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Pressure-volume loops: feasible for the evaluation of right ventricular function in an experimental model of acute pulmonary regurgitation?

Case Report

Interactive CardioVascular and Thoracic Surgery 9 (2009) 163–168

Can Yerebakana,1,*, Christian Klopscha,1, Stephanie Prietza, Johannes Boltzeb,c, Brigitte Vollmard, Andreas Liebolda, Gustav Steinhoffa, Eugen Sandicaa Institutional Report

Department of Cardiac Surgery, Medical Faculty, University of Rostock, Schillingallee 35, 18057 Rostock, Germany b Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany c Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany d Institute for Experimental Surgery, Medical Faculty, University of Rostock, Rostock, Germany


Received 7 November 2008; received in revised form 27 April 2009; accepted 29 April 2009



All procedures were approved by the local Animal Care Committee of MecklenburgyVorpommern in Rostock, Germany. Animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals

Brief Communication

䊚 2009 Published by European Association for Cardio-Thoracic Surgery

2.1. Animals


Authors equally contributed to the work. *Corresponding author. Tel.: q49 494 381 6101; fax: q49 494 381 6102. E-mail address: [email protected] (C. Yerebakan). 1

2. Materials and methods

Proposal for BailWork in out Procedure Progress Report

Pressure-volume loops obtained by the conductance catheter method have been applied to the left ventricle (LV) for investigations of a wide spectrum of cardiovascular pathologies w1, 2x. In contrast, the techniques for the functional monitoring of the right ventricle (RV) are still discussed controversially. Magnetic resonance (MR) imaging for volumetric measurement as well as micromanometer tipped catheters for pressure measurements are currently considered as most accurate for the examination of right ventricular performance w3x. However, it has been shown that the application of conductance catheters reveals reliable data with the advantage of instantaneous beat-tobeat functional evaluation, including preload-independent parameters that are representative for the actual right ventricular function w4, 5x.

Pulmonary regurgitation (PR) is a common condition after the repair of congenital heart defects, such as the Tetralogy of Fallot (TOF), post-valvotomy for pulmonary stenosis or it may be primarily present in rare cases such as in absent pulmonary valve syndrome and in isolated congenital PR. This condition still constitutes one major risk factor for the development of late right ventricular dysfunction and failure following chronic right ventricular volume overload. This manuscript aims to present cardiac conductance catheterization as a tool feasible to investigate postoperative changes in RV performance immediately after surgically induced PR in a novel experimental design.

Best Evidence Topic

1. Introduction

Follow-up Paper

Keywords: Right ventricle; Pulmonary insufficiency; Volume overload; Pressure-volume loops; Conductance catheterization

Negative Results

Pressure-volume loop measurements by cardiac catheterization constitute a highly reliable method for the direct beat-to-beat functional analysis of the heart. We aimed to prove its feasibility for the instantaneous evaluation of right ventricular performance in a novel experimental model of pulmonary regurgitation (PR). Four-month-old sheep (ns18, weighing 35–45 kg) were operated via left anterior thoracotomy. A transannular patch (TAP) was sutured to the right ventricular outflow tract (RVOT). Pulmonary valve annulus was transsected through an incision over the patch without the need for cardiopulmonary bypass. Baseline right ventricular function was obtained by inserting conductance catheters through the pulmonary artery before and immediately after surgical induction of PR. All animals survived. Pressure-volume loop analysis presented immediate significant elevations in pressure and volume loading of the right ventricle. Maximum developed pressure incremented from 26.9"1.1 mmHg to 30.5"0.9 mmHg (P-0.01). End-diastolic volume w62.4"3.4–102.7"8.6 ml (P-0.01)x increased as well. Peak rate of pressure rise increased during ejection phase, and heart rate rose from 427.1"21.4 mmHgys to 492.6"24.7 mmHgys (P-0.01) and from 89.0"3.0/min to 93.0"3.3/min (Ps0.04), respectively. Right ventricular ejection fraction decreased from 74.1"2.7% to 56.6"3.0% (P-0.01). Our results demonstrate that the conductance catheter method is feasible for the evaluation of acute right ventricular volume overload in this new model of PR with TAP augmentation of RVOT. 䊚 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.


C. Yerebakan et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 163–168

prepared by the Institute of Laboratory Animal Resources and published by the US National Institutes of Health (NIH publication No. 85–23, revised 1996). This study was carried out with the use of 18 four-month-old domestic sheep, randomized as male and female (sexperimental animals; mean weight: 39.4"1.4 kg). In one additional control animal we tested the safety of methodological execution. 2.2. Anesthesia General anesthesia was administered prior to all surgical procedures. Animals received an intramuscular injection of 0.5 mgykg xylazine (Rompun 2%, Bayer Vital GmbH, Leverkusen, Germany) and 10 mgykg ketamine 10% (Ketamin 10%, Bela-Pharm GmbH & Co. KG, Vechta, Germany), followed by intubation and inhalation anesthesia with 1.5– 2.5% isoflurane delivered through a ventilator (Excel 210 SE, Ohmeda-BOC Group, Madison, WI, USA). 2.3. Surgical induction of PR PR was induced surgically by transannular patch (TAP) augmentation and pulmonary valve distortion in the right ventricular outflow tract (RVOT). After left anterior thoracotomy through the 5th or 6th intercostal space, the RVOT was exposed. A TAP (Gelweave woven vascular prosthesis, Vascutek Ltd, Terumo, Renfrewshire, Scotland) was sutured continuously from the RVOT (infundibulum) to the main pulmonary artery (MPA), reaching ;2 cm below and 2 cm above the pulmonary annulus level using 5y0 polypropylene (Ethicon, Norderstedt, Germany). Thereafter, an incision in the RVOT was performed through an opening in the patch. The pulmonary valve annulus (PVA) was transsected with scissors. An infundibulotomy followed without the need for cardio-pulmonary bypass. Following the surgical procedure and functional evaluations in the control animal and a 3-month postoperative follow-up in addition to the 18 experimental animals, the hearts were arrested with potassium chloride. 2.4. Beat-to-beat evaluation of right ventricular function Baseline analysis of right ventricular myocardial performance was achieved prior to transannular patching and immediately after the creation of PR. Pressure-volume loops were recorded using the conductance-micromanometer-tipped catheter technique as described previously w6x. We applied a combined pressure-volume conductance catheter 5 F (Millar Instruments, Houston, TX, USA), which was inserted retrogradely into the RV through a small stab wound in the pulmonary artery following a purse string suture for fixation and subsequent closure of the hole. Catheter position was corrected until the tip was placed at the right ventricular apex and the two most proximal electrodes were positioned above the pulmonary valve (Fig. 1). The conductance catheter was connected to one pressure-volume transducer system for pressure (Millar MPVS 300, EMKA Technologies, Paris, France) and another volume transducer system for volume analysis (Sigma 5 DF, CD Leycom, Zoetermeer, The Netherlands). The transducer systems were linked to the Millar PowerLab data-acquisition hardware (Type ITF 16, emka Technologies, Paris, France)

Fig. 1. A 12 electrode conductance-micromanometer-tipped catheter was inserted retrogradely in the RV via a stab wound in the main pulmonary artery. Following accurate positioning (electrodes 1 in the apex and 11 above the aortic valve level for the applied current), electrodes 3–10 measured conductances in five segments. The catheter was provided with a micromanometer sensor (MMS) between electrodes 5 and 6.

and real-time signal processing was performed by IOX software (EMKA Technologies). The pressure signal received from one micromanometer sensor (MMS) was directly converted and displayed online. Interposed electrodes 3–10 (7 mm inter-electrode spacing) measured five segmental conductances, the sum of which presented a total time-varying conductance wG(t)x. For instantaneous online visualization of time-varying volume wV(t)x, total conductance was converted as follows: V(t) s (1ya)*(L2ysb)*G(t) – Vp where a is a dimensionless constant, L is the inter-electrode distance, and sb is the specific conductivity of blood measured by a specially designed curette. Parallel volume (Vp) assessment was obtained by hypertonic saline infusion (injection of 10 ml of 10% NaCl) into the right atrium. For the factor a, calibration reference values were gained in triplicate from invasive cardiac output measurements with the thermodilution method (Swan-Ganz-catheter, Arrow International Inc, Reading, PA, USA). Inferior caval vein occlusions, performed preoperatively with a 23-mm balloon catheter (Fogarty Occlusion Catheter, 8–22 F, Edward Lifesciences LLC, Irvine, CA, USA), were not repeated after surgical induction of PR in order to prevent acute cardiac decompensation. Echocardiographic evaluation of the


Table 1 RV hemodynamics before and immediately after surgical PR induction P*

Day 0 After TAPA Baseline functions (ns18)

Pmax (mmHg) EDP (mmHg) ESP (mmHg) dpydt max (mmHgys) dpydt min (mmHgys) t (ms) EDV (ml) ESV (ml) EF (%) CO (mlymin) SV (ml) HR (1ymin) Ees (mmHgyml) Eed (mmHgyml) PRSW (ml=mmHg)

26.9"4.6 10.8"3.1 19.8"3.5 427.1"91.0 –319.7"71.9 96.0"30.4 62.4"14.6 16.7"9.4 74.1"11.2 4016.6"807.3 45.8"11.3 89.0"12.8 0.5"0.2 0.3"0.1 9.5"2.6

-0.01 -0.01 0.02 -0.01 0.16 0.13 -0.01 -0.01 -0.01 -0.01 0.01 0.04

30.5"3.7 13.9"3.6 21.7"3.1 492.6"98.9 –327.9"60.5 119.6"35.4 102.7"34.5 45.6"22.9 56.6"11.9 5297.1"2003.2 57.1"19.5 93.0"13.2 n.a. n.a. n.a.

2.5. Statistics Data are presented as mean"standard deviations (S.D.). Statistical analysis was carried out with the SPSS software package (SPSS Inc). For procedural dependent comparison between the pre- and postsurgical RV function of each animal in this experimental approach, the Wilcoxon signedrank test was chosen. P-values -0.05 were considered statistically significant. 3. Results 3.1. Immediate beat-to-beat right ventricular functional analysis

Follow-up Paper Best Evidence Topic

3.1.1. Systolic functions Right ventricular ejection fraction (EF) reflected a remarkable decrease of 24% after ventricular incision (P-0.01). Pressure load parameters, Pmax as well as endsystolic pressure (ESP) and the peak rate of maximum pressure rise determined by dpydt max, were elevated by 13%, 10% and 15%, respectively (P-0.01; Ps0.02;

Values are presented as mean"S.D.; *comparison between pre- and postoperative RV function by Wilcoxon signed-rank test at day 0 visualized clear, immediate effects on RV performance by transannular patch augmentation (TAPA) and pulmonary regurgitation under baseline conditions. Pmax indicates maximum pressure; EDP indicates end-diastolic pressure; ESP, endsystolic pressure; dpydt, peak rate of maximum and minimum pressure rise (dpydt max) and decline (dpydt min); t, relaxation time; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction; CO, cardiac output; SV, stroke volume; HR, heart rate; Ees, slope of end-systolic pressure volume relation; Eed, slope of end-diastolic pressure volume relation; PRSW, preload recruitable stroke work; and n.a., not assessed.

Negative Results

Following accurate program setting (Fig. 2) data were obtained from the invasive monitoring of hemodynamics before and immediately after the creation of PR (Table 1). Fig. 3 depicts represent pressure-volume loops in changing right ventricular performance.

Institutional Report

Day 0 Before TAPA Baseline functions (ns18)



Case Report

animals was preformed 6 weeks postoperatively to determine the grade of surgically induced pulmonary insufficiency.


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C. Yerebakan et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 163–168

Proposal for Bailout Procedure Work in Progress Report State-of-the-art Nomenclature

P-0.01). Further, volume charge clearly increased. Endsystolic volume (ESV) was 2.7-fold higher than preoperative values (P-0.01). Stroke volume (SV) and cardiac output (CO) enlarged 25% and 32%, respectively (Ps0.01;

Brief Communication

Fig. 2. Software analyzers were set exactly during online visualization prior to the surgical induction of pulmonary regurgitation for maximum pressure (Pmax), end-diastolic and end-systolic pressure (EDP, ESP), end-diastolic and end-systolic volume (EDV, ESV), relaxation time (t), stroke volume (SV), maximum and minimum rates of pressure rise and decline during ejection (dpydt max) and relaxation phase (dpydt min). Pressure (upper graph) and volume (lower graph) curves illustrate the various phases of one single cardiac cycle; systole: VIC, ventricular isovolumetric contraction; EP, ejection phase; diastole: RP, relaxation phase; FP, filling phase; AC, atrial contraction.

Fig. 3. Beat-to-beat examinations displayed major differences in pre- and post-procedural RV performance. Representative single heartbeats obtained from the RV of one sheep revealed the increments of maximum pressure (Pmax – dashed arrow), end-systolic volume and pressure (ESV, ESP – solid arrow) during systole as well as end-diastolic volume and pressure (EDV, EDP – dotted arrow) during diastole in post-surgical measurements (dashed loops) when compared with pre-surgical recordings (solid loops).


C. Yerebakan et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 163–168

P-0.01). Moreover, postoperative examinations revealed an increment of 5% in heart rate (HR) (Ps0.04). 3.1.2. Diastolic functions Following the surgical procedure, end-diastolic pressure (EDP) and end-diastolic volume (EDV) augmented by 28% and 64%, respectively (P-0.01; P-0.01). Interestingly, parameters reflecting the tissue elasticity of RV did not differ significantly at the postoperative stage compared to the preoperative levels. t and peak rate of maximum pressure decline determined by dpydt min developed to a similar extent as recorded prior to surgical induced PR (Ps0.13; Ps0.15). 3.1.3. Vena cava occlusion maneuvers The Ees and Eed as well as preload recruitable stroke work (PRSW) obtained from caval vein occlusions performed only at the preoperative stage reflected the contractility and elasticity of the healthy right heart (Fig. 4). The linear end-systolic pressure volume relation (ESPVR) had a large negative extrapolated Vo. Vo indicates the volume at which ESP is 0 mmHg; it should not be negative. Drawing a curvilinear ESPVR might have been more appropriate, although the tendency of ESPVR to be curvilinear w7x also constitutes a source of error. 3.2. Safety and feasibility of methodology All animals survived the surgical procedure. Moreover, no PR related complications occurred during the postoperative period. Following the reopening of the TAP at day 0 for the control animal and at day 90 for the experimental animals, we were able to confirm PR as a consequence of pulmonary annulus distortion and anterior pulmonary valve cusp (aPVC) transsection in all animals (Fig. 5). An echocardiographic analysis confirmed the presence of grade II–III (2.7"0.3, ns12) in all investigated subjects at 6 weeks postoperatively.

Fig. 4. Caval vein occlusions performed only at the preoperative stage reflected the contractility and elasticity of the healthy right heart. The slopes of end-diastolic pressure volume relation (EDPVR – dashed graph) and end-systolic pressure volume relation (ESPVR – solid graph) were determined. The linear ESPVR exposed a negative extrapolated Vo.

Fig. 5. (a) Pulmonary regurgitation was well tolerated after its surgical induction. The image portays the surgical field with right ventricular outflow tract (RVOT), an implanted transannular patch (TAP) and the main pulmonary artery (MPA); (b1, b2) following the post-procedural right ventricular function examinations and the sacrifice of the control animal, the TAP was reopened confirming the pulmonary valve annulus (PVA) distortion and transsection of the anterior pulmonary valve cusp (aPVC).


3.3. Study limitations

Work in Progress Report State-of-the-art Brief Communication Nomenclature

w1x Dekker AL, Barenbrug PJ, van der Veen FH, Roekaerts P, Mochtar B, Maessen JG. Pressure-volume loops in patients with aortic stenosis. J Heart Valve Dis 2003;12:325–332. w2x Hasnat AK, van der Velde ET, Hon JK, Yacoub MH. Reproducible model of post-infarction left ventricular dysfunction: haemodynamic characterization by conductance catheter. Eur J Cardiothorac Surg 2003;24: 98–104. w3x Vogel M. The optimal method with which to assess right ventricular function. Cardiol Young 1999;9:547–548. w4x Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R. Single-beat estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart Circ Physiol 2003; 284:H1625–H1630. w5x Faber MJ, Dalinghaus M, Lankhuizen IM, Steendijk P, Hop WC, Schoemaker RG, Duncker DJ, Lamers JM, Helbing WA. Right and left ventricular function after chronic pulmonary artery banding in rats assessed with biventricular pressure-volume loops. Am J Physiol Heart Circ Physiol 2006;291:H1580–H1586. w6x Baan J, Van Der Velde ET, De Bruin HG, Smeenk GJ, Koops J, Van

Proposal for Bailout Procedure


Best Evidence Topic

Our experimental approach was safe and feasible, presenting the conductance catheter method to be relevant for investigation of direct RV functional changes. Our novel experimental model, i.e., carrying on the work of Tuffier and Carrel in 1914, deepens the knowledge about RV functions and reveals an immediate increase of right ventricular load after surgical induction of PR with TAP augmentation w11x. The incremented wall stress appeared to be a consequence of both elevated pressure and volume parameters during systole as well as diastole. Astonishingly, our data revealed that the speed of contraction during systole rose while the speed of relaxation and relaxation time did not change. In addition, heart rate increased. The SV after PR induction was elevated by ;25% when compared to the initial SV. Thus, direct, general RV charge boost, especially preload increment, seemed to increase contractile force following Starling’s law of the heart. This process, which is highly essential for acute changes of

We thank Ms Margit Fritsche, the Institute of Clinical Chemistry and Laboratory Medicine, the Institute for Pathology, and Prof. M. Peuster from the Department of Pediatric Cardiology and Intensive Care, University of Rostock for their excellent technical assistance and fruitful discussions.

Follow-up Paper

4.2. Immediate increase of right ventricular work load after surgically induced PR


Negative Results

The conductance catheter technique constitutes a highly reliable method for the direct beat-to-beat functional analysis of the conically shaped LV w1, 2x. The accurate functional assessment of the RV currently presents a more difficult challenge because of its irregular shape and motion. Besides three-dimensional echocardiography, MR imaging is considered the gold standard for right ventricular volumetry, wall motion and architecture w3x. However, it is not routinely applied for several different reasons, such as extensive time consumption and costs or limited availability. Considering these facts, more recent studies have employed the conductance catheter technique for the examination of right ventricular function. Moreover, evidence has come to light that the instantaneous beat-tobeat evaluation of the RV reveals valid and mostly important data for elucidating disease mechanisms w10x.

At present, little is known about the compensatory mechanisms of RV in chronic volume overload. Since the extended cardiac workload started immediately after PR induction in our experimental setup, both the supply and expenditure of energy and oxygen might have increased directly. This increase may contribute to an elevated vulnerability of heart mitochondria leading to cardiac remodeling and potentially right ventricular failure w12x. However, it is well known that PR and chronic RV volume overload following early TOF repair are well tolerated over a long period of time w8, 10x. With regard to the unique RV of patients with Eisenmenger syndrome or the univentricular heart after Norwood’s staged palliations in infants with hypoplastic left heart syndrome, the right ventricular compensatory functional reserve obviously appears to be immense w13, 14x. On the contrary, it has been reported recently that the adaptive right ventricular mechanisms in TOF children might be less competent w15x. In conclusion, our novel experimental technique in conjunction with the pressurevolume loop evaluation might be a helpful tool to study the early and late impact of surgically induced right ventricular overload on the right ventricular function in large animals in order to gain more insights into hemodynamics for the clinical practice in the surgical treatment of congenital heart diseases.

Institutional Report

4.1. Current techniques applied in RV functional monitoring

4.3. Compensatory mechanisms in chronic RV volume overload


4. Discussion

cardiac loading conditions, may continue and result in prolonged additive cardiac work.

Case Report

Hypertonic saline injections, which were applied in the study, are known to produce a significant effect on cardiac volume and pressure parameters in mice and small mammals w8x. Another limitation is the open-chest approach that may lower blood pressure and heart rate w9x. One solution for future projects may be the right ventricular cannulation via the superior caval vein. The accurate positioning of the conductance catheters for the assessment is very crucial especially for longer term studies. This aspect cannot be addressed in our setting. Further, our study focused exclusively on the immediate functional property changes of the RV after surgical TAP augmentation and induction of PR. However, we were not able to provide desired indices of the changing right ventricular contractile and elastic functions, such as Ees and Eed, because of lacking preload reduction maneuvers in the acute phase.


New Ideas

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w7 x

w8 x

w9 x w10x

C. Yerebakan et al. / Interactive CardioVascular and Thoracic Surgery 9 (2009) 163–168 Dijk AD, Temmerman D, Senden J, Buis B. Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 1984;70:812–823. Burkhoff D, Sugiura S, Yue DT, Sagawa K. Contractility-dependent curvilinearity of end-systolic pressure-volume relations. Am J Physiol 1987;252:H1218–H1227. Cassidy SC, Teitel DF. The conductance volume catheter technique for measurement of left ventricular volume in young piglets. Pediatr Res 1992;31:85–90. Kass DA, Hare JM, Georgakopoulos D. Murine cardiac function: a cautionary tail. Circ Res 1998;82:519–522. Leather HA, Ama R, Missant C, Rex S, Rademakers FE, Wouters PF. Longitudinal but not circumferential deformation reflects global contractile function in the right ventricle with open pericardium. Am J Physiol Heart Circ Physiol 2006;290:H2369–H2375.

w11x Tuffier T, Carrel A. Patching and section of the pulmonary orifice of the heart. J Exp Med 1914;20:9–18. w12x Marcil M, Ascah A, Matas J, Be ´langer S, Deschepper CF, Burelle Y. Compensated volume overload increases the vulnerability of heart mitochondria without affecting their functions in the absence of stress. J Mol Cell Cardiol 2006;41:998–1009. w13x Connor JA, Thiagarajan R. Hypoplastic left heart syndrome. Orphanet J Rare Dis 2007;2:23. w14x Hopkins WE, Waggoner AD. Severe pulmonary hypertension without right ventricular failure: the unique hearts of patients with Eisenmenger syndrome. Am J Cardiol 2002;89:34–38. w15x Reddy S, Osorio JC, Duque AM, Kaufman BD, Phillips AB, Chen JM, Quaegebeur J, Mosca RS, Mital S. Failure of right ventricular adaptation in children with tetralogy of Fallot. Circulation 2006;114:I37–I42.