Abstract
Background
Elevated right atrial (RA) pressure is an established prognostic measure in pulmonary arterial hypertension (PAH). However, little is known about perturbations in RA function in PAH.
Methods and Results
Reservoir (RA longitudinal strain [RA LS]), conduit (RA early longitudinal strain rate [LSR]), and active (RA late LSR) phases were assessed by 2D speckle tracking in 65 patients with PAH, 6-minute walk distance ≤ 450 meters, and a PVR >800 dynes·sec·cm−5 despite therapy with at least two PAH-specific medications enrolled in the Imatinib in Pulmonary arterial hypertension, a Randomized Efficacy Study (IMPRES) trial, and were compared to 30 healthy controls of similar age and sex. We studied the association of RA functional measures with invasive pulmonary hemodynamics, cardiac structure and function, and NT-proBNP. RA LS and early LSR were reduced in PAH patients compared to controls (27.1±11.6 vs 56.9±12.7, adjusted p<0.001 and −0.6±0.5 vs −1.5±0.5, adjusted p<0.001, respectively) even after adjusting for RA area and invasive RA pressure, while RA late SR was similar between groups (−1.4±0.7 vs −1.5±0.4, p=0.42). Among PAH patients, worse RA LS correlated with greater RA size (r=−0.50, p<0.0001) and pressure (r=−0.37, p=0.002), but not pulmonary artery pressure (r=−0.07, p=0.58). Worse RA LS was also associated with right ventricular enlargement and dysfunction and higher NT-proBNP independent of RA size and pressure.
Conclusions
RA reservoir and passive conduit functions are impaired in PAH, independent of RA size and pressure, and likely reflect RV failure and overload.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174.
Keywords: pulmonary heart disease, echocardiography, pulmonary hypertension, trials
Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance (PVR)1 secondary to pulmonary vascular remodeling, with resulting in right ventricular (RV) dilatation and dysfunction.2,3 Once present, RV failure is associated with a heightened risk of mortality. Elevated right atrial pressure (RAP) reflects RV overload in PAH and is an established risk factor for mortality.4,5 RA size is prognostic of adverse outcomes in PAH,6 in addition to other cardiovascular conditions such as heart failure with reduce ejection fraction and RV dysfunction.7 However, little is known about the prevalence and correlates of RA dysfunction in PAH.8,9
Strain imaging allows for the quantitative assessment of cardiac deformation. While initially developed to assess left ventricular (LV) function, it has also been used to assess RV,10 left atrial,11 and more recently RA function.12 We hypothesized that RA reservoir, conduit and active function are impaired in PAH compared to controls, and that among patient with advanced PAH, impaired RA LS reflects RV decompensation.
Methods
Study Population
We studied patients with advanced PAH enrolled in the echocardiographic substudy of the Imatinib in PAH, a randomized, efficacy study (IMPRES) trial.13 The IMPRES trial was a multicenter (71 sites, 14 countries) trial that enrolled 202 adult patients with Group 1 pulmonary hypertension,1 decreased exercise capacity defined by a 6-minute walk distance ≤ 450 meters, and a pulmonary vascular resistance <800 dynes·sec·cm−5 despite optimal treatment with at least two PAH-specific therapies (endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin or prostacyclin analogues). Patients were excluded if they had a prolonged QTc (>450 msec for males and >470 msec for females), syncope in the prior 3 months, or history of a bleeding disorder. Patients were randomized 1:1 to imatinib or placebo. Participation in the echocardiography sub-study of the IMPRES trial was voluntary and offered to all participating sites, as previously described in detail.13 We analyzed echocardiograms performed at the baseline study visit. Patients in atrial fibrillation were excluded from this analysis. The study protocol was approved by the Institutional Review Boards of all participating institutions and all patients provided written informed consent, which included consent for the echocardiographic analysis.
As previously described,14 we retrospectively identified 30 healthy control subjects with similar age and sex to the PAH patients included in the IMPRES cohort from patients referred to the echocardiographic laboratory at the Brigham and Women’s Hospital (BWH) to serve as a healthy comparator group. Patients were referred for echocardiography for any of the following indications: murmur, evaluation of LV function, syncope, or atypical chest pain. Subjects we included if they were free of cardiovascular disease or cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, smoking, renal dysfunction), were not taking any cardiovascular medications, were free of significant systemic diseases by retrospective review of the electronic medical record, and had adequate image quality with an LVEF>55%, no regional wall motion abnormalities, and no other cardiac structural or functional abnormality based on current recommendations of the American Society of Echocardiography (ASE)15. The BWH Institutional Review Board approved the study protocol.
Standard Echocardiographic Methods
Details of the IMPRES echocardiography sub-study, including reproducibility metrics, have been previously published.13 Briefly, all IMPRES patients underwent an echocardiography following the same echocardiographic protocol. RV functional measures, including tricuspid annular peak systolic velocity (TA S’), tricuspid annular plane systolic excursion (TAPSE), RV Tei index, and RV fractional area change (RVFAC) were measured in accordance with the ASE guidelines.16 Right heart size was quantified as RV diastolic area and RA area at end-systole. Tricuspid regurgitation (TR) severity was assessed by measuring the “jet area” of the TR and graduated as none, mild (TR area <5 cm2), moderate (TR area between 5–10 cm2) and severe (TR area > 10 cm2).17 LV volumes and ejection fraction (EF), and diastolic measures were assessed according to ASE recommendations.15,18
Strain Analysis
Digitally acquired baseline echocardiographic images in DICOM format with acceptable image quality were uploaded to the Tomtec system (Munich, Germany). Strain analysis was performed in all studies with adequate image quality. Inadequate quality was defined as poor visualization or poor tracking of two or more atrial segments. RV performance by speckle tracking we calculated RV free wall longitudinal strain (FWLS) as previously described.14 For RA deformation, the RA endocardial border was traced at ventricular end-systole in the apical four-chamber view. The software then tracks speckles along the endocardial border throughout the cardiac cycle and derives the longitudinal strain (LS) and longitudinal strain rate (LSR). Three different LSR measures are calculated: 1) peak LSR which is coincident with RV systole and reflects the maximal RA distension; 2) early LSR which is coincident with RV E wave and reflects the passive RA emptying; and 3) late LSR which is coincident with RV A wave and reflects active RA emptying. The following phasic RA volumes were also determined: 1) RA maximal volume; 2) RA pre-emptying volume which is measured at the beginning of the p wave of the ECG; and 3) RA minimal volume. RA emptying fraction was defined as: (RA maximal volume – RA minimal volume)/RA maximal volume. RA passive emptying fraction was defined as: (RA maximal volume – RA pre-emptying volume)/ RA maximal volume. RA active emptying fraction was defined as: (RA pre-emptying volume – RA minimal volume)/ RA pre-emptying volume. To assess the contribution of each RA emptying phase to the total RV filling, we also calculated the ratio of RA passive and active emptying fraction to the total RA emptying fraction. As previously published,9 three different phases of RA function can be defined (Figure 1): 1) Reservoir function which reflects the ability of the RA to distend and is assessed by the RA LS, RA peak LSR, and RA emptying fraction; 2) Conduit function which reflects the passive emptying phase of the RA as a result of tricuspid valve opening and RV relaxation and is assessed by RA early LSR and RA passive emptying fraction; and 3) RA active contraction which is assessed by RA late LSR and RA active emptying fraction.
Figure 1.
Representative examples of right atrial measurements in a patient with PAH. (A) RA endocardial trace at RV end-systole; (B) RA longitudinal strain (LS); (C) RA time-volume curve: RA maximal volume (Max), RA pre-emtying volume (Pre) and RA minimal volume (Min); (D) RA longitudinal strain rate (LSR): peak LSR, early LSR and late LSR. RA LS: RA longitudinal strain; RA Max Vol: RA maximal volume; RA Pre Vol: RA preejective volume; RA min vol: RA minimal volume; LSR: longitudinal strain rate
All measurements were performed by a single investigator blinded to clinical status. Intra-observer variability for RA LS was assessed in a sample of 30 randomly selected patients (20 subjects from the IMPRES group and 10 subjects from the control group). The coefficients of variation for RA measures were as follows: RA LS 11%, peak LSR 17%, early LSR 20%, late LSR 25%.
Right Heart Catheterization
All IMPRES patients underwent right heart catheterization on the same day as baseline echocardiography as previously described.13,14 Invasive hemodynamic measurements were not available in the control group.
Statistical Analysis
Continuous variables are presented as mean and standard deviation or median and first and third quartiles if not normally distributed. Categorical variables are presented as percentages. Comparisons between PAH patients and controls were performed using a Student’s t-test for continuous normally distributed variables, Mann-Whitney test for continuous non-normally distributed variables, and a Fisher exact test for categorical variables. Additional comparison of between group differences was performed using multivariable linear regression adjusting for RA maximal area and maximum IVC width, an established echocardiographic surrogate of RA pressure. Finally, between group comparisons were performed after additional multivariable adjustment for the following demographic, clinical and echocardiographic variables that may influence RA size or function: age, sex, body mass index (BMI), heart rate, systolic blood pressure, maximal RA area, maximal IVC width, right ventricular function as measured by RVFAC, and TR severity. In a sub-group analysis, we further divided the PAH group into normal RA size (RA area <18 cm2)15 and enlarged RA (RA area ≥ 18 cm2). In addition, given the differences in race/ethnicity between the control group and PAH subjects, we performed a sensitivity analysis restricted to white control and PAH subjects. Among patients with PAH, we determined the association between RA LS and invasive hemodynamic measurements, NT-proBNP, and echocardiographic measures of RV structure and function using Pearson’s correlation and after adjustment for RA maximal volume using multivariable linear regression. All analyses were performed using STATA 12.0 (StataCorp LP. 2009. Texas).
Results
Of the 74 patients included in the echocardiographic sub-study, RA function could be assessed in 65. Six studies could not be analyzed due to technical issues, 2 patients could not be analyzed due to inadequate quality, and 1 patient was excluded due to atrial fibrillation (Figure 2). Patients included in the strain study did not significantly differ from the overall IMPRES population in demographics, clinical characteristics, or invasive hemodynamics at baseline.
Figure 2.
Study population, including IMPRES patients with PAH and healthy controls.
PAH patients from the IMPRES study were 50.0 ± 13.6 years old, white (100%), and the majority were women (83%; Table 1). No significant differences in age, sex, or BMI were noted between the PAH and control groups. However, patients with PAH showed significantly lower blood pressure, higher heart rate and severely impaired RV function based on echocardiographic measurements. Patients with PAH also had significantly larger RA area compared to controls (15.0 ± 4.7 cm2 vs 8.5 ± 1.4 cm2, p<0.001) and larger inferior vena cava (IVC) diameter. Among PAH patients, those with enlarged RA compared to those with normal RA size were older, had lower RV stroke volume, higher NT-proBNP, worse RV function (reflected in lower RVFAC and RV FWLS, and more severe tricuspid regurgitation (Table 2).
Table 1.
Demographic, clinical, hemodynamic and echocardiographic characteristics in Control group versus PAH group
| CONTROLS (n=30) |
PAH (n=65) |
P value | |
|---|---|---|---|
| Age (years) | 49.2±12.3 | 50.0 ± 13.6 | 0.71 |
| Female (%) | 20 (67) | 54 (83) | 0.11 |
| White (%) | 20 (67) | 65 (100) | 0.0001 |
| BMI | 23.9±3.9 | 25.4 ± 5.5 | 0.14 |
|
| |||
| WHO class (class III–IV) | 0 | 41 (63) | NA |
|
| |||
| SBP (mmHg) | 124±12 | 108±17 | <0.0001 |
| DBP (mmHg) | 71±9 | 64±15 | 0.04 |
| HR (bpm) | 69±11 | 79±12 | <0.0001 |
|
| |||
| NT-proBNP | – | 121 [44 227] | – |
|
| |||
| 6 MWDT (meters) | – | 357±73 | – |
|
| |||
|
Right Heart Catheterization
| |||
| RAP (mmHg) | – | 10±5 | – |
| MPAP (mmHg) | – | 61±12 | – |
| PCWP (mmHg) | – | 10±3 | – |
| PVR (dy.sec/cm5) | – | 1131 [935 1350] | – |
| RV SVI (ml/m2) | – | 27.2±6.6 | – |
|
| |||
|
Echocardiography: Right side (morphology and function)
| |||
| RA area index (cm/m2) | 8.5 ± 1.4 | 15.0 ± 4.7 | 0.001 |
| IVC max (cm) | 1.6 ± 0.4 | 1.9 ± 0.5 | 0.005 |
| RVEDA (cm2) | 19.7 ± 4.5 | 35.8 ± 11.7 | <0.0001 |
| RVFAC (%) | 54 ± 6 | 22 ± 8 | <0.0001 |
| Tei Index | 0.24 ± 0.14 | 0.69 ± 0.21 | <0.0001 |
| TAPSE (cm) | 2.15 ± 0.11 | 1.75 ± 0.38 | 0.04 |
| TA S’ (cm/sec) | 14.2 ± 2.3 | 10.5 ± 2.5 | <0.0001 |
| RV FWLS (%) | −30.8 ± 4.3 | −16.1 ± 5.3 | 0.0001 |
| TR severity: mild (%) | 16 (54) | 31 (48) | <0.0001 |
| Moderate/severe (%) | 0 | 34 (52) | |
|
| |||
|
Echocardiography: Left side (morphology and function)
| |||
| LA volume index (cm/m2) | 23.9 ± 7.2 | 18.4 ± 6.7 | 0.0001 |
| LVEDV (ml) | 93.1 ± 20.1 | 70.0 ± 20.3 | 0.0001 |
| LVEF (%) | 61 ± 5 | 58 ± 6 | 0.02 |
| Ewave (cm/sec) | 78.6 ± 11.3 | 67.3 ± 18.1 | 0.004 |
| E/E’ | 6.58 ± 1.71 | 7.11 ± 3.13 | 0.41 |
Table 2.
Demographic, clinical, hemodynamic and echocardiographic measures among PAH patients with normal right atrial size and with right atrial enlargement.
| PAH-Normal RA (n=11) | PAH-Enlarged RA (n=54) | Unadjusted P value | |
|---|---|---|---|
| Age (years) | 58 ± 11 | 48 ± 13 | 0.04 |
| Female (%) | 10 (91) | 45 (82) | 0.45 |
| White (%) | 11 (100) | 55 (100) | 0.65 |
| BMI | 22.7 ± 3.3 | 25.9 ± 5.7 | 0.07 |
|
| |||
| WHO class (class III–IV) | 5 (46) | 37 (67) | 0.31 |
|
| |||
| SBP (mmHg) | 113 ± 19 | 107± 16 | 0.31 |
| DBP (mmHg) | 66± 11 | 64 ± 15 | 0.65 |
| HR (bpm) | 73 ± 8 | 81 ± 14 | 0.07 |
|
| |||
| 6 MWDT (meters) | 386 ± 55 | 353 ± 75 | 0.17 |
|
| |||
|
Right Heart Catheterization
| |||
| RAP (mmHg) | 7 ± 4 | 12 ± 9 | 0.12 |
| MPAP (mmHg) | 57 ± 11 | 61 ± 12 | 0.23 |
| PCWP (mmHg) | 9 ± 3 | 10 ± 3 | 0.63 |
| PVR (dy.sec/cm5) | 1083 [912 1224] | 1138 [935 1371] | 0.37* |
| RV SVI (ml/m2) | 3.2 ± 0.02 | 2.6 ± 0.01 | 0.008 |
|
| |||
| NT-proBNP | 29 [19 56] | 149 [54 244] | 0.0002† |
|
| |||
|
Echocardiography: Right side (morphology and function)
| |||
| RA area index (cm/m2) | 10.0 ± 1.4 | 16.0 ± 4.7 | 0.0001 |
| IVC max (cm) | 1.7 ± 0.4 | 1.9 ± 0.5 | 0.20 |
| RVEDA (cm2) | 25.5 [22.6 26.8] |
35.8 [29.8 41.1] |
<0.0001* |
| RVFAC (%) | 29 ± 5 | 21 ± 8 | 0.002 |
| Tei Index | 0.55 ± 0.23 | 0.72 ± 0.20 | 0.02 |
| TAPSE (cm) | 1.88 ± 0.33 | 1.70 ± 0.39 | 0.21 |
| TA S’ (cm/sec) | 10.9 ± 1.2 | 10.4 ± 2.7 | 0.57 |
| RV FWLS (%) | −20.8 ± 2.7 | −14.9 ± 5.4 | 0.003 |
| TR severity: mild (%) | 9 (82) | 23 (42) | 0.0001 |
| Moderate/severe (%) | 2 (18) | 31 (58) | |
|
| |||
|
Echocardiography: Left side (morphology and function)
| |||
| LA volume index (cm/m2) | 22.1 ± 4.7 | 17.6 ± 6.7 | 0.10 |
| LVEDV (ml) | 81.8 ± 20.4 | 67.1 ± 19.4 | 0.04 |
| LVEF (%) | 60 ± 6 | 58 ± 6 | 0.28 |
| Ewave (cm/sec) | 68 ± 16 | 68 ± 19 | 0.96 |
| E/E’ | 7.0 ± 2.2 | 7.1 ± 3.3 | 0.93 |
Based on Mann-Whitney test.
Based on t-test performed with log-transformed values
Right atrial reservoir function
Compared to controls patients with PAH had significantly impaired RA reservoir function as reflected by impaired RA LS (56.9 ± 12.7 vs 27.1 ± 11.6, p<0.0001), RA peak LSR (2.07 ± 0.55 vs 1.40 ± 0.63, p<0.0001), and RA emptying fraction (66 ± 10 vs 55 ± 15, p<0.0001; Table 3). All differences were independent of age, sex, BMI, systolic blood pressure and heart rate, but only differences in RA LS remained significant after additionally adjusting for RA area, IVC width, RVFAC and TR severity. The between group difference in RA strain remained significant when adjusting for Tei index instead of RVFAC as a measure of RV function in the multivariable model (p=0.002), although the between group difference did not achieve statistical significance when adjusting for RV FWLS instead of RVFAC as measure of RV function (p=0.21). In a sub-group analysis, RA LS and RA peak LSR remained significantly impaired in the PAH patients with normal RA size (n=11) compared to controls (Figure 3; Supplemental Table 1), while RA emptying fraction was not significantly different. Concordant results were seen for the RA reservoir function in a sensitivity analysis excluding non-white subjects from the control group (Supplemental Table 2).
Table 3.
Measurements of RA function in Control group versus PAH group.
| Controls (n=30) |
PAH (n=65) |
Unadjusted P value | |
|---|---|---|---|
|
RA reservoir function
| |||
| RA LS (%) | 56.9 ± 12.7 | 27.1 ± 11.6 | <0.0001*,† |
| RA peak LSR (%) | 2.1 ± 0.6 | 1.4 ± 0.6 | <0.0001* |
| RA total emptying fraction (%) | 66 ± 10 | 51 ± 15 | <0.0001* |
|
| |||
|
RA conduit function
| |||
| RA early LSR (%) | −1.5 ± 0.5 | −0.6 ± 0.5 | <0.0001*,† |
| LA passive emptying fraction (%) | 39 ± 12 | 13 ± 16 | <0.0001* |
| RA passive emptying fraction/RA total emptying fraction | 59 ± 14 | 22 ± 36 | <0.0001* |
|
| |||
|
RA active function
| |||
| RA late LSR (%) | −1.5 ± 0.4 | −1.4 ± 0.7 | 0.42 |
| RA active emptying fraction (%) | 44 ± 13 | 43 ± 15 | 0.82 |
| RA active emptying fraction/RA total emptying fraction | 66 ± 14 | 86 ± 22 | <0.0001* |
P value<0.05 after adjusting for age, sex, BMI, HR, SBP.
P value<0.05 after adjusting for age, sex, BMI, heart rate, systolic blood pressure, RV function assessed as RVFAC, tricuspid regurgitation severity, RA area and maximal IVC width.
RA: right atrial, LS: longitudinal strain; LSR: longitudinal strain rate
Figure 3.
Right atrial longitudinal strain in Control group versus patients with PAH with normal right atrium and patients in the IMPRES group with enlarged RA. *Based on T-test comparison.
Right atrial conduit and active function
Measures of passive conduit function, RA early LSR and RA passive emptying fraction, as well as the RA passive emptying fraction/total RA emptying fraction ratio – which reflects the contribution of RA passive emptying to total RA emptying – were significantly impaired in PAH patients compared to controls (Table 3). In contrast, measures of active contraction, RA late LSR and RA active emptying fraction, did not significantly differ in PAH patients compared to controls (Table 3). The RA active emptying fraction/RA total emptying fraction ratio was significantly higher in among PAH patients (Table 3), reflecting a greater relative contribution of the active phase to the RA total emptying fraction in PAH. Sensitivity analysis excluding non-white subjects from the control group demonstrated concordant results with the primary analysis with respect to RA active and conduit function (Supplemental Table 2).
Relationship of RA LS with RV structure and function, pulmonary hemodynamics, and biomarkers in PAH
RA LS was moderately correlated with RA maximal area (Pearson’s r=−0.50, p<0.0001), and was more modestly correlated with RAP (Pearson’s r= −0.37, p=0.002; Table 4). RA LS was associated with invasively measured RV stroke volume, with echocardiographic measures of RV longitudinal function such as RV FWLS and TAPSE, and with indirect measures of RV overload including RV end diastolic area, the RV:LV area ratio, and the diastolic LV eccentricity index. Worse RA LS also correlated with higher NT-proBNP. Adjustment of tricuspid regurgitation severity did not substantively alter the association between RA LS and RA size or pressure, echocardiographic measurements of RV function, or NT-proBNP. Despite associations with RV dysfunction and overload, RA LS was not associated with invasively measured MPAP or PVR.
Table 4.
Correlation between RA longitudinal strain and RA size, RA pressure, invasively measured pulmonary hemodynamics, measures of RV systolic function (invasive and echocardiographic) and measures of inferred RV overload (echocardiographic and NT-proBNP).
| Right atrium longitudinal strain Pearson’s correlation (P value) |
|
|---|---|
| Right Atrial Measures | |
|
| |
| Invasive RA pressure | −0.37 (p=0.002) |
| RA area | −0.50 (p<0.0001) |
|
| |
| Pulmonary Invasive Hemodynamics | |
|
| |
| Mean pulmonary artery pressure | −0.07 (p=0.58) |
| Pulmonary vascular resistance | −0.04 (p=0.74) |
|
| |
| Measures RV systolic function | |
|
| |
| Invasive RV stroke volume index | 0.29 (p=0.02) |
| RV free wall longitudinal strain | −0.48 (p=0.0002)† |
| Tricuspid annular plane systolic excursion | 0.44 (p=0.008)† |
| Tricuspid annular peak systolic velocity | 0.24 (p=0.06) |
| RV fractional area change | 0.13 (p=0.32) |
| RV Tei Index | −0.17 (p=0.20) |
|
| |
| Measures of inferred RV overload | |
|
| |
| RV end diastolic area | −0.40 (p=0.001) |
| Ratio RV area to LV area | −0.33 (p=0.01) |
| Eccentricity Index | 0.28 (p=0.02) |
| NT-proBNP* | −0.55 (p<0.0001)† |
Based on log-transformed values.
Significant (p<0.05) after adjusting by RA area
Discussion
In patients with severe PAH, RA function is impaired compared to healthy controls, as reflected by lower values of RA LS independent of RA size. The impairment in RA LS is mainly due to a significant reduction in RA passive reservoir and conduit functions, while RA active function is preserved and has a greater relative contribution to RV diastolic filling. Independent of its associations with RA size and pressure, impaired RA LS is associated with RV dysfunction and overload but not pulmonary hemodynamics.
RA LS was reduced in PAH patients compared to controls, even in the 11 PAH patients with preserved RA size suggesting that RA function may play a role in the progression of PAH. Both reservoir function, occurring coincident with ventricular contraction, and conduit function, corresponding to rapid passive ventricular filling due to tricuspid valve opening, were impaired in PAH compared to controls. In contrast, RA contraction was preserved in PAH compared to controls and responsible for a greater proportion of RV diastolic filling in PAH, likely as a compensatory mechanism for the reduced passive conduit emptying. Similar results were previously described by Willens et al.8 in a group of PAH patients. That group also described similar adaptations associated with aging. Interestingly, a similar pattern of alteration in atrial phasic function has also been described for LA function in the presence of severe aortic stenosis, where LV filling becomes highly dependent of LA contraction. These findings suggest that the loss of this compensatory mechanism, either due to atrial fibrillation or possibly RA fatigue, may play an important role in the prognosis of patients with PAH.
RA LS showed moderate correlations with RA size measured by echocardiography and with RAP measured invasively, both of which have demonstrated prognostic value in PAH.5,6 These associations suggest that RA LS may also provide prognostic information in these patients. Interestingly, parallel associations have been observed with LA strain in patients with LV failure. Cameli et al.19 showed that LA LS is associated with invasive pulmonary capillary wedge pressure in patients with left heart failure, and proposed LA LS as an estimator of LA filling pressures.
RA LS did not showed associations with invasive pulmonary hemodynamics. In contrast, RA LS was significantly correlated with RV longitudinal function (RV FWLS and TAPSE) and with measures of RV overload including NT-proBNP. These findings suggest that impaired RA function may manifest in PAH primarily when the RV becomes overloaded and begins to fail. Indeed, RV failure is one of the most important risk factors for death in PAH. However, RV structure and function have been difficult to reliably assess in PAH by echocardiography likely due to distortion of the already complex geometry of the RV in these patients.1 The RA is a simpler geometric structure and it is therefore possible that RA LS may provide a simpler, easier, more reliable, and faster non-invasive measure of RV decompensation and – potentially – prognosis than other standard echocardiographic RV measurements. In our study of patients with advanced PAH, assessment of RA deformation was faster and feasible in a greater proportion of patients than were quantitative measures of RV function (97% versus 88% respective), particularly among patients with a massively dilated RV that was unable to be fully included in the echo acquisition window. However, it is still too early to claim incremental value of RA deformation assessment beyond conventional assessment of RA size.
Several limitations of this post-hoc analysis should be noted. We have analyzed RA function measures using an LV specific software, as no vendor-independent commercial software was available for dedicated RA analysis by deformation imaging at the time of this study. Importantly, although validation of speckle-tracking echocardiography based measures of LS with sonomicrometry or MRI have been performed for the LV, the use of such software initially developed for the LV to assess the RV is well established,20 and previous studies have shown the validity of such software in the analysis of LA strain11,19 and RA strain.12 RV diastolic pressures was not assessed, limiting our ability to study the potential association of RV diastolic pressure with RA function and its potential contribution to the observed between group differences in RA function. Intra-reader reproducibility of RA LS was acceptable, while intra-reader variability of RA LSR measurements (particularly late LSR) was higher and should therefore be interpreted with caution. Finally, IMPRES was not powered for outcomes limiting our ability to study the predictive value of measurements of RA deformation.
Conclusions
RA reservoir and passive conduit functions are impaired in PAH, independent of RA size and pressure. Worse RA LS in PAH is associated with greater RV dysfunction and overload, but not with pulmonary hemodynamics. Additional studies are necessary to determine whether RA LS has prognostic value in PAH.
Supplementary Material
Clinical Perspective.
Elevated right atrial (RA) pressure is an established prognostic measure in pulmonary arterial hypertension (PAH), but little is known about perturbations in RA function in PAH. We used deformation imaging to characterize RA function in 65 patients with advanced PAH compared to 30 healthy controls of similar age and sex, and related these measures to pulmonary hemodynamics, cardiac structure and function, and NT-proBNP. RA function was impaired in PAH compared to healthy controls, as reflected by lower values of RA longitudinal strain independent of RA size. The impairment in RA longitudinal strain was mainly due to a significant reduction in RA passive reservoir and conduit functions, while RA active function was preserved and had a greater relative contribution to RV diastolic filling. Independent of its associations with RA size and pressure, impaired RA longitudinal strain was associated with RV dysfunction and overload but not pulmonary hemodynamics. The RA is a simpler geometric structure than the RV, and it is possible that RA longitudinal strain may provide an easier, more reliable, and faster non-invasive measure of RV decompensation and – potentially – prognosis than other standard echocardiographic RV measurements. However, additional studies are necessary to determine whether RA LS has prognostic value in PAH, and it remains too early to claim incremental value of RA deformation assessment beyond conventional assessment of RA size clinically.
Acknowledgments
Sources of Funding: The IMPRES trial was sponsored by Novartis. The work for this manuscript was also supported by NHLBI grant 1K08HL116792 (A.M.S.) and American Heart Association grant 14CRP20380422 (A.M.S.).
Disclosures: Drs Shah and Solomon have received research support from and have consulted for Novartis.
Footnotes
The remaining authors report no relevant financial conflicts.
References
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