The evaluation of fetal cardiac function is increasingly recognized as an important part of a complete fetal echocardiographic study. Various methods have demonstrated evidence of both systolic and diastolic dysfunction in a variety of fetal and maternal disease states, including twin-twin transfusion syndrome, maternal pregestational diabetes mellitus (DM), and space-occupying chest lesions. Early detection of myocardial dysfunction may help guide management and may improve outcomes. Noninvasive detection of subtle abnormalities of cardiac function during development may also have implications for our understanding of disease and management. However, noninvasive evaluation of global cardiac function has been challenging in fetuses. Given the unique fetal physiology, functional assessments cannot be extrapolated directly from pediatric and adult studies. The fetal circulation is right ventricular (RV) dominant, whereas most validated measures used in adult and pediatric populations have examined the left ventricle rather than the right ventricle.

A noninvasive measure of combined systolic and diastolic myocardial function, the myocardial performance index (MPI), first described by Tei et al. in adults, is now being used in fetuses. MPI, traditionally derived from spectral Doppler (pulsed wave), is the ratio of ventricular isovolumic time to ejection time. Myocardial dysfunction results in prolongation of isovolumetric intervals and decreased ejection time, yielding an increased MPI. Typically obtained from a spectral Doppler trace simultaneously displaying mitral inflow and aortic outflow, spectral Doppler MPI measurements are reproducible and relatively easy to obtain. Spectral Doppler–derived MPI is widely accepted in the adult population as a quantitative measure of global cardiac function, and more recently it has been validated in children. In mid and late trimester fetal studies, age-related changes in MPI appear for both the left and right ventricles. Since then, other groups have examined the utility of assessing global MPI using spectral Doppler in fetal disease states such as twin-twin transfusion syndrome and pregestational DM in later gestation.

Spectral Doppler imaging in the right ventricle for the purpose of measuring MPI is more difficult than in the left ventricle, given the difficulty of simultaneously recording both inflow and outflow in a single Doppler sample. If the inflow and outflow Doppler signals are obtained separately, heart rate fluctuations may introduce errors and will increase variability in measurement. An easier alternative method for determining MPI for the right ventricle may be Doppler tissue imaging (DTI) of the lateral tricuspid annulus, which allows simultaneous recording of diastolic and systolic events in a single Doppler sample. Although smaller studies have begun to apply the newer DTI MPI method to the assessment of fetal cardiac function in various fetal disease states, it is not known if the pulsed-wave DTI and spectral Doppler methods of determining MPI are interchangeable and produce similar values in a normal population. In addition, it is unclear if they are equally sensitive in demonstrating subtle abnormalities of global myocardial performance in at-risk midgestation fetuses without signs of overt dysfunction on standard imaging.

We hypothesized that the pulsed-wave DTI method is more reproducible and more precise and that it is more sensitive for distinguishing subtle differences in cardiac function in a diseased group.

Our aims were to measure RV MPI using both pulsed-wave DTI and spectral Doppler in midgestation fetuses (gestational age, 17–23 weeks) with and without subtle abnormalities of cardiac function and to compare the agreement, precision, and variability of the two methods. Prior studies have demonstrated subtle abnormalities in RV diastolic function in the fetuses of mothers with pregestational DM using spectral Doppler and DTI. In these fetuses, diastolic myocardial velocities at the level of the mitral and tricuspid valve annuli were significantly higher, and E′/A′ ratios were higher than in normal fetuses, while the ratio of early diastolic peak inflow velocity to peak annular velocity (E′/E) was lower in the fetuses of mothers with DM. These changes in diastolic function are independent of the presence of myocardial hypertrophy. Using spectral Doppler, many of these patients did not show changes in transmitral or transtricuspid inflow, suggesting that DTI may be more sensitive than spectral Doppler for the diagnosis of fetal diastolic dysfunction. Therefore, we chose this population, known to have subclinical, subtle diastolic abnormalities, as a “disease” population to evaluate sensitivity of the spectral Doppler or pulsed-wave DTI methods of determining MPI for the detection of subtle cardiac functional abnormalities in fetuses who were otherwise normal.

Methods

DTI using spectral pulsed-wave sampling at the lateral tricuspid valve annulus has been part of the routine fetal echocardiographic protocol at our institution since 2008. We searched the database of the University of California, San Francisco, Fetal Cardiovascular Program for singleton-gestation fetuses with structurally normal hearts without evidence of ventricular hypertrophy in normal sinus rhythm and performed a retrospective cross-sectional study reviewing fetal echocardiograms from 2008 to 2010. All pregnant mothers underwent standard two-dimensional, spectral Doppler, pulsed-wave DTI, and color Doppler examinations using an Acuson Sequoia ultrasound system (Siemens Medical Solutions USA, Inc., Mountain View, CA) equipped with 8.0-MHz or 6.0-MHz curvilinear transducers. We used spectral pulsed-wave Doppler methods to record RV inflow and outflow blood velocities and also to measure annular tissue velocities. Doppler blood flow recordings are termed “spectral Doppler,” while tissue Doppler recordings are termed “DTI.” We then compared RV MPI using the two different “pulsed Doppler” methods.

Local institutional review board approval was obtained for this research. Criteria for inclusion in the study included a referral indication of family history of congenital heart disease (normal fetuses) or pregestational DM (DM fetuses). To eliminate issues related to gestational age–related changes in MPI previously reported by Tsutsumi et al. , we included only studies of fetuses aged 17 to 23 weeks as determined by history of last menstrual period or documented first-trimester ultrasound dating, using measurements of biparietal diameter and femur length as secondary measures.

Previously stored digital images demonstrating good-quality spectral Doppler and DTI recordings of tricuspid inflow, pulmonary outflow, and longitudinal myocardial wall motion obtained at the level of the tricuspid valve annulus in an apical four-chamber view were chosen for measurement ( Figure 1 ). For spectral pulsed-wave Doppler, tricuspid inflow and pulmonary outflow were obtained from tracings with similar heart rates. Significant heart rate differences (>5 beats/min) in the RV inflow and outflow tracing resulted in rejection of the patient for data collection. Peak tricuspid inflow velocities (peak E and peak A) and peak lateral tricuspid annular diastolic tissue velocities (E′ and A′) were measured on three consecutive beats and averaged, and the E/E′, E/A, and E′/A′ ratios were calculated for each fetus. MPI, defined as the sum of the isovolumetric contraction time and the isovolumetric relaxation time divided by the ejection time, was calculated. By convention, our measurements of ejection time were exclusive of valve clicks on the Doppler traces, as noted in the figure (which would shorten the measured ejection time and lengthen the measured isovolumetric time). Two independent investigators measured MPI using both DTI and spectral Doppler over three cardiac cycles and averaged them as previously described. Specifically, for spectral Doppler, three measures of a were averaged and three measures of b (ejection time) were averaged, with MPI calculated as (average a −average b )/average b . For DTI, the MPI was calculated on each of three consecutive beats, and the results were averaged.

Doppler-derived measurements of MPI. (A–C) Measurement of MPI by pulsed-wave (A,B) or tissue Doppler method (C) . (A) Doppler trace of tricuspid inflow, with measurement of the time between inflows ( a ). (B) Spectral Doppler in the RV outflow tract at the level of the pulmonary valve, with measurement of the ejection time ( b ). Our measurement of ejection time was exclusive of valve clicks on the Doppler trace (which would shorten the measured ejection time and lengthen the measured isovolumetric time). (C) Tissue Doppler trace obtained at the lateral tricuspid annulus, allowing measurement of end-diastole to onset of diastole ( a ) and systolic ejection ( b ) (the initial positive deflection in the trace represents isovolumic tissue acceleration and is not included in the ejection time). For both methods, MPI is calculated as ( a − b )/ b .

Study Sample Size

Using an expected mean difference of 8% in MPI and 80% power to detect this difference in fetuses of mothers with DM from previously published MPI DTI data in normal fetuses, we determined that a study sample size of 51 DM fetuses would be necessary to detect this difference.

Reproducibility

To assess intraobserver variability, measurements (with both methods) for 33 fetuses in each study group were repeated 1 week after the initial measurements were completed. Additionally, a subset in each group had all measurements independently performed by a second observer. Each observer was blinded to the original measurements.

Statistical Analysis

Data are expressed as mean values ± SD. Differences in peak diastolic tissue and blood pool velocities and E′/A′ and E/E′ ratios between groups were assessed using unpaired Student’s t tests. To evaluate the agreement between the two methods for determining MPI within the same individual in a group, Student’s sample paired t tests were performed, and Bland-Altman plots for assessment of bias (difference between measurements) were generated. The precision was taken to be the standard deviation of these differences, indicating variability. Differences between the study groups using the same method of MPI were additionally assessed using unpaired t tests. A difference was considered significant at P < .05. For assessment of reproducibility, Bland-Altman plots of difference (bias) between the two repeated measurements for each method were generated. Interobserver and intraobserver variability was also expressed as mean percentage error, calculated as the absolute value of the difference between the two repeated measurements, divided by the average of the two observations and expressed as a percentage.