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Ventricular strain changes in monochorionic twins with and without twin-to-twin transfusion syndrome
Marisa C. Taylor-Clarke, BMBCh; Hikoro Matsui, PhD; Michael Roughton, MSc; Ruwan C. Wimalasundera, PhD; Helena M. Gardiner, PhD
OBJECTIVE: The objective of the study was to investigate whether vector velocity imaging (VVI), a non-Doppler speckle tracking ultrasound technology, is feasible in twin pregnancies and can aid management of twin-twin transfusion syndrome (TTTS). STUDY DESIGN: Twenty-seven women pregnant with monochorionic RESULTS: The VVI strain measurements could be analyzed in 182 of

diamniotic twins affected by TTTS and 28 monochorionic pregnancies that did not develop TTTS were included in a prospective case-control study at a fetal medicine center. Fetal echocardiograms were recorded with dummy electrocardiography to retain original frame rates when exported for ofine speckle tracking analysis using Syngo-VVI software (Siemens Corp, Munich, Germany). Right and left ventricular (LV) free wall Lagrangian strain was measured from the original coordinates. Within-twin pair ventricular strain differences including relationship to Quintero staging and response to laser therapy for TTTS were analyzed by Wilcoxon signed-rank test.

200 TTTS and 96 of 112 non-TTTS control ventricles. Within-pair strain was concordant in non-TTTS controls. Recipient LV strain was reduced at all Quintero stages compared with donors (P < .01). Recipient right ventricular strain was reduced only in stages 3 and 4 (P < .01). Strain improved at a median of 2 weeks following successful laser therapy. Intertwin differences in strain were independent of weight discordance.
CONCLUSION: Recipient LV strain is reduced in stages 1 and 2 TTTS.

Within-pair strain discordance may distinguish early TTTS from growth discordance and guide timing of and management following treatment. Key words: fetus, myocardial strain, speckle tracking, twin-twin transfusion syndrome

Cite this article as: Taylor-Clarke MC, Matsui H, Roughton M, et al. Ventricular strain changes in monochorionic twins with and without twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2013;208:462.e1-6.

rediction of development and progression of twin-twin transfusion syndrome (TTTS) in genetically identical monochorionic diamniotic (MCDA) twins remains difcult. Current measurements cannot reliably identify

pregnancies that will progress rapidly to advanced disease, or even fetal demise, within days.1,2 Attempts to nd improved methods of characterizing and risk stratifying in TTTS have turned to measures of cardiac

From the Division of Cancer, Faculty of Medicine, Imperial College (Drs Taylor-Clarke, Matsui, Wimalsundera, and Gardiner); Centre for Fetal Care, Queen Charlottes and Chelsea Hospital, Imperial Healthcare National Health Service Trust (Drs Taylor-Clarke and Wimalasundera); Royal College of Physicians (Mr Roughton); and Royal Brompton National Health Service Foundation Trust Hospital (Dr Gardiner), London, UK. Received Nov. 6, 2012; revised Jan. 21, 2013; accepted Feb. 28, 2013. This work was supported by the Tiny Tickers charity, the Richard and Jack Wiseman Trust, the National Institute of Health Research Biomedical Research Centre funding scheme, and Genesis Research Fund at the Institute of Reproduction and Developmental Biology, Imperial College and Queen Charlottes and Chelsea Hospital, London, UK. The authors report no conict of interest. Presented at the 16th Annual Conference of the British Maternal and Fetal Medicine Society, Glasgow, Scotland, UK, April 19-20, 2012; during fetal cardiac function workshops at the 22nd World Congress on Ultrasound in Obstetrics and Gynecology, Copenhagen, Denmark, Sept. 9-13, 2012; and at the European Echocardiography Course Symposium on Fetal Cardiac Function, Barcelona, Spain, Oct. 2-6, 2012. Reprints: Helena M. Gardiner, PhD, MD, FRCP, FRCPCH, DCH, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Queen Charlottes and Chelsea Hospital, Du Cane Road, London W12 0HS, UK. helena.gardiner@imperial.ac.uk.
0002-9378/$36.00  2013 Mosby, Inc. All rights reserved.  http://dx.doi.org/10.1016/j.ajog.2013.02.051

dysfunction.3,4 The Tei or Myocardial Performance Index (MPI) index compares the time the heart spends in relaxation and in contraction from simultaneous Doppler assessment of mitral and aortic ow proles. A prolonged isovolumic relaxation time has been described in recipients with early-stage disease and the resultant increased MPI proposed as one measurement distinguishing early TTTS from discordant growth and an aid to assessment in TTTS.5-7 However, the Tei index is not a measure of intrinsic myocardial function but alters in response to acute changes in load and distal impedance8; it therefore reects the pathophysiology faced by the recipient early in the disease process and probably before the effects of unbalanced inter-twin transfusion satisfy the Quintero staging.9 To date the ability of cardiovascular parameters to predict the need for, or response to, treatment is unsatisfactory, with only a weak correlation with Quintero staging and wide variation at each stage.4,9-11

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Vector velocity imaging (VVI) is a non-Doppler ultrasound technology that tracks myocardial speckles frame by frame to produce measures of myocardial deformation, including strain. Strain signies the fractional change in ventricular wall length and allows quantication of myocardial performance ofine. Although strain, like MPI, is load dependent, the assessment of cardiac wall deformation provides a more direct reection of intrinsic cardiomyocyte function. The feasibility and pitfalls of speckle tracking in normal singleton fetuses has been described.12 Many studies of VVI speckle tracking in the fetus have been limited by measurement at low frame rates, resulting in falsely low measures of strain, particularly in the left ventricle,13-19 or the use of software calculated global or natural strain20-23 rather than Lagrangian strain. Global strain is the software-averaged sum of short segmental strain values, whereas Lagrangian strain is manually calculated from stored coordinates of the entire length of the ventricular wall and produces values with less variation and therefore greater reliability.12 These technical factors may limit the ability of VVI to measure strain and have resulted in an inaccurate measure of strain, masking gestational changes and reporting interventricular differences in strain that are not present when high frame rate clips are measured.12,24 In this study, we assessed the feasibility of using VVI speckle tracking to measure Lagrangian strain in twin pregnancies including those complicated by TTTS. We investigated whether ventricular strain measurement might aid risk stratication of TTTS, specically whether within-pair differences in ventricular strain exist in early TTTS. Finally, we assessed whether VVI measurements can reect functional recovery following fetal laser therapy for TTTS.

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TABLE 1

Patient characteristics
Characteristic EFW, g Gestational age, wks Maternal age, y EFW discordance, % Heavy 527 (60.5) Light 458 (51.6) 22.6 (20e25) 32.5 (30e35) 13 (2.0) Recipient 462 (36.4) Donor 343 (28.6)

21.3 (18e24) 33.4 (24e37) 23 (2.1)

Median gestational and maternal age characteristics for the TTTS group and the non-TTTS control group are presented, and the interquartile range is shown in parentheses. The mean EFW and EFW discordance (percentage) are shown with SEs in parentheses. There were 3 cases of EFW discordance greater than 20% in the non-TTTS group and 17 cases in the TTTS group. EFW, estimated fetal weight; TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

M ATERIALS

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M ETHODS

This was a prospective case-control study enrolling consecutive women with MCDA pregnancies referred for ultrasound assessment of their pregnancy from local maternity units.

Fetal echocardiograms were performed using dummy electrocardiogram gating (described in the following text) to ensure optimal transfer of frame rates to the Syngo software (Siemens Corp, Munich, Germany) to perform ofine speckle tracking. The institutional review board deemed ethical approval was unnecessary because the evaluation was an integral part of routine clinical visits in which the mother had consented to the examination. Twenty-seven pregnancies with TTTS (as dened by standard Quintero staging criteria25) and 28 controls who did not develop TTTS were studied. Single scans were performed for each control. Eighteen of the 27 TTTS pregnancies underwent serial scans and data from a total of 50 TTTS scans (200 ventricles) were available for analysis. Sonographic data were collected prospectively by several of the coauthors to a standard protocol using Acuson Sequoia ultrasound systems (Siemens Corp) with a 6-2 multi-Hertz curvilinear probe (Acuson, Mountain View, CA). The 4-chamber image was optimized to achieve high contrast between the myocardial walls and cavity, and the clearest loop of each image acquired during the clinical examination was stored digitally in a DICOM format. As previously described, we attached a commercially available metronome (BOSS DB-60; Roland Corp, Hamamatsu, Japan), to the line input of the ultrasound system with the metronomes dummy spike signals, set to 60 beats per

minute, to permit the storage of 2 virtual cycles (2 seconds) at their original frame rate.12 The identity of the clips were blinded, assigned a code so that twin pairs could not be identied, and imported in batches retrospectively by one examiner (H.M.) into Syngo Work Station (Siemens Corp) using Syngo VVI version 1 for ofine analysis of ventricular strain. The fetal heart rate was determined by mitral valve closure and a single heartbeat selected for analysis. The endocardial border was tracked manually in end-diastole and tracking curves created automatically in subsequent frames. The 2 orthogonal X,Y tracking coordinates stored by the softwares database were used to calculate peak

TABLE 2

Perinatal outcomes
Outcome Live birth Single fetal demise Double fetal demise Fetocide TTTS (n [ 27) 22 3 1 1 Non-TTTS (n [ 28) 27 1 0 0

Fetocide by radiofrequency ablation was necessary in 1 recipient for persistent TTTS despite laser therapy. One spontaneous single fetal demise occurred in the nonTTTS control group at 23/40 weeks of gestation. TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

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(22 4 vs 21 2; P .18). A trend toward decreasing ventricular strain with gestational age was observed in the non-TTTS group, which did not reach statistical signicance (LV, P .052; RV, P .18). No congenital or chromosomal abnormalities were identied in either group. To enable comparisons controlling for differences in fetal weight, non-TTTS control twins were described as heavy or light controls. The mean estimated fetal weight at examination is shown in Table 1. Recipient and donor twins were generally lighter than heavy and light twins, respectively. A trend toward decreasing ventricular strain with increasing estimated fetal weight was observed in the non-TTTS group, which did not reach statistical signicance (LV, P .054; RV, P .2). The mean estimated fetal weight discordance was greater in the TTTS group compared with the non-TTTS group as expected; however, Kendalls tau showed no signicant relationship between estimated weight discordance and strain discordance for either left or right ventricles (LV: tau, b 0.14; 95% condence interval [CI], 0.07 to 0.35; P .13; RV: tau, b 0.08; 95% CI, 0.27 to 0.11; P .40). The Quintero stages of TTTS at presentation were as follows: 1 (n 2); 2 (n 3); 3 (n 19); 4 (n 1). Two pregnancies were studied initially at prestage disease and later developed TTTS. All underwent laser therapy for TTTS at a median gestational age of 20 5 (range, 16 3 to 25 5) weeks. Sixteen women had serial VVI assessment before and following treatment. Outcomes for all pregnancies are shown in Table 2. The mean ventricular strain values for heavy and light non-TTTS control twins and recipient and donor TTTS twins are shown in Table 3. In TTTS, within-pair differences were signicant for both the LV strain and RV strain, with lower values seen in recipients compared with donors. Interventricular strain differences were signicant in recipients but not donors or controls. Differences observed in the TTTS cohort were investigated further by

Ventricular strain in cases (all Quintero stages) and controls

Variable Heavy LV RV Light Recipient Donor 22.07 4.4 22.21 3.0 P .11 18.28 2.7 22.90 2.2 P < .001 22.41 3.3 22.53 4.0 P .93 19.60 3.4 22.59 3.4 P < .01 P .77 P .6 P .013 P .77

Mean strain values (percentage, SD) for LVs and RVs are given for non-TTTS controls (heavy and light) and TTTS cases (recipient and donor) at rst examination. P values are given for Wilcoxon signed-ranks test for intertwin and interventricular comparisons. LV, left ventricular; RV, right ventricular; TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

negative systolic strain along the whole length of the right and left free wall (Lagrangian strain12). Strain is dened as a relative change in length and is represented in this paper as a positive percentage change. We allowed 10 minutes for tracking and considered recordings taking longer unsuitable for analysis.

Outcome measures 1. Within-twin pair differences in left (LV) and right (RV) ventricular strain between heavier vs lighter nonTTTS control pairs and recipient vs donor TTTS pairs. 2. Relationship of Quintero staging to strain: within-twin pair differences in LV strain and RV strain between recipient vs donor TTTS in early (prestage, stages 1 and 2) and advanced (stages 3 and 4) TTTS. 3. Effect of laser therapy for TTTS on ventricular strain: within-twin pair differences in LV strain and RV strain between recipient vs donor TTTS before and after treatment.

Statistical analysis Outcomes 1 and 2 were analyzed using Wilcoxon signed ranks test and signicance of 2-tailed test taken as P < .05. Because some twins had serial measurements, a mixed-effects linear regression model was used to analyze the effect of staging and laser intervention, with patients entered as a random effect. All analyses were performed using Stata 12.1 (StataCorp, College Station, TX).

R ESULTS
VVI tracking was suitable for analysis in 96 of 112 (86%) non-TTTS control scans and in 182 of 200 (91%) TTTS scans; RV strain and LV strain for each twin were tracked with similar success in both cohorts. Reproducibility was good with an intraclass correlation for RV and LV strain (0.894 and 0.928, respectively). Median gestational age at examination was 21 3 (range, 16 3 to 32 5) weeks and was similar between non-TTTS controls and TTTS cases

TABLE 4

Ventricular strain in cases by Quintero stage

Quintero stage 2 or less Variable LV RV Recipient 20.34 (10.1) 22.3 (11.4) Donor 23.0 (7.7) 21.8 (14.1) P value .018 > .9 Quintero stages 3 and 4 Recipient 17.8 (8.8) 19.8 (12.0) Donor 22.6 (8.8) 22.6 (10.1) P value < .001 < .001

Median and interquartile ranges are shown for LVs and RVs and are presented for TTTS cases (recipient and donor) at Quintero stage 2 or less (including 2 cases of prestage disease) and Quintero stages 3 and 4. P values are given for Wilcoxon signedranks test for within-pair comparisons. LV, left ventricular; RV, right ventricular; TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

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analyzing the effect of Quintero stage on ventricular strain; the mean values are shown in Table 4. Within-twin pair comparison of strain was signicant for the left ventricle but not the right at Quintero stage 2 or less and signicant for both ventricles at higher Quintero stages. The Figure represents mean ventricular strain values for non-TTTS controls and TTTS cases at early and later Quintero stages with signicant within-twin pair differences indicated. In a subgroup of 16 TTTS pregnancies, twins were studied before and at a median 2.1 (range, 0.2e7) weeks following laser therapy for TTTS. The mean within-pair difference in the LV strain and RV strain before and after treatment is shown in Table 5. The signicant within-twin pair differences compared with controls in both the left and right ventricles before laser therapy disappeared following a successful procedure.

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FIGURE

Within-twin pair comparison of ventricular strain

Comparison of ventricular strain values between heavy vs light non-TTTS twins and recipients vs donors with TTTS stage less than 2 and stage greater than 2. Mean strain, SE bars, and signicance are shown.
SE, standard of error; TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

C OMMENT
Our study, in contrast to previous reports,20 shows that the VVI measurement of Lagrangian strain is feasible in complicated MCDA twins. We have demonstrated that within-pair and between-ventricle values of strain in MCDA twin pairs without TTTS are similar. In contrast left ventricular strain is reduced from early stage TTTS in recipients but not their donor cotwins. Previous studies have used singleton cohorts as a control groups for twins with lower values of strain19,20 than in our normal singleton cohort reported previously.12 We consider that uncomplicated MCDA twin pregnancies form a more useful control group because all monochorionic twins share a placenta and their circulations are connected by vascular anastamoses permitting between-twin transfusion. Our study is the rst to show that strain measurements do not differ either between LVs and RVs or between each genetically identical twin pair, provided the between-twin transfusion remains balanced. The early reduction in recipient LV strain results in a delay in generating the pressure drop across the mitral

valve required to initiate diastolic lling and thus is a credible explanation for the early initiating mechanism of RV loading. This is compatible with the nding of increased left ventricular isovolumic relaxation time described in the early-stage recipients in a previous study.5 Reduced recipient ventricular strain is to be expected in established TTTS,9,19,20 but altered recipient LV strain in disease that does not yet satisfy the Quintero staging system merits consideration as a potential early indicator of TTTS. In our study (as shown for MPI), discordant growth in control MCDA cotwins did not result in discordance in strain values, further enhancing

the utility of strain measurements in this disease. As anticipated in recipients with stages 3 and 4 TTTS, strain is reduced in both ventricles relative to donor cotwins but our data also demonstrated that when examined a median of 2 weeks following laser therapy for TTTS, ventricular function is similar between ex-recipients and ex-donors, suggesting it is a useful quantitative method to assess clinical progress. The observed improvement in recipient ventricular strain by 2 weeks is earlier than in reports using MPI to monitor cardiovascular response to treatment.26,27 However, strain and MPI measurements reect different aspects of

TABLE 5

Ventricular strain before and after laser therapy for TTTS

Before laser Variable LV RV Recipient-donor 4.34 2.9 3.65 4.1 P value .01 .02 After laser Recipient-donor 2.44 3.5 1.25 3.3 P value .69 .43

Mean within-pair ventricular strain difference (percentage, SD) for those TTTS cases with serial echocardiography performed before and following laser therapy. LV, left ventricular; RV, right ventricular; TTTS, twin-twin transfusion syndrome. Taylor-Clarke. Speckle tracking in TTTS. Am J Obstet Gynecol 2013.

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our own data showing that Lagrangian free wall ventricular strain is similar in both ventricles in singletons and that it decreases with gestational age.12 We suspect that the lack of a statistically signicant decrease in strain with gestational age in the current study reects the narrower gestational age range compared with our previous report.12 The gestational decrease in strain is not a consideration in this study because there was no signicant difference in gestational age between the non-TTTS MCDA controls and TTTS cases, and furthermore, gestational age is inherently controlled for in our within-twin pair analysis. In addition, the increase in ventricular strain observed following FLAP in recipient fetuses was in the opposite direction to that predicted by their advancing gestation. The utility of VVI to predict TTTS development or prognosis requires a larger study than ours because we had only small numbers of twins at lower Quintero stages, with only a few cases of fetal demise. We would suggest that cardiac assessment be incorporated into a standard protocol of investigation for all MCDA pregnancies, particularly in staging of TTTS. Lagrangian strain measurements are highly reproducible and could form an integral part of the cardiac assessment in all MCDA pregnancies to assess their utility in predicting twins that will develop unbalanced transfusion. The wide range of follow-up is inuenced by a small number of families that had laser therapy for TTTS less than 18 weeks and had traveled long distances for treatment. They could be monitored closer to home, so we were pragmatic in planning review. VVI is an informative and feasible method to assess cardiac function in twin pregnancies. We propose that VVI may assist in predicting the risk of progression in early-stage TTTS and therefore aid in selection of pregnancies in which early intervention with laser therapy (as opposed to continued monitoring) may be of benet. It may also be a useful tool to monitor recovery from TTTS following intervention. Furthermore, VVI measurements may

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be useful in differentiating early TTTS from discordant growth in monochorionic twin pregnancies.
REFERENCES
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function, the former reecting cardiac deformation and ability of the myocardium to shorten and lengthen, whereas the MPI compares the ratio of time within the cardiac cycle spent in relaxation and contraction. Both measurement techniques are load dependent, but strain estimates cardiomyocyte shortening28 and as loading conditions and myocardial function alter with TTTS, so should strain. Reduced strain reects ventricular response to increased afterload and may reect early placental factors in the disease process. For instance, changing the hemodynamic balance of the anastamoses, the alteration of recipient viscosity or early transfusion of substances such as angiotensin may alter ventricular myocardial responses, permitting the initiation of the unbalanced intertwin transfusion characteristic of TTTS. By Quintero stages 3 and 4, both right and left ventricular strain is reduced in recipient twins compared with the heavier twin in non-TTTS controls, indicating the collapse of the FrankStarling curve and ventriculovascular uncoupling.29 Although we cannot draw conclusions from only 2 prestage cases, we suggest that within-pair differences may be more informative than absolute strain values in distinguishing early TTTS from growth discordance. High frame rates are essential to the accurate measurement of strain. Speckle tracking is technically more challenging than Doppler techniques, although it is portrayed as deceptively simple because of the automated software generation of values for strain and strain rate. Unfortunately, the literature contains many studies that have performed ofine analysis on stored data that is imported into VVI software at the standard video capture rate of the country; this is a low frame rate of 25-30 Hz. The resultant analysis of data stored in this way has failed to measure peak strain, particularly of the LV, and reports conclude that strain is constant throughout gestation and there are interventricular differences.13-16,18,19,24 These results are not reproduced in studies using high frame rates, including

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of vector velocity imaging in the human fetal heart. Ultrasound Obstet Gynecol 2011;37: 150-7. 13. Barker PC, Houle H, Li JS, Miller S, Herlong JR, Camitta MG. Global longitudinal cardiac strain and strain rate for assessment of fetal cardiac function: novel experience with velocity vector imaging. Echocardiography 2009;26:28-36. 14. Di Salvo G, Russo MG, Paladini D, et al. Two-dimensional strain to assess regional left and right ventricular longitudinal function in 100 normal foetuses. Eur J Echocardiogr 2008;9: 754-6. 15. Peng QH, Zhou QC, Zeng S, et al. Evaluation of regional left ventricular longitudinal function in 151 normal fetuses using velocity vector imaging. Prenat Diagn 2009;29:1149-55. 16. Pu DR, Zhou QC, Zhang M, Peng QH, Zeng S, Xu GQ. Assessment of regional right ventricular longitudinal functions in fetus using velocity vector imaging technology. Prenat Diagn 2010;30:1057-63. 17. Younoszai AK, Saudek DE, Emery SP, Thomas JD. Evaluation of myocardial mechanics in the fetus by velocity vector imaging. J Am Soc Echocardiogr 2008;21:470-4. 18. Ishii T, McElhinney DB, Harrild DM, et al. Circumferential and longitudinal ventricular strain in the normal human fetus. J Am Soc Echocardiogr 2012;25:105-11. 19. Rychik J, Zeng S, Bebbington M, et al. Speckle tracking-derived myocardial tissue deformation imaging in twin-twin transfusion syndrome: differences in strain and strain rate between donor and recipient twins. Fetal Diagn Ther 2012;32:131-7. 20. Van Mieghem T, Giusca S, DeKoninck P, et al. Prospective assessment of fetal cardiac function with speckle tracking in healthy fetuses and recipient fetuses of twin-to-twin transfusion syndrome. J Am Soc Echocardiogr 2010;23: 301-8. 21. Willruth AM, Geipel AK, Berg CT, Fimmers R, Gembruch UG. Comparison of global and regional right and left ventricular longitudinal peak systolic strain, strain rate and velocity in healthy fetuses using a novel feature tracking technique. J Perinat Med 2011;39:549-56. 22. Willruth AM, Geipel AK, Fimmers R, Gembruch UG. Assessment of right ventricular global and regional longitudinal peak systolic strain, strain rate and velocity in healthy fetuses and impact of gestational age using a novel speckle/feature-tracking based algorithm. Ultrasound Obstet Gynecol 2011;37:143-9. 23. Ta-Shma A, Perles Z, Gavri S, et al. Analysis of segmental and global function of the

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fetal heart using novel automatic functional imaging. J Am Soc Echocardiogr 2008;21: 146-50. 24. Germanakis I, Gardiner HM. Assessment of fetal myocardial deformation using speckle tracking techniques. Fetal Diagn Ther 2012;32: 39-46. 25. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550-5. 26. Habli M, Michelfelder E, Livingston J, et al. Acute effects of selective fetoscopic laser photocoagulation on recipient cardiac function in twin-twin transfusion syndrome. Am J Obstet Gynecol 2008;199:412.e1-6. 27. Van Mieghem T, Klaritsch P, Done E, et al. Assessment of fetal cardiac function before and after therapy for twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2009;200:400. e1-7. 28. Freeman GL, LeWinter MM, Engler RL, Covell JW. Relationship between myocardial ber direction and segment shortening in the midwall of the canine left ventricle. Circ Res 1985;56:31-9. 29. Gardiner HM. Response of the fetal heart to changes in load: from hyperplasia to heart failure. Heart 2005;91:871-3.

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