Challenges in Interpreting Deformation Values by Two-Dimensional Speckle-Tracking Echocardiography in Preterm and Term Infants

We read with great interest the article by Schubert et al. titled “Preterm Birth Is Associated with Altered Myocardial Function in Infancy,” recently published in JASE .

Schubert et al. performed a detailed serial analysis of myocardial function in preterm and term infants and compared its evolution from the neonatal period into early infancy. The investigators used deformation imaging by two-dimensional speckle-tracking echocardiography to characterize ventricular function in these infants. This is one the first studies to longitudinally track the maturational adaptation of left ventricular (LV), right ventricular (RV), and intraventricular septal wall function using deformation imaging beyond the early neonatal period. Schubert et al. conclude that preterm infants exhibit reduced LV myocardial function, as measured by LV free wall strain, at 6 months after birth (3 months corrected age) compared with term-born infants at the same time frame (−20.0% vs −22.0%, P = .010). There were no significant group differences in RV or intraventricular septal wall measurements. Furthermore, there were no statistically significant age-related intragroup changes in LV strain in preterm infants.

We believe that some aspects of the messages may be misleading given the methodology of the study and the interpretation of the strain results. First, the limited sample size of preterm infants ( n = 25) with large disease heterogeneity (20% of the preterm infants had hemodynamically significant patent ductus arteriosus [PDA] on the basis of the need for pharmacological treatment, 16% had bronchopulmonary dysplasia, and 40% had septicemia) that can confound ventricular function significantly limits the interpretation of the linked conclusions. We acknowledge that power analysis always involves assumptions, but the calculations used by Schubert et al. might be appropriate only when comparing indices between term-born infants and preterm-born infants with one outcome variable (i.e., a cohort of uncomplicated preterm-born infants). A sample size calculation based on 25 preterm infant with a wide range of disease heterogeneity and 25 healthy term infants appears to be too small to detect group differences in “any outcome variable,” as suggested by the investigators, and all but excludes the identification of the physiologic maturational patterns (i.e., reference values) in healthy preterm infants that must be “firmly established before routine clinical adoption” of strain measurements can be implemented. Said in other words, a cohort of 25 preterm infants with wide disease heterogeneity is too small to make generalized statements for an entire preterm population, let alone compare with a term-born cohort. There is a need for a methodologic mechanism in the study to separate health and disease status that affects cardiac function in the preterm population, rather than lumping them all together, which makes the interpretation of the conclusion challenging. Schubert et al. began this process with a separate analysis between appropriate and small for gestational age neonates. Recent studies assessing the evolution of postnatal hemodynamics in preterm infants have interpreted these maturational process on the basis of cardiorespiratory healthiness (presence of chronic lung disease, echocardiographic signs of pulmonary hypertension, and presence of hemodynamically significant PDA).

Second, although Schubert et al. state that “causality cannot be proved,” one could argue that the observation that LV strain still was relatively unchanged throughout maturation, despite the small sample size with wide disease heterogeneity, is the most important finding of the study. El-Khuffash et al. even found that infants who required PDA ligation had relatively stable LV strain (−19.7 ± 3.8) immediately before surgery, further highlighting the relative stability of LV function in the setting of different disease states. Schubert et al. observed that there were no statistically significant age-related intragroup changes in LV strain patterns in preterm infants from birth to 6 month of age. The LV strain values should not change markedly with age or heart rate. The stability of LV strain is due to the balancing effect of torsion, which is a major contributor of myocardial deformation. Intrinsic myocardial contractile properties are established after the first trimester and remain constant throughout gestation and after birth. Several studies in preterm infants have demonstrated a similar stable maturational pattern of LV strain by both two-dimensional speckle-tracking echocardiography and Doppler tissue imaging from birth through 6 months of age.

Third, Schubert et al. chose smoking during pregnancy, birthweight SD score, and weight at 3 months of corrected age as potential confounders or covariates. The small sample size prevents the inclusion of more than the three confounders, but other maternal characteristics (i.e., chorioamnionitis, pre-eclampsia, gestational hypertension, diabetes mellitus, asthma, etc), neonatal influences (surfactant replacement therapy, mechanical ventilation, presence of hemodynamic significant PDA, medication use [vasopressors, postnatal steroids], and pulmonary diseases [pulmonary hypertension or pulmonary vascular disease]) will have significant effects on RV and LV deformation patterns.

Fourth, although this study analyzes myocardial mechanics by quantification of LV, RV, and septal longitudinal strain and strain rate (and provides an important blueprint for future studies to emulate), Schubert et al. measured deformation in the lateral walls of both ventricles from the apical four-chamber view only and considered it “an approximation of global ventricular function.” LV, RV, and septal global strain values are acquired from completely different views of the heart and can have different interpretation (i.e., free wall strain does not account for the interventricular interaction achieved though the intraventricular septal wall that may be prevalent in this population). LV global longitudinal strain is calculated by averaging all values of the segmental peak longitudinal strain obtained from 17 segments in four-chamber, two-chamber, and apical long-axis views, and RV global longitudinal strain should be measured from an RV-focused apical four-chamber view and calculated as the average of the regional longitudinal strain for a six-segment model. We do not think using free wall deformation patterns from one view is a substitute for global strain.

Finally, the study of Schubert et al. is the first to compare preterm and term infants in the first year of age at similar time points using two-dimensional speckle-tracking echocardiography to measure myocardial strain and to find a small statistical difference between the groups at 3 months of age (−20.0% vs −22.0%, P < .01). However, the difference in deformation values is probably clinically irrelevant, as the values fall within the reference ranges of longitudinal strain (−19.7% to −21.8%) recently outlined in two separate meta-analyses.

In our opinion, the results should be interpreted within the framework of the study limitations but are important to share with the neonatal hemodynamic community in order to add to the growing literature on speckle-tracking-derived strain values in preterm infants. Larger multicenter prospective studies that track extremely preterm infants from birth to 1 year of age with echocardiography at multiple time points (with appropriate sample size power calculation, stratified by age and gender, and adjusting for all of the potential confounding factors that may contribute to the variance in measures) have recently been completed, with results forthcoming.

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Apr 15, 2018 | Posted by in CARDIOLOGY | Comments Off on Challenges in Interpreting Deformation Values by Two-Dimensional Speckle-Tracking Echocardiography in Preterm and Term Infants

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