CLINICAL RESEARCH
akinesia becoming dyskinesia after exercise testing: prevalence and relationship to clinical outcome
Graham S. Hillis, MBChB, PhD*,
Jae K. Oh, MD, FACC*,
Douglas W. Mahoney, MS*,
Robert B. McCully, MBChB, FACC* and
Patricia A. Pellikka, MD, FACC*,*
* Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA
Manuscript received May 20, 2003;
revised manuscript received August 1, 2003,
accepted August 25, 2003.
* Reprint requests and correspondence: Dr. Patricia A. Pellikka, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.
pellikka.patricia{at}mayo.edu
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Abstract
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OBJECTIVES: The aim of this study was to determine the prevalence and prognostic implications of dyskinesia developing after exercise.
BACKGROUND: The prevalence and prognostic implications of new-onset dyskinesia with exercise testing have not been previously described.
METHODS: We considered 1,005 consecutive patients who underwent exercise echocardiography and had akinetic segments at rest. Patients were divided according to the presence or absence of exercise-induced dyskinesia. Baseline clinical and echocardiographic parameters were compared, and patients were followed up for a median of 2.7 years.
RESULTS: One hundred four (10%) patients developed dyskinesia after exercise. Compared to patients with segments that remained akinetic, these patients were more likely to have electrocardiographic (ECG) evidence of prior myocardial infarction and, during exercise, had a less pronounced rise in systolic blood pressure and more often had ECG evidence of ischemia. Their resting left ventricular (LV) ejection fraction was worse and improved little after exercise. However, all-cause mortality and the incidence of major adverse cardiac events were similar in the two groups, even after correction for age, gender, and resting LV function (hazard ratio for major adverse cardiac events = 1.36, 95% confidence interval [CI] 0.82 to 2.26, p = 0.23; hazard ratio for total mortality = 1.20, 95% CI 0.75 to 1.94, p = 0.45).
CONCLUSIONS: One in 10 patients with akinetic myocardium at rest will develop dyskinesia after exercise. This is associated with poorer LV function at rest and little improvement in systolic function after exercise. However, this response has no impact on prognosis.
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Abbreviations and Acronyms
| | BP | = blood pressure | | DSE | = dobutamine stress echocardiography | | ECG | = electrocardiogram/electrocardiographic/electrocardiography | | HR | = hazard ratio | | LV | = left ventricle/ventricular | | LVESV | = left ventricular end-systolic volume | | MI | = myocardial infarction | | WMA | = wall motion abnormality | | WMSI | = wall motion score index |
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Exercise echocardiography is a widely used and well-validated technique with which to determine the prognosis of patients with known or suspected coronary artery disease. Several echocardiographic parameters are recognized as predicting an adverse outcome. These include reduced resting left ventricular (LV) ejection fraction, worsening LV ejection fraction with exercise, the response of the LV end-systolic volume (LVESV) to exercise, the presence and extent of any regional wall motion abnormality (WMA) at rest, and the development of a new or worsening WMA after exercise (1–6). This latter category incorporates the appearance of dyskinesia in an area of myocardium that exhibited hypokinesis or normal wall motion at rest and is considered to represent a severe ischemic response (1–6). However, very little is known regarding the prevalence and prognostic implications of the occurrence of dyskinesia in an area that was akinetic at rest. Indeed, there are very few data regarding this response in any field of cardiac imaging.
Development of dyskinesia in previously akinetic segments has been observed in approximately one in five patients undergoing dobutamine stress echocardiography (DSE), albeit in a small and selected cohort (7). In this setting, the development of dyskinesia in segments that are akinetic at rest appears to represent a mechanical phenomenon, related to the increased motion of adjacent tissue. It suggests that the affected segments are non-perfused, infarcted, and unlikely to recover after revascularization (7–9).
The prevalence and clinical implications of new-onset dyskinesia during exercise echocardiography may differ from those reported during DSE. First, the presence of a biphasic response (whereby akinetic but viable hypoperfused myocardium may exhibit improved contraction initially but then become worse) may be appreciated during DSE, but is unlikely to be identified during exercise echocardiography. Second, the hemodynamic effects of exercise differ from those observed during DSE. Exercise stress is associated with a more marked increase in systolic blood pressure (BP) and a much higher rate-pressure product than DSE (10). This induces a greater ischemic burden that, in patients with severe coronary artery disease, is reflected in more striking electrocardiographic changes, worsening of the wall motion score index (WMSI), a decline in ejection fraction, and abnormal volumetric responses to stress (10,11). Thus, the prevalence and significance of stress-induced dyskinesia may differ for exercise and dobutamine. The aims of this study were, therefore, to determine the prevalence and prognostic implications of exercise-induced dyskinesis in a large cohort of consecutive patients undergoing clinically indicated stress testing.
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Methods
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Patients.
The study was approved by the Mayo Foundation Institutional Review Board. From January 1990 to December 1995, 6,444 patients had an exercise echocardiogram performed at the Mayo Clinic, Rochester, Minnesota, for the evaluation of known or suspected coronary heart disease. Two hundred fifty-six patients (4%) had inadequate echocardiographic images and 121 (2%) did not wish to participate in research. Follow-up data were obtained for 5,806 (96%) of the remaining 6,067 patients. Of these, 2,971 (51%) had normal wall motion at rest and after exercise, 570 (10%) had only hypokinesia at rest that did not worsen after exercise, and 1,260 (22%) had normal wall motion or hypokinesis at rest, with worsening of wall motion in at least one segment after exercise. The remaining 1,005 patients, who had akinesia in at least one myocardial segment at rest, formed the study cohort.
Two hundred ninety-two of the cohort of 1,005 patients with resting akinesia (29%) underwent cardiac catheterization within six months (before or after) of the index exercise echocardiogram. Of these, 265 (91%) had a stenosis of  50% in at least one major epicardial coronary artery. Additionally, 841 of the cohort (84%) were identified as having coronary artery disease at the time of their exercise echocardiogram. This was established on the basis of previous angiographic findings, a history of prior myocardial infarction (MI), electrocardiographic (ECG) evidence of prior MI (the presence of pathological Q waves), or a history of revascularization.
Exercise echocardiography.
All patients underwent symptom-limited treadmill exercise testing, according to the Bruce protocol in 801 patients (80%), the Naughton protocol in 116 (11%), or the modified Bruce protocol in 88 (9%). Two-dimensional echocardiographic images were obtained from standard parasternal and apical windows before and immediately after exercise (12).
Both videotape-recorded and quad-screen digitized images were used for the interpretation of studies (13). Left ventricular ejection fraction at rest was measured either by using the modified method of Quinones and colleagues or by using visual estimation, and it was measured after exercise by visual estimation (3,14). Regional wall motion was assessed before and after exercise by an experienced echocardiographer according to a 16-segment model and a five-point grading system (1 = normal, 2 = hypokinesia, 3 = akinesia, 4 = dyskinesia, and 5 = aneurysm) (15,16). Dyskinesia was defined as the absence of systolic thickening with systolic outward bulging away from the center of the LV cavity (8,9). The WMSI was determined at rest and peak exercise as the sum of the segmental scores divided by the number of visualized segments. The change in LVESV from rest to exercise was determined by visual estimation, using a side-by-side comparison of rest and exercise digitized images, and was recorded as normal (decreased LVESV) or abnormal (no change or increase) (17). The levels of intra- and inter-observer agreement regarding the visually assessed ejection fraction and categorization of the LVESV response to exercise in this patient population have been previously reported (3).
Study groups.
Patients were divided into two groups. Group A included patients who had akinesia at rest but developed dyskinesia after exercise in at least one cardiac segment (n = 104). Group B included patients who had akinesia at rest and after exercise in at least one myocardial segment but who did not develop dyskinesia after exercise (n = 901). Patients who had normokinetic or hypokinetic segments that became dyskinetic after exercise were also identified (Group C). The clinical and echocardiographic features of this group were compared with Group A.
Follow-up.
Follow-up was obtained by mailed questionnaires and scripted telephone interviews. All events were verified by reviewing medical records and death certificates and by contacting the patients' physician where necessary (3–5).
Statistical analysis.
Categorical variables are expressed as absolute values and percentages and compared using the chi-square test. Continuous variables are reported as the mean value ± SD and compared using the Wilcoxon rank-sum test. The primary study end point was the occurrence of a major adverse cardiac event (cardiac death, including sudden death without other explanation, and non-fatal MI). Patients who had coronary revascularization before other events were censored at the time of the procedure. A secondary end point of all-cause mortality was also evaluated and, in this analysis, no censoring was performed. Event-free survival was determined by the Kaplan-Meier method. The influence of akinesia becoming dyskinesia on outcome after correction for age, gender, and resting LV function was assessed using a Cox proportional-hazards model and expressed as the hazard ratio (HR) with 95% confidence intervals (CI). Logistic regression analyses were performed to identify univariable predictors of outcome. Significant univariable predictors (p < 0.05) were then entered into a stepwise forward regression model to determine independent prognostic factors. In addition, it was prospectively determined that the development of dyskinesia during exercise would be entered into this model regardless of its power as a univariable predictor.
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Results
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Study group.
The clinical and exercise echocardiographic features of patients with resting akinesia who did and did not develop dyskinesia with exercise echocardiography are shown in Tables 1 and 2, respectively. The two groups were very similar in terms of cardiovascular risk factors and exercise capacity. However, patients who had akinetic segments that became dyskinetic after exercise were more likely to have a history or ECG evidence of prior MI, had less increase in BP with exercise, and exhibited more ischemic changes on their exercise ECG. In addition, their resting LV systolic function (as reflected by the number of akinetic segments at rest, WMSI, and ejection fraction) was slightly worse. These differences became more marked after exercise.
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Table 1 Clinical Features of Patients With Akinesia at Rest Who Did (Group A) and Did Not (Group B) Develop Dyskinesia With Exercise Echocardiography
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Table 2 Exercise Echocardiographic Features of Patients With Akinesia at Rest Who Did (Group A) and Did Not (Group B) Develop Dyskinesia With Exercise Echocardiography
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Prevalence of new onset dyskinesia during exercise echocardiography.
The number of segments that were akinetic at rest ranged from one to 15 per patient (mean 3.6 ± 2.5), and was higher in the 104 (10%) patients who developed dyskinesia with exercise echocardiography than in the 901 in which akinesia persisted (4.4 ± 2.6 vs. 3.6 ± 2.4, p = 0.0004). Sixty-six (63%) of these 104 subjects developed dyskinesia in one myocardial segment and 38 (37%) in more than one segment. On average, 47% of segments that were akinetic at rest became dyskinetic after exercise in this group (range 8% to 100%). The distribution of segments that were akinetic at rest and became dyskinetic after exercise (n = 165) is shown in Figure 1.
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Figure 1 Distribution of segments that were akinetic at rest and became dyskinetic after exercise. Number refers to the total number of segments in this distribution exhibiting this response (total = 165).
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Of the 901 patients who had akinesia at rest and did not develop dyskinesia after exercise, 143 (16%) showed improvement in at least one akinetic segment. The mean number of akinetic segments exhibiting improvement was 2 ± 1.2 per patient (range, 1 to 6 segments).
Outcome.
During a median follow-up of 2.7 years (mean 2.9 ± 1.9, range 1 day to 8.1 years), there were 116 major adverse cardiac events (62 cardiac deaths and 54 non-fatal MIs). One hundred fifty-five patients underwent coronary revascularization during follow-up, 91 within the first month after the exercise echocardiogram and 64 more than a month later. Seventeen (10 early, 7 late) of these procedures were performed in patients in Group A (16.3%) and 138 (81 early, 57 late) in patients in Group B (15.3%).
Prognostic impact of akinesia becoming dyskinesia during exercise echocardiography.
Patients who developed dyskinesia after exercise tended to have a higher event rate throughout follow-up, but this did not attain statistical significance (Fig. 2). Similarly, when the secondary end point of total mortality was considered, no significant differences were apparent (Fig. 3).
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Figure 2 Major adverse cardiac event (cardiac death and non-fatal acute myocardial infarction) rate in patients with akinetic myocardium at rest who did and did not develop dyskinesia with exercise echocardiography (p = 0.12).
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Figure 3 All-cause mortality in patients with akinetic myocardium at rest who did and did not develop dyskinesia with exercise echocardiography (p = 0.27).
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After correction for age, gender, and resting LV function, patients who developed dyskinesia had an outcome similar to those whose myocardium remained akinetic (HR for major adverse cardiac events = 1.36, 95% CI 0.82 to 2.26, p = 0.23; HR for total mortality = 1.20, 95% CI 0.75 to 1.94, p = 0.45, respectively).
Univariable and multivariable predictors of outcome.
The univariable and multivariable predictors of major adverse cardiac events and all-cause mortality for patients with akinesia at rest are shown in Tables 3 and 4, respectively. In a multivariable model, the independent predictors of major adverse cardiac events were diabetes mellitus and an abnormal end systolic volume response to exercise. In a second multivariable model, all-cause mortality was inversely and independently related to the number of metabolic equivalents achieved and the exercise ejection fraction. The occurrence of dyskinesia during exercise had no univariable (HR for major adverse cardiac events 1.49, 95% CI 0.90 to 2.46, p = 0.12; HR for all-cause mortality 1.31, 95% CI 0.81 to 2.10, p = 0.27) or multivariable (HR for major adverse cardiac events 1.19, 95% CI 0.67 to 1.87, p = 0.67; HR for all-cause mortality 1.05, 95% CI 0.65 to 1.70, p = 0.84) prognostic value.
The prevalence and prognostic significance of exercise-induced dyskinesia in areas of resting normokinesia and hypokinesia.
Fifty-two patients (out of 4,801 subjects; 1%) developed dyskinesia after exercise in myocardium that was normokinetic or hypokinetic at rest. This occurred in a total of 71 segments (32 normal at rest, 39 hypokinetic at rest). Four of these subjects also developed dyskinesia in an area of myocardium that was akinetic at rest (and were included in Group A) and 14 had akinetic myocardium both at rest and after exercise (and were included in Group B). Compared with patients who had akinetic myocardium at rest that became dyskinetic after exercise (Group A), the 34 remaining patients (who developed dyskinesia in normal or hypokinetic myocardium and did not have akinesia at rest, Group C) were less likely to have a history or ECG evidence of prior MI (Table 5). They had better LV systolic function and were more likely to experience angina during or after exercise. In this small group, there was only one cardiac event, a non-fatal MI, which occurred five years after the index echocardiogram (p = 0.045 vs. major adverse cardiac event rate in patients with akinesia becoming dyskinesia).
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Table 5 Clinical and Echocardiographic Features of Patients With Akinesia at Rest Who Developed Dyskinesia Following Exercise (Group A) and Patients Who Developed Dyskinesia in Normal or Hypokinetic Myocardium and Did Not Have Akinesia at Rest (Group C)
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Discussion
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The current study demonstrates that 1 in 10 patients with akinesia at rest will develop dyskinesia after exercise. The development of dyskinesia in previously akinetic myocardium is associated with a less marked BP increase with exercise, more frequent ischemic changes on the exercise ECG, poorer LV function at rest, and little improvement in systolic function after exercise. However, although the appearance of dyskinesia after exercise is associated with other features that generally confer an adverse prognosis, we found no evidence that it foretells a worse outcome.
Previous studies have shown that development of ischemia with exercise echocardiography identifies patients who are risk of cardiac events (1–6). Conventionally, such studies have characterized any worsening of wall motion with exercise as an ischemic response (1–6,10,16). However, the finding that patients with exercise-induced dyskinesis had an outcome similar to that of patients with persistent akinesis suggests that it represents a mechanical phenomenon, rather than a marker of ischemia. Thus, the observed paradoxic outward motion in systole is secondary to tethering of necrotic and fibrosed myocardium and increased motion of surrounding viable tissue. In contrast, the development of dyskinesia after exercise in myocardium that exhibited normal contraction or hypokinesia at rest may well be an ischemic response. Certainly, these patients are more likely to experience angina during or after exercise. They also have better LV systolic function and a more favorable prognosis.
Study limitations.
The results of exercise echocardiography were used in the management of patients and, in particular, may have influenced decisions regarding coronary revascularization. For this reason, such procedures were not used as end points in the study and were regarded as censoring events in the primary analysis. This may, however, have influenced the prognostic value of the exercise echocardiogram. Nevertheless, the number of patients undergoing coronary revascularization was relatively small (and similar in both groups), to some extent minimizing this effect. Conversely, the limited number of revascularized patients, and the absence of systematic follow-up echocardiograms, precludes any evaluation of functional recovery in segments that exhibited exercise-induced dyskinesia.
Conclusion.
In this cohort of 1,005 patients with akinetic myocardium at rest, 10% developed dyskinesia in at least one segment after exercise. This pattern was associated with worse resting LV systolic function and less improvement of ejection fraction after exercise. Despite this the pattern had little impact on long-term outcome.
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Acknowledgments
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We are grateful to Marion Barnes, Brenda Decker, and Marcella Musel for their assistance with the data collection, and to all the cardiac sonographers, nurses, technicians, and clinicians who performed the studies.
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Footnotes
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Dr. Hillis is supported by an International Fellowship grant from the British Heart Foundation.
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References
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Abstract
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