Left Ventricular Dysfunction on Exercise Long Term After Total Repair of Tetralogy of Fallot
Background Excellent results regarding mortality are well recognized in the long-term period after intracardiac repair of tetralogy of Fallot. However, it is still unclear how postoperative sequelae affect cardiac performance during exercise.
Methods and Results Twenty-nine patients with tetralogy of Fallot were studied 16±2 years after intracardiac repair by use of radionuclide first-pass ventriculography with an ultra-high-sensitive gamma camera at rest and at peak exercise on a semi-upright bicycle ergometer. The results were compared with those from 10 age- and sex-matched control subjects. Left and right ventricular ejection fraction and absolute ventricular volume were measured at rest and peak exercise. Regional right ventricular wall motion and diastolic function of the left ventricle were also assessed. Cardiac output of tetralogy was normally preserved both at rest and during exercise. Nevertheless, the incremental response of left ventricular ejection fraction during exercise was depressed in the patients. Left ventricular ejection fraction during exercise was inversely correlated with the right ventricular end-diastolic volume and the severity of pulmonary regurgitation. Regional wall motion at the right ventricular outflow tract was not decreased in the patients. Left ventricular diastolic function was not impaired in the patients compared with control subjects.
Conclusions Latent left ventricular dysfunction during exercise is related to an enlarged right ventricle due to pulmonary regurgitation after intracardiac repair of tetralogy. Careful follow-up is required in patients having significant pulmonary regurgitation.
Long-term results of intracardiac repair of tetralogy of Fallot have shown a low risk of late mortality and good activity in daily life. In one study, the 32-year survival rate of patients with tetralogy of Fallot who survived a perioperative period was 86%, which is only slightly lower than that expected for the general population.1 Although the majority of patients with repaired tetralogy show a good physical condition, many of the patients have residual lesions and sequelae requiring close follow-up and sometimes medical or surgical treatment. Among the postrepair sequelae, significant pulmonary regurgitation or residual pulmonary stenosis limits exercise capacity and increases the risk of sudden cardiac death due to ventricular arrhythmia.2 3 4 5 6 7 The limited physical capacity of such patients may be related to postoperative cardiovascular dysfunction provoked by exercise. However, it is still unclear how the postoperative sequelae affect cardiac performance during exercise. The purpose of the present study was to clarify the long-term status of ventricular performance on exercise in repaired tetralogy with a newly developed radionuclide angiographic system specially designed for exercise cardiac studies.
Patients and Control Subjects
Seventy survivors of intracardiac repair of tetralogy of Fallot operated on between January 1973 and December 1980 at the Heart Institute of Japan were contacted by mail. Among them, 29 patients who gave informed consent and agreed to answer a questionnaire about daily activity and to participate in exercise nuclear studies are the subjects of this report. The selection criteria of the subjects for this study did not include physical status, surgical results, complications, the presence or absence of rhythm disturbances, or lifestyle, from sedentary to participating in athletics. The only exclusion criterion was the presence of a disability due to cerebral complications, that restricted the patient from performing maximum exercise. Results from the patients were compared with those from 10 age- and sex-matched control subjects who were admitted to our hospital for some other reason but had no obvious heart disease on physical or echocardiographic evaluations. Informed consent regarding the purpose of the study and the possible risks of the exercise test and radiation exposure was obtained from all the patients.
No significant differences were found between the patients and control subjects regarding age, sex, height, weight, and body surface area (Table 1⇓). The age at operation was 5±2 years (range, 2 to 10 years), and the follow-up period from surgery was 16±2 years (range, 14 to 20 years). Seven patients had had a previous Blalock-Taussig shunt. All patients except 1 had a right ventriculotomy. RV outflow tract repair consisted of a transannular patch in 20 patients, an RV outflow patch plus valvotomy in 3, an RV outflow patch alone in 1, infundibular resection plus valvotomy in 3, and infundibular resection alone in 2. A cuspid patch was used in 1 patient only. No patient was repaired with an external conduit.
All patients were graded as being in New York Heart Association functional class I at the time of the study. The patient group consisted of 9 full-time workers, one part-time worker, and 19 college or high-school students. One patient was taking digitalis to control supraventricular tachyarrhythmia. Heart murmurs characteristic of pulmonary regurgitation were audible in 23 patients and of tricuspid regurgitation in only 2 patients. All patients had regular sinus rhythm at rest. Complete right bundle-branch block was found in 27 patients.
First-Pass Radionuclide Ventriculography and Exercise Protocol
All patients were studied with first-pass radionuclide ventriculography at rest and at peak exercise with a multicrystal gamma camera (SIM-400, Scinticor Inc) equipped with a high-sensitivity, parallel-hole collimator and interfaced with a microcomputer (Macintosh II, Apple Inc). The matrix size was 20×20 pixels, with a center-to-center pixel spacing of 10 mm. The photo energy peak was centered on the 140-keV emissions of 99mTc by use of a 35% window. Rest and exercise data were collected with intervals of 50 and 25 milliseconds, respectively. For both studies, patients were placed anteriorly to the camera while seated in the semi-upright position of 70° on an electrically braked bicycle ergometer (Angioergometer WLP-300 ST, Lode Inc). Blood pressure and heart rate were measured with an automatic sphygmomanometer (STBP-680, Nippon Colin Inc). An 18-gauge indwelling polytetrafluoroethylene catheter was placed in an antecubital vein.
Exercise studies were performed at first to minimize statistical data error due to background radioactivity. Graded bicycle exercise was started at 20 W/min, and the workload was increased every minute with increments of 20 W/min. Heart rate, blood pressure, and ECGs were recorded before each increment in the workload. All patients exercised to the end point of leg fatigue or shortness of breath, irrespective of the heart rate attained. The end point of the exercise was defined as peak exercise in the current study. 99mTc-Pertechnetate (500 MBq) dissolved in less than 1 mL saline was injected at peak exercise and flushed by 20 mL saline. Acquisition was started just before the radionuclide was injected and finished after the first transit through the LV. After acquisition of the exercise data, the patients were instructed to abruptly stop pedaling. Motion artifacts due to vigorous peak exercise were corrected automatically with a software program bundled to the camera system. After completion of the exercise test, the patients were told to continue resting in the same position. Twenty minutes later, a second injection of 300 to 400 MBq of the radionuclide was repeated at rest. Background radioactivity due to prior injection during exercise was subtracted from the raw data at rest.
Absolute LV and RV volumes and EFs were calculated with a count-based ratio method, which can be applied to first-pass angiography without blood sampling, distance measurements, or assumptions about ventricular size or attenuation.8 9 In this method, ventricular volume is simply derived from the total counts and maximum pixel count in the ventricular ROI. Details of the principles and results of the validation of this technique have been described elsewhere.8 9
Each frame of raw data for the entire study was temporally smoothed. The LV phase was identified to select an ROI over the LV. A time-activity curve was generated by displaying the counts per frame within the LV ROI. The same ROI as the end-diastolic LV ROI was applied to the lung images just before the LV phase and used for measuring the background activity for LV analysis. An LV volume curve was generated from temporal changes of radioactivity through one cardiac cycle. Data processing for the RV was almost the same as that for the LV except that the background was not subtracted for the RV. Valvular planes at the inflow or outflow tract of the ventricle were selected with the help of phase images. The concentration of radioactivity in the RV was obtained from a rectangular ROI placed across the RV outflow tract. This ROI count profile, assumed to represent a circular disk ROI of 10-mm thickness, was used to calculate the counts per milliliter of each pixel in the RV.
Parameters indicating global cardiac performance included the LV and RV volumes at end-diastole and end-systole, stroke volume, EF, and cardiac output. The grade of pulmonary regurgitation was assessed by using the stroke volume ratio between the RV and the LV. Besides measurement of the global function, the regional function of the RV also was assessed. The RV ROI was divided equally into eight sectors starting from the 12 o’clock position that were numbered in a clockwise direction (Fig 1⇓). Regional EF was calculated from the end-diastolic and end-systolic counts within the ROI of each sector. Finally, LV diastolic function was derived from analysis of the LV volume curve. The diastolic function was represented by one third filling fraction and peak filling rate.10 The peak filling rate was divided by end-diastolic, end-systolic, or stroke volume of the LV to standardize the effects of differences in the chamber size of each patient.11
Data are presented as mean±SD. Comparisons between data at rest and peak exercise in each group were made by paired t test. The difference between the LV and RV stroke volumes in each group was analyzed with the nonpaired t test. ANOVA was used to compare data between the patients and control subjects at rest as well as during exercise. Least-squares linear regression was used for examining the effect of pulmonary regurgitation and RV end-diastolic volume on LVEF. A value of P<.05 was considered significant.
No significant differences were found at rest regarding blood pressure and rate-pressure product between the patients and control subjects. Although there were no significant differences in endurance time, workload, and blood pressure at peak exercise between the two groups, maximum heart rate and rate-pressure product were lower in the patients than in control subjects (Table 1⇑). Supraventricular or ventricular ectopy was not induced by exercise, except in 1 patient who had transient isolated ventricular premature beats after exercise.
Ventricular Function at Rest
RV volume at rest in the patients was markedly enlarged to about twice that of the control subjects (Table 2⇓). RVEF at rest showed no difference between the two groups. LV volume in the patients was significantly greater than that in the control subjects. However, LVEF and cardiac index at rest were not reduced in the patients compared with the control subjects. Stroke volumes from the RV and the LV were nearly equal in the control subjects. In contrast, RV stroke volume was greater than LV stroke volume in the patients.
Ventricular Function at Peak Exercise
Ventricular volumes in the patients at peak exercise were greater than in the control subjects in both the LV and the RV (Table 2⇑). The cardiac index in the patients was well preserved at peak exercise compared with the control subjects. Although LVEF was increased from rest to exercise in the two groups, the increment of EF on exercise was attenuated significantly in the patients compared with the control subjects, both in the RV and the LV (Fig 2⇓).
Correlation of Cardiac Parameters in Tetralogy Group
LVEF at peak exercise in the patients was inversely correlated with the RV end-diastolic volume (Fig 3⇓), and with the RV-to-LV stroke volume ratio (Fig 4⇓). There was no significant difference in the stroke volume ratio at rest and during exercise. The RV end-diastolic volume correlated positively with the stroke volume ratio both at rest and during exercise (P=.03 and .005, respectively). However, neither the LVEF nor the RV end-diastolic volume correlated with endurance time or rate-pressure product at peak exercise in the patients.
The age at operation and the interval from surgery did not affect these parameters. Although the mean value of the exercise LVEF from a patient subgroup with transannular patching was 7% less than that of the patients who had an RV patch that did not extend into the pulmonary artery, the difference did not reach statistical significance (P=.14).
Diastolic Function of the LV
The diastolic function of the LV during exercise in the patients was not reduced significantly compared with the control subjects (Table 3⇓).
Regional Function of the RV
Regional wall motion of the RV on exercise was abnormally reduced at the RV inlet portions in the patients (Table 4⇓). In contrast, wall motion was not reduced at the RV outflow and apex in the patients compared with the control subjects. Wall motion at the RV outflow was not significantly different between a subgroup of patients with tetralogy repaired using infundibular resection and those with patch outflow reconstruction (data not shown).
This is the first report documenting latent LV dysfunction during exercise in patients with repaired tetralogy of Fallot and its relation to RV enlargement and pulmonary regurgitation, despite the patients’ well-preserved exercise capacity and cardiac output.
Normal or nearly normal resting and exercise cardiac output in patients with repaired tetralogy has been shown in previous studies.12 13 14 This will probably explain the clinical evidence of satisfactory conditions of the patients with regard to their daily activity.1 However, several investigators have pointed out that the circulation of tetralogy patients tends to be hypodynamic when they perform maximum exercise.12 14 Cardiac output during bicycle exercise is clustered in the lower half of the normal range in most patients.14 Cardiac output response to treadmill exercise is only slightly below normal, but there is an abnormally low cardiac index at the point when pulmonary arterial oxygen saturation falls to 30%.12 The work performance of postoperative tetralogy repair patients on bicycle exercise is 82% to 86% of healthy subjects, according to a study of a large number of patients.3
All of these studies suggest that some insidious dysfunction of the heart presents and limits functional capacity in postoperative tetralogy repair patients.
The present study demonstrated that the RV in tetralogy patients was enlarged to about twice that of control subjects long after the repair. A number of studies have reported RV dysfunction in tetralogy of Fallot patients after operation.15 16 The enlargement of the RV may be caused by several factors. RV contractile dysfunction due to infundibular resection or outflow patch may induce RV enlargement.17 However, this factor is unlikely to be the primary reason for the enlargement of the RV in the present study group, because global and outflow regional contractions of the RV were not reduced at rest. Apparently, valvular regurgitation is another factor responsible for RV enlargement. Murmurs suggestive of pulmonary regurgitation were audible in almost all of the patients in the present study. The volume of the RV was correlated with the degree of regurgitation estimated by the stroke volume ratio. Therefore, a primary reason for the RV enlargement in the present study is most likely pulmonary regurgitation.
Many investigations have pointed out the functional significance of the pulmonary regurgitation and resultant enlarged RV after repair of tetralogy of Fallot.2 3 4 5 6 16 Although RV volume overload due to pulmonary regurgitation after transannular patching did not affect the late mortality,18 moderate to severe pulmonary regurgitation is associated with a reduction in exercise endurance time,3 oxygen consumption at maximum exercise,2 6 maximum heart rate,4 vital capacity,5 and exercise cardiac output at a pulmonary arterial oxygen saturation of 30%.2 RV volume or pressure overload is also important as a substrate of ventricular arrhythmias that sometimes cause sudden cardiac death in adults with repaired tetralogy.7 19 20 Furthermore, pulmonary regurgitation seems to affect not only the RV function but also the LV function under exercise stress, as shown in the present study.
Latent LV dysfunction in repaired tetralogy has been described in several studies reported in the literature.21 22 23 Although most of these reports emphasize normal hemodynamics at rest, Jarmakani et al22 found a depressed LVEF in both preoperative and postoperative tetralogy patients. In addition, Borow et al23 showed that, under methoxamine challenge to increase afterload in patients with postoperative tetralogy, LV end-diastolic pressure was markedly elevated compared with healthy subjects despite only a small to moderate increase in ventricular work. Their results suggest that a decrease in LV contractile reserve or compliance abnormality may be present after repair of tetralogy. From the findings of our present study, RV volume overload seems to alter LV function under exercise. RV dilation affects the geometry of the interventricular septum to prevent the LV from appropriately changing shape or accommodating an increased preload during diastolic filling.24 Moreover, fibrosis or hypertrophy of the septum, induced by chronic overload, could adversely affect systolic function. As shown in the present study, diastolic function of the LV was not decreased significantly in patients compared with control subjects. Therefore, rather than inflow disturbances, impairments of contractile reserve due to myocardial damage in the septum may be one of the major causes of the LV dysfunction during exercise. However, this issue regarding relations between LV dysfunction and myocardial damage in tetralogy may require more direct evidence and further studies combining radionuclide ventriculography, myocardial perfusion, and metabolic imaging, which are currently being undertaken in our laboratory.25
Exercise cardiac function of tetralogy previously was evaluated by radionuclide ventriculography in several reports.2 21 26 Many of these researchers used an ECG-gated equilibrium technique from a left anterior oblique view for resting or exercise study. However, this method is considered inappropriate for patients with tetralogy. Because of the RV enlargement, optimal separation of the LV and the RV is almost always very difficult. The 90° left lateral view, which is sometimes required for patients with tetralogy, usually precludes the proper positioning of patients and clear separation of the ventricle from the atrium. All of these difficulties seem inevitably to limit maximum exercise performed and accurate measurements of volume and EF. On the other hand, the intrinsic problem of the equilibrium technique can be avoided in a first-pass technique, which is generally performed from an anterior or right oblique view, enabling separation of the ventricle from the atrium without overlapping. Reduto et al16 used a first-pass technique with a multicrystal scinticamera to study postoperative tetralogy. However, their system was a prototype of the one we used, and the very poor spatial resolution of their system may have limited edge detection required for chamber volume measurements. Contrary to these previous techniques, the system used in the present study is especially useful in examining cardiac function during exercise. High count rate data from a first-pass study taken with the multicrystal camera make it possible to calculate ventricular volumes and EF accurately.8
In conclusion, latent LV dysfunction that is unmasked by exercise testing is present in patients after total repair of tetralogy of Fallot. Origin of the dysfunction is related, at least in part, to enlarged RV due to pulmonary regurgitation. Although at present the occurrence of pulmonary regurgitation after repair may be one of the intrinsic limitations in patients with tetralogy, further careful follow-up is necessary in patients with significant pulmonary regurgitation.
Selected Abbreviations and Acronyms
|LV||=||left ventricle, left ventricular|
|ROI||=||region of interest|
|RV||=||right ventricle, right ventricular|
- Copyright © 1995 by American Heart Association
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