Population

We prospectively studied 66 patients who had the diagnosis of acute submassive (hemodynamically stable) PE using personal histories, physical examinations, echocardiography, lower limb venous ultrasonography, and laboratory tests. PE diagnosis was confirmed by the presence of thrombi in the pulmonary arteries on thoracic computed tomography, in line with current European Society of Cardiology guidelines. Submassive or intermediate-risk PE was defined as RV dysfunction without systemic hypotension. Patients with at least one of the following echocardiographic findings were diagnosed with acute RV dysfunction: (1) RV hypokinesia assessed by qualitative interpretation of systolic RV free wall motion, (2) RV dilatation (end-diastolic diameter > 30 mm in the apical four-chamber view), and (3) paradoxical septal systolic motion. Exclusion criteria were moderate or greater valvular disease, chronic obstructive pulmonary disease or congestive heart failure, a prior documented episode of PE, comorbidity with life expectancy < 6 months, and insufficient ultrasound image quality (defined as more than three myocardial segments that were not optimally visualized using conventional two-dimensional echocardiography). Transthoracic echocardiography was performed at the onset of the acute episode and after median follow-up periods of 30 days and 6 months. Information about symptoms and functional class (according to the New York Heart Association) was collected. Written informed consent was obtained. Adverse clinical outcome was defined as the occurrence of one or more of the following: death, cardiopulmonary resuscitation, and acute PE recurrence. These adverse events were selected on the basis of the Management Strategies and Prognosis of Pulmonary Embolism 3 trial. Sixty-six healthy age-matched and sex-matched adults with no histories of cardiopulmonary disease, no known coronary risk factors, and normal electrocardiographic and echocardiographic results were selected as a control group.

Standard Echocardiography

All patients underwent transthoracic echocardiography using a commercially available cardiovascular ultrasound system (Vivid E9; GE Vingmed Ultrasound AS, Horten, Norway). Established criteria were used for measurement of the right chambers. The RV–to–left ventricular (LV) end-diastolic diameter ratio was calculated in the apical four-chamber view. RV end-diastolic area and end-systolic area were assessed using manual planimetry and RV fractional area change (FAC) was derived. Tricuspid annular plane systolic excursion (TAPSE) was measured using apical views adjusted to optimize RV structures and to achieve proper orientation for M-mode measures. RV myocardial performance index (MPI) was determined as the sum of the isovolumic contraction time and isovolumic relaxation time divided by the ejection time. Pulmonary acceleration time was calculated as the interval between the onset of ejection and peak pulmonary flow velocity from the parasternal short-axis view. RV systolic pressure (RVSP) was obtained by continuous-wave Doppler echocardiography. A systematic search was performed using two-dimensional and color flow Doppler to identify the most complete tricuspid regurgitation (TR) jet followed by continuous-wave Doppler acquisition of spectral envelopes of the greatest maximal velocity and density. Right atrial pressure was estimated by visualizing the inferior vena cava (IVC) diameter from long-axis subcostal views and its phasic response to respiration. Right atrial pressure was estimated as 5 mm Hg if the IVC was <2.0 cm in diameter at the junction of the right atrium, 15 mm Hg if the IVC was dilated and collapsed with respiration (>50%), and 20 mm Hg if the IVC was dilated and did not collapse with respiration. Pulmonary arterial hypertension (PAH) was classified according to baseline RVSP as mild (40–49 mm Hg), moderate (50–59 mm Hg), or severe (≥60 mm Hg). Normalization of pressures was defined as RVSP < 40 mm Hg. Estimation of pulmonary vascular resistance (PVR) was determined on the basis of the ratio of peak TR velocity to RV outflow tract time-velocity integral that was shown to be a good correlate of PVR despite reflecting pulmonary systolic pressure and not the transpulmonary pressure gradient. The peak TR velocity (meters/second) was determined using continuous-wave Doppler using the highest velocity obtained from multiple views. The RV outflow tract time-velocity integral (centimeters) was obtained by placing a 1-mm to 2-mm pulsed-wave Doppler sample volume in the proximal RV outflow tract just within the pulmonary valve when imaged from the parasternal short-axis view. PVR was calculated using the following equation: PVR (Wood units) = 10 × TR velocity/RV outflow tract time-velocity integral.

Tricuspid annular systolic velocity was measured at the lateral corner of the tricuspid annulus using apical views adjusted to optimize RV structures and to achieve proper orientation for Doppler measures.

McConnell’s sign was defined as reduced RV free wall contraction with preserved apical wall motion on two-dimensional echocardiography, and those signs were read blinded.

3D Echocardiography

Three-dimensional echocardiography was done using a dedicated broadband, wide-angle, matrix-array transducer to enable full coverage of the entire right ventricle by the pyramidal volume, with particular attention to the upper anterior wall and RV outflow tract. Before each acquisition, the images were optimized for endocardial border visualization by increasing the overall gain and modifying the time gain and compression. Echocardiographic images were stored digitally for offline analysis using TomTec software (TomTec Imaging Systems, Unterschleissheim, Germany). Within the 3D data set, three orthogonal main cut planes were selected to define the end-diastolic and end-systolic frames within the sequence as well as several landmarks. On the basis of the initial view adjustment and the landmarks, the program automatically provides four-chamber, sagittal, and coronal RV views. RVEDV and RV end-systolic volume (RVESV) were measured from each 3D echocardiographic data set. Tracing was done through the bases of the papillary muscles. RVEF was calculated as follows: RVEF = [(RVEDV − RVESV)/RVEDV] × 100 ( Figure 1 ). The process of volume determination was done two times for each patient.

Three-dimensional echocardiography and speckle-tracking imaging in a normal subject ( top ) and a patient with acute PE ( bottom ). In acute PE, note the decreases in 3D RVEF and global RVLS, especially at the MFW. ( Top left ) Three-dimensional RVEF, 59%; ( top right ) MFW RVLS, −25%; ( bottom left ) 3D RVEF, 35%; ( bottom right ) MFW RVLS, −8%.

STE

The general principles that underlie the speckle-tracking echocardiographic modalities have been previously described. The acquisitions were obtained successively for all patients by the same physician, with analyses being performed retrospectively and offline. Apical four-chamber views were used, and special care was taken to ensure an adequate field of view to image the entire right ventricle by narrowing the two-dimensional sector width or positioning the transducer down an intercostal space and laterally. Two-dimensional peak systolic RV longitudinal strain (RVLS) was measured adopting a six-segment RV model (basal free wall, mid free wall [MFW], apical free wall, apical septum, mid septum, and basal septum). Peak systolic strain was recorded for the three RV myocardial free wall and septal segments and the entire RV wall ( Figure 1 ). RV dyssynchrony was quantified using the standard deviation of the heart rate–corrected intervals from QRS onset to peak systolic strain for the six segments. The echocardiographic results were analyzed by an echocardiologist blinded to the clinical data, using dedicated software (EchoPAC BT11, 4D Auto LVQ; GE Vingmed Ultrasound AS, Horten, Norway).

Statistic Analysis

Data are expressed as mean ± SD. Student’s t test was used for comparisons of normally distributed data. Univariate and multivariate Cox proportional-hazards regression models were used to calculate hazard ratios and 95% confidence intervals for different variables. Multivariate analyses were performed using a stepwise forward regression model in which each variable with a P value ≤ .10 on univariate analysis was entered into the model. Variance inflation factors were used to identify collinearity among explanatory variables. The cutoff values of the investigated parameters enabling the prediction of adverse events with the highest sensitivity and specificity were identified by means of receiver operating characteristic curves of different indexes. Statistical significance was set at P < .05. To analyze intraobserver variability, measurements of parameters were made at multiple sites in 15 different patients on two different occasions. For interobserver variability, a second investigator randomly made measurements at the above different sites (same recorded loops) without knowledge of other echocardiographic parameters. Intraobserver and interobserver variability was determined as the difference between the two sets of observations divided by the mean of the observations and expressed as a percentage.

Baseline Characteristics

The baseline characteristics of all patients with PE and of those with and without adverse events are given in Table 1 . There were no significant differences between groups with regard to baseline characteristics except for elevated troponin. Troponin I levels were elevated in 42% of patients. Sixty-four percent ( n = 42) of the patients had limitations of functional capacity (New York Heart Association functional class ≥ II). Fourteen patients (21%) had tachycardia (heart rate ≥ 100 beats/min). Eighteen patients had adverse events. Thirty-day and 6-month all-cause deaths occurred in four and nine patients, respectively. Cardiopulmonary resuscitation was performed in two patients. Three patients had acute PE recurrence.

Echocardiographic Parameters

Overall, 3D RVEFs were significantly reduced compared with controls ( Table 2 ). TAPSE and FAC decreased and MPI increased significantly. Global RVLS was significantly lower than in the control group. Speckle-tracking strain was especially reduced in the RV MFW and basal free wall segments ( Table 2 ). There was a direct correlation between MFW RVLS and 3D RVEF and a negative correlation between MFW RVLS and RV dyssynchrony ( Figure 2 ).

Relations ( top ) between MFW RVLS and 3D RVEF and ( bottom ) between MFW RVLS and RV dyssynchrony (RV-Dyss).

McConnell’s sign (RV wall hypokinesia with apical sparing) was observed in 35 patients (53%) with acute PE and was associated with a higher RV/LV ratio (1.26 ± 0.79 vs 0.83 ± 0.12, P < .05), lower 3D RVEF (37 ± 6% vs 44 ± 7%, P < .005), and lower MFW RVLS (−13.4 ± 4.1% vs −15.6 ± 4.4%, P < .005). Global RV wall strain was not different in patients with McConnell’s sign compared with those without that sign (−18.1 ± 4.8% vs −18.9 ± 4.5%, P = .073).

Correlations with Pulmonary Hypertension and Outcome Results

Mean baseline RVSP was 53 ± 14 mm Hg, mean pulmonary acceleration time was 64.2 ± 11.7 msec, and mean PVR was 3.9 ± 1.8 Wood units ( Table 2 ). Seventy-one percent of patients ( n = 47) had mild to moderate PAH and 29% ( n = 19) had severe PAH at the onset of the acute episode. Most patients with PE had mild or minimal TR, and no patient with severe TR was observed at the time of PE diagnosis. RVSP decreased from 53 ± 14 to 47 ± 12 mm Hg at 30-day follow-up and to 31 ± 7 mm Hg at 6-month follow-up ( P < .005). Forty-three percent of patients ( n = 29) had normalization of RVSP, 21 patients with moderate PAH and four patients with severe PAH. Twenty-four percent of patients ( n = 16) remained in New York Heart Association class ≥ II. Sixty-eight percent of these patients ( n = 11) had residual PAH.

Figure 3 analyzes MFW RVLS, 3D RVEF, and RVSP in normal subjects, patients with acute PE at the time of diagnosis, and on 30-day and 6-month follow-up echocardiography. The figure depicts earlier reversal of MFW RVLS values at 30-day follow-up and longer reversal of 3D RVEF and RVSP values at 6-month follow-up.

Bar graph depicting MFW RVLS ( top ), 3D RVEF ( middle ), and RVSP ( bottom ) in normal controls (C), patients with acute PE at time of diagnosis, and on 30-day and 6-month follow-up echocardiography. Note earlier significant reversal of MFW RVLS values at 30-day follow-up and longer significant reversal of 3D RVEF and RVSP values at 6-month follow-up. ^∗ P < .0001 (30-day vs PE); ^† P < .005 (6-month vs PE); ^‡ P < .005 (6-month vs PE).

By multivariate analysis, 3D RVEF ( P = .001) and MFW RVLS ( P = .002) were independently associated with adverse outcomes (independently of clinical characteristics, laboratory data, and comorbidities) in patients with PE ( Table 3 ). By receiver operating characteristic curve analysis, we compared the ability of various echocardiographic parameters to predict adverse clinical outcomes ( Table 4 , Figure 4 ). Cutoff points for RV FAC, RV/LV ratio, RVSP, MFW RVLS, and 3D RVEF of 37%, 1.05, 43 mm Hg, −12%, and 40% had sensitivity of 73%, 74%, 79%, 84%, and 88% and specificity of 64%, 69%, 68%, 74%, and 79%, respectively, in predicting adverse events after 6-month follow-up. On the basis of the data presented in Table 4 and Figure 4 , we selected RVSP, MFW RVLS, and 3D RVEF for assessing prognostic value. RVSP > 43 mm Hg was present in 14 of 18 patients (78%) who experienced adverse events and in 19 of 48 patients (40%) who did not experience adverse events ( P = .019). MFW RVLS > −12% occurred in 15 of 18 patients (83%) with adverse events and in 14 of 48 (29%) with no adverse events ( P = .002), and 3D RVEF < 40% occurred in 16 of 18 (89%) and 11 of 48 (23%) patients, respectively ( P = .001). The combination of all three parameters was seen in 94% of patients with adverse clinical events and 23% of patients with no adverse events ( P < .001). Values of RVSP, MFW RVLS, and 3D RVEF in patients with adverse events and without adverse events are plotted in Figure 5 (RVSP, 55 ± 13 vs 37 ± 7 mm Hg, P < .05; MFW-RVLS −7.5 ± 4.1% vs −13.9 ± 4.2%, P < .01; 3D RVEF, 34 ± 6% vs 47 ± 7%, P < .01).

Table 3

Results of univariate and multivariate Cox proportional-hazards analysis of the relation between clinical variables and 6-month adverse outcomes

Variable	HR	95% CI	P
Univariate analysis
Age	1.99	1.54–2.91	.005
SBP	1.92	1.77–2.71	.025
Diabetes mellitus	1.16	1.01–1.76	.014
Sepsis	1.21	1.08–1.83	.019
Renal insufficiency	1.93	1.67–2.82	.037
Troponin I	2.07	1.15–3.24	<.001
RVSP	2.19	2.17–3.46	.002
RV/LV ratio	1.22	1.08–1.74	.004
TAPSE	1.74	1.53–2.86	<.05
RV FAC	1.98	1.63–2.95	<.01
MFW RVLS	2.27	1.49–3.92	<.0005
3D RVEF	4.32	2.43–8.09	<.0001
Multivariate analysis
Troponin I	1.93	0.91–2.79	.008
RVSP	2.14	1.12–2.91	.007
MFW RVLS	2.95	1.31–3.23	.002
3D RVEF	3.51	1.66–4.51	.001

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