CLINICAL RESEARCH: CARDIAC IMAGING
Role of Right Ventricular Wall Motion Abnormalities in Risk Stratification and Prognosis of Patients Referred for Stress Echocardiography
Sripal Bangalore, MD, MHA,
Siu-Sun Yao, MD, FACC and
Farooq A. Chaudhry, MD, FACC*
Department of Medicine, Division of Cardiology, St. Luke’s-Roosevelt Hospital and Columbia University, New York, New York.
Manuscript received April 20, 2007;
revised manuscript received July 6, 2007,
accepted July 15, 2007.
* Reprint requests and correspondence: Dr. Farooq A. Chaudhry, Director of Echocardiography, Division of Cardiology, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, New York 10025. (Email: fchaudhr{at}chpnet.org).
Presented in part at the 2005 Annual Scientific Session of the American Heart Association, November 16, 2005, New Orleans, Louisiana.
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Abstract
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Objectives: The purpose of this study was to evaluate the prognostic value of assessing right ventricular (RV) wall motion abnormalities during stress echocardiography (SE).
Background: The results of SE are usually interpreted based on wall motion abnormalities of the left ventricle (LV). There is increasing recognition of the prognostic importance of RV. However, RV is still a "forgotten" chamber during routine SE.
Methods: We evaluated 2,703 patients referred for SE. The LV was evaluated on a 16-segment model 5-point scale and the RV was evaluated on a 3-segment model 5-point scale for wall motion abnormalities. An abnormal RV or LV was defined as one with new (ischemic) or fixed (infarction) wall motion abnormalities. Follow-up (2.7 ± 1.0 years) for confirmed myocardial infarction and cardiac death (n = 122) were obtained.
Results: An abnormal RV was seen in 112 patients (4%). In the presence of an abnormal LV, patients with abnormal RV had a worse prognosis than those with normal RV. Abnormal RV was a significant predictor of events (adjusted hazard ratio 2.69, 95% confidence interval 1.22 to 5.92; p = 0.014) independent of LV ischemia and ejection fraction. A forward conditional Cox model showed that peak RV wall motion score index provided incremental prognostic value over rest and conventional SE variables (global chi-square increased from 141.4 to 161.8 to 197.0; p < 0.0001 and p = 0.006, respectively).
Conclusions: In patients referred for SE, RV wall motion analysis provides prognostic value independent of LV ischemia and ejection fraction and provides incremental value over rest and conventional SE variables. Right ventricular wall motion analysis should be routinely performed in patients referred for SE for effective risk stratification.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | ECG = electrocardiogram/electrocardiography | | LV = left ventricular/ventricle | | MI = myocardial infarction | | MPHR = maximum predicted heart rate | | RV = right ventricular/ventricle | | WMSI = wall motion score index |
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Stress echocardiography is routinely used for risk stratification and prognosis of patients with known or suspected coronary artery disease (CAD) (1–3). Conventional stress echocardiography evaluates stress-induced wall motion abnormalities of the left ventricle (LV). The American Society of Echocardiography guidelines for stress echocardiography state that "for greater accuracy segmental wall motion analysis using 16-segment model of the left ventricle is recommended" (4). It therefore appears that the right ventricle (RV) during routine stress echocardiography is a "forgotten chamber" (5).
Increasing evidence from clinical studies emphasize the importance of evaluating RV function during routine 2-dimensional echocardiography. The RV function has been found to be related to exercise capacity (6) and prognosis (6,7) in patients with heart failure. It also influences prognosis in patients with inferior myocardial infarction (MI). Stress echocardiography studies have shown that in patients with right coronary artery disease, a stress-induced decrease in the RV function and RV asynergy was noted (8,9).
However, the prognostic value of evaluating such wall motion abnormalities of the RV during routine stress echocardiography is not known. The objective of the present study was 2-fold: 1) to evaluate the prognostic value of RV wall motion abnormalities during routine stress echocardiography; and 2) to evaluate the incremental prognostic value of routine RV wall motion analysis over conventional LV wall motion analysis during stress echocardiography.
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Methods
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Study population.
We identified 2,703 consecutive patients with known or suspected CAD referred for stress echocardiography. Patients with acute MI (<3 days), hemodynamically significant valvular abnormalities, hemodynamic instability, poor acoustic windows (<13 of 16 segments visualized by echo), inability to assess RV wall motion ( 10% of patients), pregnancy, or inability to give informed consent were excluded from the study. Informed written consent was obtained from all patients, and the study was approved by institutional review board.
Exercise echocardiography protocol.
Maximal exercise treadmill testing was performed using standard Bruce protocol. Patients exercised to general fatigue, with premature termination for severe angina, ventricular tachycardia, hemodynamically significant arrhythmias, or hemodynamic instability. The maximal degree of ST-segment change at 80 ms after the J point on the electrocardiogram (ECG) was measured. Patients with  1 mm ST-segment change after stress (if no baseline ST-segment changes) or 2 mm ST-segment change (if baseline ST-segment changes) were considered to have a positive stress ECG response. Post-exercise echocardiographic images were acquired within 30 to 60 s after termination of treadmill exercise.
Dobutamine echocardiography protocol.
Dobutamine was administered intravenously beginning at a dose of 5 to 10 µg/kg/min and increased by 5 to 10 µg/kg/min every 3 min up to a maximum of 50 µg/kg/min or until a study end point was achieved. The end points for termination of the dobutamine infusion included development of new segmental wall-motion abnormalities, attainment of 85% maximum predicted heart rate (MPHR) or the development of significant adverse effects related to the dobutamine infusion. Atropine was administered intravenously in 0.25-mg increments every 3 min up to a maximum of 2.0 mg if a study end point was not achieved at the maximum dobutamine dose.
During both types of stress echocardiography, transthoracic echocardiographic images were obtained with the patient in the left lateral decubitus position using commercially available ultrasound equipment (Acuson Sequoia, Mountain View, California; Hewlett Packard Sonos 5500, Andover, Massachusetts). Six standard echocardiographic views were obtained with each acquisition: parasternal long-axis, parasternal short-axis, apical 4-chamber, apical 3-chamber, apical 2-chamber, and subcostal views. The acquisition sequences were as follows. For each patient, the apical 4-chamber was acquired first, followed by 3-chamber, 2-chamber, and then parasternal long- and short-axis views (typically within 30 to 40 s). This was then followed by the subcostal views (typically within the next 5 to 10 s). All images were acquired within 60 s and then the whole sequence were repeated again so as to acquire 2 runs of images. Echocardiographic images were acquired at baseline, with each increment of dobutamine infusion, and during the recovery phase. Cardiac rhythm was monitored throughout the stress echocardiography protocol, and 12-lead ECGs and blood pressure measurements were obtained at baseline, at each level of stress, and during the recovery phase.
Echocardiographic image analysis.
The LV was divided into 16 segments as recommended by the American Society of Echocardiography and a score assigned to each segment at baseline, with each stage of stress and during the recovery phase (10). Each segment was scored as follows: 1 = normal; 2 = mild to moderate hypokinesis (reduced wall thickening and excursion); 3 = severe hypokinesis (marked reduced wall thickening and excursion); 4 = akinesis (no wall thickening and excursion); 5 = dyskinesis (paradoxical wall motion away from the center of the LV during systole) (2,11). All echocardiograms were interpreted by consensus agreement of experienced echocardiographers who were blinded to patients’ treatment and outcome.
A normal response to stress was defined as normal wall motion at rest, with an increase in wall thickening and excursion during stress. An abnormal response to stress was defined as: 1) an LV wall segment that did not increase in thickness and excursion during stress (fixed wall motion abnormality); 2) deterioration of LV segment wall thickening and excursion during stress (increase in wall motion score of 1 grade); and/or 3) a biphasic response with dobutamine stress. The peak wall motion score index (WMSI) after stress was derived from the cumulative sum score of 16 LV wall segments divided by the number of visualized segments. The stress echocardiograms with a peak WMSI of 1.0 were considered to be normal, and those with a WMSI >1.0 were considered to be abnormal. Maximal severity of ischemia was the score of the LV wall segment(s) with the greatest value (worst wall motion grade) at peak stress (range 0 to 5) (3). Ischemic extent was the number of new (ischemic) wall motion abnormalities during stress that increase in wall motion score of >1 (range 0 to 16) (3). Resting LV ejection fraction used in the study analysis was a visual estimation by experienced echocardiographers.
RV wall motion analysis.
For each patient, RV wall motion was analyzed in the parasternal long-axis, parasternal short-axis, apical 4-chamber, and subcostal views, at rest and with each stage of dobutamine infusion and after exercise. The RV was divided into 3 segments: apical, mid, and basal. Each segment was scored on a 1- to 5-point scale similar to the LV wall motion scale (Fig. 1). The RV WMSI was calculated as the cumulative sum score of the 3 segments divided by the number of visualized RV segments. An abnormal response of RV to stress was defined as: 1) a fixed wall motion abnormality; 2) an increase in wall motion score of 1 grade; and/or 3) a biphasic response with dobutamine stress. The RVs with a peak WMSI of 1.0 were considered to be normal and those with a WMSI >1.0 were considered to be abnormal. An RV wall motion analysis was feasible in 90% of studies. In the present analysis, only patients where RV wall motion analysis was feasible were included.
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Figure 1 Schematic of the RV Wall Segments and Scoring
The right ventricle (RV) was analyzed using a 3-segment model and 5-point scale for wall motion. Top right is the "bull’s eye" incorporating the 17-segment model for the left ventricle and the 3-segment model for the RV. APx = apex.
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Patient follow-up.
Serial prospective follow-up (mean 2.7 ± 1.0 years) was obtained in all patients by means of a physician-directed telephone interview using a standardized questionnaire. The physicians were blinded to the patient’s echocardiography results. If the patient died during follow-up, the closest surviving relative and the patient’s physician were interviewed to determine the cause of death. Cardiac death was confirmed by review of the hospital medical record and/or death certificate. Autopsy records were reviewed when available (<1%).
The primary end point of the study was a composite of nonfatal MI and cardiac death. Nonfatal MI was documented by evidence of an appropriate combination of clinical symptoms, electrocardiographic findings, and cardiac enzyme changes. Adjudication of cardiac death and MI were done by physicians who were blinded to the clinical, stress ECG, and echocardiographic outcome of the patients. The secondary end point of the study was all-cause mortality.
Statistical analysis.
All analysis was carried out using a standard statistical package (SPSS for Windows, Version 13.0, SPSS Inc., Chicago, Illinois). Continuous variables were reported as mean ± SD. Patient groups were compared using the Student t test (for normally distributed variables) or the Wilcoxon rank sum test (for other variables) for continuous variables and the chi-square test or the Fisher exact test for categorical variables. The p value was considered to be significant at <0.05.
Univariate analysis was performed to determine the relationship between clinical, echocardiographic variables, and cardiac events. Cumulative survival rates as a function of time after stress echocardiography were performed using Kaplan-Meier survival analysis and compared using the log-rank test. A forward conditional (Wald) Cox proportional hazard model was used to find out the incremental prognostic value of RV wall motion score analysis over conventional rest echocardiographic and stress echocardiographic parameters. Selection of variables for entry criteria were based on both univariate statistical significance and clinical judgment. The variables were entered in the order in which they were available to the physicians, with rest echocardiographic variables entered first, followed by conventional stress echocardiographic variables and finally the RV wall motion score. A p value of <0.10 was considered to be significant for entry, and <0.05 was required for retention in the model. All model assumptions were tested.
To avoid loss of data inherent to dichotomizing a continuous variable (12), the RV wall motion analysis was considered as a continuous variable (WMSI) for most of the univariate, multivariate, and incremental prognostic value analyses.
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Results
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From the study cohort of 2,703 patients, 1,193 (44%) were men and 1,510 (56%) were women.
Patient characteristics: normal versus abnormal RV.
Among the 2,703 patients, 2,591 patients (96%) had a normal RV and 112 patients (4%) had an abnormal RV as assessed by stress RV WMSI (Table 1). Among clinical characteristics, patients with an abnormal RV were older and had a greater number of cardiovascular risk factors (greater percentage of men, diabetes, hypertension, prior MI, known congestive heart failure, prior percutaneous coronary intervention, and coronary bypass surgery). Among the stress electrocardiographic characteristics, patients with an abnormal RV had a higher resting heart rate, lower peak heart rate, lower 85% MPHR, and lower rest and peak systolic blood pressure than the patients with normal RV. Among echocardiographic characteristics, patients with an abnormal RV had a lower ejection fraction, higher rest/stress (RV and LV) WMSI, greater number of ischemic segments, greater extent and severity of ischemia, and were more likely to undergo dobutamine stress echocardiography study, compared with those with a normal RV.
Patient characteristics: RV and LV wall motion analysis.
Among the 2,703 patients, 2,101 patients (78%) had both normal LV and RV post stress, 490 patients (18%) had abnormal LV but normal RV, 110 patients (4%) had both an abnormal LV and RV, and only 2 patients had normal LV but an abnormal RV wall motion after stress (Table 2). Among clinical characteristics, patients with both an abnormal LV and RV had a greater number of cardiovascular risk factors (greater percentage of men, diabetes, smoker, known congestive heart failure, and lower percentage of patients with prior angioplasty) compared with the group with an abnormal LV but preserved RV wall motion. Among the stress electrocardiographic characteristics, patients with both abnormal LV and RV had a higher resting heart rate, lower peak heart rate, lower 85% MPHR, and lower peak systolic blood pressure than the patients with an abnormal LV but preserved RV. Among echocardiographic characteristics, patients with both abnormal LV and RV had a lower ejection fraction, higher rest/stress (RV and LV) WMSI, greater extent and severity of ischemia, and underwent a greater number of dobutamine stress echocardiography studies compared with those with an abnormal LV but preserved RV.
Primary outcome.
Patients were followed for up to 4 years (mean 2.7 ± 1.0 years) for confirmed nonfatal MI and cardiac death (n = 122). Stress RV WMSI was able to effectively risk-stratify a normal versus abnormal subgroup (event rates 1.3%/year vs. 9.3%/year; p <0.0001) (Fig. 2). When stress LV wall motion analysis was also taken into consideration, patients with both abnormal LV and RV had a worse prognosis (Fig. 3). In the group with an abnormal RV but normal LV post stress, both of the patients had an event during follow-up. However, given the small sample size (n = 2) of this cohort any comparison with the rest of the group cannot be made with confidence. The age-adjusted hazard ratio for various combinations of LV and RV wall motion abnormalities are given in Table 3. An abnormal RV was able to further risk-stratify the abnormal LV group. Presence of an abnormal RV after stress portended a worse prognosis (Table 3).
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Figure 2 Event-Free Survival as a Function of RV Stress Wall Motion Abnormalities
The number of patients at risk for each follow-up period is given below the graph. Patients with abnormal right ventricle (RV) have a 7-fold higher event rate compared with those with a normal RV.
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Figure 3 Event-Free Survival as a Function of LV and RV Stress Echocardiography Results
The number of patients at risk for each follow-up period is given below the graph. Right ventricular (RV) wall motion analysis during stress further risk-stratified the results of stress echocardiography based on the left ventricle (LV). Patients with abnormal RV and LV both had a worse prognosis. Abn = abnormal.
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Predictors of cardiovascular events.
Univariate clinical predictors of cardiac events were older age, hypertension, diabetes, family history of premature CAD, prior MI, known heart failure, and prior coronary bypass surgery (Table 4). Among stress electrocardiographic variables, a higher resting heart rate and lower achieved peak heart rate and peak systolic blood pressure were significant univariate predictors of cardiovascular events. Among echocardiographic variables, a higher rest LV WMSI, higher stress LV WMSI, lower ejection fraction, higher number of ischemic segments, greater extent and severity of ischemia, higher number of segments with biphasic response, and inability to exercise were significant univariate predictors of cardiovascular events (Table 4). Both rest and peak RV WMSI were significant univariate predictors of cardiovascular events. The risk of cardiovascular events increased exponentially with increase in peak RV WMSI (Fig. 4), implying a greater risk with higher peak RV WMSI.
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Table 4 Univariate and Multivariate Predictors of Cardiovascular Events (Myocardial Infarction and Cardiac Death)
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Prior MI, inability to exercise, number of ischemic LV segments, and peak RV WMSI were significant multivariable predictors of cardiovascular events.
Incremental value of assessing RV wall motion abnormalities.
To avoid overfitting, the incremental value of RV wall motion analysis was analyzed after entering only the rest echocardiography, the conventional stress echocardiographic variables, and finally the RV wall motion variables into a forward conditional Cox proportional hazard model. Stress RV WMSI provided incremental prognostic value over rest echocardiographic and conventional stress echocardiographic parameters as assessed by an increase in global chi-square values (global chi-square increased from 141.4 to 161.8 to 197.0; p <0.0001 and p = 0.006, respectively) (Table 5).
Secondary outcomes.
For the secondary outcome of all-cause mortality, RV wall motion analysis was able to effectively risk-stratify a normal versus an abnormal subgroup (event rates 3.6%/year vs. 13.6%/year; p <0.0001). The RV wall motion analysis was able to further risk-stratify both the normal and the abnormal LV subgroups and provided incremental value over rest echocardiographic and conventional stress echocardiographic variables for the prediction of all-cause mortality (global chi-square increased from 93.5 to 99.6 to 106.7; p = 0.009 and p = 0.016, respectively).
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Discussion
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The present study assessed the prognostic value of RV wall motion analysis, during routine stress echocardiography, for risk stratification and prognosis of patients with known or suspected CAD. The results show that an abnormal RV portends a worse prognosis and further risk-stratifies the result of stress echocardiography (based on LV segmental wall motion analysis). The risk of cardiovascular events increased with increasing peak RV WMSI. Stress RV WMSI was an independent predictor of cardiovascular events, independent of LV ischemia and LV function (ejection fraction) and provided incremental prognostic value over rest and conventional stress echocardiographic variables.
RV.
Historically, the RV has been considered less important than the LV, because common cardiac diseases, specifically ischemic heart disease, was considered to be a disease of the LV. The RV was considered to be a passive conduit between the venous system and the lungs. When compared with the LV, the RV has lesser mass with lower systolic and end-diastolic pressure and therefore, unlike the LV, receives blood flow in both systole and diastole, creating more favorable coronary supply and demand characteristics (5). However, despite this, given that both the RV and LV share a common septum, have an overlapping blood supply, and are enclosed by spiraling muscle fibers and are bound together by the pericardium, there is interventricular interdependence, such that hemodynamic and functional changes of one affects the other chamber (5). The functional importance of the RV is, therefore, being increasingly recognized.
Prognostic value of RV function.
Most of the evidence on the prognostic value of RV function is from patients with acute MI. In patients with inferoposterior MI, 50% have RV involvement. In patients with acute RV infarction (proximal right coronary artery occlusion), severe hemodynamic compromise arises in patients when both RV free wall and septum are involved. In these patients, the compromised RV systolic function reduces LV preload and therefore the cardiac output. In addition, RV dysfunction leads to an elevated RV end-diastolic pressure that shifts the septum toward the left, thereby further limiting left-sided filling and compliance. In addition, acute RV dilation can cause a constrictive pericarditis-like physiology secondary to the pericardial constraint, exaggerating the ventricular interdependence (5).
On the other hand, successful reperfusion results in improvement in RV function with associated improvement in hemodynamics (13). Conversely, unsuccessful revascularization of the RV, in one study, was associated with severe hemodynamic compromise and a 58% in-hospital mortality rate despite preserved LV function, attesting to the importance of RV (13). Other studies in patients with RV infarction have also documented increased rates of morbidity and mortality attributable to arrhythmias and cardiogenic shock (14,15), particularly in patients with unsuccessful reperfusion (16). In patients with chronic heart failure, RV function is a better guide to exercise capacity (6) and prognosis (17) than LV function, particularly in patients with ischemic and valvular heart disease (18). In patients awaiting cardiac transplant, RV ejection fraction >24% was an independent predictor of survival in a multivariate model that included LV ejection fraction. One-year survival in the 2 groups were 44% and 93%, respectively (19). In patients with atrial septal defects, a preserved RV function is a predictor of postoperative improvement in symptoms and RV function (20). Similarly, in patients with chronic obstructive pulmonary disease and pulmonary embolism, prognosis is dependent, in part, on the RV function (21). However, it should be noted that these prognostic data were mainly derived by assessment of global RV function during resting echocardiography.
RV wall motion analysis during stress testing.
Although the prognostic value of RV function is being increasingly recognized, there are limited data evaluating wall motion abnormalities of the RV during stress echocardiography. In fact, the guidelines proposed by the American Society of Echocardiography emphasize evaluation of LV wall motion segments during stress echocardiography (4) and thus, from a stress echocardiography perspective, the RV is still a "forgotten" chamber.
San Roman et al. (9) evaluated RV wall motion abnormalities in patients with right coronary artery disease undergoing dobutamine stress echocardiography. The RV wall motion analysis was feasible in 80% of patients, and the results showed that in patients with right coronary artery disease, RV wall motion analysis was a reliable technique for assessing RV dysfunction (sensitivity 68%; specificity 92%) (9). However, there was no prognostic data in that study. Maurer and Nanda (22) evaluated 41 patients undergoing exercise stress echocardiography and correlated them with thallium perfusion scans. They found that 3 patients with coronary artery disease experienced new isolated RV asynergy with exercise that would have been missed if only the LV had been evaluated, and the results correlated well with thallium perfusion scans (22). However, again, prognostic data was not evaluated in this study. Other studies using radionuclide angiography at rest and after exercise have demonstrated abnormal performance of RV during exercise in patients with proximal right coronary artery disease (8,23). However, in those studies only ejection fraction was evaluated and there was no prognostic data.
To our knowledge, this is the first study to evaluate the prognostic value of RV asynergy during routine stress echocardiography. The results of this study show that an abnormal RV (ischemia or infarction) can further risk-stratify and prognosticate the results of stress echocardiography (based on LV wall motion abnormalities). Patients with abnormal RV and LV both have a worse prognosis. In the present study, patients with an abnormal RV but normal LV had the worst prognosis. However, this result was based on only 2 patients, both of whom had an event during the follow-up. Our results show that RV wall motion analysis during stress provides prognostic value independent of LV ischemia and LV ejection fraction and provides incremental prognostic value over rest and conventional stress echocardiography variables.
Study limitations.
As in other studies with stress echocardiography, though the stress echocardiography was interpreted by 2 experienced observers, it is subjective, and extrapolation of our results to those of other centers may be limited. As in other echocardiography studies, patients with an abnormal stress echocardiography tend to proceed to angiography and revascularization, thereby decreasing the outcomes from an abnormal test. Although we used only a 3-segment model for RV wall motion analysis, it provides an easy to use and an effective model for RV wall motion analysis. Given 112 patients with RV abnormalities, we combined RV infarct and RV ischemia to represent an abnormal RV.
Clinical implications.
In this group of patients with known or suspected coronary artery disease referred for routine stress echocardiography, RV wall motion analysis provided prognostic value independent of LV ischemia and ejection fraction and provided incremental value over rest and conventional stress echocardiographic parameters. Patients with abnormal RV and LV wall motion during stress have a worse prognosis and should be managed aggressively. Right ventricular wall motion analysis should be performed routinely in all patients referred for stress echocardiography.
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References
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Stress echocardiography: recommendations for performance and interpretation of stress echocardiographyStress Echocardiography Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97-104.[CrossRef][Web of Science][Medline] 5. Rigolin VH, Robiolio PA, Wilson JS, Harrison JK, Bashore TM. The forgotten chamber: the importance of the right ventricle Catheter Cardiovasc Diagn 1995;35:18-28.[Web of Science][Medline] 6. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure J Am Coll Cardiol 1995;25:1143-1153.[Abstract] 7. de Groote P, Millaire A, Foucher-Hossein C, et al. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure J Am Coll Cardiol 1998;32:948-954.[Abstract/Free Full Text] 8. Brown KA, Okada RD, Boucher CA, Strauss HW, Pohost GM. 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Abstract
Methods