Abstract
Background
Through ventricular interdependence, pulmonary hypertension (PH) induces left ventricular (LV) dysfunction. We hypothesized that LV strain/strain rate, surrogate measures of myocardial contractility, are reduced in pediatric PH and relate to invasive hemodynamics, right ventricular (RV) strain, and functional measures of PH.
Methods and Results
At two institutions, echocardiography was prospectively performed in 54 pediatric PH patients during cardiac catheterization, and in 54 matched controls. PH patients had reduced LV global longitudinal strain (LS) (-18.8 [-17.3 - -20.4]% vs. -20.2 [-19.0 - -20.9]%, P=0.0046) predominantly due to reduced basal (-12.9 [-10.8 - -16.3]% vs. -17.9 [-14.5 - -20.7]%, P<0.0001) and mid (-17.5 [-15.5 - -19.0]% vs. -21.1 [-19.1 - -23.0]%, P<0.0001) septal strain. Basal global circumferential strain (CS) was reduced (-18.7 [-15.7 - -22.1]% vs. -20.6 [-19.0 - -22.5]%, P=0.0098), as were septal and free-wall segments. Mid CS was reduced within the free-wall. Strain rates were reduced in similar patterns. “Basal septum” LS, the combined average LS of basal and mid interventricular septal segments, correlated strongly with degree of PH (r=0.66, P<0.0001), pulmonary vascular resistance (r=0.60, P<0.0001), and RV free-wall LS (r=0.64, P<0.0001). Brain natriuretic peptide levels correlated moderately with septal LS (r=0.48, P=0.0038). PH functional class correlated moderately with LV free-wall LS (r=-0.48, P=0.0051). The septum, shared between ventricles and affected by septal shift, was the most affected LV region in PH.
Conclusions
Pediatric PH patients demonstrate reduced LV strain/strain rate, predominantly within the septum, with relationships to invasive hemodynamics, RV strain, and functional PH measures.
Keywords: echocardiography, pediatric, hypertension, pulmonary, ventricular mechanics, myocardial contraction
While RV failure is an important determinant of morbidity and mortality in PH,1-3 the RV shares muscle fibers, the interventricular septum (IVS), and the pericardial sac with the left ventricle (LV). Consequently, changes in one ventricle affect the other – a concept termed ventricular interdependence.4-6 Through ventricular interdependence – mediated in part by leftward septal shift – RV dysfunction in PH induces LV dysfunction.7-13 Though LV dysfunction, particularly altered LV myocardial performance, is emerging as a determinant of outcomes in PH,9 few studies characterize LV function simultaneously with invasive hemodynamics or evaluate the mechanisms of such changes. Likewise, little is known about LV myocardial function and its association with RV function and pulmonary hemodynamics in pediatric PH, including those with congenital heart disease (CHD).
Accordingly, we aimed to define LV segmental myocardial (dys)function in pediatric PH by speckle-tracking echocardiography (STE) performed during cardiac catheterization, and the relationships with RV myocardial function and invasively-determined PH severity. We hypothesized that (1) children and young adults with PH have reduced LV longitudinal and circumferential strain/strain rate, and (2) that such alterations relate to invasive hemodynamics, RV mechanics, and functional PH measures.
Methods
Study Population
Children and adolescents were prospectively enrolled at Children's Hospital Colorado (CHCO) and the Hospital for Sick Children (SickKids) in Toronto. Between November 1, 2008 and October 1, 2013, patients underwent simultaneous transthoracic echocardiography and clinically-indicated right-heart catheterization for initial evaluation of suspected PH or routine follow-up of previously documented pre-capillary PH (mean pulmonary artery pressure ≥25 mmHg, pulmonary capillary wedge pressure [PCWP] ≤15 mmHg at catheterization)14 under general anesthesia. The study was approved by the Institutional Review Board at both institutions. Informed consent was obtained for all patients.
Sixty-four patients underwent simultaneous catheterization and echocardiography − 44 at CHCO, 20 at SickKids. To avoid confounding LV changes in PH, we excluded single ventricle physiology, actively paced patients, cardiomyopathies, heart transplant, (branch) pulmonary artery stenosis, uncontrolled systemic hypertension, left-sided obstructive lesions or PCWP >15 mmHg.14 Ten patients were excluded (Supplemental Material), leaving 54 patients – 37 from CHCO, 17 from SickKids.
Right-Heart Catheterization
Right-heart catheterization was performed under general anesthesia, by individuals blinded to echocardiographic measurements. Cardiac index was either measured (thermodilution) or calculated (modified Fick equation); pulmonary (Qp) and systemic (Qs) blood flow were documented. We measured right atrial, RV, pulmonary artery, PCWP and/or left atrial, and systemic arterial pressures (Supplemental Material). Pulmonary vascular resistance was indexed to body surface area (PVRi).
Echocardiography
During the baseline condition of cardiac catheterization with the catheter in the main pulmonary artery, we performed echocardiography optimized for STE strain imaging,15 using a General Electric (GE) Vivid 7 or E9 (GE Healthcare, USA). Images included apical four- and two-chamber views, and LV parasternal short-axis views at the “base” (mitral valve), “mid” (papillary muscles) and “apex” (apical to papillary muscles). We calculated Simpson's biplane LV ejection fraction (EF) and volumes,16 and eccentricity index (mid parasternal short-axis).17 All measurements were performed on 3-5 cardiac cycles and results averaged.
Speckle-Tracking Echocardiography
For STE analysis (EchoPAC version 113, GE Healthcare), endomyocardial borders were traced on two-dimensional images with the region of interest adjusted to myocardial wall thickness. RV free-wall (RVFW) and LV (IVS included as part of the LV analysis) longitudinal strain (LS) and strain rate (LSR) were assessed from the apical four-chamber view, dividing each wall into 3 segments: basal, mid, and apical. LV circumferential strain (CS) and strain rate (CSR) were assessed at the parasternal short-axis base, mid and apex, each divided into 6 segments: anteroseptal (1), anterior (2), lateral (3), posterior (4), inferior (5), septal (6). Wall tracking was visually assessed throughout the cardiac cycle and the region of interest adjusted as needed to ensure accurate tracking.18 If ≥4 segments tracked well (visually and by EchoPAC assessment), the curve was accepted and segments that tracked poorly were not analyzed.
Ensuring similar heart rates to images used for strain, aortic valve closure (from pulsed-wave Doppler) defined end-systole. We documented peak systolic strain (before/at aortic valve closure) for (1) individual segmental strain curves and (2) global strain (average of peak systolic strain from segments tracking well). In 70.0% of strain analyses, 2-4 consecutive heartbeats were analyzed and averaged to account for beat-to-beat variability; in 20.4%, one beat was available for analysis; 9.6% were inadequate for analysis; RV and LV image quality were similar. In total, 595 strain analyses were completed for the 54 study patients.
Apical minus basal rotation at aortic valve closure provided twist, indexed to LV length to provide torsion. Peak apical minus basal systolic rotation rates provided peak twist rate, indexed to LV length to provide torsion rate.
Demographics & Functional Classification
We documented PH etiology, CHD (and repair), intra-/extra-cardiac shunting, medications, and plasma brain natriuretic peptide (BNP; CHCO patients) at the time of catheterization. World Health Organization (WHO) functional classifications documented <6 months from catheterization were recorded. Transplant and death status were collected at study completion. Predicted 1-, 3-, and 5-year survival for PH patients was estimated using the Pulmonary Hypertension Connection equation.19, 20
Control Population
Echocardiograms were obtained on 54 (37 at CHCO, 17 at SickKids) age-, gender-, and institution-matched healthy children who were volunteers or underwent evaluation for murmur, chest pain, palpitations, syncope, or family history of CHD, with a normal medical history (Supplemental Material) and echocardiogram.16 Analyses followed the same protocol as study patients. No controls underwent catheterization.
Reproducibility
A single observer (D.B.) analyzed echocardiograms for all PH patients and CHCO controls; a separate observer (C.S.) analyzed echocardiograms for SickKids controls. Both observers were blinded to clinical and catheterization data. To assess interobserver variability, SickKids PH echocardiograms (31.5% of PH patients) were re-analyzed by a second observer (C.S.). To assess intraobserver variability, 10% of all echocardiograms were re-analyzed at least 8 weeks apart.
Statistical Analysis
Data were not normally distributed when assessed by the Shapiro-Wilk test. Continuous data are presented as median with interquartile range (unless otherwise noted); categorical data are presented as frequencies (%). Comparative analysis was performed using Wilcoxon Mann-Whitney and Chi-square testing as appropriate. Exact methods were utilized as necessary. Spearman correlation coefficients were used to assess relationships between LV mechanics, invasive hemodynamics, RV mechanics, and functional PH measures. Some significant relationships identified through correlation analyses were re-evaluated using regression analysis to control for potential confounders. Inter-rater and intra-rater reliability were calculated using intraclass correlation coefficients with 95% confidence interval (CI). Given multiple comparisons between PH and controls, a P-value of <0.01 was considered significant. Statistical analyses used SAS software, version 9.3 (SAS Corporation, Cary, NC).
Results
Patient Characteristics
Patient characteristics are presented in Table 1. In total, 108 subjects were analyzed: 54 PH patients and 54 controls. The only study patient <1 year-old (7 months) did not have PH on initial evaluation so he and his matched control were not used in comparisons between PH versus controls. Most patients were female (34/53, 64.2%) and born with CHD (33/53, 62.3%) (Supplemental Material). Some (21/53, 39.6%) had a potentially active shunt at catheterization; these patients had a median Qp:Qs of 1.16 (1.00 – 1.55).
Table 1. Patient Characteristics.
| PH Patients (n = 53) | Control Subjects (n = 53) | P-Value | |
|---|---|---|---|
| Age, yr (range) | 8 (0 - 23) | 8 (0 - 23) | 0.99 |
| Female, n (%) | 34 (64.2%) | 34 (64.2%) | 1.00 |
| Weight, kg | 32.5 (14.7 - 51.4) | 30.6 (16.3 - 54.8) | 0.67 |
| Height, cm | 133.0 (98.0 - 161.0) | 136.0 (104.5 - 162.0) | 0.60 |
| Body Surface Area, m2 | 1.12 (0.63 - 1.52) | 1.10 (0.69 - 1.57) | 0.68 |
| Heart Rate, bpm | 81 (70 - 100) | 79 (65 - 93) | 0.33 |
| Congenital Heart Disease, n (%) | 33 (62.3%) | … | … |
| Shunt Present at Catheterization | 21 (39.6%) | … | … |
| Idiopathic PH, n (%) | 14 (26.4%) | ||
| World Health Organization Class, n (%) | |||
| Not Available | 15 (28.3%) | … | … |
| I / II | 15 (28.3%) / 16 (30.2%) | … | … |
| III / IV | 6 (11.3%) / 1 (1.9%) | … | … |
| Cardiac Catheterization | |||
| MPAP, mm Hg | 33.0 (25.0 - 43.0) | … | … |
| MAP, mm Hg | 58.0 (55.0 - 63.0) | … | … |
| MPAP/MAP | 0.59 (0.42 - 0.72) | … | … |
| SPAP, mm Hg | 52.0 (38.0 - 63.0) | … | … |
| DPAP, mm Hg | 23.0 (15.0 - 32.0) | … | … |
| Transpulmonary Gradient, mm Hg | 23.0 (16.0 - 35.0) | … | … |
| Diastolic Transpulmonary Gradient, mm Hg | 13.0 (6.0 - 26.0) | … | … |
| Mean RAP, mm Hg | 7.0 (5.0 - 8.0) | … | … |
| Cardiac Index, L/min/m2 | 3.38 (2.98 - 3.82) | … | … |
| Qp/Qs | 1.00 (1.00 - 1.00) | … | … |
| PVRi, WU·m2 | 6.79 (4.10 - 10.89) | … | … |
| PVR/SVR | 0.37 (0.25 - 0.60) | … | … |
| Echocardiography | |||
| LV End-Diastolic Volume, ml | 52.0 (26.0 - 90.0) | 49.0 (29.0 - 79.5) | 0.86 |
| Indexed LV End-Diastolic Volume, ml/m2 | 44.3 (37.2 - 59.8) | 37.9 (32.8 - 48.4) | 0.07 |
| LV End-Systolic Volume, ml | 19.0 (12.0 - 46.0) | 16.5 (9.5 - 27.5) | 0.27 |
| Indexed LV End-Systolic Volume, ml/m2 | 20.3 (14.2 - 28.1) | 12.9 (9.8 - 16.5) | 0.0006* |
| LV Ejection Fraction, % | 56.0 (50.0 - 63.0) | 66.0 (62.0 - 69.0) | <0.0001* |
| LV End-Diastolic Eccentricity Index | 1.18 (1.09 - 1.28) | 1.02 (0.96 - 1.06) | <0.0001* |
| LV End-Systolic Eccentricity Index | 1.27 (1.11 - 1.50) | 0.99 (0.96 - 1.03) | <0.0001* |
Presented as n (%) or median (interquartile range), unless otherwise noted. PH indicates pulmonary hypertension; MPAP, mean pulmonary artery pressure; MAP, mean arterial (systemic) pressure; SPAP, systolic pulmonary artery pressure; DPAP, diastolic pulmonary artery pressure; RAP, right atrial pressure; Qp/Qs, pulmonary-to-systemic blood flow ratio; PVRi, indexed pulmonary vascular resistance; PVR/SVR, pulmonary-to-systemic vascular resistance ratio; LV, left ventricle.
One quarter (14/53, 26.4%) of patients had idiopathic PH. “Other” etiologies included CHD, lung disease/hypoxia, hematologic disorders, chronic thromboembolism, or combination of etiologies.
Most PH patients (47/53, 88.7%) were on single (15/53, 28.5%), dual (12/53, 22.6%), triple (9/53, 17.0%), or quadruple (11/53, 20.7%) medical therapy. Medications included: phosphodiesterase type 5 inhibitors (35/53, 66.0%), endothelin receptor antagonists (26/53, 49.1%), prostacyclin analogues (18/53, 34.0%), anticoagulants (15/53, 28.3%), calcium channel blockers (12/53, 22.6%), supplemental oxygen (10/53, 18.9%), and digoxin (1/53, 1.9%).
There was 1 lung transplant and 1 death during the study period. Estimated 1-, 3-, and 5-year survival rates were 94.7 (92.7-96.8)%, 85.0 (79.5-90.6)%, and 76.3 (68.3-84.9)% (respectively).
Cardiac index was preserved in PH patients and did not correlate with mean pulmonary artery pressure (r=0.06, P=0.67) or PVRi (r=-0.27, P=0.07). LV eccentricity index was increased in PH patients, consistent with leftward septal shift. Indexed LV end-systolic volume was larger in PH patients, despite controlling for shunts. LV EF was decreased in PH patients compared to controls, though within normal limits.
Comparison of CHCO and SickKids controls demonstrated no differences in global strain measures (P>0.05 for all).
1) Ventricular Mechanics
Longitudinal Strain/Strain Rate
Representative strain curves are shown in Figure 1. LS data are shown in Table 2, LSR data in Supplemental Table 1. LV global and IVS LS were decreased, as were basal and mid IVS segments. Mid IVS segment LSR was reduced. LS was decreased in the RVFW and its 3 segments. Basal and mid RVFW segments' LSR were reduced.
Figure 1.
Representative left ventricular strain curves. (A-B), Longitudinal strain, of control (A) and pulmonary hypertension (B) patients. (C-D), Mid circumferential strain, of control (C) and pulmonary hypertension (D) patients.
Table 2. Left and Right Ventricular Longitudinal Strain.
| Longitudinal Strain, % | PH Patients (n=53) | Control Subjects (n=53) | P-Value |
|---|---|---|---|
| LV Global | -18.8 (-17.3 - -20.4) | -20.2 (-19.0 - -20.9) | 0.0046* |
| LV Free-Wall | -20.5 (-17.9 - -22.2) | -19.9 (-17.9 - -21.0) | 0.30 |
| Basal | -20.6 (-17.5 - -23.5) | -18.9 (-16.3 - -22.5) | 0.24 |
| Mid | -18.0 (-14.9 - -20.8) | -18.0 (-16.0 - -21.2) | 0.61 |
| Apical | -22.2 (-18.4 - -26.1) | -22.0 (-18.6 - -24.5) | 0.31 |
| IVS | -17.0 (-15.3 - -19.5) | -20.8 (-19.4 - -22.2) | <0.0001* |
| Basal | -12.9 (-10.8 - -16.3) | -17.9 (-14.5 - -20.7) | <0.0001* |
| Mid | -17.5 (-15.5 - -19.0) | -21.1 (-19.1 - -23.0) | <0.0001* |
| Apical | -23.4 (-19.1 - -26.2) | -23.0 (-20.7 - -26.0) | 0.84 |
| RVFW | -21.5 (-18.5 - -25.4) | -29.1 (-26.6 - -33.8) | <0.0001* |
| Basal | -23.6 (-18.4 - -28.3) | -30.4 (-24.1 - -36.0) | 0.0002* |
| Mid | -22.7 (-20.1 - -26.8) | -30.5 (-27.1 - -35.8) | <0.0001* |
| Apical | -19.1 (-13.0 - -22.8) | -28.2 (-23.6 - -32.0) | <0.0001* |
Presented as median (interquartile range). PH indicates pulmonary hypertension; LV, left ventricle; IVS, interventricular septum; RVFW, right ventricular free-wall.
Circumferential Strain/Strain Rate
LV CS data are shown in Table 3, CSR data in Supplemental Table 2. Basal CS was decreased globally, and within septal (6) and lateral (3) segments, with trends towards reduction within the septum – comprised of both septal (6) and anteroseptal (1) segments. Basal CSR was reduced within the septum and the septal (6) segment, with a trend towards reduced lateral (3) CSR.
Table 3. Left ventricular circumferential strain.
| Circumferential Strain, % | PH Patients (n=53) | Control Subjects (n=53) | P-Value |
|---|---|---|---|
| Basal | |||
| Global | -18.7 (-15.7 - -22.1) | -20.6 (-19.0 - -22.5) | 0.0098* |
| Septum (6, 1) | -22.0 (-16.6 - -24.7) | -24.1 (-21.0 - -28.1) | 0.0140 |
| Septal (6) | -19.7 (-14.5 - -24.7) | -23.2 (-20.9 - -27.7) | 0.0009* |
| Anteroseptal (1) | -23.8 (-18.8 - -26.7) | -24.4 (-21.2 - -30.5) | 0.14 |
| Free-Wall (2, 3, 4, 5) | -17.1 (-14.8 - -21.3) | -19.3 (-16.6 - -21.2) | 0.057 |
| Anterior (2) | -21.5 (-14.6 - -26.7) | -20.9 (-16.6 - -24.0) | 0.68 |
| Lateral (3) | -12.9 (-9.0 - -18.1) | -19.5 (-16.0 - -21.0) | 0.0002* |
| Posterior (4) | -13.6 (-8.5 - -19.1) | -18.0 (-12.4 - -20.4) | 0.057 |
| Inferior (5) | -17.7 (-13.1 - -23.1) | -18.8 (-14.7 - -24.0) | 0.38 |
| Mid | |||
| Global | -19.4 (-16.8 - -20.8) | -19.7 (-17.8 - -21.3) | 0.20 |
| Septum (6, 1) | -23.1 (-19.6 - -26.0) | -23.4 (-19.5 - -25.8) | 0.87 |
| Septal (6) | -22.0 (-18.3 - -24.7) | -23.0 (-20.6 - -25.4) | 0.21 |
| Anteroseptal (1) | -23.4 (-19.9 - -26.6) | -23.0 (-20.0 - -26.0) | 0.70 |
| Free-Wall (2, 3, 4, 5) | -17.2 (-14.4 - -19.6) | -18.8 (-16.6 - -19.8) | 0.0493 |
| Anterior (2) | -23.1 (-18.5 - -25.8) | -21.2 (-19.0 - -24.2) | 0.32 |
| Lateral (3) | -15.2 (-12.7 - -17.4) | -17.6 (-14.3 - -20.8) | 0.0033* |
| Posterior (4) | -12.6 (-10.1 - -16.3) | -16.0 (-12.3 - -18.3) | 0.0237 |
| Inferior (5) | -18.9 (-13.8 - -21.6) | -19.0 (-15.7 - -21.0) | 0.66 |
| Apical | |||
| Global | -22.5 (-19.7 - -25.8) | -22.0 (-19.5 - -24.2) | 0.35 |
| Septum (6, 1) | -23.0 (-20.1 - -26.7) | -23.4 (-18.7 - -26.2) | 0.72 |
| Septal (6) | -22.4 (-18.6 - -26.7) | -23.5 (-18.3 - -25.9) | 0.95 |
| Anteroseptal (1) | -24.3 (-20.5 - -26.3) | -23.0 (-19.0 - -26.0) | 0.33 |
| Free-Wall (2, 3, 4, 5) | -23.0 (-19.1 - -26.3) | -20.5 (-18.3 - -24.5) | 0.26 |
| Anterior (2) | -26.3 (-20.6 - -30.5) | -23.9 (-20.0 - -28.0) | 0.0475 |
| Lateral (3) | -22.8 (-16.4 - -26.7) | -21.0 (-16.4 - -26.0) | 0.58 |
| Posterior (4) | -20.2 (-15.8- -25.0) | -20.5 (-16.0 - -24.7) | 0.99 |
| Inferior (5) | -22.1 (-18.2 - -26.3) | -22.7 (-18.2 - -25.0) | 0.59 |
Presented as median (interquartile range). PH indicates pulmonary hypertension.
Mid CS was reduced in the lateral (3) segment, with trends towards reduction in the posterior (4) segment and the free-wall – comprised of anterior (2), lateral (3), posterior (4) and inferior (5) segments. There were no significant changes in mid CSR.
Apical CS and CSR were unchanged in PH patients.
Rotational Mechanics
There were non-significant trends towards increased torsion (1.47 [1.03-2.08] vs. 1.27 [0.69-1.59]0/cm, P=0.08) and torsion rate (15.09 [11.76-22.13] vs. 11.60 [9.82-20.08]0/cm/s, P=0.06) in PH.
Sub-group Analysis
Separating PH patients by presence of CHD or an active shunt revealed no differences in LV mechanics between groups (P>0.05 for all). Separating PH patients with shunts (n=21) by those with pre- versus post-tricuspid valve shunts revealed no differences in LV mechanics (P>0.05 for all); those with right-to-left shunts had pre-tricuspid valve shunts.
To quantify ventricular dysfunction with increasingly severe PH, patients were separated into quartiles by the ratio of pulmonary-to-systemic mean arterial pressures (MPAP/MAP) - a more meaningful representation of PH in children than pulmonary pressures alone. Median MPAP/MAP (1.00 [0.81-1.04]) and PVRi (15.8 [11.7-19.1]WU·m2) for the most severe quartile (Quartile 4) were significantly higher than each of the other three quartiles (P<0.0001 for both). Cardiac index was similar across quartiles (P>0.05). Quartile 4, compared to each of the other quartiles (Figure 2) and to controls (Supplemental Table 3), demonstrated reduced IVS (including basal and mid segments) and RVFW LS; LV free-wall trended towards increased LS compared to controls (P=0.0354). CS measures did not vary significantly between quartiles, but the basal lateral (3) segment was decreased compared to matched controls.
Figure 2.
Bar graph demonstrating regional median longitudinal strain for controls and pulmonary hypertension quartiles (based on mean pulmonary-to-systemic arterial pressure ratio). Comparisons are between quartiles and all controls, as matched controls for each quartile were not different from the entire control cohort (P>0.05 for all). * indicates quartile is significantly different from controls (P<0.007); † indicates quartile 4 significantly different than all other quartiles and controls (P<0.009); ‡ indicates quartiles 3 and 4 significantly different than 1, 2 and controls (P<0.0004); § indicates quartiles 2, 3, and 4 significantly different than 1 and controls. LV indicates left ventricle; IVS, interventricular septum; RVFW, right ventricular free-wall.
As PVRi often guides clinical decisions, patients were separated into mild (<5), moderate (5-8), and significant (>8) PVRi elevation tertiles to identify potential strain differences. Basal IVS and RVFW LS were reduced with at least moderately elevated PVRi (≥5), compared to PVRi <5 (Figure 3). The highest PVRi tertile also demonstrated significantly reduced mid IVS and IVS LS compared to those with PVRi <5.
Figure 3.
Bar graph demonstrating regional median longitudinal strain in pulmonary hypertension patients divided by pulmonary vascular resistance tertiles. * indicates tertile 3 is significantly different from 1 and 2 (P<0.005); † indicates tertile is significantly different from tertile 1 (P<0.006).
2) LV Free-Wall and Septal Strain Relationships
Invasive Hemodynamics, RV Mechanics, and LV Strain
Correlations between MPAP/MAP or PVRi, RVFW LS, and LV strain are presented in Figure 4 and Table 4; for Table 4, Bonferoni's correction was used to lower significance to P<0.001. Strong correlations were seen between invasive measures and basal septum LS – an average of the longitudinal strains of basal and mid IVS segments; moderate correlations were seen with IVS and RVFW LS.
Figure 4.
Relations between LV strain, invasive hemodynamics and RVFW strain. A, MPAP/MAP vs. basal septal LS. B, PVRi vs. basal septal LS. C, RVFW LS vs. LV global LS. D, RVFW LS vs. basal septal LS. E, Brain natriuretic peptide vs. septal LS. F, Predicted 5-year survival for Quartile 4 vs. LV free-wall LS. LV indicates left ventricle; RVFW, right ventricular free-wall; MPAP/MAP, mean pulmonary-to-systemic arterial pressure; LS, longitudinal strain; PVRi, indexed pulmonary vascular resistance.
Table 4. Correlations Between LV Strain, Invasive Hemodynamics, & RVFW Strain.
| Strain Variable | MPAP/MAP | PVRi, WU·m2 | RVFW Strain, % | |||
|---|---|---|---|---|---|---|
|
|
|
|
||||
| r | P-Value | r | P-Value | r | P-Value | |
| Longitudinal Strain, % | ||||||
| LV Global | 0.16 | 0.28 | 0.19 | 0.18 | 0.41 | <0.0001* |
| LV Free-Wall | -0.30 | 0.0391 | -0.21 | 0.15 | -0.02 | 0.82 |
| IVS | 0.50 | 0.0003* | 0.48 | 0.0003* | 0.62 | <0.0001* |
| Basal Septal | 0.66 | <0.0001* | 0.60 | <0.0001* | 0.64 | <0.0001* |
| RVFW | 0.55 | <0.0001* | 0.50 | 0.0002* | … | … |
| Circumferential Strain, % | ||||||
| Basal | ||||||
| Global | 0.06 | 0.71 | 0.13 | 0.40 | 0.37 | 0.0004* |
| Septum (6, 1) | -0.07 | 0.67 | 0.002 | 0.99 | 0.37 | 0.0004* |
| Septal (6) | -0.16 | 0.30 | -0.06 | 0.68 | 0.35 | 0.0009* |
| Anteroseptal (1) | 0.04 | 0.82 | 0.05 | 0.75 | 0.33 | 0.0014 |
| Free-Wall (2, 3, 4, 5) | 0.17 | 0.28 | 0.25 | 0.09 | 0.23 | 0.0305 |
| Lateral (3) | 0.31 | 0.06 | 0.15 | 0.38 | 0.38 | 0.0005* |
| Mid | ||||||
| Global | 0.15 | 0.30 | 0.30 | 0.0349 | 0.26 | 0.0127 |
| Septum (6, 1) | 0.16 | 0.30 | 0.31 | 0.0304 | 0.27 | 0.0077 |
| Septal (6) | 0.08 | 0.30 | 0.28 | 0.0501 | 0.24 | 0.0215 |
| Anteroseptal (1) | 0.25 | 0.82 | 0.33 | 0.0201 | 0.26 | 0.0128 |
| Free-Wall (2, 3, 4, 5) | 0.09 | 0.54 | 0.15 | 0.29 | 0.14 | 0.18 |
| Lateral (3) | 0.37 | 0.0105 | 0.27 | 0.056 | 0.25 | 0.0147 |
| Posterior (4) | 0.15 | 0.32 | 0.12 | 0.40 | 0.29 | 0.0066 |
P<0.001 considered significant. LV indicates left ventricle; RVFW, right ventricular free-wall; MPAP/MAP, mean pulmonary-to-systemic arterial pressure ratio; PVRi, indexed pulmonary vascular resistance; IVS, interventricular septum; Basal Septal, average longitudinal strain of basal and mid IVS segments.
Basal septum LS correlated strongly with MPAP/MAP (r=0.68, P<0.0001) and moderately with PVRi (r=0.57, P=0.0001) after adjusting for RVFW LS, and strongly with MPAP/MAP (r=0.62, P<0.0001) after adjusting for both RVFW LS and eccentricity index.
RVFW LS correlated strongly with septal and basal septum LS, and moderately with LV global LS. RVFW LS correlated weakly with the following CS measures: basal global and septum, and the septal (6) and lateral (3) segments. Trends were seen with mid CS measures; there were no correlations with apical CS (P>0.05 for all).
Systolic eccentricity index correlated moderately with mid IVS segment (r=0.57, P<0.0001) and basal septum (r=0.46, P<0.0001) LS, and weakly with basal IVS segment LS (r=0.35, P=0.0011) and CS of the basal septum (r=0.34, P=0.0017), basal septal (6) segment (r=0.30, P=0.0074) and anteroseptal (1) segment (r=0.32, P=0.0032).
Functional Measures and Ventricular Strain
BNP levels correlated moderately with IVS LS (r=0.48, P=0.0038), but neither free-wall. WHO functional classification correlated moderately with RVFW LS (r=0.44, P=0.0089) and (inversely) with LV free-wall LS (r=-0.48, P=0.0051). LV free-wall LS correlated strongly with expected 5-year survival in those with the most severe PH (Quartile 4) (r=-0.85, P=0.0008).
Reproducibility
Intraobserver intraclass correlation coefficients (95% CI) were: RV global LS = 0.99 (0.99-0.99); LV global LS = 0.87 (0.71-0.95); basal global CS = 0.93 (0.83-0.98); mid global CS = 0.94 (0.85-0.97); apical global CS = 0.91 (0.81-0.97). Interobserver intraclass correlation coefficients (95% CI) were: RVFW = 0.72 (0.50-0.86); LV global LS = 0.70 (0.41-0.86); basal global CS = 0.75 (0.52-0.88); mid global CS = 0.60 (0.32-0.79); apical global CS = 0.90 (0.80-0.96).
Discussion
Using simultaneous STE and cardiac catheterization, we evaluated segmental LV strain/strain rate in pediatric PH, and relations to invasive hemodynamics, RV mechanics, and functional PH measures. Our main findings are the following: (1) LV myocardial mechanics, primarily within the septum, are altered in pediatric PH; (2) altered LV myocardial mechanics are associated with invasive hemodynamics, RV myocardial function, and functional PH measures.
Altered LV Mechanics
Though decreased compared to controls, EF was within normal limits in PH, as was cardiac index, and yet LV strain/strain rate were reduced, primarily at the basal septum. Though this requires further study, LV strain could be an earlier marker of LV dysfunction in this setting, consistent with literature in PH and other conditions.8, 9, 21, 22
Reduced LV global LS was predominantly due to decreased basal and mid IVS segment LS, as the apex and free-wall were preserved. Septal strain progressively decreased with worsening PH. Nonetheless, reduced CS in free-wall segments suggests LV involvement beyond the septum, consistent with observations in adult PH.8 CS generally demonstrated smaller reductions than LS, and minimal differences in severe PH. Leftward septal shift or other interventricular interactions may affect longitudinal fibers more than circumferential and predominate in severe PH. These changes occurred independent of an active shunt, CHD, or a post-tricuspid valve shunt, though all patients with right-to-left shunts had pre-tricuspid valve shunts.
A smaller apical cavity radius imparting less wall-stress, or that the apex shares less septum with the dysfunctional RV apex,23, 24 might explain preserved LV apical mechanics. Rotational mechanics were also preserved, in contrast to findings in adult PH.8 Although our pediatric population generally had less severe PH than published adult populations,8, 9 which could explain preserved mechanics, we still observed reduced LV septal (more so than free-wall) mechanics.
Possible etiologies for the observed changes include reduced LV filling, geometric changes, and altered myocardial contractility. Smaller LV volumes in adult PH suggest reduced filling.8-10 We unexpectedly found larger indexed end-systolic volumes despite age- and gender-matching. A lower EF in PH patients may result in larger end-systolic volumes. Still, LV filling is likely altered by leftward septal shift and/or reduced RV output,7, 10-13 which might account for strain (which is load-dependent) being more altered than strain rate (less load-dependent).
Myocardial injury could also impair mechanics. LV fibrosis develops in experimental RV pressure-loading,25 while LV free-wall atrophy, decreased myosin-based cross-bridges, and fibrosis/edema are seen in chronic adult PH.26 The distribution of such changes and presence in pediatric PH require further study.
LV Free-Wall and Septal Strain Relationships
The strongest correlations with RVFW strain, and only LV correlations with invasive hemodynamics, occurred with LS of the basal septum, which shifts leftward in PH. Eccentricity index, which quantifies this septal shift, also correlated with basal septum strain, supporting an association between LV geometry and myocardial mechanics. Basal septum LS correlated with invasive hemodynamics even after adjusting for both RV strain and septal shift, suggesting direct pressure-loading effects on septal function. CS demonstrated weaker relationships than LS, and correlated with RVFW strain, perhaps reflecting that superficial, circumferentially-oriented fibers are shared with the RV.
Although basal septal strain was substantially reduced in severe PH, increased free-wall LS maintained global LS within normal limits. Increasing LV free-wall LS correlated with worsening WHO functional class and predicted survival in severe PH, suggesting LV free-wall longitudinal function may impact outcomes in severe PH by compensating for septal dysfunction to maintain LV pump function. Additionally, although BNP levels are not associated with basic LV echocardiographic parameters in PH,27 they correlated with septal strain here, possibly suggesting increased wall stress in the flattened septum.
To separately evaluate the RV and LV, some have excluded the IVS.9 However, this region was one of the most affected in PH and correlated better with invasive hemodynamics and functional measures than other regions, including the RVFW.
Limitations
Although pediatric studies commonly have low patient numbers, this study is larger than many regarding PH. Few deaths/transplants limited our ability to evaluate relationships with these outcomes. We attempted to predict survival using available estimates, recognizing these have not been validated in children. Though heterogeneous, our patients reflect the pediatric PH population. Patients presented to tertiary care centers for clinically indicated catheterization, potentially introducing selection bias. However, the hemodynamic range suggests a mixture of well-, and poorly-controlled PH.
Though we attempted to have a consistent catheterization protocol between sites, differences were present. SickKids utilized Millar catheters for RV pressure measurements; otherwise, fluid-filled catheters were used at both locations. Oxygen consumption was measured by mass spectrometry at SickKids and estimated by the LaFarge table at CHCO. Both methods are compliant with respective institutional practice, accepted standards of care, and used to guide PH management. Over-/under-wedged PCWP affects estimations of left atrial pressure. However, wedge pressures are accepted estimations of mean left atrial pressure during right heart catheterization, and mean left atrial pressure was preferentially used when obtained.
Though all PH patients were under general anesthesia, we did not dictate the induction, maintenance, or duration. Subtle differences in anesthetics and ventilation strategies could potentially affect hemodynamics, and thus strain/strain rate and comparisons with unsedated controls. Results could be confounded if anesthesia altered strain/strain rate independent of hemodynamics, though we are unaware of data documenting that maintenance anesthetics alone alter strain/strain rate. Altitude differences between Denver and Toronto can affect PVRi and MPAP; thus we used matched controls from respective institutions.
Conclusions
Pediatric PH patients demonstrate reduced LV longitudinal and circumferential strain and strain rate, primarily within the septum, with relationships to invasive hemodynamics, altered RV strain, septal shift, and functional PH measures.
Supplementary Material
Acknowledgments
Sources of Funding: This research was supported in part by The Frederick and Margaret L Weyerhaeuser Foundation, The Jayden de Luca Foundation, the Canadian Institutes of Health Research, and NIH grants R01HL114753, U01HL121518, and UL1TR000154.
Footnotes
Disclosures: None.
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