AOGS ORIGINAL RESEARCH ARTICLE

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1 AOGS ORIGINAL RESEARCH ARTICLE Ventricular outputs, central blood flow distribution and flow pattern through the aortic isthmus of fetuses with simple transposition of the great arteries JULIE BLANC 1,2, JEAN-CLAUDE FOURON 1, SVEN-ERIK SONESSON 3, MARIE-JOS EE RABOISSON 1,4, IAN HUGGON 5,, ROXANNE GENDRON 1, ANNIE BERGER 1 & SOPHIE BRISEBOIS 1 1 Pediatric Cardiology, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada, 2 Pediatric Department, Hospital Center of Avignon, Avignon, France, 3 Pediatric Cardiology, Karolinska Institute, Stockholm, Sweden, 4 Pediatric Cardiology, Cardiological Hospital Louis-Pradel, Lyon, France, and 5 Pediatric Cardiology, King s College, London, UK Key words Transposition of the great arteries, fetus, ventricular outputs, lungs flow Correspondence Jean-Claude Fouron, Fetal Cardiology Unit, Pediatric Cardiology Service, CHU Sainte- Justine, 3175 C^ote-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. fouron@sympatico.ca Conflict of interest As senior and corresponding author, I certify that all co-authors of this multicenter observational clinical investigation had no potential conflicts of interest while working on this project. Deceased. Please cite this article as: Blanc J, Fouron J-C, Sonesson S-E, Raboisson M-J, Huggon I, Gendron R, et al. Ventricular outputs, central blood flow distribution and flow pattern through the aortic isthmus of fetuses with simple transposition of the great arteries. Acta Obstet Gynecol Scand 2016; 95: Received: 26 October 2015 Accepted: 1 March 2016 DOI: /aogs Abstract Introduction. Our objective was to determine the impact of simple transposition of the great arteries (TGA) on fetal left ventricular (LV) and right ventricular (RV) performances and central circulatory dynamics including the aortic isthmus. Material and methods. Ventricular stroke volumes were calculated as the product of the cross-sectional area of the corresponding semi-lunar valve and the flow velocity integral through these valves. Volume flow in ductus arteriosus (Q DA ) was evaluated using the same technique. Flow through the lungs (Q LUNGS ) was calculated by subtracting net Q DA from flow in main pulmonary artery [ net Q DA = Q DA minus retrograde ductus arteriosus (DA) diastolic flow]. Relative performance of each ventricle expressed as percentage of combined cardiac output was also indirectly assessed by the aortic isthmus systolic index (ISI) (nadir of incisura/peak systolic of the Doppler waveforms in the isthmus); the relation between ISI and Q LUNGS was investigated. Results. - Fifty-one fetuses with TGA were compared with 74 normal controls matched for gestational age. TGA fetuses had higher Q LV at T2 ( % vs %, p < 0.001) and T3 ( % vs %, p < 0.001). Q LUNGS was higher in fetuses with TGA, in the second ( % vs %, p = 0.007) and third trimesters of gestation ( % vs %, p = 0.005). No difference was found between ISI values from normal and TGA groups. A significant inverse correlation was observed between ISI and Q LUNGS (r = 0.55, p = 0.006). Conclusions. Central distribution of combined cardiac output of fetuses with simple TGA is characterized by a greater Q LUNGS leading to a dominant LV. In prenatal TGA, changes in Q LUNGS could be monitored by measuring ISI. The clinical importance of this last observation deserves further investigations. Abbreviations: AoI, aortic isthmus; CCO, combined cardiac output; DA, ductus arteriosus; ISI, isthmic systolic index; LV, left ventricular; net Q DA, systolic antegrade minus diastolic retrograde flows (when present) through the DA; Q DA, volume flow in DA; Q LUNGS, lungs flow = Q LV net Q DA ;Q LV, left ventricular output; Q RV, right ventricular output; RV, right ventricular; T2, second trimester of gestation; T3, third trimester of gestation; TGA, transposition of the great arteries. ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

2 Flow patterns in fetuses with transposition J. Blanc et al. Introduction Normal fetal cardio-circulatory dynamics have been well investigated both in animal experiments (1,2) and, more recently, in humans, with echocardiographic Doppler studies (3 5) always demonstrating right heart dominance during the last two trimesters of gestation. Complete transposition of the great arteries (TGA) is one malformation where both pre- and postnatal fundamental characteristics of the central circulatory dynamics are profoundly disturbed. Individual ventricular performances and central distribution of blood flow in human fetuses with simple TGA have been the subject of speculative reports based either on patterns of prenatal growth (6) or on gathering of experimental data on the physiology and pathophysiology of the fetal cardio-circulatory system (7). To the best of our knowledge, a direct attempt to clarify the impact of simple TGA on ventricular respective performances and on central prenatal flow patterns, including the aortic isthmus (AoI), has never been reported. Since the outputs coming from the two fetal arterial arches have an opposite effect on the isthmic flow, forward for the aortic and retrograde for the pulmonary ductus arteriosus (DA) arches, variations in their respective flow volumes should alter the usual appearance of the Doppler AoI waveforms (8). The objectives of this multicenter study were therefore twofold: first to determine the relative performance of each ventricle and the central partition of the left ventricular (LV) output toward the DA and lungs of fetuses with simple TGA; and secondly to assess the relation between the cardio-circulatory changes observed and potential alterations of AoI flow velocity waveforms. Material and methods This observational retrospective study was performed on two groups of fetuses: the normal controls and the TGA group, further classified as pertaining to the second (T2) or third trimester (T3). Scans with missing waveforms on pulmonary and aortic valves or DA were excluded. In all cases, gestational ages were confirmed by sonographic biometry in early pregnancy. This retrospective study did not require formal ethical approval, but the use of routinely collected clinical data was approved by the chairman of Medical and University affairs, CHU Sainte-Justine, University of Montreal on Control group The control group comprised fetuses from normal singleton pregnancies referred for irregular fetal heart beats or increased risk of fetal cardiac abnormalities, which were not documented. Bi-dimensional and Doppler echocardiographic recordings and measurements were all performed by experienced echocardiographers from the Fetal Cardiology Unit at the CHU Sainte-Justine. TGA group The TGA group comprised singleton fetuses with a prenatal diagnosis of TGA and intact ventricular septum or small ventricular septal defect with normal postnatal pulmonary pressure and no outflow track obstructions. Experienced examiners from four fetal echocardiographic centers performed the echocardiographic studies. All prenatal diagnoses were confirmed by postnatal echocardiograms. Except for the presence of a TGA, both groups shared the same inclusion criteria: no systemic fetal malformations, appropriate size for gestational age, normal amniotic fluid volume, no maternal diabetes, hypertension or increased uterine or umbilical artery resistance indices. All ultrasound recordings were stored on compact disks for later off-line analysis. Recordings and measurements High-resolution color Doppler ultrasound equipments with 3 6 MHz broadband transducers were used in all centers. The diameters (trailing to leading edge method) of the DA at its middle part and of the aortic and pulmonary valves annuli, were determined from 2D recordings with an insonation angle perpendicular to the long axis of the arteries. Doppler velocity waveforms above the aortic and pulmonary valves as well as in the middle part of the DA were recorded at an insonation angle below 20, without using angle correction. Fetal heart rate (FHR) and systolic time velocity integrals (TVI) were determined on three consecutive cycles and averaged, allowing calculation of stroke volumes and flows per minute (Q = FHR*TVI (p*d²)/4) where d is the diameter of the vessel or the valve. Ventricular outputs were obtained from tracings recorded above the aortic (Q LV for controls and Q RV for the TGA group) and pulmonary valves (Q RV for controls and Q LV for the TGA group). Ventricular dominance was based on the ratio of Q LV or Q RV to Key Message Fetuses with transposition of the great arteries have greater lungs flow than normal, with secondary left ventricular dominance. Inverse correlation has been observed between lungs flow and aortic isthmus systolic index. 630 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

3 J. Blanc et al. Flow patterns in fetuses with transposition Table 1. Clinical and hemodynamic characteristics (mean SD) of fetuses with TGA and controls, studied during the second (T2) and third (T3) trimesters of pregnancy. T2 T3 TGA Control p TGA Control p Examinations (n) GA (week) DA diameter (mm) CCO (ml/min) Q RV (% CCO) < <0.001 Q LV (% CCO) < <0.001 netq DA (% Q PA ) Q LUNGS (% Q PA ) TGA, transposition of the great arteries; DA, ductus arteriosus; CCO, combined cardiac output; GA, gestational age; Q RV and Q LV, right and left ventricular output; net Q DA and Q LUNGS, blood flow to DA and lungs; Q PA, blood flow in the main pulmonary artery. combined cardiac output (CCO = Q LV + Q RV ). In the TGA group, the retrograde influence of the ductal flow coming from the LV, on the AoI Doppler waveforms was assessed by measurements of the isthmic systolic index (ISI) (ISI = nadir/peak of the AoI systolic Doppler waveforms) (9). In both groups, lungs flow (Q LUNGS ) was calculated by subtracting net flow through the DA (Q DA ) from the flow above the pulmonary valve (Q PA ), where netq DA was defined as forward minus reverse flows when present in diastole. Statistical analyses Due to the retrospective nature of this study, adequate scans of TGA fetuses were not systematically available in both T2 and T3 trimesters. To avoid possible co-dependency between scans of TGA fetuses recorded twice, once in each trimester, comparisons with the control group (composed of single studies for each fetus during T2 or T3) were computed separately for each trimester. To minimize the influence of the range of gestational ages and fetal weights within each trimester on our volume flow measurements, values of Q LV and Q RV were analyzed as percent of CCO, and net Q DA and Q LUNGS were expressed as percent of Q PA. Comparisons between groups within each trimester were done using t-test adjusted with the Levene s test on variances when necessary. Logarithmic transformation of the data was done when indicated to meet normality criteria. ISI values obtained from adequate Doppler recordings in the AoI were compared with normal reference data previously published for the same gestational ages (9). Q LUNGS and ISI relation was estimated by regression analysis; autocorrelation of fetuses with data both in T2 and T3 trimesters was assessed by Durbin Watson test. All analyses were computed with SPSS 20 (SPSS Inc., Chicago, IL, USA) and significance level was set at p < Results The control group contained 74 normal fetuses, 52 studied during T2 (18 28 weeks) and 22 during T3 (29 37 weeks). The TGA group was composed of 51 singleton fetuses; 23 had technically satisfactory examinations during both T2 and T3, resulting in a total of 74 studies, 35 during T2 (19 28 weeks), and 39 during T3 (29 38 weeks). There was no case of neonatal demise or severe post-natal hypoxia in the TGA group. Results obtained from examinations during the second and third trimester are presented in Table 1. Comparing controls and TGA fetuses within each period of gestation, there was no difference in gestational ages or DA diameters. Ventricular performances No difference was found between the CCO of TGA and control fetuses either at T2 (p < 0.57) or at T3 (p < 0.89) (Table 1). There was a significant LV dominance in the TGA group during T2, approximately 58% of the CCO (p < 0.001), maintained throughout the observation per- Table 2. Ventricular outputs of TGA fetuses with examinations in both T2 and T3 (n = 23). Absolute values of Q RV and Q LV and their relative influence on CCO. T2 T3 F p GA (week) Q RV (ml/min) (% CCO) Q LV (ml/min) (% CCO) (42.0) (58.0) (43.6) (56.4) 81.2 < <0.001 CCO (ml/min) <0.001 TGA, transposition of the great arteries; CCO, combined cardiac output; GA, gestational age; Q RV and Q LV, right and left ventricular output. ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

4 Flow patterns in fetuses with transposition J. Blanc et al. (a) (b) Figure 1. Ventricular performances (a) and central blood flow distribution (b) in fetuses with transposition of the great arteries (TGA) and normal controls (Control) during the second (T2) and third (T3) trimesters of pregnancy expressed as percentage of combined ventricular output (CCO) or pulmonary artery blood flow (Q PA ). Q RV and Q LV, right and left ventricular output, Q DA and Q PULM, blood flow through ductus arteriosus and lungs. iod; this was also confirmed by the subgroup of TGA fetuses with examinations in both the second and third trimesters, where the LV dominance was of 58% in T2 and 56% in T3 (Table 2). In contrast, the controls had a dominant Q RV (56% of the CCO, p < 0.001), a magnitude comparable to that of the LV of the TGA group (Table 1, Figure 1a). r = 0.55 (p = 0.006); fetuses with data in T2 and T3 had a minimal weight on this relation (Durbin Watson has been calculated at 2.21 eliminating any significant auto-correlation between the two measurements in this subgroup of fetuses). Central distribution of blood flow The distribution of the main pulmonary artery blood flow is shown together with its standard deviation in Table 1 and visualized by its average in Figure 1b. Compared to controls, TGA fetuses have a greater fraction of their main pulmonary artery flow perfusing the lungs, 50% compared with 39% in the control group, leaving a smaller fraction for the DA (49% vs. 61%; p < 0.014). This difference in distribution was observed during both T2 and T3, without any significant change between the two gestational age periods. Reverse diastolic flow in the DA was observed in 10 fetuses, 19.6% of the TGA group. Scans with AoI and complete blood flow Doppler were available for 15 TGA fetuses, nine had scans both in T2 and T3, four fetuses had scans in T2 only, and two in T3 only, adding up to 24 scans in T2 and T3. The same levels of ISI values were found for TGA and normal fetuses (Figure 2). The ISI values were significantly correlated to Q LUNGS (Figure 3) with a correlation coefficient Figure 2. The distribution of the isthmic systolic indices (ISI) calculated on the 24 ultrasound studies recorded in 15 fetuses with simple transposition of the great arteries (TGA) shows values within the range previously reported in normal fetuses (9). 632 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

5 J. Blanc et al. Flow patterns in fetuses with transposition Figure 3. Shows the significant inverse linear correlation found between isthmic systolic indices (ISI) values and flows through the lungs (Q LUNGS ) of fetuses with transposition of the great arteries (r = 0.55, p = 0.006). Discussion Two major differences have been observed between TGA and normal fetuses. First, in TGA fetuses, the fraction of Q PA going to the lungs was significantly greater than that observed in our group of normal fetuses, both in the second and third trimesters of gestation. This finding confirms speculations about a decrease in pulmonary vascular resistances caused by a higher PA po 2 in fetuses with TGA (7). However, the increased pulmonary blood flow in TGA fetuses perceptible as early as the second trimester of gestation goes against previous reports showing that, in normal fetuses, lung circulation does not respond to increased fetal po 2 before 30 weeks of gestation (10,11). This difference between normal and TGA fetuses could be due to at least two factors. First, a significant proportion of the blood perfusing the lungs of TGA fetuses is composed of relatively better oxygenated red cells coming from the placenta through the ductus venosus and recirculating in the pulmonary circulation without going through the systemic circulation. Secondly, in the clinical studies published (10,11), the time of exposure of normal fetuses to higher level of O 2 was relatively limited while in TGA fetuses the PA po 2 is elevated as soon as the fetal circulatory system is functional with the right to left preferential streaming of the well-oxygenated blood from the ductus venosus through the foramen ovale. This early and long lasting exposure to higher O 2 could induce a premature pulmonary vasoreactivity, characterized by an increased of either production or responsiveness of endothelin-1b-mediated vasodilator receptors. A similar speculation has been previously proposed to explain the higher incidence of persistent pulmonary hypertension of neonates with TGA that would be related to enhanced responsiveness of endothelin A-mediated vasoconstriction receptor due to chronic lack of stimulation (12). Another explanation for the increase in lung flow of TGA fetuses as early as the second trimester of gestation could be due to an active constriction of the DA in reaction to the higher level of PA po 2. Constriction of the DA was not corroborated in the present investigation either by the similar ductal diameters found in our TGA and control groups, or by the normal ISI values in the AoI of the TGA fetuses, expressing unrestricted retrograde influence of the DA on the AoI flow (9). The pathophysiological concept of a lower pulmonary vascular resistance would mean that fetuses with TGA have a greater blood volume recirculating within their independent pulmonary circulation compared with normal fetuses. Also, the lower pulmonary vascular resistances of TGA fetuses could explain the presence of reverse diastolic flow in the DA, as previously described (13) and observed in 19.6% of our TGA fetuses. The second major difference between the two groups of fetuses is the left ventricular dominance found in the TGA group, a logical consequence of the increase in venous return from the lungs. This observation reinforces speculations on a rise of LV end-diastolic filling pressure and consequently higher left atrial pressure, reducing the gradient and right to left shunting between the two atria as well as the size of the foramen ovale, causing major hypoxemia at birth (7,13). However, ultrasonographic combination of restrictive foramen ovale and DA constriction has been reported to show a high specificity (100%) but poor sensitivity (31%) to predict the need for emergency neonatal care (14). On the other hand, severe occlusive intimal proliferation found in the pulmonary arterioles of TGA neonates with intact septum who died within 1 week after birth, underlines the possibility of significant prenatal injury of the pulmonary vascular network occurring during prenatal life (15,16). In such conditions, intra-uterine elevated vascular pulmonary resistances associated with lower Q LUNGS should be expected. The findings, on the one hand, of the normal evolution of ISI throughout the gestation of our TGA fetuses and more importantly, on the other hand, the negative correlation found between ISI and Q LUNGS, lead to consider this index as a possible reliable marker of TGA fetuses at risk of severe post-natal hypoxemia. The relatively small number of TGA fetuses in whom ISI could have been calculated in the present study, reduces the strength of this hypothesis. Further investigations are warranted to validate this assumption. ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 95 (2016)

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