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* From the Methodist Debakey Heart Center, The Methodist Hospital, Houston, TX.
Correspondence to: Sherif F. Nagueh, MD, 6550 Fannin St, SM-667, Houston, TX 77030-2717; e-mail: snagueh{at}tmh.tmc.edu
Abstract
Background: Tissue Doppler (TD) echocardiographic imaging of mitral and tricuspid annulus has been applied to assess right ventricular (RV) and left ventricular (LV) function in many cardiac diseases, but its clinical application, including response to long-term targeted therapy in patients with idiopathic pulmonary hypertension (PH), has not been addressed.
Methods: Seventy patients with idiopathic PH were compared with 35 age-matched control subjects to examine myocardial velocities by TD. Of these, 35 patients underwent repeat imaging after long-term targeted therapy. In addition, 50 consecutive patients with idiopathic PH with simultaneous right-heart catheterization and echocardiography were examined.
Results: No significant differences were noted between PH patients and the control group in lateral mitral annulus systolic velocity and early diastolic velocity (Ea) by TD, but septal velocities were significantly lower (p < 0.01). With targeted therapy, myocardial velocities at the septum and RV free wall increased significantly (p < 0.05). Likewise, E/Ea ratio increased, albeit still in the normal range. In all 50 patients with invasive measurements, lateral E/Ea ratio readily identified normal mean pulmonary capillary wedge pressure (PCWP).
Conclusions: TD imaging of the lateral mitral annulus can reliably predict the presence of normal/reduced mean PCWP in patients with idiopathic PH, and track the improvement in RV function and LV filling with long-term targeted therapy.
Key Words: idiopathic pulmonary hypertension • tissue Doppler imaging
Left ventricular (LV) filling is frequently abnormal in patients with pulmonary hypertension (PH) not due to a cardiac etiology.123456 Typically, the mitral inflow pattern is one of late diastolic filling and has been shown to have a significant inverse relationship with the severity of PH in patients with pulmonary thromboembolic disease.4 This may be the result of reduced left atrial (LA) filling and/or abnormal LV relaxation. In fact, the presence of abnormal LV geometry because of right ventricular (RV) enlargement and septal displacement1234567 and possible myocardial edema have been postulated to cause abnormal LV diastolic function. However, conclusions drawn from mitral inflow are limited given the confounding effects of preload on these signals. Therefore, additional noninvasive parameters that are less load dependent are needed to gain insight into LV diastolic function in these patients.
Tissue Doppler (TD) echocardiographic imaging of mitral and tricuspid annulus has been applied to assess RV and LV function.8910111213141516 However, the accuracy of TD-derived estimation of LV filling pressures and its relation to the severity of PH are not yet defined. Furthermore, whether these measurements provide incremental information that can be helpful in this disease is unknown. We therefore undertook this study to examine the diagnostic accuracy of TD imaging for the prediction of LV filling pressures and its utility in assessing the changes in cardiac function with long-term targeted therapy.
Materials and Methods
Patient Population
Seventy consecutive patients with World Health Organization class III/IV idiopathic PH who underwent transthoracic echocardiography were enrolled. The diagnosis of idiopathic PH was established by standard criteria.7 Inclusion criteria included the following: sinus rhythm, adequate echocardiographic images for interpretation, no evidence LV myocardial or valvular disease, and pulmonary artery (PA) systolic pressure 
50 mm Hg. Five patients were excluded because of suboptimal Doppler alignment with the mitral annulus plane of motion, but there were no exclusions for other reasons. An age-matched comparison group of 35 subjects without cardiac disease and normal echocardiographic findings was included. Of the 70 patients with idiopathic PH, 35 patients underwent a repeat echocardiographic examination 3 to 6 months after targeted therapy (continuous IV epoprostenol, and/or bosentan). These were patients with complete echocardiographic data at the follow-up examination.
We also sought to determine the accuracy of TD in determining the presence of normal/reduced mean pulmonary capillary wedge pressure (PCWP) in patients with primary PH. To achieve that objective, we included 50 consecutive patients with idiopathic PH and 25 age-matched patients with secondary PH (PA systolic pressure, 61 ± 10 mm Hg) due to diastolic heart failure or valvular heart disease (ejection fraction [EF], 63 ± 9%; mean PCWP by invasive measurements, 23 ± 5 mm Hg [mean ± SD]), who were included in previous studies from our laboratory. Both groups of patients underwent simultaneous right-heart catheterization and transthoracic echocardiography. Patients provided informed consent after institutional review board approval of the protocol.
Echocardiographic Studies
All examination procedures were performed to provide a comprehensive echocardiographic examination that would enable assessment of LV and RV systolic and diastolic function using several indexes. After acquiring two-dimensional images in the parasternal and apical views, pulsed-wave Doppler was utilized to record transmitral and pulmonary vein (PV) flow in the apical four-chamber view. The sample volume size for acquiring mitral and PV flow signals was 1 to 2 mm, and recordings were acquired for two to three respiratory cycles at a sweep speed of 100 mm/s. TD (similar acquisition to pulsed-wave Doppler) was applied to record mitral annular velocities at the septal and lateral areas111213 and tricuspid annular velocities at its lateral area.14 Care was taken to have the ultrasound beam well aligned with the plane of mitral and tricuspid annulus motion and to avoid angulation (five patients were excluded because of suboptimal alignment). Echocardiographic images were stored and analyzed off-line.
Echocardiographic Analysis
The analysis was performed off-line without knowledge of clinical status. Measurements of LV end-diastolic dimension, EF, and LA maximum volume were performed per American Society of Echocardiography recommendations.17 RV fractional area change (FAC) was calculated from the RV end-diastolic and end-systolic areas as follows: 100 x (RV end-diastolic area – RV end-systolic area)/RV end-diastolic area.17 LV eccentricity index was measured at end-diastole from the parasternal short-axis view at the level of the chordae tendineae. This was calculated as D2/D1, where D2 is the minor-axis dimension parallel to the septum, and D1 is the minor-axis diameter perpendicular to and bisecting the septum.18
Doppler measurements represent the average of three beats. RV outflow tract acceleration time (AT) was measured from pulsed-wave Doppler flow velocity profile of RV outflow tract as the interval from onset to maximal velocity of forward flow. RV ejection time (ET) was measured as the interval from the onset of flow to pulmonic valve closure. Continuous-wave Doppler was utilized to record the tricuspid regurgitation (TR) jet from multiple windows, and the PA systolic pressure was derived using the modified Bernoulli equation (PA systolic pressure = 4v2 + RA pressure, where v is the peak velocity of TR in meters per second), and an estimate of mean RA pressure using the diameter and collapse index of the inferior vena cava and the hepatic venous flow pattern.19 Systemic stroke volume (SV) was calculated as cross-sectional area of LV outflow tract x LV outflow tract time velocity integral.19 As a surrogate for pulmonary vascular resistance (PVR), the ratio of peak TR velocity (meters per second) to RV outflow tract time velocity integral was calculated.20
Mitral inflow was analyzed for peak early diastolic velocity (E), peak late diastolic velocity (A), E/A ratio and deceleration time of E. From the PV flow signals (feasible in 45 PH patients and all 35 control subjects), the peak velocity of systolic, diastolic, and atrial flow were determined. Systolic velocity (Sa), early diastolic velocity by TD (Ea), and late diastolic velocity by TD (Aa) at the septal and lateral areas of the mitral annulus and the RV free wall (lateral area of the tricuspid annulus) were measured.11121314
Right-Heart Catheterization
Medex transducers were balanced prior to the acquisition of the hemodynamic data, with the zero level at the midaxillary line. Pressure measurements were acquired at end-expiration and represent the average of five cardiac cycles. PCWP was verified by chest radiograph and changes in pressure waveform. Cardiac output was derived by thermodilution, in which three cardiac cycles with < 10% variation were averaged. PVR was calculated.
Statistics
Demographic and echocardiographic variables were compared between patients with idiopathic PH and the normal group using unpaired t tests. Changes after therapy in the idiopathic PH group were evaluated using paired t tests. Linear regression analysis was used to relate invasive hemodynamic measurements to Doppler variables; p < 0.05 was considered significant.
Results
RV and LV Structure and Function in Patients With PH
As expected, patients with PH had a significantly larger RV area and LV eccentricity index but a lower RV FAC in comparison with age-matched control subjects (Table 1
). RV outflow tract AT and ET were shorter in the PH group with a higher index of PVR. The mitral inflow pattern showed predominant late diastolic flow with an E/A ratio < 1. However, mitral annulus lateral Sa and Ea velocities were similar to those of the control group. While septal E/Ea ratio was significantly higher in patients with PH vs control subjects, lateral E/Ea ratio was significantly lower (Table 2
). An example from a patient is shown in Figure 1
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Estimation of Mean PCWP in Patients With PH
A significant correlation was noted between mean PCWP and lateral (Fig 2
) and septal E/Ea ratio (r = 0.45, p < 0.05) in patients with idiopathic PH. The correlation coefficient was lower than that reported in other patient groups, likely due to the narrow range of PCWP (2 to 11 mm Hg).
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12 mm Hg (the 50 patients with idiopathic PH and invasive hemodynamic measurements), we included the results from the 25 patients with secondary PH due to a cardiac etiology (see "Materials and Methods" section). A lateral E/Ea ratio < 8 readily identified all the 50 idiopathic PH patients with mean PCWP 12 mm Hg. For patients with secondary PH, a lateral E/Ea ratio > 10 was present in all patients. However, E/Ea ratio using septal Ea resulted in overestimation of PCWP in 25 patients (50%) when using a threshold ratio of 10, whereas a ratio < 18 (by receiver operating characteristic curve analysis) resulted in the correct identification of normal mean PCWP in all patients with idiopathic PH.
Correlation of Invasive With Doppler-Derived Measurements
Table 3
provides a summary of the findings at the time of right-heart catheterization. Invasively derived PVR was significantly related to AT (r = – 0.6, p < 0.01), AT/ET (r = – 0.65, p < 0.01), and ratio of TR peak velocity to RV outflow tract time velocity integral (r = 0.69, p < 0.01). Likewise, SV (r = 0.8, p < 0.01; SEE, 5 mL) and mean PCWP predicted by lateral E/Ea ratio (r = 0.65, p < 0.01; SEE, 3 mm Hg) were significantly correlated with their corresponding invasive measurements.
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Novel observations in this study include the ability of TD imaging of the lateral mitral annulus to reliably predict the presence of normal/reduced mean PCWP in patients with idiopathic PH, and to track the improvement in LV filling with long-term targeted therapy. In addition, systolic and diastolic myocardial velocities by TD at the septum and RV free wall readily identify the improvement of RV systolic and diastolic function with therapy.
TD Estimation of LV Filling Pressures in Patients With Idiopathic PH
Most patients with PH not due to a cardiac etiology will exhibit a mitral inflow pattern of predominant late diastolic filling in the presence of normal sinus rhythm.123456 This is largely due to increased PVR and reduced LA filling and mean LA pressure as noted in this (Table 3) and a previous study.4 Our observations using TD show that early diastolic LV pressures are reduced given the reduced E/Ea ratio using Ea at lateral mitral annulus.111213
Patients with a noncardiac etiology of PH usually have a reduced E/Ea ratio when Ea is measured at the lateral side of the mitral annulus. The ratio is reduced, given the presence of a normal lateral Ea velocity and a reduced mitral E velocity (due to reduced LV filling). However, patients with a cardiac etiology for PH have an increased E/Ea ratio due to the increase in mitral E (because of increased LA pressure) and a reduced annular Ea (due to impaired LV relaxation). Therefore, the current study highlights a potentially important application of TD in the evaluation of patients presenting with PH, as a normal or reduced E/Ea ratio indicates the presence of normal or reduced LA pressure and therefore a noncardiac etiology for PH.
Application of TD To Detect RV Response to Long-term Targeted Therapy
Successful therapy for PH results in a decrease in PVR and PA pressures. The extent of improvement varies, but the detection of a response, or lack thereof, is still important in the management of these patients. Echocardiography plays an important role, given its noninvasive nature, its portability, and its versatility.6 Previous studies421 have shown the utility of conventional two-dimensional and Doppler echocardiography in studying the changes in PA pressure and RV function after pulmonary thromboendarterectomy, and longer-term use of prostacyclin22 and bosentan.23 In this study, we report on the application of TD imaging in detecting changes in biventricular function with long-term targeted therapy.
At baseline, RV systolic function was depressed and the depressed Sa velocity at the RV free wall is consistent with the reduced RV FAC by two-dimensional imaging. Sa increased with therapy, signifying an improvement in RV systolic function. While FAC and Sa share the same hemodynamic determinants of intrinsic contractility, preload and afterload, Sa has the advantage of being a single measurement and the lower impact of suboptimal two-dimensional images on its accuracy.
RV diastolic function was abnormal in this sample of patients with idiopathic PH as surmised from RV free-wall Ea velocity that was significantly reduced in comparison with age-matched control subjects. Given the interdependence between myocardial systolic and diastolic function at the cellular and organ level, we noted several significant correlations between Ea and Sa, both at the septum and the RV free wall. Likewise, the magnitude of improvement with long-term targeted therapy was similar for Sa and Ea. The improvement of RV relaxation, which nevertheless remains impaired, leads to lower RV filling pressures and a reduced degree of systemic congestion. Therefore, TD indexes of RV diastolic function can provide incremental information to systolic function data.
Application of Changes in TD Velocities at Mitral Annulus To Detect Changes in LV Function With Long-term Targeted Therapy
At baseline, septal Sa and Ea were reduced, whereas these velocities at the lateral side of the mitral annulus were normal. This is likely due to the contribution of RV myocardium to annular velocities measured at the interventricular septum. This notion is supported by the direct and significant relation between septal Sa and each of RV FAC and free-wall Sa. Similar correlations were also noted for septal Ea and Ea measured at the RV free wall. After therapy, both velocities increased reflecting the improvement in RV, and not LV, function.
Sa and Ea measured at the lateral side of the mitral annulus were normal at baseline and remained so at follow-up. We believe that this observation supports the presence of normal LV function in the patients with idiopathic PH included in this study. However, the significant increase in lateral E/Ea ratio after medical therapy is indicative of an improvement in LV filling and an increase in LA pressure, albeit still in the normal range. In contrast, septal E/Ea ratio did not change significantly with therapy. We believe this is due to a similar change in the numerator and denominator that make up that ratio. Mitral E increased because of an improvement in LV filling resulting from the decrease in RV diastolic area/volume and the decrease in PVR. Unlike Ea at the lateral side of the mitral annulus, septal Ea increased because of the improvement in RV relaxation. Therefore, lateral and not septal, E/Ea ratio should be applied to track changes in LV filling and LA pressure with long-term targeted therapy for idiopathic PH.
Limitations
Recording mean PCWP in patients with severe PH can be challenging. The wedge position was verified by the changes in mean value, wave form, and if needed oxygen saturation. The fact that mean PCWP range was from 2 to 11 mm Hg in this series of patients with idiopathic PH supports the conclusion that the true wedge pressure was indeed acquired. Measurements of SV by thermodilution are not reliable in patients with severe TR, and therefore thermodilution is not necessarily the "gold standard" in these cases. However, the routine measurement of cardiac output for these patients is usually achieved by thermodilution, and only three patients had severe TR in this series.
Likewise, there are limitations to the application of echocardiography for the assessment of cardiac hemodynamics in patients with PH. These range from the suboptimal alignment of the ultrasound beam with the plane of flow or cardiac motion in some patients to the lack of adequate windows altogether. Nevertheless, it is possible to achieve high feasibility rates by an experienced team of sonographers and physicians. While Doppler echocardiography can estimate PA systolic pressure with reasonable accuracy in most patients, it may not reflect the exact magnitude of change with therapy when compared against invasive measurements. This is particularly true when small changes (< 5 mm Hg) are considered.
There are special limitations to TD as applied in this study. We included only patients in sinus rhythm, and the impact of the non-sinus rhythm on its accuracy in patients with idiopathic PH remains to be seen. Nevertheless, E/Ea ratio was shown to be accurate in cardiac patients with atrial fibrillation and sinus tachycardia. The optimal E/Ea ratio using septal Ea was derived based on a select group of 25 patients with PH secondary to cardiac disease and awaits validation in a prospective group. Ea measured at the RV free wall was not validated against invasive measurements of RV relaxation (first derivative of ventricular pressure during diastole and 
). However, the group with idiopathic PH likely had abnormal RV diastolic function as inferred from the increased mean right atrial pressure. We cannot address the issue of whether echocardiographic changes by TD reflect changes in functional status or exercise capacity because these data were not captured, and additional studies are needed to answer this question.
Conclusions and Clinical Implications
TD imaging has a number of useful applications in the clinical evaluation of patients with PH. These include its ability to identify patients with normal or reduced PCWP and, therefore, a noncardiac etiology. In patients with an established diagnosis, it can track the changes in RV function and LV filling in response to long-term targeted therapy.
Footnotes
Abbreviations: A = late diastolic velocity at mitral valve tips; Aa = late diastolic velocity; AT = acceleration time; E = early diastolic velocity at mitral valve tips; Ea = early diastolic velocity; EF = ejection fraction; ET = ejection time; FAC = fractional area change; LA = left atrial; LV = left ventricular; PA = pulmonary artery; PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; PV = pulmonary vein; PVR = pulmonary vascular resistance; RV = right ventricular; Sa = systolic velocity by tissue Doppler; SV = stroke volume; TD = tissue Doppler; TR = tricuspid regurgitation
The authors have no conflicts of interest to disclose.
Received for publication June 22, 2006. Accepted for publication September 5, 2006.
References
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