Right Ventricular Dyssynchrony in Patients With Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension

Yuki Yamagata; Satoshi Ikeda; Sanae Kojima; Yuki Ueno; Tomoo Nakata; Seiji Koga; Chikara Ohno; Tsuyoshi Yonekura; Tsuyoshi Yoshimuta; Takako Minami; Hiroaki Kawano; Koji Maemura

doi:10.1253/circj.CJ-21-0849

Abstract

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.

Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC.

Conclusions: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are dyspnea-fatigue syndromes in patients with clear lungs that are caused by progressive elevations in pulmonary vascular resistance (PVR), leading to pulmonary hypertension (PH).¹ PH is associated with functional and structural changes of the right ventricle (RV), characterized by RV dilatation and hypertrophy, abnormal RV geometry with leftward deviation of the interventricular septum, and dyssynchronous RV contraction that leads to RV dysfunction.²^–⁴ RV dysfunction is associated with poor clinical outcomes independently of the underlying mechanism of disease: across the spectrum of left ventricular (LV) ejection fraction in patients with acute and chronic heart failure, after cardiac surgery, acute myocardial infarction, congenital heart disease, and PH.⁵^,⁶ Therefore, assessment of RV function is important for managing PH patients, but these assessments are challenging because of the complex geometry of the RV.⁷

Editorial p 945

Echocardiography using Doppler tissue imaging (DTI) and 2-dimensional speckle tracking (2DST) can facilitate quantification of regional and global myocardial function.⁸ 2DST can quantify complex cardiac motions on the basis of frame-to-frame tracking of ultrasonic speckles in grayscale images. Moreover, it is angle-independent and shows less preload dependency than DTI.⁹ 2DST has recently become the most widely used tool for RV function assessment, and the technique offers several parameters for evaluating RV function.¹⁰^,¹¹ We reported that the peak systolic strain of the RV free wall measured using 2DST echocardiography was associated with pulmonary arterial pressure (PAP) and PVR in PAH patients.¹² RV dyssynchrony, an echocardiographic parameter obtained with speckle tracking, has been shown to be associated with reduced RV systolic function,¹³ cardiac output, and indirectly exercise capacity,¹⁴^,¹⁵ suggesting that it has a negative effect on cardiac function. RV dyssynchrony has been evaluated in patients with PAH or CTEPH.¹⁴^–¹⁹ Although the RV’s structure and function in these patients show a similar pattern of RV hypertrophy, namely dilatation, wall thickening, and loss of function, the pathogenesis of these diseases is fundamentally different.²⁰ Remodeling of small pulmonary arteries is the main cause of PAH,²¹ whereas large vascular occlusions due to thrombi and small arterial disease in non-occluded areas are primarily associated with CTEPH.²⁰ Giusca et al demonstrated that patients with CTEPH exhibit a trend of lower RV free wall strain on 2DST compared to those with Eisenmenger syndrome and idiopathic PAH. This is despite the tendency for the mean PAP to be lower in CTEPH patients, suggesting that the etiology of PH itself may affect regional motion in the RV wall.²² Therefore, findings of RV dyssynchrony on 2DST echocardiography may differ between patients with CTEPH and PAH. However, few studies have compared RV dyssynchrony between these 2 disorders. The aim of this study was to investigate the difference in RV dyssynchrony between CTEPH and PAH patients, and to determine the factors associated with RV dyssynchrony across all PH patients.

Methods

Patient Population

We enrolled 44 patients, of whom 26 were diagnosed with CTEPH and 18 with PAH (idiopathic PAH, 9; connective tissue disease [CTD]-associated PAH, 8; and drug-induced PAH, 1) at Nagasaki University Hospital between January 2011 and March 2019. Patients with a bundle branch block or paced rhythm; atrial fibrillation or flutter; severe renal or liver dysfunction; LV ejection fraction <50%; congenital heart diseases; history of balloon pulmonary angioplasty, pulmonary endarterectomy, or thoracotomy; or echocardiographic images unsuitable for analysis using 2DST, such as those lacking a fine endocardial border and apex view, were excluded from this study. Patients were diagnosed according to the guidelines for the treatment of pulmonary hypertension (JCS 2017/JPCPHS 2017).²³ CTEPH and PAH patients were diagnosed using transthoracic echocardiography, lung ventilation-perfusion scintigraphy, contrast-enhanced lung computed tomography, pulmonary angiography, and right heart catheterization (RHC).

Comorbidities were defined as follows. Hypertension was defined as either being treated with antihypertensive agents or having systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Diabetes mellitus was defined as having fasting blood glucose ≥126 mg/dL, HbA1c ≥6.5%, or receiving with anti-diabetic drugs. Dyslipidemia was defined as receiving lipid-lowering agents, or as having low-density lipoprotein cholesterol (LDL-C) ≥140 mg/dL, triglycerides ≥150 mg/dL, and/or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL.²⁴

This study complied with the Declaration of Helsinki regarding investigations in humans, and the Ethics Committee of Nagasaki University Hospital approved the protocol (approval number: 16020812-8). Patients enrolled between February 2016 and March 2019 provided written informed consent before RHC. For patients enrolled between January 2011 and January 2016, an opt-out model was provided through the Nagasaki University Hospital website instead of obtaining informed consent.

Echocardiography

All patients underwent transthoracic echocardiography using commercially available equipment (Vivid E9, Vivid E95 and Vivid q; GE Healthcare). Measurements were performed in accordance with the guidelines of the American Society of Echocardiography.¹⁰ The measured RV parameters were maximal tricuspid valve regurgitant pressure gradient (TRPG), pulmonary valve regurgitant end pressure gradient (PRPG), RV dimension (RVD), RV fractional area change (RVFAC), and tricuspid annular plane systolic excursion (TAPSE). Systolic LV function was evaluated based on the LV ejection fraction and diastolic function based on the mitral E/A and E/e’.²⁵

2DST Echocardiography

For 2DST echocardiography analysis of RV free wall/septum strain, an apical 4-chamber view was acquired using second-harmonic imaging, with depth, sector width, and frequency adjusted for frame-rate optimization (between 36.0 and 53.9 frames/s). The RV endocardial border was manually traced, and fine-tuning of the region of interest was performed to ensure that the segments were tracked appropriately. Finally, the software automatically divided the myocardium into 6 standard segments (basal, middle, and apex for the RV free wall and the interventricular septum), and time-strain longitudinal curves were generated from each segment. All images were stored digitally and analyzed offline using dedicated software (EchoPac ver 201.42.3). RV free wall peak strain (RV-PS) was calculated as the mean peak strain from the 3 basal-middle-apex RV free walls. To quantify RV dyssynchrony, we calculated the standard deviation of the times from the peak QRS to peak strain for the 6 basal-mid-apex RV free and septal wall (RV-SD6) (Figure 1).²⁶

Figure 1.

(A) A 6-segment model of the right ventricle (RV) created by the tracking algorithm after manual delineation of the endocardial border. (B) Colored curves that match the segment color in (A) are strain curves in each segment of the RV wall. (C) The length of the colored arrows represents the interval between QRS onset (white vertical line) and peak systolic strain in each segment of the RV free wall and septum. RV dyssynchrony was calculated as the standard deviation of the times from QRS onset to peak strain for the 6 segments in the RV free wall and septum (RV-SD6).

Pulmonary Hemodynamic Measurements

RHC was performed for pulmonary hemodynamic measurements in all patients. The measured indices were PAP, pulmonary arterial wedge pressure (PAWP), right atrial pressure (RAP), and PVR. Pulse pressure (PP) was defined as the absolute value of systolic PAP minus diastolic PAP. Cardiac output was determined using the thermo-dilution method and indexed to the body surface area for the cardiac index (CI). Pulmonary arterial compliance (PAC) was calculated as the pulmonary stroke volume (SV) divided by the pulmonary arterial PP.²⁷

Statistical Analysis

All statistical analyses were performed using SPSS (version 23.0; SPSS, Inc., Chicago, IL, USA). Continuous values were tested for normal distribution using the Shapiro-Wilk test and expressed as mean±SD for parametric data or as medians (first to third quartile) for non-parametric data. The groups were tested for statistical significance using unpaired t-tests or Mann-Whitney U-tests. Multiple comparisons were assessed using Kruskal-Wallis tests with post hoc Dunn-Bonferroni tests. Multiple logistic regression analysis adjusted by age only was performed to determine the odds ratio and 95% confidence intervals (CIs) for identification of CTEPH compared to PAH. We selected the following variables for multiple logistic regression analysis according to previous studies on PH patients: RV dyssynchrony-related echocardiographic parameters, pulmonary hemodynamics, exercise capacity, blood test results,¹⁵^,¹⁶^,²⁶^,²⁸ and pulmonary arterial pressure waveform-derived parameters that differ between CTEPH and PAH.²⁹ Correlations between pulmonary hemodynamic and echocardiographic parameters and RV-SD6 were evaluated using Spearman’s rank correlation coefficient. Outlier PAC measurements were identified using the Smirnov–Grubbs test. Statistical significance was set at P<0.05. For RV-SD6, inter-rater and intra-rater reproducibility was determined by calculating the intra-class correlation coefficient. Absolute reproducibility was assessed using the Bland-Altman method with 95% CIs.

Results

Comparisons of Demographics, Pulmonary Hemodynamics, and Echocardiographic Parameters Between CTEPH and PAH Patients

The baseline characteristics of the CTEPH and PAH groups are presented in Table 1. The patients in the CTEPH group were significantly older than those in the PAH group (median, 72.0 and 41.0 years, respectively; P=0.001). The CTEPH group showed a significantly shorter 6-min walk distance (6MWD). In contrast, NT-proBNP levels did not significantly differ between the 2 groups. Among the pulmonary hemodynamic data assessed by RHC, PAC was significantly lower in the CTEPH group. In contrast, the PAP, PAWP, and RAP values were comparable between the 2 groups. Among echocardiographic parameters, TRPG and RV-6SD were significantly greater in the CTEPH group than in the PAH group. The 2 groups showed no significant differences in the administered medicines, except anticoagulants. None of the patients in the PAH group had diabetes.

Table 1. Patient Characteristics

Variables	CTEPH (n=26)	PAH (n=18)	P value
Age, years	72.0 (62.3–77.3)	41.0 (26.3–67.8)	0.001
Female/male	25/1	15/3	0.146
BMI, kg/m²	21.0±2.9	22.8±5.4	0.197
WHO-FC, I/II/III	0/10/16	1/12/5	0.059
NT proBNP, pg/mL	424.1 (110.8–1,043.0)	177.5 (81.8–597.8)	0.181
6MWD, m	293.2±97.4	386.5±110.0	0.008
Right heart catheterization
Systolic PAP, mmHg	70.6±16.4	65.0±19.8	0.315
Mean PAP, mmHg	38.9±8.3	40.5±12.9	0.636
Diastolic PAP, mmHg	19.9±6.1	23.9±8.4	0.073
PP, mmHg	50.7±14.1	41.1±12.9	0.026
Mean PAWP, mmHg	6.2±2.3	7.0±3.2	0.355
Mean RAP, mmHg	4.0 (2.0–5.0)	4.5 (3.0–6.0)	0.267
CO, L/min	3.9±0.7	4.4±1.1	0.051
PVR, Wood units	8.7±2.4	8.4±4.6	0.793
PAC, mL/mmHg	1.12±0.30	1.68±0.68	0.003
Echocardiography
TRPG, mmHg	68.0±16.3	51.7±15.4	0.002
RVD, mm	35.8±5.5	34.2±4.6	0.329
RVFAC, %	30.3±9.2	34.8±9.8	0.127
TAPSE, mm	16.7±2.9	17.5±3.2	0.367
PR-end PG, mmHg	11.9±6.1	11.2±5.7	0.695
LVEF, %	69.6±7.5	69.2±6.3	0.870
2D speckle tracking echocardiography
RV-PS, %	−16.9±4.6	−18.5±5.5	0.193
RV-6SD, ms	87.2 (58.3–126.8)	62.3 (48.9–77.0)	0.005
Time interval, days^†	6.5 (5–21)	2.5 (1–14.3)	0.141
Medicines, n (%)
Ca antagonists	7 (26.9)	6 (33.3)	0.647
ERAs	4 (15.4)	5 (27.8)	0.316
PDE-V inhibitors	3 (11.5)	5 (27.8)	0.170
sGC stimulator	3 (11.5)	0 (0.0)	0.135
Prostacyclin	7 (26.9)	1 (5.6)	0.071
Diuretics	15 (57.7)	5 (27.8)	0.050
Anticoagulants	25 (96.2)	8 (44.4)	<0.001
Comorbidities, n (%)
Hypertension	14 (53.8)	6 (33.3)	0.179
Dyslipidemia	6 (23.1)	5 (27.8)	0.723
Diabetes	5 (19.2)	0 (0.0)	0.048

6MWD, 6-min walk distance; BMI, body mass index; Ca antagonists, calcium antagonists; CO, cardiac output; CTEPH, chronic thromboembolism pulmonary hypertension; ERA, endothelin receptor antagonist; NT-proBNP, N-terminal pro B-natriuretic peptide; PAC, pulmonary arterial compliance; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure; PDE-V, phosphodiesterase-V; PP, pulse pressure; PR-end PG, pulmonary valve regurgitation end systolic pressure gradient; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV-6SD, standard deviation of the time-to-peak longitudinal strain of 6 right ventricular segments; RVD, right ventricular dimension; RVFAC, right ventricular functional area change; RV-PS, right ventricular free wall peak strain; sGC, soluble guanylate cyclase; TAPSE, tricuspid annular plane systolic excursion; TRPG, tricuspid regurgitation pressure gradient; WHO-FC, WHO functional class. ^†Time interval indicates the number of days between right heart catheterization and echocardiography.

Age-adjusted multivariate logistic analysis identified that PAC, TRPG, and RV-6SD were significantly associated with CTEPH compared to PAH (Table 2).

Table 2. Multiple Logistic Regression Analysis for Identifying CTEPH Compared to PAH

Variables	OR	95% CI	P value
BMI	0.956	0.782–1.170	0.663
Systolic PAP	1.032	0.986–1.080	0.173
Mean PAP	1.028	0.953–1.108	0.481
Diastolic PAP	1.006	0.899–1.126	0.916
PP	1.058	0.991–1.129	0.090
Mean PAWP	1.013	0.766–1.341	0.926
Mean RAP	0.936	0.735–1.192	0.591
CO	0.668	0.273–1.637	0.377
PVR	1.046	0.856–1.278	0.663
PAC	0.129	0.024–0.705	0.018
TRPG	1.063	1.001–1.130	0.047
RVD	1.097	0.931–1.286	0.275
RVFAC	0.928	0.855–1.007	0.074
TAPSE	0.970	0.757–1.242	0.970
6MWD	0.994	0.986–1.002	0.120
NT-proBNP	1.000	0.999–1.001	0.646
RV-6SD	1.030	1.000–1.030	0.048

Age adjusted. CI, confidence interval; OR, odds ratio. Other abbreviations are as per Table 1.

Correlations of RV-6SD With Patient Demographics, Pulmonary Hemodynamics, and Echocardiographic Parameters

Table 3 shows how RV-6SD was significantly correlated with systolic PAP, PP, PAC, RVD, and NT-proBNP levels.

Table 3. Correlations Between Right Ventricular Dyssynchrony and Pulmonary Hemodynamics, Echocardiographic Measurements, Patients’ Demographics, and NT-proBNP Values

Variables	RV-6SD
Variables	rho	P value
Age	0.255	0.094
BMI	−0.060	0.697
Systolic PAP	0.328	0.030
Mean PAP	0.251	0.100
Diastolic PAP	−0.035	0.821
PP	0.422	0.004
Mean PAWP	0.137	0.374
Mean RAP	0.215	0.161
CO	−0.197	0.200
PVR	0.274	0.071
PAC	−0.423	0.004
TRPG	0.262	0.085
RVD	0.427	0.004
RVFAC	−0.270	0.076
TAPSE	−0.166	0.281
6MWD	−0.297	0.059
NT-proBNP	0.478	0.001

Abbreviations are as per Table 1.

The time from the peak of QRS on electrocardiography to peak strain (time-to-peak strain) in each RV segment is shown in Figure 2. The time-to-peak strain at the basal and mid-free wall were significantly longer than that at the basal and mid-septum. Table 4 shows the correlations between the time-to-peak strain in each RV segment and RV-6SD, PAC, and PP. Time-to-peak strain was significantly correlated with RV-6SD at the mid-RV free wall as well as PP at the entire RV free wall.

Figure 2.

Differences in time from onset of QRS to peak strain in the 6 segments of the right ventricular free wall and septum. *P<0.001, ^†P<0.01.

Table 4. Correlations Between Time From Onset of QRS on Electrocardiography to Peak Strain in Each Segment of the RV and Right Ventricular Dyssynchrony, PAC, or PP

Variables	rho	P value
RV-6SD
RV free wall - basal	0.271	0.075
RV free wall - mid	0.308	0.042
RV free wall - apex	0.223	0.146
Septum - basal	−0.134	0.386
Septum - mid	−0.018	0.905
Septum - apex	0.108	0.486
PAC
RV free wall - basal	−0.289	0.057
RV free wall - mid	−0.286	0.060
RV free wall - apex	−0.082	0.598
Septum - basal	−0.008	0.957
Septum - mid	−0.034	0.826
Septum - apex	0.112	0.469
PP
RV free wall - basal	0.554	<0.001
RV free wall - mid	0.465	0.001
RV free wall - apex	0.310	0.040
Septum - basal	0.168	0.274
Septum - mid	0.290	0.056
Septum - apex	0.159	0.304

RV, right ventricle. Other abbreviations are as per Table 1.

Reproducibility of 2DST Echocardiography Analysis

The intra- and inter-rater reproducibility were high (ICC, 0.937, 95% CI, 0.835–0.982; ICC, 0.991, 95% CI, 0.978–0.996, respectively]. Bland-Altman plots showed that almost all differences were within the 95% limits of agreement, with a very low mean difference between the 2 raters (Figure 3).

Figure 3.

Bland-Altman plot for the assessment of interobserver variability.

Discussion

The main findings of this study are as follows: (1) CTEPH patients were older and had a greater RV-6SD and PP, and a lower PAC than PAH patients, although PAP was comparable between the 2 groups. A greater RV-6SD and lower PAC could significantly identify CTEPH in comparison to PAH. (2) RV-6SD was significantly correlated with PAC, PP, RVD, and NT-proBNP levels. RV-6SD had a significant correlation with time-to-peak strain at the middle of the RV free wall. Time-to-peak strain at the basal and mid-RV free wall were significantly longer than those at the basal and mid-septum.

RV dysfunction is an important determinant of clinical outcomes in patients with advanced PH.³⁰^,³¹ However, the complex geometry of the RV makes it difficult to assess RV function.⁷ RV muscle is predominantly composed of longitudinal muscle fibers, and the tricuspid annulus moves toward the apex during the systolic phase.³²^,³³ Therefore, uncoordinated contraction in the longitudinal direction may result in reduced RV function.²⁶ 2DST echocardiography is a useful modality to assess the longitudinal deformation of the RV. Studies using speckle-tracking echocardiography have demonstrated that severe PH may be associated with a prolonged RV contraction until the LV diastole, resulting in post-systolic shortening or inter-ventricular asynchrony, and also showed regional heterogeneity of RV contraction, or dyssynchrony.²^,³⁴^,³⁵ The standard deviation of the time-to-peak strain, derived from myocardial deformation recorded using tissue data in the longitudinal direction with 2DST echocardiography, has been proposed to be an index of RV dyssynchrony.⁴^,²⁶ Furthermore, RV dyssynchrony assessments by this index have been reported to have a high feasibility and good reproducibility in patients with PH.²⁶ Patients with PH have been shown to have RV dyssynchrony with abnormal RV deformation and mechanical delay between the RV free wall and interventricular septum.⁴^,³⁴^,³⁵ In addition, Morita et al demonstrated that RV dyssynchrony was impaired under a mild RV pressure overload condition in a dog model.³² Lamia et al showed that RV dyssynchrony amounted to 69±34 ms in PAH patients, 47±23 ms in borderline PH patients, and 8±6 ms in controls.¹⁶ These findings suggest that RV dyssynchrony using 2DST echocardiography may be sensitive to assess RV function. Therefore, we chose this parameter to evaluate RV function in patients with CTEPH and PAH.

We found that RV-6SD was greater in CTEPH patients than in PAH patients, although PAP did not significantly differ between the 2 groups. In addition, the time-to-peak strain at the basal and middle RV free wall was delayed compared to that at the septum, and was associated with RV-6SD. Driessen et al had previously reported prolonged RV free wall contraction in PH patients, resulting in intra-ventricular dyssynchrony.³⁶ Lumens et al conducted a computer simulation that demonstrated that interventricular mechanical asynchrony was associated with prolonged RV free wall shortening and inhomogeneous distribution of myofiber load over the ventricular walls in severely decompensated PAH.³⁷ Kalogeropoulos et al reported that in comparison with control participants, heterogeneous impairment of RV function at the mid and apical RV free wall was larger in patients with PAH.²⁶ These may be caused by the complex structure and the distortion imposed by RV remodeling. Specifically, the differential effects of elevated pressure overload on RV regional contractility might be attributed to the uneven distribution of mechanical properties across the RV free wall, which comprises thinner structures from the base to the apex and different fiber orientations.¹⁷^,²⁶

In the present study, compared to PAH patients, CTEPH patients exhibited a larger PP and lower PAC, both of which were significantly correlated with RV-6SD. In addition, PAC was a significant predictor of CTEPH. Nakayama et al reported that a PAP waveform obtained using a fluid-filled system containing a balloon-tipped flow-directed catheter showed a larger PP in CTEPH than in PAH patients.²⁹ CTEPH is characterized by lodged thrombi in the proximal pulmonary arteries, resulting in stenosis of the large pulmonary arteries, stiffening of the arterial wall, and distal arteriopathy as a consequence of non-occluded area over-perfusion.²⁰ In contrast, PAH primarily affects the peripheral pulmonary arteries, and involves intimal thickening and fibrosis of the pulmonary arterioles, increased thickness of the media of the muscular pulmonary arteries, and muscularization of the arterioles.²⁹ The proximal location of pulmonary artery obliteration in CTEPH affects pressure wave reflection, and increased wave reflection increases the PP.²⁰ The widened PP is attributed to decreased arterial compliance and increased impedance in the arteries.²⁹ Taken together, PP and PAC could have a greater impact on RV regional contractility and dyssynchrony in CTEPH patients.

RV-6SD was also significantly correlated with RVD. RV dyssynchrony is a marker of the maladaptive stage characterized by more eccentric hypertrophy and worse systolic function.³⁸^,³⁹ Cheng et al demonstrated that patients with greater RV dilatation had more significant RV dyssynchrony and poor pump function.¹⁷ Haeck et al also presented an association between the presence of RV dyssynchrony and impaired RV function and enlarged dimensions of the RV.⁴

In contrast, RV dyssynchrony did not correlate with pulmonary hemodynamics assessed by right heart catheterization, such as PAP, PAWP, RAP, or CO. Lamia et al also found that RV dyssynchrony was not correlated with mean PAP or PVR in PAH and borderline PAH, and suggested that it is the systolic function adaptation to afterload, not afterload per se, which determines the heterogeneity of RV contraction.¹⁶ In contrast, Morita et al demonstrated that RV dyssynchrony was a significant predictor of mean PAP, PVR, and CI in a dog model.³² Chen et al showed that RV dyssynchrony had a negative correlation with CI and a positive correlation with PVR, but not with mean PAP patients in idiopathic PAH.¹⁷ Badagliacca et al have reported 3 papers on the clinical significance of RV dyssynchrony and its correlation with RV hemodynamics. They showed that RV dyssynchrony was significantly correlated with CI in 60 patients with IPAH.¹⁴ In addition, they found that PVR was an independent predictor of RV dyssynchrony in 83 patients with idiopathic, heritable, and anorexigen-induced PAH.¹⁵ In their final paper, the upper and intermediate tertiles of RV dyssynchrony distribution were found to be associated with a more impaired mean PAP, CI, and PVR in 108 patients with IPAH.²⁸ These findings suggested that the association of RV dyssynchrony with pulmonary hemodynamics may vary depending on the number of patients; the patients’ clinicopathological features, such as the severity of PH, underlying diseases and treatment; and the method of assessing RV dyssynchrony; that is, RV-6SD vs. RV-4SD, the standard deviation of times to peak longitudinal strain for the 4 basal and middle (septal and free wall) segments.

Study Limitations

First, this study was conducted retrospectively with a small patient cohort from a single center. Second, we used RV-6SD to assess RV dyssynchrony in this study. However, RV-4SD has been also used as an index of RV dyssynchrony.¹⁵ In the normal RV, contraction starts at the inlet and trabeculated myocardium and ends at the infundibulum, indicating that contraction of the RV apex occurs after that of the basal and mid-RV walls.³³ Apical traction, in which the RV apex is pulled towards the LV during systole due to LV traction, may occur with impaired RV systolic function.⁴⁰ This suggests that RV apical motion may play a crucial role in RV function. Murata et al demonstrated that assessing RV dyssynchrony using 6 RV segments resulted in a better correlation with hemodynamics and clinical outcomes than assessments using 4 segments (not including the apex).¹⁸ Therefore, we chose RV-6SD for assessing RV dyssynchrony. Indeed, there were some differences in the correlations of pulmonary hemodynamics and echocardiographic parameters between RV-6SD and RV-4SD (Supplementary Table 1), where only RV-6SD was correlated with PP and PAC. Third, the duration of the illness can affect RV function; however, the exact duration could not be investigated. Fourth, LV function may affect RV-6SD. We investigated the relationship between RV-6SD and LVEF, E/e’, and E/A in our patients. E/e’ was significantly higher in patients with CTEPH than in those with PAH (Supplementary Table 2). E/e’ and E/A are considered to be age-dependent parameters,⁴¹ and we also observed a significant correlation between them and age (Supplementary Table 3). Because CTD, especially scleroderma, can potentially impair LV function, we compared LV function between patients with and without CTD. CTD–PAH patients had a higher E/e’; however, no significant differences in RV-6SD, PP, and PAC were found between these disorders (Supplementary Table 2). In the entire population, RV-6SD did not correlate with LV function (Supplementary Table 3). Thus, we believe that LV dysfunction may have had less of an impact on RV dyssynchrony in this study. Fifth, a few patients had a small amount of pericardial effusion. Alnsasra et al recently reported that pericardiocentesis, with an average effusion of approximately 700 mL, did not significantly change RV function indices, including FAC and free-wall longitudinal strain, in PH patients.⁴² This may suggest that small pericardial effusion without hemodynamic compromise does not affect the measurements of RV using 2DST echocardiography in PH patients. Therefore, we believed that the pericardial effusion in our patients did not significantly affect our results. Finally, considering the exclusion criteria mentioned in the Methods section, the results of this study may not be applicable to all PAH and CTEPH patients and may have been influenced by patient selection bias.

Conclusions

CTEPH patients were older, had a higher RV-6SD and PP, and showed a lower PAC than PAH patients, although the mean PAP was comparable between the 2 groups. Considering the significant correlations of RV-6SD with PP and PAC, RV dyssynchrony appears to develop through low compliance and a widened PP in the pulmonary arteries.

Acknowledgments

The authors thank all sonographers at the Ultrasound Diagnosis Center of Nagasaki University Hospital for obtaining fine echocardiographic images, and Yurika Kawazoe and Shuntaro Sato at the Clinical Research Center of Nagasaki University Hospital for their advice on statistical analysis.

Disclosures

The authors declare that there are no conflicts of interest. K.M. is a member of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Nagasaki University Hospital Ethics Committee (approval number 16020812-8).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0849

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