Background
Right ventricular function is a strong determinant of prognosis in severe pulmonary hypertension.
Methods
The aim of this study was to evaluate the prognostic value of estimates of right ventricular function obtained by echocardiography and Doppler tissue imaging and of functional class and 6-min walk distance (6MWD) in 142 patients with either pulmonary arterial hypertension ( n = 104) or chronic thromboembolic pulmonary hypertension ( n = 38). Echocardiography was prospectively performed, and demographics, medications, associated medical conditions, New York Heart Association class, and 6MWD at inclusion in addition to vital status, transplantation, and hospital admission related to pulmonary hypertension at follow-up were then collected by review of the medical records.
Results
Variables associated with overall survival by univariate analysis were 6MWD ( P = .009), functional class ( P = .024), tricuspid annular plane systolic excursion ( P = .03) and isovolumic peak velocity at the tricuspid annulus (IVCv) ( P = .003). On multivariate analysis, IVCv ( P = .015) and 6MWD ( P = .016) were the only independent predictors of survival. Kaplan-Meier estimates of survival at 1 year were 95% in patients with IVCv > 9 cm/sec and 80% in those with IVCv ≤ 9 cm/sec ( P = .002). Intraobserver and interobserver variability of IVCv measurement were 5% and 9%, respectively.
Conclusions
Measurement of right ventricular function by Doppler tissue imaging, an easy, noninvasive, and reproducible method, is an independent predictor of clinical outcomes in patients with severe pulmonary hypertension.
Despite major advances achieved with the introduction of targeted medical therapies, the prognosis of pulmonary arterial hypertension (PAH) remains poor, with a 3-year survival rate of approximately 65%. The prognosis of medically treated inoperable chronic thromboembolic pulmonary hypertension (CTEPH) is also poor, with a reported median survival time of 5 to 6 years. In both PAH and CTEPH, predictors of outcomes have been shown to be related to the functional state of the right ventricle and cardiac index rather than to the severity of pulmonary vasculopathy as defined by pulmonary artery pressure (PAP) or pulmonary vascular resistance. However, right ventricular (RV) function measurements during standard right-heart catheterization are limited to right atrial pressure, cardiac output, and PAP or pulmonary vascular resistance, which are imperfect surrogates of preload, contractility, and afterload.
Recent studies have shown that RV function adaptation to pulmonary hypertension is initially systolic, with further diastolic and dimensional changes when contractility fails to remain coupled to afterload. This has been illustrated by magnetic resonance imaging coupled to RV pressure measurements showing increased end-systolic elastance (contractility) to match increased arterial elastance (afterload) for the preservation of RV-arterial coupling in patients with advanced PAH but no clinical signs of RV failure.
Several indices of both systolic and diastolic function of the right ventricle can be obtained by echocardiography with or without Doppler tissue imaging (DTI). Many of these indices have shown sensitivity to prognosis and to therapeutic interventions in PAH. Awaiting further validation, only two of them are recommended for the definition of therapeutic goals in guidelines: tricuspid annular plane systolic excursion (TAPSE) as an index of systolic function and pericardial effusion, presumably as an index of failed diastolic function with increased filling pressures.
In an attempt to identify novel noninvasive predictors of outcomes related to RV function, we evaluated the prognostic relevance of echocardiographic and DTI measurements of systolic function, compared with previously reported functional, exercise capacity, and standard echocardiographic predictors of survival, in medically treated patients with PAH and CTEPH in a cohort with predominantly severe disease. We focused on isovolumic contraction phase measurements, because they have been proposed as relatively load independent indices of RV contractility, and on longitudinal strain, an indicator of global RV contractility. Our hypothesis was that these indices of RV systolic function would emerge as predictors of outcomes and survival.
Methods
Study Population
One hundred forty-two patients who underwent echocardiography for the evaluation of pulmonary hypertension were prospectively screened at two institutions: Louis Pradel University Hospital, Lyon, France (91 patients), and Erasme University Hospital, Brussels, Belgium (51 patients). The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.
In all patients, a diagnosis of PAH or inoperable CTEPH had been made following the currently recommended stepwise approach, with right-heart catheterization confirming a mean PAP ≥ 25 mm Hg at rest and a pulmonary capillary wedge pressure <15 mm Hg. Inoperability of CTEPH was evaluated on the basis of pulmonary angiographic results and expert multidisciplinary advice.
Entry into the cohort was defined as the date of echocardiography. Echocardiography was prospectively performed, and demographics, medications, associated medical conditions, New York Heart Association (NYHA) class, and 6-min walk distance (6MWD) at inclusion in addition to vital status, transplantation, and hospital admission related to pulmonary hypertension at follow-up were then collected by review of the medical records. Because of the observational nature of this study, right-heart catheterization was not repeated at inclusion.
Exclusion criteria were as follows: age <18 years, unstable severe pulmonary hypertension, arrhythmia, pulmonary hypertension associated with lung diseases and/or hypoxemia, left-heart disease including severe valvular heart disease and systolic dysfunction (defined as a left ventricular ejection fraction <45%), terminal malignancies, and poor acoustic window.
Echocardiography
Transthoracic echocardiography was performed using similar commercially available ultrasound systems at both centers (Vivid 7, GE Vingmed Ultrasound AS, Horten, Norway). Acquisitions were digitally stored in raw data format for offline analysis (EchoPAC; GE Vingmed Ultrasound AS). Analysis was performed at a single core lab (Louis Pradel Hospital) by two observers, who were blinded to the patients’ clinical status.
Left ventricular dimensions were measured according to the current guidelines. Left ventricular ejection fraction was calculated using the modified Simpson’s biplane method. RV basal diameter and left ventricular diameter were measured at end-diastole in the apical four-chamber view to calculate the ratio of RV to left ventricular diameter. The left ventricular diastolic eccentricity index was measured from the parasternal short-axis view at the mid left ventricular level. Left and right atrial areas were measured by planimetry on the apical four-chamber view. Right atrial area was indexed to height as previously described.
Using pulsed Doppler, we measured cardiac output using aortic time-velocity integral, mitral inflow velocities (E and A), early mitral annulus velocity (e′) at the lateral site of the mitral annulus and pulmonary acceleration time using the RV outflow tract velocity profile. Left ventricular filling pressure was assessed on the value of left atrial area in addition to the E/A and E/e′ ratios. In addition, the presence or absence of midsystolic pulmonary notching was noted.
Systolic PAP was calculated by adding the systolic transtricuspid pressure gradient assessed on peak tricuspid regurgitation velocity and right atrial pressure. Evaluation of right atrial pressure was estimated from the size of the inferior vena cava and its inspiratory collapsibility. Finally, the presence of pericardial effusion was noted.
Study of RV Function
The study of RV function is summarized in Figure 1 . TAPSE was measured on the M-mode tracing obtained from the apical four-chamber view. Pulsed DTI at the lateral site of the tricuspid annulus was acquired from the apical four-chamber view to measure the following parameters: isovolumic contraction peak velocity at the tricuspid annulus (IVCv), isovolumic acceleration (IVA), systolic velocity (S′), isovolumic relaxation time (IVRT), and early diastolic (E′) and atrial contraction (A′) peak velocities. The instantaneous IVA was measured on the same velocity profile obtained by pulsed DTI at the lateral site of the tricuspid annulus as the difference between the baseline and the peak velocity divided by their time interval during the isovolumic period. DTI recording of the right ventricle was performed using an apical four-chamber view centered on RV free wall with a high frame rate (240 frames/sec). Peak systolic longitudinal strain of the RV free wall was measured at the basal, mid, and apical segments. The average of these three values (ϵ mean ) was calculated. All measurements were performed on three consecutive cycles, and the mean value was calculated.
Angle-dependant parameters, including TAPSE, velocity profile using pulsed DTI at the lateral site of the tricuspid annulus, and longitudinal strain, were obtained with the optimal angle of incidence available (with a predetermined range of angle of incidence <20° off angle).
To define the reproducibility of RV functional parameters, 20 patients were randomly selected. RV functional analysis was repeated three months apart by the same observer and was performed by a second blinded observer. Interobserver and intraobserver variability were calculated as the difference between the two observations divided by the means of the observations and expressed as percentages. Intraobserver and interobserver variability were 6% and 7% for S′, 9% and 11% for TAPSE, 6% and 11% for ϵ mean , 5% and 9% for IVCv, and 19% and 43% for IVA, respectively.
Feasibility of RV function parameters measurements was 98% for TAPSE; 95% for IVCv, IVA, S′, and IVRT; and 97%, 96%, and 97% for longitudinal strain at the basal, mid, and apical level, respectively.
Statistical Analysis
Follow-up duration was the time interval from the date of echocardiography to the last visit or death. Overall survival was estimated using the Kaplan-Meier method. Continuous data are expressed as mean ± SD if normally distributed; data deviating from normality are expressed as median (interquartile range) and categorical variables as absolute and relative (percentage) frequencies.
On the basis of prior literature and potential clinical relevance, the prognosis value of the following clinical and echocardiographic candidate variables was tested: age, sex, 6MWD, NYHA class, diastolic eccentricity index, mitral inflow pattern, RV basal diameter, RV/left ventricular diameter, cardiac index, pericardial effusion, systolic PAP, midsystolic notching, TAPSE, IVCv, IVA, S′, IVRT, and ϵ mean . Collinearity between quantitative variables was tested using Pearson’s bivariate correlation. Cutoff values of quantitative variables were determined using the median value in the population. Using Cox regression univariate analysis, hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were generated for categorical or dichotomized candidate variables. Then, multivariate Cox proportional-hazards regression models using the stepwise backward elimination technique ( P value for exclusion = .05) on categorical and dichotomized variables were used to identify independent predictors of death in the whole population (model 1), independent predictor of death in the PAH group (model 2), and independent predictors of a composite end point including death, transplantation, and emergency admission for worsening of pulmonary hypertension in the whole population (model 3). To confirm the prognostic analysis, analysis was also performed using Cox proportional-hazards regression models using the forward inclusion technique and/or entry technique. Candidate variables significantly predictive of death or of the composite end point on univariate analysis ( P < .10) were included in the corresponding multivariate model.
Kaplan-Meier survival curves were created for the independent predictors of mortality that had statistical significance on multivariate analysis. Kaplan-Meier survival curves were compared using the log-rank test.
To determine if independent prognostic echocardiographic parameter(s) improved prognosis significance over clinical prognostic parameter(s), the predictive accuracy of 6MWD and 6MWD associated with IVCv was determined by Harrell’s C-index (equivalent to receiver operating characteristic analysis in the Cox method). In addition, to test the information gain for predicting the outcome when adding IVCv, the multivariate models with and without IVCv were compared using likelihood ratio tests.
Finally, we used smoothing splines to determine the functional form of the association between independent predictors of mortality and death.
P values < .05 were considered statistically significant. Statistical analysis was performed using SPSS Statistics version 17.0 (IBM, Chicago, IL) and Stata version 10 (StataCorp LP, College Station, TX) for the C-index, likelihood ratio test, and smoothing splines.
Results
Baseline Characteristics
Table 1 summarizes the demographic characteristics of the study population. Seventy-three percent of the patients had PAH, and 27% had CTEPH. The median delay between the diagnosis of pulmonary hypertension and inclusion with echocardiography and DTI was 1.4 years (range, 0–14 years). A majority of patients ( n = 119) presented with established diagnoses of pulmonary hypertension (≥3 months), whereas in 23 patients, diagnoses were newly established (<3 months before the date of echocardiography). Right-heart catheterization performed with a median delay of 7 months (range, 0–49 months) compared with the date of echocardiography date and showed a mean systolic PAP of 77 ± 18 mm Hg, a mean diastolic PAP of 30 ± 9 mm Hg, a mean PAP of 46 ± 12 mm Hg, a mean right atrial pressure of 8 ± 4 mm Hg, a mean cardiac index of 2.3 ± 0.7 L/min/m 2 , and a mean pulmonary vascular resistance of 11.3 ± 5.8 Wood units.
| Variable | Value |
|---|---|
| Demographics | |
| Men | 50 (35%) |
| Age (y) | 59 ± 15 (range, 25–83) |
| Etiology of pulmonary hypertension | |
| Idiopathic PAH | 44 (31%) |
| PAH drugs and toxins induced | 13 (9%) |
| PAH associated with connective tissue diseases | |
| Systemic sclerosis | 23 (16%) |
| Others | 4 (3%) |
| PAH associated with human immunodeficiency virus infection | 2 (1%) |
| PAH associated with portal hypertension | 5 (4%) |
| PAH associated with congenital heart disease | 13 (9%) |
| CTEPH | 38 (27%) |
| Clinical and exercise capacity parameters at inclusion | |
| Heart rate (beats/min) | 79 ± 13 |
| Systolic blood pressure (mm Hg) | 119 ± 18 |
| Diastolic blood pressure (mm Hg) | 72 ± 11 |
| NYHA class | |
| I | 8 (5%) |
| II | 72 (51%) |
| III | 58 (41%) |
| IV | 4 (3%) |
| 6MWD (m) | 379 ± 133 |
NYHA class III or IV symptoms were present in 44% of patients. The 6MWD was lower in patients in NYHA classes III and IV than those in NYHA classes I and II (298 ± 125 vs 438 ± 105 m, respectively, P < .0001).
Seventy-five percents of the patients ( n = 107) received PAH therapy at inclusion (at the time of echocardiography), including bosentan ( n = 73), intravenous epoprostenol ( n = 12), subcutaneous treprostinil ( n = 10), sildenafil ( n = 11), ambrisentan ( n = 1), beraprost ( n = 7), sitaxsentan ( n = 5), and inhaled iloprost ( n = 2). Atrial septostomy was performed in four patients before inclusion. In addition, 10 patients received calcium channel blockers. Among the remaining 25 patients without PAH-targeted therapies and/or calcium channel blockers, 20 were patients with new diagnoses of pulmonary hypertension.
Echocardiographic Data
Left ventricular dimensions and function were normal and comparable between patients in NYHA classes I and II and those in classes III and IV ( Table 2 ). No significant aortic or mitral valvular abnormality was observed. Left ventricular filling pressure was normal. Echocardiographic parameters of elevated PAP were found in all patients, with increased tricuspid regurgitation velocity gradients, shortened pulmonary acceleration times, and increased IVRTs. The level of systolic PAP was similar in patients in NYHA classes I and II and those in classes III and IV.
| Variable | All patients ( n = 142) | NYHA classes I and II ( n = 80) | NYHA classes III and IV ( n = 62) |
|---|---|---|---|
| Standard parameters | |||
| LV EDD (mm) | 42 ± 8 | 43 ± 7 | 41 ± 9 |
| LV ESD (mm) | 25 ± 6 | 25 ± 6 | 25 ± 7 |
| LV ejection fraction (%) | 66 ± 11 | 66 ± 11 | 66 ± 11 |
| Cardiac index (mL/min/m 2 ) | 3.0 ± 0.6 | 3.0 ± 0.6 | 3.0 ± 0.7 |
| E/A ratio | 0.86 ± 0.44 | 0.95 ± 0.48 | 0.74 ± 0.34 ∗ |
| E-wave deceleration time (msec) | 254 ± 85 | 261 ± 85 | 243 ± 87 |
| E/e′ ratio | 6.7 ± 3.0 | 6.5 ± 3.2 | 6.9 ± 2.8 |
| LA area (cm 2 ) | 17 ± 8 | 18 ± 8 | 16 ± 8 |
| RV/LV diameter ratio | 1.2 ± 0.6 | 1.2 ± 0.5 | 1.2 ± 0.7 |
| RA area/height (cm 2 /m) | 15.2 ± 5.8 | 15.7 ± 5.9 | 14.5 ± 5.6 |
| Transtricuspid gradient (mm Hg) | 69 ± 21 | 70 ± 22 | 67 ± 19 |
| RA pressure (mm Hg) | 9 ± 4 | 9 ± 4 | 10 ± 5 |
| Systolic PAP (mm Hg) | 79 ± 21 | 79 ± 22 | 78 ± 20 |
| Diastolic eccentricity index | 1.5 ± 0.5 | 1.4 ± 0.4 | 1.5 ± 0.5 |
| RV acceleration time (msec) | 72 ± 16 | 73 ± 14 | 72 ± 18 |
| Midsystolic notching | 75/142 (53%) | 47/80 (59%) | 28/62 (45%) |
| Pericardial effusion | 24/142 (17%) | 12/80 (15%) | 12/62 (19%) |
| RV function parameters | |||
| TAPSE (mm) | 18 ± 5 | 19 ± 5 | 17 ± 5 ∗ |
| IVCv (cm/sec) | 9.5 ± 4.0 | 9.5 ± 4.3 | 9.5 ± 3.6 |
| IVA (m/sec 2 ) | 2.7 ± 1.17 | 2.5 ± 1.1 | 2.9 ± 1.2 |
| S′ (cm/sec) | 11.5 ± 3.3 | 11.8 ± 3.1 | 11.2 ± 3.6 |
| IVRT (msec) | 69 ± 42 | 69 ± 41 | 69 ± 43 |
| E′ (cm/sec) | 9.7 ± 4.7 | 9.4 ± 3.1 | 10.1 ± 6.1 |
| A′ (cm/sec) | 13.6 ± 5.7 | 13.7 ± 6.1 | 13.4 ± 5.2 |
| ϵ base (%) | −20.5 ± 8.1 | −20.2 ± 7.5 | −20.9 ± 9.0 |
| ϵ mid (%) | −17.8 ± 8.9 | −18.5 ± 8.0 | −16.9 ± 10 |
| ϵ apex (%) | −14.9 ± 8.5 | −15.4 ± 8.5 | −14.4 ± 8.7 |
| ϵ mean (%) | −17.9 ± 7.1 | −18.3 ± 6.3 | −17.4 ± 7.9 |
∗ P < .05 for NYHA classes III and IV versus NYHA classes I and II group.
Right ventricles were dilated, with a mean RV/left ventricular diameter ratio >1. RV systolic function was altered, as shown by low values of TAPSE, tricuspid annular velocities, and longitudinal RV systolic strain ( Table 2 ). These parameters were similar in patients in NYHA classes I and II and those in classes III and IV, although slightly lower TAPSE was observed in patients in functional classes III and IV.
Outcomes
During a mean follow-up period of 13.0 ± 9.6 months (median, 10.8 months; range, 6.0–39.4 months), 28 patients died. All deaths were sudden deaths or deaths associated with heart failure. Kaplan-Meier estimates of survival were 85.1 ± 3.4% at 1 year, 70.0 ± 6.2% at 2 years, and 48.7 ± 11.1% at 3 years. Survival rates were not significantly different between the PAH and CTEPH groups (82% vs 92% at 1 year [ P = .15] 69% vs 82% at 2 years [ P = .25], and 53% vs 27% at 3 years [ P = .50] in the PAH and CTEPH groups respectively).
During the same follow-up period, 53 patients reached the composite end point of mortality ( n = 28), transplantation ( n = 1), or emergency hospital admission related to pulmonary hypertension ( n = 24).
Predictors of Mortality
Predictors of death identified by univariate analysis were 6MWD ≤ 400 m, NYHA class III-IV, TAPSE ≤ 17 mm, and IVCv ≤ 9 cm/sec ( Table 3 ). S′ (≤11 cm/sec) and ϵ mean ≤ 18.7% were of marginal significance. Of note, age, sex, mitral inflow pattern, diastolic eccentricity index, RV basal dimension, right atrial area, systolic PAP, RV/left ventricular diameter ratio, cardiac index, pericardial effusion, midsystolic notching, IVRT, and IVA were not predictors of death.
| Variable | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age (≥62 y) | 1.78 (0.83–3.80) | .14 | ||
| Male sex (yes or no) | 1.16 (0.77–1.75) | .47 | ||
| 6MWD (≤400 m) | 3.5 (1.4–8.9) | .009 | 3.28 (1.25–8.61) | .016 |
| NYHA class (III and IV or I and II) | 2.44 (1.12–5.28) | .024 | ||
| E velocity <60 cm/sec | 1.57 (0.74–3.31) | .24 | ||
| E/A ratio <1 | 1.33 (0.49–3.61) | .57 | ||
| Diastolic eccentricity index (≥1.4) | 1.65 (0.75–3.65) | .22 | ||
| RV basal dimension (≥42 mm) | 1.11 (0.52–2.37) | .78 | ||
| RV/LV diameter ratio (≥1.1) | 1.12 (0.53–2.37) | .77 | ||
| RA area/height (≥14 cm 2 /m) | 1.17 (0.44–3.08) | .76 | ||
| Cardiac index (≤2.8 L/min/m 2 ) | 1.22 (0.41–3.63) | .73 | ||
| Pericardial effusion (yes or no) | 1.47 (0.62–3.47) | .38 | ||
| Systolic PAP (≥78 mm Hg) | 1.05 (0.50–2.21) | .90 | ||
| Midsystolic notching (yes or no) | 1.11 (0.51–2.40) | .79 | ||
| TAPSE (≤17 mm) | 2.62 (1.10–6.19) | .03 | ||
| IVCv (≤9 cm/sec) | 3.68 (1.54–8.81) | .003 | 3.29 (1.26–8.62) | .015 |
| IVA (≤2.4 m/s 2 ) | 1.20 (0.53–2.72) | .66 | ||
| S′ (≤11 cm/sec) | 1.98 (0.91–4.31) | .08 | ||
| IVRT (>80 msec) | 1.21 (0.57–2.56) | .62 | ||
| ϵ mean (≤18.7%) | 2.17 (0.97–4.84) | .06 | ||
Among all the variables selected by univariate analysis ( P < .10), IVCv and 6MWD were the only independent predictors of death on multivariate analysis (results of multivariate model 1, including 6MWD, NYHA class, TAPSE, IVCv, S′, and ϵ mean , are provided in Table 3 ). Those results were confirmed using the forward inclusion technique (6MWD: HR, 3.3; 95% CI, 1.2–8.6; P = .02; IVCv: HR, 3.3; 95% CI, 1.26–8.6; P = .02). Of note, no significant collinearity between variables was observed (Pearson’s coefficients <0.80).
Survival curves according to IVCv and 6MWD are shown in Figure 2 . By log-rank test, IVCv ( P = .002) and 6MWD ( P = .005) were significant predictors of death. When the population was classified according to the lowest tertiles of 6MWD and IVCv, 6MWD was a predictor of death (6MWD ≤ 330 m, log-rank test, P < .0001), and IVCv was of marginal significance (IVCv ≤ 7.5 cm/sec, log-rank test, P = .10).
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