Prognostic value of mitral regurgitation assessment during exercise echocardiography in patients with left ventricular dysfunction: A follow-up study of 1.7 ± 1.5 years
1 Unit of Echocardiography, Juan Canalejo Hospital, University of A Coruña, A Coruña, Spain
2 Department of Cardiology, Juan Canalejo Hospital, University of A Coruña, A Coruña, Spain
3 Unit of Codification, Juan Canalejo Hospital, University of A Coruña, A Coruña, Spain
Received 6 August 2006; accepted after revision 26 November 2006; online publish-ahead-of-print 22 January 2007.
* Corresponding author. P/Ronda 5-4° izda.15011-A Coruña, Spain. Tel: +34 81 917859; fax: 34 81 178001. E-mail address: peteiro{at}canalejo.org
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Aims: The value of exercise echocardiography (EE) over resting echocardiography when this last incorporates information on mitral regurgitation (MR) is only partially known. Furthermore, limited data exist regarding the value of MR worsening during exercise in patients with left ventricular (LV) dysfunction. We investigate whether EE has incremental value over a resting echo-Doppler study; and whether post-exercise MR increments the value of EE for predicting outcome in patients with LV dysfunction.
Methods and results: Three hundred and twenty-three consecutive patients with LV dysfunction (LV ejection fraction 
45%) referred for EE were followed for 1.7 ± 1.5 years. There were 43 hard events (myocardial infarction in 9 and cardiac death in 34). Resting MR, peak heart rate x blood pressure, and number of involved territories at exercise were independently associated to hard events (incremental P-value of EE =0.02). Independent variables associated to cardiac death were resting MR, peak heart rate x blood pressure, peak wall motion score index, and MR worsening (incremental P-value of MR worsening = 0.04).
Conclusions: EE maintains its prognostic value over resting echocardiography even when this last incorporates information on MR. Exercise-induced MR worsening has independent prognostic value for cardiac death in patients with LV dysfunction.
Keywords: Exercise echocardiography; Mitral regurgitation; Left ventricular dysfunction
Several recent reports have proven the prognostic value of exercise echocardiography (EE).1–4 However limited data exist regarding the incremental value of EE over resting echocardiography in patients with left ventricular (LV) dysfunction, particularly when knowledge of resting mitral regurgitation (MR) is available. Furthermore, although MR can be assessed during EE5–7 it is not a common practice and only a recent report focused on the ability of exercise MR for predicting outcome in patients with LV dysfunction.8
The purpose of this study was to determine (1) whether EE has incremental value over a resting echo-Doppler study; and (2) whether post-exercise mitral regurgitation (MR) increments the value of EE for predicting outcome in patients with left ventricular dysfunction.
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Patients
From a database of 2479 patients who underwent treadmill EE at our institution in a 4.2-year period, from December 1997 to March 2002, we selected those with LV dysfunction as defined by LVEF
45%. Patients with organic mitral regurgitation, significant aortic valve disease, demonstrated hypertrophic or dilated cardiomyopathy were excluded. Hypertrophic cardiomyopathy was diagnosed by the presence of an unexplained hypertrophied and non-dilated left ventricle (wall thickness 
15 mm), whereas dilated cardiomyopathy was defined as LV enlargement (5.2 cm) and LV dysfunction (LVEF 45%) of proven non-coronary origin. The final group was composed of 323 patients [mean age 65 ± 10 years; 260 men; severe LVEF (<30%) in 98 patients (30%)]. Table 1 summarizes the clinical baseline characteristics. At the time of the EE, only 6% of the patients were taking beta-blockers, as our policy is to stop them before the exercise testing.
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Exercise echocardiography
Heart rate, blood pressure and a 12-lead ECG were obtained at baseline and at each stage of the exercise protocol. Patients were encouraged to perform a treadmill exercise test (Bruce protocol 86%, modified Bruce 11%, Naughton 3%) until exhaustion or until they reached an end point. End points included ST segment depression >2 mm, significant arrhythmia, severe hypertension (systolic blood pressure >240 mmHg or diastolic blood pressure > 110 mmHg), hypotensive response (decrease >20 mmHg from baseline) or limiting symptoms. The exercise ECG was considered positive in case of ascent or horizontal or downsloping ST segment depression of at least 1 mm at 80 ms after the J point, and nondiagnostic when the baseline ECG was abnormal.
Two-dimensional echocardiography (2-DE) using either fundamental or harmonic imaging was performed in standard parasternal and apical views, at baseline, peak exercise9,10 and immediately after exercise. Peak EE was performed when signs of exhaustion were present or an end point was reached. Image acquisition was performed on-line and stored on an optical disk.
Two-dimensional echocardiography analysis
2-DE analysis was performed on a digital quad screen display system. The LV was divided into 16 segments.11 Each of the 16 segments was assigned to one of the three coronary artery territories.12 The development of new regional wall motion abnormality (WMA) or worsening from hypokinesia was considered an ischaemic response. The persistence of a WMA affecting at least one segment in one coronary artery territory, or worsening from akinesia, was considered as necrosis, except for the case of isolated hypokinesia of the posterobasal segment13 or septal hypokinesia in patients with left bundle branch block, pacemakers or recent cardiac surgery. In these cases hypokinesia was not considered necrosis. A normal result was defined as increased systolic wall thickness and motion with exercise. Therefore, a response of global improvement was considered as normal, suggesting non-ischaemic LV dysfunction.14,15 In the rest of the patients, a positive EE for CAD was defined when there was ischaemia or necrosis in at least one coronary territory.16–18 Remote ischaemia was defined as a WMA at rest and development of a new WMA in another territory. A wall motion score index (WMSI) at rest and at exercise was calculated, with normal wall motion scoring 1, hypokinetic 2, akinetic 3 and dyskinetic 4. Rest and exercise images were analysed for every patient from stored images. Rest and exercise LV ejection fractions were measured by visual estimation.19
Colour Doppler measurements
MR was assessed by colour Doppler in the 4-chambers' apical view at rest and in the immediate post-exercise period (within 30 s). The MR area was based on total jet area and graded as mild (<4 cm2), moderate (4–8 cm2), or severe (>8 cm2), as described.20 MR worsening was defined as MR increase in at least one degree from rest to post-exercise. Inter- and intra-observer variabilities in resting and post-exercise MR grade were measured by reviewing the recordings of 30 randomized patients having MR signal.
Follow-up
Follow-up and events were determined by reviewing the medical recordings and death certificates. Considered end-points were hard cardiac events, defined as cardiac death and nonfatal MI. Cardiac death was considered in case of sudden death, death preceded by an acute coronary syndrome or heart failure, cardiac transplantation, defibrillator appropriate discharge, and also when noncardiac causes were excluded by death certificates. Sudden death that occurred without another explanation was considered as cardiac death. Coronary revascularization procedures during the follow-up were noted.
Statistical analysis
Continuous variables were reported as mean ±1SD. Categorical variables were reported as percentages and comparison between groups based on the Chi-square test. Hard event-free survival was estimated by the Kaplan–Meier method using a time to first event approach. Patients who died of noncardiac causes were censored at the time of death, and patients who had revascularization before any event were censored at the time of the procedure. Univariate associations of clinical, echo-Doppler, exercise testing, EE variables, and MR worsening with hard events were assessed with the Cox proportional hazards model. A P-value of <0.05 was considered significant for entering in a multivariate Cox regression analysis model. The 95% confidence intervals (CI) and hazard ratios (HR) are given. The first step was based on clinical data. The second step consisted of resting echo-Doppler data including resting MR. In the third step the exercise testing variables were added. The fourth step consisted of EE. Because the different EE variables may express the same concept of LV function worsening, the best EE variable related with outcome was chosen by ROC (receiver operator curve) analysis. The final step was MR at post-exercise. The Chi-square value of each model and the incremental value of adding the different variables are given.
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Exercise testing
The ECG, clinical and haemodynamic data at rest and exercise are shown in Table 2. The exercise testing was ended because of exhaustion in 285 patients (88%), angina in 16 patients (5%) and lower limbs pain in 22 patients (7%).
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Exercise echocardiography data
The EE was considered normal in 59 patients (18%) and abnormal in 264 (82%). Resting WMAs were detected in 204 patients (63%). Ischaemia was detected in 194 patients (60%). Of these, 134 (69%) had also resting WMAs. Exercise WMAs occurred in a single-vessel distribution in 66 patients (20%) and in a multi-vessel distribution in 198 patients (61%). WMAs in left anterior descending artery coronary artery (LAD) distribution were detected in 246 (76%), and in right or left circumflex coronary arteries (RC/LCx) distribution in 212 (66%).
Mitral regurgitation at rest and post-exercise
MR was presented at rest in 205 patients (64%) and it was moderate or severe in 97 (30%); whereas it was detected at post-exercise in 215 patients (67%), being moderate or severe in 139 (43%). MR increase occurred in 67 patients (21%), and it was mild in 11 patients, moderate in 44, and severe in 12 patients. Most of these patients with MR worsening had mild MR at rest (41 patients, 61%), whereas 18 had no MR (27%) and 8 had moderate MR (12%). Figure 1 is an example of a patient with exercise-induced MR worsening. Table 3 shows how echocardiographic data at rest and exercise were more abnormal in patients with MR worsening than in patients without.
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Variability in MR assessment
Inter-observer variabilities for assigning resting and post-exercise MR grades were 3% and 10%, whereas intra-observer variability was 0% and 3%, respectively.
Revascularization procedures
During follow-up, 89 patients (28%) were submitted to revascularization by either coronary artery by-pass grafting in 41 patients or angioplasty in 48 patients. Of these, 85 patients submitted to revascularization before any coronary events were censored. As expected, patients who underwent revascularization had more severely positive tests than patients without revascularizations, with a greater prevalence of angina on exercise (34% vs. 13%, P < 0.0001), positive ECG (18% vs. 6%, P = 0.002), abnormal EE (90% vs. 79%, P = 0.02), ischaemia on EE (76% vs. 54%, P < 0.0001), and multi-territory involvement (71% vs. 58%, P = 0.04).
Events
During a mean follow-up of 1.7 ± 1.5 years (median 1.3 years, maximum 5 years) 53 hard cardiac events occurred. Of these 53 events, 43 occurred before any revascularization procedure and were used for estimating the hard event-free survival rate by the Kaplan–Meier method and to build Kaplan–Meier survival curves. Causes of these 43 hard events were nonfatal MI in 9 patients (21%) and death in 34 (79%). Causes of cardiac death were fatal documented MI in 4, deterioration of cardiac failure in 4, and sudden death in 2. At-home cardiac death was considered in 19 patients after excluding noncardiac causes by death certificates. Cardiac transplantation in 2 patients and a defibrillator appropriate discharge in 3 patients were also considered cardiac death. Of the 43 events, 40 occurred in the 264 patients with abnormal EE and 3 events in the 59 patients with normal EE (15% vs. 5%, P = 0.04). Events were more frequent in patients with moderate resting MR (20% vs. 11%, P = 0.03), and with moderate exercise MR (19% vs. 9%, P = 0.005). Patients with either MR worsening or moderate exercise MR had more cardiac events (19% vs. 8%, P = 0.003) and cardiac deaths (17% vs. 5%, P < 0.0001).
Predictors of cardiac death and myocardial infarction
Clinical, resting echo-Doppler, exercise testing, EE, and post-exercise MR variables significantly associated with risk of hard cardiac events in univariate analysis are shown in Table 4. Figure 2 shows the Chi-square at each step for the prediction of cardiac events. Independent predictors in the final model were resting MR (HR = 1.2, 95% CI = 1.1–1.4, P = 0.005), peak heart rate x blood pressure (HR = 0.92, 95% CI = 0.87–0.98, P = 0.01), and number of involved territories on EE (HR = 1.5, 95% CI = 1.1–2.0, P = 0.02). MR worsening did not increase the significance of the model (P = 0.2). The 
in LV ejection fraction and multi-territory involvement had also incremental prognostic value when they were introduced in the model instead of the number of involved territories (P = 0.009, and P = 0.04, respectively). Independent predictors of cardiac death were resting MR (HR = 1.2, 95% CI = 1.0–1.5, P = 0.02), peak heart rate x blood pressure (HR = 0.91, 95% CI = 0.84–0.98, P = 0.01), peak WMSI (HR = 3.7, 95% CI = 1.1–13.2, P = 0.04) and MR worsening (HR = 2.3, 95% CI = 1.0–5.0, P = 0.04). Figure 3 shows the Chi-square at each step for the prediction of cardiac death. Figure 4 shows the per cent of survival according to the resting MR grades. The per cent of survival according to the EE results and presence/absence of MR worsening is represented in Figure 5.
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Discussion |
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The most relevant findings of this study were that exercise echocardiography maintains its incremental prognostic value over clinical variables and resting echocardiography when this last incorporates information on MR, and that MR worsening has incremental prognostic information for cardiac death over exercise echocardiography in patients with LV dysfunction.
Mitral regurgitation as a predictor of events
Resting MR has been demonstrated to be a strong predictor of cardiac death in CAD patients.21–23 However, to our knowledge there are no studies with large series of patients focusing on MR assessment during resting and exercise echocardiography for the prediction of cardiac events. A recent study by Lancellotti et al.8 performed in patients with ischaemic left ventricular dysfunction found that exercised-induced increases in MR identified a high risk patients group. However the authors did not attempt to compare this parameter with exercise echocardiography findings, therefore the relative value of MR assessment over exercise echocardiography was not investigated. Previous work has demonstrated that increased or newly developed MR as assessed by colour Doppler during exercise was associated with ischaemic LV dysfunction and more extensive CAD demonstrated by angiography.5,6 In this study we extended those results by showing that MR worsening stratifies patients into different risk categories. However, as shown in Figure 5 MR worsening was only of prognostic relevance in patients with abnormal EE results, the percentage of cardiac death being 17% in those with abnormal EE and MR worsening vs. 10% in those with abnormal EE and no MR worsening.
Mechanisms of MR worsening and link to events
Previous work has demonstrated the role of global and particularly global remodelling in the genesis of MR worsening during exercise in patients with ischaemic LV dysfunction.24 Regional dyssynergia irrespective of papillary muscle involvement may alter the papillary muscle orientation and contraction resulting in insufficient coaptation of the mitral leaflets.25 Increased chamber sphericity may also cause MR by lateral migration of the papillary muscles.26 Contractility increase during stress may reduce the regurgitant orifice area by diminishing mitral leaflets separation.27 The opposite mechanism may be present when MR develops or increases during exercise inducing dilation, sphericity, volume increase, and impairment of contractility on an ischaemic LV. According to our results, patients with MR worsening had more ischaemic burden and worse LV function during exercise than patients without MR worsening. Thus, the inducible ischaemia and worsening LV function during exercise can play an important role in the generation of MR. Therefore the presence of MR worsening as a marker of severe CAD and worse LV function during stress could be a link between MR and cardiac events. The link between MR increase and cardiac death could also involve other mechanisms as intermittent increases in MR during daily life,8 LV volume overload, and myocardial disease progression.
MR assessment during stress
The feasibility of acquiring confident MR signals during stress has been previously demonstrated.5,6 However, MR assessment is not integrated in the traditional stress test protocol. Our approach consisted of acquiring 2-DE images at peak exercise and MR images at post-exercise. Others have used supine bicycle5,7,24 or dobutamine27 to assess MR during stress. As supine bicycle seems to be an excellent method to assess MR during stress, dobutamine is not. Dobutamine produces both significant afterload decrease and inotropic effect that may reduce the effective MR. Heinle et al.27 did not find association between ischaemic response and MR during dobutamine echocardiography. Therefore, even under ischaemic conditions during dobutamine stress, MR was not associated to global or regional left ventricular dysfunction.
Exercise echocardiography
Our finding of incremental value of exercise echocardiography over clinical, exercise and resting echocardiographic variables has been previously reported.1–4 We extended those results by demonstrating that such incremented prognostic value is maintained when knowledge of resting MR is available and by demonstrating that exercise-induced MR has incremental prognostic value for cardiac death over EE.
Limitations
This is a retrospective analysis of patients consecutively admitted for EE. Therefore it is likely less susceptible to selection bias and more applicable to real-life populations of patients with LV dysfunction.
We performed peak instead of post-exercise imaging because higher sensitivity has been demonstrated with the former.9,10,28 If we had used post-exercise imaging, the superiority of EE over other variables could have been underestimated. Similarly, post-exercise MR may have been underestimated if we had used the immediate post-exercise period to acquire 2-DE images, because MR may rapidly recover. However, although we have demonstrated that peak exercise imaging acquisition is feasible and images are of similar quality to those obtained in the post-exercise period,10 post-exercise treadmill or exercise bicycle may be preferable in inexperienced hands.
Colour assessment of MR is an operator and instrument dependent method affected by gain, filters settings, transducer frequency and frame rate.29 To minimize these factors the settings were the same at rest and post-exercise. Variability for assigning resting and post-exercise MR grades in this study was less than 5% and 10% respectively, similar to that obtained in a study performed during dobutamine stress echocardiography.27 MR assessment based on only one plane as we did in this study may be simplistic as it only measures one dimension. Quantitative MR assessment, although feasible during supine bicycle,7,24 would not be during treadmill exercise. However, we feel that this is a strengthening point of this work, because even without the use of a quantitative method, MR worsening remained as an additional prognostic marker.
Unfortunately, we have no data on the incidence of heart failure during follow-up that could be predicted by MR findings during EE, as in a previous study.8
MI was defined by the pre-troponinic criteria for most of the patients. Thus, MI likely represents infarctions with true entity.
As the EE results were used by the responsible physicians, the apparent prognostic information value of EE may be reduced, because most of the patients with mainly severe positive tests that were to revascularization may have gone on to have cardiovascular events.
Approximately 25% of the EE were performed using fundamental imaging. Imaging technology has dramatically improved from this time, with the development of harmonic imaging and continuous imaging capture. Unfortunately this is a common problem affecting longitudinal studies in this field.
Clinical implications
Resting MR has independent prognostic value for cardiac events and cardiac death. Exercise echocardiography maintains its higher prognostic value over resting echocardiography even when this last incorporates information on MR. Exercise-induced MR has incremental prognostic value for cardiac death over EE. The results of this study emphasized the importance of MR assessment during EE to define outcome.
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Study supported by the Spanish Network of Cardiovascular Studies (RECAVA). 
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References |
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