Background
The aim of this study was to noninvasively investigate right ventricular and left ventricular (LV) adaptation to right ventricular pressure overload in patients with acute pulmonary thromboembolism (APTE) and chronic pulmonary artery hypertension (CPAH).
Methods
Thirty-seven patients with APTE, 36 patients with CPAH, and 33 controls were retrospectively enrolled. Myocardial deformation and wall motion were analyzed using speckle-tracking strain and displacement imaging echocardiography in the right and left ventricles. The standard deviation of the heart rate–corrected intervals from QRS onset to peak systolic strain and peak systolic displacement (PSD) for the six segments was used to quantify right ventricular and LV mechanical dyssynchrony (peak systolic strain dyssynchrony and PSD dyssynchrony). The myocardial performance index in both ventricles was also evaluated.
Results
The APTE and CPAH groups had reduced ventricular performance (LV myocardial performance index, 0.40 ± 0.10, 0.66 ± 0.18 [ P < .05 vs controls], and 0.58 ± 0.19 [ P < .05 vs controls] in the control, APTE, and CPAH groups, respectively) and large mechanical dyssynchrony (LV longitudinal PSD dyssynchrony, 58 ± 41 msec, 119 ± 49 msec [ P < .05 vs controls], and 83 ± 37 msec [ P < .05 vs controls and the APTE group] in the control, APTE, and CPAH groups, respectively) in both ventricles. Multiple regression analysis indicated that LV longitudinal PSD dyssynchrony in the APTE group and the LV eccentricity index in the CPAH group were independent determinants of LV myocardial performance index.
Conclusions
Pathophysiologic mechanisms that regulate ventricular performance vary depending on whether the ventricles are exposed to acute or chronic right ventricular pressure overload.
Right ventricular (RV) pressure overload affects left ventricular (LV) performance via ventricular interdependence. Because of ventricular interdependence within the restricted intrapericardial space, marked RV dilatation causes a significant alteration in LV geometry and exerts a constraining effect on LV performance. Recent clinical studies have demonstrated that RV pressure overload induces RV mechanical dyssynchrony. In addition, impairment of LV mechanical synchrony can also be observed in the setting of RV pressure overload and has the potential to contribute to further deterioration of LV performance. We previously and independently reported that acute and chronic RV pressure overload negatively affected LV mechanical synchrony associated with LV functional impairment. However, it has not been determined if the contribution of RV and LV mechanical dyssynchrony to each ventricle’s performance varies depending on whether the heart is exposed to acute or chronic RV pressure overload. Speckle-tracking strain and displacement echocardiography can measure global and regional myocardial kinetics, including mechanical dyssynchrony, independent of echo angle and chamber translation. Accordingly, we extended our previous investigation and investigated the potential role of regional wall motion abnormalities and mechanical dyssynchrony in the pathophysiologic processes leading to development of LV functional deterioration using speckle-tracking echocardiography in combination with quantitative assessment of ventricular geometric remodeling in patients with acute pulmonary thromboembolism (APTE) and chronic pulmonary artery hypertension (CPAH).
Methods
Study Population
A total of 86 consecutive patients with massive or submassive APTE ( n = 40) and CPAH ( n = 46) who were referred to Mie University Hospital between May 2005 and March 2012 were retrospectively screened for inclusion in this study. The diagnosis of APTE was confirmed or excluded using a combination of personal history, physical examination, laboratory tests, electrocardiography, echocardiography, thoracic computed tomography, and right heart catheterization, as previously described. All patients with CPAH met the restrictive criteria of a diagnosis of pulmonary artery hypertension by right heart catheterization, and their etiology had been identified by personal history, physical examination, laboratory tests, echocardiography, and thoracic computed tomography. We excluded three patients with APTE because of suboptimal images. We also excluded 10 patients with CPAH (four with atrial fibrillation, four with ischemic heart disease, one with a pacer wire in the right ventricle, and one with technically inadequate images). Accordingly, the patient study groups consisted of 37 subjects with APTE (mean age, 61 ± 15 years) and 36 with CPAH (mean age, 55 ± 19 years). Twenty-five of 37 patients with APTE and 17 of 36 patients with CPAH in this study had been included in previously published reports. We also studied 33 age-matched normal subjects (the control group; mean age, 57 ± 14 years) who had no histories of cardiopulmonary disease, normal electrocardiographic results, and normal echocardiographic results. Twenty-five of the 33 control subjects in this study had also been included in previously published reports. The protocol was approved for use by the Human Studies Subcommittee of Mie University Graduate School of Medicine.
Echocardiography
All subjects underwent complete transthoracic echocardiography using a Vivid 7 system (GE-Vingmed Ultrasound AS, Horten, Norway), as previously described. Echocardiography was performed on hospital admission (4 ± 5 days after initial symptoms) but before initiating primary treatment in all patients with APTE. The mean duration of symptomatic pulmonary hypertension was 52 ± 69 months until echocardiographic examination in patients with CPAH. Arm-cuff blood pressure measurements were performed at the beginning of the echocardiographic study for all subjects. Peak systolic pulmonary artery pressure was calculated from the sum of the mean right atrial pressure, as estimated by the diameter of the inferior vena cava and its respiratory variation, and the maximal pressure difference between the right ventricle and the right atrium, as calculated by the continuous-wave Doppler flow velocity. The RV end-diastolic area index, the end-systolic area index, and the fractional area change from the apical four-chamber view were also measured. Pulmonary vascular resistance (PVR) was noninvasively estimated using echocardiography. LV volume indices and ejection fraction were assessed using the biplane Simpson’s rule. The LV eccentricity index, defined as the ratio of the LV anterior-to-posterior dimension to the septal-to-lateral dimension at end-diastole from the midventricular short axis image, was used as an index of septal geometric abnormality caused by RV diastolic pressure overload. The Doppler-derived stroke volume was normalized to body surface area. The ratio of peak early to late diastolic transmitral flow velocity (mitral E/A) was calculated using pulsed Doppler echocardiography. Peak early diastole mitral annular velocity (Ea) at the inferior septum was measured from the apical four-chamber view. The E/Ea ratio was calculated as a Doppler parameter reflecting LV diastolic pressure. The myocardial performance indexes (MPIs) in the left and right ventricles was assessed as previously described. Systemic vascular resistance was calculated as follows: systemic vascular resistance (Wood units) = (mean arterial blood pressure − mean right atrial pressure)/cardiac output. All echocardiographic measurements represent the average of three beats.
Speckle-Tracking Strain and Displacement Analysis
Speckle-tracking analysis was used to generate regional myocardial strain and displacement in both the left and right ventricles ( Figures 1–3 ). RV and LV longitudinal strain and displacement were assessed in the apical four-chamber views. LV radial and circumferential regional strain and LV radial displacement were assessed in the parasternal short-axis views at the mid-LV level. We did not perform circumferential displacement analysis in the present study, because EchoPAC software (GE-Vingmed Ultrasound AS) has no capability to measure circumferential displacement. The average frame rate for the analysis was 76 ± 15 Hz. For speckle-tracking echocardiographic assessment, routine B-mode grayscale images were analyzed using EchoPAC. Myocardial strain is expressed as the percentage change from the original dimension at end-diastole, myocardial thickening or lengthening was represented as a positive value, and myocardial thinning or shortening was represented as a negative value. Myocardial displacement toward the contractile center in the short-axis view or toward the apex in the longitudinal direction was represented as a positive value. The software automatically divided the short-axis and apical 4-chamber image into six standard segments ( Figure 1 ). Peak systolic strain (PSS) and peak systolic displacement (PSD) obtained from time-strain and time-displacement curves were defined as the indices of myocardial systolic deformation and wall motion. The standard deviation of the heart rate–corrected regional time to PSD and time to PSS from the onset of QRS was used to quantify LV mechanical dyssynchrony (PSS dyssynchrony and PSD dyssynchrony, respectively). If there were multiple distinct peaks, the largest peak was taken as the PSS or PSD. Although PSS or PSD occurs at or near aortic valve closure, the timing of these events may be shortened or prolonged, occurring well after aortic valve closure in various cardiac diseases. Accordingly, time to PSS and time to PSD were measured throughout the whole cardiac cycle.
Statistical Analysis
Data are presented as mean ± SD. The association among indices of cardiac function was investigated using regression analysis. Between-group comparisons were assessed using analysis of variance for continuous variables and Fisher’s exact tests for categorical data. Bonferroni’s correction was applied for multiple comparisons. Intraobserver variability was determined by having one observer repeat the measurements of time to PSS and time to PSD for each of the six segments in the RV longitudinal direction and the LV longitudinal, radial, and circumferential directions in 10 randomly selected subjects. Interobserver variability was determined by having a second observer measure these variables in the same data sets. Intraobserver and interobserver variability values were calculated as the absolute differences between the corresponding two measurements as a percentage of the mean. P values < .05 were considered statistically significant. Analyses were performed using SPSS for Windows version 19 (SPSS, Inc., Chicago, IL).
Results
Clinical and Echocardiographic Characteristics
Nineteen patients exhibited massive APTE representing RV dysfunction and hemodynamic exacerbation, and 18 patients exhibited submassive APTE representing RV dysfunction without hemodynamic instability. The CPAH group was composed of 12 patients with idiopathic pulmonary arterial hypertension, 16 with chronic thromboembolic pulmonary hypertension, seven with connective tissue disorder, and one with portopulmonary hypertension. Table 1 shows the clinical characteristics and echocardiographic hemodynamic parameters of the study groups. There were fewer men in the CPAH group compared with the other two groups. Although there were no statistical differences in systolic blood pressure among the three groups, heart rate was significantly higher in the CPAH group compared with the control group, and the elevation of heart rate in the APTE group was more pronounced than that in the CPAH group. There were no statistical differences in QRS duration among the three groups. Although the CPAH group had more pronounced high systolic pulmonary artery pressure than that in the APTE group, PVR was similar in both patient groups. There were no statistical differences in systemic vascular resistance among the three groups.
| Variable | Controls ( n = 33) | Patients with APTE ( n = 37) | Patients with CPAH ( n = 36) |
|---|---|---|---|
| Mean age (y) | 57 ± 14 | 61 ± 15 | 55 ± 19 |
| Men | 45% | 35% | 11% ∗,† |
| Height (cm) | 159 ± 10 | 160 ± 11 | 156 ± 8 |
| Weight (kg) | 56 ± 12 | 64 ± 19 | 51 ± 12 † |
| Body mass index (kg/m 2 ) | 22 ± 3 | 25 ± 6 ∗ | 21 ± 4 † |
| Systolic blood pressure (mm Hg) | 117 ± 12 | 121 ± 22 | 112 ± 19 |
| Diastolic blood pressure (mm Hg) | 69 ± 10 | 79 ± 17 ∗ | 70 ± 14 † |
| Heart rate (beats/min) | 63 ± 10 | 93 ± 15 ∗ | 76 ± 16 ∗,† |
| QRS duration (msec) | 87 ± 8 | 90 ± 12 | 90 ± 18 |
| Systolic pulmonary artery pressure (mm Hg) | — | 54 ± 17 | 77 ± 28 † |
| PVR (Wood units) | — | 5.0 ± 2.4 | 4.5 ± 2.0 |
| SVR (Wood units) | 20.1 ± 3.7 | 23.2 ± 7.6 | 24.1 ± 9.1 |
Table 2 shows the echocardiographic data of the study subjects. Although the CPAH group had larger RV chamber size compared with the APTE group, RV fractional area change was similarly reduced in both patient groups. The APTE group had smaller LV chamber size associated with lower stroke volume index compared with the other two groups. LV ejection fractions were similar in the three groups. The LV eccentricity index was similarly high in both patient groups compared with that in the control group. Both patient groups had reduced mitral E/A ratios and Ea values compared with the control group, but mitral E/Ea ratios were higher only in the CPAH group. RV and LV MPIs were similarly high in both patient groups compared with those in the control group.
| Variable | Controls ( n = 33) | Patients with APTE ( n = 37) | Patients with CPAH ( n = 36) |
|---|---|---|---|
| RV EDA index (cm 2 /m 2 ) | 9 ± 2 | 14 ± 2 ∗ | 17 ± 4 ∗,† |
| RV ESA index (cm 2 /m 2 ) | 4 ± 1 | 10 ± 2 ∗ | 12 ± 4 ∗,† |
| RV FAC (%) | 52 ± 5 | 28 ± 7 ∗ | 29 ± 8 ∗ |
| LV EDV index (mL/m 2 ) | 42 ± 8 | 29 ± 9 ∗ | 40 ± 14 † |
| LV ESV index (mL/m 2 ) | 15 ± 4 | 11 ± 5 ∗ | 14 ± 7 |
| LV ejection fraction (%) | 66 ± 5 | 63 ± 7 | 68 ± 9 |
| LV eccentricity index | 1.05 ± 0.06 | 1.47 ± 0.27 ∗ | 1.51 ± 0.40 ∗ |
| Stroke volume index (mL/m 2 ) | 40 ± 6 | 25 ± 7 ∗ | 30 ± 10 ∗,† |
| Mitral E/A ratio | 1.0 ± 0.4 | 0.7 ± 0.3 ∗ | 0.8 ± 0.3 ∗ |
| Mitral Ea (cm/sec) | 6.3 ± 1.9 | 5.4 ± 2.0 ∗ | 4.5 ± 1.4 ∗ |
| Mitral E/Ea ratio | 10 ± 3 | 10 ± 3 | 13 ± 5 ∗,† |
| RV MPI | 0.27 ± 0.11 | 0.71 ± 0.21 ∗ | 0.70 ± 0.26 ∗ |
| LV MPI | 0.40 ± 0.10 | 0.66 ± 0.18 ∗ | 0.58 ± 0.19 ∗ |
Displacement and Strain Measurements
Speckle-tracking was possible in 100% of 636 attempted segments in the RV apical four-chamber view, 98% in the LV apical four-chamber view, and 99% in the LV short-axis view, from the 106 echocardiographic studies with technically adequate images. Figures 2 and 3 show typical examples of strain imaging ( top ) and corresponding time-strain ( middle ) and time-displacement curves ( bottom ) in a normal subject, a patient with massive APTE, and a patient with severe CPAH. A normal subject had synchronous RV and LV regional strain and displacement through a cardiac cycle ( Figures 2 and 3 , left , and Video 1 for the LV longitudinal displacement image; available at www.onlinejase.com ). In contrast, dyssynchronous RV and LV longitudinal regional myocardial shortening and wall motion were observed in a patient with massive APTE and a patient with severe CPAH ( Figures 2 and 3 , respectively, middle and right ). Notably, the patient with APTE had larger dispersions of longitudinal regional time-displacement curves with abnormal septal motion in the left ventricle than the patient with CPAH throughout the entire cardiac cycle ( Videos 2 and 3 for LV longitudinal displacement images; available at www.onlinejase.com ). Table 3 and Figure 4 show comparisons of global and segmental PSS in the 3 groups. Apical-to-lateral RV longitudinal PSS was reduced in the both patient groups, resulting in reduced global PSS compared with the control group. Notably, mid to basal lateral segments in the APTE group were distinctly reduced compared with the CPAH group. Regional LV longitudinal PSS was impaired, except for basal segments, resulting in reduced global PSS in the APTE group. In the CPAH group, although regional PSS in the mid to basal septum was reduced, global PSS was maintained, because of preserved apical-to-lateral PSS. Global and regional LV radial PSS was reduced in both patient groups to the same extent. Global and regional circumferential PSS was impaired in the APTE group. In the CPAH group, although regional PSS in the anteroseptal, anterior, and lateral segments were reduced, the other three segments were maintained, resulting in only mild reduction in global PSS. Comparisons of PSS dyssynchrony and PSD dyssynchrony in both ventricles among the three groups are shown in Table 3 . All dyssynchrony indices except LV radial PSS dyssynchrony were significantly greater in both the APTE and CPAH groups compared with those in the control group. In particular, LV longitudinal PSS dyssynchrony and PSD dyssynchrony were significantly greater in the APTE group compared with those in the CPAH group.
| Variable | Controls ( n = 33) | Patients with APTE ( n = 37) | Patients with CPAH ( n = 36) |
|---|---|---|---|
| Global RV longitudinal PSS (%) | −26 ± 4 | −14 ± 4 ∗ | −16 ± 5 ∗ |
| Global LV longitudinal PSS (%) | −20 ± 2 | −16 ± 3 ∗ | −20 ± 4 † |
| Global LV radial PSS (%) | 55 ± 15 | 40 ± 16 ∗ | 39 ± 14 ∗ |
| Global circumferential PSS (%) | −23 ± 4 | −17 ± 5 ∗ | −21 ± 5 ∗,† |
| RV PSS dyssynchrony (msec) | 38 ± 17 | 94 ± 42 ∗ | 83 ± 37 ∗ |
| RV PSD dyssynchrony (msec) | 68 ± 33 | 106 ± 52 ∗ | 107 ± 54 ∗ |
| LV PSS dyssynchrony (longitudinal) (msec) | 43 ± 14 | 87 ± 33 ∗ | 63 ± 22 ∗,† |
| LV PSD dyssynchrony (longitudinal) (msec) | 58 ± 41 | 119 ± 49 ∗ | 83 ± 37 ∗,† |
| LV PSS dyssynchrony (radial) (msec) | 25 ± 23 | 25 ± 29 | 22 ± 29 |
| LV PSD dyssynchrony (radial) (msec) | 38 ± 21 | 71 ± 34 ∗ | 65 ± 35 ∗ |
| LV PSS dyssynchrony (circumferential) (msec) | 34 ± 21 | 66 ± 38 ∗ | 56 ± 21 ∗ |
