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Transesophageal Echocardiography in Swine: Establishment of a Baseline
Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–7, 2017 Ó 2016 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2016.12.011
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Original Contribution TRANSESOPHAGEAL ECHOCARDIOGRAPHY IN SWINE: ESTABLISHMENT OF A BASELINE KATHARINA HUENGES, SASKIA POKORNY, ROUVEN BERNDT, JOCHEN CREMER, and GEORG LUTTER Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (Received 12 May 2016; revised 21 November 2016; in final form 19 December 2016)
Abstract—The porcine model is a commonly used animal model in cardiovascular research. Along with new innovative operative techniques, choice of the optimal imaging technique is crucial. Transesophageal echocardiography (TEE) is a reliable imaging tool is highly important in a large number of experimental evaluations. But so far, TEE data for swine are limited, and few standard values have been established for the porcine model. The experience and baseline results for TEE in 45 swine are presented in this study. A full TEE examination was conducted in 45 German landrace or German large white swine, with an average body weight of 49 ± 3 kg, before experimental off-pump mitral valved stent implantation. Additionally hemodynamic measurements were evaluated. The valve implantation procedure was guided solely by real-time 3-D TEE. Baseline values of standard echocardiographic parameters are provided and, where appropriate, compared with human reference values. TEE proved to be an adequate imaging technique in this experimental porcine animal model. The baseline TEE and hemodynamic parameters established for the widely used porcine model can serve as a reference in future studies. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Transesophageal echocardiography, Porcine model, Mitral valve.
TEE) has become very important in routine diagnosis, and RT-3-D-TEE is widely used in functional evaluation. Because of the similarities of the human and the porcine cardiovascular systems, the porcine model is frequently chosen for experimental cardiovascular research (Abduch et al. 2014; Ren et al. 1997; Sundermann et al. 2016). Notably, the anatomy of the mitral valve is comparable in humans and swine (van Rijk-Zwikker et al. 1994). However, to date, published data on echocardiographic parameters in swine are very limited. Transthoracic echocardiography (TTE) in swine can be challenging because of the keel-shaped thorax and is not applicable in certain minimally invasive surgical interventions where the heart is exposed. In such procedures, TEE is the method of choice and provides betterquality images of the cardiac structures. Our experience with echocardiography and hemodynamics in swine is described here. The aim of this study was to establish a large set of baseline values for cardiac TEE and hemodynamic parameters of swine with an average weight of 50 kg.
INTRODUCTION The encouraging results obtained with transcatheter aortic valve implantation (TAVI) procedures have spurred increasing interest in novel transcatheter therapies for the treatment of other valvular heart diseases in the beating heart. Current research is focused on new therapeutic options for the treatment of insufficient mitral valves. Choosing the appropriate imaging technique is an important issue with great influence on the feasibility and outcome of such procedures, even during experimental studies. Real-time 3-D transesophageal echocardiography (RT-3-D-TEE) has been used to guide different minimally invasive cardiac interventions with promising results, and as a diagnostic method for various cardiac pathologic morphologies (Becerra et al. 2009; Nunez-Gil et al. 2011; Uno et al. 2009). Twodimensional transesophageal echocardiography (2-D-
Address correspondence to: Katharina Huenges, Department of Cardiovascular Surgery, University Hospital Schleswig Holstein Campus Kiel, Arnold Heller Strasse 3, Hs. 18, D-24105 Kiel, Germany. E-mail: [email protected] Conflict of interest disclosure: Georg Lutter is a consultant for Tendyne, Minneapolis, Minnesota, USA. All other authors have no conflicts of interest.
METHODS The main focus of this study was the establishment of baseline cardiac TEE parameters of the experimental 1
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porcine model. These were determined before implantation of a nitinol mitral valved stent, in a catheter-based off-pump procedure in our well-established porcine model (Attmann et al. 2011; Lozonschi et al. 2008; Lutter et al. 2009, 2010). Forty-five German Landrace or German large white pigs, or crossbreds thereof, weighing an average of 49.16 6 2.82 kg (range: 46–57.5 kg, females: n 5 43, and males: n 5 2), were evaluated. All animals received humane care, as approved by the Center for Experimental Animal Research at the University of Kiel, Kiel, Germany, in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised in 2011. Evaluation procedure Swine were placed in dorsal recumbence with the limbs fixed. General total intravenous anesthesia (propofol, B. Braun, Melsungen, Germany; and fentanyl, Janssen-Cilag, Neuss, Germany) and continuous fivelead electrocardiogram (ECG) monitoring (original Datex Ohmeda, now GE-Healthcare, Chalfont, St. Giles, England), as well as invasive pressure measurements for hemodynamic evaluation, were conducted, as previously described (Pokorny et al. 2014). A full TEE examination according to an institutional protocol was conducted before the lower ministernotomy, which affords the best access to the apex of the heart in the porcine model. The focus of the assessment was global heart function, valve performance and detection of possible valvular regurgitation. Echocardiography Echocardiographic evaluation was carried out using multiplane 3-D TEE device (Philips iE33 xMatrix in combination with the Phillips RT-3-D TEE-probe X72 t, Philips Healthcare, Bothell, WA, USA) (Fig. 1). A
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self-made teething ring was used for TEE probe protection. Best imaging of the native mitral valve was achieved at the mid-esophageal probe position and a beam rotation of 40 –80 with slight acclination in live 3-D-mode. The tricuspid valve was best imaged at 106 –115 with slight acclination and a clockwise rotation of approximately 30 . A four-chamber view (4CV) was obtained in midesophageal position at 0 –10 in the RT 3-D probe by slightly rotating clockwise. TEE standard views in human clinical practice and the experimental porcine study are compared in Table 1. Echocardiography conditions in the porcine model were evaluated and graded before and immediately after mitral valve stent implantation as follows: Excellent: All structures are visualized with clear contours and can be easily identified. Good: Structures are mostly of good contrast (distinct) and can be identified. Sufficient: Main structures can be visualized and evaluated. Poor: Visualization of structures is possible to only a limited degree. Evaluation of parameters is limited. Not Possible: Visualization of structures is not possible even in different views, and evaluation or guidance cannot be conducted.
Heart function Heart function—systolic and global ventricular function—was assessed as follows. Systolic left ventricular function. The left ventricular ejection fraction (LVEF) was determined by different methods, and the results were compared: LVEF was measured in the 2 2CV by Simpson’s rule. It was then defined by using the 3CV for measuring end-diastolic (EDV) and end-systolic (ESV) volumes. Whenever possible, LVEF was determined in both views. In humans, an LVEF $55% is considered in the physiologic
Fig. 1. Three-dimensional transesophageal echocardiography images revealing the guidance during mitral valved stent implantation (a) Applicator in the left ventricle (LV) and left atrium (LA) before stent deployment. (b) Atrial view of the deployed mitral valved stent. (c) Lateral view of the mitral valved stent.
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Table 1. Comparison of standard views in clinical practice and the experimental porcine setting View
Swine
Two-chamber
30 –40 (transatrial view)
Three-chamber
80 (transatrial view)
Four-chamber
0 –10
Human (Flachskampf et al. 2001) 90 –100 transgastric (apical view) 90 lower-middle esophagus 110 –130 transgastric (apical view) 130 –150 lower-middle esophagus 0 lower-middle esophagus
range, as are an EDV of 56–104 mL and ESV 19–49 mL (Lang et al. 2005). Global left ventricular function. Global left ventricular function was described by the Doppler-derived Tei index, which is calculated as (MCOT2LVET)/LVET, where MCO 5 mitral valve closure to opening time, and LVET 5 left ventricular ejection time. The standard value for this myocardial performance index in humans is 0.39 6 0.05 (Tei et al. 1995). Longitudinal left ventricular function. The mitral annular plane systolic excursion (MAPSE) was used to estimate the longitudinal left ventricular function, acquired in M-mode with the sample gate placed on the lateral annulus aligned with the lateral wall and the apex. In studies evaluating human MAPSE at four annular regions, it ranged between 12 and 15 mm, with values ,8 mm found to be associated with depressed left ventricular function (Hu et al. 2013; Pai et al. 1991; Simonson and Schiller 1989). Left ventricular diastolic function. Diastolic function of the left ventricle was evaluated with the transmitral E/A ratio, pulmonary vein flow pattern, velocity of flow progression, as well as tissue Doppler imaging-derived E0 and A0 , acquired septally and laterally. Maintenance of unimpaired diastolic LV function is mandatory for a good clinical outcome (Nagueh et al. 2009a, 2009b). In humans, an E/E0 ratio ,8 represents normal diastolic function and normal LV filling pressures, whereas an E/E0 ratio .15 is indicative of dysfunction and abnormal pressures. An E/E0 ratio of 8–15 may indicate diastolic dysfunction; in this case, additional parameters have to be considered such as transmitral E/A, pulmonic flow pattern and LA dimensions (Buck et al. 2009). LV diastolic function for the age group 21–40 y in humans is characterized by the following values (Ha et al. 2003, Nagueh et al. 2009a, 2009b): E/A 5 1.53 6 0.40;
S/D 5 0.98 6 0.32, E0 lateral 5 19.8 6 2.9, E0 septal 5 15.5 6 2.7, normal E/E0 septal 5 6.7 are considered elevated capillary wedge pressure (Paulus et al. 2007).
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AR 5 21 6 8 cm/s; E0 /A0 lateral 5 1.9 6 0.6; E0 /A0 septal 5 1.6 6 0.5, 6 2.2. Filling pressures if the mean pulmonary (PCWP) is .12 mm Hg
Left atrium Because left atrium remodeling influences echocardiographic indices of diastolic function (Paulus et al. 2007) and also to identify stent-related changes in the long-term observation, assessment of the left atrium is important. Left ventricular outflow tract (LVOT) and aortic valve (AV) diameters were measured in the long-axis 3CV (80 ). Left atrium dimensions were assessed in the end-systolic 2CV, as obtaining a 4CV is challenging in swine and cannot be reliably performed. Compared with that of humans, the porcine left atrium appears more oval shaped. Block et al. (2002) described the normal adult human left atrium as having a length (major diameter) of 4.35 6 1.29 cm and width (minor diameter) of 4.35 6 1.3 cm. The atrial area is considered to be #20 cm2, and the left atrial volume, 23.3 6 6.5 mL (Lang et al. 2005). Transvalvular flow Transvalvular flow patterns, velocities (maximum and mean), pressure gradients (maximum and mean) and velocity time integrals over the AV, LVOT and mitral valve (MV) were assessed using two different methods: pulsed-waved and continuous-wave Doppler. Possible mitral regurgitation (MR) was judged using color Doppler and graded by standards. Hemodynamics Because swine are known to be very vulnerable to stress, acute ventricular fibrillation after manipulation of the heart and sudden heart failure, anesthesia was controlled and hemodynamic stability was closely monitored. Heart rate and rhythm were monitored by electrocardiogram. Arterial and central venous catheters (Arrow International, Reading, PA, USA) were inserted. A pulmonary artery catheter (Swan-Ganz CCO, 7.5F, Edwards Lifesciences, Irvine, CA, USA) was inserted to measure right atrial, ventricular and pulmonary artery pressures, as well as to monitor PCWP and continuously record cardiac output. PCWP correlates with left atrial pressure and is considered abnormal at values .12 mm Hg with elevated filling pressures. The PCWP was also calculated using echocardiographic parameters and the Nagueh formula PCWP 5 1.9 1 [(E/E0 ) 3 1.24] (Nagueh et al.
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1997). The invasively measured and non-invasively calculated PCWP values were compared. Statistical analysis Echocardiographic and hemodynamic measurements were measured in three to five different cardiac cycles and averaged. All quantitative measurements are expressed as the mean 6 standard deviation. Statistical analysis was performed using the SPSS Statistics Software Version 21 (IBM, Armonk, NY, USA). RESULTS A full echocardiographic TEE examination was conducted in all 45 animals before starting the implantation procedure. Echocardiographic quality was graded by two independent examiners pre- and post-implantation (Table 2). Heart function Systolic left ventricular function. The ejection fraction of the left ventricle was evaluated with two different methods. End-diastolic volume in the 2CV (68 6 13 mL) was significantly higher than that in the 3CV (63 6 13 mL) (p 5 0.012). There was no difference between the ejection fractions obtained with the two different methods: 64 6 6% (2CV) and 64 6 5% (3CV). Global left ventricular function. Global left ventricular function was also estimated by using the Tei index. MCOT was 422.36 6 45.87 ms and LVET was 317.57 6 32.87 ms, resulting in a TEI index of 0.34 6 0.13, suggestive of normal global LV function. Longitudinal left ventricular function. Longitudinal left ventricular function (MAPSE) obtained at the lateral annulus was 1.2 6 0.2 cm in this study, which was normal (Fig. 2). Left ventricular diastolic function. The transmitral E/A ratio was 1.42 6 0.5, and the pulmonary vein flow pattern S/D ratio was 1.12 6 0.17 (Fig. 3). Tissue Doppler imaging-derived parameters were E0 lateral 5 7.22 6 1.94,
Table 2. Echocardiographic quality Assessment of echocardiographic quality
Before implantation
During implantation
After implantation
Excellent Good Sufficient Poor Not possible
7 (15.5%)* 28 (62.2%) 9 (20.0%) 1 (2.2%) 0 (0%)
3 (6.7%) 22 (48.9%) 18 (40.0%) 2 (4.4%) 0 (0%)
1 (2.2%) 18 (40%) 21 (46.7%) 5 (11.1%) 0 (0%)
* Number (%).
Fig. 2. M-Mode transesophageal echocardiography image of the beam crossing the mitral annulus and the apex of the heart to measure mitral annular plane systolic excursion (MAPSE).
E0 /A0 lateral 5 1.04 6 0.32 and E/E0 lateral 5 9.06 6 2.55. The Septal tissue Doppler imaging-derived parameters were E0 septal 5 7.54 6 2.41, E0 /A0 septal 5 1.1 6 0.4 and E/E0 septal 5 9.35 6 3.92. An E/E0 ratio .8 indicated slight diastolic dysfunction, if compared with normal human values. Transmitral flow propagation velocity Vp was 69.7 6 20.26. Left atrium The major diameter of the left atrium was 5.3 6 0.6 cm, and the minor diameter, 2.6 6 0.4 cm. This validates the more oval shape of the porcine left atrium compared with that of humans. Transvalvular flow pattern Transvalvular results for the aortic valve, LVOT and mitral valve are summarized in Table 3. The aortic valve diameter measured in the long-axis view was 2.05 6 0.24 cm. The dimension of the LVOT measured 1 cm beneath the aortic valve was 2.0 6 0.2 cm. Mitral valve dimensions were C–C (30 –40 ) 2CV 5 32.38 6 4.62 in systole and 32.5 6 3.47 in diastole, and A–P (80 ) 3CV 5 23.29 6 3.73 in systole and 23.9 6 4.43 in diastole. Pressure half-time (PHT) of the mitral valve was 59.3 6 13.96 ms, and the mitral orifice area (MOA) was calculated as 3.9 6 0.83. There was no MR in 40 of the 45 animals, mild MR in four animals and mild to moderate MR in one animal in the pre-operative TEE evaluation. Hemodynamics The baseline heart rate 60 min before implantation was 64 6 11 bpm and did not essentially increase up to 69 6 17 bpm 5 min before the transapical procedure was performed. Mean arterial pressure slightly decreased from 77 6 15 to 71 6 13 mm Hg (p 5 0.021). Central
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Fig. 3. (a) Pulsed wave Doppler image used to determine the E/A ratio. (b) Tissue Doppler image used to determine septal E0 .
venous pressure remained within physiologic range (4 6 2) in the time before implantation. Right heart pressures measured with a pulmonary artery catheter are listed in Table 4. The direct invasively measured PCWP was 7.8 6 3.6 mm Hg. PCWP estimated with Nagueh’s method was E/E0 lateral PCWP 5 13.6 6 3.2 mm Hg and E/E0 septal PCWP 5 13.1 6 4.9 mm Hg. Compared with the invasively derived PCWP of 7.8 6 3.6 mm Hg, the lateral PCWP (p , 0.001) and septal PCWP (p , 0.001) were significantly higher. The acquired values were higher as previously described in humans, with a difference of 0.1 6 3.6 mm Hg (Nagueh et al. 1997). DISCUSSION Transesophageal echocardiography imaging is of increasing importance in the experimental development Table 3. Echocardiographic results: Aortic valve, LVOT and mitral valve
Aortic valve Vmax$PW$AV (cm/s) Pmax$PW$AV (mm Hg) Pmean$PW$AV (mm Hg) Vmax$CW$AV (cm/s) LVOT Vmax$PW$LVOT (cm/s) Pmax$PW$LVOT (mm Hg) Pmean$PW$LVOT (mm Hg) VTI$PW$LVOT (cm/s2) Vmax$CW$LVOT [cm/s] Mitral valve Vmax$PW$MV (cm/s) Pmax$PW$MV (mm Hg) Pmean$PW$MV (mm Hg) VTI$PW$MV (cm/s2) Vmax$CW$MV (cm/s) Emax (cm/s) Amax (cm/s) E/A
Mean
SD
91.82 3.48 1.62 108.52
15.31 1.13 0.61 19.02
66.38 1.80 0.95 14.74 101.19
10.40 0.60 0.22 3.07 21.93
63.38 1.70 0.29 15.37 78.96 61.29 48.61 1.42
11.86 0.66 0.40 4.82 12.49 10.31 12.04 0.50
LVOT 5 left ventricular outflow tract, CW 5 continuous wave, PW 5 pulsed wave, AV 5 aortic valve, MV 5 mitral valve.
of novel cardiac devices. The swine is a widely used animal for experimental cardiac studies because of the similarities to human cardiac anatomy. For the design of new studies as well as for their evaluation, knowledge of physiologic references for TEE parameters is crucial. TEE evaluation is highly important in the evaluation of heart function and the success of various cardiac procedures. However, to date, very few studies have been conducted to establish echocardiographic baseline values for this widely used porcine model. In this study, the pre-operative TEE data from 45 swine were collected. Previous studies had evaluated echocardiography in smaller groups (Sundermann et al. 2016). The swine used in this study had an average weight of 49.2 kg and were about 3 mo of age. In human echocardiography, reference values are published for sex and age groups. Because differences are also expected in animals, the age and size of animals, as well as the breed, should always be considered in establishment of reference values. In this study, all 45 swine were comparable with respect to weight, age and size at baseline. In their experience with TEE in 20 pigs, Sundermann et al. (2016) cited one main difference was the wider weight range of the pigs included (56–106 kg). Because of the lack of reference parameters for echocardiographic evaluation of swine, correct validation Table 4. Right heart pressures measured with the pulmonary artery catheter
RA mean (mm Hg) RV systolic (mm Hg) RV diastolic (mm Hg) RV mean (mm Hg) PAP systolic (mm Hg) PAP diastolic (mm Hg) PAP mean (mm Hg) CO (L/min)
Mean
SD
4.30 21.48 3.85 10.57 20.15 9.55 14.19 3.71
2.18 4.61 2.97 3.13 4.72 4.09 4.07 0.64
RA 5 right atrium, RV 5 right ventricle, PAP 5 pulmonary arterial pressure, CO 5 cardiac output.
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of experimental results can be difficult. Especially in the context of research and the development of new innovative techniques, accurate baseline values are very important. Nevertheless, in a recent study by Janiszewski et al. (2013), mitral valve action in swine with a body weight of 70–100 kg was similar to that of human adults. Real-time 3-D TEE holds the potential for increasing clinical application as a standard diagnostic, an evaluation method in valvular heart diseases and a real-time guidance method during surgical valve repair (Hung et al. 2007; La Canna et al. 2011; Uno et al. 2009; Vegas and Meineri 2010). The mitral valve is particularly suited to 3-D-TEE assessment because of the complex interrelationships among the valve, chordae, papillary muscles and myocardial wall (Hung et al. 2007). RT-3-D-TEE can therefore be an adequate imaging technique for guidance and evaluation, for example, of mitral valved stent implantation in an experimental in vivo setting. It provides dependable spatial visualization of the left heart, the mitral apparatus, the delivery system and the valved stent. Furthermore, with 3-D visualization, the orientation for the surgical team can notably be facilitated in comparison to common 2-D-TEE guidance. In humans, the ejection fraction is usually determined by TTE, whereas in this study only TEE results were obtained. A combination of the two methods would have been ideal to determine differences, but was not practicable in this experimental setting: TTE is difficult in the porcine model because of the keel-shaped thorax and because, in this setting, it is inhibited by the open pericardial sac distancing the heart from the thorax wall and thus impeding imaging by TTE. Echocardiographic right heart parameters are not presented because the focus of this study was mitral valve replacement. The MAPSE is a reliable parameter of ventricular function. Lateral MAPSE values are higher than septal MAPSE values. In the porcine model, the septal MAPSE cannot always be reliably obtained in TEE. Therefore, the lateral MAPSE is presented where alignment was found appropriate. In a previous TEE study, Ren et al. (1997) described significant correlations between cardiac structures and weight, as expressed in Doppler derived stroke volume and cardiac output: The cardiac output of swine, estimated by Doppler-derived measurements, was higher than that of humans. This was not seen in our study with an invasively measured cardiac output of 3.71 6 0.64 L/min. Intracardiac echocardiography has been used in porcine beating heart procedures with promising feasibility results (Naqvi et al. 2006). Better imaging could possibly be achieved by the use of intracardiac/epicardial probes (Hutchinson et al. 2010), but intra-operative space
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is limited in small incision procedures. Intracardiac echocardiography should be evaluated in further studies to provide a wider range and comparison of cardiac baseline parameters of the widely used porcine model. CONCLUSIONS Transesophageal echocardiography is an adequate imaging technique for evaluation of cardiac structures in the experimental porcine animal model. The aim of this study was met. Baseline TEE values and hemodynamic parameters were established for the widely used porcine model and can serve as a reference in future studies. Acknowledgments—The project was gratefully supported by the German Research Foundation (DFG) under LU 663/8-1.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.12.011
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Original Contribution TRANSESOPHAGEAL ECHOCARDIOGRAPHY IN SWINE: ESTABLISHMENT OF A BASELINE KATHARINA HUENGES, SASKIA POKORNY, ROUVEN BERNDT, JOCHEN CREMER, and GEORG LUTTER Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany (Received 12 May 2016; revised 21 November 2016; in final form 19 December 2016)
Abstract—The porcine model is a commonly used animal model in cardiovascular research. Along with new innovative operative techniques, choice of the optimal imaging technique is crucial. Transesophageal echocardiography (TEE) is a reliable imaging tool is highly important in a large number of experimental evaluations. But so far, TEE data for swine are limited, and few standard values have been established for the porcine model. The experience and baseline results for TEE in 45 swine are presented in this study. A full TEE examination was conducted in 45 German landrace or German large white swine, with an average body weight of 49 ± 3 kg, before experimental off-pump mitral valved stent implantation. Additionally hemodynamic measurements were evaluated. The valve implantation procedure was guided solely by real-time 3-D TEE. Baseline values of standard echocardiographic parameters are provided and, where appropriate, compared with human reference values. TEE proved to be an adequate imaging technique in this experimental porcine animal model. The baseline TEE and hemodynamic parameters established for the widely used porcine model can serve as a reference in future studies. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine & Biology. Key Words: Transesophageal echocardiography, Porcine model, Mitral valve.
TEE) has become very important in routine diagnosis, and RT-3-D-TEE is widely used in functional evaluation. Because of the similarities of the human and the porcine cardiovascular systems, the porcine model is frequently chosen for experimental cardiovascular research (Abduch et al. 2014; Ren et al. 1997; Sundermann et al. 2016). Notably, the anatomy of the mitral valve is comparable in humans and swine (van Rijk-Zwikker et al. 1994). However, to date, published data on echocardiographic parameters in swine are very limited. Transthoracic echocardiography (TTE) in swine can be challenging because of the keel-shaped thorax and is not applicable in certain minimally invasive surgical interventions where the heart is exposed. In such procedures, TEE is the method of choice and provides betterquality images of the cardiac structures. Our experience with echocardiography and hemodynamics in swine is described here. The aim of this study was to establish a large set of baseline values for cardiac TEE and hemodynamic parameters of swine with an average weight of 50 kg.
INTRODUCTION The encouraging results obtained with transcatheter aortic valve implantation (TAVI) procedures have spurred increasing interest in novel transcatheter therapies for the treatment of other valvular heart diseases in the beating heart. Current research is focused on new therapeutic options for the treatment of insufficient mitral valves. Choosing the appropriate imaging technique is an important issue with great influence on the feasibility and outcome of such procedures, even during experimental studies. Real-time 3-D transesophageal echocardiography (RT-3-D-TEE) has been used to guide different minimally invasive cardiac interventions with promising results, and as a diagnostic method for various cardiac pathologic morphologies (Becerra et al. 2009; Nunez-Gil et al. 2011; Uno et al. 2009). Twodimensional transesophageal echocardiography (2-D-
Address correspondence to: Katharina Huenges, Department of Cardiovascular Surgery, University Hospital Schleswig Holstein Campus Kiel, Arnold Heller Strasse 3, Hs. 18, D-24105 Kiel, Germany. E-mail: [email protected] Conflict of interest disclosure: Georg Lutter is a consultant for Tendyne, Minneapolis, Minnesota, USA. All other authors have no conflicts of interest.
METHODS The main focus of this study was the establishment of baseline cardiac TEE parameters of the experimental 1
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porcine model. These were determined before implantation of a nitinol mitral valved stent, in a catheter-based off-pump procedure in our well-established porcine model (Attmann et al. 2011; Lozonschi et al. 2008; Lutter et al. 2009, 2010). Forty-five German Landrace or German large white pigs, or crossbreds thereof, weighing an average of 49.16 6 2.82 kg (range: 46–57.5 kg, females: n 5 43, and males: n 5 2), were evaluated. All animals received humane care, as approved by the Center for Experimental Animal Research at the University of Kiel, Kiel, Germany, in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised in 2011. Evaluation procedure Swine were placed in dorsal recumbence with the limbs fixed. General total intravenous anesthesia (propofol, B. Braun, Melsungen, Germany; and fentanyl, Janssen-Cilag, Neuss, Germany) and continuous fivelead electrocardiogram (ECG) monitoring (original Datex Ohmeda, now GE-Healthcare, Chalfont, St. Giles, England), as well as invasive pressure measurements for hemodynamic evaluation, were conducted, as previously described (Pokorny et al. 2014). A full TEE examination according to an institutional protocol was conducted before the lower ministernotomy, which affords the best access to the apex of the heart in the porcine model. The focus of the assessment was global heart function, valve performance and detection of possible valvular regurgitation. Echocardiography Echocardiographic evaluation was carried out using multiplane 3-D TEE device (Philips iE33 xMatrix in combination with the Phillips RT-3-D TEE-probe X72 t, Philips Healthcare, Bothell, WA, USA) (Fig. 1). A
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self-made teething ring was used for TEE probe protection. Best imaging of the native mitral valve was achieved at the mid-esophageal probe position and a beam rotation of 40 –80 with slight acclination in live 3-D-mode. The tricuspid valve was best imaged at 106 –115 with slight acclination and a clockwise rotation of approximately 30 . A four-chamber view (4CV) was obtained in midesophageal position at 0 –10 in the RT 3-D probe by slightly rotating clockwise. TEE standard views in human clinical practice and the experimental porcine study are compared in Table 1. Echocardiography conditions in the porcine model were evaluated and graded before and immediately after mitral valve stent implantation as follows: Excellent: All structures are visualized with clear contours and can be easily identified. Good: Structures are mostly of good contrast (distinct) and can be identified. Sufficient: Main structures can be visualized and evaluated. Poor: Visualization of structures is possible to only a limited degree. Evaluation of parameters is limited. Not Possible: Visualization of structures is not possible even in different views, and evaluation or guidance cannot be conducted.
Heart function Heart function—systolic and global ventricular function—was assessed as follows. Systolic left ventricular function. The left ventricular ejection fraction (LVEF) was determined by different methods, and the results were compared: LVEF was measured in the 2 2CV by Simpson’s rule. It was then defined by using the 3CV for measuring end-diastolic (EDV) and end-systolic (ESV) volumes. Whenever possible, LVEF was determined in both views. In humans, an LVEF $55% is considered in the physiologic
Fig. 1. Three-dimensional transesophageal echocardiography images revealing the guidance during mitral valved stent implantation (a) Applicator in the left ventricle (LV) and left atrium (LA) before stent deployment. (b) Atrial view of the deployed mitral valved stent. (c) Lateral view of the mitral valved stent.
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Table 1. Comparison of standard views in clinical practice and the experimental porcine setting View
Swine
Two-chamber
30 –40 (transatrial view)
Three-chamber
80 (transatrial view)
Four-chamber
0 –10
Human (Flachskampf et al. 2001) 90 –100 transgastric (apical view) 90 lower-middle esophagus 110 –130 transgastric (apical view) 130 –150 lower-middle esophagus 0 lower-middle esophagus
range, as are an EDV of 56–104 mL and ESV 19–49 mL (Lang et al. 2005). Global left ventricular function. Global left ventricular function was described by the Doppler-derived Tei index, which is calculated as (MCOT2LVET)/LVET, where MCO 5 mitral valve closure to opening time, and LVET 5 left ventricular ejection time. The standard value for this myocardial performance index in humans is 0.39 6 0.05 (Tei et al. 1995). Longitudinal left ventricular function. The mitral annular plane systolic excursion (MAPSE) was used to estimate the longitudinal left ventricular function, acquired in M-mode with the sample gate placed on the lateral annulus aligned with the lateral wall and the apex. In studies evaluating human MAPSE at four annular regions, it ranged between 12 and 15 mm, with values ,8 mm found to be associated with depressed left ventricular function (Hu et al. 2013; Pai et al. 1991; Simonson and Schiller 1989). Left ventricular diastolic function. Diastolic function of the left ventricle was evaluated with the transmitral E/A ratio, pulmonary vein flow pattern, velocity of flow progression, as well as tissue Doppler imaging-derived E0 and A0 , acquired septally and laterally. Maintenance of unimpaired diastolic LV function is mandatory for a good clinical outcome (Nagueh et al. 2009a, 2009b). In humans, an E/E0 ratio ,8 represents normal diastolic function and normal LV filling pressures, whereas an E/E0 ratio .15 is indicative of dysfunction and abnormal pressures. An E/E0 ratio of 8–15 may indicate diastolic dysfunction; in this case, additional parameters have to be considered such as transmitral E/A, pulmonic flow pattern and LA dimensions (Buck et al. 2009). LV diastolic function for the age group 21–40 y in humans is characterized by the following values (Ha et al. 2003, Nagueh et al. 2009a, 2009b): E/A 5 1.53 6 0.40;
S/D 5 0.98 6 0.32, E0 lateral 5 19.8 6 2.9, E0 septal 5 15.5 6 2.7, normal E/E0 septal 5 6.7 are considered elevated capillary wedge pressure (Paulus et al. 2007).
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AR 5 21 6 8 cm/s; E0 /A0 lateral 5 1.9 6 0.6; E0 /A0 septal 5 1.6 6 0.5, 6 2.2. Filling pressures if the mean pulmonary (PCWP) is .12 mm Hg
Left atrium Because left atrium remodeling influences echocardiographic indices of diastolic function (Paulus et al. 2007) and also to identify stent-related changes in the long-term observation, assessment of the left atrium is important. Left ventricular outflow tract (LVOT) and aortic valve (AV) diameters were measured in the long-axis 3CV (80 ). Left atrium dimensions were assessed in the end-systolic 2CV, as obtaining a 4CV is challenging in swine and cannot be reliably performed. Compared with that of humans, the porcine left atrium appears more oval shaped. Block et al. (2002) described the normal adult human left atrium as having a length (major diameter) of 4.35 6 1.29 cm and width (minor diameter) of 4.35 6 1.3 cm. The atrial area is considered to be #20 cm2, and the left atrial volume, 23.3 6 6.5 mL (Lang et al. 2005). Transvalvular flow Transvalvular flow patterns, velocities (maximum and mean), pressure gradients (maximum and mean) and velocity time integrals over the AV, LVOT and mitral valve (MV) were assessed using two different methods: pulsed-waved and continuous-wave Doppler. Possible mitral regurgitation (MR) was judged using color Doppler and graded by standards. Hemodynamics Because swine are known to be very vulnerable to stress, acute ventricular fibrillation after manipulation of the heart and sudden heart failure, anesthesia was controlled and hemodynamic stability was closely monitored. Heart rate and rhythm were monitored by electrocardiogram. Arterial and central venous catheters (Arrow International, Reading, PA, USA) were inserted. A pulmonary artery catheter (Swan-Ganz CCO, 7.5F, Edwards Lifesciences, Irvine, CA, USA) was inserted to measure right atrial, ventricular and pulmonary artery pressures, as well as to monitor PCWP and continuously record cardiac output. PCWP correlates with left atrial pressure and is considered abnormal at values .12 mm Hg with elevated filling pressures. The PCWP was also calculated using echocardiographic parameters and the Nagueh formula PCWP 5 1.9 1 [(E/E0 ) 3 1.24] (Nagueh et al.
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1997). The invasively measured and non-invasively calculated PCWP values were compared. Statistical analysis Echocardiographic and hemodynamic measurements were measured in three to five different cardiac cycles and averaged. All quantitative measurements are expressed as the mean 6 standard deviation. Statistical analysis was performed using the SPSS Statistics Software Version 21 (IBM, Armonk, NY, USA). RESULTS A full echocardiographic TEE examination was conducted in all 45 animals before starting the implantation procedure. Echocardiographic quality was graded by two independent examiners pre- and post-implantation (Table 2). Heart function Systolic left ventricular function. The ejection fraction of the left ventricle was evaluated with two different methods. End-diastolic volume in the 2CV (68 6 13 mL) was significantly higher than that in the 3CV (63 6 13 mL) (p 5 0.012). There was no difference between the ejection fractions obtained with the two different methods: 64 6 6% (2CV) and 64 6 5% (3CV). Global left ventricular function. Global left ventricular function was also estimated by using the Tei index. MCOT was 422.36 6 45.87 ms and LVET was 317.57 6 32.87 ms, resulting in a TEI index of 0.34 6 0.13, suggestive of normal global LV function. Longitudinal left ventricular function. Longitudinal left ventricular function (MAPSE) obtained at the lateral annulus was 1.2 6 0.2 cm in this study, which was normal (Fig. 2). Left ventricular diastolic function. The transmitral E/A ratio was 1.42 6 0.5, and the pulmonary vein flow pattern S/D ratio was 1.12 6 0.17 (Fig. 3). Tissue Doppler imaging-derived parameters were E0 lateral 5 7.22 6 1.94,
Table 2. Echocardiographic quality Assessment of echocardiographic quality
Before implantation
During implantation
After implantation
Excellent Good Sufficient Poor Not possible
7 (15.5%)* 28 (62.2%) 9 (20.0%) 1 (2.2%) 0 (0%)
3 (6.7%) 22 (48.9%) 18 (40.0%) 2 (4.4%) 0 (0%)
1 (2.2%) 18 (40%) 21 (46.7%) 5 (11.1%) 0 (0%)
* Number (%).
Fig. 2. M-Mode transesophageal echocardiography image of the beam crossing the mitral annulus and the apex of the heart to measure mitral annular plane systolic excursion (MAPSE).
E0 /A0 lateral 5 1.04 6 0.32 and E/E0 lateral 5 9.06 6 2.55. The Septal tissue Doppler imaging-derived parameters were E0 septal 5 7.54 6 2.41, E0 /A0 septal 5 1.1 6 0.4 and E/E0 septal 5 9.35 6 3.92. An E/E0 ratio .8 indicated slight diastolic dysfunction, if compared with normal human values. Transmitral flow propagation velocity Vp was 69.7 6 20.26. Left atrium The major diameter of the left atrium was 5.3 6 0.6 cm, and the minor diameter, 2.6 6 0.4 cm. This validates the more oval shape of the porcine left atrium compared with that of humans. Transvalvular flow pattern Transvalvular results for the aortic valve, LVOT and mitral valve are summarized in Table 3. The aortic valve diameter measured in the long-axis view was 2.05 6 0.24 cm. The dimension of the LVOT measured 1 cm beneath the aortic valve was 2.0 6 0.2 cm. Mitral valve dimensions were C–C (30 –40 ) 2CV 5 32.38 6 4.62 in systole and 32.5 6 3.47 in diastole, and A–P (80 ) 3CV 5 23.29 6 3.73 in systole and 23.9 6 4.43 in diastole. Pressure half-time (PHT) of the mitral valve was 59.3 6 13.96 ms, and the mitral orifice area (MOA) was calculated as 3.9 6 0.83. There was no MR in 40 of the 45 animals, mild MR in four animals and mild to moderate MR in one animal in the pre-operative TEE evaluation. Hemodynamics The baseline heart rate 60 min before implantation was 64 6 11 bpm and did not essentially increase up to 69 6 17 bpm 5 min before the transapical procedure was performed. Mean arterial pressure slightly decreased from 77 6 15 to 71 6 13 mm Hg (p 5 0.021). Central
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Fig. 3. (a) Pulsed wave Doppler image used to determine the E/A ratio. (b) Tissue Doppler image used to determine septal E0 .
venous pressure remained within physiologic range (4 6 2) in the time before implantation. Right heart pressures measured with a pulmonary artery catheter are listed in Table 4. The direct invasively measured PCWP was 7.8 6 3.6 mm Hg. PCWP estimated with Nagueh’s method was E/E0 lateral PCWP 5 13.6 6 3.2 mm Hg and E/E0 septal PCWP 5 13.1 6 4.9 mm Hg. Compared with the invasively derived PCWP of 7.8 6 3.6 mm Hg, the lateral PCWP (p , 0.001) and septal PCWP (p , 0.001) were significantly higher. The acquired values were higher as previously described in humans, with a difference of 0.1 6 3.6 mm Hg (Nagueh et al. 1997). DISCUSSION Transesophageal echocardiography imaging is of increasing importance in the experimental development Table 3. Echocardiographic results: Aortic valve, LVOT and mitral valve
Aortic valve Vmax$PW$AV (cm/s) Pmax$PW$AV (mm Hg) Pmean$PW$AV (mm Hg) Vmax$CW$AV (cm/s) LVOT Vmax$PW$LVOT (cm/s) Pmax$PW$LVOT (mm Hg) Pmean$PW$LVOT (mm Hg) VTI$PW$LVOT (cm/s2) Vmax$CW$LVOT [cm/s] Mitral valve Vmax$PW$MV (cm/s) Pmax$PW$MV (mm Hg) Pmean$PW$MV (mm Hg) VTI$PW$MV (cm/s2) Vmax$CW$MV (cm/s) Emax (cm/s) Amax (cm/s) E/A
Mean
SD
91.82 3.48 1.62 108.52
15.31 1.13 0.61 19.02
66.38 1.80 0.95 14.74 101.19
10.40 0.60 0.22 3.07 21.93
63.38 1.70 0.29 15.37 78.96 61.29 48.61 1.42
11.86 0.66 0.40 4.82 12.49 10.31 12.04 0.50
LVOT 5 left ventricular outflow tract, CW 5 continuous wave, PW 5 pulsed wave, AV 5 aortic valve, MV 5 mitral valve.
of novel cardiac devices. The swine is a widely used animal for experimental cardiac studies because of the similarities to human cardiac anatomy. For the design of new studies as well as for their evaluation, knowledge of physiologic references for TEE parameters is crucial. TEE evaluation is highly important in the evaluation of heart function and the success of various cardiac procedures. However, to date, very few studies have been conducted to establish echocardiographic baseline values for this widely used porcine model. In this study, the pre-operative TEE data from 45 swine were collected. Previous studies had evaluated echocardiography in smaller groups (Sundermann et al. 2016). The swine used in this study had an average weight of 49.2 kg and were about 3 mo of age. In human echocardiography, reference values are published for sex and age groups. Because differences are also expected in animals, the age and size of animals, as well as the breed, should always be considered in establishment of reference values. In this study, all 45 swine were comparable with respect to weight, age and size at baseline. In their experience with TEE in 20 pigs, Sundermann et al. (2016) cited one main difference was the wider weight range of the pigs included (56–106 kg). Because of the lack of reference parameters for echocardiographic evaluation of swine, correct validation Table 4. Right heart pressures measured with the pulmonary artery catheter
RA mean (mm Hg) RV systolic (mm Hg) RV diastolic (mm Hg) RV mean (mm Hg) PAP systolic (mm Hg) PAP diastolic (mm Hg) PAP mean (mm Hg) CO (L/min)
Mean
SD
4.30 21.48 3.85 10.57 20.15 9.55 14.19 3.71
2.18 4.61 2.97 3.13 4.72 4.09 4.07 0.64
RA 5 right atrium, RV 5 right ventricle, PAP 5 pulmonary arterial pressure, CO 5 cardiac output.
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of experimental results can be difficult. Especially in the context of research and the development of new innovative techniques, accurate baseline values are very important. Nevertheless, in a recent study by Janiszewski et al. (2013), mitral valve action in swine with a body weight of 70–100 kg was similar to that of human adults. Real-time 3-D TEE holds the potential for increasing clinical application as a standard diagnostic, an evaluation method in valvular heart diseases and a real-time guidance method during surgical valve repair (Hung et al. 2007; La Canna et al. 2011; Uno et al. 2009; Vegas and Meineri 2010). The mitral valve is particularly suited to 3-D-TEE assessment because of the complex interrelationships among the valve, chordae, papillary muscles and myocardial wall (Hung et al. 2007). RT-3-D-TEE can therefore be an adequate imaging technique for guidance and evaluation, for example, of mitral valved stent implantation in an experimental in vivo setting. It provides dependable spatial visualization of the left heart, the mitral apparatus, the delivery system and the valved stent. Furthermore, with 3-D visualization, the orientation for the surgical team can notably be facilitated in comparison to common 2-D-TEE guidance. In humans, the ejection fraction is usually determined by TTE, whereas in this study only TEE results were obtained. A combination of the two methods would have been ideal to determine differences, but was not practicable in this experimental setting: TTE is difficult in the porcine model because of the keel-shaped thorax and because, in this setting, it is inhibited by the open pericardial sac distancing the heart from the thorax wall and thus impeding imaging by TTE. Echocardiographic right heart parameters are not presented because the focus of this study was mitral valve replacement. The MAPSE is a reliable parameter of ventricular function. Lateral MAPSE values are higher than septal MAPSE values. In the porcine model, the septal MAPSE cannot always be reliably obtained in TEE. Therefore, the lateral MAPSE is presented where alignment was found appropriate. In a previous TEE study, Ren et al. (1997) described significant correlations between cardiac structures and weight, as expressed in Doppler derived stroke volume and cardiac output: The cardiac output of swine, estimated by Doppler-derived measurements, was higher than that of humans. This was not seen in our study with an invasively measured cardiac output of 3.71 6 0.64 L/min. Intracardiac echocardiography has been used in porcine beating heart procedures with promising feasibility results (Naqvi et al. 2006). Better imaging could possibly be achieved by the use of intracardiac/epicardial probes (Hutchinson et al. 2010), but intra-operative space
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is limited in small incision procedures. Intracardiac echocardiography should be evaluated in further studies to provide a wider range and comparison of cardiac baseline parameters of the widely used porcine model. CONCLUSIONS Transesophageal echocardiography is an adequate imaging technique for evaluation of cardiac structures in the experimental porcine animal model. The aim of this study was met. Baseline TEE values and hemodynamic parameters were established for the widely used porcine model and can serve as a reference in future studies. Acknowledgments—The project was gratefully supported by the German Research Foundation (DFG) under LU 663/8-1.
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