Cardiorespiratory exercise capacity and its relation to a new doppler index in children previously treated with anthracycline

doi:10.1067/mje.2001.110586

Journal of the American Society of Echocardiography

Volume 14, Issue 4, April 2001, Pages 256-263

https://doi.org/10.1067/mje.2001.110586 Get rights and content

Abstract

The purpose of this study was to assess the exercise capacity of patients treated with anthracycline and to evaluate the relation between the exercise capacity and a new Doppler index. The study patients consisted of 70 subjects: 41 healthy subjects and 29 who had been treated with various cumulative doses of anthracycline (range 45 to 873 mg per body surface area). The following conventional echocardiographic parameters were measured: rate-corrected mean velocity of fiber shortening (mVcfc), end-systolic wall stress (ESS), stress-velocity index, and early and late diastolic mitral inflow velocities and their ratio. A new Doppler index, the Tei index, was calculated as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time. Peak oxygen uptake (pVo₂) and anaerobic threshold (AT) were measured during an upright bicycle exercise test. The pVo₂ and AT in the patient group were significantly lower than those in the control group (pVo₂: 22.0 ± 3.7 versus 28.5 ± 7.1 mL/min/kg; AT: 12.7 ± 1.9 versus 17.3 ± 4.3 mL/min/kg, respectively; P <.01). There were no significant differences in the mVcfc, ESS, stress-velocity index, E wave, A wave, or E/A wave ratio between the two groups. However, the mean Tei index of the patients was significantly greater than that of the controls (0.41 ± 0.11 versus 0.33 ± 0.04, P <.01). The pVo₂ and AT decreased significantly with an increase in the Tei index (r = −0.64 and −0.60, respectively; P <.01). A weak positive correlation was found between the AT and E/A wave ratio (r = 0.54, P <.05). However, no significant correlations were seen between the exercise parameters and the mVcfc, ESS, stress velocity index, or transmitral velocities. Our findings suggest that cardiopulmonary exercise testing revealed an inverse correlation between exercise capacity and the Tei index. (J Am Soc Echocardiogr 2001;14:256-63.)

Introduction

Anthracycline is one of the most important chemotherapeutic agents used in the treatment of a wide range of childhood cancers, but its total dose is limited by its critical cardiac toxicity. Manifestations of resting ventricular systolic and diastolic dysfunction have been reported during anthracycline administration as well as after short- and long-term follow-up periods.1, 2, 3, 4, 5, 6, 7 Exercise intolerance is a cardinal symptom of patients treated with anthracycline.6, 8, 9 However, the factors that limit the exercise capacity of these patients remain uncertain.

Recently, the Tei index, a new Doppler index combining systolic and diastolic time intervals of cardiac function, has been proposed. The index is defined as the sum of isovolumic contraction and relaxation times divided by ejection time; it is independent of heart rate and can be easily and reproducibly obtained.10, 11, 12 The index discriminates between healthy persons and those with various heart diseases. Furthermore, this index has been reported to be useful for early detection of subclinical cardiac global dysfunction during chemotherapy with anthracycline.¹³ This index potentially can allow the assessment of cardiac reserve and enable earlier and more accurate detection of myocardial dysfunction. The purpose of this study was to assess the exercise capacity of patients treated with anthracycline and to evaluate the relations between the exercise capacity and conventional left ventricular (LV) systolic and diastolic parameters and this new Doppler index.

Section snippets

Subjects

Twenty-nine patients were studied at least 6 months after anthracycline therapy. They were in complete continuous remission of cancer and had not received radiotherapy to the mediastinum. The child's agreement and parental consent were obtained.

The control group consisted of 41 subjects (range 8 to 18 years) who had been referred to our hospital because of murmurs or noncardiac chest pain. These subjects were not found to have heart disease on echocardiographic and physical examinations.

Echocardiography

Studies

Results

Complete results are summarized in Tables 1 and 2.

. Characteristics of the patients

Patient	Diagnosis	Age (y)	Heart rate (bpm)	Cumulative dose (mg/m²)	Anaerobic threshold (mL/min/kg)	Po₂ (mL/min/kg)	Follow-up (mo)
1	ALL	15	88	351	8.9	15.9	20
2	ALL	14	76	461	13.9	20.4	45
3	AML	10	103	354	12.5	19.0	36
4	ALL	18	88	520	12.9	22.0	35
5	ALL	11	100	534	12.3	21.0	43
6	ALL	15	81	780	12.0	18.0	31
7	AML	15	107	476	11.8	18.7	20
8	ALL	15	65	360	10.7	18.8	18
9	NHL	19	57	377	9.8	17.6	24
10	AML	9	78	826	10.7	20.0	25
11	ALL	16	73	500	10.0	21.6	30
12	ALL	10	101	360	15.5	30.0	6
13	ALL	10	61	873	12.2	21.0	18
14	ALL	15	75	480	11.5	24.0

Discussion

In this study, we demonstrated a reduction in the exercise capacity of children treated with anthracycline. We also found that a Doppler index, defined as the sum of isovolumic relaxation and contraction times divided by ejection time, was correlated with exercise capacity. The present data suggest that in patients treated with anthracycline, LV dysfunction detected by the Tei index may be a determinant of exercise intolerance.

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Evaluation of the myocardial performance index and tissue doppler imaging by comparison to near-simultaneous catheter measurements in pediatric cardiac transplant patients
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Interestingly, this statistical difference held true only for the left ventricle. In another study involving patients exposed to anthracyclines, MPI inversely correlated with performance in cardiopulmonary testing.12 In contrast, McMahon et al found that, in children with dilated cardiomyopathy, neither RVMPI nor LVMPI predicted death, transplantation or need for hospitalization.13
Parameters derived from Doppler echocardiography, such as the myocardial performance index (MPI) and the ratio of peak velocity of early diastolic prograde flow (E) across the atrioventricular valve (AVV) divided by the peak velocity of early diastolic tissue motion at the AVV annulus (E') (E:E' ratio), are routinely used to assess ventricular function. However, they have not been compared with measurements obtained by cardiac catheterization (CC) in children.
We prospectively studied post–cardiac transplant children undergoing CC with near-simultaneous echocardiographic imaging for MPI and E:E'. CC data included right atrial pressure (RAp), pulmonary artery wedge pressure (PAWp) and cardiac index (CI). One investigator, who was blinded to the CC data, measured right ventricular (RV) and left ventricular (LV) MPI and E:E' offline. Correlations between echocardiographic and catheter measurements were calculated. Receiver-operating-characteristics (ROC) curves were created to evaluate the utility of echocardiographic measurements that exhibited statistically significant correlations with CC measurements.
Twenty-four patients (age range 0.8 to 21 years) underwent 142 CCs during the study period. Of the 12 correlations studied, 3 met statistical significance (p < 0.05) (RV E:E' vs RAp, RV E:E' vs PAWp and LV MPI vs CI). The ROC areas for these correlations were 0.38, 0.42 and 0.68, respectively. There were no cut-off points where both the sensitivity and specificity for any measurement were >0.80.
Our data suggest that MPI and E:E' are poor predictors of simultaneously obtained, catheter-derived hemodynamic parameters in post-transplant children. These limitations should be carefully considered before ascribing diagnostic value to these measurements.
Evaluation of Tei Index in Heart Failure
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Elevated Brain Natriuretic Peptide and Reduced Exercise Capacity in Adult Patients Operated on for Tetralogy of Fallot Is Due to Biventricular Dysfunction as Determined by the Myocardial Performance Index
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The relation between exercise capacity and LV function is underscored by the significant inverse correlation between the LV Tei index and peak oxygen uptake in the TOF group (Figure 2). This has not been shown previously for operated CHD but only in children treated with anthracycline.24 Most of our patients with TOF (78%) had right bundle branch block (Table 1).
Although tetralogy of Fallot (TOF) can be repaired surgically, residual lesions that cause abnormal ventricular load can eventually lead to heart failure. Subclinical biventricular dysfunction in these patients may be detected only by using suitably sensitive indexes. The Tei index determined by the pulsed Doppler method enables the measurement of left ventricular (LV) and right ventricular (RV) function. This study was designed to evaluate the biventricular Tei indexes in adults with operated congenital heart disease and to correlate these indexes with cardiopulmonary capacity and neurohormonal activation. Fifty-nine patients with surgically corrected TOF and 52 patients with operated left-to-right-shunt defects were included in the study. Patients with TOF showed significantly greater LV and RV Tei indexes than those with left-to-right-shunt defects (LV Tei index 0.50 ± 0.09 vs 0.34 ± 0.05, RV Tei index 0.37 ± 0.1 vs 0.25 ± 0.06; p <0.0001). Peak oxygen uptake was significantly reduced in the patients with TOF (25 ± 6 vs 32 ± 6 ml · kg⁻¹ · min⁻¹, p <0.0001) and was correlated inversely with the LV Tei index (r = −0.61, p <0.0001). N-terminal–pro-brain natriuretic peptide was significantly increased in patients with TOF (150 ± 141 vs 57 ± 39 pg/ml, p <0.0001). In conclusion, in asymptomatic or minimally symptomatic patients with TOF, biventricular dysfunction is detected by the Tei index. Further indexes for heart failure in these patients are increased circulating plasma N-terminal–pro-brain natriuretic peptide and impaired peak oxygen uptake. The combined determinations of these 3 variables enable the identification of congenital heart disease with impaired cardiac function before they become clinically symptomatic.
Relation of systemic ventricular function quantified by myocardial performance index (Tei) to cardiopulmonary exercise capacity in adults after mustard procedure for transposition of the great arteries
2005, American Journal of Cardiology
Citation Excerpt :
The interrelation between exercise capacity and system ventricular function in our study is underscored by a significantly inverse correlation between the Tei index and VO2max in the TGA group (Figure 2). This has not been shown previously for operated congenital heart disease but in children treated with anthracycline.20 In our study cohort, the patients with TGA had significantly lower heart rates and blood pressures under exercise.
After Mustard repair for transposition of the great arteries, the right ventricle serves as a chronically overloaded systemic ventricle (SV). Thus, during long-term follow-up, dysfunction of the right ventricle with consecutive heart failure (HF) is not unusual. Early signs and symptoms of HF are depressed parameters of right ventricular (RV) function at rest and exercise intolerance. It was hypothesized that the measurement of RV function parameters, N-terminal pro–brain natriuretic peptide (NT–pro-BNP), and peak oxygen uptake (VO_2max) during exercise testing were suitable for the early detection of subclinical HF. In 33 asymptomatic adolescents and adults who had undergone Mustard repair, RV function was analyzed by the myocardial performance index (Tei index). NT–pro-BNP and VO_2max were also determined. The corresponding data from 52 patients operated on for left-to-right shunt defects without residual lesions served as reference data. In patients who underwent the Mustard procedue, the Tei index and NT–pro-BNP were elevated (mean Tei index of the SV 0.63 ± 0.17 vs 0.34 ± 0.05, p <0.002; mean NT–pro-BNP 240 ± 230 vs 57 ± 39 pg/ml, p <0.0001), and VO_2max was reduced (27 ± 6 vs 32 ± 6 ml · kg⁻¹ · min⁻¹, p <0.002). A good correlation was found between the Tei index and VO_2max (r = −0.83, p <0.0001). In conclusion, RV function is depressed in most patients with Mustard repair. Ventricular dysfunction in such asymptomatic or minimally symptomatic patients can be detected by measurement of the Tei index, NT–pro-BNP, and VO_2max. These parameters are simple and reliable screening methods to stratify patients with impaired cardiac dysfunction before they become symptomatic.
Effect of central hypothyroidism on Doppler-derived myocardial performance index
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Myocardial performance index (MPI) has been used to assess global ventricular function in different types of cardiac disease. Thyroid hormones influence cardiac performance directly and indirectly by changes in peripheral circulation. The aim of this study was to evaluate the possible effect of central hypothyroidism (CH) on MPI.
The study included 28 control subjects and 7 patients with CH without cardiac disease. MPI was defined as the sum of isovolumetric contraction time (ICT) and isovolumetric relaxation time divided by ejection time. Patients were submitted to hormonal therapy with thyroxin and the study was repeated after 35 to 42 days.
MPI was significantly higher in patients with CH (0.54 ± 0.08) than in control subjects (0.40 ± 0.05) (P = .002). The increase in MPI was caused by the prolongation of ICT without a significant variation of isovolumetric relaxation time and ejection time. After hormonal therapy there was a significant reduction of MPI (0.54 ± 0.08 vs 0.42 ± 0.07; P = .028) and ICT.
MPI was increased in patients with untreated CH. The increase was related to prolongation of ICT and reverted by hormonal therapy.
Myocardial performance index in pediatric patients after cardiac transplantation
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Myocardial performance index (MPI) has been shown to be a reliable indicator of ventricular performance. This study determined MPI values in pediatric patients after cardiac transplantation without endomyocardial rejection.
MPI was determined in 41 pediatric patients after cardiac transplantation, without evidence of microscopic rejection, and in 31 pediatric control subjects.
MPI in the transplantation group (0.41 ± 0.12) was higher than in the control group (0.31 ± 0.09; P = .0003). Isovolumic relaxation time and isovolumic relaxation time/ejection time were higher in the transplant group (55 ± 20 milliseconds and 0.22 ± 0.07, respectively) compared with the control group (41 ± 10 milliseconds and 0.16 ± 0.06, respectively; P = .0002). Isovolumic contraction time and isovolumic contraction time/ejection time were similar in the transplant group (48 ± 23 milliseconds and 0.19 ± 0.09, respectively) and control group (43 ± 21 milliseconds and 0.16 ± 0.08, respectively; P = not significant).
Pediatric patients after cardiac transplantation without endomyocardial rejection have a higher MPI compared with a normative pediatric control population. The difference appears to be related to abnormal diastolic function.

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^*: Reprint requests: Kenji Harada, MD, Department of Pediatrics, Akita University School of Medicine, Akita 010-8543, Japan.

^**: J Am Soc Echocardiogr 2001;14:256-63

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Original ArticlesCardiorespiratory exercise capacity and its relation to a new doppler index in children previously treated with anthracycline*,**

Abstract

Introduction

Section snippets

Subjects

Echocardiography

Results

Discussion

Am Heart J

Am J Cardiol

Am Heart J

Am J Cardiol

Am J Cardiol

Mayo Clin Proc

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Soc Echocardiogr

J Am Coll Cardiol

Original Articles
Cardiorespiratory exercise capacity and its relation to a new doppler index in children previously treated with anthracycline*,**