Summary
Background
Adults with Eisenmenger syndrome have a survival advantage over those with idiopathic pulmonary arterial hypertension. Improved survival may result from preservation of right ventricular (RV) function.
Aims
To assess left ventricular (LV) and RV remodelling in patients with Eisenmenger syndrome compared to a control population, using speckle-tracking imaging.
Methods
Adults with Eisenmenger syndrome and healthy controls were enrolled into this prospective two-centre study. Patients with Eisenmenger syndrome with low acoustic windows, irregular heart rhythm or complex congenital heart disease were excluded. Clinical assessment, B-type natriuretic peptide (BNP), 6-minute walk test and echocardiography (including dedicated views to perform offline two-dimensional-speckle-tracking analysis) were performed on inclusion.
Results
Our patient population ( n = 37; mean age 42.3 ± 17 years) was mostly composed of patients with ventricular septal defect (37.8%) or atrial septal defect (35.1%). Compared with the control population ( n = 30), patients with Eisenmenger syndrome had reduced global LV longitudinal strain (–17.4 ± 3.5 vs. –22.4 ± 2.3; P < 0.001), RV free-wall longitudinal strain (–15.0 ± 4.7 vs. –29.9 ± 6.8; P < 0.001) and RV transverse strain (25.8 ± 25.0 vs. 44.5 ± 15.1; P < 0.001). Patients with Eisenmenger syndrome also more frequently presented a predominant apical longitudinal and transverse strain profile. Among patients with Eisenmenger syndrome, those with a post-tricuspid shunt presented with reduced global LV longitudinal strain but increased RV transverse strain, compared to patients with pre-tricuspid shunt.
Conclusion
Patients with Eisenmenger syndrome had impaired longitudinal RV and LV strain, but present a relatively important apical deformation. RV and LV remodelling, as assessed by speckle-tracking imaging, differ between patients with pre- and post-tricuspid shunt.
Résumé
Contexte
Les patients avec syndrome d’Eisenmenger présentent un avantage de survie par rapport aux patients avec hypertension artérielle pulmonaire non liée aux cardiopathies congénitales. La préservation de la fonction ventriculaire droite (VD) pourrait expliquer cet avantage.
Objectifs
D’étudier le remodelage ventriculaire droit et gauche (VG) à l’aide du « speckle-tracking imaging » chez les patients avec syndrome d’Eisenmenger.
Méthodes
Nous avons inclus de façon prospective patients avec syndrome d’Eisenmenger et des patients témoins au sein d’une étude bicentrique. Les patients atteints d’un syndrome d’Eisenmenger lié à une cardiopathie congénitale complexe, peu échogènes ou en arythmie ont été exclus.
Résultats
Notre population de syndrome d’Eisenmenger ( n = 37 ; âge moyen 42,3 ± 17 années) se compose majoritairement de patients avec communication inter-ventriculaire (37,8 %) et inter-atriale (35,1 %). Comparativement à la population témoin ( n = 30), les patients présentent une réduction du strain global longitudinal VG (–17,4 ± 3,5 vs –22,4 ± 2,3 ; p < 0,001), du strain longitudinal (–15,0 ± 4,7 vs –29,9 ± 6,8 ; p < 0,001) et transverse VD (25,8 ± 25,0 vs 44,5 ± 15,1 ; p < 0,001). Ils présentent également de façon plus fréquente un profil de déformation apicale important. Au sein de la population avec syndrome d’Eisenmenger, les patients avec shunt post-tricuspide ont un strain longitudinal VG réduit tandis que leur strain transverse VD est meilleur par rapport aux patients avec shunt pré-tricuspide.
Conclusion
Les patients avec syndrome d’Eisenmenger présentent une altération du strain longitudinal VD et VG, mais un profil de déformation VD avec déformation apicale prédominante. Le remodelage VD et VG évalué par la technique du speckle-tracking a aussi permis de constater des différences dans la population syndrome d’Eisenmenger en fonction de la localisation du shunt pré- ou post-tricuspide.
Introduction
Pulmonary hypertension is a severe disorder defined as an increase in mean pulmonary arterial pressure > 25 mmHg at rest . Patients with pulmonary hypertension can be divided into subgroups sharing similar underlying pathophysiology . Eisenmenger syndrome is the most advanced form of pulmonary artery hypertension (PAH) associated with congenital heart disease. Patients with Eisenmenger syndrome have a survival advantage over those with other causes of PAH . Survival and symptoms are closely related to right ventricular (RV) function and adaptation . Improved survival may result from preservation of RV function, as the right ventricle may not undergo ‘normal’ remodelling at birth and sustain raised pulmonary vascular resistance. Differences within the spectrum of Eisenmenger syndrome have already been described, especially between patients with pre- and post-tricuspid shunt . Thus, we hypothesize that different cardiac remodelling might explain the differences observed between patients with pre- and post-tricuspid shunt.
Speckle-tracking imaging is a relatively recent tool used to investigate RV and left ventricular (LV) functions, especially in the setting of pulmonary hypertension . Speckle-tracking imaging has been related to cardiovascular events and mortality in patients with pulmonary hypertension ; however, little is known about the role of speckle-tracking imaging in Eisenmenger syndrome.
The aim of our study was to identify LV and RV remodelling differences in patients with Eisenmenger syndrome compared to healthy controls, using speckle-tracking imaging. We also aimed to describe LV and RV remodelling differences between patients with pre- and post-tricuspid shunt.
Methods
Study design and patients
We performed a prospective two-centre case-control study on patients with Eisenmenger syndrome who were followed up at our centres (Pasteur University Hospital, Nice, France and Haut-Leveque University Hospital, Bordeaux, France) between September 2012 and June 2015.
Adults with Eisenmenger syndrome were included in the study. Patients with low acoustic windows, irregular heart rhythm or complex congenital heart disease (e.g. univentricular heart and systemic right ventricle) were excluded from this study to standardize the interpretation of echocardiographic data. Demographic and clinical data (age, sex, diagnosis, New York Heart Association [NYHA] class, heart rate, specific advanced therapy), B-type natriuretic peptide (BNP) plasma concentrations and 6-minute walk test distance were collected on inclusion (at the time of echocardiography).
Adult healthy controls were enrolled either in the outpatient clinic or from hospital employees and fellows in training. All underwent echocardiography examination and none were competitive athletes. Criteria for recruitment included age ≥ 18 years, no history or symptoms of cardiovascular or lung disease, no ongoing or previous cardio- or vasoactive treatment, and normal results on electrocardiogram (ECG) and physical examinations. Exclusion criteria included tricuspid regurgitation more than mild, poor acoustic window, pregnancy and obesity.
All study subjects gave informed consent to participate in the study. Our local ethics committee approved the study protocol.
Echocardiographic measurements
Echocardiographic examination was performed using an IE-33 (Philips Medical system, Andover, MA, USA) or a Vivid 7 ultrasound system (General Electric Healthcare, Milwaukee, WI, USA). Doppler echocardiography was performed according to the recommendations of the American Society of Echocardiography . The ratio of RV wall thickness to RV diameter was calculated to distinguish between more concentric and eccentric hypertrophy.
RV myocardial strain was studied using speckle-tracking echocardiography of the apical long axis, obtained from the apical four-chamber view during a quiet breath hold with a frame rate of 55–75/s ( Fig. 1 ). LV myocardial global longitudinal strain was assessed using speckle-tracking echocardiography of the apical long axis, obtained from apical four-, three- and two-chamber views of the left ventricle. LV circumferential strain was obtained by analysing the parasternal short axis of the LV mid-cavity.
Two consecutive heart cycles were recorded and averaged (excluding premature beats). The offline analysis was performed using commercially available semiautomated two-dimensional (2D) strain software: Tomtec Cardiac Performance Analysis (TomTec Imaging Systems GmbH, Germany) for longitudinal, transverse and circumferential strain analysis. The peak RV free-wall longitudinal strain was defined as the peak negative value on the strain curve; peak RV free-wall transverse strain was defined as the peak positive value on the strain curve before pulmonary valve closure. The RV cavity was traced manually, delineating a region of interest composed of three segments of the lateral wall: basal, mid-cavity and apical. After segmental tracking, the RV longitudinal and transverse curves were generated and the average values of longitudinal and transverse strain calculated. A predominant apical deformation pattern was defined by an apical peak strain value above the peak strain value of the median and basal segments. The Eisenmenger echocardiographic prognostic score has been calculated for each patient .
Ultrasound scanning was performed in both centres. The physician performing the ultrasound for a clinical purpose interpreted the echocardiography immediately. Images were then stored on a hard drive or digital videodisc (DVD) in native Digital Imaging and Communications in Medicine (DICOM) format. Images from Bordeaux were sent electronically or via mail (DVDs) to Nice. One staff cardiologist with advanced training in echocardiography interpreted 2D echo datasets and performed the offline speckle-tracking analysis. In a subset of 20 controls, included and scanned in Nice, intra-operator variability was assessed for RV longitudinal and transverse strain reproducibility.
Statistical analysis
Data are summarized as mean ± standard deviation (SD) for continuous variables and number (%) for categorical variables. Normally distributed variables were tested by a two-tailed Student’s t -test for unpaired data. Variables that were not normally distributed were tested by the Mann–Whitney U -test. Categorical variables were compared using Fisher’s exact test. Variability was assessed, with good agreement defined as > 0.80, using intra-class correlation analysis. Given the rarity of the disease, no sample size calculation was possible, hence consecutive patients were included according to the capabilities of our centres.
For all analyses, statistical significance was defined as P < 0.05. Statistical analyses were performed using MedCalc 15.8 for Windows (MedCalc Software, Ostend, Belgium).
Results
General characteristics of the population
A total of 37 consecutive patients with Eisenmenger syndrome (mean age 42.3 ± 17 years; 73.0% female) and 30 healthy controls (mean age 33.8 ± 11 years; 66.7% female) were included in this study. The underlying congenital heart defect was ventricular septal defect in 14 patients (37.8%), atrial septal defect in 13 (35.1%) patients, complete atrioventricular septal defect in seven (18.9%) patients and patent ductus arteriosus in 3 (8.1%) patients. Patient characteristics are detailed in Table 1 .
| Eisenmenger syndrome ( n = 37) | |
|---|---|
| Age (years) | 42.3 ± 17 |
| Women | 27 (73.0) |
| NYHA class III/IV | 20 (54.1) |
| Resting O 2 saturation (%) | 88.6 ± 5 |
| B-type natriuretic peptide (ng/L) | 165.1 ± 224 |
| 6-minute walk distance (m) | 345.5 ± 109 |
| Advanced therapy at baseline | 29 (78.4) |
| Death or hospitalization | 10 (27.0) |
Regarding standard echocardiographic characteristics, patients with Eisenmenger syndrome had overall dilated right hearts (both atria and ventricles), and mean RV fractional area changes and tricuspid annular plane systolic excursion (TAPSE) were lower than normal established values. Standard echocardiographic characteristics of our patient population are described in Table 2 .
| Total population ( n = 37) | Pre-tricuspid shunt ( n = 13) | Post-tricuspid shunt ( n = 24) | P | |
|---|---|---|---|---|
| RA area (cm 2 ) | 24.5 ± 9 | 27.2 ± 10 | 22.7 ± 8 | 0.19 |
| RA/LA area ratio | 1.45 ± 0.4 | 1.32 ± 0.3 | 1.53 ± 0.4 | 0.17 |
| RA pressure (mmHg) | 10.0 ± 3.2 | 11.1 ± 3.3 | 8.6 ± 2.3 | 0.10 |
| RV inlet (mm) | 46.5 ± 8 | 48.9 ± 9 | 44.5 ± 6 | 0.10 |
| RV wall thickness (mm) | 11.8 ± 3.0 | 9.6 ± 2.4 | 13.6 ± 2.2 | < 0.001 |
| RV wall/diameter ratio | 0.26 ± 0.09 | 0.19 ± 0.05 | 0.32 ± 0.07 | < 0.001 |
| TAPSE (mm) | 18.8 ± 5.9 | 21.5 ± 6.3 | 17.4 ± 5.4 | 0.08 |
| TV s′ (cm/s) | 9.9 ± 2.7 | 10.5 ± 3.2 | 9.6 ± 2.4 | 0.41 |
| RV FAC (%) | 36.9 ± 10 | 32.0 ± 10 | 40.1 ± 8 | 0.09 |
| IVA/√RR 2 (m/s 2 ) | 2.2 ± 0.9 | 2.4 ± 1.3 | 2.4 ± 0.8 | 0.96 |
| RV OT VTI (cm) | 16.6 ± 5.8 | 13.8 ± 2.2 | 18.6 ± 6.8 | 0.05 |
| PV acceleration time (ms) | 68.6 ± 21 | 67.0 ± 18 | 70.0 ± 24 | 0.92 |
| Tei index | 0.68 ± 0.3 | 0.69 ± 0.3 | 0.67 ± 0.2 | 0.90 |
| S/D ratio | 1.07 ± 0.6 | 1.32 ± 0.8 | 0.84 ± 0.2 | 0.49 |
| TV E/A | 1.07 ± 0.6 | 0.90 ± 0.4 | 1.18 ± 0.7 | 0.50 |
| TV E/e′ | 5.5 ± 3.1 | 4.0 ± 1.0 | 6.7 ± 3.7 | 0.06 |
| TV e′ (cm/s) | 9.4 ± 3.6 | 10.4 ± 2.9 | 8.7 ± 4.0 | 0.34 |
| RV-RA gradient (mmHg) | 95.7 ± 25 | 87.3 ± 29 | 102.4 ± 21 | 0.21 |
| LV EF (%) | 63.1 ± 14 | 67.1 ± 14 | 59.5 ± 14 | 0.21 |
| LV EDD (mm) | 41.9 ± 7.4 | 40.1 ± 7.0 | 43.7 ± 7.7 | 0.27 |
| LA area (cm 2 ) | 17.3 ± 6.9 | 20.1 ± 5.8 | 15.6 ± 7.0 | 0.04 |
| MV E/A | 1.2 ± 0.6 | 1.0 ± 0.4 | 1.4 ± 0.7 | 0.29 |
| MV E/e′ | 6.8 ± 3.2 | 7.7 ± 4.1 | 6.2 ± 2.2 | 0.50 |
| MV e′ (cm/s) | 10.4 ± 4.0 | 10.7 ± 4.8 | 10.2 ± 3.5 | 0.84 |
| LV diastolic eccentricity index | 1.58 ± 0.3 | 1.63 ± 0.2 | 1.55 ± 0.3 | 0.46 |
| Pericardial effusion | 3 (8.1) | 2 (15.4) | 1 (4.2) | 0.55 |
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