It is unknown whether the echocardiographic changes observed after treatment of patients with pulmonary arterial hypertension have prognostic value.
Subjects with pulmonary arterial hypertension, confirmed by right heart catheterization, who underwent Doppler echocardiography before (baseline) and after 1 year of treatment (follow-up) with parenteral prostacyclin analogues were retrospectively identified. Echocardiographic parameters were measured offline by two investigators.
A total of 48 patients were included (mean age, 45 ± 14 years; 83% women). Compared with baseline, follow-up echocardiography showed reductions in right atrial area (mean percentage change, 12 ± 25%; P < .001), right ventricular (RV) basal and middle cavity dimensions (mean percentage change, 8.5 ± 14% [ P < .001] and 6.8 ± 17% [ P = .005], respectively), and peak tricuspid regurgitant velocity (mean percentage change, 10 ± 14%; P < .001). Tricuspid annular plane systolic excursion (mean percentage change, 36 ± 43%; P < .001) and RV outflow tract time-velocity integral (mean percentage change, 48 ± 66%; P < .001) increased. During a median follow-up period of 52.5 months (interquartile range, 20.5–80 months), 18 patients (37.5%) died, mostly (n = 15 [83%]) from progression of pulmonary arterial hypertension. The changes in RV end-diastolic area (hazard ratio [HR per 10% decrease, 0.73; 95% confidence interval [CI], 0.57–0.93), tricuspid valve regurgitation velocity (HR per 10 cm/sec decrease, 0.58; 95% CI, 0.37–0.89), RV outflow tract velocity-time integral (HR per 10% increase, 0.90; 95% CI, 0.83–0.98), and subjective RV function (HR per 1 unit of improvement [e.g., from moderate to mild], 0.55; 95% CI, 0.31–0.96) were associated with overall mortality.
Echocardiographic parameters that estimate RV systolic pressure and assess RV morphology and function improve after 1 year of prostacyclin analogue treatment, and the degree of change has prognostic implications.
Pulmonary arterial hypertension (PAH) is a severe and progressive pulmonary vascular condition due to narrowing of the blood vessels in the lung that can lead to right heart failure and premature death. Nine pharmacologic agents are approved by the US Food and Drug Administration for the treatment of PAH, including two parenteral prostacyclin analogues: epoprostenol (intravenous [IV]) and treprostinil (IV and subcutaneous). These two parenteral therapies alleviated symptoms and improved exercise capacity and hemodynamic status in patients with PAH. Furthermore, treatment with epoprostenol was associated with a survival benefit in patients with idiopathic PAH. Notwithstanding major therapeutic advances in the past decade, the morbidity and mortality of PAH continue to be unacceptably high, with 1-, 3-, and 5-year survival rates from the time of diagnosis of 85%, 68%, and 57%, respectively.
Echocardiography is a well-established and widely available technique that is routinely used during the initial assessment of patients suspected of having PAH. In addition, it continues to be an important method to follow patients with PAH and evaluate their treatment response. This noninvasive technology permits the serial evaluation of right ventricular (RV) size and function as well as the estimated RV systolic pressure. Over the years, limited attention has been paid to the effects of PAH-specific treatment on echocardiographic parameters and their prognostic implications.
Although a few echocardiographic parameters are known to improve after the initiation of PAH-specific therapies, it is not clear whether these changes have prognostic value. We hypothesized that improvements in certain echocardiographic parameters are associated with longer survival. We sought to investigate the effect of 1 year of treatment with parenteral prostacyclin analogues on echocardiographic parameters. Our main study objective is to determine whether changes in echocardiographic parameters resulting from advanced PAH-specific therapies have prognostic significance.
Study Design and Inclusion and Exclusion Criteria
This retrospective study was approved by the Cleveland Clinic Institutional Review Board (Protocol No. 10-1127). We identified eligible subjects using the Cleveland Clinic Pulmonary Hypertension Registry. All patients had the diagnosis of precapillary pulmonary hypertension confirmed by right heart catheterization (mean pulmonary artery pressure ≥ 25 mm Hg with a pulmonary artery occlusion pressure ≤ 15 mm Hg). During right heart catheterization, patients were supine in a steady state, relaxed, and breathing room air or oxygen to maintain pulse oximetry > 90%. Patient received no sedation. We cannulated preferably the right internal jugular vein using minimal local anesthesia (lidocaine 2%). We zeroed pressure transducers at the fourth intercostal space of the midaxillary line. Cardiac output was determined by thermodilution and Fick methodology. The resting oxygen consumption (milliliters per minute) for the Fick equation was estimated using the formula of Dehmer et al ., whereas oxygen consumption = 125 × body surface area. Body surface area was calculated according to the formula of DuBois and DuBois. Mixed venous oxygenation was measured in the blood obtained from the pulmonary artery during the right heart catheterization.
We identified 112 consecutive patients who received parenteral prostacyclin analogues for ≥1 year, from January 1, 2004, until January 8, 2011. We selected the initiation date (January 1, 2004) on the basis of the availability of syngo Dynamics (Siemens Medical Solutions USA, Inc, Malvern, PA), a system that allows offline echocardiographic measurements.
Each patient underwent a thorough clinical evaluation to identify the cause of pulmonary hypertension. We excluded patients who had pulmonary hypertension other than group I as defined by the Fourth World Symposium on Pulmonary Hypertension (chronic thromboembolic pulmonary hypertension [n = 10] and pulmonary hypertension due to sarcoidosis [n = 4]). We also excluded patients with complex congenital heart diseases or those in whom surgical correction was performed in the 2 years before initiation of the study (n = 5), moderate or severe mitral and/or aortic valve stenosis and/or insufficiency (n = 16), echocardiography either not done in the predetermined time window (n = 10) or not available for offline review (studies done at an outside hospital or not retrievable [n = 19]). Patients with pulmonary hypertension due to congenital intracardiac shunts were not excluded. No patient had evidence of left ventricular (LV) myocardial disease.
Measurements and Calculations
Transthoracic Doppler echocardiography was performed during the initial evaluation (before the initiation of parenteral prostacyclin analogues) and at the end of a 1-year treatment with parenteral prostacyclin analogues. We arbitrarily chose 1 year of treatment to assess patients receiving an adequate and stable dose of prostacyclin analogue and to allow enough time for this medication to exert a noticeable effect. Studies were performed according to American Society of Echocardiography guidelines. All recordings were reviewed with our offline quantification system (syngo Dynamics). Measurements were obtained by experienced physicians blinded to the patients’ clinical histories and survival status. All new determinations were compared with the ones provided in the report at the time of echocardiography. In cases of discrepancies, another physician reviewed the echocardiographic images, and consensus was obtained.
In all but three echocardiographic studies, the patients were in sinus rhythm during image acquisition. In three studies, patients had atrial fibrillation with well-controlled heart rates (two patients during the initial study and one during the 1-year study), so measurements were made on three beats and the results averaged. Left atrial area was measured using planimetry at end-ventricular systole in the apical four-chamber view. We measured RV basal and middle cavity and longitudinal dimensions of the right ventricle in the apical four-chamber view. In addition, RV area was obtained at end-diastole by tracing the endocardial border in the apical four-chamber view and including trabeculations, tricuspid leaflets, and chords as part of the chamber. The intraclass correlation coefficients for RV end-diastolic area determination (n = 15) for the same and different raters were 0.95 (95% confidence interval [CI], 0.85–0.98) and 0.93 (95% CI, 0.81–0.97), respectively. Abnormal LV diastolic function was divided into three grades, according to recommendations from the American Society of Echocardiography and the European Association of Echocardiography (grade I, impaired LV relaxation; grade II, pseudonormal LV filling; grade III, restrictive LV filling). RV systolic function was visually estimated as normal, mild, moderate, or severe by experienced operators. The severity of tricuspid regurgitation was graded as mild, moderate, or severe according to recommendations of the American Society of Echocardiography. Pericardial effusion was evaluated on two-dimensional echocardiography at end-diastole and graded as trace (separation of pericardial layers only in systole), small (separation < 1 cm), moderate (separation ≥ 1 but < 2 cm), or large (separation ≥ 2 cm).
The RV outflow acceleration time was measured between the onset and the maximal velocity of the pulsed-wave Doppler flow profile. In addition, we determined the time-velocity integral of the RV outflow tract and noted the presence or absence of midsystolic notching. Maximal tricuspid regurgitant jet velocity was obtained during quiet respiration after analyzing the continuous-wave Doppler from different echocardiographic views. In cases of noticeable respiratory spectral oscillations, measurements were obtained during brief held-expiration, or three consecutive signals were averaged. We estimated the pulmonary vascular resistance on echocardiography using the model proposed by Opotowsky et al . (pulmonary vascular resistance = [pulmonary artery systolic pressure/RV outflow tract velocity-time integral] + 3 if RV outflow tract notch is present). For all echocardiographic measurements, absolute changes were calculated by subtracting the determination performed after 1 year of treatment from the baseline value. Percentage change was obtained by dividing the absolute change over the baseline value and multiplying by 100.
Patients were followed in our clinic at least every 3 months after the initiation of parenteral prostacyclin analogues. Echocardiography was performed before the initiation of PAH-specific therapies and every 3 to 6 months. After 1 year of treatment, patients were continued on parenteral prostacyclin analogues unless they underwent lung transplantation or died. In no patient was prostacyclin analogue discontinued on the basis of echocardiographic deterioration or lack of improvement. Patients underwent transplantation in the event of refractory PAH, using criteria suggested by the International Society for Heart and Lung Transplantation. Death of study participants was ascertained by reviewing our records and querying the US Social Security Death Index.
Means and standard deviations and numbers of patients with percentages are provided for continuous and categorical variables, respectively. Comparison of echocardiographic variables at baseline and after 1 year of treatment was performed using McNemar or paired Student t tests, as appropriate. Interrater and intrarater agreement for single measures was calculated using intraclass correlation coefficients and their respective 95% CIs. Each subject was rated by the same two raters. We tested for absolute agreement because systematic differences are considered relevant. Survival at each time point was assessed using Kaplan-Meier methodology. The start point was the date of the echocardiogram obtained after 1 year of parenteral treatment. The end of follow-up was marked by the patient’s death. Patients were censored either at the time of lung transplantation or at the end of the study in May 2013. Cox proportional-hazards modeling adjusted for age and gender was used to examine the relationship between survival and selected echocardiographic variables. The results are expressed as hazard ratios (HRs) and the corresponding 95% CI. We generated models testing three outcome variables (overall mortality, PAH-associated death, and the combination of death and lung transplantation). Predictors with HRs < 1 are associated with lower risk for the outcome tested. As an example, an HR of 0.73 means that the outcome of interest (i.e., mortality) decreases by a factor of 0.73 (27% less) for each specified unit change of the predictor (e.g., a 10% decrease in RV end-diastolic area). For a 20% decrease in RV area, the HR for the outcome decreases by a factor of (0.73) 2 = 0.53 (47% lower risk for having the outcome).
Receiver operating characteristic curve analysis was used to determine the sensitivity and specificity of different cutoffs of the change in tricuspid regurgitation velocity to discriminate patients who died during follow-up. All P values reported are two tailed. P values < .05 were considered significant. The statistical analyses were performed using SPSS version 17 (SPSS, Inc, Chicago, IL).
Overall Characteristics of the Patients
We included a total of 48 patients ( Table 1 ) with PAH, of whom 32 (67%) had either idiopathic (n = 25 [52%]) or heritable (n = 7 [15%]) PAH. A few patients had Eisenmenger syndrome due to ventricular septal defects (n = 2) and an atrial septal defect with anomalous pulmonary venous return (n = 1). Six-minute walk tests were performed the same day as echocardiography. Right heart catheterization was done within 1 month of the first echocardiographic assessment in 39 patients (81%).
|Number of patients||48|
|Age (years)||44 ± 14|
|Cause of PAH|
|Connective tissue disease||10 (21%)|
|Congenital heart diseases||3 (6%)|
|NYHA class ∗|
|6-min walk distance (m)||317 ± 107|
|6-min walk distance (% of predicted)||54 ± 17|
|RA pressure (mm Hg)||12 ± 7|
|Mean PAP (mm Hg)||54 ± 12|
|PAOP (mm Hg)||11 ± 5|
|CO by thermodilution (L/min)||4 ± 1|
|CO by Fick method (L/min) †||4 ± 1|
|PVR (Wood units)||13 ± 6|
|Mixed venous oxygenation (%)||60 ± 9|
Prostacyclin Analogue Treatment
All patients were treated with parenteral prostacyclin analogues for ≥1 year. The prostacyclin analogues used during this period were IV epoprostenol in 42 patients (88%), IV treprostinil in three (6%), and subcutaneous treprostinil in two (4%). One patient (2%) was converted from IV epoprostenol to IV treprostinil during the first year of treatment. Twenty-five patients (52%) were receiving other PAH-specific therapies before the initiation of prostacyclin analogues (endothelin receptor antagonists, 17 [68%]; phosphodiesterase-5 inhibitors, three [12%]; combination of endothelin receptor antagonists and phosphodiesterase-5 inhibitors, five [20%]). One patient was initiated on a phosphodiesterase-5 inhibitor during the first year of treatment with prostacyclin analogue.
Serial Echocardiographic Determinations
We analyzed the initial echocardiogram and echocardiograms obtained after 1 year of treatment with parenteral prostacyclin analogues ( Figure 1 ). The median time between these two echocardiograms was 12.9 months (interquartile range [IQR], 11–14.8 months). Significant echocardiographic differences between studies reflected an increase in the sizes of left-sided cardiac chambers, reductions of the sizes of right-sided heart cavities, improvements in LV and RV function, and a reduction in the leftward shifting of the interventricular septum ( Table 2 ). On the echocardiogram obtained after 1 year of prostacyclin analogue treatment, the peak tricuspid regurgitant velocity, estimated RV systolic pressure, ratio of tricuspid regurgitant velocity to RV outflow tract time-velocity integral, estimated pulmonary vascular resistance, percentage of studies showing RV outflow tract notching, and grade of LV diastolic dysfunction decreased, while RV outflow tract flow acceleration time increased ( Table 3 ). Echocardiographic parameters that did not reach statistical significance are shown in Supplemental Table 1 (available at www.onlinejase.com ).
|Variable||n||Initial echocardiographic study||Echocardiographic study after 1 year of treatment||Difference between studies||Difference between studies||Percentage change||P (paired Student t or McNemar test)|
|Lower 95% confidence limit||Upper 95% confidence limit|
|Heart rate (beats/min)||45||87.7 ± 15||81.9 ± 10||5.8 ± 18||0.5||11.2||3.3 ± 26||.03|
|Body surface area (kg/m 2 )||48||1.9 ± 0.3||1.9 ± 0.3||0.02 ± 0.1||−0.02||0.06||0.4 ± 7.4||.38|
|Left atrial area (cm 2 )||45||14.4 ± 5||16.2 ± 4||1.7 ± 4||0.4||3.1||20 ± 39||.01|
|LV end-diastolic diameter (cm)||44||3.3 ± 0.6||4 ± 0.7||0.7 ± 0.7||0.5||0.9||24 ± 27||<.001|
|LV end-systolic diameter (cm)||44||2.1 ± 0.5||2.5 ± 0.6||0.4 ± 0.7||0.2||0.6||26 ± 40||<.001|
|LV ejection fraction (%)||46||55.5 ± 3||57.5 ± 4||1.9 ± 6||0.2||3.7||4 ± 11||.03|
|Right atrial area (cm 2 )||45||25.1 ± 7||21.4 ± 8||−3.6 ± 6||−5.6||−1.7||−12 ± 25||<.001|
|RV end-diastolic basal dimension (cm)||48||5.3 ± 0.8||4.6 ± 0.8||−0.5 ± 0.7||−0.7||−0.3||−8.5 ± 14||<.001|
|RV end-diastolic mid cavity dimension (cm)||48||4.2 ± 0.7||3.9 ± 0.9||−0.3 ± 0.7||−0.5||−0.1||−6.8 ± 17||.005|
|RV end-diastolic longitudinal dimension (cm)||48||8 ± 1||8 ± 1||−0.04||−0.3||0.2||0.1 ± 10||.75|
|RV end-diastolic area (cm 2 )||44||33.9 ± 9||31 ± 8||−2.9||−5||−0.8||−7 ± 22||.008|
|TAPSE (cm)||44||1.5 ± 0.5||1.9 ± 0.5||0.42||0.3||0.6||36 ± 43||<.001|
|Normal||0 (0%)||4 (9%)||<.001|
|Mild||5 (11%)||13 (28%)|
|Moderate||19 (40%)||19 (40%)|
|Severe||23 (49%)||11 (23%)|
|Leftward shifting of the IVS||45|
|Absent||6 (13%)||20 (44%)||.001|
|Present||39 (87%)||25 (56%)|
|Inferior vena cava collapse||40|
|Absent||20 (50%)||11 (28%)||.035|
|Present||20 (50%)||29 (72%)|
|Variable||n||Initial echocardiographic study||Echocardiographic study at 1 year of treatment||Difference between studies||Difference between studies||Percentage change||P (paired Student t or McNemar test)|
|Lower 95% confidence limit||Upper 95% confidence limit|
|Tricuspid regurgitation severity||46|
|Mild||9 (20%)||26 (57%)||<.001|
|Moderate||22 (48%)||14 (30%)|
|Severe||15 (32%)||6 (13%)|
|Peak tricuspid regurgitant velocity (m/sec)||46||4.3 ± 0.5||3.8 ± 0.6||−0.5 ± 0.6||−0.6||−0.3||−10 ± 14||<.001|
|RVSP (mm Hg)||46||82.4 ± 16||67.4 ± 18||−15 ± 17||−20.1||−9.8||−17 ± 21||<.001|
|RV outflow tract flow acceleration time (msec)||35||55.1 ± 17||73 ± 20||18.4 ± 17||10.7||26.1||43 ± 50||<.001|
|RV outflow tract time-velocity integral (cm)||42||12.6 ± 3.6||17.5 ± 6.6||4.9 ± 7||2.8||7.1||48 ± 66||<.001|
|Doppler RV outflow tract notching||40|
|Absent||15 (35%)||29 (67%)||<.001|
|Present||28 (65%)||14 (33%)|
|Ratio of tricuspid regurgitant velocity to RV outflow tract time-velocity integral||40||0.37 ± 0.1||0.25 ± 0.1||−0.13 ± 0.1||−0.2||0.09||−30 ± 28||<.001|
|PVR estimation||38||9 ± 3.2||5.3 ± 2.6||−3.7||−4.8||−2.7||−38 ± 28||<.001|
|Peak E velocity (cm/sec)||45||60.5 ± 25||76.8 ± 22||16.2 ± 30||7.1||25||46 ± 76||.001|
|E/A ratio||43||0.91 ± 0.5||1.1 ± 0.4||0.19 ± 0.6||0.01||0.38||47 ± 77||.04|
|Peak S velocity (cm/sec)||33||49 ± 12||54 ± 13||5 ± 10||1.5||8||12 ± 22||.006|
|Peak D velocity (cm/sec)||33||39 ± 15||48 ± 13||9.1 ± 16||3.4||14.7||33 ± 42||.002|
|S/D ratio||33||1.4 ± 0.4||1.2 ± 0.4||−0.18||−0.31||−0.06||−10 ± 24||.004|
|LV diastolic function||47|
|Normal||15 (32%)||28 (60%)||.02|
|Grade I||31 (66%)||17 (36%)|
|Grade II||1 (2%)||2 (4%)|