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

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 Kambiz Norozi, MDa,*, Reiner Buchhorn, MD, PhDc, Valentin Alpersc, Jan O. Arnholdc, Stephan Schoof, MDa, Monika Zoege, PhDb, Siegfried Geyer, PhDb, and Armin Wessel, MD, PhDa After Mustard repair for transposition of the great arteries, the right ventricle serves as a chronically overloaded systemic ventricle (SV). Thus, during long-term followup, 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 (VO2max) 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 VO2max 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 ⴞ 0.17 vs 0.34 ⴞ 0.05, p <0.002; mean NT–pro-BNP 240 ⴞ 230 vs 57 ⴞ 39 pg/ml, p <0.0001), and VO2max was reduced (27 ⴞ 6 vs 32 ⴞ 6 ml · kgⴚ1 · minⴚ1, p <0.002). A good correlation was found between the Tei index and VO2max (r ⴝ ⴚ0.83, 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 VO2max. These parameters are simple and reliable screening methods to stratify patients with impaired cardiac dysfunction before they become symptomatic. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: 1721–1725)

The myocardial performance index (Tei index) has been used to assess the function of the systemic right ventricle in transposition of the great arteries (TGA) after the atrial diversion procedure,1,2 but the correlation of the Tei index with peak oxygen uptake (VO2max) and brain natriuretic peptide (BNP) in patients who undergo Mustard repair has not been evaluated. We hypothesized that there is a correlation between systemic ventricular function determined in terms of the Tei index and more global variables of cardiac status, such as a Department of Paediatric Cardiology and Intensive Care Medicine and bMedical Sociology Unit, Medical School Hannover, Hannover; and c Department of Paediatric Cardiology and Intensive Care Medicine, GeorgAugust-University, Göttingen, Germany. Manuscript received May 14, 2005; revised manuscript received and accepted July 12, 2005. This study was supported by grants from the German Research Foundation to Dr. Wessel (WE 2670/1-1) and Dr. Geyer (GE 1167/3-1), Bonn, Germany. * Corresponding author: Tel: 49-511-532-9126; fax: 49-511-532-9038. E-mail address: [email protected] (K. Norozi).

0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.07.096

BNP and exercise capacity, in asymptomatic or minimally symptomatic patients with chronic right ventricular (RV) overload due to operated TGA by the Mustard procedure.

Methods Study population: From May 2003 to May 2004, we evaluated the cardiopulmonary status of 377 adults with operated congenital heart disease; 85 patients of this cohort were included in the present analysis. Of these patients, 33 were young adults (5 women) who had undergone Mustard repair. As reference, we took the corresponding data from 52 patients (25 women), all operated on for left-to-right shunt defects (LRSs) (atrial or ventricular septal defect or patent ductus arteriosus), without residual defects, in whom we could anticipate normal values for functional parameters. All patients were treated at the University Hospital of Göttingen (Göttingen, Germany). Patients were consecutively recruited from our congenital heart disease outpatient www.AJConline.org

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clinic. We performed a prospective protocol. For each patient, the protocol was completed on the same day. Exclusion criteria: The exclusion criteria were acute infection, chronic lung disease, acute or chronic hepatitis, severe mental retardation, and chromosomal abnormalities. Informed consent: After adequate explanation of the purpose of the study, informed consent was obtained from all patients. The study protocol was approved by the local ethical committee. Clinical investigation: All patients underwent physical examinations and measurements of blood pressure, body weight, and height. A standard 12-lead electrocardiogram was recorded to analyze spontaneous rhythm and QRS duration. Exercise testing: Exercise testing was performed on all patients on an upright bicycle ergometer beginning with a workload of 0.5 W/kg body weight and increasing by 0.5 W/kg every 2 minutes. Oxygen uptake (VO2) was measured using breath-by-breath analysis (Oxycon pro, Jaeger Company, Hoechberg, Germany) throughout the exercise procedure. All patients were exercised to maximum exercise capability. VO2max was determined as the largest value in the terminal phase of exercise. A 6-lead electrocardiogram and heart rate were recorded continuously during the test. Blood pressure was recorded every 2 minutes by a cuff sphygmomanometer. Neurohormonal assessment: Peripheral venous blood samples were obtained from all participants, after resting for ⱖ15 minutes before exercise testing. The blood samples were immediately placed on ice and subsequently centrifuged at 5,000 rpm for 10 minutes. Plasma and serum aliquots were stored at ⫺80°C until further analysis. N-terminal pro-BNP (NT–pro-BNP) was determined using immunoassay (Elecsys 2010, Roche Diagnostics GmbH, Mannheim, Germany). Echocardiography: We performed routine transthoracic 2-dimensional, M-mode, and Doppler echocardiography using a Philips Sonos 5500 ultrasound system (Philips Medical Systems, Andover, Massachusetts) interfaced with multifrequency transducers. The Tei index, which has been reported previously,3–5 was calculated as the sum of isovolumetric relaxation time and isovolumetric contraction time divided by ventricular ejection time: Tei index ⫽ (isovolumetric relaxation time ⫹ isovolumetric contraction time)/ventricular ejection time. Measurements were done in the usual manner in a supine position, and the 2-dimensional and Doppler tracings were stored on stripcharts, at a paper speed of 50 or 100 mm/s, and videotape for offline analysis. Interobserver error: Interobserver variability for the left ventricular and the RV Tei index measurements was assessed in a randomly selected subset of 20 patients by independent

Table 1 Characteristics of patients Variable Women Age (yrs) New York Heart Association class I II III NT–pro-BNP (ng/ml) Spiroergometry Peak oxygen uptake (ml · kg⫺1 · min⫺1) Peak oxygen uptake (% predicted) Heart rate at rest (beats/min) Maximal heart rate (beats/min) Systolic blood pressure at rest (mm Hg) Maximal systolic blood pressure under exercise (mm Hg) Drugs at time of testing Beta blocker Digoxin Diureticum

TGA (n ⫽ 33)

LRS (n ⫽ 52)

5 (15%) 23.4 ⫾ 7.4

25 (49%) 21.9 ⫾ 6.8

NS

20 10 3 240 ⫾ 230

52 0 0 57 ⫾ 39

⬍0.0001

27 ⫾ 6

32 ⫾ 6

0.002

71 ⫾ 16

89 ⫾ 17

0.0001

74 ⫾ 15 152 ⫾ 30 119 ⫾ 12

67 ⫾ 11 170 ⫾ 14 125 ⫾ 13

NS 0.0001 NS

180 ⫾ 25

199 ⫾ 30

0.013

5 2 1

p Value

0 0 0

Values are expressed as mean ⫾ SD.

evaluation by 2 experienced cardiologists. The analysis was performed using the method of Bland and Altman.6 Statistical analysis: All results are reported as mean ⫾ SD. Because most clinical and echocardiographic variables were not normally distributed, the nonparametric MannWhitney test was used. For all parameters, a p value ⬍0.05 was considered statistically significant. Multivariate logistic regression analysis was used to investigate the relations between impaired exercise capacity (defined as VO2max ⬍60% of the predicted normal value), patient characteristics, echocardiographic and Doppler findings, and plasma NT– pro-BNP. Receiver-operating characteristic curves were used to identify cut-off points providing the best combination of sensitivity and specificity for variables identified by multivariate analysis as being independently associated with impaired clinical status. The data analyses were performed using Excel 2000 (Microsoft Corporation, Redmond, Washington) and SPSS version 12.0 (SPSS, Inc., Chicago, Illinois).

Results Patient characteristics: The clinical and demographic characteristics of the 85 patients included in this study are given in Table 1. Mean age at follow-up in the TGA group was 23.4 years (range 14.5 to 42.7). Mean age at repair was 2 years (range 0.4 to 12). At the time of their last follow-up, 20 patients were in New York Heart Association class I, 10 in class II, and 3 in class III. Except for 11 patients with

Table 2 Doppler-derived parameters of the system ventricle in patients with TGA and LRS Variable Ejection time of system ventricle (ms) Isovolumetric contraction time ⫹ isovolumetric relaxation time (ms) Tei index of systemic ventricle

TGA (n ⫽ 33)

LRS (n ⫽ 52)

p Value

290 ⫾ 37

300 ⫾ 21

NS

179 ⫾ 36

108 ⫾ 4

⬍0.0001

0.63 ⫾ 0.17 0.34 ⫾ 0.05 ⬍0.0001

Values are expressed as mean ⫾ SD.

Tei index of systemic ventricle

Congenital Heart Disease/Tei Index in Mustard Patients

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1.2

*** 1.0

0.8

0.6

0.4

0.2

0.0

Neurohormonal assessment: Patients in the TGA group had significantly greater levels of circulating NT–pro-BNP than LRS patients in the reference group (240 ⫾ 230 vs 57 ⫾ 39 ng/ml, p ⬍0.0001; Table 1). Patients with pacemakers tended to have higher NT–pro-BNP levels than those without (290 ⫾ 295 vs 214 ⫾ 188 pg/ml). We found an inverse correlation between NT–pro-BNP and exercise capacity in terms of VO2max in the TGA group (r ⫽ ⫺0.46, p ⫽ 0.03; data not shown). There was no correlation between NT–pro-BNP and New York Heart Association class. Exercise testing: In the TGA group, the mean VO2max during exercise testing by spiroergometry was significantly less than in the LRS group (27 ⫾ 6 vs 32 ⫾ 6 ml · kg⫺1 · min⫺1, p ⬍0.002). Heart rate and systolic blood pressure at rest were similar in the 2 groups, but under exercise conditions, these parameters were significantly reduced in the TGA group (Table 1). If all of the TGA patients who received negative chronotropic medications were excluded, the heart rate (151 ⫾ 31 vs 172 ⫾ 16 beats/min) and systolic blood pressure (183 ⫾ 28 vs 196 ⫾ 30 mm Hg) remained reduced during exercise. This suggests that chronotropic incompetence in patients with TGA after atrial diversification must be regarded as a common finding. The comparison of the data between patients with and without pacemakers in the TGA group showed only lower heart rates at rest and during exercise in patients with pacemakers (data not shown). Echocardiographic parameters: Four patients in the TGA group had moderate tricuspid regurgitation, and the rest had trivial to mild regurgitation. The Doppler-derived parameters are listed in Table 2. The sum of isovolumetric contraction time and isovolumetric relaxation time of the

LRS

TGA

Figure 1. The Tei index for the systemic ventricle in TGA after the Mustard procedure and LRS. The gray area shows the normal range in healthy patients described by Tei et al.10 ***p ⬍0.0001.

40

VO2 max [ml. Kg-1.min-1]

ventricular pacemakers, all patients were in sinus rhythm. In the reference group, the mean age at follow-up was 21.9 years (range 14.8 to 45.7). Mean age at repair was 6.8 years (range 0.3 to 29.6). All of these patients were in New York Heart Association functional class I. All patients were in sinus rhythm. As anticipated, the mean values of all parameters in the reference group were in the normal range and were taken as reference values for comparison with the corresponding data of the TGA group.

30

20

10 p < 0.0001 r = - 0.83

0 0.2

0.4

0.6

0.8

1.0

1.2

Tei Index Figure 2. Correlation between the systemic ventricular Tei index and cardiopulmonary exercise capacity in patients with TGA.

systemic right ventricle in the TGA group was prolonged in comparison with the reference group operated on for shunt defects. However, the mean value of the ejection time of the right ventricle in the systemic position was comparable with that found for the systemic left ventricle in the reference group, which was in the normal range.3,7,8 Thus, the Tei index of the systemic ventricle in TGA was abnormally large for a morphologic right ventricle (0.63 ⫾ 0.17). This value was significantly greater than the RV Tei index in LRS patients (0.25 ⫾ 0.05) and exceeded even the Tei index of the normal left ventricle, which amounted in mean to a normal left ventricular Tei index (0.34 ⫾ 0.05; Table 2 and Figure 1). The increment of the RV Tei index in TGA hints at dysfunction that is hidden at rest but becomes obvious under exercise conditions, because there was a significant correlation between the RV Tei index and exercise capacity in

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terms of VO2max (r ⫽ ⫺0.83, p ⬍0.0001; Figure 2). There were no significant differences between patients with and without pacemakers with regard to their RV Tei indexes. Factors associated with impaired clinical status (defined as VO2max ⬍60% of predicted) were detected by univariate analysis. To identify independent factors associated with impaired clinical status, the variables were entered into a logistic regression multivariate analysis. Of these variables, an elevated Tei index for the systemic ventricle and elevated circulating NT–pro-BNP were independently associated with impaired clinical status. The area under the receiver-operating characteristic for the systemic ventricular Tei index was 0.955 and for NT–pro-BNP was 0.760. The best cut-off point for the Tei index was 0.53, with a sensitivity of 100% and a specificity of 85%. The best cut-off point for NT–pro-BNP was 146 pg/ml, with a sensitivity of 67% and a specificity of 85%. Interobserver error: The mean of the differences of the Tei indexes measured by the 2 investigators amounted to 0.001 (95% confidence interval ⫺0.1 to ⫹0.1) for the left ventricle and 0.002 for the right ventricle (95% confidence interval ⫺0.12 to ⫹0.12). The measurements of the 2 observers were not significantly different because the 95% confidence intervals of the differences included zero. The SDs of the mean difference were 0.05 for the right ventricle and 0.06 for the left ventricle.

Discussion In the present study, we evaluated the clinical status, exercise capacity, systemic RV function variables, and neurohormonal activation of patients after the Mustard operation. For all parameters, we determined reference values from patients operated on for LRS defects. All reference values obtained were within normal ranges known from published research (Table 1). This indicates that these patients may be regarded as normal with respect to their present cardiocirculatory status. In our study group, the patients who had undergone the Mustard procedure demonstrated elevation of the RV Tei index (Figure 1). These patients also showed elevated NT– pro-BNP, which is a well-known marker for the diagnosis, prognosis, and risk stratification of heart failure.9 –13 The data of our and other studies show the favorable qualitative assessment of RV systolic pump function determined by 2-dimensional echocardiography.14 –16 The increased Tei index in these patients indicates impaired global RV pump function, probably caused predominantly by diastolic dysfunction. More recently, Salehian et al1 showed that the quantitative echocardiographic assessment of global systemic RV function by the Tei index in patients with TGA correlates highly with the RV ejection fraction obtained by cardiac magnetic resonance. Although cardiac magnetic resonance and multislice spiral computed tomography are ac-

curate and reliable noninvasive techniques for evaluating RV measurement,17,18 their practicability in routine diagnosis remains a handicap. Another sign of subclinical heart failure becoming overt under exercise conditions is diminished cardiopulmonary capacity in terms of VO2max, which was significantly reduced in the TGA group. Li et al19 showed that the right ventricles of adults who had undergone the Mustard procedure are key determinants of exercise capacity. 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. This chronotropic incompetence may further explain the diminished exercise capacity in TGA group, as reported previously.21,22 Because of postoperative sick sinus syndrome, many patients who undergo the Mustard operation need pacemakers. In our cohort, this rate was 33%. Therefore, the question could arise whether the electromechanical delay affects clinical, neurohormonal, and cardiopulmonary status or even the Tei index. With the exception of lower heart rates at rest and under exercise in patients with pacemakers, the other data did not differ significantly. Thus, the suitability of the Tei index is not limited to patients with normal conduction, and we conclude that the pacemakers in the TGA group did not affect the validity of the Tei index in these patients. Some methodologic aspects of the Tei index need consideration. The age dependence of the index can be neglected because the age of the 2 groups in our cohort did not differ significantly. The same is true for pharmacologic effects, because the Tei index of the 7 patients receiving drugs and those patients without medication were not significantly different. In patients with acute myocardial infarctions, special limitations of the Tei index have been addressed,23–25 but it is unclear whether these drawbacks are valid for the systemic right ventricle without infarction. There are some limitations to our work. The number of patients in the TGA group is small, therefore, there is not sufficient statistical power to conclude that the comparison between patients with and without pacemakers are truly not significant. Seven patients with pacemakers took negative chronotropic medications (5 patients took ␤ blockers, 2 patients took digoxin). This could have negatively affected heart rate and cardiopulmonary exercise capacity in this group.

Acknowledgment: We thank Barbara Formanek, RN, who worked as a study nurse; Renate Lucyga, Ursula Baumgarten, and Sabine Laurenzano for expert technical assistance;

Congenital Heart Disease/Tei Index in Mustard Patients

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