Longitudinal but not Circumferential Deformation Reflects Global ...

Articles in PresS. Am J Physiol Heart Circ Physiol (January 6, 2006). doi:10.1152/ajpheart.01211.2004

RV regional deformation and global contractility

Longitudinal but not Circumferential Deformation Reflects Global Contractile Function in the Right Ventricle with Open Pericardium

H. Alex Leather1, Ruggero Ama’1, Carlo Missant1, Steffen Rex1,3, Frank E. Rademakers2 and Patrick F. Wouters1

(1) Department of Anesthesiology, Katholieke Universiteit Leuven, Belgium (2) Department of Cardiology, Katholieke Universiteit Leuven, Belgium (3) Department of Anesthesiology, University Hospital of the RWTH Aachen, Germany

Address correspondence to: Patrick F. Wouters, Department of Anesthesiology University Hospitals K.U.Leuven Herestraat 49 B-3000 Leuven Belgium Tel: +32 16 344270 Fax: +32 16 344245 E-mail: [email protected]

1 Copyright © 2006 by the American Physiological Society.

RV Regional deformation

Abstract The clinical evaluation of right ventricular (RV) contractility is problematic because instantaneous RV volumetry is difficult to achieve. Our aim was to test whether global RV contractility can be assessed using regional indices in the longitudinal and/or circumferential axis. Six anesthetized adult ewes were instrumented with a right ventricular conductance catheter and four RV free wall sonomicrometry crystals (interrogating the longitudinal and circumferential axes). Global and regional preload recruitable stroke work (PRSW) was measured using acute vena cava occlusions at baseline, during esmolol and dobutamine infusion, and during stable low preload and high afterload conditions. The agreement between regional and global PRSW was assessed with regression and Bland-Altman analysis. Both regional PRSW indices correlated well with global PRSW in baseline conditions, during inotropic modulation (R2=0.83 and 0.74 for longitudinal and circumferential regional PRSW respectively) and during preload reduction (R2 = 0.62 and 0.83 respectively), but only longitudinal regional PRSW correlated with global PRSW in increased afterload conditions (R2=0.59 and 0.13 for longitudinal and circumferential regional PRSW respectively). We conclude that in the open chest-open pericardium animal model, deformation in the longitudinal axis accurately reflects global RV contractile function in baseline conditions and during acute load modulation, whereas circumferential motion is influenced by changes in afterload.

Key Words: Right Ventricle, Heart Contractility, Regional Function, Preload Recruitable Stroke Work, Sheep.

RV regional deformation and global contractility

Introduction Right ventricular (RV) contractile function is an important predictor of outcome in a wide variety of disease states (10;27). At present, accurate assessment of RV contractility is difficult in clinical practice. The “gold standard” indices (such as the slope of the preload recruitable stroke work relationship (PRSW)) require pressure-volume analysis, which is particularly difficult to achieve in the RV due to its geometry. While the conductance technique has been validated in the RV (5;8;9;32) and is routinely used in the laboratory setting (7;21;23;24;26), its clinical application remains difficult. Surrogates to the pressurevolume-derived indices that are often used in the left ventricle (LV), such as ejection fraction, dP/dtmax and preload-adjusted maximal power are unacceptably load-dependent (25), particularly in the RV (22). There is hence a need for an index of RV contractility that behaves like the pressure-volume derived indices in terms of inotropic sensitivity and loadindependence, but that does not require instantaneous volumetry. One way of circumventing the problem of instantaneous volumetry is the analysis of regional contractility as a surrogate for global ventricular contractile function. Regional PRSW has been validated as a contractile index in the LV (30), and has been used as a surrogate for global contractile indices in the RV (12). Surprisingly, however, regional PRSW has not been adequately validated in the RV. To our knowledge, only two studies have addressed this question. In one study, regional PRSW in the longitudinal axis was shown to be sensitive to changes in inotropic state (28); in another study, regional PRSW in the circumferential axis was found to have a weak and possibly load-dependent relationship with global PRSW in baseline and during afterload modulation (17). Unfortunately, neither of these studies was designed to fully assess the regional indices: loading conditions were not modulated in the former study, while inotropic state was not modulated in the latter.

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RV regional deformation and global contractility The aim of the present study was to test whether regional PRSW in the longitudinal and circumferential axes can be used as a substitute for the volume-derived indices of global RV contractility. We hypothesized that longitudinal and circumferential regional PRSW would be as sensitive to changes in inotropy, and as insensitive to changes in loading conditions, as global PRSW. To test these hypotheses we examined the agreement between longitudinal regional PRSW, circumferential regional PRSW and global PRSW respectively (measured using validated, invasive measurement techniques) during modulation of inotropic state, preload and afterload in open chest sheep.

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RV regional deformation and global contractility

Materials and Methods This investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was approved by the ethics committee of the Katholieke Universiteit Leuven. Instrumentation Six adult ewes (weight 55 ± 6 kg) were included in this study. The animals were premedicated with ketamine hydrochloride 10 mg.kg-1. Anesthesia was induced with intravenous sodium pentobarbital 8 mg.kg-1 and piritramide 1 mg.kg-1 and maintained with sodium pentobarbital 3 mg.kg-1.hr-1 and piritramide 1 mg.kg-1.hr-1.

The lungs were

mechanically ventilated with a mixture of oxygen and room air to maintain normocapnia and normoxia. Lactated Ringer’s solution was administered at a rate of 5 ml.kg-1.hr-1. A triplelumen catheter was inserted in the right jugular vein. A fluid-filled catheter was advanced into the proximal aorta via the right carotid artery for monitoring of systemic arterial pressure. Via a midline sternotomy, a tourniquet was placed around the inferior vena cava (IVC) for controlled alterations of preload. The pericardium was opened, and a 20 mm perivascular flow probe (Transonic Systems Inc., Ithaca, NY, USA) and a tourniquet were placed around the main pulmonary artery. A combined pressure-conductance catheter (Millar Instruments, Houston, TX, USA) was inserted into the RV through a small stab wound in the pulmonary outflow tract. A pair of sonomicrometry crystals (Sonometrics Corporation, London, Ontario, Canada) was sutured to the right ventricular free wall in the axis perpendicular to the atrial groove (along an imaginary line extending to the apex), with the basal crystal 10 - 15 mm from the atrial groove (inter-crystal distance 24 ± 5 mm). A second pair of crystals was sutured at right angles to the first pair.

5 LV

RV regional deformation and global contractility

Data Acquisition and Analysis The conductance catheter was connected to a signal-processing unit (Sigma 5 DF, CDLeycom, Zoetermeer, The Netherlands). Parallel conductance and blood resistivity were measured at regular intervals using the hypertonic saline method (injection of 5 ml NaCl 10% into the right atrium) and the CDLeycom resistivity meter respectively. The correction factor M was re-calculated for each measurement. The sonomicrometry crystals were connected to a sonomicrometry system (Sonometrics Corporation, London, Ontario, Canada). All parameters were digitized at 960 Hz and stored for off-line analysis (Cardiosoft , Sonometrics Corporation, London, Ontario, Canada). Global RV contractility was quantified using global PRSW (11). Regional stroke work and maximal regional segment length were calculated beat by beat during caval vein occlusion. Linear regression lines were fitted to the resulting datasets using Excel (Microsoft Corporation); the slope of the regression line was defined as regional PRSW.

Experimental protocol Two sub-protocols were performed in random order: Inotropic sensitivity After completion of instrumentation and calibration and achievement of hemodynamic steady state, baseline measurements were performed with the ventilation suspended at endexpiration. Data were acquired during steady state conditions (for general hemodynamics), and during a brief period of IVC occlusion (for the calculation of global and regional PRSW). Following baseline measurements, esmolol was administered I.V. (bolus followed by infusion titrated to achieve a decrease in heart rate of approximately 25%; mean dose 66 µg.kg-1.min-1). Measurements were performed at least 15 minutes after the start of the infusion, following

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RV regional deformation and global contractility stabilization of heart rate. The esmolol infusion was then stopped. After the heart rate had returned to baseline values, dobutamine was administered at 1.5 and 3 µg.kg-1.min-1 I.V. consecutively. Measurements were performed at least 15 minutes after the start of each infusion, following stabilization of heart rate. Sensitivity to alterations in preload and afterload After achievement of hemodynamic steady state, baseline measurements were performed. Preload reduction and afterload increase were then imposed in random order. For preload reduction, the inferior vena cava was partially occluded in order to achieve a new hemodynamic steady state. A tourniquet was gradually adjusted until end-diastolic RV volumes shown on the oscilloscope decreased to about 75 % or 50 % of baseline values,. This position was maintained while hemodynamics were allowed to stabilize for at least five minutes. All measurements, including a brief period of IVC occlusion for the calculation of global and regional PRSW, were performed at two degrees of preload reduction in a random order. For afterload increase, the main pulmonary artery was partially occluded with a tourniquet to obtain an increase of systolic pulmonary artery pressures to about 25 % or 50 % of baseline values. The tourniquet was fixed in this position and hemodynamics allowed to stabilize for at least five minutes. Measurements were performed at two degrees of increased afterload in a random order. Statistical analysis The effects of alterations in inotropic state and loading conditions on the measured parameters were analyzed using analysis of variance for repeated measurements (using Statview

5.0 (Sas Institute Inc., Cary, NC, USA)). Fisher’s protected least significant

difference test was used as a post hoc test. The agreement between the regional indices and global PRSW in the various conditions was analyzed using linear regression analysis and Bland-Altman analysis (1). Aggregate data are expressed as mean ± SD.

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RV regional deformation and global contractility

Results Inotropic sensitivity Global PRSW and longitudinal regional PRSW both decreased during esmolol administration, and increased in a dose-related fashion during dobutamine administration (Table 1). Circumferential regional PRSW increased in a dose-related fashion during dobutamine administration, but did not change in response to esmolol. Regression analysis of the regional indices versus global PRSW showed a strong linear correlation between both longitudinal and circumferential regional PRSW and global PRSW (Figure 1). Bland-Altman analysis of longitudinal regional PRSW versus global PRSW showed a bias of 2 mmHg, with limits of agreement of 10 and –7 mmHg. Circumferential regional PRSW had a bias of 2 mmHg, with limits of agreement of 11 and –8 mmHg (Figure 1). Sensitivity to alterations in preload and afterload The changes in end-diastolic volume produced by acute alterations of RV loading correlated better with longitudinal than with circumferential changes of end-diastolic segment length (r² = 0.73 vs 0.30). Similarly, loading-induced changes in RV stroke volume correlated better with longitudinal than with circumferential changes of segment shortening (r² = 0.81 vs 0.33) (Figure 2). Global PRSW and longitudinal and circumferential regional PRSW did not change significantly in response to preload reduction (Table 2). Both regional indices maintained a strong correlation with PRSW, but regression analysis suggested an overestimation by circumferential regional PRSW at high contractile states, and an underestimation at low contractile states (Figure 3). Longitudinal regional PRSW displayed a bias of 0 mmHg, with limits of agreement of 8 and –7 mmHg. Circumferential regional PRSW displayed a bias of 0 mmHg, with limits of agreement of 7 and –6 mmHg (Figure 3).

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RV regional deformation and global contractility Global PRSW and longitudinal regional PRSW increased in response to increased afterload, while circumferential regional PRSW did not change significantly (Table 3). Longitudinal regional PRSW maintained a good agreement with global PRSW during afterload modulation (bias 1 mmHg, limits of agreement 8 and –6 mmHg) although the slope of the regression line did decrease (Figure 4). In contrast, the agreement between circumferential regional PRSW and global PRSW deteriorated severely. Linear regression no longer reported a significant correlation between circumferential regional PRSW and global PRSW. While the bias only increased slightly (to 4 mmHg), the limits of agreement became unacceptably high (29 and -22 mmHg).

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RV regional deformation and global contractility

Discussion Our findings suggest that, in the ovine right ventricle, regional contractility in the longitudinal axis accurately reflects global contractile function while data derived from the circumferential axis are unreliable when loading conditions vary. The slope of the global preload recruitable stroke work relationship accurately reflects contractility in both the left (11) and the right (18) ventricle. It has been previously shown that the relationship between end-diastolic segment length and segmental stroke work is also linear (30), allowing the quantification of regional PRSW relationships in any dimension of the ventricle. However, the fact that the relationship between end-diastolic segment length and segmental stroke work is linear does not automatically imply that the slope of this relationship is a reliable contractile index. In the present study longitudinal regional PRSW displayed a strong agreement with global PRSW during modulation of inotropic state and loading conditions, suggesting that, like global PRSW, longitudinal regional PRSW is inotropically sensitive and relatively loadindependent. Our data therefore suggest that longitudinal regional PRSW is a robust index of global RV contractile function. Circumferential regional PRSW did not detect the esmololinduced decrease in contractility (p=0.43). Most importantly, in response to increased afterload, circumferential regional PRSW became inaccurate in comparison to global PRSW. Our findings therefore suggest that circumferential regional PRSW is unreliable in settings where loading conditions, and particularly afterload, may fluctuate. While the present study does not provide information as to why the longitudinal axis provides a better approximation to global RV contractile function than the circumferential axis, our findings are compatible with historical observations (3) and more recent insights in global cardiac mechanics. Although the RV shares four (bulbospiral and sinospiral) muscle

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RV regional deformation and global contractility bundles with the LV, (2) which run in the circumferential direction, it has been suggested that the heart can be described as a single functional muscle band arranged in a dual helix form (33). There is evidence that, during systole, contraction of the basal segment causes the entire heart to mimic a stiff cylinder, which then shortens (in the base-to-apex direction) due to contraction of the descending segment, leading to ventricular ejection. In other words, this suggests that volume displacement during the heart cycle is mainly thanks to longitudinal deformation. This is in agreement with our findings that global contractile function in the ejection phase is assessed more accurately by regional deformation in the longitudinal axis than by regional deformation in the circumferential axis. There is indeed increasing evidence that RV longitudinal deformation provides reliable information concerning global ventricular function both in the experimental and clinical setting (4;13;14;16;20;29;34). Our findings concerning regional PRSW are in agreement with several previous studies. Nicolosi and co-workers previously showed that RV longitudinal regional PRSW increases in response to calcium administration, and decreases in response to administration of pentobarbital in bolus (28). Unfortunately, they did not mathematically analyze the agreement between longitudinal regional PRSW and global PRSW in their study. Karunanithi and co-workers examined the relationship between RV circumferential regional PRSW and global PRSW at baseline, during increased RV afterload, and during increased LV afterload (17). They reported a weak relationship between circumferential regional PRSW and global PRSW at baseline (R2=0.25). Moreover, circumferential regional PRSW but not global PRSW decreased during pulmonary artery constriction (according to multiple linear regression analysis). The present study has two main implications. Firstly, it may be feasible to calculate regional PRSW in the longitudinal axis as an alternative to the volume-dependent indices in the clinical setting, by integrating a RV pressure signal with non-invasively acquired

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RV regional deformation and global contractility echocardiographic deformation data and performing minor load modifications (for instance, by altering the position of the patient). A second and more important implication of this study is that it confirms a train of thought that clinicians have held for decades (19), but that has not been adequately validated: that regional RV contractile function is accurately reflected by motion in the longitudinal axis but not in the circumferential axis. This information therefore confirms that future investigations into less invasive RV contractile indices should probably focus on longitudinal function. Limitations of this study include the fact that the data were obtained in an acutely instrumented open chest-open pericardium model, which is relevant primarily for the intraoperative setting during cardiac surgery. However, hemodynamic data obtained in openchest anesthetized animal models may differ considerably from those obtained in conscious animals with intact pericardium.(15;31) Particularly the shape of the RV may change when the constraints of a closed pericardium are no longer present.

Therefore, these data should

not be transposed to the intact organism without further validation. Finally, the current study was performed in normal animals and additional studies are required to examine the effects of chronic pathological states (including chronic changes in loading conditions) on the regional contractile indices.

An intrinsic limitation of any regional index that is used to describe

global function is the fact that it cannot be used in diseases with a regional effect on contractile performance, such as myocardial ischemia. Our observation that an increase in afterload caused an increase in contractility as assessed using global PRSW is in agreement with previous studies (6;7;26), and most probably reflects the physiological phenomenon of homeometric autoregulation (26) Alternatively, we can not exclude sympathetic activation as a possible cause of this effect since the autonomic nervous system was left intact in our animals. In this respect, previous studies in autonomically blocked animals have shown global PRSW to be relatively afterload independent (18;22) Regardless of the mechanism, the

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RV regional deformation and global contractility increase in PRSW during acute augmentation of afterload should not be confused with loadinduced errors in the index itself. Since the aim of the present study was to examine the agreement between the regional indices and the “gold standard”, global PRSW, in different conditions, this physiological behaviour does not constitute a limitation to the present observations.

Conclusion We conclude that in an experimental model with open chest and opened pericardium, longitudinal regional deformation accurately reflects global right ventricular contractile function, while circumferential motion responds differently to changes in afterload. Regional PRSW in the longitudinal axis is a reliable alternative to global, volumetry-dependent RV PRSW.

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RV regional deformation and global contractility

Acknowledgments

This study was supported by grants from the Fund for Scientific Research – Flanders, Belgium (1.5.156.02) and the Research Fund K.U. Leuven (PW). AL is a research assistant for the Fund for Scientific Research – Flanders, Belgium. The authors thank Kevin Lathouwers for his technical assistance.

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RV regional deformation and global contractility

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RV regional deformation and global contractility 12, 2000. 18. Karunanithi, M. K., J. Michniewicz, S. E. Copeland, and M. P. Feneley. Right ventricular preload recruitable stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations compared as indexes of right ventricular contractile performance in conscious dogs. Circ Res 70: 1169-79, 1992. 19. Kaul, S., C. Tei, J. M. Hopkins, and P. M. Shah. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 107: 526-31, 1984. 20. Koyama, J., R. Davidoff, and R. H. Falk. Longitudinal myocardial velocity gradient derived from pulsed Doppler tissue imaging in AL amyloidosis: a sensitive indicator of systolic and diastolic dysfunction. J Am Soc Echocardiogr 17: 36-44, 2004. 21. Leather, H. A., P. Segers, N. Berends, E. Vandermeersch, and P. F. Wouters. Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med 30: 2548-52, 2002. 22. Leather, H. A., P. Segers, Y. Y. Sun, H. A. De Ruyter, E. Vandermeersch, and P. F. Wouters. The limitations of preload-adjusted maximal power as an index of right ventricular contractility. Anesth Analg 95: 798-804, 2002. 23. Leather, H. A., K. Ver Eycken, P. Segers, P. Herijgers, E. Vandermeersch, and P. F. Wouters. Effects of levosimendan on right ventricular function and ventriculovascular coupling in open chest pigs. Crit Care Med 31: 2339-43, 2003. 24. Leeuwenburgh, B. P., W. A. Helbing, P. Steendijk, P. H. Schoof, and J. Baan. Biventricular systolic function in young lambs subject to chronic systemic right ventricular pressure overload. Am J Physiol Heart Circ Physiol 281: H2697-704, 2001. 25. Little, W. C., C. P. Cheng, M. Mumma, Y. Igarashi, J. Vinten-Johansen, and W. E. Johnston. Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs. Circulation 80: 1378-87, 1989. 26. Lopes Cardozo, R. H., P. Steendijk, J. Baan, H. A. Brouwers, M. De Vroomen, and F. Van Bel. Right ventricular function in respiratory distress syndrome and subsequent partial liquid ventilation. Homeometric autoregulation in the right ventricle of the

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RV regional deformation and global contractility newborn animal. Am J Respir Crit Care Med 162: 374-9, 2000. 27. Monchi, M., F. Bellenfant, A. Cariou, L. M. Joly, D. Thebert, I. Laurent, J. F. Dhainaut, and F. Brunet. Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 158: 1076-81, 1998. 28. Nicolosi, A. C., D. A. Hettrick, and D. C. Warltier. Assessment of right ventricular function in swine using sonomicrometry and conductance. Ann Thorac Surg 61: 1381-7; discussion 1387-8, 1996. 29. Nikitin, N. P., K. K. Witte, S. D. Thackray, R. de Silva, A. L. Clark, and J. G. Cleland. Longitudinal ventricular function: normal values of atrioventricular annular and myocardial velocities measured with quantitative two-dimensional color Doppler tissue imaging. J Am Soc Echocardiogr 16: 906-21, 2003. 30. Pagel, P. S., J. P. Kampine, W. T. Schmeling, and D. C. Warltier. Comparison of endsystolic pressure-length relations and preload recruitable stroke work as indices of myocardial contractility in the conscious and anesthetized, chronically instrumented dog. Anesthesiology 73: 278-90, 1990. 31.

Pasipoularides, A.D., M. Shu, A. Shah, and D.D. Glower. Right ventricular diastolic relaxation in conscious dog models of pressure overload, volume overload, and ischemia. J Thoracic Cardiovasc Surg 124:964-72, 2002

32. Stamato, T. M., R. S. Szwarc, and L. N. Benson. Measurement of right ventricular volume by conductance catheter in closed-chest pigs. Am J Physiol 269: H869-76, 1995. 33. Torrent-Guasp, F., M. Ballester, G. D. Buckberg, F. Carreras, A. Flotats, I. Carrio, A. Ferreira, L. E. Samuels, and J. Narula. Spatial orientation of the ventricular muscle band: physiologic contribution and surgical implications. J Thorac Cardiovasc Surg 122: 389-92, 2001. 34. Vogel, M., M. R. Schmidt, S. B. Kristiansen, M. Cheung, P. A. White, K. Sorensen, and A. N. Redington. Validation of myocardial acceleration during isovolumic contraction as a novel noninvasive index of right ventricular contractility: comparison with ventricular pressure-volume relations in an animal model. Circulation 105: 1693-9, 2002.

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Figure Legends

Figure 1: Regression and Bland-Altman analysis of regional PRSW versus global PRSW during baseline and inotropic modulation Scatterplot with regression analysis (Panel A) and Bland-Altman analysis (Panel B) of longitudinal regional PRSW versus global PRSW; scatterplot with regression analysis (Panel C) and Bland-Altman analysis (Panel D) of circumferential regional PRSW versus global PRSW. PRSW, slope of the preload recruitable stroke work relationship; Long Reg, longitudinal regional; Circ Reg, circumferential regional. In Panels A and C, the thick line represents the linear regression line. In panels B and D, the thick line represents the bias while the dotted lines represent the limits of agreement.

Figure 2: Regression analysis of volume changes versus changes in regional deformation during acute modulation of RV loading conditions. Top panels show changes from baseline in end-diastolic volume versus end-diastolic segment length during lowering of preload (Q) and elevation of afterload (R) Bottom panels display stroke volume and segment shortening. Longitudinal deformation (A,B) consistently show higher coëfficients of determination as compared to circumferential deformation (C, D)

Figure 3: Preload reduction protocol. Scatterplot with regression analysis (Panel A) and Bland-Altman analysis (Panel B) of longitudinal regional PRSW versus global PRSW; scatterplot with regression analysis (Panel C) and Bland-Altman analysis (Panel D) of circumferential regional PRSW versus global PRSW. PRSW, slope of the preload recruitable stroke work relationship; Long Reg, longitudinal regional; Circ Reg, circumferential regional.

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RV regional deformation and global contractility In Panels A and C, the thick line represents the linear regression line. In panels B and D, the thick line represents the bias while the dotted lines represent the limits of agreement.

Figure 4: Afterload increase protocol. Scatterplot with regression analysis (Panel A) and Bland-Altman analysis (Panel B) of longitudinal regional PRSW versus global PRSW; scatterplot with regression analysis (Panel C) and Bland-Altman analysis (Panel D) of circumferential regional PRSW versus global PRSW. PRSW, slope of the preload recruitable stroke work relationship Long Reg, longitudinal regional; Circ Reg, circumferential regional. In Panels A and C, the thick line represents the linear regression line. In panels B and D, the thick line represents the bias while the dotted lines represent the limits of agreement.

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RV regional deformation and global contractility

Tables

Table 1: General Hemodynamics and contractile indices during inotropic modulation

Global PRSW

Slope (mmHg) x-intercept (ml) R2

Esmolol

Baseline

DBT 1.5

DBT 3

10 ± 3* 53 ± 22 0.98 ± 0.04

15 ± 5 50 ± 21 0.99 ± 0.01

20 ± 6*† 45 ± 18 0.98 ± 0.01

26 ± 9*†‡ 49 ± 27 0.96 ± 0.1

11 ± 7* 20 ± 2 0.97 ± 0.03

16 ± 8 20 ± 1 0.99 ± 0.01

23 ± 9*† 20 ± 1 0.99 ± 0.01†

31 ± 10*†‡ 20 ± 1 0.99 ± 0.01

14 ± 4 24 ± 6 0.99 ± 0.01 65 ± 28* 26 ± 3* 462 ± 103 77 ± 9* 3.7 ± 0.7* 8±3 134 ± 28*

16 ± 3 23 ± 6 0.99 ± 0.01 74 ± 20 31 ± 3 651 ± 129 101 ± 11 4.1 ± 0.8 7±1 97 ± 10

23 ± 6*† 31 ± 8*†‡ 23 ± 6 22 ± 6† 0.99 ± 0.03 0.98 ± 0.02 83 ± 22† 90 ± 18*† 36 ± 3† 44 ± 8*† 989 ± 271*† 1358 ± 358*†‡ 122 ± 19*† 143 ± 16*†‡ 4.7 ± 0.6† 5.8 ± 1.1*†‡ 6±2 8±2 94 ± 19† 89 ± 25†

Longitudinal PRSW Slope (mmHg) x-intercept (mm) R2

Circumferential PRSW Slope (mmHg) x-Intercept (mm) R2 Mean AoP (mmHg) Peak RVP (mmHg) dP/dtmax (mmHg.sec-1) HR (beats.min-1) CO (L.min-1) RVEDP (mmHg) RVEDV (ml)

PRSW, preload recruitable stroke work relationship; DBT 1.5, dobutamine infusion at 1.5 µg.kg-1.min-1; DBT 3, dobutamine infusion at 3 µg.kg-1.min-1; AoP, aortic pressure; RVP, right ventricular pressure; dP/dtmax, maximal rate of right ventricular pressure rise; HR, heart rate; CO, cardiac output; RVEDP, right ventricular end-diastolic pressure; RVEDV, right ventricular end-diastolic volume; *, p