Evaluation of Right Intraventricular Dyssynchrony by Two-Dimensional Strain Echocardiography in Patients With Pulmonary Arterial Hypertension

RV FUNCTION IN PULMONARY HYPERTENSION

Evaluation of Right Intraventricular Dyssynchrony by Two-Dimensional Strain Echocardiography in Patients With Pulmonary Arterial Hypertension Andreas P. Kalogeropoulos, MD, Vasiliki V. Georgiopoulou, MD, Sharon Howell, RDCS, Maria-Alexandra Pernetz, RDCS, Micah R. Fisher, MD, Stamatios Lerakis, MD, and Randolph P. Martin, MD, Atlanta, Georgia

Background: Right ventricular (RV) function has major prognostic implications for patients with pulmonary arterial hypertension (PAH). Intraventricular dyssynchrony might play an important role in RV dysfunction in these patients. Methods: Thirty-six patients with PAH without right bundle branch block (mean age 44 ⫾ 14 yr, 24 women) and 39 controls (mean age 43 ⫾ 18 yr, 26 women) were evaluated. Global and segmental RV longitudinal deformation parameters were recorded by 2-dimensional strain echocardiography from apical 4-chamber views using a 6-segment RV model. The standard deviation of the heart rate– corrected intervals from QRS onset to peak strain for the 6 segments (RV-SD6) was used to quantify right intraventricular dyssynchrony. Results: RV-SD6 was significantly higher in patients with PAH compared with controls (63 ⫾ 21 vs 25 ⫾ 15ms, P ⬍ .001). Dyssynchrony in patients with PAH was found to derive mainly from delayed contraction of the basal and mid RV free wall. In patients with PAH, RV-SD6 was strongly correlated with RV fractional area change (␤ ⫽ ⫺.519, P ⫽ .002), RV myocardial performance index (␤ ⫽ .427, P ⫽ .009), and RV global strain (␤ ⫽ .512, P ⫽ .002); in models controlling for RV systolic pressure, RV size, and QRS duration, RV-SD6 was still an independent predictor of RV fractional area change (␤ ⫽ ⫺.426, P ⫽ .005) and RV global strain (␤ ⫽ .358, P ⫽ .031). RV function was significantly worse in the subgroup of patients with PAH (n ⫽ 25) with RV-SD6 ⬎ 55 ms (the upper 95% limit in controls). Conclusion: Right intraventricular dyssynchrony, as quantified by 2-dimensional strain echocardiography, is prevalent in PAH and is associated with more pronounced RV dysfunction. The clinical implications of these findings remain to be determined in follow-up studies. (J Am Soc Echocardiogr 2008;21:1028-1034.) Keywords: Right ventricular dyssynchrony, 2-Dimensional strain echocardiography, Pulmonary arterial hypertension

Left ventricular (LV) dyssynchrony leads to a worsening of LV function and increased risk for adverse outcomes in patients with impaired LV ejection fraction,1,2 and this effect is independent from QRS duration.1,2 However, the impact of mechanical dyssynchrony on right ventricular (RV) function has received considerably less attention. The quantification of RV function by echocardiography is challenging because of the complex geometry of the right ventricle; this becomes more evident when it comes to RV synchrony. Doppler tissue imaging (DTI) studies have correlated septal-to-free RV wall mechanical delay with the severity of RV dysfunction in patients with

From the Division of Cardiology and the Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University Hospital, Atlanta, Georgia. Reprint requests: Andreas Kalogeropoulos, MD, Emory University Hospital, Noninvasive Cardiology, 1364 Clifton Rd NE, Suite D-433, Atlanta, GA 30322 (E-mail: [email protected]). 0894-7317/$34.00 Copyright 2008 by the American Society of Echocardiography. doi:10.1016/j.echo.2008.05.005

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pulmonary hypertension of various etiologies.3,4 Recently, LopezCandales et al5 demonstrated an increased septal-to-free RV wall delay in patients with mild pulmonary hypertension, despite the absence of gross abnormalities in RV size or function. Because of the inherent limitations of DTI, however, the evaluation of temporal patterns in the right ventricle has been virtually limited to the basal portions of the septal and free walls.3,4 This approach may not appropriately describe RV dyssynchrony in patients with RV dysfunction, however, because the RV remodeling process remains largely unexplored,6 and recent data suggest significant regional heterogeneity of RV function in patients with pulmonary hypertension.7 In the case of the left ventricle, composite indices of intraventricular dyssynchrony, which incorporate data from multiple segments, have demonstrated enhanced prognostic value over opposing wall delay alone in clinical studies.8,9 Two-dimensional strain (2DS) echocardiography (“speckle tracking”) was recently validated as a tool for myocardial deformation imaging.10,11 The angle-independent nature of 2DS echocardiography may be advantageous in the evaluation of the right ventricle given the complex nature of this chamber. In this study, we investigated the temporal contraction patterns of the right ventricle using

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2DS echocardiography in a population with pulmonary arterial hypertension (PAH), in comparison with a matched control population. Our aims were to comprehensively assess right intraventricular dyssynchrony by incorporating activation times across all RV segments and to evaluate its prevalence in patients with PAH. For this purpose, we propose a new 2DS echocardiographically derived parameter as a means to quantify RV dyssynchrony. METHODS Patients Forty stable outpatients with PAH were selected according to the following criteria: (1) PAH defined according to the World Health Organization’s Revised Nomenclature and Classification of Pulmonary Hypertension (Category 1)12,13 and (2) clinically stable for ⱖ1 month before evaluation. Patients with (1) congenital heart disease, (2) bundle branch block or paced rhythm, (3) atrial fibrillation or flutter, or (4) LV ejection fraction ⱕ45% by the modified Simpson’s rule were excluded from the study. Forty healthy individuals without known or suspected structural heart disease were selected as controls on the basis of demographic characteristics (age, gender, and race). The protocol was approved by the institutional review board. Standard Echocardiography Studies were performed using commercially available cardiovascular ultrasound systems (Vivid 7, probes M3S and M4S; GE Healthcare, Milwaukee, WI) by 2 experienced sonographers (S.H. and M.-A.P.). The images were transferred via network for offline analysis on a dedicated workstation. Special care was taken during acquisition to ensure (1) an adequate field of view to image the entire RV free wall throughout the cardiac cycle, yet with minimal foreshortening, and (b) the maintenance of a frame rate ⬎40 frames/s to facilitate optimal tracking of the myocardium during postprocessing. Chamber dimensions and Doppler-derived hemodynamics were assessed according to the recommendations of the American Society of Echocardiography.14,15 The size of the right ventricle was determined by the mid-RV diameter and the end-diastolic and end-systolic areas. Standard echocardiographic measures of RV function included RV fractional area change, tricuspid annular plane systolic excursion, and the myocardial performance index, as previously described.16,17 2DS Echocardiography Myocardial deformation imaging by 2DS echocardiography is based on frame-by-frame tracking of small rectangular speckle patterns within the myocardial region of interest on grayscale (B-mode) echocardiographic images. The principles of 2DS echocardiography have been described in detail elsewhere.10,11 The echocardiograms were analyzed by an echocardiographer experienced in myocardial deformation imaging (A.P.K.), blinded to the clinical data, using dedicated software (EchoPAC ’06; GE Healthcare). To assess the segmental contractile characteristics of the right ventricle, we adopted a 6-segment RV model. In the apical 4-chamber view, the endocardial border was manually drawn; the myocardium was automatically tracked by the algorithm and divided into 6 segments (Figure 1A). The software detects the onset of QRS from the simultaneous electrocardiographic recording to define the point of zero strain and plots both segmental and global strain and strain rate curves (Figure 1B). Global strain and strain rate are calculated using the entire length of the tracked RV myocardium as baseline length. Peak systolic strain (S), systolic strain rate (SRs), early diastolic strain rate (SRe), and late diastolic strain rate (SRa), as well as the interval

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from QRS onset to peak S (ts) were recorded for the 6 RV segments (segmental values) and for the entire RV myocardium (global values) in the longitudinal direction. Displacement of the basal free RV wall was also recorded. Intervals were corrected for heart rate according to Bazett: corrected interval ⫽ measured interval/(RR)1/2.18 We defined RV dyssynchrony (RV-SD6) as the standard deviation of the 6 corrected ts values (Figure 1B). In addition, we calculated the septalto-free wall delay from the onset of QRS to peak S. The following 2DS echocardiographically derived measures of RV function were considered in the analyses: global S and global SRs of the right ventricle and displacement of the basal free RV wall. A set of 32 random (16 PAH and 16 control) studies was analyzed by an experienced sonographer (S.H.) without access to the main echocardiographic data set. The same set of images was reanalyzed in random order to obtain intraobserver variability data. Statistical Analysis Symmetric continuous variables were compared between groups using Student’s t test and are expressed as mean ⫾ SD. Asymmetric variables were compared using the Mann-Whitney U test and are expressed as median (25th percentile, 75th percentile). Normality was assessed using the Shapiro-Wilk statistic. Categorical variables were compared using Fisher’s exact test and are expressed as numbers and percentages. Two-way analysis of variance with repeated measures across 1 factor was used to investigate the effect of PAH on the behavior of segmental parameters of the right ventricle (strain, strain rate, and time to peak strain). The significance of post hoc comparisons was adjusted according to Bonferroni’s method. Multiple regression was used to identify univariate and multivariate effects of RV-SD6 on measures of RV function. Interobserver and intraobserver reproducibility were assessed by (1) the mean absolute deviation (MAD), defined as the absolute value of (measurement 2 ⫺ measurement 1), and (2) Bland-Altman plots for bias and agreement limits. Analyses were performed using Stata version 9.2 (StataCorp LP, College Station, TX).

RESULTS Baseline Characteristics and Standard Echocardiography Optimal tracking of all RV segments was possible in 36 of 40 patients with PAH (90.0%) and 39 of 40 controls (97.5%). Only these patients were included in subsequent analyses. The baseline characteristics and standard echocardiographic parameters of the study groups are presented in Table 1. Of the 36 patients with PAH included in the study, 6 had underlying autoimmune diseases (2 with systemic lupus erythematosus, 1 with scleroderma, 1 with mixed connective tissue disease, 1 with Sjögren’s syndrome, and 1 with sarcoidosis), 2 had human immunodeficiency virus infection as the underlying cause, and 2 had history of anorexigen use. The remaining patients had no identifiable underlying causes of PAH (idiopathic). All patients had been diagnosed with PAH ⱖ3 months prior to index echocardiography. The functional and right-heart catheterization data of patients with PAH are presented in Table 2. Baseline demographic characteristics were comparable between patients with PAH and controls. Patients with PAH exhibited higher heart rate and blood pressure and longer QRS duration compared with controls. As expected, RV size was significantly increased with significantly reduced measures of RV function in patients with PAH. The size of the left ventricle was substantially reduced in patients with PAH; this resulted in a marginally higher ejection fraction in these

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Figure 1 (A) A 6-segment model of the right ventricle is created by the tracking algorithm after manual delineation of the endocardial border. (B) The onset of QRS (yellow dot in the QRS complex in A, yellow dotted vertical line in B) signifies the zero deformation point; the global (dotted line) and segmental (colored lines) strain curves represent the relative (percentage) shortening of the region of interest as a function of time. The interval from QRS onset to peak strain (ts) for the 6 segments is recorded (exemplified here for the mid right ventricular (RV) free wall and basal RV free wall with the cyan and yellow lines, respectively). RV dyssynchrony (RV-SD6) is calculated offline as the standard deviation of the 6 intervals after correction for heart rate. In this control subject, RV-SD6 was 13 ms. (C) In this patient with pulmonary arterial hypertension, global RV strain is severely depressed, while both the mid and the basal RV free wall segments (cyan and yellow curves, respectively, in D) present with significantly delayed ts (arrows in D). RV-SD6 in this patient was 70 ms. patients. In addition, mild pericardial effusion was present in 15 of 36 (41.7%) patients with PAH. Dyssynchrony Parameters of the Right Ventricle The median frame rate during the acquisition of 2DS echocardiographic images was 48 frames/s (range, 39-66) and was similar for patients with PAH and controls (median, 50 and 47 frames/s, respectively; P ⬎ .5). Segmental time to peak S (ts) patterns are summarized in Figure 2A. These patterns were significantly different between the PAH and control groups, as formally confirmed by analysis of variance (P ⬍ .001 for interaction). The basal and mid RV free wall segments of patients with PAH were significantly delayed compared with those of controls, while the remaining 4 segments had similar ts values. The increased heterogeneity of segmental ts in patients with PAH was effectively described by the proposed RV-SD6 parameter: 63 ⫾ 21 ms in patients with PAH compared with 25 ⫾ 15 ms in controls (P ⬍ .001; Figure 2B). Finally, time from QRS onset to peak global S and septal-to-free wall delay were both significantly higher in patients with PAH compared with controls (415 ⫾ 46 vs 386 ⫾ 14 ms, P ⫽ .003, and 65 ⫾ 71 vs 31 ⫾ 48 ms, P ⫽ .007, respectively). Deformation Parameters of the Right Ventricle RV deformation parameters were significantly impaired in patients with PAH compared with controls (except for SRa; Table 3). The segmental distribution of S and SRs in the right ventricle is depicted in Figures 2C and 2D, respectively. All RV free wall segments of patients

with PAH exhibited significant decreases in segmental S and SRs compared with those of controls; however, these decreases were more exaggerated at the mid and apical free wall segments and more prominent for SRs values. We did not observe statistically significant differences in S and SRs values regarding the interventricular septal segments between patients with PAH and controls. Correlation of RV-SD6 With RV Function In patients with PAH, RV-SD6 was a univariate predictor of RV fractional area change, RV myocardial performance index, global RV strain, and global RV strain rate (Table 4); statistical significance was retained after including in the model pulmonary arterial systolic pressure, RV end-diastolic area, and QRS duration on electrocardiography (Table 4). Using the upper 95% limit of normal (mean ⫹ 2 ⫻ SD) of the control population, we defined a cutoff point of ⬎55 ms as criterion for RV intraventricular dyssynchrony by the RV-SD6 parameter. According to this criterion, RV dyssynchrony was present in 25 of 36 patients with PAH (69.4%) and in 2 of 39 controls (5.1%) (P ⬍ .001). Patients with PAH and RV dyssynchrony (n ⫽ 25) had significantly worse RV function (fractional area change, 27 ⫾ 7% vs 36 ⫾ 6%; global S, ⫺14.6 ⫾ 4.3% vs ⫺18.1 ⫾ 3.7%), larger right ventricles (mid-RV diameter, 52 ⫾ 6 vs 45 ⫾ 7 mm; areas in diastole and systole, 30 ⫾ 7 vs 23 ⫾ 6 cm2 and 21 ⫾ 7 vs 15 ⫾ 4 cm2, respectively), and higher mean pulmonary arterial pressure (37 ⫾ 11 vs 29 ⫾ 5 mm Hg) compared with patients with PAH without RV dyssynchrony (all P ⬍ .05). There were no significant differences in

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Table 1 Clinical and echocardiographic characteristics of the study groups Parameter

Age (yr) Men/women (n) Caucasian/African American (n) Body surface area (m2) Heart rate (beats/min) QRS duration (ms) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LV end-diastolic volume index (mL/m2) LV end-systolic volume index (mL/m2) LV ejection fraction (%) RV diastolic diameter (mid) (mm) RV end-diastolic area (cm2) RV end-systolic area (cm2) RV fractional area change (%) Pulmonary arterial systolic pressure* (mm Hg) Pulmonary arterial diastolic pressure† (mm Hg) Pulmonary arterial mean pressure† (mm Hg) Pulmonary acceleration time (ms) RV myocardial performance index Tricuspid annular plane excursion (mm)

Patients with PAH (n ⴝ 36)

Controls (n ⴝ 39)

P value

44 ⫾ 14 12/24 30/6

43 ⫾ 18 13/26 31/8

.789 1.000 .771

1.86 82 100 123

⫾ ⫾ ⫾ ⫾

0.19 9 16 17

1.80 69 86 113

⫾ ⫾ ⫾ ⫾

0.24 .290 12 ⬍.001 13 ⬍.001 17 .013

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Table 2 Clinical and right-heart catheterization data in patients with PAH (n ⫽ 36) Parameter

Value

WHO class B-type natriuretic peptide (ng/mL) Oxygen saturation at rest (on 4-6 L/min O2) (%) Oxygen saturation during 6MWT (on 4-6 L/min O2) (%) Walking distance on 6MWT (m) Endothelin receptor antagonists (n) Sildenafil (n) Prostacyclin analogs (n) Systolic pulmonary arterial pressure (mm Hg) Diastolic pulmonary artery pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Pulmonary vascular resistance (dynes/cm/s) Cardiac index (Fick) (L/min/m2)

2.8 ⫾ 0.6 90 (19-289) 95 ⫾ 3 80 ⫾ 12 339 ⫾ 158 9 10 10 77 ⫾ 21 31 ⫾ 13 48 ⫾ 13 800 ⫾ 368 2.15 ⫾ 0.65

78 ⫾ 13

70 ⫾ 13

.007

36 ⫾ 15

52 ⫾ 15

⬍.001

13 ⫾ 5

20 ⫾ 7

⬍.001

65 ⫾ 8 49 ⫾ 7

62 ⫾ 6 37 ⫾ 5

.051 ⬍.001

PAH, Pulmonary arterial hypertension; 6MWT, 6-minute walk test; WHO, World Health Organization. Diagnostic right-heart catheterization preceded the echocardiographic study by 6 months (range, 3-12).

⫾ ⫾ ⫾ ⫾

5 3 8 7

⬍.001 ⬍.001 ⬍.001 ⬍.001

DISCUSSION

29 ⫾ 8

10 ⫾ 2

⬍.001

45 ⫾ 13

19 ⫾ 3

⬍.001

79 ⫾ 18

141 ⫾ 15

⬍.001

28 19 31 84

⫾ ⫾ ⫾ ⫾

7 7 10 21

0.72 ⫾ 0.25 12 ⫾ 3

18 10 45 28

0.31 ⫾ 0.12 ⬍.001 18 ⫾ 3

⬍.001

LV, Left ventricular; PAH, pulmonary arterial hypertension; RV, right ventricular. *Tricuspid regurgitation signal was detectable in 37 of 39 controls. †Pulmonary regurgitation signal was detectable in 32 of 36 patients with PAH and 20 of 39 controls.

QRS or RR duration between these subgroups (101 ⫾ 18 vs 96 ⫾ 13 ms and 0.75 ⫾ 0.15 vs 0.80 ⫾ 17 s for patients with and without dyssynchrony, respectively). Reproducibility of RV-SD6 and 2DS Echocardiographically Derived Parameters In the 32 randomly selected studies, RV-SD6 had interobserver and intraobserver MAD of 7.8 and 5.6 ms, respectively. Interobserver variability was slightly higher for controls than for patients with PAH (MAD, 10.3 vs 5.3 ms, P ⫽ .025), whereas intraobserver variability was comparable. Interobserver and intraobserver bias for RV-SD6 was ⫺0.3 ⫾ 10.1 ms (95% limits, ⫺20.2 to ⫹19.5) and ⫺0.7 ⫾ 7.2 ms (95% limits, ⫺14.7 to ⫹14.1), respectively (Figure 3). Interobserver MAD for global RV S, SRs, SRe, and SRa was 0.7%, 0.05/s, 0.09/s, and 0.06/s, respectively. The corresponding intraobserver values were 0.5%, 0.06/s, 0.05/s, and 0.06/s, respectively. None of these parameters had significant different reproducibility in patients with PAH compared with controls.

We found a considerable degree of mechanical intraventricular dyssynchrony in the right ventricles of patients with PAH. This was clearly demonstrated by the comparative analyses of the segmental ts in patients with PAH and controls in our 6-segment RV model and was effectively described by the proposed RV-SD6 parameter (63 ⫾ 21 ms in patients with PAH vs 25 ⫾ 15 ms in controls). We identified the mid and basal free wall as the main regions causing intraventricular delay; our findings are in line with those of Lopez-Candales et al,3 who demonstrated a significant septal-to-free wall delay by DTIderived S at the basal level in a population with pulmonary hypertension of varying etiologies. In contrast to the well-studied pathophysiology of LV dyssynchrony, the underlying mechanisms of dyssynchrony in the right ventricle remain largely unexplored. Recently, Zeltser et al19 showed that the experimental induction of RV pressure and/or volume overload leads to significant increases in QRS duration after 6 months. Despite the exclusion of patients with right bundle branch block, QRS duration in our PAH population was higher than in controls (100 ⫾ 16 vs 86 ⫾ 13 ms, P ⬍ .001). Therefore, RV pressure overload may result in intraventricular conduction delays that do not fall under the right bundle branch block criteria but still play an important role in RV dyssynchrony, despite the lack of a direct correlation of QRS duration with RV-SD6 in our study. In addition, our data indicate that size is an important factor for mechanical delay within the right ventricle, which is in line with studies of LV dyssynchrony.20,21 In concordance with a recent study,7 we found heterogeneous impairment of RV function in patients with PAH, with the mid and apical RV free wall showing the largest impairment. This differential effect of pressure overload on RV regional contractility might be attributed to the uneven distribution of mechanical properties across the RV free wall (thinner structure from base to apex, different fiber orientation) and the distortion imposed by RV remodeling. There is no clear answer, however, as to why the most dyssynchronous RV segments do not coincide with the most affected ones in our study.

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Figure 2 (A) Corrected time from onset of QRS to peak strain in the 6 segments of the right ventricle. (B) Distribution of right ventricular (RV) dyssynchrony (RV-SD6) in patients with pulmonary arterial hypertension (PAH) and controls. Long lines represent means, and short lines represent standard deviations. (C and D) Strain and systolic strain rate in the 6 segments of the right ventricle. Error bars in A, C, and D represent standard deviations. *P ⬍ .001; †P ⬍ .05. IVS Ap, Apical segment of the interventricular septum; IVS Bas, basal segment of the interventricular septum; IVS Mid, mid segment of the interventricular septum; RV Ap, Apical segment of the RV free wall; RV Bas, basal segment of the RV free wall; RV Mid, mid segment of the RV free wall. Table 3 RV deformation parameters in the study groups

Parameter

Global RV strain (%) Global RV SRs (1/s) Global RV SRe (1/s) Global RV SRa (1/s) RV free wall strain* (%) RV free wall displacement* (mm)

Patients with PAH (n ⴝ 36)

⫺15.7 ⫺0.87 0.81 0.77 ⫺19.0 15.7

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

4.4 0.24 0.33 0.38 6.8 5.3

Controls (n ⴝ 39)

⫺22.8 ⫺1.12 1.25 0.80 ⫺27.3 22.0

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

2.9 0.21 0.34 0.24 5.5 4.2

Table 4 Correlation of RV-SD6 with measures of RV function in patients with PAH Univariate

Multivariate*

P value

⬍.001 ⬍.001 ⬍.001 .936 ⬍.001 ⬍.001

PAH, Pulmonary arterial hypertension; RV, right ventricular; SRa, late diastolic strain rate; SRe, early diastolic strain rate; SRs, systolic strain rate. *Measured at the base. Global RV parameters were measured in the 6-segment model (ie, both the RV free wall and the septum were included in the analyses).

Prevalence of Dyssynchrony in PAH and Impact on RV Function Taking the upper 95% limit of our control population as a cutoff point for RV-SD6, two thirds of our patients with PAH were found to have significant RV dyssynchrony despite the exclusion of patients with right bundle branch block. This mechanical dyssynchrony appears to be a function of pulmonary pressures and RV enlargement in our analyses. The effect of dyssynchrony on RV function, however, was beyond that which could be attributed to confounding increases in right-side pressures or RV size, as demonstrated in multivariate analyses with global RV function measures as the dependent variables. The right ventricle relies predominantly on longitudinal function to perform its tasks.22,23 Therefore, uncoordinated contraction in the

Parameter

␤

P value

␤

P value

RV fractional area change RV myocardial performance index Tricuspid annular plane systolic excursion RV global strain RV global systolic strain rate RV basal displacement

⫺0.519 0.427

.002 .009

⫺0.426 0.307

.005 .076

⫺0.264

.126

⫺0.190

.272

0.512 0.352

.002 .038

0.358 0.292

.031 .081

⫺0.324

.057

⫺0.268

.109

PAH, Pulmonary arterial hypertension; RV, right ventricular; RV-SD6, RV dyssynchrony. *Adjusted for pulmonary artery systolic pressure, RV end-diastolic area, and QRS duration on electrocardiography.

longitudinal direction may result in a decrease in RV function in excess to what might be expected from a loss of contractility alone. These findings point to dyssynchrony as a potential clinical target in patients with RV dysfunction. In patients with systemic right ventricles due to congenital heart disease, for example, cardiac resynchronization therapy has been reported to effectively alleviate dyssynchrony and improve clinical status.24 Our data, however, should be regarded as preliminary; the clinical impact of the current findings needs assessment in long-term follow-up studies. Feasibility and Reproducibility The evaluation of RV function by 2DS echocardiography appears to be highly feasible in patients with RV dysfunction as well as in patients

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Figure 3 Interobserver (A) and intraobserver (B) reproducibility Bland-Altman plots for right ventricular dyssynchrony (RV-SD6) (standard deviation of the segmental QRS to peak strain intervals). Solid lines represent bias, and dotted lines represent 95% limits of agreement. PAH, Pulmonary arterial hypertension.

without structural heart disease. What is more important from a clinical standpoint is that 2DS echocardiographically derived parameters demonstrate low interobserver and intraobserver variability. Indeed, the reproducibility of global measures of RV function and synchrony, including global S and SRs and the RV-SD6 parameter of dyssynchrony, was remarkable. Limitations The main limitations of our study are inherent to the 2-dimensional approach and the observational nature of the study. In the apical 4-chamber view, the right ventricle is represented only by its inflow portion, and the RV free wall is not seen in its full extent. However, in an elegant study using both echocardiography and magnetic resonance, Geva et al25 showed that the inflow region of the right ventricle performs most of the pump function, and the outflow tract serves mostly as a pulsatile conduit. Moreover, the apical 4-chamber view mainly encompasses the lateral portion of the free wall, which is the RV portion with the maximal fractional shortening, according to an earlier magnetic resonance study.26 Therefore, although still far from conclusive, our approach might provide a clinically adequate model to evaluate RV function and synchrony. This was a cross-sectional study involving patients with PAH from a tertiary referral center. Therefore, we cannot exclude the possibility of biased estimates for the prevalence and degree of RV dyssynchrony in PAH, because these patients may represent the severe end of the spectrum of this entity. In addition, we did not serially evaluate the effect of baseline clinical characteristics or therapeutic interventions on the course of RV function and synchrony; thus, we were not able to provide insight into possible clinical implications or links to the pathophysiologic mechanisms that underlie dyssynchrony in the right ventricle. CONCLUSION In summary, our findings suggest that right intraventricular dyssynchrony can be effectively described by a feasible and reproducible 2DS echocardiographically derived measure, the RV-SD6. On the basis of this metric, we found that RV dyssynchrony was present in a substantial proportion of patients with PAH and that this dyssynchrony adversely affected RV function. It is unclear at this point, however, whether this dyssynchrony is merely a synonym for RV dysfunction or represents an independent marker of adverse outcomes.

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