to the total cross-sectional area of the blood vessel and also differs per cross-section, because in normal condition the blood flow haslaminar characteristics. For this reason the blood flow velocity is the fastest in the middle of the vessel and slowest at the vessel wall. Blood velocities inarteries are higher during systole than during diastole; in most cases the mean velocity is used.

The flow velocity u is a vector field u = u(𝑥, 𝑡) which gives the velocity of an element of fluid at position 𝑥 and time 𝑡. The flow speed 𝑞 is the length of the flow velocity vector 𝑞 = ‖u‖ and is a scalar field. Therefore, the need arises to distinguish between flow velocity and flow speed when it comes to measure a specific value and give it an interpretation: since a vector needs a module (length) and an orientation to be completely defined, the catheter will measure a flow speed rather than a flow velocity. The flow sensor that will be used is made up by two perpendicular hot wire anemometers; the system though is still being investigated by Medyria, that holds all patents for it, and measuring with both anemometers at the same time is not possible at the present time. It will be possible, as a future development step, to integrate information from both sensors and obtain the orientation and exact length of the blood flow velocity vector. For the purposes

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of the present work, only one sensor has been used and therefore the measured flow will be relative.

Why measurements of the flow? The answer is in a simple physics principle: the Bernoulli’s Principle. In fluid dynamics, Bernoulli’s principle states that for an inviscid flow of a nonconductive fluid, an increase in the speed of the fluid occurs simultaneously with a decrease in pressure or a decrease in the fluid’s potential energy. The principle is named after Daniel Bernoulli who published it in his book Hydrodynamica in 1738.

Bernoulli's principle can be applied to various types of fluid flow, including blood, which is a non-Newtonian fluid, but can be considered a Newtonian one on first approximation [1]. Considering this, it is intuitive to understand that if a stenosis of an aortic valve produces a tightening in the cross-sectional area of the vessel, and if the heart is pumping a known amount of blood in a certain period of time, in a AVS affected patient the blood flow will be very high near the valve’s small opening, and a very low one (near to none) away from it.

This difference between center and side flow, in the proximity of a stenotic aorta has been measured via a hot wire anemometry system mounted on a standard type of vascular catheter already widely used by surgeons all over the world for T.A.V.I., and taken advantage of, in order to properly visualize flow data and help surgeons to evaluate the position of the catheter related to the stenotic valve in real time.

The approximation of measuring only one component of the blood flow velocity is acceptable because the objective of this work only requires to distinguish between a “high” and a “low” flow and doesn’t need exact blood flow values. In the first part, all efforts will be put in building the test catheters and integrating the blood flow measurement system (already developed by Medyria) with the CASCADE platform software. The blood flow will have to be correctly and reliably transferred from Medyria’s system onto the machine and the software via USB connection, then filtered and made available in real time to both the other parts of the software itself and the surgeon for consultation. The blood flow information will have to be delivered in two different forms.

The first of those is a 2D graph displaying the Flow VS Time, that is supposed to give the surgeon a simple visual feedback on the position of the catheter in real time. Since the

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blood flow is higher near the opening of the aortic valve (tightened by the AVS), a few minutes scanning will identify a “maximum” and “minimum” values for the flow: therefore, when the flow in the graph is close to its maximum value, the catheter will be in front of the valve opening and the surgeon will proceed with the cannulation of the guide-wire. Other than the visualization of this type of information, the graph will also need to have a line drawn at the maximum value measured during the scanning of the environment. The second modality of delivering the flow information is a 3D colormap of the flow. The catheter will need to be equipped with both a flow sensor and a tracking system, so that the software will be able to draw a plane representing the aortic cross-section and update it in real time by combining the flow and position informations. This instrument will be usable by the surgeon to scan the environment in the represented cross-section and draw a map of the flow distribution across it. This knowledge will be useful to the surgeon that will now have a visual feedback on where the catheter’s tip is, and be able to cannulate in a faster and safer way, due both to reduced probability of hitting the soft tissue of the valve with the tip and causing detachment of calcium plaques responsible for the risk of suffering strokes in T.A.V.I. patients, and reduced use of contrast mediums and X-radiations (introduced by the use of fluoroscopy).

Once the whole implementation will be finished, the second part of the work will start with the assembling of appropriate experimental setups to test the resulting system in order to evaluate its performances, correct flaws and improve the overall user experience, as the whole catheter-software complex is intended to be used in a highly stressful environment, as a general anesthesia delivered surgery often is even for the most experienced surgeon. This will also allow running two different kinds of planned validations: an internal and an external one.

The internal validation will consist of prolonged tests in which the author itself will try to maneuver the catheter inside a phantom vessel filled with water, scan the environment and obtain useful images and insights on how well the system will perform in the actual clinical conditions.

The external validation will be conducted from actual surgeons who perform T.A.V.I. in their everyday working life. Another experimental setup with a phantom vessel filled with

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water will be built and the surgeons will try the system as it is meant to be used, by looking at the graphs while maneuvering the catheter. After that, they will be asked for an opinion of the overall experience and on the usability of the whole complex during real surgeries. Medyria Headquarters have been the most important place in which the majority of the required tasks have been carried out: from defining a prototype building protocol through planning all the necessary steps and writing most of the code required, alongside with all the early tests on the developed system.