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Exercise Radionuclide Ventriculography for Predicting Post-Operative Left Ventricular Function in Chronic Aortic Regurgitation

Éva Tamás, MD, PhD^_*,_*, Mats Broqvist, MD, PhD, Eva Olsson, MD, Stefan Franzén, MD^_*, Eva Nylander, MD, PhD

^_* Department of Cardiothoracic Surgery, Heart Centre in Östergötland, University Hospital Linköping, Linköping, Sweden
Department of Cardiology, Heart Centre in Östergötland, University Hospital Linköping, Linköping, Sweden
Department of Clinical Physiology, Heart Centre in Östergötland, University Hospital Linköping, Linköping, Sweden

	Abstract

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Objectives: Ejection fraction (EF) reaction upon exercise by radionuclide ventriculography and standard echocardiographic parameters was evaluated as predictors for post-operative left ventricular (LV) function in chronic aortic regurgitation (AR).

Background: The optimal timing of surgery for chronic AR is when the left ventricle is still compensating for the volume and pressure overload without irreversible dysfunction. For asymptomatic patients when EF is normal and LV diameters are borderline, exercise testing is recommended by present guidelines. However, only a limited number of studies have been performed, and data are scarce on this subject.

Methods: Radionuclide ventriculography with multiple gated acquisition at rest and during exercise was performed in 29 consecutive patients with severe chronic aortic regurgitation pre-operatively and 6 months post-operatively. Patient subgroups were formed based on pre-operative EF exercise response (EF) and were categorized as decreasing (EF <–5%), unaltered (–5% EF 5%), and increasing (EF > 5%). A 5% or higher increase was considered normal. The LV diameters and mass were measured by echocardiography.

Results: Pre-operative LV diameters were markedly elevated before surgery and diminished significantly after surgery. Left ventricular diameters, LV mass, EF at rest (EF_rest), and EF change from rest to exercise (EF) were independent of New York Heart Association functional class. Pre-operative end-diastolic diameter proved to be a predictor for pre- and post-operative EF (p = 0.003; p = 0.04) but not for the nature of the exercise response post-operatively. Patients with decreasing and unaltered EF pre-operatively presented a significantly higher but still abnormal EF post-operatively. Those with increasing EF pre-operatively had a similar response and a normal EF post-operatively. Pre-operative EF was not only a predictor for post-operative EF (p = 0.02) but also classified patients into post-operative subgroups (EF decreasing, p = 0.03; unaltered, p = 0.02; increasing, p = 0.0008).

Conclusions: An abnormal EF response to exercise may also occur in patients who do not fulfill criteria for surgery based on LV dimensions or EF. A follow-up of exercise LV function and adjusting the timing of surgery according to the nature of exercise response could, therefore, be beneficial.

Key Words: radionuclide ventriculography • ejection fraction • exercise testing • aortic regurgitation • cardiac surgery

Abbreviations and Acronyms   AR = aortic regurgitation   EF = ejection fraction   EF = change in ejection fraction   HR = heart rate   LV = left ventricular   LVF = left ventricular function   LVEF = left ventricular ejection fraction   LVEDD = left ventricular end-diastolic diameter   LVESD = left ventricular end-systolic diameter   NYHA = New York Heart Association

In this study, LVF of patients with chronic AR was examined by echocardiography and by radionuclide ventriculography, using radionuclide ventriculography, at rest and during exercise, before and 6 months after surgery. Our aim was to examine the changes in the ejection fraction (EF), from rest to exercise, as a measure of LVF both pre- and post-operatively. Moreover, we wished to study whether any of the pre-operative parameters could reliably predict LVF after surgery.

	Methods

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Patients.   Twenty-nine consecutive patients referred for surgery with severe chronic AR were included in this study. Patients with concomitant coronary artery disease and with heart valve disease other than chronic AR (aortic stenosis defined as aortic orifice area 1.6 cm²; any history of congenital heart disease or active endocarditis) were excluded. Twenty-six patients completed the study. One patient moved abroad, 1 had mild claustrophobic symptoms and abstained from the post-operative study, and 1 patient had a stroke peri-operatively with incapacitating neurological symptoms. The pre-operative results of these patients were analyzed.

Radionuclide ventriculography.   Radionuclide ventriculography with radionuclide ventriculography was performed 2 days before planned surgery and 6 months post-operatively. Erythrocytes were labeled with 10 MBq/kg Tc-99m pertechnetate using the modified in vitro technique. Electrocardiogram gated imaging was performed using a General Electric XR/T gamma camera equipped with a general purpose, low-energy collimator and a Genie ACQ collecting station (General Electric Medical Systems, Milwaukee, Wisconsin). For optimal separation of the left and the right ventricles, left anterior oblique (45°) positioning was used. Supine multigated blood pool imaging was performed first at rest. After this, the patients performed supine bicycle exercise at a pedal rate of 60/min. Besides continuous electrocardiography and heart rate registration, the blood pressure was also measured every 2 min. The initial workload was 50 W and was increased by 50 W at the next level.

The Xeleris Functional Imaging Workstation, EF Analysis (General Electric Medical Systems) was used for image and data analysis. A total of 5 Mcounts were collected at rest and 2.5 Mcounts during steady-state exercise, with 32 frames per heart cycle in a matrix size 64 x 64. Cycle length windowing with dynamic arrhythmia filtration (6) with forward gating was used. A heart rate (HR) histogram was generated and observed for 1 to 3 min. When steady state HR was achieved, a window was centered at a peak HR ±10% for patients with sinus rhythm. Beats outside this interval were rejected. In patients with atrial fibrillation, the window of acceptable beats was widened up to 15% to 20% to reduce imaging time. Left ventricular end-diastolic and -systolic outlines were marked manually by each of 2 operators separately, who made 3 measurements each. The mean of these measurements was used. The automatic algorithms of the computer program were used for background (BG) correction. Left ventricular ejection fraction (LVEF) was calculated from LV and BG counts as:

Definition of subgroups.   Subgroups were formed based on pre-operative EF exercise response (EF) during radionuclide ventriculography and were categorized as decreasing (EF <–5%), unaltered (–5% EF 5%), and increasing (EF > 5%). A 5% or higher increase of EF was considered normal. The above subgroups were defined considering the above limits and a 5% bias of the method (7–9).

Echocardiography.   All the patients underwent a transthoracic ultrasonography scan at rest (GE Vingmed, Vivid 5, or Vivid 7 echocardiograph) 1 day before the planned surgery and 6 months post-operatively. Images were recorded, stored digitally, and analyzed off line. Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and LV end-diastolic wall thickness were measured by M-mode, and LV mass was calculated according to Devereaux's formula. The velocity of E and A waves, E/A ratio, and pulmonary venous systolic and diastolic velocity were analyzed and used for an integrated description of diastolic function (10). Left ventricular end-diastolic and -systolic volumes and EF were calculated according to Simpson's rule. Volume measurements, an average of 3 tracings in each registration, were performed by an experienced investigator who was unaware of the results of radionuclide ventriculography.

Statistical analyses.   General discriminant analysis (forward stepwise) model, general linear models, Student's unpaired t test, Pearson's correlation coefficient, and Bland-Altman analysis were used to verify connections among variables as applicable for data sets. Comparison of pre- and post-operative data was performed by Wilcoxon's matched pairs test. Data are presented as mean ± SD. Significance was set at p < 0.05. Analyses were performed by STATISTICA 8.0 (Statsoft, Tulsa, Oklahoma). The ethics committee of the Faculty of Health Sciences, University of Linköping, approved the study. All the patients gave their written informed consent.

	Results

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Patients.   All patients were men. Mean age was 51 ± 14 years, body mass index was 27.4 ± 3.1 kg/m², and body surface area was 2.0 ± 0.2 m². Pre-operatively, 13 patients were in New York Heart Association (NYHA) functional class I, 10 were in NYHA class II, 5 were in NYHA class III, and 1 was in NYHA class IV. Pre-operatively, the majority (25) of the patients were in sinus rhythm and 4 had atrial fibrillation. At the 6-month follow-up, 25 patients were in sinus rhythm and 1 had atrial fibrillation. Eight patients were free from medication pre-operatively whereas 12 were receiving beta-blockers; 14, angiotensin-converting enzyme inhibitors; 1, digitalis; 5, calcium antagonists; and 6, diuretics. Post-operatively, 10 patients received beta-blockers; 6, angiotensin-converting enzyme inhibitors; 3, angiotensin II antagonists; 2, calcium antagonists; and 6, diuretics. Table 1 shows the baseline characteristics of the patients in the different subgroups.

View this table: [in this window] [in a new window]   Table 1 Baseline Characteristics of the Subgroups, Based on EF

LV diameters, mass, and volumes.   Pre-operatively, the patients had a pronounced LV dilatation with wall thickness within the upper normal range, which resulted in a high LV mass. Left ventricular diameters diminished markedly and generally fell within normal limits post-operatively, and the overall comparison of pre- and post-operative LV masses and LV end-diastolic volume showed significant reduction after surgery (Table 2). Pre- and post-operative blood pressure and heart rate are shown in Table 3.

LV function at rest and during exercise.   Resting EF calculation by echocardiography according to Simpson's rule gave significantly lower EF compared with radionuclide ventriculography (p = 0.0001). Measurements by the 2 different methods showed a modest correlation at rest (r = 0.53), and upon Bland-Altman analysis, the standard deviation for EF by the 2 methods was 7%.

Figure 1 shows the distribution of pre-operative and post-operative EF at rest (EF_rest) by radionuclide ventriculography for the study population, and Figure 2 illustrates EF from rest to exercise for the whole group pre- and post-operatively. Pre-operative EF_rest was not a predictor for post-operative EF_rest. On the other hand, we found that both pre- and post-operative EF at maximal workload (EF_max) could be predicted from pre-operative EF_rest (p = 0.000002 and p = 0.007, respectively). Analyses of subgroups, formed according to EF, showed that patients with decreasing and unaltered EF pre-operatively presented a significantly improved but still abnormal EF during exercise post-operatively. The group of patients with increasing EF pre-operatively responded similarly to exercise post-operatively (Fig. 3, Table 2). Pre-operative EF proved to be a predictor for post-operative EF (p = 0.02) in this study. Moreover, pre-operative EF was the single and only predictor as to which subgroup (EF decreasing, p = 0.03; unaltered, p = 0.02; increasing, p = 0.0008) patients were to be classified post-operatively.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 1 EF at Rest Pre- and Post-Operatively Measured by Radionuclide Ventriculography Ejection fraction (EF) at rest is one of the most frequently used parameters when evaluating left ventricular function. The majority of patients with severe chronic aortic regurgitation in the present study had a normal resting EF pre-operatively. Post-operatively, 8 of 28 patients had an EF below 56%, which is considered as the lower reference limit with this method, raising the question of whether subclinical left ventricular dysfunction had been present already pre-operatively.

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Figure 2 EF at Rest and During Exercise by Radionuclide Ventriculography Pre- and Post-Operatively The color-coded graph shows ejection fraction (EF) at rest and at every workload from 50 W, increased in steps of 50 W for each patient before and after surgery. Patient number is shown on the horizontal axis (x), and the different workloads pre- and post-operatively are shown on the vertical axis (y). Vertical bars illustrate individual left ventricular function, measured as EF, at increasing levels of exercise, with green meaning low EF and yellow-red meaning normal to high EF.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 3 EF by Radionuclide Ventriculography Pre- Versus Post-Operatively Based on Pre-Operative EF Response to Exercise Comparison of pre-operative (preop) and post-operative (po) ejection fraction (EF) change upon exercise (EF) revealed that patients with abnormal EF reaction and unaltered EF had improved EF reaction post-operatively, albeit still not normal. Patients with a normally increasing EF during exercise pre-operatively had preserved their good left ventricular function after surgery. This finding can be relevant for timing of surgical interventions because the aim should be to choose a time when it can be assumed that the patient will be improved post-operatively.

Echocardiographic LV parameters at rest versus EF response to exercise.   Pre-operative LVEDD proved to be a predictor for both pre-operative and post-operative EF (p = 0.003 and 0.04, respectively) in general but did not have any predictive value in placing the patients in the different subgroups based on EF response post-operatively. However, LVESD was independent of any exercise response. Pre-operative LV volumes could not be connected to EF_rest or EF during exercise.

Parameters of diastolic function (velocity of E and A waves, E/A ratio, classification according to diastolic pattern) were not found to be connected to EF_rest, EF_max, or EF, either pre- or post-operatively in this study (Table 4).

	Discussion

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Our choice of when to evaluate post-operative LV function was a compromise between the risk of losing patients for follow-up, or other factors affecting LV function to interfere, and on the other hand a desire to detect the long-term effects adequately. Remodulation of heart muscle starts as early as a few hours after heart valve surgery (12). Left ventricular function shows improvement at discharge and at 6-month follow-up, but according to data from Gelsomino et al. (13), there was no significant difference in LVF at rest between 6-month and 1-year follow-up. Earlier studies on the absolute maximal EF during exercise after surgery showed an improvement up to 3 years in patients with severe chronic AR (14). As EF at rest and during exercise is influenced by the presence or absence of valve regurgitation, we have studied EF as a more independent parameter, and found a relation between the pre- and post-operative reaction, which would be of interest to evaluate also after a longer observation period.

It was a clinical decision not to withdraw the medication before the examinations. This may possibly have influenced the results, although this effect would be reduced by evaluating EF rather than absolute data. The incidence and the prevalence of chronic aortic insufficiency explain the lack of women among patients in this study (15–17), and there was no selection bias involved. The decision about surgery was based on either progressive LV dilation, indication of a declining LV function despite a normal EF, or the appearance of symptoms, together with an awareness not to delay surgery too long. Our patient population had an overall normal EF_rest. We did not find any connection or correlation between NYHA functional class and LVEF, which is concordant with results from earlier studies (18). Radionuclide ventriculography is dependent upon accumulation of data over several cardiac cycles. When irregular beats constitute >10% of the electrocardiographic cycles, errors are introduced into the shape of the time-activity curve (19). Most of these errors are introduced in the diastolic part of the cardiac cycle with minor effect on the systolic part and calculation of ejection fraction (20). Cycle length windowing was introduced to reduce the problems caused by irregular beats (20,21). Wallis et al. (22) reported that windowing in cardiac blood pool studies in atrial fibrillation did not give significant differences in EF determination and that the exact location of the window was not critical. Thus, it is possible to analyze EF by radionuclide ventriculography also in patients with atrial fibrillation, and therefore we did not exclude those patients from this study.

Previous studies of radionuclide ventriculography showed that EF during exercise and exercise EF response have predictive value for the predicted length of the period until symptoms develop and there is an absolute indication for surgery (23,24). These studies were performed in an era when asymptomatic patients were not operated on. Furthermore, these variables had predictive value for the risk of sudden cardiac death in the natural history of the disease (3). In the present study, pre-operative EF_rest was found to be significantly correlated to EF_max, separately both pre- and post-operatively, which was in concordance with previous studies (7,11,25,26). However, pre-operative EF_rest was not connected to post-operative EF increase upon exercise and was, therefore, not found to be informative for LV performance during exercise post-operatively.

Furthermore, we found that pre-operative exercise response was not only a predictor of post-operative exercise response but also that pre-operative EF predicted which type of exercise response the patient was going to have post-operatively. This finding is an extension of results in accordance with earlier studies of cardiac catheterization (23) and echocardiography at rest and after stress (24), even if the present results do not allow conclusions regarding clinical outcome. Patients in the different subgroups defined by pre-operative EF exercise response showed a similar exercise response pattern post-operatively. Decreasing EF during exercise pre-operatively meant an improved but still not normally increasing EF during exercise on follow-up. The general pattern was that the group of patients with unaltered EF pre-operatively responded to exercise normally after operation whereas patients who had had normal EF had preserved it. This finding might indicate that at least patients with decreasing EF should have been operated on earlier to preserve LVF, which had obviously deteriorated at the time of the operation in spite of normal EF_rest. That the left ventricular diameters lay within intervals presented in guidelines (1,2), in which regular follow-up and consideration of hemodynamic response before a decision about surgery is recommended, emphasizes the importance of functional evaluation by exercise testing. Left ventricular volumes significantly diminished post-operatively in the whole study group, as expected and described in previous studies (12,27). We found that EF calculations by radionuclide ventriculography and by ultrasonography were in agreement, although echocardiography gave a lower level of EF in our study, as has been reported by others (28). This indicates that a careful choice and use of validated methods is important for follow-up over time. Determination of EF by radionuclide ventriculography has high reproducibility, even during exercise, and therefore adds valuable information in borderline cases.

	Conclusions

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The present study demonstrates that the pre-operative exercise response measured with radionuclide ventriculography can identify patients at risk for an abnormal post-operative LVF response during exercise. Moreover, it can predict what kind of exercise response (increasing, unaltered, or increasing EF during exercise) to expect after surgery. An abnormal EF response to exercise might also occur in patients who do not fulfill the criteria for surgery based on LV dimensions by echocardiography or EF at rest. We conclude that patients with significant chronic AR could benefit from follow-up of LV function at exercise and by considering surgery when the character of the exercise response is abnormal.

	Acknowledgments

 
The authors thank the Swedish Heart-Lung Foundation, the County Council of Östergötland, and the Research Foundations of the Heart Centre in Östergötland, Linköping, Sweden, for their financial support.

	Footnotes

 
The study received research grants from the Swedish Heart-Lung Foundation, Stockholm, Sweden, the County Council of Östergötland, and the Research Foundations of the Heart Centre in Östergötland, Linköping, Sweden.

^_* Reprint requests and correspondence: Dr. Éva Tamás, Department of Cardiothoracic Surgery, University Hospital, Linköping, S-581 85, Sweden (Email: eva.tamas{at}liu.se).

Manuscript received May 12, 2008; revised manuscript received August 29, 2008, accepted September 9, 2008.

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This Article Abstract Figures Only Full Text (PDF) View Related Keeping an Eye on Imaging on CVN View Related Cardiosource Journal Scan Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tamás, E. Articles by Nylander, E. Search for Related Content PubMed Articles by Tamás, E. Articles by Nylander, E. Related Collections Related Article