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Echocardiography predictors and prognostic value of pulmonary artery systolic pressure in chronic organic mitral regurgitation
  1. Thierry Le Tourneau,
  2. Marjorie Richardson,
  3. Francis Juthier,
  4. Thomas Modine,
  5. Georges Fayad,
  6. Anne-Sophie Polge,
  7. Pierre-Vladimir Ennezat,
  8. Christophe Bauters,
  9. André Vincentelli,
  10. Ghislaine Deklunder
  1. Inserm, UMR 915, Institut du Thorax, Nantes, and Hôpital Cardiologique, Centre Hospitalier Régional et Universitaire, Lille, France
  1. Correspondence to Dr Thierry Le Tourneau, Laboratoire d'Explorations Fonctionnelles, Hotel Dieu, 1 Place Alexis Ricordeau, 44093 Nantes Cedex, France; thletourneau{at}yahoo.fr

Footnotes

  • Funding This work was supported by a grant from the Société Septentrionale d'Echocardiographie, Clinique de Bois Bernard, route de Neuvireuil, 62320 Bois-Bernard.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of Lille University Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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Pulmonary hypertension is common in patients with chronic organic mitral regurgitation (MR) even with normal left ventricular systolic function.1 2 Whereas predictors of pulmonary artery systolic pressure (PASP) have been extensively studied in heart failure and functional MR,3–6 physiological predictors of PASP are poorly explored in the setting of chronic organic MR.1 2 In patients with heart failure due to left ventricular (LV) systolic dysfunction the magnitude of functional MR and parameters of LV diastolic function have been identified as the main determinants of PASP.3–6 Both LV diastolic impairment and functional MR contribute to the increase in left atrial (LA) pressure and pulmonary capillary wedge pressure (PCWP) and therefore to the increase in PASP.2 4 In chronic organic MR, the left atrium enlarges as a compensatory mechanism of volume overload.1 7 LA enlargement is thought to reduce pulmonary pressure and pulmonary congestion in organic MR,1 but is also a marker of poor prognosis under medical management.7–9 Hence, the echocardiography predictors of PASP in organic MR, and particularly the relation of LA enlargement to PASP, deserve further consideration. Severe pulmonary hypertension (≥50 mmHg) is considered as an indication for surgery in organic MR, even in asymptomatic patients10 11 but data for the impact of PASP on postoperative outcome are scarce.

In this study we sought to evaluate the echocardiography predictors of PASP in patients with chronic organic MR referred for surgery, and the influence of PASP on postoperative outcome.

Materials and methods

Study population

Two hundred and fifty-six patients with chronic organic MR requiring surgery and with recordable tricuspid regurgitant jet by Doppler echocardiography were included in this study conducted between January 1998 and December 2006. Patients with other significant valve disease (excepted tricuspid regurgitation), mitral stenosis of any degree, previous mitral valve surgery or previous myocardial infarction were excluded from the study. The study was approved by the local ethics committee.

Cardiac catheterisation

Right-heart catheterisation performed within 48 h before or after echocardiography was available in 38 patients referred for invasive measurements at the earliest period of the study. Right-heart catheterisation was performed under fluoroscopic guidance using a 7F Swan–Ganz balloon-tipped catheter. PASP and PCWP were recorded. LV pre-A end-diastolic pressure (LVEDP) was measured at the same time in 26 patients.

Doppler and two-dimensional echocardiography

All echocardiography was carried out by experienced investigators (TLT, ASP) using a commercially available echocardiograph (HDI-5000, ATL, Philips, Bothell, Washington or Sonos 5500, Philips, Andover, Massachusetts, USA). All values were obtained from the mean of three beats and from the mean of five to 10 beats in patients with atrial fibrillation (AF). Data were prospectively recorded and were transferred without alteration for the purpose of this study. The tricuspid regurgitant velocity was recorded from any view with continuous-wave Doppler imaging and was used to determine the PASP using the modified Bernouilli equation (PASP=4V2+RAP), where V is the peak tricuspid regurgitation velocity and RAP is the right atrial pressure, adding an estimated RAP of 5–20 mmHg.12–14 The reproducibility of PASP measurement was assessed in 20 random patients in our laboratory. The intraobserver and interobserver variabilities of PASP, calculated as the average difference between measurements, were 1.8±1.0 mmHg and 3.6±1.9 mmHg, respectively, in agreement with previous publications.15

Left atrial diameter (LAD) was measured at ventricular end systole in the parasternal long-axis view.16 Left atrial volume (LAV) was calculated as previously described using the ellipse formula: LAV=π/6 (LAD1 × LAD2 × LAD3), where LAD1=LAD in the M-mode, LAD2 and LAD3 are respectively measurements of the short axis and long axis in the apical four-chamber view.17–19 Apical biplane left atrial area was also measured allowing the calculation of LAV using the area–length method.7 14 LAV was indexed to body surface area (LA index). LV volumes (biplane modified Simpson rule) and ejection fraction (EF) were measured from the apical chamber views. The degree of MR was assessed either by a quantitative or semiquantitative method according to current guidelines.20 The mitral flow profile was recorded in the four-chamber apical view, with the sample positioned at the tips of the leaflets. The peak Doppler velocities of early (E) and late diastolic mitral flow (A), the mitral E-wave deceleration time (mitral DT), and the E/A ratio were measured. Tissue Doppler profiles were recorded in 169 patients at the medial and lateral mitral annulus from the apical four-chamber view. Systolic tissue velocity (S′), early diastolic (E′) and late diastolic (A′) tissue velocities were recorded, and the medial and lateral E/E′ ratios were calculated.

Surgery

All operations were performed through a median sternotomy on cardiopulmonary bypass using mild hypothermia; the heart was protected and arrested with cold blood antegrade cardioplegia. The decision about the type of corrective surgery was made by the cardiovascular surgeon on the basis of preoperative data and after assessment of the anatomical status of the mitral valve during surgery. All patients were postoperatively anticoagulated for 3 months. After 3 months, oral anticoagulation was continued in patients with AF, flutter and mechanical valves, but discontinued in other patients.

Follow-up

Follow-up was achieved by phone contacts with patients, family doctors and cardiologists. Mean follow-up time was 4.1±3.4 years after surgery, giving a total follow-up of 1050 years; no patient was lost of follow-up. The main end points were overall mortality and cardiovascular mortality.

Statistical analysis

Results are expressed as mean±SD. Comparisons between groups were performed with the Student t tests or with χ2 tests, as appropriate. Correlations between variables were assessed by linear regression analysis. Linearity assessment was performed by plotting studentised residuals against each covariable. A multivariate regression analysis was performed to identify independent echocardiography factors associated with PASP. Echocardiography predictors of PASP were also evaluated according to the presence of AF, and to the value of EF ≤60% or >60%. Goodness of fit of the multiple regression models was assessed by residual analysis, the hypothesis of homoscedasticity being checked with the plot of the residuals against the predicted values, and the hypothesis of normality with the normal probability plot of the residuals. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values that best predict PASP ≥50 mmHg.10 11 Survival rates were calculated by the Kaplan–Meier method. The log-rank test was used to compare event rates. Univariate association of patient characteristics with end points used Cox proportional-hazards models. Stepwise Cox proportional-hazards models adjusted for age and gender were used for multivariate analyses. Multivariate analyses were further adjusted for known predictive variables of postoperative outcome (symptoms, LVEF, AF and the type of surgery performed) in chronic organic MR. End-systolic diameter was not included in the multivariate model because of co linearity with LVEF (r>0.5, p<0.0001) in this study. The incremental value of PASP for survival, over preoperative clinical data, AF, LVEF and the type of surgery performed, was tested using a likelihood-ratio test of Cox models. A p value ≤0.05 was considered statistically significant.

Results

Baseline characteristics

Baseline characteristics of the entire patient population are shown in the left part of table 1. Mean age was 63±12 and 170 (66%) patients were male. AF was present in 75 (29%) patients at the time of surgery, 92 (37%) patients were in new York Heart Association (NYHA) class 3–4. The main cause of MR was degenerative (prolapse or flail leaflet) in 234 (91%), rheumatic in 17 (7%) and endocarditic in five (2%). Mitral regurgitation was grade 3 or grade 4 in all patients. In 159 patients with MR measurement, effective regurgitant orifice averaged 51±19 mm2 and regurgitant volume 77±26 ml. Mean LVEF was 65±10% and 76 (29%) patients had a preoperative LVEF ≤60 % (range 39–60).

Table 1

Baseline clinical, echocardiography and surgical characteristics of the entire patient population and after stratification according to preoperative PASP

Haemodynamic measurements

Averaged PASP, PCWP and LVEDP were 47±18 mmHg, 20±8 mmHg and 17±4 mmHg, respectively. Invasive PASP correlated with age (r=0.44, p=0.007). Invasive measurement of PASP correlated with echo-Doppler measurement (r=0.74, p<0.0001, figure 1), whereas the correlation with tricuspid regurgitant gradient was weaker (r=0.66), confirming the validity of PASP evaluation by echo-Doppler in our laboratory. The difference between invasive and Doppler measurements was 7.6±4.8 mmHg. LVEDP correlated weakly with invasive PASP (r=0.40, p=0.037). However, PCWP correlated with invasive and Doppler PASP (r=0.71 and r=0.66, respectively, both p<0.0001).

Figure 1

Relation of invasive to echo-Doppler pulmonary artery systolic pressure (PASP) measurements (A) and Bland-Altman analysis (B).

Echocardiography predictors of pulmonary artery systolic pressure

Baseline PASP averaged 45±14 mmHg, ranging from 25 to 105 mmHg. Eighty-two patients (32%) had a PASP≥50 mmHg before surgery. Baseline characteristics of patients with PASP <50 mmHg or≥50 mmHg are shown in the right part of table 1, demonstrating substantial clinical and echocardiography differences. Patients with PASP ≥50 mmHg were older, more often in NYHA class 3–4, had more severe MR, with a larger left ventricle and left atrium, and parameters of left ventricular diastolic function were more severely impaired (table 1).

In univariate analysis, echocardiography predictors of PASP were MR grade (r=0.29, p<0.0001), LA surface (r=0.21, p=0.006), LA index (r=0.31, p<0.0001), mitral E velocity (r=0.42, p<0.0001), mitral DT (r=−0.40, p=0.0001), mitral E/E′ ratio (r=0.48, p<0.0001), stroke volume (r=−0.31, p<0.0001), LV end-diastolic diameter indexed to body surface area (LVEDD index, r=0.17, p=0.007) and LV end-systolic diameter index (r=0.14, p=0.035) (figure 2). Correlations with MR orifice or volume in the subgroup with MR measurement did not reach significance. By multivariate analysis (table 2), independent echocardiography predictors of PASP were mitral medial E/E′ (p<0.0001), mitral DT (p<0.0001), and LA index (p=0.003). The model remained as strong in patients in sinus rhythm or in patients with LVEF ≤60% or >60% (table 2). However, the LA index was no longer a predictor of PASP in patients in AF (table 2).

Figure 2

Relationship between pulmonary artery systolic pressure (PASP) by echo-Doppler and mitral medial E/E′, mitral deceleration time, left atrial (LA) index and stroke volume.

Table 2

Echocardiography predictors of PASP in multivariate analysis

When the LA index was calculated using the apical biplane area–length method, the model remained similar (R=0.64, p<0.0001). When peak tricuspid regurgitant gradient was used, the multivariate model was not improved (R=0.60, p<0.0001).

ROC curve analyses (figure 3) demonstrated that a medial E/E′≥16 predicted a PASP≥50 mmHg with an accuracy of 78%, a sensitivity of 83% and a specificity of 64%, a positive predictive value of 52% and a negative predictive value of 89%. Threshold values for LA index and mitral DT in predicting PASP≥50 mmHg were 50 ml/m2 and 175 ms, respectively (figure 3).

Figure 3

Receiver operating characteristic curves for mitral medial E/E′, left atrial (LA) index and mitral deceleration time in predicting pulmonary artery systolic pressure ≥50 mmHg in organic mitral regurgitation. AUC, area under the curve.

Surgery and outcome

One hundred and ninety-four patients (76%) underwent mitral valve repair and 62 (24%) mitral valve replacement with either mechanical (n=34, 13%) or bioprosthetic valves (n=28, 11%). Mitral valve repair was performed in 80.3% of patients with degenerative valve prolapse, but in only 27.3% of patients with other aetiology. Associated procedures included left atrial radiofrequency ablation in 51 patients (20%), tricuspid annuloplasty in 14 (5.5%) and coronary artery bypass in nine (3.5%).

Six (2.3%) of 256 patients died within 30 days of surgery. Early postoperative mortality was only 1% (two patients) after mitral valve repair (related to massive stroke and sudden death), but 6.4% (four patients) after mitral valve replacement (related to atrioventricular dissociation, septic shock, intractable heart failure and mechanical valve thrombosis). Operative mortality was associated with preoperative NYHA class (OR=6.2 (95% CI 1.7 to 22.4), p=0.005) and mitral valve repair (OR=0.15 (95% CI 0.03 to 0.85), p=0.032). LVEF, PASP and coronary artery bypass surgery did not reach significance (p=0.12, p=0.09 and p=0.12, respectively).

Compared with patients with preoperative PASP<50 mmHg, patients with PASP≥50 mmHg remained more symptomatic (p=0.039) early after surgery and had a lower postoperative LVEF (52±10 vs 57±10%, p=0.004). PASP decreased promptly after surgery (45±14 to 33±7 mmHg, p<0.0001) but remained moderately higher in patients with preoperative PASP≥50 mmHg than in the others (35±7 vs 32±6 mmHg, p<0.0001).

Thirty-one patients died during a postoperative follow-up of 4.1±3.4 years. Cause of death was cardiovascular in 16 patients. Symptomatic patients (NYHA class 3–4 versus class 1–2) had a lower survival (at 8 years 67.7% vs 80.8%, p=0.003; figure 4) with a univariate HR of 2.5 (95% CI 1.3 to 5.1, p=0.009). Patients with impaired (<60%) compared with preserved (≥60%) preoperative LVEF trended to have a lower survival at 8 years (62.7% versus 80.6%, p=0.076) with a HR of 2.19 (95% CI 1.04 to 4.63, p=0.04). Patients with PASP≥50 mmHg compared with those with PASP<50 mmHg experienced a lower survival rate (at 8 years 58.6% versus 86.6%, p<0.0001; figure 4) with a HR per 10 mmHg of 1.55 (95% CI 1.22 to 1.96, p<0.0001). Valve repair was associated with a better survival than valve replacement (at 8 years 81.1% vs 61.8%, p=0.037; figure 4) with a HR of 0.42 (95% CI 0.21 to 0.85, p=0.016). The other predictive factors were age (p=0.001), history of AF (p=0.012) and coronary artery bypass surgery (p=0.05). End-systolic diameter did not emerge as a significant predictor of postoperative outcome in this series of patients.

Figure 4

Postoperative prognostic value of the type of surgery performed (A), and of preoperative pulmonary artery systolic pressure (PASP) (B), symptoms (C) and left ventricular ejection fraction (LVEF) (D) in organic mitral regurgitation. NYHA, New York Heart Association.

In a stepwise Cox proportional-hazards analysis adjusted for age and gender, the type of mitral valve surgery performed (repair versus replacement; HR=0.41 (95% CI 0.20 to 0.85), p=0.016), and preoperative PASP (HR=1.43 (95% CI 1.09 to 1.88) per increment of 10 mmHg, p=0.011, or HR=2.58 (95% CI 1.21 to 5.45) for PASP≥50 mmHg, p=0.014) were independent predictive factors of overall mortality. Mitral valve repair (p=0.022) and PASP (p=0.023) remained independent predictive of overall mortality even after further adjustment for known predictors. Finally, PASP provided incremental prognostic value (p=0.011) to gender, age, preoperative NYHA class, AF, LVEF and the type of surgery performed (repair/replacement) with a χ2 ranging from 13 to 35. ROC curve analysis (figure 5) demonstrated the relationship between PASP and long-term survival after mitral valve surgery (accuracy=0.7, p<0.0001). A threshold of 45 mmHg was slightly weaker in predicting survival but with a better sensitivity.

Figure 5

Receiver operating characteristic curves for pulmonary artery systolic pressure (PASP) in predicting long-term survival after mitral valve surgery. Different thresholds of PASP are shown with different sensitivities and specificities. A threshold of 45 mmHg is slightly weaker in predicting survival in this series of patients but has a better sensitivity. AUC, area under the curve.

In a stepwise Cox proportional-hazards analysis adjusted for age and gender, preoperative PASP (HR=1.49 (95% CI 1.03 to 2.16) per 10 mmHg, p=0.033, or HR=2.47 (95% CI 1.01 to 6.88) for PASP≥50 mmHg, p=0.05) was also an independent predictive factor of cardiovascular mortality. After further adjustment for baseline symptoms, AF, LVEF and the type of surgery, PASP (p=0.05) remained marginally predictive of cardiovascular mortality.

Discussion

The aims of this study were to assess the echocardiography predictors of PASP in chronic organic MR, and to evaluate the influence of preoperative PASP on postoperative outcome. We demonstrate that mitral medial E/E′, mitral DT and LA index are the main echocardiography predictors of PASP in organic MR, in the entire patient population and in subsets of patients stratified according to LVEF. However, LA index did not remain a significant predictor of PASP in patients with AF. Mitral medial E/E′≥16 could be carefully used in patients with poor echogenicity or unreliable tricuspid regurgitant jet as a predictor of severe PASP. Finally, PASP emerged as a significant predictor of long-term outcome after mitral valve surgery, and should be assessed and used in the clinical decision-making process in chronic organic MR.

Echocardiography predictors of PASP

In patients with chronic organic MR referred to surgery the strongest echocardiography predictors of PASP are E/E′ ratio, mitral DT and LA enlargement. Although PASP can be abnormally elevated owing to pulmonary vascular remodelling or abnormal vasoconstriction with an increase in pulmonary vascular resistance,1 2 PASP is usually proportionate to LA pressure and PCWP, independently of the degree of MR.4 In this study, PCWP correlated with both invasive and echo-Doppler PASP, while LVEDP correlated weakly with PASP.

The degree of MR and LA compliance were thought to be the main determinants of PCWP and PASP in organic MR.1 2 The degree of MR is recognised, along with AF, as a determinant of LA remodelling.7 21 22 LA remodelling is a progressive23 adaptive mechanism in response to volume overload,1 7 24 which aims at normalising atrial wall stress and therefore reducing atrial and pulmonary vascular bed pressure.1 24 LA compliance can improve with LA enlargement24 and normalise LA pressure.1 However, LA enlargement is often associated with atrial interstitial fibrosis,25 reduced LA compliance and increased LA pressure.1 2 21 26 27 Hence, the positive association between LA enlargement and PASP probably reflects histological and haemodynamic alterations related to LA volume and pressure overload. This association could explain, at least in part, the poor prognosis of patients with LA enlargement in organic MR.7 8

The degree of MR and LV filling pressure can influence LV diastolic parameters in patients with MR.28 29 Despite controversies about the value of diastolic parameters in organic MR,30–32 mitral DT and E/E′ have been shown to correlate with LV filling pressure in this setting.30 31 In patients with LV dysfunction, mitral DT predicts PCWP irrespective of the degree of MR.4 5 33 In chronic organic MR, mitral DT correlates negatively with LVEDP30 and shortens with LV dysfunction. Likewise, mitral E/E′ ratio correlates weakly31 or tightly30 with mean PCWP or LVEDP, respectively, in MR. Although mitral E/E′≥16 predicts severe PASP in this study, it could be carefully used in patients with poor echogenicity since specificity is only 64%. Of note, mitral E/E′ predicted exercise capacity in organic MR,34 whereas the degree of regurgitation was not an independent determinant of functional capacity in two studies.34 35 Hence, mitral E/E′ could be useful in evaluating consequences of organic MR.

In patients with AF the LA index was no longer a predictor of PASP whereas E/E′ ratio and mitral DT convey a similar predictive value. AF leads to greater LA enlargement in MR,7 8 independently of volume overload.19 36 Therefore, AF is a confounding factor in the relationship between LA index and PASP.

In patients with LV dysfunction the degree of functional MR is a strong determinant of pulmonary hypertension.3 6 In this study including only patients referred to surgery with moderate-to-severe or severe organic MR the degree of MR does not emerge as an independent predictor of PASP. Hence, PASP primarily reflects ventricular, atrial and pulmonary consequences of regurgitant volume in patients with moderate-to-severe or severe organic MR rather than the amount of volume overload.

Postoperative outcome

Age,37–39 symptoms,37 38 40 LV function and size,37–39 41 AF8 42and the type of valve surgery38 39 43–46 are predictors of postoperative outcome in organic MR. While pulmonary hypertension is considered as an indication for surgery in organic MR,10 11 data regarding the influence of PASP on postoperative outcome are surprisingly scarce.46–48 As aforementioned, pulmonary hypertension probably reflects ventricular, atrial and pulmonary consequences of regurgitation in chronic organic MR. In this study PASP emerges as an independent predictor of long-term mortality and cardiovascular mortality, even after adjustment for known predictive factors. Hence, the present results reinforce current guidelines, by demonstrating that PASP≥50 mmHg is a marker of poor prognosis after surgery in patients with chronic organic MR. PASP should be used as an indicator of prognosis in patients undergoing surgery for chronic organic MR, taking into account an increase of about 50% in the long-term risk of mortality per 10 mmHg increment. Pulmonary hypertension has been associated with postoperative LV dysfunction in chronic MR.47 Likewise, in this study, patients with PASP≥50 mmHg were more symptomatic and had a greater LV remodelling before surgery. Moreover, patients with preoperative pulmonary hypertension remained more symptomatic early after surgery and had a lower LVEF than those without pulmonary hypertension. These results further confirm that pulmonary hypertension is a marker of consequences of chronic regurgitation and reflects an advanced stage of the disease. Thus, PASP should be carefully estimated during echocardiography examination by tricuspid regurgitant gradient and RA pressure14 in patients with chronic organic MR. Finally, these results should be an incentive to refer patients with chronic organic MR to surgery before PASP reaches 50 mmHg.

Limitations

RA pressure was estimated according to inferior vena cava collapsibility and dilatation and was added to peak tricuspid regurgitant gradient in order to calculate PASP. All echocardiographic examinations were performed by only two experienced investigators using the same methodology. Although the estimation of RA pressure could introduce a subjective bias in PASP evaluation, its use for PASP measurement is in accordance with the current recommendation,14 and this method has been shown to improve the estimation of PASP.49 Moreover, the correlation between estimated and invasive RA pressure measured in 33 patients in this study was good (r=0.72, p<0.0001); in addition, we found a better correlation between invasive PASP and echo-Doppler PASP than with tricuspid regurgitant gradient. Therefore, we do think that PASP should be used rather than the tricuspid regurgitant gradient. Finally, this measurement is in agreement with daily clinical practice and with guidelines for the management of MR based on PASP10 11 rather than on tricuspid regurgitant gradient.

Another limitation of this study is the small number of events. Despite this small number our results were coherent in predicting death or cardiovascular mortality, and remained quite similar even after adjustment for known predictors of outcome. However, we are aware that further studies are required to confirm our results in a larger patient group.

Echocardiography evaluation was performed only at rest in this study. Although current guidelines introduce a threshold of 60 mmHg for PASP during exercise, this recommendation is based on sparse data. Hence, whether PASP at exercise might provide additional information compared with PASP at rest in patients with severe MR remains to be investigated.

Conclusion

Independent echocardiography predictors of PASP in organic MR are mitral medial E/E′, mitral DT and LA index. Hence, pulmonary hypertension primarily reflects ventricular, atrial and pulmonary consequences of regurgitation in patients with chronic organic MR referred to surgery. PASP conveys important prognostic information in patients with chronic organic MR with an increase of about 50% in the long-term risk of mortality per 10 mmHg increment. Therefore, patients should be referred to mitral valve surgery before severe pulmonary hypertension develops.

References

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Footnotes

  • Funding This work was supported by a grant from the Société Septentrionale d'Echocardiographie, Clinique de Bois Bernard, route de Neuvireuil, 62320 Bois-Bernard.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of Lille University Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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