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Pulmonary Vascular Resistance, Collateral Flow and Ventricular Function in Fontan Patients at Rest and During Dobutamine Stress Running Title: Schmitt et al: Fontan Hemodynamic at Rest and During Stress Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Boris Schmitt, MD, Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany Paul Steendijk, PhD, Departments of Cardiology and Cardiothoracic Surgery, Leiden University Medical Center, Leiden, the Netherlands Stanislav Ovroutski, MD, Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany Karsten Lunze, MD, MPH, Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany Pedram Rahmanzadeh, MD, Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany Nizar Maarouf, MD, Department of Congenital Heart Diseasee an Pediatric Cardiology, and d Pe Pedi diat di atri at ricc C ri Deutsches Herzzentrum Berlin, Berlin, Germany erm man any y Peter Ewert, MD, Department of Congenital Heart Disease and Pe Pediatric Pedi d at di atri ricc Cardiology, ri C r Ca Deutsches Herzzentrum Berlin, Berlin, Germany Felix Berger, MD, M PhD, Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany Titus Kuehne, MD, PhD, Unit of Cardiovascular Imaging, Department of Cong Congenital Heart Disease and Germany d Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, G Correspondence to: Titus Kuehne Unit of Cardiovascular Imaging Department of Congenital Heart Disease and Pediatric Cardiology Deutsches Herzzentrum Berlin Augustenburger Platz 1 13353 Berlin Germany Telephone: +49 30 4593-2846/-2078 Fax: +49 30 450 576 983; Email: [email protected] Subject Codes: 41 (Congenital Heart Disease), 11 (heart failure), 18 (pulmonary circulation), 30 (MRI) ABSTRACT Background: The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood. Methods and Results: Using a MRI catheterization technique, we performed a differential analysis of pulmonary vascular resistance (PVR) and aorto-pulmonary collateral blood flow in conjunction with global ventricular pump function, myocontractility (ESPVR), and diastolic Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 compliance (EDPVR) in 10 Fontan patients at rest and during dobutamine stress. Pulmonary ro oni n ze zed d wi with th vvelocity elo el o and ventricular pressures were measured invasively and synchronized encoded MRII de deri rive ri v ventricular (VEC) MRI derived pulmonary and aortic blood flows and cine MR derived ressur volumes. PVR, ESPVR and EDPVR were determined from these pressurepressure-volume data. Aorto-pulmonary y collateral flow was calculated as the difference between betwe n aortic and Co ared to rest, dobutamine caused a small increase in mean mea pulmonary pulmonary flow. Compared pressures (p<0.05). Collateral flow was significantly augmented (p<0.001) and contributed importantly to an increase in pulmonary flow (p<0.01). PVR decreased significantly (p<0.01). Dobutamine failed to increase significantly stroke volumes despite slightly enhanced contractility (ESPVR). Active early relaxation (Tau, dP/dtMin) was inconspicuous but the EDPVR shifted upwards indicating reduced compliance. Conclusions: In Fontan patients, aorto-pulmonary collateral flow contributes substantially to enhanced pulmonary flow during stress. Our data indicate that pulmonary vascular response to augmented cardiac output was adequate but decreased diastolic compliance was identified as an important component of ventricular dysfunction. Key Words: heart defects/congenital, pulmonary heart disease, heart failure, magnetic resonance imaging INTRODUCTION Ventricular function and pulmonary vascular resistance (PVR) are important variables that determine the outcome of patients with a Fontan circulation. Impaired growth of the pulmonary arteries failing to match somatic growth was described in recent studies.1, 2 Other authors report significant left-to-right shunting through aorto-pulmonary collaterals.3, 4 Both factors may have a direct impact on the PVR that, however, can not be measured in the Fontan circulation by conventional techniques such as thermodilution or oxymetry. In addition to pulmonary vascular factors, heart failure was identified as an important cause of Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 morbidity and the right-type systemic ventricle seems to have higher risk to develop heart failure than the left-type ventricle.5, 6 However, the onset, coursee an and d th thee pr pred predominant edom ed om form of heart failure varies and remains unpredictable. Systolic dysfunction was tion w as described des escr crib cr i e but the role ib and mechanisms of diastolic dysfunction are less known.7-10 Diastolic filling is considered to be impaired due to low preload that by itself is, at least in part, controlled bby pulmonary nce. In addition, ventricular compliance co liance is likely like to be alt aaltered because vascular resistance. congenital abnormalities as well as prolonged cyanosis and volume load may have impact on the fibrous matrix of the myocardium.7, 11 In this study we performed a differential analysis of PVR and aorto-pulmonary collateral blood flow in conjunction with global ventricular pump function, ventricular contractility and diastolic compliance. Measurements were obtained at rest and during dobutamine stress using a MRI catheterization technique. We hypothesized that exposure to dobutamine stress would have a specific impact on PVR and aorto-pulmonary collateral flow as well as systolic and diastolic ventricular function and hence improve our understanding of cardiovascular pathophysiology in Fontan patients. METHODS Study design The study was conducted in 10 preselected Fontan patients. The patients were referred to our institution for cardiac catheterisation and MRI because of decreasing exercise capacity at routine follow-up and therefore to determine ventricular systolic and diastolic function and cardiovascular anatomy. The assessment of exercise capacity was based on NYHA classification and ergometry. Only patients with extracardiac total cavopulmonary connection that had no fenestration of the tunnel were included. Exclusion criteria were the presence of Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 pulmonary artery stenosis, atrio-ventricular valve insufficiency, arrythmias, protein-loss syndrome, thromboembolism, effusion or oedema. In addition, n, patients pati pa t en ti ents ts with wit ith h beta-blocker medication were not included because this would have impacted effect cted th thee ef effe fect fe ct oof dobutamine infusion. All patients that was ients and/or their guardians ardians gave ve informed consent for the study stt approved by the responsible r institutional review board and ethic committee. Atrio-ventricular valvar function and ventricular inflow profiles (E/A-wavee ratio) were evaluated by Doppler-echocardiography. Exercise capacity was quantified by oxygen uptake during ergometry. During catheterization, ventricular pressures were measured with 4-5F fluid-filled pigtail catheters (Cordis, Warren, USA) and pulmonary pressures with 5F wedge catheters (Arrow, USA). Catheters were advanced over a femoral artery and femoral or cubital vein approach, respectively. At the end of the study a 24-36 mm sizing-balloon (AGA Medical, Plymouth, USA) was placed at the level of the tunnel-to-pulmonary artery connection. Then, patients were transferred to the neighbouring MRI laboratory keeping all catheters in place. Details about the use of the catheters during MRI are given below. MRI assessment of blood flow and pulmonary vascular resistance All MRI studies were performed at a 1.5 Tesla scanner (Philips Intera, release 2.6.1, Best, The Netherlands), maximum gradient performance 30 mT/m, slew rate 150 T/m/s. A 5- element cardiac phased arrayed coil was used for signal acquisition (Philips, Best, The Netherlands). In all patients, MRI was performed without sedation. Quantitative blood flow was measured using VEC MRI orthogonal to the dominating flow direction in the superior and inferior vena cave, left and right pulmonary artery and the ascending aorta as reported elsewhehre.12, 13, 14 In the ascending aorta, flow was measured just distal to the coronary arteries and the semilunar valves. In the inferior and superior vena cava, flow was measured in a segment approximately 5-10 mm below or above its connection to the pulmonary artery, respectively. Pulmonary flow was measured simultaneously with invasive pulmonary Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 pressure. Technical details for pressure recording are given below. All measurements were μg/k μg /kg/ /k g/mi g/ min mi n dobutamine. performed free-breathing at rest and during continuous infusion of 1100 μg/kg/min sin ing g fr from om tthe h concomitant he Automated correction was performed for potential phase errors aris arising magnetic field. Sequence e ence parameters equence arameters were: TR and TE shortest, acquired ac ired spatial s ti l resolution of 2x2x6 mm, 2 numbers umbers of excitation, phase encoding velocity 70 cm/sec for f r venous and a 150 cm/sec for aortic flow, 35 reconstructed phases per card d cycle. pulmonary flow and cardiac Data analysis was done with View Forum software (release 6.1, Philips, Best, The Netherlands). Antegrade and retrograde flows were measured as described elsewhere.12, 15 Aorto-pulmonary collateral flow (mL) was defined as the difference between effective antegrade aortic flow and the sum of antegrade right and left pulmonary blood flow as measured with VEC MRI in the right and left pulmonary artery. Pulmonary vascular resistance was the quotient between transpulmonary gradient and effective antegrade pulmonary flow.16, 17 The transpulmonary gradient was calculated as the difference between mean pulmonary and ventricular enddiastolic pressures. Total effective pulmonary flow was defined as the sum of antegrade flow as measured with VEC MRI in the right and left pulmonary artery plus collateral blood flow. The Nakata index was calculated as the sum of the crosssectional areas of the left and right pulmonary artery divided by body surface area.18 The areas were obtained from the magnitude images of the right and left pulmonary VEC MRI measurements. MRI assessment of global ventricular function Ventricular chamber volumes and myocardial mass were determined from axial stacks of multislice-multiphase steady state free precession cine-MRI covering the entire heart.12, 19, 20 Sequence parameters were: TR/TE 3.4/1.7 msec, slice thickness 6 mm, no gap, in-plane Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 resolution 1.9x1.3 mm2, 45 phases per cardiac cycle, number of averages 1, SENSE-reduction ellea ease se 66.1, .1,, Philips, .1 Phil Ph ilip il ip Best, The factor 2. Analysis was done using View Forum software (release manuual ally ly traced tra race ced ce d for f computing Netherlands). Biventricular endo- and epicardial borders were manually mes and myocardial ocardial mass where the septum se um was accounted as left lee ventricular ventricular volumes mass. Papillary muscles and prominent right ventricular trabeculation were excluded for m ments. Stroke volume was calculated as the difference between the diastolic volume measurements. and systolic volumes. Ejection fraction was calculated as the ratio of stroke volume to enddiastolic volumes. MRI assessment of myocontractile and diastolic function Parameters of myocontractile and diastolic function were derived from pressure-volume loops that were measured by a MRI catheterization technique. This MRI method was previously validated in animal experiments and is described in detail in a recent report.21 Briefly, ventricular volumes of the single ventricle were acquired over several cardiac beats with cine MRI. During MRI invasive ventricular pressures were measured and averaged. At postprocessing, volumes and pressures were synchronized in time using a trigger signal. From these measures apressure-volume loop under steady-state conditions was constructed. The endsystolic pressure-volume relation (ESPVR) was estimated from this loop using a single- beat approach as previously described.22-24 Emax, the slope of the ESPVR was defined as a measure of contractility and was indexed to 100 mg myocardial muscle mass (Emax,i). Effective arterial elastance (Ea) was calculated as end-systolic pressure divided by stroke volume. Ventricular-arterial coupling was determined as the ratio of Emax to Ea.23, 25. In a second step, instantaneous blood flows were measured using real-time VEC MRI in the ascending aorta just distal to the orifices of the coronary arteries.13, 21 The sequence parameters were: TR/TE 23/6.5 msec, matrix 128x256, FOV 400 mm, slice thickness 8 mm, encoding velocity 150 cm/sec, SENSE reduction factor 3, halfscan factor 0.6, EPI factor 41. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 The scan time was 31 msec for the acquisition of one phase-contrast image. During flow allo al loon lo on oocclusion cclu cc lusi lu sion si on of the vena measurements, ventricular preload was reduced by transient bballoon each ch uunloaded nloa nl o cava. The balloon was inflated with isotonic saline solution. Forr ea beat, we icular chamber volumes and ssynchronized chronized them with ventricular ventricula ventricu a pressures to determined ventricular generate a set off pressure-volume loops, as previous described.21 The absolutee enddiastolic etermined by matchin volumes were determined matching the VEC MRI derived volumes with th the intercept of the ESPVR. The resulting enddiastolic pressure-volume points were used to determine the enddiastolic pressure-volume relation (EDPVR). The stiffness constant ß, a load-independent measure of ventricular compliance, was calculated from the EDPVR with an exponential regression: EDP=Aeß·EDV with EDP=enddiastolic pressure, EDV=enddiastolic volume and A=curve fitting constant. ß was indexed to ventricular volumes to create a dimensionless index (ß,i). From pressure measurements we derived relaxation time constant Tau as a parameter of early diastolic relaxation. Pressure recordings and catheter visualization during MRI The fluid-filled catheters (details were provided above) were connected to pressure transducers (Becton-Dickinson, Franklin Lakes, USA) and pressures were amplified, recorded and analyzed with Ponemah software (DSI, St. Paul, USA). An additional pressure transducer was positioned within the bore of the scanner to obtain a trigger signal for synchronizing measured pressures with cine and VEC MRI derived ventricular and blood flow volumes.21 The position of the catheters was visualized on cine MR images (Figure 1). Appropriate inflation of the balloon catheter with saline solution was confirmed on interactive-real time MRI (Figure 1).26 Statistical analysis Measurements at rest and during dobutamine were analyzed with paired Student’s t-test and Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Bonforroni-Holm correction for multiple comparisons of n=20 parameters. Data are expressed as mean ± SD. The correlation was determined between ventricular iccul u ar vvolumes, olum ol umes um es,, cardiac index es and aorto-pulmonary collateral flow. In addition, correlation determined between on wa wass de dete term te rmi rm measurements off collateral flow, pulmonary ergometry derived ulmona vascular resistance and ergom e m parameters of functional nctional capacity. The agreement between pulmonary and caval flow volumes was assessed using n the Bland-Altman test. ng RESULTS General characteristics We investigated 10 Fontan patients; n=5 with a right- and n=5 with a left-type single ventricle. Eight patients were Caucasian, two of Arabic ethnicity. All patients were compliant to the study. The duration of dobutamine exposure ranged between 15 and 25 minutes. There were no side effects to dobutamine. Due to the length of the study protocol, flow measurements in the inferior and superior vena cava were not performed in n=2 patients at rest and in n=4 patients during dobutamine. All patients were at NYHA I-II. Ergometry showed decreased functional capacity as compared to published reference levels (Table).27 Angiograms revealed no obstruction within the Fontan circulation and either no or only visibly small veno-venous or aorto-pulmonary collaterals. Oxygen saturation at rest ranged between 91 and 97% and did not decrease significantly during dobutamine. There were no statistically significant differences between parameters as measured for the left versus right type single ventricle. This comprises also the function parameters as given below. Blood flow and pulmonary vascular resistance The Nakata index of the pulmonary arteries was 150±45 mm2/m2 and thus substantially below published reference values of healthy controls.1, 18 Quantitative flow volumes measured in the Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 inferior and superior vena cava were similar to those measured in the left and right pulmonary blle) e).. In all all ppatients, atie at ien ie n there was artery and they all increased during dobutamine (p<0.05) (Table). elll as dduring urin ur ing in g stress (Figure only trivial retrograde flow in the pulmonary arteries, at rest ass wel well tman analysis showed good ood agreement reement between flow measurem 2). The Bland-Altman measurements obtained ure 3).. During augmented pul ppulmonary flow, in the vena cava and the pulmonary arteries (Figure y artery arter pressure essure and trans transpulmonary lmonar pressure essure gradient radient did only change mean pulmonary slightly and, consequently, vascular resistance was decreased (Table). Blood flow volumes were significantly larger when measured in the aorta compared to the pulmonary arteries and, compared to rest, this difference increased during stress (Table). Thus, the calculated collateral blood flow increased significantly during dobutamine (p<0.01). There was no significant correlation between collateral blood flow and ventricular enddiastolic volumes (r=0.072 at rest and r=-0.062 during dobutamine) or between collateral blood flow and cardiac index (r=-0.072 at rest and r=-0.062 during dobutamine). However, there were statistically significant inverse correlations between collateral blood flow (APC) and both PVR and ergometry derived peak oxygen uptake (r=-0.6, p=0.03 and r=-0.7, p=0.01). Blood flow patterns in the pulmonary arteries were similar at rest and during dobutamine (Figure 2). The profiles showed, in concordance to other reports, some degree of inter-individual variability.28, 29 Global pump and myocontractile function During dobutamine, heart rate and cardiac output increased significantly, but stroke volume did not (Table). Differences in ejection fraction just failed of being significant when using Bonferroni-Holm adjustments for multiple comparisons (p=0.009, Table). Myocontractile and diastolic function During dobutamine there was increase of Emax,I that however failed of being significant Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 when adjusting for multiple comparisons (p=0.026, Table). Ventricular-arterial coupling omi m ta tant nt increase inc ncre reeas asee in Ea.25 By (Emax/Ea) did not improve during dobutamine due to concomitant echocardiography, the ratio of the E and A wave was above 0.7 patients. 7 in n al alll pa pati tien ti ents en ts During MRI catheterization, att rest, the relaxation time constant Tau was at published referen reference n levels for healthy controls and shortened significantly the same time, s nificant during dobutamine (Table). Tabl . At th there was a decrease Enddiastolic pressure c crease of enddiastolic volumes (Table, Figure 4) Enddiast t increased slightly, but not significantly. There were no significant changes of the stiffness constant ß, but the pressure-volume loops shifted towards the left in the pressure-volume diagram in all patients (Table, Figure 4). DISCUSSION A progressive decrease of exercise capacity is commonly observed in patients with Fontan circulation and, at late follow-up, heart failure contributes importantly to morbidity.5 The pathophysiologic causes for failure seem to be multifactorial. In this study, MRI catheterization was used to obtain, at rest and during dobutamine, information about pulmonary vascular resistance, global ventricular pump function, myocardial contractility and diastolic function. The major findings are that left-to-right shunt through aorto-pulmonary collaterals increased during dobutamine but pulmonary vascular resistance decreased. In addition, during stress the single ventricle had signs for abnormal diastolic compliance. Blood flow and pulmonary vascular resistance Several authors reported a diminished growth of the pulmonary arteries despite somatic growth and assume that this might have an impact on pulmonary vascular resistance.1, 2 However, only sparse data is available about the functional status of the pulmonary arteries at rest and during stress. This is partly due to the fact that vascular properties like PVR can not Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 be evaluated in the Fontan patients with conventional techniques such as thermodilution or ue tool by combining com mbi b Fick method. In this setting, MRI catheterization forms a unique invasive oll llat ater at erral aaorto-pulmonary o or pressures and VEC MRI derived flow data that also accounts for co collateral blood flow.3, 16, 288 For reliable assessment of the PVR in the Fontan circulation, which is very anges in volume load, pulmonary pressures and blood flow we weree measured in susceptible to changes a aneously this study simultaneously and not sequentially. The MRI method used in this study for measuring collateral blood flow was adopted from the work published by Whitehead and Grosse-Wortmann.3, 14 In these studies, collateral flow was estimated by two approaches. Simplified, collateral flow was defined as the differences between (i) flow volumes measured in the ascending aorta and the four pulmonary veines or, alternatively as the difference between (ii) flow volumes in the ascending aorta and the systemic venous return. The latter was determined in the descending aorta (GrosseWortmann) or the inferior and superior vena cava (Whitehead). In both studies, the different methods had overall good agreement. In our study, we modified the approach of Whitehead and colleagues slightly by measuring directly pulmonary arterial flow instead of caval flow. Comparing pulmonary with caval flow volumes showed good agreement (Figure 3). In concordance with the study by Whitehead and Grosse-Wortmann, we noted important contribution of aorto-pulmonary collateral flow to total effective pulmonary blood flow.3, 14 The latter is considered being the amount of blood that passes through the pulmonary arteriole level, thus the sum of antegrade pulmonary and collateral flow. Recirculating blood through collaterals contributed about 13% to total effective pulmonary flow at rest and this percentage increased substantially to over 25% during dobutamine. Interestingly, there was statistically significant inverse correlation between the amount of collateral flow and peak oxygen uptake during ergometry. Collateral flow also correlated inversely with PVR. However, the relatively small sample size in this study limits the clinical interpretation of this finding. This issue must be addressed systematically in future research. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 In the studied patients, PVR at rest was slightly above published control values that were etter eter eriz izat iz a io at ion n method. meth me th 16 During determined in a former study using the same MRI catheterization dobutamine, mean pulmonary pressures increased, but transpulmonary lmona nary na ry ggradient radi ra dieen did not and di thus PVR decreased ased in the presence esence of augmented au ented pulmonary lmonar throughput. thro hput. PVR is generally considered being resistive g a valid indicator of structural changes at the small resistiv v pulmonary arteriole level. Hence we concluded that in the studied patients least tients there is at lea l a a partially functioning pulmonary vasculature regulation to variation in pulmonary perfusion. However, one must keep in mind, when interpreting these data, that dobutamine was shown to increase pulmonary blood flow but does not affect the pulmonary vascular tone.30, 31 In addition, Hjortdal and colleagues demonstrated that in Fontan patients with total-cavo pulmonary connection blood flow through the lung is driven by cardiac, respiratory and peripheral muscular mechanisms.32 The relative contributions of these pumping mechanisms are influenced by many factors that include cardiac performance, physical exercise, body position and respiratory patterns. These different mechanisms can not be simulated in the MRI environment realistically. Global ventricular, myocontractile and distolic function Similar to earlier studies, we noted no substantial stroke volume augmentation under dobutamine stress in the Fontan patients.10, 33 Myocardial contractility increased only slightly and not significantly during inotropic stimulation and thus the increase in cardiac output was mainly regulated by heart rate. This is again in line with earlier studies.33 In conjunction with slightly improved parameters of contractility, endsystolic volumes decreased adequately suggesting that systolic dysfunction is not the predominant cause of the abnormal response to stress. At the same time, enddiastolic volumes decreased, again similar to previous observations, and Emax/Ea, a parameter for the efficiency of ventriculo-arterial coupling Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 remained at a low level.10, 23 These findings suggest an abnormal diastolic function of the ill llin ing in g is thought tho houg ught ug ht to t be affected single ventricle during dobutamine stress. In Fontan, diastolic filling entric icle ic le aactively ctiv ct ivel iv e y pumping an el by a limited preload reserve as there is no subpulmonary ventricle u of blood through the pulmonary system.6, 10, 32 One might aalso speculate unt appropriate amount that, in the presence dysfunction ence of diminished preload recruitment, diastolic dysfunctio o is induced tricle is “not trained” to be ful elderl patien ti n with atrial because the ventricle fully loaded. From elderly patients septal defect it is known, that chronic underloading can lead to a small and stiff left ventricle. In these patients, pharmacological priming before defect closure mostly improved diastolic function.34 On the contrary, recirculating blood through aorto-pulmonary collaterals contributes increasingly to ventricular filling under stress and thus would attenuate a deficient preload reserve. Other authors even discussed that collateral flow can impose a volume load on the single ventricle.3, 35, 36 Overall, one should consider that there is important individual variation in the presence of collaterals and the resulting amount of collateral flow.37 In our study, active early diastolic relaxation appeared to be normal, as indicated by a decrease of tau during dobutamine.38 However, there was evidence of abnormal diastolic compliance. During dobutamine, the stiffness constant ß remained at similar levels as measured at rest, but, the EDPVR shifted towards the upper-left in the pressure-volume diagram. Such a shift of the EDPVR was not observed in recent studies that were performed in healthy pig left and right ventricles.21, 39 In addition, these studies showed that dobutamine has no major impact on the stiffness constant ß. It seems that chamber properties for filling do not improve during dobutamine stress but rather filling must be accomplished in a system with increased stiffness. In our study we exposed the patients to moderate dobutamine stress that caused no substantial increase in enddiastolic pressures. In more severe stress situations, diastolic dysfunction might unmask even further which could go along with more increased enddiastolic pressures. An abnormal ventricular stiffness could be explained by several reasons. The geometry of the single ventricle has a direct impact on its mechanical pump Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 function and thus on its systolic and diastolic properties.40 In addition, prolonged cyanosis and caard card rdia iall fi ia fibr bros br osis os is..66, is volume load during infancy are thought to induce myocardial fibrosis. 41 Finally, histopathologic studies in tricuspid atresia showed abnormal form formation mat atio ion io n an and d ar aarrangement of the fibrous matrix x and the aggregation of myocyte chains.11 Thus, the potential ccauses for the development of heart and pulmonary vascular dysfunction are multifactoria multifactorial a as are the function. This implies i lies that it is essential to investigate investi te tthese patients resulting forms of ddysfunction. with methods that give a differential insight into the predominant form of failure which in turn will allow optimizing treatment concepts. In summary, the findings of this study indicate that during dobutamine stress blood flow through aorto-pulmonary collaterals contributes progressively to pulmonary perfusion. The pulmonary arteries had abnormal growth index but vascular regulation appeared to be unsuspicious. Pulmonary vascular resistance decreased during stress and thus did not contribute to impaired diastolic filling in the studied patients. In contrast we noted, in the presence of normal early relaxation, alteration of ventricular compliance during stress. Limitations There is no established animal model for studying the Fontan circulation. Also extrapolating findings from healthy human controls to a univentricular physiology must be made with great care. Therefore, this patient study has a descriptive nature and findings must be related to parameters that were obtained in other research. Care must be taken when comparing changes of ventricular and pulmonary vascular function induced by physical exercise with dobutamine stress.30, 42, 43, 32 Therefore, it would be inappropriate to directly translate our findings to exercise conditions. In addition, heart rate effects must be considered when interpreting our data of diastolic compliance. Collateral flow through intrapulmonary shunts and veno-venous Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 collaterals was not determined in our study. However, arterial oxygen saturation did not at flow fllow through thr hrou ough ou gh these t decrease significantly during stress and thus one can assume that types of surin ng bl bloo ood oo d fl fflow o in all four shunt was relatively constant during the study protocol. Measuring blood uantifyi the amount of veno pulmonary veinss would have allowed quantifying veno-venous and protoco proto o which was intrapulmonary flow but at the expense of a substantially lengthened protocol n nding. flo o sequences judged too demanding. In general velocity-encoded (VEC) phase-contrast MR flow must be used with great care when measuring quantitative flow. Finally, there is a broad range of varieties in Fontan regarding anatomical conditions and the onset and time-course of cardiovascular dysfunction. Therefore, one can not extrapolate our data of preselected patients to other forms of Fontan. However, the method used in this study allows differentiating between pulmonary, systolic and/or diastolic dysfunction which will potentially improve the planning of individual treatment strategies. Sources of Funding This work was supported by the German Science Association (DFG) and the German Federal Ministry of Education and Research, grant 01EV0704. Responsibility for the contents rests with the authors. Disclosures None. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 References 1. 2. 3. 4. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Ovroutski S, Ewert P, Alexi-Meskishvili V, Holscher K, Miera O, Peters B, Hetzer R, Berger F. Absence of pulmonary artery growth after fontan operation and its possible impact on late outcome. Ann Thorac Surg. 2009;87:826-831. Tatum GH, Sigfusson G, Ettedgui JA, Myers JL, Cyran SE, Weber HS, Webber SA. Pulmonary artery growth fails to match the increase in body surface area after the Fontan operation. Heart. 2006;92:511-514. Grosse-Wortmann L, Al-Otay A, Yoo SJ. Aortopulmonary collaterals after bidirectional cavopulmonary connection or Fontan completion: quantification with MRI. Circ Cardiovasc Imaging. 2009;2:219-225. Spicer RL, Uzark KC, Moore JW, Mainwaring RD, Lamberti JJ. 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Table: Patient characteristics and parameters of ventricular and pulmonary function Patient number Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 1 2 3 4 5 6 7 8 9 10 Mean±SD Patient number 1 2 3 4 5 6 7 8 9 10 mean±SD p-value Patient number 1 2 3 4 5 6 7 8 9 10 mean±SD p-value Leading diagnosis Mitral Atresia, TGA Tricuspid Atresia Pulmonary Atresia Unbalanced AV canal Tricuspid Atresia, TGA DILV, TGA Univentricular heart Tricuspid Atresia DORV, TGA DORV, Heterotaxia Systemic Ventricle (left/right) RV LV LV LV LV RV RV LV RV RV Age (years) Body weight (kg) 14 16 40 14 39 13 26 21 18 18 22±10 24 27 59 29 69 29 86 57 39 56 48±20 BSI (m2) 0.9 1.0 1.6 1.1 1.9 1.0 1.9 1.6 1.3 1.5 1.4±0.4 Myocardial MM (g) 44 61 101 56 103 54 97 55 76 88 73±21 73±2 73 ±211 ±2 NYHA (I-IV) I I I I II I I II II I VE/VCO2 slope (ml/min/kg) 21.8 22.4 20.5 15.1 16.9 18 21.6 22.2 20.1 14.9 19.4±2.9 Heart rate Contractility (beats/min) Emax (mmHg/mL/100 g) Rest Dobu obu Rest Dobu 1 83 149 1.5 2.6 107 143 1.9 3.2 76 134 3.1 4.6 89 136 2.3 4.2 73 87 3.4 3.5 52 87 3.6 4.8 98 142 4.0 4.2 91 113 4.1 5.5 81 129 3.5 3.9 88 141 4.2 6.8 84±14 126.1±21.6 3.2±0.9 4.3±1.1 0.00002* 0.0264 Coupling Emax/Ea Rest 0.4 0.3 0.6 0.7 0.7 0.8 0.6 0.8 0.2 0.9 0.6±0.2 0.2171 Ventricular volumes EDV (mL/m2) ESV (mL/m2) Rest Dobu Rest Dobu 86.4 77.8 49.5 48.7 83.9 77.2 48.2 41.5 72.3 66.1 49.4 43.3 45.3 36.3 22.3 13.4 77.9 69.3 53.3 43.7 46.3 37.6 20.1 12.9 38.0 38.2 19.5 9.2 71.5 61.7 43.4 31.2 89.9 71.5 54.1 40.0 48.6 43.8 25.7 18.0 66±18.5 57.9±16.2 38.6±14 30.2±14.5 0.0004* 0.0001* SV (mL/m2) EF (%) CI (L/min/m2) Rest Dobu Rest Dobu Rest 36.9 29.1 42.7 37.4 2.9 35.7 35.7 42.5 46.3 3.8 22.9 22.9 31.6 34.6 1.7 23.0 22.9 50.7 63.1 2.0 24.5 25.6 31.5 36.9 1.8 26.3 24.6 56.7 65.6 1.4 18.5 22.6 48.6 71.0 1.8 28.1 30.5 39.3 49.5 2.6 28.0 31.5 39.8 44.1 2.3 22.9 25.9 47.1 59.0 2.0 26.7±5.5 27.1±4.2 43.1±7.6 50.7±12.4 2.2±0.7 0.6877 0.0092 0.0002* Dobu 0.5 0.3 0.5 0.4 0.7 0.5 0.6 0.9 0.2 0.8 0.5±0.2 Distolic compliance ß (1/mL/100 ml EDV) Rest Dobu 0.7 0.5 1.2 0.9 1.8 2.1 1.4 1.3 0.9 1.4 1.1 1.0 1.6 1.7 1.2 1.3 1.8 1.9 1.7 1.8 1.3±0.4 1.4±0.5 0.5212 VO2max 47 36 27 40 28 30 29 28 34 33 33.3±6.3 Early distolic relaxation Tau Rest Dobu 48.2 28.4 27.3 25.0 31.5 25.3 33.8 22.6 32.4 27.5 40.1 36.0 23.5 18.0 49.2 23.0 57.6 43.0 23.1 15.0 36.7±11.1 26.4±7.8 0.0023* Dobu 2.9 5.1 3.1 3.1 2.2 2.1 3.2 3.5 4.1 3.6 3.3±0.8 Patient number Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 1 2 3 4 5 6 7 8 9 10 mean±SD p-value Patient number 1 2 3 4 5 6 7 8 9 10 mean±SD p-value Blood flow volumes SVC+IVC (L/min/m2) Rest Dobu na na 1.4 na na na 3.0 4.4 2.0 2.6 1.9 3.3 1.5 2.4 1.9 2.3 1.8 na 1.8 3.1 1.9±0.4 3.0±0.7 0.0022* LPA+RPA (L/min/m2) Rest Dobu 1.9 2.6 1.3 2.1 2.8 5.3 2.8 4.0 2.1 2.6 1.7 3.1 1.5 2.3 1.7 1.9 2.0 3.4 2.0 3.2 2.0±0.5 3.1±1.0 0.0004* Aorta (L/min/m2) Rest Dobu 2.1 3.2 1.4 2.8 3.4 6.7 3.2 5.6 2.3 3.3 1.9 3.4 1.6 2.7 1.9 2.6 2.2 4.0 2.3 4.1 2.2±0.6 3.8±1.3 0.0001* Ventricular pressures EDP (mmHg) Rest Dobu 2.2 4.1 6.0 8.2 7.7 7.9 4.6 5.6 4.0 6.2 5.8 5.9 5.5 8.3 5.6 7.1 71 6.3 7.0 8.3 9.0 5.6±1.7 6.9±1.4 0.084 ESP (mmHg) Rest Dobu 90.0 110.0 98.0 104.0 82.1 101.0 80.0 97.0 105.0 103.0 91.6 85.0 78.0 97.0 96.0 96 0 111.0 111 0 91.0 117.0 93.1 119.0 90.5±8.0 104.4±9.7 0.0034* Pulomonary pressures aand nd rres resistance e is es ista tanc ta ncee Mean PAP (mmHg) TPG TPG (mmHg) (mmH (m mHg) mH g) Rest Dobu Rest Reest Dobu Dob obuu 9.7 11.7 7.5 7.6 10.6 12.8 4.6 4.6 11.3 12.9 3.6 4.2 9.0 13.3 4.4 7.7 10.1 11.7 6.1 5.5 10.0 13.2 4.2 6.4 12.7 12.9 7.2 4.3 12.2 12 2 13.3 13 3 6.6 66 5.8 58 12.5 12.0 6.2 5.0 12.4 12.9 4.1 3.5 11.1±1.3 12.7±0.6 5.5±1.3 5.5±1.4 0.0057* 0.986 APC (L/min/m2) Rest Dobu 0.2 0.6 0.1 0.7 0.6 1.4 0.4 1.5 0.3 0.7 0.2 0.3 0.2 0.4 0.2 0.6 0.2 0.6 0.3 0.9 0.3±0.1 0.8±0.4 0.0004* APC contribution to Qp (%) Rest Dobu 13.3 24.2 8.5 33.3 21.7 26.6 14.4 37.5 13.4 26.8 12.0 8.1 10.3 19.4 12.6 33.6 9.7 17.6 14.7 28.7 13.1±3.5 25.6±8.3 0.0015* PVR (wood units/BSI) Rest Dobu 3.6 2.4 3.2 1.7 1.0 0.6 1.4 1.4 2.6 1.7 2.2 1.9 4.5 1.6 3.5 2.3 2.9 1.2 1.8 0.8 2.7±1.0 1.6±0.5 0.0022* TGA=Transposition of the Great Arteries, RV=right ventricle, LV=left ventricle, BSI=body surface index, AV=atrioventricular, DORV=double outlet right ventricle, DILV=double inlet left ventricle, MM=muscle mass, VO2max=peak oxygen uptake, VE/VCO2-slope=minute ventilation to carbon dioxide production relationship, Dobu=Dobutamine, Emax=slope of the endsystolic pressure volume relationship indexed to 100g muscle mass, Ea= arterial elastance, Emax/Ea=efficiency of ventriculararterial coupling, ß=stiffness constant indexed to 100 mL of enddiastolic volume, EDV=enddiastolic volume, ESV=endsystolic volume, SV=stroke volume, EF=ejection fraction, CI=cardiac index, SVC=superior vena cava, IVC=inferior vena cava, LPA=left pulmonary artery, RPA=right pulmonary artery, APC=aorto-pulmonary collateral, EDP=end diastolic pressure, ESP=end systolic pressure, PAP=pulmonary arterial pressure. TPG=transpulmonary gradient, PVR=pulmonary vascular resistance, Qp=pulmonary blood flow. Significance levels of p-values were adjusted by BonferroniHolm correction for multiple comparisons. In the table uncorrected p-values derived from paired Student´s t-test are given for differences between rest and dobutamine. Significant differences after Bonferroni-Holm correction are indicated by *. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 FIGURE LEGENDS Figure 1: Cine MR images of catheters as used for ventricular and pulmonary pressure measurements (arrows, panels A and B). The catheters are visible due to small local signal voids. Panel C shows an interactive real-time MR image of a balloon catheter in the inferior vena cave during inflation with isotonic saline solution. Panel D illustrates the position of the catheters in the pulmonary artery, the single ventricle and the inferior vena cava. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Figure 2: Representative flow volumes and pressures of a patient with Fontan measured at um ooff th thee fl flow ow measured in rest and during dobutamine. The pulmonary flow is shown as thee ssum ta that at w as measured mea easu s the left and right pulmonary artery. For illustration purposes, data was at two different heart rates t (rest and dobutamine) were scaled to 35 heart phases. tes Figure 3: Bland-Altman Altman plot lot of pulmonary ulmona and caval blood flow volumes (mL) ffor measurements obtained at rest and during dobutamine. Figure 4: Pressure-volumes loops (left panel) and enddiastolic pressure-volume points with regression line (right panel) in a representative patient at rest and during dobutamine. Note the left shift of the loops and enddiastolic pressure-volume points during dobutamine. Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Pulmonary Vascular Resistance, Collateral Flow and Ventricular Function in Fontan Patients at Rest and During Dobutamine Stress Boris Schmitt, Paul Steendijk, Stanislav Ovroutski, Karsten Lunze, Pedram Rahmanzadeh, Nizar Maarouf, Peter Ewert, Felix Berger and Titus Kuehne Downloaded from http://circimaging.ahajournals.org/ by guest on May 3, 2017 Circ Cardiovasc Imaging. published online July 14, 2010; Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2010 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. 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