Cardiovascular magnetic resonance imaging derived septal curvature in neonates with bronchopulmonary dysplasia associated pulmonary hypertension

Neonates included in the study were enrolled with Institutional Review Board approval. Inclusion criteria for neonates with BPD included BPD diagnosis per the 2001 National Institute of Child Health and Human Development and National Heart, Blood, and Lung Institute consensus definition [25] and post-menstrual age of 48 weeks or less at the time of CMR. Inclusion criteria for control infants included full-term birth (≥ 37 weeks gestational age) or pre-term birth in the absence of BPD, no clinically significant lung disease, and post-menstrual age 48 weeks or less at CMR. Control subjects were comprised of infants with primary neurologic or gastrointestinal diagnosis. Exclusion criteria for all study subjects consisted of evidence of significant genetic abnormalities or congenital malformations, evidence of respiratory infection at time of CMR, and standard CMR exclusion criteria.

Research CMR acquisitions were performed using a 1.5 T scanner (originally manufactured by ONI Medical Systems; currently GE Healthcare, Waukesha, Wisconsin, USA) sited in the neonatal intensive care unit [26]. CMR studies were conducted free breathing and without sedation unless indicated as part of their clinical care. CMR sequences used for cardiac analysis included a short-axis, retrospective electrocardiogram-gated balanced steady-state free-precession (bSSFP) imaging acquisition and an axial electrocardiogram-triggered double inversion-recovery fast spin echo acquisition. As previously described typical short-axis bSSFP acquisition parameters included: echo time = 1.6 ms; repetition time = 3.7 ms; flip angle = 45 degrees; effective temporal resolution = 20 ms; field of view 28–32 cm; pixel resolution 1.09–1.25 mm; slice thickness = 5–6 mm; number of averages = 3; and estimated scan time = 2 min and typical fast spin echo acquisition parameters included: echo time = 43.0 ms; repetition time = 736.2 ms; flip angle = 90 degrees; field of view 16–17 cm; pixel resolution 0.63–0.66 mm; slice thickness = 4 mm; number of averages = 3; and estimated scan time = 3 min [20].

The right ventricle (RV) and left ventricle (LV) were contoured throughout the cardiac cycle in the short axis stack. RV end systolic volume indexed to body surface area (RVESVi), RV end diastolic volume indexed to body surface area (RVEDVi), RV mass indexed to body surface area, LV end systolic volume indexed to body surface area (LVESVi), LV end diastolic volume indexed to body surface area (LVEDVi), LV and RV ejection fraction (EF), and cardiac index (CI) were determined (cvi42, Circle Cardiovascular Imaging, Calgary, Canada). CMR-Eccentricity Index (CMR-EI) was measured as the ratio of the lateral to anterior-posterior diameter of the LV at end systole from the short axis stack at the level of the papillary muscles (Fig. 1).

Septal curvature was measured from the short axis stack at the level of the papillary muscles as previously described [17] using ImageJ (National Institutes of Health, Bethesda, Maryland, USA). A total of 8 points were placed along the LV lateral wall contoured from anterolateral to inferolateral septum and the interventricular septum contoured from RV insertion point to RV insertion point. Contours were propagated throughout the cardiac cycle and manually adjusted across 20 phases. Curvature analysis was performed for each phase of the cardiac cycle. The septal curvature was determined from the ratio of the curvature of the interventricular septum and LV lateral wall. Lower septal curvature values represent increased septal flattening with a negative septal curvature representing septal bowing into the LV. The minimum septal curvature was the minimum value of the septal curvature throughout the cardiac cycle (Fig. 1). All measurements were conducted by a single cardiologist. A second cardiologist analyzed 10 (25%) randomly selected studies, and interobserver and intraobserver intraclass correlation coefficients were determined.

Univariate ANOVA tests were used to determine group differences in CMR indices, birth weight, gestational age, BPD severity, and short term clinical outcomes including length of stay (LOS), duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy for three groups: subjects who did not receive PH therapy, patients who received PH therapy in the hospital, but not at discharge, and patients who received PH therapy in the hospital and at discharge. Univariate ANOVA tests were used to determine association of septal curvature with short term outcomes and of CMR indices and clinical variables with septal curvature. Mean and standard deviation are reported for parametric group data and mean and interquartile range for non-parametric group data.

Demographics for the cohort are shown in Table 1. The study cohort consisted of 52 neonates including 40 with moderate or severe BPD and 12 mild BPD or control infants. The median age at CMR was 41 weeks post-menstrual age [interquartile range (IQR) 39.6–42.5] and median heart rate was 157 beats per minute (IQR 143–166). CMR was completed in all infants without adverse events and septal curvature was measured in 46 (88%) infants. The interobserver intraclass correlation coefficient for septal curvature was 0.953 with 95% confidence interval 0.820–0.989 and the intraobserver intraclass correlation coefficient was 0.889 with 95% confidence interval 0.614–0.972.

Eighteen (35%) of the infants received PH therapy in the hospital. PH therapy was discontinued prior to discharge in eight (44%) infants treated with PH therapy in the hospital. Need for PH therapy was inversely correlated with birthweight and gestational age and directly correlated with hospital LOS, duration of total respiratory support, and discharge respiratory support.

CMR indices RV mass, CMR-EI, and septal curvature were associated with PH therapy. Higher RV mass (p = 0.04), CMR-EI (p < 0.001) and lower septal curvature (< 0.001) were associated with PH therapy on univariate analysis. CMR indices RVESVi, RVEDVi, LVESVi, LVEDVi, RVEF, LVEF, and CI were not significantly associated with need for PH therapy (Table 2). Clinical variables including gestational age (p = 0.03), birthweight (p = 0.01), and BPD severity (p = 0.004) were associated with need for PH therapy on univariate analysis. On multivariable analysis including clinical variables and CMR indices, only septal curvature was independently associated with PH therapy (Table 3). The median percent of the cardiac cycle for minimum septal curvature was 53% (IQR 42–67%), 54% (IQR 51–75%), and 60% (IQR 58–74%) in patients never treated with PH therapy, treated with PH therapy in hospital but not at discharge, and patients treated with PH therapy at discharge (p = 0.16).

The median hospital LOS was 166.0 days (IQR 109.5–237.5) and the median length of total respiratory support was 167 (86.0–313.5) days. On univariate analysis septal curvature was inversely associated with hospital LOS (R² = 0.17, parameter estimate ± standard error = − 172.0 ± 56.6, and p value = 0.004), and length of total respiratory support (R² = 0.29, parameter estimate ± standard error = − 305.3 ± 74.3, and p value = 0.0002). Including clinical variables and CMR indices in multivariable analysis hospital LOS was associated with BPD severity and CMR-EI, and length of total respiratory support was associated with BPD severity, body weight, and CMR-EI (Table 3). Twelve infants were discharged from the hospital on supplemental oxygen, 15 required tracheostomy, and two died of respiratory complications. Septal curvature was associated with level of discharge respiratory support on univariate analysis (R² = 0.45, p value < 0.0001) and septal curvature and BPD severity were the only clinical or CMR variables significantly associated on multivariable analysis.

The following variables were associated with septal curvature on univariate analysis: birthweight (R² = 0.17, p = 0.005), gestational age (R² = 0.15, p = 0.007), BPD Severity (R² = 0.17, p = 0.018), RV mass (R² = 0.25, p = 0.0005), CMR-EI (R² = 0.55, p = < 0.0001), RVEDVi (R² = 0.10, p = 0.035), and RVESVi (R² = 0.21, p = 0.002). On multivariable analysis including clinical variable and excluding CMR indices, gestational age was the only independent variable associated with septal curvature (R² = 0.15, p = 0.007).