Standard Echocardiography

All patients underwent transthoracic echocardiography with a commercially available cardiovascular ultrasound system (Vivid E9; GE, Horten, Norway). Established criteria were used for measurements of left and right chambers.¹² 2D and M‐mode left ventricular (LV) dimensions were obtained. Doppler mitral peak early (E) and late (A) diastolic velocities, and tissue Doppler imaging mitral valve annulus velocities (MV S_a, E_a, A_a) were measured on the transthoracic 4‐chamber views. MV E/E_a ratio is a parameter reflecting LV filling pressure¹² and was determined by measuring velocities of the lateral mitral valve annulus. RV to LV end‐diastolic diameter ratio was calculated in the apical 4‐chamber view. RV end‐diastolic area and end‐systolic area were assessed by manual planimetry, and RV fractional area change (RVFAC) was derived using the formula RVFAC=[(RVEDarea−RVESarea)/RVEDarea]×100 (where ED=end diastolic and ES=end systolic). 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. Myocardial performance index was derived from the analysis of RV function Doppler parameters. Pulmonary acceleration time (PAT) was measured as the interval between the onset of ejection and peak pulmonary flow velocity from the parasternal short‐axis view. Right ventricular systolic pressure (RVSP) was determined by continuous‐wave Doppler echocardiography and was considered elevated when reaching values >30 mm Hg. RA pressure was estimated according to caval dimensions. Estimation of pulmonary vascular resistance (PVR) was determined on the basis of the ratio of peak tricuspid regurgitation 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.¹³ Pulmonary artery capacitance was calculated as Doppler‐derived stroke volume/pulmonary artery pulse pressure.¹⁴ Tricuspid annulus systolic velocity (TV S_a) and diastolic velocity (TV E_a) were measured at the lateral corner of the tricuspid annulus on the transthoracic 4‐chamber view. TV E/E_a reflects increased RA pressure^12,15 and was taken as the parameter of RV diastolic function

Three‐Dimensional Echocardiography

3DE was done using a dedicated wide‐angle, broadband matrix‐array transducer to allow for full cover of the entire RV by the pyramidal volume, with special attention to the outflow tract and upper anterior wall. Before acquisitions, images were optimized for the endocardial border visualization, modifying overall gain and adjusting time gain and compression. Then they were digitally stored for offline analysis by TomTec software (TomTec Imaging Systems, Unterschleissheim, Germany). Three orthogonal planes and various landmarks were selected to define the end‐diastolic and end‐systolic frames. The program automatically supplies 4‐chamber, sagittal, and coronal RV views on the basis of the initial view adjustment. RVEDV and RVESV were calculated from 3D echocardiographic data sets. RVEF was determined as follows: RVEF =[(RVEDV−RVESV)/RVEDV]×100 (Figure 1). Total RVEF was automatically generated by the software. Inflow, outflow, and apex RVEFs were measured by subtracting the minimum (end‐systolic) volume from the maximum (end‐diastolic) volume of the respective compartment divided by the end‐diastolic volume. Volume changes during the cardiac cycle were assessed.

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Figure 1.

Representative 3D RV volumes and ejection fraction in normal controls and PH patients. A, Three‐dimensional RV ejection fraction (3D‐RVEF) in a normal subject. 3D‐RVEF=59%. B, Decrease of 3D‐RVEF in a patient with chronic PH. 3D‐RVEF=35%. C, Regional three‐dimensional RV ejection fraction. RV components are illustrated in a three‐dimensional reconstruction of the echocardiographic images seen in a front view. 1, inlet; 2, apical trabecular; 3, outlet component. EDV indicates end‐diastolic volume; EF, ejection fraction; ESV, end‐systolic volume; P, pulmonary outflow; PH, pulmonary hypertension; RV, right ventricular; RVEF, RV ejection fraction; SV, stroke volume; T, tricuspid inflow.

Speckle‐Tracking Echocardiography

The general principles that underlie 2D speckle‐tracking modalities have been previously described.^15–21 Patients were placed in the left lateral decubitus position and examined with an active matrix single‐crystal phased‐array transducer (GE‐M5S). Grayscale recordings were optimized at a mean frame rate of ≥50 frames/s. Apical 4‐chamber views were used to assess the RV inflow compartment, and special care was taken to ensure a proper image of the entire RV by narrowing the width of the 2D sector, or by placing the transducer in 1 intercostal space lower and side. To assess regional and global longitudinal RV systolic function, we adopted a 6‐segment RV model (basal RV free wall, mid RV free wall, apical RV wall, apical septum, mid septum, and basal septum). Peak systolic strain was recorded for the 3 RV myocardial free wall and septal segments, and the entire RV wall and RV free‐wall segments were selected for measurements (Figure 2). RV outflow compartment was assessed by tracing along the right ventricular outflow tract wall in parasternal short axis views as previously described²⁰ and displaying the corresponding segmental and global strain curves. Time to peak negative strain with respect to the onset of the Q‐wave of the superimposed ECG was measured for inflow and outflow segments. The echocardiographic results were analyzed by an echocardiologist (A.V.) blinded to the clinical data, using dedicated software (EchoPAC BT12, 4D Auto LVQ; GE Vingmed Ultrasound, Horten, Norway).

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Figure 2.

Representative 2D and 3D RV strain images in normal controls and PH patients. A, Speckle‐tracking apical view showing global and regional RV longitudinal strain in a normal subject. Global RV longitudinal strain (G‐RVLS)=−28%. B, Speckle‐tracking apical view showing global and regional free‐wall RV longitudinal strain in a normal subject. Free wall (FW) is labeled by asterisks. Global free‐wall RV longitudinal strain (GFW‐RVLS)=−36%. C, Decrease of GFW‐RVLS in a patient with chronic PH. GFW‐RVLS=−13%. D, 3D RV speckle‐tracking multiplane view in a normal subject. 3D global longitudinal strain (3D G‐RVLS) was −26%. 3D global longitudinal strain of RV free‐wall (3D GFW‐RVLS) was then calculated excluding septal segments. FW is labeled by asterisks. AVC indicates aortic valve closure; ED, end‐diastolic; ES, end‐systolic; PH, pulmonary hypertension; RV, right ventricular.

3D speckle‐tracking analysis was performed after imaging the RV chamber in apical views by using a 4V phased array transducer with high volume rate (≥30 image frames/s) and 6‐beat acquisition. 3D global longitudinal strain of whole RV (17 segments) was calculated using the Echo PAC BT12 (Figure 2). 3D global longitudinal strain of RV free‐wall only (3D Global‐FW RVLS) was calculated using Excel data.¹⁰ 3D global area strain (AS) was determined as the percentage decrease in the size of endocardial surface area defined by the vectors of longitudinal and circumferential deformations.¹¹ 3D global area strain of RV free‐wall only (3D Global‐FW AS) was then calculated.

Cardiac Catheterization

PH was confirmed by cardiac catheterization and right‐heart hemodynamic measurements. These studies were performed under fluoroscopic guidance via a femoral vein approach within 3 days of echocardiography with a mean interval of 1.4±0.4 days. Measurements were obtained at end expiration after zero‐pressure calibration and included right atrial, pulmonary arterial peak systolic and end‐diastolic, and pulmonary capillary wedge pressures. Mean pulmonary artery pressure, PVR, transpulmonary pressure gradient (mean pulmonary artery pressure minus mean wedge pressure), and pulmonary artery capacitance (ratio of stroke volume over pulmonary pulse pressure) were calculated. Cardiac output was determined by thermodilution²² and indexed to body surface area to obtain cardiac index.

Previous Studies

Despite the prominent role of RV in PH prognosis, little is known about segmental patterns of RV function, and literature results have been conflicting. Previous studies using tissue Doppler imaging, STE, and 3DE^{6–9,21,25–29} reported various patterns of RV remodeling in patients with chronic PH. A reduced apical RV longitudinal strain allowed feasible and reliable estimation of PH and appeared helpful to distinguish between pre‐ and postcapillary PH.²⁶ An apical dysfunction was also emphasized by magnetic resonance imaging (MRI) studies.²⁷ Other authors showed moderate or severe RV dysfunction with decrease of strain of the basal segment of the RV free wall in patients with COPD⁶ and PH of mixed etiologies.^21,25 There was improvement in regional 2D deformation parameters with long‐term oral vasodilator therapy.²¹ Low values of RV lateral free‐wall 2D strain were found in patients with arterial and thromboembolic PH.⁸ The importance of RV outflow tract function has been stressed by STE and MRI studies^20,28 showing increase of infundibular wall stress and decrease of fractional wall thickening in patients with PH of different etiologies. Serial quantitative assessment of RV function by strain²⁹ independently predicted clinical deterioration and mortality in patients with PAH after the institution of medical therapy.

The use of 3DE in the assessment of chronic PH^4,30 showed a different extent of contribution to the overall systolic function for the inflow, apical, and outflow tract compartments. Other studies described a significant association of 3D longitudinal strain¹⁰ and area strain¹¹ with RVEF and a prognostic value independent of other variables.

Present Study

Our report differs from previous literature in some respects. First, we analyzed comparatively the diagnostic accuracy of 3DE and 2D‐3D‐strain indices showing a better association with hemodynamic variables reflecting right heart failure than standard echo indices. To the best of our knowledge, this is the first study assessing the relation between these echocardiographic indices and the hemodynamic parameters indicative of RV failure. Second, RV strain impairment was more marked in patients with precapillary PH and less pronounced in patients with postcapillary PH and LV diastolic dysfunction and, even if overlap between groups limits its clinical utility, this finding showed an additional value compared to standard echo parameters, and this is of interest since current guidelines point out the importance of early diagnosis of precapillary PH and differentiation from other PH entities.^1–2,26 Third, the apex involvement was a constant feature of RV dysfunction in chronic PH. This pattern is different from that seen in the acute pulmonary embolism setting as reported by ourselves³¹ and others,³² where reduced RV free wall contraction is found with preserved apical wall motion on 2DE. No bulging of the mid–RV free wall relative to the apex and base occurs in chronic PH since RV hypertrophy may limit shape changes and tethering effects.

The global and regional RV deformation patterns that we found in chronic PH can be explained by the complex and different pathophysiologic mechanisms in PH groups.^33–38 To group PH entities according to their pathophysiological–clinical mechanisms and response to medical therapy certainly helps clinical practice, although it is an oversimplification since differences exist within various subgroups. Systemic sclerosis–associated pulmonary artery hypertension (PAH‐SS) has a poorer prognosis³³ than that of other types of PH,³⁴ with a median survival of 3 years. This could be explained by intrinsic myocardial involvement of the disease related to abnormal collagen deposition, or an increased vulnerability to ischemia due to coronary vasculopathy in addition to enhanced pulmonary vascular resistive and/or pulsatile loading. Patients with systemic sclerosis–associated pulmonary artery hypertension had higher values of pulmonary artery pressure and PVR, lower values of pulmonary artery capacitance, a more diffuse impairment in RV strain, and lower strain values compared to PAH‐congenital heart disease, COPD, and MR patients. Actually, disorders associated with chronic lung disease or hypoxia are generally characterized by moderate PH, and RV dysfunction is characterized by hypertrophy with preserved cardiac function.³⁵ Nevertheless, RV failure can occur during disease exacerbations or when multiple comorbidities are present. PH is only mildly elevated also in chronic MR; it develops after the increased left atrial pressure (postcapillary), and the right ventricle is less dilated compared to PAH.³⁶ However, the presence of PH secondary to MR is a determinant of long‐term survival, and RVEF has been shown to be an independent predictor of survival in patients with heart failure. The findings of our study are in line with previous reports^4,28 that described different global and regional RV changes in patients with different RV pressure overload.

In our population, both 2D‐STE and 3D‐STE were shown to be more sensitive to detect subtle myocardial damage compared to conventional indices of RV function. 3D area strain is a combination of longitudinal and circumferential function and has already been validated as a useful measurement of LV function.³⁹ Since it has integrated 2‐directional components of myocardial deformation (longitudinal and circumferential), area strain might decrease the tracking error and emphasize synergistically the magnitude of deformation. Thus it is reasonable to expect that deteriorated ventricular function can be detected at an earlier stage by using 3D speckle‐tracking analysis in comparison with 1‐directional strain.⁴⁰ However, the superiority of 3D‐STE over 2D‐STE for the evaluation of all 3 components of LV deformation (longitudinal, circumferential, and radial) has been questioned.⁴¹ The 3D mode avoids foreshortening of apical views, consumes less time in data acquisition, helps to solve the problem of out‐of‐plane motion present in the 2D modality tracking motion of speckles in all 3 dimensions, but this advantage is achieved at the expense of lower volume rate. Similar considerations can be made for the right ventricle; however, our results showed that the new 3D‐STE measurements had strong associations with hemodynamic parameters indicative of RV failure, albeit we did not find any superior clinical advantage over 2D‐STE except for a more rapid acquisition and offline‐analysis time.

Our finding is partially coincident with previous research^3–4,30,37 suggesting that the change of volume and systolic function was at least in part related to high RV afterload caused by increased pulmonary artery pressure and PVR and existed in all of the 3 RV compartments. Furthermore, we showed that decrease in RV strain can be localized at the regional level (basal, apical) or widespread in the RV free wall. The decrease of EF and strain in the body and inflow compartment compared to controls were more significant than those in the outflow chamber. The early impairment of RV inflow systolic function could be explained by the predominant role of inflow contraction in RV global performance, and this is in keeping with the phylogenetic research that showed³⁷ that the RV sinus (inflow and body) compartments developed a million years after the outflow compartment, probably as an adaptation of the cardiovascular system to breathing air.

The moderate correlation we obtained between PVR and RVEF is in keeping with previous studies⁴² that showed that in chronic PH, RV function does not fully adapt to changes in vascular properties and can decline independent of PVR, and RV contractility may increase during early PH and then decrease in a more advanced stage when pulmonary artery pressures fail to increase further. Other factors may play an important role in the changes in RVEF over time, including older age, genetic differences in RV adaptation to pressure overload, and ventricular wall tension.⁴² Moreover, correlations between RV function echocardiographic parameters and mean pulmonary artery pressure obtained via catheterization may be stronger in pulmonary hypertensive patients solely with right‐sided disease and weaker in mixed populations including patients with LV overload and/or dysfunction.⁷

We have already reported^18,31 that the newer technologies appear to be superior to conventional technologies, including RVFAC, TAPSE, and myocardial performance index. In our cohort of patients with chronic PH, the assessment of 3D RVEF and strain gave us valuable information on global and regional RV function with better diagnostic accuracy in predicting RV failure hemodynamics compared to the other methods. Also, in our study we have found some common strong prognostic factors with chronic PH, such as age, New York Heart Association functional class, invasive right atrial pressure, pulmonary artery capacitance, pulmonary vascular resistance, TAPSE, 3D‐GFW‐RVLS, and 3D‐RVEF. The results concerning the prognostic value of pulmonary artery capacitance provide further evidence that pulsatile components (pulmonary artery capacitance) of RV afterload give additional information compared to the static part (PVR) of RV afterload.^14,43 STE and 3D echocardiographic parameters tended to be associated with adverse events in univariate analysis and were independently associated with adverse events in multivariate analysis, and these data are in keeping with recent reports¹¹ showing that reduced RV strain was associated with poor outcome in PH patients.

Clinical Implications

We have shown that in chronic PH patients, 3D RV volumes and 2D‐3D strains are better predictors of the hemodynamic indices of RV failure compared to conventional RV parameters as well as better predictors of mortality. Both RV global function parameters and regional strain indices of the inflow region and apex appeared to detect early signs of ventricular failure. Their use could improve the evaluation of subtle RV changes when TAPSE, tricuspid valve annular systolic velocity, and FAC are not conclusive or in the first stages of PH when TAPSE is known to be still normal. The described cutoff values for global and regional RV echo parameters (3D‐RVEF 39%, 3D global‐FW RVLS −17%, basal‐FW RVLS −19%, apical‐FW RVLS −16%) may allow PH patients to be followed serially and to assess the response to medical therapy.