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Comparison of four right ventricular systolic echocardiographic parameters to predict adverse outcomes in Chronic Heart Failure. Running head: RV function prognostic importance in CHF. Thibaud Damy a, e, f,*, Caroline Viallet a, Olivier Lairez a, Guillaume Deswarte a, Alexandra Paulino a, Patrick Maison d, Emmanuelle Vermes c, Pascal Gueret a, f, Serge Adnot S a, e, f, Jean-Luc Dubois-Randé a, e, f, Luc Hittinger a, e, f a b Service de Physiologie- Explorations Fonctionnelles, c d Fédération de cardiologie, Service de Chirurgie Cardio-thoracique, Service de Pharmacologie Clinique and Unité de Recherche Clinique; all at the AP-HP, Groupe Henri-Mondor Albert-Chenevier, e f INSERM, Unité U955 ; Université Paris 12, Faculté de Médecine ; All at Créteil, F-94010 France. *Corresponding author: Fédération de Cardiologie, Hôpital Henri Mondor, 51 Avenue Maréchal de Lattre de Tassigny, 94010 Créteil, France. Tel: 33 1 49 81 22 53 Fax: 33 1 49 81 42 24 Abstract: 202 Word count: Number of tables: 3, and figures: 2 Number of references: 29 + 2 (after reviewing) = 31 No relationships with industry. 1 ABSTRACT Background and aims: Heart failure (HF) has a poor prognosis. Several RV echocardiographic parameters have been proposed as sensitive markers to detect patients at risk. Our objective was to compare four right ventricular (RV) systolic echocardiographic parameters for their outcomes predictive values in HF. Methods: 136 patients with stable HF and a left ventricular ejection fraction below 35% were assessed for the following: 1-RV fractional area (RVFA), 2-Tricuspid annular plane systolic excursion (TAPSE), 3-Integral of the systolic wave (ISWtdi) and 4-Peak systolic velocity (PSVtdi). ISWtdi and PSVtdi were measured using tissue Doppler imaging at the tricuspid annulus. The primary endpoint was death or an urgent transplant or an urgent ventricular assist device implant or an acute HF episode. Results: During a mean follow-up of 295 days, 33 patients reached the primary endpoint. The thresholds of RVFA, TAPSE, PSVtdi and ISWtdi defined using ROC curves were respectively 36.8%, 13.5mm, 9.5cm.s-1 and 1.75cm. On Cox multivariate analysis, NYHA, log BNP, and only PSVtdi as RV systolic parameter, were found to be independent predictors of outcome. Conclusion: PSVtdi is a strong independent predictor of outcome in HF for a threshold value of 9.5cm.s-1 and appears to be superior to the other RV systolic echocardiographic parameters. Keywords: Congestive heart failure, right ventricle, echocardiography. 2 1. Introduction Despite recent advances in new therapies, patients with congestive heart failure (HF) still have a poor prognosis [1], and it is, therefore, important to establish a reliable means of estimating the prognosis of a subgroup of patients at greatest risk. Recently, Spiranova demonstrated that the presence of right ventricular (RV) dysfunction in HF is connected with adverse haemodynamic and humoral response [2]. Several studies showed that RV function correlated with outcome in HF assessed by techniques such as radionuclide, thermodilution, and conventional echocardiographic variables [3,4]. Thus, a need for diagnosis and quantification of RV dysfunction is important in HF. Echocardiography is frequently used as the first line imaging modality for assessment of RV size and RV function because of its widespread availability. Two dimensional echocardiography assessing RV fractional area (RVFA) is the mainstay for analysis of RV function, but recently, alternative parameters have been suggested, including tricuspid annular plane systolic excursion (TAPSE) using M-Mode [5,6], tissue Doppler imaging (TDI) measuring the peak systolic velocity (PSVtdi) [7,8], and the integral systolic wave velocity (ISWtdi) of the tricuspid annulus [9]. All these parameters can be routinely assessed during echocardiography. However, there is still discussion about the best echocardiographic parameters for predicting outcome in HF and also the cut-off to use for each parameter, although a value of 14mm for TAPSE has been used by Ghio to predict death or urgent transplantation [10]. This cut-off has since been used in several studies to determine the prognosis value of the RV function [11]. In addition, Meluzin et al have demonstrated that a PSVtdi <11·5 cm.s-1 predicts right ventricular dysfunction (RV ejection fraction <45%) and also a worse prognosis in HF [12]. Recently, Dokainish et al [13] demonstrated that a PSVtdi less than 9 cm.s-1 predicted death and rehospitalization in HF. However, in these last studies the prognosis value of PSVtdi was not compared to TAPSE and there is currently no echocardiographic gold standard to assess RV function. 3 The aim of this study was to evaluate which routinely assessed RV systolic echocardiographic parameters could better predict death or decompensated HF episodes in HF patients with systolic left ventricle (LV) dysfunction. 2. Methods The present study included 136 consecutive patients who were admitted to our department from 2005 to 2008 for cardiological investigation and the assessment of further therapy including orthotopic heart transplantation or chronic LV assist device implantation. Patients with a LVEF<35% were included in the study if they had had appropriate medication and had been clinically stabilized for at least one month. Patients with congenital or valvular heart and severe pulmonary diseases were excluded. Patients with coronary disease that warranted revascularization and other terminal diseases were also excluded. Clinical examination, Brain Natriuretic Peptide (BNP) and echocardiography were carried out within 48h after inclusion in the study. The study was approved by the Henri Mondor AP-HP ethics committee as part of a genetic substudy and patients gave their written consent to the investigation. The study complied with the Declaration of Helsinki. 2.1 Echocardiographic examination Results of 2D dimensional and Doppler (pulsed, continuous and TDI) echocardiography were obtained for all the patients using VIVID 7 with a 3.5-MHz transducer (GE-Vingmed, Horten, Norway). All patients were examined at rest while in the left lateral recumbent position. Echocardiographic data were stored using EchoPAC (GE-Vingmed, Horten, Norway) and analyzed by an echocardiographist blinded to all clinical and outcome data. Twodimensional, M-mode, Doppler echocardiography measurements and quantification were 4 performed according to recommendations of the American Society of Echocardiography [14,15]. Briefly, the LV end diastolic diameter was normalized by the body surface area (LVEDDind). LV ejection fraction (LVEF) was calculated according to the biplanar disc sum method (Simpson’s rule). The peak mitral early diastolic velocity (Em) and its deceleration time (E wave TD) were measured in pulse wave Doppler. The early peak velocities of the septal and lateral mitral annulus were measured in pulsed TDI and their average was calculated (Ea). The ratio of Em/Ea was then calculated to estimate the LV filling pressure [16]. For right ventricle 2D and TDI, care was taken to obtain an ultrasound beam parallel to the tricuspid annulus motion. RV endocardium was traced manually in systole and diastole and the fractional area change was calculated using (end-diastolic area-end-systolic area)/ end-diastolic area. TAPSE was measured as recommended by [10]. PSVtdi of tricuspid annulus was measured as recommended by [8] (sample TDI volume less than 5ml and an angle between the TDI sample volume and the longitudinal myocardial wall vector less than 20°). The ISWtdi was measured with a minimized gain to obtain the maximal net bordure [9]. The systolic Pulmonary Artery systolic Pressure (sPAP) was assessed by measuring the gradient between the right ventricle and the right atrium using the peak velocity (Vmax) of the tricuspid regurgitation (sPAP=4Vmax²+Right atrial pressure). The right atrial pressure was estimated to be 10mmHg for all the patients. All parameters were measured on 3 heart cycles if the patient was in sinus rhythm or on 5 cycles if the patient was on arrhythmia. The mean value was calculated. In seven patients, the right ventricle endocardial border was not sufficiently delimited to be measured. The peak velocity of the tricuspid regurgitation was measurable in 120 patients. In one patient E and A were merged and no value was measurable. All the other variables were measured for each patient. 2.2 Clinical follow up and endpoint definition. 5 At study termination, the vital status of each patient was confirmed by a review of medical records or phone contact (family and physician). The primary end-point was death or an urgent heart transplant or an urgent ventricular assist device implant or an acute episode of heart failure (AHF). The first event was considered for each patient. However, if AHF was followed during the same hospitalization by a death or an urgent transplantation or LV assist device implantation, only the last main outcomes were recorded. Patients (n=8) who had had non urgent heart transplant or non urgent ventricular assist devices were censored at the date of the surgical treatment for the Cox and Kaplan Meyer analysis and were excluded from the ROC curve analysis so as not to bias the results. 2.3 Data analysis. We first tested the diagnostic accuracy of each variable to predict the main combined endpoint. Data without normal distribution were logarithmically transformed (BNP, Em/Ea, E wave TD). Continuous variables were summarized by mean ± SD. Means were compared by two-tailed unpaired Student’s test. Discontinuous variables, presented with percentages (n), were compared using chi-square test. P<0.05 was considered significant. We then examined the diagnostic performance to predict the combined endpoint of each RV systolic parameter using receiver-operating characteristic curves analysis. The area under the curve was the primary efficacy measurement. If the lower 95% CI of the area under the curve was >0.5, we considered that the parameter was suitable for a diagnostic test and then the threshold was determined to produce the highest likelihood ratio positive and this was used as a cut-off point. Thereafter, we performed a time-to-event analysis (univariate Cox proportional hazard model) using the dichotomous variable defined by the ROC curve and the other clinical, biological and echocardiographic CHF markers: NYHA (used as a continuous variable), LVEF, LVEDDind, and the logarithmic transformation of BNP, Em/Ea 6 and E wave TD. The significant univariate parameters (p <0.10) were put through a multivariate COX proportional hazard analysis and the independent prognostic factors were identified by a backward stepwise selection algorithm. Finally, a Kaplan-Meier curve was constructed to show event-free survival according to time for the independent multivariable RV predictor of outcome with a log-rank test for significant differences in survival. Reproducibility of RVFA, TAPSE, PSVtdi and ISWtdi (intra and inter-observer variability) was assessed by the coefficients of variation for repeated measures in a random sample of 30 patients and was respectively for the intra-observator variability: 15%, 6%, 5%, 5% and for the inter-observator variability : 18%, 8%, 5%, 8%. Analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, IL). 3 Results 3.1 Clinical and echocardiographic variables. One hundred and thirty six patients were included. The follow-ups were available for all patients and the mean (SD) follow-up time was 295±221 days. Thirty three (24%) patients reached the primary endpoint (10 death or urgent transplant or urgent ventricular implant device, 23 AHF). Eight patients had non urgent cardiac surgery (7 heart transplants and 1 non urgent left ventricular assist device implantation). Table 1 shows the clinical variables in the patients with and without cardiac events. Briefly, those in the group who had an event had a significant increase in NYHA, BNP and diuretic treatment. Echocardiographic variables in patients with and without events are listed in table 2. The LV and RV parameters were significantly impaired in the group which reached the combined primary endpoint. 3.2 RV systolic echocardiographic parameters. 7 The receiving-operating curves and the area under the curve of each RV systolic parameter are shown in Figure 1. The four parameters were suitable for a diagnostic test as their ROC curve area was significantly greater than 0.50. The cut-offs defined for RVFA, TAPSE, PSVtdi, ISWtdi were respectively: 36.8%, 13.5mm, 9.5cm.sec-1 and 1.75cm. On the univariate COX proportional hazards analysis, the four RV dichotomous variables, using the threshold defined by the ROC curves, were predictors of the combined endpoint (P < 0.001). The other clinical, biological and LV echocardiographic parameters were also significant with a P <0.001, except the LVEDDind (P =0.36). When all these significant variables were computed in a multivariate Cox proportional hazards model, only PSVtdi, NYHA and BNP proved to be independent predictors of outcome (table 3). PSVtdi was the only independent RV systolic parameter predictor of outcome. The Kaplan Meier event free survival graph and analysis demonstrated that a PSVtdi patient with a value <9.5cm.sec-1 had the worst prognosis (figure 2). 4 Discussion The present study showed, for the first time, that the PSVtdi derived from the tricuspid annulus motion is an independent predictor of outcome (death, or urgent heart transplantation or urgent ventricle assist device implantation or acute heart failure episode) in HF when other important clinical, biological and echocardiographic markers such as NYHA, BNP, LVEF and Em/Ea are considered. It also demonstrated that PWStdi, with a threshold value of 9.5cm.sec-1, is a better predictor of outcome than other RV systolic parameters (RVFA, TAPSE, and ISWtdi). This finding is important because it might help both to identify the HF patients with a poor prognosis and target the medical supervision of the patients at highest risk. 8 4.1. Prognosis markers in CHF and RV function. The association between RV systolic function and NYHA functional class has already been observed by Ghio et al [10]. In our study, the filling pressure (Em/Ea) did not prove to be an independent marker of the prognosis associated to RV dysfunction as was shown by Dokainish [13]. However, in that study, patients were included only a few days after an AHF episode. Echocardiography was performed within 48 hours of hospital discharge and patients would not have had sufficient time to be stabilized and to have received the recommended dose of appropriate medication. Furthermore, patients with preserved LVEF function were also included in his study and this indicates that Em/Ea may have different properties depending on the LVEF as already described [17]. More recently, Mullens et al have demonstrated that E/Ea ratio may be less reliable in predicting LV filling pressure in patients with pronounced LV dilatation, LV dysfunction, and with bi-ventricular pacing. These characteristics were present in most of our patients and may explained that E/Ea ratio was not an independent predictor of outocome in our study [18]. In our study, BNP also was shown to be an independent marker of prognosis. Several studies have demonstrated that there is a correlation between BNP and LV filling pressure [19] or LV function [20] and adding it (BNP) to the predictive model may have decreased the effectiveness of Em/Ea and LVEF to predict the outcome in stable HF patients with LV dysfunction. 4.2. Role of PSVtdi to determine RV function and prognosis. In the current study, PSVtdi was shown to be a highly sensitive predictor of outcomes. The threshold value determined in our study, 9.5cm.sec-1, for the distinction of the prognosis was near that found by Dokainish et al [13] in predischarge AHF patients. Interestingly, this threshold corresponded in the study of Tuller et al [21] to the patients with severe impairment 9 of the RVEF (< 30%). Meluzin et al found a higher threshold value for PSVtdi (10.8 cm.sec-1) [12]. This lower threshold in Meluzin study could be explained by a lower mean pulmonary artery pressure observed in their patients (28±2 mmHg). Pulmonary artery pressure determines the RV afterload and is known to be associated with a worse RV function [22] and prognosis when combined with RV dysfunction [23]. 4.3. Comparison of the RV echocardiographic parameters to predict the outcome. ISWtdi, TAPSE, RVFA were also correlated with the combined endpoint. However, they were not independent predictors of prognosis. The reason why PSVtdi was better than the other RV parameters is that it overcomes many of the limitations of the traditional methods of RV assessment. Despite involving the tricuspid annulus velocity, ISWtdi was not an independent predictor of mortality. This result could be explained by a weaker correlation between ISWtdi and the RVEF than PSVtdi and TAPSE, as demonstrated by Ueti el al [9]. TAPSE is also an important marker as shown by [10,11]. In our study we observed that TAPSE had a lower sensitivity. This discrepancy may result from the higher variability and difficulties of acquiring this measurement than PSVtdi. In our study, we found that 13.5mm was the best threshold value for prediciting outcome. Interestingly Ghio et al used a similar threshold in their study (14mm) [10]. However, this threshold was not obtained by ROC curve. Despite the lack of data, this threshold was used by others [10,11] with similar results. It is worthy of mention that in this last study the same value as we used (<13.5mm) determined the first quartile group and patients with the worst prognoses. In our study, RVFA showed the weakest correlation with the prognosis. The complex shape of the right ventricle may limit the use of its area assessment; the endothelial borders are often badly defined due to trabeculations and impede accurate calculation of the areas of the right ventricle cavity. Similar difficulties have been reported by other observers [24,25]. However, tricuspid 10 annulus systolic motion is still more pronounced with RV dysfunction than RV free wall, and less influenced by the shape of the RV, suggesting that annular measurements should be easier to take and more reproducible. 4.4. Study limitation. The main limitation of this study was that our patient population was referred in our centre as potential candidates for heart transplantation or LV assist devices. Most of the patients included were less than 65 years old, without serious co-morbidities and with a poor prognosis. Consequently this population does not represent an average cohort of HF patients. However, the outcomes in this population related only to HF worsening and were not polluted by other death causes which might have impaired the subtle predictive value comparison of RV parameters. We excluded anyone with severe tricuspid regurgitation because the accuracy of the RV systolic parameter has not been established with such patients. We did not assess the influence of sustained expiration during acquisition of the variables. However, to minimize this possible problem, we used data from at least 3 heart beats in each patient in sinus rhythm and 5 in atrial fibrillation. Furthermore, we did not assess several RV parameters, such as the myocardial performance index or Tei index [26,27] and tricuspid annulus acceleration during isovolumic contraction [28], which were also correlated to RV dysfunction and CHF prognosis [29]. However, these parameters had high variability depending on the heart rate, and patients with atrial fibrillation and pacing were excluded from these studies and this may bias the extrapolation to a large HF population [29]. Another limitation was to estimate arbitrarily the right atrial pressure as 10 mmHg for the entire cohort when calculating systolic pulmonary artery pressure. Right atrial pressure in heart failure could be in a broad range between 0 to 30 mm Hg and by estimating the right atrial pressure with a fixed value; it may have decreased the range of the pulmonary artery 11 pressure and potential group differences and lowered the prognosis power of the pulmonary artery systolic pressure. However, the systematic use of 10 mm Hg has been previously validated [30]. Furthermore, other formulae which use venous cava diameters and/or their ratio to predict the mean right atrial pressure are still being investigated [31]. 5. Conclusion Our study shows the importance of the RV systolic parameters for the risk stratification of patients with HF and LV dysfunction. The PSVtdi was the best predictor of the combined endpoint. Patients with a PSVtdi <9.5cm.s-1 have a worse prognosis and should be carefully followed up. Finally, PSVtdi, NYHA and BNP added independent and incremental contributions to prognostic stratification in patients with stable HF and LV dysfunction. 6. Acknowledgments This study was supported by the Délégation à la Recherche Clinique de l’APHP. We thank warmly Mr. Ian Dennett for his help in writing the manuscript. 12 FIGURES LEGENDS Figure 1: ROC for prediction of primary combined endpoint (death or urgent heart transplantation or urgent ventricular assist device acute heart failure; n=128). A) PSVtdi , B) TAPSE, C) ISWtdi, D) RVFA AUC: Area under the ROC curve; CI: confidence interval. 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