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Exp Fluids (2010) 48:837–850 DOI 10.1007/s00348-009-0771-x RESEARCH ARTICLE Assessment of left heart and pulmonary circulation flow dynamics by a new pulsed mock circulatory system David Tanné • Eric Bertrand • Lyes Kadem Philippe Pibarot • Régis Rieu • Received: 20 February 2008 / Revised: 2 October 2009 / Accepted: 2 October 2009 / Published online: 4 November 2009 Ó Springer-Verlag 2009 Abstract We developed a new mock circulatory system that is able to accurately simulate the human blood circulation from the pulmonary valve to the peripheral systemic capillaries. Two independent hydraulic activations are used to activate an anatomical-shaped left atrial and a left ventricular silicon molds. Using a lumped model, we deduced the optimal voltage signals to control the pumps. We used harmonic analysis to validate the experimental pulmonary and systemic circulation models. Because realistic volumes are generated for the cavities and the resulting pressures were also coherent, the left atrium and left ventricle pressure–volume loops were concordant with those obtained in vivo. Finally we explored left atrium flow pattern using 2C3D?T PIV measurements. This gave a first overview of the complex 3D flow dynamics inside realistic left atrium geometry. D. Tanné E. Bertrand R. Rieu Equipe Biomécanique Cardiovasculaire, IRPHE-UMR 6594, CNRS, Aix-Marseille Université, Marseille, France D. Tanné P. Pibarot Quebec Heart and Lung Institute/Laval Hospital, Laval University, Sainte-Foy, QC, Canada D. Tanné Protomed, Marseille, France Abbreviations MCS Mock circulatory system LA Left atrium LV Left ventricle PA Pulmonary arteries AO Aorta PIV Particle image velocimetry LV, LA xx Vxx(t) Volume of the cavity in ml Vaxx ðtÞ Volume of the residual air inside the activation box in ml Vacxx ðtÞ Volume of the activation fluid in ml Qacxx ðtÞ Activation flow in l/min Qaxx ðtÞ Residual air flow that is the variation of the air volume due to compressibility in l/min Qav(t) Aortic valve flow in l/min Qmv(t) Mitral valve flow in l/min Qpv(t) Pulmonary venous flow in l/min Pxx(t) Pressure in the cavity in mmHg Paxx ðtÞ Pressure in the residual air compliance in mmHg Ucxx ðtÞ Reference voltage signal that actuates the gear pump in V hxx ðtÞ Open loop transfer function of the pump Caxx ; Eaxx Residual air compliance (Caxx ) and elastance (Eaxx ¼ 1=Caxx ) in ml/mmHg and mmHg/ml, respectively L. Kadem Department of Mechanical and Industrial Engineering, Concordia University, Montreal, QC, Canada R. Rieu (&) Equipe Biomécanique Cardiovasculaire, ECM, IMT Technopole de Château-Gombert, 38 Rue Joliot-Curie, 13383 Marseille cedex 13, France e-mail: [email protected] 1 Introduction Mitral valve dysfunction includes the following: (1) mitral stenosis that occurs when the valve orifice is narrowed, 123 838 which leads to an augmentation of the pressure difference across the valve or (2) mitral regurgitation that occurs when the valve is leaking during cardiac contraction, which leads to a volume overload in the left atrium (LA). Both types of dysfunction will thus cause an increase in the LA pressure and then to a passive elevation of the pressure in the pulmonary arteries (PA). When mitral valve disease and PA hypertension become severe, it is necessary to perform a surgical correction of the valve dysfunction. The surgeon generally attempts to repair the diseased native valve. However, in a substantial proportion of the patients (10–30%), the valve cannot be repaired and needs to be replaced by a prosthetic (biological or mechanical) valve. The main goals of mitral valve replacement are, therefore, to restore normal valvular hemodynamics and to normalize PA pressure. Unfortunately, the regression of PA pressure after the replacement may vary extensively from one patient to the other and is often incomplete (Leavitt et al. 1991; Zielinski et al. 1993). Moreover, some patients with normal or mildly elevated PA pressure before operation may develop moderate or severe PA hypertension after mitral valve replacement suggesting that the implantation of a prosthetic valve may cause an elevation in LA and PA pressures. Indeed, the implantation of an under-sized prosthetic valve (prosthesis–patient mismatch) is associated with persistent PA hypertension (Leavitt et al. 1991; Li et al. 2005; Zielinski et al. 1993) and higher mortality (Lam et al. 2007; Magne et al. 2007). These findings underline the importance of identifying and, whenever it is possible, avoiding the factors that promote the persistence or progression of PA hypertension following mitral valve replacement. As opposed to in vivo studies, mock circulatory systems (MCS) are powerful tools to dissect out the independent contribution of each prosthesis- and/or patient-related factor to the variation of LA and PA pressures. We therefore developed a new MCS able to reproduce the left heart hemodynamics and the systemic and pulmonary circulatory systems. In the vast majority of the atrio-ventricular models published in the literature, the LA shape is very simplified, most likely because these studies were primarily focused on the intra-ventricular flow dynamics. Some investigators have used a spherical-shaped LA with one pulmonary venous inlet (Kadem et al. 2005; Reul et al. 1981), a rigid box (Balducci et al. 2004; Marassi et al. 2004; Morsi and Sakhaeimanesh 2000), whereas others simply used a box-tank as a LA chamber (Akutsu and Masuda 2003; Cenedese et al. 2005; Kini et al. 2001; Pierrakos et al. 2004; Steen and Steen 1994). Mouret et al. (2004) used particle image velocimetry (PIV) measurements to explore LA flow dynamics in normal sinus rhythm and in atrial fibrillation conditions using a more realistic 123 Exp Fluids (2010) 48:837–850 LA shape with two symmetrical pulmonary veins. Verdonck et al. (1992) also used this kind of LA shape. The purpose of this study was to develop a MCS that accurately simulates the human blood circulation from the pulmonary valve, i.e., the right ventricular outflow, to the peripheral systemic capillaries. To this effect, it was essential to control flows and pressures in each subsystem (pulmonary circulation, LA, LV, aorta and systemic circulation) to ensure a fluid dynamic behavior close to the one found in the human circulation. Furthermore, to study the flow dynamics inside the LV and the LA, an optical access to the two cavities is required for the acquisition of velocity fields by PIV. In this paper, we present validation data for pressures, flows and volumes, harmonic analysis and PIV measurements in experimental conditions mimicking the physiological situation of a healthy subject without PA hypertension. 2 MCS design We enhanced our previous dual activation atrio-ventricular simulator (Mouret et al. 2000) to study LA and PA flow dynamics. The LA activation was modified to allow a complete control of the atrial volume. We added a model of the pulmonary circulation that simulates the compliance and the resistance of vessels in the lungs. An additional gear pump was also incorporated to simulate the right ventricular ejection into the pulmonary circulation. Figure 1 shows a schematic representation of this new MCS and a photo of the atrio-ventricular device. Two deformable silicon molds are independently compressed or stretched using two gear pumps (Issartier et al. 1978) in order to mimic both LA and LV contractions and relaxations and to allow the displacement inside the molds of the fluid of interest, a blood analog named circulatory fluid. Each mold is enclosed in a rectangular box completely filled with a fluid, named activation fluid, to ensure adequate atrio-ventricular synchronization and to enable PIV measurements (see Sects. 2.2.3, 4.3 for more details). 2.1 Silicon mold production The rationale for using transparent deformable silicon molds is not only to reproduce the deformation of cardiac cavities but also to assess the flow patterns within the cavity using optical techniques such as PIV. The geometry of the cavity strongly influences the velocity fields. Furthermore, Munson et al. (2005) have reported for orifices a loss coefficient and differences in flow organization depending on the shape of the entrance region, i.e., the LA shape before the mitral prosthesis. We thus elected to reproduce a human anatomical-shaped LA cavity. Images Exp Fluids (2010) 48:837–850 839 Fig. 1 a Description of the new left heart and pulmonary circulation mock circulatory system. Two independent activation fluid circuits (dash line) allow the circulation of the blood analog fluid (continuous line). Aortic valve (AV); mitral valve (MV); pulmonary valve (PV); right ventricle (RV); resistance (R); compliance (C); pump (P); see list for other abbreviations. b The left atrio-ventricular device were obtained by multidetector computed tomography (512 pixels 9 512 pixels) in a healthy subject in sinus rhythm (heart rate: 66 bpm). The field of view was 250 mm 9 250 mm resulting in a spatial resolution of 0.488 mm. To reconstruct the 3D end-systolic internal volume of the LA, 190 slices (voxel thickness = 0.625 mm) were used (Fig. 2a). Each slice was segmented by a simple threshold method, and the resulted contours were smoothed using cubic splines. We used SolidWorks (SolidWorks, MA, USA) to slightly modify the shape of the LA (Fig. 2b). The native oval shape of the mitral orifice became circular (diameter = 29 mm) to better simulate the situation of patients with a mitral prosthetic valve. The shape of the ostial sections of the pulmonary veins were preserved over a distance of 1 cm and then smoothed to a 10 mm circular section, which were extended by a tube of length 60 mm to pass through the wall of the activation box. The LA appendage is a long, hooked and crenellated structure which length and orifice size vary considerably in vivo (Ernst et al. 1995). Figure 2a confirms this very complex shape. We therefore elected to simulate it by a 5 ml volume smoothed cavity with length of 18 mm and a minimum and maximum orifice size of 14 and 28 mm, respectively (Fig. 2b). These values are in agreement with those of Ernst et al. (1995). Then, an aluminum matrix (Fig. 2c) was manufactured using a 5-axis milling machine to allow the casting of external successive layers of silicon (Silopren LSR 2050, GE Bayer Silicones). We added cylindrical aluminum parts to the matrix at the end of the pulmonary veins and the mitral valve to simultaneously mold the atrium and flanges. These flanges ensure the watertightness and allow an Fig. 2 a Three-dimensional atrial volume reconstruction from images acquired by computed tomography in a healthy subject. The mitral valve (MV) is in the back. Two of the pulmonary veins are visible (LLPV left lower pulmonary vein, RUPV right upper pulmonary vein), whereas the two others are hidden by the atrial body. The atrial appendage (LAA) is below the mitral valve. The image also shows the ascending (in transparency on the left of the atrium) and the descending (in transparency on the right) aorta. The right (RV) and left (LV) ventricles are displayed on the lowest slice while the upper slice shows the pulmonary arteries (AP). b Design of the simplified atrial volume. c The aluminum matrix. d The final silicon mold that is inserted in the atrial activation box 123 840 adequate and reproducible positioning of the cast. The removal from the mold consisted first in undoing the veins and then the atrial body (Fig. 2d). 2.2 Numerical model of the LA and LV hydraulic activation Recently, Colacino et al. (2007) have developed a numerical model of pneumatically driven LV mold. In the past, we used a hydro-pneumatic activation for the LA box (Mouret et al. 2000) to attenuate pressure oscillations. Now, we elected to validate the idea of two independent hydraulic activations using a lumped model. The two main advantages of hydraulic activations are the assessment and the control of the volume of the two cavities and the minimization of the distance between the LA and the LV by removing the flowmeter that was inserted in the mitral position in our previous MCS (Mouret et al. 2000). In counterpart, this necessitates an optimal synchronization between the two cavities to prevent high pressure variations. In this context, the lumped model allowed us to find the relationship between instantaneous pressures, volumes, flows and the pump voltage signals inside the LA and LV activation circuits. 2.2.1 Lumped model Figure 3a and b shows a schematic representation of the two activation boxes. Although these boxes are completely filled with fluid, some air bubbles may still remain in the Fig. 3 Schematic representation of the ventricular (a) and atrial (b) activation boxes and the corresponding deformable control volumes including the molds (Vxx(t), Pxx(t): light gray), the activation fluids (Qacxx ðtÞ, Vacxx ðtÞ: mid gray), and the residual air compliances (Qaxx ðtÞ, Paxx ðtÞ, Vaxx ðtÞ: dark gray) 123 Exp Fluids (2010) 48:837–850 circuit. It is therefore important to analyze the effect of a residual compliance, due to the compressibility of air, on the activation performance. We have represented schematically the remaining air bubbles as a global volume Vaxx ðtÞ at the top of the boxes. Because the internal total volumes of the LV and LA boxes remain constant during the cardiac cycle, the first time derivatives of VLV(t) and VLA(t), the ventricular and atrial volumes, respectively, are related to the variations of, on one hand, the volume of the activation fluid Vacxx ðtÞ and, on the other hand, the volume of air Vaxx ðtÞ: oVxx ðtÞ oVa ðtÞ oVacxx ðtÞ ¼ xx where xx ¼ LV; LA ot ot ot ð1Þ Vxx ðtÞ; Vacxx ðtÞ and Vaxx ðtÞ are deformable control volumes defined by their respective control surfaces (fixed walls of the boxes, moving walls of the molds and moving activation fluid-air interfaces). Using the Reynolds transport theorem, the flow Qaxx ðtÞ that crosses the control surface defining the volume of air Vaxx ðtÞ is proportional to the variations of Vaxx ðtÞ: oVaxx ðtÞ ¼ Qaxx ðtÞ where xx ¼ LV; LA ot ð2Þ The volume of air is a Windkessel model characterized by the compliance Caxx . The related pressure Paxx ðtÞ is therefore: oPaxx ðtÞ Qaxx ðtÞ ¼ ot Caxx where xx ¼ LV; LA ð3Þ Exp Fluids (2010) 48:837–850 841 Since there was no communication between the activation and the circulatory fluids, the Reynolds transport theorem applied to the mass leads to: oVLV ðtÞ ot ¼ Qmv ðtÞ Qav ðtÞ ð4Þ oVLA ðtÞ ¼ Qpv ðtÞ Qmv ðtÞ ot where Qav(t), Qmv(t) and Qpv(t) are, respectively, the aortic valve, mitral valve and pulmonary venous flows. Similarly, the variation of the volume of the activation fluid is proportional to activation flow Qacxx ðtÞ: oVacxx ðtÞ ¼ Qacxx ðtÞ ot where xx ¼ LV; LA ð5Þ (LV: gain = 10 dB, -3 dB cut-off frequency = 1.7 Hz. LA: gain = 9.2 dB, -3 dB cut-off frequency = 1.8 Hz) using a frequency analysis. Therefore, one way to compute reference voltage signals actuating the pumps is simply to define the three flows Qav(t), Qmv(t) and Qpv(t) either manually or from in vivo flow echocardiographic or magnetic resonance imaging data. Furthermore, to increase the rapidity of the pump response and attenuate the dynamical error between Ucxx ðtÞ and Qacxx ðtÞ; a standard proportional–integral–derivative algorithm has been implemented on a CompactRIO real time servo-controller (National Instrument, Austin, USA). 2.2.2 Determination of the residual compliance Caxx 2.2.4 Mitral prosthetic valve mounting For the hydraulic activation, Vaxx ðtÞ must be as small as possible. To determine this residual volume of air after the complete filling of the boxes, we measured its corresponding compliance. If Qav(t), Qmv(t) and Qpv(t) are equal to 0, there are no variations of the ventricular and atrial volumes since they still remain filled with the circulatory fluid. Using the Eqs. 1, 3 and 5 and assuming in first approximation that the pressure inside the box is the same at any location (i.e., Paxx ¼ Pxx ), the compliance Caxx verifies: The prosthetic valve is mounted on a ring, adaptable to the model and the size of the prosthesis, which is inserted in the external wall of the LA and LV activation boxes. Whereas the atrial box is fixed, the ventricular one is placed on ball-bearing rails. A compression using a rapid tightening system allows the watertightness between the two boxes and the valve ring. Only the circulatory fluid has to be drained to change the prosthesis. Therefore, the mitral valve can be rapidly and easily changed to perform, for instance, preclinical evaluation of prosthesis in standardized physiological and pathological conditions. Another major improvement is that the double hydraulic activation allows us to avoid the insertion of a flowmeter probe in the mitral position so that the circulatory fluid goes directly from the LA through the mitral valve into the LV. Inserting a flowmeter proximal to the mitral valve funnels the flow by adding a straight tube, which leads to unphysiological flow dynamics. However, according to the numerical model, the mitral flow can be derived by two ways from the measurement of the aortic, the pulmonary venous and the two activation flows as described in: Qacxx ðtÞ Caxx ¼ oPxx ðtÞ=ot where xx ¼ LV; LA ð6Þ In practice, we will demonstrate in Sect. 3.1.1 that the compliance Caxx is about 0 ml/mmHg so that the LV and LA activations are not hydro-pneumatic (i.e., Vaxx 0 ml). Therefore, in the future equations, we will assume that Qaxx ðtÞ 0. 2.2.3 References for the pump voltage signals As opposed to pneumatic or hydro-pneumatic activation where the compressibility of air acts as a smooth filter on the pressures, the use of two independent hydraulic activations implies an optimal synchronization between the two pumps to avoid, for instance, an atrial contraction which is more pronounced than the ventricular relaxation and consequently the occurrence of LA and LV high pressures. If hxx(t) is the pump open loop transfer function, the combination of Eqs. 1, 4 and 5 leads for a hydraulic activation to: U ðtÞ ¼ h ðtÞ Q ðtÞ ¼ h ðtÞ ½Q ðtÞ Q ðtÞ cLV LV acLV LV av mv UcLA ðtÞ ¼ hLA ðtÞ QacLA ðtÞ ¼ hLA ðtÞ Qmv ðtÞ Qpv ðtÞ ð7Þ where Ucxx ðtÞ is the reference voltage signal, i.e., the voltage signal that control the pump, and is the convolution product. hxx(t) has been found to be a low-pass filter Qmv ðtÞ ¼ Qav ðtÞ QacLV ðtÞ ¼ Qpv ðtÞ þ QacLA ðtÞ ð8Þ 2.2.5 LA and LV volume computation Finally, the numerical model predicts that the instantaneous volume of each cavity can be accessed from the measurement of the activation flows by integrating Eq. 1 and replacing the third term by Eq. 5: Z Vxx ðtÞ ¼ Qacxx ðtÞ þ Vxx0 where xx ¼ LV; LA ð9Þ t The initial volume is the volume of each mold at rest. It is equal to 76 ml for the LA and 93 ml for the LV. The reference voltage signals Ucxx ðtÞ can thus be also derived from reference LA and LV volumes defined 123 842 Exp Fluids (2010) 48:837–850 manually or by in vivo imaging (magnetic resonance or echocardiography). We differentiate these volumes to assess the aortic, mitral and pulmonary venous flows (Eq. 4). Then, we compute the reference signals for optimal synchronization using the Eq. 7. In case of pulmonary hypertension, the left atrium is generally dilated with reduced contractility (Otto 2004). The high percentage of elongation of the Silopren LSR2050 allows us to simulate spherical-like atrial shape by further modifying the LA pump reference voltage signal. 2.3 Similitude Designing a pulsed cardiac simulator that adequately mimics the circulatory physiology of the human being is a complex task. As underlined by Cenedese et al. (2005), the fluid has strong structure interactions with the valvular prosthesis and the wall of the cavities such that the most reliable scale is 1:1. As the design of the MCS is based on an anatomical-shaped LA and we use commercially available mechanical or biological valve prostheses, this scale 1:1 is mandatory. For a confined unsteady flow, the two dimensionless numbers that govern fluid dynamic phenomena are the Reynolds number Re and the Strouhal number St (Marassi et al. 2004): Re ¼ qUD D and St ¼ l UT where D is the diameter of the mitral valve, U is the mitral E-wave peak velocity and T is the cardiac period. The density q and the dynamic viscosity l are dependent on the choice of the circulatory fluid. There are two Newtonian fluids typically used: water and a mixture of glycerol and water. We used the latter fluid because its viscosity is similar to the one of blood (4.10-3 N s m-2) by adjusting the proportion of glycerol (around 40%) in the mixture (Kadem et al. 2005; Marassi et al. 2004; Nguyen et al. 2004). We favoured the matching for the refractive index and the viscosity at the expense of the density. The mixture density is nevertheless close to the one of blood (1,130 kg m-3 and 1,060 kg m-3, respectively). Thus, the factor of similitude is 1 for all the dimensions as opposed to Cenedese et al. (2005) and Marassi et al. (2004) who increased the cardiac period by threefold since their circulatory fluid was simply water. Salt was added to the mixture (concentration: 1 g/L) for the use of the electromagnetic flowmeter. composed of a compliance, which accounts for the capacity of arteries and veins to accumulate and release some energy during the cardiac cycle, and a resistance, which models the total pressure loss. For the pulmonary circulation, we used a third pump to simulate the systolic right ventricular ejection, i.e., the pulmonary valve flow. The pump is inserted in the physiological circuit without addition of an activation box. The reference voltage signal is calculated so as the pump carries the same stroke volume as the LV does. To allow the diastolic decline of the PA pressure, a bioprosthetic valve (model Perimount, size 21, Carpentiers Edwards) is placed between the pump and the pulmonary compliance and resistance. As opposed to the systemic model, we added a second compliance between the resistance and the LA to mimic the pulmonary veins and capillaries compliance. Finally, the pulmonary vascular load results in a p-filter, which we also used in previous numerical simulations (Tanné et al. 2008). 3 Validation of the MCS We first verified the control and the application of the numerical model. Harmonic analysis was also performed to validate the pulmonary and systemic circulations. 3.1 Validation of the numerical model 3.1.1 Residual compliance measurement We have closed the LA and LV cavities by six quarter turn valves. In this context, the pumps are excited by a random disturbance. The activation flow is in that case a limitedbandwidth white noise (Eq. 7). The transfer function between the input Qacxx ðtÞ and the output P0xx ðtÞ ¼ oPxx ðtÞ=ot is therefore in the frequency domain: P^0 xx ðf Þ E^axx ðf Þ ¼ where xx ¼ LV; LA Q^acxx ðf Þ where ^ represents the Fourier transform. The Fourier transform of Eq. 6 implies that the compliance Caxx is the inverse of E^axx ðf Þ; so that, in the bandwidth, Caxx is equal to the inverse of the low frequency gain E^axx ð0Þ. We found that CaLV ¼ 0:061 ml/mmHg and CaLA ¼ 0:096 ml/mmHg: Compared to the systemic (2 ml/mmHg) or the pulmonary compliance (40 ml/mmHg), the residual air compliance can be neglected. Consequently, the flow Qaxx ðtÞ is about 0 ml and Eqs. 7–9 are, therefore, valid. 2.4 Systemic and pulmonary circulations 3.1.2 Mitral valve flow Regarding the aortic and pulmonary pressures, they are not only determined by the flows ejected by the ventricles but also by the vascular load. The systemic circulation is 123 In order to further validate the numerical model, we verified the suitability of Eq. 8. We have used our previous left Exp Fluids (2010) 48:837–850 heart simulator (Mouret et al. 2000) to measure simultaneously the aortic flow, the mitral flow and the LV activation flow. As opposed to the MCS reported in this article, this simulator includes an electromagnetic flowmeter (model SR670, Carolina Medical) between the atrium and the mitral prosthetic valve. Figure 4 depicts the mitral flow measured with our previous left heart simulator and that calculated from Eq. 8. During the diastole, there is a very good agreement between measured and calculated mitral flows. The residual air compliance has no significant effect, thus validating the Eq. 8. However, at the opening and closing of the valve, i.e., at high amplitude pressure drops, the remaining air is highly compressed or dilated and the flow Qaxx ðtÞ is then not null. Our previous simulator was not designed to easily remove air from the activation box and the pump so that an amount of air stayed inside the activation circuit. In the new circulatory system, particular efforts have been done to eliminate the residual air in the activation system. The pumps have been positioned vertically. All the connections have been machined to avoid stagnation region, and a dome has been hollowed out in the top of the ventricular box. We cannot verify the second part of the Eq. 8 because of the hydro-pneumatic atrial activation used in our previous simulator. However, as CaLA CaLV 0 ml/mmHg, we assume that the mitral flow can also be measured from the pulmonary venous and atrial activation flows. 3.2 Harmonic analysis Because the heart is a periodic pump, instantaneous flows and pressures can be decomposed in the frequency domain 843 using Fourier series. In particular, the ratio of the Fourier coefficients of pressure to those of flow describes the input impedance, which is in the aorta and the pulmonary arteries a measure of the left and right ventricle afterload, respectively (Nichols and O’Rourke 1998). The input resistance is the impedance at 0 Hz (ratio between the mean values) and the characteristic impedance is the mean value of the impedance for frequencies [2 Hz. Instead of analyzing the temporal variation of the measurements, the in vitro harmonic analysis is an efficient way to verify that the artificial arterial system operates in conditions similar to the human circulation (Westerhof et al. 1971). 3.2.1 Pressure spectrum Patel et al. (1965b) have described in vivo normal values for the pressure spectrum modulus. For each harmonic, we plot in Fig. 5a, the range of these normal values that we have normalized to the mean pressure. We have also plotted the spectrum of the AO, LV, LA and PA pressures measured with the MCS. The AO and PA moduli are in very good agreement with in vivo data suggesting that these in vitro simulated pressures are representative of the human circulatory physiology. The fundamental and the first harmonic of the LV spectrum modulus are also in the physiologic range. However, the amplitude of the other harmonics is too high. The amplitude variations of the instantaneous diastolic (time 0.45–0.85 s) ventricular pressure are too high compared to the systolic phase inducing high amplitude of the high-ranked harmonics (Fig. 5a). The phenomenon is more pronounced in the LA spectrum so that we have to normalize with the harmonic of higher amplitude. Nonetheless, if we scale (factor 1/20 to describe normal pressure amplitudes) our measured LA pressure, the relative amplitudes of each harmonic (spectrum modulus) come close to the normal values of Patel et al. (1965b), therefore, validating the shape of the LA pressure waveform (see Sect. 4.1 for more details). The high amplitude of the LA pressure does not significantly influence the mean value and waveform of the PA pressure because the mean LA pressure is within the normal range and the fluctuations in the LA pressure are damped by the pulmonary model. 3.2.2 AO and PA input impedances Fig. 4 Comparison between the measured (dash line) and the calculated (continuous line) mitral valve flow in our previous mock circulatory system (Mouret et al. 2000). Important differences are seen at the onset of valve closing and opening where the effect of the residual compliance is maximal, due to the sub optimal de-airing of the activation box in this previous simulator. This aspect has now been corrected in the new simulator We also measured the AO input impedance (Fig. 5b). The modulus and the phase are in accordance with previous published in vivo data (Patel et al. 1965a) or in vitro measurements (Cornhill 1977; Mouret et al. 2000). The input resistance is 1,680 dyn s cm-5. The characteristic 123 844 Exp Fluids (2010) 48:837–850 Fig. 5 a Normalized spectrum modulus (bold line) of the respective aortic, ventricular, atrial and pulmonary arterial pressures. Normal lines indicate the range of in vivo data from Patel et al. (1965b). Furthermore, we have added the ventricular and atrial spectrum modulus (dotted line) of our previous duplicator (Mouret et al. 2000). We have also simulated lower amplitude atrial pressure. Its modulus (bold dashed line) is in accordance with in vivo data suggesting that the variations of the atrial pressure are correct. b Normalized aortic and pulmonary input impedance modulus and phase (bold lines). These data are compared to aortic (Patel et al. 1965a) and pulmonary (Milnor et al. 1969) in vivo impedances. The results of Mouret et al. (2000) are also plotted (dotted line) for the aortic impedance impedance is 125 dyn s cm-5, representing 7% of the resistance and is smaller than the characteristic impedance measured on our previous MCS (Mouret et al. 2000). The shared property of all phase curves is the negative values up to 3 Hz, meaning that the flow leads in phase the pressure. In turn, we compared the PA input impedance (Fig. 5b) with the in vivo data of Milnor et al. (1969). The measured PA resistance and characteristic impedance are 369 and 35 dyn s cm-5, respectively, which is similar to the normal range of 160–430 dyn s cm-5 for the resistance and 18– 30 dyn s cm-5 reported in humans. In the case of PA hypertension, Huez et al. (2004) found that these values reach 1,506 ± 138 and 124 ± 18 dyn s cm-5, respectively. In this new MCS, values of pulmonary resistance and compliances can be changed easily to simulate PA hypertension. 123 4 Fluid dynamics analysis 4.1 Pressures, volumes and flows The AO, LV, LA and PA pressures are measured using Millar catheters (model MPC 500, accuracy 0.5% full scale). They are calibrated against a water column. Electromagnetic flowmeters (Gould Statham SP2202, accuracy within 10% full scale) are used to acquire the AO, pulmonary venous and valve flows whereas the two activation flows are measured using ultrasonic flowmeters (model 28A, accuracy 2% full scale with in situ calibration, Transonic System Inc., Ithaca, USA). The probes are clamped on homemade supports that limited acoustic impedance mismatches. They further allow in situ calibrations which have consisted in randomly distributed repeated measures of the time to fill a calibrated test-tube. Exp Fluids (2010) 48:837–850 845 The linearity of the calibration curve is assessed over the whole flow range of interest [0–35 L/min]. The volume of each cavity is calculated from the respective activation flow according to Eq. 9. The analog signals are sampled at 1 kHz using the CompactRIO controller (National Instrument). Figure 6a, b and c shows typical pressure, flow and volume waveforms obtained at a heart rate of 70 bpm. These waveforms are very similar to those obtained in humans (Braunwald et al. 2001; Klein and Tajik 1991). The small oscillations (harmonics [6) visible on the ventricular and aortic pressures are due to the vibration of the aortic mold wall which is presently too rigid. The major improvement offered by our MCS is that the synchronization of the LV and LA cavities allows the simulation of physiological variations of the LA pressure. Despite too high amplitude, the shape of the pressure waveform is very realistic (Neema et al. 2008): at the beginning of the ventricular systole, there is a decrease in LA pressure (A–x wave), which corresponds to the atrial relaxation, which is followed by the filling of the LA cavity by the pulmonary venous flow (S-wave). During this latter phase, the LA pressure therefore increases until aortic valve closure (V-wave) in late ventricular systole. At the beginning of the diastole, the mitral valve opens and the LV is filled rapidly, which translates into a decay in the LA pressure (V–y wave). During the diastasis, the atrium acts as a conduit and the flow goes directly from the pulmonary veins to the ventricle. At the end of the diastole the mitral flow increases (A wave) because of the atrial contraction, which in turn induces a LA pressure rise (A) and a reversal flow in the pulmonary veins (RevA wave). The good concordance between the shape of the LA pressure waveform and in vivo data has been already evidenced in Fig. 5a when a 1/20 scaling LA pressure spectrum has been found coherent with clinical data. Although a servo-controller was designed to ensure the optimal atrioventricular synchronization, a residual error persisted for the difference Qav ðtÞ QacLV ðtÞ Qpv ðtÞ QacLA ðtÞ; which theoretically should be 0. This is probably the main cause of high LA pressure variations. Since mathematically correct reference voltage signals were generated, the minimization of this error should be achievable by improving the servo-control algorithm by determining and correcting the nonlinearities in the system. Fig. 6 a Left ventricular (solid line) and left atrial (dotted line) volumes. b Aortic (dashed line), left ventricular (dotted line), left atrial (solid line) and pulmonary arterial (dot-dashed line) pressure. A–x and V–y are the two nadirs of the atrial pressure. V and A are the two specific peaks of atrial pressure. Despite the higher amplitude, the variations of the atrial pressure are in very good accordance with physiologic waveforms. c Aortic valve (solid line) and mitral valve (dot-dashed line) flows. E and A correspond to the rapid filling of the ventricle and the atrial contraction, respectively. d Pulmonary venous (dotted line) and pulmonary valve (dashed line) flows. S, D and RevA are the systolic, the diastolic and the reversal waves of the pulmonary venous flow. The dots correspond to the instant of the PIV measurements 4.2 Pressure–volume loops Another way to characterize the cardiac cavity is to plot the pressure–volume relationship. An excellent review of possible applications of these loops, mainly in the LV can 123 846 be found in (Burkhoff et al. 2005). Figure 7a and b report the ventricular and atrial pressure–volume loops obtained with our MCS. Because realistic volumes are generated for the cavities using hydraulic activations and the resulting pressures are also coherent, the in vitro pressure–volume loops are concordant with those obtained in vivo (Alter et al. 2008; Braunwald et al. 2001). In particular, the LA pressure–volume loop is composed of the two typical A- and V-loops (Dernellis et al. 1998; Hoit et al. 1994; Matsuda et al. 1983) corresponding, respectively, to the atrial contraction and relaxation. Due to the high LA and diastolic LV pressures variations, some parameters such as pressure–volume area and stroke work (Suga 2003) are over-estimated. Nonetheless, the end-systolic (Sensaki et al. 1996) and the effective arterial (Kelly et al. 1992) elastances remain quite close to normal values (2.4 and 1.7 mmHg/ml, respectively). The acquisition of such realistic experimental LA pressure–volume loops confirms the efficacy of our MCS to simulate human atrial flow dynamics. 4.3 Particle image velocimetry measurements 4.3.1 Methods We have designed the present MCS to have an optical access to both the LV and LA chambers. Furthermore, the silicon molds have been cured at ambient temperature, which provides a refractive index (n = 1.42) very close to the circulatory fluid (n = 1.38). They are also very thin (0.4 mm) so that the optical distortions are elusive despite the large deformations of the wall. To illustrate potential applications of our new MCS, we therefore describe results from two-components multi-planes (2C-3D?T) PIV in the left atrium under normal hemodynamic conditions (heart rate = 70 bpm, no pulmonary hypertension, no atrial dilatation). A double pulsed mini-YAG laser (120 mJ, 15 Hz, above the top wall of the LA activation box) and a CCD PIVCAM 10–30 camera (8 bits, 1,000 pixels 9 1,016 pixels, 30 Hz, at right angle with the laser Fig. 7 a Left ventricular pressure–volume loop. b Left atrial pressure–volume loop. The two physiologic A- and V-loops are well simulated 123 Exp Fluids (2010) 48:837–850 sheet on the rear side of the LA activation box, TSI Inc., Shoreview, MN, USA) are both mounted on a z-traverse micrometric displacement system. Twenty-two planes (z-axis resolution = 3 mm) slice the whole atrial body and the ostia of the pulmonary veins. The plane z = 0 mm coincides with the center of the mitral valve. For each plane, image pairs are acquired every 0.02678 s (32 phases per cardiac cycle) and repeated 30 times, which has been found sufficient to reach a statistical convergence for the velocities (Kadem et al. 2005). The circulatory fluid is seeded with Nylon polyamide particles (mean size: 15–20 lm, mean density: 1,130 kg/m3, Goodfellow, Huntingdon, England). The PIV system is synchronized with the pressure-flow measurements using an external trigger delivered by the CompactRIO controller. To decrease the total time of acquisition (some 6 h for the acquisition and the storage of 21 220 image pairs/41.9 GB), eight pairs are acquired per cardiac cycle (frequency = 9.3 Hz) with a constant pulse separation time equal to 300 ls. This time is calculated from the classical one-quarter displacement rule and from the measurement of the peak pulmonary venous flow rate stored by the electromagnetic flow-meter. Ensemble-averaged recursive cross-correlation is performed (Insight3G, TSI Inc.) starting from a 64 pixels 9 64 pixels interrogation area to a 16 9 16 spot size. A Nyquist FFT correlator algorithm is used. The calibration procedure consists in aligning a calibrated target with the laser sheet and acquiring one image per plane. The resulting x-axis and y-axis resolution varies from 98.6 lm/pixel (first plane near the camera, z = -24 mm) to 91.6 lm/ pixel (last plane far the camera, z = 39 mm). The center of the coordinate system (x- and y-axis) is assigned to the center of the mitral valve (see the coordinate system in Fig. 3). Vorticity maps are computed using the eight-points method. 4.3.2 Comparisons with magnetic resonance visualizations Figure 8 shows six instants using three-dimensional isosurfaces of the two-components velocity vector magnitude. Exp Fluids (2010) 48:837–850 847 Fig. 8 Iso-surfaces of the velocity magnitude, from 0.03 m/s (dark blue, e, f) to 0.6 m/s (green blue, b) passing through 0.41 m/s (a), 0.3 m/s (a, b, c, d), 0.16 m/s (c, d, e, f) and 0.08 m/s (e, f), measured by two-components multi-plane PIV at mid-systole (a, t = 0.187 s), at end-systole b, t = 0.321 s), at mitral valve opening (c, t = 0.455 s), at D-wave peak (d, t = 0.589 s), at mid-diastole (e, t = 0.696 s) and at atrial contraction (f, t = 0.776 s). The contour of the atrial silicon mold is colored in pale yellow. The two inserts (a, b) display two acquisition planes (z = 0 mm and z = -9 mm) to help for the visualization. Note the regurgitation jet located at the central strut of the mono-leaflet prosthetic valve. Mitral valve (MV); left upper pulmonary vein (LUPV); left lower pulmonary vein (LLPV); right upper pulmonary vein (RUPV) The flows from the left pulmonary veins are not clearly seen because these two veins are almost orthogonal to the acquisition plane so that their projections measured by 2C-3D?T PIV are largely under-estimated and almost equal to 0. Nevertheless, the iso-surfaces of the two right pulmonary veins, which are almost collinear to the acquisition plane, depict short and large jets with a ball-like surface at the end due to the formation of small asymmetric vortices (vortex rings) at mid-systole (Fig. 8a). Indeed, the jets enter into the atrium where no residual structures remain after the closing of the mitral valve. At the end of the systole, the two jets have progressed toward the valve. They are thinner and longer than at mid-systole while the atrial volume increases (Fig. 8b). The jet from the right upper pulmonary vein strikes the wall and seems to be widened. At the mitral valve opening (Fig. 8c), the flow converges and slightly accelerates toward the valve. Figure 8d occurs at the D-wave onset. Four new jets come into the left atrium. However, at the opposite of the S-wave, the mitral valve is now opened and the flow passes directly from the pulmonary veins to the left ventricle. Indeed, Fig. 8e shows iso-velocities contours mimicking two tubes, one from each group of two pulmonary veins. Finally, Fig. 8f shows a nearly uniform low amplitude field directed toward the mitral valve. The left atrial contraction acts, at the end of the diastole, as a booster pump which completely vanishes all vortical structures (Mouret et al. 2000; Zhang and Gay 2008). Figure 9 describes the evolution of a vortical structure within the left atrium (z = 12 mm) during systole. The vorticity magnitude is the highest where the jets from the right pulmonary veins are located (Fig. 9a, b, c). An anticlockwise structure is forming while the flow from the right veins continues to circulate according to a clockwise rotation (Fig. 9d and e). Figure 9f confirms that the jet from the right upper pulmonary vein passes along the wall and the periphery of a vortical structure located at the center of the left atrium, near the mitral valve and the left pulmonary veins. This is very relevant since Fyrenius et al. (2001) have described such flow organization in vivo using 123 848 Exp Fluids (2010) 48:837–850 Fig. 9 Two-components velocity fields (arrows, third vectors represented) and z-axis vorticity magnitude (background) at the plane located at z = 12 mm at different phases: t = 0.187 s (S-wave, a), t = 0.214 s (b), t = 0.241 s (c), t = 0.268 s (d), t = 0.295 (e), t = 0.321 s (f), t = 0.402 s (g), t = 0.509 s (E-wave, h). During the ventricular end-systole (t = [0.268–0.509] s), the vorticity maps show the presence of a large systolic vortex magnetic resonance phase contrast imaging in healthy subject. Indeed they support the idea that the left pulmonary venous flows recirculate in vortices at the center of the atrium whereas the flow from the right upper pulmonary vein passes along the vortex periphery with 123 minimal entrainment (Fyrenius et al. 2001). The formation of this vortex cannot be really observed in our study because of very important drop-out velocities which are not acquired by 2C-3D?T PIV measurements. However, the Figs. 8 and 9 strongly corroborate a flow organization such Exp Fluids (2010) 48:837–850 as reported in the literature. The vortex vanishes at the onset of mitral valve opening (Fig. 9h) resulting in a vortex duration of 0.24 s, which is very closed to the value reported by Fyrenius et al. (0.28 ± 0.077 s). Furthermore, according to Kilner et al. (2000), the eccentricity of the pulmonary veins avoids the collision of the four jets by allowing swirling flows such as observed in our MCS. This justifies the choice of an anatomical-shaped left atrium and underlines the fact that oversimplified geometries, as previously used in the past, cannot accurately mimic the cardiac flow dynamics. However, three components PIV measurements are necessary in the future to explore the full velocity fields in the atrium. Apart from another way of validating our MCS, stereoscopic PIV measurements are necessary to calculate three-dimensional based vortex identification criteria (such as k2, Q, D or more complex methods) that will enable a better understanding of the left atrial flow organization. Therefore, they may be useful to identify the prosthesis- or patient-related factors that may alter the normal blood flow pattern within the left atrium and therefore predispose to thromboembolism in patients with mitral prosthetic valves with atrial dilatation and pulmonary hypertension. 5 Summary We constructed a novel mock circulatory system to assess the left heart and pulmonary circulation flow dynamics. A lumped model allows us to derive the correct references for voltage signals to control the pumps ensuring a synchronization between ventricular and atrial contractions and relaxations. The main distinctive feature of our MCS is the two independent hydraulic activations so that the ventricular and atrial volumes are completely controlled. The harmonic analysis has validated the models of the pulmonary and systemic circulations since their respective input impedance are similar to those measured in vivo. The shape of the measured pulmonary arterial and aortic pressure waveforms is therefore realistic. The ventricular and atrial pressure–volume loops can be used to study the dynamics of the two cavities. Finally, the MCS allows PIV measurements to assess flow velocity fields both in the LV and LA. Two-components three-dimensional PIV measurements in normal hemodynamic conditions depict a flow organization very closed to the one described in vivo by magnetic resonance, providing a strong validation of the duplicator. Mainly, a large vertical structure at the center of the left atrium during systole is described as previously reported in the literature. The MCS described in this article is able to accurately reproduce the atrioventricular function, the mitral valve flow dynamics, and the systemic and pulmonary circulations. 849 Hence, this new simulator provides a powerful tool to explore in vitro the main prosthesis- and patient-related factors that determine the evolution of LA and PA pressures and the LV and LA flow patterns following mitral valve replacement. The main advantage of this in vitro approach is that each factor can be modified separately, which is difficult or impossible to achieve in vivo. Moreover, the MCS provides a realistic environment that is highly relevant to the clinical situation. Most of the hemodynamic factors are acquired using techniques that are currently used in the clinical setting, which will facilitate the transposition of the results acquired in vitro to the in vivo situation. 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