Comparison between abdominal aorta and common carotid artery distension waveforms. MSc thesis Karel van den Hengel December 2009 BMTE 09.

Transcription

1 Comparison between abdominal aorta and common carotid artery distension waveforms MSc thesis Karel van den Hengel December 9 BMTE 9.44

2 MSC. THESIS-MEDICAL ENGINEERING 9 Karel van den Hengel - -

3 MSC. THESIS-MEDICAL ENGINEERING 9 Comparison between abdominal aorta and common carotid artery distension waveforms Master Thesis Medical Engineering 3 November 8 11 December 9 Candidate BSc. Karel G. van den Hengel Supervisors dr. ir. Marielle Bosboom 3 dr. ing. Peter Brands prof. dr. ir. Frans van de Vosse 1 Extra committee dr. ir. Koen Reesink 3 dr. ir. Hans van Assen 1 Eindhoven University of Technology 1 Esaote Europe Maastricht Maastricht University Medical Centre 3 Karel van den Hengel - 3 -

4 MSC. THESIS-MEDICAL ENGINEERING 9 5 Wall Velocity Wall velocity [mm/s] C C A A o rta Tim e [s] Distension Wall distension [um] C C A A o r ta T im e [s ] Karel van den Hengel - 4 -

5 MSC. THESIS-MEDICAL ENGINEERING 9 Abstract Cardiovascular disease (CVD) is a major cause of death nowadays. Cardiac and arterial functioning is reflected in the change in diameter (distension) waveforms of central arteries. Therefore, distension waveforms are measured and analysed to determine the risk on cardiovascular diseases. Risk indicators that can be accessed from distension waveforms, are local pulse pressure, pulse wave velocity and certain time characteristics. Commonly, the distension waveform of the common carotid artery (CCA) is used, as the CCA is superficially positioned and easily accessible with ultrasound (US). However, the abdominal aorta (AA) is directly connected to the aortic root and therefore a more pronounced influence of CVD on the AA pulse waveform is expected. Therefore, the aim of this study is to find a relation between CVD risk indicators determined from the distension waveforms of the AA and the CCA. Successive and simultaneous measurements of the distension waveforms in the AA and CCA are performed using an ultrasound scanner with ART.LAB functionality (Picus, Esaote Europe) on respectively fourteen and three healthy volunteers. The AA distension waveforms and CCA distension waveforms were synchronized by ECG triggering and averaged. In addition, radial blood pressure is recorded continuously (Colin, USA). The measurements show that during synchronous measurements a higher distension waveform in the CCA does not correspond to a higher distension waveform in the AA. The arterial distensibility was on average similar for both arteries, but for a volunteer large difference between the AA and CCA distensibility could be found. Local pulse pressure in the AA was higher than the local pulse pressure in the CCA, whereas local pulse wave velocity in the AA was significantly different from the local pulse wave velocity in the CCA. The ejection period of the heart, that was assessed from the AA distension waveforms was proportional to the ejection period of the heart assessed from the CCA distension waveform. However, the start of the isovolumic heart contraction could not be detected in the AA distension waveform. From analysis with a 1D wave propagation model is became clear that this characteristic ripple is attenuated along the aorta, so that it is no longer distinguishable in the waveform. Determination of a general transfer function between the AA and CCA distension waveforms could be used to assess the AA distension waveform from the measured CCA distension waveform. However, large differences in transfer function are observed between individuals. A general transfer function therefore, results in large errors between measured and estimated AA distension waveforms. From analysis with a 1D wave propagation model it became clear that the transfer functions are largely influenced by the arterial elastic modulus and arterial radii. It might thus be useful to make transfer functions more specific by including the arterial elastic modulus and arterial radii. In conclusion, currently it is not possible for most CVD risk indicators to replace the measurement of the AA distension waveform by the measurement of the CCA distension waveform. Only the ejection period and the local pulse pressure are similar. Karel van den Hengel - 5 -

6 MSC. THESIS-MEDICAL ENGINEERING 9 Measurements in the aorta remain necessary to obtain other CVD risk indicators. In order to be able to apply transfer functions in the future, including patient-specific information, for example elastic modulus and radius seems required, but more research is needed. Further research including CVD patients is also necessary, to determine whether the conclusions still hold in diseased arteries. Karel van den Hengel - 6 -

7 MSC. THESIS-MEDICAL ENGINEERING 9 Index Abstract...5 List of figures...9 Acronyms overview...1 Chapter 1 - Introduction Aim of project Chapter - Materials & Methods Measurement techniques Distension measurement with ultrasound Protocol Synchronic measurement....3 Off-line analyses Pre processing Wave characteristics Transfer function One-dimensional wave propagation model Model geometry Boundary conditions Wave splitting Statistics... 9 Chapter 3 - Results Wave characteristics Diameter, distension and brachial pressure Local blood pressure Compliance and distensibility Elastic modulus Pulse wave velocity Characteristic time values Synchronic measurements Transfer function Wave propagation model Characteristic time points Effect of the radius and E-modulus on the transfer function Chapter 4 - Discussion Measurements Wave characteristics Transfer function Wave propagation model... 5 Chapter 5 - Conclusion...53 Karel van den Hengel - 7 -

8 MSC. THESIS-MEDICAL ENGINEERING Recommendations Samenvatting...55 References...57 Appendixes...61 Appendix 1 Protocol Appendix Informed Consent Appendix 3 Measurement form...65 Appendix 4 Volunteer information Appendix 5 Schematic overview data processing Appendix 6 Values Main measurements Appendix 7 Characteristics values main measurements Appendix 8 Time Characteristics Main measurements Appendix 9 Model pressure plots along arterial tree Appendix 1 C3M Appendix 11 Modification standard model input Karel van den Hengel - 8 -

9 MSC. THESIS-MEDICAL ENGINEERING 9 List of figures Number Page Description.1 4 Synchronic CCA and AA, velocity and distension waveform Characteristics of the distension waveform and the derived acceleration signal.1 15 Raw RF-signal and medical ultrasound image of the CCA. 17 Determination of the arterial wall with threshold function T(X).3 18 An amplitude of 1 RF line and RF matrix for C3M detection.4 19 A schematic overview of scaling the measured pressure wave (Collin).5 Schematic view of longitudinal M-mode ultrasound measurements.6 1 The line up of the synchronic measurements with two researchers.7 1 Median filters on AA velocity waveform.8 Typical example of a mean wall velocity AA (left) and mean wall distension AA.9 5 Characteristics of the distension waveform and the derived acceleration signal.1 6 Geometry of the wave propagation model.11 7 The three element windkessel model of the end-segments A typically mean wall velocity AA and mean wall distension AA A box plot and Bland-Altman plot of the diameters A box plot and Bland-Altman plot of the distension A box plot and Bland-Altman plot of the brachial blood pressure The local pulse pressure of the CCA plotted against the local pulse pressure of the AA Compliance and distensibility of the CCA plotted against the AA E-modulus of the CCA plotted against the E-modulus of the AA Local pulse wave velocity (PWV) of the CCA plotted against the PWV the of AA Regional PWV of the AA plotted against the local PWV the of AA Time characteristics of the CCA against the AA Synchronic measurements Aorta and CCA beats Time characteristics plotted of the Aorta against the CCA Diameter, compliance and distensibility of the CCA plotted against the AA Amplitude and phase spectrum of the Fourier transform of the distension waveforms Transfer function between CCA and AA Result of transfer function on 1 heartbeat transfer function Results using the main transfer function of 1 volunteer Results used the main transfer function of all 3 volunteer Transfer function between CCA and AA of successive measurement Results used the main transfer function of all 14 volunteer The splinted acceleration of the pressure pulse Pulse pressure and pressure acceleration at the ascending aorta, AA and CCA Amplitude spectrum and phase spectrum of the transfer function with various E-modulus Amplitude spectrum and phase spectrum of the transfer function with various radius Amplitude of the transfer function Nichols and O Rourke and present study Karel van den Hengel - 9 -

10 MSC. THESIS-MEDICAL ENGINEERING 9 Acronyms overview Acronym Literature Description ECG Electrocardiography t r-r R-R time time differences between two consecutive R peaks in the ECG, time of heartbeat v w Vel wall velocity d w Diam diameter artery Δd Dist distension artery a w Acc acceleration wall p BP blood pressure p d DBP diastole blood pressure p s SBP systole blood pressure p MAP mean blood pressure Δp PP pulse pressure (SBP-DBP) t sic SIC start time of isovolumic contraction t avo AVO time of aortic valve opening t avc AVC time of aortic valve closure t pr PR time of lower body peripheral reflection wave t icp ICP time of isovolumic contraction; (t avo - t sic) t ep EP time of ejection period; (t avc - t avo) t rp relaxation period Δd/Δt, v max dd/dt maximum velocity of the arterial wall R s R total peripheral resistance of the arterial system c PWV pulse wave velocity c,r PWV regional pulse wave velocity c,l PWV local pulse wave velocity C CC compliance coefficient D DC distensibility coefficient CCA AA common carotid artery abdominal aorta Karel van den Hengel - 1 -

11 MSC. THESIS-MEDICAL ENGINEERING 9 Chapter 1 - Introduction Nowadays cardiovascular disease (CVD) is a major cause of death, and because of the ageing of the world population, more and more people will suffer from CVD [3]. CVD is a disorder of the heart or the blood vessels. Symptoms are stenoses, hypertension and aneurisms [4, 5]. CVD can result in a heart attack or cerebral infarction, so it is important to detect CVD in an early stage. To detect CVD, several risk predictors are identified [6]. Nowadays, all risk predictors are related to arterial stiffness. If linear isotropic behaviour is assumed, then the arterial stiffness is the product between the Young s modulus (E) and the arterial wall thickness (h) [7]. The Young s modulus is a material parameter defining the elasticity of the wall. However, usually the distensibility (D) is used to describe the stiffness of the arterial wall, defined as D C = C C /A. A is the diastolic surface of the artery, measurable with ultrasound, and the compliance (C) is defined as C = ΔA/ΔP, where the surface change (ΔA) can be measured with ultrasound and blood pressure change (ΔP) with tonometry. For linear elastic infinitesimal wall motion, the arterial stiffness (S) can be calculated with S = d(1-µ )/D, with d the diameter and µ the Poisson s ratio [8]. When the arterial stiffness is increased the pulse wave velocity is increased too [9].Previous research indicated that regional aortic pulse wave velocity is the best predictor for CVD risk. The common way to determine the regional pulse wave velocity is to measure the pulse pressure at two positions in the arterial tree, most commonly in the common carotid artery (CCA) and the femoral artery. The time difference between the foot of the pressure wave divided by the distance results in the regional pulse wave velocity [1]. For the waveform registration both tonometry and ultrasound can be used. With tonometry the blood pressure can be measured non-invasively, by placing a pressure sensor above an artery. Ultrasound employs high frequency sound to estimate the diameter and distension of the arterial wall. The regional pulse wave velocity reflects the average arterial stiffness over a segment [11]. Another possibility is to estimate the local pulse wave velocity. The local pulse wave velocity can be measured or computed by means of the Moens Korteweg relation. The local pulse wave velocity (c,l ) is based on 1 the distensibility (D) measured with ultrasound and the density (ρ) of blood ( c, l ) D [1]. To derive the Moens Korteweg relation it assumed that the arteries behave as a linear elastic, isotropic, incompressible and thin-walled tube [1, 13]. Blood pressure is related to the arterial stiffness. An increase in arterial stiffness causes an early return of reflected waves in late systole, increasing both the mean pressure and the pulse pressure and thus also the systolic blood pressure [7]. The increase in blood pressure leads to extra load on the heart [6]. The heart must generate more power to pump against a higher systolic pressure, while the often decreased diastolic pressure leads to less blood circulation in the coronary perfusion; this can lead to myocardial ischemia [7, 14]. The pulse pressure is thus also a risk predictor for CVD [7]. Karel van den Hengel

12 MSC. THESIS-MEDICAL ENGINEERING 9 Beside arterial stiffness, some recent studies [4, 15] estimated characteristic time points of the pressure or distension waveforms. The waveform consists of several characteristic time points, typical shapes in the waveform such as peaks or minimums. To find all time points in the distension waveform, the velocity waveform and also the acceleration waveform are necessary, see figure 1.1 [4, 15]. The velocity waveform can be measured with ultrasound. The characteristic time points can change position during life. These changes are caused by the deformation of the structure and tissue of the total circulation. Because this close relation between arterial and cardiac functioning, quantifying the left ventricular function can be done with pressure waveform measurements in the systemic arteries [15]. For dysfunction of the left ventricle, a decreased ejection period, an increase of the isovolumic contraction period (t ep = t avc - t avo and t icp = t avo - t sic ) (figure 1.1) and ratio between isovolumic contraction period and ejection period, are considered to be good indicators of CVD. The maximal upstroke of the distension waveform, caused by stiffer arteries or an intensive pumping heart, is shown to be a good risk predictor in previous studies [15, 16]. Figure 1.1: Characteristics of the distension waveform and the derived acceleration signal. R, ECG R wave peak; SIC, start of isovolumic contraction; AVO, aortic valve opening; AVC, aortic valve closure; PR, lower body peripheral reflection wave; dd/dt max, maximum distension velocity; au, arbitrary units. [15] So characteristic time points, pulse wave velocity, pulse pressure and distensibility are all risk indicators for CVD. Of all these indicators the regional pulse wave velocity is the most used in population studies and the so called gold standard for prediction of CVD risk at a group level [6]. All these risk predictors are assessed in the CCA, however the aorta is directly connected to the aortic root and therefore a more pronounced influence of CVD on the aortic pulse waveform is expected [6]. The aorta is the start of the arterial tree, all effects and reflections return to the root. As the aorta is the most defuse artery, all information of the arterial tree should be in the aortic waveform [17, 18]. Therefore, effects of therapy are preferably studied using aortic pressure, as it reflects effects in the whole body [19]. However it is not easy to measure the distension of the aorta, as only the abdominal aorta (AA) is directly visible with ultrasound from outside the belly without obstruction of Karel van den Hengel - 1 -

13 MSC. THESIS-MEDICAL ENGINEERING 9 bones. But ultrasound measurements in the AA are cumbersome, because of air in the intestines and its deep position. It is easier to measure the CCA distension with ultrasound, which is also a central artery and therefore often used for research [5, 15]. Because it is easier to measure the distension waveform in the CCA, a transfer function between the distension waveforms of the CCA and AA can be a way to find the distension waveform of the AA. Transfer function for radial-aorta and carotid-aorta were made by averaging transfer functions over large human populations []. Such generalized transfer functions have been used for commercially available systems for the prediction of derived indexes, such as augmentation index. However a large error in reconstructed central pressure is shown using generalized transfer functions [1]. Previous research is done on transfer functions between aortic blood pressure and CCA blood pressure. The transfer functions that were estimated from the pressure waveforms, which were measured with a catheter, show large variations between individuals [4] [1]. In literature worse results are thus shown using general transfer functions [1], however individual transfer function not always resulted in significant better results []. Better results with transfer functions were shown using more patient specific characteristics as age, blood pressure, or splitting the pressure waveform into its forward and backward components [1, 3, 4]. Transfer models based on anatomical data from patients, as Young s modulus, wall viscosity and blood density, result in an accurate individualized description of pressure transfer [19]. Another way to study the relation between the waveform of the AA and CCA are computational models. Computational models have been developed to analyse pressure and flow phenomena in the arterial tree [5, 6]. To analyse pressure and flow waveforms a one dimensional wave propagation model of the large arteries can be used [7, 8]. In clinical validation studies wave propagation models have demonstrated their ability to qualitatively describe blood pressure and blood volume flow waveforms [9]. 1.1 Aim of project To assess CVD risk, several indicators are used, which can be determined from the arterial distension waveform. The most pronounced influence of CVD is expected on the aorta, and for CVD risk it might thus be better to study the AA distension waveform and not the CCA distension waveform. The latter is current clinical practice. The goal of this study is to investigate the relationship between (characteristics of) the distension waveforms as measured in the AA and in the CCA. When this relationship is known, in future it might be sufficient to measure CCA distension to estimate arterial stiffness and heart condition for CVD screening. To get more insight in the relation between the AA and CCA distension waveforms, they are measured with ultrasound in a small group of volunteers. In chapter the principles of the ultrasound detection, the measurement protocol and waveform analysis are described. Section.3. will focus on the characteristic values of the distension waveform. In section.3.3, the determination of the transfer function in the Fourier domain will be described. This transfer function can be applied to estimate the distension waveform of the AA from the distension waveform of the CCA. In section.4, we describe the wave propagation model to gain insight into Karel van den Hengel

14 MSC. THESIS-MEDICAL ENGINEERING 9 the transfer function and into the feature changes in the distension waveforms between the AA and CCA. In chapter 3 the results of the measurements, the analyses and the model simulations are shown. The discussion of the research is written in chapter 4. The final conclusion and recommendation of this study can be found in chapter 5. Karel van den Hengel

15 MSC. THESIS-MEDICAL ENGINEERING 9 Chapter - Materials & Methods To investigate the relation between the distension pulse waveform in common carotid artery (CCA) and the distension pulse waveform in abdominal aorta (AA), the distension waveform of both arteries was measured with ultrasound..1 Measurement techniques Ultrasound measurements were performed with the ART.LAB Picus ultrasound system (ESAOTE, The Netherlands). This machine has the ability to export the raw radio frequency data (RF-data) to an external computer. Simultaneously the blood pressure and the ECG are recorded to get a full data set. A pressure transducer, Colin 7 sensor [Colin, France, Europe] is used. On the Picus ultrasound machine, all data (RF-data, blood pressure and ECG) was exported to the ART.LAB computer and recorded with the ART.LAB v.1 program..1.1 Distension measurement with ultrasound Ultrasound is a high frequency sound (ranging between MHz and MHz), which is higher than the range of our hearing system. In medical ultrasound applications the echo of the ultrasound waves is used. A piezoelectric transducer generates the ultrasound waves. Electric pulses administered to the transducer generate a wave; the ultrasound. The reflection of the ultrasound waves caused by a density transition is received and measured. The transducer is fixed in a probe, which also catches the returned signal. The A B Figure.1: A) raw RF-signal and B) medical ultrasound image of the CCA returning sound wave vibrates the transducer, and the transducer translates the vibration into an electrical signal. This signal will be converted from an analogue into a digital Radio Frequency signal (RF-signal) (figure.1). This is the basic signal for signal processing that is used in medical research. In a clinical setting this signal is translated Karel van den Hengel

16 MSC. THESIS-MEDICAL ENGINEERING 9 into a gray scale ultrasound image for real-time analysis, by means of non-linear signal processing [3]. The returned signal gives information about the anatomy along the line of the wave. Changes in density of tissue cause a reflection; the fraction of reflection depends on the amount of change in density. With a two-dimensional image of different wave lines anatomic structures can be recognized [31]. The frequency of the transmitted ultrasound sound (f n ) and the duration of the transmission pulse determine the images resolution. Reflections of two points closely behind each other can best be differentiated with a short wavelength and thus a high transmission frequency. A higher frequency means a shorter wavelength, what results in high differentiation precision, what results in high detail. Higher frequency also increases the dynamic range (range of detectable velocity of tissue) and signal to noise ratio. The disadvantage of a high frequency is a high attenuation, which means that the sound will not reach the same depth in the tissue as lower frequencies. Because the AA lies relatively deep under the surface, usually a relatively low frequency of sound, of around 5 MHz, is used. The temporal frequency (f p ) or temporal resolution of the ultrasound machine is the pulse frequency of the machine. It determines the maximal penetration depth as: D p 1 c (1) f p with D p the penetration depth and c sound velocity. The scanner sends 1 pulse and receives all reflected information before sending the next pulse. The penetration depth thus determines the repetition time. The signal travels away and returns with the speed of sound, so the larger the depth the longer the travel time. A temporal sample frequency of 98 Hz is used for the M-mode measurements. However the D p will not be reached, because the signal is damped by lot of reflections and scattering. The spatial sample frequency (f s ) used was 33 MHz. The sample frequency of the reflected signal is thus much higher than the ultrasound frequency. The resolution is thus not limited by the detection, because one sample captures the information of a smaller distance in the tissue than the resolution defined by the frequency of the sound. Signal processing in ART.LAB The assessment of the distension waveform is based on a two-step approach: The detection of the position of the blood vessel walls (posterior and anterior) and the assessment of blood vessel wall velocity. The distension waveform is estimated from the cumulative integration of the wall velocity. Detection of the position of the blood vessel wall For the wall position an envelope is placed over the RF data and the RF envelope is further processed. First a region of interest (ROI) is placed around the expected walls, to limit the maximum reference signal; as high signal intensity due to reflections could be present outside the artery. The so-called sustained attack low-pass filter is used [3]. A reference signal (SA(x,t)) as function of depth(x) and time (t) is defined as a decreasing exponential function which is reset to the RF amplitude if SA is lower than the RF Karel van den Hengel

17 MSC. THESIS-MEDICAL ENGINEERING 9 amplitude [3]. If the SA(x,t) is not smaller than RF amplitude for a x larger than half the expected radius, the SA(x,t) is set. SA(x,t) is determined in each first frame of the heartbeat if an ECG is recorded by to the system. Else the starting point of the beat is based on the detected change in lumen position. Next, the SA(x,t) is multiplied with a fractional threshold, resulting in T(x,t), to detect the wall every line during next heartbeat [1]. The detection starts from the middle of the ROI towards the outside, the first time the envelope crosses the T(x,t) indicates the position of the wall (figure.). This method is applied towards the probe for the anterior and away from the probe for the posterior wall detection. The limitation of the wall position detection are a) low resolution (15 µm) and b) sensitivity of the method for noise [1]. Figure.: Estimation the SA(X) reference signal (a) and determination of the wall with threshold function T(X) (b)[1]. Assessment of blood vessel wall velocity The start position for blood vessel wall velocity detection is the result of the position detection described above. The integration over time of blood vessel wall velocity gives the change in diameter. Even a very small bias in the estimation of the blood vessel wall velocity will be reflected in a huge bias in the distension waveform []. Therefore, an unbiased estimation of blood vessel wall velocity is essential for the assessment of the distension. Different cross-correlation models are proposed, but the C3M estimator [] is a robust, accurate, unbiased and broadband estimator for blood vessel wall velocity [1, 33]. Karel van den Hengel

18 MSC. THESIS-MEDICAL ENGINEERING 9 1 ms λ depth time Figure.3: On the right the amplitude of 1 RF line is plot in depth. These lines come into a circular buffer side by side (left), on this matrix an estimation window is placed at the position of the wall with size of 1 λ by 1 ms. The C3M estimator uses RF-signal processing in the time domain because it is fast and can be applied online. It works as follows, the single RF-lines coming into ART.LAB during time form a matrix, as shown in figure.3. On the matrix a window is placed of 1 pulse wavelength (λ), by 1 ms. The position of the window is based on the wall detection. For all points in the window the complex value (u rf ) is calculated, based on the Hilbert transformation in spatial direction. z ( k mi, ) z ( k mi, ) u ( k, i) z ( k, i) j () rf rf H w rf rf m 1 m with k the position in depth, i the position in time, z ( k, i ) a sample of the RF-data and H w the length of the spatial Hilbert transformation window, where m contains only odds. R(k,i) is a complex correlation function with k the depth shift and i the time shift of the estimation. The complex correlation function (R(k,i)) is a model based on the complex data points (u rf ) of the RF-signal (see appendix 9 and in literature of Brands (1997)). For the estimation of the dimensionless velocity φ the functions R(,1), the correlation function between the neighbour points in time direction, and R(1,), the correlation function between the neighbour points in depth direction, are used. Based on correlation between the analytic RF-signal in this window the velocity parameter of the RF-data can be derived as arg( R(,1)) (3) arg( R(1,)) rf Karel van den Hengel

19 MSC. THESIS-MEDICAL ENGINEERING 9 where is the dimensionless velocity, arg the function operating on complex numbers resulting in angle between real and complex component. After the velocity estimation, the window is repositioned with a time shift of 5 ms (half overlapping windows in time) at the new wall position, and the velocity is estimated again. In this way the velocity is estimated with a frequency content of Hz, enough to cover the information content of the wall velocity, which is within 8 Hz. The mean velocity v (m/s) is finally computed form the dimensionless velocity by v c f p (4) f s with c the speed of sound, f p the temporal sampling frequency and fs the spatial sampling frequency.. Protocol Measurements are performed on 14 young presumably healthy volunteers. Volunteers had an age between 19 and 3 years and 5 were female. All volunteers signed informed consent before entering the measurements (Appendix ). For each volunteer first the distension in the AA was measured with ultrasound and then the distension of the CCA was measured with ultrasound. Ultrasound measurements were performed with the ART.LAB Picus ultrasound system (Esaote Europe, Maastricht). For the AA a 5 MHz probe was used and for the CCA a 1 MHz probe (Esaote, The Netherlands). The M-mode recording is obtained with a temporal frequency of 98 Hz and a spatial frequency of 33 MHz. [34]. A measurement session is shortly described here, the complete protocol can be found in appendix 1. Figure.4: A schematic overview of scaling of the pressure wave [34]. To allow for stabilization of the cardiovascular system, the measurement session was started with 15 minutes rest in supine position. ECG sensors connectors were placed on the left side of the body, near the armpit and 1 cm below. This connector positioning ensured that, the R top of the ECG was high compared to the rest of the ECG signal. In Karel van den Hengel

20 MSC. THESIS-MEDICAL ENGINEERING 9 addition the blood pressure device Collin was connected, a cuff around upper-arm and a pressure sensor above the radial artery in the wrist of the contra lateral arm. The Collin consist the cuff and pressure sensor, because the pressure sensor can only measure relative pressure waveform. It is assumed that the systolic and diastolic pressures in the radial artery are the same as the pressures obtained from an oscillometric cuff measurement in the brachial artery in the contra lateral upper arm (figure.4) The ultrasound measurement was started by locating the artery with the ultrasound probe in longitudinal position (figure.5). Distension along one RF-line (M-Mode) was detected. A 6 second M-mode recording was made (5 or 6 consecutive heartbeats). First the AA distension and next the CCA was measured. During the AA record measurements the volunteer has to hold his breath. 5 records of artery were made. The measurement session was repeated three times during successive weeks. Aorta CCA Figure.5: Schematic view of longitudinal M-mode ultrasound measurements of the AA (left) and CCA (right). The M-mode signal crosses the artery longitudinal and in the middle of the artery...1 Synchronic measurement To study the effect of performing the distension measurements of AA and CCA not simultaneously a small extra study is done, where the distension of the CCA and the distension of the AA were measured simultaneously with two ultrasound machines. In these synchronic measurements the distension waveforms could be compared within one heart beat. The ECG was used to synchronize the CCA and AA distension waveform. The synchronic ultrasound measurements were performed by two researchers (figure.6) in one session on three volunteers. Karel van den Hengel - -

21 MSC. THESIS-MEDICAL ENGINEERING 9 Figure.6: The line up of the synchronic measurements with two researchers..3 Off-line analyses The recordings of the distension waveform with ART.LAB are further processed with Matlab (R7b, MathWorks Inc.)..3.1 Pre processing The wall velocity and blood pressure signals are separated into heartbeats based on the R peaks in the ECG signal. The wall velocity waveforms are then filtered to remove artefacts spikes, caused by failing wall detection with a median filter (5 sample points). The second filter that is applied is a local median filter. This filter is used to remove spot noise from the waveform, as discontinuities are present resulting from discrete steps in the segmentation, caused by high reflections in the artery. The discontinuities will lead to as delta function in the derivative of the velocity. A median length of 3 samples was chosen which resulted in a smooth waveform (figure.7). The blood pressure waveforms were not filtered, as they are show smooth waveforms. Smooth filter Median filter Figure.7: Median filters on AA velocity waveform (left before, right after). Firstly remove the delta peaks and secondly the little plateaus. Karel van den Hengel - 1 -

22 MSC. THESIS-MEDICAL ENGINEERING 9 From the wall velocity and blood pressure waveforms a mean waveform for each artery of each volunteer for each week is estimated by averaging the velocity at each time point. At the tail of the waveform, only the waveforms were averaged that yielded data, which were, long enough. For the synchronic measurements it was not necessary to average the waveforms, as the AA and CCA waveforms were measured simultaneously. This resulted in a velocity waveform of the AA, a velocity waveform of the CCA and a blood pressure waveform for each heartbeat..3. Wave characteristics Using the arterial distension waveforms, a comparison is made between the CCA and AA. The following parameters will be determined; diameter, distension, local pulse pressure, distensibility, Young s modulus, pulse wave velocity and several characteristic time points. For each volunteer the mean distension waveforms of the three weeks will be used. For the synchronic measurements, comparisons are made for the distension waveforms per heartbeat, so the single beat waveforms will be used (figure.8). 5 Wall velocity AA 1 Wall distension AA 8 Velocity [mm/s] Distension [um] Time [s] Time [s] Figure.8: Typical example of a mean wall velocity AA (left) and mean wall distension AA (right). Diameter The diameter of the artery is the end diastolic diameter. It is estimated from time averaged difference between the positions of the anterior and posterior arterial wall minus the time averaged distension. Distension The result of the ART.LAB processing is the velocity of the anterior and posterior wall. Cumulative integration of the difference in wall velocity results in the wall distension, see figure.8. The maximum of this waveform is the distension of the artery. Local pressure Each of the distension waveforms can be transformed to a local pressure waveform of the artery assuming a linear relationship between pressure and distension. It is assumed that Karel van den Hengel - -

23 MSC. THESIS-MEDICAL ENGINEERING 9 the diastolic pressure and mean arterial pressure are the same in the whole arterial system [35]. The pressure waveform of AA can then be estimated from p pd p() t d() t pd with (5) & (6) d with Δd(t) the distension, p d the diastolic pressure measured in the brachial artery, p the mean arterial pressure measured in the brachial artery and d the mean distension. The pulse pressure is the difference between the maximum and minimum of the blood pressure (p(t)) and the systole pressure the maximum of the blood pressure (p(t)). Compliancy and distensibility The compliancy (C) is the change of cross sectional lumen area per unit pressure change as C C A d d d p 4 p (7) with the ΔA the change of lumen area, Δp the local pulse pressure,, d the diastolic diameter and Δd the distension. The distensibility (D) is defined as the change of lumen area due to pressure change per cross sectional area as D C A C A p A C (8) with A the diastolic lumen area. Young s modulus From the distensibility (D C ), an estimation of the Young s Modulus (E-modulus) can be made, assuming that the artery can be modelled as linear, isotope and thin walled artery. The E-modulus for an isotropic linear elastic thin walled tube with constant wall thickness, the E-modulus is given by 3 d 1 d 1 (9) h C h D C C with d the diastolic diameter, h the wall thickness and Poisson s ratio. The wall thickness is assumed to be 1/1 of the diameter for the AA and CCA. Karel van den Hengel - 3 -

24 MSC. THESIS-MEDICAL ENGINEERING 9 Pulse wave velocity When it assumed that the fluid is isotropic, incompressible and inviscid, and the wall is thin and linear elastic, the local pulse wave velocity ( c,l ) can be estimated from the distensibility by applying the Moens-Korteweg equation: c 1 w,, l cpwv DC dw, dw dw d p (1) where is the density of the blood. The regional pulse wave velocity (c,r ) can be estimated from c,r l t (11) with l the distance between measurement sites and foot of the distension waveform [36]. t the time difference between the Characteristics time points Several characteristic time points in the distension waveform reflect the interaction between arterial system and the heart. In table.1 an overview of those time points is given. The time points are defined as a maximum in either the wall distension waveform, of the wall velocity waveform or the wall acceleration waveform in a certain period. The table below describes how the time points are estimated. The ejection period (t ep ) and the isovolumic contraction period (t ivc ) are no time points but time periods, and can be calculated by respectively time point aortic value closing (t avc ) minus time point aortic value opening (t avo ) and t avo minus time point start isovolumic contraction (t sic ). Point Waveform Time period Method t avo acc Begin end max t avc acc 1 e min after t avo end max t sic acc Begin min before t avo max t pr dist t avc end max Period t ep acc - t avc - t avo t ivc acc - t avo - t sic Table.1: The characteristic time points and periods. In which type of waveform the characteristics can be found, in which time period of the waveform and with which method. Karel van den Hengel - 4 -

25 MSC. THESIS-MEDICAL ENGINEERING 9 CCA local waveforms Aorta local waveforms Distention - Velocity - Accelaration - Blood Pressure t avo Δd Δp time [s] Distention - Velocity - Accelaration - Blood Pressure t avo t sic t avc t avc t pr Δp Δd time [s] Figure.9: Waveforms of the (from up to down) local estimate blood pressure (1), the acceleration of the arterial wall (), the measured velocity of the arterial wall (3) and de distension of the arterial wall (4). With the characteristic parameters, the Δp, the t tic, the t avo, the t avc, the t pr and the Δd (left CCA, right Aorta)..3.3 Transfer function A transfer function between the CCA and AA is used to study the relation between the distension waveform of the CCA and AA. A transfer function in the frequency domain can be derived from H( f) S / S (1) xy xx with S xy the cross correlation of the signal and S xx the auto spectrum of the signal [37, 38]. The auto spectrum (S xx ) is defined as Sxx * XX (13) with X the Fourier of the waveform of the CCA and X * the conjugate of X. The cross correlation is defined as Sxy * YX (14) with Y * the conjugate of the Fourier of the waveform of the AA [37, 38]. For the transfer function we will focus on the first 15 harmonics, because prior studies have shown that significant harmonic information content of aortic pressure waveforms only is contained within the first 15 harmonics [1, 39]. Karel van den Hengel - 5 -

26 MSC. THESIS-MEDICAL ENGINEERING 9 For the synchronic measurements a transfer function per heartbeat is determined. To see whether it is possible to make a generic transfer function, first an average transfer function of the synchronic measurement for one volunteer will be created to compare the estimate and measured aortic distension waveform and than for three volunteers an overall average transfer function. To see the result of the transfer functions, the AA waveform will be estimated from the CCA waveform and compared with the real measured waveform. Finally the transfer function will be evaluated for the population based on the mean waveforms per week..4 One-dimensional wave propagation model A wave propagation model will be used to study the change in the characteristic time points in the distension waveform along the arterial tree from the heart to the AA and CCA. In addition, the effect of changing diameter and Young s modulus on the distension waveforms in the AA and CCA, and their transfer function is evaluated. In this research we used the one dimensional wave propagation finite element model of the large arteries developed by Bessems [7, 8]. In this model the mass conservation and momentum equations were solved with the spectral element method. The model is based on the boundary layer theory..4.1 Model geometry The model includes the main arteries of the head, the trunk and limbs up to the feet and hands. The geometry of the model is based on data from Stergiopulos [4] who primarily used the physiological parameters of the data of Westerhof [41]. To fit the model to characteristics of the population in the current study, the mean diameter ratio between the AA and CCA of the Stergiopulos data and the measured AA and CCA diameters was determined[4]. All diameters in the model were corrected with this ratio. The geometry of the model is shown in figure.1. Common Carotid Artery Ascending Aorta Abdominal Aorta Figure.1: Geometry of the model with the segment points of the CCA, AA and the ascending aorta. The blood is modeled as a Newtonian fluid with a dynamic viscosity of Pa s and density of kg/m 3 [43]. The aortic inflow of the blood volume is prescribed Karel van den Hengel - 6 -

27 MSC. THESIS-MEDICAL ENGINEERING 9 (harmonics of the inflow are written in appendix 11). In the model the arteries are modelled like linear elastic thick walled tubes..4. Boundary conditions Arteries are truncated ended by 3-element Windkessel models (figure.11) [4]. Figure.11: The three element windkessel model of the end-segments The peripheral resistance (Rp) of a truncated artery can be calculated from the mean pressure (p) and the mean flow (q) of the geometry, the radius of the truncated artery (a ) and the sum of all radii of truncated arteries(a t ), as p a Rp Z Rv (15) qa 3 3 t where R v the characteristic resistance and Z is the characteristic impedance of the truncated artery determined as he Z (16) 5 (1 ) a where is the density, h the wall thickness and E the Young s modulus. The terminal compliance ( C ) of the truncated artery is defined as v C v (17) R v where R v is the resistance parallel to C v and the τ is the characteristic time constant defined by blood pressure. The RC time constant (τ) is put to 1.5 second. The results of the tenth heartbeat in the model are used for further analysis [6, 44]. The model pressure waveforms are used to compare with the estimated local pressure waveforms of the measurements..4.3 Wave splitting For research the source of changes in the pressure waveform and time points, the pressure waveform can be split into forward and backward travelling waves using the model, because the pressure waveform is generated at different points along the arterial tree. To extract the waveforms, the Fourier Transform method will be used [45]. This method can only be applied when of 1) M u / c 1 (In this case in orde of 1-3 ) and ) the Karel van den Hengel - 7 -

28 MSC. THESIS-MEDICAL ENGINEERING 9 Womersley number r / 1 (In this case Womersley number of the AA of 1) [45, 46]. To split the waves we assume that the dynamic pressure can be written as p(, z ) p (, z ) p (, z ) (18) where p is the pressure wave travelling in the positive (forward) z-direction in the artery and p is the pressure wave travelling in the negative (backward) z-direction in the artery in the frequency domain. The reflection coefficient can be calculated as R z p (, z ) (19) p (, z ) The forward and negative traveling pressure wave can be derived using equation (18) and (19) as and 1 p (, z ) p(, z ) () R 1 z Rz p (, z ) p(, z ) (1) 1 R z However R z is still unknown. To find R z, the transfer function between two points (proximal z p and distal z d ) located near point z must be estimated as H pz (, ) e R e jk ( z p z) jk ( z p z) p z pd jk( zd z) jk( zd z) pz ( d, ) e Rz e () using equations (18) till (1). This result in R jk ( zp z) jk ( zd z) e Hpd e z jk ( z ) jk ( z p z) d z H pd e e (3) Taking subsequently the inverse Fourier transformation of equation () and (1), results in respectively the forward and backward pressure waveform [45, 46]. Karel van den Hengel - 8 -

29 MSC. THESIS-MEDICAL ENGINEERING 9.5 Statistics The computer program SPSS Statistics (version 17) is used to do the statistic tests. Because of different weeks and arteries a test with repeated measures with multiple variables is necessary, the multiple variable test. Between arteries and between the weeks significant different (<.5) is tested. Normality and homogeneity of variance is tested and noticed if it is not proved. The Sphericity, the variances of the differences between all pairs of the repeated measurements are equal, is noticed by each test if the value was below.5. The averaged parameter between the CCA and AA will be compared with a paired sample T-test to be significant different (<.5), assumed normal distribution. The correlation between values of the CCA and AA were tested based on the Pearson test. If the values were not normal distributed, the correlation was tested with the Spearman test. Karel van den Hengel - 9 -

30 MSC. THESIS-MEDICAL ENGINEERING 9 Karel van den Hengel - 3 -

31 MSC. THESIS-MEDICAL ENGINEERING 9 Chapter 3 - Results To study the relation between the distension waveforms of the common carotid artery (CCA) and the abdominal aorta (AA), ultrasound measurements were performed on 14 healthy volunteers (5 female, 9 male). In table 3.1 an overview is shown of age, BMI, the time between the first and second measurement and the time between the second and third measurement. Volunteers Age BMI Δ days 1 Δ days Mean 4,6 6,9 7, Std 3 1,8,9,4 Table 3.1: Volunteer characteristics: Age, BMI (Weight/lenght ), difference in days between first and second measurement (Δ days 1), and difference in days between second and third measurement (Δ days ). All measurements were done by 1 researcher and 1 person who controlled the capturing and storing of the data with ART.LAB. A measurement session took between 4 and 5 minutes. During the measurements in total 17 recordings of 6 seconds were made of the distension waveform of the AA and 1 recordings of the distension waveform of the CCA. Three recordings of the AA and four recordings of the CCA could not be reread by ART.LAB. In twelve recordings, all in the AA, the position of the arterial wall could not be detected. Hence, recordings of the AA velocity and 6 recordings of the CCA velocity remained, resulting in 161 velocity waveform of one heart beat for the AA and 16 for the CCA. These velocity waveforms were filtered. Velocity waveforms without continuous blood pressure signal or which the shape deviated largely from the pressure waveform were removed. This was the case for 96 distension waveforms of the AA and 44 of the CCA. Thus, in total, 965 velocity waveforms of one heart beat for the AA and 116 velocity waveforms of one heart beat for the CCA were included in further analyses. Per session both the pressure and velocity waveforms were averaged over the heartbeats to an average velocity and average blood pressure waveform for both the AA and CCA of each volunteer. The arterial wall velocity waveform was then integrated to obtain the arterial wall distension waveform (figure 3.1). Karel van den Hengel

32 MSC. THESIS-MEDICAL ENGINEERING 9 A 5 Wall velocity AA B 1 8 Wall distension AA Velocity [mm/s] Distension [um] Time [s] Time [s] Figure 3.1: A) A typical average wall velocity waveform for the AA and B) a typical average wall distension waveform for the AA. 3.1 Wave characteristics Of each average distension waveform the following parameters are determined: diameter, distension, local blood pressure, pulse pressure, distensibility, Young s modulus, pulse wave velocity and characteristic time points Diameter, distension and brachial pressure In table 3. the mean diastolic diameter (D), the mean distension (ΔD) and the mean brachial pulse pressure (Δp) for the 14 volunteers is given. The data for each volunteer individually can be found in appendix 6. Over the weeks CCA AA CCA AA CCA AA D [mm] ΔD [um] ΔP [mmhg]* Mean Within subjects Std % of mean 4% 6% 11% 1% 6% 7% Between subjects Std % of mean 7% 19% 6% 5% 1% 16% Table 3.: Overview of the mean diastolic diameter, distension and pulse pressure and the standard deviation within and between volunteers. As expected, the absolute distensions of AA and CCA differ largely, however relative distensions are comparable. The brachial pulse pressure was similar during the measurements in the CCA and AA. Karel van den Hengel - 3 -

33 MSC. THESIS-MEDICAL ENGINEERING 9 Diameter A B 3 week 1 & week week & week 3 week 3 & week 1 Delta Diameter (%) Mean Diameter (mm) Figure 3.: A) A box plot of diameters in mm of the CCA and AA in week 1, and 3. The number is the volunteer number. B) A Bland-Altman comparing the diameter over the three weeks. The diastolic diameters of the AA and CCA in the three weeks are shown in figure 3.. There is no significant difference between the weeks (p=.88). The limit of agreement between the diameters measured in two different sessions is 18%, while the mean difference in diameter measured in two different sessions is 7.6%. The reproducibility of the diameter measurement in the CCA was slightly higher than the reproducibility of the diameter measurement for the aorta. Differences in AA diameters between volunteers are larger than differences in CCA diameters. Distension A B 4 3 week 1 & week week & week 3 week 3 & week 1 Delta distension (%) Mean distension (mm) Figure 3.3: A) A box plot of distension in µm of the CCA and AA in week 1, and 3. The number is the volunteer number. (B) A Bland-Altman plot comparing the distension in the three weeks. The maximum distensions of the AA and CCA in the three weeks are shown in figure 3.3. There is no significant difference between the weeks within volunteer (p=.8). The limit of agreement between the distension measured in two different sessions is 3%, while the mean difference in distension measured in two different sessions is 1.%. The reproducibility of the distension measurements in the CCA and AA was comparable. Differences in AA distension between volunteers are larger than differences in CCA distension. Karel van den Hengel

34 MSC. THESIS-MEDICAL ENGINEERING 9 Blood pressures A B 4 3 week 1 & week week & week 3 week 3 & week 1 Delta Pulse Pressure (%) Mean Pulse Pressure (mm) Figure 3.4: A) A box plot of brachial pulse pressures (PP) during the measurements in the CCA (C) and AA (A) in week 1, and 3. The number is the volunteer number. B) A Bland-Altman plot comparing the brachial pulse pressure in three different weeks. The brachial blood pressure during measurements in the AA and CCA are shown in figure 3.4. The standard deviation between the volunteers is much higher than the standard deviation within the volunteers. There is no difference in brachial pulse pressure over the different weeks (p=.48), or over the different arteries (p=.8). The limits of agreement between the pulse pressures in two different sessions is 8%, while the mean difference in pulse pressure in two different sessions is 11%. Unfortunately, brachial pressure data are missing for volunteer 1 and 4 in week 1. Therefore, also no local blood pressure, compliance, distensibility, Young s modulus and pulse wave velocity could be calculated Local blood pressure rho =.83 Pulse pressure CCA Pulse pressure AA Figure 3.5: The local pulse pressure in the CCA plotted against the local pulse pressure of the AA. The rho in the top of the plot is the correlation coefficient. Karel van den Hengel

35 MSC. THESIS-MEDICAL ENGINEERING 9 Volunteer ΔP CCA ΔP AA Mean Std between volunteers Mean Std between volunteers Average Table 3.3: The pulse blood pressure of the local blood pressure in the CCA and AA. The correlation between the local pulse pressure in the AA and the local pulse pressure in the CCA is high (figure 3.5). On average the local pulse pressure in the AA is 3 mmhg higher than the local pulse pressure in the CCA. This difference is significant (paired sample test, p<.1) Compliance and distensibility In figure 3.6 the compliance of the CCA is plotted against the compliance of the AA, and the distensibility of the CCA is plotted against the distensibility of the AA. A 1 CC [mm/kpa] B rho =.5 rho =.4 15 DC [MPa-1] 8 1 CCA 6 CCA Aorta Aorta Figure 3.6: Compliance (A) and distensibility (B) of the CCA plotted against the AA. In the top of each plot stays the correlation coefficient (rho) between the CCA and AA values. The compliance of the CCA ranges between.78 and 3.9 mm /kpa, whereas the compliance of the AA ranges between 3.66 and 1.57 mm /kpa. The distensibility of the CCA ranges between 3.6 and 76.5 MPa -1, whereas the distensibility of the AA ranges between and 8.38 MPa -1. The distensibilities of the AA and CCA thus lay in the same range; although large differences between the distensibilities of the AA and CCA can be present for a volunteer Elastic modulus In table 3.4 the mean and standard deviation of the E-moduli for the AA and for the CCA can be found. On average, the E-modulus of the AA is slightly higher than the E-modulus of the CCA. This difference is not significant (paired sample test, p=.6) Karel van den Hengel

36 MSC. THESIS-MEDICAL ENGINEERING 9 Volunteer E-modulus AA [kpa] E-modulus CCA [kpa] Mean std Mean Std Average Table 3.4: The local E-modulus [Pa] of the AA and CCA. Correlation between the E-modulus of the CCA and the E-modulus of the AA is poor (figure 3.7). 35 rho =.5 3 E-Modulus CCA [kpa] E-Modulus AA [kpa] Figure 3.7: E-modulus of the CCA plotted against the E-modulus of the AA. Rho in the top of the plot is the correlation coefficient Pulse wave velocity Table 3.4 gives the local pulse wave velocity (c,l ) determined from the distensibility The local pulse wave velocity in the AA is slightly higher than the local pulse wave velocity in the CCA, respectively 5.1 m/s and 4.8 m/s. This difference is not significant (paired sample test, p=.3). Volunteer c,l AA [m/s] c,l CCA [m/s] Mean std Mean Std Average 5,1,4 4,8,3 Table 3.4: The local pulse wave velocity (m/s) in the AA and CCA. Correlation between the local pulse wave velocities in the CCA and AA is poor (figure 3.8). Karel van den Hengel

37 MSC. THESIS-MEDICAL ENGINEERING rho =.14 Local pulse wave velocity CCA [m/s] Local pulse wave velocity AA [m/s] Figure 3.8: The local pulse wave velocity of the CCA plotted against the local pulse wave velocity of the AA. Regional pulse wave velocity For all volunteers the local pulse wave velocity (c,l ) was compared to the regional pulse wave velocity (c,r ), determined by dividing the distance between the measurements sites on the body surface by the time difference in the onset of the distension waveform (t avo ). For volunteers 3 and 5 also MRI data were available and thus the true travel distance difference between the measurements sites could be determined. This resulted in the regional pulse wave velocity in table 3.5. Volunteer Distance [cm] Δt avo [ms] c,r [m/s] 3 31,6 7 4,5 5 34,6 59 5,9 Table 3.5: The regional pulse wave velocity (cm/s) in the AA and CCA based on MRI. In figure 3.9 the regional pulse wave velocity (c,r ) are compared to the local pulse wave velocity of the AA (c,l ). Karel van den Hengel

38 MSC. THESIS-MEDICAL ENGINEERING 9 9 Regional pulse wave velocity aorta [m/s] rho =.8 Gold standard MRI Local pulse wave velocity AA [m/s] Figure 3.9: Regional pulse wave velocity of the AA plotted against the local pulse wave velocity of the AA. The regional pulse wave velocity determined using distances on the body surface is plotted in blue and the regional pulse wave velocity determined using MRI is plotted in red. The regional pulse wave velocities were higher than the local pulse wave velocities. However, differences seem to be smaller when MRI data is used Characteristic time values The characteristic time points in the distension waveforms for all volunteers individually can be found in appendix 7. In table 3.6 the mean values are shown. All these time points are relative to the start of the electrical activation of the ventricles (R-top in the ECG), which is taken as t = s. The start of the isovolumic contraction could only be detected in the CCA distension waveforms. The wave and thus the characteristics associated with aortic valve opening and closing arrived later in the AA than in the CCA. Over the weeks t AVO [s] t AVC [s] t EP [s] RR-time [s] t SIC [s] t ICP [s] CCA AA CCA AA CCA AA CCA AA CCA AA CCA AA Mean,8,15,38,43,3,8 1,9 1,4,4 -,4 - Std,1,,,3,,,15,15,1 -,1 - % Std-mean 16,1 11,7 5,9 6,7 5,1 5,6 13,7 14,5-8 - Significant P <.1 P <.1 P <.1 Not sign - - Table 3.6: Overview of the characteristic time points: aortic value opening (t AVO ), aortic value closing (t AVC ) and start isovolumic contraction (t ICP ), the time periods: ejection period (t EP ) and isovolumic contraction period (t ICP ), and the heart beat duration (RR-time) In figure 3.1 the characteristic time points of the CCA distension waveform are plotted against the characteristic time points of the AA distension waveform. Karel van den Hengel

39 MSC. THESIS-MEDICAL ENGINEERING 9.5. AVO [s].5 rho =.8 rho =.9.45 AVC [s] CCA.15 CCA CCA Aorta.3.5 EP [s] Aorta 1.6 rho =.91 rho =.86 CCA RRtime [s] Aorta Aorta Figure 3.1: Characteristic time points of the CCA distension waveform plotted against characteristic time points of the AA distension waveform. The rho in the top of each plot is the correlation coefficient. The heartbeats during the CCA measurements were shorter than the heart beats during the AA measurements. Also the ejection periods (t ep ) were shorter during the CCA measurement than the ejection periods during the AA measurements. 3. Synchronic measurements The synchronic measurements were performed by two researchers and 1 person who handled the capturing and storing of the data with ART.LAB.Measurements resulted in CCA and AA distension waveforms for volunteer 1, 45 CCA and AA distension waveforms for volunteer 1 and 5 CCA and AA distension waveforms for volunteer 6. In figure 3.11 for every volunteer one synchronic measurement of 6 heartbeats is shown. Karel van den Hengel

40 MSC. THESIS-MEDICAL ENGINEERING 9 Distension [um] CCA Volunteer 1 1 Volunteer 1 16 Beat 1 Beat Beat 3 AA Beat 4 Beat AA Distension [um] CCA Beat 1 Beat Beat 3 Beat 4 Beat Time [s] Time [s] Distension [um] CCA Volunteer 3 6 AA Beat 1 Beat Beat 3 Beat 4 Beat Time [s] Figure 3.11: Synchronic measurements of Aorta and CCA distension wave forms.6 consecutive heart beats for every volunteer are shown. Same colors indicate corresponding distension waveforms. From figure 3.11 it becomes clear that a relatively higher AA distension not always coincides with a relatively higher CCA distension. In figure 3.1 the characteristic time points of the AA waveform are plotted against the characteristic time points of the CCA waveform for the synchronic measurements. Karel van den Hengel - 4 -

41 MSC. THESIS-MEDICAL ENGINEERING 9.5. AVO [s] AVC [s] rho =.9.5 rho = CCA.15 CCA CCA Aorta EP [s] Aorta RRtime [s] rho = rho = CCA Aorta Aorta Figure 3.1: Characteristic time points of the Aorta distension waveform against the characteristic time points of the CCA. The rho in the top of each plot is the correlation coefficient. Because synchronic measurements are performed on only 3 volunteers, the range in values differ form the range in figure 3.1, and the correlation coefficients are lower. As now measurements are performed synchronically, heart beat duration is equal. As a result ejection period determined from the AA distension waveform is similar to ejection period determined from CCA distension waveform. A Diameter [mm] B CC [mm/kpa] C DC [MPa-1] CCA CCA 6 4 CCA Aorta Aorta Aorta Figure 3.13: A) Diameter, B) compliance and C) distensibility of the CCA plotted against the AA for the synchronic measurements. Karel van den Hengel

42 MSC. THESIS-MEDICAL ENGINEERING 9 In contrast to the results of the sequential measurements (figure 3.6), distensibility of the AA is twice as low as distensibility of the CCA. 3.3 Transfer function To determine the transfer function between AA distension waveform and CCA distension waveform, the synchronic measurements will be used as transfer functions per heart beat can be assessed. When looking at the amplitude spectrum of the distension waveforms of the CCA and AA, the power of the waveform is in the first15 harmonics Amplitude 15 Amplitude Frequency [Hz] Frequency [Hz] -5-5 Phase [radius] Phase [radius] Frequency [Hz] Frequency [Hz] Figure 3.14: Above: Amplitude spectrum of the Fourier transform of the AA (right) and CCA (left) distension waveforms of 3 volunteers. Below: The unwrapped phase spectrum of the Fourier transform of the AA (right) and CCA (left) distension waveforms of 3 volunteers. Figure 3.14 shows the power and phase spectrum of the distension waveform of the CCA and the AA in the first 15 harmonics. The variation in the phase for harmonics over 8 Hz is large, but the power of these harmonics is relatively low. The transfer function, determined by dividing the cross correlation and auto correlation is shown in figure Karel van den Hengel - 4 -

43 MSC. THESIS-MEDICAL ENGINEERING 9 A B 7 6 Amplitude ratio [-] Frequency [Hz] Phase ratio [ radius ] Frequency [Hz] Figure 3.15:The amplitude (A) and phase B) of the transfer function between CCA and AA distension waveforms for three volunteers in blue and the mean in red. When a transfer function is based on the AA and CCA distension waveforms of one heartbeat, and this transfer function is applied to the CCA distension waveform of that same heart beat, the AA distension waveform that results is equal to the measured AA distension waveform (figure 3.16) CCA Aorta - Estimated Aorta - Measured Distension [um] Time [s] Figure 3.16: Result of applying the transfer function determined from AA and CCA distension waveforms of one heart beat on the AA distension waveform of that same heart beat. With the measured CCA waveform (red), measured AA waveform (green) and the estimated AA waveform (blue). In figure 3.17 results are shown of applying an average transfer function per volunteer. The estimated AA distension waveform is similar to the measured AA distension waveform in shape, however the measured AA waveform is more smooth than the estimated AA waveform. Karel van den Hengel

44 MSC. THESIS-MEDICAL ENGINEERING 9 14 Volunteer 1 1 Volunteer 1 Volunteer Distension [um] Distention [um] 6 4 Distension [um] Time [s] Time [s] Time [s] Figure 3.17: Results of applying an average transfer function per volunteer with the measured CCA waveform (red), measured AA waveform (green) and the estimated AA waveform (blue).for volunteers 1,(left) 1 (middle) and 6 (right) In figure 3.18 the results are shown when applying a transfer function that is averaged over the three volunteers CCA Model Aorta Real Aorta CCA Model Aorta Real Aorta CCA Model Aorta Real Aorta Distension [um] 5 Distension [um] 6 4 Distension [um] Time [s] Time [s] Time [s] Figure 3.18: Results of applying an average transfer function over the 3 volunteers with the measured CCA waveform (red), measured AA waveform (green) and the estimated AA waveform (blue) for volunteer 1 (left), 1 (middle) and 6 (right). Applying this mean transfer function, results in larger differences between estimated and measured AA distension waveforms than applying a volunteer specific transfer function (figure 3.17 & 3.18). Figure 3.19 shows the transfer functions for the 14 volunteers. A B 7 6 Amplitude ratio [-] Frequency [Hz] Phase ratio [ radius ] Frequency [Hz] Figure 3.19: Amplitude (A) and phase (B) spectrum of the transfer functions for all 14 volunteers determined from the successive measurements. Karel van den Hengel

45 MSC. THESIS-MEDICAL ENGINEERING 9 Large variations are found in the amplitude and phase spectrum, especially for frequencies over 7 Hz. When the average transfer function over all 14 volunteers is applied to estimate the AA distension waveform for a volunteer, results are comparable to applying the average transfer function of the three volunteers (figure 3.19 and 3.). Especially for volunteer 1, there are large differences between the estimated and measured AA distension waveform CCA Model Aorta Real Aorta CCA Model Aorta Real Aorta CCA Model Aorta Real Aorta Distension [um] 5 Distension [um] 6 4 Distension [um] Time [s] Time [s] Time [s] Figure 3.: Results of applying the average transfer function over all 14 volunteers with the measured CCA waveform (red), measured AA waveform (green) and the estimated AA waveform (blue) for volunteer 1 (left), 1 (middle) and 6 (right). 3.4 Wave propagation model In this part the measurement results are compared to simulation results from the wave propagation model. For the simulations the input as described in section.4 is used Characteristic time points To study the changes in the pressure waveform along the arterial tree, the simulated pressure waveform and the first and second derivative are plotted along the arterial tree. Figure 3. shows the simulated pressure and the second derivative of the pressure at 3 sites in the arterial tree; the ascending aorta, the AA and the CCA. The second derivative of the pressure is shown as the second derivative of the distension waveform is used to determine the characteristic time points. Pressure waveforms at other sites in the arterial tree can be found in appendix 9. Splitting the pressure waveform in a forward and backward travelling pressure wave (figure 3.1), can give insight into the origin of certain characteristics in the waveform. Total waveform Forward Backward.5 1 Time [s].5 1 Time [s].5 1 Time [s] Figure 3.1: The simulated acceleration of the pressure pulse with the total wave (left) the forward traveling wave (middle) and the backward traveling wave (right).the place of the start of the isovolumic contraction is indicated with an arrow. Karel van den Hengel

46 MSC. THESIS-MEDICAL ENGINEERING 9 Acceleration [mmhg/s ] Pulse pressure [mmhg] 1 5 Ascending total distension Aorta Abdominal Aorta Common Carotid Artery total acceleration Time [s] Time [s] Sample number [-] Time [s] Time [s] Time [s] Time [s] Figure 3.: The simulated pressure (top) and pressure acceleration (bottom) in the ascending aorta (left), AA (middle) and CCA (right). The place of the start of the isovolumic contraction is indicated with an arrow. In the pressure waveforms the start of the isovolumic contraction is defined as the maximum in the pressure acceleration wave just before aortic valve opening. In the pressure acceleration wave in the ascending aorta and in the CCA this time point is easily detectable as it is the local maximum. However in the pressure acceleration wave in the AA, it is difficult to distinguish this time point from other maxima, as it is no longer the local maximum Effect of the radius and E-modulus on the transfer function To investigate the influence of the arterial stiffness and the arterial radii on the transfer function between the AA and CCA distension waveforms, the radius and E-modules in the wave propagation model are varied. The transfer function is calculated from the simulated pressure waveforms in the AA and CCA. Figure 3.3 shows the amplitude spectrum and phase spectrum of the transfer functions when using different E-moduli. Karel van den Hengel

47 MSC. THESIS-MEDICAL ENGINEERING 9 A Amplitude factor [-] E =.75 E =.875 E = 1. E = 1.15 E = Frequency [Hz] B Phase factor [-] 6 4 E =.75 - E =.875 E = E = 1.15 E = Frequency [Hz] Figure 3.3: The amplitude spectrum (A) and phase spectrum (B) of the transfer function between the simulated CCA and AA pressure waveforms for different E-modulus. Above 5 Hz differences between the transfer functions are large both in amplitude and in phase. With higher arterial stiffness (higher E-modulus) the upstroke of the pressure waveform in the CCA arrives earlier and is steeper in the AA waveform. Figure 3.4 shows the amplitude spectrum and phase spectrum of the transfer functions when decreasing all arterial radii in the wave propagation model with different factors. A Amplitude factor [-] r =.75 r =.815 r =.875 r =.9375 r = Frequency [Hz] B Phase factor [-] r =.75 r =.815 r =.875 r =.9375 r = Frequency [Hz] Figure 3.4: The amplitude spectrum (A) and phase spectrum (B) of the transfer function between the simulated CCA and AA pressure waveforms for different arterial radii. Again, differences in phase of the transfer functions are large above 5 Hz. The differences in amplitude of the transfer functions are found for all harmonics. An increase of amplitude ratio in all the frequencies by decreased arterial radius, results in relative more increase in amplitude in the AA waveform than amplitude in the CCA waveform. Karel van den Hengel

48 MSC. THESIS-MEDICAL ENGINEERING 9 Karel van den Hengel

49 MSC. THESIS-MEDICAL ENGINEERING 9 Chapter 4 - Discussion Arterial stiffness and heart dysfunction influence pulse pressure which affects the distension waveform of the central arteries, for example the abdominal aorta (AA) [7]. Because the aorta is the main artery, which is directly connected to the heart; effects of cardiovascular diseases are expected to be most pronounced in this artery. Because of the easy accessibility of the common carotid artery (CCA), it is interesting to investigate the relations between the CCA and the aorta. In this study we compared the distension waveforms of the CCA and AA to determine whether there is a relation. This research is focused on three aspects; first the distension waveform characteristics and the characteristic time points of the distension waveform of the CCA and AA, second the transfer function between both arteries distension waveforms and last simulated pressure waveforms generated by a one dimensional wave propagation model of the large arteries. To compare the distension waveforms, repeated ultrasound measurements were performed on 14 volunteers during three consecutive weeks. Also a session of simultaneous measurements of the distension waveforms of CCA and AA were done on 3 volunteers using two ultrasound machines. 4.1 Measurements The performed ultrasound measurements show reproducible waveforms for the CCA and the AA. The automatic wall detection algorithm worked well for the CCA, but for the AA the segmentation was sometimes wrong. This was caused by high reflections in the arterial lumen which were detected instead of the arterial wall. The wrong segmentation caused jumps in the wall velocity estimation. These jumps were removed by a local median filter (3 samples). As filtered waveforms showed no large differences compared to completely correctly measured waveforms, these filtered waveforms were included in the evaluation. 4. Wave characteristics The CCA diameter determined in this study is within the range of the CCA diameters of previous studies. Also the standard deviation is of the same size. Mean CCA diameter SD Method N Age Study US young adult Lentner US Demolis US Ferrara US Hansen US Present study Table 4.1: CCA diameter measurements from previous studies. All previous studies include normal, healthy subjects. Mean CCA measurements and SD are given in millimeters. The mean age of the subject group is given in years + SD.[47-5] Karel van den Hengel

50 MSC. THESIS-MEDICAL ENGINEERING 9 The observed average diameter of the AA of 14.5 mm is similar to the diameter found by other studies on healthy mid-age volunteers (+ 5 years) [51, 5], but a little higher than found in other studies on healthy young volunteers [53, 54]. The mean AA distension in the present study is comparable to the distension found by Long [54] and Hansen [5], but twice as high as the distension found by Boutouyrie [51] and Jondeau [53]. In the synchronic measurements the CCA and AA distension waveforms can be compared one by one for each heartbeat, which was the advantage that influence of side effects, such as length of the heart beat, are comparable for both arteries. In the synchronic measurements increased distension in the CCA does not correspond to increased distension in the AA. This is likely due to backward travelling pressure waves, because the forward wave is generated by the same heart contraction. Distension is thus also dependent on pressure generated in previous heartbeats. The local pulse pressure in the AA and CCA was lower than the pulse pressure (Δp) in the brachial artery, and the pulse pressure in the CCA was lower than the pulse pressure in the AA. This results from the larger relative mean distension to the maximal distension in the CCA than in the AA. This is consistent with literature [55, 56] as the mean pressure is decreased and the systolic pressure is increased more distally in the arterial tree, and measurements in the CCA were performed closer to the heart than the measurements in the AA. However the correlation between the pulse pressure of the CCA and AA is about.83, and the pulse pressure of the AA can thus be approximated based on the pulse pressure of the CCA. The compliance (C) and distensibility (D) are determined by using the estimated distension and local pulse pressure. The determined compliance and distensibility results of different weeks were in the same range. The AA compliance was on average 4 times the CCA compliance. The CCA distensibility was on average equal to the AA distensibility, however large differences between CCA and AA distensibility up to a factor of two for some volunteers are observed. The distensibility of the AA ranged between and 8 MPa -1 ; which is similar to the distensibility found by Long [54] with a mean of 4 MPa -1 and a standard deviation of 13 MPa -1. The Young s modulus (E-modulus) and the local pulse wave velocity (c,l ) are derived from the distensibility of the artery. Thus, also the E-modulus and the pulse wave velocity are on average similar in the CCA and AA, but large differences between values for the CCA and AA can be found in some subjects. The pulse wave velocity is also measured over a segment, resulting in a regional pulse wave velocity. When MRI was used to estimate the path length, the local and regional pulse wave velocities were of the same order. When the path length was measured outside the body, regional pulse wave velocities were higher than local pulse wave velocities. The average regional pulse wave velocity of 6.5 m/s is similar to the regional pulse wave velocity found of 6.8 m/s by Rogers [57] for young volunteers. With regards to the time characteristics of the CCA and AA distension waveforms, the start of the isovolumic contraction phase (t sic ) could not be found in the AA distension waveform. Between both arteries, the difference in the aortic valve opening time points (t avo ) is smaller than the difference in the aortic valve closing time points (t avc ). This result in differences in the ejection period (t ep ) of ms. But also the duration of a heart beat was longer during the CCA measurements than during the AA measurements, which Karel van den Hengel - 5 -

51 MSC. THESIS-MEDICAL ENGINEERING 9 could result in a difference in ejection period. In the synchronic measurements no difference in ejection period between CCA and AA was visible, which suggests that the ejection period depends on the heart rate. The ejection period and isovolumic contraction period measured in the CCA distension waveforms are similar to Reesink et. al [15]. 4.3 Transfer function If a general transfer function between the distension waveforms can be determined, this can be used to assess the AA distension waveform from the CCA distension waveform. For assessment of the transfer function, the distension waveforms of the synchronic measurements are used. In the amplitude spectra of the CCA and AA distension waveform, all relevant information is in the first 15 harmonics. In literature, the transfer function (figure 4.1) is based on the pressure waveforms in the ascending aorta and CCA estimated with tonometry [4]. The transfer function between the AA and CCA distension waveforms found in the present study, differs from this transfer function found in literature; the transfer function in literature is from ascending aorta to CCA, the transfer function in present study is from CCA to AA. Turn the transfer function in present study upside down, the shape look similar to the transfer function of Chen et al [4]. In contrast to literature the transfer function in present study is higher than, this, this due to the velocity pulse in AA is twice the velocity pulse in the CCA. Other small differences could be caused by the different measurement position in the aorta. A B 15 Amplitude ratio [-] Frequency [Hz] Figure 4.1:A) Amplitude of the transfer function between ascending aorta and carotid artery as determined by Chen et al. (large circles and error bars which represent 95 per cent confidence limits), and by Nichols and O Rourke (left) [4, 4] and B) amplitude of the transfer function between AA and CCA based on synchronic measurements. The transfer function for the 3 volunteers based on the synchronic measurements differs largely in amplitude after the 8 th harmonic and in phase shift after the nd harmonic. The amplitude spectra of the transfer functions based on the successive measurements differ from the 1 st harmonic. This is caused by the large differences in distension ratio between AA and CCA for the different volunteers. Also the phase shift of the transfer function based on the successive measurements varied from the 1 st harmonic. Using the transfer function of one heartbeat, the estimated and measured AA distension waveforms were similar. Only small errors were present, which resulted from the fact that Karel van den Hengel

52 MSC. THESIS-MEDICAL ENGINEERING 9 only 15 harmonics were included in the analysis. When the transfer function was based on all measurements of one volunteer, the estimated AA distension waveforms still resembled the measured AA distension waveforms. When a general transfer function was determined based on the synchronic measurements of all 3 volunteers, the estimated AA distension waveforms significantly differed from the measured AA distension waveforms. The same was the case for a transfer function based on the successive measurements of all volunteers. It is therefore expected that if more volunteers of different ages are included the results of a general transfer function will not improve, as reported in the literature [4]. This might be solved by including more patient-specific information, for example age and length [58]. 4.4 Wave propagation model To get more insight in the relation between the distension waveforms in the CCA and AA, the wave propagation model of Bessems is used [7]. The time point start isovolumic contraction can be detected in the CCA distension waveform, but not in the AA distension waveform. If the pressure waveforms along the arterial tree in the wave propagation model are studied, it can be observed that the peak caused by the isovolumic contraction is well distinguishable at the aortic arch. Looking at the CCA the peak caused by the isovolumic contraction is also well visible and even becomes larger. However, going in the direction of the AA the peak caused by the isovolumic contraction is attenuated and neighbouring peaks are increased, so that the start of the isovolumic contraction cannot be detected in the abdominal aorta. Thus to detect the start of the isovolumic contraction, it is necessary to measure the distension waveform of the CCA. The wave propagation model is also used to study the influence of the E-modulus and arterial diameters on the transfer function. The amplitude spectra of the transfer function are sensitive to variation in radius and E-modulus, thus the radius and E-modulus have a different influence on the distension waveform of the AA and CCA. Therefore it can be said that the radius and E-modulus are deciding factors in the transfer function and it is recommended to include these in the transfer function between CCA and AA. Karel van den Hengel - 5 -

53 MSC. THESIS-MEDICAL ENGINEERING 9 Chapter 5 - Conclusion The goal of this study was to investigate the relationship between (characteristics of) the distension waveforms as measured in the abdominal aorta (AA) and in the common carotid artery (CCA). It is shown that a higher distension waveform in the CCA does not correspond to a higher distension waveform in the AA within a subject. However the correlation between the pulse pressure of the AA and CCA is.83 between subjects, so the pulse pressure of the AA can be approximated based on the pulse pressure of the CCA. The E-modulus and the pulse wave velocity of the CCA and the AA are similar; however as correlations are not significant, E-modulus nor pulse wave velocity in the AA can be approximated from respectively E-modulus and pulse wave velocity in the CCA. With regards to the time characteristics of the CCA and AA distension waveforms, the start of the isovolumic contraction is no detectable in the AA, so for this time point it is necessary to measure in the CCA. The correlation between the ejection period of the CCA and the ejection period of the AA is.91, and ejection period can thus be assessed from either distension waveforms. It is favourable to use the CCA distension waveform for screening based on time characteristics, because a decreased ejection period and an increase of the isovolumic contraction are both cardiovascular disease (CVD) risk indicators. Applying transfer functions based on single beats or individual volunteer measurements to estimate the AA distension waveform from the CCA distension waveform result in only small errors. General transfer functions between CCA and the AA distension waveforms show larger variations in amplitude and phase, and this result in large errors in amplitude and time shift of the estimated AA distension waveform. Research with the wave propagation model showed significant influence of the radius and E-modulus of the arteries on the transfer function. Therefore the radius and E-modulus should be included in the transfer function between the AA and CCA distension waveform. The overall conclusion of this study is that it is currently not possible to translate the CCA distension waveform to the AA distension waveform, or to derive most cardiovascular disease indicators in the AA distension waveform from the CCA distension waveform, it is still necessary to measure the AA. Patient-specific information is necessary, such as Young s modulus from the arterial tree and radius from both arteries, to determine a reliable transfer function between CCA and AA. 5.1 Recommendations For transfer function determination more complex computational models can be developed which include more patient-specific information. It would also be interesting to compare these models with transfer functions used in commercial products. It seems possible to derive the pulse pressure and the characteristic time point ejection period for the AA based on the CCA distension waveform. This research can also be performed on patients to investigate possible differences caused by cardiovascular diseases. Karel van den Hengel

54 MSC. THESIS-MEDICAL ENGINEERING 9 Measurements done in Paris at Paris HEGP by Pierre Boutouyrie for ESAOTE Europe, showed that it was possible to measure in patients suffering from cardiovascular disease, even when the age of the patients was over 6 years and the AA at a depth of 11 cm. Such measurements demand good ultrasound skills, but first results showed good opportunities for further AA research. Karel van den Hengel

55 MSC. THESIS-MEDICAL ENGINEERING 9 Samenvatting Hart en vaat ziektes zijn hedendaags een belangrijke oorzaak van overlijden. Hart en arterieel functioneren is zichtbaar in verandering van de diameter (distensie) golfvorm van de centrale slagaderen. Daarom wordt de distensie golfvorm gemeten en geanalyseerd voor het bepalen van het risico op hart en vaat ziektes. Risico indicatoren zichtbaar in the distensie golfvorm zijn puls druk, puls golf snelheid en karakteristieke tijdspunten. Tot nu toe wordt de distensie golfvorm van de halsslagader gebruikt, omdat deze dicht onderhuids ligt en eenvoudig bereikbaar is met ultrageluid. Echter is the aorta direct verbonden aan het hart en zal daarom de meeste invloed ondervinden van hart en vaat ziektes op de distensie golfvorm. Het doel van deze studie is daarom om een relatie te vinden tussen de risico-indicatoren bepaalt uit de distensie golfvorm van de abdominale aorta (AA) en de distensie golfvorm van de halsslagaders. Opeenvolgende en simultane metingen van de distensie golfvormen in de AA en halsslagader zijn gedaan met een ultrageluid scanner met ART.LAB technologie (Picus, Esaote Europe) op respectievelijk veertien en drie gezonde vrijwilligers. De AA distensie golfvormen en halsslagader golfvormen zijn gesynchroniseerd en gemiddeld door synchrone ECG metingen. Tevens is de radiale bloeddruk continue mee gemeten (Colin, USA). De metingen tonen dat tijdens synchrone metingen een grotere distensie golfvorm in de halsslagader niet correspondeert met een grotere distensie golfvorm in de AA. De arteriële distensibiliteit was gemiddeld gelijk voor beide slagaders, maar voor een proefpersoon kan grote variatie tussen de AA and halsslagader distensibiliteit gevonden worden. De lokale pulsgolf snelheid was significant hoger in de AA dan in de halsslagader. De gemeten pomp periode van het hart bepaald uit de distensie golfvorm van de AA, was gelijk aan the pomp periode van het hart bepaald uit de distensie golfvorm van de halsslagader. Echter, de start van isovolumische hart contractie was niet herkenbaar in de AA distensie golfvorm. Uit analyse met een 1D golfvoortplantingsmodel bleek dat deze karakteristieke golf uitgedempt was langs the aorta, het was niet langer te onderscheiden in de golfvorm. Als er een generale overdrachtsfunctie tussen de AA en halsslagader distensie golfvormen bepaald wordt, zou de distensie golfvorm van de AA bepaald kunnen worden uit de distensie golfvorm van de halsslagader. Echter is er grote variatie in overdrachtsfunctie tussen individu. Bij gebruik van een generale overdrachtsfunctie om de AA distensie golfvorm te genereren uit de gemeten halsslagader distensie golfvormen, resulteerde in grote afwijkingen tussen gemeten en gegenereerde AA distensie golfvormen. Uit analyse met een 1D golfvoortplantingsmodel blijkt dat de transfer functie sterk wordt beïnvloed door arteriële elasticiteitsmodulus en arteriële radii. Het zou misschien beter zijn om de transfer functie meer specifiek te maken door er de arteriële elasticiteitsmodulus en arteriële radii in op te nemen Karel van den Hengel

56 MSC. THESIS-MEDICAL ENGINEERING 9 Conclusie, hedendaags is het nog niet mogelijk om de meeste hart en vaat ziekte indicatoren uit de AA distensie golfvorm te benaderen met de distensie golfvorm van de halsslagader. Enkel the pomp periode en puls druk zijn gelijk. Het blijft noodzakelijk de aorta te meten om de andere hart en vaat ziekte indicatoren te bepalen. Om het gebruik van een transfer functie mogelijk te maken is het toevoegen van individuele informatie noodzakelijk, bijvoorbeeld arteriële elasticiteitsmodulus en arteriële radii, maar meer onderzoek in nodig. Toekomstig onderzoek op hart en vaat ziekte patiënten is ook nodig, om te kijken of de conclusies nog steeds gelden voor zieke slagaders. Karel van den Hengel

57 MSC. THESIS-MEDICAL ENGINEERING 9 References 1. Meinders, J.M., et al., Assessment of the spatial homogeneity of artery dimension parameters with high frame rate -D B-mode. Ultrasound in Medicine & Biology, 1. 7(6): p Brands, P.J., et al., A radio frequency domain complex cross-correlation model to estimate blood flow velocity and tissue motion by means of ultrasound. Ultrasound in Medicine & Biology, (6): p Leng, G.C., et al., Incidence, Natural History and Cardiovascular Events in Symptomatic and Asymptomatic Peripheral Arterial Disease in the General Population. Oxford Journals, (6): p W. Nichols, M.O.R., Mc Donald's Blood Flow in Arteries. fifth ed. 5: Hodder Arnold Dijk, J.M., et al., Carotid stiffness and the risk of new vascular events in patients with manifest cardiovascular disease. The SMART study. European Heart Journal, 5. 6(1): p Laurent, S., et al., Expert consensus document on arterial stiffness: methodological issues and clinical applications. European Heart Journal, 6. 7(1): p Van Bortel, L.M.A.B., H.A.J. Struijker-Boudier, and M.E. Safar, Pulse Pressure, Arterial Stiffness, and Drug Treatment of Hypertension. Hypertension, 1. 38(4): p Reneman, R.S., J.M. Meinders, and A.P.G. Hoeks, Non-invasive ultrasound in arterial wall dynamics in humans: what have we learned and what remains to be solved. European Heart Journal, 5. 6(1): p De Simone, G., Roman MJ, Koren MJ, Mensah GA, Genau A, Devereux RB., Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension. Hypertension, : p Westerhof, N., N. Stergiopulos, M.I.M. Noble, Snapshots of hemodynamis: an aid for clinical research and graduate education. 5: Springer Science+Business Media, Inc. 11. Shao, X., D.-Y. Fei, and K.A. Kraft, Computer-assisted evaluation of aortic stiffness using data acquired via magnetic resonance. Computerized Medical Imaging and Graphics, 4. 8(6): p Stevanov, M., J. Baruthio, and B. Eclancher, Fabrication of elastomer arterial models with specified compliance.. p Leguy, C.A.D., et all, Estimation of arterial mechanical properties using a reverse method and a patient specific wave propagation model. IN Press, IN PRESS, Safar, M.E., New problems raised by increased pulse pressure. European Heart Journal, 5. 6(): p Reesink, K.D., et al., Carotid artery pulse wave time characteristics to quantify ventriculoarterial responses to orthostatic challenge. Journal of Applied Physiology, 7. 1(6): p Karel van den Hengel

58 MSC. THESIS-MEDICAL ENGINEERING Rhodes, J., et al., A new noninvasive method for the estimation of peak dp/dt. Circulation, (6): p Ahlgren, Å.R., et al., Stiffness and diameter of the common carotid artery and abdominal aorta in women. Ultrasound in Medicine & Biology, (7): p Asmar, R., et al., Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. American Journal of Hypertension, 1. 14(): p Westerhof, B.E., et all, Arterial pressure tranfer characteristics: effects of travel time. american journal of physiology : heart and circulatory physiology, 6. 9: p. H8-H87.. Karamanoglo, M.a.F., Derivation of the ascending aorta-carotid pressure tranfoer function with an arterial model. American journal of physiology : heart and circulatory physiology, : p. H399-H Segers, P., et al, Individualizing the aorto-radial pressure transfer function: feasibility of a model-based approach. American journal of physiology : heart and circulatory physiology. 79: p. H54-H549.. Westerhof, B.E., et al., Individualization of transfer function in estimation of central aortic pressure from the peripheral pulse is not required in patients at rest. Journal of Applied Physiology, 8. 15(6): p Stergiopulos, N., et all, Physical basis of pressure transfer form periphery to aorta: a model-based study. American journal of physiology : heart and circulatory physiology, : p. H1386-H Chen, C.-H., et al., Estimation of Central Aortic Pressure Waveform by Mathematical Transformation of Radial Tonometry Pressure : Validation of Generalized Transfer Function. Circulation, (7): p Lowe, A., et all, Non-invasive model-based estimation of aortic pulse pressure using suprasystolic brachial pressure waveforms. Journal of Biomechanics, 9. 4: p Bessems, D., M. Rutten, and F. Van De Vosse, A wave propagation model of blood flow in large vessels using an approximate velocity profile function (-1): p Bessems, D., et al., Experimental validation of a time-domain-based wave propagation model of blood flow in viscoelastic vessels. Journal of Biomechanics, 8. 41(): p Leguy, C.A.D., et al., A Patient Specific Wave Propagation Model of the Upper Limb. Artery Research, 7. 1(): p Reymond, P., et all, Validation of a one-demensional model of the systemic arterial tree. American journal of physiology : heart and circulatory physiology, 9. 91: p. H8-H. 3. Cobbold, R.S.C.U.o.T., Foundations of Biomedical Ultrasound. First Edition ed. 7: Oxford University Press. 31. Hill, C.R., Bamber,J.C., ter Haar,G.R., Medical Ultrasonics. Second Edition ed. 4: Wiley. Karel van den Hengel

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60 MSC. THESIS-MEDICAL ENGINEERING Demolis P D, A.R.G., Levy B I and Safar M E Non-invasive evaluation of the conduit function and the buffering function of large arteries in man Clinical Physiological, 1991(11): p Ferrara L A, M.M., Iannuzzi R, Marotta T, Gaeta I, Pasanisi F, Postiglione A and Guida L Carotid diameter and blood flow velocities in cerebral circulation in hypertensive patients Stroke : p Hansen F, M.P., Sonesson and L anne T Diameter and compliance in the human common carotid artery variations with age and sex Ultrasound Medicine Biology, : p Boutouryrie, P., et all, Associations entre propriétés viscoélastiques des grosses arteres et les composants de la matrice extracellulaire dans l'anévrysme de 'l aorte abdominale chez l'homme. Thérapie, : p Hansen, F., et al., Non-invasive measurement of pulsatile vessel diameter change and elastic properties in human arteries: a methodological study. Clinical Physiology and Functional Imaging, (6): p Jondeau, G., et al., Central Pulse Pressure Is a Major Determinant of Ascending Aorta Dilation in Marfan Syndrome. Circulation, (): p Long, A., et al., Aortic compliance in healthy subjects: evaluation of tissue Doppler imaging. Ultrasound in Medicine & Biology, 4. 3(6): p Wemple, R.R. and L.F. Mockros, Pressure and flow in the systemic arterial system. Journal of Biomechanics, (6): p Safar, M.E. and A. Benetos, The shape of the blood pressure curve and genetic hypertension. Trends in Cardiovascular Medicine, (3): p Rogers, W.J., et al., Age-associated changes in regional aortic pulse wave velocity. Journal of the American College of Cardiology, 1. 38(4): p Hope, S.A.a., et al., Use of arterial transfer functions for the derivation of aortic waveform characteristics. Journal of Hypertension, 3. 1(7): p Karel van den Hengel - 6 -

61 MSC. THESIS-MEDICAL ENGINEERING 9 Appendixes Appendix 1 Protocol Research Protocol - Ultrasound wall velocity measurements on AA and CCA - Introduction Cardiac and arterial functioning is reflected in the distension (change in diameter) waveforms of central arteries. For analyses, the distension waveform of the common carotid artery (CCA) is used, as the CCA is superficial and is easily accessible with ultrasound (US). However, the abdominal aorta (AA) is directly connected to the aortic root and therefore more pronounced influence of cardiovascular diseases on the AA pulse waveform is expected. The aim of this study is to compare the pulse waveforms in AA and CCA. Aim The aim of this study is to compare the pulse waveforms in AA and CCA. Study Population The measurements will be done on healthy subjects (in the rest of the protocol called volunteer). Research group: o 14 healthy volunteers Inclusion criteria: o Informed consent o Age >18 year Exclusion criteria: o Familiar / a history of with cardio vascular diseases o Diastolic blood pressure over 11 mmhg (Hypertension). o Smoking. Method To collect the ultrasound data, the following steps are made. Requirements 1. PICUS Esoate Ultrasound System with ART.LAB.. 1 MHz probe 3. 5 MHz probe 4. Colin 5. ECG sensor stickers 6. Body marker Karel van den Hengel

62 MSC. THESIS-MEDICAL ENGINEERING 9 7. Harddisk to save the data. 8. Tape line Preparation 1. The volunteer is welcomed in the measurement room en informed about the measurement,. The volunteer has to sign the Informed Consent (Appendix 1). 3. The volunteer is asked to undress his upper trunk and to lie down on the measuring table on his back. The volunteer has to rest 15 min before ultrasound measurements can take place and the blood pressure must be constant (3 times cuff measurements within 1 mmhg). Measurement Conditions [6]: Confounding factor Room temperature Rest Time of the day Smoking, eating Alcohol Speaking, sleeping Position White coat effect Cardiac arrhythmia In practice Controlled environment kept at C At least 15 min in recumbent position Similar time of the day for repeated measurements Subjects have to refrain, for at least 3 h before measurements, particularly from drinking beverages containing caffeine Refrain from drinking alcohol 1 h before measurements Subjects may neither speak nor sleep during measurements Supine position is necessary. Influence on blood pressure and pressure-dependent stiffness Be aware of possible disturbance 4. The system is started, the ECG sensors are stuck to the body and the Colin system is installed. CCA - Ultrasound 1 MHz Probe - Heart - ECG sensors - ECG Brachial - Colin - Waveform Aorta - Ultrasound 5 MHz Probe - Figure A1.1: Overview measurement sides. Karel van den Hengel - 6 -