Abstract
Background
Elevated right atrial (RA) pressure is a risk factor for mortality and RA size is prognostic of adverse outcomes in pulmonary hypertension (PH). There is limited data on phasic RA function (reservoir, conduit, and pump) in pediatric PH. We sought to evaluate 1) the RA function in pediatric PH patients compared to controls, 2) compare the RA deformation indices with Doppler indices of diastolic dysfunction, functional capacity, biomarkers, invasive hemodynamics, and right ventricular (RV) functional indices, and 3) evaluate the potential of RA deformation indices to predict clinical outcomes.
Methods and Results
Sixty-six PH patients (mean age 7.9 ±4.7 years) were compared with 36 controls (7.7 ±4.4 years). RA and RV deformation indices were obtained using two-dimensional speckle tracking (2DCPA, TomTec). RA strain, strain rates, emptying fraction (EF), and RV longitudinal strain (LS) were measured. RA function was impaired in PH patients versus controls (p<0.001). There were significant associations between RA function with invasive hemodynamics (p<0.01). RA reservoir, pump function, the rate of RA filling, and atrial minimum volume predicted adverse clinical outcomes (HR (CI) 0.15 (0.03–0.73), p<0.01; 0.05 (0.003–0.43), p <0.004; 0.04 (0.006–0.56), p<0.01; 8.6 (1.6–37.2), p<0.01 respectively).
Conclusions
RA deformation properties are significantly altered in pediatric PH patients. Progressive worsening of RA reservoir and conduit functions are related to changes in RV diastolic dysfunction. RA reservoir function, pump function, the rate of atrial filling, and atrial minimum volume emerged as outcome predictors in pediatric PH.
Keywords: right atrial function, pediatric pulmonary hypertension, right ventricular function, myocardial strain and strain rate, clinical outcomes
Pediatric pulmonary hypertension (PH) is a progressive disease that results in right ventricular (RV) hypertrophy, dilation, and dysfunction 1–3. PH secondarily affects right atrial (RA) size and pressure, and these changes correlate with prognosis, including mortality 4–11. RA function can be highly relevant in PH, as shown in adults who demonstrated clinical deterioration and poor clinical outcomes upon losing RA function due to atrial fibrillation 12.
The assessment of RA function and its relation to RV function could provide an improved understanding of right heart function in PH. Atrial function consists of three phases: the reservoir phase during atrial filling, the conduit phase during passive emptying into the ventricle, and the active pump phase during atrial systole 13. Atrial emptying fractions measure changes in the atrial volume between phases of the cardiac cycle, and are also indicators of atrial function 14. Preliminary work using RA speckle tracking has shown promise for evaluation of RA function in adult PH patients 5–8, 11, 14–20. However, the nature of RA-RV axis interdependence in pediatric PH and the role of speckle tracking of RA deformation in its evaluation have yet to be established. The purpose of this study is 1) to evaluate RA function using 2D speckle tracking in pediatric PH patients compared to controls, 2) to correlate the RA deformation indices with traditional Doppler indices, functional capacity, biomarkers of PH severity, invasive hemodynamics, and RV functional indices, and 3) to evaluate potential of RA deformation indices for prediction of clinical outcomes in pediatric PH.
METHODS
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
Study Population
This study was a retrospective analysis of pediatric PH patients (identified from the PH database at the Children’s Hospital Colorado) who underwent transthoracic echocardiographic evaluation, 6-minute walk test (6MWT) and biomarkers of plasma B-type natriuretic peptide (BNP) and serum N-Terminal pro-BNP (NT pro-BNP) levels drawn on the same day, cardiac catheterization within 48 hours of the echocardiograms, and presented with clinical outcomes between January 2007 and March 2017. Data from clinical chart review included 6MWT, biomarkers, and invasive hemodynamics of mean RA pressure (mRAP), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance index (PVRi), pulmonary capillary wedge pressure, mPAP/mean systolic arterial pressure (mPAP/mSAP), and cardiac index (CI). Sixty-six PH patients and 36 controls with echocardiographic images in the apical 4-chamber view deemed suitable for deformation analyses were included. Control subjects had been referred for evaluation of heart murmurs and chest pain and had normal echocardiograms and electrocardiograms. Exclusion criteria consisted of (1) patients in whom echocardiographic images were of suboptimal quality for deformation analysis, (2) patients with associated pulmonary hypertension with congenital heart disease (APAH-CHD) who underwent open heart surgery, and (3) patients with atrial fibrillation or flutter. The institutional review board approved of the study and appropriate data user agreements were in place between participating institutions.
Transthoracic Echocardiography
Echocardiography was performed on all subjects using IE-33 (Philips Ultrasound, Bothell, WA) or Vivid (GE Ultrasound, Milwaukee, WI) ultrasound systems. Images were digitally acquired using a standard protocol with appropriate sized transducers for patient size. Tricuspid and mitral valves inflow Doppler and annular tissue Doppler imaging (TDI) velocities, RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), tricuspid regurgitation (TR) Doppler, and left ventricular ejection fraction were measured. TR severity was graded as trace, mild, moderate, and severe.
RA and RV Strain Analysis
Echocardiographic images were uploaded to a PC based workstation with the two-dimensional speckle tracking software (2DCPA TomTec, Germany). RA and RV deformation indices were obtained in the apical 4-chamber view. The RV endocardial border was traced, speckle tracked throughout the cardiac cycle, and RV longitudinal strain (LS) obtained. This software was used to determine RA deformation as described previously 21. Briefly, the RA endocardial border was traced at ventricular end-systole with the QRS onset as the reference point 18, and the longitudinal ε and SR data were generated (Figure 1). Three indices of RA deformation were obtained: (1) Peak RA strain (εS) – indicative of RA reservoir function when maximal RA filling occurs, (2) RA conduit function (εE) indicates passive RA emptying, and (3) RA pump function (εA) indicates active RA emptying. The three longitudinal SR measures obtained were: (1) peak positive SR (SRS) for reservoir function, (2) early negative SR (SRE) for conduit function, and (3) late negative SR (SRA) for atrial pump function. RA volumes were determined with RA emptying fraction (EF) defined as (maximal RA volume – minimal RA volume)/maximal RA volume).
Figure 1.
Right atrial strain (A) and strain rate (B) in normal and pulmonary hypertension patient.
Clinical Outcomes
Clinical outcomes were analyzed in all PH patients with predefined adverse clinical events. An adverse clinical event was defined as 1) initiation of intravenous prostacyclin, 2) PAH related hospitalization with increased RV failure or hemoptysis, 3) creation of an atrial septostomy, 4) Pott’s shunt, 5) lung transplant, or 6) death. These adverse clinical outcomes were composite endpoints similar to previous medication trials in PAH.22 All patients were followed up until the clinical event or the end of the study period.
Statistical Analysis
Analyses were performed using JMP 13 (SAS Institute, Cary, NC). Variables were checked for normality. Variables that were positively skewed were natural log-transformed for analysis. Normally distributed group specific data sets are reported as mean with standard deviations. Non-normally distributed values are reported as median with interquartile ranges. Demographic and clinical characteristics among PH and control patients were compared using a student’s t-test for normally distributed continuous variables, Wilcoxon ranked sum test for non-normally distributed variables, and χ2 for categorical variables. Generalized linear regression models were employed to evaluate the correlations between RA deformation indices, inflow Doppler, TDI velocities, atrial volumes, 6MWT, biomarkers, and catheterization indices in PH patients.
To estimate the change in the RA deformation indices over time, a random coefficient model with an intercept and slope fit for each patient with at least two measurements was used as described previously 23, 24. In addition, a bivariate version of the random coefficients model was applied to investigate whether the trends in RV functional variables over time are associated with changes in the RA indices. This modeling approach is achieved by simultaneously fitting two univariate mixed effects models, one for each outcome, and specifying a joint multivariate distribution on the random effects. A benefit of this method is that it does not require the outcomes to be measured at the same time.
Intraobserver and interobserver variability of RA deformation measurements were assessed in 10 randomly selected studies using intraclass correlation coefficients (ICC). Intraobserver variability was based on measurements by the same observer (LL) 6 months apart. Interobserver variability was evaluated from two independent observers (LL and MC), blinded to the images.
Cox proportional hazards analysis is used to model the time to the first of these adverse clinical events. Separate Cox proportional hazard analyses were applied to assess the predictive ability of each right atrial deformation indices adjusting for duration of disease, age, sex, and BSA in all 66 PH patients. Significance was based on an α-level of 0.05.
RESULTS
PH patients and Controls
There were 148 echocardiograms and 80 cardiac catheterizations performed in 66 PH patients (age: 7.9 ± 4.7 years (range: [0.2 – 18]; 41 subjects were female). Thirty-six controls (age: 7.7 ± 4.4 years (range: [0.8 – 18]; 21 subjects were female) echocardiograms were acquired for comparative analysis. RA measurements could not be obtained in 2 studies out of 148 echocardiograms due to suboptimal image quality, yielding 146 studies for analysis. There were 91 6MWT, 121 BNP, and 98 NT pro-BNP in PH patients for analysis. The first echocardiograms were used for predictive analysis. Twenty-eight out of 66 (42%) of the traditional Doppler velocities and 21/66 (32%) of the TDI velocities were not measurable due to fusion of E and A waves. Table 1 shows clinical characteristics of PH patients and controls. Forty-nine PH patients had idiopathic pulmonary arterial hypertension, 7 had APAH-CHD, and 10 had other causes of PH. There were no statistically significant differences in demographics between PH and controls.
Table 1.
Patient Characteristics
| PH (n = 66) | Control (n = 36) | p-value | |
|---|---|---|---|
| age (yrs) | 7.9 ± 4.7 | 7.7 ± 4.4 | 0.8689 |
| sex (F) | 41 (62%) | 21 (58%) | 0.4662 |
| BSA | 0.94 ± 0.44 | 1.01 ± 35 | 0.4587 |
| WHO-FC | |||
| I | 18 (27%) | ||
| II | 23 (34.8%) | ||
| III | 13 (19.6%) | ||
| IV | 10 (15%) | ||
| IPAH | 49 (74.2%) | ||
| ASD s/p device closure | 3 (4.5%) | ||
| VSD unrepaired | 2 (3%) | ||
| PDA | 1 (1.5%) | ||
| Coarctation s/p repair | 1 (1.5%) | ||
| HAPE | 2 (3%) | ||
| Sickle cell disease | 2 (3%) | ||
| Connective tissue disease | 1 (1.5%) | ||
| Pulmonary fibrosis | 1 (1.5%) | ||
| Interstitial lung disease | 1 (1.5%) | ||
| Chronic lung disease | 2 (3%) | ||
| Pulmonary capillaritis | 1 (1.5%) | ||
| BNP | 61 [18 – 275] | ||
| NT-proBNP | 372 [116 – 2740] | ||
| 6-MWT | 455 ± 134 | ||
| Medications | |||
| IV Treprostinil | 16 (24%) | ||
| IV Epoprostenol | 6 (9%) | ||
| PDE5 inhibitors | 55 (83%) | ||
| ERA | 22 (33%) | ||
| CCB | 19 (24%) | ||
| Inhaled Treprostinil | 6 (9%) | ||
Data are reported as average ± SD. ASD = atrial septal defect, AVSD = atrioventricular septal defect, BNP = B-type natriuretic peptide, BSA = body surface area, CCB = calcium channel blockers, ERA = endothelin receptor antagonist, HAPE = high altitude pulmonary edema, IV = intravenous, IPAH = Idiopathic pulmonary hypertension, NT-proBNP = N-Terminal pro-BNP, PDE5 = phosphodiesterase 5, PDA = patent ductus arteriosus, 6-MWT = six-minute walk test, TAPVR = total anomalous pulmonary venous return, TGA = transposition of great arteries, VSD = ventricular septal defect, WHO-FC = world health organization – functional class.
Table 2 depicts comparative analysis of RA deformation indices along with standard echocardiographic and invasive hemodynamic measures. Significant differences were observed in all RA deformation indices but SRA between PH patients and controls. Furthermore, PH patients had significantly elevated both indexed maximal and minimal atrial volumes (p < 0.0001), while the RA EF was decreased. RV LS was decreased in PH patients. TR was rated as none in 12, trace in 17, mild in 24, moderate in 8, and severe in 1 PH patients. The ICC for both intraobserver and interobserver comparisons in strain, strain rate, and volume measurements are shown in supplemental Table S1.
Table 2.
RA and RV indices and Invasive Hemodynamics between PH patients and Controls
| RA Function | PH (n = 66) | Control (n = 36) | p-value |
|---|---|---|---|
| εS (%) | 38 ± 13 | 58 ± 10 | < 0.0001 |
| εE (%) | 26 ± 11 | 42 ± 11 | < 0.0001 |
| εA (%) | 12 ± 7 | 16 ± 5 | 0.0002 |
| SRS (s-1) | 1.6 ± 1.4 | 2.0 ± 0.4 | 0.0243 |
| SRE (s-1) | −1.6 ± 1.1 | −2.1 ± 0.6 | 0.0151 |
| SRA (s-1) | −1.8 ± 1.3 | −1.4 ± 0.5 | 0.0833 |
| Minimum volume (mL/m2) | 16 [12 – 24] | 9 [6 – 11] | < 0.0001 |
| Maximum volume (mL/m2) | 39 [30 – 50] | 24 [21 – 31] | < 0.0001 |
| Atrial EF (%) | 55 ± 11 | 64 ± 9 | 0.0001 |
| Heart rate (bpm) | 90 ± 24 | 83 ± 18 | 0.1056 |
|
| |||
| RV Function | |||
|
| |||
| RV LS (%) | −15 ± 5 | −24 ± 5 | < 0.0001 |
| FAC (%) | 31 ± 11 | ||
| TAPSE (cm) | 1.26 ± 0.50 | ||
|
| |||
| 2D Echo Indices | |||
|
| |||
| TR est RVP (mmHg) | 69 ± 28 | ||
| IVC size (mm) | 10 ± 4 | ||
| TV E (m/s) | 0.61 ± 18 | ||
| TV A (m/s) | 0.51 ± 0.16 | ||
| TV TDI S′ (m/s) | 0.11 ± 0.03 | ||
| TV TDI E′ (m/s) | 0.12 ± 0.05 | ||
| TV TDI A′ (m/s) | 0.12 ± 0.04 | ||
| MV E (m/s) | 0.86 ± 0.25 | ||
| MV A (m/s) | 0.59 ± 0.21 | ||
| MV TDI S′ (m/s) | 0.09 ± 0.04 | ||
| MV TDI E′ (m/s) | 0.14 ± 0.05 | ||
| MV TDI A′ (m/s) | 0.09 ± 0.10 | ||
| LVEF (%) | 72 ± 11 | ||
|
| |||
| Catheterization | |||
|
| |||
| mPAP (mmHg) | 43 ± 17 | ||
| PVRi (WU/m2) | 10.8 ± 9.3 | ||
| mRAP (mmHg) | 5 ± 2 | ||
| mPAP/mSAP | 0.74 ± 0.31 | ||
| CI (L/min/m2) | 4.2 ± 2.4 | ||
Data are reported as average ± SD or medians with interquartile ranges. εS = total atrial strain, εE = peak positive strain, εA = peak negative strain, EF = ejection fraction, LS = longitudinal strain, RV = right ventricle, SRA = late negative strain rate; SRE = early negative strain rate, SRS = peak positive strain rate. FAC = functional area change, TAPSE = tricuspid annular plane systolic excursion, TR = tricuspid regurgitation, RVP = right ventricular pressure, IVC = inferior vena cava, TV = tricuspid valve, MV = mitral valve, TDI = tissue Doppler imaging, LVEF = left ventricular ejection fraction, mPAP = mean pulmonary arterial pressure, PVRi = pulmonary vascular resistance index, mRAP = mean right atrial pressure, mSAP = mean systolic arterial pressure, CI = cardiac index
Correlations between RA function and traditional Doppler indices, tissue Doppler velocities, and atrial volumes in PH patients
We investigated the relationship between RA functional indices with tricuspid inflow Doppler and annular TDI indices. There was a statistically significant correlation between εE and tricuspid valve TDI E’ (r=0.302, p<0.009) and between εA and tricuspid inflow Doppler A (r=0.419, p<0.0008). There were no significant correlations between RA functional indices and other Doppler indices. The RA maximal volume correlated significantly with εS and εE (r=−0.381, p<0.0002; r=−0.395, (0.0001 respectively), whereas RA minimum volume correlated with all RA functional indices (Table S2).
Correlations between RA function and invasive hemodynamics in PH patients
To investigate potential relationship between the RA function and hemodynamic condition, we correlated mRAP, mPAP, PVRi, and mPAP/mSAP with RA deformation indices from 80 cardiac catheterizations. Significant negative correlation (reported as β ± SE, r-value (p-value)) existed between mPAP and εS (−0.42 ± 0.16, −0.371 (0.01)) and εE (−0.45 ± 0.21, −0.331 (0.0357)) (Figure 2). Statistically significant correlations were also observed between PVRi and εS (−0.20 ± 0.07, −0.390 (0.003)), εE (−0.21 ± 0.09, −0.331 (0.0230)), and εA (−0.29 ± 0.13, −0.320 (0.03)). There were no significant correlations between RA indices and mRAP or mPAP/mSAP (Table S3).
Figure 2.
Correlation between right atrial deformation indices with invasive hemodynamics. Impaired atrial function was found in high mean pulmonary artery pressures and high pulmonary vascular resistance index.
Correlation with RA and RV functional indices with 6MWT and biomarkers in PH patients
To evaluate the functional performance data and severity of PH using biomarkers, we correlated 6MWT, BNP, and NT-pro BNP with RA and RV indices. The εS, εE, RV LS, and FAC had statistically significant correlation with 6MWT, BNP, and NT-pro BNP (Table 3). There was modest correlation with εA with BNP (r= −0.386, p<0.0024). TAPSE had statistically significant negative correlation with 6MWT and BNP (r= −0.517, p<0.0003, r=−0.3, p<0.02 respectively).
Table 3.
Correlations between RA & RV Functional indices with 6MWT and biomarkers
| 6-MWT (N=91) | Log BNP (N= 121) | Log NTproBNP (N=98) | |
|---|---|---|---|
| εS | 2.55 ± 0.97, 0.337 (0.0106) | −0.04 ± 0.01, −0.506, (<0.0001) | −0.04 ± 0.01, −0.465 (0.0019) |
| εE | 3.03 ± 1.35, 0.308 (0.0275) | −0.05 ± 0.01, −0.431, (0.0005) | −0.06 ± 0.02, −0.444 (0.0038) |
| εA | 3.54 ± 1.94, 0.278 (0.0716) | −0.06 ± 0.02, −0.386, (0.0024) | −0.05 ± 0.03, −0.331 (0.0752) |
| SRS | 9.06 ± 10.82, 0.219 (0.4045) | −0.08 ± 0.13, −0.129 (0.5348) | 0.04 ± 0.20, 0.253 (0.8502) |
| SRE | −7.12 ± 11.32, −0.210 (0.5309) | 0.14 ± 0.13, 0.173 (0.2689) | 0.00 ± 0.17, 0.229 (0.9757) |
| SRA | −0.04 ± 11.7, −0.199 (0.9971) | −0.03 ± 0.14, −0.106 (0.8141) | −0.38 ± 0.19, −0.342 (0.0586) |
| RV LS | −8.09 ± 2.81, −0.373 (0.0052) | 0.14 ± 0.03, 0.555 (<0.0001) | 0.18 ± 0.03, 0.639 (<0.0001) |
| FAC | −0.75 ± 0.22, −0.489 (0.0011) | −0.04 ± 0.02, −0.298 (0.0250) | −0.05 ± 0.02, −0.386 (0.0196) |
| TAPSE | −0.037 ± 0.010, −0.517 (0.0003) | −0.79 ± 0.34, −0.300 (0.0243) | −0.80 ± 0.43, −0.333 (0.0721) |
Data are reported as beta ± SE, r-value (p-value). Please see abbreviations from Table 2.
Investigation of RA-RV interaction in PH patients
The bivariate random coefficient model was applied to estimate and correlate random slopes of RA deformation indices with functional RV indices to investigate the mechanism of RA-RV interdependence. This was performed in 45 patients using their first and their last echocardiograms during the study period. Table S4 summarizes the correlations between RA deformation indices with RV LS, FAC, and TAPSE. RV LS were significantly correlated with εS (−0.13 ± 0.04, −0.482 (0.0016)), εE (−0.23 ± 0.08, −0.394 (0.0117)), and εA (−0.18 ± 0.06, −0.441 (0.0044)). Figure 3 portrays the most significant correlations between random slopes of RA and RV variables.
Figure 3.
Correlation between random slopes of right atrial deformation indices and standard right ventricular functional echocardiography indices. Found relationships imply that right ventricular deterioration through the course of disease simultaneously mechanically impair the right atrial function.
Outcome analysis in PH patients
Over the 10 year follow-up, 30 patients had adverse clinical events (4 patients died, 6 underwent clinically indicated septostomy, 14 were started on IV prostacyclin, 3 underwent Pott’s shunt, and 3 had RV failure related hospitalization). The median time to adverse clinical events was 3.6 (2.0–4.7) years. RA reservoir, pump function, the rate of RA filling, and atrial minimum volume predicted adverse clinical outcomes (HR (CI) 0.15 (0.03–0.73), p<0.01; 0.05 (0.003–0.43), p <0.004; 0.04 (0.006–0.56), p<0.01; 8.6 (1.6–37.2), p<0.01 respectively). Specific predictors values are depicted in Figure 4. Traditional Doppler and TDI were not predictive of adverse clinical events.
Figure 4.
Cox proportional hazards analysis is used to model the time to the composite adverse clinical events. Data are reported as hazard ratios with 95% confidence intervals. εS, εA, SRS, and atrial minimum volume predicted adverse clinical outcomes. All variables are adjusted for duration of disease, age, sex, and BSA.
DISCUSSION
Main Study Findings
The data presented here demonstrate that 1) pediatric PH patients have impaired RA function compared to controls, 2) RA deformation indices correlate with functional capacity, biomarkers of PH severity, and invasive hemodynamics, 3) significant trends exist between RA and RV functional changes through the course of PH disease, and 4) RA functional indices have prognostic potential to determine adverse clinical outcomes.
Similar to observations in adults, pediatric PH patients exhibit RA functional impairment relative to controls 6. Unlike adult PH studies of RA function, we found that RA pump function was preserved until late in the course of pediatric PH. Normally the RA promotes high volume low pressure RV inflow, thus preventing hepatic congestion and peripheral edema 15. RV stiffness increases with chronic RV pressure overload, resulting in RV diastolic dysfunction 5. In response to this, the RA contractility (pump function) improves, and RA becomes more distensible (reservoir function) to maintain the filling of the stiffened RV 5. Increase RV stiffness requires higher RA pressure to move a given amount of blood across the tricuspid valve. This results in decreased passive emptying (conduit function) from the RA to the RV and greater reliance on the active pump function of the RA. Depressed RA conduit function is therefore a reflection of impaired RV relaxation or compliance 15. Relative enhancement of active pump function appears to be one compensatory mechanism that compensates for RV failure in chronic PH.
Although TDI E′ of the tricuspid valve correlated with conduit function and tricuspid valve inflow A correlated with active pump function, we did not find them to be predictive of adverse clinical events. RA strain indices derived from speckle tracking were obtained in 99% of our PH cohort (while Doppler and TDI were measurable in 58–68%), so RA strain is potentially a clinically useful adjunct in the evaluation of diastolic dysfunction. Decreased RA reservoir and conduit function correlated with lower functional capacity and higher severity of PH as indicated in worse 6MWT, higher biomarkers, and worse hemodynamics. No correlation was found for RA function with invasive measures of RA pressure, which we speculate might be related to lower mRAP in pediatric PH compared to adult PH patients.25
RA-RV Interactions
As PH progresses, RV hypertrophy and stiffness increase. To a point, RA function can overcome RV diastolic dysfunction sufficiently to blunt right heart failure symptoms. However, RV failure will result in an adverse outcome when it is so severe that the RA can no longer generate enough preload to compensate.
Atrial minimum volume must be maintained during active filling of the RV to compensate for RV failure, so it is not surprising that high RA minimum volume was associated with adverse events in our pediatric PH patients. Atrial emptying fraction did not emerge as a predictor of outcome, probably because it increases with atrial contractility but decreases with high RA minimum volume. RA maximal volumes correlated negatively with reservoir and conduit functions and RA minimum volumes correlated positively with all 3 phases of atrial function, confirming the findings established in adult studies 7, 14.
The current investigation found that as PH progressed, deterioration of all three phases of the atrial function correlate with worsening of in RV LS, FAC, and TAPSE. This type of RA-RV coupled relationship, with increased RV afterload and diastolic dysfunction, has also been observed in patients with repaired Tetralogy of Fallot and adult PH 16, 21. Although RA function correlated with RV LS, RV LS was not a predictor of adverse clinical events in this cohort, but the study may be underpowered to detect this.
RA Function and Outcomes
Our results indicate that diminished RA reservoir and pump function are predictors of overt clinical events in pediatric PH. The normal atrium compensates to maintain ventricular filling with greater atrial compliance and atrial pump function 5, 15, 17. Our findings demonstrate that RA reservoir and pump function, the rate of atrial filling, and minimum atrial volume are better preserved in patients who are free from adverse clinical events. In contrast, those patients with reduced RA function are more likely to experience overt right heart failure and other adverse clinical events as shown in this study. Sakata et al showed that the peak atrial strain and strain rate to be useful for evaluation of right heart failure in adult PH 19. Similar to Sato et al, we found εS to be predictive of clinical worsening7.
A comprehensive right heart evaluation using speckle tracking could be valuable in the assessment of right heart failure in pediatric PH patients. The maintenance of atrial pump function has been demonstrated as an important marker in adult patients with diastolic dysfunction and atrial deformation parameters may be more sensitive markers of heart failure 26–28. In pediatric PH, the RA pump function is preserved until late in the disease, but impairment of reservoir and the conduit function can occur earlier, resulting in an adverse clinical outcome. Incorporating RA functional evaluation may thus provide insights into status of right heart failure in pediatric PH.
Study Limitations
Limitations of this study include those inherent to a retrospective study. We included patients with diverse etiologies of PH and could not meaningfully analyze subgroups due to sample size limitations. 2D atrial speckle tracking echocardiography is technically difficult because the RA has thinner myocardium which can impair signal quality especially in the RA roof. At the present time, there is no speckle-tracking software specific to the RA. We used speckle tracking software developed for left ventricular deformation which has been used previously for measuring RA deformation 18. The RV LS was an apical 4-chamber strain which include the RV lateral wall and the interventricular septum. The interventricular septum is shared between the right and the left ventricle thus hard to determine whether the septum is a RV or LV structure. The analysis was not performed on an RV centric view because this was retrospective analysis.
CONCLUSION
The RA deformation properties are significantly altered in pediatric PH. Progressive worsening of RA reservoir and conduit functions are related to changes in RV diastolic dysfunction. RA pump function is preserved in pediatric PH until late in the disease. RA reservoir and pump function, atrial filling rate, and atrial minimum volume emerged as outcome predictors in pediatric PH patients.
Supplementary Material
Clinical Perspective.
We investigated indices of right atrial (RA) function using two-dimensional speckle tracking echocardiography in pediatric patients with pulmonary hypertension (PH), and tested their association with clinical outcomes. Measurement of atrial deformation is feasible and reproducible in children. Our results demonstrate RA deformation indices to be significantly altered in PH patients compared to controls. Progressive worsening of RA reservoir and conduit function are related to changes in right ventricular diastolic dysfunction in pediatric PH, whereas RA pump function remains relatively preserved. We also found reduced filling and passive emptying of the RA in pediatric PH patients. Among the indices, RA reservoir function, pump function, rate of RA filling, and RA minimum volume emerged as predictors of adverse clinical outcome. RA functional evaluation using two-dimensional speckle tracking may provide incremental quantitative information regarding right heart burden during clinical evaluation of pediatric PH.
Acknowledgments
The authors appreciate the assistance of Karl Stessy Bisselou Moukagna, MS, David A. Danford MD, and Zhaoxing Pan MD PhD.
Sources of Funding: This study is support by the Jayden DeLuca Foundation; the Leah Bult Foundation; the Frederick and Margaret L Weyerhaeuser Foundation; NIH UL1 TR001082.
Footnotes
Disclosures: None
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