European Heart Journal Advance Access originally published online on January 22, 2007
European Heart Journal 2007 28(10):1250-1257; doi:10.1093/eurheartj/ehl477
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Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension
1 Department of Pulmonary Diseases, Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
2 Department of Physics and Medical Technology, Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
3 Department of Cardiology, Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
4 Clinical Epidemiology and Biostatistics, Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Received 19 June 2006; revised 11 December 2006; accepted 21 December 2006; online publish-ahead-of-print 22 January 2007.
* Corresponding author. Tel: ±31 20 4444728; fax: ±31 20 4444382. E-mail address: a.vonk{at}vumc.nl
See page 1187 for the editorial comment on this article (doi:10.1093/eurheartj/ehm074)
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Abstract |
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Aims: This study investigated the relationship between right ventricular (RV) structure and function and survival in idiopathic pulmonary arterial hypertension (IPAH).
Methods and results: In 64 patients, cardiac magnetic resonance, right heart catheterization, and the six-minute walk test (6MWT) were performed at baseline and after 1-year follow-up. RV structure and function were analysed as predictors of mortality. During a mean follow-up of 32 months, 19 patients died. A low stroke volume (SV), RV dilatation, and impaired left ventricular (LV) filling independently predicted mortality. In addition, a further decrease in SV, progressive RV dilatation, and further decrease in LV end-diastolic volume (LVEDV) at 1-year follow-up were the strongest predictors of mortality. According to Kaplan–Meier survival curves, survival was lower in patients with an inframedian SV index 
25 mL/m2, a supramedian RV end-diastolic volume index 
84 mL/m2, and an inframedian LVEDV40 mL/m2.
Conclusions: The RV contains prognostic information in IPAH. A large RV volume, low SV, and a reduced LV volume are strong independent predictors of mortality and treatment failure.
Key Words: Pulmonary hypertension • Prognosis • Magnetic resonance imaging • Right ventricle
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Introduction |
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Idiopathic pulmonary arterial hypertension (IPAH) is characterized by obstructive lesions of the small pulmonary vessels leading to increased pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR).1 In recent years, several treatment options for patients with IPAH have become available which have demonstrated to improve the prognosis in patients with this devastating disease.2–4 However, some patients are refractory to the initially proposed therapy. In these patients, a further increase of PAP and PVR leads to a severe burden on the right ventricle (RV). A failing adaptation of the RV to the increased afterload will lead to RV failure, which is the main cause of mortality in patients with IPAH. Direct measurements of RV structure and function might provide useful prognostic information to identify those patients who do not respond to the given therapy.
Until now there is limited information on the prognostic significance of RV parameters. Raymond et al.5 found that the right atrial (RA) area index, the diastolic eccentricity index, and the presence of pericardial effusion assessed by echocardiography were predictors of the combined endpoint death or transplantation. Other parameters obtained by echocardiography, which have been found to be related to a poor prognosis were the degree of tricuspid regurgitation and the Doppler-derived Tei index.6,7 More direct RV parameters such as diastolic and systolic volumes and myocardial mass have not been evaluated on their prognostic significance. These determinants of the RV can be assessed accurately with cardiac magnetic resonance imaging (CMR).8,9 In addition, CMR has a high degree of reproducibility, which makes it an ideal tool to monitor changes in RV parameters in response to therapy.10–12 However, whether changes in these RV parameters have prognostic value and will predict the response to therapy in patients with IPAH is unknown.
In the present study we performed CMR to investigate whether parameters of RV structure and function measured at baseline and after 1-year follow-up have prognostic significance in patients with IPAH.
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Methods |
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Patients
Between January 1999 and August 2005, 607 consecutive patients were evaluated with a right heart catheterization (RHC) for the diagnosis of pulmonary hypertension. Patients were included when pulmonary hypertension, defined as mean PAP >25 mmHg and pulmonary capillary wedge pressure (PCWP) < 15 mmHg, was found at RHC without an identifiable cause of pulmonary hypertension after pulmonary hypertension related to chronic thrombo-embolic disease, connective tissue disease, congenital heart disease, portal hypertension, HIV infection, or a hypoxic origin was excluded by further diagnostic work-up.13 One hundred and thirty-five patients were diagnosed with IPAH and 64 patients were included in the study after informed consent was obtained. The characteristics of the patients are summarized in Table 1. Patients underwent CMR, RHC, and a six-minute walk test (6MWT) within 1 week at baseline and again after 1 year follow-up (Figure 1). Patients’ functional status was scored according to the New York Heart Association (NYHA) classification. According to clinical guidelines, NYHA class III patients with a positive acute vasodilator challenge during RHC were treated with calcium-antagonists.13 Before 2002, all unresponsive patients were given intravenous prostacyclin (epoprostenol), after 2002 NYHA class III patients were started on oral monotherapy and NYHA class IV patients were started on intravenous prostacyclin (epoprostenol). In case of clinical worsening intravenous prostacyclin (epoprostenol) or combination therapy was given. Thirty patients (47%) were treated with intravenous prostacyclin (epoprostenol), 25 (40%) were treated with an endothelin receptor antagonist (sitaxentan or bosentan), four (6%) with sildenafil, and five (8%) with calcium-antagonists. All patients were treated with oral anticoagulants. The study protocol was approved by Institutional Ethics Review Commission.
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Follow-up evaluation
One year follow-up measurements including CMR, RHC, and 6MWT were performed in 54 patients (Figure 1). Ten patients had died in the period from baseline to follow-up. Long-term clinical follow-up was performed by regular, 3–6 months interval, follow-up visits at the outpatient clinic, and by telephone contact. No patients were lost to follow-up.
Six-minute walk test
The 6MWT was performed according to ATS guidelines.14 Immediately after the 6MWT the Borg dyspnoea score was obtained.
Right heart catheterization
RHC was performed to obtain measurements of PAP, RA pressure, PCWP, cardiac output, PVR, and mixed venous oxygen saturation. Cardiac output was determined using the Fick method. Oxygen consumption was measured during RHC. All patients had a vasodilatory test with inhaled nitric oxide (20 ppm). Patients who were classified as acute responders were treated with calcium-antagonists according to treatment guidelines.13
Cardiac magnetic resonance imaging
CMR imaging was performed on a Siemens 1.5 T Sonata scanner (Siemens Medical Solutions, Erlangen, Germany) with simultaneous ECG recording according to a protocol described previously, with correction for phase offset errors.11,15 Short-axis cine images of the heart from apex to base were acquired, covering the whole LV and RV. For the cine images, a gradient-echo pulse sequence (TrueFISP by Siemens) was applied (repetition time ms/echo time ms, 34/1.6; flip angle, 60°; field of view, 280 x 340 mm2; matrix, 150 x 256 pixels; pixel size, 1.9 x 1.3; slice thickness, 6 mm; slice distance, 4 mm). The endo- and epicardial contours of the RV and LV were delineated manually by a blinded observer and processed using MASS software (Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands) to obtain RV and LV masses and end-diastolic volumes. The American Heart Association 17-segment model for the LV was used to analyse LV wall thickness.16 The mid-ventricular short-axis slice was divided into six segments. LV wall thickness was measured in each segment and the mean value was reported. Three measurements of RV wall thickness were obtained for the RV free wall at the mid-ventricular level and the mean value was reported. Stroke volume (SV) was determined from the flow in the main pulmonary artery (PA) in an image plane positioned perpendicular to the main PA using a two-dimensional, spoiled gradient-echo pulse sequence, and one-dimensional velocity-encoding signal parallel to the flow in the PA (velocity sensitivity, 120 cm/s; repetition time ms/echo time ms, 22/4.8; flip angle, 15°; field of view, 260 x 320 mm2; matrix, 150 x 256 pixels; pixel size, 1.9 x 1.3; slice thickness, 8 mm). Cardiac output was determined by multiplying SV by heart rate. Parameters were indexed by correcting for body surface area. RV and LV ejection fractions were determined by dividing SV by right and left end-diastolic volumes, respectively.
Statistical analysis
All data are expressed as mean ± SD. The endpoint of the study was defined as all-cause mortality. No patient died from non-cardiopulmonary causes. One patient received a lung transplantation and was treated as a censored case at the time of transplantation. Comparisons between groups were made by the paired t-test or Fisher's exact test. Cox proportional hazards analysis was performed to assess the association between baseline variables and mortality and between the change in follow-up variables and mortality. The following variables were tested: age, gender, NYHA functional class, 6MWT, mean RA pressure, mean PA pressure, pulmonary vascular resistance index (PVRI), cardiac index (Fick and MRI method), SV index (SVI) (Fick and MRI method), heart rate, mixed venous oxygen saturation, RV mass index, LV mass index, RV wall thickness, LV wall thickness, RV ejection fraction (EF), LVEF, RVEDVI, and LVEDVI. The follow-up analysis was performed using the changes between baseline and follow-up evaluation in the 54 patients still alive after 1-year follow-up. Hazard ratios and 95% confidence intervals were calculated. Multivariable analysis was then performed using all variables with a P < 0.05 in the univariate model. The linearity and the proportional hazard assumption were tested and satisfied for all covariates. Stepwise backward elimination was used to identify variables associated with mortality. Survival curves were constructed with the Kaplan–Meier method and were compared by means of the log-rank test. Continuous variables were separated into two groups on both sides of the median value. A value of P < 0.05 was considered statistically significant.
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Results |
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Patient characteristics
The demographic, haemodynamic, and CMR data of the patients are summarized in Table 1. During the mean follow-up period of 32 ± 16 months, 19 out of 64 patients (30%) died from cardiopulmonary causes. Ten patients died during the first year, and 9 patients died during the subsequent follow-up (Figure 1). In nine patients medical therapy was changed because of clinical worsening. Sildenafil was added in three patients with calcium-antagonists, in two patients with epoprostenol, and in one patient with bosentan treatment. In one patient with epoprostenol, bosentan was added. In two patients, bosentan treatment was changed to epoprostenol treatment.
Follow-up assessment with 6MWT, RHC, and CMR imaging
After 1 year, a follow-up assessment with 6MWT, RHC, and CMR was performed. Of the 64 patients included in the study, a follow-up assessment was obtained in 54 patients. Ten patients died in the interval between baseline assessment and 1-year follow-up assessment. Nine additional patients died during a mean follow-up of 17 ± 14 months, after the 1-year follow-up assessment was obtained (Figure 1). In Table 2, the mean changes in 6MWT, RHC, and CMR variables are reported of the 54 patients analysed at follow-up. After 1-year follow-up, there was a significant increase in mean 6MWT, cardiac index, SVI, RVEF, and LVEDVI and a significant decrease in mean RA pressure, PVRI, and RVEDVI.
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Univariate and multivariable predictors of mortality
Univariate analysis with reference to baseline assessment demonstrated that NYHA functional class, 6MWT, mean RA pressure, PVRI, mixed venous oxygen saturation, SVI, RVEDVI, and LVEDVI predict mortality in IPAH (Figure 2).
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Univariate analysis with reference to the change in variables after 1-year follow-up demonstrated that mean change in RA pressure, PVRI, SVI, RVEF, RVEDVI, and LVEDVI predict mortality in IPAH (Figure 3).
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Multivariable Cox proportional hazards analysis was performed using baseline and changes in follow-up variables. Multivariable analysis showed that at baseline, 6MWT, SVI, RVEDVI, and LVEDVI were independent predictors of prognosis in IPAH (Table 3). At 1-year follow-up, the change in SVI, PVRI, RVEDVI, and LVEDVI were independent predictors of mortality in the multivariable analysis (Table 3).
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Kaplan–Meier survival analysis
Kaplan–Meier survival curves according to the median value of CMR variables at baseline are shown in Figure 4. Patients with a baseline SVI >25 mL/m2 (median value) had a significantly better survival than those with a baseline SVI
25 mL/m2 (log-rank test, P = 0.010). Patients with an RVEDVI < 84 mL/m2 (median value) had a significantly better survival than those with a baseline RVEDVI 84 mL/m2 (log-rank test, P = 0.011). Finally, patients with an LVEDVI >40 mL/m2 (median value) had a significantly better prognosis than those with an LVEDVI 40 mL/m2 (log-rank test, P = 0.016).
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Discussion |
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In the present study we investigated the prognostic significance of RV and LV structural and functional parameters in patients with IPAH. The results demonstrate that a large RV end-diastolic volume (RVEDV), low LV end-diastolic volume (LVEDV), and a low SV at baseline were associated with a poor prognosis. Progressive dilatation of the RV, a further decrease of LV diastolic volume, and a further decrease in SV at follow-up predict treatment failure and a poor long-term outcome.
Significance of decreased RV SV
RV dysfunction is related to the severity of pulmonary hypertension and the degree of symptoms in patients with pulmonary hypertension. Our study showed that a low SV measured at baseline is predictive for a poor survival. The prognostic value of cardiac output in IPAH is studied in several studies and it was found that cardiac index contains prognostic information.2,3,17,18 Less attention has been paid to SV. Our results showed that there is a stronger correlation between SV and prognosis than between cardiac index and prognosis. The discrepancy between SV and cardiac index might be explained by the fact that a decrease in SV can be compensated by an increase in heart rate, flawing the relation between cardiac output and prognosis. In addition, our results showed that a decrease in SV during treatment is related to treatment failure. Thus SV, more than cardiac index, should be considered as a parameter to monitor during treatment.
Both SV measured with CMR or with the Fick method were predictors of prognosis, with comparable results. However, CMR systematically underestimated SV when compared with the Fick method, both at baseline and at follow-up. This might be explained by the turbulent flow patterns observed in the main PA of the IPAH patients. In turbulent flow patterns, some of the flow will be measured at an angle, which decreases flow sensitivity in our CMR flow imaging sequence and might cause an underestimation of total flow in the main PA.19
RV hypertrophy and dilatation
In pulmonary hypertension, a chronically increased PAP and PVR leads to secondary RV remodelling. The RV compensates for the increased afterload with RV enlargement and hypertrophy. At some point the RV is unable to adapt further to the increased RV afterload and RV failure will occur, leading to short-term death. Although this is well known, it remains difficult how to ascertain this process before the patient is dying of RV failure based on currently available parameters. Reports on the prognostic value of PAP have contradicted each other.2,3 Sitbon et al.3 has found that the change in 6MWT during treatment was not related to prognosis. More promising is a rise in BNP that has shown to be related to poor outcome.20,21 Our results showed that an increased RVEDV and especially progressive RV dilatation during treatment, are predictors of a poor survival. This is of clinical importance, since it provides a direct RV parameter predicting RV failure at an early stage which enables the prediction of treatment failure, and thus offers an opportunity to change treatment or list on a transplantation list before RV failure causes death of the IPAH patient. The evidence provided in this study that progressive RV dilatation may indicate impending fatal decompensation also indirectly validates cardiac biomarkers such as BNP or cardiac troponin as potential methods of monitoring RV status in patients with PAH since changes in BNP concentration or persisting cardiac troponin leakage have been shown to be related to RV structure and function and prognosis.20–24
RV hypertrophy did not appear to be as strongly related to mortality as RV dilatation. Two earlier studies showed that RV mass and PAP are related to each other.25,26 Therefore, an increase in RV mass might reflect a normal adaptation to an increase in RV afterload.
RV wall thickness provides additional data, as it can be used to describe the pattern of hypertrophy. Quaife et al.27 used wall thickness to describe a pattern of concentric hypertrophy (predominant increase wall thickness) or eccentric hypertrophy (increase in wall thickness in proportion to increase in RV volume). Quaife et al. also added a functional classification to the pattern of hypertrophy, with an RVEF40% defined as compensated, and an RVEF < 40% as failing. As expected, most of our pulmonary hypertension patients (49/64) had a pattern of concentric RV hypertrophy to compensate for the increased afterload (defined by them as an RV wall thickness >0.7 cm and an RV mass >56 g). The degree of wall thickness seemed to be related to the level of PAP in our patients with less severe PAPs having a lesser degree of wall thickness (R = 0.40; P = 0.004). In concordance with the data on RV mass, RV wall thickness also was not a significant predictor of mortality.
LV end-diastolic volume
LVEDV appeared to be a strong predictor of poor survival in our study. The decrease in LVEDV in IPAH is a consequence of impaired LV filling in IPAH. Impaired LV filling in RV pressure overload might be the result of two mechanisms: a decrease in SV or compression of the LV due to an increased RVEDV.28,29 Since both SV and RVEDV appeared to be strong predictors of mortality in IPAH it is understandable that a low LVEDV at baseline and a further decrease during treatment is related to a poor prognosis. This finding fits also with an earlier observation that a favourable treatment response to bosentan in IPAH patients measured by the 6MWT was associated with a decrease in RV dilatation and an increase in LVEDV.30
Other measures of RV function
Raymond et al.5 had previously shown that RA size measured with echocardiography was of prognostic significance in patients with IPAH. In addition, a large RVED area index, an indirect measure of RVEDV, was related to a poor prognosis, although not significant in the univariate analysis. The prognostic significance of an RV dilatation during treatment has not been studied by echocardiography until now.
Hinderliter et al.31 found that pericardial effusion was present in 43 of 79 patients (54%) with pulmonary hypertension and also found that pericardial effusion was related to a worse outcome. CMR can readily detect pericardial effusion when present, especially when pericardial effusion is localized.32 In fact, in almost all our patients some degree of pericardial effusion was detected with CMR. However, a scoring system of pericardial effusion with CMR does not exist to our knowledge and should be validated before used to predict prognosis. Therefore, at this time we consider echocardiography as the primary imaging modality for the evaluation of pericardial effusion in IPAH. There are several other echocardiographic parameters that can be measured in patients with IPAH. However, the reproducibility of measurements of the RV remains difficult with echocardiography and its value in the assessment of changes in RV parameters after 1-year follow-up has not been determined. The reason that we chose CMR was because of its accuracy and reproducibility in measurements of RV parameters and our experience with CMR. Recent developments in three-dimensional echocardiography and tissue Doppler imaging may offer accurate tools to measure RV structure and function in experienced hands.33–36
Clinical implications
The prognosis of patients with IPAH remains difficult to predict, despite assessment of clinical and haemodynamic parameters. In this study we demonstrate that non-invasive measures of RV and LV function accurately predict outcome. Moreover, they also provide detailed information about the patients’ performance at 1-year re-evaluation. Although other parameters such as the 6MWT and BNP have clinical value, they provide indirect information on RV function, and their prognostic value can be flawed by unwanted confounding factors such as a training effect or renal failure. In certain patients, there is a need to have an objective parameter of RV function, in addition to measures such as the 6MWT and BNP to guide clinical treatment.
Study limitations
Therapy was not controlled in this study. Most patients in this study were treated either with intravenous epoprostenol or with endothelin receptor antagonists. However, there was no significant difference in the measures of RV and LV structure and function between patients treated with intravenous epoprostenol or with endothelin receptor antagonists. In addition, a study that compared survival between epoprostenol and bosentan found no significant difference.37 Another limitation of this study is that these data were obtained in a single centre. These data should be reproduced in other centres to validate the prognostic value of the CMR parameters.
Conclusion
RV parameters are of prognostic importance in IPAH. A decreased SV, an increased RVEDV, and a decreased LVEDV measured at baseline are associated with a poor prognosis. RV dilatation and a decrease in SV and LV diastolic volume are strong predictors of treatment failure and death at follow-up.
Conflict of interest. none declared.
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